JP4866992B2 - Ep4受容体作動薬としてのプロスタグランジン類縁体 - Google Patents
Ep4受容体作動薬としてのプロスタグランジン類縁体 Download PDFInfo
- Publication number
- JP4866992B2 JP4866992B2 JP2006504090A JP2006504090A JP4866992B2 JP 4866992 B2 JP4866992 B2 JP 4866992B2 JP 2006504090 A JP2006504090 A JP 2006504090A JP 2006504090 A JP2006504090 A JP 2006504090A JP 4866992 B2 JP4866992 B2 JP 4866992B2
- Authority
- JP
- Japan
- Prior art keywords
- difluoro
- hydroxy
- enyl
- phenylbut
- oxopiperidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000003180 prostaglandins Chemical class 0.000 title description 7
- 101150109738 Ptger4 gene Proteins 0.000 title description 3
- 239000000018 receptor agonist Substances 0.000 title 1
- 229940044601 receptor agonist Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 56
- -1 CF 3 Chemical group 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 239000002253 acid Substances 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- RBTSOQUDIUTCGL-AWHXWDPHSA-N 7-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]heptanoic acid Chemical compound C(/[C@@H](O)C(F)(F)C=1C=CC=CC=1)=C\[C@H]1CCCC(=O)N1CCCCCCC(O)=O RBTSOQUDIUTCGL-AWHXWDPHSA-N 0.000 claims description 5
- KPSZWAJWFMFMFF-UHFFFAOYSA-N delta-Hexylen-alpha-carbonsaeure Natural products CC=CCCCC(O)=O KPSZWAJWFMFMFF-UHFFFAOYSA-N 0.000 claims description 5
- AVHYJFWNZORGIE-RTBURBONSA-N 7-[(2r)-2-[(3r)-4-(3-bromophenyl)-4,4-difluoro-3-hydroxybutyl]-6-oxopiperidin-1-yl]heptanoic acid Chemical compound C([C@@H](O)C(F)(F)C=1C=C(Br)C=CC=1)C[C@H]1CCCC(=O)N1CCCCCCC(O)=O AVHYJFWNZORGIE-RTBURBONSA-N 0.000 claims description 4
- NNCOVBBHNMYKAF-UBJZUDALSA-N (4R)-4-[(E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-heptyl-1,3-oxazinan-2-one Chemical compound FC([C@@H](/C=C/[C@@H]1N(C(OCC1)=O)CCCCCCC)O)(C1=CC=CC=C1)F NNCOVBBHNMYKAF-UBJZUDALSA-N 0.000 claims description 3
- GWHUEQZFJDKLKP-QFBILLFUSA-N (4s)-4-[(3r)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-3-[3-[5-(2h-tetrazol-5-yl)thiophen-2-yl]propyl]-1,3-oxazinan-2-one Chemical compound C([C@@H]1CC[C@@H](O)C(F)(F)C=2C=CC=CC=2)COC(=O)N1CCCC(S1)=CC=C1C=1N=NNN=1 GWHUEQZFJDKLKP-QFBILLFUSA-N 0.000 claims description 3
- JGJQBAPTMJLFRH-CUVMAEJSSA-N (6R)-6-[(E,3R)-4-(3-chlorophenyl)-4,4-difluoro-3-hydroxybut-1-enyl]-1-heptylpiperidin-2-one Chemical compound ClC=1C=C(C=CC1)C([C@@H](/C=C/[C@@H]1N(C(CCC1)=O)CCCCCCC)O)(F)F JGJQBAPTMJLFRH-CUVMAEJSSA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 3
- NNCOVBBHNMYKAF-ZPSQSSEPSA-N (4R)-4-[(E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-heptyl-1,3-oxazinan-2-one Chemical compound C1COC(=O)N(CCCCCCC)[C@H]1\C=C\C(O)C(F)(F)C1=CC=CC=C1 NNCOVBBHNMYKAF-ZPSQSSEPSA-N 0.000 claims description 2
- UJUYPENCNZSXKR-UBJZUDALSA-N (4R)-4-[(E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-heptyl-1,3-thiazinan-2-one Chemical compound FC([C@@H](/C=C/[C@@H]1N(C(SCC1)=O)CCCCCCC)O)(C1=CC=CC=C1)F UJUYPENCNZSXKR-UBJZUDALSA-N 0.000 claims description 2
- DQCMQKAZSFOUAS-PGUYEUBTSA-N (4r)-4-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-[3-[5-(2h-tetrazol-5-yl)thiophen-2-yl]propyl]-1,3-oxazinan-2-one Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)COC(=O)N1CCCC(S1)=CC=C1C=1N=NNN=1 DQCMQKAZSFOUAS-PGUYEUBTSA-N 0.000 claims description 2
- ZUZKNFXCXAPVLA-PGUYEUBTSA-N (4r)-4-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-[3-[5-(2h-tetrazol-5-yl)thiophen-2-yl]propyl]-1,3-thiazinan-2-one Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CSC(=O)N1CCCC(S1)=CC=C1C=1N=NNN=1 ZUZKNFXCXAPVLA-PGUYEUBTSA-N 0.000 claims description 2
- HBWRYTFJZCBILL-AAIOHFERSA-N (4r)-4-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-[6-(2h-tetrazol-5-yl)hexyl]-1,3-oxazinan-2-one Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)COC(=O)N1CCCCCCC=1N=NNN=1 HBWRYTFJZCBILL-AAIOHFERSA-N 0.000 claims description 2
- FZMZUEQLSKWWCZ-AAIOHFERSA-N (4r)-4-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-3-[6-(2h-tetrazol-5-yl)hexyl]-1,3-thiazinan-2-one Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CSC(=O)N1CCCCCCC=1N=NNN=1 FZMZUEQLSKWWCZ-AAIOHFERSA-N 0.000 claims description 2
- DUMBBSQVZDHVOV-AAIOHFERSA-N (5s)-5-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-4-[6-(2h-tetrazol-5-yl)hexyl]morpholin-3-one Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)OCC(=O)N1CCCCCCC=1N=NNN=1 DUMBBSQVZDHVOV-AAIOHFERSA-N 0.000 claims description 2
- UQSVUSYISXAUOT-AAIOHFERSA-N (5s)-5-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-4-[6-(2h-tetrazol-5-yl)hexyl]thiomorpholin-3-one Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)SCC(=O)N1CCCCCCC=1N=NNN=1 UQSVUSYISXAUOT-AAIOHFERSA-N 0.000 claims description 2
- ZVSXMDHGXALDAD-KAAYJFPCSA-N (6R)-6-[(E,3R)-4,4-difluoro-3-hydroxy-4-naphthalen-2-ylbut-1-enyl]-1-heptylpiperidin-2-one Chemical compound FC([C@@H](/C=C/[C@@H]1N(C(CCC1)=O)CCCCCCC)O)(C1=CC2=CC=CC=C2C=C1)F ZVSXMDHGXALDAD-KAAYJFPCSA-N 0.000 claims description 2
- UCFLFWQCQYWUNB-DENIHFKCSA-N (6r)-6-[(3r)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbutyl]-1-[6-(2h-tetrazol-5-yl)hexyl]piperidin-2-one Chemical compound C([C@@H]1CC[C@](O)(C)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCCCCC1=NN=NN1 UCFLFWQCQYWUNB-DENIHFKCSA-N 0.000 claims description 2
- HDSTYLLDZUKASQ-YLJYHZDGSA-N (6r)-6-[(3r)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-1-[3-[5-(2h-tetrazol-5-yl)thiophen-2-yl]propyl]piperidin-2-one Chemical compound C([C@@H]1CC[C@@H](O)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCC(S1)=CC=C1C=1N=NNN=1 HDSTYLLDZUKASQ-YLJYHZDGSA-N 0.000 claims description 2
- UCFLFWQCQYWUNB-KNQAVFIVSA-N (6r)-6-[(3s)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbutyl]-1-[6-(2h-tetrazol-5-yl)hexyl]piperidin-2-one Chemical compound C([C@@H]1CC[C@@](O)(C)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCCCCC1=NN=NN1 UCFLFWQCQYWUNB-KNQAVFIVSA-N 0.000 claims description 2
- LJLDJACVIZRWIH-JSVQFZOWSA-N (6r)-6-[(e,3r)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbut-1-enyl]-1-[6-(2h-tetrazol-5-yl)hexyl]piperidin-2-one Chemical compound C([C@@H]1/C=C/[C@](O)(C)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCCCCC1=NN=NN1 LJLDJACVIZRWIH-JSVQFZOWSA-N 0.000 claims description 2
- NZKVYAHKTQUHRQ-KYEAHMHCSA-N (6r)-6-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-1-[(z)-4-(2h-tetrazol-5-ylmethylsulfanyl)but-2-enyl]piperidin-2-one Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1C\C=C/CSCC1=NN=NN1 NZKVYAHKTQUHRQ-KYEAHMHCSA-N 0.000 claims description 2
- TVDDWSNLUDJXJO-PVQLQXKBSA-N (6r)-6-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-1-[3-[5-(2h-tetrazol-5-yl)thiophen-2-yl]propyl]piperidin-2-one Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCC(S1)=CC=C1C=1N=NNN=1 TVDDWSNLUDJXJO-PVQLQXKBSA-N 0.000 claims description 2
- CMPZCNXCJCXZJY-AWHXWDPHSA-N (6r)-6-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-1-[6-(2h-tetrazol-5-yl)hexyl]piperidin-2-one Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCCCCC=1N=NNN=1 CMPZCNXCJCXZJY-AWHXWDPHSA-N 0.000 claims description 2
- LJLDJACVIZRWIH-NAQYQCNUSA-N (6r)-6-[(e,3s)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbut-1-enyl]-1-[6-(2h-tetrazol-5-yl)hexyl]piperidin-2-one Chemical compound C([C@@H]1/C=C/[C@@](O)(C)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCCCCC1=NN=NN1 LJLDJACVIZRWIH-NAQYQCNUSA-N 0.000 claims description 2
- KVGBRCOLKPRWEV-AAIOHFERSA-N (6s)-6-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-1-[6-(2h-tetrazol-5-yl)hexyl]piperazin-2-one Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)NCC(=O)N1CCCCCCC=1N=NNN=1 KVGBRCOLKPRWEV-AAIOHFERSA-N 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 2
- UUKVDIFMDKOXFA-WJCALDQNSA-N (e)-7-[(2r)-2-[(3r)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-6-oxopiperidin-1-yl]hept-5-enoic acid Chemical compound C([C@@H](O)C(F)(F)C=1C=CC=CC=1)C[C@H]1CCCC(=O)N1C\C=C\CCCC(O)=O UUKVDIFMDKOXFA-WJCALDQNSA-N 0.000 claims description 2
- QFCZIIULIYGUEQ-TXDYLXKNSA-N (e)-7-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]hept-5-enoic acid Chemical compound C(/[C@@H](O)C(F)(F)C=1C=CC=CC=1)=C\[C@H]1CCCC(=O)N1C\C=C\CCCC(O)=O QFCZIIULIYGUEQ-TXDYLXKNSA-N 0.000 claims description 2
- XZMUVPPVAXNPFU-OPPJKZBZSA-N (e)-7-[(4r)-4-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-thiazinan-3-yl]hept-5-enoic acid Chemical compound C(/[C@@H](O)C(F)(F)C=1C=CC=CC=1)=C\[C@H]1CCSC(=O)N1C\C=C\CCCC(O)=O XZMUVPPVAXNPFU-OPPJKZBZSA-N 0.000 claims description 2
- GBMXNBVDLWBHLY-PYAHUTRISA-N (e)-7-[(4s)-4-[(3r)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-oxazinan-3-yl]hept-5-enoic acid Chemical compound C([C@@H](O)C(F)(F)C=1C=CC=CC=1)C[C@H]1CCOC(=O)N1C\C=C\CCCC(O)=O GBMXNBVDLWBHLY-PYAHUTRISA-N 0.000 claims description 2
- MXHGMNQKBINKSD-PYAHUTRISA-N (e)-7-[(4s)-4-[(3r)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-2-oxo-1,3-thiazinan-3-yl]hept-5-enoic acid Chemical compound C([C@@H](O)C(F)(F)C=1C=CC=CC=1)C[C@H]1CCSC(=O)N1C\C=C\CCCC(O)=O MXHGMNQKBINKSD-PYAHUTRISA-N 0.000 claims description 2
- DUGCTYORQDUADH-OFHUKCQUSA-N 2-[3-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]propyl]-1,3-oxazole-5-carboxylic acid Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCC1=NC=C(C(O)=O)O1 DUGCTYORQDUADH-OFHUKCQUSA-N 0.000 claims description 2
- YDSZEGRJRZUDNR-OFHUKCQUSA-N 2-[3-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]propyl]-1h-imidazole-5-carboxylic acid Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCC1=NC=C(C(O)=O)N1 YDSZEGRJRZUDNR-OFHUKCQUSA-N 0.000 claims description 2
- FFZVZZWJFLTRDP-LLSOJIOMSA-N 2-[4-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]butylsulfanyl]acetic acid Chemical compound C(/[C@@H](O)C(F)(F)C=1C=CC=CC=1)=C\[C@H]1CCCC(=O)N1CCCCSCC(O)=O FFZVZZWJFLTRDP-LLSOJIOMSA-N 0.000 claims description 2
- FGZKRZAIFCYSFR-NDZBKKTDSA-N 3-[3-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]propylsulfanyl]propanoic acid Chemical compound C(/[C@@H](O)C(F)(F)C=1C=CC=CC=1)=C\[C@H]1CCCC(=O)N1CCCSCCC(O)=O FGZKRZAIFCYSFR-NDZBKKTDSA-N 0.000 claims description 2
- UKZSDNBDMWJCRG-IXACGEDUSA-N 5-[(e)-3-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]prop-1-enyl]thiophene-2-carboxylic acid Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1C\C=C\C1=CC=C(C(O)=O)S1 UKZSDNBDMWJCRG-IXACGEDUSA-N 0.000 claims description 2
- UKZSDNBDMWJCRG-MGWHWSQYSA-N 5-[(z)-3-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]prop-1-enyl]thiophene-2-carboxylic acid Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1C\C=C/C1=CC=C(C(O)=O)S1 UKZSDNBDMWJCRG-MGWHWSQYSA-N 0.000 claims description 2
- WQSYEWMCCMJSRC-LLSOJIOMSA-N 5-[3-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]propyl]-1h-imidazole-2-carboxylic acid Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCC1=CN=C(C(O)=O)N1 WQSYEWMCCMJSRC-LLSOJIOMSA-N 0.000 claims description 2
- ODXXQDZWJCBNEQ-PVQLQXKBSA-N 5-[3-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)CCC(=O)N1CCCC1=CC=C(C(O)=O)S1 ODXXQDZWJCBNEQ-PVQLQXKBSA-N 0.000 claims description 2
- LZXYUADMJUXEQR-VPWSRKDSSA-N 5-[3-[(4R)-4-[(E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-4H-1,3-thiazin-3-yl]propyl]thiophene-2-carboxylic acid Chemical compound FC([C@@H](/C=C/[C@H]1N(C(SC=C1)=O)CCCC1=CC=C(S1)C(=O)O)O)(C1=CC=CC=C1)F LZXYUADMJUXEQR-VPWSRKDSSA-N 0.000 claims description 2
- WHMZVCSJCXYZHK-PGUYEUBTSA-N 5-[3-[(4r)-4-[(e,3r)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-2-oxo-1,3-oxazinan-3-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@@H]1/C=C/[C@@H](O)C(F)(F)C=2C=CC=CC=2)COC(=O)N1CCCC1=CC=C(C(O)=O)S1 WHMZVCSJCXYZHK-PGUYEUBTSA-N 0.000 claims description 2
- XHWYSVWEWFFCGJ-RTBURBONSA-N 7-[(2r)-2-[(3r)-4,4-difluoro-3-hydroxy-4-phenylbutyl]-6-oxopiperidin-1-yl]heptanoic acid Chemical compound C([C@@H](O)C(F)(F)C=1C=CC=CC=1)C[C@H]1CCCC(=O)N1CCCCCCC(O)=O XHWYSVWEWFFCGJ-RTBURBONSA-N 0.000 claims description 2
- KNLXVJWNBDVJMR-JSVQFZOWSA-N 7-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-3-methyl-4-phenylbut-1-enyl]-6-oxopiperidin-1-yl]heptanoic acid Chemical compound C(/[C@](O)(C)C(F)(F)C=1C=CC=CC=1)=C\[C@H]1CCCC(=O)N1CCCCCCC(O)=O KNLXVJWNBDVJMR-JSVQFZOWSA-N 0.000 claims description 2
- QSJZXOKUIGPEFI-JQBOOCOKSA-N 7-[(2r)-2-[(e,3r)-4,4-difluoro-3-hydroxy-4-(3-methoxyphenyl)but-1-enyl]-6-oxopiperidin-1-yl]heptanoic acid Chemical compound COC1=CC=CC(C(F)(F)[C@H](O)\C=C\[C@@H]2N(C(=O)CCC2)CCCCCCC(O)=O)=C1 QSJZXOKUIGPEFI-JQBOOCOKSA-N 0.000 claims description 2
- ADIAUQQKWOQBOV-JQBOOCOKSA-N 7-[(2r)-2-[(e,3r)-4-(1-benzofuran-2-yl)-4,4-difluoro-3-hydroxybut-1-enyl]-6-oxopiperidin-1-yl]heptanoic acid Chemical compound C(/[C@@H](O)C(F)(F)C=1OC2=CC=CC=C2C=1)=C\[C@H]1CCCC(=O)N1CCCCCCC(O)=O ADIAUQQKWOQBOV-JQBOOCOKSA-N 0.000 claims description 2
- PTOSDIVFVLCYIY-JQBOOCOKSA-N 7-[(2r)-2-[(e,3r)-4-(1-benzothiophen-2-yl)-4,4-difluoro-3-hydroxybut-1-enyl]-6-oxopiperidin-1-yl]heptanoic acid Chemical compound C(/[C@@H](O)C(F)(F)C=1SC2=CC=CC=C2C=1)=C\[C@H]1CCCC(=O)N1CCCCCCC(O)=O PTOSDIVFVLCYIY-JQBOOCOKSA-N 0.000 claims description 2
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- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- YPPQYORGOMWNMX-UHFFFAOYSA-L sodium phosphonate pentahydrate Chemical compound [Na+].[Na+].[O-]P([O-])=O YPPQYORGOMWNMX-UHFFFAOYSA-L 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960002385 streptomycin sulfate Drugs 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004589 thienofuryl group Chemical group O1C(=CC2=C1C=CS2)* 0.000 description 1
- 125000004587 thienothienyl group Chemical group S1C(=CC2=C1C=CS2)* 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 229940019375 tiludronate Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 229950008081 unoprostone isopropyl Drugs 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000004382 visual function Effects 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
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- A61P19/00—Drugs for skeletal disorders
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- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- 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
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- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
- C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
X及びYは独立して、CH2、O、NR9又はSを表すが、但し、X及びYは同時にO、NR9又はSではなく、
UはH、C1〜3アルキルを表すか、又はWが=Oのときは存在せず、
WはOH又は=Oを表し、但し、Wが=OのときUは存在せず、
R1は、(CH2)pヒドロキシ、(CH2)pCN、(CH2)pCO2R10、(CH2)nSO3R6、−(CH2)pCF2SO2NH2、−(CH2)pSO2NH2、−(CH2)pCONHSO2R2、−(CH2)pSO2NHCOR2、−(CH2)pPO(OH)2、(CH2)pCONHPO2R6、(CH2)pCONHR8、(CH2)pC1〜4アルコキシ、−(CH2)pシクロアルキル、(CH2)p−ヒドロキシメチルケトン又は(CH2)pヘテロシクリルを表し、前記ヘテロシクリルは非置換であるか、又は1個から3個のRa基によって置換されており、場合によって酸性水酸基を含有し、
R2は、独立して、C1〜10アルキル、(CH2)mC6〜10アリール、(CH2)mC5〜10ヘテロシクリル、(CH2)mC3〜10ヘテロシクロアルキル、(CH2)mC3〜8シクロアルキル、O−C1〜10アルキル、O−C6〜10アリール、O−C3〜10シクロアルキル、O−C3〜10ヘテロシクロアルキル、O−C3〜10ヘテロシクロアルキルを表し、但し、R2がO−C1〜10アルキル、O−C6〜10アリール、O−C3〜10シクロアルキル、O−C3〜10ヘテロシクロアルキル又はO−C3〜10ヘテロシクロアルキルのとき、R3及びR4はハロゲンではなく、前記アルキル、シクロアルキル、ヘテロシクロアルキル、アリール又はヘテロシクリルは非置換であるか、又は1個から3個のRa基で置換されており、
R3及びR4は独立して、水素、ハロゲン若しくはC1〜6アルキルを表し、又はR3及びR4は一緒になって、O、S、SO、SO2及びNR9から選択された1個から2個のヘテロ原子が場合によって割り込んだ3員から7員炭素環を形成し、
R6及びR7は独立して水素又はC1〜4アルキルを表し、
R8は、水素、アシル又はスルホニルを表し、
R9は、水素、C1〜6アルキルを表し、前記アルキルは、1個から3個のハロゲン、CN、OH、C1〜6アルコキシ、C1〜6アシルオキシ又はアミノで場合によって置換されており、
R10は、水素、C1〜6アルキル、C3〜10シクロアルキル、(CH2)pC6〜10アリール、(CH2)pC5〜10ヘテロシクリル、CR6R7OC(O)OC3〜10シクロアルキル又はCR6R7OC(O)OC1〜10アルキルを表し、
Zは、三重結合、O、S、(C(Rb)2)n又はCH=CHを表し、
Rbは、水素、C1〜6アルキル又はハロゲンを表し、
Raは、C1〜6アルコキシ、C1〜6アルキル、CF3、ニトロ、アミノ、シアノ、C1〜6アルキルアミノ、ハロゲンを表し、又は、Raはさらにアリール及びヘテロシクリル、SC1〜6アルキル、SC6〜10アリール、SC5〜10ヘテロシクリル、CO2R6、OC6〜10アリール、OC5〜10ヘテロシクリル、CH2OC1〜6アルキル、CH2SC1〜6アルキル、CH2Oアリール、CH2Sアリールを表し、
---は、二重結合又は一重結合を表し、
pは、0から3を表し、
nは、0から4を表し、
mは、0から8を表す。)
又はそれらの薬剤として許容される塩、エナンチオマー、ジアステレオマー、プロドラッグ又は混合物に関する。
各Rcは、独立してH、フッ素、シアノ又はC1〜4アルキルであり、
各Rdは、独立してH、C1〜4アルキル又は薬剤として許容される陽イオンであり、
各Reは、独立してH、−C(=O)−Rf、又は−SO2Reであり、
RfはC1〜4直鎖状アルキル又はフェニルである。
7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸;
7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}ヘプタン酸;
7−{(2R)−2−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸;
7−{(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−2−オキソ−1,3−チアジナン−3−イル}ヘプタン酸;
7−{(2R)−2−[(3R)−3−ヒドロキシ−4−フェニルブチル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(4S)−4−[(3R)−3−ヒドロキシ−4−フェニルブチル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸;
7−{(4S)−4−[(3R)−3−ヒドロキシ−4−フェニルブチル]−2−オキソ−1,3−チアジナン−3−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸イソプロピル;
7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸イソプロピル;
7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}ヘプタン酸イソプロピル;
(6R)−6−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−1−[6−(2H−テトラアゾール−5−イル)ヘキシル]ピペリジン−2−オン;
(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−3−[6−(2H−テトラアゾール−5−イル)ヘキシル]−1,3−オキサジナン−2−オン;
(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−3−[6−(2H−テトラアゾール−5−イル)ヘキシル]−1,3−チアジナン−2−オン;
(5S)−5−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−4−[6−(2H−テトラアゾール−5−イル)ヘキシル]モルホリン−3−オン;
(6S)−6−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−1−[6−(2H−テトラアゾール−5−イル)ヘキシル]ピペラジン−2−オン;
(5S)−5−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−4−[6−(2H−テトラアゾール−5−イル)ヘキシル]チオモルホリン−3−オン;
5−(3−{(2R)−2−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)チオフェン−2−カルボン酸;
5−(3−{(4R)−4−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}プロピル)チオフェン−2−カルボン酸;
5−(3−{(4R)−4−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}プロピル)チオフェン−2−カルボン酸;
5−(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)チオフェン−2−カルボン酸;
5−(3−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}プロピル)チオフェン−2−カルボン酸;
5−(3−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}プロピル)チオフェン−2−カルボン酸;
(6R)−6−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−1−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}ピペリジン−2−オン;
(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−3−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}−1,3−オキサジナン−2−オン;
(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−3−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}−1,3−チアジナン−2−オン;
(6R)−6−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−1−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}ピペリジン−2−オン;
(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−3−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}−1,3−オキサジナン−2−オン;
(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−3−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}−1,3−チアジナン−2−オン;
5−(3−{(2R)−2−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)チオフェン−2−カルボン酸イソプロピル;
5−(3−{(4R)−4−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}プロピル)チオフェン−2−カルボン酸イソプロピル;
5−(3−{(4R)−4−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}プロピル)チオフェン−2−カルボン酸イソプロピル;
5−(3−{(2R)−2−[(1E,3S)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)チオフェン−2−カルボン酸イソプロピル;
5−(3−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}プロピル)チオフェン−2−カルボン酸イソプロピル;
5−(3−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}プロピル)チオフェン−2−カルボン酸イソプロピル;
(5E)−7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプト−5−エン酸;
(5E)−7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプト−5−エン酸;
(5E)−7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}ヘプト−5−エン酸;
(5E)−7−{(2R)−2−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−6−オキソピペリジン−1−イル}ヘプト−5−エン酸;
(5E)−7−{(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプト−5−エン酸;
(5E)−7−{(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−2−オキソ−1,3−チアジナン−3−イル}ヘプト−5−エン酸;
2−(3−{(2R)−2−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1,3−チアゾール−5−カルボン酸;
5−(3−{(2R)−2−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1,3−チアゾール−2−カルボン酸;
5−(3−{(2R)−2−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1,3−オキサゾール−2−カルボン酸;
2−(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1,3−オキサゾール−5−カルボン酸;
5−(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1H−イミダゾール−2−カルボン酸;
2−(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1H−イミダゾール−5−カルボン酸;
2−(3−{(2R)−2−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1,3−オキサゾール−5−カルボン酸;
5−(3−{(2R)−2−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1,2λ5,5λ5−オキサジアゾール−2−カルボン酸;
5−(3−{(2R)−2−[(1E,3S)−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−4H−1,2,4−トリアゾール−3−カルボン酸;
5−((1E)−3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロプ−1−エニル)チオフェン−2−カルボン酸;
5−(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロプ−1−イニル)チオフェン−2−カルボン酸;
5−((1Z)−3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロプ−1−エニル)チオフェン−2−カルボン酸;
(6R)−6−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−1−{(2Z)−4−[(1H−テトラアゾール−5−イルメチル)チオ]ブト−2−エニル}ピペリジン−2−オン;
[(4−{(2R)−2−[(1E,3S)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ブト−2−イニル)チオ]酢酸;
[((2Z)−4−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ブト−2−エニル)チオ]酢酸;
[(4−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ブチル)チオ]酢酸;
(4−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ブトキシ)酢酸;
3−[(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)チオ]プロパン酸;
7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3S)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−(2−ナフチル)ブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
(6R)−6−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブト−1−エニル]−1−[6−(1H−テトラアゾール−5−イル)ヘキシル]ピペリジン−2−オン;
(6R)−6−[(1E,3S)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブト−1−エニル]−1−[6−(1H−テトラアゾール−5−イル)ヘキシル]ピペリジン−2−オン;
7−{(2R)−2−[(1E,3R)−4−(1−ベンゾチエン−2−イル)−4,4−ジフルオロ−3−ヒドロキシブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
(6R)−6−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブチル]−1−[6−(1H−テトラアゾール−5−イル)ヘキシル]ピペリジン−2−オン;
(6R)−6−[(3S)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブチル]−1−[6−(1H−テトラアゾール−5−イル)ヘキシル]ピペリジン−2−オン;
7−{(2R)−2−[(1E,3R)−4−(1−ベンゾフラン−2−イル)−4,4−ジフルオロ−3−ヒドロキシブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3R)−4−(3−クロロフェニル)−4,4−ジフルオロ−3−ヒドロキシブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3R)−4−(3−クロロフェニル)−4,4−ジフルオロ−3−ヒドロキシブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−(3−メトキシフェニル)ブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
6−[(1E)−(3R)−3−ヒドロキシ−4−フェニル−ブト−1−エニル]−1−[6−(1H−テトラゾール−5−イル)−ヘキシル]−ピペラジン−2−オン;
7−{[(1E)−(2R)−2−(3R)−3−ヒドロキシ−4−フェニル−ブト−1−エニル]−6−オキソ−ピペリジン−1−イル}ヘプタン酸;
7−{[(1E)−(2R)−2−(3S)−3−ヒドロキシ−4−フェニル−ブト−1−エニル]−6−オキソ−ピペリジン−1−イル}ヘプタノエート;
イソプロピル7−{(2R)−2−[(3R)−3−ヒドロキシ−4−フェニル−ブチル]−6−オキソ−ピペリジン−1−イル}ヘプタン酸イソプロピル;
7−{(2R)−2−[(3R)−3−ヒドロキシ−4−フェニル−ブチル]−6−オキソ−ピペリジン−1−イル}ヘプタン酸;
5−{3−[(2R)−2−((1E)−(3S)3−ヒドロキシ−4−フェニル−ブト−1−エニル]−6−オキソ−ピペリジン−1−イル]−プロピル)−チオフェン−2−カルボン酸メチル;
5−{3−[(2R)−2−[(1E)−(3S)3−ヒドロキシ−4−フェニル−ブト−1−エニル)−6−オキソ−ピペリジン−1−イル]−プロピル}−チオフェン−2−カルボン酸;
5−{3−[(2R)−2−((3S)3−ヒドロキシ−4−フェニル−ブチル)−6−オキソ−ピペリジン−1−イル]−プロピル}−チオフェン−2−カルボン酸;
5−{3−[(2R)−2−[(1E)−(3S)3−ヒドロキシ−4−フェニル−ブト−1−エニル)−6−オキソ−ピペリジン−1−イル]−プロピル}−チオフェン−2−カルボン酸イソプロピル;
5−{3−[(2R)−2−(3S)3−ヒドロキシ−4−フェニル−ブチル)−6−オキソ−ピペリジン−1−イル]−プロピル}−チオフェン−2−カルボン酸イソプロピル;
6−[(3R)−3−ヒドロキシ−4−フェニル−ブチル]−1−[6−(1H−テトラゾール−5−イル)−ヘキシル]−ピペリジン−2−オン;
7−{(2R)−2−[(1E)−4,4−ジフルオロ−3−オキソ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸イソプロピル;
7−{(2R)−2−[(3R)−4−(3−ブロモフェニル)−4,4−ジフルオロ−3−ヒドロキシブチル]−6−オキソピペリジン−1−イル}ヘプタン酸;
5−{3−[(2R)−2−[(1E)−(3S)3−ヒドロキシ−4−フェニル−ブト−1−エニル)−6−オキソ−ピペリジン−1−イル]−プロピル}−チオフェン−2−カルボン酸メチル;
5−{3−{(2R)−2−((3S)3−ヒドロキシ−4−フェニル−ブチル)−6−オキソ−ピペリジン−1−イル]−プロピル}−チオフェン−2−カルボン酸;
5−{3−[(2R)−2−(3S)3−ヒドロキシ−4−フェニル−ブチル)−6−オキソ−ピペリジン−1−イル}−プロピル}−チオフェン−2−カルボン酸イソプロピル;
6−[(3R)−3−ヒドロキシ−4−フェニル−ブチル]−1−[6−(1H−テトラゾール−5−イル)−ヘキシル]−ピペリジン−2−オン;
(5Z)−7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−1−イル]−6−オキソピペリジン−1−イル}ヘプト−5−エン酸イソプロピル;
(5Z)−7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−1−イル]−6−オキソピペリジン−1−イル}ヘプト−5−エン酸;
7−{(4R)−4−[(1E)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−イル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸イソプロピル;
7−{(4R)−4−[(1E)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−イル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸;
又は薬剤として許容されるそれらの塩、エナンチオマー、ジアステレオマー、プロドラッグ若しくは混合物である。
リン酸ナトリウム14の調製
化合物16の調製
該触媒は、PrOH中で、[RuCl2(p−シメン)2]1モル当量、(R,R)−N−トシル−1,2−ジフェニルエチレン−1,2−ジアミン2モル当量及びEt3N 4.2モル当量を80℃で1h(時間)混合することによって調製した。溶媒を除去した後、固形物を冷H2Oで洗浄して、MeOHで再結晶化して、該触媒をオレンジ色の固形物として得た。
MS(+ESI):M/Z490.1(M+1)+。
1H NMR(400MHZ、CD3OD):δ7.3−7.1(M、5H)、3.8〜3.7(M、2H)、3.4(M、1H)、2.9〜2.7(M、3H)、2.3(M、4H)、1.9〜1.3(M、16H);MS(−ESI):M/Z374.2(M−1)−。
1H NMR(400MHz、CDCl3):δ7.6(d、1H)、7.2〜7.1(m、5H)、6.7(d、1H)、5.5(m、2H)、4.3(m、1H)、3.8〜3.7(m、2H)、3.8(s、3H)、2.8〜2.6(m、6H)、2.3〜2.2(m、2H)、1.9〜1.2(m、6H)。
1H NMR(400MHZ、CD3OD):δ7.6(D、1H)、7.2〜7.1(M、5H)、6.9(D、1H)、5.5(M、2H)、4.3(M、1H)、3.9(M、1H)、3.7(M、1H)、2.9〜2.6(M、5H)、2.2(M、2H)、1.〜1.5(M、6H);MS(−ESI):M/Z412.1(M−1)−。
1H NMR(400MHZ、CD3OD):δ7.6(D、1H)、7.3〜7.1(M、5H)、6.9(D、1H)、3.8(M、2H)、3.4(M、1H)、3.0〜2.9(M、1H)、2.8〜2.5(M、4H)、2.3(M、2H)、2.0〜1.3(M、10H);MS(−ESI):M/Z414.1(M−1)−。
1H NMR(400MHz、CDCl3):δ7.6(d、1H)、7.3〜7.1(m、5H)、6.8(d、1H)、5.5(m、2H)、5.1(m、1H)、4.4(m、1H)、3.9〜3.8(m、2H)、3.3(brs、1H)、2.8(m、4H)、2.7(m、1H)、2.3(m、2H)、1.9〜1.6(m、6H)、1.3(dd、6H);MS(+ESI):M/Z456.4(M+1)+。
1H NMR(400MHz、CDCl3):δ7.6(d、1H)、7.3〜7.1(m、5H)、6.8(d、1H)、5.2(m、1H)、3.9〜3.8(m、2H)、3.3(m、1H)、2.9〜2.8(m、4H)、2.7〜2.6(m、1H)、2.4〜2.3(m、3H)、2.0〜1.2(m、10H)、1.3(d、6H);MS(+ESI):M/Z458.2(M+1)+。
1H NMR(400MHz、CD3OD):δ7.3〜7.1(m、5H)、3.8〜3.7(m、2H)、3.3(m、1H)、2.9〜2.7(m、5H)、2.3(m、2H)、1.9〜1.3(m、16H);MS(+ESI):M/Z400.3(M+1)+。
MS(+ESI):M/Z450.3(M+1)+。
MS(−ESI):m/z406.1(M−1)−。
MS(+ESI):M/Z454(M+1)+。
(4S)−4−[2−(4−メトキシフェノキシ)エチル]−2,2−ジメチル−1,3−ジオキソランの調製
THFに溶かした2−[(4S)−2,2−ジメチル−1,3−ジオキソラン−4−イル]エタノール(Aldrich、5g、34.2mmol)の溶液に、水素化ナトリウム60%(1.504g、37.6mmol、1.1当量)を小分けして添加し、該混合物を1時間撹拌した(不透明な溶液)。該混合物を0℃まで冷却して、該混合物に4−メトキシベンジルクロリド(5.89g、37.6mmol、1.1当量(eq.))を1回で添加し、該混合物を室温で30分間撹拌して、65℃から70℃で一晩加熱した。室温まで冷却した後、飽和NH4Cl/水で反応停止し、該混合物を酢酸エチル(2x)で抽出して、有機抽出物を水、食塩水で洗浄して、MgSO4で乾燥した。該混合物を濾過して、濾液を真空中で濃縮した。粗生成物をシリカゲルクロマトグラフィー(15%酢酸エチル/ヘキサン)によって精製して、所望する生成物を無色油状物として得た。1H NMR(400MHz、アセトン−d6):δ7.28(2H、d)、6.93〜6.91(2H、m)、4.43(2H、s)、4.20〜4.14(1H、m)、4.04〜3.98(1H、m)、3.80(3H、s)、3.56〜3.50(3H、m)、1.88〜1.76(2H、m)、1.31(3H、s)、1.28(3H、s)。
(2S)−4−(4−メトキシフェノキシ)ブタン−1,2−ジオールの調製
AcOH/水に溶かした(4S)−4−[2−(4−メトキシフェノキシ)エチル]−2,2−ジメチル−1,3−ジオキソラン(8.2g、30.8mmol)の溶液をrtで5時間撹拌して、真空中で濃縮した。残渣をトルエン(3x)と共に留去して、次に高い真空状態下で吸引すると所望する生成物が得られた。1H NMR(400MHz、アセトン−d6):δ7.28(2H、d)、6.91(2H、d)、4.43(2H、s)、3.80(3H、s)、3.77(1H、m)、3.66〜3.42(5H、m)、1.86〜1.76(1H、m)、1.68〜1.60(1H、m)。
(1S)−1−({[tert−ブチル(ジメチル)シリル]オキシ}メチル)−3−(4−メトキシフェノキシ)プロピルメタンスルホネート
DMF(50mL)に溶かした(2S)−4−(4−メトキシフェノキシ)ブタン−1,2−ジオール(7g、30.9mmol)及びイミダゾール(4.21g)の溶液に、t−ブチルジメチルシリルクロリド(4.88g、32.4mmol、1.05当量)を0℃で1回で添加し、該混合物を室温で1時間撹拌して、水/エーテルで希釈した。層を分離して、水層をエーテル(2x)で抽出した。抽出物を一緒にして、水、食塩水で洗浄して、乾燥して濾過した。濾液を真空中で濃縮して、粗生成物(2S)−1−{[tert−ブチル(ジメチル)シリル]オキシ}−4−(4−メトキシフェノキシ)ブタン−2−オール10.8gを無色油状物として得た。粗生成物のNMRによって、該生成物は純度が95%を上回ることが示されたので、生成せずに直接使用した。1H NMR(400MHz、アセトン−d6)δ7.28(2H、d)、6.92〜6.90(2H、m)、4.43(2H、s)、3.80(3H、s)、3.75(1H、m)、3.67〜3.51(5H、m)、1.89〜1.81(1H、m)、1.66〜1.58(1H、m)、0.91(s、9H)、0.09(s、6H)。
{[(2R)−2−アジド−4−(4−メトキシフェノキシ)ブチル]オキシ}(tert−ブチル)ジメチルシランの調製
DMF(50mL)に溶かした(1S)−({[tert−ブチル(ジメチル)シリル]オキシ}メチル)−3−(4−メトキシフェノキシ)プロピルメタンスルホネート(13g)及びNaN3(10g)の溶液をN2下において60℃から70℃でo/nで加熱して、rtまで冷却した。該混合物をエーテル/水で希釈して、エーテル(3x)で抽出した。エーテル抽出物を水、食塩水で洗浄して、その後通常通り処理した。粗生成物をフラッシュクロマトグラフィー(5%酢酸エチル/ヘキサン)によって精製して、所望するアジド生成物を得た。1H NMR(400MHz、アセトン−d6):δ7.29(2H、d)、6.92(2H、d)、4.45(2H、s)、3.87(1H、dd)、3.80(3H、s)、3.70〜3.54(4H、m)、1.85〜1.77(1H、m)、1.68〜1.60(1H、m)、0.93(9H、s)、0.11(6H、s)。
(3R)−3−アミノ−4−{[tert−ブチル(ジメチル)シリル]オキシ}ブタン−1−オールの調製
DCM/水19:1に溶かした{[(2R)−2−アジド−4−(4−メトキシフェノキシ)ブチル]オキシ}(tert−ブチル)ジメチルシリル(4.7g、12.86mmol)の溶液に、0℃でDDQ(2,3−ジクロロ−5,6−ジシアノ−1,4−ベンゾキノン)(3.5g、15.43mmol、1.2当量)添加し、開始物質が全て消失したことがTLC(薄層クロマトグラフィー)分析で示されるまで該混合物を撹拌した(0℃からrtまで)。次に、DCMのほとんどを真空中で除去し、残渣を酢酸エチルに溶解した。淡黄色の有機溶液が得られるまで、該酢酸エチル溶液を水及び飽和NaHCO3で繰り返し洗浄した。該有機溶液を乾燥し、粗生成物をシリカゲルクロマトグラフィー(5%アセトン/トルエン)で精製して、所望する生成物(3R)−3−アジド−4−{[tert−ブチル(ジメチル)シリル]オキシ}ブタン−1−オールを得た。1H NMR(400MHz、アセトン−d6):δ3.89(1H、dd)、3.73〜3.65(5H、m)、1.76〜1.68(1H、m)、1.62〜1.54(1H、m)、0.94(9H、s)、0.13(6H、s)。
(4R)−4−({[tert−ブチル(ジメチル)シリル]オキシ}メチル)−1,3−オキサジナン−2−オンの調製
DCM(100mL)に溶かした(3R)−3−アミノ−4−{[tert−ブチル(ジメチル)シリル]オキシ}ブタン−1−オール(2.63g、12mmol)の溶液に0℃でピリジン(3mL)次いでホスゲン(20%トルエン溶液、1.9M、8.5mL)を滴下し、該混合物を30分撹拌し、rtまで加温して、水で反応を停止した。層を分離して、水層をDCMで1回抽出した。有機層を無水MgSO4で乾燥して、濾過して濃縮した。所望する生成物(4R)−4−({[tert−ブチル(ジメチル)シリル]オキシ}メチル)−1,3−オキサジナン−2−オンは、エーテル/ヘキサンから−20℃で結晶化することによって淡黄色固形物として得た。1H NMR(400MHz、CDCl3)5.52(brs、1H)、4.38〜4.33(m、1H)、4.28〜4.22(m、1H)、3.70〜3.59(m、2H)、3.46(t、1H)、1.97〜1.93(m、1H)、1.72〜1.67(m、1H)、0.91(s、9H)、0.90(s、6H)。
7−[(4R)−4−(ヒドロキシメチル)−2−オキソ−1,3−オキサジナン−3−イル]ヘプタン酸イソプロピルの調製
DMF(10mL)に溶かした(4R)−4−({[tert−ブチル(ジメチル)シリル]オキシ}メチル)−1,3−オキサジナン−2−オン(0.51g、2.078mmol)の溶液に、N2下においてrtでKHMDS(0.5Mトルエン溶液、5mL)を滴下し(ゲル様沈殿の形成)、該混合物を10分間撹拌した。次に、イソプロピル7−ヨードヘプタノエート(1.24g、4.16mmol、2当量)を1回で添加し、該混合物を65℃でさらに5時間撹拌し、rtまで冷却して、水/エーテルで希釈した。層を分離して、水性層をエーテルで抽出した。有機層を一緒にして、水及び食塩水で洗浄して、MgSO4で乾燥して濾過した。濾液を真空中で濃縮して、残渣をカラムクロマトグラフィー(15〜30%アセトン/トルエン)によって精製して、所望する生成物イソプロピル7−[(4R)−4−({[tert−ブチル(ジメチル)シリル]オキシ}メチル)−2−オキソ−1,3−オキサジナン−3−イル]ヘプタノエートを無色油状物として得た。1NMR(400MHz、アセトン−d6):δ4.98〜4.90(1H、m)、4.38〜4.30(1H、m)、4.16〜4.12(1H、m)、3.83〜3.77(2H、m)、3.56〜3.48(2H、m)、3.15〜3.07(1H、m)、2.26(2H、t)、2.11〜2.09(2H、m)、1.69〜1.53(4H、m)、1.41〜1.27(4H、m)、1.21(6H、d)、0.92(9H、s)、0.12(6H、s)。
7−{(4R)−4−[(1E)−4,4−ジフルオロ−3−オキソ−4−フェニルブト−1−エン−1−イル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸イソプロピルの調製
A:アルコールの酸化:DCM(5mL)に溶かしたDMSO(ジメチルスルホキシド)(113μL、1.592mmol、1.2当量)の溶液に、−78℃で塩化オキサリル(128μL、1.46mmol、1.1当量)を滴下し、該混合物を室温で15分間撹拌した。DCM(3mL)に溶かした7−[(4R)−4−(ヒドロキシメチル)−2−オキソ−1,3−オキサジナン−3−イル]ヘプタン酸イソプロピル(400mg、1.327mmol)をカニューレによって添加し、該混合物をさらに15分間撹拌した。次に、トリエチルアミン(429μL、3.05mmol、2.3当量)を1回で添加し、該混合物を−78℃で30分間撹拌して、0℃までゆっくり温め、真空中で濃縮した。該混合物を酢酸エチルに再懸濁して、濾過した。濾液を真空中で濃縮して、粗アルデヒド、7−[(4R)−4−ホルミル−2−オキソ−1,3−オキサジナン−3−イル]ヘプタン酸イソプロピルを良好な純度で得た。1H NMR(400MHz、CDCl3):δ9.69(1H、d)、5.04〜4.96(1H、m)、4.29〜4.23(1H、m)、4.16〜4.00(2H、m)、3.79〜3.71(1H、m)、3.02〜2.94(1H、m)、2.30〜2.24(4H、m)、1.66〜1.58(4H、m)、1.42〜1.28(4H、m)、1.24(6H、d)。
化合物29:7−{(4R)−4−[(1E)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−1−イル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸イソプロピル
トルエン(1mL)に溶かしたカテコールボラン(107mg)の溶液に、N2下において−78℃で(S)−2−メチル−CBS−オキサボロリジン(1Mトルエン溶液、0.89mL)を添加し、該混合物をその温度で1時間撹拌した。トルエン(2mL)に溶かした7−{(4R)−4−[(1E)−4,4−ジフルオロ−3−オキソ−4−フェニルブト−1−エン−1−イル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸イソプロピル(200mg)をカニューレによってゆっくり添加し、該混合物をさらに1時間撹拌して、1N HClで反応を停止した。該混合物を室温まで温めて、DCM(x2)で抽出した。有機層をNa2SO4で乾燥して、濾過した。濾液を真空中で濃縮して、残渣をカラムクロマトグラフィー(80〜100%酢酸エチル/ヘキサン)で精製して、表題化合物を得た。MS(+ESI):m/z454(M+1)+。
MS(−ESI):m/z410(M−I)−
動物
薬剤未処理の雄のDutch Beltedウサギ及び雌のカニクイザルをこの研究に使用した。この研究の動物の管理及び処置は、アメリカ国立衛生研究所(NIH)の指針及び視覚眼科学研究協会(Association for Research in Vision and Ophthalmology)(ARVO)の決議に従う。実験方法は全て、Merck and Companyの所内動物管理使用委員会によって承認された。
薬剤濃度は、活性成分(ベース)に関して表す。本発明の化合物は、ウサギ用には0.01、0.001、0.0001%で、サル用には0.05、0.005%で生理食塩水に溶解する。薬剤及びビヒクルの一定分量(25μl)を局所的に、片側又は両側に投与する。片側に適用する場合、反対側の目には同量の生理食塩水を与える。眼圧測定前にプロパラカイン(0.5%)を角膜に適用して、不快感を最小限に抑える。眼圧(IOP)は、気道眼圧計(Alcon Applanation Pneumatonograph)又は同等物を使用して記録する。
結果は、薬剤又はビヒクルを投与する直前に測定した基準レベルからのIOP変化として表し、平均±標準偏差で示す。統計的な比較は、薬物処理動物の応答とビヒクル処理動物の応答との非対データ、さらに比較可能な時間間隔での同じ側の眼と反対側の眼との対データに関するステューデントt検定を使用して行う。アスタリスクは、p<0.05の有意水準を表す。
体重2.5kgから4.0kgのオスのDutch Beltedウサギを、12時間の明/暗サイクルで維持し、食餌を与える。全ての実験は、日周リズムに関係したばらつきを最小限に抑えるため、1日のうちの同じ時間で実施する。IOPを、処理前に測定し、次いで本発明の化合物またはビヒクルを、片眼または両眼に点眼し(1滴25ul)、点眼後30、60、120、180、240、300、および360分でIOPを測定する。場合によっては、ビヒクルのみで両眼を処理した同じ数の動物について評価し、並行対照として、薬物処理した動物と比較する。
Lee他の方法(1985)を使用した、アルゴンレーザシステム(Coherent NOVUS 2000、Palo Alto、USA)による小柱網の光凝固によって、体重2kgから3kgの雌のカニクイザルの右眼に片側高眼圧症を誘発させる。眼圧(IOP)の増加が長引くことによって、緑内障患者に見られるものと同様の変化が視神経乳頭に生じる。
これらの化合物の試験に使用される測定法は、本質的に、Abramovitz M、Adam M、Boie Y、Carriere M、Denis D、Godbout C、Lamontagne S、Rochette C、Sawyer N、Tremblay NM、Belley M、Gallant M、Dufresne C、Gareau Y、Ruel R、Juteau H、Labelle M、Ouimet N、Metters KM、「プロスタグランジン及び関連類縁体の親和性および選択性を決定するための、組換えプロスタノイド受容体の利用(The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs.)」、Biochim Biophys Acta 2000年1月17日;1483(2):285〜293に記載されたように、また以下に論じるように、実施した。
完全長コード配列に対応するプロスタノイド受容体(PG)cDNAを、哺乳動物発現ベクターpCEP4(Invitrogen)の適切な部位にサブクローニングし、製造業者の取扱説明書に従い、Qiagenプラスミド調製キット(QIAGEN)を使用してpCEP4PGプラスミドDNAを調製し、LipofectAMINE(GIBCO−BRL)を使用してHEK293(EBNA)細胞にトランスフェクトした。ハイグロマイシン耐性遺伝子と共にcDNAを発現するHEK293(EBNA)細胞を、10%熱不活性化ウシ胎児血清、ピルビン酸ナトリウム 1mM、ペニシリン−G 100U/ml、硫酸ストレプトマイシン 100μg/ml、活性GENETICIN(商標)(G418)250μg/ml(全てLife Technologies,Inc./BRLから)、及びハイグロマイシン(Calbiochem)200μg/mlを補ったダルベッコ変法イーグル培地(DMEM)で選択した。個々のコロニーを、クローニングリング法を使用して選択した状態で2〜3週間増殖させた後に単離し、その後、クローン細胞系内に増殖させた。受容体cDNAの発現を、受容体結合測定法によって評価した。
プロスタノイド受容体結合測定法は、EDTA 1mM、MgCl2 10mM(EPサブタイプ)又はMnCl2 10mM(DP、FP、IP、およびTP)および放射リガンド[EPサブタイプでは0.5〜1.0nM[3H]PGE2(181Ci/mmol)、DPでは0.7nM[3H]PGD2(115Ci/mmol)、FPでは0.95nM[3H]PGF2α(170Ci/mmol)、IPでは5nM[3H]イロプロスト(16Ci/mmol)、TPでは1.8nM[3H]SQ29548(46Ci/mmol)]を含有する10mM MES/KOH(pH6.0)(EPサブタイプ、FPおよびTP)又は10mM HEPES/KOH(pH7.4)(DP及びIP)において、最終インキュベーション量0.2mlで行った。EP3アッセイはまた、GTPγS 100μMを含有していた。反応は、160000xg画分からの膜タンパク質(EP1では約30μg、EP2では約20μg、EP3では約2μg、EP4では約10μg、FPでは約60μg、DPでは約30μg、IPでは約10μg、及びTPでは約10μg)を添加することによって開始した。リガンドをジメチルスルホキシド(Me2SO)に添加し、これを全インキュベーションにおいて1%(v/v)で一定に保った。対応する非放射性プロスタノイド1μMの存在下で、非特異的結合を測定した。インキュベーションを60分間(EPサブタイプ、FP及びIP)または30分間(DP及びTP)、30℃(EPサブタイプ、DP、FP及びTP)または室温(IP)で実施し、Tomec Mach III 96ウェル半自動化細胞収集機を使用して、EDTAを含まないインキュベーション緩衝液で事前に湿潤させた96ウェルUnifilter GF/C(Canberra Packard)に(4℃で)通して急速濾過して終了させた。フィルターを、同緩衝液3mlから4mlで洗浄し、55℃で90分間乾燥し、個々のフィルターに結合した残留放射能を、1450 MicroBeta(Wallac)を使用してUltima Gold F(Canberra Packard)50μlを添加してシンチレーションカウントすることにより決定した。全結合から非特異的結合を差し引くことによって、特異的結合を算出した。特異的結合は全結合の90%から95%を占め、使用した放射リガンドおよびタンパク質の濃度に対して直線的であった。全結合は、インキュベーション培地に加えられた放射リガンドの5〜10%を占めた。
1.動物の処置:
mRNA局在化測定法では、5週齢のSprague−Dawleyラット(Charles River)をCO2で安楽死させ、その脛骨および頭蓋冠を切除し、軟組織を取り除いてすぐに液体窒素で凍結させる。EP4調節実験では、6週齢のラットに対し、ビヒクル(エタノールの7%滅菌水溶液)又はタンパク質同化用量のPGE2(Cayman Chemical、Ann Arbor、MI)(同ビヒクル中3〜6mg/kg)を、腹腔内に1回注射する。動物は、注射後の複数の時点で安楽死させ、その脛骨及び頭蓋冠、並びに肺及び腎臓組織の試料を液体窒素中で凍結させる。
4週齢のSprague−Dawleyラットの脛骨の骨膜細胞の初代培養から、RP−1骨膜細胞を自発的に不死化させ、10%ウシ胎児血清(JRH Biosciences、Lenexa、KS)を含むDMEM(BRL、Gaithersburg、MD)で培養する。これらの細胞は、初期の培養では骨芽細胞表現型マーカーを発現しないが、集密状態になると、I型コラーゲン、アルカリホスファターゼ、及びオステオカルシンを発現し、ミネラル化細胞外基質を生成する。
凍結した骨試料を組織ホモジナイザによって微粉砕した後、イソチオシアン酸グアニジニウム−フェノール−クロロホルム法を使用して、脛骨の骨幹端又は骨幹及び頭蓋冠から全RNAを抽出する。その全体を本明細書に参考として援用する、P.Chomczynski他、「酸チオシアネートグアニジウム−フェノール−クロロホルム抽出によるRNAの1段階精製法(Single−step method of RNA isolation by acid guanidium thiocyanate−phenol−chloroform extraction.)」、Analyt Biochem、162、156〜159(1987)を参照されたい。0.9%アガロース/ホルムアルデヒドゲル上でRNA試料(20mg)を分離し、ナイロン膜(Boehringer Mannheim、ドイツ)に移す。膜を、Hybrisol I(Oncor、Gaithersburg、MD)及び超音波処理したサケの***DNA(Boehringer)0.5mg/ml中において42℃で3時間予備ハイブリダイズさせ、rediprimeキット(Amersham)を使用したランダムプライミングによって[32P]−dCTP(Amersham、Buckinghamshire、UK)で標識したラットEP2およびマウスEP4cDNAプローブと42℃でハイブリダイズさせる。ハイブリダイゼーション後、膜を、2×SSC+0.1%SDSで4回、合わせて1時間室温で洗浄し、0.2×SSC+0.1%SDSで1回、55℃で1時間洗浄し、次いで増感紙を使用して、Kodak XAR2フィルムに−70℃で露光する。フィルム現像後、結合したプローブを、80℃の0.1%SDSで2回除去し、負荷対照用に、膜をヒトGAPDH(グリセルアルデヒド3リン酸脱水素酵素)cDNAプローブ(Clontech、Palo Alto、CAから購入)とハイブリダイズさせる。
凍結した脛骨を7mmの厚さで冠状に切り取り、その切片を荷電スライド(Probe On Plus、Fisher Scientific、Springfield、NJ)に載せ、ハイブリダイゼーションまで−70℃に保つ。cRNAプローブを、RiboprobeIIキット(Promega Madison、WI)を使用して35S−UTPgS(ICN、Costa Mesa、CA)で標識する。ハイブリダイゼーションは50℃で一晩実施する。いずれもその全体を本明細書に参考として援用する、M.Weinreb他、「インサイツハイブリダイゼーションによって視覚化したラット骨の発達中におけるアルカリホスファターゼ、オステオポンチン及びオステオカルシン発現の様々なパターン(Different pattern of alkaline phosphatase、osteopontin and osteocalcin expression in developing rat bone visualized by in−situ hybridization)」J.Bone Miner Res.、5、831〜842(1990)及びD.Shiner他、「ラット破骨細胞内のインサイツにおけるアルファv及びベータ3インテグリンサブユニットの発現(Expression of alphav and beta3 integrin subunits in rat osteoclasts in situ)」J.Bone Miner.Res.、8、403〜414(1993)を参照されたい。ハイブリダイゼーション及び洗浄の後、グリセロールの6%水溶液で2:1に希釈した42℃のIlford K5エマルジョンに切片を浸漬し、12日から14日の間、4℃で暗闇に曝す。水で1:1に希釈したKodak D−19で15°でスライドを現像し、固定し、蒸留水で洗浄し、ヘマトキシリン染色後にグリセロール−ゼラチン(Sigma)を施す。染色した切片を、明視野または暗視野光学部品を使用して、顕微鏡(Olympus、Hamburg、ドイツ)で見る。
骨芽細胞に富む初代ラット頭蓋冠細胞、ラット胎児頭蓋冠又は成体ラット脛骨からの不死化骨芽細胞系及び骨芽細胞骨肉腫細胞系を含む様々な骨由来細胞での、EP4およびEP2 mRNAの発現について調べる。ラット骨肉腫細胞系ROS17/2.8を除いて骨芽細胞及び細胞系のほとんどは、相当な量の3.8kb EP4 mRNAを示す。この知見と一致して、PGE2によって、RCT−3及びTRAB−11細胞では細胞内cAMPが顕著に誘導されるが、ROS17/2.8細胞では影響を及ぼさない。レチノイン酸でRCT−1細胞を処理すると、その分化を促進するが、EP4mRNAの濃度を低下させる。NRK線維芽細胞はEP4mRNAを発現しないが、陽性対照として使用したP815肥満細胞腫細胞は大量のEP4mRNAを発現する。EP4mRNAとは対照的に、検出可能な量のEP2 mRAを全RNA試料中に発現する骨芽細胞及び細胞系はない。骨芽細胞でのEP4mRNAの発現で、EP4はまた、5週齢のラットの脛骨及び頭蓋冠から単離された全RNAで発現する。これとは対照的に、脛骨幹のRNAにEP2mRNAは見られない。
PGE2は、骨芽細胞及び骨組織においてシクロオキシゲナーゼ2発現を上方制御することによってそれ自体の生成を高め、したがってそれ自体の効果が自動増幅する。PGE2はまた、EP4mRNA濃度を増大させる。RP−1細胞を、成体ラット脛骨膜の初代培養から不死化させ、調べる。これらの細胞は、集密化すると骨芽細胞表現型マーカーを発現し、ヌードマウスに移植すると、ミネラル化骨基質を形成する。試験したその他の骨芽細胞と同様に、RP−1骨膜細胞は、3.8kbのEP4転写物を発現する。PGE2(10−6M)で処理することにより、EP4mRNA濃度が急速に増大し、処理後2時間でピークに達する。PGE2は、より分化したRCT−3細胞においてEP4mRNA濃度に影響を及ぼさず、PGE2によるEP4発現は細胞型特異的調節であることを示している。EP2mRNAは、PGE2による処理の前後でRP−1細胞において発現しない。
骨中でEP4を発現する細胞を局在化させるため、インサイツハイブリダイゼーションを使用する。対照実験(ビヒクル注射)のラットでは、骨髄細胞で検出されるEP4発現は少ない。単回タンパク同化用量のPGE2を投与することにより、骨髄細胞内でのEP4発現が増加した。骨髄全体の銀粒子の分布は均一ではなく、骨幹端の多くの領域で塊や斑が生じる。脛骨の骨幹端では、EP4発現は二次海綿質領域に限定され、一次海綿質には見られない。同様の切片とセンスプローブとのハイブリダイゼーション(陰性対照)は、いかなるシグナルも示さない。
作動薬活性を測定するための標準的な方法を使用して、以下の化合物を細胞培養及びEP4受容体を含まない無細胞系で評価し、この化合物の作動薬活性をそのEC50値に関して決定する。
Claims (7)
- 構造式Iで表わされる化合物
X及びYは、独立して、CH2、又はOを表すが、但し、X及びYは同時にOではなく、
UはH、C1〜3アルキルを表すか、又はWが=Oのときは存在せず、
WはOH又は=Oを表し、但し、Wが=OのときUは存在せず、
R1は、(CH2)pヒドロキシ、(CH2)pCN、(CH2)pCO2R10、(CH2)nSO3R6、−(CH2)pCF2SO2NH2、−(CH2)pSO2NH2、−(CH2)pCONHSO2R2、−(CH2)pSO2NHCOR2、−(CH2)pPO(OH)2、(CH2)pCONHPO2R6、(CH2)pCONHR8、(CH2)pC1〜4アルコキシ、−(CH2)pシクロアルキル、(CH2)p−ヒドロキシメチルケトン又は(CH2)pヘテロシクリルを表し、前記ヘテロシクリルは非置換であるか、又は1個から3個のRa基によって置換されており、
R2は、独立して、C1〜10アルキル、又は(CH2)mC6〜10アリールを表し、但し、前記アルキル、又はアリールは非置換であるか、又は1個から3個のRa基で置換されており、
R3及びR4は、ハロゲンを表し、
R6及びR7は、独立して、水素又はC1〜4アルキルを表し、
R8は、水素、アシル又はスルホニルを表し、
R10は、水素、C1〜10アルキル、C3〜10シクロアルキル、(CH2)pC6〜10アリール、(CH2)pC5〜10ヘテロシクリル、CR6R7OC(O)OC3〜10シクロアルキル又はCR6R7OC(O)OC1〜10アルキルを表し、
Zは、O、S、(C(Rb)2)n又はCH=CHを表し、
Rbは、水素、C1〜6アルキル又はハロゲンを表し、
Raは、C1〜6アルコキシ、C1〜6アルキル、CF3、ニトロ、アミノ、シアノ、C1〜6アルキルアミノ、ハロゲンを表し、又は、Raはさらにアリール及びヘテロシクリル、SC1〜6アルキル、SC6〜10アリール、SC5〜10ヘテロシクリル、CO2R6、OC6〜10アリール、OC5〜10ヘテロシクリル、CH2OC1〜6アルキル、CH2SC1〜6アルキル、CH2Oアリール、CH2Sアリールを表し、
---は、二重結合又は一重結合を表し、
pは、0から3を表し、
nは、0から4を表し、
mは、0から8を表す。)
又は薬剤として許容されるそれらの塩、エナンチオマー、若しくはジアステレオマー。 - R1が、(CH2)pCN、(CH2)pCO2R10、−(CH2)pPO(OH)2、(CH2)pCONHPO2R6、(CH2)pCONHR8又は(CH2)pヘテロシクリルであり、前記ヘテロシクリルは非置換であるか、又は1個から3個のRa基で置換されており、その他の可変要素は全て最初に説明した通りである、請求項1に記載の化合物。
- R1が(CH2)pCO2R10であり、X及びYがCH2であり、Zが(C(Rb)2)nであり、Qが(CH2)mであり、R3及びR4がハロゲンであり、R2が(CH2)mC6〜10アリールであり、前記アリールは非置換であるか、又は1個から3個のRa基で置換されている、請求項1に記載の化合物。
- R1が(CH2)pC5〜10ヘテロシクリルであり、UがH又はC1〜3アルキルであり、WがOHであり、Zが結合又はSであり、R2が(CH2)mC6〜10アリールであり、前記アリールは非置換であるか、又は1個から3個のRa基で置換されており、前記ヘテロシクリルは非置換であるか、又は1個から3個のRa基で置換されており、その他の可変要素全てが最初に説明した通りである、請求項2に記載の化合物。
- 7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸;
7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}ヘプタン酸;
7−{(2R)−2−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸;
7−{(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−2−オキソ−1,3−チアジナン−3−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸イソプロピル;
7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸イソプロピル;
7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}ヘプタン酸イソプロピル;
(6R)−6−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−1−[6−(2H−テトラアゾール−5−イル)ヘキシル]ピペリジン−2−オン;
(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−3−[6−(2H−テトラアゾール−5−イル)ヘキシル]−1,3−オキサジナン−2−オン;
(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−3−[6−(2H−テトラアゾール−5−イル)ヘキシル]−1,3−チアジナン−2−オン;
(5S)−5−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−4−[6−(2H−テトラアゾール−5−イル)ヘキシル]モルホリン−3−オン;
(6S)−6−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−1−[6−(2H−テトラアゾール−5−イル)ヘキシル]ピペラジン−2−オン;
(5S)−5−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−4−[6−(2H−テトラアゾール−5−イル)ヘキシル]チオモルホリン−3−オン;
5−(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)チオフェン−2−カルボン酸;
5−(3−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}プロピル)チオフェン−2−カルボン酸;
5−(3−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}プロピル)チオフェン−2−カルボン酸;
(6R)−6−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−1−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}ピペリジン−2−オン;
(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−3−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}−1,3−オキサジナン−2−オン;
(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−3−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}−1,3−チアジナン−2−オン;
(6R)−6−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−1−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}ピペリジン−2−オン;
(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−3−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}−1,3−オキサジナン−2−オン;
(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−3−{3−[5−(2H−テトラアゾール−5−イル)チエン−2−イル]プロピル}−1,3−チアジナン−2−オン;
5−(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)チオフェン−2−カルボン酸イソプロピル;
5−(3−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}プロピル)チオフェン−2−カルボン酸イソプロピル;
5−(3−{(4R)−4−[(1E,3S)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}プロピル)チオフェン−2−カルボン酸イソプロピル;
(5E)−7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプト−5−エン酸;
(5E)−7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプト−5−エン酸;
(5E)−7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−チアジナン−3−イル}ヘプト−5−エン酸;
(5E)−7−{(2R)−2−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−6−オキソピペリジン−1−イル}ヘプト−5−エン酸;
(5E)−7−{(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプト−5−エン酸;
(5E)−7−{(4S)−4−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブチル]−2−オキソ−1,3−チアジナン−3−イル}ヘプト−5−エン酸;
2−(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1,3−オキサゾール−5−カルボン酸;
5−(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1H−イミダゾール−2−カルボン酸;
2−(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)−1H−イミダゾール−5−カルボン酸;
5−((1E)−3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロプ−1−エニル)チオフェン−2−カルボン酸;
5−((1Z)−3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロプ−1−エニル)チオフェン−2−カルボン酸;
(6R)−6−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−1−{(2Z)−4−[(1H−テトラアゾール−5−イルメチル)チオ]ブト−2−エニル}ピペリジン−2−オン;
[((2Z)−4−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ブト−2−エニル)チオ]酢酸;
[(4−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ブチル)チオ]酢酸;
[(4−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ブトキシ)酢酸;
3−[(3−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}プロピル)チオ]プロパン酸;
7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3S)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−(2−ナフチル)ブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
(6R)−6−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブト−1−エニル]−1−[6−(1H−テトラアゾール−5−イル)ヘキシル]ピペリジン−2−オン;
(6R)−6−[(1E,3S)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブト−1−エニル]−1−[6−(1H−テトラアゾール−5−イル)ヘキシル]ピペリジン−2−オン;
7−{(2R)−2−[(1E,3R)−4−(1−ベンゾチエン−2−イル)−4,4−ジフルオロ−3−ヒドロキシブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
(6R)−6−[(3R)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブチル]−1−[6−(1H−テトラアゾール−5−イル)ヘキシル]ピペリジン−2−オン;
(6R)−6−[(3S)−4,4−ジフルオロ−3−ヒドロキシ−3−メチル−4−フェニルブチル]−1−[6−(1H−テトラアゾール−5−イル)ヘキシル]ピペリジン−2−オン;
7−{(2R)−2−[(1E,3R)−4−(1−ベンゾフラン−2−イル)−4,4−ジフルオロ−3−ヒドロキシブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3R)−4−(3−クロロフェニル)−4,4−ジフルオロ−3−ヒドロキシブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−(3−メトキシフェニル)ブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸;
7−{(2R)−2−[(1E)−4,4−ジフルオロ−3−オキソ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸イソプロピル;
7−{(2R)−2−[(3R)−4−(3−ブロモフェニル)−4,4−ジフルオロ−3−ヒドロキシブチル]−6−オキソピペリジン−1−イル}ヘプタン酸;
(5Z)−7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−1−イル]−6−オキソピペリジン−1−イル}ヘプト−5−エン酸イソプロピル;
(5Z)−7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−イル]−6−オキソピペリジン−1−イル}ヘプト−5−エン酸;
イソプロピル−7−{(4R)−4−[(1E)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−1−イル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタノエート;
7−{(4R)−4−[(1E)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−イル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸である化合物、
又は薬剤として許容されるそれらの塩、エナンチオマー、若しくはジアステレオマー。 - 7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸、
7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸、
7−{(2R)−2−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸イソプロピル、
7−{(4R)−4−[(1E,3R)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エニル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸イソプロピル、
7−{(2R)−2−[(1E)−4,4−ジフルオロ−3−オキソ−4−フェニルブト−1−エニル]−6−オキソピペリジン−1−イル}ヘプタン酸イソプロピル、
7−{(2R)−2−[(3R)−4−(3−ブロモフェニル)−4,4−ジフルオロ−3−ヒドロキシブチル]−6−オキソピペリジン−1−イル}ヘプタン酸、
イソプロピル−7−{(4R)−4−[(1E)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−1−イル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタノエート、
7−{(4R)−4−[(1E)−4,4−ジフルオロ−3−ヒドロキシ−4−フェニルブト−1−エン−1−イル]−2−オキソ−1,3−オキサジナン−3−イル}ヘプタン酸、
又は薬剤として許容されるそれらの塩、エナンチオマー、若しくはジアステレオマー。 - 医学的治療に使用するための、請求項1から6に記載された式Iの化合物又は薬剤として許容されるそれらの塩、エナンチオマー、若しくはジアステレオマー。
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Publication number | Priority date | Publication date | Assignee | Title |
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JP2006515015A (ja) * | 2003-01-10 | 2006-05-18 | エフ.ホフマン−ラ ロシュ アーゲー | プロスタグランジンアゴニストとしての2−ピペリドン誘導体 |
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JP2006520758A (ja) | 2006-09-14 |
EP1613621B1 (en) | 2010-07-21 |
US20040198701A1 (en) | 2004-10-07 |
AR040806A1 (es) | 2005-04-20 |
MXPA05010189A (es) | 2006-02-22 |
CN1764659A (zh) | 2006-04-26 |
IS7999A (is) | 2005-08-25 |
US20050227969A1 (en) | 2005-10-13 |
HRP20050845A2 (en) | 2006-05-31 |
AU2004224261A1 (en) | 2004-10-07 |
DE602004028229D1 (de) | 2010-09-02 |
ATE474837T1 (de) | 2010-08-15 |
TW200427670A (en) | 2004-12-16 |
CA2519938C (en) | 2010-11-30 |
BRPI0408690A (pt) | 2006-03-28 |
US7053085B2 (en) | 2006-05-30 |
NO20054951L (no) | 2005-12-22 |
WO2004085431A1 (en) | 2004-10-07 |
RU2005132930A (ru) | 2006-02-10 |
CA2519938A1 (en) | 2004-10-07 |
ES2347434T3 (es) | 2010-10-29 |
NO20054951D0 (no) | 2005-10-25 |
US20110237511A1 (en) | 2011-09-29 |
MA27667A1 (fr) | 2005-12-01 |
USRE42562E1 (en) | 2011-07-19 |
PE20050522A1 (es) | 2005-07-06 |
CL2004000655A1 (es) | 2005-01-21 |
EP1613621A1 (en) | 2006-01-11 |
KR20060002873A (ko) | 2006-01-09 |
WO2004085430A1 (en) | 2004-10-07 |
US7238710B2 (en) | 2007-07-03 |
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