JP4985400B2 - プロスタグランジン誘導体 - Google Patents
プロスタグランジン誘導体 Download PDFInfo
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- JP4985400B2 JP4985400B2 JP2007522354A JP2007522354A JP4985400B2 JP 4985400 B2 JP4985400 B2 JP 4985400B2 JP 2007522354 A JP2007522354 A JP 2007522354A JP 2007522354 A JP2007522354 A JP 2007522354A JP 4985400 B2 JP4985400 B2 JP 4985400B2
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- 230000001419 dependent effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- YNLAOSYQHBDIKW-UHFFFAOYSA-M diethylaluminium chloride Chemical compound CC[Al](Cl)CC YNLAOSYQHBDIKW-UHFFFAOYSA-M 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- ZSYZSZTWBOHQQK-UHFFFAOYSA-L dilithium;dichloride Chemical compound [Li+].[Li+].[Cl-].[Cl-] ZSYZSZTWBOHQQK-UHFFFAOYSA-L 0.000 description 1
- DPFCZRAGEMLFTN-UHFFFAOYSA-N dimethylsilyl trifluoromethanesulfonate Chemical compound C[SiH](C)OS(=O)(=O)C(F)(F)F DPFCZRAGEMLFTN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- CAERSDJFKGMKLY-UHFFFAOYSA-N ethyl 2-(3-bromophenyl)acetate Chemical compound CCOC(=O)CC1=CC=CC(Br)=C1 CAERSDJFKGMKLY-UHFFFAOYSA-N 0.000 description 1
- CGBSXVBKHFNSRZ-UHFFFAOYSA-N ethyl 2-(3-phenylphenyl)acetate Chemical compound CCOC(=O)CC1=CC=CC(C=2C=CC=CC=2)=C1 CGBSXVBKHFNSRZ-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000012155 injection solvent Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 108010021666 lipase II Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- GWGVDNZFTPIGDY-UHFFFAOYSA-M magnesium;ethyne;chloride Chemical compound [Mg+2].[Cl-].[C-]#C GWGVDNZFTPIGDY-UHFFFAOYSA-M 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- JJYKJUXBWFATTE-UHFFFAOYSA-N mosher's acid Chemical compound COC(C(O)=O)(C(F)(F)F)C1=CC=CC=C1 JJYKJUXBWFATTE-UHFFFAOYSA-N 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
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- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- ZZRPJWCNCLSOLR-UHFFFAOYSA-N trimethyl(prop-2-ynoxy)silane Chemical compound C[Si](C)(C)OCC#C ZZRPJWCNCLSOLR-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
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- A—HUMAN NECESSITIES
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Description
以下、反応式2を説明する。
1H-NMR(CDCl3, 300MHz) δppm; 1.26(t, J=7.2Hz, 3H), 3.58(s, 2H), 4.16(q, J=7.2Hz, 2H), 7.15-7.28(m, 2H), 7.36-7.48(m, 2H),
IR(neat):2982,1736,1596,1570,1475,1430,1368,1334,1250,1219,1157,1091,1073,1031,998,944,891,841,781,682,432 cm-1
3-ビフェニル酢酸 エチル エステル
1H-NMR(CDCl3, 300MHz) δppm; 1.27(t, J=7.1Hz, 3H), 3.68(s, 2H), 4.17(q, J=7.1Hz, 2H), 7.24-7.64(m, 9H)
IR(neat):3033,2982,1733,1600,1576,1480,1455,1423,1368,1294,1252,1206,1155,1096,1032,899,846,754,699,616,409cm-1
1-(3-ビフェニル)-3-ブチン-2-オール
1H-NMR(CDCl3, 300MHz) δppm; 1.91(d, J=5.9Hz, 1H), 2.52(d, J=2.2Hz, 1H), 3.07(dd, J=13.5,6.5Hz, 1H), 3.12(dd,J=13.5,6.1Hz, 1H), 4.59-4.70(m, 1H), 7.24-7.63(m, 9H),
IR(neat):3544,3378,3289,3033,2926,2117,1600,1575,1480,1455,1421,1386,1291,1093,1036,973,899,850,797,757,729,701,646,584,550cm-1
(S)-1-(3-ビフェニル)-3-ブチン-2-オール
(S)-1-(3-ビフェニル)-2-(t-ブチルジメチルシリルオキシ)-3-ブチン
1H-NMR(CDCl3, 300MHz) δppm; 0.06(s, 3H), 0.07(s, 3H), 0.89(s, 9H), 2.51(d, J=2.0Hz, 1H), 3.03-3.18(m, 12H), 4.56-4.64(m, 1H), 7.26-7.69(m, 9H),
[α]D 26 27.8° (C.1.38 CHCl3)
(3R,4R)-3-((S)-4-ビフェニル-3-イル-(3- t-ブチルジメチルシリルオキシ)-1-ブチン-1-イル)-(4- t-ブチルジメチルシリルオキシ)-2-メチレンシクロペンタノン
(2E)-17,18,19,20-テトラノル-16-(3-ビフェニル)-2,3,13,14-テトラデヒドロ-PGE1 メチル エステル 11,15-ビス(t-ブチルジメチルシリル エーテル)
1H-NMR(CDCl3, 300MHz) δppm; -0.09(s, 3H), -0.05(s, 3H), 0.06(s, 3H), 0.09(s, 3H), 0.82(s, 9H), 0.88(s, 9H), 1.10-1.80(m, 6H), 2.05-2.25(m, 3H), 2.13(dd, J=17.7, 6.5Hz, 1H), 2.51-2.71(m, 2H), 2.91-3.07(m, 2H), 3.72(s, 3H), 4.16-4.27(m, 1H), 4.49-4.60(m, 1H), 5.81(dt, J=15.6, 1.5Hz, 1H), 6.94(dt, J=15.6, 6.9Hz, 1H), 7.16-7.61(m, 9H)
IR(neat): 2952, 2930, 2858, 2234, 1747, 1727, 1659, 1600, 1472, 1463, 1436, 1361, 1258, 1196, 1123, 1082, 1006, 940, 883, 838, 779, 757, 702, 669 cm-1
MS(ES+) m/z: 711(M+Na)+
1H-NMR(CDCl3, 300MHz) δppm; 1.12-1.78(m, 6H), 2.06-2.23(m, 3H), 2.14(dd, J=18.5, 9.2Hz, 1H), 2.32(d, J=3.4Hz, 1H), 2.46(d, J=5.9Hz, 1H), 2.39-2.70(m, 1H), 2.63(ddd, J=18.5, 7.3, 1.4Hz, 1H), 2.99-3.16(m, 2H), 3.71(s, 3H), 4.07-4.21(m, 1H), 4.63-4.74(m, 1H), 5.80(dt, J=15.6, 1.5Hz, 1H), 6.94(dt, J=15.6, 7.1Hz, 1H), 7.21-7.62(m, 9H)
IR(neat): 3406, 3232, 2930, 2859, 2235, 1743, 1722, 1655, 1600, 1575, 1480, 1437, 1320, 1277, 1203, 1157, 1077, 1038, 988, 858, 800, 758, 728, 702, 616, 415 cm-1
MS(ES+) m/z: 483(M+Na)+
1H-NMR(CDCl3, 300MHz) δppm; 1.10-3.40(m, 14H), 2.14(dd, J=18.7, 9.0Hz, 1H), 3.05(dd, J=13.5, 6.4Hz, 1H), 3.10(dd, J=13.5, 6.6Hz, 1H), 4.07-4.22(m, 1H), 4.63-4.75(m, 1H), 5.80(d, J=15.7Hz, 1H), 7.02(dt, J=15.7, 7.2Hz, 1H), 7.21-7.63(m, 9H)
IR(neat): 3384, 2930, 2859, 2238, 1740, 1694, 1652, 1606, 1480, 1422, 1285, 1236, 1156, 1076, 1036, 988, 799, 757, 728, 702, 616 cm-1
MS(ES+) m/z: 469(M+Na)+ ; MS(ES-) m/z: 445(M-H)-
IR(neat): 3400, 2930, 2860, 2236, 1744, 1697, 1652, 1448, 1384, 1284, 1194, 1159, 1085, 1039, 886, 793, 758, 703, 667, 552 cm-1
MS(ES+): 437(M+Na)+; MS(ES-): 413(M-H)-
参考例1〜5または特開2001-89444に記載の方法と同様の操作を行うことにより得られた末端アセチレン化合物を用い、参考例6と同様の操作を行い、参考例7において(4E)-5-カルボメトキシペント-4-エニル亜鉛(II)ヨージドのかわりに、対応する有機亜鉛試薬を用い、実施例1および実施例2と同様の操作を行うことにより以下の本発明化合物を得た。
IR(neat); 3386, 3031, 2932, 2864, 2622, 2235, 1738, 1699, 1600, 1588, 1480, 1455, 1421, 1328, 1259, 1157, 1074, 1036, 900, 797, 757, 728, 702, 616, 594 cm-1
MS(ES-) m/z: 443 (M-H)-
IR(neat): 3392, 3208, 2931, 2864, 2236, 1736, 1698, 1496, 1455, 1385, 1244, 1157, 1077, 1032, 755, 702 cm-1
MS(FAB)(+KI)m/z: 407(M+K)+
IR(neat): 3400, 3029, 2930, 2860, 2236, 1734, 1496, 1455, 1385, 1288, 1157, 1078, 1034, 894, 746, 702, 540 cm-1
MS(ES+) m/z: 413(M+Na) +; MS(ES-) m/z: 389(M-H) -
IR(neat):3400, 3032, 2930, 2860, 2236, 1734, 1600, 1480, 1456, 1421, 1288, 1157, 1090, 1038, 901, 799, 758, 729, 703, 668, 616, 579, 503 cm-1
MS(ES+) m/z: 489(M+Na) +; MS(ES-) m/z: 465(M-H) -
IR(neat): 3400, 2930, 2860, 2236, 1740, 1733, 1488, 1448, 1385, 1287, 1159, 1087, 1039, 891, 791, 757, 704, 667, 555 cm-1
MS(ES-) m/z: 433(M-H) -
IR(neat): 3400, 2931, 2857, 2236, 1740, 1715, 1610, 1488, 1450, 1385, 1363, 1346, 1287, 1157, 1073, 955, 891, 790, 757, 703, 666 cm-1
MS(ES+): 525(M+Na)+; MS(ES-): 501(M-H)-
IR(neat): 3418, 3027, 2934, 2861, 2235, 1739, 1603, 1496, 1455, 1436, 1286, 1152, 1065, 1011, 919, 749, 702, 589 cm-1
MS(ES+) m/z: 471(M+Na)+ ; MS(ES-) m/z: 447(M-H)-
IR(neat): 3385, 2971, 2928, 2863, 2236, 1738, 1488, 1446, 1384, 1334, 1286, 1140, 1041, 908, 787, 702, 554 cm-1
MS(ES+) m/z: 485(M+Na)+;MS(ES-) m/z: 461(M-H)-
IR(neat):3418, 2932, 2862, 2654, 2237, 1732, 1609, 1488, 1446, 1417, 1385, 1286, 1157, 1103, 1043, 902, 786, 757, 705, 666, 568 cm-1
MS(ES+) m/z: 471(M+Na) +; MS(ES-) m/z: 447(M-H) -
IR(neat):3385, 2929, 2234, 1731, 1607, 1446, 1384, 1288, 1157, 1033, 798, 736, 703 cm-1
MS(ES+) m/z: 441(M+Na) +; MS(ES-) m/z: 417(M-H) -
IR(neat):3418, 2959, 2926, 2865, 2238, 1738, 1732, 1715, 1606, 1488, 1463, 1445, 1384, 1286, 1152, 1088, 1035, 792, 727, 706 cm-1
MS(ES+) m/z: 455(M+Na) +; MS(ES-) m/z: 431(M-H) -
IR(neat): 3400, 2930, 2859, 2236, 1740, 1448, 1385, 1239, 1193, 1160, 1085, 1039, 793, 758, 703, 618 cm-1
MS(ES+)m/z: 439(M+Na)+ ; MS(ES-)m/z: 415(M-H)-
IR(neat): 3386, 2932, 2858, 2236, 1736, 1708, 1600, 1576, 1480, 1455, 1420, 1324, 1236, 1158, 1102, 1077, 1037, 1001, 901, 800, 757, 728, 702, 616 cm-1
MS(ES+) m/z: 471(M+Na) +; MS(ES-) m/z: 447(M-H) -
IR(neat): 3388, 3034, 2930, 2857, 2237, 1738, 1713, 1600, 1576, 1480, 1455, 1421, 1324, 1285, 1236, 1159, 1077, 1037, 1001, 900, 799, 757, 728, 702, 616 cm-1
MS(ES+) m/z: 485 (M+Na)+; MS(ES-) m/z: 461 (M-H)-
(1)(E)−[(4R,5R)-2,4-ビス(t-ブチルジメチルシロキシ)-5-(3-ヒドロキシプロパ-1-イル)シクロペント-1-エニル]ヘプト-2-エン酸 メチル エステル
1H-NMR(CDCl3,300MHz)δppm: 0.09(s,3H), 0.11(s,3H), 0.12(2s,6H), 0.90(s,9H), 0.93(s,9H), 1.22-1.63(m,4H), 1.74(t,J=6.1Hz,1H), 1.90-2.30(m,5H), 2.49-2.62(m,1H), 3.18-3.27(m,1H), 3.73(s,3H), 4.23-4.35(m,1H), 4.27(dd,J=6.1,1.6Hz,2H), 5.83(dt,J=15.6,1.5Hz,1H)
IR(neat):3445,2953,2931,2898,2858,2221,1728,1683,1657,1472,1463,1437,1408,1390,1362,1316,1228,1217,1178,1151,1103,1026,1007,979,939,912,876,839,812,780,672cm-1
MS(ES+):545(M+Na)+ ; MS(ES-):521(M-H)-
1H-NMR(CDCl3,300MHz)δppm: 0.09(s,3H), 0.11(s,3H), 0.13(s,3H), 0.14(s,3H), 0.89(s,9H), 0.93(s,9H), 1.30-1.58(m,4H), 1.90-2.06(m,1H), 2.12-2.34(m,4H), 2.51-2.70(m,1H), 3.34-3.41(m,1H), 3.72(s,3H), 4.39(dt,J=7.3,4.6Hz,1H), 5.81(dt,J=15.6,1.6Hz,1H), 6.96(dt,J=15.6,7.0Hz,1H), 9.21(d,J=0.8Hz,1H)
MS(ES+):543(M+Na)+
1H-NMR(CDCl3, 300MHz) δppm; 1.18-2.85(m, 14H), 2.89-3.06(m, 2H), 3.73(s, 3H), 4.20-4.34(m, 1H), 4.57-4.72(m, 1H), 5.73-5.90(m, 1H), 6.85-7.37(m, 5H)
IR(neat):3419,2932,2860,2236,1744,1723,1657,1599,1574,1478,1436,1316,1279,1206,1158,1080,1038,870,781,703,685,556,442 cm-1
MS(ES+) m/z: 441(M+Na)+; MS(ES-) m/z: 417(M-H)+
1H-NMR(CDCl3, 300MHz) δppm; 1.14-1.84(m, 9H), 2.09-2.39(m, 3H), 2.321(d, J=18.5,9.2Hz, 1H), 2.52-2.80(m, 2H), 2.86-3.11(m, 2H), 4.19-4.32(m, 1H), 4.58-4.68(m, 1H), 5.76-5.88(m, 1H), 6.96-7.36(m, 1H)
IR(neat):3383,2932,2860,2237,1740,1694,1652,1599,1574,1477,1430,1311,1283,1235,1207,1158,1079,1035,985,870,780,703,685,554 cm-1
MS(ES+) m/z: 427(M+Na)+; MS(ES-) m/z: 403(M-H)+
実施例20(3)において、3-クロロベンジルブロミドの変わりに対応するベンジルハライドを用い、実施例20と同様の操作を行うことにより、以下の本発明化合物を得た。
IR(neat):3384,3064,3020,2929,2859,2236,1731,1695,1652,1494,1456,1384,1286,1158,1108,1075,1030,986,870,800,746,667,559,451,418 cm-1
MS(ES+) m/z: 407(M+Na)+; MS(ES-) m/z: 383(M-H)-
IR(neat):3384,3024,2929,2860,2237,1741,1697,1652,1610,1590,1488,1417,1310,1285,1236,1158,1095,1078,1037,985,882,777cm-1
MS(ES+) m/z: 407(M+Na)+
IR(neat):3386,3022,2927,2860,2236,1741,1697,1652,1516,1417,1285,1235,1158,1108,1077,1036,984,883,863,846,805,760,666,554,491cm-1
MS(ES+) m/z: 407(M+Na)+; MS(ES-) m/z: 383(M-H)-
IR(neat): 3386, 3059, 2932, 2860, 2233, 1738, 1694, 1652, 1480, 1436, 1313, 1282, 1235, 1159, 1038, 1010, 986, 876, 753, 704, 665, 617, 541, 469 cm-1
MS(ES+) m/z: 469(M+Na)+; MS(ES-) m/z: 445(M-H)-
IR(neat):3385,3060,3033,2929,2859,2235,1741,1695,1652,1606,1576,1480,1455,1420,1310,1285,1235,1156,1076,1036,985,892,799,757,728,702,668,616 cm-1
MS(ES+) m/z: 469(M+Na)+; MS(ES-) m/z: 445(M-H)-
IR(neat): 3388, 3029, 2931, 2860, 2236, 1732, 1694, 1652, 1520, 1488, 1412, 1312, 1286, 1236, 1157, 1038, 1008, 847, 823, 761, 699, 560 cm-1
MS(ES+) m/z: 469(M+Na)+; MS(ES-) m/z: 445(M-H)-
IR(neat): 3382, 2934, 2861, 2237, 1732, 1694, 1652, 1573, 1475, 1444, 1312, 1283, 1159, 1053, 1041, 985, 874, 754, 684, 548 cm-1
MS(ES+) m/z: 427(M+Na)+; MS(ES-) m/z: 403(M-H)+
IR(neat): 3382, 2933, 2861, 2236, 1739, 1694, 1652, 1493, 1408, 1282, 1158, 1090, 1036, 1016, 985, 841, 808, 671, 548 cm-1
MS(ES+) m/z: 427(M+Na)+; MS(ES-) m/z: 403(M-H)-
IR(neat):3387,2934,2860,2236,1741,1695,1651,1603,1585,1490,1454,1437,1313,1258,1154,1080,1042,994,876,779,746,696,555 cm-1
MS(ES+) m/z: 423(M+Na)+
MS(ES-) m/z: 399(M-H)+
IR(neat): 3413, 3030, 2933, 2860, 2238, 1740, 1694, 1652, 1496, 1455, 1402, 1385, 1309, 1275, 1232, 1205, 1158, 1100, 1078, 1032, 989, 744, 701, 668, 547 cm-1
MS(ES+) m/z: 393(M+Na)+; MS(ES-) m/z: 369(M-H)+
IR(neat): 3412, 2933, 2861, 2236, 1739, 1694, 1652, 1618, 1589, 1488, 1448, 1403, 1310, 1274, 1249, 1142, 1099, 1077, 1037, 984, 868, 840, 783, 754, 520, 462, 425 cm-1
MS(ES+) m/z: 411(M+Na)+; MS(ES-) m/z: 387(M-H)+
IR(neat):3383,2935,2863,2236,1739,1694,1652,1493,1451,1418,1329,1287,1236,1201,1163,1124,1096,1075,1037,985,920,884,800,754,704,666,544 cm-1
MS(ES+) m/z: 461(M+Na)+; MS(ES-) m/z: 437(M-H)+
IR(neat):3412,2934,2860,2237,1739,1694,1652,1588,1562,1467,1395,1310,1282,1233,1202,1157,1098,1048,985,878,813,728,667,551,466 cm-1
MS(ES+) m/z: 461(M+Na)+; MS(ES-) m/z: 437(M-H)+
IR(neat): 3384, 2932, 2860, 2237, 1739, 1694, 1652, 1503, 1486, 1446, 1418, 1371, 1313, 1285, 1220, 1193, 1156, 1078, 1035, 1014, 985, 926, 886, 791, 738, 699, 667, 595 cm-1
MS(ES+) m/z: 459(M+Na)+; MS(ES-) m/z: 435(M-H)+
IR(neat): 3412, 3020, 2932, 2860, 2234, 1742, 1695, 1651, 1477, 1421, 1402, 1385, 1311, 1284, 1232, 1158, 1076, 1031, 987, 799, 758, 728, 715, 666, 624, 464 cm-1
MS(ES+) m/z: 483(M+Na)+; MS(ES-) m/z: 459(M-H)+
IR(neat): 3385, 3030, 2928, 2859, 2235, 1742, 1694, 1652, 1604, 1581, 1475, 1461, 1417, 1311, 1284, 1234, 1158, 1091, 1036, 984, 882, 778, 700, 667, 552 cm-1
MS(ES+) m/z: 483(M+Na)+; MS(ES-) m/z: 459(M-H)+
IR(neat): 3385, 3026, 2931, 2861, 2238, 1743, 1694, 1652, 1606, 1528, 1484, 1434, 1418, 1402, 1312, 1285, 1234, 1188, 1157, 1095, 1078, 1035, 985, 824, 787, 759, 708, 667, 558 cm-1
MS(ES+) m/z: 483(M+Na)+; MS(ES-) m/z: 459(M-H)+
文献(Takayama, K., ら(2002). Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biol Chem 277, 44147-44154.)記載の方法にしたがい抗炎症活性を求めた。具体的には、ヒト末梢血単球を精製し1週間培養しマクロファージに分化させた。分化マクロファージに評価化合物を10nM最終濃度になるように添加し30分間培養した。培養後、大腸菌由来リポポリサッカライド(LPS)を最終濃度5ng/mlになるように添加し、さらに18時間培養した。培養後、細胞上清を回収し、ケモカイン(MIP-1β)産生量をELISA法にて測定した。抗炎症活性の陰性対照としては媒体溶液を、陽性対照としてはPGE2を用いた。陰性対照を添加した際のMIP-1β産生量を100%として、それぞれの化合物10nMを加えて培養した時の残存MIP-1β量(%of control)とした。結果を試験例2と合わせて表2に示した。
分化マクロファージに評価化合物を1〜1000nM最終濃度になるように添加し45分間培養した。培養後、細胞を破砕し、細胞内のcAMPをEIA法にて定量した。1000nMPGE2を同一条件下で処理した時のcAMP量を100%とした際、それぞれの化合物のED50値を算出した。結果を、試験例1と合わせて表2に示した。
文献(Takayama, K., ら(2002). Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biol Chem 277, 44147-44154.)記載の方法に従って行った。具体的には、精製したヒト末梢血単球を1週間培養しマクロファージに分化させた。分化マクロファージに評価化合物を0.1〜100nM最終濃度になるように添加し30分間培養した。培養後、大腸菌由来リポポリサッカライド(LPS)を最終濃度5ng/mlになるように添加し、さらに18時間培養した。培養後、細胞上清を回収し、サイトカイン(TNFα)、ケモカイン(MCP-1、MIP-1β)産生量をELISA法にて測定した。抗炎症活性の陰性対照としては媒体溶液を、陽性対照としてはPGE2を用いた。陰性対照を添加した際のサイトカイン産生量を100%として、それぞれの化合物の産生阻害濃度(IC50値)を算出した。結果を表3に示した。
BALB/cマウスにD-Galactosamine 450mg/kg 腹腔内投与 と同時に Indomethacine 3mg/kg経口投与を行い65min 放置したのちLPS 500μg/kg腹腔内投与し、敗血症を発症させた。被験化合物はLPS 腹腔内投与の1min前にリン酸緩衝液に溶解し皮下投与した。
麻酔したラットに人工呼吸器を接続後、開胸手術を行い、心臓を露出させた。スネアー法にて冠動脈の起始部から 3-4 mm 遠位部を結さくし、心筋を30 分虚血状態としたのち、再灌流することにより、心筋梗塞後の再灌流障害を誘発させた。再灌流24時間後、梗塞領域を切除し、蛋白分解酵素阻害剤、界面活性剤含有のTris緩衝液中で組織を破砕し、遠心分離により可溶性分画を得た。可溶性分画の総蛋白質量はBCA法で測定した。可溶性分画のMCP−1量はELISA法にて測定した。被験化合物(化合物34)は再灌流5分前、6時間後、12時間後の3回リン酸緩衝液に溶解し皮下投与した。結果を図2に示した。
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