CN1196678C - 前列腺素e1衍生物 - Google Patents
前列腺素e1衍生物 Download PDFInfo
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- CN1196678C CN1196678C CNB008087415A CN00808741A CN1196678C CN 1196678 C CN1196678 C CN 1196678C CN B008087415 A CNB008087415 A CN B008087415A CN 00808741 A CN00808741 A CN 00808741A CN 1196678 C CN1196678 C CN 1196678C
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- methyl
- dehydrogenations
- pge
- dimethyl
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- 150000003165 prostaglandin E1 derivatives Chemical class 0.000 title description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 21
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 19
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims abstract description 13
- 150000003180 prostaglandins Chemical class 0.000 claims abstract description 12
- 208000037803 restenosis Diseases 0.000 claims abstract description 6
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims abstract description 5
- 238000007887 coronary angioplasty Methods 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 210000002464 muscle smooth vascular Anatomy 0.000 claims abstract description 4
- -1 ethylidene, vinylidene Chemical group 0.000 claims description 315
- 150000003839 salts Chemical class 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 230000035755 proliferation Effects 0.000 claims description 5
- 239000000470 constituent Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 9
- 125000000304 alkynyl group Chemical group 0.000 abstract description 4
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 abstract 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 133
- 238000005160 1H NMR spectroscopy Methods 0.000 description 91
- 229910052739 hydrogen Inorganic materials 0.000 description 63
- 239000001257 hydrogen Substances 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 150000004702 methyl esters Chemical class 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 244000005700 microbiome Species 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 102000004882 Lipase Human genes 0.000 description 4
- 108090001060 Lipase Proteins 0.000 description 4
- 239000004367 Lipase Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 235000019421 lipase Nutrition 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000190932 Rhodopseudomonas Species 0.000 description 3
- 241000282894 Sus scrofa domesticus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 3
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 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 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane Chemical compound CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- PAYROHWFGZADBR-UHFFFAOYSA-N 2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propane-1,3-diol Chemical compound C1=C(I)C(OC)=CC(C(C)C)=C1OC1=CN=C(NC(CO)CO)N=C1N PAYROHWFGZADBR-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- KIFPIAKBYOIOCS-UHFFFAOYSA-N 2-methyl-2-(trioxidanyl)propane Chemical compound CC(C)(C)OOO KIFPIAKBYOIOCS-UHFFFAOYSA-N 0.000 description 1
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 1
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0033—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing sulfur
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明是下式表示的前列腺素衍生物、其可药用盐或其水合物,(式中,A表示亚乙基、亚乙烯基、亚乙炔基、O(CH2)q或S(O)r(CH2)q,R1表示C3-10环烷基、C1-4烷基C3-10环烷基、C3-10环烷基C1-4烷基、C1-10烷基、羟基或C1-4烷氧基取代的C1-10烷基、C2-10链烯基、羟基或C1-4烷氧基取代的C2-10链烯基、C2-10炔基、羟基或C1-4烷氧基取代的C2-10炔基或者桥环式烃基,R2表示氢原子、C1-10烷基或C3-10环烷基,m表示1~5的整数,n表示1~4的整数,p表示0、1或2,q表示1~5的整数,r表示0、1或2)。提供一种具有优良的血管平滑肌增殖抑制作用,作为防止PTCA后再狭窄的药物有用的新型PG衍生物。
Description
技术领域
本发明涉及新型的前列腺素衍生物、其可药用盐或其水合物。
背景技术
前列腺素(以下称为PG)由于微量即可发挥各种重要的生理作用,为了应用于医药,对天然PG以及其多数衍生物的合成和生物活性不断进行研究,包括多数文献在内,例如特开昭52-100446号公报、美国专利第4131738号公报等中已有报道。
作为PG及其衍生物的生理作用,可以例举血管扩张作用、亲炎性作用、血小板凝集抑制作用、子宫肌收缩作用、肠道收缩作用、眼压下降作用等,对于心肌梗塞、心绞痛、动脉硬化、高血压、分娩诱导等的治疗或预防是有用的。
另一方面,经皮冠状动脉成形术(PTCA)由于作为缺血性心脏病的治疗方法对患者侵袭力低,具有优良的初期治疗效果,因而是近年来快速发展起来的手术方法。但是,在PTCA后数个月中以30~40%的频率出现冠状动脉的再狭窄,这一缺点尚未解决。
非常期待能抑制与发生再狭窄密切相关的血管平滑肌细胞由内膜向中膜游走以及在中膜上增殖的化合物作为防止PTCA后再狭窄的药物,但是临床上尚未发现有用的药物。
本发明的目的在于提供一种具有优良的血管平滑肌增殖抑制作用,作为防止PTCA后再狭窄的药物有用的新型PG衍生物。
发明公开
本发明人进行了悉心的研究,结果发现13-14位间具有三键,而且11位上具有羟基烷硫基的前列腺素衍生物可以实现上述目的,从而完成了本发明。
也就是说,本发明是下式(I)表示的前列腺素衍生物、其可药用盐或其水合物。
(式中,A表示亚乙基、亚乙烯基、亚乙炔基、O(CH2)q或S(O)r(GH2)q,R1表示C3-10环烷基、C1-4烷基C3-10环烷基、C3-10环烷基C1-4烷基、C1-10烷基、羟基或C1-4烷氧基取代的C1-10烷基、C2-10链烯基、羟基或C1-4烷氧基取代的C2-10链烯基、C2-10炔基、羟基或C1-4烷氧基取代的C2-10炔基或者桥环式烃基,R2表示氢原子、C1-10烷基或C3-10环烷基,m表示1~5的整数,n表示1~4的整数,p表示0、1或2,q表示1~5的整数,r表示0、1或2)
本发明的优选化合物是式(I)中R1为C5-10烷基、羟基或C1-4烷氧基取代的C5-10烷基、C5-10链烯基、羟基或C1-4烷氧基取代的C5-10链烯基、C5-10炔基、或者羟基或C1-4烷氧基取代的C5-10炔基,q为1或2的化合物,更优选式(I)中m为2~4的整数,n为2或3的化合物。
另外,本发明还涉及药物,其特征在于以式(I)表示的化合物、其可药用盐或其水合物为有效成分。
本发明中使用的用语定义如下。
亚乙烯基是指顺式或反式亚乙烯基。
C3-10环烷基是指碳原子数3~10个的环烷基,例如环丙基、环丁基、环戊基、环己基、环庚基等。
C1-4烷基C3-10环烷基是指直链状或支链状的碳原子数1~4个的烷基取代的碳原子数3~10个的环烷基,例如甲基环丙基、甲基环己基、乙基环己基等。
C3-10环烷基C1-4烷基是指碳原子数3~10的环烷基取代的直链状或支链状的碳原子数1~4个的烷基,例如环丙基甲基、环丁基甲基、环戊基甲基、环戊基乙基、环己基甲基、环己基乙基、环庚基甲基等。
C1-10烷基是指直链或支链状的碳原子数1~10的烷基,例如甲基、乙基、丙基、丁基、异丁基、叔丁基、戊基、异丙基、己基、庚基、辛基、1-甲基戊基、2-甲基戊基、1-甲基己基、2-甲基己基、2,4-二甲基戊基、2-乙基戊基、2-甲基庚基、2-乙基己基、2-丙基戊基、2-丙基己基、2,6-二甲基庚基、壬基、癸基等。
羟基或C1-4烷氧基取代的C1-10烷基是指羟基或者直链或支链状的碳原子数1~4的烷氧基取代的直链或支链状的碳原子数1~10的烷基,例如5-羟基-2-甲基戊基、4,5-二羟基戊基、5-甲氧基-2-甲基戊基、4-乙氧基丁基、4-烯丙氧基丁基等。
C2-10链烯基是指直链或支链状的碳原子数2~10的链烯基,例如乙烯基、烯丙基、2-丙烯基、3-戊烯基、4-己烯基、5-庚烯基、4-甲基-3-戊烯基、2,4-二甲基-3-戊烯基、6-甲基-5-庚烯基、2,6-二甲基-5-庚烯基等。
羟基或C1-4烷氧基取代的C2-10链烯基是指羟基或者直链或支链状的碳原子数1~4的烷氧基取代的直链或支链状碳原子数为2~10的链烯基,例如6-羟基-2-甲基-3-己烯基、6-甲氧基-3-己烯基等。
C2-10炔基是指直链或支链状的碳原子数2~10的炔基,例如乙炔基、2-丙炔基、3-戊炔基、3-己炔基、4-己炔基、1-甲基戊-3-炔基、2-甲基戊-3-炔基、1-甲基己-3-炔基、2-甲基己-3-炔基等。
羟基或C1-4烷氧基取代的C2-10炔基是指羟基或者直链或支链状的碳原子数1~4烷氧基取代的直链或支链状的碳原子数2~10的炔基,例如5-羟基-1-甲基戊-3-炔基、6-甲氧基-3-己炔基等。
桥环式烃基是指例如龙脑基、降冰片烷基、金刚烷基、蒎烷基、苧基、蒈烷基、樟脑基等。
可药用盐是指例如与钠、钾等碱金属形成的盐,与钙、镁等碱土金属形成的盐,与氨、甲胺、二甲胺、环戊胺、苯甲胺、哌啶、一乙醇胺、二乙醇胺、一甲基一乙醇胺、氨基丁三醇、赖氨酸、四烷基铵、三(羟甲基)氨基甲烷等形成的盐。
式(I)的化合物可以按照以下反应式概括的方法进行制备。
(反应式中,A1表示亚乙基、亚乙烯基、亚乙炔基、O(CH2)q或S(CH2)q,A2表示亚乙基、亚乙烯基、亚乙炔基、O(CH2)q或S(O)r1(CH2)q,R3表示除氢原子以外的R2,p1表示1或2,r1表示1或2,R1、m、n、q与上述定义相同。)
以下,按照反应式说明本发明的制备方法。
(1)首先,在有机溶剂(例如甲醇、乙醇、乙酸乙酯、二氧六环等)、水或其混合溶剂中,使用有机酸(例如甲酸、醋酸等)或无机酸(例如硫酸、盐酸等),在0~60℃下,使特许第2641622号(WO92/18472号)、特开平4-818473号公报、特开平5-117230号公报、特开平5-294924号公报、特开平6-192219号公报记载的或按照这些记载得到的化合物(II)进行脱水反应,得到式(III)的化合物。
(2)其次,在惰性溶剂(例如苯、甲苯、二甲苯、正己烷、正戊烷、丙酮等)中,-78~100℃下,使式(III)的化合物与式(IV)的化合物反应,得到11位的立体结构各不相同的式(Ia)和(Ia’)的本发明化合物。该反应中,必要时也可以加入胺(例如三乙胺、二异丁基胺等)或游离基发生剂(例如偶氮二异丁腈、偶氮二环己烷甲腈、过氧化苯甲酰、三乙基甲硼烷等)。这些式(Ia)和(Ia’)的化合物可以通过柱色谱法等通常使用的分离法进行精制。
(3)在磷酸缓冲液、Tris-盐酸缓冲液等缓冲液中,必要时加入有机溶剂(丙酮、甲醇、乙醇等与水混合的溶剂),通过酶使式(Ia)(或式(Ia’))的化合物水解,得到式(Ib)(或式(Ib’))的本发明化合物。
酶是微生物产生的酶(例如属于白念珠菌属、假单胞菌属的微生物产生的酶)、由动物脏器制备的酶(例如由猪肝脏或猪胰脏制备的酶)等,市售的酶中具体的例子是脂肪酶VII(Sigma公司生产,来源于念珠菌属的微生物)、脂肪酶AY(天野制药生产,来源于念珠菌属的微生物)、脂肪酶PS(天野制药生产,来源于假单胞菌属的微生物)、脂肪酶MF(天野制药生产,来源于假单胞菌属的微生物)、PLE(Sigma公司生产,由猪肝脏制备)、脂肪酶II(Sigma公司生产,由猪胰脏制备)、脂蛋白脂肪酶(东京化成工业社生产,由猪胰脏制备)等。
酶的用量可以根据酶的效价和底物〔式(Ia)的化合物〕的量适当选择,通常为底物的0.1~20倍重量。反应温度为25~50℃,优选30~40℃。
(4)使用偏高碘酸钠、过氧化氢水、过乙酸、间氯过苯甲酸、叔丁基氢过氧化物(tert-butyl hydroxyperoxide)等氧化剂,在乙醚、甲醇、乙醇、二氯甲烷、水或它们的混合溶剂中,在-20~50℃下,使式(Ia)或(Ia’)的化合物反应进行氧化,得到式(Ic)或(Ic’)的本发明化合物。
(5)将式(Ib)或(Ib’)的化合物与上述(4)同样进行氧化,得到式(Id)或(Id’)的本发明化合物。
本发明的药物可以全身或局部给药,口服或者直肠内、皮下、肌肉内、静脉内、经皮等非口服给药。其中,优选口服给药或静脉内给药。本发明的药物,可以配合可药用载体进行制备。具体而言,口服给药用时,可以加入赋形剂、粘合剂、崩解剂、增量剂、包覆剂、糖衣剂、或者水性或非水性溶剂等,按照常规方法制成片剂、粉剂、颗粒剂、散剂、胶囊剂、溶液剂、乳剂、悬浊剂等形态。另外,静脉给药用时,可以按照常规方法制成水性或非水性溶液剂、乳剂、悬浊剂或使用前溶解于注射溶剂后使用的固体制剂等形态。另外,本发明的化合物也可以与α、β或γ-环糊精或甲基化环糊精等形成包合化合物,制成制剂。而且,该水性或非水性溶液剂、乳化剂、悬浊剂等也可以通过注射等给药。
本发明化合物的给药量根据疾病、症状、体重、年龄、性别、给药途径等不同,对于成人优选0.1ng~10mg/日,将其1日1次或分数次给药。另外,用作血管平滑肌增殖抑制剂时,对于成人优选1ng~1mg/日,将其1日1次或分数次给药。
本发明涉及的代表性的式(I)化合物可以举例如下。
化合物 A m n p R1 R2 11-位 15-OH
1 CH2CH2 2 2 0 (R)-2-甲基己基 甲基 α α
2 CH2CH2 2 2 0 (R)-2-甲基己基 氢 α α
3 CH2CH2 3 2 0 (R)-2-甲基己基 叔丁基 α α
4 CH2CH2 3 2 0 (R)-2-甲基己基 叔丁基 β α
5 CH2CH2 3 2 0 (R)-2-甲基己基 甲基 α α
6 CH2CH2 3 2 0 (R)-2-甲基己基 甲基 β α
7 CH2CH2 3 2 0 (R)-2-甲基己基 氢 α α
8 CH2CH2 3 2 0 (R)-2-甲基己基 氢 β α
9 CH2CH2 3 2 0 (R)-2-甲基己基 甲基 α β
10 CH2CH2 3 2 0 (R)-2-甲基己基 甲基 β β
11 CH2CH2 3 2 0 (R)-2-甲基己基 氢 α β
12 CH2CH2 3 2 0 (R)-2-甲基己基 氢 β β
13 CH2CH2 3 3 0 (R)-2-甲基己基 甲基 α α
14 CH2CH2 3 3 0 (R)-2-甲基己基 甲基 β α
15 CH2CH2 3 3 0 (R)-2-甲基己基 氢 α α
16 CH2CH2 3 3 0 (R)-2-甲基己基 氢 β α
17 CH2CH2 4 2 0 (R)-2-甲基己基 甲基 α α
18 CH2CH2 4 2 0 (R)-2-甲基己基 氢 α α
19 CH2CH2 2 2 0 (S)-2-甲基己基 甲基 α α
20 CH2CH2 2 2 0 (S)-2-甲基己基 甲基 β α
21 CH2CH2 2 2 0 (S)-2-甲基己基 氢 α α
22 CH2CH2 2 2 0 (S)-2-甲基己基 氢 β α
23 CH2CH2 2 2 0 (S)-2-甲基己基 氢 α β
24 CH2CH2 3 2 0 (R)-1-甲基己基 氢 α α
25 CH2CH2 3 2 0 (S)-1-甲基己基 氢 α α
26 CH2CH2 3 2 0 (S)-2,6-dMe-5-Hp 环己基 α α
27 CH2CH2 3 2 0 (S)-2,6-dMe-5-Hp 甲基 α α
28 CH2CH2 3 2 0 (S)-2,6-dMe-5-Hp 氢 α α
29 CH2CH2 3 2 0 (S)-2,6-dMe-5-Hp 氢 α β
30 CH2CH2 3 2 0 (RS)-1-甲基-3-己炔基 甲基 α α
31 CH2CH2 3 2 0 (RS)-1-甲基-3-己炔基 甲基 β α
32 CH2CH2 3 2 0 (RS)-1-甲基-3-己炔基 氢 α α
33 CH2CH2 3 2 0 (S)-1-甲基-3-己炔基 甲基 α α
34 CH2CH2 3 2 0 (S)-1-甲基-3-己炔基 甲基 β α
35 CH2CH2 3 2 0 (S)-1-甲基-3-己炔基 氢 α α
36 CH2CH2 3 2 0 (R)-1-甲基-3-己炔基 甲基 α α
37 CH2CH2 3 2 0 (R)-1-甲基-3-己炔基 氢 α α
38 CH2CH2 3 2 0 环己基 甲基 α α
39 CH2CH2 3 2 0 环己基 甲基 β α
40 CH2CH2 3 2 0 环己基 氢 α α
41 CH2CH2 3 2 0 环己基甲基 甲基 α α
42 CH2CH2 3 2 0 环己基甲基 甲基 β α
43 CH2CH2 3 2 0 环己基甲基 氢 α α
44 CH=CH(E) 3 2 0 (R)-2-甲基己基 甲基 α α
45 CH=CH(E) 3 2 0 (R)-2-甲基己基 氢 α α
46 CH=CH(E) 3 2 0 (R)-2-甲基己基 甲基 β α
47 CH=CH(E) 3 2 0 (R)-2-甲基己基 氢 β α
48 CH=CH(Z) 3 2 0 (S)-2-甲基己基 甲基 α α
49 CH=CH(E) 3 2 0 (S)-2-甲基己基 氢 α α
50 CH=CH(E) 3 2 0 (S)-2-甲基己基 氢 β α
51 CH=CH(Z) 3 2 0 (R)-2,6-dMe-5-Hp 氢 α α
52 CH=CH(E) 3 2 0 (R)-2-甲基戊基 甲基 α α
53 CH=CH(E) 3 2 0 (R)-2-甲基戊基 甲基 β α
54 CH=CH(E) 3 2 0 (R)-2-甲基戊基 氢 α α
55 CH=CH(E) 3 2 0 2-甲基丙基 甲基 α α
56 CH=CH(E) 3 2 0 2-甲基丙基 甲基 β α
57 CH=CH(E) 3 2 0 2-甲基丙基 氢 α α
58 C≡C 3 2 0 (R)-2-甲基己基 甲基 α α
59 C≡C 3 2 0 (R)-2-甲基己基 甲基 β α
60 C≡C 3 2 0 (R)-2-甲基己基 氢 α α
61 C≡C 3 2 0 (R)-2-甲基己基 氢 β α
62 C≡C 3 2 0 (S)-2-甲基己基 甲基 α α
63 C≡C 3 2 0 (S)-2-甲基己基 氢 α α
64 C≡C 3 2 0 (S)-2-甲基己基 甲基 α β
65 C≡C 3 2 0 (S)-2-甲基己基 氢 α β
66 C≡C 3 2 0 (R)-1-甲基己基 氢 α α
67 C≡C 3 2 0 (S)-1-甲基己基 氢 α α
68 C≡C 3 2 0 2,2-二甲基己基 氢 α α
69 C≡C 3 2 0 2,2-二甲基己基 氢 β α
70 OCH2 3 2 0 (R)-2-甲基己基 甲基 α α
71 OCH2 3 2 0 (R)-2-甲基己基 甲基 β α
72 OCH2 3 2 0 (R)-2-甲基己基 甲基 α β
73 OCH2 3 2 0 (R)-2-甲基己基 甲基 β β
74 OCH2 3 2 0 (R)-2-甲基己基 氢 α α
75 OCH2 3 2 1 (R)-2-甲基己基 甲基 α α
76 OCH2 3 2 0 (R)-2-甲基己基 氢 α β
77 OCH2 3 2 2 (R)-2-甲基己基 甲基 α α
78 OCH2 3 2 0 (S)-2-甲基己基 甲基 α α
79 OCH2 3 2 0 (S)-2-甲基己基 甲基 β α
80 OCH2 3 2 0 (S)-2-甲基己基 甲基 α β
81 OCH2 3 2 0 (S)-2-甲基己基 甲基 β β
82 OCH2 3 2 0 (S)-2-甲基己基 氢 α α
83 OCH2 3 2 0 (S)-2-甲基己基 氢 β α
84 OCH2 3 2 0 (S)-2-甲基己基 氢 α β
85 O(CH2)22 2 0 (R)-2-甲基己基 甲基 α α
86 O(CH2)22 2 0 (R)-2-甲基己基 甲基 β α
87 O(CH2)22 2 0 (R)-2-甲基己基 氢 α α
88 OCH2 3 2 0 (R)-1-甲基-3-己炔基 氢 α α
89 OCH2 3 2 0 (S)-2,6-dMe-5-Hp 甲基 α α
90 OCH2 3 2 0 (S)-2,6-dMe-5-Hp 甲基 β α
91 OCH2 3 2 0 (S)-2,6-dMe-5-Hp 氢 α α
92 OCH2 3 2 0 (R)-2,6-dMe-5-Hp 甲基 α α
93 OCH2 3 2 0 (R)-2,6-dMe-5-Hp 甲基 β α
94 OCH2 3 2 0 (R)-2,6-dMe-5-Hp 氢 α α
95 OCH2 3 2 0 n-戊基 甲基 α α
96 OCH2 3 2 0 n-戊基 甲基 β α
97 OCH2 3 2 0 n-戊基 氢 α α
98 SCH2 3 2 0 (R)-2-甲基己基 甲基 α α
99 SCH2 3 2 0 (R)-2-甲基己基 甲基 β α
100 SCH2 3 2 0 (R)-2-甲基己基 氢 α α
101 OCH2 3 2 0 (S)-1-甲基己基 甲基 α α
102 OCH2 3 2 0 (S)-1-甲基己基 甲基 β α
103 OCH2 3 2 0 (S)-1-甲基己基 氢 α α
104 OCH2 3 2 0 (R)-1-甲基己基 甲基 α α
105 OCH2 3 2 0 (R)-1-甲基己基 甲基 β α
106 OCH2 3 2 0 (R)-1-甲基己基 氢 α α
107 OCH2 3 2 0 1,1-二甲基戊基 甲基 α α
108 OCH2 3 2 0 1,1-二甲基戊基 甲基 β α
109 OCH2 3 2 0 1,1-二甲基戊基 氢 α α
110 SCH2 3 2 0 (R)-2,6-dMe-5-Hp 氢 α β
111 SCH2 3 2 0 (S)-1-甲基-3-己炔基 氢 α α
112 SCH2 3 2 0 (S)-1-甲基-3-己炔基 氢 α β
113 SCH2 3 2 0 (R)-1-甲基-3-己炔基 氢 α α
114 SCH2 3 2 0 (R)-1-甲基-3-己炔基 氢 α β
115 S(O)CH2 3 2 1 (S)-1-甲基-3-己炔基 氢 α α
116 S(O)2CH2 3 2 2 (R)-1-甲基-3-己炔基 氢 α α
117 S(CH2)2 2 2 0 (R)-2-甲基己基 氢 α α
118 S(O)(CH2)2 2 2 1 (R)-2-甲基己基 氢 α α
119 CH=CH(E) 3 2 0 (R)-5-OH-2-甲基戊基 甲基 α α
120 CH=CH(E) 3 2 1 (R)-5-OH-2-甲基戊基 甲基 α α
121 CH=CH(E) 3 2 0 (R)-5-OH-2-甲基戊基 甲基 β α
122 CH=CH(E) 3 2 0 (R)-5-OH-2-甲基戊基 氢 α α
123 CH=CH(E) 3 2 1 (R)-5-OH-2-甲基戊基 氢 α α
124 CH=CH(E) 3 2 0 (R)-5-OMe-2-甲基戊基 甲基 α α
125 CH=CH(E) 3 2 2 (R)-5-OMe-2-甲基戊基 甲基 α α
126 CH=CH(E) 3 2 0 (R)-5-OMe-2-甲基戊基 甲基 β α
127 CH=CH(E) 3 2 1 (R)-5-OMe-2-甲基戊基 甲基 β α
128 CH=CH(E) 3 2 0 (R)-5-OMe-2-甲基戊基 氢 α α
129 CH=CH(E) 3 2 1 (R)-5-OMe-2-甲基戊基 氢 α α
130 CH=CH(E) 3 2 2 (R)-5-OMe-2-甲基戊基 氢 α α
2,6-dMe-5-Hp:2,6-二甲基-5-庚烯基,
5-OH-2-甲基戊基:5-羟基-2-甲基戊基,
5-OMe-2-甲基戊基:5-甲氧基-2-甲基戊基
11-位:S(O)p(CH2)nOH基和环戊烷环的碳原子的键
15-位:与R1相邻的碳原子和OH基之间的键
CH=CH(E):反式亚乙烯基
CH=CH(Z):顺式亚乙烯基
发明的最佳实施方式
以下,结合实施例和试验例更详细地说明本发明,但是本发明并不受这些记载的任何限定。另外,化合物的命名中,例如“17,18,19,20-四去甲”中的“去甲”是指其位置上没有碳链(上述例的场合,是指没有17~20位的碳链)。
实施例1
(11R,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物5)以及(11S,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物6)
(1)室温下向(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯(370mg,0.94mmol)的乙酸乙酯(37ml)溶液中加入盐酸的乙酸乙酯溶液(4M,2.8ml,11.3mmol),搅拌1.5小时。将反应液用饱和碳酸氢钠水溶液中和后,分离出有机层,用饱和食盐水洗涤,用无水硫酸镁干燥,过滤。减压浓缩滤液,将得到的粗产物用硅胶柱色谱法(展开溶剂:己烷∶乙酸乙酯=3∶1)精制,得到(17R)-17,20-二甲基-13,14-二去氢-PGA1甲酯(230mg)。
1H-NM R(CDCl3,200MHz)δppm;
0.82-1.01(m,6H),1.04-2.00(m,20H),2.21-2.48(m,1H),2.32(t,J=7.4Hz,2H),3.40-3.47(m,1H),3.67(s,3H),4.39-4.50(m,1H),6.18(dd,J=5.7,2.4Hz,1H),7.47(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3438,2930,2858,2209,1739,1715,1592,1463,1438,1379,1199,1174,1065,885,599
(2)向上述(1)得到的化合物(220mg,0.58mmol)的氯仿(2.9ml)溶液中加入2-巯基乙醇(82μl,1.19mmol)和二异丙胺(16μl,0.12mmol),室温下搅拌过夜。用短硅胶柱色谱法(展开溶剂:乙酸乙酯)处理反应液,将得到的粗产物用硅胶柱色谱法(展开溶剂:己烷∶乙酸乙酯=1∶1)精制,得到(11R,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(106mg)和(11S,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(136mg)。(11R,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.84-1.04(m,6H),1.08-2.01(m,21H),2.11(dd,J=18.7,11.9Hz,1H),2.17-2.41(m,1H),2.31(t,J=7.4Hz,2H),2.57-3.02(m,3H),3.07-3.37(m,2H),3.67(s,3H),3.79-3.92(m,2H),4.37-4.53(m,1H)。
IR(neat)cm-1;
3431,2929,2859,2231,1742,1438,1380,1201,1159,1049,772(11S,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.82-1.02(m,6H),1.06-1.90(m,21H),2.31(t,J=7.4Hz,2H),2.43-2.69(m,3H),2.85-3.15(m,3H),3.56-3.88(m,3H),3.67(s,3H),4.42-4.55(m,1H)
IR(neat)cm-1;
3432,2930,2858,2234,1741,1462,1438,1383,1282,1201,1166,1048,728
实施例2
(11R,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1(化合物7)
向实施例1得到的(11R,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(100mg,0.22mmol)的丙酮(0.55ml)溶液中加入水(5.5ml)、磷酸缓冲液(pH=8.0,0.2M,5.5ml),再加入PLE(Sigma公司生产,2.53单位/μl,硫酸铵水溶液,87μl),室温下搅拌2天。用1M盐酸调节至pH=4后,用硫酸铵盐析,用乙酸乙酯萃取,用饱和食盐水洗涤有机层,用无水硫酸镁干燥,过滤。减压浓缩滤液,将得到的粗产物用硅胶柱色谱法(展开溶剂:己烷∶乙酸乙酯=1∶2)精制,得到标题化合物(76mg)。
1H-NMR(CDCl3,300MHz)δppm;
0.81-0.99(m,6H),1.02-1.81(m,19H),2.11(dd,1=18.9,11.8Hz,1H),2.20-2.39(m,1H),2.35(t,J=7.3Hz,2H),2.61-3.36(m,8H),3.79-3.95(m,2H),4.38-4.52(m,1H)
IR(neat)cm-1;
3392,2929,2858,2235,1741,1713,1463,1403,1283,1158,1048,728
实施例3
(11S,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1(化合物8)
使用实施例1中得到的(11S,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯,实质上与实施例2同样,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.81-1.00(m,6H),1.06-1.82(m,22H),2.35(t,J=7.0Hz,2H),2.44-2.68(m,3H),2.86-3.13(m,3H),3.57-3.95(m,3H),4.39-4.53(m,1H)
IR(neat)cm-1;
3392,2930,2858,2233,1739,1714,1637,1464,1403,1380,1285,1163,1049,728,605
实施例4
(11R,16RS)-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14,18,18,19,19-六去氢-PGE1甲酯(化合物30)以及(11S,16RS)-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14,18,18,19,19-六去氢-PGE1甲酯(化合物31)
(1)实施例(1)中,使用(16RS)-16,20-二甲基-13,14,18,18,19,19-六去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(16RS)-16,20-二甲基-13,14,18,18,19,19-六去氢-PGA1甲酯。
1H-NMR(CDCl3,300MHz)δppm;
1.02-1.16(m,3H),1.12(t,J=7.4Hz,3H),1.20-2.46(m,17H),2.31(t,J=7.5Hz,2H),3.42-3.48(m,1H),3.67(s,3H),4.37-4.47(m,1H),6.19(dd,J=5.6,2.3Hz,1H),7.48(dd,J=5.6,2.4Hz,1H)
IR(neat)cm-1;
3453,2934,2858,2213,1734,1713,1591,1456,1437,1346,1320,1200,1174,1098,1027,984,885,606
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,16RS)-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14,18,18,19,19-六去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
1.08(d,J=6.9Hz,3/2H),1.09(d,J=6.7Hz,3/2H),1.12(t,J=7.3Hz,3H),1.24-2.34(m,17H),2.30(t,J=7.4Hz,2H),2.50-3.00(m,5H),3.13(dt,J=13.8,6.9Hz,1H),3.23-3.35(m,1H),3.67(s,3H),3.80-3.90(m,2H),4.37-4.48(m,1H)
IR(neat)cm-1;
3400,2932,2858,2242,1740,1436,1376,1320,1278,1205,1169,1097,1022(11S,16RS)-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14,18,18,19,19-六去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
1.08(d,J=7.1Hz,3/2H),1.10(d,J=6.7Hz,3/2H),1.12(t,J=7.5Hz,3H),1.18-3.16(m,23H),2.30(t,J=7.4Hz,2H),3.58-3.68(m,1H),3.67(s,3H),3.75-3.84(m,2H),4.40-4.49(m,1H)
IR(neat)cm-1;
3437,2933,2858,2233,1739,1456,1437,1375,1320,1281,1202,1167,1024
实施例5
(11R,16RS)-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14,18,18,19,19-六去氢-PGE1(化合物32)
使用实施例4中得到的(11R,16RS)-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14,18,18,19,19-六去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
1.08(d,J=6.9Hz,3/2H),1.10(d,J=6.7Hz,3/2H),1.12(t,J=7.5Hz,3H),1.22-2.46(m,20H),2.35(t,J=7.3Hz,2H),2.63-2.93(m,3H),3.07-3.18(m,1H),3.23-3.36(m,1H),3.85(t,J=6.5Hz,2H),4.40-4.48(m,1H)
IR(neat)cm-1;
3392,2933,2858,2235,1741,1458,1403,1320,1282,1157,1096,1019,935,725,624
实施例6
(11R)-11-去氧-11-(2-羟基乙硫基)-16,17,18,19,20-五去甲-15-环己基-13,14-二去氢-PGE1甲酯(化合物38)以及(11S)-11-去氧-11-(2-羟基乙硫基)-16,17,18,19,20-五去甲-15-环己基-13,14-二去氢-PGE1甲酯(化合物39)(1)实施例(1)中,使用16,17,18,19,20-五去甲-15-环己基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到16,17,18,19,20-五去甲-15-环己基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.97-2.00(m,22H),2.20-2.46(m,1H),2.31(t,J=7.4Hz,2H),3.40-3.49(m,1H),3.67(s,3H),4.11-4.21(m,1H),6.19(dd,J=5.7,2.4Hz,1H),7.48(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1:
3437,2929,2855,2213,1738,1713,1450,1346,1198,1174,1097,1017,893
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R)-11-去氧-11-(2-羟基乙硫基)-16,17,18,19,20-五去甲-15-环己基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.94-1.98(m,21H),2.12(dd,1=18.8,11.8Hz,1H),2.18-2.40(m,1H),2.31(t,J=7.4Hz,2H),2.48-2.98(m,5H),3.06-3.38(m,2H),3.68(s,3H),3.86(t,J=6.2Hz,2H),4.12-4.26(m,1H)
IR(neat)cm-1:
3426,2928,2854,1740,1450,1260,1206,1171,1044,1013,893,725,594(11S)-11-去氧-11-(2-羟基乙硫基)-16,17,18,19,20-五去甲-15-环己基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.90-1.94(m,21H),2.31(t,J=7.4Hz,2H),2.36-3.17(m,5H),3.11(ddd,J=9.8,5.4,1.8Hz,1H),3.56-4.01(m,5H),3.67(s,3H),4.09-4.26(m,1H)
IR(neat)cm-1:
3410,2928,2854,1739,1638,1450,1401,1278,1207,1169,1046,1014,893,726,580
实施例7
(11R)-11-去氧-11-(2-羟基乙硫基)-16,17,18,19,20-五去甲-15-环己基-13,14-二去氢-PGE1(化合物40)
使用实施例6中得到的(11R)-11-去氧-11-(2-羟基乙硫基)-16,17,18,19,20-五去甲-15-环己基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.96-1.91(m,23H),2.12(dd,J=18.7,11.7Hz,1H),2.22-2.39(m,1H),2.35(t,J=7.3Hz,2H),2.62-2.98(m,4H),3.14(dt,J=13.8,6.6Hz,1H),3.29(ddd,J=11.7,10.4,8.1Hz,1H),3.85(t,J=6.6Hz,2H),4.18(dd,J=6.0,1.8Hz,1H)
IR(neat)cm-1:
3399,2928,2854,1740,1450,1402,1278,1157,1044,1011,956,893,757,596
实施例8
(11R)-11-去氧-11-(2-羟基乙硫基)-17,18,19,20-四去甲-16-环己基-13,14-二去氢-PGE1甲酯(化合物41)以及(11S)-11-去氧-11-(2-羟基乙硫基)-17,18,19,20-四去甲-16-环己基-13,14-二去氢-PGE1甲酯(化合物42)(1)实施例1(1)中,使用17,18,19,20-四去甲-16-环己基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到17,18,19,20-四去甲-16-环己基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.82-1.98(m,24H),2.23-2.46(m,1H),2.32(t,J=7.4Hz,2H),3.38-3.49(m,1H),3.68(s,3H),4.35-4.55(m,1H),6.19(dd,J=5.7,2.4Hz,1H),7.48(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3448,2925,2853,1739,1713,1448,1347,1200,1174,1099,887
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R)-11-去氧-11-(2-羟基乙硫基)-17,18,19,20-四去甲-16-环己基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.85-1.82(m,24H),2.11(dd,J=18.9,11.8Hz,1H),2.22-2.35(m,1H),2.31(t,J=7.4Hz,2H),2.60-2.93(m,2H),2.79(ddd,J=18.9,8.0,1.4Hz,1H),2.87(dt,J=14.0,6.2Hz,1H),3.14(dt,J=14.0,6.6Hz,1H),3.27(ddd,J=11.8,10.4,8.0Hz,1H),3.67(s,3H),3.86(dd,J=6.6,6.2Hz,2H),4.39-4.53(m,1H)
IR(neat)cm-1;
3400,2924,2852,1740,1447,1348,1261,1201,1170,1045,895,725
(11S)-11-去氧-11-(2-羟基乙硫基)-17,18,19,20-四去甲-16-环己基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.82-1.88(m,23H),2.13-3.04(m,7H),2.31(t,J=7.4Hz,2H),3.10(ddd,J=9.8,5.3,1.8Hz,1H),3.62(ddd,J=7.1,5.3,3.9Hz,1H),3.67(s,3H),3.74-3.96(m,2H),4.40-4.55(m,1H)
IR(neat)cm-1;
3410,2924,2852,1740,1638,1447,1347,1282,1201,1168,1045,726,581,430
实施例9
(11R)-11-去氧-11-(2-羟基乙硫基)-17,18,19,20-四去甲-16-环己基-13,14-二去氢-PGE1(化合物43)
使用实施例8中得到的(11R)-11-去氧-11-(2-羟基乙硫基)-17,18,19,20-四去甲-16-环己基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.85-1.82(m,25H),2.11(dd,J=18.8,11.7Hz,1H),2.22-2.39(m,1H),2.35(t,J=7.3Hz,2H),2.62-2.94(m,3H),2.87(dt,J=13.8,6.4Hz,1H),3.14(dt,J=13.8,6.6Hz,1H),3.28(ddd,J=11.7,10.5,8.0Hz,1H),3.86(dd,J=6.6,6.4Hz,2H),4.47(dt,J=1.8,7.0Hz,1H)
IR(neat)cm-1;
3378,2924,2853,1740,1448,1402,1347,1281,1158,1044,896,757,605
实施例10
(2E,11R,17S)-11-去氧-(2-羟基乙硫基)-17,20-二甲基-2,3,13,14-四去氢-PGE1(化合物49)以及(2E,11S,17S)-11-去氧-(2-羟基乙硫基)-17,20-二甲基-2,3,13,14-四去氢-PGE1(化合物50)
(1)实施例1(1)中,使用(2E,17S)-17,20-二甲基-2,3,13,14-四去氢-PGE1代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(2E,17S)-17,20-二甲基-2,3,13,14-四去氢-PGA1。
1H-NM R(CDCl3,300MHz)δppm;
0.78-0.97(m,6H),1.04-1.97(m,17H),2.14-2.33(m,2H),2.34-2.45(m,1H),3.40-3.46(m,1H),4.45(dt,J=2.0,7.1Hz,1H),5.85(dd,J=15.6,1.6Hz,1H),6.19(dd,J=5.7,2.3Hz,1H),7.08(dt,J=15.6,6.9Hz,1H),7.47(dd,J=5.7,2.5Hz,1H)
IR(neat)cm-1;
3400,2929,2859,2230,1698,1653,1592,1542,1460,1418,1379,1345,1285,1224,1043,983,875,757,667
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(2E,11R,17S)-11-去氧-(2-羟基乙硫基)-17,20-二甲基-2,3,13,14-四去氢-PGE1
1H-NMR(CDCl3,300MHz)δppm;
0.84-0.95(m,6H),1.06-1.86(m,15H),2.03-2.34(m,3H),2.11(dd,J=18.9,11.7Hz,1H),2.59-3.67(m,8H),3.86(t,J=6.5Hz,2H),4.46(dt,J=1.8,7.2Hz,1H),5.84(dt,J=15.6,1.5Hz,1H),7.04(dt,J=15.6,7.1Hz,1H)
IR(neat)cm-1;
3388,2929,2858,2230,1743,1697,1653,1460,1402,1379,1283,1158,1045,1017,984,729,670,539,447
(2E,11S,17S)-11-去氧-(2-羟基乙硫基)-17,20-二甲基-2,3,13,14-四去氢-PGE1
1H-NMR(CDCl3,300MHz)δppm;
0.82-0.97(m,6H),1.05-1.78(m,15H),2.08-2.82(m,8H),2.86-3.13(m,3H),3.59-3.88(m,3H),4.38-4.53(m,1H),5.80-5.90(m,1H),7.05(dt,J=15.8,7.0Hz,1H)
IR(neat)cm-1;
3389,2929,2858,2230,1739,1696,1653,1461,1402,1378,1285,1164,1046,984,729,670
实施例11
(11R,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-2,2,3,3,13,14-六去氢-PGE1甲酯(化合物58)以及(11S,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-2,2,3,3,13,14-六去氢-PGE1甲酯(化合物59)
(1)实施例1(1)中,使用(17R)-17,20-二甲基-2,2,3,3,13,14-六去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(17R)-17,20-二甲基-2,2,3,3,13,14-六去氢-PGA1甲酯。
1H-NMR(CDCl3,300MHz)δppm;
0.82-0.99(m,6H),1.08-2.00(m,16H),2.27-2.46(m,3H),3.41-3.48(m,1H),3.77(s,3H),4.33-4.49(m,1H),6.19(dd,J=5.7,2.3Hz,1H),7.48(dd,J=5.7,2.5Hz,1H)
IR(neat)cm-1;
3416,2953,2929,2860,2237,1715,1591,1459,1435,1379,1258,1179,1077,819,753,561
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-2,2,3,3,13,14-六去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.83-1.01(m,3H),0.94(d,J=6.7Hz,3H),1.08-1.84(m,15H),2.12(dd,J=18.9,11.8Hz,1H),2.22-2.41(m,3H),2.47-2.94(m,3H),2.79(ddd,J=18.9,8.0,1.2Hz,1H),2.88(dt,J=13.8,6.2Hz,1H),3.14(dt,13.8,6.6Hz,1H),3.28(ddd,J=11.8,10.4,8.0Hz,1H),3.76(s,3H),3.80-3.91(m,2H),4.39-4.50(m,1H)
IR(neat)cm-1;
3409,2953,2929,2869,2236,1745,1714,1460,1435,1402,1379,1258,1155,1076,819,753,561
(11S,17R)-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-2,2,3,3,13,14-六去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.79-1.02(m,6H),1.04-1.93(m,16H),2.24-3.15(m,7H),3.10(ddd,J=10.1,5.3,1.7Hz,1H),3.60-3.69(m,3H),3.65(ddd,J=6.9,5.3,3.6Hz,1H),3.76(s,3H),4.37-4.54(m,1H)
IR(neat)cm-1;
3410,2953,2927,2858,2236,1743,1712,1638,1459,1435,1402,1377,1261,1158,1076,820,753,561
实施例12
(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物70)以及(11S,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物71)
(1)实施例(1)1中,使用(17R)-3-氧杂-17,20-二甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(17R)-3-氧杂-17,20-二甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.80-2.18(m,22H),2.35-2.50(m,1H),3.42-3.65(m,3H),3.76(s,3H),4.09(s,2H),4.37-4.50(m,1H),6.19(dd,J=5.7,2.4Hz,1H),7.48(dd,J=5.7,2.4Hz,1H)。
IR(neat)cm-1;
3435,2953,2929,2870,1755,1711,1591,1458,1438,1379,1346,1286,1212,1139,1061,812,707,582
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.84-1.86(m,18H),0.91(t,J=7.0Hz,3H),2.12(dd,J=18.8,11.9Hz,1H),2.22-2.36(m,1 H),2.40-2.97(m,5H),3.13(dt,J=13.8,6.6Hz,1H),3.27(ddd,J=11.9,10.3,8.0Hz,1H),3.47-3.63(m,2H),3.75(s,3H),3.78-3.90(m,2H),4.08(s,2H),4.37-4.49(m,1H)
IR(neat)cm-1;
3435,2953,2929,2870,1745,1458,1439,1401,1379,1284,1214,1140,1048,706,593
(11S,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.84-1.82(m,18H),0.92(t,J=7.1Hz,3H),2.35-2.70(m,5H),2.86-3.05(m,2H),3.11(ddd,J=9.9,5.3,1.7Hz,1H),3.54(t,J=5.8Hz,2H),3.59-3.67(m,1H),3.71-3.86(m,2H),3.75(s,3H),4.07(s,2H),4.41-4.52(m,1H)
IR(neat)cm-1;
3435,2953,2929,2870,1745,1638,1459,1439,1401,1379,1286,1214,1139,1049,706,579
实施例13
(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1(化合物74)
使用实施例12中得到的(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.80-1.90(m,18H),0.92(t,J=7.0Hz,3H),2.07-2.93(m,8H),3.05-3.17(m,1H),3.22-3.34(m,1H),3.55-3.65(m,2H),3.85(t,J=6.2Hz,2H),4.08(s,2H),4.38-4.51(m,1H)
IR(neat)cm-1;
3400,2928,2870,2236,1740,1621,1460,1429,1348,1228,1131,1049,726,677,542
实施例14
(11R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物78)以及(11S,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物79)
(1)实施例(1)中,使用(17S)-3-氧杂-17,20-二甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(17S)-3-氧杂-17,20-二甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.84-0.96(m,6H),1.08-2.10(m,15H),2.13(d,J=5.9Hz,1H),2.38-2.50(m,1H),3.42-3.62(m,3H),3.76(s,3H),4.09(s,2H),4.35-4.52(m,1H),6.19(dd,J=5.7,2.2Hz,1H),7.47(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3442,2953,2929,2870,2242,1752,1712,1591,1459,1439,1378,1346,1285,1212,1139,1043,811,706,581
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.84-0.96(m,6H),1.09-1.90(m,15H),2.12(dd,J=18.8,11.6Hz,1H),2.20-2.36(m,1H),2.48-2.98(m,5H),3.13(dt,J=14.0,6.7Hz,1H),3.27(ddd,J=11.6,10.5,8.0Hz,1H),3.48-3.64(m,2H),3.76(s,3H),3.78-3.89(m,2H),4.08(s,2H),4.37-4.50(m,1H)
IR(neat)cm-1;
3400,2929,2870,2242,1745,1458,1439,1401,1379,1352,1284,1214,1138,1045,705,669
(11S,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.83-0.97(m,6H),1.08-1.81(m,15H),2.46-3.05(m,5H),2.91(dt,J=13.3,5.8Hz,1H),2.99(dt,J=13.3,5.8Hz,1H),3.12(ddd,J=9.9,5.4,1.8Hz,1H),3.54(t,J=6.8Hz,2H),3.59-3.68(m,1H),3.71-3.88(m,2H),3.75(s,3H),4.07(s,2H),4.47(t,J=6.8Hz,1H)
IR(neat)cm-1;
3435,2953,2929,2870,2242,1745,1459,1439,1401,1378,1286,1217,1138,1045,1018,706,580
实施例15
(11R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1(化合物82)
使用实施例14中得到的(11R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.82-0.96(m,6H),1.06-1.86(m,15H),2.13(dd,J=18.9,11.7Hz,1H),2.22-2.36(m,1H),2.62-3.21(m,6H),3.11(dt,J=13.8,6.7Hz,1H),3.28(ddd,J=11.3,10.5,8.0Hz,1H),3.52-3.64(m,2H),3.80-3.98(m,2H),4.08(s,2H),4.39-4.52(m,1H)
IR(neat)cm-1;
3400,2928,2870,2242,1740,1459,1401,1380,1352,1224,1131,1045,1018,729,676
实施例16
(11R,17R)-3-硫杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物98)以及(11S,17R)-3-硫杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物99)
(1)实施例1(1)中,使用(17R)-3-硫杂-17,20-二甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(17R)-3-硫杂-17,20-二甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.83-0.98(m,6H),1.12-1.98(m,16H),1.87(d,J=5.7Hz,1H),2.34-2.47(m,1H),2.67(t,J=6.9Hz,2H),3.24(s,2H),3.41-3.49(m,1H),3.75(s,3H),6.19(dd,J=5.7,2.3Hz,1H),7.48(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3435,2952,2928,2858,2229,1734,1708,1590,1541,1458,1436,1383,1345,1282,1155,1132,1054,1010,590
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,17R)-3-硫杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.82-1.02(m,6H),1.08-1.86(m,17H),2.12(dd,J=18.9,11.6Hz,1H),2.17-2.37(m,1H),2.54-2.97(m,5H),3.05-3.37(m,2H),3.23(s,2H),3.75(s,3H),3.85(t,J=6.3Hz,2H),4.37-4.50(m,1H)
IR(neat)cm-1;
3400,2952,2928,2858,2360,2235,1740,1459,1436,1402,1379,1348,1282,1196,1153,1046,1011,729,593
(11S,17R)-3-硫杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.83-0.99(m,6H),1.10-1.85(m,17H),2.49-2.70(m,5H),2.91-3.03(m,2H),3.04-3.15(m,1H),3.23(s,2H),3.57-3.68(m,1H),3.75(s,3H),3.71-3.85(m,2H),4.40-4.54(m,1H)
IR(neat)cm-1;
3400,2952,2928,2858,2229,1740,1638,1459,1436,1405,1379,1283,1222,1197,1154,1049,1010,848,730
实施例17
(11R,17R)-3-硫杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1(化合物100)
使用实施例16中得到的(11R,17R)-3-硫杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.86-0.97(m,6H),1.10-1.90(m,16H),2.14(dd,J=18.7,11.6Hz,1H),2.23-2.37(m,1H),2.65-2.95(m,7H),3.04-3.16(m,1H),3.20-3.34(m,1H),3.23(s,2H),3.86(t,J=6.3Hz,2H),4.44-4.55(m,1H)
IR(neat)cm-1;
3399,2928,2858,2360,2229,1740,1459,1401,1380,1348,1284,1154,1048,1009,729,669
实施例18
(11R,15R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物72)以及(11S,15R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物73)(1)实施例1(1)中,使用(15R,17R)-3-氧杂-17,20-二甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(15R,17R)-3-氧杂-17,20-二甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.77-1.00(m,6H),1.06-2.16(m,15H),2.08(d,J=5.7Hz,1H),2.36-2.52(m,1H),3.37-3.66(m,3H),3.76(s,3H),4.09(s,2H),4.30-4.54(m,1H),6.19(dd,J=5.7,2.4Hz,1H),7.47(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3435,2953,2929,2870,2229,1953,1755,1708,1591,1542,1458,1438,1378,1346,1286,1210,1139,1042,846,809,757,706,596
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,15R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.83-0.96(m,6H),1.08-1.88(m,1 4H),2.03-2.97(m,7H),2.12(dd,J=18.8,11.8Hz,1H),3.12(dt,J=13.8,6.5Hz,1H),3.26(ddd,J=11.8,10.5,7.8Hz,1H),3.46-3.63(m,2H),3.75(s,3H),3.77-3.90(m,2H),4.07(s,2H),4.36-4.52(m,1H)
IR(neat)cm-1;
3400,2929,2870,1745,1459,1439,1401,1380,1352,1284,1213,1138,1045,706,596
(11S,15R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.81-0.97(m,6H),1.06-1.81(m,15H),2.26-2.78(m,5H),2.85-3.05(m,2H),3.12(ddd,J=9.8,5.5,1.9Hz,1H),3.54(t,J=5.8Hz,2H),3.63(ddd,J=6.9,5.5,4.4Hz,1H),3.71-3.85(m,2H),3.75(s,3H),4.07(s,2H),4.39-4.51(m,1H)
IR(neat)cm-1;
3400,2952,2929,2870,1742,1697,1638,1438,1401,1378,1285,1214,1138,1045,846,769
实施例19
(11R,15R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1(化合物76)
使用实施例18中得到的(11R,15R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.78-1.00(m,6H),1.04-1.88(m,15H),2.13(dd,J=18.9,11.7Hz,1H),2.22-2.37(m,1H),2.52-3.01(m,3H),3.11(dt,J=14.0,6.4Hz,1H),3.28(ddd,J=11.7,10.5,7.7Hz,1H),3.22-3.96(m,5H),3.85(t,J=6.4Hz,2H),4.09(s,2H),4.40-4.53(m,1H)
IR(neat)cm-1;
3399,2929,2870,2235,1740,1460,1429,1402,1379,1351,1283,1223,1135,1045,1018,756,676,578
实施例20
(11R,15R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物80)以及(11S,15R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物81)
(1)实施例1(1)中,使用(15R,17S)-3-氧杂-17,20-二甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(15R,17S)-3-氧杂-17,20-二甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.82-2.10(m,21H),2.04(d,J=5.7Hz,1H),2.36-2.51(m,1H),3.42-3.64(m,3H),3.76(s,3H),4.09(s,2H),4.35-4.52(m,1H),6.18(dd,J=5.7,2.4Hz,1H),7.47(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3435,2953,2929,2870,2224,1952,1755,1708,1590,1458,1438,1379,1346,1286,1210,1139,1061,846,809,742,590,503
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,15R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.84-1.88(m,21H),2.12(dd,J=18.8,11.8Hz,1H),2.14-2.36(m,1H),2.51(t,J=6.2Hz,1H),2.63-2.97(m,2H),2.68(ddd,J=11.5,10.5,1.9Hz,1H),2.88(dt,J=13.9,6.1Hz,1H),3.12(dt,J=13.9,6.5Hz,1H),3.26(ddd,J=11.8,10.5,7.9Hz,1H),3.48-3.63(m,2H),3.75(s,3H),3.79-3.90(m,2H),4.07(s,2H),4.37-4.51(m,1H)
IR(neat)cm-1;
3400,2953,2929,2870,2235,1745,1458,1439,1401,1379,1284,1214,1140,1047,706,579
(11S,15R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.84-1.81(m,21H),2.37(t,J=6.2Hz,1H),2.52-2.61(m,4H),2.86-3.05(m,2H),3.12(ddd,J=9.7,5.4,1.9Hz,1H),3.54(t,J=5.9Hz,2H)3.63(ddd,J=6.8,5.4,4.0Hz,1H),3.73-3.84(m,2H),3.75(s,3H),4.07(s,2H),4.41-4.50(m,1H)
IR(neat)cm-1;
3431,2952,2929,2870,2229,1745,1697,1638,1456,1439,1401,1379,1287,1217,1138,1049,846,706,580
实施例21
(11R,15R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1(化合物84)
使用实施例20中得到的(11R,15R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.84-0.96(m,6H),1.09-1.86(m,15H),2.13(dd,J=18.9,11.7Hz,1H),2.23-2.36(m,1H),2.64-3.36(m,7H),2.88(dt,J=13.9,6.4Hz,1H),3.54-3.64(m,2H),3.85(t,J=6.4Hz,2H),4.09(s,2H),4.42-4.52(m,1H)
IR(neat)cm-1;
3400,2929,2870,2235,1740,1460,1402,1379,1351,1223,1135,1050,955,729,676
实施例22
(11R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯(化合物89)以及(11S,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯(化合物90)
(1)实施例1(1)中,使用(17S)-3-氧杂-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(17S)-3-氧杂-20-亚异丙基-17-甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.82-2.10(m,16H),1.60(s,3H),1.68(d,J=0.9Hz,3H),2.15(d,J=5.7Hz,1H),2.35-2.50(m,1H),3.42-3.64(m,3H),3.76(s,3H),4.08(s,2H),4.37-4.51(m,1H),5.03-5.17(m,1H),6.19(dd,J=5.7,2.4Hz,1H),7.47(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3436,2929,2866,2229,1952,1755,1711,1591,1545,1438,1377,1346,1287,1211,1140,1033,886,811,706,580
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.84-2.06(m,16H),1.61(s,3H),1.68(d,J=0.9Hz,3H),2.13(dd,J=18.8,11.7Hz,1H),2.20-2.36(m,1H),2.46(t,J=6.4Hz,1H),2.62-2.98(m,3H),2.87(dt,J=13.8,6.1Hz,1H),3.12(dt,J=13.8,6.5Hz,1H),3.26(ddd,J=11.7,10.5,7.9Hz,1H),3.46-3.64(m,2H),3.75(s,3H),3.78-3.90(m,2H),4.07(s,2H),4.37-4.52(m,1H),5.05-5.14(m,1H)
IR(neat)cm-1;
3400,2928,2869,2229,1745,1438,1401,1378,1284,1213,1138,1045,705,580
(11S,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.85-2.08(m,16H),1.61(s,3H),1.68(d,J=1.1Hz,3H),2.40-2.68(m,4H),2.78(d,J=4.8Hz,1H),2.86-3.05(m,2H),3.11(ddd,J=9.9,5.3,1.7Hz,1H),3.53(t,J=5.9Hz,2H),3.63(ddd,J=6.8,5.3,3.8Hz,1H),3.70-3.86(m,2H),3.75(s,3H),4.07(s,2H),4.38-4.53(m,1H),5.04-5.15(m,1H)
IR(neat)cm-1;
3431,2924,2869,2235,1745,1697, 1641,1439,1401,1376,1287,1214,1138,1045,706,580
实施例23
(11R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1(化合物91)
使用实施例22中得到的(11R,17S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.84-2.09(m,16H),1.61(s,3H),1.68(s,3H),2.13(dd,J=18.9,11.7Hz,1H),2.22-2.37(m,1H),2.52-3.20(m,6H),3.11(dt,J=13.8,6.5Hz,1H),3.28(ddd,J=11.7,10.5,7.9Hz,1H),3.52-3.67(m,2H),3.74-3.93(m,2H),4.08(s,2H),4.40-4.53(m,1H),5.04-5.15(m,1H)
IR(neat)cm-1;
3400,2928,2235,1740,1434,1401,1378,1351,1227,1132,1045,676
实施例24
(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯(化合物92)以及(11S,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯(化合物93)(1)实施例1(1)中,使用(17R)-3-氧杂-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(17R)-3-氧杂-20-亚异丙基-17-甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,300MHz)δppm;
0.90-0.97(m,3H),1.10-2.05(m,13H),1.60(s,3H),1.68(s,3H),2.08(d,J=5.8Hz,1H),2.38-2.50(m,1H),3.43-3.63(m,3H),3.76(s,3H),4.09(s,2H),4.39-4.50(m,1H),5.04-5.14(m,1H),6.16-6.21(m,1H),7.43-7.50(m,1H)
IR(neat)cm-1;
3435,2929,2866,2229,1755,1711,1591,1545,1438,1377,1346,1287,1210,1139,1059,887,812,706,579,429
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.90-0.97(m,3H),1.10-2.03(m,15H),1.60(s,3H),1.68(s,3H),2.12(dd,J=18.8,11.7Hz,1H),2.27-2.36(m,1H),2.62-2.93(m,2H),2.87(dt,J=13.8,6.1Hz,1H),3.12(dt,J=13.8,6.4Hz,1H),3.27(ddd,J=11.7,10.5,7.8Hz,1H),3.48-3.58(m,2H),3.75(s,3H),3.80-3.87(m,2H),4.07(s,2H),4.39-4.49(m,1H),5.05-5.13(m,1H)
IR(neat)cm-1;
3435,2928,2869,2235,1745,1439,1401,1378,1284,1213,1139,1046,705,580
(11S,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.94(d,J=6.5Hz,3H),1.12-2.06(m,15H),1.60(s,3H),1.68(s,3H),2.47-2.66(m,3H),2.85-3.05(m,2H),3,07-3.16(m,1H),3.48-3.57(m,2H),3.59-3.67(m,1H),3.69-3.83(m,2H),3.75(s,3H),4.07(s,2H),4.41-4.48(m,1H),5.05-5.13(m,1H)
IR(neat)cm-1;
3400,2928,2869,1742,1438,1401,1377,1284,1213,1138,1046,846,741,579
实施例25
(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1(化合物94)
使用实施例24中得到的(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-20-亚异丙基-17-甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.95(d,J=6.7Hz,3H),1.12-2.06(m,16H),1.61(s,3H),1.68(d,J=1.1Hz,3H),2.13(dd,J=19.0,11.7Hz,1H),2.22-2.36(m,1H),2.62-2.86(m,2H),2.88(dt,J=13.8,6.2Hz,1H),3.11(dt,J=13.8,6.6Hz,1H),3.27(ddd,J=11.7,10.3,8.0Hz,1H),3.54-3.64(m,2H),3.81-3.88(m,2H),4.09(s,2H),4.39-4.51(m,1H),5.04-5.14(m,1H)
IR(neat)cm-1;
3400,2929,2235,1740,1434,1402,1378,1351,1223,1135,1049,676
实施例26
(11R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-13,14-二去氢-PGE1甲酯(化合物95)以及(11S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-13,14-二去氢-PGE1甲酯(化合物96)
(1)实施例1(1)中,使用3-氧杂-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到3-氧杂-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,300MHz)δppm;
0.86-0.93(m,3H),1.22-1.80(m,14H),2.12(d,J=5.8Hz,1H),2.40-2.47(m,1H),3.44-3.59(m,3H),3.76(s,3H),4.08(s,2H),4.30-4.40(m,1H),6.18(dd,J=5.7,2.4Hz,1H),7.47(dd,J=5.7,2.5Hz,1H)
IR(neat)cm-1;
3436,2934,2860,2235,1954,1755,1708,1591,1545,1438,1399,1378,1345,1287,1211,1139,1028,888,847,811,773,706,580
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.86-0.94(m,3H),1.22-1.88(m,16H),2.12(dd,J=18.7,11.7Hz,1H),2.22-2.37(m,1H),2.63-2.93(m,3H),3.12(dt,J=14.0,6.4Hz,1H),3.27(ddd,J=11.7,10.8,8.1Hz,1H),3.48-3.60(m,2H),3.76(s,3H),3.84(t,J=6.4Hz,2H),4.08(s,2H),4.30-4.42(m,1H)
IR(neat)cm-1;
3435,2933,2860,2229,1745,1439,1401,1348,1283,1214,1138,1045,707,580
(11S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.86-0.94(m,3H),1.20-1.80(m,16H),2.52-2.66(m,3H),2.86-3.05(m,2H),3,08-3.16(m,1H),3.48-3.58(m,2H),3.60-3.67(m,1H),3.72-3.83(m,2H),3.76(s,3H),4.08(s,2H),4.34-4.42(m,1H)
IR(neat)cm-1;
3400,2930,2862,2229,1740,1439,1401,1284,1218,1138,1046,1014,847,706,580
实施例27
(11R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-13,14-二去氢-PGE1(化合物97)
使用实施例26中得到的(11R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.85-0.95(m,3H),1.22-1.84(m,18H),2.13(dd,J=18.8,11.7Hz,1H),2.23-2.36(m,1H),2.69(ddd,J=13.5,10.6,1.9Hz,1H),2.80(ddd,J=18.8,7.9,1.4Hz,1H),2.88(dt,1=13.9,6.3Hz,1H),3.11(dt,J=13.9,6.3Hz,1H),3.28(ddd,J=11.7,10.6,7.9Hz,1H),3.54-3.64(m,2H),3.85(t,J=6.3Hz,1H),4.09(s,2H),4.41(dt,J=1.9,6.6Hz,1H)
IR(neat)cm-1;
3400,2933,2860,2235,1740,1402,1347,1223,1132,1046,729,676
实施例28
(2E,11R,17R)-11-去氧-17,20-二甲基-11-(2-羟基乙硫基)-2,3,13,14-四去氢-PGE1甲酯(化合物44)以及(2E,11S,17R)-11-去氧-17,20-二甲基-11-(2-羟基乙硫基)-2,3,13,14-四去氢-PGE1甲酯(化合物46)
(1)实施例1(1)中,使用(2E,17R)-17,20-二甲基-2,3,13,14-四去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(2E,17R)-17,20-二甲基-2,3,13,14-四去氢-PGA1甲酯。
1H-NMR(CDCl3,300MHz)δppm;
0.81-0.99(m,6H),1.06-2.08(m,16H),2.13-2.48(m,3H),3.38-3.48(m,1H),3.74(s,3H),4.37-4.56(m,1H),5.84(dt,J=15.6,1.4Hz,1H),6.19(dd,J=5.6,2.2Hz,1H),6.98(dt,J=15.6,7.0Hz,1H),7.48(dd,J=5.6,2.4Hz,1H)
IR(neat)cm-1:
3441,2952,2929,2858,2224,1718,1697,1654,1591,1457,1436,1379,1342,1273,1201,1177,1155,1110,1038,981,855
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(2E,11R,17R)-11-去氧-17,20-二甲基-11-(2-羟基乙硫基)-2,3,13,14-四去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.83-0.97(m,6H),1.06-1.85(m,15H),2.04-2.97(m,7H),2.11(dd,J=18.8,11.7Hz,1H),2.87(dt,J=13.9,6.2Hz,1H),3.14(dt,J=13.9,6.8Hz,1H),3.28(ddd,J=11.7,10.4,7.9Hz,1H),3.73(s,3H),3.79-3.91(m,2H),4.45(ddd,J=8.0,5.9,1.8Hz,1H),5.83(dt,J=15.6,1.5Hz,1H),6.96(dd,J=15.6,7.0Hz,1H)
IR(neat)cm-1:
3416,2952,2929,2859,2229,1740,1723,1653,1457,1436,1401,1376,1311,1278,1202,1174,1158,1045,984,844
(2E,11S,17R)-11-去氧-17,20-二甲基-11-(2-羟基乙硫基)-2,3,13,14-四去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.84-0.99(m,6H),1.08-1.83(m,15H),2.15-3.13(m,9H),3.08(ddd,J=10.2,5.4,1.6Hz,1H),3.62(ddd,J=6.9,5.4,3.7Hz,1H),3.66-3.90(m,2H),3.73(s,3H),4.40-4.53(m,1H),5.83(dt,J=15.7,1.5Hz,1H),6.96(dt,J=15.7,7.0Hz,1H)
IR(neat)cm-1:
3432,2952,2929,2862,2229,1734,1709,1654,1460,1436,1401,1376,1314,1278,1201,1163,1045,981,847
实施例29
(2E,11R,17R)-11-去氧-17,20-二甲基-11-(2-羟基乙硫基)-2,3,13,14-四去氢-PGE1(化合物45)
使用实施例28中得到的(2E,11R,17R)-11-去氧-17,20-二甲基-11-(2-羟基乙硫基)-2,3,13,14-四去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.83-0.96(m,6H),1.06-1.84(m,18H),2.11(dd,J=19.0,11.7Hz,1H),2.18-2.33(m,3H),2.60-2.96(m,2H),2.87(dt,J=14.0,6.4Hz,1H),3.15(dt,J=14.0,6.2Hz,1H),3.28(ddd,J=11.7,10.4,7.8Hz,1H),3.79-3.89(m,2H),4.38-4.49(m,1H),5.84(dt,J=15.7,1.6Hz,1H),7.06(dt,J=15.7,7.0Hz,1H)
IR(neat)cm-1:
3368,2929,2857,1743,1697,1653,1460,1384,1284,1155,1048
实施例30
(2E,11S,17R)-11-去氧-17,20-二甲基-11-(2-羟基乙硫基)-2,3,13,14-四去氢-PGE1(化合物47)
使用实施例28中得到的(2E,11S,17R)-11-去氧-17,20-二甲基-11-(2-羟基乙硫基)-2,3,13,14-四去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.83-0.96(m,6H),1.08-1.82(m,18H),2.17-2.34(m,2H),2.46-2.67(m,2H),2.86-3.12(m,3H),3.58-3.66(m,1H),3.73-3.88(m,3H),4.45-4.55(m,1H),5.79-5.89(m,1H),7.05(dt,J=15.7,7.1Hz,1H)
IR(neat)cm-1:
3390,2929,2862,1739,1697,1653,1462,1404,1284,1163,1048,984
实施例31
(11R,16S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1甲酯(化合物101)以及(11S,16S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1甲酯(化合物102)
(1)实施例1(1)中,使用(16S)-3-氧杂-16,20-二甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(16S)-3-氧杂-16,20-二甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.89(t,J=6.6Hz,3H),0.97(d,J=6.6Hz,3H),1.04-2.06(m,15H),2.10(d,J=5.9Hz,1H),2.30-2.48(m,1H),3.43-3.64(m,3H),3.76(s,3H),4.08(s,2H),4.22-4.34(m,1H),6.19(dd,J=5.7,2.2Hz,1H),7.48(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1:
3467,2929,2859,2212,1752,1708,1591,1459,1438,1383,1346,1285,1211,1139,1026,895,810,768,605
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,16S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.89(t,J=6.8Hz,3H),1.00(d,J=6.7Hz,3H),1.16-1.76(m,15H),2.13(dd,J=18.8,11.7Hz,1H),2.24-2.36(m,1H),2.39-2.52(m,1H),2.61-2.94(m,4H),3.11(dt,J=14.0,6.6Hz,1H),3.18-3.36(m,1H),3.46-3.58(m,2H),3.76(s,3H),3.77-3.89(m,2H),4.07(s,2H),4.24-4.32(m,1H)
IR(neat)cm-1:
3435,2928,2859,1745,1459,1439,1401,1380,1352,1283,1214,1140,1044,1016,726,580
(11S,16S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.89(t,J=6.8Hz,3H),1.00(d,J=6.7Hz,3H),1.12-1.80(m,15H),2.36(br s,1H),2.47-2.67(m,4H),2.84-3.03(m,2H),3.1 3(ddd,J=9.6,5.6,1.9Hz,1H),3.47-3.58(m,2H),3.60-3.68(m,1H),3.70-3.84(m,2H),3.75(s,3H),4.07(s,2H),4.28-4.34(m,1H)
IR(neat)cm-1:
3435,2928,2859,1742,1638,1459,1438,1401,1378,1284,1215,1139,1045,1016,706,579
实施例32
(11R,16S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1(化合物103)
使用实施例31中得到的(11R,16S)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.89(t,J=6.7Hz,3H),1.00(d,J=6.7Hz,3H),1.10-1.88(m,15H),2.13(dd,J=18.9,11.6Hz,1H),2.22-2.39(m,1H),2.52-2.61(m,1H),2.65-3.01(m,4H),3.10(dt,J=13.8,6.5Hz,1H),3.22-4.22(m,1H),3.29(ddd,J=11.6,10.7,8.1Hz,1H),3.51-3.63(m,2H),3.84(t,J=6.4Hz,2H),4.09(s,2H),4.26-4.36(m,1H)
IR(neat)cm-1:
3400,2929,2859,2235,1740,1460,1402,1351,1224,1134,1044,1014,728,676
实施例33
(11R,16R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1甲酯(化合物104)以及(11S,16R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1甲酯(化合物105)
(1)实施例1(1)中,使用(16R)-3-氧杂-16,20-二甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(16R)-3-氧杂-16,20-二甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.89(t,J=6.8Hz,3H),0.96(d,J=6.8Hz,3H),1.05-2.02(m,15H),2.38-2.49(m,1H),3.45-3.59(m,3H),3.76(s,3H),4.08(s,2H),4.24(dd,J=4.9,1.9Hz,1H),6.19(dd,J=5.7,2.4Hz,1H),7.48(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1:
3468,2930,2859,2211,1752,1708,1592,1545,1459,1439,1380,1346,1283,1212,1139,1027,887,811,772,706,580
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,16R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.83-1.03(m,3H),0.99(d,J=6.7Hz,3H),1.08-1.90(m,15H),2.13(dd,J=18.8,11.8Hz,1H),2.23-2.38(m,1H),2.63-2.97(m,3H),3.12(dt,J=13.8,6.5Hz,1H),3.28(ddd,J=11.8,10.5,7.8,1H),3.46-3.65(m,2H),3.76(s,3H),3.83(t,J=6.5Hz,2H),4.07(s,2H),4.20-4.30(m,1H)
IR(neat)cm-1:
3435,2929,2859,2235,1745,1459,1439,1401,1378,1283,1214,1139,1045,726,580,428
(11S,16R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.83-1.03(m,3H),1.00(d,J=6.7Hz,3H),1.12-1.82(m,15H),2.00-2.44(m,2H),2.47-2.78(m,3H),2.84-3.04(m,2H),3.13(ddd,J=9.8,5.4,1.9Hz,1H),3.53(t,J=5.8Hz,2H),3.59-3.68(m,1H),3.71-3.87(m,2H),3.75(s,3H),4.07(s,2H),4.20-4.34(m,1H)
IR(neat)cm-1:
3432,2929,2859,2235,1745,1697,1637,1456,1439,1401,1376,1284,1217,1138,1046,1015,888,706,580
实施例34
(11R,16R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1(化合物106)
使用实施例33中得到的(11R,16R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.83-1.05(m,6H),1.10-1.90(m,17H),2.13(dd,J=18.8,11.8Hz,1H),2.23-2.37(m,1H),2.52-3.03(m,2H),2.87(dt,J=14.0,6.1Hz,1H),3.11(dt,J=14.0,6.5Hz,1H),3.28(ddd,J=11.8,10.3,7.9Hz,1H),3.40-4.00(m,3H),3.57(t,J=5.8Hz,2H),4.09(s,2H),4.23-4.33(m,1H)
IR(neat)cm-1:
3426,2929,2859,1740,1459,1401,1379,1348,1224,1135,1045,1013,940,727,676
实施例35
(11R,15RS)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,16-二甲基-13,14-二去氢-PGE1甲酯(化合物107)以及(11S,15RS)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,16-二甲基-13,14-二去氢-PGE1甲酯(化合物108)
(1)实施例1(1)中,使用(15RS)-3-氧杂-16,16-二甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(15RS)-3-氧杂-16,16-二甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,300MHz)δppm;
0.86-0.99(m,9H),1.18-2.02(m,13H),2.38-2.47(m,1H),3.46-3.60(m,3H),3.76(s,3H),4.04-4.15(m,1H),4.08(s,2H),6.19(dd,J=5.7,2.4Hz,1H),7.48(dd,J=5.7,2.3Hz,1H)
IR(neat)cm-1:
3468,2955,2933,2870,2207,1752,1708,1591,1542,1458,1438,1384,1345,1283,1212,1139,1033,811,706,579
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,15RS)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,16-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.86-0.99(m,9H),1.16-3.36(m,20H),2.14(dd,J=18.7,11.7Hz,1H),3.48-3.58(m,2H),3.76(s,3H),3.78-3.91(m,2H),4.04-4.15(m,1H),4.07(s,2H)
IR(neat)cm-1:
3435,2955,2932,2870,1745,1439,1384,1283,1214,1139,1039,767,729,579(11S,15RS)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,16-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.86-0.98(m,9H),1.16-1.78(m,13H),2.31-2.41(m,1H),2.43-2.60(m,4H),2.82-3.02(m,2H),3.11-3.18(m,1H),3.48-3.84(m,4H),3.76(s,3H),4.03-4.15(m,1H),4.07(s,2H)
IR(neat)cm-1:
3435,2955,2932,2870,2229,1742,1638,1439,1384,1284,1215,1139,1039,706,579
实施例36
(11R,15RS)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,16-二甲基-13,14-二去氢-PGE1(化合物109)
使用实施例35中得到的(11R,15RS)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-16,16-二甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.85-1.02(m,9H),1.14-1.86(m,12H),2.14(dd,J=18.9,11.4Hz,1H),2.24-3.36(m,9H),3.54-3.66(m,2H),3.79-3.88(m,2H),4.06-4.17(m,1H),4.09(s,2H)
IR(neat)cm-1:
3431,2933,2870,2229,1740,1468,1432,1385,1364,1281,1223,1135,1024,761,676
实施例37
(11R,17R)-4-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物85)以及(11S,17R)-4-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物86)
(1)实施例1(1)中,使用(17R)-4-氧杂-17,20-二甲基-13,14-二去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(17R)-4-氧杂-17,20-二甲基-13,14-二去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.81-1.05(m,3H),6.92(d,J=6.6Hz,3H),1.07-2.04(m,14H),2.42(ddd,J=9.2,4.6,3.3Hz,1H),2.58(t,J=6.3Hz,2H),3.39-3.60(m、3H),3.61-3.83(m,2H),3.70(s,3H),4.28-4.54(m,1H),6.18(dd,J=5.7,2.2Hz,1H),7.47(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1:
3436,2955,2930,2871,2214,1740,1708,1457,1438,1376,1326,1262,1198,1179,1116,1068,1028,848
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(11R,17R)-4-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.75-1.02(m,3H),0.93(d,J=6.6Hz,3H),1.04-3.00(m,19H),2.12(dd,J=18.9,11.6Hz,1H),2.57(t,J=6.4Hz,2H),3.15(dt、J=20.4,6.3Hz,1H),3.28(ddd,J=11.6,10.4,7.8Hz,1H),3.36-3.55(m,2H),3.68(t,J=6.4Hz,2H),3.70(s,3H),3.85(t,J=6.3Hz,2H),4.34-4.53(m,1H)
IR(neat)cm-1:
3432,2955,2929,2871,2236,1746,1740,1456,1440,1402,1380,1326,1282,1197,1179,1154,1116,1062,849,590
(11S,17R)-4-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.81-1.04(m,3H),0.93(d,J=6.6Hz,3H),1.08-3.18(m,20H),2.58(t,J=6.4Hz,2H),3.11(ddd,J=9.8,5.3,1.8Hz,1H),3.31-3.85(m,5H),3.69(t,J=6.4Hz,2H),3.70(s,3H),4.36-4.56(m,1H)
IR(neat)cm-1:
3432,2953,2929,2871,2236,1740,1456,1439,1402,1376,1338,1284,1198,1177,1116,1062,849,593
实施例38
(11R,17R)-4-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1(化合物87)
使用实施例37中得到的(11R,17R)-4-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,200MHz)δppm;
0.78-1.00(m,3H),0.93(d,J=6.6Hz,3H),1.06-2.00(m,14H),2.12(dd,J=18.9,11.5Hz,1H),2.23-4.63(m,9H),2.58(t,J=5.8Hz,2H),2.79(ddd、J=18.9,7.8,1.6Hz,1H),2.87(dt,J=14.0,6.2Hz,1H),3.12(dt,J=14.0,6.4Hz,1H),3.30(ddd,J=11.5,10.4,7.8Hz,1H),3.70(t,J=5.8Hz,2H)
IR(neat)cm-1:
3400,2956,2930,2870,2236,1746,1740,1456,1402,1380,1326,1283,1196,1158,1116,1056,935,844,594
实施例39
(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙基亚磺酰基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物75)
室温下向实施例12得到的(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(40mg)的甲醇(2.2ml)溶液中加入高碘酸钠(71mg)的水(0.9ml)溶液,相同温度下搅拌1.5小时。将反应液加入到乙酸乙酯-饱和食盐水的混合液中,分离有机层后,用乙酸乙酯萃取水层,合并有机层,用饱和食盐水洗涤,用无水硫酸镁干燥。过滤、浓缩后,将得到的粗产物用硅胶柱色谱法(展开溶剂:乙酸乙酯)精制,得到标题化合物(39mg)。
1H-NMR(CDCl3,300MHz)δppm;
0.82-0.97(m,6H),1.08-2.16(m,15H),2.30-2.63(m,3H),2.71-3.02(m,2H),2.90(d,J=5.4Hz,1H),3.17-3.64(m,5H),3.76(s,3H),4.08(s,2H),4.10-4.26(m,2H),4.37-4.49(m,1H)
IR(neat)cm-1:
3368,2930,2871,2236,1746,1456,1440,1402,1380,1288,1214,1138,1034,996,705
实施例40
(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙基磺酰基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(化合物77)
在室温下向实施例12得到的(11R,17R)-3-氧杂-11-去氧-11-(2-羟基乙硫基)-17,20-二甲基-13,14-二去氢-PGE1甲酯(40mg)的氯仿(3ml)溶液中加入间氯过苯甲酸(45mg),在相同温度下搅拌30分钟。将反应液加入到乙酸乙酯-饱和碳酸氢钠水溶液的混合液中,分离有机层后,用乙酸乙酯萃取水层,合并有机层,用饱和食盐水洗涤,用无水硫酸镁干燥。过滤、浓缩后,将得到的粗产物用硅胶柱色谱法(展开溶剂:己烷∶乙酸乙酯=1∶2)精制,得到标题化合物(33mg)。
1H-NMR(CDCl3,300MHz)δppm;
0.85-0.99(m,6H),1.10-1.96(m,15H),2.39-2.51(m,1H),2.66-2.94(m,4H),3.06-3.17(m,1H),3.35(ddd,J=14.9,5.5,4.3Hz,1H),3.45-3.65(m,2H),3.76(s,3H),3.81(ddd,J=14,9,7.8,4.7Hz,1H),3.92-4.05(m,1H),4.08(s,2H),4.10-4.28(m,2H),4.40-4.53(m,1H)
IR(neat)cm-1:
3470,2956,2930,2870,2236,1752,1746,1456,1440,1402,1380,1321,1284,1224,1127,1062,708,526
实施例41
(2E,11R,17R)-11-去氧-11-(2-羟基乙硫基)-17-甲基-2,3,13,14-四去氢-PGE1甲酯(化合物52)以及(2E,11S,17R)-11-去氧-11-(2-羟基乙硫基)-17-甲基-2,3,13,14-四去氢-PGE1甲酯(化合物53)
(1)实施例1(1)中,使用(2E,17R)-17-甲基-2,3,13,14-四去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(2E,17R)-17-甲基-2,3,13,14-四去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.76-2.50(m,20H),0.92(d,J=6.6Hz,3H),3.34-3.52(m,1H),3.74(s,3H),4.29-4.57(m,1H),5.85(dt,J=15.7,1.5Hz,1H),6.19(dd,J=5.7,2.4Hz,1H),6.99(dt,J=15.7,7.0Hz,1H),7.48(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1:
3436,2954,2930,2871,2214,1718,1654,1594,1546,1460,1437,1381,1274,1201,1178,1044,983,871
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(2E,11R,17R)-11-去氧-11-(2-羟基乙硫基)-17-甲基-2,3,13,14-四去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.81-1.00(m,3H),0.93(d,J=6.6Hz,3H),1.07-1.90(m,13H),2.00-3.00(m,7H),2.11(dd,J=18.8,11.7Hz,1H),2.88(dt,J=14.1,6.4Hz,1H),3.14(dt,J=14.1,6.4Hz,1H),3.27(ddd,J=11.7,10.4,7.9Hz,1H),3.74(s,3H),3.86(t,J=6.4Hz,2H),4.45(ddd,J=8.1,5.8,1.9Hz,1H),5.83(dt,J=15.6,1.5Hz,1H),6.97(dt,J=15.6,7.0Hz,1H)
IR(neat)cm-1:
3400,2930,2871,2230,1746,1724,1654,1460,1438,1384,1314,1278,1202,1175,1045,984,720
(2E,11S,17R)-11-去氧-11-(2-羟基乙硫基)-17-甲基-2,3,13,14-四去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.78-1.00(m,3H),0.93(d,J=6.6Hz,3H),1.04-1.88(m,1 3H),2.12-3.16(m,10H),3.57-3.68(m,1H),3.73(s,3H),3.87(dt,J=1.8,5.9Hz,2H),4.41-4.55(m,1H),5.83(dt,J=15.7,1.5Hz,1H),6.97(dt,J=15.7,7.0Hz,1H)
IR(neat)cm-1:
3400,2930,2871,2230,1740,1734,1654,1460,1437,1402,1384,1278,1202,1163,1046,984,740
实施例42
(2E,11R,17R)-11-去氧-11-(2-羟基乙硫基)-17-甲基-2,3,13,14-四去氢-PGE1(化合物54)
使用实施例41中得到的(2E,11R,17R)-11-去氧-11-(2-羟基乙硫基)-17-甲基-2,3,13,14-四去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,200MHz)δppm;
0.81-1.02(m,3H),0.93(d,J=6.6Hz,3H),1.06-3.42(m,24H),2.11(dd,J=18.8,11.8Hz,1H),3.87(t,J=6.4Hz,2H),4.46(ddd,J=10.9,5.9,1.8Hz,1H),5.85(dt,J=15.7,1.5Hz,1H),7.06(dt,J=15.7,7.0Hz,1H)
IR(neat)cm-1:
3368,2930,2871,2236,1740,1697,1654,1460,1402,1383,1347,1283,1228,1158,1048,1016,985,876,740,670
实施例43
(2E,11R)-11-去氧-11-(2-羟基乙硫基)-19,20-二去甲-17-甲基-2,3,13,14-四去氢-PGE1甲酯(化合物55)以及(2E,11S)-11-去氧-11-(2-羟基乙硫基)-19,20-二去甲-17-甲基-2,3,13,14-四去氢-PGE1甲酯(化合物56)
(1)实施例1(1)中,使用19,20-二去甲-17-甲基-2,3,13,14-四去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(2E)-19,20-二去甲-17-甲基-2,3,13,14-四去氢-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.93(d,J=6.6Hz,3H),0.94(d,J=6.4Hz,3H),1.20-2.50(m,13H),3.35-3.49(m,1H),3.74(s,3H),4.26-4.55(m,1H),5.85(dt,J=15.7,1.5Hz,1H),6.19(dd,J=5.7,2.4Hz,1H),6.98(dt,J=15.7,6.9Hz,1H),7.48(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1:
3436,2953,2868,2214,1718,1654,1594,1541,1466,1437,1386,1368,1274,1202,1176,1114,1039,983,860,720
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(2E,11R)-11-去氧-11-(2-羟基乙硫基)-19,20-二去甲-17-甲基-2,3,13,14-四去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.94(d,J=6.6Hz,3H),0.96(d,J=6.6Hz,3H),1.18-1.96(m,10H),2.02-2.36(m,4H),2.12(dd,J=18.8,11.7Hz,1H),2.58-2.97(m,1H),2.66(ddd,J=11.7,10.5,1.9Hz,1H),2.88(dt,J=13.9,6.4Hz,1H),3.14(dt,J=13.9,6.4Hz,1H),3.27(ddd,J=11.7,10.5,7.9Hz,1H),3.74(s,3H),3.86(t,J=6.4Hz,2H),4.44(dt,J=1.9,7.3Hz,1H),5.84(dt,J=15.7,1.5Hz,1H),6.97(dt,J=15.7,6.9Hz,1H)
IR(neat)cm-1:
3427,2930,2869,2236,1734,1654,1462,1456,1436,1402,1368,1278,1202,1174,1045,986,924,844,720,536
(2E,11S)-11-去氧-11-(2-羟基乙硫基)-19,20-二去甲-17-甲基-2,3,13,14-四去氢-PGE1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.94(d,J=6.6Hz,3H),0.96(d,J=6.6Hz,3H),1.19-2.01(m,10H),2.11-3.15(m,9H),3.57-3.68(m,1H),3.73(s,3H),3.81(dt,J=1.7,6.0Hz,2H),4.47(dt,J=1.8,7.3Hz,1H),5.83(dt,J=15.6,1.5Hz,1H),6.97(dt,J=15.6,7.0Hz,1H)
IR(neat)cm-1:
3400,2930,2867,2230,1734,1654,1466,1437,1402,1385,1368,1278,1202,1164,1045,844,720
实施例44
(2E,11R)-11-去氧-11-(2-羟基乙硫基)-19,20-二去甲-17-甲基-2,3,13,14-四去氢-PGE1(化合物57)
使用实施例43中得到的(2E,11R)-11-去氧-11-(2-羟基乙硫基)-19,20-二去甲-17-甲基-2,3,13,14-四去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,200MHz)δppm;
0.94(d,J=6.6Hz,3H),0.96(d,J=6.4Hz,3H),1.34-1.96(m,9H),2.01-3.38(m,8H),2.11(dd,J=18.9,11.7Hz,1H),2.87(dt,J=14.0,6.4Hz,1H),3.15(dt,J=14.0,6.4Hz,1H),3.28(ddd,J=11.7,10.5,7.9Hz,1H),3.86(t,J=6.4Hz,2H),4.44(dt,J=1.8,7.3Hz,1H),5.84(dt,J=15.6,1.4Hz,1H),7.06(dt,J=15.6,7.0Hz,1H)
IR(neat)cm-1:
3368,2930,2869,2236,1740,1697,1654,1466,1402,1368,1284,1218,1163,1046,985,670,539
实施例45
(2E,11R,17R)-11-去氧-11-(2-羟基乙硫基)-20-羟基-17-甲基-2,3,13,14-四去氢-PGE1甲酯(化合物119)以及(2E,11S,17R)-11-去氧-11-(2-羟基乙硫基)-20-羟基-17-甲基-2,3,13,14-四去氢-PGE1甲酯(化合物121)
(1)实施例1(1)中,使用(2E,17R)-20-羟基-17-甲基-2,3,13,14-四去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(2E,17R)-20-羟基-17-甲基-2,3,13,14-四去氢-PGA1甲酯。
1H-NMR(CDCl3,300MHz)δppm;
0.92-0.98(m,3H),1.15-1.98(m,15H),2.14-2.45(m,3H),3.39-3.45(m,1H),3.64(t,J=6.6Hz,2H),3.74(s,3H),4.40-4.52(m,1H),5.85(d,J=15.7Hz,1H),6.19(dd,J=5.8,2.3Hz,1H),6.98(dt,J=15.7,7.0Hz,1H),7.47(dd,J=5.8,2.5Hz,1H)
IR(neat)cm-1:
3400,2934,2860,2214,1708,1702,1654,1437,1384,1277,1202,1179,1055,876,719
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(2E,11R,17R)-11-去氧-11-(2-羟基乙硫基)-20-羟基-17-甲基-2,3,13,14-四去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.88-1.00(m,3H),1.16-2.34(m,19H),2.12(dd,J=18.9,11.7Hz,1H),2.60-2.97(m,3H),3.13(dt,J=13.6,6.8Hz,1H),3.21-3.34(m,1H),3.59-3.70(m,2H),3.73(s,3H),3.77-3.89(m,2H),4.40-4.52(m,1H),5.79-5.89(m,1H),6.90-7.04(m,1H)
IR(neat)cm-1:
3400,2930,2860,2236,1740,1724,1654,1438,1402,1384,1283,1203,1176,1046,720
(2E,11S,17R)-11-去氧-11-(2-羟基乙硫基)-20-羟基-17-甲基-2,3,13,14-四去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.89-1.01(m,3H),1.35-1.86(m,13H),2.15-2.29(m,4H),2.47-2.66(m,4H),2.87-3.13(m,3H),3.58-3.88(m,5H),3.73(s,3H),4.44-4.54(m,1H),5.83(dt,J=15.6,1.5Hz,1H),6.96(dt,J=15.6,7.1Hz,1H)
IR(neat)cm-1:
3400,2934,2864,2230,1740,1724,1654,1437,1402,1380,1284,1202,1177,1050,720
实施例46
(2E,11R,17R)-11-去氧-11-(2-羟基乙硫基)-20-甲氧基-17-甲基-2,3,13,14-四去氢-PGE1甲酯(化合物124)以及(2E,11S,17R)-11-去氧-11-(2-羟基乙硫基)-20-甲氧基-17-甲基-2,3,13,14-四去氢-PGE1甲酯(化合物126)
(1)实施例1(1)中,使用(2E,17R)-20-甲氧基-17-甲基-2,3,13,14-四去氢-PGE1甲酯代替(17R)-17,20-二甲基-13,14-二去氢-PGE1甲酯,与实施例1(1)实质上相同,得到(2E,17R)-20-甲氧基-17-甲基-2,3,13,14-四去氢-PGA1甲酯。
1H-NMR(CDCl3,300MHz)δppm;
0.90-0.98(m,3H),1.14-2.46(m,18H),3.30-3.45(m,2H),3.33(s,3H),3.73(s,3H),4.39-4.52(m,1H),5.84(dt,J=15.7,1.6Hz,1H),6.19(dd,J=5.6,2.3Hz,1H),6.98(dt,J=15.7,7.1Hz,1H),7.47(dd,J=5.6,2.3Hz,1H)
IR(neat)cm-1:
3436, 2930,2860,2214,1718,1702,1654,1437,1384,1273,1201,1116,1039,984,670
(2)使用上述(1)得到的化合物,与实施例1(2)实质上相同,得到标题化合物。
(2E,11R,17R)-11-去氧-11-(2-羟基乙硫基)-20-甲氧基-17-甲基-2,3,13,14-四去氢-PGE1甲酯1H-NMR(CDCl3,300MHz)δppm;
0.89-0.99(m,3H),1.15-1.85(m,15H),2.11(dd,J=19.0,11.7Hz,1H),2.14-2.33(m,3H),2.60-2.93(m,3H),3.13(dt,J=13.7,6.8Hz,1H),3.20-3.41(m,3H),3.33(s,3H),3.73(s,3H),3.78-3.89(m,2H),4.39-4.50(m,1H),5.83(d,J=15.5Hz,1H),6.96(dt,J=15.5,7.0Hz,1H)
IR(neat)cm-1:
3420,2930,2860,2236,1745,1724,1654,1456,1436,1402,1278,1202,1116,1045,848,720,595
(2E,11S,17R)-11-去氧-11-(2-羟基乙硫基)-20-甲氧基-17-甲基-2,3,13,14-四去氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.95(d,J=6.4Hz,3H),1.13-1.84(m,1 3H),2.16-2.28(m,3H),2.46-2.67(m,4H),2.86-3.13(m,3H),3.30-3.41(m,2H),3.33(s,3H),3.58-3.66(m,1H),3.71-3.86(m,2H),3.73(s,3H),4.44-4.53(m,1H),5.83(dt,J=15.6,1.6Hz,1H),6.96(dt,J=15.6,7.0Hz,1H)
IR(neat)cm-1:
3427,2930,2860,2236,1740,1724,1654,1437,1401,1278,1202,1178,1116,1045,720
实施例47
(2E,11R,17R)-11-去氧-11-(2-羟基乙硫基)-20-甲氧基-17-甲基-2,3,13,14-四去氢-PGE1(化合物128)
使用实施例46中得到的(2E,11R,17R)-11-去氧-11-(2-羟基乙硫基)-20-甲氧基-17-甲基-2,3,13,14-四去氢-PGE1甲酯,与实施例2实质上相同,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.91-0.98(m,3H),1.16-1.86(m,16H),2.11(dd,J=18.9,11.9Hz,1H),2.24-2.34(m,3H),2.59-2.93(m,3H),3.07-3. 51(m,4H),3.37(s,3H),3.85(t,J=6.5Hz,2H),4.40-4.50(m,1H),5.84(d,J=15.6Hz,1H),7.01(dt,J=15.6,7.2Hz,1H)
IR(neat)cm-1:
3394,2930,2860,2236,1745,1697,1654,1461,1402,1283,1206,1157,1114,1046,986,876,666
试验例
〔PGE1衍生物对人体血管平滑肌细胞的DAN合成抑制活性的测定〕
以1×104细胞/孔向24孔板(Corning公司生产)中接种来源于正常人体主动脉的血管细胞(Kurabo公司生产)的5代培养细胞,培养2天。将培养基由增殖用培养基(SG2,Kurabo公司生产)更换为基础培养基(SB2,Kurabo公司生产),培养24小时。向其中加入添加有含被测化合物的乙醇溶液的增殖用培养基(SG2)。这时,以0.01mci/孔加入3H-胸腺嘧啶脱氧核苷(第1化学药品制),培养24小时后,抽吸除去培养上清液,用磷酸缓冲液(PBS)洗涤。
加入5%三氯醋酸(TCA),4℃下放置20分钟后,用TCA洗涤1次。用PBS洗涤后,用0.5M氢氧化钾水溶液溶解。量取溶解有核内掺入了3H-胸腺嘧啶脱氧核苷的细胞的氢氧化钾水溶液20μl,使用液体闪烁计数器(Hewlett-Packard公司生产),测定3H-胸腺嘧啶脱氧核苷的掺入量。
其结果如表1所示。
被测化合物 | 增殖抑制率(相对于对照组%) |
化合物7 | 98.4 |
化合物70 | 95.6 |
化合物92 | 99.3 |
注)表中的化合物7、70和92是实施例中制备的化合物。
将被测化合物制成乙醇溶液(加入的化合物浓度为1×10-5M),以溶剂处理组作为对照组进行比较。
根据以上结果,判断出化合物7、70和92对血管平滑肌细胞具有较高的增殖抑制活性。
工业实用性
按照本发明可以提供显示优良的血管平滑肌细胞的增殖抑制作用的PG衍生物,作为血管的肥厚(例如经皮冠状动脉成形术后再狭窄的原因)、闭塞的抑制剂,或者血管肥厚、闭塞的预防、治疗剂是有用的。
Claims (7)
1.下式表示的前列腺素衍生物、其可药用盐或其水合物,
式中,A表示亚乙基、亚乙烯基、亚乙炔基、O(CH2)q或S(O)r(CH2)q,R1表示C3-10环烷基、C1-4烷基C3-10环烷基、C3-10环烷基C1-4烷基、C1-10烷基、羟基或C1-4烷氧基取代的C1-10烷基、C2-10链烯基、羟基或C1-4烷氧基取代的C2-10链烯基、C2-10炔基、羟基或C1-4烷氧基取代的C2-10炔基或者桥环式烃基,R2表示氢原子、C1-10烷基或C3-10环烷基,m表示1~5的整数,n表示1~4的整数,p表示0、1或2,q表示1~5的整数,r表示0、1或2。
2.根据权利要求1所述的前列腺素衍生物、其可药用盐或其水合物,式(I)中R1为C5-10烷基、羟基或C1-4烷氧基取代的C5-10烷基、C5-10链烯基、羟基或C1-4烷氧基取代的C5-10链烯基、C5-10炔基、或者羟基或C1-4烷氧基取代的C5-10炔基,q为1或2。
3.根据权利要求1或2所述的前列腺素衍生物、其可药用盐或其水合物,式(I)中m为2~4的整数,n为2或3。
4.根据权利要求1或2所述的前列腺素衍生物、其可药用盐或其水合物,式(I)中p为0。
5.根据权利要求3所述的前列腺素衍生物、其可药用盐或其水合物,式(I)中p为0。
6.一种血管平滑肌增殖抑制作用剂,其特征在于以权利要求1~5中任意一项所述的前列腺素衍生物、其可药用盐或其水合物为有效成分。
7.一种经皮冠状动脉成形术后再狭窄的预防或治疗剂,其特征在于以权利要求1~5中任意一项所述的前列腺素衍生物、其可药用盐或其水合物为有效成分。
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CN109071427A (zh) * | 2016-05-09 | 2018-12-21 | Agc株式会社 | 新型的前列腺素衍生物 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001019789A1 (fr) * | 1999-09-10 | 2001-03-22 | Taisho Pharmaceutical Co.,Ltd. | Derives de prostaglandine |
US6586462B2 (en) * | 2000-10-20 | 2003-07-01 | Allergan, Inc. | ω-Cycloalkyl 17-heteroaryl prostaglandin E2 analogs as EP2-receptor agonists |
JP6705974B2 (ja) * | 2017-11-08 | 2020-06-03 | Agc株式会社 | 新規なプロスタグランジン誘導体を有効成分として含有する医薬 |
CN109288848A (zh) * | 2018-11-27 | 2019-02-01 | 西安力邦肇新生物科技有限公司 | 前列腺素e1甲酯在制备扩张血管药物中的应用 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4029681A (en) | 1976-02-13 | 1977-06-14 | The Upjohn Company | 13,14-Didehydro-PG analogs |
US4131738A (en) | 1977-07-05 | 1978-12-26 | The Upjohn Company | 6-Hydroxy-PGE1 compounds |
FR2608924B1 (fr) | 1986-12-29 | 1990-07-20 | Pasteur Institut | Compositions therapeutiques contenant des derives soufres de prostaglandines, nouveaux derives soufres et leur procede de preparation |
US5516796A (en) | 1994-03-24 | 1996-05-14 | Kabi Pharmacia Ab | Thioprostaglandins and -prostaglandin-like compounds and therapeutic uses thereof |
JP3865843B2 (ja) | 1996-12-17 | 2007-01-10 | 大正製薬株式会社 | プロスタグランジンe1類縁体 |
-
2000
- 2000-04-07 US US09/937,782 patent/US6455584B1/en not_active Expired - Fee Related
- 2000-04-07 WO PCT/JP2000/002286 patent/WO2000061550A1/ja not_active Application Discontinuation
- 2000-04-07 AU AU36743/00A patent/AU765162B2/en not_active Ceased
- 2000-04-07 CN CNB008087415A patent/CN1196678C/zh not_active Expired - Fee Related
- 2000-04-07 CA CA002369662A patent/CA2369662A1/en not_active Abandoned
- 2000-04-07 EP EP00915427A patent/EP1170286A4/en not_active Withdrawn
- 2000-04-07 KR KR1020017012789A patent/KR20020004993A/ko not_active Application Discontinuation
-
2002
- 2002-10-11 HK HK02107434.7A patent/HK1045836A1/zh unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109071427A (zh) * | 2016-05-09 | 2018-12-21 | Agc株式会社 | 新型的前列腺素衍生物 |
AU2017264102B2 (en) * | 2016-05-09 | 2020-09-24 | AGC Inc. | Novel prostaglandin derivative |
Also Published As
Publication number | Publication date |
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CA2369662A1 (en) | 2000-10-19 |
EP1170286A4 (en) | 2003-05-28 |
KR20020004993A (ko) | 2002-01-16 |
US6455584B1 (en) | 2002-09-24 |
AU3674300A (en) | 2000-11-14 |
CN1355788A (zh) | 2002-06-26 |
HK1045836A1 (zh) | 2002-12-13 |
AU765162B2 (en) | 2003-09-11 |
EP1170286A1 (en) | 2002-01-09 |
WO2000061550A1 (fr) | 2000-10-19 |
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