CN1190417C - ***素衍生物 - Google Patents
***素衍生物 Download PDFInfo
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- CN1190417C CN1190417C CNB008155658A CN00815565A CN1190417C CN 1190417 C CN1190417 C CN 1190417C CN B008155658 A CNB008155658 A CN B008155658A CN 00815565 A CN00815565 A CN 00815565A CN 1190417 C CN1190417 C CN 1190417C
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- alkyl
- hydroxyl
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- 150000003180 prostaglandins Chemical class 0.000 title claims abstract description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 8
- 208000037803 restenosis Diseases 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims abstract description 6
- -1 ethylidene, vinylidene Chemical group 0.000 claims description 177
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 238000007887 coronary angioplasty Methods 0.000 claims description 5
- 239000000470 constituent Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 abstract description 14
- 125000000217 alkyl group Chemical group 0.000 abstract description 11
- 125000002252 acyl group Chemical group 0.000 abstract description 7
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 abstract description 6
- KKJUPNGICOCCDW-UHFFFAOYSA-N 7-N,N-Dimethylamino-1,2,3,4,5-pentathiocyclooctane Chemical compound CN(C)C1CSSSSSC1 KKJUPNGICOCCDW-UHFFFAOYSA-N 0.000 abstract description 4
- 125000000304 alkynyl group Chemical group 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 210000002464 muscle smooth vascular Anatomy 0.000 abstract description 2
- 229910052760 oxygen Inorganic materials 0.000 abstract description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 abstract 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 3
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 abstract 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 abstract 2
- 125000006843 cycloalkyl-C1-5-alkyl Chemical group 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 136
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 126
- 238000005160 1H NMR spectroscopy Methods 0.000 description 96
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 34
- 239000002585 base Substances 0.000 description 20
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 235000002639 sodium chloride Nutrition 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 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 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 244000005700 microbiome Species 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 102000004882 Lipase Human genes 0.000 description 5
- 108090001060 Lipase Proteins 0.000 description 5
- 239000004367 Lipase Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000004140 cleaning Methods 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 235000019421 lipase Nutrition 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- 241000282894 Sus scrofa domesticus Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940125810 compound 20 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 229940127204 compound 29 Drugs 0.000 description 3
- 229940126540 compound 41 Drugs 0.000 description 3
- 229940127113 compound 57 Drugs 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 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 3
- 239000012442 inert solvent Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
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- 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 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 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 2
- 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 2
- 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
- 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 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 2
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 2
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 2
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 2
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P9/08—Vasodilators for multiple indications
Abstract
下式所示的***素衍生物,其药学上可接受的盐或其水合物:[式中,X表示CH2、O或S(O)q1所示基团,Y表示亚乙基、亚乙烯基、亚乙炔基、式O(CH2)t1或S(O)q2(CH2)t1所示基团,Z表示亚乙基、亚乙烯基、亚乙炔基,R1表示氢原子、C1-10烷基或C3-10环烷基,R2表示C1-10烷基、C2-10链烯基、C2-10炔基、C3-10环烷基、C1-5烷基C3-10环烷基、C3-10环烷基烷基C1-5烷基、羟基C1-5烷基、卤代C1-5烷基、C1-5烷氧基C1-5烷基、C2-4烷氧基羰基C1-5烷基、羧基C1-5烷基、氰基C1-5烷基、式-NR7R8所示基团取代的C1-5烷基、酰基、式-(CH2)t2CH(NH2)COOR9所示基团等,R3表示氢原子、C1-10烷基等。]本发明的新的***素衍生物,具有优秀的血管平滑肌增殖抑制作用,作为PTCA后的再狭窄等疾病的预防或治疗剂是有用的。
Description
发明所属技术领域
本发明涉及新的***素衍生物,其药学上可接受的盐或其水合物。
背景技术
***素(PG),由于微量时就可发挥各种生理作用,因此进行了很多试图于医药用途的多种天然PG或合成PG衍生物的生理活性研究,并在很多文献,例如特开昭52-100446号公报,美国专利第4,131,738号等专利中有报道。作为天然PG和PG衍生物的生理作用,可列举血管扩张作用,引起炎症作用,抑制血小板凝集作用,子宫收缩作用,肠道收缩作用,降低眼压作用的,在心肌梗塞,心绞痛,动脉硬化,高血压,十二指肠溃疡等的治疗或预防,以及诱发、终止分娩等中有用。
另一方面,经皮的冠状动脉成形术(PTCA)作为缺血性心脏病的治疗方法,由于对患者的伤害程度低,具有优秀的初期治疗效果,是近年来迅速发展的手术方法。但是,PTCA术后数月中以30~40%的频率出现冠状动脉再狭窄的缺点至今没有解决。人们强烈期望开发可抑制与再狭窄发生强烈相关的血管平滑肌细胞的内膜向中膜游走,中膜的增殖的化合物作为抑制再狭窄的药物,但是临床上还没发现有用的药物。
本发明的目的是提供,具有优秀的抑制血管平滑肌增殖作用,作为PTCA术后再狭窄等疾病的预防或治疗药被强烈期待的新的PG衍生物。
发明的公开
本发明者进行了认真研究,结果发现,在11位具有烷硫基或芳硫基等的下式(I)所示新的***素衍生物可达到上述目的,并因此完成了本发明。
即,本发明是,式(I)所示的***素衍生物,其药学上可接受的盐或其水合物。
[式中,X表示CH2、O或S(O)q1(式中,q1表示0~2的整数)所示基团,
Y表示亚乙基、亚乙烯基、亚乙炔基、式O(CH2)t1或S(O)q2(CH2)t1(式中,q2表示0~2的整数,t1表示1~3的整数。)所示基团,
Z表示亚乙基、亚乙烯基、亚乙炔基,
R1表示氢原子、C1-10烷基或C3-10环烷基,
R2表示C1-10烷基、C2-10链烯基、C2-10炔基、C3-10环烷基、C1-5烷基C3-10环烷基、C3-10环烷基烷基C1-5烷基、羟基C1-5烷基、卤代C1-5烷基、C1-5烷氧基C1-5烷基、C2-4烷氧基羰基C1-5烷基、羧基C1-5烷基、氰基C1-5烷基、式-NR7R8(式中,R7和R8可相同或不同,表示氢原子或C1-5烷基,或与相邻的氮原子一起形成吡咯烷基、哌啶子基、哌嗪基、吗啉代基或硫代吗啉代基。)所示基团取代的C1-5烷基、酰基、式-(CH2)t2CH(NH2)COOR9(式中,R9表示氢原子或C1-5烷基、t2表示1或2。)所示基团或下式所示基团
(式中,R4和R5可相同或不同,表示氢原子、羟基、卤原子、C1-10烷基、C1-10烷氧基、C2-10链烯基、C2-10炔基、羟基C1-5烷基、卤代C1-5烷基、C1-5烷氧基C1-5烷基、C2-4烷氧基羰基、羧基、酰基、硝基、氨基或C1-5烷基单或二取代的氨基,r表示0~3的整数。)
R3表示氢原子、C1-10烷基、C3-10环烷基、C1-5烷基C3-10环烷基、C3-10环烷基C1-5烷基、C2-10链烯基或C2-10炔基,
m表示0~3的整数,n表示1~3的整数,p表示0~5的整数,q表示0~2的整数。]
另外,本发明是以含有本发明式(I)所示化合物、其药学上可接受的盐或其水合物为有效成分的药物。
在本发明中,亚乙烯基是指顺或反亚乙烯基。卤原子是指氟原子、氯原子、溴原子或碘原子。
C1-10烷基是指碳原子数1~10的直链或支链烷基,可列举例如,甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、2-乙基丙基、己基、辛基、癸基等。
C1-10烷氧基是指碳原子数1~10的直链或支链烷氧基,可列举例如,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基、辛氧基等。
C2-10链烯基是指碳原子数2~10的直链或支链链烯基,可列举例如,乙烯基、烯丙基、3-戊烯基、4-己烯基、5-庚烯基、4-甲基-3-戊烯基、2,4-二甲基戊烯基、6-甲基-5-庚烯基、2,6-二甲基-5-庚烯基等。
C2-10炔基是指碳原子数2~10的直链或支链炔基,可列举例如,乙炔基、丙炔基、3-戊炔基、4-己炔基、5-庚炔基、4-甲基-3-戊炔基、2,4-二甲基戊炔基、6-甲基-5-庚炔基、2,6-二甲基-5-庚炔基等。
C3-10环烷基是指碳原子数3~10的环烷基,可列举例如,环丙基、环丁基、环戊基、环己基、环庚基等。
C1-5烷基C3-10环烷基是指被碳原子数1~5的直链或支链烷基取代的碳原子数3~10的环烷基,可列举例如,甲基环丙基、甲基环己基、乙基环己基等。
C3-10环烷基C1-5烷基是指被碳原子数3~10的环烷基取代的碳原子数1~5的直链或支链烷基,可列举例如,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。
羟基C1-5烷基是指被羟基取代的碳原子数1~5的直链或支链烷基,可列举例如,羟甲基、羟乙基、2-羟基丙基、3-羟基丙基、4-羟基丁基、5-羟基戊基等。
卤代C1-5烷基是指被1个以上氟原子、氯原子、溴原子取代的碳原子数1~5的直链或支链烷基,可列举例如,氯乙基、2-溴丙基、3-氯丙基、4-氟丁基、5-氯戊基、三氟甲基等。
C1-5烷氧基C1-5烷基是指被碳原子数1~5的直链或支链烷氧基取代的碳原子数1~5的直链或支链烷基,可列举例如,乙氧基甲基、甲氧基乙基、2-乙氧基丙基、3-甲氧基丙基、叔丁氧基乙基等。
C2-4烷氧基羰基C1-5烷基是指被碳原子数2~4的直链或支链烷氧羰基取代的C1-5直链或支链烷基,可列举例如,甲氧羰基甲基、乙氧羰基甲基、1-乙氧羰基乙基、3-甲氧羰基丙基等。
羧基C1-5烷基是指被羧基取代的碳原子数1~5的直链或支链烷基,可列举例如,羧甲基、1-羧基乙基、2-羧基乙基、3-羧基丙基等。
氰基C1-5烷基是指被氰基取代的碳原子数1~5的直链或支链烷基,可列举例如,氰基甲基、2-氰基乙基、2-氰基丙基、3-氰基丙基等。
作为被式-NR7R8所示基团取代的C1-5烷基,可列举例如,2-氨基乙基、3-氨基丙基、2-N,N-二甲基氨基乙基、3-N,N-二乙基氨基丙基、2-哌啶子基乙基等。
酰基包括脂肪族酰基或芳香族酰基,脂肪族酰基是指C2-10烷酰基、C2-10链烯酰基或C3-10环烯酰基、芳香族酰基是指未取代的或被羟基或卤原子取代的具有苯环的酰基。作为它们的例子可列举,乙酰基、丙酰基、异丁酰基、新戊酰基、丙炔酰基、巴豆酰基、苯甲酰基、烟酰基、环己基羰基等。
药学上可接受的盐是指,可列举例如,与钠、钾等碱金属成的盐,与钙、镁等碱土金属成的盐,与氨、甲基胺、二甲基胺、环戊基胺、苄胺、哌啶、单乙醇胺、二乙醇胺、单甲基单乙醇胺、氨丁三醇、赖氨酸、四烷基铵、三(羟甲基)氨基甲烷等成的盐。
在本发明中,X定义中优选的基团是CH2或S(O)q1(式中,q1定义同前)所示基团,更优选CH2。
Y定义中的优选基团是亚乙基、亚乙烯基、亚乙炔基、式O(CH2)t1或S(O)q2(CH2)t1(式中,q2和t1定义同前)所示基团,更优选亚乙基、亚乙烯基、OCH2或SCH2。
Z定义中的优选基团是亚乙烯基或亚乙炔基。
R1定义中的优选基团是氢原子或C1-10烷基。
R2定义中的优选基团是C1-10烷基、羟基C1-5烷基、C1-5烷氧基C1-5烷基、C2-4烷氧羰基C1-5烷基、氰基C1-5烷基、式-NR77R88(式中,R77和R88可相同或不同,表示氢原子或C1-5烷基。)所示基团取代的C1-5烷基、酰基、式-(CH2)t2CH(NH2)COOR9(式中,R9和t2定义同前。)所示基团或下式所示基团
(式中,R44表示氢原子、卤原子、C1-10烷基、C1-10烷氧基、硝基或氨基,r表示0~3的整数。),更优选羟基C1-5烷基、C2-4烷氧羰基C1-5烷基、二C1-5烷基氨基取代的C1-5烷基、C2-10烷酰基、式-(CH2)t2CH(NH2)COOR9(式中,R9和t2定义同前。)所示基团或下式所示基团
(式中,R44定义同前)。
R3定义中优选的基团是氢原子、C1-10烷基、C3-10环烷基、C3-10环烷基C1-5烷基或C2-10链烯基,更优选氢原子或C1-10烷基。
式(I)化合物例如可按照下述反应式中概括的方法制备。
(反应式中,TBS表示叔丁基二甲基甲硅烷基,Z’表示亚乙基或亚乙烯基,Et表示乙基,R6表示C1-10的直链或支链烷基或C3-10的环烷基,q3表示1或2,X、Y、Z、R2、R3、m、n、p定义同前。)
下面对上述反应式进行说明。
(1)首先,按照佐藤等的方法[J.Org.Chem.第53卷,第5590页(1988年)],向公知的式(II)化合物中加入式(III)或式(III’)所示化合物0.8~2.0当量,使它们在-78~30℃在惰性溶剂(例如,苯、甲苯、四氢呋喃、***、二氯甲烷、正己烷等)中反应,得到具有特定立体构型的式(IV)化合物。这里,为得到Z是亚乙基或亚乙烯基的化合物(即,Z是Z’的化合物),使用式(III)化合物在-78℃~0℃反应,为得到Z是亚乙炔基的化合物,使用式(III’)化合物在0~30℃反应。另外,式(III)或式(III’)所示化合物,可使用按照Skotnicki等的方法[J.Med.Chem.第20卷,第1042页(1977年)]得到的化合物调制。
(2)使式(IV)化合物与式(V)所示的有机铜化合物0.5~4当量和三甲基氯硅烷0.5~4当量在惰性溶剂(例如,苯、甲苯、四氢呋喃、***、二氯甲烷、正己烷、正戊烷)中,在-78~40℃反应,进一步通过使用无机酸(例如,盐酸、硫酸、硝酸等)或有机酸(例如,乙酸、对甲苯磺酸等)或其胺盐(例如,对甲苯磺酸吡啶盐等),在有机溶剂(例如,丙酮、甲醇、乙醇、异丙醇、***或它们的混合溶剂等)中,在0~40℃水解,得到立体选择性式(VI)化合物。
(3)将式(VI)化合物使用氢氟酸、聚(氟化氢)吡啶鎓、盐酸等,在甲醇、乙醇、乙腈或它们的混合溶剂、或它们与水的混合溶剂中,在通常使用的条件下除去叔丁基二甲基甲硅烷基,得到式(VII)所示化合物。
(4)将式(VII)化合物在有机溶剂(例如,甲醇、乙醇、乙酸乙酯、二噁烷等)、水或它们的混合溶剂中,用有机酸(例如甲酸、乙酸等)或无机酸(例如硫酸、盐酸等)在0~60℃进行脱水反应,得到式(VIII)化合物。
(5)将式(VIII)化合物与式(IX)所示化合物1~5当量,根据需要使用胺(例如,三乙胺、二异丁胺等)或自由基产生剂(例如,偶氮双异丁腈,偶氮双环己烷腈,过氧化苯甲酰,三乙基硼烷等)0.05~2当量,在惰性溶剂(例如,氯仿、苯、甲苯、二甲苯、正己烷、正庚烷、丙酮等)中,在-78~100℃进行反应,得到11位立体构型不同的本发明式(Ia)和式(Ia’)的PG衍生物。该式(Ia)和式(Ia’)化合物可使用柱色谱等常用的分离方法进行纯化。
(6)通过使式(Ia)(或式(Ia’))化合物在磷酸缓冲液、Tris-盐酸缓冲液等缓冲液中,根据需要使用有机溶剂(丙酮、甲醇、乙醇等与水的混合溶剂),与酶反应进行水解,得到式(Ib)(或式(Ib’))的PG衍生物。
作为酶,有微生物产生的酶(例如,属于念珠菌属、假单胞菌属的微生物产生的酶)、从动物脏器调制的酶(例如,从猪肝脏或猪胰脏调制的酶)等,市售酶的具体例可列举,脂肪酶VII(希格玛社制,来自念珠菌属微生物)、脂肪酶AY(天野制药制,来自念珠菌属微生物)、脂肪酶PS(天野制药制,来自假单胞菌属微生物)、脂肪酶MF(天野制药制,来自假单胞菌属微生物)、PLE(希格玛社制,来自猪肝脏)、脂肪酶II(希格玛社制,来自猪胰脏)、脂蛋白脂肪酶(东京化成工业社制,来自猪胰脏)等。
酶的使用量,可根据酶的效价和基质[式(Ia)化合物]的量适当选择,通常为基质的0.1~20倍重量份。反应温度为25~50℃,优选30~40℃。
(7)可使用偏过碘酸钠、过氧化氢水、过乙酸、间氯过苯甲酸、叔丁基过氧化氢等氧化剂,使式(Ia)或式(Ia’)化合物在***、甲醇、乙醇、二氯甲烷、水或它们的混合溶剂中,在-20~50℃反应进行氧化,得到式(Ic)或式(Ic’)的PG衍生物。
(8)可将式(Ic)或式(Ic’)的化合物使用与上述(6)同样的酶进行水解,得到式(Id)或式(Id’)的PG衍生物。另外,使用式(Ib)或式(Ib’)化合物与上述(7)进行同样的氧化,可得到式(Id)或式(Id’)的PG衍生物。
作为本发明代表性化合物可列举如下的化合物。
化合物 X Y Z m n p q R1 R2 R3 11位 16-OH
1 CH2 CH2CH2 CH2CH2 2 0 1 0 Me HO(CH2)2 nPr α β
2 CH2 CH2CH2 CH2CH2 2 0 1 0 Me HO(CH2)2 nPr β β
3 CH2 CH2CH2 CH2CH2 2 0 1 0 H HO(CH2)2 nPr α β
4 CH2 CH2CH2 CH2CH2 2 0 2 0 Me HO(CH2)2 cHex α β
5 CH2 CH2CH2 CH2CH2 2 0 2 0 Me HO(CH2)2 cHex β β
6 CH2 CH2CH2 CH2CH2 2 0 2 0 H HO(CH2)2 cHex α β
7 CH2 (E)CH=CH CH2CH2 3 0 1 0 Me HO(CH2)2 nPr α β
8 CH2 (E)CH=CH CH2CH2 3 0 1 0 Me HO(CH2)2 nPr β β
9 CH2 (E)CH=CH CH2CH2 3 0 1 0 H HO(CH2)2 nPr α β
10 CH2 CH2CH2 CH2CH2 2 0 1 0 Me NC(CH2)2 nPr α β
11 CH2 CH2CH2 CH2CH2 2 0 1 0 Me NC(CH2)2 nPr β β
12 CH2 CH2CH2 CH2CH2 2 0 1 0 H NC(CH2)2 nPr α β
13 CH2 CH2CH2 (E)CH=CH 3 0 1 0 Me HO(CH2)2 H α β
14 CH2 CH2CH2 (E)CH=CH 3 0 1 0 Me HO(CH2)2 H β β
15 CH2 CH2CH2 (E)CH=CH 3 0 1 0 H HO(CH2)2 H α β
16 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 Me α β
17 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 Me β β
18 CH2 CH2CH2 (E)CH=CH 2 0 1 0 H HO(CH2)2 Me α β
19 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α β
20 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β β
21 CH2 CH2CH2 (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α β
22 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α α
23 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β α
24 CH2 CH2CH2 (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α α
25 CH2 CH2CH2 (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr β α
26 CH2 (Z)CH=CH (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α β
27 CH2 (Z)CH=CH (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β β
28 CH2 (Z)CH=CH (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α β
29 CH2 (E)CH=CH (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α β
30 CH2 (E)CH=CH (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β β
31 CH2 (E)CH=CH (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α β
32 CH2 (E)CH=CH (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α α
33 CH2 (E)CH=CH (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β α
34 CH2 (E)CH=CH (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α α
35 CH2 C≡C (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α β
36 CH2 C≡C (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β β
37 CH2 C≡C (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α β
38 CH2 C≡C (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α α
39 CH2 C≡C (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β α
40 CH2 C≡C (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α α
41 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me HO(CH2)3 nPr α α
42 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me HO(CH2)3 nPr β α
43 CH2 CH2CH2 (E)CH=CH 2 0 1 0 H HO(CH2)3 nPr α α
44 CH2 CH2CH2 (E)CH=CH 2 0 1 0 iPr HO(CH2)3 nPr α α
45 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me MeO2CCH2 nPr α α
46 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me MeO2CCH2 nPr β α
47 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me HO2CCH2 nPr α α
48 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me El2N(CH2)2 nPr αβ α
49 CH2 CH2CH2 (E)CH=CH 2 0 1 0 cHex nPr nPr α α
50 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me nPr nPr α α
51 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me nPr nPr β α
52 CH2 CH2CH2 (E)CH=CH 2 0 1 0 H nPr nPr α α
53 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me CH3CO nPr β α
54 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me Cys(OMe) nPr α α
55 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me Cys(OMe) nPr β α
56 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me m-NO2Ph nPr α α
57 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me p-MeOBn nPr α α
58 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me p-MeOBn nPr β α
59 CH2 CH2CH2 (E)CH=CH 2 0 1 0 H p-MeOBn nPr α α
60 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me p-ClPh nPr α α
61 CH2 CH2CH2 (E)CH=CH 2 0 1 0 H p-ClPh nPr α α
62 CH2 CH2CH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 cPrCH2 α β
63 CH2 CH2CH2 (E)CH=CH 2 0 1 0 H HO(CH2)2 cPrCH2 α β
64 CH2 OCH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α β
65 CH2 OCH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β β
66 CH2 OCH2 (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α β
67 CH2 0CH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α α
68 CH2 OCH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β α
69 CH2 OCH2 (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α α
70 CH2 OCH2 (E)CH=CH 2 0 2 0 Me HO(CH2)2 nPr α α
71 CH2 OCH2 (E)CH=CH 2 0 2 0 Me HO(CH2)2 nPr β α
72 CH2 OCH2 (E)CH=CH 2 0 2 0 H HO(CH2)2 nPr α α
73 CH2 OCH2 (E)CH=CH 2 0 2 0 Me HO(CH2)2 nPr α β
74 CH2 OCH2 (E)CH=CH 2 0 2 0 Me HO(CH2)2 nPr β β
75 CH2 OCH2 (E)CH=CH 2 0 2 0 H HO(CH2)2 nPr α β
76 CH2 OCH2 (E)CH=CH 1 1 3 0 Me HO(CH2)2 nPr α β
77 CH2 OCH2 (E)CH=CH 1 1 3 0 Me HO(CH2)2 nPr β β
78 CH2 OCH2 (E)CH=CH 1 1 3 0 H HO(CH2)2 nPr α β
79 CH2 SCH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α β
80 CH2 SCH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β β
81 CH2 SCH2 (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α β
82 CH2 SCH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr α α
83 CH2 SCH2 (E)CH=CH 2 0 1 0 Me HO(CH2)2 nPr β α
84 CH2 SCH2 (E)CH=CH 2 0 1 0 H HO(CH2)2 nPr α α
85 CH2 CH2CH2 C≡C 2 0 1 0 Me HO(CH2)2 nPr α αβ
86 CH2 CH2CH2 C≡C 2 0 1 0 Me HO(CH2)2 nPr β αβ
87 CH2 CH2CH2 C≡C 2 0 1 0 H HO(CH2)2 nPr α αβ
88 CH2 CH2CH2 C≡C 2 0 1 0 H HO(CH2)2 nPr β αβ
89 CH2 (E)CH=CH C≡C 2 0 1 0 Me HO(CH2)2 nPr α αβ
90 CH2 (E)CH=CH C≡C 2 0 1 0 Me HO(CH2)2 nPr β αβ
91 CH2 (E)CH=CH C≡C 2 0 1 0 H HO(CH2)2 nPr α αβ
92 CH2 C≡C C≡C 2 0 1 0 Me HO(CH2)2 nPr α αβ
93 CH2 C≡C C≡C 2 0 1 0 Me HO(CH2)2 nPr β αβ
94 CH2 C≡C C≡C 2 0 1 0 H HO(CH2)2 nPr α αβ
95 CH2 O(CH2)2 C≡C 1 0 1 0 Me HO(CH2)2 nPr α αβ
96 CH2 O(CH2)2 C≡C 1 0 1 0 Me HO(CH2)2 nPr β αβ
97 CH2 O(CH2)2 C≡C 1 0 1 0 H HO(CH2)2 nPr α αβ
98 CH2 OCH2 C≡C 2 0 2 0 Me HO(CH2)2 nPr α β
99 CH2 OCH2 C≡C 2 0 2 0 Me HO(CH2)2 nPr β αβ
100 CH2 OCH2 C≡C 2 0 2 0 H HO(CH2)2 nPr α αβ
101 CH2 OCH2 C≡C 2 0 2 0 Me MeO(CH2)2 nPr α αβ
102 CH2 OCH2 C≡C 2 0 2 0 Me MeO(CH2)2 nPr β αβ
103 CH2 OCH2 C≡C 2 0 2 0 H MeO(CH2)2 nPr α αβ
104 CH2 OCH2 C≡C 2 0 2 0 Me HO(CH2)2 CH=CH2 α αβ
105 CH2 OCH2 C≡C 2 0 2 0 Me HO(CH2)2 CH=CH2 β αβ
106 CH2 OCH2 C≡C 2 0 2 0 H HO(CH2)2 CH=CH2 α αβ
107 CH2 SCH2 C≡C 2 0 1 0 Me HO(CH2)2 nPr α αβ
108 CH2 SCH2 C≡C 2 0 1 0 Me HO(CH2)2 nPr β αβ
109 S CH2CH2 C≡C 0 2 1 0 H HO(CH2)2 nPr α αβ
110 S CH2CH2 C≡C 0 2 1 0 H HO(CH2)3 nPr α αβ
111 S CH2CH2 CH2CH2 0 3 1 0 Me HO(CH2)2 nPr α α
112 S CH2CH2 CH2CH2 0 3 1 0 H HO(CH2)2 nPr α β
113 S CH2CH2 CH2CH2 0 3 2 0 Me HO(CH2)2 cHex α β
114 S (E)CH=CH CH2CH2 0 2 1 0 tBu HO(CH2)2 nPr α β
115 S (E)CH=CH CH2CH2 0 2 1 0 Me HO(CH2)2 nPr α β
116 S CH2CH2 (E)CH=CH 0 3 1 0 Me HO(CH2)2 H α β
117 S CH2CH2 (E)CH=CH 0 3 1 0 cHex HO(CH2)2 Me α β
118 S CH2CH2 (E)CH=CH 0 2 1 0 Me HO(CH2)2 nPr α β
119 S CH2CH2 (E)CH=CH 0 2 1 0 H HO(CH2)2 nPr α β
120 S CH2CH2 (E)CH=CH 0 2 1 0 Me HO(CH2)2 nPr α α
121 S CH2CH2 (E)CH=CH 0 2 1 0 H HO(CH2)2 nPr α α
122 S CH2CH2 (E)CH=CH 0 3 1 0 Me HO(CH2)3 nPr α α
123 S CH2CH2 (E)CH=CH 0 3 1 0 H HO(CH2)3 nPr α α
124 S (Z)CH=CH CH2CH2 0 2 1 0 H HO(CH2)2 nPr α β
125 S (E)CH=CH CH2CH2 0 2 1 0 Me HO(CH2)2 nPr α α
126 S (E)CH=CH CH2CH2 0 2 1 0 Me HO(CH2)2 nPr β α
127 S C≡C (E)CH=CH 0 2 1 0 H HO(CH2)2 nPr α β
128 S OCH2 (E)CH=CH 0 2 1 0 Me HO(CH2)2 nPr α α
129 S OCH2 (E)CH=CH 0 2 1 0 H HO(CH2)2 nPr α α
130 S OCH2 (E)CH=CH 0 3 2 0 Me HO(CH2)2 nPr α β
131 S OCH2 (E)CH=CH 0 3 2 0 Me HO(CH2)2 nPr β β
132 S SCH2 (E)CH=CH 0 2 1 0 Me HO(CH2)2 nPr α α
133 S SCH2 (E)CH=CH 0 2 1 0 H HO(CH2)2 nPr α α
134 S(O) S(O)CH2 (E)CH=CH 0 2 1 1 Me HO(CH2)2 Me α αβ
135 S(O)2 S(O)2CH2 (E)CH=CH 0 2 1 2 Me HO(CH2)2 Me α αβ
136 S CH2CH2 C≡C 0 2 1 0 H HO(CH2)2 nPr α αβ
137 S CH2CH2 C≡C 0 2 1 0 H HO(CH2)2 nPr β αβ
138 S (E)CH=CH C≡C 0 2 1 0 Me HO(CH2)2 nPr α αβ
139 S (E)CH=CH C≡C 0 2 1 0 H HO(CH2)2 nPr α αβ
140 S C≡C C≡C 0 3 1 0 Me HO(CH2)2 nPr α αβ
141 S C≡C C≡C 0 3 1 0 H HO(CH2)2 nPr α αβ
142 S C≡C C≡C 0 2 1 0 Me HO(CH2)2 nPr α αβ
143 S OCH2 C≡C 0 2 1 0 H HO(CH2)2 nPr α αβ
144 S OCH2 C≡C 0 2 2 0 H HO(CH2)2 nPr α αβ
145 S OCH2 C≡C 0 2 2 0 Me HO(CH2)2 CH=CH2 α αβ
146 S OCH2 C≡C 0 2 2 0 H HO(CH2)2 CH=CH2 α αβ
147 S S(CH2)2 C≡C 0 2 1 0 Me HO(CH2)2 nPr α αβ
148 S SCH2 C≡C 0 2 1 0 Me HO(CH2)2 nPr β αβ
149 S SCH2 C≡C 0 2 1 0 H HO(CH2)2 nPr α αβ
150 S O(CH2)2 C≡C 0 2 1 0 H HO(CH2)3 nPr α αβ
nPr:正丙基,iPr:异丙基,cHex:环己基,cPrCH2:环丙基甲基,m-NO2Ph:间硝基苯基,p-MeOBn:对甲氧苄基,p-ClPh:对氯苯基,Cys-Ome:MeO2CCH(NH2)CH2
11位:R2基团与环戊环结合,16-位:16位的碳原子与羟基的结合,(E)CH=CH:反式亚乙烯基,(Z)CH=CH:顺式亚乙烯基
本发明化合物可以全身或局部,经口服或直肠内、皮下、肌肉内、静脉内非口服给药,但优选口服或静脉内给药。作为口服给药的制剂,有用常规方法可制备的片剂、粉剂、颗粒剂、散剂、胶囊剂、溶液剂、乳剂、悬浮剂等,作为静脉内给药的制剂,有水性或非水性溶液剂、乳剂、悬浮剂、使用前溶解在注射溶剂中使用的固体制剂等。另外,可将本发明化合物与α、β或γ-环糊精或甲基化环糊精等形成包接化合物进行制剂化。进一步,其水性或非水性溶液剂、乳剂、悬浮剂等可通过注射给药。给药量根据年龄、体重等变化,但对于成人为1ng~1mg/天,可将其1天1次或分数次给药。
发明实施的最佳方式
下面将列举实施例和试验例对本发明进行更详细地说明,但本发明并不限于下述记载。
实施例1
(11R,16R)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物19)和(11S,16R)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物20)
(1)在氩气流下,-78℃,向(1E,4RS)-1-碘-4-(叔丁基二甲基甲硅烷氧基)-5,5-三亚甲基-1-辛烯(11.94g)的***(117ml)的溶液中,加入叔丁基锂(2.13M,戊烷溶液,27.5ml),在同温下搅拌30分钟。在-78℃,向该溶液中加入2-噻吩基氰基キュ一プレ一ト锂(0.25M、四氢呋喃溶液、140.3ml),在同温下搅拌20分钟。在-78℃,向该溶液中滴加入(4R)-2-(N,N-二乙基氨基)甲基-4-(叔丁基二甲基甲硅烷氧基)环戊-2烯-1-酮(0.25M、***溶液、117ml),用约1小时升温至0℃。将搅拌的同时,将反应液注入己烷(300ml)-饱和氯化铵水溶液(300ml)的混合液中,分离有机层,水层用己烷(150ml)萃取。合并所得有机层,用无水硫酸镁干燥,过滤。将滤液减压浓缩,所得粗产物用硅胶柱色谱纯化(展开溶剂:己烷∶乙酸乙酯=49∶1),得到(3R,4R)-2-亚甲基-3-[(1E,4RS)-4-叔丁基二甲基甲硅烷氧基-5,5-三亚甲基辛-1-烯基]-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮(9.28g)。
1H-NMR(CDCl3,200MHz)δppm;
0.05(s,9H),0.06(s,3H),0.70-1.10(m,3H),0.87(s,9H),0.91 and 0.92(2S,9H),
1.15-2.52(m,13H),2.63(dd,J=17.9,6.3Hz,1H),3.18-3.31(m,1H),
3.52-3.62(m,1H),3.98-4.12(m,1H),5.18-5.38(m,2H),5.54-5.79(m,1H),
6.07-6.13(m,1H)
IR(neat)cm-1;
2957,2930,2897,2858,1734,1643,1472,1362,1256,1090,1007,972,939,837,
812,776,670
(2)在氩气流下,-70℃,向5-甲氧羰基戊基碘化锌(II)(0.77M,四氢呋喃溶液,33.6ml)中加入氰化铜(I)·2氯化锂(1.0M,四氢呋喃溶液,27.6ml),在同温下搅拌20分钟。在-70℃,向该溶液中加入上述(1)得到的化合物(0.25M,***溶液,69.2ml)和氯三甲基甲硅烷(3.8ml),搅拌的同时用约2小时升温至0℃。向反应液中加入饱和氯化铵水溶液,用己烷萃取。有机层用饱和碳酸氢钠水溶液和饱和食盐水洗净后,用无水硫酸镁干燥,过滤。浓缩滤液,将所得残渣溶于***(3.5ml)-异丙醇(13.8ml)中,加入对甲苯磺酸吡啶鎓盐(100mg),在室温搅拌一夜。向反应液中加入己烷(150ml),用饱和碳酸氢钠水溶液和饱和食盐水洗净后,干燥、过滤、浓缩,所得粗产物用硅胶柱色谱纯化(展开溶剂:己烷∶乙酸乙酯=49∶1~9∶1),得到(16RS)-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲基酯11,16-双(叔丁基二甲基甲硅烷基醚)(7.56g)。
1H-NMR(CDCl3,200MHz)δppm;
0.02(s,3H),0.05(s,3H),0.06(s,3H),0.07(s,3H),0.70-1.00(m,3H),
0.89(s,9H),0.92 and 0.93(2s,9H),1.10-2.50(m,27H),2.51-2.68(m,1H),
3.55-3.64(m,1H),3.68(s,3H),3.92-4.06(m,1H),5.23-5.39(m,1H),
5.53-5.74(m,1H)
IR(neat)cm-1;
2955,2931,2857,1746,1606,1464,1436,1361,1256,1159,1098,1007,973,939,
837,775,670
(3)在0℃向(2)得到的化合物(7.56g)的乙腈(396ml)溶液中加入46%氢氟酸水溶液(89ml),在同温度搅拌3小时。边搅拌边将反应液注入乙酸乙酯(2000ml)-饱和碳酸氢钠水溶液(2670ml)中后,分离有机层,水层用乙酸乙酯萃取。合并有机层,用饱和碳酸氢钠水溶液和饱和食盐水洗净后,用无水硫酸镁干燥,过滤。减压浓缩滤液,所得粗产物用硅胶柱色谱纯化(展开溶剂:己烷∶乙酸乙酯=1∶1),得到(16R)-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯(2.07g)和(16S)-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯(2.15g)。
(16R)-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.95(t,J=6.8Hz,3H),1.20-2.12(m,22H),2.16-2.42(m,4H),
2.23(dd,J=18.4,9.6Hz,1H),2.29(t,J=7.5Hz,2H),
2.74(ddd,J=18.4,7.5,1.2Hz,1H),3.58(dd,J=10.0,2.4Hz,1H),3.66(s,3H),
4.00-4.12(m,1H),5.48(dd,J=15.3,8.5Hz,1H),
5.75(ddd,J=15.3,7.8,6.4Hz,1H)
IR(neat)cm-1;
3436,2932,2859,1742,1437,1244,1167,1075,972
(16S)-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.95(t,J=6.9Hz,3H),1.22-2.10(m,22H),2.20-2.41(m,3H),
2.22(dd,J=18.4,9.8Hz,1H),2.29(t,J=7.4Hz,2H),2.62-2.86(br,1H),
2.73(ddd,J=18.4,7.4,1.2Hz,1H),3.56(dd,J=10.2,2.4Hz,1H),3.66(s,3H),
3.98-4.08(m,1H),5.43(dd,J=15.2,8.8Hz,1H),
5.72(ddd,J=15.2,8.3,5.8Hz,1H)
IR(neat)cm-1;
3401,2932,2859,1742,1437,1244,1168,1074,969
(4)在室温向(3)得到的(16R)-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯(640mg)的乙酸乙酯(52ml)溶液中加入盐酸的乙酸乙酯溶液(4M,2.35ml),搅拌1.5小时。将反应液用饱和碳酸氢钠水溶液中和后,分取有机层,用饱和食盐水洗净,无水硫酸镁干燥,过滤。将滤液减压浓缩,所得粗产物用硅胶柱色谱纯化(展开溶剂:己烷∶乙酸乙酯= 5∶1),得到(16R)-15-脱氧-16-羟基-17,17-环丙烷-PGA1甲酯(447mg)。
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.9Hz,3H),1.25-2.38(m,23H),1.60(d,J=4.9Hz,1H),
2.30(t,J=7.5Hz,2H),3.15-3.30(m,1H),3.48-3.71(m,1H),3.67(s,3H),
5.42-5.76(m,1H),5.50(dd,J=15.6,7.5Hz,1H),6.15(dd,J=5.7,2.0Hz,1H),
7.49(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3496,2930,2858,1739,1707,1587,1465,1436,1351,1197,1174,1068,1030,971,
881,800,430
(5)向(4)得到的化合物(438mg)的氯仿(5.6ml)溶液中,加入2-巯基乙醇(0.157ml)和二异丙基胺(0.031ml),在室温搅拌一夜。将反应液用短硅胶柱色谱纯化(展开溶剂;乙酸乙酯),所得粗纯化物用硅胶柱色谱纯化(展开溶剂:己烷∶乙酸乙酯=1∶1~乙酸乙酯),得到化合物19(293mg)和化合物20(198mg)。
化合物19
1H-NMR(CDCl3,300MHz)δppm;
0.95(t,J=7.1Hz,3H),1.21-2.45(m,26H),2.19(dd,J=18.6,11.3Hz,1H),
2.29(t,J=7.5Hz,2H),2.73-2.90(m,3H),2.96-3.09(m,1H),3.54-3.63(m,1H),
3.65-3.82(m,2H),3.66(s,3H),5.47(dd,J=15.2,8.6Hz,1H),5.66-5.80(m,1H)
IR(neat)cm-1;
3435,2930,2859,1739,1460,1436,1278,1202,1173,1065,1046,971,847,742,
500
化合物20
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.20-2.91(m,30H),2.29(t,J=7.5Hz,2H),
3.53-3.63(m,2H),3.65-3.82(m,2H),3.66(s,3H),
5.61(ddd,J=15.5,7.5,5.5Hz,1H),5.71(dd,J=15.5,7.1Hz,1H)
IR(neat)cm-1;
3435,2930,2859,1739,1436,1384,1276,1199,1169,1066,973,772
实施例2
(11R,16R)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1(化合物21)
向实施例1得到的(11R,16R)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(187mg)的丙酮(2ml)溶液中加入水(10ml)、磷酸缓冲液(pH=8.0,0.2M,10ml),进一步加入PLE(希格玛社制,3.36单位/μl,硫酸铵水溶液59μl),在室温搅拌2天。用1M盐酸调至pH=4后,用硫酸铵进行盐析,用乙酸乙酯萃取,有机层用饱和食盐水洗净,用无水硫酸镁干燥,过滤。减压浓缩滤液,所得粗产物用硅胶柱色谱纯化(展开溶剂;乙酸乙酯),得到标题化合物(130mg)。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=7.0Hz,3H),1.20-2.45(m,27H),2.20(dd,J=18.5,11.2Hz,1H),
2.33(t,J=7.2Hz,2H),2.71-2.89(m,3H),2.96-3.09(m,1H),
3.62(dd,J=9.6,2.5Hz,1H),3.74(t,J=6.0Hz,2H),5.46(dd,J=15.3,8.6Hz,1H),
5.66-5.80(m,1H)
IR(neat)cm-1;
3455,2930,2859,1739,1465,1429,1402,1278,1239,1180,1160,1047,970,757
实施例3
(11R,16S)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物22)和(11S,16S)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物23)
(1)在实施例1(4)中,使用实施例1(3)得到的化合物(16S)-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯代替(16R)-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例1(4)进行实际上相同的操作,得到(16S)-15-脱氧-16-羟基-17,17-三亚甲基-PGA1甲酯。
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.9Hz,3H),1.20-2.37(m,24H),2.30(t,J=7.5Hz,2H),
3.18-3.29(m,1H),3.48-3.61(m,1H),3.67(s,3H),5.48(dd,J=15.2,7.9Hz,1H),
5.68(dt,J=15.2,6.9Hz,1H),6.15(dd,J=5.7,2.2Hz,1H),
7.48(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3468,2930,2858,1739,1707,1587,1436,1351,1173,1069,1030,972,881,809,
504
(2)使用(1)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物22:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.20-2.11(m,23H),2.13-2.43(m,2H),
2.20(dd,J=18.6,11.3Hz,1H),2.29(t,J=7.5Hz,2H),2.52-2.66(m,1H),
2.71-2.90(m,3H),2.95-3.08(m,1H),3.52-3.61(m,1H),3.63-3.81(m,2H),
3.66(s,3H),5.41(dd,J=15.0,9.3Hz,1H),5.66(ddd,J=15.0,9.5,5.2Hz,1H)
IR(neat)cm-1;
3435,2930,2859,1740,1457,1436,1401,1364,1275,1205,1173,1065,1048,970,
847,742
化合物23:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.20-2.91(m,30H),2.29(t,J=7.5Hz,2H),
3.44-3.68(m,1H),3.53(dd,J=10.3,2.1Hz,1H),3.66(s,3H),
3.76(t,J=5.5Hz,2H),5.57-5.73(m,2H)
IR(neat)cm-1;
3436,2930,2859,1739,1436,1384,1277,1199,1170,1066,973,875,726
实施例4
(11R,16S)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1(化合物24)
使用实施例3得到的(11R,16S)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.19-2.10(m,25H),2.20(dd,J=18.5,11.3Hz,1H),
2.23-2.44(m,2H),2.33(t,J=7.4Hz,2H),2.71-2.89(m,1H),
2.80(dt,J=8.5,5.9Hz,1H),2.96-3.08(m,1H),3.58(dd,J=10.4,2.2Hz,1H),
3.74(t,J=5.9Hz,2H),5.42(dd,J=15.1,8.8Hz,1H),
5.67(ddd,J=15.1,9.1,5.3Hz,1H)
IR(neat)cm-1;
3432,2930,2859,1739,1465,1402,1279,1180,1065,970,876,757,667
实施例5
(11S,16S)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1(化合物25)
使用实施例3得到的(11S,16S)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.17-2.09(m,25H),2.24-2.38(m,2H),
2.34(t,J=7.2Hz,2H),2.45-2.92(m,4H),3.52-3.64(m,1H),
3.55(dd,J=10.3,2.1Hz,1H),3.76(t,J=5.8Hz,2H),5.63-5.69(m,2H)
IR(neat)cm-1;
3400,2930,2859,1734,1465,1401,1281,1164,1046,1013,972,875,805,756,
666
实施例6
(11R,16S)-11,15-二脱氧-11-(3-羟基丙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物41)和(11S,16S)-11,15-二脱氧-11-(3-羟基丙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物42)
使用实施例3(1)得到的化合物,用3-巯基丙醇代替实施例1(5)中的2-巯基乙醇,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物41:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=7.0Hz,3H),1.22-2.46(m,28H),2.20(dd,J=18.4,11.2Hz,1H),
2.29(t,J=7.5Hz,2H),2.74(t,J=7.1Hz,2H),2.82(ddd,J=18.4,7.7,1.2Hz,1H),
2.91-3.04(m,1H),3.50-3.59(m,1H),3.65-3.80(m,2H),3.66(s,3H),
5.42(dd,J=15.2,8.9Hz,1H),5.63(ddd,J=15.2,9.6,5.1Hz,1H)
IR(neat)cm-1;
3454,2930,2859,1740,1734,1436,1363,1262,1174,1065,970,876,724
化合物42:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.23-2.90(m,32H),2.29(t,J=7.5Hz,2H),
3.49-3.58(m,2H),3.65-3.80(m,2H),3.66(s,3H),5.55-5.72(m,2H)
IR(neat)cm-1;
3453,2930,2859,1739,1734,1436,1363,1262,1201,1170,1066,973
实施例7
(11R,16S)-11,15-二脱氧-11-(3-羟基丙基硫)-16-羟基-17,17-三亚甲基-PGE1(化合物43)
使用实施例6得到的(11R,16S)-11,15-二脱氧-11-(3-羟基丙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.21-2.10(m,28H),2.20(dd,J=18.4,11.3Hz,1H),
2.23-2.44(m,1H),2.33(t,J=7.3Hz,2H),2.73(t,J=7.1Hz,2H),
2.82(ddd,J=18.4,7.8,0.9Hz,1H),2.91-3.04(m,1H),
3.56(dd,J=10.5,2.1Hz,1H),3.74(dt,J=0.8,6.0Hz,2H),
5.43(dd,J=15.1,8.9Hz,1H),5.65(ddd,J=15.1,9.3,5.4Hz,1H)
IR(neat)cm-1;
3432,2930,2859,1739,1465,1434,1402,1268,1182,1065,970,907,876,765,
666
实施例8
(11R,16S)-11,15-二脱氧-11-甲氧羰基甲基硫-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物45)和(11S,16S)-11,15-二脱氧-11-甲氧羰基甲基硫-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物46)
使用实施例3(1)得到的化合物,用巯基乙酸甲酯代替实施例1(5)中的2-巯基乙醇,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物45:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.20-2.44(m,25H),2.19(dd,J=18.5,11.1Hz,1H),
2.29(t,J=7.5Hz,2H),2.86(ddd,J=18.5,7.6,0.9Hz,1H),
3.16(dt,J=7.6,11.1Hz,1H),3.29(d,J=14.8Hz,1H),3.36(d,J=14.8Hz,1H),
3.49-3.58(m,1H),3.66(s,3H),3.75(s,3H),5.43(dd,J=15.2,8.7Hz,1H),
5.65(ddd,J=15.2,9.0,5.4Hz,1H)
IR(neat)cm-1;
3545,2930,2858,1740,1436,1279,1159,1009,970,876
化合物46:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.22-2.14(m,21H),2.11(d,J=3.4Hz,1H),
2.23-2.35(m,2H),2.29(t,J=7.5Hz,2H),2.43-2.54(m,1H),
2.64(dd,J=18.7,7.2Hz,1H),2.82-2.93(m,1H),3.22(d,J=14.8Hz,1H),
3.34(d,J=14.8Hz,1H),3.49-3.57(m,1H),3.65-3.79(m,1H),3.66(s,3H),
3.74(s,3H),5.55-5.73(m,2H)
IR(neat)cm-1;
3543,2930,2858,1739,1436,1281,1197,1160,1070,1010,974,876
实施例9
(11RS,16S)-11,15-二脱氧-11-[2-(N,N-二乙基氨基)乙基硫]-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物48)
使用实施例3(1)得到的化合物,用2-(N,N-二乙基氨基)乙硫醇代替实施例1(5)中的2-巯基乙醇,与实施例1(5)进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.02(t,J=7.2Hz,6H),1.20-3.64(m,37H),
2.29(t,J=7.5Hz,2H),3.66(s,3H),5.38-5.74(m,2H)
IR(neat)cm-1;
3523,2930,2858,1740,1456,1436,1375,1198,1173,1068,1030,970,876,785,
726
实施例10
(11R,16S)-11,15-二脱氧-11-丙基硫-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物50)和(11S,16S)-11,15-二脱氧-11-丙基硫-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物51)
使用实施例3(1)得到的化合物,用1-丙硫醇代替实施例1(5)中的2-巯基乙醇,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物50:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),0.98(t,J=7.3Hz,3H),1.20-2.42(m,26H),
2.17(d,J=2.8Hz,1H),2.20(dd,J=18.3,11.2Hz,1H),2.29(t,J=7.5Hz,2H),
2.53(dt,J=1.4,7.9Hz,2H),2.81(dd,J=18.3,7.6Hz,1H),
2.96(dt,J=7.6,11.2Hz,1H),3.48-3.57(m,1H),3.66(s,3H),
5.42(dd,J=14.8,9.0Hz,1H),5.62(ddd,J=14.8,9.0,5.4Hz,1H)
IR(neat)cm-1;
3535,2930,2859,1740,1456,1436,1376,1243,1173,1067,1029,970,876,724
化合物51:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),0.98(t,J=7.4Hz,3H),1.20-2.13(m,27H),
2.11(d,J=3.3Hz,1H),2.29(t,J=7.5Hz,2H),2.48(t,J=7.2Hz,2H),
2.59(dd,J=18.6,6.6Hz,1H),2.77-2.88(m,1H),3.47-3.56(m,1H),3.66(s,3H),
5.54-5.70(m,2H)
IR(neat)cm-1;
3523,2930,2859,1740,1456,1436,1376,1198,1170,1070,972,726
实施例11
(11R,16 S)-11,15-二脱氧-11-丙基硫-16-羟基-17,17-三亚甲基-PGE1(化合物52)
使用实施例10得到的(11R,16S)-11,15-二脱氧-11-丙基硫-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.7Hz,3H),0.98(t,J=7.3Hz,3H),1.20-2.13(m,26H),
2.20(dd,J=18.3,11.2Hz,1H),2.23-2.42(m,2H),2.34(t,J=7.5Hz,2H),
2.53(dt,J=1.4,7.3Hz,2H),2.81(dd,J=18.3,7.5Hz,1H),2.89-3.03(m,1H),
3.55(dd,J=9.9,2.2Hz,1H),5.43(dd,J=15.3,8.8Hz,1H),
5.63(ddd,J=15.3,8.5,5.1Hz,1H)
IR(neat)cm-1;
3467,2930,2859,1740,1708,1456,1402,1282,1239,1180,1067,1030,969,875,
724
实施例12
(11RS,16S)-11,15-二脱氧-11-乙酰基硫-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物53)
使用实施例3(1)得到的化合物,用硫代乙酸代替实施例1(5)中的2-巯基乙醇,与实施例1(5)进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.20-2.50(m,26H),2.13(dd,J=18.9,11.4Hz,1H),
2.29(t,J=7.5Hz,2H),2.34(s,3H),2.84-3.00(m,1H),3.46-3.56(m,1H),
3.59-3.74(m,1H),3.66(s,3H),5.40(dd,J=15.3,8.9Hz,1H),
5.63(ddd,J=15.3,8.6,5.8Hz,1H)
IR(neat)cm-1;
3544,2930,2858,1741,1692,1435,1384,1355,1171,1126,969,631
实施例13
(11R,16S)-11,15-二脱氧-11-[(2R)-2-甲氧羰基-2-氨基乙基硫]-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物54)和(11S,16S)-11,15-二脱氧-11-[(2R)-2-甲氧羰基-2-氨基乙基硫]-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物55)
使用实施例3(1)得到的化合物,用L-半胱氨酸甲酯代替实施例1(5)中的2-巯基乙醇,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物54:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.18-2.06(m,25H),2.14(dd,J=18.5,11.5Hz,1H),
2.22-2.43(m,2H),2.29(t,J=7.5Hz,2H),2.75-2.87(m,1H),2.91-3.08(m,3H),
3.53(dd,J=10.4,2.0Hz,1H),3.66(s,3H),3.67(dd,J=6.5,4.9Hz,1H),
3.75(s,3H),5.34-5.45(m,1H),5.59-5.72(m,1H)
IR(neat)cm-1;
3368,2930,2858,1740,1594,1436,1198,1174,1071,1011,970,876
化合物55:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.20-2.07(m,25H),2.24-2.34(m,2H),
2.29(t,J=7.5Hz,2H),2.44-2.55(m,1H),2.61(dd,J=18.8,7.2Hz,1H),
2.77-2.88(m,1H),2.84(dd,J=13.2,7.1Hz,1H),2.96(dd,J=13.2,5.2Hz,1H),
3.48-3.70(m,2H),3.66(s,3H),3.76(s,3H),5.57-5.71(m,2H)
IR(neat)cm-1;
3377,2930,2858,1739,1436,1198,1174,1071,1101,973
实施例14
(11RS,16S)-11,15-二脱氧-11-(3-硝基苯基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物56)
使用实施例3(1)得到的化合物,用3-硝基苯硫醇代替实施例1(5)中的2-巯基乙醇,与实施例1(5)进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.18-2.16(m,23H),2.19-2.36(m,1H),
2.26(dd,J=18.7,10.7Hz,1H),2.30(t,J=7.4Hz,2H),2.44-2.58(m,1H),
2.98(dd,J=18.7,7.6Hz,1H),3.50-3.69(m,2H),3.67(s,3H),
5.48(dd,J=15.0,9.6Hz,1H),5.66-5.80(m,1H),7.32-7.66(m,2H),
8.08-8.24(m,2H)
IR(neat)cm-1;
3523,2930,1740,1577,1514,1436,1338,1091,852,742
实施例15
(11R,16S)-11,15-二脱氧-11-(4-甲氧苄基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物57)和(11S,16S)-11,15-二脱氧-11-(4-甲氧苄基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物58)
使用实施例3(1)得到的化合物,用4-甲氧基-α-甲苯硫醇代替实施例1(5)中的2-巯基乙醇,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物57:
1H-NMR(CDCl3,300MHz)δppm;
0.95(t,J=6.9Hz,3H),1.16-2.17(m,23H),2.10(dd,J=18.7,11.3Hz,1H),
2.12(d,J=2.8Hz,1H),2.22-2.41(m,2H),2.28(t,J=7.5Hz,1H),2.54-2.66(m,1H),
2.81(dt,J=7.5,11.3Hz,1H),3.48-3.57(m,1H),3.66(s,3H),3.74(s,2H),
3.80(s,3H),5.33(dd,J=15.2,9.4Hz,1H),5.58(ddd,J=15.2,9.2,5.4Hz,1H),
6.80-6.87(m,2H),7.18-7.25(m,2H)
IR(neat)cm-1:
3535,2930,2858,1739,1610,1584,1510,1465,1438,1362,1301,1250,1174,
1098,1067,1034,970,877,831,745,675,546,517
化合物58:
1H-NMR(CDCl3,300MHz)δppm;
0.95(t,J=6.9Hz,3H),1.18-2.16(m,21H),2.12(d,J=3.3Hz,1H),
2.20-2.34(m,2H),2.29(t,J=7.5Hz,21H),2.38-2.55(m,2H),2.72-2.83(m,1H),
3.28-3.38(m,1H),3.45-3.54(m,1H),3.64(d,J=13.4Hz,1H),
3.73(d,J=13.4Hz,1H),3.66(s,3H),3.80(s,3H),5.49-5.67(m,2H),
6.80-6.88(m,2H),7.17-7.24(m,2H)
IR(neat)cm-1;
3523,2930,2858,1739,1610,1584,1510,1465,1438,1362,1301,1250,1174,
1107,1070,1034,973,832,735
实施例16
(11R,16S)-11,15-二脱氧-11-(4-甲氧苄基硫)-16-羟基-17,17-三亚甲基-PGE1(化合物59)
使用实施例15得到的(11R,16S)-11,15-二脱氧-11-(4-甲氧苄基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物57),与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.95(t,J=6.8Hz,3H),1.21-2.13(m,25H),2.11(dd,J=18.6,11.1Hz,1H),
2.22-2.41(m,1H),2.33(t,J=7.5Hz,2H),2.54-2.66(m,1H),2.75-2.87(m,1H),
3.54(dd,J=10.3,2.3Hz,1H),3.74(s,2H),3.80(s,3H),5.28-5.40(m,1H),
5.51-5.64(m,1H),6.80-6.88(m,2H),7.17-7.27(m,2H)
IR(neat)cm-1;
3467,2930,2858,1739,1708,1610,1584,1510,1465,1440,1301,1249,1175,
1067,1034,970,875,831,745,675,516
实施例17
(11R,16R)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物64)和(11S,16R)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGR1甲酯(化合物65)
(1)用5-甲氧羰基-4-氧杂戊基碘化锌(II)代替实施例1(2)中的5-甲氧羰基戊基碘化锌(II),与实施例1(2)进行实际上相同的操作,得到(16RS)-3-氧杂-15脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯11,16-双(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl3,200MHz)δppm;
0.01-0.08(m,12H),0.78-0.98(m,3H),0.88(s,9H),0.91(s,9/2H),0.92(s,9/2H),
1.15-2.25(m,19H),2.16(dd,J=18.1,8.0Hz,1H),2.32-2.50(m,1H),
2.60(ddd,J=18.1,7.0,1.0Hz,1H),3.43-3.65(m,1H),3.50(t,J=6.5Hz,2H),
3.75(s,3H),3.91-4.08(m,1H),4.06(s,2H),5.21-5.38(m,1H),5.51-5.73(m,1H)
IR(neat)cm-1;
2955,2930,2857,1745,1472,1463,1436,1406,1361,1256,1207,1142,1099,
1006,972,938,881,836,811,775,705,669,577
(2)使用(1)得到的化合物,与实施例1(3)进行实际上相同的操作,得到下述化合物。
(16R)-3-氧杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.23-2.43(m,22H),2.24(dd,J=18.5,9.6Hz,1H),
2.75(ddd,J=18.5,7.4,1.3Hz,1H),3.47-3.64(m,1H),3.52(t,J=6.1Hz,2H),
3.75(s,3H),3.99-4.17(m,1H),4.07(s,2H),5.49(dd,J=15.1,8.5Hz,1H),
5.75(ddd,J=15.1,8.3,6.1Hz,1H)
IR(neat)cm-1;
3435,2953,2869,1741,1438,1282,1214,1139,1075,1032,973,882,706,579
(16S)-3-氧杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.95(t,J=6.9Hz,3H),1.28-2.44(m,21H),2.22(dd,J=18.5,9.6Hz,1H),
2.67-2.85(br,1H),2.73(dd,J=18.5,8.0Hz,1H),3.51(t,J=6.3Hz,2H),
3.57(dd,J=10.3,2.3Hz,1H),3.75(s,3H),3.97-4.10(m,1H),4.07(s,2H),
5.44(dd,J=15.1,8.4Hz,1H),5.73(ddd,J=15.1,8.4,6.2Hz,1H)
IR(neat)cm-1;
3400,2952,2869,1740,1437,1348,1282,1213,1140,1074,1032,969,881,706,
579
(3)使用(2)得到的(16R)-3-氧杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例1(4)进行实际上相同的操作,得到(16R)-3-氧杂-15-脱氧-16-羟基-17,17-三亚甲基-PGA1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.90-0.98(m,3H),1.23-2.29(m,18H),3.23-3.30(m,1H),3.48-3.59(m,1H),
3.53(t,J=6.3Hz,2H),3.75(s,3H),4.08(s,2H),5.43-5.55(m,1H),
5.58-5.74(m,1H),6.15(dd,J=5.6,2.0Hz,1H),7.48(dd,J=5.6Hz,2.4Hz,1H)
IR(neat)cm-1;
3501,2933,2869,1755,1703,1587,1456,1437,1397,1351,1281,1211,1140,
1068,1031,972,886,802,741,706,580
(4)使用(3)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物64:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=7.0Hz,3H),1.22-2.46(m,22H),2.20(dd,J=18.7,11.2Hz,1H),
2.73-2.89(m,3H),2.96-3.09(m,1H),3.47-3.62(m,1H),3.51(t,J=6.2Hz,2H),
3.68-3.79(m,2H),3.75(s,3H),4.07(s,2H),5.42-5.53(m,1H),5.67-5.80(m,1H)
IR(neat)cm-1;
3459,2952,2869,1740,1437,1401,1283,1214,1138,1047,972,885,706
化合物65:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.23-2.92(m,26H),3.47-3.62(m,2H),
3.51(t,J=6.2Hz,2H),3.69-3.80(m,2H),3.75(s,3H),4.07(s,2H),
5.55-5.77(m,2H)
IR(neat)cm-1;
3459,2930,2869,1740,1436,1400,1283,1214,1138,1048,975,885,706,580
实施例18
(11R,16R)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1(化合物66)
使用实施例17得到的(11R,16R)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.22-2.47(m,20H),2.21(dd,J=18.5,11.2Hz,1H),
2.72-3.78(m,7H),3.55(t,J=5.5Hz,2H),3.66(dd,J=10.0,2.4Hz,1H),
3.74(t,J=6.0Hz,2H),4.06(s,2H),5.41-5.52(m,1H),5.62-5.79(m,1H)
IR(neat)cm-1;
3437,2930,2870,1739,1455,1430,1402,1279,1223,1134,1048,970,876,755,
675
实施例19
(11R,16S)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物67)和(11S,16S)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物68)
(1)使用实施例17(2)得到的(16S)-3-氧杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例1(4)进行实际上相同的操作,得到(16S)-3-氧杂-15脱氧-16-羟基-17,17-三亚甲基-PGA1甲酯。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.23-2.28(m,20H),3.22-3.30(m,1H),3.48-3.58(m,1H),
3.53(t,J=6.3Hz,2H),3.75(s,3H),4.08(s2H),5.48(dd,J=15.4,8.1Hz,1H),
5.63-5.76(m,1H),6.15(dd,J=5.7,2.1Hz,1H),7.48(dd,J=5.7Hz,2.4Hz,1H)
IR(neat)cm-1;
3498,2933,2869,1755,1706,1587,1437,1384,1350,1281,1210,1140,1068,
1031,973,886,809,705,579
(2)使用(1)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物67:
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.8Hz,3H),1.21-2.48(m,21H),2.20(dd,J=18.5,11.2Hz,1H),
2.52-3.11(m,5H),3.45-3.64(m,1H),3.51(t,J=6.3Hz,2H),3.67-3.86(m,2H),
3.75(s,3H),4.07(s,2H),5.42(dd,J=15.2,9.1Hz,1H),
5.68(ddd,J=15.2,9.2,5.2Hz,1H)
IR(neat)cm-1;
3467,2952,2869,1740,1437,1401,1384,1282,1213,1138,1048,971,876,741
化合物68:
1H-NMR(CDCl3,200MHz)δppm;
0.87-1.00(m,3H),1.21-2.95(m,26H),3.43-3.66(m,1H),3.54(t,J=6.3Hz,2H),
3.67-3.83(m,2H),3.76(s,3H),3.85-3.98(m,1H),4.07(s,2H),5.55-5.77(m,2H)
IR(neat)cm-1;
3453,2930,2869,1740,1437,1399,1282,1214,1139,1048,974,885,706,580
实施例20
(11R,16S)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1(化合物69)
使用实施例19得到的(11R,16S)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.22-3.43(m,27H),2.21(dd,J=18.7,11.3Hz,1H),
3.52-3.63(m,1H),3.56(t,J=5.8Hz,2H),3.74(t,J=5.9Hz,2H),4.01-4.15(m,2H),
5.38-5.51(m,1H),5.63-5.75(m,1H)
IR(neat)cm-1;
3443,2930,2870,1739,1455,1430,1402,1278,1223,1135,1049,970,876,756,
667,577
实施例21
(11R,16S)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-四亚甲基-PGE1甲酯(化合物70)和(11S,16S)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-四亚甲基-PGE1甲酯(化合物71)
(1)使用(1E,4RS)-1-碘-4-(叔丁基二甲基甲硅烷氧基)-5,5-四亚甲基-1-辛烯代替实施例(1)中的(1E,4RS)-1-碘-4-(叔丁基二甲基甲硅烷氧基)-5,5-三亚甲基-1-辛烯,与实施例1(1)进行实际上相同的操作,得到(3R,4R)-2-亚甲基-3-[(1E,4RS)-4-叔丁基二甲基甲硅烷氧基-5,5-四亚甲基辛-1-烯基]-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮。
1H-NMR(CDCl3,200MHz)δppm;
0.04(s,9H),0.05(s, 9H),0.79-1.72(m,15H),0.88(s,9H),0.89(s,9H),
2.15-2.47(m,3H),2.56-2.72(m,1H),3.19-3.33(m,1H),3.50-3.64(m,1H),
3.98-4.14(m,1H),5.21-5.37(m,2H),5.63-5.85(m,1H),6.06-6.14(m,1H)
IR(neat)cm-1;
2955,2930,2858,1734,1641,1472,1463,1387,1361,1255,1190,1087,1006,972,
939,880,836,812,774,669
(2)使用(1)得到的化合物,用5-甲氧羰基-4-氧杂戊基碘化锌(II)代替实施例1(2)中的5-甲氧羰基戊基碘化锌(II),与实施例1(2)进行实际上相同的操作,得到(16RS)-3-氧杂-15脱氧-16-羟基-17,17-四亚甲基-PGE1甲酯11,16-双(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl3,200MHz)δppm;
0.03(s,3H),0.04(s,6H),0.06(s,3H),0.78-1.72(m,21H),0.88(s,9H),
0.89(s,9H),1.86-2.04(m,1H),2.06-2.51(m,3H),2.17(dd,J=18.2,8.1Hz,1H),
2.61(ddd,J=18.2,6.9,1.2Hz,1H),3.42-3.65(m,3H),3.75(s,3H),
3.92-4.13(m,1H),4.07(s,2H),5.22-5.39(m,1H),5.61-5.80(m,1H)
IR(neat)cm-1;
2954,2930,2858,1745,1472,1462,1438,1361,1255,1207,1142,1099,1006,973,
938,881,837,812,775,669
(3)使用(2)得到的化合物,与实施例1(3)进行实际上相同的操作,得到下述化合物。
(16R)-3-氧杂-15-脱氧-16-羟基-17,17-四亚甲基烷-PGE1甲酯
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.90(t,J=6.8Hz,3H),1.20-1.76(m,18H),1.96-2.14(m,2H),
2.23(dd,J=18.3,9.6Hz,1H),2.30-2.45(m,2H),2.74(dd,J=18.3,7.5Hz,1H),
3.46-3.57(m,1H),3.51(t,J=6.2Hz,2H),3.75(s,3H),3.98-4.17(m,1H),
4.07(s,2H),5.48(dd,J=15.4,8.7Hz,1H),5.71(ddd,J=15.4,7.9,5.5Hz,1H)
IR(neat)cm-1;
3436,2952,2869,1740,1455,1439,1283,1213,1138,1075,974,883,706,579,
429
(16S)-3-氧杂-15-脱氧-16-羟基-17,17-四亚甲基-PGE1甲酯
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.91(t,J=6.8Hz,3H),1.20-1.73(m,18H),1.93-2.13(m,2H),
2.22(dd,J=18.4,9.9Hz,1H),2.30-2.43(m,2H),
2.72(ddd,J=18.4,7.5,1.2Hz,1H),3.46-3.54(m,1H),3.51(t,J=6.4Hz,2H),
3.75(s,3H),3.97-4.17(m,1H),4.07(s,2H),5.42(dd,J=15.3,8.5Hz,1H),
5.71(ddd,J=15.3,8.8,5.7Hz,1H)
IR(neat)cm-1;
3400,2952,2869,1742,1438,1282,1211,1140,1073,967,883,705,579
(4)使用(3)得到的(16S)-3-氧杂-15-脱氧-16-羟基-17,17-四亚甲基-PGE1甲酯,与实施例1(4)进行实际上相同的操作,得到(16S)-3-氧杂-15-脱氧-16-羟基-17,17-四亚甲基-PGA1甲酯
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.89(t,J=6.8Hz,3H),1.19-1.90(m,18H),1.96-2.13(m,2H),
2.29(dd,J=14.6,6.4Hz,1H),3.22-3.30(m,1H),3.46(dd,J=10.4,2.2Hz,1H),
3.53(t,J=6.4Hz,2H),3.75(s,3H),4.07(s,2H),5.47(dd,J=15.4,8.3Hz,1H),
5.70(dt,J=15.4,7.1Hz,1H),6.14(dd,J=5.7,2.0Hz,1H),
7.48(dd,J=5.7,2.6Hz,1H)
IR(neat)cm-1;
3519,2951,2869,1756,1704,1587,1455,1438,1376,1350,1281,1210,1141,
1062,974,885,809,742,706,579
(5)使用(4)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物70:
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.90(t,J=6.8Hz,3H),1.20-1.71(m,18H),1.95-2.11(m,1H),
2.20(dd,J=18.6,11.3Hz,1H),2.30-2.44(m,2H),2.69-2.90(m,4H),
2.95-3.09(m,1H),3.41-3.56(m,1H),3.51(t,J=6.3Hz,2H),3.72(t,J=6.0Hz,2H),
3.75(s,3H),4.07(s,2H),5.41(dd,J=15.2,9.4Hz,1H),
5.66(ddd,J=15.2,9.5,5.2Hz,1H)
IR(neat)cm-1;
3464,2952,2869,1740,1438,1401,1283,1212,1139,1046,971,882,706
化合物71:
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.90(t,J=6.9Hz,3H),1.19-1.69(m,18H),1.96-2.10(m,1H),2.24-2.93(m,7H),
3.46(dd,J=11.0,2.0Hz,1H),3.51(t,J=6.4Hz,2H),3.55-3.64(m,1H),
3.74(t,J=5.8Hz,2H),3.75(s,3H),4.07(s,2H),5.57-5.73(m,2H)
IR(neat)cm-1;
3436,2951,2869,1740,1438,1400,1282,1214,1139,1046,976,705,579
实施例22
(11R,16S)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-四亚甲基-PGE1(化合物72)
使用实施例21得到的(11R,16S)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-四亚甲基-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.90(t,J=6.9Hz,3H),1.18-1.70(m,21H),1.98-2.13(m,1H),
2.20(dd,J=18.4,11.3Hz,1H),2.31-2.46(m,2H),2.70-2.92(m,4H),
2.94-3.08(m,1H),3.47-3.61(m,1H),3.56(t,J=5.4Hz,2H),3.74(t,J=5.8Hz,2H),
4.07(s,2H),5.43(dd,J=14.8,8.9Hz,1H),5.60-5.76(m,1H)
IR(neat)cm-1;
3453,2952,2869,1739,1455,1430,1402,1223,1135,1046,970,880,756,676
实施例23
(11R,16R)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-四亚甲基-PGE1甲酯(化合物73)和(11S,16R)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-四亚甲基-PGE1甲酯(化合物74)
(1)使用实施例21(3)得到的(16R)-3-氧杂-15-脱氧-16-羟基-17,17-四亚甲基-PGE1甲酯,与实施例1(4)进行实际上相同的操作,得到(16R)-3-氧杂-15-脱氧-16-羟基-17,17-四亚甲基-PGA1甲酯。
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.89(t,J=6.8Hz,3H),1.18-1.92(m,18H),1.97-2.13(m,2H),
2.30(dd,J=14.1,5.4Hz,1H),3.22-3.30(m,1H),3.46(dd,J=10.4,1.9Hz,1H),
3.53(t,J=6.2Hz,2H),3.76(s,3H),4.08(s,2H),5.49(dd,J=15.3,8.0Hz,1H),
5.66(ddd,J=15.3,7.8,5.9Hz,1H),6.15(dd,J=5.7,1.9Hz,1H),
7.48(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3497,2952,2868,1755,1702,1587,1546,1438,1384,1350,1281,1210,1139,
1062,972,884,806,705
(2)使用(1)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物73:
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.90(t,J=6.8Hz,3H),1.18-1.70(m,18H),1.98-2.16(m,2H),
2.20(dd,J=18.5,11.2Hz,1H),2.27-2.46(m,2H),2.72-2.89(m,3H),
2.96-3.09(m,1H),3.47-3.56(m,1H),3.51(t,J=6.2Hz,2H),3.72(t,J=6.0Hz,2H),
3.75(s,3H),4.07(s,2H),5.47(dd,J=15.2,8.6Hz,1H),
5.75(ddd,J=15.2,8.1,5.8Hz,1H)
IR(neat)cm-1;
3459,2952,2869,1740,1455,1438,1401,1283,1213,1138,1046,974,884,706
化合物74:
1H-NMR(CDCl3+D2O,300MHz)δppm;
0.90(t,J=6.8Hz,3H),1.19-1.69(m,18H),2.00-2.14(m,1H),2.30-2.43(m,2H),
2.49-2.93(m,4H),2.74(dt,J=4.2,5.9Hz,1H),3.44-3.55(m,1H),
3.51(t,J=6.2Hz,2H),3.56-3.63(m,1H),3.74(t,J=5.9Hz,2H),3.75(s,3H),
4.07(s,2H),5.62(ddd,J=15.5,7.8,5.1Hz,1H),5.72(dd,J=15.5,6.7Hz,1H)
IR(neat)cm-1;
3453,2951,2869,1740,1455,1438,1400,1282,1214,1138,1046,977,884,706,
580
实施例24
(11R,16R)3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-四亚甲基-PGE1(化合物75)
使用实施例23得到的(11R,16R)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-四亚甲基-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.90(t,J=6.9Hz,3H),1.18-1.72(m,21H),1.98-2.18(m,1H),
2.21(dd,J=18.6,11.3Hz,1H),2.29-2.47(m,2H),2.72-2.93(m,2H),
2.80(dt,J=1.9,6.OHz,2H),2.95-3.08(m,1H),3.54(t,J=5.6Hz,2H),
3.59(dd,J=10.6,1.9Hz,1H),3.74(t,J=6.0Hz,2H),4.06(s,2H),
5.46(dd,J=15.3,9.2Hz,1H),5.73(ddd,J=15.3,8.5,5.6Hz,1H)
IR(neat)cm-1;
3435,2951,2869,1739,1455,1402,1281,1223,1133,1046,969,881,676
实施例25
(11R,16RS)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-13,14-二脱氢-PGE1甲酯(化合物85)和(11S,16RS)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-13,14-二脱氢-PGE1甲酯(化合物86)
(1)在氩气流下,在0℃,向(4RS)-4-(叔丁基二甲基甲硅烷氧基)-5,5-三亚甲基-1-辛炔(1.09)的甲苯(12ml)溶液中,加入正丁基锂(2.5M、己烷溶液、1.44ml),在室温搅拌30分钟。在0℃向该溶液中,加入二乙基氯化铝(0.95M、己烷溶液、4.42ml),在室温搅拌30分钟。在0℃向该溶液中滴加入(4R)-2-(N,N-二乙基氨基)甲基-4-(叔丁基二甲基甲硅烷基)环戊-2-烯-1-酮(0.25M、甲苯溶液、12.0ml),在室温搅拌20分钟。搅拌的同时将反应液注入己烷(32ml)-饱和氯化铵水溶液(32ml)-盐酸(3M)(9ml)的混合液中,分离有机层,水层用己烷(150ml)萃取。合并所得有机层,用饱和碳酸氢钠水溶液和饱和食盐水洗净后,用无水硫酸镁干燥,过滤。减压浓缩滤液,所得粗产物用硅胶柱色谱纯化(展开溶剂:己烷∶乙酸乙酯=49∶1),得到(3R,4R)-2-亚甲基-3-[(4RS)-4-叔丁基二甲基甲硅烷氧基-5,5-三亚甲基辛-1-炔基]-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮(620mg)。
1H-NMR(CDCl3,300MHz)δppm;
0.08(s,3H),0.10(s,3H),0.11(s,3H),0.13(s,3H),0.80-0.98(m,3H),
0.89(s,9H),0.90(s,9H),1.20-2.39(m,12H),2.31(dd,J=18.0,7.1Hz,1H),
2.70(dd,J=18.0,6.2Hz,1H),3.42-3.50(m,1H),3.71(t,J=5.0Hz,1H),
4.21-4.30(m,1H),5.53(d,J=2.7Hz,1H),6.12(d,J=2.9Hz,1H)
IR(CHCl3)cm-1;
2956,2931,2895,2858,2218,1735,1713,1622,1472,1464,1362,1256,1094,
1006,931,837,776,671
(2)使用(1)得到的化合物代替实施例1(2)中的(3R,4R)-2-亚甲基-3-[(1E,4RS)-4-叔丁基二甲基甲硅烷氧基-5,5-三亚甲基辛-1-烯基]-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮,与实施例1(2)进行实际上相同的操作,得到(16RS)-15-脱氧-16-羟基-17,17-三亚甲基-13,14-二脱氢-PGE1甲酯11,16-双(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl3,200MHz)δppm;
0.08(s,3H),0.09(s,3H),0.12(s,3H),0.13(s,3H),0.81-1.01(m,3H),0.90(s,9H),
0.91(s,9H),1.18-2.41(m,23H),2.15(dd,J=18.1,6.7Hz,1H),
2.30(t,J=7.5Hz,2H),2.56-2.76(m,2H),3.65-3.77(m,1H),3.67(s,3H),
4.19-4.36(m,1H)
IR(neat)cm-1;
2954,2931,2858,1747,1471,1464,1436,1362,1255,1165,1098,1007,938,838,
777,670
(3)使用(2)得到的化合物,与实施例1(3)进行实际上相同的操作,得到(16RS)-15-脱氧-16-羟基-17,17-三亚甲基-13,14-二脱氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=7.0Hz,3H),1.23-2.45(m,25H),2.22(dd,J=18.4,9.2Hz,1H),
2.31(t,J=7.5Hz,2H),2.56-2.67(m,1H),2.75(ddd,J=18.4,7.3,1.2Hz,1H),
3.67(s,3H),3.69(dd,J=9.0,3.4Hz,1H),4.25-4.36(m,1H)
IR(neat)cm-1;
3435,2932,2860,2237,1741,1437,1362,1321,1201,1168,1104,1076,931,848,
726
(4)使用(3)得到的化合物,与实施例1(4)进行实际上相同的操作,得到(16RS)-15-脱氧-16-羟基-17,17-三亚甲基-13,14-二脱氢-PGA1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.93(t,J=7.0Hz,3H),1.22-2.43(m,23H),2.23(ddd,J=16.6,9.0,2.3Hz,1H),
2.31(t,J=7.4Hz,2H),3.36-3.43(m,1H),3.59-3.70(m,1H),3.67(s,3H),
6.16(dd,J=5.6,2.3Hz,1H),7.47(dd,J=5.6,2.4Hz,1H)
IR(neat)cm-1;
3468,2932,2859,2242,1736,1712,1590,1437,1346,1198,1174,1073,885
(5)使用(4)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物85:
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=7.0Hz,3H),1.21-2.44(m,24H),2.30(t,J=7.5Hz,2H),
2.55-2.97(m,4H),2.86(dt,J=13.9,6.1Hz,1H),3.10(dt,J=13.9,6.2Hz,1/2H),
3.11(dt,J=13.9,6.3Hz,1/2H),3.18-3.36(m,1H),3.56-3.75(m,1H),3.67(s,3H),
3.78-3.89(m,2H)
IR(neat)cm-1;
3435,2930,2859,2242,1740,1437,1352,1202,1170,1045,725
化合物86:
1H-NMR(CDCl3,300MHz)δppm;
0.93(t,J=7.0Hz,3H),1.20-2.64(m,26H),2.30(t,J=7.4Hz,2H),
2.80(dt,J=13.8,5.6Hz,1/2H),2.81(dt,J=13.8,5.6Hz,1/2H),2.86-2.98(m,2H),
3.02-3.12(m,1H),3.60-3.74(m,1H),3.67(s,3H),3.70(dt,J=9.7,3.2Hz,1H),
3.76-3.86(m,2H)
IR(neat)cm-1;
3464,2931,2860,2242,1740,1436,1277,1202,11 69,1070,847,726
实施例26
(11R,16RS)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-13,14-二脱氢-PGE1(化合物87)
使用实施例25得到的(11R,16RS)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-13,14-二脱氢-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=7.0Hz,3H),1.21-2.44(m,26H),2.11(ddd,J=18.9,11.7,2.3Hz,1H),
2.35(t,J=7.3Hz,2H),2.56-2.69(m,1H),2.73-2.92(m,2H),3.04-3.16(m,1H),
3.21-3.36(m,1H),3.72(ddd,J=9.7,6.9,3.0Hz,1H),3.80-3.88(m,2H)
IR(neat)cm-1;
3414,2931,2860,2242,1741,1465,1402,1348,1280,1216,1045,932,757,
666
实施例27
(11S,16RS)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-13,14-二脱氢-PGE1(化合物88)
使用实施例25得到的(11S,16RS)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-13,14-二脱氢-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.93(t,J=7.0Hz,3H),1.22-2.65(m,28H),2.35(t,J=7.3Hz,2H),
2.77-2.99(m,2H),3.03-3.14(m,1H),3.60-3.71(m,1H),
3.71(dd,J=9.6,3.2Hz,1H),3.78-3.85(m,2H)
IR(neat)cm-1;
3436,2932,2860,2237,1739,1465,1402,1281,1227,1165,1069,932,726
实施例28
(11R,16RS)-3-氧杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-四亚甲基-13,14-二脱氢-PGE1甲酯(化合物98)
(1)用(4RS)-4-(叔丁基二甲基甲硅烷氧基)-5,5-四亚甲基-1-辛炔代替实施例25(1)中的(4RS)-4-(叔丁基二甲基甲硅烷氧基)-5,5-三亚甲基-1-辛炔,与实施例25(1)进行实际上相同的操作,得到(3R,4R)-2-亚甲基-3-[(4RS)-4-叔丁基二甲基甲硅烷氧基-5,5-四亚甲基辛-1-炔基]-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮。
1H-NMR(CDCl3,200MHz)δppm;
0.04-0.16(m,12H),0.81-0.99(m,3H),0.89(s,9H),0.90(s,9H),
1.16-1.75(m,12H),2.20-2.40(m,1H),2.32(dd,J=18.0,7.1Hz,1H),
2.51(ddd,J=17.2,4.7,2.6Hz,1H),2.71(dd,J=18.0,6.4Hz,1H),
3.43-3.58(m,1H),3.67(t,J=4.8Hz,2H),4.20-4.35(m,1H),5.54(d,J=2.6Hz,1H),
6.13(d,J=3.1Hz,1H)
IR(neat)cm-1;
2955,2930,2858,2235,1736,1646,1472,1463,1387,1361,1283,1252,1221,
1186,1121,1089,1006,940,919,837,776,670,525
(2)分别用(1)得到的化合物代替实施例1(2)中的(3R,4R)-2-亚甲基-3-[(1E,4RS)-4-叔丁基二甲基甲硅烷氧基-5,5-三亚甲基辛-1-烯基]-4-(叔丁基二甲基甲硅烷氧基)环戊烷-1-酮,用5-甲氧基羰基-4-氧杂戊基碘化锌(II)代替5-甲氧基羰基戊基碘化锌(II),与实施例1(2)进行实际上相同的操作,得到(16RS)-3-氧杂-15-脱氧-16-羟基-17,17-四亚甲基-13,14-二脱氢-PGE1甲酯11,16-双(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl3,200MHz)δppm;
0.07(s,3H),0.09(s,3H),0.12(s,6H),0.86-0.96(m,3H),0.89(s,18H),
1.15-1.79(m,18H),2.06-2.78(m,5H),2.16(dd,J=18.0,6.4Hz,1H),
3.52(t,J=6.5Hz,2H),3.65(t,J=4.9Hz,1H),3.76(s,3H),4.07(s,2H),
4.21-4.35(m,1H)
IR(neat)cm-1;
2954,2930,2858,1746,1472,1463,1438,1406,1375,1361,1252,1206,1141,
1094,1006,920,885,837,811,776,670,577
(3)使用(2)得到的化合物,与实施例1(3)进行实际上相同的操作,得到(16RS)-3-氧杂-15-脱氧-16-羟基-17,17-四亚甲基-13,14-二脱氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.90(t,J=6.8Hz,3H),1.14-1.89(m,18H),2.16-2.50(m,4H),
2.23(dd,J=18.6,9.0Hz,1H),2.58-2.74(m,2H),
2.74(ddd,J=18.6,7.0,1.2Hz,1H),3.54(t,J=6.1Hz,2H),3.60-3.69(m,1H),
3.76(s,3H),4.08(s,2H),4.25-4.37(m,1H)
IR(neat)cm-1;
3435,2952,2869,1745,1455,1439,1283,1214,1139,1080,772,706,580
(4)使用(3)得到的化合物,与实施例1(4)进行实际上相同的操作,得到(16RS)-3-氧杂-15-脱氧-16-羟基-17,17-四亚甲基-13,14-二脱氢-PGA1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.85-0.95(m,3H),1.18-2.80(m,23H),3.40-3.60(m,2H),3.73-3.77(m,1H),
3.75(s,3H),4.02-4.10(m,2H),5.85(d,J=5.9Hz,1H),7.78(d,J=5.3Hz,1H)
IR(neat)cm-1;
3468,2952,2869,2217,1755,1698,1610,1519,1438,1383,1286,1209,1138,
1060,706
(5)使用(4)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物98:
1H-NMR(CDCl3,200MHz)δppm;
0.75-3.02(m,30H),3.20-3.34(m,1H),3.41-3.88(m,6H),3.75(s,3H),
4.08(s,2H)
IR(neat)cm-1;
3466,2952,2869,1742,1660,1445,1439,1399,1352,1284,1212,1138,1048,943,
756,706,579
实施例29
(2E,11R,16R)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1甲酯(化合物29)和(2E,11S,16R)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1甲酯(化合物30)
(1)用(4E)-5-甲氧基羰基-4-戊烯基碘化锌(II)代替5-甲氧基羰基戊基碘化锌(II),与实施例1(2)进行实际上相同的操作,得到(2E,16RS)-15脱氧-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1甲酯11,16-双(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl3,200MHz)δppm;
0.04(s,3H),0.05(s,3H),0.06(2s,6H),0.81-0.98(m,3H),0.88(s,9H),
0.91 and 0.92(2s,9H),1.14-2.69(m,24H),3.50-3.63(m,1H),3.73(s,3H),
3.90-4.09(m,1H),5.21-5.37(m,1H),5.51-5.89(m,2H),
6.95(dt,J=15.8,6.8Hz,1H)
IR(neat)cm-1;
2955,2930,2857,1746,1728,1659,1472,1464,1436,1361,1257,1155,1095,
1006,974,939,837,775,670
(2)使用(1)得到的化合物,与实施例1(3)进行实际上相同的操作,得到下述化合物。
(2E,16R)-15-脱氧-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.95(t,J=6.8Hz,3H),1.23-2.43(m,25H),2.69-2.81(m,1H),3.54-3.63(m,1H),
3.73(s,3H),4.01-4.17(m,1H),5.40-5.54(m,1H),5.67-5.82(m,1H),
5.82(dt,J=15.7,1.6Hz,1H),6.95(d t,J=15.7,7.0Hz,1H)
IR(neat)cm-1;
3432,2930,2860,1740,1734,1654,1436,1274,1202,1175,1076,974,860,720
(2E,16S)-15-脱氧-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.95(t,J=7.0Hz,3H),1.22-2.42(m,24H),2.22(dd,J=18.3,9.6Hz,1H),
2.74(ddd,J=18.3,7.6,1.1Hz,1H),3.57(dd,J=10.1,2.3Hz,1H),3.72(s,3H),
3.98-4.10(m,1H),5.38-5.49(m,1H),5.66-5.81(m,1H),
5.81(dt,J=15.6,1.6Hz,1H),6.94(dt,J=15.6,7.0Hz,1H)
IR(neat)cm-1;
3400,2930,2860,1740,1728,1436,1273,1202,1158,1072,969,876,720
(3)使用(2)得到的(2E,16R)-15-脱氧-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1甲酯,与实施例1(4)进行实际上相同的操作,得到(2E,16R)-15-脱氧-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGA1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.9Hz,3H),1.16-2.32(m,22H),3.15-3.30(m,1H),
3.55(dd,J=9.8,2.7Hz,1H),3.73(s,3H),5.49(dd,J=15.4,7.5Hz,1H),
5.66(ddd,J=15.4,7.0,5.9Hz,1H),5.83(dt,J=15.6,1.6Rz,1H),
6.16(dd,J=5.7,2.0Hz,1H),6.96(dt,J=15.6,7.0Hz,1H),
7.49(dd,J=5.7,2.5Hz,1H)
IR(neat)cm-1;
3503,2930,2860,1708,1702,1654,1588,1540,1457,1436,1346,1314,1273,
1199,1177,1070,1034,977,930,870,805
(4)使用(3)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物29:
1H-NMR(CDCl3,200MHz)δppm;
0.95(t,J=6.8Hz,3H),1.16-2.47(m,23H),2.20(dd,J=18.6,11.0Hz,1H),
2.37(ddd,J=11.4,10.5,8.6Hz,1H),2.81(dt,J=2.6,5.9Hz,2H),
2.84(ddd,J=18.6,7.8,1.2Hz,1H),3.04(ddd,J=11.0,10.5,7.8Hz,1H),
3.59(dd,J=9.7,2.9Hz,1H),3.73(s,3H),3.74(t,J=5.9Hz,2H),
5.47(dd,J=15.6,8.6Hz,1H),5.61-5.88(m,1H),5.82(dt,J=15.6,1.5Hz,1H),
6.95(dt,J=15.6,7.0Hz,1H)
IR(neat)cm-1;
3459,2930,2870,1740,1734,1654,1456,1436,1402,1315,1278,1202,1176,
1045,975,930,876,848,740,720,666
化合物30:
1H-NMR(CDCl3,200MHz)δppm;
0.95(t,J=6.8Hz,3H),1.16-2.44(m,23H),2.52-2.93(m,5H),3.47-3.67(m,1H),
3.58(dd,J=9.8,2.3Hz,1H),3.73(s,3H),3.76(t,J=5.9Hz,2H),5.52-5.81(m,2H),
5.82(dt,J=15.6,1.5Hz,1H),6.95(dt,J=15.6,7.0Hz,1H)
IR(neat)cm-1;
3454,2930,2870,1740,1734,1654,1456,1436,1401,1315,1278,1202,1176,
1046,980,930,876,848,757,720,669
实施例30
(2E,11R,16R)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1(化合物31)
向脂肪酶PS(3.70g)的水(20.8ml)悬浮液中,加入实施例29得到的(2E,11R,16R)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1甲酯(153mg)的丙酮(7.1ml)溶液、磷酸缓冲液(pH=7.0,0.2M,3.56ml)和水(50.9ml),在30℃搅拌一夜。过滤反应液后,用1当量盐酸将滤液调至pH=5,之后用硫酸铵盐析,用乙酸乙酯萃取,有机层用饱和食盐水洗净,用无水硫酸镁干燥干燥,过滤。减压浓缩滤液,所得粗产物用硅胶柱色谱纯化(展开溶剂:己烷∶乙酸乙酯=1∶2~乙酸乙酯),得到标题化合物(92mg)。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.18-2.46(m,24H),2.20(dd,J=18.7,11.2Hz,1H),
2.62-3.15(m,5H),3.60(dd,J=9.7,2.7Hz,1H),3.74(t,J=5.9Hz,2H),
5.47(dd,J=15.3,8.9Hz,1H),5.63-5.90(m,2H),7.03(dt,J=15.5,7.0Hz,1H)
IR(neat)cm-1;
3414,2930,2870,1740,1702,1654,1466,1424,1402,1283,1246,1218,1202,
1065,1047,1012,976,930,876,854,757,666
实施例31
(2E,11R,16S)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1甲酯(化合物32)和(2E,11S,16S)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1甲酯(化合物33)
(1)使用实施例29(2)得到的(2E,16S)-15-脱氧-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGR1甲酯,与实施例1(4)进行实际上相同的操作,得到(2E,16S)-15-脱氧-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGA1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.9Hz,3H),1.18-2.44(m,22H),3.15-3.30(m,1H),
3.55(dd,J=9.7,2.6Hz.1H),3.73(s,3H),5.47(dd,J=15.2,8.1Hz,1H),
5.68(dt,J=15.2,6.9Hz,1H),5.83(dt,J=15.7,1.5Hz,1H),
6.15(dd,J=5.7,2.0Hz,1H),6.96(dt,J=15.7,7.0Hz,1H),
7.48(dd,J=5.7,2.5Hz,1H)
IR(neat)cm-1;
3468,2931,2860,1708,1702,1654,1588,1456,1436,1384,1346,1314,1273,
1199,1176,1034,977,930,870,806,719
(2)使用(1)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物32:
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.8Hz,3H),1.12-2.46(m,24H),2.20(dd,J=18.3,11.1Hz,1H),
2.54-3.16(m,2H),2.80(dt,J=4.4,5.9Hz,1H),3.57(dd,J=10.2,2.1Hz,1H),
3.73(s,3H),3.74(t,J=5.9Hz,2H),5.41(dd,J=15.1,9.1Hz,1H),
5.67(ddd,J=15.1,9.4,5.4Hz,1H),5.81(dt,J=15.6,1.5Hz,1H),
6.95(dt,J=15.6,7.0Hz,1H)
IR(neat)cm-1;
3448,2930,2870,1740,1734,1654,1456,1436,1402,1385,1314,1274,1201,
1176,1062,1045,974,930,876,848,720
化合物33:
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.8Hz,3H),1.16-2.94(m,26H),2.75(dt,J=11.9,5.8Hz,2H),
3.47-3.67(m,1H),3.54(dd,J=10.3,2.2Hz,1H),3.73(s,3H),
3.76(t,J=5.8Hz,2H),5.55-5.89(m,2H),5.81(dt,J=15.7,1.5Hz,1H),
6.95(dt,J=15.7,7.0Hz,1H)
IR(neat)cm-1;
3459,2930,2870,1740,1734,1654,1436,1401,1315,1278,1202,1175,1046,979,
930,876,848,720,670
实施例32
(2E,11R,16S)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1(化合物34)
使用实施例31得到的(2E,11R,16S)-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-2,3-二脱氢-PGE1甲酯,与实施例30进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.21-2.45(m,25H),2.20(dd,J=18.7,11.2Hz,1H),
2.66-3.12(m,3H),2.80(dt,J=9.8,5.9Hz,1H),3.57(dd,J=10.5,2.3Hz,1H),
3.74(t,J=5.9Hz,2H),5.42(dd,J=14.8,8.6Hz,1H),
5.66(ddd,J=14.8,9.7,5.2Hz,1H),5.81(dt,J=15.5,1.5Hz,1H),
7.04(dt,J=15.5,7.0Hz,1H)
IR(neat)cm-1;
3436,2930,2870,1740,1697,1648,1466,1424,1402,1283,1223,1180,1065,
1049,974,930,876,756,670
实施例33
(11R,16R)-3-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物79)和(11S,16R)-3-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物80)
(1)用5-甲氧基羰基-4-硫杂戊基碘化锌(II)代替实施例1(2)中的5-甲氧基羰基戊基碘化锌(II),与实施例1(2)进行实际上相同的操作,得到(16RS)-3-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯11,16-双(叔丁基二甲基甲硅烷基醚)。
1H-NMR(CDCl3,200MHz)δppm;
0.04(s,3H),0.05(s,3H),0.06(s,3H),0.07(s,3H),0.70-1.03(m,3H),
0.88(s,9H),0.91和0.92(2s,9H),1.13-2.24(m,19H),2.16(dd,J=18.0,8.1Hz,1H),
2.32-2.82(m,4H),3.21(s,2H),3.51-3.63(m,1H),3.74(s,3H),3.90-4.08(m,1H),
5.20-5.38(m,1H),5.52-5.74(m,1H)
IR(neat)cm-1;
2955,2930,2857,1746,1472,1436,1385,1257,1094,1007,939,837,775,670
(2)使用(1)得到的化合物,与实施例1(3)进行实际上相同的操作,得到下述化合物。
(16R)-3-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯
1HNMR(CDCl3,300MHz)δppm;
0.94(t,J=7.0Hz,3H),1.23-2.13(m,20H),2.17-2.43(m,2H),
2.23(dd,J=18.5,9.6Hz,1H),2.52-2.81(m,2H),
2.75(ddd,J=18.5,7.5,1.2Hz,1H),3.22(bs,2H),3.59(dd,J=9.9,2.6Hz,1H),
3.74(s,3H),4.01-4.13(m,1H),5.48(dd,J=15.2,8.6Hz,1H),
5.75(ddd,J=15.2,8.2,6.2Hz,1H)
IR(neat)cm-1;
3432,2952,2930,2870,1740,1734,1456,1436,1284,1154,1073,1011,971,594
(16S)-3-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.95(t,J=6.8Hz,3H),1.22-2.11(m,20H),2.23(dd,J=18.5,9.5Hz,1H),
2.23-2.42(m,1H),2.36(dt,J=12.3,8.7Hz,1H),2.54-2.70(m,2H),
2.74(ddd,J=18.5,7.4,1.1Hz,1H),3.22(s,2H),3.58(dd,J=10.3,2.6Hz,1H),
3.74(s,3H),4.04(ddd,J=9.5,8.7,7.4Hz,1H),5.44(dd,J=14.8,8.7Hz,1H),
5.67-5.83(m,1H)
IR(neat)cm-1;
3400,2952,2930,2870,1740,1734,1456,1436,1283,1154,1075,1011,968,876,
736
(3)使用(2)得到的(16R)-3-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例1(4)进行实际上相同的操作,得到(16R)-3-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGA1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.9Hz,3H),1.18-2.32(m,19H),2.55-2.76(m,1H),
2.65(t,J=7.0Hz,2H),3.18-3.31(m,1H),3.23(s,2H),3.56(dd,J=9.8,2.7Hz,1H),
3.74(s,3H),5.49-5.75(m,1H),5.50(dd,J=15.4,7.7Hz,1H),
6.16(dt,J=5.7,2.2Hz,1H),7.49(dd,J=5.7,2.5Hz,1H)
IR(neat)cm-1;
3497,2930,2860,1735,1702,1588,1436,1384,1351,1279,1133,1070,1010,972,
930,880,800
(4)使用(3)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物79:
1H-NMR(CDCl3,200MHz)δppm;
0.85-1.06(m,3H),1.18-2.50(m,22H),2.20(dd,J=18.3,11.1Hz,1H),
2.62(t,J=6.8Hz,2H),2.72-3.13(n,4H),3.22(s,2H),3.60(dd,J=9.7,2.6Hz,1H),
3.69-3.84(m,2H),3.74(s,3H),5.47(dd,J=15.2,8.6Hz,1H),
5.75(ddd,J=15.2,7.7,6.3Hz,1H)
IR(neat)cm-1;
3460,2952,2930,2870,1740,1734,1456,1436,1406,1283,1217,1190,1154,
1148,1062,1046,1011,971,930,876
化合物80:
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.8Hz,3H),1.14-2.94(m,28H),3.22(s,2H),3.48-3.66(m,2H),
3.74(s,3H),3.76(t,J=5.8Hz.2H).5.51-5.80(m,2H)
IR(neat)cm-1;
3436,2952,2930,2870,1740,1734,1456,1436,1402,1283,1218,1195,1158,
1137,1062,1046,1011,974
实施例34
(11R,16R)-3-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1(化合物81)
使用实施例33得到的(11R,16R)-3-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.7Hz,3H),1.20-4.26(m,25H),2.20(dd,J=18.5,11.0Hz,1H),
2.66(t,J=6.2Hz,2H),2.81(t,J=5.9,2H),2.83(ddd,J=18.5,7.9,1.2Hz,1H),
3.19(s,1H),3.75(t,J=5.9Hz,2H),5.44(dd,J=15.2,8.6Hz,1H),
5.75(ddd,J=15.2,8.4,5.6Hz,1H)
IR(neat)cm-1;
3436,2930,2870,1740,1734,1456,1402,1352,1284,1179,1153,1062,1047,
1009,970,931,876,670
实施例35
(11R,16S)-3-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物82)和(11S,16S)-3-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物83)
(1)使用实施例33(2)得到的(16S)-3-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例1(4)进行实际上相同的操作,得到(16S)-3-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGA1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.8Hz,3H),1.21-2.32(m,19H),2.60-2.84(m,3H),3.14-3.32(m,1H),
3.23(bs,2H),3.56(dd,J=9.7,2.6Hz,1H),3.74(s,3H),
5.48(dd,J=15.4,8.1Hz,1H),5.58-5.80(m,1H),6.15(dt,J=5.7,2.0Hz,1H),
7.49(dd,J=5.7,2.4Hz,1H)
IR(neat)cm-1;
3486,2930,2860,1740,1702,1588,1436,1346,1279,1133,1009,972
(2)使用(1)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
化合物82:
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.7Hz,3H),1.16-2.47(m,22H),2.20(dd,J=18.5,11.0Hz,1H),
2.55-3.12(m,4H),2.62(t,J=7.0Hz,2H),3.22(s,2H),
3.57(dd,J=10.3,2.0Hz,1H),3.65-3.85(m,2H),3.74(s,3H),
5.42(dd,J=15.2,8.4Hz,1H),5.68(ddd,J=15.2,9.3,5.5Hz,1H)
IR(neat)cm-1;
3460,2952,2930,2870,1740,1735,1457,1436,1406,1396,1282,1218,1153,
1137,1065,1049,1011,970,930,876,741
化合物83:
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.8Hz,3H),1.20-2.16(m,19H),2.22-2.96(m,5H),
2.62(t,J=7.0Hz,2H),2.75(dt,J=11.6,5.7Hz,2H),3.22(s,2H),
3.48-3.66(m,1H),3.54(dd,J=10.3,2.2Hz,1H),3.74(s,3H),
3.76(t,J=5.7Hz,2H),5.53-5.82(m,2H)
IR(neat)cm-1;
3436,2952,2930,2870,1740,1734,1456,1436,1402,1283,1218,1195,1158,
1136,1065,1046,1011,974,876,742,590
实施例36
(11R,16S)-3-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1(化合物84)
使用实施例35得到的(11R,16S)-3-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,200MHz)δppm;
0.95(t,J=6.8Hz,3H),1.16-2.52(m,20H),2.21(dd,J=18.3,11.1Hz,1H),
2.53-4.00(m,7H),2.81(dt,J=2.5,5.9Hz,2H),3.18(d,J=14.9Hz,1H),
3.26(d,J=14.9Hz,1H),3.63(dd,J=10.4,2.1Hz,1H),3.75(t,J=5.9Hz,2H),
5.45(dd,J=15.3,8.7Hz,1H),5.74(ddd,J=15.3,8.4,6.4Hz,1H)
IR(neat)cm-1;
3436,2930,1734,1456,1424,1402,1284,1179,1158,1049,1009,971,930,876,
757,670
实施例37
(11R,16R)-6-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGB1甲酯(化合物118)
(1)在室温向实施例1(1)得到的化合物(1.03g)的甲苯(2.0ml)溶液中加入5-巯基戊酸甲酯(363mg),在同温度下搅拌一夜。接着,加入二异丙基胺(3μl),在室温搅拌3小时。将反应液用硅胶柱色谱纯化(展开溶剂:己烷∶乙酸乙酯=49∶1~9∶1),得到(16RS)-6-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯11,16-双(叔丁基二甲基甲硅烷基醚)(818mg)。
1H-NMR(CDCl3,200MHz)δppm;
0.04(s,3H),0.06(s,3H),0.07(2s,6H),0.75-1.02(m,3H),0.88(s,9H),
0.91 and0.92(2s,9H),1.16-2.38(m,20H),2.41-2.93(m,4H),
2.50(t,J=6.9Hz,2H),3.52-3.76(m,JH),3.67(s,3H),3.98-4.13(m,1H),
5.24-5.42(m,1H),5.52-5.77(m,1H)
IR(neat)cm-1:
2955,2930,2857,1746,1472,1435,1361,1257,1154,1089,1006,939,836,775,
669
(2)使用(1)得到的化合物,与实施例1(3)进行实际上相同的操作,得到下述化合物。
(16R)-6-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.23-2.11(m,18H),2.24-2.36(m,2H),
2.28(dd,J=18.5,9.3Hz,1H),2.33(t,J=7.2Hz,2H),2.52(t,J=7.2Hz,2H),
2.58-2.70(m,1H),2.71-2.90(m,3H),3.58(dd,J=10.2,2.4Hz,1H),3.67(s,3H),
4.06-4.17(m,1H),5.47-5.52(m,1H),5.70-5.83(m,1H)
IR(neat)cm-1;
3436,2952,2930,2870,1740,1436,1277,1208,1158,1073,973,757
(16S)-6-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.9Hz,3H),1.23-2.12(m,17H),2.24-2.36(m,2H),
2.27(dd,J=18.3,9.4Hz,1H),2.33(t,J=7.2Hz,2H),2.47-2.58(m,2H),
2.62-2.90(m,4H),3.59(dd,J=9.6,2.4Hz,1H),3.67(s,3H),4.04-4.17(m,1H),
5.48(dd,J=15.2,8.2Hz,1H),5.72-5.84(m,1H)
IR(neat)cm-1;
3400,2952,2871,1740,1436,1342,1262,1207,1158,1076,969,877,806
(3)使用(2)得到的(16R)-6-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例1(4)进行实际上相同的操作,得到(16R)-6-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGA1甲酯
1H-NMR(CDCl3+D2O,200MHz)δppm;
0.94(t,J=6.8Hz,3H),1.20-2.12(m,14H),2.16-2.40(m,2H),
2.33(t,J=6.9Hz,2H),2.46-2.62(m,1H),2.54(t,J=7.0Hz,2H),
2.66(dd,J=12.7,9.0Hz,1H),3.02(dd,J=12.7,4.2Hz,1H),3.46-3.63(m,2H),
3.68(s,3H),5.47-5.78(m,1H),5.55(dd,J=15.8,7.OHz,1H),
6.19(dd,J=5.8,2.2Hz,1H),7.56(dd,J=5.8,2.5Hz,1H)
IR(neat)cm-1;
3480,2952,2870,1740,1708,1584,1436,1352,1273,1174,1070,972,800
(4)使用(3)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.8Hz,3H),1.20-2.15(m,18H),2.20-2.40(m,1H),
2.24(dd,J=18.5,11.2Hz,1H),2.33(t,J=6.9Hz,2H),2.44-3.32(m,9H),
2.51(t,J=6.7Hz,2H),3.58(dt,J=9.9,2.7Hz,1H),3.67(s,3H),
3.75(dt,J=2.1,5.9Hz,2H),5.41-5.86(m,2H)
IR(neat)cm-1;
3470,2952,2930,2870,1740,1735,1436,1376,1294,1277,1208,1174,1066,
1046,971,876,746
实施例38
(11R,16R)-6-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物119)
使用实施例37得到的化合物,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.8Hz,3H),1.21-2.18(m,16H),2.20-4.21(m,13H),
2.24(dd,J=18.5,11.2Hz,1H),2.37(t,J=6.8Hz,2H),3.63(dd,J=10.1,2.4Hz,1H),
3.75(t,J=5.9Hz,2H),5.48(dd,J=15.3,8.7Hz,1H),
5.78(ddd,J=15.3,7.8,5.9Hz,1H)
IR(neat)cm-1;
3400,2930,2870,1740,1734,1456,1402,1283,1218,1179,1158,1066,1046,971,
930,876,757
实施例39
(11R,16S)-6-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1甲酯(化合物120)
(1)使用实施例37(2)得到的(16S)-6-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGE1甲酯,与实施例1(4)进行实际上相同的操作,得到(16S)-6-硫杂-15-脱氧-16-羟基-17,17-三亚甲基-PGA1甲酯
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.9Hz,3H),1.14-2.12(m,15H),2.16-2.40(m,2H),
2.33(t,J=7.3Hz,2H),2.44-2.60(m,1H),2.54(t,J=6.9Hz,2H),
2.68(dd,J=12.9,8.6Hz,1H),3.00(dd,J=12.9,4.2Hz,1H),3.46-3.62(m,2H),
3.67(s,3H),5.48-5.80(m,1H),5.55(dd,J=15.5,7.4Hz,1H),
6.19(dd,J=5.7,2.2Hz,1H),7.56(dd,J=5.7,2.5Hz,1H)
IR(neat)cm-1;
3468,2952,2870,1740,1708,1584,1436,1351,1274,1205,1174,1070,1031,972
(2)使用(1)得到的化合物,与实施例1(5)进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,200MHz)δppm;
0.94(t,J=6.8Hz,3H),1.18-2.13(m,19H),2.21-2.40(m,1H),
2.24(dd,J=18.7,11.2Hz,1H),2.33(t,J=7.1Hz,2H),2.44-3.32(m,7H),
2.51(t,J=7.0Hz,2H),3.57(ddd,J=10.2,4.3,2.5Hz,1H),3.67(s,3H),
3.76(dt,J=2.5,5.8Hz,1H),5.35-5.83(m,2H)
IR(neat)cm-1;
3459,2952,2870,1740,1456,1436,1278,1208,1174,1066,1050,971,876
实施例40
(11R,16S)-6-硫杂-11,15-二脱氧-11-(2-羟基乙基硫)-16-羟基-17,17-三亚甲基-PGE1(化合物121)
使用实施例39得到的化合物,与实施例2进行实际上相同的操作,得到标题化合物。
1H-NMR(CDCl3,300MHz)δppm;
0.94(t,J=6.8Hz,3H),1.20-2.13(m,17H),2.13-2.44(m,1H),
2.25(dd,J=18.5,11.2Hz,1H),2.37(t,J=6.9Hz,2H),2.45-3.15(m,11H),
3.60(dd,J=10.2,2.3Hz,1H),3.75(t,J=5.9Hz,2H),5.44(dd,J=15.2,9.2Hz,1H),
5.75(ddd,J=15.2,9.0,5.9Hz,1H)
IR(neat)cm-1;
3436,2930,2870,1740,1730,1456,1402,1284,1218,1180,1158,1065,1046,970,
935,876,757,670
试验例[测定PGE1衍生物对人血管平滑肌细胞DAN合成的抑制活性]
在24孔板(Corning社制)中,播种正常人大动脉血管细胞(Kurabo制)的5次培养细胞,达到1×104细胞/孔,培养2天。将培养基从增殖培养基(SG2;Kurabo制)交换为基础培养基(SB2;Kurabo制),培养24小时。向其中加入添加了含有被验化合物乙醇溶液的增殖培养基(SG2),此时,加入3H-胸腺嘧啶脱氧核苷(第1化学药品制)0.01mci/孔,培养24小时后,吸引除去培养上清液,用磷酸缓冲液(PBS)洗净。
加入5%三氯乙酸(TCA),在4℃放置20分钟后,用TCA洗涤1次。用PBS洗净后,溶解于0.5M氢氧化钾水溶液中。取20μl溶解有核内摄取了3H-胸腺嘧啶脱氧核苷细胞的氢氧化钾水溶液,用液体闪烁计数器(Hewlett Packard社制),测定摄取的3H-胸腺嘧啶脱氧核苷量。
结果如表1所示。
表1
1×10-5M(加入化合物的浓度) | 增殖抑制率(相对于对照组%) |
化合物23 | 91.5 |
化合物29 | 100 |
化合物32 | 100 |
化合物41 | 93.2 |
化合物54 | 100 |
化合物55 | 94.3 |
注:被验化合物制成乙醇溶液,对照组使用溶剂处理进行比较。
从以上结果可知,化合物23、29、32、41、54和55对人血管平滑肌细胞具有高的增殖抑制活性。
产业上可利用性
通过本发明,提供了显示优秀的血管平滑肌细胞增殖抑制作用的PG衍生物。本发明的PG衍生物,作为经皮冠状动脉成形术后的再狭窄为起因的血管肥厚、闭塞的预防或治疗剂是有用的。
Claims (9)
1.式(I)所示的***素衍生物,其药学上可接受的盐或其水合物:
式中,X表示CH2或S,
Y表示亚乙基、亚乙烯基、或式O(CH2)t1或S(CH2)t1表示的基团,其中t1为1~3的整数,
Z表示亚乙基、亚乙烯基或亚乙炔基,
R1表示氢原子或C1-10烷基,
R2表示C1-10烷基;羟基C1-5烷基;C2-4烷氧基羰基C1-5烷基;式-NR7R8所示基团取代的C1-5烷基,其中R7和R8可相同或不同,表示氢原子或C1-5烷基;C2-10烷酰基;式-(CH2)t2CH(NH2)COOR9表示的基团,其中R9表示氢原子或C1-5烷基,t2表示1或2;或下式所示基团,
其中R4和R5可相同或不同,表示氢原子、C1-10烷氧基或硝基,r表示0~3的整数;
R3表示氢原子或C1-10烷基,
m表示0~3的整数,n表示1~3的整数,p表示0~5的整数,q表示0。
2.权利要求1记载的***素衍生物,其药学上可接受的盐或其水合物,
其中,X表示CH2或S,
R2表示C1-10烷基;羟基C1-5烷基;C2-4烷氧基羰基C1-5烷基;式-NR77R88所示基团取代的C1-5烷基,其中R77和R88可相同或不同,表示氢原子或C1-5烷基;C2-10烷酰基;式-(CH2)t2CH(NH2)COOR9表示的基团,其中R9表示氢原子或C1-5烷基,t2表示1或2;或下式所示基团,
其中R44表示氢原子、C1-10烷氧基或硝基,r表示0~3的整数;
R3表示氢原子、C1-10烷基。
4.一种药物,含有权利要求1中记载的***素衍生物、其药学上可接受的盐或其水合物作为有效成分。
5.一种药物,含有权利要求2中记载的***素衍生物、其药学上可接受的盐或其水合物作为有效成分。
6.一种药物,含有权利要求3中记载的***素衍生物、其药学上可接受的盐或其水合物作为有效成分。
7.权利要求1中记载的***素衍生物、其药学上可接受的盐或其水合物在制备经皮的冠状动脉成形术后再狭窄的预防或治疗药中的用途。
8.权利要求2中记载的***素衍生物、其药学上可接受的盐或其水合物在制备经皮的冠状动脉成形术后再狭窄的预防或治疗药中的用途。
9.权利要求3中记载的***素衍生物、其药学上可接受的盐或其水合物在制备经皮的冠状动脉成形术后再狭窄的预防或治疗药中的用途。
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JP256726/99 | 1999-09-10 | ||
JP25672699 | 1999-09-10 | ||
JP256726/1999 | 1999-09-10 | ||
JP79147/00 | 2000-03-21 | ||
JP79147/2000 | 2000-03-21 | ||
JP2000079147 | 2000-03-21 |
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CN1390199A CN1390199A (zh) | 2003-01-08 |
CN1190417C true CN1190417C (zh) | 2005-02-23 |
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CNB008155658A Expired - Fee Related CN1190417C (zh) | 1999-09-10 | 2000-09-08 | ***素衍生物 |
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US (1) | US6613932B1 (zh) |
EP (1) | EP1219601A4 (zh) |
KR (1) | KR20020043582A (zh) |
CN (1) | CN1190417C (zh) |
AU (1) | AU766900B2 (zh) |
CA (1) | CA2384715A1 (zh) |
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Publication number | Priority date | Publication date | Assignee | Title |
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US4029681A (en) | 1976-02-13 | 1977-06-14 | The Upjohn Company | 13,14-Didehydro-PG analogs |
US4189597A (en) * | 1977-03-30 | 1980-02-19 | American Cyanamid Company | 11-(2-Hydroxyethylthio)prostenoic acid E series derivatives |
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 |
CA2369662A1 (en) | 1999-04-09 | 2000-10-19 | Taisho Pharmaceutical Co., Ltd. | Prostaglandin e1 derivatives |
WO2001062724A1 (fr) * | 2000-02-28 | 2001-08-30 | Taisho Pharmaceutical Co., Ltd. | Derives de prostaglandine e |
-
2000
- 2000-09-08 AU AU68766/00A patent/AU766900B2/en not_active Ceased
- 2000-09-08 US US10/070,752 patent/US6613932B1/en not_active Expired - Fee Related
- 2000-09-08 CA CA002384715A patent/CA2384715A1/en not_active Abandoned
- 2000-09-08 CN CNB008155658A patent/CN1190417C/zh not_active Expired - Fee Related
- 2000-09-08 KR KR1020027003166A patent/KR20020043582A/ko not_active Application Discontinuation
- 2000-09-08 WO PCT/JP2000/006161 patent/WO2001019789A1/ja not_active Application Discontinuation
- 2000-09-08 EP EP00957063A patent/EP1219601A4/en not_active Withdrawn
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KR20020043582A (ko) | 2002-06-10 |
EP1219601A4 (en) | 2004-10-27 |
WO2001019789A1 (fr) | 2001-03-22 |
CA2384715A1 (en) | 2001-03-22 |
CN1390199A (zh) | 2003-01-08 |
HK1051181A1 (en) | 2003-07-25 |
AU766900B2 (en) | 2003-10-23 |
US6613932B1 (en) | 2003-09-02 |
EP1219601A1 (en) | 2002-07-03 |
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