CN1286686A - 紫杉烷衍生物 - Google Patents
紫杉烷衍生物 Download PDFInfo
- Publication number
- CN1286686A CN1286686A CN98813173A CN98813173A CN1286686A CN 1286686 A CN1286686 A CN 1286686A CN 98813173 A CN98813173 A CN 98813173A CN 98813173 A CN98813173 A CN 98813173A CN 1286686 A CN1286686 A CN 1286686A
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- Prior art keywords
- compound
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- furyl
- hydrogen atom
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- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 title claims abstract description 40
- 229940123237 Taxane Drugs 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 27
- -1 piperidino, pyrrolidino Chemical group 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 125000002541 furyl group Chemical group 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 12
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 4
- 125000001207 fluorophenyl group Chemical group 0.000 claims abstract description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims 2
- 229940034982 antineoplastic agent Drugs 0.000 claims 2
- 125000004050 enoyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 212
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 9
- 125000004665 trialkylsilyl group Chemical group 0.000 abstract description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 6
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 125000004663 dialkyl amino group Chemical group 0.000 abstract description 3
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 description 186
- 238000005160 1H NMR spectroscopy Methods 0.000 description 80
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 51
- 239000013078 crystal Substances 0.000 description 41
- 239000000203 mixture Substances 0.000 description 32
- 230000002829 reductive effect Effects 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 10
- 229930012538 Paclitaxel Natural products 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 229960001592 paclitaxel Drugs 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- RXWIQTKYCZUYPP-UHFFFAOYSA-N 4-(furan-2-yl)-2,2-dimethyl-3-phenylmethoxycarbonyl-1,3-oxazolidine-5-carboxylic acid Chemical compound CC1(C)OC(C(O)=O)C(C=2OC=CC=2)N1C(=O)OCC1=CC=CC=C1 RXWIQTKYCZUYPP-UHFFFAOYSA-N 0.000 description 8
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 description 8
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- HVYWMOMLDIMFJA-UHFFFAOYSA-N 10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical compound C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 HVYWMOMLDIMFJA-UHFFFAOYSA-N 0.000 description 6
- BDUBTLFQHNYXPC-UHFFFAOYSA-N 3-methylbut-2-enoyl chloride Chemical compound CC(C)=CC(Cl)=O BDUBTLFQHNYXPC-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- KNWCDYSKJSREAQ-UHFFFAOYSA-N 1,3-oxazolidine-2-carboxylic acid Chemical compound OC(=O)C1NCCO1 KNWCDYSKJSREAQ-UHFFFAOYSA-N 0.000 description 5
- 229930014667 baccatin III Natural products 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- QGPGUZIKJKOKRF-UHFFFAOYSA-M potassium;acetonitrile;dihydrogen phosphate Chemical compound [K+].CC#N.OP(O)([O-])=O QGPGUZIKJKOKRF-UHFFFAOYSA-M 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- HAKYFVXFJWASLJ-UHFFFAOYSA-N 4-(4-fluorophenyl)-2,2-dimethyl-3-phenylmethoxycarbonyl-1,3-oxazolidine-5-carboxylic acid Chemical compound CC1(C)OC(C(O)=O)C(C=2C=CC(F)=CC=2)N1C(=O)OCC1=CC=CC=C1 HAKYFVXFJWASLJ-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000000160 oxazolidinyl group Chemical group 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- IYCJGGPKTOJIFT-UHFFFAOYSA-N 4-(2-fluorophenyl)-2,2-dimethyl-3-phenylmethoxycarbonyl-1,3-oxazolidine-5-carboxylic acid Chemical compound CC1(C)OC(C(O)=O)C(C=2C(=CC=CC=2)F)N1C(=O)OCC1=CC=CC=C1 IYCJGGPKTOJIFT-UHFFFAOYSA-N 0.000 description 3
- WHNPOQXWAMXPTA-UHFFFAOYSA-N Amide-3-Methyl-2-butenoic acid Natural products CC(C)=CC(N)=O WHNPOQXWAMXPTA-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 3
- 238000007083 alkoxycarbonylation reaction Methods 0.000 description 3
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000011088 calibration curve Methods 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000003381 deacetylation reaction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 2
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 235000021028 berry Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- VJLYHTOSFSGXGH-CQSZACIVSA-N (2R)-1-[3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxybenzoyl]pyrrolidine-2-carboxylic acid Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)N2[C@H](CCC2)C(=O)O)C=CC=1 VJLYHTOSFSGXGH-CQSZACIVSA-N 0.000 description 1
- ZXAQFYZQHPGMMN-BZSJEYESSA-N (3R)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylcyclohexane-1-carboxamide Chemical compound C1C[C@H](CC(C1)C(=O)NC2=CC=CC=C2)OC3=CC(=CC(=N3)C(F)(F)F)CN ZXAQFYZQHPGMMN-BZSJEYESSA-N 0.000 description 1
- ZWHOTPNCEFWATE-CQSZACIVSA-N (3R)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylpyrrolidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@H]1CN(CC1)C(=O)NC1=CC=CC=C1 ZWHOTPNCEFWATE-CQSZACIVSA-N 0.000 description 1
- ZWHOTPNCEFWATE-AWEZNQCLSA-N (3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylpyrrolidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CC1)C(=O)NC1=CC=CC=C1 ZWHOTPNCEFWATE-AWEZNQCLSA-N 0.000 description 1
- SNAKUPLQASYKTC-AWEZNQCLSA-N (3S)-3-[[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxymethyl]-N-phenylpiperidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC[C@@H]1CN(CCC1)C(=O)NC1=CC=CC=C1 SNAKUPLQASYKTC-AWEZNQCLSA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- RAVIQFQJZMTUBX-AWEZNQCLSA-N 1-[(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidin-1-yl]-2-(3,4-dichlorophenyl)ethanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(CC1=CC(=C(C=C1)Cl)Cl)=O RAVIQFQJZMTUBX-AWEZNQCLSA-N 0.000 description 1
- XAOMFUPJQYNDEG-LBPRGKRZSA-N 1-[(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidin-1-yl]-2-methylpropan-1-one Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(C(C)C)=O XAOMFUPJQYNDEG-LBPRGKRZSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- RNIUHIHTGPHJEN-AWEZNQCLSA-N 2-[(3S)-1-[2-(3,4-dichlorophenyl)acetyl]piperidin-3-yl]oxy-6-(trifluoromethyl)pyridine-4-carbonitrile Chemical compound ClC=1C=C(C=CC=1Cl)CC(=O)N1C[C@H](CCC1)OC=1C=C(C#N)C=C(N=1)C(F)(F)F RNIUHIHTGPHJEN-AWEZNQCLSA-N 0.000 description 1
- DCGQVDFBDSTUML-AWEZNQCLSA-N 2-[(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidine-1-carbonyl]chromen-4-one Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(=O)C=1OC2=CC=CC=C2C(C=1)=O DCGQVDFBDSTUML-AWEZNQCLSA-N 0.000 description 1
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- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
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- 150000004579 taxol derivatives Chemical class 0.000 description 1
- UHURYWKBJOLLBM-UHFFFAOYSA-N tert-butyl 4,6-dimethyl-2-sulfanylidene-1h-pyrimidine-5-carboxylate Chemical compound CC1=NC(S)=NC(C)=C1C(=O)OC(C)(C)C UHURYWKBJOLLBM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C07D211/94—Oxygen atom, e.g. piperidine N-oxide
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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Abstract
由通式(Ⅰ)表示的紫杉烷衍生物或其盐以及包含它们作为活性组分的药物,其中,A1表示(a)(其中,R1表示H或任选取代的烷基)或者(b)(其中,R2表示氨基、单烷基氨基或二烷基氨基、哌啶子基、吡咯烷基或吗啉代);X表示H、烷氧羰基或苯甲酰;Y表示H或三烷基甲硅烷基;A2表示呋喃基、烷基呋喃基、烷基或氟苯基;Ac表示乙酰基;并且Bz表示苯甲酰。这些化合物具有优异的水溶性和抗肿瘤活性。
Description
本发明涉及具有优异的水溶性的紫杉烷衍生物、包含它们的药物和用于合成该紫杉烷衍生物的中间体。
由下式(ⅰ)表示的紫杉酚(Taxol，注册商标)(ⅰ)：
是一种可从近太平洋的浆果紫杉树“短叶紫杉”(Taxus brevifolia)的树皮提取而得的二萜，并且首次由Wall等于1971年分离并测定了结构(美国化学学会会志(J.Am.Chem.Soc.),93,2325,1971)。据报道，它表现出抗卵巢癌和乳腺癌的高功效(内科学纪事(Ann.Int.Med.)111,273,1989)。
但是，将紫杉酚配成注射液需要特殊溶剂，因为它是微溶于水的化合物。所以，紫杉酚伴随的问题是难于生产注射液和可能由溶剂引起的副作用。
因此，近年来为了开发紫杉酚的水溶性衍生物进行了大量工作[Nicolaou等，自然(Nature),364,464,1993]。然而，在目前的情况下，尚未发现具有良好性质的衍生物。
所以，本发明的一个目的是提供一种具有改善的水溶性和高抗恶性肿瘤活性的新型紫杉酚衍生物。
鉴于上述情况，本发明人进行了广泛研究。结果，发现了一种由下述式表示的紫杉烷(紫杉酚骨架的通称)的衍生物具有水溶性和抗恶性肿瘤活性，每种性质都远远高于紫杉酚，所以适用作药物，导致本发明的完成。
因此，本发明提供了由下式(1)表示的紫杉烷衍生物：
(其中，A1表示基
(其中，R1表示氢原子，或者取代的或未取代的烷基)或者基
(其中，R2表示氨基、单烷基氨基或二烷基氨基、哌啶子基、吡咯烷基(pyrrolidino)或吗啉代基)，X表示氢原子、烷氧羰基、可被氟原子取代的烷酰基、烯酰基、噻吩基羰基、糠酰基或苯甲酰基，Y表示氢原子或三烷基甲硅烷基，A2表示呋喃基、烷基呋喃基、烷基或氟苯基，Ac表示乙酰基，并且Bz表示苯甲酰基]或其盐。
此外，本发明还提供了一种药物，它包含作为活性组分的、式(1)表示的紫杉烷衍生物或其盐。
本发明还进一步提供了一种抗肿瘤剂，它包含作为活性组分的、式(1)表示的紫杉烷衍生物或其盐。
本发明还进一步提供了一种药物组合物，它包含式(1)表示的紫杉烷衍生物或其盐和药物上可接受的载体。
本发明还进一步提供了式(1)表示的紫杉烷衍生物或其盐作为药物的应用。
本发明还进一步提供了式(1)表示的紫杉烷衍生物或其盐作为抗肿瘤剂的应用。
本发明还进一步提供了一种治疗肿瘤的方法，它包括施用有效量式(1)表示的紫杉烷衍生物或其盐。
本发明的紫杉烷衍生物由式(1)表示。在式(1)中，在A1表示的基中，由R1表示的、作为哌嗪基上取代基的烷基可能是具有1～10个碳原子的烷基，它们的实例可包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基、正庚基、正壬基和正癸基。在这些烷基中，具有1～6个碳子的那些、尤其具有1～4个碳原子的那些是优选的，甲基、乙基和正丙基是更优选的。该烷基的例举性取代基有单烷基氨基羰基和二烷基氨基羰基。C1-6烷基氨基羰基可被提及为更优选的单烷基氨基羰基，并且二(C1-6烷基)氨基羰基可被提及为更优选的二烷基氨基羰基。作为哌啶子基上的取代基而由R2表示的单烷基氨基或二烷基氨基的烷基部分的实例，可提及类似于上面列举的由R1表示的烷基的烷基，甲基、乙基、正丙基和异丙基是优选的。
式(1)中的X表示的基是氢原子或烷氧羰基、烷酰基、烯酰基、噻吩基羰基、糠酰或苯甲酰基，其中，C1-6烷氧羰基是优选的，以叔丁氧羰基为特别优选的。可被氟原子取代的烷酰基的实例包括：线型C1-6烷酰基、支化C1-6烷酰基和环状C3-6烷酰基，及其氟取代的烷酰基-至于氟取代的烷酰基，可提及三氟乙酰基。所述烷氧羰基的烷基部分可以是线型、支化的和环状的任一种。Y表示的基是氢原子或三烷基甲硅烷基。至于该三烷基甲硅烷基，可提及三(C1-6烷基)甲硅烷基。不过，Y优选是氢原子。至于A2表示的烷基呋喃基的烷基部分，可提及与上述由R1表示的烷基类似的基，甲基是特别优选的。
A2表示的烷基的实例包括：线型C1-6烷基、环状烷基和支化烷基，更具体地说，包括乙基、丙基、丁基、环丙基、环丙基甲基、叔丁基和异丁基。
本发明的紫杉烷衍生物(1)的例举性盐是药物上可接受的盐，例如，阴离子盐，例如盐酸盐、氢溴酸盐、氢碘酸盐、酒石酸盐、醋酸盐、甲磺酸盐、马来酸盐、琥珀酸盐和戊二酸盐，以及与氨基酸(例如精氨酸、赖氨酸或丙氨酸)的盐。此外，本发明的紫杉烷衍生物或其盐还可呈水合物的形式。水合物也包括于本发明中。
本发明的紫杉烷衍生物例如可按下列反应图式制备。
[其中，A1、A2、X、Y、Ac和Bz具有与前述相同的含义；X’表示氢原子或烷氧羰基；Y’表示三烷基甲硅烷基；R3表示氢原子、烷氧羰基、烯丙氧羰基或苄氧羰基；并且R4和R5各自表示氢原子、烷基或烷氧苯基，但条件是，R4和R5不同时表示氢原子，或者当R4或R5中的任一个表示烷氧苯基时，则另一个是氢原子]。
具体地说，靶紫杉烷衍生物(1)是通过这样获得的：提供一种已知的化合物10-脱乙酰基浆果赤霉素Ⅲ(ⅱ)作原料，用三烷基甲硅烷基保护它的7-羟基，在形成的化合物(ⅲ)中引入A基而酰化(甲氨酰化)它，于是赋予它水溶性，为了引入赋予水溶性的A基，将形成的化合物(ⅳ)的13-羟基噁唑烷基化，使形成的化合物(Ⅴ)的噁唑烷环开环，如果需要的话，往它的氨基中引入基X。
可按已知方法进行10-脱乙酰基浆果赤霉素Ⅲ的7-羟基的保护，更具体地说，通过用三烷基甲硅烷基氯在吡啶中处理。保护基是三烷基甲硅烷基，以三(C1-6烷基)甲硅烷基为更优选的，三乙基甲硅烷基是特别优选的。
然后酰化(甲氨酰化)化合物(ⅲ)的10-羟基，引入具有赋予水溶性的功能的侧链(A1-)。
酰化(甲氨酰化)方法的实例可包括在合适的碱存在下应用前面列举的酸衍生物的方法和应用缩合剂的方法。
本文可应用的酰化(甲氨酰化)试剂实例有酰基氯、酸酐和酸性酯，以及与这些试剂等效的衍生物。
作为一种引入基(A1-)的特定方法，例如4-二甲氨基哌啶子基羰基化，可通过这样实现：在合适的碱(例如正丁基锂)存在下，同时应用合适的溶剂(例如THF)，用4-二甲氨基哌啶子基碳酰氯进行处理。
然后将13-羟基噁唑烷基化而得化合物(Ⅴ)。噁唑烷基化例如可通过这样进行：在缩合剂(例如DCC)的存在下，将噁唑烷羧酸的衍生物(例如N-苄氧羰基(Cbz)-2,2-二甲基-4-A2-噁唑烷羧酸、N-烯丙氧羰基-2,2-二甲基-4-A2-噁唑烷羧酸、N-烷氧羰基-2-烷氧苯基)-4-A2-噁唑烷羧酸等)与化合物(ⅳ)反应。
接着，可通过这样打开噁唑烷环：用酸在溶剂(例如乙醇)中处理形成的化合物(Ⅴ)，于是除去保护基(除去TES)，然后，在披钯碳的存在下进行催化还原，从而得化合物(1’)。也可应用四(三苯膦)钯进行噁唑烷环的开环反应。在该开环反应之后可进行去保护。当N-烷氧羰基-2-(烷氧苯基)-4-Ar-噁唑烷羧酸被用于所述噁唑烷基化时，则可通过用酸(例如对甲苯磺酸)处理而打开形成的噁唑烷环。在该情况下，可获得具有烷氧羰基(例如X1)的化合物(1’)。
当化合物(1’)中的X1表示氢原子时，本发明的化合物(1)可通过将它的氨基进行烷氧羰基化、烷酰化、烯酰化、噻吩基羰基化或苯甲酰化而获得。这里，优选的烷氧羰基化是C1-6烷氧羰基化，叔丁氧羰基化是特别优选的。叔丁氧羰基化例如可通过用叔丁氧羰基-4,6-二甲基-2-巯基嘧啶和三乙胺处理而实现，而烷酰化、烯酰化、噻吩基羰基化或苯甲酰化则可通过与酸酐或酰基卤反应来实现。
用于本发明化合物(1)的制备方法中并由式(2)表示的化合物：[其中，A1、Y、Ac和Bz具有与前述相同的含义，Z表示氢原子或如下基：(其中，A2、R3、R4和R5具有与前述相同的含义)]是一种新型化合物且适用作为合成化合物(1)的中间体。
R4或R5表示的烷基实例包括C1-10(尤其C1-6)烷基，甲基是更优选的。作为烷氧苯基，4-(C1-6烷氧基)苯基是优选的，4-甲氧苯基是特别优选的。
通过实验(实验2)证实了本发明的紫杉烷衍生物(1)具有优异的抗肿瘤活性，所述实验是通过应用抗细胞株KB的生长抑制效果作为指标而进行的。
由于本发明的紫杉烷衍生物及其盐具有很高的水溶性(是紫杉酚的1000倍或更高)，所以它们可被用作药物制剂(药物组合物)(例如注射液)而无需应用任何特殊溶剂。作为药物制剂，注射液(例如静脉内注射液或肌内注射液)是优选的。除了这类注射液之外，它们还可被配制成液体制剂，例如吸入剂、糖浆剂或乳剂；固体制剂，例如片剂、胶囊或颗粒剂；或者外用制剂，例如软膏或栓剂。
这些制剂通常可含药物上可接受的载体，例如溶解助剂、稳定剂、湿润剂、乳化剂、吸收增强剂和表面活性剂(根据需要)。其它载体的实例有注射级蒸馏水、林格氏注射液、葡萄糖、蔗糖糖浆、明胶、食用油、可可脂、硬脂酸镁和滑石粉。
含于上述各药物制剂中的紫杉烷衍生物(1)的量根据被施给该药物制剂的患者状况、它的剂型等而变。不过，一般说来，每单位剂型它的量可根据需要在约0.5～100mg范围内(就注射液来说)，在约5～1,000mg范围内(就口服制剂来说)和在约5～1,000mg范围内(就栓剂来说)。此外，具有上述剂型的药物的日剂量根据各位患者的状况、体重、年龄、性别等而变，不能以成批方式确定。不过，日剂量通常可以是约0.1～50mg/kg、优选约1～20mg/kg/成人)。优选以单剂量或以分份剂型(每天二～四次)施用该剂量。
实施例
下面将通过实施例更详细地描述本发明。但是应记住，本发明不限于它们或者不受它们的限制。
实施例110-O-(4-哌啶子基哌啶子基羰基)-13-O-[3-叔丁氧羰基-4-(3-呋喃基)-2-(4-甲氧苯基)-5-噁唑烷羰基]-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-1)
在甲苯(20mL)中溶解10-O-(4-哌啶子基哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.117mmol)和3-(叔丁氧羰基)-4-(3-呋喃基)-2-(4-甲氧苯基)-5-噁唑烷羧酸(228mg,0.59mmol)，接着添加DCC(133mg,0.64mmol)和二甲氨基吡啶(10mg)。在室温下的氩气氛中搅拌形成的混合物达3小时。通过过滤从该反应混合物除去沉淀。往滤液中添加饱和碳酸氢钠溶液，用乙酸乙酯萃取形成的混合物。用饱和氯化钠溶液洗涤有机层，在无水硫酸钠上干燥，然后减压浓缩至干。通过色谱法在硅胶柱上纯化残余物[氯仿-甲醇混合物(98∶2)]。合并洗脱的只有一个TLC斑点的各级分，接着减压浓缩至干，于是得标题化合物(120mg,90％)。1H-NMR(CDCl3)δ:0.58-0.65(6H,m,Si-CH2x3),0.93(9H,t,J=7Hz,-Mex3),1.23(6H,s,C16-Me和C17-Me),1.32(9H,s,t-Bu),1.41-1.74(8H,m),1.69(3H,s,C19-Me),1.80-1.95(1H,m),1.89(1H,m,C6-H),2.11(3H,s,C18-Me),2.17(3H,s,C4-OAc),2.27(2H,m,C14-H),2.49-3.05(8H,m),2.53(1H,m,C6-H),3.83(3H,s,OMe),3.86(1H,d,J=7Hz,C3-H),4.10-4.53(2H,m),4.15(1H,d,J=8Hz,C20-H),4.28(1H,d,J=8Hz,C20-H),4.49(1H,dd,J=6Hz,10Hz,C7-H), 4.84(1H,s),4.92(1H,d,J=8Hz,C5-H),5.36(1H,s),5.66(1H,d,J=7Hz,C2-H),6.32(1H,t,J=8Hz,C13-H),6.40(3H,m,C10-H，呋喃基-H，噁唑烷-H),6.88-6.91(2H,m,ArH),7.32-7.64(5H,m,ArH),8.06-8.08(2H,m,ArH).SIMS m/z:1224(M+H)+
实施例213-O-[3-(叔丁氧羰基氨基)-3-(3-呋喃基)-2-羟基丙酰]-10-O-(4-哌啶子基哌啶子基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-1)
将实施例1中获得的化合物(2-1)(60mg,0.049mmol)溶于甲醇(9ml)，接着添加对-甲苯磺酸(25mg,0.146mmol)。在室温下搅拌形成的混合物达12小时。在往该反应混合物中添加饱和碳酸氢钠溶液之后，用氯仿萃取形成的混合物。在无水硫酸钠上干燥有机层，然后减压浓缩至干。通过色谱法在硅胶柱上纯化残余物(氯仿-甲醇=95∶5)，再进一步通过反相高效液相色谱法[洗脱液：10mM磷酸二氢钾-乙腈(1∶1)]纯化，于是得标题化合物(22mg,46％)无色固体。1H-NMR(CDCl3)δ:1.14(3H,s,C17或C16-Me),1.26(3H,s,C17或C16-Me),1.34(9H,s,t-Bu),1.48-1.96(9H,m),1.67(3H,s,C19-Me),1.89(3H,s),2.35(3H,s,C4-OAc),2.35(1H,m,C14-H),2.50-2.58(1H,m,C6-H),2.52-3.47(8H,m),3.81(1H,d,J=6Hz,C3-H),4.17-4.32(2H,m),4.18(1H,d,J=8Hz,C20-H),4.31(1H,d,J=8Hz,C20-H),4.44(1H,m,C7-H),4.54(1H,s,C2′-H),4.97(1H,d,J=8Hz,C5-H),5.10-5.12(1H,m),5.20(1H,d,J=10Hz,C3,-H), 5.67(1H,d,J=7Hz,C2-H),6.25(1H,t,J=8Hz,C13-H),6.26(1H,s,C10-H),6.45(1H,s，呋喃基H),7.42-7.65(5H,m,ArH),8.10-8.14(2H,m,ArH)。SIMS m/z:992(M+H)+
实施例313-O-[3-苄氧羰基-2,2-二甲基-4-(3-呋喃基)-5-噁唑烷羰基]-10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-2)
按与实施例1类似的方法，通过应用10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.127mmol)和3-苄氧羰基-2,2-二甲基-4-(3-呋喃基)-5-噁唑烷羧酸(200mg,0.57mmol)进行反应和后处理，于是得标题化合物(60mg,43％)。1H-NMR(CDCl3)δ:0.56-0.62(6H,m,Si-CH2x3),0.93(9H,t,J=8Hz,-Mex3),1.19(3H,s,C16-Me或C17-Me),1.20(3H,s,C16-Me或C17-Me),1.66-1.72(9H,m,C19-Me和噁唑烷Mex2),1.80-1.94(1H,m),2.13(6H,m,C18-Me和C4-OAc),2.22(2H,m,C14-H),2.32(3H,s,N-Me),2.39-2.55(5H,m),3.38-3.90(4H,m),3.84(1H,d,J=7Hz,C3-H),4.14(1H,d,J=8Hz,C20-H),4.29(1H,d,J=8Hz,C20-H),4.47(1H,dd,J=7Hz,11Hz,C7-H),4.60(1H,s),4.93(1H,d,J=8.1Hz,C5-H),5.38(1H,s),5.67(1H,d,J=7Hz,C2-H),6.22(1H,t,J=8Hz,C13-H),6.39(3H,m,C10-H，和呋喃基-H),7.27-7.64(10H,m,ArH),8.05-8.08(2H,m,ArH)。
实施例413-O-[3-(叔丁氧基碳酰氨基)-3-(3-呋喃基)-2-羟基丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-2)
将实施例3中获得的化合物(2-2)(50mg,0.045mmol)溶于乙醇(16mL)，接着添加0.1N盐酸(4.5mL)。在室温下搅拌形成的混合物达17小时。减压蒸馏出溶剂，往残余物中添加饱和碳酸氢钠水溶液。用氯仿萃取形成的混合物。在硫酸钠上干燥有机层，再减压浓缩至干。往残余物中添加甲醇(5mL)、水(0.5mL)和10％披钯活性炭(20mg)，接着在常温和常压下的氢气氛中搅拌3小时。过滤该反应混合物，减压浓缩滤液至干。往残余物中添加饱和碳酸氢钠溶液，用乙酸乙酯萃取形成的混合物。在硫酸钠上干燥有机层，减压浓缩至干，于是得残余物(28mg)。将残余物溶于四氢呋喃(8mL)，接着添加碳酸氢钠(20mg)和二叔丁基二碳酸酯(9mg,0.04mmol)。在室温下搅拌形成的混合物达20小时。往该反应混合物中添加饱和碳酸氢钠溶液，用乙酸乙酯萃取所得混合物。用饱和氯化钠溶液洗涤有机层，在硫酸钠上干燥，再减压浓缩至干。通过色谱法在硅胶柱上纯化残余物[氯仿-甲醇(95∶5)]，然后，通过反相高效液相色谱法[洗脱液：10mM磷酸二氢钾-乙腈(3∶2)]进一步纯化，于是得标题化合物(10mg,23％)无色固体。1H-NMR(CDCl3)δ:1.15(3H,s,C17或C16-Me),1.26(3H,s,C17或C16-Me),1.34(9H,s,t-Bu),1.68(3H,s,C19-Me),1.89(1H,m),1.90(3H,s,C18-Me),2.35(6H,s,C4-OAc和N-Me),2.35(2H,m,C14-H),2.42-2.58(5H,m),3.40-3.75(4H,m),3.81(1H,d,J=7Hz,C3-H),4.18(1H,d,J=9Hz,C20-H),4.31(1H,d,J=9Hz,C20-H),4.44(1H,dd,J=7Hz,11Hz,C7-H),4.54(1H,d,J=2Hz,C2′-H),4.97(1H,d,J=8Hz,C5-H),5.11(1H,d,J=10Hz),5.20(1H,d,J=10Hz),5.67(1H,d,J=7Hz,C2-H),6.24(1H,t,J=8Hz,C13-H),6.28(1H,s,C10-H),6.45(1H,s，呋喃基H),7.43-7.44(1H,m,ArH),7.48- 7.52(3H,m,ArH),7.58-7.62(1H,m,ArH),8.10-8.14(2H,m,ArH).SIMS m/z:924(M+H)+
实施例513-O-[3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羰基]-10-O-(4-二丙氨基哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-3)
按与实施例1类似的方法，通过应用10-O-(4-二丙氨基哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.127mmol)和3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羧酸(183mg,0.52mmol)进行反应和后处理，于是得标题化合物(130mg,93％)。1H-NMR(CDCl3)δ:0.55-0.63(6H,m,Si-CH2x3),0.86(9H,t,J=8Hz,-Mex3),0.87(6H,m),1.19(3H,s,C16-Me或C17-Me),1.21(3H,s,C16-Me或C17-Me),1.30-1.80(8H,m),1.67(3H,s,C19-Me),1.70-1.80(6H,m，噁唑烷Mex2),1.80-1.94(1H,m),2.13(3H,s,C18-Me或C4-OAc),2.17(3H,s,C18-Me或C4-OAc),2.22(2H,m,C14-H),2.35-3.02(7H,m),2.50(1H,m,C6-H),3.85(1H, d,J=7Hz,C3-H),4.06-4.51(2H,m),4.13(1H,d,J=8Hz,C20-H),4.29(1H,d,J=8Hz,C20-H),4.47(1H,dd,J=7Hz,11Hz,C7-H),4.78(1H,s),4.92(1H,d,J=8Hz,C5-H),4.93-5.20(2H,m),5.43(1H,s),5.67(1H,d,J=7Hz,C2-H),6.20(1H,m,C13-H),6.30-6.42(2H,m,C10-H，和呋喃基-H),7.10-7.50(8H,m,ArH),7.59-7.63(1H,m,ArH).8.05-8.08(2H,m,ArH)。实施例613-O-[3-(叔丁氧基羰基氨基)-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-二丙氨基哌啶子基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-3)
通过应用实施例5中获得的化合物(2-3)(140mg,0.118mmol)象实施例4中那样进行反应和后处理，接着通过反相高效液相色谱法[洗脱液：10mM磷酸二氢钾-乙腈(3∶2)]纯化，于是得标题化合物(34mg,30％)无色晶体。1H-NMR(CDCl3)δ:0.84-O.94(6H,m),1.15(3H,s,C17或C16-Me),1.26(3H,s,C17或C16-Me),1.34-1.99(7H,m),1.35(9H,s,t-Bu),1.68(3H,s,C19-Me),1.89(1H,m),1.91(3H,s,C18-Me),2.25-3.10(7H,m),2.35(2H,m,C14-H),2.40(3H,s,C4-OAC),2.55(1H,m),3.82(1H,d,J=7Hz,C3-H),4.10-4.32(2H,m),4.18(1H,d,J=9Hz,C20-H),4.31(1H,d,J=9Hz,C20-H),4.44(1H,m,C7-H),4.72(1H,s,C2′-H),4.98(1H,d,J=8Hz,C5-H),5.22(1H,d,J=10Hz),5.35(1H,d,J=10Hz),5.67(1H,d,J=7Hz,C2-H),6.25(1H,br-t,C13-H),6.27(1H,s,C10-H),6.31-6.33(1H,m，呋喃基H),6.37-6.38(1H,m，呋喃基H),7.41-7.42(1H,m,ArH),7.48-7.52(3H,m,ArH),7.58-7.62(1H,m,ArH),8.11-8.14(2H,m,ArH).SIMS m/z:1008(M+H)+实施例713-O-[3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羰基]-10-O-(4-乙基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-4)
按与实施例1类似的方法，通过应用10-O-(4-乙基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.125mmol)和3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羧酸(195mg,0.56mmol)进行反应和后处理，于是得标题化合物(140mg,99％)。1H-NMR(CDCl3)δ:0.55-0.62(6H,m,Si-CH2x3),0.92(9H,t,J=8Hz,-Mex3),1.11(3H,t,J=7Hz,-Et),1.19(3H,s,C16-Me或C17-Me),1.20(3H,s,C16-Me或C17-Me),1.30-1.40(1H,m),1.67(3H,s,C19-Me),1.73(6H,m，噁唑烷Mex2),1.82-1.97(2H,m),2.13(3H,s,C18-Me或C4-OAc),2.17(3H,s,C18-Me或C4-OAc),2.22(2H,m),2.40-2.56(4H,m),2.45(2H,q,J=7Hz,-Et),3.33-3.92(4H,m),3.85(1H,d,J=7Hz,C3-H),4.13(1H,d,J=8Hz,C20-H),4.28(1H,d,J=8Hz,C20-H),4.47(1H,dd,J=7Hz,11Hz,C7-H),4.63(1H,s),4.92(1H,d,J=8Hz,C5-H),4.93-5.20(2H,m),5.43(1H,s),5.67(1H,d,J=7Hz,C2-H),6.20(1H,t,J=8Hz,C13-H),6.34(2H,br-s，呋喃基-H),6.39(1H,s,C10-H),7.10-7.42(6H,m,ArH),7.45-7.49(2H,m,ArH),7.59-7.63(1H,m,ArH),8.05-8.08(2H,m,ArH)。实施例813-O-[3-(叔丁氧基羰基氨基)-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-乙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-4)
按与实施例4类似的方法，通过应用实施例7中获得的化合物(2-4)(140mg,0.124mmol)进行反应和后处理，通过反相高效液相色谱法[洗脱液：10mM磷酸二氢钾-乙腈(3∶2)]纯化这样获得的化合物，于是得标题化合物(60mg,53％)无色晶体。1H-NMR(CDCl3)δ:1.10-1.15(6H,m,C17或C16-Me和N-Et),1.2 (3H,s,C17或C16-Me),1.35(9H,s,t-Bu),1.68(3H,s,C19-Me),1.89(1H,m),1.90(3H,s,C18-Me),2.35(2H,m,C14-H),2.38(6H,s,C4-OAc),2.45-2.62(7H,m),3.40-3.85(4H,m),3.82(1H,d,J=7Hz,C3-H),4.18(1H,d,J=9Hz,C20-H),4.31(1H,d,J=9Hz,C20-H),4.46(1H,dd,J=7Hz,11Hz,C7-H),4.72(1H,d,J=2Hz,C2′-H),4.98(1H,d,J=8Hz,C5-H),5.23(1H,d,J=10Hz),5.35(1H,d,J=10Hz),5.67(1H,d,J=7Hz,C2-H),6.25(1H,t,J=8Hz,C13-H),6.28(1H,s,C10-H),6.32-6.33(1H,m，呋喃基H),6.38-6.39(1H,m,呋喃基H),7.41-7.42(1H,m,ArH),7.48-7.52(2H,m,ArH),7.59-7.63(1H,m,ArH),8.11-8.12(2H,m,ArH)。SIMS m/z:938(M+H)+
实施例913-O-[3-芳氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羰基]-10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-5)
在无水甲苯中溶解10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(138mg,0.18mmol)，接着添加3-烯丙氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羧酸(93mg,0.31mmol)、DCC(0.18mmol)和DMAP(0.01mmol)。在室温下搅拌形成的混合物达3小时。将反应混合物过滤，浓缩滤液。用饱和碳酸氢钠水溶液洗涤残余物，再用氯仿萃取。在无水硫酸镁上干燥有机层，减压浓缩至干。通过色谱法在硅胶柱上纯化残余物[氯仿-甲醇混合物(97∶3)]。收集洗脱的只有一个TLC斑点的各级分，再减压浓缩至于，于是得标题化合物(164mg,88％)。1H-NMR(CDCl3)δ:0.52-0.62(6H,m),0.90(9H,t,J=7.93Hz),1.16(3H,s),1.17(3H,s),1.64(3H,s),1.65(3H,s),1.72(3H,s),1.82(3H,s),1.83(1H,m),2.14(3H,s),2.30(3H,s),2.05-2.56(7H,m),3.32-3.65(4H,m),8.04(2H,d,J=8.Hz),3.81(1H,d,J=7Hz,C3-H),4.11(1H,d,J=8Hz,C20-H),4.26(1H,d,J=8Hz,C20-H),4.38-4.61(3H,m),4.78(1H,d,J=6Hz),4.91(1H,d,J=9Hz,C5-H),5.08-5.25(2H,m),5.53(1H,d,J=6Hz),5.64(1H,d,J=7Hz,C2-H),5.73(1H,m),6.19(1H,brs,C13-H),6.36(1H,s,C10-H),6.34-6.38(2H,m),7.38(1H,t,J=1Hz),7.54(2H,t,J=8Hz),7.59(1H,t,J=7Hz)。
实施例1013-O-[3-苯甲酰氨基-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-5)
将实施例9中获得的化合物(2-5)(55mg,0.05mmol)溶于四氢呋喃(2mL)，接着添加Pd(PPh3)4(8mg,0.007mmol)和双甲酮。在室温下搅拌形成的混合物达12小时。减压蒸馏出溶剂，将残余物溶于乙醇，然后往形成的溶液中添加0.1N盐酸(2.5mL)。在室温下搅拌该混合物达36小时。用饱和碳酸氢钠水溶液洗涤该反应混合物，再用氯仿萃取。在无水硫酸镁上干燥有机层，减压蒸馏而除去溶剂。往残余物中添加二氯甲烷(3mL)、苯甲酸酐(9mg,0.04mmol)和三乙胺(4mg,0.04mmol)，接着在冰浴上搅拌3小时。减压蒸馏出溶剂。然后通过色谱法在硅胶柱上纯化残余物[氯仿-甲醇混合物(95∶5)]，再通过反相高效液相色谱法[洗脱液：10mM磷酸二氢钾-乙腈(1∶1)]进一步纯化，于是得标题化合物(40mg,85％)无色晶体。1H-NMR(CDCl3)δ:1.06(3H,s),1.17(3H,s),1.62(3H,s),1.80(1H,m),1.83(3H,s),2.18-2.65(7H,m),2.33(3H,s),2.37(3H,s),2.98(1H,brs),3.32-3.70(4H,m),3.75(1H,d,J=7Hz,C3-H),4.13(1H,d,J=9Hz,C20-H),4.25(1H,d,J=8Hz,C20-H),4.38(1H,m,C7-H),4.76(1H,d,J=2Hz,C2′-H),4.90(1H,d,J=10Hz,C5-H),5.61(1H,d,J=7Hz,C2-H),5.83(1H,dd,J=9Hz,2Hz,C3′-H),6.20(1H,t,J=9Hz,C13-H),6.33-6.34(2H,m),6.21(1H,s,C10-H),6.80(1H,d,J=9Hz,NH),7.32-7.39(6H,m),7.44(2H,t,J=8Hz),7.54(1H,t,J=7Hz),7.68(2H,d,J=7Hz),8.07(2H,d,J=7Hz)。SIMS m/z 928(M+H)+
实施例1113-O-[3-(2-呋喃基)-2-羟基-3-正戊基羰基氨基丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-6)
按与实施例10类似的方法，通过应用实施例9的化合物(2-5)(55mg,0.05mmol)和正戊基碳酰氯(5mg,0.04mmol)进行反应和后处理，于是得标题化合物(8mg,35％)无色晶体。1H-NMR(CDCl3)δ:0.77(3H,t,J=7Hz),1.07(3H,s),1.19(3H,s),1.16-1.22(4H,m),1.49(2H,m),1.61(3H,s),1.79(1H,m),1.83(3H,s),2.32(3H,s),2.35(3H,s),2.64-2.08(9H,m),3.00(1H,s),3.70-3.30(4H,m),3.73(1H,d,J=7Hz,C3-H),4.12(1H,d,J=9Hz,C20-H),4.24(1H,d,J=8Hz,C20-H),4.38(1H,m,C7-H),4.66(1H,d,J=2Hz,C2′-H),4.90(1H,d,J=7Hz,C5-H),5.58-5.63(2H,m),6.06(1H,d,J=9Hz,NH),6.1 6(1H,t,J=9Hz,C13-H),6.21(1H,s,C10-H),6.26(1H,d,J=3Hz),6.32(1H,dd,J=3Hz,2Hz),7.36(1H,d,J=1Hz),7.44(2H,t,J=8Hz),7.54(1H,t,J=7Hz),8.05(2H,d,J=7Hz)。Ms m/z 922[M+H]+
实施例1213-O-[3-(2-呋喃基)-2-羟基-3-(噻吩甲酰氨基)丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-7)
按与实施例10类似的方法，通过应用实施例9的化合物(2-5)(55mg,0.05mmol)和2-噻吩甲酰氯(6mg,0.04mmol)进行反应和后处理，于是得标题化合物(3mg,12％)无色晶体。1H-NMR(CDCl3)δ:1.05(3H,s),1.19(3H,s),1.62(3H,s),1.83(3H,s),1.85(m,1H),2.33(3H,s),2.35(3H,s),2.21-2.97(7H,m),3.59(1H,s),3.37-3.98(4H,m),3.74(1H,d,J=7Hz,C3-H),4.13(1H,d,J=9Hz,C20-H),4.24(1H,d,J=9Hz,C20-H),4.38(1H,m,C7-H),4.76(1H,d,J=2Hz,C2′-H),4.89(1H,d,J=8Hz,C5-H), 5.60(1H,d,J=7Hz,C2-H),5.79(1H,dd,J=9Hz,2Hz,C3″-H),6.19(1H,t,J=9Hz,C13-H),6.21(1H,s,C10-H),6.32-6.35(2H,m),6.68(1H,d,J=9Hz,NH),7.00(1H,dd,J=5Hz,4Hz),7.38-7.48(5H,m),7.56(1H,t,J=7Hz),8.07(2H,d,J=7Hz).MS m/z 932[M+H]+
实施例1313-O-[3-烯丙氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羰基]-10-O-(4-吗啉代哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-6)
按与实施例9类似的方法，从10-O-(4-吗啉代哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(64mg,0.075mmol)和3-烯丙氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羧酸(30mg,0.1mmol)获得标题化合物(85mg,100％)。1H-NMR(CDCl3)δ:0.53-0.59(6H,m),0.90(9H,t,J=8Hz),1.14(3H,s),1.17(3H,s),1.64(3H,s),1.65(3H,s),1.72(3H,s),1.82(3H,s),1.30-1.93(5H,m),2.13(3H,s),2.00-3.09(10H,m),3.62-3.75(4H,m),3.80(1H,d,J=7Hz,C3-H),4.10(1H,d,J=8Hz,C20-H),4.10-4.60(5H,m),4.25(1H,d,J=8Hz,C20-H),4.78(1H,d,J=6Hz),4.90(1H,d,J=10Hz,C5-H),5.24-5.06(2H,m),5.64(1H,d,J=7Hz,C2-H),5.73(1H,brs),6.17(1H,brs,C13-H),6.30-6.37(2H,m),6.35(1H,s,C10-H),7.38(1H,d,J=1Hz),7.46(2H,t,J=8Hz),7.59(1H,t,J=7Hz),8.04(2H,d,J=8Hz)。实施例1413-O-[3-(3,3-二甲基丙烯酰氨基)-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-吗啉代哌啶子基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-8)
按与实施例10相似的方法，通过应用实施例13的化合物(2-6)(42mg,0.037mmol)和3,3-二甲基丙烯酰氯(5mg,0.04mmol)进行反应和后处理，于是得标题化合物(9mg,25％)无色晶体。1H-NMR(CDCl3)δ:1.07(3H.s),1.19(3H.s),1.32-2.00(5H,m),1.60(3H.s),1.7 6(3H.s),1.83(3H.s),1.95(3H.s),2.15-3.10(10H,m),2.35(3H.s),3.25-3.95(4H,m),4.11(1H,d,J=9Hz,C20-H),4.10-4.27(2H,m),4.24(1H,d,J=8Hz,C20-H),4.38(1H,m,C7-H),4.86(1H,brs,C2′-H),4.90(1H,d,J=8Hz,C5-H),5.52(1H,s),5.62(1H,brs,C3′-H),5.67(1H,d,J=7Hz,C2-H),6.16(1H,brs,C13-H),6.20(1H,s,C10-H),6.26(1H,d,J=3Hz),6.31(1H,dd,J=3Hz,2Hz),7.36(1H,d,J=2Hz),7.43(2H,t,J=7Hz),7.54(1H,t,J=7Hz),8.05(2H,d,J=7Hz).MS m/z 976[M+H]+
实施例1513-O-[3-苄氧羰基-2,2-二甲基-4-(4-氟苯基)-5-噁唑烷羰基]-10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-7)
按与实施例1相似的方法，应用10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.128mmol)和3-苄氧羰基-2,2-二甲基-4-(4-氟苯基)-5-噁唑烷羧酸(191mg,0.512mmol)进行反应和后处理，于是得标题化合物(118mg,81％)无色晶体。1H-NMR(CDCl3)δ:0.53-0.63(6H,m),0.93(9H,t,J=8Hz),1.17(3H,s),1.20(3H,s),1.55-1.61(3H,m),1.66(3H,s),1.75(3H,s),1.80-1.92(2H,m),1.81(3H,s),1.96(3H,s),2.08(3H,s),2.17(2H,d,J=9Hz),2.48-2.66(m,5H),3.55-3.80(m,4H),3.79(1H,d,J=7Hz),4.10(1H,d,J=9Hz),4.27(1H,d,J=9Hz),4.43-4.47(m,2H),4.80-5.03(m,1H),4.88-4.90(1H,m),5.21(brs,1H),5.65(1H,d,J=7Hz),6.23(1H,t,J=10Hz),6.39(1H,s),6.83(1H,brs),7.00-7.29(m,9H),7.49(2H,t,J=8Hz),7.63(1H,t,J=7Hz),8.04(2H,d,J=7Hz)。SI-MS m/z:1140[M+H]+
实施例1613-O-[3-(叔丁氧基羰基氨基)-3-(4-氟苯基)-2-羟基丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-9)
将实施例15中获得的化合物(2-7)(110mg,0.097mmol)溶于乙醇(30mL)，接着在冰冷却和搅拌下添加0.1N盐酸(9.7mL,0.97mmol)。在室温下搅拌形成的混合物达3天。减压蒸馏出溶剂，往残余物中添加饱和碳酸氢钠水溶液。用氯仿萃取形成的混合物。用水和饱和盐水洗涤有机层，在无水硫酸钠上干燥，再减压蒸馏而除去溶剂。通过色谱法在硅胶柱上纯化残余物[氯仿-甲醇混合物(30∶1)]。往残余物中添加甲醇(10mL)、水(1mL)和10％披钯碳(31mg,0.029mmol)，接着在常温常压和氢气氛中强烈搅拌3小时。将反应混合物过滤，减压浓缩滤液至干。往残余物中添加饱和碳酸氢钠溶液，用乙酸乙酯萃取形成的混合物。用水和饱和盐水洗涤有机层，在无水硫酸钠上干燥，再减压浓缩至干，于是得无色油(80mg,88％)。将该油溶于四氢呋喃(20mL)，接着添加碳酸氢钠(74mg,0.88mmol)和二叔丁基二碳酸酯(23mg,0.106mmol)。在室温下搅拌形成的混合物达19小时。往反应混合物中添加饱和碳酸氢钠溶液，用乙酸乙酯萃取形成的混合物。用饱和氯化钠溶液洗涤有机层，在硫酸钠上干燥，减压浓缩至干。通过色谱法在硅胶柱上纯化残余物[氯仿-甲醇混合物(50∶1)]，然后通过反相高效液相色谱法[洗脱液：10mM磷酸二氢钾-乙腈(55∶45)]进一步纯化，于是得标题化合物(15mg,18％)无色固体。1H-NMR(CDCl3)δ:1.14(3H,s),1.26(3H,s),1.33(9H,s),1.68(3H,s),1.85-1.92(m,5H),2.25(3H,m),2.37(3H,s),2.44(3H,s),2.50-2.63(4H,m),3.45-3.80(m,4H),3.80(1H,d,J=7Hz),4.18(1H,d,J=8Hz),4.31(1H,d,J=8Hz),4.44(1H,dd,J=7,11Hz),4.60(1H,s),4.94-4.97(1H,m),5.24-5.26(1H,m),5.38-5.40(1H,m),5.66(1H,d,J=7Hz),6.24-6.28(1H,m),6.28(1H,s),7.06-7.11(2H,m),7.36-7.39(2H,m),7.50(2H,t,J=8Hz),7.59-7.63(1H,m),8.11(2H,d,J=7Hz).SI-MS m/z:952[M+H]
实施例1713-O-[3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羰基]-10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-8)
按与实施例1类似的方法，应用10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.127mmol)和3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羧酸(190mg,0.55mmol)进行反应和后处理，于是得标题化合物(140mg,99％)。1H-NMR(CDCl3)δ:0.56-0.62(6H,m,Si-CH2x3),0.93(9H,t,J=8Hz,-Mex3),1.19(6H,s,C16-Me和C17-Me),1.66-1.73(9H,m,C19-Me和噁唑烷Mex2),1.82-1.92(1H,m),2.05(3H,s),2.13(3H,s),2.22(2H,m,C14-H),2.39-2.55(5H,m),2.41(3H,s),3.39-3.99(4H,m),3.84(1H,d,J=7Hz,C3-H),4.14(1H,d,J=8Hz,C20-H),4.28(1H,d,J=8Hz,C20-H),4.47(1H,dd,J=7Hz,11Hz,C7-H),4.78(1H,s),4.93(1H,d,J=8Hz,C5-H),4.95-5.18(2H,m),5.45(1H,s),5.66(1H,d,J=7Hz,C2-H),6.22(1H,t,J=8Hz,C13-H),6.34(2H,m),6.39(3H,s,C10-H),7.10-7.40(6H,m,ArH),7.45-7.49(2H,m,ArH),7.59-7.64(1H,m,ArH),8.05-8.07(2H,m,ArH)。
实施例1813-O-[3-(叔丁氧基羰基氨基)-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-10)
按与实施例4类似的方法，应用实施例17中获得的化合物(2-8)(130mg,0.117mmol)进行反应和后处理，于是得标题化合物(22mg,21％)无色晶体。1H-NMR(CDCl3)δ:1.14(3H,s,C17或C16-Me),1.26(3H,s,C17或C16-Me),1.35(9H,s,t-Bu),1.68(3H,s,C19-Me),1.89(1H,m),1.92(3H,s,C18-Me),2.35(2H,m,C14-H),2.39(3H,s),2.40(3H,s),2.50-2.60(6H,m),3.15(1H,s),3.40-3.85(4H,m),3.82(1H,d,J=7Hz,C3-H),4.18(1H,d,J=9Hz,C20-H),4.31(1H,d,J=9Hz,C20-H),4.46(1H,dd,J=7Hz,11Hz,C7-H),4.72(1H,d,J=2Hz,C2′-H),4.97(1H,d,J=8Hz,C5-H),5.27(1H,d,J=10Hz),5.35(1H,d,J=10Hz),5.67(1H,d,J=7Hz,C2-H),6.25(1H,t,J=8Hz,C13-H),6.28(1H,s,C10-H),6.32-6.33(1H,m，呋喃基H),6.37-6.38(1H,m，呋喃基H),7.43-7.44(1H,m,ArH),7.48-7.53(2H,m,ArH),7.59-7.64(1H,m,ArH),
8.11-8.13(2H,m,ArH).SIMS m/z:924(M+H)+
实施例1913-O-[3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羰基]-10-O-(4-吗啉代哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-9)
按与实施例1类似的方法，应用10-O-(4-吗啉代哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.117mmol)和3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羧酸(174mg,0.50mmol)进行反应和后处理，于是得标题化合物(130mg,94％)。1H-NMR(CDCl3)δ:0.56-0.62(6H,m,Si-CH2x3),0.93(9H,t,J=8Hz,-Mex3),1.18(6H,s,C16-Me和C17-Me),1.59-1.73(9H,m,C19-Me和噁唑烷Mex2),1.82-1.92(1H,m),2.11(3H,s),2.17(3H,s),2.22(2H,m,C14-H),2.48-2.55(1H,m),2.49-3.10(6H,m),3.70-4.00(4H,m),3.84(1H,d,J=7Hz,C3-H),4.13(1H,d,J=8Hz,C20-H),4.28(1H,d,J=8Hz,C20-H),4.47(1H,dd,J=7Hz,11Hz,C7-H),4.78(1H,m),4.93(1H,d,J=8Hz,C5-H),4.95-5.20(2H,m),5.43(1H,m),5.67(1H,d,J=7Hz,C2-H),6.20(1H,t,J=8Hz,C13-H),6.34(2H,m),6.39(3H,s,C10-H),7.10-7.40(6H,m,ArH),7.45-7.49(2H,m,ArH),7.59-7.63(1H,m,ArH),8.05-8.07(2H,m,ArH)。
实施例2013-O-[3-(叔丁氧基羰基氨基)-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-吗啉代哌啶子基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-11)
按与实施例4类似的方法，应用实施例19的化合物(2-9)(130mg,0.11mmol)进行反应和后处理，于是得标题化合物(23mg,21％)无色晶体。1H-NMR(CDCl3)δ:1.14(3H,s,C17或C16-Me),1.26(3H,s,C17或C16-Me),1.35(9H,s,t-Bu),1.40-2.00(6H,m),1.67(3H,s,C19-Me),1.91(3H,s,C18-Me),2.32-2.45(2H,m,C14-H),2.40(3H,s),2.50-2.72(5H,m),2.75-3.20(2H,m),3.13(1H,s),3.70-3.95(5H,m),4.19-4.32(2H,m),4.19(1H,d,J=9Hz,C20-H),4.31(1H,d,J=9Hz,C20-H),4.44(1H,dd,J=7Hz,11Hz,C7-H),4.72(1H,d,J=2Hz,C2′-H),4.98(1H,d,J=8Hz,C5-H),5.25(1H,d,J=10Hz),5.36(1H,d,J=10Hz),5.66(1H,d,J=7Hz,C2-H),6.25(1H,t,J=8Hz,C13-H),6.27(1H,s,C10-H),6.31-6.33(1H,m，呋喃基H),6.37-6.39(1H,m，呋喃基H),7.41-7.42(1H,m,ArH),7.50-7.53(2H,m,ArH),7.59-7.64(1H,m,ArH),8.11-8.12(2H,m,ArH).SIMS m/z:994[M+H]+
实施例2110-O-(4-二乙氨基哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-10)
在四氢呋喃(5mL)中溶解7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.15mmol)，接着在-40℃的氢气氛中添加1.6M正丁基锂己烷溶液(0.13mL,0.206mmol)。搅拌形成的混合物达1小时。往该反应混合物中添加通过将4-二乙氨基哌啶子基碳酰氯(37.1mg,0.17mmol)溶于四氢呋喃(1mL)而获得的溶液。在-20℃下搅拌形成的混合物，再在逐渐加热后，在室温下搅拌一夜。往该反应混合物中添加氯化铵水溶液(50mL)，用乙酸乙酯萃取形成的混合物。用饱和氯化钠水溶液洗涤有机层，在无水硫酸钠上干燥，再减压浓缩至干。通过色谱法在硅胶柱上纯化残余物[氯仿-甲醇(95∶5)]。合并洗脱的只有一个TLC斑点的各级分，减压浓缩至干，于是得标题化合物(67mg,54％)。1H-NMR(CDCl3)δ:0.55-0.65(6H,m,Si-CH2x3),0.93(9H,t,J=8Hz,-Mex3),1.00-1.20(6H,m),1.04(3H,s,C17或C16-Me),1.18(3H,s,C17或C16-Me),1.40-1.50(1H,m),1.64(1H,s),1.68(3H,s,C19-Me),1.80-1.92(2H,m),2.17-2.32(3H,m),2.25(3H,s),2.28(3H,s),2.49-2.58(1H,m),2.60-3.00(7H,m),3.90(1H,d,J=7Hz,C3-H),4.15(1H,d,J=8Hz,C20-H),4.20-4.50(2H,m),4.30(1H,d,J=8Hz,C20-H),4.48(1H,dd,J=7Hz,11Hz,C7-H),4.81(1H,m),4.96(1H,d,J=8Hz,C5-H),5.64(1H,d,J=7Hz,C2-H),6.39(3H,s,C10-H),7.46-7.50(2H,m,ArH),7.58-7.61(1H,m,ArH),8.10-8.12(2H,m,ArH).
实施例2213-O-[3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羰基]-10-O-(4-二乙氨基哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-11)
按与实施例1类似的方法，应用实施例21的化合物(2-10)(67mg,0.079mmol)和3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羧酸(138mg,0.39mmol)进行反应和后处理，于是得标题化合物(93mg,99％)。1H-NMR(CDCl3)δ:0.56-0.62(6H,m,Si-CH2x3),0.92(9H,t,J=8Hz,-Mex3),1.17-1.23(12H,m),1.40-2.00(5H,m),1.67(3H,s,C19-Me),1.67-1.80(6H,m，噁唑烷Mex2),1.81-1.91(1H,m),2.11(3H,s),2.17(3H,s),2.22(2H,m,C14-H),2.48-2.56(1H,m),2.70-3.15(6H,m),3.84(1H,d,J=7Hz,C3-H),4.13(1H,d,J=8Hz,C20-H),4.20-4.50(2H,m),4.28(1H,d,J=8Hz,C20-H),4.47(1H,dd,J=7Hz,11Hz,C7-H),4.78(1H,m),4.93(1H,d,J=8Hz,C5-H),4.95-5.20(2H,m),5.43(1H,m),5.67(1H,d,J=7Hz,C2-H),6.20(1H,t,J=8Hz,C13-H),6.35(2H,m),6.39(3H,s,C10-H),7.10-7.43(6H,m,ArH),7.45-7.49(2H,m,ArH),7.59-7.63(1H,m,ArH),8.05-8.07(2H,m,ArH).
实施例2313-O-[3-(叔丁氧基羰基氨基)-3-(2-呋喃基)-2-(羟基丙酰)-10-O-(4-二乙氨基哌啶子基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-12)
按与实施例4类似的方法，应用实施例22的化合物(2-11)(93mg,0.081mmol)进行反应和后处理，于是得标题化合物(29mg,37％)无色晶体。1H-NMR(CDCl3)δ:1.10-1.16(9H,m),1.26(3H,s,C17或C16-Me),1.35(9H,s,t-Bu),1.50-2.05(5H,m),1.67(3H,s,C19-Me),1.89(1H,m),1.91(3H,s,C18-Me),2.30-2.40(2H,m,C14-H),2.40(3H,s),2.55(1H,m),2.60-3.10(6H,m),3.17(1H,s),3.82(1H,d,J=7Hz,C3-H),4.18(1H,d,J=9Hz,C20-H),4.18-
4.34(2H,m),4.31(1H,d,J=9Hz,C20-H),
4.46(1H,dd,J=7Hz,11Hz,C7-H),4.72(1H,d,J=2Hz,C2′-H),
4.97(1H,d,J=8Hz,C5-H),5.25(1H,d,J=10Hz),
5.35(1H,d,J=10Hz),5.67(1H,d,J=7Hz,C2-H),
6.25(1H,t,J=8Hz,C13-H),6.27(1H,s,C10-H),6.32-
6.33(1H,m，呋喃基H),6.37-6.38(1H,m，呋喃基H),7.41-
7.42(1H,m,ArH),7.48-7.53(2H,m,ArH),7.59-7.64(1H,m,ArH),
8.11-8.12(2H,m,ArH).SIMS m/z:980[M+H]+
实施例2410-O-(4-二正丁基氨基哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-12)
按与实施例21类似的方法，应用7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.15mmol)和4-二正丁基氨基哌啶子基碳酰氯(46.5mg,0.17mmol)进行反应和后处理，于是得标题化合物(79mg,59％)。1H-NMR(CDCl3)δ:0.55-0.65(6H,m,Si-CH2x3),0.89-1.00(6H,m),0.93(9H,t,J=8Hz,-Mex3),1.05(3H,s,C17或C16-Me),1.17(3H,s,C17或C16-Me),1.23-2.18(13H,m),1.62(1H,s),1.68(3H,s,C19-Me),1.80-1.92(1H,m),2.23-2.30(2H,m),2.23(3H,s),2.29(3H,s),2.40-3.10(6H,m),2.49-2.58(1H,m),3.90(1H,d,J=7Hz,C3-H),4.15(1H,d,J=8Hz,C20-H),4.20-4.52(2H,m),4.31(1H,d,J=8Hz,C20-H),4.48(1H,dd,J=7Hz,11Hz,C7-H),4.84(1H,m),4.96(1H,d,J=8Hz,C5-H),5.64(1H,d,J=7Hz,C2-H), 6.39(3H,s,C10-H),7.4 6-7.50(2H,m,ArH),7.59-7.62(1H,m,ArH),8.10-8.12(2H,m,ArH).
实施例2513-O-[3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羰基]-10-O-(4-二正丁氨基哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-13)
按与实施例1类似的方法,应用实施例24的化合物(2-12)(79mg,0.088mmol)和3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羧酸(152mg,0.44mmol)进行反应和后处理，于是得标题化合物(107mg,99％)。1H-NMR(CDCl3)δ:0.56-0.62(6H,m,Si-CH2x3),0.90-0.99(15H,m),1.19(6H,s,C16-Me和C17-Me),1.25-1.40(4H,m),1.50-2.00(9H,m),1.66(3H,s,C19-Me),1.66-1.80(6H,m,oxazolidine Mex2),1.81-1.91(1H,m),2.09(3H,s),2.17(3H,s),2.18-2.25(2H,m,C14-H),2.46-2.56(1H,m),2.500-3.10(6H,m),3.84(1H,d,J=7Hz,C3-H),4.13(1H,d,J=8Hz,C20-H),4.25-4.50(2H,m),4.28(1H,d,J=8Hz,C20-H),4.47(1H,dd,J=7Hz,11Hz,C7-H),4.78(1H,m),4.93(1H,d,J=8Hz,C5-H),4.95-5.20(2H,m),5.43(1H,m),5.66(1H,d,J=7Hz,C2-H),6.20(1H,t,J=8Hz,C13-H),6.34(2H,m),6.39(3H,s,C10-H),7.10-7.41(6H,m,ArH),7,45-7.49(2H,m,ArH),7.59-7.63(1H,m,ArH),8.05-8.07(2H,m,ArH).
实施例2613-O-[3-(叔丁氧基羰基氨基)-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-二正丁氨基哌啶子基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-13)
按与实施例4类似的方法，应用实施例25的化合物(2-13)(107mg,0.087mmol)进行反应和后处理，于是得标题化合物(20mg,23％)无色晶体。1H-NMR(CDCl3)δ:0.88-0.98(6H,m),1.15(3H,s,C17或C16-Me),1.20-2.00(13H,m),1.26(3H,s,C17或C16-Me),1.35(9H,s,t-Bu),1.67(3H,s,C19-Me),1.89(1H,m),1.91(3H,s,C18-Me),2.30-2.40(2H,m,C14-H),2.40(3H,s),2.45-3.05(7H,m),3.20(1H,s),3.82(1H,d,J=7Hz,C3-H),4.18(1H,d,J=9Hz,C20-H),4.18-4.32(2H,m),4.30(1H,d,J=9Hz,C20-H),4.46(1H,dd,J=7Hz,11Hz,C7-H),4.72(1H,d,J=2Hz,C2′-H),4.97(1H,d,J=8Hz,C5-H),5.27(1H,d,J=10Hz),5.35(1H,d,J=10Hz),5.67(1H,d,J=7Hz,C2-H),6.25(1H,t,J=8Hz,C13-H),6.2 6(1H,s,C10-H),6.32-6.33(1H,m，呋喃基H),6.37-6.38(1H,m，呋喃基H),7.43-7.44(1H,m,ArH),7.48-7.53(2H,m,ArH),7.59-7.64(1H,m,ArH),8.11-8.13(2H,m,ArH).SIMS m/z:1036[M+H]+
实施例2710-O-(4-丙基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-14)
按与实施例21类似的方法，应用7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(400mg,0.61mmol)和4-丙基哌嗪基碳酰氯(232mg,1.22mmol)进行反应和后处理，于是得标题化合物(344mg,70％)。1H-NMR(CDCl3)δ:0.56-0.63(6H,m,Si-CH2x3),0.89-0.99(3H,m),0.93(9H,t,J=8Hz,-Mex3),1.05(3H,s,C17或C16-Me),1.15(3H,s,C17或C16-Me),1.65-2.00(2H,m),1.68(3H,s,C19-Me),1.84-1.90(1H,m),2.23-2.80(6H,m),2.23(3H,s),2.29(3H,s),2.49-2.57(1H,m),3.89(1H,d,J=7Hz,C3-H),4.15(1H,d,J=8Hz,C20-H),3.50-4.10(4H,m),4.31(1H,d,J=8Hz,C20-H),4.49(1H,dd,J=7Hz,11Hz,C7-H),4.83-4.87(1H,m),4.95-4.97(1H,m,C5-H),5.63(1H,d,J=7Hz,C2-H),6.40(3H,s,C10-H),7.46-7.50(2H,m,ArH),7.59-7.63(1H,m,ArH),8.10-8.12(2H,m,ArH).
实施例2813-O-[3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羰基]-10-O-(4-丙基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-15)
按与实施例1类似的方法，应用实施例27的化合物(2-14)(100mg,0.123mmol)和3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羧酸(170mg,0.54mmol)，于是得标题化合物(140mg,99％)。1H-NMR(CDCl3)δ:0.51-0.66(6H,m),0.92(3H,t,J=7Hz),0.92(9H,t,J=8Hz),1.18(3H,s),1.20(3H,s),1.51-1.56(2H,m),1.67(3H,s),1.74(6H,s),1.84-1.93(2H,m),2.13(3H,s),2.17(s,3H),2.20-2.23(1H,m),2.32-2.36(2H,m),2.41-2.55(5H,m),3.39-3.92(4H,m),3.84(1H,d,J=7Hz),4.13(1H,d,J=8Hz),4.28(1H,d,J=8Hz),4.47(1H,dd,J=7,11Hz),4.78(1H,brs),4.91-4.93(1H,m),5.02-5.20(2H,m),5.43(1H,brs),5.67(1H,d,J=7Hz),6.18-6.22(1H,m),6.33-6.39(2H,m),6.39(1H,s),7.16-7.40(6H,m),7.47(2H,t,J=8Hz),7.59-7.63(1H,m),8.04-8.07(2H,m).
实施例2913-O-[3-(叔丁氧基羰基氨基)-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-14)
按与实施例16类似的方法，应用实施例28的化合物(2-15)(130mg,0.114mmol)进行反应和后处理，于是得标题化合物(65mg,60％)无色晶体。1H-NMR(CDCl3)δ:0.95(3H,t,J=7Hz),1.14(3H,s),1.26(3H,s),1.35(9H,s,t-Bu),1.68(3H,s),1.82-1.88(3H,m),1.92(3H,s),2.32-2.38(2H,m),2.40(3H,s),2.29-2.70(6H,m),3.12(1H,s),3.32-3.85(4H,m),3.73-3.76(2H,m),3.82(1H,d,J=7Hz),4.18(1H,d,J=8Hz),4.31(1H,d,J=8Hz),4.42-4.48(1H,m),4.72(1H,d,J=2Hz,C2′-H),4.96-4.98(1H,m),5.23-55(1H,m),5.33-5.36(1H,m),5.67(1H,d,J=7Hz),6.23-6.27(1H,m),6.28(1H,s),6.32-6.33(1H,m),6.38-6.39(1H,m),7.42-7.43(1H,m),7.48-7.52(2H,m),7.59-7.63(1H,m),8.11-8.13(2H,m).SI-MS m/z:952[M+H]+
实施例3013-O-[3-苄氧羰基-2,2-二甲基-4-{2-(5-甲基呋喃基)}-5-噁唑烷羰基]-10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-16)
按与实施例1类似的方法，应用10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.1 27mmol)和3-苄氧羰基-2,2-二甲基-4-(2-呋喃基)-5-噁唑烷羧酸(198mg,0.55mmol)进行反应和后处理，于是得标题化合物(100mg,70％)。1H-NMR(CDCl3)δ:0.56-0.62(6H,m,Si-CH2x3),0.93(9H,t,J=8Hz,-Mex3),1.19(6H,s,C16-Me和C17-Me),1.67(3H,m,C19-Me),1.67-1.75(6H,m，噁唑烷Mex2),1.83-1.92(1H,m),2.12(3H,s),2.16(3H,s),2.22(2H,m,C14-H),2.27(3H,s),2.39-2.55(5H,m),2.39(3H,s),2.39-2.70(4H,m),3.40-4.00(4H,m),3.84(1H,d,J=7Hz,C3-H),4.14(1H,d,J=8Hz,C20-H),4.28(1H,d,J=8Hz,C20-H),4.47(1H,dd,J=7Hz,11Hz,C7-H),4.78(1H,s),4.93(1H,d,J=8Hz,C5-H),4.95-5.20(2H,m),5.45(1H,s),5.66(1H,d,J=7Hz,C2-H),5.88-6.12(2H,m),6.20(1H,t,J=8Hz,C13-H),6.39(3H,s,C10-H),7.10-7.40(5H,m,ArH),7.45-7.49(2H,m,ArH),7.59-7.64(1H,m,ArH),8.05-8.07(2H,m,ArH).
实施例3113-O-[3-(叔丁氧基羰基氨基)-3-{2-(5-甲基呋喃基)}-2-羟基丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-15)
按与实施例4类似的方法，应用实施例30的化合物(2-16)(100mg,0.088mmol)进行反应和后处理，于是得标题化合物(20mg,25％)无色晶体。1H-NMR(CDCl3)δ:1.15(3H,s,C17或C16-Me),1.2 6(3H,s,C17或C16-Me),1.35(9H,s,t-Bu),1.68(3H,s,C19-Me),1.89(1H,m), 1.92(3H,s,C18-Me),2.29(3H,s),2.32-2.40(2H,m,C14-H),2.36(3H,s),2.42(3H,s),2.46-2.59(5H,m),3.17(1H,s),3.40-3.78(4H,m),3.82(1H,d,J=7Hz,C3-H),4.18(1H,d,J=9Hz,C20-H),4.31(1H,d,J=9Hz,C20-H),4.46(1H,dd,J=7Hz,11Hz,C7-H),4.69(1H,d,J=2Hz,C2,-H),4.98(1H,d,J=8Hz,C5-H),5.22(1H,d,J=10Hz),5.30(1H,d,J=10Hz),5.67(1H,d,J=7Hz,C2-H),5.94-5.95(1H,m，呋喃基H),6.17-6.18(1H,m，呋喃基H),6.23(1H,t,J=8Hz,C13-H),6.28(1H,s,C10-H),7.48-7.53(2H,m,ArH),7.59-7.64(1H,m,ArH),8.11-8.12(2H,m,ArH).SIMS m/z:938[M+H]+
实施例3213-O-[3-苄氧羰基-2,2-二甲基-4-(4-氟苯基)-5-噁唑烷羰基]-10-O-[4-(异丙氨基羰基甲基)哌嗪基羰基]-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-17)
按与实施例1类似的方法，应用10-O-[4-(异丙氨基羰基甲基)哌嗪基羰基]-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.115mmol)和3-苄氧羰基-2,2-二甲基-4-(4-氟苯基)-5-噁唑烷羧酸(172mg,0.460mmol)进行反应和后处理，于是得标题化合物(140mg,99％)。1H-NMR(CDCl3)δ:0.53-0.63(6H,m),0.92(9H,t,J=8Hz),1.18(6H,s),1.19(6H,d,J=7Hz),1.66(3H,s),1.75(3H,s),1.80-1.92(1H,m),1.81(3H,s),1.96(3H,s),2.09(3H,s),2.17(2H,d,J=8Hz),2.46-2.54(1H,m),2.40-3.10(4H,m),3.47-4.15(5H,m),3.79(1H,d,J=7Hz),4.10(1H,d,J=8Hz),
4.26(1H,d,J=8Hz),4.43-4.48(2H,m),4.80-5.03(2H,m),4.88-
4.90(1H,m),5.20(brs,1H),5.65(1H,d,J=7Hz),6.21-
6.25(1H,m),6.38(1H,s),6.85-7.36(m,9H),7.47-7.52(2H,m),
7.60-7.64(1H,m),8.02-8.05(2H,m)。SI-MS m/z:
实施例3313-O-[3-(叔丁氧基羰基氨基)-3-(4-氟苯基)-2-羟基丙酰]-10-O-[4-(异丙氨基羰基甲基)哌嗪基羰基]-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-16)
按与实施例16类似的方法，应用实施例32的化合物(2-17)(140mg,0.114mmol)进行反应和后处理，于是得标题化合物(27mg,23％)无色晶体。1H-NMR(CDCl3)δ:1.10(3H,s),1.19(6H,d,J=7Hz),1.26(3H,s),1.33(9H,s),1.67(3H,s),1.88(3H,s),1.85-1.91(1H,m),2.29-2.32(2H,m),2.37(3H,s),2.50-2.73(5H,m),3.08(3H,brs),3.55-3.75(m,4H),3.79(1H,d,J=7Hz),4.06-4.15(1H,m),4.17(1H,d,J=9Hz),4.30(1H,d,J=9Hz),4.41-4.4 6(1H,m),4.60-4.61(1H,m),4.95-4.97(1H,m),5.24-5.27(1H,m),5.46-5.48(1H,m),5.66(1H,d,J=7Hz),6.24-6.28(1H,m),6.28(1H,s),7.06-7.11(2H,m),7.36-7.39(2H,m),7.50(2H,t,J=8Hz),7.59-7.63(1H,m),8.10(2H,d,J=8Hz).SI-MS m/z:1037[M+H]+
实施例3413-O-[3-苄氧羰基-2,2-二甲基-4-(4-氟苯基)-5-噁唑烷羰基]-10-O-(4-哌啶子基哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-18)
按与实施例1类似的方法，应用10-O-(4-哌啶子基哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.117mmol)和3-苄氧羰基-2,2-二甲基-4-(4-氟苯基)-5-噁唑烷羧酸(175mg,0.469mmol)进行反应和后处理，于是得标题化合物(140mg,99％)。1H-NMR(CDCl3)δ:0.55-0.62(6H,m),0.92(9H,t,J=8Hz),1.19(6H,s),1.55-1.61(10H,m),1.65(3H,s),1.75(3H,s),1.88-1.91(1H,m),1.81(3H,s),1.95(3H,s),2.08(3H,s),2.17(2H,d,J=10Hz),2.4 6-2.54(1H,m),2.60-3.00(7H,m),3.79(1H,d,J=7Hz),4.10(1H,d,J=9Hz),4.20-4.46(4H,m),4.27(1H,d,J=9Hz),4.80-5.10(2H,m),4.88-4.90(1H,m),5.20(1H,brs),5.66(1H,d,J=7Hz),6.21-6.25(1H,m),6.38(1H,s),6.83(1H,brs),7.00-7.37(9H,m),7.47-7.51(2H,m),7.61-7.65(1H,m),8.03-8.05(2H,m)。SI-MS m/z:1208[M+H]+
实施例3513-O-[3-(叔丁氧基羰基氨基)-3-(4-氟苯基)-2-羟基丙酰]-10-O-(4-哌啶子基哌啶子基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-17)
按与实施例16类似的方法，应用实施例34的化合物(2-18)(140mg,0.116mmol)进行反应和后处理，于是得标题化合物(43mg,26％)无色晶体。1H-NMR(CDCl3)δ:1.15(3H,s),1.26(3H,s),1.33(9H,s),1.48-1.94(11H,m),1.67(3H,s),1.86(3H,s),2.30-2.32(2H,m),2.37(3H,s),2.52-3.10(8H,m),3.80(1H,d,J=7Hz), 4.16(1H,d,J=8Hz),4.20-4.30(2H,m),4.31(1H,d,J=8Hz),4.41-4.47(1H,m),4.60(1H,s),4.95-4.97(1H,m),5.21-5.26(2H,m),5.66(1H,d,J=7Hz),6.26-6.31(1H,m),6.25(1H,s),7.06-7.11(2H,m),7.36-7.39(2H,m),7.50(2H,t,J=7Hz),7.59-7.63(1H,m),8.11(2H,d,J=7Hz).SI-MS m/z:1020[M+H]+
实施例3613-O-[3-苄氧羰基-2,2-二甲基-4-(2-氟苯基)-5-噁唑烷羰基]-10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-19)
按与实施例1类似的方法，应用10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.128mmol)和3-苄氧羰基-2,2-二甲基-4-(2-氟苯基)-5-噁唑烷羧酸(191mg,0.512mmol)进行反应和后处理，于是得标题化合物(127mg,87％)。1H-NMR(CDCl3)δ:0.51-0.65(6H,m),0.92(9H,t,J=8Hz),1.19(3H,s),1.20(3H,s),1.66(3H,s),1.75(3H,s),1.80-1.89(1H,m),1.81(3H,s),1.96(3H,s),2.10(3H,s),2.17(2H,d,J=9Hz),2.45(3H,s),2.48-2.80(5H,m),3.50-3.97(4H,m),3.80(1H,d,J=7Hz),4.11(1H,d,J=8Hz),4.27(1H,d,J=8Hz),4.43-4.48(m,2H),4.80-5.15(3H,m),5.21(brs,1H),5.65(1H,d,J=7Hz),6.21-6.25(1H,m),6.38(1H,s),6.84(1H,brs),7.00-7.38(m,9H),7.47-7.51(2H,m),7.61-7.64(1H,m),8.03-8.05(2H,m).SI-MS m/z:1140[M+H]+实施例3713-O-[3-(叔丁氧基羰基氨基)-3-(2-氟苯基)-2-羟基丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-18)
按与实施例16类似的方法，应用实施例36的化合物(2-19)(120mg,0.105mmol)进行反应和后处理，于是得标题化合物(17mg,17％)无色晶体。1H-NMR(CDCl3)δ:1.14(3H,s),1.26(3H,s),1.33(9H,s),1.67(3H,s),1.84-1.94(m,4H),2.22-2.33(2H,m),2.36(3H,s),2.41(3H,s),2.47-2.63(5H,m),3.40-3.80(4H,m),3.80(1H,d,J=7Hz),4.18(1H,d,J=8Hz),4.30(1H,d,J=8Hz),4.44(1H,dd,J=7,11Hz),4.60-4.61(1H,m),4.95-4.97(1H,m),5.24-5.26(1H,m),5.39-5.41(1H,m),5.66(1H,d,J=7Hz),6.24-6.27(1H,m),6.27(1H,s),7.06-7.11(2H,m),7.36-7.39(2H,m),7.50(2H,t,J=8Hz),7.59-7.63(1H,m),8.10(2H,d,J=7Hz).SI-MS m/z:952[M+H]+
实施例3813-O-[3-苄氧羰基-2,2-二甲基-4-(2-氟苯基)-5-噁唑烷羰基]-10-O-(4-乙基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-20)
按与实施例1类似的方法，应用10-O-(4-乙基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.125mmol)和3-苄氧羰基-2,2-二甲基-4-(2-氟苯基)-5-噁唑烷羧酸(187mg,0.500mmol)进行反应和后处理，于是得标题化合物(143mg,99％)。1H-NMR(CDCl3)δ:0.53-0.63(6H,m),0.92(9H,t,J=8Hz),1.14- 1.18(3H,m),1.20(6H,s),1.58-1.63(1H,m),1.66(3H,s),1.95(3H,s),2.11(s,3H),2.18(1H,d,J=9Hz),2.35-2.65(7H,m),3.50-4.07(4H,m),3.81(1H,d,J=7Hz),4.12(1H,d,J=8Hz),4.25(1H,d,J=8Hz),4.45(1H,dd,J=7,11Hz),4.55(1H,d,J=5Hz),4.88-5.08(3H,m),5.58(1H,d,J=6Hz),5.65(1H,d,J=7Hz),6.20-6.25(1H,m),6.39(1H,s),6.85(1H,brs),7.00-7.40(9H,m),7.49(2H,t,J=8Hz),7.63(1H,t,J=7Hz),8.04-8.06(2H,m).SI-MS m/z:1154[M+H]+
实施例3913-O-[3-(叔丁氧基羰基氨基)-3-(2-氟苯基)-2-羟基丙酰]-10-O-(4-乙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-19)
按与实施例16类似的方法，应用实施例38的化合物(2-20)(143mg,0.124mmol)进行反应和后处理，于是得标题化合物(32mg,27％)无色晶体。1H-NMR(CDCl3)δ:1.13,(3H,t,J=7Hz),1.14(3H,s),1.28(3H,s),1.30(9H,s),1.67(3H,s),1.84-1.94(m,4H),2.20-2.31(2H,m),2.43(3H,s),2.50(2H,q,J=7Hz),2.51-2.56(5H,m),3.40-3.80(m,4H),3.80(1H,d,J=7Hz),4.18(1H,d,J=8Hz),4.31(1H,d,J=8Hz),4.46(1H,dd,J=7,11Hz),4.60-4.61(1H,m),4.97-4.99(1H,m),5.49-5.51(1H,m),5.56-5.59(1H,m),5.66(1H,d,J=7Hz),6.25-6.29(1H,m),6.27(1H,s),7.08-7.21(2H,m),7.29-7.38(2H,m),7.50(2H,t,J=8Hz),7.58-7.62(1H,m),8.12(2H,d,J=7Hz)。SI-MS m/z:966[M+H]+实施例4013-O-[3-苄氧羰基-2,2-二甲基-4-(2-氟苯基)-5-噁唑烷羰基]-10-O-(4-吗啉代哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-21)
按与实施例1类似的方法，应用10-O-(4-吗啉代哌啶子基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.117mmol)和3-苄氧羰基-2,2-二甲基-4-(2-氟苯基)-5-噁唑烷羧酸(175mg,0.468mmol)进行反应和后处理，于是得标题化合物(140mg,99％)。1H-NMR(CDCl3)δ:0.54-0.60(6H,m),0.91(9H,t,J=8Hz),1.19(6H,s),1.55-1.92(5H,m),1.66(3H,s),1.77(3H,s),1.82(3H,s),1.94(3H,s),2.10(3H,s),2.20(2H,d,J=9Hz),2.45-2.52(1H,m),2.53-3.10(4H,m),3.76-3.81(5H,m),4.05-4.44(4H,m),4.12(1H,d,J=8Hz),4.25(1H,d,J=8Hz),4.45(1H,dd,J=7,11Hz),4.55(1H,d,J=6Hz),4.87-5.08(3H,m),5.58(1H,d,J=5Hz),5.66(1H,d,J=7Hz),6.22(1H,t,J=9Hz),6.38(1H,s),6.85(1H,brs),7.00-7.31(m,9H),7.49(2H,t,J=8Hz),7.63(1H,t,J=7Hz),8.03-8.06(2H,m)。
实施例4113-O-[3-(叔丁氧基羰基氨基)-3-(2-氟苯基)-2-羟基丙酰]-10-O-(4-吗啉代哌啶子基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-20)
按与实施例16类似的方法，应用实施例40的化合物(2-21)(140mg,0.116mmol)进行反应和后处理，于是得标题化合物(29mg,25％)无色晶体。1H-NMR(CDCl3)δ:1.15(3H,s),1.28(3H,s),1.33(9H,s),1.40-1.90(4H,m),1.67(3H,s),1.85-1.88(1H,m),1.92(3H,s),2.20-2.38(2H,m),2.43(3H,s),2.49-3.12(7H,m),3.74-3.78(4H,m),3.80(1H,d,J=7Hz),4.06-4.24(2H,m),4.18(1H,d,J=8Hz),4.31(1H,d,J=8Hz),4.43-4.48(1H,m),4.61-4.62(1H,m),4.96-4.99(1H,m),5.47(1H,d,J=10Hz),5.56-5.59(1H,m),5.66(1H,d,J=7Hz),6.26-6.30(1H,m),6.26(1H,s),7.08-7.21(2H,m),7.29-7.39(2H,m),7.50(2H,t,J=8Hz),7.58-7.62(1H,m),8.12(2H,d,J=8Hz)。SI-MS m/z:1022[M+H]+
实施例4213-O-[3-(2-呋喃基)-3-正己酰氨基-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-21)
将实施例28中获得的化合物(2-15)(215mg,0.188mmol)溶于乙醇(33mL)，接着添加0.1N盐酸(19mL)。在室温下搅拌形成的混合物达17小时。减压蒸馏出溶剂。往残余物中添加饱和碳酸氢钠水溶液，用氯仿萃取形成的混合物。在硫酸钠上干燥有机层，减压浓缩至干。往残余物中添加甲醇(25mL)、水(2.5mL)和10％披钯活性炭(49mg)，接着，在室温和常压的H2气氛中搅拌3小时。将该反应混合物过滤，减压浓缩滤液至干。往残余物中添加饱和碳酸氢钠水溶液，用氯仿萃取形成的混合物。在硫酸钠上干燥有机层并减压浓缩至干，于是得无色晶体。将形成的晶体(110mg,0.129mmol)溶于乙酸乙酯(7mL)，接着添加饱和碳酸氢钠水溶液(7.1mL)和净化水(7mL)。在不断搅拌时滴加正己酰氯(19mg,0.14mmol)。在室温下搅拌形成的混合物达15分钟。用乙酸乙酯萃取反应混合物。用饱和氯化钠溶液洗涤有机层，在硫酸钠上干燥，减压浓缩至干。通过色谱法在硅胶柱上纯化残余物[CHCl3-MeOH(96∶4)]，于是得标题化合物(100mg,55％)无色晶体。1H-NMR(CDCl3)δ:0.78-0.82(3H,m,),0.89(3H,t,7Hz),1.12(3H,s),1.18(7H,m),1.47-1.59(4H,m),1.65(3H,s,C19-Me),1.80-1.89(1H,m),1.86(3H,s,C18-Me),2.14-2.20(2H,m),2.25-2.40(5H,m),2.36(3H,s),2.40-2.55(4H,m),3.15(1H,br-s),3.35-3.73(4H,m),3.76(1H,d,J=7Hz,C3-H),4.17(1H,d,J=9Hz,C20-H),4.26(1H,d,J=9Hz,C20-H),4.42(1H,dd,J=7Hz,11Hz,C7-H),4.70(1H,d,J=2Hz,C2′-H),4.94(1H,d,J=8Hz,C5-H),5.67(2H,d,J=7Hz),6.15(1H,d,J=9Hz),6.20(1H,t,J=8Hz,C13-H),6.24(1H,s,C10-H),6.27-6.30(1H,m),6.34-6.37(1H,m),7.37-7.40(1H),7.44-7.51(2H,m),7.55-7.61(1H,m),8.06-8.11(2H,m).SIMS m/z:950(M+H)+
实施例4313-O-[3-(3,3-二甲基丙烯酰氨基)-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-22)
按与实施例42类似的方法，应用实施例28的化合物(2-15)(215mg,0.188mmol)和3,3-二甲基丙烯酰氯(17mg,0.14mmol)进行反应和后处理，于是得标题化合物(90mg,51％)无色晶体。1H-NMR(CDCl3)δ:0.92(3H,t,7Hz),1.14(3H,s),1.24(3H,s),1.49-1.59(2H,m),1.67(3H,s,C19-Me),1.79(3H,s),1.89(3H,s,C18-Me),2.02(3H,s),2.28-2.43(5H,m),2.41(3H,s),2.44-2.58(4H,m),3.17(1H,br-s),3.37-3.75(4H,m),3.81(1H,d,J=7Hz,C3-H),4.18(1H,d,J=9Hz,C20-H),4.30(1H,d,J=9Hz,C20-H),4.44(1H,dd,J=7Hz,11Hz,C7-H), 4.74(1H,d,J=2Hz,C2′-H),4.98(1H,d,J=8Hz,C5-H),5.58(1H,s),5.65-5.73(2H,m),6.05(1H,d,J=9Hz),6.23(1H,t,J=8Hz,C13-H),6.26(1H,s,C10-H),6.30-6.34(1H,m),6.35-6.39(1H,m),7.40-7.43(1H,m),7.4 9-7.52(2H,m),7.57-7.63(1H,m),8.10-8.13(2H,m).SIMS m/z:934(M+H)+
实施例4413-O-[3-(2-呋喃基)-2-羟基-3-(2-噻吩甲酰氨基)丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-23)
按与实施例42类似的方法，应用实施例28的化合物(2-15)(215mg,0.188mmol)和2-噻吩甲酰氯(21mg,0.14mmol)进行反应和后处理，于是得标题化合物(80mg,44％)无色晶体。1H-NMR(CDCl3)δ:0.92(3H,t,7Hz),1.14(3H,s),1.24(3H,s),1.49-1.58(2H,m),1.69(3H,s,C19-Me),1.83-1.93(1H,m),1.89(3H,s,C18-Me),2.27-2.43(5H,m),2.41(3H,s),2.44-2.58(4H,m),3.15(1H,br-s),3.37-3.76(4H,m),3.80(1H,d,J=7Hz,C3-H),4.21(1H,d,J=9Hz,C20-H),4.30(1H,d,J=9Hz,C20-H),4.44(1H,dd,J=7Hz,11Hz,C7-H),4.82(1H,d,J=2Hz,C2′-H),4.98(1H,d,J=8Hz,C5-H),5.67(1H,d,J=7Hz,C2-H),5.85(1H,m),6.26(1H,t,J=8Hz,C13-H),6.26(1H,s,C10-H),6.38-6.42(2H,m),6.71(1H,d,J=9Hz),7.05-7.08(1H,m),7.43-7.55(5H,m),7.61-7.65(1H,m),8.10-8.15(2H,m)。SIMS m/z:962(M+H)+实施例4513-O-[3-(2-糠酰氨基)-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-24)
按与实施例42类似的方法，应用实施例28的化合物(2-15)(215mg,0.188mmol)和2-糠酰氯(18mg,0.14mmol)进行反应和后处理，于是得标题化合物(101mg,56％)无色晶体。1H-NMR(CDCl3)δ:0.92(3H,t,7Hz),1.14(3H,s),1.24(3H,s),1.49-1.58(2H,m),1.68(3H,s,C19-Me),1.85-1.94(1H,m),1.89(3H,s,C18-Me),2.27-2.43(5H,m),2.42(3H,s),2.44-2.58(4H,m),3.15(1H,m),3.37-3.76(4H,m),3.81(1H,d,J=7Hz,C3-H),4.21(1H,d,J=9Hz,C20-H),4.30(1H,d,J=9Hz,C20-H),4.44(1H,m),4.82(1H,d,J=2Hz,C2’-H),4.98(1H,d,J=8Hz,C5-H),5.67(1H,d,J=7Hz,C2-H),5.83(1H,m),6.26(1H,t,J=8Hz,C13-H),6.26(1H,s,C10-H),6.38-6.42(2H,m),6.47(1H,m),7.01-7.09(2H,m),7.44-7.55(5H,m),7.60-7.65(1H,m),8.12-8.15(2H,m).SIMS m/z:946(M+H)+
实施例4613-O-[3-(2-呋喃基)-2-羟基-3-异丙氧基羰基氨基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-25)
按与实施例42类似的方法，应用实施例28的化合物(2-15)(215mg,0.188mmol)和氯甲酸异丙酯(17mg,0.139mmol)进行反应和后处理，于是得标题化合物(60mg,34％)无色晶体。1H-NMR(CDCl3)δ:0.92(3H,t,J=7Hz),1.11(3H,d,J=6Hz),1.15(3H,s),1.17(3H,d,J=6Hz),1.26(3H,s),1.49-1.58(2H,m),1.68(3H,s,C19-Me),1.87-1.96(1H,m),1.91(3H,s,C18-Me),2.25-2.43(5H,m),2.40(3H,s),2.4 4-2.58(4H,m),3.20(1H,br-s),3.40-3.76(4H,m),3.81(1H,d,J=7Hz,C3-H),4.19(1H,d,J=9Hz,C20-H),4.29(1H,d,J=9Hz,C20-H),4.44(1H,dd,J=7Hz,11Hz,C7-H),4.73(1H,s),4.75-4.83(1H,m),4.98(1H,d,J=8Hz,C5-H),5.38(2H,s),5.67(1H,d,J=7Hz,C2-H),6.27(1H,t,J=8Hz,C13-H),6.27(1H,s,C10-H),6.30-6.34(1H,m),6.37-6.39(1H,m),7.40-7.4 4(1H,m),7.49-7.53(2H,m),7.59-7.65(1H,m),8.10-8.15(2H,m)。SIMS m/z:938(M+H)+
实施例4713-O-[3-(叔戊氧基羰基氨基)-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-26)
按与实施例4类似的方法，应用实施例28的化合物(2-15)(215mg,0.188mmol)和二叔戊基二碳酸酯(35mg,0.141mmol)进行反应和后处理，于是得标题化合物(81mg,45％)无色晶体。1H-NMR(CDCl3)δ:0.80(3H,t,J=7Hz),0.92(3H,t,J=7Hz),1.15(3H,s),1.26(3H,s),1.31(6H,d,J=4Hz),1.49-1.58(2H,m),1.68(3H,s,C19-Me),1.85-1.96(1H,m),1.92(3H,s,C18-Me),2.28-2.43(5H,m),2.40(3H,s),2.45-2.58(4H,m),3.19(1H,br-s),3.40-3.76(4H,m),3.81(1H,d,J=7Hz,C3-H),4.19(1H,d,J=9Hz,C20-H), 4.29(1H,d,J=9Hz,C20-H),4.44(1H,m,C7-H),4.72(1H,s),4.98(1H,d,J=8Hz,C5-H),5.21-5.27(1H,m),5.32-5.38(1H,m),5.67(1H,d,J=7Hz,C2-H),6.25(1H,t,J=8Hz,C13-H),6.27(1H,s,C10-H),6.30-6.34(1H,m),6.36-6.39(1H,m),7.40-7.44(1H,m),7.48-7.53(2H,m),7.59-7.65(1H,m),8.10-8.14(2H,m).SIMS m/z:966(M+H)+
实施例4813-O-[3-环己基羰基氨基-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-27)
按与实施例42类似的方法，应用实施例28的化合物(2-15)(215mg,0.188mmol)和环己基碳酰氯(21mg,0.138mmol)进行反应和后处理，于是得标题化合物(102mg,56％)无色晶体。1H-NMR(CDCl3)δ:0.92(3H,t,J=7Hz),1.15(3H,s),1.18-1.42(2H,m),1.26(3H,s),1.49-1.58(2H,m),1.60-1.95(9H,m),1.68(3H,s,C19-Me),1.85-1.96(1H,m),1.89(3H,s,C18-Me),2.28-2.43(5H,m),2.39(3H,s),2.43-2.58(4H,m),3.15(1H,m),3.40-3.76(4H,m),3.81(1H,d,J=7Hz,C3-H),4.19(1H,d,J=9Hz,C20-H),4.29(1H,d,J=9Hz,C20-H),4.44(1H,m,C7-H),4.73(1H,d,J=2Hz,C2′-H),4.98(1H,d,J=8Hz,C5-H),5.64-5.71(2H,m),6.12-6.17(1H,m),6.20(1H,t,J=8Hz,C13-H),6.27(1H,s,C10-H),6.30-6.33(1H,m),6.37-6.40(1H,m),7.40-7.44(1H,m),7.48-7.53(2H,m),7.59-7.65(1H,m),8.10-8.14(2H,m)。SIMS m/z:962(M+H)+实施例4913-O-[3-环戊基羰基氨基-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-28)
按与实施例42类似的方法，应用实施例28的化合物(2-15)(215mg,0.188mmol)和环戊基碳酰氯(18mg,0.138mmol)进行反应和后处理，于是得标题化合物(106mg,60％)无色晶体。1H-NMR(CDCl3)δ:0.92(3H,t,J=7Hz),1.15(3H,s),1.26(3H,s),1.49-1.58(2H,m),1.55-1.75(9H,m),1.68(3H,s,C19-Me),1.86-1.96(1H,m),1.90(3H,s,C18-Me),2.28-2.42(5H,m),2.39(3H,s),2.43-2.58(4H,m),3.16(1H,m),3.40-3.76(4H,m),3.81(1H,d,J=7Hz,C3-H),4.19(1H,d,J=9Hz,C20-H),4.29(1H,d,J=9Hz,C20-H),4.44(1H,m,C7-H),4.73(1H,d,J=2Hz,C2′-H),4.98(1H,d,J=7Hz,C5-H),5.67-5.71(2H,m),6.10-6.15(1H,m),6.21(1H,t,J=8Hz,C13-H),6.27(1H,s,C10-H),6.30-6.33(1H,m),6.37-6.40(1H,m),7.41-7.44(1H,m),7.48-7.53(2H,m),7.59-7.65(1H,m),8.10-8.14(2H,m).SIMS m/z:948(M+H)+
实施例5013-O-[3-环己氧基羰基氨基-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-29)
按与实施例42类似的方法，应用实施例28的化合物(2-15)(215mg,0.188mmol)和氯甲酸环己酯(23mg,0.14mmol)进行反应和后处理，于是得标题化合物(74mg,40％)无色晶体。1H-NMR(CDCl3)δ:0.93(3H,t,J=7Hz),1.15(3H,s),1.26(3H,s),1.49-1.58(2H,m),1.60-1.75(11H,m),1.68(3H,s,C19-Me),1.85-1.96(1H,m),1.91(3H,s,C18-Me),2.22-2.45(5H,m),2.41(3H,s),2.46-2.59(4H,m),3.19(1H,m),3.40-3.76(4H,m),3.81(1H,d,J=7Hz,C3-H),4.18(1H,d,J=9Hz,C20-H),4.30(1H,d,J=9Hz,C20-H),4.46(1H,m,C7-H),4.74(1H,d,J=2Hz,C2′-H),4.98(1H,d,J=8Hz,C5-H),5.32-5.43(2H,m),5.66(1H,d,J=7Hz,C2-H),6.21(1H,t,J=8Hz,C13-H),6.27(1H,s,C10-H),6.31-6.35(1H,m),6.38-6.41(1H,m),7.41-7.45(1H,m),7.47-7.54(2H,m),7.59-7.65(1H,m),8.11-8.17(2H,m).SIMS m/z:978(M+H)+
实施例5113-O-[3-环戊氧基羰基氨基-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-30)
按与实施例42类似的方法，应用实施例28的化合物(2-15)(215mg,0.188mmol)和氯甲酸环戊酯(21mg,0.14mmol)进行反应和后处理，于是得标题化合物(66mg,36％)无色晶体。1H-NMR(CDCl3)δ:0.92(3H,t,J=7Hz),1.15(3H,s),1.27(3H,s),1.49-1.58(2H,m),1.60-1.75(9H,m),1.68(3H,s,C19-Me),1.85-1.96(1H,m),1.91(3H,s,C18-Me),2.25-2.42(5H,m),2.40(3H,s),2.44-2.60(4H,m),3.19(1H,m),3.40-3.77(4H,m),3.81(1H,d,J=7Hz,C3-H),4.19(1H,d,J=9Hz,C20-H),4.30(1H,d,J=9Hz,C20-H),4.44(1H,m,C7-H), 4.73(1H,d,J=2Hz,C2′-H),4.97(1H,d,J=8Hz,C5-H),5.30-5.43(2H,m),5.67(1H,d,J=2Hz,C2-H),6.27(1H,t,J=8Hz,C13-H),6.27(1H,s,C10-H),6.30-6.34(1H,m),6.37-6.40(1H,m),7.40-7.45(1H,m),7.46-7.55(2H,m),7.58-7.65(1H,m),8.10-8.16(2H,m).SIMS m/z:964(M+H)+
实施例5213-O-[3-环丙烷羰基氨基-3-(2-呋喃基)-2-羟基丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-31)
按与实施例42类似的方法，应用实施例17的化合物(2-8)(0.12g,0.11mmol)和环丙烷碳酰氯(10mg,0.1mmol)进行反应和后处理，于是得标题化合物(26mg,20％)。1H-NMR(CDCl3)δ:0.65-0.71(m,2H),0.75-0.84(m,2H),1.08(s,3H),1.19(s,3H),1.32(m,1H),1.61(s.3H),1.70(s,1H),1.80(m,1H,C6-H),1.83(s,3H),2.17(m,1H,C14-H),2.27(m,1H,C14-H),2.28(s,3H),2.32(s,3H),2.35-2.52(m,5H),3.07(d,J=4Hz,1H),3.31-3.68(m,4H),3.73(d,J=7Hz,1H,C3-H),4.11(d,J=8Hz,1H,C20-H),4.22(d,J=8Hz,1H,C20-H),4.38(m,1H,C7-H),4.66(d,J=3Hz,1H,C2′-H),4.89(d,J=7Hz,1H,C5-H),5.60(d,J=7Hz,1H,C2-H),5.62(dd,J=9,2Hz,1H,C3′-H),6.16(t,J=10Hz,1H,C13-H),6.20(s,1H,C10-H),6.23(d,J=9Hz,1H,NH),6.29(m,1H),6.32(m,1H),7.36(m,1H),7.43(t,J=8Hz,2H),7.54(t,J=7Hz,1H),8.04(d,J=8Hz,2H)SI-MS m/z:892[M+H]+实施例5313-O-[3-(2-呋喃基)-2-羟基-3-三氟乙酰氨基丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-32)
按与实施例16类似的方法，应用实施例17的化合物(2-8)(0.12g,0.11mmol)和三氟乙酸酐(21mg,0.1mmol)进行反应和后处理，于是得标题化合物(5mg,5％)。1H-NMR(CDCl3)δ:1.08(s,3H),1.19(s,3H),1.62(s.3H),1.68(s,1H),1.78(m,1H,C6-H),1.81(s,3H),2.1-2.28(m,2H,C14-Hx2),2.29(s,3H),2.30(s,3H),2.38-2.50(m,5H),3.06(s,1H),3.37-3.66(m,4H),3.73(d,J=7Hz,1H,C3-H),4.14(d,J=8Hz,1H,C20-H),4.23(d,J=8Hz,1H,C20-H),4.36(m,1H,C7-H),4.71(d,J=2Hz,1H,C2′-H),4.88(d,J=8Hz,1H,C5-H),5.60(d,J=7Hz,1H,C2-H),5.61(dd,J=9,2Hz,1H,C3′-H),6.20(s,1H,C10-H),6.21(t,J=10Hz,1H,C13-H),6.35-6.36(m,2H),7.03(d,J=9Hz,1H,NH),7.39(m,1H),7.43(t,J=8Hz,2H),7.54(t,J=7Hz,1H),8.03(d,J=8Hz,2H)。SI-MS m/z:919[M+H]+
实施例5413-O-[3-苄氧羰基-2,2-二甲基-4-乙基-5-噁唑烷羰基]-10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-22)
按与实施例1类似的方法，应用10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.13mmol)和3-苄氧羰基-2,2-二甲基-4-乙基-5-噁唑烷羧酸(200mg,0.65mmol)进行反应和后处理，于是得标题化合物(140mg,100％)。1H-NMR(CDCl3)δ:0.56(m,6H),0.91(t,J=8Hz,9H),0.92(t,J=8Hz,3H),1.14(s,3H),1.18(s,3H),1.54(s,3H),1.60(s,3H),1.65(s,3H),1.70-1.95(m,3H),2.06(s,3H),2.18-2.90(m,7H),2.33(s,3H),2.50(s,3H),3.20-3.90(m,4H),3.82(d,J=7Hz,1H,C3-H),4.11(d,J=9Hz,1H,C20-H),4.26-4.33(m,2H),4.32(d,J=9Hz,1H,C20-H),4.46(m,1H,C7-H),4.92(d,J=10Hz,1H,C5-H),5.11(brs,1H),5.17(d,J=12Hz,1H),5.65(d,J=7Hz,1H,C2-H),6.16(t,J=9Hz,1H,C13-H),6.38(s,1H,C10-H),7.30-7.40(m,5H),7.46(t,J=8Hz,2H),7.60(t,J=7Hz,1H),8.05(d,J=8Hz,2H)
实施例5513-O-[3-(叔丁氧基羰基氨基)-2-羟基戊酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-33)
按与实施例16类似的方法，应用实施例54的化合物(2-22)(0.14g,0.13mmol)和二叔丁基二碳酸酯(32mg,0.15mmol)进行反应和后处理，于是得标题化合物(20mg,18％)。1H-NMR(CDCl3)δ:0.94(t,J=7Hz,3H),1.19(s,3H),1.24(s,3H),1.26(s,9H),1.61(s.3H),1.65(m,2H),1.81(m,1H,C6-H),1.85(s,3H),2.20-2.98(m,7H),2.33(s,3H),2.36(s,3H),3.14(s,1H),3.23-3.92(m,4H),3.73(d,J=7Hz,1H,C3-H),3.98(m,1H,C3′-H),4.11(d,J=9Hz,1H,C20-H),4.21(d,J=3Hz,1H,C2′-H),4.25(d,J=9Hz,1H,C20-H),4.36(m,1H,C7-H),4.58(d,J=10Hz,1H,NH),
4.9上(d,J=10Hz,1H,C5-H),5.60(d,J=7Hz,1H,C2-H),
6.14(t,J=9Hz,1H,C13-H),6.22(s,1H,C10-H),
7.43(t,J=7Hz,2H),7.55(t,J=7Hz,1H),8.05(d,J=7Hz,2H)
SI-MS m/z:886[M+H]+
实施例5613-O-(3-苄氧羰基-4-(叔丁基)-2,2-二甲基-5-噁唑烷羰基)-10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-23)
按与实施例1类似的方法，应用10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(100mg,0.13mmol)和3-苄氧羰基-4-(叔丁基)-2,2-二甲基-5-噁唑烷羧酸(80mg,0.24mmol)进行反应和后处理，于是得标题化合物(0.14mg,98％)。1H-NMR(CDCl3)δ:0.57(m,6H),0.91(t,J=8Hz,9H),0.93(s,9H),1.16(s,3H),1.17(s,3H),1.53(s,3H),1.64(s,3H),1.66(s,3H),1.86(m,1H,C6-H),2.11(s,3H),2.17-2.90(m,7H),2.34(s,3H),2.42(s,3H),3.35-4.05(m,4H),3.85(d,J=7Hz,1H,C3-H),4.16(d,J=8Hz,1H,C20-H),4.30(d,J=8Hz,1H,C20-H),4.40(d,J=2Hz,1H),4.45(dd,J=9Hz,6Hz,1H,C7-H),4.55(brs,1H),4.93(d,J=8Hz,1H,C5-H),5.10(brs,1H),5.15(d,J=12Hz,1H),5.66(d,J=7Hz,1H,C2-H),6.14(t,J=9Hz,1H,C13-H),6.38(s,1H,C10-H),7.27-7.38(m,5H),7.46(t,J=8Hz,2H),7.59(t,J=7Hz,1H),8.07(d,J=8Hz,2H)
实施例5713-O-[3-(叔丁氧基羰基氨基)-4,4-二甲基-2-羟基戊酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-34)
按与实施例16类似的方法，应用实施例56的化合物(2-23)(0.08g,0.08mmol)和二叔丁基二碳酸酯(15mg,0.07mmol)进行反应和后处理，于是得标题化合物(9mg,14％)。1H-NMR(CDCl3)δ:1.03(s,9H),1.09(s,3H),1.24(s,3H),1.28(s,9H),1.65(s,3H),1.86(m,1H,C6-H),1.90(s,3H),2.20-3.02(m,7H),2.37(s,3H),2.40(s,3H),3.05(s,1H),3.20-3.97(m,4H),3.76(d,J=7Hz,1H,C3-H),3.77(m,1H,C3′-H),4.16(d,J=8Hz,1H,C20-H),4.30(d,J=8Hz,1H,C20-H),4.41(m,1H,C7-H),4.55(d,J=2Hz,1H,C2′-H),4.87(d,J=11Hz,1H,NH),4.96(d,J=8Hz,1H,C5-H),5.65(d,J=7Hz,1H,C2-H),6.17(t,J=9Hz,1H,C13-H),6.28(s,1H,C10-H),7.48(t,J=7Hz,2H),7.60(t,J=7Hz,1H),8.11(d,J=7Hz,2H)SI-MS m/z:914[M+H]+
实施例5813-O-(3-苄氧羰基-4-环丙基-2,2-二甲基-5-噁唑烷羰基)-10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-24)
按与实施例1类似的方法，应用10-O-(4-甲基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(503mg,0.64mmol)和3-苄氧羰基-4-环丙基-2,2-二甲基-5-噁唑烷羧酸(306mg,0.96mmol)进行反应和后处理，于是得标题化合物(定量地(quant.))。1H-NMR(CDCl3)δ:0.21(m,1H),0.45(m,1H),0.52-0.81(m,8H),0.90(t,J=8Hz,9H),1.06(m,1H),1.17(s,3H),1.18(s,3H),1.63(s,3H),1.65(s,3H),1.66(s,3H),1.86(m,1H,C6-H),2.12(s,3H),2.22(m,2H),2.26-2.55(m,5H),2.30(s,3H),2.34(s,3H),3.23-3.80(m,4H),3.85(d,J=7Hz,1H,C3-H),3.90(m,1H),4.13(d,J=8Hz,1H,C20-H),4.29(d,J=8Hz,1H,C20-H),4.44(d,J=2Hz,1H),4.47(m,1H,C7-H),4.93(d,J=8Hz,1H,C5-H),5.09(d,J=12Hz,1H),5.16(d,J=12Hz,1H),5.66(d,J=7Hz,1H,C2-H),6.13(t,J=9Hz,1H,C13-H),6.37(s,1H,C10-H),7.30-7.40(m,5H),7.45(t,J=8Hz,2H),7.59(t,J=7Hz,1H),8.06(d,J=7Hz,2H)
实施例5913-O-[3-(叔丁氧基羰基氨基)-3-环丙基-2-羟基丙酰]-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-35)
按与实施例16类似的方法，应用实施例58的化合物(2-24)(0.15g,0.14mmol)和二叔丁基二碳酸酯(32mg,0.15mmol)进行反应和后处理，于是得标题化合物(22mg,17％)。1H-NMR(CDCl3)δ:0.25(m,1H),0.46(m,1H),0.56-0.68(m,2H),1.12(s,3H),1.21(m,1H),1.23(s,3H),1.30(s.9H),1.58(s,3H),1.65(s,1H),1.86(m,1H,C6-H),1.90(s,3H),2.00-2.10(m,2H),2.31(m,1H,C6-H),2.33(s,3H),2.34(s,3H),2.36-2.58(m,4H),3.12(s,1H),3.28(dt,J=9,2Hz,1H),3.36-3.76(m,4H),3.77(d,J=7Hz,1H,C3-H),4.15(d,J=8Hz,1H,C20-H),4.29(d,J=8Hz,1H,C20-H),4.37(d,J=2Hz,1H),4.43(m,1H,C7-H), 4. 6(d,J=8Hz,1H,NH),4.96(d,J=7Hz,1H,C5-H),5.64(d,J=7Hz,1H,C2-H),6.16(t,J=9Hz,1H,C13-H),6.25(s,1H,C10-H),7.48(t,J=8Hz,2H),7.59(t,J=7Hz,1H),8.09(d,J=7Hz,2H)SI-MS m/z:898[M+H]+
实施例6013-O-(3-丁酰氨基-3-环丙基-2-羟基丙酰)-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-36)
按与实施例42类似的方法，应用实施例58的化合物(2-24)(0.15g,0.14mmol)和丁酰氯(13mg,0.12mmol)进行反应和后处理，于是得标题化合物(19mg,15％)。1H-NMR(CDCl3)δ:0.31(m,1H),0.43(m,1H),0.56-0.73(m,2H),0.89(t,J=7Hz,3H),1.14(s,3H),1.25(s,3H),1.28(m,1H),1.57(m,2H),1.68(s,3H),1.82(m,1H,C6-H),1.91(s,3H),2.12(m,2H),2.26-2.38(m,3H),2.36(s,3H),2.37(s,3H),2.42-2.58(m,4H),3.14(s,1H),3.40-3.79(m,4H),3.61(dt,J=9.1Hz,1H),3.78(d,J=7Hz,1H,C3-H),4.19(d,J=8Hz,1H,C20-H),4.31(d,J=8Hz,1H,C20-H),4.43(d,J=1Hz,1H),4.45(m,1H,C7-H),4.98(d,J=9Hz,1H,C5-H),5.68(d,J=7Hz,1H,C2-H),5.84(br,1H,NH),6.16(t,J=9Hz,1H,C13-H),6.27(s,1H,C10-H),7.50(t,J=8Hz,2H),7.59(t,J=7Hz,1H),8.11(d,J=8Hz,2H)SI-MS m/z:867[M+H]+
实施例6113-O-(3-环丙基-3-正己酰氨基-2-羟基丙酰)-10-O-(4-甲基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-37)
按与实施例42类似的方法,应用实施例58的化合物(2-24)(0.15g,0.14mmol)和正己酰氯(16mg,0.12mmol)进行反应和后处理，于是得标题化合物(11mg,9％)。1H-NMR(CDCl3)δ:0.31(m,1H),0.43(m,1H),0.56-0.73(m,2H),0.84(t,J=7Hz,3H),1.14(s,3H),1.22-1.34(m,5H),1.26(s,3H),1.55(m,2H),1.67(s,3H),1.84(m,1H,C6-H),1.91(s,3H),2.12(m,2H),2.26-2.39(m,3H),2.34(s,3H),2.38(s,3H),2.41-2.58(m,4H),3.12(s,1H),3.36-3.79(m,4H),3.61(dt,J=10,2Hz,1H),3.78(d,J=7Hz,1H,C3-H),4.19(d,J=8Hz,1H,C20-H),4.31(d,J=8Hz,1H,C20-H),4.43(d,J=2Hz,1H),4.45(m,1H,C7-H),4.98(d,J=7Hz,1H,C5-H),5.68(d,J=7Hz,1H,C2-H),5.77(d,J=9Hz,1H,NH),6.17(t,J=9Hz,1H,C13-H),6.26(s,1H,C10-H),7.50(t,J=8Hz,2H),7.61(t,J=7Hz,1H),8.11(d,J=7Hz,2H)SI-MS m/z:896[M+H]+
实施例6213-O-(3-苄氧羰基-4-环丙基-2,2-二甲基-5-噁唑烷羰基)-10-O-(4-丙基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-25)
按与实施例1类似的方法，应用实施例27的化合物(2-14)(820mg,1.00mmol)和3-苄氧羰基-4-环丙基-2,2-二甲基-5-噁唑烷羧酸(500mg,1.56mmol)进行反应和后处理，于是得标题化合物(定量地)。1H-NMR(CDCl3)δ:0.21(m,1H),0.46(m,1H),0.50-0.58(m,8H),0.90(t,J=8Hz,3H),0.95(t,J=8Hz,9H),1.11(s,3H),1.21(m,1H),1.22(s,3H),1.52(m,2H),1.64(s,3H),1.65(s,3H),1.66(s,3H),1.75-2.00(m,3H),1.94(s,3H),2.23(m,2H),2.33(m,1H),2.34(s,3H),2.40-2.61(m,4H),3.34-3.73(m,4H),3.81(d,J=7Hz,1H,C3-H),3.89(m,1H),4.13(d,J=8Hz,1H,C20-H),4.30(d,J=8Hz,1H,C20-H),4.45(d,J=3Hz,1H),4.50(m,1H,C7-H),4.97(d,J=8Hz,1H,C5-H),5.09(d,J=12Hz,1H),5.16(d,J=12Hz,1H),5.64(d,J=7Hz,1H,C2-H),6.17(t,J=8Hz,1H,C13-H),6.25(s,1H,C10-H),7.27-7.38(m,5H),7.47(t,J=8Hz,2H),7.60(t,J=7Hz,1H),8.06(d,J=7Hz,2H)
实施例6313-O-[3-(叔丁氧基羰基氨基)-3-环丙基-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-38)
按与实施例16类似的方法，应用实施例62的化合物(2-25)(0.20g,0.20mmol)和二叔丁基二碳酸酯(85mg,0.40mmol)进行反应和后处理，于是得标题化合物(33mg,18％)。1H-NMR(CDCl3)δ:0.26(m,1H),0.45(m,1H),0.60-0.64(m,2H),0.90(t,J=7Hz,3H),1.12(s,3H),1.20(m,1H),1.23(s,3H),1.30(s,9H),1.52(m,2H),1.65(s,3H),1.66(s,1H),1.86(m,1H,C6-H),1.90(s,3H),2.25-2.38(m,5H),2.34(s,3H),2.41-2.58(m,4H),3.15(s,1H),3.29(dt,J=10,2Hz,1H),3.36-3.74(m,4H),3.77(d,J=7Hz,1H,C3-H),4.15(d,J=8Hz,1H,C20-H),4.29(d,J=8Hz,1H,C20-H),4.37(d,J=2Hz,1H),4.43(m,1H,C7-H), 4.86(d,J=9Hz,1H,NH),4.96(d,J=8Hz,1H,C5-H),5.64(d,J=7Hz,1H,C2-H),6.1 6(t,J=9Hz,1H,C13-H),6.25(s,1H,C10-H),7.47(t,J=8Hz,2H),7.59(t,J=7Hz,1H),8.09(d,J=7Hz,2H)SI-MS m/z:926[M+H]+
实施例6413-O-[3-环丙基-2-羟基-3-(2-噻吩甲酰氨基)丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-39)
按与实施例42类似的方法,应用实施例62的化合物(2-25)(0.20g,0.20mmol)和2-噻吩甲酰氯(48mg,0.33mmol)进行反应和后处理，于是得标题化合物(70mg,33％)。1H-NMR(CDCl3)δ:0.38(m,1H),0.52(m,1H),0.60-0.75(m,2H),0.90(t,J=7Hz,3H),1.11(s,3H),1.20(s,3H),1.35(m,1H),1.50(m,2H),1.66(s,3H),1.71(s,1H),1.88(s,3H),1.90(m,1H,C6-H),2.20-2.35(m,3H),2.40(s,3H),2.41-2.58(m,6H),3.13(s,1H),3.34-3.74(m,5H),3.77(d,J=7Hz,1H,C3-H),3.83(dt,J=9,1Hz,1H),4.19(d,J=8Hz,1H,C20-H),4.28(d,J=8Hz,1H,C20-H),4.43(m,1H,C7-H),4.51(d,J=1Hz,1H),4.96(d,J=8Hz,1H,C5-H),5.64(d,J=7Hz,1H,C2-H),6.23(t,J=10Hz,1H,C13-H),6.26(s,1H,C10-H),6.33(d,J=9Hz,1H,NH),7.03(dd,J=4,5Hz,1H),7.24-7.47(m,2H),7.50(t,J=8Hz,2H),7.60(t,J=7Hz,1H),8.11(d,J=7Hz,2H)SI-MS m/z:936[M+H]+实施例6513-O-[3-(3,3-二甲基丙烯酰氨基)-3-环丙基-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-40)
按与实施例42类似的方法，应用实施例62的化合物(2-25)(0.20g,0.20mmol)和3,3-二甲基丙烯酰氯(18mg,0.15mmol)进行反应和后处理，于是得标题化合物(20mg,11％)。1H-NMR(CDCl3)δ:0.24(m,1H),0.37(m,1H),0.51-0.65(m,2H),0.85(t,J=7Hz,3H),1.07(s,3H),1.18(s,3H),1.21(m,1H),1.46(m,2H),1.60(s,3H),1.73(d,J=1Hz,3H),1.80(m,1H,C6-H),1.84(s,3H),1.92(d,J=1Hz,3H),2.20-2.34(m,5H),2.33(s,3H),2.35-2.50(m,4H),3.09(s,1H),3.31-3.70(m,4H),3.55(dt,J=10,2Hz,1H),3.72(d,J=7Hz,1H,C3-H),4.11(d,J=8Hz,1H,C20-H),4.37(d,J=8Hz,1H,C20-H),4.37(d,J=2Hz,1H),4.48(m,1H,C7-H),4.92(d,J=8Hz,1H,C5-H),5.46(s,1H),5.60(d,J=7Hz,1H,C2-H),5.64(d,J=8Hz,1H,NH),6.11(t,J=9Hz,1H,C13-H),6.20(s,1H,C10-H),7.42(t,J=8Hz,2H),7.54(t,J=7Hz,1H),8.03(d,J=7Hz,2H)SI-MS m/z:908[M+H]+
实施例6613-O-[3-苄氧羰基-2,2-二甲基-4-(4-氟苯基)-5-噁唑烷羰基]-10-O-(4-丙基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-26)
按与实施例1类似的方法，应用实施例27的化合物(2-14)(2.1g,2.59mmol)和3-苄氧羰基-2,2-二甲基-4-(4-氟苯基)-5-噁唑烷羧酸(1.16g,3.11mmol)进行反应和后处理，于是得标题化合物(3.02g,99％)。1H-NMR(CDCl3)δ:0.53-0.65(6H,m,SiCH2),0.92(3H,t,J=7Hz,CH2CH2CH3),0.92(9H,t,J=8Hz,SiCH2CH3),1.19(2x3H,s,C16,17),1.48-1.57(2H,m,CH2CH2CH3),1.66(3H,s,C19),1.75(3H,s，异亚丙基)，1.81(3H,s，异亚丙基)，1.82-1.90(1H,m,C6),1.97(3H,s),2.12(s,3H),2.16(2H,d,J=9.0Hz,C14),2.31-2.35(2H,m,CH2CH2CH3),2.36-2.55(4H,m，哌嗪)，2.45-2.53(1H,m,C6),3.35-3.90(4H,m，哌嗪)，3.81(1H,d,J=6.8Hz,C3),4.11(1H,d,J=8.4Hz,C20),4.26(1H,d,J=8.4Hz,C20),4.43-4.47(1H,m,C7),4.47(1H,d,J=6.1Hz,C2′),4.80-5.10(2H,m,PhCH2),4.89-4.91(1H,m,C5),5.21(1H,brs,C3′),5.66(1H,d,J=7.1Hz,C2),6.21-6.25(1H,m,C13),6.38(1H,s,C10),6.80-7.40(9H,m，芳族的)，7.49(2H,t,J=7.7Hz,Bz),7.60-7.64(1H,m,Bz),8.03-8.05(2H,m,Bz).
实施例6713-O-[3-(叔丁氧基羰基氨基)-3-(4-氟苯基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-41)
按与实施例16类似的方法，应用实施例66的化合物(2-26)(0.16g,0.13mmol)和二叔丁基二碳酸酯(32mg,0.15mmol)进行反应和后处理，于是得标题化合物(88mg,75％)。1H-NMR(CDCl3)δ:0.96(t,J=7Hz,3H),1.13(s,3H),1.24(s,3H),1.31(s,9H),1.51(m,2H),1.65(s,3H),1.68(s,1H), 1.85(s,3H),1.86(m,1H,C6-H),2.26-2.38(m,4H),2.34(s,3H),2.45-2.57(m,5H),3.14(s,1H),3.30-3.76(m,4H),3.78(d,J=7Hz,1H,C3-H),4.15(d,J=8Hz,1H,C20-H),4.28(d,J=8Hz,1H,C20-H),4.42(m,1H,C7-H),4.58(s,1H,C2′-H),4.94(d,J=8Hz,1H,C5-H),5.18(brs,1H,NH),5.32(d,1H,J=9Hz,C3′-H),5.64(d,J=7Hz,1H,C2-H),6.24(m,1H,C13-H),6.24(s,1H,C10-H),7.07(t,J=9Hz,2H),7.36(m,2H),7.48(t,J=8Hz,2H),7.59(t,J=7Hz,1H),8.09(d,J=7Hz,2H)
实施例6813-O-[3-(4-氟苯基)-3-(正己酰氨基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-42)
按与实施例42类似的方法，应用实施例66的化合物(2-26)(361mg,0.309mmol)和正己酰氯(46mg,0.342mmol)进行反应和后处理，于是得标题化合物(201mg,75％)无色晶体。1H-NMR(CDCl3)δ:0.83(3H,t,J=7.0Hz，己酰-CH3),0.92(3H,t,J=7.3Hz,NCH2CH2CH3),1.15(3H,s,C16或C17),1.21-1.26(4H,m，己酰-CH2x2),1.26(3H,s,C16或C17),1.48-1.57(4H,m，己酰-CH2和NCH2CH2CH3),1.68(3H,s,C19),1.85-1.94(1H,m,C6),1.86(3H,s,C18),2.16-2.20(2H,m,C14),2.30-2.37(4H,m，己酰-CH2和CH2CH2CH3),2.33(3H,s),2.45-2.56(4H,m，哌嗪)，2.50-2.60(1H,m,C6),3.17(1H,d,J=3.4Hz,C7-OH),3.40-3.75(4H,m，哌嗪)，3.78(1H,d,J=6.8Hz,C3),4.19(1H,d,J=8.4Hz,C20),4.30(1H,d,J=8.4Hz,C20),4.40-4.45(1H,m,11Hz,C7),4.65(1H,d,J=2.4Hz,C2′),4.94-4.96(1H,m,C5),5.56-5.59(1H,m,C3,),5.67(1H,d,J=7.1Hz,C2),6.22- 6.25(1H,m,C13),6.22-6.26(1H,brs,NH),6.2 6(1H,s,C10),7.06-7.11(2H,m,4FC6H4),7.38-7.42(2H,m,4FC6H4),7.49-7.52(2H,m,Bz),7.59-7.63(1H,m,Bz),8.10-8.12(2H,m,Bz).SIMS m/z:977(M)+
实施例6913-O-[3-(4-氟苯基)-2-羟基-3-(2-噻吩甲酰氨基)丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-43)
按与实施例42类似的方法，应用实施例66的化合物(2-26)(361mg,0.309mmol)和2-噻吩甲酰氯(50mg,0.342mmol)进行反应和后处理，于是得标题化合物(65mg,21％)无色晶体。1H-NMR(CDCl3)δ:0.92(3H,t,J=7.3Hz,CH2CH2CH3),1.13(3H,s,C16或C17),1.22(3H,s,C16或C17),1.48-1.57(2H,m,CH2CH2CH3),1.68(3H,s,C19),1.83(3H,s,C18),1.87-1.93(1H,m,C6),2.24-2.37(4H,m,C14和CH2CH2CH3),2.36(3H,s),2.40-2.55(5H,m，哌嗪和C6),3.20(1H,brs,C7-OH),3.41-3.71(4H,m，哌嗪)，3.78(1H,d,J=7.1Hz,C3),4.20(1H,d,J=8.4Hz,C20),4.29(1H,d,J=8.4Hz,C20),4.39-4.44(1H,m,C7),4.75(1H,d,J=2.4Hz,C2′),4.94-4.96(1H,m,C5),5.66(1H,d,J=7.1Hz,C2),5.73-5.75(1H,m,C3′),6.23-6.27(1H,m,C13),6.24(1H,s,C10),6.93-7.11(4H,m,4FC6H4，噻吩甲酰和NH),6.38-6.39(1H,m),7.46-7.53(6H,m,Bz,4FC6H4和噻吩甲酰)，7.60-7.64(1H,m,Bz),8.12(2H,d,J=7.3Hz,Bz)。SIMS m/z:989(M)+实施例7013-O-[3-(3,3-二甲基丙烯酰氨基)-3-(4-氟苯基)-2-羟基丙酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-44)
按与实施例42类似的方法，应用实施例66的化合物(2-26)(361mg,0.309mmol)和3,3-二甲基丙烯酰氯(41mg,0.342mmol)进行反应和后处理，于是得标题化合物(100mg,36％)无色晶体。1H-NMR(CDC13)δ:0.93(3H,t,J=7.3Hz CH2CH2CH3),1.14(3H,s,C16或C17),1.25(3H,s,C16或C17),1.52-1.62(2H,m,CH2CH2CH3),1.68(3H,s,C19),1.81(3H,s),1.82-1.92(1H,m,C6),1.86(3H,s,C18),2.01(3H,s),2.2 6-2.41(4H,m,C14和CH2CH2CH3),2.37(3H,s),2.49-2.60(5H,m，哌嗪和C6),3.13(1H,brs,C7-OH),3.40-3.73(4H,m，哌嗪)，3.79(1H,d,J=6.8Hz,C3),4.18(1H,d,J=8.3Hz,C20),4.30(1H,d,J=8.3Hz,C20),4.41-4.45(1H,m,C7),4.66(1H,d,J=2.4Hz,C2′),4.95-4.97(1H,m,C5),5.58(1H,s，丙烯酰)，5.58-5.62(1H,m,C3′),5.67(1H,d,J=7.1Hz,C2),6.12(1H,d,J=9.0Hz,NH),6.22-6.26(1H,m,C13),6.26(1H,s,C10),7.05-7.10(2H,m,4FC6H4),7.39-7.42(2H,m,4FC6H4),7.48-7.52(2H,m,Bz),7.59-7.63(1H,m,Bz),8.10-8.12(2H,m,Bz).SIMS m/z:961(M)+实施例7113-O-[3-苄氧羰基-2,2-二甲基-4-(2-甲基丙基)-5-噁唑烷羰基]-10-O-(4-丙基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-27)
按与实施例1类似的方法，应用实施例27的化合物(2-14)(2.1g,2.59mmol)和3-苄氧羰基-2,2-二甲基-4-(2-甲基丙基)-5-噁唑烷羧酸(1.04g,3.11mol)进行反应和后处理，于是得标题化合物(1.86g,64％)。1H-NMR(CDCl3)δ:0.51-0.66(6H,m,SiCH2),0.90-0.94(6H,m,iBu-CH3),0.92(3H,t,J=7.4Hz,CH2CH2CH3),0.92(9H,t,J=7.9Hz,SiCH2CH3),1.19(3H,s,C16或C17),1.21(3H,s,C16或C17),1.48-1.57(2H,m,CH2CH2CH3),1.60-1.67(3H,m,iBu-CH,CH2),1.61(3H,s，异亚丙基)，1.65(3H,s，异亚丙基)，1.68(3H,s,C19),1.85-1.92(1H,m,C6),2.15(s,3H),2.24(2H,d,J=9.0Hz,C14),2.31-2.34(2H,m,CH2CH2CH3),2.36(3H,s),2.36-2.55(4H,m，哌嗪)，2.45-2.56(1H,m,C6),3.38-3.85(4H,m，哌嗪)，3.87(1H,d,J=6.8Hz,C3),4.15(1H,d,J=8.3Hz,C20),4.31(1H,d,J=8.3Hz,C20),4.32(1H,brs,C2′或C3′),4.49(1H,dd,J=6.6,10.5Hz,C7),4.52(1H,brs,C2′或C3′),4.95-4.97(1H,m,C5),5.07-5.21(2H,m,PhCH2),5.68(1H,d,J=7.1Hz,C2),6.15-6.20(1H,m,C13),6.40(1H,s,C10),7.31-7.37(5H,m,z),7.46-7.50(2H,m,Bz),7.59-7.63(1H,m,Bz),8.08-8.10(2H,m,Bz).实施例7213-O-[3-(正己酰氨基)-2-羟基-5-甲基己酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-45)
按与实施例42类似的方法，应用实施例71的化合物(2-27)(334mg,0.296mmol)和正己酰氯(48mg,0.355mmol)进行反应和后处理，于是得标题化合物(182mg,66％)无色晶体。1H-NMR(CDCl3)δ:0.84(3H,t,J=6.9Hz，己酰-CH3),0.92(3H,t,J=7.3Hz,NCH2CH2CH3),0.98(3H,d,J=6.6Hz,iBu-CH3),0.99(3H,d,J=6.6Hz,iBu-CH3),1.14(3H,s,C16或C17),1.24(3H,s,C16或C17),1.25-1.37(2H,m，己酰-CH2),1.48-1.94(10H,m，己酰-CH2x2,NCH2CH2CH3,C6,iBu-CH2和iBu-CH),1.68(3H,s,C19),1.90(3H,s,C18),2.08-2.13(2H,m,C14),2.33-2.41(4H,m，己酰-CH2和CH2CH2CH3),2.37(3H,s),2.47-2.52(4H,m，哌嗪)，2.50-2.57(1H,m,C6),3.17(1H,brs,C7-OH),3.43-3.73(4H,m，哌嗪)，3.79(1H,d,J=7.1Hz,C3),4.20(1H,d,J=1.7Hz,C2′),4.23(1H,d,J=8.4Hz,C20),4.29(1H,d,J=8.4Hz,C20),4.44-4.49(2H,m,C7,NH),4.97-4.99(1H,m,C5),5.53-5.57(1H,m,C3′),5.67(1H,d,J=7.1Hz,C2),6.13-6.17(1H,m,C13),6.25(1H,s,C10),7.44-7.48(2H,m,Bz),7.57-7.61(1H,m,Bz),8.10-8.12(2H,m,Bz).SIMS m/z:940(M+H)+
实施例7313-O-[2-羟基-5-甲基-3-(2-噻吩甲酰氨基)己酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-46)
按与实施例42类似的方法，应用实施例71的化合物(2-27)(334mg,0.296mmol)和2-噻吩甲酰氯(52mg,0.355mmol)进行反应和后处理，于是得标题化合物(124mg,44％)无色晶体。1H-NMR(CDCl3)δ:0.92(3H,t,J=7.3Hz,CH2CH2CH3),1.00-1.02(6H,m,iBu-CH3x2),1.13(3H,s,C16或C17),1.22(3H,s,C16或C17),1.42-1.92(6H,m,CH2CH2CH3,C6,iBu-CH2和iBu-CH),1.68(3H,s,C19),1.89(3H,s,C18),1.87-1.93(1H,m,C6),2.29-2.39(4H,m,C14和CH2CH2CH3),2.42(3H,s),2.46-2.58(5H,m，哌嗪和C6),3.16(1H,brs,C7-OH),3.41-3.73(4H,m，哌嗪),3.80(1H,d,J=7.1Hz,C3),4.24(1H,d,J=8.4Hz,C20),4.30(1H,d,J=8.4Hz,C20),4.32(1H,d,J=1.9Hz,C2′),4.42-4.47(1H,m,C7),4.63-4.69(1H,m,C3′),4.97-5.00(1H,m,C5),5.67(1H,d,J=7.1Hz,C2),6.18-6.23(2H,m,C13和NH),6.25(1H,s,C10),7.46-7.53(3H,m,Bz和噻吩甲酰)，7.59-7.61(1H,m,Bz),8.13-8.15(2H,m,Bz).SIMS m/z:951(M)+
实施例7413-O-[3-(3,3-二甲基丙烯酰氨基)-2-羟基-5-甲基己酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-47)
按与实施例42类似的方法，应用实施例71的化合物(2-27)(334mg,0.296mmol)和3,3-二甲基丙烯酰氯(42mg,0.355mmol)进行反应和后处理，于是得标题化合物(91mg,33％)无色晶体。1H-NMR(CDCl3)δ:0.89(3H,t,J=7.4Hz CH2CH2CH3),0.96(3H,d,J=6.8Hz,iBu-CH3),0.96(3H,d,J=6.8Hz,iBu-CH3),1.11(3H,s,C16或C17),1.21(3H,s,C16或C17),1.31-1.90(6H,m,CH2CH2CH3,C6,iBu-CH2和iBu-CH),1.66(3H,s,C19),1.76(3H,s),1.87(3H,s,C18),1.94(3H,s),2.31-2.40(4H,m,C14和CH2CH2CH3),2.37(3H,s),2.47-2.59(5H,m，哌嗪和C6),3.15(1H,brs,C7-OH),3.40-3.70(4H,m，哌嗪)，3.77(1H,d,J=6.8Hz,C3),4.19(1H,d,J=8.2Hz,C20),4.20(1H,d,J=2.0Hz,C2,),4.27(1H,d,J=8.2Hz,C20),4.40-4.45(2H,m,C7和C3′),4.95-4.97(1H,m,C5),5.41-5.44(1H,m),5.48(1H,s，丙烯酰)，5.64(1H,d,J=7.1Hz,C2),6.13-6.17(1H,m,C13),6.23(1H,s,C10),7.42-7.46(2H,m,Bz),7.55-7.59(1H,m,Bz),8.08-8.10(2H,m,Bz).SIMS m/z:924(M+H)+
实施例7513-O-[3-(叔丁氧基羰基氨基)-2-羟基-5-甲基己酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-48)
按与实施例16类似的方法，应用实施例71的化合物(2-27)(334mg,0.296mmol)和二叔丁基二碳酸酯(50mg,0.229mmol)进行反应和后处理，于是得标题化合物(15mg,32％)无色晶体。1H-NMR(CDCl3)δ:0.93(3H,t,J=7.4Hz CH2CH2CH3),0.97-0.99(6H,m,iBu-CH3x2),1.14(3H,s,C16或C17),1.24(3H,s,C16或C17),1.31(9H,s,tBu),1.49-1.95(6H,m,CH2CH2CH3,C6,iBu-CH2和iBu-CH),1.68(3H,s,C19),1.92(3H,s,C18),2.31-2.40(4H,m,C14和CH2CH2CH3),2.38(3H,s),2.47-2.59(5H,m，哌嗪和C6),3.15(1H,brs,C7-OH),3.40-3.72(4H,m，哌嗪)，3.80(1H,d,J=6.8Hz,C3),4.10-4.18(2H,m,C27和NH),4.20(1H,d,J=8.7Hz,C20),4.30(1H,d,J=8.7Hz,C20),4.43-4.48(1H,m,C7),4.60(1H,d,J=9.5Hz,C3′),4.96-4.99(1H,m,C5),5.66(1H,d,J=7.1Hz,C2),6.17-6.21(1H,m,C13),6.27(1H,s,C10),7.46-7.49(2H,m,Bz),7.59-7.62(1H,m,Bz),8.11-8.13(2H,m,Bz).SIMS m/z:941(M)+
实施例7613-O-(3-苄氧羰基-4-环丙基甲基-2,2-二甲基-5-噁唑烷羰基)-10-O-(4-丙基哌嗪基羰基)-7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素Ⅲ(化合物2-28)
按与实施例1类似的方法，应用实施例27的化合物(2-14)(300mg,0.369mmol)和3-苄氧羰基-4-环丙基甲基-2,2-二甲基-5-噁唑烷羧酸(135mg,0.405mmol)进行反应和后处理，于是得标题化合物(330mg,79％)无色固体。1H-NMR(CDCl3)δ:-0.01-0.20(2H,m,cPr-CH2),0.40-0.50(2H,m,CPr-CH2),0.54-0.66(7H,m,SiCH2和CPr-CH),0.92(3H,t,J=7.3Hz,CH2CH2CH3),0.92(9H,t,J=7.9Hz,SiCH2CH3),1.20(3H,s,C16或C17),1.21(3H,s,C16或C17),1.48-1.57(2H,m,CH2CH2CH3),1.60-1.67(2H,m,CH2), 1.61(6H,s，异亚丙基)，1.68(3H,s,C19),1.85-1.92(1H,m,C6),2.16(s,3H),2.24-2.27(2H,m,C14),2.31-2.34(2H,m,CH2CH2CH3),2.35(3H,s),2.36-2.55(4H,m，哌嗪)，2.47-2.56(1H,m,C6),3.38-3.88(4H,m，哌嗪)，3.87(1H,d,J=6.8Hz,C3),4.15(1H,d,J=8.4Hz,C20),4.49(1H,d,J=8.4Hz,C20),4.49(1H,dd,J=6.6,10.5Hz,C7),4.54(1H,br,C2′和C3′),4.95-4.97(1H,m,C5),5.05-5.19(2H,m,PhCH2),5.69(1H,d,J=7.1Hz,C2),6.1 6-6.20(1H,m,C13),6.40(1H,s,C10),7.31-7.40(5H,m,z),7.46-7.50(2H,m,Bz),7.59-7.63(1H,m,Bz),8.07-8.9(2H,m,Bz).
实施例7713-O-[4-环丙基-3-(正己酰氨基)-2-羟基丁酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-49)
按与实施例42类似的方法，应用实施例76的化合物(2-28)(56mg,0.0494mmol)和正己酰氯(8mg,0.0593mmol)进行反应和后处理，于是得标题化合物(17mg,37％)无色晶体。1H-NMR(CDCl3)δ:0.13-0.21(2H,m,cPr-CH2),0.50-0.59(2H,m,cPr-CH2),0.66-0.75(1H,m,cPr-CH),0.83(3H,t,J=7.0Hz，己酰-CH3),0.94(3H,t,J=7.3Hz,NCH2CH2CH3),1.14(3H,s,C16或C17),1.20-1.26(4H,m，己酰-CH2x2),1.26(3H,s,C16或C17),1.48-1.65(6H,m，己酰-CH2,NCH2CH2CH3和CH2),1.68(3H,s,C19),1.85-1.93(1H,m,C6),1.91(3H,s,C18),2.04- 2.58(11H,m,C14，己酰-CH2,CH2CH2CH3，哌嗪和C6),2.42(3H,s),3.15(1H,brs,C7-0H),3.40-3.73(4H,m，哌嗪)，3.79(1H,d,J=7.1Hz,C3),4.21(1H,d,J=8.4Hz,C20),4.31(1H,d,J=8.4Hz,C20),4.41-4.46(2H,m,C7和C3′),4.47(1H,d,J=1.7Hz,C2,),4.96-4.99(1H,m,C5),5.67-5.69(2H,m,C2和NH),6.16-6.20(1H,m,C13),6.27(1H,s,C10),7.48-7.54(2H,m,Bz),7.59-7.63(1H,m,Bz),8.11-8.14(2H,m,Bz)。SIMS m/z:938(M+H)+
实施例7813-O-[4-环丙基-2-羟基-3-(2-噻吩甲酰氨基)丁酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-50)
按与实施例42类似的方法，应用实施例76的化合物(2-28)(56mg,0.0494mmol)和2-噻吩甲酰氯(9mg,0.0593mmol)进行反应和后处理，于是得标题化合物(21mg,45％)无色晶体。1H-NMR(CDCl3)δ:0.15-0.23(2H,m,cPr-CH2),0.51-0.60(2H,m,cPr-CH2),0.75-0.80(1H,m,cPr-CH),0.93(3H,t,J=7.4Hz,CH2CH2CH3),1.13(3H,s,C16或C17),1.22(3H,s,C16或C17),1.54-1.93(5H,m,CH2CH2CH3,C6和iBu-CH2),1.68(3H,s,C19),1.89(3H,s,C18),2.25-2.31(2H,m,C14),2.38-2.44(2H,m,CH2CH2CH3),2.43(3H,s),2.50-2.59(5H,m，哌嗪和C6),3.14(1H,brs,C7-OH),3.40-3.80(4H,m，哌嗪)，3.80(1H,d,J=7.1Hz,C3),4.22(1H,d,J=8.3Hz,C20),4.31(1H,d,J=8.3Hz,C20),4.40- 4.47(1H,m,C7),4.56(1H,d,J=2.0Hz,C2′),4.62-4.68(1H,m,C3′),4.97-4.99(1H,m,C5),5.67(1H,d,J=7.1Hz,C2),6.21-6.25(1H,m,C13),6.25(1H,s,C10),6.30(1H,d,J=9.3Hz,NH),7.02-7.04(1H,m，噻吩甲酚)，7.42-7.45(2H,m，噻吩甲酰)，7.51-7.54(2H,m,Bz),7.60-7.64(1H,m,Bz),8.14-8.16(2H,m,Bz).SIMS m/z:949(M)+
实施例7913-O-[4-环丙基-3-(3,3-二甲基丙烯酰氨基)-2-羟基丁酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-51)
按与实施例42类似的方法，应用实施例76的化合物(2-28)(56mg,0.0494mmol)和3,3-二甲基丙烯酰氯(7mg,0.0593mmol)进行反应和后处理，于是得标题化合物(17mg,37％)无色晶体。1H-NMR(CDCl3)δ:0.15-0.19(2H,m,cPr-CH2),0.53-0.55(2H,m,cPr-CH2),0.70-0.78(1H,m,cPr-CH),0.95(3H,t,J=7.3Hz CH2CH2CH3),1.14(3H,s,C16或C17),1.25(3H,s,C16或C17),1.50-1.90(5H,m,CH2CH2CH3,C6和CH2),1.68(3H,s,C19),1.79(3H,s),1.91(3H,s,C18),1.98(3H,s),2.29-2.41(4H,m,C14和CH2CH2CH3),2.45(3H,s),2.47-2.58(5H,m，哌嗪和C6),3.11(1H,brs,C7-OH),3.47-3.80(4H,m，哌嗪)，3.80(1H,d,J=6.8Hz,C3),4.19(1H,d,J=8.5Hz,C20),4.32(1H,d,J=8.5Hz,C20),4.41-4.47(2H,m,C7和C3’),4.50(1H,d,J=2.0Hz,C2’),4.98- 4.99(1H,m,C5),5.50(1H,s，丙烯酰)，5.56-5.58(1H,m,NH),5.68(1H,d,J=7.1Hz,C2),6.18-6.23(1H,m,C13),6.28(1H,s,C10),7.48-7.52(2H,m,Bz),7.59-7.63(1H,m,Bz),8.11-8.13(2H,m,Bz).SIMS m/z:922(M+H)+
实施例8013-O-[4-环丙基-3-(叔丁氧基羰基氨基)-2-羟基丁酰]-10-O-(4-丙基哌嗪基羰基)-10-脱乙酰基浆果赤霉素Ⅲ(化合物1-52)
按与实施例16类似的方法，应用实施例76的化合物(2-28)(56mg,0.0494mmol)和二叔丁基二碳酸酯(13mg,0.0593mmol)进行反应和后处理，于是得标题化合物(23mg,48％)无色晶体。1H-NMR(CDCl3)δ:0.15-0.20(2H,m,cPr-CH2),0.51-0.55(2H,m,cPr-CH2),0.67-0.75(1H,m,cPr-CH),0.94(3H,t,J=7.3Hz CH2CH2CH3),1.14(3H,s,C16或C17),1.26(3H,s,C16或C17),1.30(9H,s,tBu),1.51-1.92(5H,m,CH2CH2CH3,C6和CH2),1.67(3H,s,C19),1.92(3H,s,C18),2.31-2.70(9H,m,C14,CH2CH2CH3，哌嗪和C6),2.42(3H,s),3.15(1H,brs,C7-OH),3.40-3.80(4H,m，哌嗪)，3.81(1H,d,J=7.1Hz,C3),4.18(1H,d,J=8.4Hz,C20),4.32(1H,d,J=8.4Hz,C20),4.43-4.48(2H,m,C7和C3′),4.46(1H,d,J=2.0Hz,C2+),4.72(1H,d,J=9.5Hz,NH),4.97-4.99(1H,m,C5),5.67(1H,d,J=7.1Hz,C2),6.20-6.24(1H,m,C13),6.28(1H,s,C10),7.49-7.52(2H,m,Bz),7.60-7.63(1H,m,Bz),8.12-8.14(2H,m,Bz)。SIMS m/z:939(M)+
上述实施例1～80中制备的化合物如表1～13中所示。
表1
表2
表3
表4
表5
表6
表7
表8 
表9 
表10 
表11
表12
表13
实验1
新型水溶性紫杉烷衍生物的溶解性
Ⅲ)校正曲线的绘制
称取重量为2.3mg的化合物(1-4)，往其中添加2.3mL乙腈，于是溶解该化合物而得标准溶液。应用一份10μL的标准溶液，通过HPLC(操作条件1)进行试验。通过自动求积分法测定化合物(1-4)的峰面积(它已得自标准溶液的色谱图)。将作为三次测量的平均值获得的峰面积对每10μL中化合物(1-4)的量(10pg)描点，于是绘制了校正曲线。
化合物(1-4)的校正曲线：Y=1.518×10-5X[X：峰面积，Y：化合物(1-4)的量(μg)][HPLC操作条件1]柱：Inertsil ODS-2(5-250),40deg.流动相：0.01M KH2PO4-CH3CN(3∶2)。流速：1.0mL/min。检测：紫外吸收光度计(225nm),0.2AUFS。Ⅱ)化合物(1-4)的溶解性试验：
称取重量为3.7mg的化合物(1-4)，然后悬浮于2.0mL净化水。往形成的悬浮液中添加41.3pL(1.05eq.)0.1N盐酸。通过超声处理，使形成的混合物变成均匀的悬浮液，再在室温下振荡2小时。通过膜滤器(0.22pm)过滤这样获得的混合物，滤液用作试液。应用一份5pL的该试液，通过HPLC(操作条件1)进行测试。从三次测定的平均值获得的面积，测得化合物(1-4)的溶解度。
作为三次测定的平均值获得的化合物(1-4)的面积(X)：518226。
溶解的化合物(1-4)的量(Y):7.87pg/5μL(1.574mg/mL)。
作为参比，溶解的紫杉酚量是0.4pg/mL。实验2紫杉烷衍生物(1)的生长抑制活性原料和方法细胞
作为得自人口腔癌的KB细胞，应用了购自DainipponPharmaceutical Co.,Ltd.和以冻干形式贮存于该公司的研究所的那些细胞。在含10％胎牛血清的Dulbecco氏改良伊格氏培养基(NISSUI PHARMACEUTICAL Co.,LTD.的产品)中培养该KB细胞，并保持在5％CO2-空气和37℃的条件下。药物
应用的每种化合物都是以10mg/mL的浓度溶于DMSO中。药物处理(1)KB
在第1天，通过应用含10％胎牛血清(不含酚红)的培养基(Dulbecco氏改良伊格氏培养基(Sigma))在96孔微量滴定板(Falcon#3072)上以2,000个细胞/100μl/孔接种处于对数生长期的细胞，并培养一夜。在第0天，将已用相同的培养基稀释到0.03～10,000ng/mL的每种化合物以100μL等分样加到各个孔中，并将这些细胞培养3天。每种药物每个浓度应用三个孔。每块板备有三个只含培养基的空白孔，还有八个孔作为未用药物处理的对比孔。XTT分析
在应用时，将XTT(Sigma)以1mg/mL的浓度溶于每种不含血清的培养基。将在5mM的浓度下溶于PBS的苏木精硫酸二甲酯(Sigma)以1/200的体积比加到形成的溶液中。以每孔50μl的量往每个孔添加这样配制的溶液。接着培养4小时，通过ELISA在450nm处测定OD。50％生长抑制浓度(GI50)的计算
GI50是通过内插法从浓度-生长抑制率(GIR)曲线计算的。按下式测定了GIR：引用的参考文献：
Scudiero.DA，等(1988)癌研究(Cancer Rds.)48:p4827-4833。
Carcinostatic Screening Special Committee的报告，“癌和化疗(Cancer and Chemotherapy),21,1306-1307(1994)”
测试结果如表14中所示。
| 化合物号 | KB | |
| GI50(ng/ML) | 活度比率 | |
| 化合物1-1 | 0.48 | 2.70 |
| 化合物1-2 | 0.28 | 4.64 |
| 化合物1-3 | 0.43 | 3.02 |
| 化合物1-4 | 0.23 | 5.65 |
| 紫杉酚 | 1.3 | 1.00 |
工业上开发的可能性
本发明的紫杉烷衍生物具有很高的水溶性，所以它们可被配成液体制剂(例如注射液)而不用任何特殊溶剂。此外，它们还表现出优良的抗肿瘤活性。
Claims (8)
1．由下式(1)表示的紫杉烷衍生物或其盐：
其中，A1表示基
(其中，R1表示氢原子，取代的或未取代的烷基)或者基
(其中，R2表示氨基、单烷基氨基或二烷基氨基、哌啶子基、吡咯烷基或吗啉代基)，X表示氢原子、烷氧羰基、可被氟原子取代的烷酰基、烯酰基、噻吩基羰基、糠酰基或苯甲酰基，Y表示氢原子或三烷基甲硅烷基，A2表示呋喃基、烷基呋喃基、烷基或氟苯基，Ac表示乙酰基，Bz表示苯甲酰基。
2．由下式(2)表示的紫杉烷衍生物或其盐：
其中，A1表示基
(其中，R1表示氢原子，或者取代的或未取代的烷基)或者基
(其中，R2表示氨基、单烷基氨基或二烷基氨基、哌啶子基、吡咯烷基或吗啉代基)，Y表示氢原子或三烷基甲硅烷基，Z表示氢原子或下式的基：(其中，R3表示氢原子、烷氧羰基、烯丙氧羰基或苄氧羰基，R4和R5各自表示氢原子、烷基或烷氧苯基，但条件是，R4和R5不同时表示氢原子，并且，当R4或R5中的任一个表示烷氧苯基时，另一个就表示氢原子，A2表示呋喃基、烷基呋喃基、烷基或氟苯基)，Ac表示乙酰基，并且Bz表示苯甲酰基。
3．一种药物，它包含作为活性组分的、权利要求1的紫杉烷衍生物或其盐。
4．一种抗肿瘤剂，它包含作为活性组分的、权利要求1的紫杉烷衍生物或其盐。
5．一种药物组合物，它包含权利要求1的紫杉烷衍生物或其盐和药物上可接受的载体。
6．权利要求1的紫杉烷衍生物或其盐作为药物的应用。
7．权利要求1的紫杉烷衍生物或其盐作为抗肿瘤剂的应用。
8．一种治疗肿瘤的方法，它包括施用有效量权利要求1的紫杉烷衍生物或其盐。
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| HUP0200995A3 (en) * | 2000-02-02 | 2005-02-28 | Univ Florida State Res Found | Taxane formulations having improved solubility |
| DE60134814D1 (de) | 2000-02-02 | 2008-08-28 | Univ Florida State Res Found | C10-carbamoyloxysubstituierte taxane als antitumormittel |
| US6649632B2 (en) | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
| US6362217B2 (en) * | 2000-03-17 | 2002-03-26 | Bristol-Myers Squibb Company | Taxane anticancer agents |
| CA2354471A1 (en) * | 2001-07-31 | 2003-01-31 | Florida State University Research Foundation, Inc. | C10 ester substituted taxanes |
| HN2005000054A (es) * | 2004-02-13 | 2009-02-18 | Florida State University Foundation Inc | Taxanos sustituidos con esteres de ciclopentilo en c10 |
| AU2006214498A1 (en) * | 2005-02-14 | 2006-08-24 | Florida State University Research Foundation, Inc. | C10 cyclopropyl ester substituted taxane compositions |
| WO2006122408A1 (en) | 2005-05-18 | 2006-11-23 | Aegera Therapeutics Inc. | Bir domain binding compounds |
| KR101506466B1 (ko) | 2006-05-16 | 2015-03-27 | 파마사이언스 인크. | Ｉａｐ ｂｉｒ 도메인 결합 화합물 |
| EP2276755A4 (en) * | 2008-03-31 | 2011-05-04 | Univ Florida State Res Found | C (10) -ETHYESTER- AND C (10) -CYCLOPROPYLESTER-SUBSTITUTED TAXANES |
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| US5250683A (en) * | 1991-09-23 | 1993-10-05 | Florida State University | Certain substituted taxanes and pharmaceutical compositions containing them |
| US5227400A (en) * | 1991-09-23 | 1993-07-13 | Florida State University | Furyl and thienyl substituted taxanes and pharmaceutical compositions containing them |
| JPH08253465A (ja) * | 1995-03-17 | 1996-10-01 | Dai Ichi Seiyaku Co Ltd | 四環性化合物 |
| FR2745814B1 (fr) * | 1996-03-06 | 1998-04-03 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent |
| WO1998002426A1 (fr) * | 1996-07-15 | 1998-01-22 | Kabushiki Kaisha Yakult Honsha | Derives de taxane et medicaments les contenant |
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| KR100551945B1 (ko) | 2006-02-20 |
| BR9813779A (pt) | 2000-10-03 |
| AU1682299A (en) | 1999-07-12 |
| WO1999032473A1 (fr) | 1999-07-01 |
| CN1221539C (zh) | 2005-10-05 |
| US6268381B1 (en) | 2001-07-31 |
| AU758418B2 (en) | 2003-03-20 |
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