CN115703755A - 2h-苯并吡喃-2-酮衍生物及其用途 - Google Patents
2h-苯并吡喃-2-酮衍生物及其用途 Download PDFInfo
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- CN115703755A CN115703755A CN202110931045.0A CN202110931045A CN115703755A CN 115703755 A CN115703755 A CN 115703755A CN 202110931045 A CN202110931045 A CN 202110931045A CN 115703755 A CN115703755 A CN 115703755A
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- alkyl
- compound
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- unsubstituted
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- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical class C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title description 326
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 27
- 229940079593 drug Drugs 0.000 claims abstract description 20
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 12
- 201000005202 lung cancer Diseases 0.000 claims abstract description 12
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 12
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 10
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 10
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 8
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 8
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 8
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 8
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 8
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims description 171
- 125000002723 alicyclic group Chemical group 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- -1 R 3 Selected from H Chemical group 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 18
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 16
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 16
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
- 125000001589 carboacyl group Chemical group 0.000 claims description 13
- 125000000524 functional group Chemical group 0.000 claims description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 12
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000003435 aroyl group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 8
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 5
- 230000000259 anti-tumor effect Effects 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 4
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 3
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 2
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000000958 aryl methylene group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 17
- 230000005764 inhibitory process Effects 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 8
- 238000002474 experimental method Methods 0.000 abstract description 7
- 230000004663 cell proliferation Effects 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 229960000956 coumarin Drugs 0.000 description 107
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 107
- 235000001671 coumarin Nutrition 0.000 description 104
- 239000007787 solid Substances 0.000 description 95
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 239000011734 sodium Substances 0.000 description 59
- 238000006243 chemical reaction Methods 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- 229960001592 paclitaxel Drugs 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- PQAMFDRRWURCFQ-UHFFFAOYSA-N 2-ethyl-1h-imidazole Chemical compound CCC1=NC=CN1 PQAMFDRRWURCFQ-UHFFFAOYSA-N 0.000 description 20
- 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 20
- 229930012538 Paclitaxel Natural products 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 229910052786 argon Inorganic materials 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 241000282414 Homo sapiens Species 0.000 description 13
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- 238000001308 synthesis method Methods 0.000 description 12
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
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- 238000003786 synthesis reaction Methods 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- 206010059866 Drug resistance Diseases 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
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- HOBFSNNENNQQIU-SNVBAGLBSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-2-phenylacetic acid Chemical group CC(C)(C)OC(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 HOBFSNNENNQQIU-SNVBAGLBSA-N 0.000 description 2
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical group OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 2
- CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical group CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 description 2
- LMHCYRULPLGEEZ-UHFFFAOYSA-N 1-iodoheptane Chemical compound CCCCCCCI LMHCYRULPLGEEZ-UHFFFAOYSA-N 0.000 description 2
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- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
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- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
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- AQTUACKQXJNHFQ-LURJTMIESA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioic acid Chemical group CC(C)(C)OC(=O)N[C@H](C(O)=O)CCC(O)=O AQTUACKQXJNHFQ-LURJTMIESA-N 0.000 description 1
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Abstract
Description
技术领域
本发明属于医药化学技术领域,具体涉及2H-苯并吡喃-2-酮衍生物及其制备方法和用途。
背景技术
据报道,全球每年约有数十万的人类死于恶性肿瘤,恶性肿瘤是危害人类健康的头号杀手。目前,临床上对肿瘤的治疗手段主要包括手术切除、放射治疗以及化学治疗。这些方案依据于肿瘤的类型疾病发展阶段而有不同。其中,寻找高效低毒,尤其是对耐药肿瘤也能发挥治疗效果的抗肿瘤药物,一直是全世界科学家一致努力的目标。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此,本发明首先提供了一类2H-苯并吡喃-2-酮衍生物,具体如式Ⅰ所示的化合物、其立体异构体、化合物或其立体异构体药学上可接受的盐:
其中,X选自卤素、杂芳基或含氮官能团;当X为卤素时,n为1~5的整数,当X选自芳基或含氮官能团时,n为0~5的整数;所述杂芳基中的杂原子为O、N或S;R8、R9独立地选自C1~C6的烷基。
其中,上述化合物中,R8和R9优选为甲基。
其中,上述化合物中,X为氯,且n为1~3的整数。
优选的,上述化合物中,X为氯时,所述化合物选自:
其中,上述化合物中,X为5~6元杂芳基。
优选地,上述化合物中,X为5元杂芳基,n为0~3的整数。
更优选地,上述化合物中,X为呋喃基,n为0~1的整数。
最优选的,上述化合物中,X为呋喃基时,所述化合物为:
其中,上述化合物中,X为含氮官能团,且n为0,所述化合物的结构如式Ⅱ所示:
R1、R2独立的选自H、烷基、烷氧羰基、烷酰基、芳酰基或芳基磺酰基,R3选自H、烷基或芳基;
或者,R1与R2相连形成芳环或脂环;
或者,R2与R3相连形成脂环。
其中,上述化合物中,当R1与R2、R2与R3均不成环时,R1、R2独立选自H、未取代的C1~C17烷基、羟基取代的C1~C17烷基、6~14元芳基取代的C1~C17烷基、叔丁氧羰基、苄氧羰基、C1~C17烷酰基、6~14元芳酰基或6~14元芳基磺酰基。
优选地,上述化合物中,当R1与R2、R2与R3均不成环时,R1、R2独立选自H、未取代的C1~C8烷基、羟基取代的C1~C8烷基、苯环上的氢任选被取代或未取代的苯基取代的C1~C8烷基、叔丁氧羰基、苄氧羰基、C1~C8烷酰基、苯环上的氢任选被取代或未取代的苯甲酰基或苯环上的氢任选被取代或未取代的苯磺酰基,所述苯环上的氢任选被取代或未取代的苯甲酰基或苯环上的氢任选被取代或未取代的苯磺酰基中的取代基为C1~C4烷基。
更优选地,上述化合物中,当R1与R2、R2与R3均不成环时,R1、R2独立选自H、未取代的C1~C8烷基、羟基取代的C2烷基、苄基、叔丁氧羰基、苄氧羰基、乙酰基、丙酰基、戊酰基、苯酰基或甲苯磺酰基。
其中,上述化合物中,当R1与R2、R2与R3均不成环时,R3选自H、未取代的C1~C6烷基、羟基取代的C1~C6烷基、-SCH3取代的C1~C6烷基、-C(=O)NH2取代的C1~C6烷基、6~14元芳亚甲基或6~14元芳基。
优选地,上述化合物中,当R1与R2、R2与R3均不成环时,R3选自H、未取代的C1~C6烷基、羟基取代的C1~C6烷基、-SCH3取代的C1~C6烷基、-C(=O)NH2取代的C1~C6烷基、苯环上的氢任选被羟基取代或未取代的苄基或苯环上的氢任选被羟基取代或未取代的苯基。
更优选地,上述化合物中,当R1与R2、R2与R3均不成环时,R3选自H、未取代的C1~C4烷基、羟基取代的C1~C2烷基、-SCH3取代的C2烷基、-C(=O)NH2取代的C2烷基、苯基、苄基、4-羟基苯甲基。
其中,上述化合物中,当R1与R2、R2与R3均不成环时,所述化合物选自:
其中,上述化合物中,当R2与R3相连形成脂环时,所述脂环为5元脂环,R1选自H、烷基、烷氧羰基、烷酰基、芳酰基或芳基磺酰基。
优选地,上述化合物中,当R2与R3相连形成脂环时,所述的5元脂环含有1个杂原子,所述杂原子为氮、氧或硫。
更优选地,上述化合物中,当R2与R3相连形成脂环时,所述5元脂环为未取代或羟基取代的5元氮杂脂环,R1选自H、叔丁氧羰基或烷酰基。
优选的,上述化合物中,当R2与R3相连形成脂环时,R1选自H、未取代的C1~C17烷基、羟基取代的C1~C17烷基、6~14元芳基取代的C1~C17烷基、叔丁氧羰基、苄氧羰基、C1~C17烷酰基、6~14元芳酰基或6~14元芳基磺酰基。
更优选地,上述化合物中,当R2与R3相连形成脂环时,R1选自H、未取代的C1~C8烷基、羟基取代的C1~C8烷基、苯环上的氢任选被取代或未取代的苯基取代的C1~C8烷基、叔丁氧羰基、苄氧羰基、未取代或氨基取代的C1~C8烷酰基、苯环上的氢任选被取代或未取代的苯甲酰基或苯环上的氢任选被取代或未取代的苯磺酰基,所述苯环上的氢任选被取代或未取代的苯甲酰基或苯环上的氢任选被取代或未取代的苯磺酰基中的取代基为C1~C4烷基。
再优选地,上述化合物中,当R2与R3相连形成脂环时,R1选自H、未取代的C1~C8烷基、羟基取代的C2烷基、苄基、叔丁氧羰基、苄氧羰基、未取代或氨基取代的乙酰基、丙酰基、戊酰基、苯酰基或甲苯磺酰基。
其中,上述化合物中,当R2与R3相连形成脂环时,所述化合物选自:
其中,上述化合物中,当R1与R2相连形成芳环或脂环时,所述芳环为5元芳环,所述脂环为4~6元脂环。
优选地,上述化合物中,当R1与R2相连形成芳环或脂环时,所述5元芳环为咪唑基,所述咪唑基上的氢未被取代或者被烷基、卤素或-C(=O)H取代。
更优选地,上述化合物中,当R1与R2相连形成芳环或脂环时,所述咪唑基上的氢未被取代或者被甲基、乙基、氯或-C(=O)H取代。
优选地,上述化合物中,当R1与R2相连形成芳环或脂环时,所述4~6元脂环含有1~2个杂原子,所述杂原子为N、O或S,所述4~6元脂环上的氢未被取代,或者被羟基、卤素或烷基取代,或者形成不饱和键。
更优选地,上述化合物中,当R1与R2相连形成芳环或脂环时,所述4~6元脂环上的氢未被取代,或者被羟基、溴或甲基取代,或者形成烯键。
其中,上述化合物中,当R1与R2相连形成芳环或脂环时,所述化合物选自:
其中,上述化合物中,X为含氮官能团,且n为2~5的整数,所述化合物的结构如式Ⅲ所示:
R4选自H或-COOH,R5选自H或烷氧羰基。
优选的,上述化合物中,X为含氮官能团,且n为2~5的整数时,R5选自H、叔丁氧羰基、苄氧羰基或芴甲氧羰基。
更优选的,上述化合物中,X为含氮官能团,且n为2~5的整数时,R5选自H或叔丁氧羰基。
其中,上述化合物中,X为含氮官能团,且n为2~5的整数时,所述化合物选自:
本发明还提供了上述化合物、其立体异构体、化合物或其立体异构体药学上可接受的盐在制备抗肿瘤的药物中的用途。优选地,所述的肿瘤为耐药肿瘤。
更具体的,上述用途中,所述的药物是治疗和/或预防结肠癌、乳腺癌、卵巢癌、肺癌或宫颈癌的药物。优选地,所述的肺癌为肺腺癌。
本发明还提供了一种抗肿瘤的药物组合物,其以上述化合物、其立体异构体、化合物或其立体异构体药学上可接受的盐为活性成分,加入药学上接受的辅料或者辅助性成分制备而成的制剂。优选地,所述的制剂为注射剂。优选地,所述的肿瘤为耐药肿瘤。
更具体的,上述药物组合物,其制剂是治疗和/或预防结肠癌、乳腺癌、卵巢癌、肺癌或宫颈癌的制剂。优选地,所述的肺癌为肺腺癌。
本发明还提供了上述化合物的制备方法,其包括如下步骤:
方法一:
方法二:
其中,上述制备方法中,所述方法一满足以下至少一项:
M05:碱的摩尔配比为1:1~2;
所述的碱选自三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸钠、氢氧化钾、氢氧化钠、氢化钠中一种或两种以上;
所述的有机溶剂选自N,N-二甲基甲酰胺、甲醇、乙醇、甲苯、乙酸乙酯、吡啶、四氢呋喃、二氯甲烷、四氯化碳中一种或两种以上;
反应温度为0℃~50℃;
反应时间为1~12小时。
其中,上述制备方法中,所述方法二满足以下至少一项:
M05:碱的摩尔配比为1:1~3;
M05:缩合剂的摩尔配比为1:1~2;
所述的缩合剂为二环己基碳二亚胺、N,N'-二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐中一种或两种以上;
所述的碱为三乙胺、二异丙基乙胺、吡啶中一种或两种以上;
所述的有机溶剂为N,N-二甲基甲酰胺、甲苯、乙酸乙酯、吡啶、四氢呋喃、二氯甲烷、四氯化碳中一种或两种以上;
反应温度为0℃~50℃;
反应时间为6~15小时。
其中,上述制备方法中,所述方法一还包括如下步骤:
其中,上述制备方法中,所述方法一满足以下至少一项:
式Ⅳ化合物:碱的摩尔配比为1:2~8;
所述的碱选自三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸钠、氢氧化钾、氢氧化钠、氢化钠中一种或两种以上;
所述的有机溶剂为N,N-二甲基甲酰胺、甲醇、乙醇、甲苯、乙酸乙酯、吡啶、四氢呋喃、二氯甲烷、四氯化碳中一种或两种以上;
反应温度为20℃~120℃;
反应时间为6~12小时。
其中,上述制备方法中,所述方法二还包括如下步骤:将式Ⅵ化合物溶于有机溶剂中,加入酸,脱去离去基团,即得。
其中,上述制备方法中,所述方法二满足以下至少一项:
式Ⅵ化合物:酸的摩尔配比为1:5~15;
所述的酸为浓盐酸、氯化氢乙酸乙酯溶液、三氟乙酸、甲磺酸、硫酸中一种或两种以上;
所述有机溶剂为N,N-二甲基甲酰胺、甲醇、乙醇、甲苯、乙酸乙酯、吡啶、四氢呋喃、二氯甲烷、四氯化碳中一种或两种以上;
反应温度为5℃~40℃;
反应时间为6~15小时。
本发明还提供了化合物中间体M05制备方法,其合成路线如下:
本发明的有益效果在于:
本发明提供了一类结构新颖的2H-苯并吡喃-2-酮衍生物。生物学实验证明,这类化合物在多种肿瘤细胞株(如结肠癌HCT116、乳腺癌MCF-7、卵巢癌A2780S、肺癌A549、宫颈癌Hela)中均能发挥明显的抑制细胞增殖的作用,对耐药肿瘤细胞也有显著的抑制效果,且毒性较小,为临床治疗肿瘤提供了新的选择。
附图说明
图1为试验例3中肿瘤体积变化曲线图。
图2为试验例3中受试小鼠体重曲线图。
图3为试验例3中荷瘤小鼠的瘤重散点图。
图4为试验例3中小鼠的肿瘤大小图。
具体实施方式
实施例1中间体4-(N-甲基-N-(3-氨基-4-甲氧基苯基)-氨基)香豆素的制备(M05)
在氩气保护下,将中间体M04(4-溴香豆素)与中间体M03(4-甲氧基-N1-甲基-1,3-苯二胺)溶于N,N-二甲基甲酰胺(DMF)中,加人2当量的而异丙基乙胺,100℃搅拌反应过夜。次日将反应液分散于乙酸乙酯和水中,萃取,有机层再以水洗涤1次后,减压回收溶剂至干,残留物经硅胶柱层析纯化,得浅黄色固体样品M05,收率75%。
ESI-MS m/z:297.2[M+H]+。
1H NMR(400MHz,DMSO)δ7.47–7.39(m,1H),7.30(dd,J=8.2,0.8Hz,1H),7.30(dd,J=8.2,0.8Hz,1H),7.10(dd,J=8.2,1.3Hz,1H),7.01–6.95(m,1H),6.77(d,J=8.5Hz,1H),6.45(d,J=2.6Hz,1H),6.37(dd,J=8.4,2.6Hz,1H),5.75(s,1H),4.90(s,2H),3.76(s,3H),3.28(s,3H)。
实施例2中间体4-(N-甲基-N-(3-氯乙酰氨基-4-甲氧基苯基)-氨基)香豆素的制备(M06)
在氩气保护下,将M05于无水二氯甲烷中溶解,加入三乙胺,室温搅拌10min后,注入氯乙酰氯,再于室温搅拌1小时,反应完全后,将反应液分散于二氯甲烷和水中,萃取,所得有机层依次以水、饱和氯化钠洗涤,无水硫酸镁干燥,浓缩,残留物经硅胶柱层析纯化,得到黄色粉末状M06产品,收率90%。
ESI-MS m/z:395.0[M+Na]+。
1H NMR(400MHz,CDCl3)δ(ppm):9.03(s,1H),8.40(d,J=2.7Hz,1H),7.33(ddd,J=8.4,7.1,1.5Hz,1H),7.27(dd,J=7.9,1.5Hz,1H),7.01(dd,J=8.3,1.3Hz,1H),6.88–6.83(m,1H),6.76(d,J=8.7Hz,1H),6.65(dd,J=8.7,2.7Hz,1H),5.84(s,1H),4.20(s,2H),3.91(s,3H),3.36(s,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):164.06,163.06,157.15,154.24,146.46,141.65,130.97,128.02,126.82,122.92,121.28,117.70,116.60,116.11,110.65,96.31,56.29,44.16,43.21。
实施例3 4-(N-甲基-N-(3-(2-(2-乙基咪唑-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-01)
氩气保护下,将M06,无水碳酸钾和碘化钾于DMF溶液中,加入2-乙基咪唑,100℃搅拌12小时至反应完全,将反应液分散于二氯甲烷和水中,萃取,所得有机层依次以水、饱和氯化钠洗涤,无水硫酸镁干燥,浓缩,残留物经硅胶柱层析纯化,得淡黄色固体,收率68%。
ESI-MS m/z:433.3[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):8.30(d,J=2.5Hz,1H),7.85(s,1H),7.36–7.29(m,1H),7.29–7.21(m,1H),7.13(d,J=1.0Hz,1H),6.99(dd,J=8.2,1.2Hz,1H),6.96(d,J=1.1Hz,1H),6.89–6.78(m,1H),6.69(d,J=8.7Hz,1H),6.63(dd,J=8.7,2.6Hz,1H),5.82(s,1H),4.76(s,2H),3.75(s,3H),3.33(s,3H),2.72(q,J=7.5Hz,2H),1.34(t,J=7.5Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):165.01,162.87,157.11,154.25,150.22,146.13,141.65,130.96,128.34,127.67,126.76,122.89,121.34,119.96,117.68,116.78,116.12,110.68,96.56,56.16,49.98,44.11,19.99,11.98。
实施例4 4-(N-甲基-N-(3-(2-(四氢吡咯-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-02)
参照实施例3的制备方法,将2-乙基咪唑替换为四氢吡咯,得淡黄色固体,收率72%。
ESI-MS m/z:408.2[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):9.80(s,1H),8.47(d,J=2.7Hz,1H),7.35–7.28(m,1H),7.28–7.23(m,1H),7.04(dd,J=8.2,1.1Hz,1H),6.88–6.81(m,1H),6.71(d,J=8.7Hz,1H),6.55(dd,J=8.6,2.7Hz,1H),5.81(s,1H),3.86(s,3H),3.35(s,3H),3.31(s,2H),2.70(t,J=5.5Hz,4H),1.92–1.81(m,4H)。
13C NMR(100MHz,CDCl3)δ(ppm):169.61,162.95,157.15,154.25,146.54,141.66,130.82,128.93,126.97,122.81,120.26,117.59,116.58,116.24,110.46,96.02,59.78,56.19,54.55,44.13,24.25。
实施例5 4-(N-甲基-N-(3-(2-(2,4-二甲基咪唑-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-03)
参照实施例3的制备方法,将2-乙基咪唑替换为2,4-二甲基咪唑,得淡黄色固体,收率40%。
ESI-MS m/z:433.1[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):8.31(d,J=2.6Hz,1H),7.84(s,1H,),7.32(dd,J=7.0,1.4Hz,1H),7.29–7.24(m,1H),6.99(dd,J=8.2,1.3Hz,1H),6.88–6.81(m,1H),6.69(d,J=8.7Hz,1H),6.65(s,1H),6.63(dd,J=8.7,2.6Hz,1H),5.83(s,1H),4.65(s,2H),3.76(s,3H),3.34(s,3H),2.40(s,3H),2.24(s,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):165.06,162.90,157.12,154.28,146.12,145.04,141.72,137.46,130.98,127.69,126.78,122.90,121.36,117.72,116.79,116.15,116.13,110.66,96.64,56.22,50.09,44.12,13.23,12.60。
实施例6 4-(N-甲基-N-(3-(2-(3-羟基氮杂环丁烷-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-04)
参照实施例3的制备方法,将2-乙基咪唑替换为3-羟基氮杂环丁烷盐酸盐,得淡黄色固体,收率17%。
ESI-MS m/z:410.1[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):9.47(s,1H),8.43(d,J=2.7Hz,1H),7.35–7.29(m,1H),7.28–7.23(m,1H),7.03(dd,J=8.3,1.3Hz,1H),6.88–6.82(m,1H),6.72(d,J=8.7Hz,1H),6.58(dd,J=8.6,2.7Hz,1H),5.81(s,1H),4.55(p,J=6.0Hz,1H),3.89(s,3H),3.88–3.82(m,2H),3.35(s,3H),3.31(s,2H),3.20–3.13(m,2H)。
13C NMR(100MHz,CDCl3)δ(ppm):168.72,163.11,157.22,154.22,146.56,141.57,130.90,128.65,126.95,122.88,120.50,117.61,116.74,116.19,110.50,95.91,65.17,63.45,62.35,56.23,44.15。
实施例7 4-(N-甲基-N-(3-(2-(4,5-二氯咪唑-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-05)
参照实施例3的制备方法,将2-乙基咪唑替换为4,5-二氯咪唑,得淡黄色固体,收率50%。
ESI-MS m/z:495.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ(ppm):8.31(d,J=2.6Hz,1H),8.06(s,1H,),7.55(s,1H),7.35–7.29(m,1H),7.24(dd,J=8.3,1.0Hz,1H),7.00(dd,J=8.2,1.3Hz,1H),6.88–6.82(m,1H),6.74(d,J=8.7Hz,1H),6.65(dd,J=8.7,2.6Hz,1H),5.81(s,1H),4.82(s,2H),3.83(s,3H),3.33(s,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):163.11,162.87,157.15,154.23,146.10,141.72,135.52,131.01,127.70,127.12,126.77,122.95,121.43,117.66,116.92,116.10,113.91,110.74,96.58,56.26,49.26,44.09。
实施例8 4-(N-甲基-N-(3-(2-N,N-二甲氨基-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-06)
参照实施例3的制备方法,将2-乙基咪唑替换为二甲胺盐酸盐,得淡黄色固体,收率73%。
ESI-MS m/z:404.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ(ppm):9.69(s,1H),8.48(d,J=2.7Hz,1H),7.35–7.29(m,1H),7.28–7.23(m,1H),7.05(dd,J=8.2,1.3Hz,1H),6.88–6.82(m,1H),6.72(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.88(s,3H),3.35(s,3H),3.11(s,2H),2.40(s,6H)。
13C NMR(100MHz,CDCl3)δ(ppm):169.29,162.98,157.17,154.26,146.57,141.63,130.84,128.84,126.97,122.82,120.35,117.62,116.69,116.25,110.48,96.07,64.12,56.17,46.23,44.14。
实施例9 4-(N-甲基-N-(3-(2-(N-甲基哌嗪-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-07)
参照实施例3的制备方法,将2-乙基咪唑替换为N-甲基哌嗪,得淡黄色固体,收率72%。
ESI-MS m/z:459.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ(ppm):9.94(s,1H),8.47(d,J=2.7Hz,1H),7.35–7.29(m,1H),7.28–7.24(m,1H),7.05(dd,J=8.2,1.2Hz,1H),6.87–6.81(m,1H),6.72(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.90(s,3H),3.35(s,3H),3.17(s,2H),2.68(s,4H),2.51(s,3H),2.33(s,3H),2.01(s,1H)。
13C NMR(100MHz,CDCl3)δ(ppm):168.81,162.97,157.18,154.27,146.44,141.76,130.85,128.84,126.94,122.81,120.34,117.64,116.44,116.26,110.43,96.20,62.04,56.15,55.62,53.44,46.26,44.14。
实施例10 4-(N-甲基-N-(3-(2-(吗啉-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-08)
参照实施例3的制备方法,将2-乙基咪唑替换为吗啉,得淡黄色固体,收率85%。
ESI-MS m/z:424.1[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):9.90(s,1H),8.46(d,J=2.7Hz,1H,),7.35–7.29(m,1H),7.28–7.24(m,2H),7.06–7.02(m,1H),6.87–6.81(m,1H),6.73(d,J=8.7Hz,1H),6.58(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.90(s,3H,),3.82–3.77(m,4H),3.35(s,3H),3.17(s,2H),2.70–2.60(m,4H)。
13C NMR(100MHz,CDCl3)δ(ppm):168.37,162.93,157.15,154.27,146.38,141.78,130.86,128.67,126.91,122.80,120.43,117.65,116.46,116.24,110.44,96.27,67.39,62.53,56.20,53.80,44.14。
实施例11 4-(N-甲基-N-(3-(2-(硫代吗啉-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-09)
参照实施例3的制备方法,将2-乙基咪唑替换为硫代吗啉,得淡黄色固体,收率66%。
ESI-MS m/z:424.1[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):9.84(s,1H),8.45(d,J=2.7Hz,1H),7.36–7.28(m,1H),7.28–7.23(m,1H),7.04(dd,J=8.2,1.2Hz,1H),6.87–6.81(m,1H),6.73(d,J=8.7Hz,1H),6.58(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.91(s,3H),3.35(s,3H),3.16(s,2H),2.88(dd,J=6.2,3.4Hz,4H),2.80–2.73(m,4H)。
13C NMR(100MHz,CDCl3)δ(ppm):168.51,162.90,157.13,154.26,146.36,141.76,130.85,128.64,126.90,122.79,120.42,117.63,116.43,116.23,110.43,96.25,63.13,56.22,55.37,44.13,28.61。
实施例12 4-(N-甲基-N-(3-(2-(4-溴哌啶-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-10)
参照实施例3的方法,将2-乙基咪唑替换为4-溴哌啶氢溴酸盐,得淡黄色固体,收率36%。
ESI-MS m/z:501.1[M+H]+。1H NMR(400MHz,CDCl3)δ(ppm):9.94(s,1H),8.46(d,J=2.7Hz,1H),7.34–7.28(m,1H),7.25(dd,J=8.8,1.5Hz,1H),7.04(dd,J=8.2,1.2Hz,1H),6.88–6.80(m,1H),6.70(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.86–5.78(m,2H),5.69(d,J=10.1Hz,1H),3.85(s,3H),3.35(s,3H),3.22(s,2H),3.18–3.13(m,2H),2.71(t,J=5.6Hz,2H),2.30–2.21(m,2H),1.24(s,1H)。
13C NMR(100MHz,CDCl3)δ(ppm):169.20,162.93,157.13,154.24,146.55,141.63,130.82,128.83,126.94,125.24,125.06,122.80,120.33,117.58,116.56,116.23,110.43,96.02,62.01,56.08,52.79,50.44,44.12,26.44。
实施例13 4-(N-甲基-N-(3-(2-(2-甲基哌啶-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-11)
参照实施例3的制备方法,将2-乙基咪唑替换为2-甲基哌啶,得淡黄色固体,收率88%。
ESI-MS m/z:436.1[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):10.21(s,1H),8.43(d,J=2.7Hz,1H,),7.32–7.26(m,1H),7.22(dd,J=8.1,0.9Hz,1H),7.03(dd,J=8.2,1.1Hz,1H),6.86–6.80(m,1H),6.70(d,J=8.7Hz,1H),6.53(dd,J=8.6,2.7Hz,1H),5.78(s,1H),3.88(s,3H),3.37(d,J=17.3Hz,1H),3.32(s,3H),2.92(d,J=17.3Hz,1H,),2.86–2.79(m,1H),2.53–2.43(m,1H),2.40–2.31(td,J=11.6,3.2Hz,1H),1.76 1.66(m,2H),1.66–1.52(m,2H),1.42–1.29(m,2H),1.06(d,J=6.3Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):170.48,162.86,157.04,154.13,146.54,141.52,130.74,128.90,126.90,122.75,120.09,117.46,116.25,116.14,110.40,95.79,59.00,56.60,56.10,54.17,44.07,34.76,26.66,23.38,18.92。
实施例14 4-(N-甲基-N-(3-(2-(3-甲基哌啶-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-12)
参照实施例3的制备方法,将2-乙基咪唑替换为3-甲基哌啶,得淡黄色固体,收率85%。
ESI-MS m/z:436.1[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):10.04(s,1H),8.48(d,J=2.3Hz,1H,),7.31(dd,J=13.6,5.9Hz,1H),7.25(d,J=8.1Hz,1H),7.06(d,J=8.1Hz,1H),6.85(t,J=7.6Hz,1H),6.73(d,J=8.6Hz,1H),6.57(dd,J=8.6,2.4Hz,1H),5.81(s,1H),3.89(s,3H),3.36(s,3H),3.10(s,2H),2.80(d,J=9.6Hz,2H),2.22(t,J=10.6Hz,1H),1.96(t,J=10.2Hz,1H),1.82–1.69(m,3H),1.68–1.55(m,1H,),1.02–0.96(m,1H),0.93(d,J=6.4Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):169.46,162.86,157.06,154.16,146.45,141.55,130.75,128.90,126.90,122.75,120.14,117.49,116.31,116.15,110.38,95.84,62.71,62.11,56.04,54.43,44.08,32.14,31.67,25.71,19.35。
实施例15 4-(N-甲基-N-(3-(2-(4-甲基哌啶-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-13)
参照实施例3的制备方法,将2-乙基咪唑替换为4-甲基哌啶,得淡黄色固体,收率86%。
ESI-MS m/z:436.1[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):10.07(s,1H),8.47(d,J=2.6Hz,1H),7.31(dd,J=14.8,6.8Hz,1H),7.25(d,J=8.0Hz,1H),7.05(d,J=7.9Hz,1H),6.85(t,J=7.5Hz,1H),6.73(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.6Hz,1H),5.81(s,1H),3.90(s,3H),3.35(s,3H),3.12(s,2H),2.88(d,J=11.5Hz,2H,),2.28(dd,J=11.3,10.2Hz,2H),1.71(d,J=12.5Hz,2H),1.49–1.36(m,1H),1.36–1.23(m,2H),0.98(d,J=6.4Hz,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):169.43,162.88,157.08,154.18,146.47,141.59,130.77,128.93,126.92,122.76,120.16,117.51,116.33,116.18,110.40,95.88,62.49,56.09,54.33,44.09,34.93,30.15,22.06。
实施例16 4-(N-甲基-N-(3-(2-(4-甲基咪唑-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-14)
参照实施例3的制备方法,将2-乙基咪唑替换为4-甲基咪唑,得淡黄色固体,收率53%。
ESI-MS m/z:419.1[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):8.33(d,J=2.5Hz,1H),7.89(s,1H,),7.51(s,1H),7.32(t,J=7.7Hz,1H),7.25(d,J=7.6Hz,1H),6.98(d,J=8.1Hz,1H),6.84(t,J=7.6Hz,1H),6.77(s,1H),6.69(d,J=8.7Hz,1H),6.62(dd,J=8.6,2.5Hz,1H),5.82(s,1H),4.75(s,2H),3.75(s,3H),3.33(s,3H),2.29(s,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):165.16,162.85,157.08,154.26,146.02,141.71,140.31,137.51,130.94,127.76,126.76,122.87,121.29,117.68,116.79,116.10,110.61,96.54,56.19,50.82,44.10,29.81,13.78。
实施例17 4-(N-甲基-N-(3-(2-(2,5-二氢吡咯-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-15)
参照实施例3的制备方法,将2-乙基咪唑替换为2,5-二氢吡咯,得淡黄色固体,收率57%。
ESI-MS m/z:406.2[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):9.71(s,1H),8.49(d,J=2.7Hz,1H),7.35–7.30(m,1H),7.28–7.24(m,1H),7.05(dd,J=8.2,1.2Hz,1H),6.88–6.82(m,1H),6.71(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.82(d,J=3.1Hz,3H),3.86(s,3H),3.70(s,4H),3.48(s,2H),3.36(s,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):169.82,162.98,157.17,154.27,146.61,141.64,130.84,128.83,127.39,126.98,122.83,120.40,117.63,116.75,116.26,110.47,96.09,61.32,56.19,44.15,29.83。
实施例18 4-(N-甲基-N-(3-(2-(四氢噻唑-N-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-16)
参照实施例3的制备方法,将2-乙基咪唑替换为四氢噻唑,得淡黄色固体,收率67%。
ESI-MS m/z:426.1[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):9.67(s,1H),8.48(d,J=2.7Hz,1H),7.36–7.29(m,1H),7.28–7.24(m,1H),7.05(dd,J=8.2,1.2Hz,1H),6.88–6.83(m,1H),6.74(d,J=8.7Hz,1H),6.59(dd,J=8.6,2.7Hz,1H),5.83(s,1H),4.11(s,2H),3.89(s,3H),3.36(s,3H),3.24(s,2H),3.18(t,J=6.3Hz,2H),2.98(t,J=6.4Hz,2H)。
13C NMR(100MHz,CDCl3)δ(ppm):168.43,162.93,157.15,154.28,146.48,141.71,130.87,128.57,126.92,122.83,120.64,117.66,116.70,116.24,110.51,96.27,61.22,58.77,58.73,56.22,44.14,29.95。
实施例19 4-(N-甲基-N-(3-(2-(N-甲基苄胺-N-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-17)
参照实施例3的制备方法,将2-乙基咪唑替换为N-甲基苄胺,得淡黄色固体,收率48%。
ESI-MS m/z:458.1[M+H]+。
1H NMR(500MHz,CDCl3)δ(ppm):9.97(s,1H),8.52(d,J=2.7Hz,1H),7.43(d,J=7.2Hz,2H),7.37(t,J=7.4Hz,2H),7.34–7.31(m,1H),7.31(d,J=1.5Hz,1H),7.27(d,J=5.5Hz,1H),7.06(d,J=7.2Hz,1H),6.87(d,J=7.0Hz,1H),6.74(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.83(s,1H),3.94(s,3H),3.68(s,2H),3.36(s,3H),3.24(s,2H),2.37(s,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):169.42,162.98,157.17,154.27,146.35,141.76,138.25,130.86,128.94,128.85,128.63,127.69,126.98,122.86,120.29,117.63,116.40,116.26,110.41,96.17,62.50,62.03,56.05,44.16,43.26。
实施例20 4-(N-甲基-N-(3-(2-(咪唑-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-18)
参照实施例3的制备方法,将2-乙基咪唑替换为咪唑,得淡黄色固体,收率38%。
ESI-MS m/z:405.1[M+H]+。
1H NMR(500MHz,CDCl3)δ(ppm):8.33(d,J=2.5Hz,1H),7.92(s,1H),7.63(s,1H),7.34–7.28(m,1H),7.25(d,J=5.5Hz,1H),7.23(d,J=2.7Hz,1H),7.07(s,1H),6.98(dd,J=8.2,1.0Hz,1H),6.87–6.80(m,1H),6.69(d,J=8.7Hz,1H),6.63(dd,J=8.6,2.6Hz,1H),5.81(s,1H),4.84(s,2H),3.75(s,3H),3.33(s,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):164.88,162.83,157.07,154.23,146.05,141.66,138.31,130.95,127.73,126.75,122.88,121.32,119.86,117.65,116.73,116.10,110.63,96.49,56.15,50.80,44.09,29.79。
实施例21 4-(N-甲基-N-(3-(2-(咪唑-4-甲醛-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-19)
参照实施例3的方法,将2-乙基咪唑替换为4-咪唑甲醛,得淡黄色固体,收率25%。
ESI-MS m/z:455.1[M+Na]+。
1H NMR(500MHz,CDCl3)δ(ppm):9.79(s,1H),8.47(s,1H),8.34(d,J=2.2Hz,1H),7.90(s,1H),7.32(t,J=7.7Hz,1H),7.25(d,J=6.7Hz,2H),7.00(d,J=8.2Hz,1H),6.86(t,J=7.6Hz,1H),6.72(d,J=8.7Hz,1H),6.60(dd,J=8.6,2.4Hz,1H),5.82(s,1H),5.16(s,2H),3.88(s,3H),3.32(s,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):163.99,162.86,157.11,154.25,146.18,141.71,130.94,128.21,126.83,122.92,121.17,117.66,116.91,116.15,110.64,96.57,56.23,44.08,29.83。
实施例22 4-(N-甲基-N-(3-(2-(哌啶-1-基)-乙酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-20)
参照实施例3的制备方法,将2-乙基咪唑替换为哌啶,得淡黄色固体,收率97%。
ESI-MS m/z:444.1[M+Na]+。
1H NMR(500MHz,CDCl3)δ(ppm):10.06(s,1H),8.48(d,J=2.6Hz,1H),7.34–7.29(m,1H),7.28–7.23(m,1H),7.05(dd,J=8.2,1.1Hz,1H),6.88–6.82(m,1H),6.71(d,J=8.6Hz,1H),6.55(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.89(s,3H),3.35(s,3H),3.10(s,2H),2.56(s,4H),1.72–1.59(m,4H),1.50(s,2H)。
13C NMR(100MHz,CDCl3)δ(ppm):169.52,162.98,157.17,154.27,146.52,141.70,130.83,129.00,126.98,122.82,120.22,117.61,116.41,116.26,110.42,96.04,63.01,56.15,55.00,44.15,26.60,23.82。
实施例23 4-(N-甲基-N-(3-(1-(呋喃-2-基)-甲酰氨基)-4-甲氧基苯基)-氨基)香豆素的制备(G-21)
参照M06的方法,将氯乙酰氯替换为α-呋喃甲酰氯,得淡黄色粉末状固体,收率92%。
ESI-MS m/z:413.1[M+Na]+。
1H NMR(500MHz,CDCl3)δ(ppm):8.84(s,1H),8.58(d,J=2.6Hz,1H),7.56(s,1H),7.35–7.30(m,1H),7.27(d,J=2.8Hz,1H),7.24(d,J=3.4Hz,1H),7.07(d,J=8.2Hz,1H),6.86(t,J=7.6Hz,1H),6.77(d,J=8.6Hz,1H),6.62(dd,J=8.6,2.6Hz,1H),6.58(dd,J=3.4,1.7Hz,1H),5.85(s,1H),3.95(s,3H),3.39(s,3H)。
13C NMR(100MHz,CDCl3)δ(ppm):162.94,157.15,156.20,154.27,147.88,146.20,144.63,141.76,130.88,128.73,126.91,122.86,120.52,117.64,116.69,116.23,115.62,112.80,110.47,96.26,56.23,44.11。
实施例24 4-(N-甲基-N-(3-(N-Boc-L-脯氨酰氨基)-4-甲氧苯基)-氨基)-香豆素的制备(G-22)
在氩气保护下,将M05和N-Boc-L-脯氨酸溶解于二氯甲烷中,加入N-甲基吗啡啉,于0℃加入EDCI,升温至室温,反应12小时,至薄层色谱(TLC)检测反应完全,将反应液分散于适量水和二氯甲烷中,萃取,所得有机层依次用水、饱和碳酸氢钠水溶液、饱和氯化钠洗涤,无水硫酸镁干燥,浓缩,残留物经硅胶柱层析纯化,得到黄色固体,收率92%。
ESI-MS m/z:516.2[M+Na]+。
1H NMR(500MHz,CDCl3)δ9.09(s,1H),8.34(s,1H),7.31(dd,J=9.9,3.6Hz,1H),7.25(d,J=5.4Hz,1H),7.06(d,J=7.1Hz,1H),6.91(s,1H),6.76(s,1H),6.65(d,J=28.2Hz,1H),5.98(s,1H),4.48(q,J=6.3Hz,1H),4.25(s,3H),4.11–3.85(m,2H),3.81(s,3H),3.12–2.95(m,1H),2.93–2.76(m,1H),2.36–2.31(m,1H),2.14(s,9H),2.03–1.97(m,1H)。
13C NMR(1MHz,CDCl3)δ170.46,162.80,157.02,154.13,146.30,141.47,130.69,129.34,126.89,122.71,120.15,117.46,116.60,116.11,110.25,95.85,80.69,60.38,55.91,47.25,43.95,29.68,28.31,27.93。
实施例25 4-(N-甲基-N-(3-L-脯氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-23)
在氩气保护下,将化合物G-22溶解于二氯甲烷/三氟乙酸(V︰V=1︰1)混合溶剂中,室温反应12小时至TLC检测反应完全,将反应液分散于适量二氯甲烷和水中,萃取,有机层依次用饱和碳酸氢钠水溶液、水洗涤,所得有机层以无水硫酸镁干燥,浓缩,残留物经硅胶柱层析纯化,得到黄色固体,收率74%。
ESI-MS m/z:416.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ10.26(s,1H),8.53(d,J=2.7Hz,1H),7.34–7.28(m,1H),7.25(dd,J=8.2,1.3Hz,1H),7.04(dd,J=8.2,1.3Hz,1H),6.84(ddd,J=8.3,7.1,1.4Hz,1H),6.70(d,J=8.7Hz,1H),6.54(dd,J=8.6,2.7Hz,1H),5.81(s,1H),3.90(t,J=5.2Hz,1H),3.87(s,3H),3.35(s,3H),3.11(dt,J=10.2,6.8Hz,1H),3.01(dt,J=10.3,6.4Hz,1H),2.27–2.15(m,1H),2.11–1.99(m,1H),1.89–1.68(m,2H)。
13C NMR(101MHz,CDCl3)δ173.85,162.83,157.00,154.08,146.56,141.42,130.63,128.85,126.85,122.63,120.01,117.41,116.13,116.10,110.24,95.76,61.42,55.96,47.37,43.95,30.76,26.32。
实施例26 4-(N-甲基-N-(3-(N-Boc-L-苯丙氨酰氨基)-4-甲氧苯基)-氨基)-香豆素的制备(G-24)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-苯丙氨酸,得黄色固体,收率82%。
ESI-MS m/z:566.3[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.42(d,J=2.6Hz,1H),8.29(s,1H),7.37–7.21(m,7H),7.02(dd,J=8.2,1.2Hz,1H),6.88(t,J=7.6Hz,1H),6.67(d,J=8.6Hz,1H),6.58(dd,J=7.7,2.6Hz,1H),5.83(s,1H),3.76(s,3H),3.36(s,3H),3.17(d,J=6.4Hz,2H),1.43(s,9H)。
13C NMR(101MHz,CDCl3)δ169.59,162.76,156.96,154.10,146.01,141.42,136.37,130.71,129.20,128.72,128.36,126.99,126.73,122.68,120.41,117.47,116.51,116.04,110.23,96.05,80.48,56.67,55.82,43.94,38.22,28.20。
实施例27 4-(N-甲基-N-(3-L-苯丙氨酰氨基-4-甲氧苯基)-氨基)-香豆素的制备(G-25)
参照G-23的制备方法,得黄色固体,收率73%。
ESI-MS m/z:466.1[M+Na]+。
1H NMR(499MHz,CDCl3)δ10.05(s,1H),8.57(d,J=2.6Hz,1H),7.38–7.31(m,3H),7.31–7.25(m,4H),7.06(dd,J=8.2,1.0Hz,1H),6.87(t,J=8.2Hz,1H),6.73(d,J=8.7Hz,1H),6.59(dd,J=8.6,2.7Hz,1H),5.84(s,1H),3.88(s,3H),3.76(dd,J=9.9,3.7Hz,1H),3.42(dd,J=13.9,3.6Hz,1H),3.39(s,3H),2.76(dd,J=13.8,10.0Hz,1H)。
13C NMR(1MHz,CDCl3)δ172.70,162.82,157.00,154.12,146.50,141.46,137.73,130.68,129.23,128.81,128.73,126.94,126.82,122.64,120.21,117.47,116.25,116.11,110.27,95.88,57.36,55.94,43.98,40.79。
实施例28 4-(N-甲基-N-(3-(N-Boc-L-苯甘氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-26)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-苯甘氨酸,具体操作如下:
将508.8mg(2.03mmol)BOC-L-苯基甘氨酸,409.50mg(4.05mmol)N-甲基吗啡加入50毫升三颈瓶中,加入15毫升二氯甲烷,使其完全溶解,然后用氮气密封容器,在冰水浴中搅拌。当溶液的温度降低到0℃时,向中滴加296.75mg(2.43mmol)氯甲酸异丙基酯。然后将其移至室温下搅拌约3小时,在氮气保护下加入400.00mg(1.35mmol)M05。然后,将混合物在室温下搅拌过夜。最后,容器内出现浅黄色固体。过滤后得到G-26,为黄色固体,收率74%。
ESI-MS m/z:552.2[M+Na]+。
1H NMR(500MHz,CDCl3)δ8.41(d,J=2.2Hz,1H),8.27(s,1H),7.48–7.30(m,6H),7.26(dd,J=7.7,1.7Hz,1H),7.02(dd,J=8.2,1.1Hz,1H),6.86(t,J=7.6Hz,1H),6.68(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.6Hz,1H),5.82(s,1H),5.30(s,1H),3.80(s,3H),3.33(s,3H),1.45(s,9H)。
13C NMR(126MHz,CDCl3)δ168.31,162.73,156.97,154.10,145.93,141.56,137.52,130.74,129.23,128.70,128.39,127.32,126.75,122.76,120.51,117.46,116.43,116.03,110.32,96.30,59.80,55.99,43.91,28.25。
实施例29 4-(N-甲基-N-(3-L-苯甘氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-27)
参照G-23的制备方法,具体操作如下:将G-26固体粉末放加入25毫升单颈烧瓶中,然后加入5毫升三氟乙酸形成黄色透明溶液,并在室温下搅拌过夜。在混合物蒸后加入15mL二氯甲烷和饱和NaHCO3溶液,萃取分液,水相用15mL二氯甲烷萃取两次,无水NaSO4干燥,过滤并浓缩。最后,将有机相蒸制得到浅黄色固体粉末,为G-27,收率78%。
ESI-MS m/z:452.0[M+Na]+。
1H NMR(400MHz,CDCl3)δ9.97(s,1H),8.50(d,J=2.7Hz,1H),7.50–7.29(m,6H),7.28–7.23(m,1H),7.03(dd,J=8.2,1.4Hz,1H),6.84(ddd,J=8.3,7.1,1.4Hz,1H),6.72(d,J=8.7Hz,1H),6.55(dd,J=8.6,2.7Hz,1H),5.80(s,1H),4.70(s,1H),3.90(s,3H),3.32(s,3H)。
13C NMR(101MHz,CDCl3)δ171.27,162.77,157.00,154.08,146.43,141.49,140.36,130.66,128.97,128.66,128.26,126.84,126.82,122.66,120.24,117.43,116.30,116.08,110.22,96.03,60.75,56.01,43.87。
实施例30 4-(N-甲基-N-(3-(N-Boc-L-缬氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-28)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-缬氨酸,得黄色固体,收率91%。
ESI-MS m/z:518.2[M+Na]+。
1H NMR(500MHz,CDCl3)δ8.46(d,J=2.2Hz,1H),8.37(s,1H),7.33(t,J=7.6Hz,1H),7.16(dd,J=12.5,7.2Hz,1H),7.04(d,J=8.1Hz,1H),6.88(t,J=7.5Hz,1H),6.72(d,J=8.6Hz,1H),6.58(d,J=8.0Hz,1H),5.83(s,1H),5.13(d,J=6.9Hz,1H),3.87(s,3H),3.36(s,3H),2.33(m,1H),1.47(s,9H),1.04(d,J=6.8Hz,3H),0.99(d,J=6.8Hz,3H)。
13C NMR(126MHz,CDCl3)δ170.06,162.77,157.00,154.11,146.02,141.53,130.72,128.99,126.78,122.73,120.38,117.46,116.53,116.06,110.26,96.18,55.96,43.93,28.27,19.41,17.65。
实施例31 4-(N-甲基-N-(3-L-缬氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-29)
参照G-23的制备方法,得黄色固体,收率80%。
ESI-MS m/z:418.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ10.04(s,1H),8.56(d,J=2.7Hz,1H),7.35–7.29(m,1H),7.17(dd,J=7.7,3.0Hz,1H),7.05(dd,J=8.3,1.3Hz,1H),6.85(ddd,J=8.3,7.1,1.4Hz,1H),6.72(d,J=8.7Hz,1H),5.82(s,1H),3.89(s,3H),3.40(d,J=3.7Hz,1H),3.37(s,3H),2.52–2.39(m,1H),1.06(d,J=7.0Hz,3H),0.90(d,J=6.9Hz,3H)。
13C NMR(101MHz,CDCl3)δ172.95,162.83,157.00,154.08,146.44,141.42,130.64,128.97,126.82,122.62,120.01,117.42,116.16,116.09,110.21,95.82,60.91,55.95,43.93,30.72,19.79,16.02。
实施例32 4-(N-甲基-N-(3-(N-Boc-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-30)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-丙氨酸,具体操作如下:
室温下将Boc-L-丙氨酸(778.80mg,4.12mmol),M05(814.00mg,2.75mmol),HATU(1567.51mg,4.12mmol),Et3N(972.14mg,8.17mmol)加入50mL单口烧瓶中,加入33mL DMF,搅拌反应过夜,TLC监控反应,以M05反应完为反应终点,反应液加入33mL二氯甲烷,132mL饱和食盐水,萃取分液,水相用33mL二氯甲烷萃取两次,合并有机相,无水硫酸钠干燥,减压蒸干得淡黄色固体,即化合物G-30,为黄色固体,收率91%。
ESI-MS m/z:490.2[M+Na]+。
1H NMR(500MHz,CDCl3)δ8.67(s,1H),8.46(s,1H),7.36–7.30(m,1H),7.27(t,J=3.6Hz,1H),7.04(d,J=8.1Hz,1H),6.88(s,1H),6.72(d,J=8.6Hz,1H),6.58(d,J=7.3Hz,1H),5.84(s,1H),4.12(d,J=7.1Hz,1H),3.86(s,3H),3.36(s,3H),1.61–1.36(m,12H)。
13C NMR(126MHz,CDCl3)δ170.99,162.89,157.05,154.10,146.12,141.53,130.74,128.78,126.80,122.76,120.36,117.48,116.59,116.07,110.27,96.03,80.49,60.40,55.94,43.96,28.28,21.04。
实施例33 4-(N-甲基-N-(3-L-丙氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-31)
参照G-23的制备方法,具体操作如下:
将化合物G-30加入25mL单口瓶中,加入5mL三氟醋酸,室温下搅拌过夜,TLC监控反应,以G-30反应完为反应终点,反应液减压蒸干,加入加入33mL二氯甲烷,132mL饱和碳酸氢钠水溶液,萃取分液,水相用33mL二氯甲烷萃取两次,合并有机相,无水硫酸钠干燥,减压蒸干的淡黄色固体,过快速硅胶柱的淡黄色固体G-31,为黄色固体,收率88%。
ESI-MS m/z:390.1[M+Na]+。
1H NMR(500MHz,CDCl3)δ10.01(s,1H),8.53(d,J=2.7Hz,1H),7.35–7.30(m,1H),7.29–7.24(m,1H),7.05(dd,J=8.2,1.2Hz,1H),6.89–6.81(m,1H),6.73(d,J=8.7Hz,1H),6.57(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.89(s,3H),3.67(q,J=7.0Hz,1H),3.36(s,3H),1.46(d,J=7.0Hz,3H)。
13C NMR(126MHz,CDCl3)δ173.99,162.84,157.03,154.10,146.51,141.45,130.66,128.84,126.83,122.66,120.10,117.43,116.20,116.10,110.25,95.79,55.95,51.53,43.94,21.56。
实施例34 4-(N-甲基-N-(3-(N-Boc-L-苏氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-32)
参照G-22的方法,将N-Boc-L-脯氨酸替换为N-Boc-L-苏氨酸,得黄色固体,收率78%。
ESI-MS m/z:520.2[M+Na]+。
1H NMR(400MHz,CDCl3)δ9.08(s,1H),8.40(d,J=2.6Hz,1H),7.38–7.30(m,1H),7.27(d,J=6.7Hz,1H),7.03(dd,J=8.2,1.0Hz,1H),6.87(t,J=7.6Hz,1H),6.73(d,J=8.7Hz,1H),6.61(dd,J=8.6,2.6Hz,1H),5.83(s,1H),5.64(d,J=7.9Hz,1H),4.54(d,J=5.8Hz,1H),3.86(s,3H),3.35(s,3H),1.50(s,9H),1.26(d,J=6.3Hz,3H)。
13C NMR(101MHz,CDCl3)δ169.79,162.83,156.99,156.51,154.06,146.30,141.40,130.74,128.48,126.72,122.75,120.61,117.46,116.75,116.00,110.42,96.00,80.62,,66.48,59.13,55.98,43.96,28.25,18.52。
实施例35 4-(N-甲基-N-(3-L-苏氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-33)
参照G-23的制备方法,得黄色固体,收率71%。
ESI-MS m/z:420.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ10.16(s,1H),8.50(d,J=2.6Hz,1H),7.36–7.30(m,1H),7.29–7.24(m,1H),7.04(dd,J=8.2,1.0Hz,1H),6.88–6.81(m,1H),6.73(d,J=8.7Hz,1H),6.59(dd,J=8.6,2.7Hz,1H),5.82(s,1H),4.52(qd,J=6.4,2.6Hz,1H),3.89(s,3H),3.37(d,J=3.5Hz,1H),3.36(s,3H),1.29(d,J=6.5Hz,3H)。
13C NMR(101MHz,CDCl3)δ172.16,162.85,156.99,154.06,146.51,141.36,130.69,128.58,126.77,122.68,120.34,117.44,116.26,116.03,110.32,95.80,67.45,60.48,55.96,43.95,19.38。
实施例36 4-(N-甲基-N-(3-(N-Boc-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-34)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-亮氨酸,得黄色固体,收率71%。
ESI-MS m/z:532.3[M+Na]+。
1H NMR(500MHz,CDCl3)δ8.61(s,1H),8.46(s,1H),7.33(t,J=7.1Hz,1H),7.27(d,J=4.7Hz,1H),7.05(d,J=7.9Hz,1H),6.89(d,J=7.1Hz,1H),6.71(d,J=8.1Hz,1H),6.58(s,1H),5.84(s,1H),3.91(t,J=6.7Hz,1H),3.87(s,3H),3.36(s,3H),1.85–1.72(m,2H),1.62–1.55(m,1H),1.48(s,9H),0.99(dd,J=6.3Hz,6H)。
13C NMR(126MHz,CDCl3)δ170.99,162.89,157.05,154.10,146.11,141.52,130.73,128.73,126.82,122.76,120.35,117.48,116.59,116.07,110.26,96.05,77.26,77.01,76.75,55.96,54.01,43.95,40.90,28.28,24.82,22.96,21.82。
实施例37 4-(N-甲基-N-(3-L-亮氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-35)
参照G-23的制备方法,得黄色固体,收率71%。
ESI-MS m/z:432.0[M+Na]+。
1H NMR(400MHz,CDCl3)δ10.07(s,1H),8.54(d,J=2.6Hz,1H),7.32(t,J=8.3Hz,1H),7.26(d,J=8.3Hz,1H),7.05(d,J=8.2Hz,1H),6.85(t,J=8.2Hz,1H),6.72(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.89(s,3H),3.55(dd,J=9.9,3.2Hz,1H),3.36(s,3H),1.75(m,2H),1.46(t,J=9.5Hz,1H),0.99(dd,J=9.6,6.1Hz,6H)。
13C NMR(101MHz,CDCl3)δ174.07,162.81,157.00,154.07,146.44,141.43,130.63,128.88,126.82,122.63,119.99,117.41,116.16,116.09,110.20,95.79,55.94,54.27,43.95,43.92,24.95,23.39,21.24。
实施例38 4-(N-甲基-N-(3-(N-Boc-L-异亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-36)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-异亮氨酸,得黄色固体,收率77%。
ESI-MS m/z:532.2[M+Na]+。
1H NMR(500MHz,CDCl3)δ8.46(s,1H),8.41(s,1H),7.33(t,J=7.3Hz,1H),7.27(d,J=8.2Hz,1H),7.04(d,J=7.8Hz,1H),6.89(d,J=7.3Hz,1H),6.72(d,J=8.5Hz,1H),6.58(d,J=7.4Hz,1H),5.84(s,1H),5.14(d,J=8.2Hz,1H),3.87(s,3H),3.36(s,3H),2.02(d,J=5.9Hz,1H),1.56(s,1H),1.47(s,9H),1.24–1.16(m,1H),1.01(d,J=6.7Hz,3H),0.96(t,J=7.3Hz,3H)。
13C NMR(126MHz,CDCl3)δ170.08,162.82,157.01,154.09,146.04,141.49,130.72,128.47,126.78,122.74,120.38,117.45,116.54,116.04,110.26,96.10,80.24,60.26,55.96,43.93,37.11,28.27,24.69,15.75,11.48。
实施例39 4-(N-甲基-N-(3-L-异亮氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-37)
参照G-23的制备方法,得黄色固体,收率84%。
ESI-MS m/z:432.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ10.06(s,1H),8.55(d,J=2.7Hz,1H),7.35–7.29(m,1H),7.28–7.25(m,1H),7.08–7.02(m,1H),6.88–6.82(m,1H),6.71(d,J=8.6Hz,1H),6.55(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.88(s,3H),3.45(d,J=3.4Hz,1H),3.37(s,3H),2.19–2.09(m,1H),1.49–1.38(m,1H),1.27–1.12(m,1H),1.04(d,J=7.0Hz,3H),0.93(t,J=7.4Hz,3H)。
13C NMR(101MHz,CDCl3)δ172.92,162.85,157.03,154.13,146.44,141.48,130.66,128.84,126.86,122.64,120.00,117.46,116.17,116.14,110.22,95.90,60.69,55.98,43.96,37.92,23.73,16.32,11.98。
实施例40 4-(N-甲基-N-(3-(N-Boc-L-酪氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-38)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-酪氨酸,得黄色固体,收率72%。
ESI-MS m/z:582.2[M+Na]+。
1H NMR(500MHz,CDCl3)δ8.35(d,J=2.3Hz,1H),8.25(d,J=4.1Hz,1H),7.33(dd,J=8.3,7.2Hz,1H),7.21–7.13(m,1H),7.05(d,J=7.7Hz,2H),7.02(d,J=8.4Hz,1H),6.93–6.85(m,1H),6.80(d,J=7.6Hz,2H),6.68(d,J=8.6Hz,1H),6.60(d,J=7.4Hz,1H),5.79(s,1H),4.53–4.39(m,1H),3.76(s,3H),3.34(s,3H),2.98(m,2H),1.44(s,9H)。
13C NMR(126MHz,CDCl3)δ169.94,163.38,157.26,153.98,146.26,145.59,141.13,130.89,130.27,128.97,128.16,126.75,125.23,122.88,120.58,117.50,116.69,115.74,110.35,95.34,80.51,55.86,43.97,37.56,28.22。
实施例41 4-(N-甲基-N-(3-L-酪氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-39)
参照G-23的制备方法,得黄色固体,收率83%。
ESI-MS m/z:482.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ9.97(s,1H),8.50(d,J=2.7Hz,1H),7.37–7.30(m,1H),7.17(dd,J=7.7,3.0Hz,1H),7.11–7.03(m,3H),6.91–6.83(m,3H),6.74(d,J=8.7Hz,1H),6.62(dd,J=8.6,2.7Hz,1H),5.81(s,1H),3.87(s,3H),3.70(dd,J=9.5,4.0Hz,1H),3.37(s,3H),3.25(dd,J=13.9,3.9Hz,1H),2.71(dd,J=13.9,9.5Hz,1H)。
13C NMR(101MHz,CDCl3)δ173.23,163.41,157.23,154.00,146.69,141.21,130.83,130.27,128.98,128.56,128.17,126.82,125.24,122.82,120.41,117.50,116.44,115.79,110.40,95.23,57.39,55.96,44.01,39.94。
实施例42 4-(N-甲基-N-(3-(N-Boc-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-40)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-蛋氨酸,得黄色固体,收率81%。
ESI-MS m/z:550.2[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.43(d,J=2.6Hz,1H),7.37–7.31(m,1H),7.30–7.23(m,1H),7.04(dd,J=8.3,1.2Hz,1H),6.88(t,J=7.4Hz,1H),6.73(d,J=8.7Hz,1H),6.64–6.56(m,1H),5.83(s,1H),4.54–4.44(m,1H),3.87(s,3H),3.36(s,3H),2.73–2.56(m,2H),2.33–2.17(m,1H),2.14(s,3H),2.09–1.94(m,1H),1.48(s,9H)。
13C NMR(101MHz,CDCl3)δ169.94,162.80,157.01,154.11,146.16,141.50,130.75,128.53,126.77,122.77,120.53,117.48,116.66,116.05,110.34,96.14,80.53,55.96,54.30,43.98,31.15,30.27,28.28,15.23。
实施例43 4-(N-甲基-N-(3-L-蛋氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-41)
参照G-23的制备方法,得黄色固体,收率60%。
ESI-MS m/z:450.2[M+Na]+。
1H NMR(500MHz,CDCl3)δ10.03(s,1H),8.52(d,J=2.7Hz,1H),7.35–7.30(m,1H),7.19–7.15(m,1H),7.05(dd,J=8.3,1.2Hz,1H),6.88–6.84(m,1H),6.73(d,J=8.7Hz,1H),6.59(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.89(s,3H),3.69(dd,J=8.5,4.4Hz,1H),3.36(s,3H),2.74–2.62(m,2H),2.34–2.28(m,1H),2.13(s,3H),2.11(dd,J=8.7,5.7Hz,1H)。
13C NMR(126MHz,CDCl3)δ173.03,162.79,156.99,154.09,146.47,141.44,130.66,128.72,126.79,122.64,120.17,117.42,116.21,116.08,110.29,95.84,55.95,54.89,43.93,33.72,30.66,21.39,15.19。
实施例44 4-(N-甲基-N-(3-(N-Cbz-L-谷氨酰胺氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-42)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Cbz-L-谷氨酸,得黄色固体,收率70%。
ESI-MS m/z:581.2[M+Na]+。1H NMR(500MHz,CDCl3)δ8.82(s,1H),8.37(d,J=2.5Hz,1H),7.38–7.22(m,,7H),7.03(d,J=8.2Hz,1H),6.87(t,J=7.5Hz,1H),6.71(d,J=8.7Hz,1H),6.61(dd,J=8.6,2.4Hz,1H),5.82(s,1H),5.15(d,J=12.3Hz,1H),5.11(d,J=12.3Hz,1H),4.41(s,1H),3.80(s,3H),3.33(s,3H),2.54–2.46(m,1H),2.41(dd,J=14.3,8.0Hz,1H),2.23(d,J=7.7Hz,1H),2.08(dt,J=13.9,7.5Hz,1H)。
13C NMR(126MHz,CDCl3)δ175.09,169.88,162.89,157.04,156.69,154.05,146.43,141.36,137.82,136.14,130.79,128.98,126.76,125.24,122.82,120.68,117.44,116.84,115.99,110.48,95.88,56.00,55.49,43.96,31.65,28.17,21.41。
实施例45 4-(N-甲基-N-(3-L-谷氨酰胺氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-43)
参照G-23的制备方法,得黄色固体,收率62%。
ESI-MS m/z:447.1[M+Na]+。
1H NMR(500MHz,CDCl3)δ8.80(s,1H),8.03(d,J=2.5Hz,1H),7.22(m,,1H),7.03(d,J=8.2Hz,1H),6.82(t,J=7.5Hz,1H),6.70(d,J=8.7Hz,1H),6.65(dd,J=8.6,2.4Hz,1H),5.82(s,1H),4.41(m,1H),3.80(s,3H),3.34(s,3H),2.54(m,1H),2.41(dd,J=14.3,8.0Hz,1H),2.23(d,J=7.7Hz,1H),2.08(dt,J=13.9,7.5Hz,1H)。
13C NMR(126MHz,CDCl3)δ173,162.89,157.05,154.05,146.43,141.08,130.82,128.98,126.76,122.82,120.68,117.44,116.84,115.99,110.48,95.88,56.00,55.49,43.96,31.65,28.17,21.41。
实施例46 4-(N-甲基-N-(3-(N-Boc-L-羟脯氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-44)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-羟脯氨酸,得黄色固体,收率71%。
ESI-MS m/z:532.2[M+Na]+。
1H NMR(400MHz,CDCl3)δ10.30(s,1H),8.50(d,J=2.6Hz,1H),7.33(m,1H),7.16(dd,J=10.4,7.5Hz,1H),7.15(dd,J=8.2,1.0Hz,1H),6.90–6.82(m,1H),6.73(d,J=8.7Hz,1H),6.58(dd,J=8.6,2.7Hz,1H),5.81(s,1H),4.50(s,1H),4.17(t,J=8.4Hz,1H),3.89(s,3H),3.36(s,3H),3.14(dd,J=12.5,1.2Hz,1H),2.90(dd,J=12.5,3.1Hz,1H),2.42–2.36(m,1H),2.14(s,9H),2.12–2.02(m,1H)。
13C NMR(101MHz,CDCl3)δ173.51,162.98,157.09,154.03,146.64,141.34,130.70,128.95,126.80,122.69,120.20,117.42,116.25,116.04,110.33,95.58,60.57,55.96,55.45,43.95,39.79,38.24,21.40。
实施例47 4-(N-甲基-N-(3-L-羟脯氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-45)
参照G-23的制备方法,得黄色固体,收率83%。
ESI-MS m/z:432.0[M+Na]+。
1H NMR(400MHz,CDCl3)δ10.31(s,1H),8.49(d,J=2.6Hz,1H),7.37–7.30(m,1H),7.16(dd,J=10.4,7.5Hz,1H),7.05(dd,J=8.2,1.0Hz,1H),6.90–6.82(m,1H),6.73(d,J=8.7Hz,1H),6.58(dd,J=8.6,2.7Hz,1H),5.81(s,1H),4.50(s,1H),4.17(t,J=8.4Hz,1H),3.89(s,3H),3.36(s,3H),3.15(dd,J=12.5,1.2Hz,1H),2.92(dd,J=12.5,3.1Hz,1H),2.42–2.36(m,1H),2.12–2.02(m,1H)。
13C NMR(101MHz,CDCl3)δ173.51,162.98,157.08,154.03,146.64,141.34,130.70,128.95,126.80,122.69,120.20,117.42,116.25,116.04,110.33,95.58,60.57,55.96,55.45,43.95,39.79,21.40。
实施例48 4-(N-甲基-N-(3-(N-Boc-L-丝氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-46)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-丝氨酸,得黄色固体,收率65%。
ESI-MS m/z:506.2[M+Na]+。
1H NMR(500MHz,CDCl3)δ9.10(s,1H),8.41(d,J=2.7Hz,1H),7.36–7.31(m,1H),7.29–7.23(m,1H),7.19–7.15(m,1H),7.03(dd,J=8.2,1.3Hz,1H),6.88(dd,J=11.2,4.1Hz,1H),6.73(d,J=8.7Hz,1H),6.61(dd,J=8.6,2.6Hz,1H),5.83(s,1H),4.36(s,1H),4.25(d,J=10.8Hz,1H),3.86(s,3H),3.78(s,1H),3.35(s,3H),1.50(s,9H)。
13C NMR(126MHz,CDCl3)δ169.64,162.89,157.04,154.09,146.30,141.44,130.78,128.99,128.18,126.75,122.79,120.64,117.49,116.76,116.03,110.44,96.00,80.76,62.46,55.98,55.85,43.97,28.26。
实施例49 4-(N-甲基-N-(3-L-丝氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-47)
参照G-23的制备方法,得黄色固体,收率73%。
ESI-MS m/z:406.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ10.08(s,1H),8.48(t,J=4.3Hz,1H),7.36–7.30(m,1H),7.18(d,J=7.3Hz,1H),7.04(d,J=7.1Hz,1H),6.86(t,J=7.6Hz,1H),6.76–6.72(m,1H),6.61(dd,J=8.6,2.7Hz,1H),5.83(s,1H),4.08–3.98(m,1H),3.89(s,3H),3.87–3.82(m,1H),3.70(d,J=9.2Hz,1H),3.36(s,3H)。
13C NMR(101MHz,CDCl3)δ171.95,162.93,157.07,154.10,146.55,141.44,130.76,129.01,128.48,126.79,122.75,120.53,117.50,116.39,116.08,110.42,95.89,65.00,56.75,56.02,44.00,29.69。
实施例50 4-(N-甲基-N-(3-(D-Boc-L-酪氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-48)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-酪氨酸,得黄色固体,收率57%。
ESI-MS m/z:582.2[M+Na]+。
1H NMR(500MHz,CDCl3)δ8.36(d,J=2.6Hz,1H),8.25(s,1H),7.36–7.31(m,1H),7.19–7.14(m,1H),7.05(d,J=8.1Hz,2H),7.02(dd,J=8.3,1.2Hz,1H),6.93–6.84(m,1H),6.80(d,J=8.4Hz,2H),6.68(d,J=8.5Hz,1H),6.60(d,J=8.5Hz,1H),5.79(s,1H),4.55–4.38(m,1H),3.77(s,3H),3.34(s,3H),3.17–2.98(m,2H),1.44(s,9H),1.42–1.37(m,1H)。
13C NMR(126MHz,CDCl3)δ170.00,163.43,157.31,155.67,154.05,146.32,141.19,130.94,130.33,129.03,128.22,126.81,122.93,120.63,117.56,116.73,115.98,115.80,110.40,95.40,55.92,44.02,37.62,28.28。
实施例51 4-(N-甲基-N-(3-D-酪氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-49)
参照G-23的制备方法,得黄色固体,收率73%。
ESI-MS m/z:482.1[M+Na]。
1H NMR(400MHz,CDCl3)δ9.95(s,1H),8.51(d,J=2.7Hz,1H),7.36–7.31(m,1H),7.29–7.25(m,1H),7.09(d,J=8.4Hz,2H),7.06(dd,J=8.3,1.3Hz,1H),6.90–6.85(m,1H),6.83(d,J=8.4Hz,2H),6.74(d,J=8.7Hz,1H),6.61(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.87(s,3H),3.71(dd,J=9.5,4.0Hz,1H),3.37(s,3H),3.26(dd,J=13.9,3.9Hz,1H),2.72(dd,J=13.9,9.5Hz,1H)。
13C NMR(101MHz,CDCl3)δ173.02,163.20,157.20,155.19,154.06,146.62,141.32,130.78,130.33,128.92,128.61,126.81,122.76,120.33,117.52,116.41,116.05,115.73,110.36,95.55,57.40,55.96,44.00,39.95。
实施例52 4-(N-甲基-N-(3-(N,N-二甲基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-50)
在氩气保护下,将G-30溶解于DMF中,加入无水碳酸钾和碘甲烷,室温搅拌48小时至反应完全,将反应液倒入乙酸乙酯中,依次用水、饱和氯化钠洗涤,有机层经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体,收率43%。
ESI-MS m/z:396.0[M+H]+。
1H NMR(500MHz,CDCl3)δ9.87(s,1H),8.52(d,J=2.3Hz,1H),7.36(t,J=7.0Hz,1H),7.33–7.27(m,1H),7.10(d,J=8.1Hz,1H),6.90(t,J=7.6Hz,1H),6.75(d,J=8.6Hz,1H),6.59(dd,J=8.5,2.6Hz,1H),5.85(s,1H),3.92(s,3H),3.39(s,3H),3.23(q,J=6.9Hz,1H),2.38(s,6H),1.33(d,J=6.9Hz,3H)。
13C NMR(126MHz,CDCl3)δ172.71,162.88,157.10,154.14,146.53,141.51,130.70,129.00,126.87,122.71,120.00,117.46,116.45,116.17,110.35,95.92,65.28,56.05,43.97,42.17,10.42。
实施例53 4-(N-甲基-N-(3-(N,N-二乙基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-51)和4-(N-甲基-N-(3-(N-乙基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-52)的制备
参照G-50的合成方法,以碘乙烷替换碘甲烷,制备得黄色固体状G-51、G-52样品,收率分别为43%和18%。
G-51:ESI-MS m/z:424.1[M+H]+。
1H NMR(400MHz,CDCl3)δ10.26(s,1H),8.51(d,J=2.6Hz,1H),7.32(t,J=7.6Hz,1H),7.28–7.23(m,1H),7.07(d,J=8.1Hz,1H),6.86(t,J=7.6Hz,1H),6.71(d,J=8.6Hz,1H),6.54(dd,J=8.6,2.3Hz,1H),5.81(s,1H),3.87(s,3H),3.53(q,J=6.9Hz,1H),3.35(s,3H),2.62(dq,J=14.5,7.3Hz,2H),2.49(dq,J=13.5,6.8Hz,2H),1.28(d,J=7.0Hz,3H),1.13(t,J=7.1Hz,6H)。
13C NMR(101MHz,CDCl3)δ173.53,162.81,157.03,154.07,146.33,141.49,130.63,129.09,126.84,122.66,119.75,117.40,116.12,116.04,110.17,95.85,60.02,55.77,44.08,43.95,13.61,8.63。
G-52:ESI-MS m/z:396.1[M+H]+。
1H NMR(500MHz,CDCl3)δ10.06(s,1H),8.52(d,J=2.6Hz,1H),7.38–7.29(m,1H),7.29–7.22(m,1H),7.07(d,J=7.0Hz,1H),6.87(t,J=7.0Hz,1H),6.71(d,J=8.6Hz,1H),6.55(dd,J=8.5,2.6Hz,1H),5.83(s,1H),3.89(s,3H),3.37(s,3H),3.34–3.25(m,1H),2.85–2.72(m,1H),2.72–2.60(m,1H),1.42(d,J=6.9Hz,3H),1.18(t,J=7.1Hz,3H)。
13C NMR(126MHz,CDCl3)δ173.65,162.88,157.09,154.14,146.52,141.54,130.71,128.95,126.90,122.72,120.04,117.47,116.25,116.17,110.26,95.96,59.17,55.97,44.00,43.16,19.76,15.55。
实施例54 4-(N-甲基-N-(3-(N,N-二丙基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-53)和4-(N-甲基-N-(3-(N-丙基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-54)的制备
参照G-50的合成方法,以碘代正丙烷替换碘甲烷,制备得黄色固体状G-53、G-54样品,收率分别为10%和44%。
G-53:ESI-MS m/z:452.2[M+H]+。
1H NMR(500MHz,CDCl3)δ10.24(s,1H),8.54(d,J=2.3Hz,1H),7.33(t,J=7.0Hz,1H),7.27–7.21(m,1H),7.09(d,J=8.0Hz,1H),6.87(t,J=7.1Hz,1H),6.71(d,J=8.5Hz,1H),6.54(dd,J=8.4,2.5Hz,1H),5.82(s,1H),3.86(s,3H),3.52(q,J=6.9Hz,1H),3.36(s,3H),2.44(t,J=7.1Hz,4H),1.65–1.43(m,4H),1.28(d,J=6.8Hz,3H),0.95(t,J=7.3Hz,6H)。
13C NMR(126MHz,CDCl3)δ173.49,162.85,157.08,154.11,146.24,141.53,130.66,129.17,126.87,122.68,119.71,117.44,116.16,115.96,110.16,95.91,60.48,55.63,52.65,43.97,21.46,11.69,7.88。
G-54:ESI-MS m/z:410.1[M+H]+。
1H NMR(500MHz,CDCl3)δ10.10(s,1H),8.55(d,J=2.1Hz,1H),7.33(t,J=7.3Hz,1H),7.27–7.21(m,1H),7.08(d,J=7.6Hz,1H),6.87(t,J=7.0Hz,1H),6.71(d,J=8.4Hz,1H),6.55(dd,J=8.1,2.0Hz,1H),5.82(s,1H),3.88(s,3H),3.37(s,3H),3.28(q,J=6.8Hz,1H),2.80–2.66(m,1H),2.65–2.50(m,1H),1.60–1.53(m,2H),1.42(d,J=6.8Hz,3H),1.01(t,J=7.2Hz,3H)。
13C NMR(126MHz,CDCl3)δ173.78,162.82,157.05,154.10,146.45,141.49,130.65,128.96,126.87,122.67,119.93,117.42,116.13(2C),110.17,95.89,59.28,55.80,50.64,43.96,23.45,19.74,11.61。
实施例55 4-(N-甲基-N-(3-(N-异丙基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-55)
参照G-50的合成方法,以碘代异丙烷替换碘甲烷,制备得黄色固体,收率为36%。
ESI-MS m/z:410.1[M+H]+。1H NMR(500MHz,CDCl3)δ10.24(s,1H),8.52(d,J=2.5Hz,1H),7.32(d,J=6.9Hz,1H),7.29–7.22(m,1H),7.08(d,J=7.2Hz,1H),6.87(t,J=7.0Hz,1H),6.71(d,J=8.6Hz,1H),6.55(dd,J=8.5,2.5Hz,1H),5.82(s,1H),3.89(s,3H),3.40–3.32(m,4H),2.91–2.77(m,1H),1.41(d,J=6.9Hz,3H),1.14(t,J=6.0Hz,6H)。
13C NMR(126MHz,CDCl3)δ174.20,162.85,157.08,154.12,146.54,141.52,130.67,128.94,126.88,122.68,119.96,117.43,116.12(2C),110.22,95.91,56.81,55.89,48.53,43.96,23.54,22.86,20.30。
实施例56 4-(N-甲基-N-(3-(N-异丁基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-56)
参照G-50的合成方法,以碘代异丁烷替换碘甲烷,制备得黄色固体,收率为38%。
ESI-MS m/z:424.1[M+H]+。
1H NMR(500MHz,CDCl3)δ10.10(s,1H),8.56(d,J=1.5Hz,1H),7.33(t,J=7.2Hz,1H),7.27–7.22(m,1H),7.09(d,J=8.0Hz,1H),6.87(t,J=7.4Hz,1H),6.71(d,J=8.5Hz,1H),6.54(dd,J=8.4,2.0Hz,1H),5.82(s,1H),3.86(s,3H),3.36(s,3H),3.26(q,J=6.8Hz,1H),2.62(dd,J=11.1,5.4Hz,1H),2.38(dd,J=10.8,7.9Hz,1H),1.84–1.69(m,1H),1.42(d,J=6.8Hz,3H),1.04(d,J=6.4Hz,3H),0.98(d,J=6.5Hz,3H)。
13C NMR(126MHz,CDCl3)δ173.79,162.83,157.10,154.16,146.44,141.55,130.68,129.05,126.91,122.70,119.92,117.46,116.20,116.13,110.17,96.00,59.48,56.94,55.69,43.98,28.92,20.57,20.42,19.73。
实施例57 4-(N-甲基-N-(3-(N,N-二丁基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-57)和4-(N-甲基-N-(3-(N-丁基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-58)的制备
参照G-50的合成方法,以碘代正丁烷替换碘甲烷,制备得黄色固体G-57、G-58样品,收率分别为10%和63%。
G-57:ESI-MS m/z:480.2[M+H]+。
1H NMR(500MHz,CDCl3)δ10.24(s,1H),8.58(d,J=2.4Hz,1H),7.36(t,J=7.1Hz,1H),7.33–7.27(m,1H),7.12(d,J=7.3Hz,1H),6.90(t,J=7.1Hz,1H),6.75(d,J=8.5Hz,1H),6.58(dd,J=8.5,2.5Hz,1H),5.86(s,1H),3.90(s,3H),3.56(q,J=6.8Hz,1H),3.40(s,3H),2.59–2.43(m,4H),1.57–1.50(m,4H),1.49–1.35(m,4H),1.31(d,J=6.9Hz,3H),0.97(t,J=7.2Hz,6H)。
13C NMR(126MHz,CDCl3)δ173.49,162.82,157.11,154.16,146.27,141.59,130.65,129.22,126.87,122.66,119.70,117.46,116.22,116.01,110.17,96.01,60.44,55.62,50.45,43.95,30.55,20.37,14.05,7.89。
G-58:ESI-MS m/z:424.1[M+H]+。
1H NMR(500MHz,CDCl3)δ10.07(s,1H),8.54(d,J=1.6Hz,1H),7.32(t,J=7.0Hz,1H),7.29–7.22(m,1H),7.08(d,J=7.9Hz,1H),6.87(t,J=7.4Hz,1H),6.71(d,J=8.5Hz,1H),6.55(dd,J=8.3,2.0Hz,1H),5.82(s,1H),3.88(s,3H),3.37(s,3H),3.28(q,J=6.5Hz,1H),2.74(dt,J=12.0,5.8Hz,1H),2.65–2.55(m,1H),1.55–1.39(m,7H),0.95(t,J=7.0Hz,3H)。
13C NMR(126MHz,CDCl3)δ173.75,162.83,157.06,154.12,146.46,141.50,130.66,128.96,126.87,122.67,119.95,117.42,116.17(2C),110.18,95.91,59.35,55.80,48.55,43.95,32.49,20.23,19.72,14.00。
实施例58 4-(N-甲基-N-(3-(N,N-二正庚基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-59)和4-(N-甲基-N-(3-(N-正庚基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-60)的制备
参照G-50的合成方法,以碘代正庚烷替换碘甲烷,制备得黄色固体状G-59和G-60样品,收率分别为19%和60%。
G-59:ESI-MS m/z:564.3[M+H]+。
1H NMR(500MHz,CDCl3)δ10.20(s,1H),8.55(d,J=1.2Hz,1H),7.32(t,J=7.5Hz,1H),7.28–7.22(m,1H),7.09(d,J=8.1Hz,1H),6.86(t,J=7.4Hz,1H),6.71(d,J=8.5Hz,1H),6.55(dd,J=8.3,1.9Hz,1H),5.82(s,1H),3.86(s,3H),3.52(q,J=6.8Hz,1H),3.36(s,3H),2.53–2.37(m,4H),1.56–1.47(m,4H),1.46–1.20(m,19H),0.86(t,J=6.2Hz,6H)。
13C NMR(126MHz,CDCl3)δ173.50,162.80,157.11,154.16,146.25,141.59,130.65,129.20,126.87,122.64,119.68,117.45,116.23,115.99,110.11,96.04,60.44,55.63,50.77,43.95,31.82,29.24,28.39,27.20,22.60,14.06,7.89。
G-60:ESI-MS m/z:466.0[M+H]+。
1H NMR(500MHz,CDCl3)δ10.07(s,1H),8.54(d,J=2.3Hz,1H),7.33(t,J=7.1Hz,1H),7.29–7.22(m,1H),7.08(d,J=7.4Hz,1H),6.87(t,J=7.0Hz,1H),6.71(d,J=8.6Hz,1H),6.54(dd,J=8.5,2.6Hz,1H),5.82(s,1H),3.88(s,3H),3.37(s,3H),3.30–3.21(m,1H),2.73(dt,J=11.1,6.6Hz,1H),2.60(dt,J=11.6,7.1Hz,1H),1.56–1.28(m,13H),0.88(t,J=6.5Hz,3H)。
13C NMR(126MHz,CDCl3)δ173.78,162.82,157.07,154.13,146.46,141.53,130.66,128.98,126.88,122.67,119.94,117.44,116.17(2C),110.18,95.96,59.37,55.84,48.92,43.96,31.79,30.42,29.25,27.09,22.61,19.76,14.06。
实施例59 4-(N-甲基-N-(3-(N,N-二正辛基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-61)和4-(N-甲基-N-(3-(N-正辛基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-62)的制备
参照G-50的合成方法,以碘代正辛烷替换碘甲烷,制备得黄色固体状G-61和G-62样品,收率分别为26%和42%。
G-61:ESI-MS m/z:592.5[M+H]+。
1H NMR(500MHz,CDCl3)δ10.21(s,1H),8.55(d,J=2.6Hz,1H),7.32(t,J=7.0Hz,1H),7.29–7.23(m,1H),7.10(d,J=8.1Hz,1H),6.86(t,J=7.0Hz,1H),6.71(d,J=8.6Hz,1H),6.55(dd,J=8.5,2.6Hz,1H),5.82(s,1H),3.86(s,3H),3.52(q,J=7.0Hz,1H),3.36(s,3H),2.54–2.35(m,4H),1.57–1.43(m,4H),1.40–1.20(m,23H),0.86(t,J=6.8Hz,6H)。
13C NMR(126MHz,CDCl3)δ173.52,162.83,157.12,154.16,146.26,141.59,130.66,129.21,126.89,122.67,119.70,117.46,116.23,115.99,110.12,96.02,60.42,55.65,50.78,43.98,31.84,29.56,29.30,28.40,27.26,22.65,14.09,7.89。
G-62:ESI-MS m/z:480.2[M+H]+。
1H NMR(500MHz,CDCl3)δ10.07(s,1H),8.54(d,J=2.5Hz,1H),7.33(t,J=7.7Hz,1H),7.30–7.22(m,1H),7.08(dd,J=8.1,1.1Hz,1H),6.87(t,J=7.0Hz,1H),6.71(d,J=8.6Hz,1H),6.55(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.88(s,3H),3.37(s,3H),3.27(q,J=6.8Hz,1H),2.81–2.67(m,1H),2.66–2.53(m,1H),1.59–1.28(m,15H),0.87(t,J=6.9Hz,3H)。
13C NMR(126MHz,CDCl3)δ173.78,162.81,157.06,154.12,146.46,141.52,130.66,128.97,126.87,122.66,119.93,117.43,116.17(2C),110.17,95.94,59.35,55.83,48.91,43.95,31.80,30.41,29.55,29.23,27.13,22.61,19.74,14.05。
实施例60 4-(N-甲基-N-(3-(N-(2-羟基乙基)-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-63)和4-(N-甲基-N-(3-(N,N-二(2-羟基乙基)-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-64)的制备
参照G-50的合成方法,以溴乙烷替换碘甲烷,制备得黄色固体状G-63、G-64样品,收率分别为13%和32%。
G-63:ESI-MS m/z:434.0[M+Na]+。
1H NMR(500MHz,CDCl3)δ9.92(s,1H),8.49(d,J=2.5Hz,1H),7.33(t,J=7.0Hz,1H),7.26(d,J=8.3Hz,1H),7.07(d,J=7.1Hz,1H),6.88(t,J=7.1Hz,1H),6.72(d,J=8.6Hz,1H),6.57(dd,J=8.6,2.6Hz,1H),5.82(s,1H),3.89(s,3H),3.83–3.73(m,2H),3.36(s,3H),3.36–3.29(m,1H),3.00–2.89(m,1H),2.84–2.73(m,1H),1.45(d,J=6.9Hz,3H)。
13C NMR(126MHz,CDCl3)δ173.33,162.92,157.07,154.06,146.41,141.50,130.72,128.69,126.83,122.74,120.14,117.42,116.24,116.06,110.28,95.81,61.79,59.10,55.97,50.48,43.96,19.67。
G-64:ESI-MS m/z:478.3[M+Na]+。
1H NMR(500MHz,CDCl3)δ10.07(s,1H),8.46(d,J=2.5Hz,1H),7.33(t,J=7.0Hz,1H),7.29–7.21(m,1H),7.07(d,J=7.3Hz,1H),6.89(t,J=7.0Hz,1H),6.72(d,J=8.7Hz,1H),6.57(d,J=6.0Hz,1H),5.80(s,1H),3.95–3.69(m,7H),3.66–3.50(m,1H),3.34(s,3H),3.00–2.67(m,4H),1.37(d,J=6.9Hz,3H)。
13C NMR(126MHz,CDCl3)δ172.32,162.96,157.08,154.03,146.47,141.48,130.74,128.86,126.85,122.82,120.16,117.41,116.48,116.04,110.51,95.68,61.81,60.24,55.97,52.20,43.98,8.92。
实施例61 4-(N-甲基-N-(3-对甲基苯磺酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-65)
在氩气保护下,将化合物G-30和DIPEA溶解于DMF中,加入对甲基苯磺酰氯,室温搅拌48小时至反应完全,加少许水终止反应,将反应液分散于乙酸乙酯和水中,萃取,所得有机层用饱和氯化钠洗涤,再经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体,收率73%。
ESI-MS m/z:544.0[M+Na]+。
1H NMR(500MHz,CDCl3)δ8.95(s,1H),8.39(d,J=2.2Hz,1H),7.84(d,J=8.0Hz,2H),7.41–7.24(m,4H),7.06(d,J=8.1Hz,1H),6.91(t,J=7.5Hz,1H),6.75(d,J=8.5Hz,1H),6.63(d,J=8.4Hz,1H),5.88(s,1H),4.04–3.95(m,1H),3.91(s,3H),3.38(s,3H),2.44(s,3H),1.37(d,J=7.0Hz,3H)。
13C NMR(126MHz,CDCl3)δ169.55,162.94,157.03,154.07,146.42,144.10,141.38,136.27,130.79,129.88,128.41,127.24,126.74,122.81,120.67,117.47,116.45,116.01,110.45,95.90,56.13,53.47,43.96,21.53,18.57。
实施例62 4-(N-甲基-N-(3-(N-苯甲酰基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-66)
在氩气保护下,将化合物G-30和DIPEA溶解于DMF中,加入苯甲酰氯,室温搅拌48小时至反应完全,加少许水终止反应,将反应液分散于乙酸乙酯和水中,萃取,所得有机层用饱和氯化钠洗涤,再经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体,收率94%。
ESI-MS m/z:494.0[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.41(d,J=2.6Hz,1H),7.86(d,J=7.5Hz,2H),7.53(t,J=7.3Hz,1H),7.45(t,J=7.6Hz,2H),7.35–7.29(m,1H),7.25(d,J=8.2Hz,1H),7.05–7.01(m,1H),6.89–6.82(m,1H),6.72(d,J=8.7Hz,1H),6.60(dd,J=8.6,2.6Hz,1H),5.81(s,1H),4.91(p,J=7.0Hz,1H),3.85(s,3H),3.33(s,3H),1.61(d,J=7.0Hz,3H)。
13C NMR(101MHz,CDCl3)δ170.63,167.58,162.97,157.14,154.20,146.34,141.58,133.60,132.11,130.90,128.77,127.22,126.89,122.93,120.69,117.59,116.85,116.15,110.56,110.14,96.13,56.16,50.32,44.11,18.11。
实施例63 4-(N-甲基-N-(3-(N-乙酰基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-67)
在氩气保护下,将化合物G-30和吡啶溶解于DCM中,加入乙酸酐,0℃搅拌2小时至反应完全,加少许水终止反应,将反应液分散于乙酸乙酯和水中,萃取,所得有机层依次用水、1mol·L-1HCl和饱和氯化钠洗涤,再经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体,收率98%。
ESI-MS m/z:432.0[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.39(d,J=2.5Hz,1H),7.33(t,J=7.7Hz,1H),7.26(d,J=8.3Hz,1H),7.03(d,J=8.2Hz,1H),6.87(t,J=7.6Hz,1H),6.73(d,J=8.7Hz,1H),6.61(dd,J=8.6,2.6Hz,1H),6.57–6.48(m,1H),5.82(s,1H),4.68(p,J=7.1Hz,1H),3.88(s,3H),3.34(s,3H),2.08(s,3H),1.48(d,J=7.0Hz,3H)。
13C NMR(101MHz,CDCl3)δ170.67,170.58,163.03,157.15,154.18,146.37,141.50,130.91,128.78,126.88,122.93,120.65,117.57,116.83,116.12,110.55,95.94,56.19,49.94,44.12,23.17,17.75。
实施例64 4-(N-甲基-N-(3-(N-丙酰基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-68)
参照G-67的制备方法,将丙酸酐替换乙酸酐,得黄色固体,收率93%。
ESI-MS m/z:446.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.66(s,1H),8.40(d,J=2.5Hz,1H),7.33(ddd,J=8.5,7.1,1.6Hz,1H),7.25(dd,J=8.3,1.5Hz,1H),7.03(dd,J=8.3,1.6Hz,1H),6.87(ddd,J=8.4,7.1,1.5Hz,1H),6.73(d,J=8.7Hz,1H),6.60(dd,J=8.6,2.5Hz,1H),6.56–6.45(m,1H),5.82(s,1H),4.69(p,J=7.1Hz,1H),3.87(s,3H),3.34(s,3H),2.32(q,J=7.6Hz,2H),1.49(d,J=7.0Hz,3H),1.21(td,J=7.6,1.5Hz,3H)。
13C NMR(101MHz,CDCl3)δ174.33,170.81,163.02,157.14,154.16,146.37,141.46,130.89,128.81,126.88,122.92,120.59,117.53,116.81,116.10,110.51,95.85,56.13,49.79,44.09,29.52,17.71,9.84。
实施例65 4-(N-甲基-N-(3-(N-戊酰基-L-丙氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-69)
参照G-67的制备方法,将戊酸酐替换乙酸酐,得黄色固体,收率98%。
ESI-MS m/z:474.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.40(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.0,1.5Hz,1H),7.27(d,J=2.4Hz,1H),7.03(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.4,7.0,1.4Hz,1H),6.72(d,J=8.6Hz,1H),6.60(dd,J=8.6,2.7Hz,1H),6.29–6.21(m,1H),5.82(s,1H),4.69(p,J=7.1Hz,1H),3.87(s,3H),3.35(s,3H),2.32–2.22(m,2H),1.66(p,J=7.6Hz,2H),1.48(d,J=7.0Hz,3H),1.44–1.31(m,2H),0.92(t,J=7.3Hz,3H)。
13C NMR(101MHz,CDCl3)δ173.64,170.72,162.98,157.16,154.24,146.33,141.57,130.90,128.83,126.91,122.92,120.61,117.60,116.83,116.18,110.51,96.10,56.13,49.77,44.12,36.35,27.84,22.47,17.84,13.93。
实施例66 4-(N-甲基-N-(3-(N,N-二乙基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-70)和4-(N-甲基-N-(3-(N-乙基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-71)的制备
在氩气保护下,将G-35溶解于DMF中,加入无水碳酸钾和碘乙烷,室温搅拌48小时至反应完全,将反应液倒入乙酸乙酯中,依次用水、饱和氯化钠洗涤,有机层经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体状G-70、G-71样品,收率分别为18%和31%。
G-70:ESI-MS m/z:466.2[M+H]+。
1H NMR(400MHz,CDCl3)δ10.32(s,1H),8.53(dd,J=2.8,1.1Hz,1H),7.33(ddd,J=8.4,7.1,1.5Hz,1H),7.28–7.24(m,1H),7.08(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.3,7.0,1.4Hz,1H),6.71(d,J=8.6Hz,1H),6.53(dd,J=8.6,2.7Hz,1H),5.81(s,1H),3.88(s,3H),3.43(dd,J=8.1,4.1Hz,1H),3.36(s,3H),2.63(dq,J=14.3,7.3,6.5Hz,2H),2.51(dq,J=13.5,6.8Hz,2H),1.98–1.79(m,2H),1.40–1.30(m,1H),1.15(t,J=7.1Hz,6H),1.01(d,J=6.5Hz,3H),0.95(d,J=6.5Hz,3H)。
13C NMR(101MHz,CDCl3)δ174.02,162.99,157.19,154.23,146.51,141.64,130.78,129.36,127.03,122.83,119.87,117.54,116.28,116.13,110.30,95.87,62.24,55.94,44.48,44.14,34.40,29.80,26.63,23.47,22.13,14.21。
G-71:ESI-MS m/z:438.1[M+H]+。
1H NMR(400MHz,CDCl3)δ10.13(s,1H),8.53(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.0,1.5Hz,1H),7.26(dd,J=9.1,1.8Hz,1H),7.08(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.4,7.1,1.4Hz,1H),6.72(d,J=8.6Hz,1H),6.55(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.89(s,3H),3.36(s,3H),3.21(dd,J=9.6,4.0Hz,1H),2.79–2.61(m,2H),1.73–1.64(m,2H),1.54–1.44(m,1H),1.18(t,J=7.1Hz,3H),1.03–0.94(m,6H)。
13C NMR(101MHz,CDCl3)δ173.95,163.01,157.19,154.22,146.59,141.61,130.81,129.10,127.02,122.83,120.05,117.56,116.31,116.25,110.33,95.98,62.40,56.07,44.10,43.59,43.04,25.40,23.40,21.87,15.75。
实施例67 4-(N-甲基-N-(3-(N,N-二丙基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-72)和4-(N-甲基-N-(3-(N-丙基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-73)的制备
参照G-70的合成方法,以碘代正丙烷替换碘乙烷,制备得黄色固体状G-72、G-73样品,收率分别为11%和56%。
G-72:ESI-MS m/z:494.1[M+H]+。
1H NMR(400MHz,CDCl3)δ10.24(s,1H),8.55(dd,J=2.7,1.1Hz,1H),7.33(ddd,J=8.4,7.0,1.5Hz,1H),7.27(d,J=1.4Hz,1H),7.08(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.4,7.1,1.4Hz,1H),6.71(d,J=8.6Hz,1H),6.53(dd,J=8.6,2.7Hz,1H),5.81(s,1H),3.86(s,3H),3.41–3.36(m,1H),3.36(s,3H),2.45(t,J=7.3Hz,4H),1.98–1.82(m,2H),1.55(ddt,J=13.9,12.0,6.9Hz,4H),1.39–1.28(m,1H),1.01(d,J=6.4Hz,3H),0.98–0.90(m,9H)。
13C NMR(101MHz,CDCl3)δ173.89,162.96,157.17,154.21,146.38,141.61,130.76,129.40,127.00,122.80,119.79,117.51,116.27,116.01,110.28,95.83,62.78,55.75,52.99,44.11,33.88,26.68,23.52,21.99,21.80,11.81。
G-73:ESI-MS m/z:452.1[M+H]+。
1H NMR(400MHz,CDCl3)δ10.13(s,1H),8.55(d,J=2.6Hz,1H),7.33(ddd,J=8.5,7.0,1.5Hz,1H),7.26(dd,J=8.3,1.5Hz,1H),7.09(dt,J=8.2,1.5Hz,1H),6.91–6.84(m,1H),6.71(d,J=8.6Hz,1H),6.54(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.87(s,3H),3.37(s,3H),3.20(dd,J=9.6,4.1Hz,1H),2.74–2.64(m,1H),2.62–2.52(m,1H),1.82–1.45(m,5H),1.04–0.94(m,9H)。
13C NMR(101MHz,CDCl3)δ174.02,162.99,157.19,154.22,146.55,141.58,130.79,129.13,127.02,122.82,120.00,117.54,116.26,110.29,95.98,62.55,55.93,51.18,44.09,43.11,25.41,23.62,23.40,21.87,11.76。
实施例68 4-(N-甲基-N-(3-(N-异丙基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-74)
参照G-70的合成方法,以碘代异丙烷替换碘乙烷,制备得黄色固体,收率为36%。
ESI-MS m/z:452.1[M+H]+。
1H NMR(400MHz,CDCl3)δ10.26(s,1H),8.53(d,J=2.3Hz,1H),7.37–7.28(m,1H),7.30–7.23(m,1H),7.08(d,J=8.1Hz,1H),6.91–6.81(m,1H),6.71(d,J=8.6Hz,1H),6.54(dd,J=8.6,2.7Hz,1H),5.82(d,J=1.7Hz,1H),3.89(s,3H),3.36(s,3H),3.28(dd,J=10.0,3.2Hz,1H),2.81(p,J=6.3Hz,1H),1.80–1.65(m,2H),1.52–1.41(m,1H),1.13(dd,J=6.5,2.7Hz,6H),1.04–0.95(m,6H)。
13C NMR(101MHz,CDCl3)δ174.54,162.99,157.19,154.21,146.60,141.59,130.79,129.09,127.02,122.81,119.98,117.54,116.25,116.21,110.29,95.98,60.11,56.00,48.77,44.08,43.54,25.29,23.84,23.54,22.93,21.77。
实施例69 4-(N-甲基-N-(3-(N-异丁基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-75)
参照G-70的合成方法,以碘代异丁烷替换碘乙烷,制备得黄色固体,收率为38%。
ESI-MS m/z:466.1[M+H]+。
1H NMR(400MHz,CDCl3)δ10.12(s,1H),8.57(d,J=2.7Hz,1H),7.33(td,J=7.7,7.0,1.5Hz,1H),7.27(dd,J=8.4,1.3Hz,1H),7.09(dd,J=8.2,1.5Hz,1H),6.88(ddd,J=8.4,7.0,1.4Hz,1H),6.70(d,J=8.6Hz,1H),6.53(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.85(s,3H),3.36(s,3H),3.18(dd,J=9.7,3.7Hz,1H),2.57(dd,J=11.3,5.5Hz,1H),2.38(dd,J=11.2,7.6Hz,1H),1.83–1.67(m,3H),1.54–1.45(m,1H),1.04(d,J=6.6Hz,3H),1.02–0.94(m,9H)。
13C NMR(101MHz,CDCl3)δ174.05,163.02,157.23,154.26,146.50,141.62,130.82,129.19,127.05,122.84,119.99,117.59,116.30,116.24,110.23,96.08,62.75,57.51,55.79,44.12,43.19,29.06,25.48,23.44,21.91,20.72,20.57。
实施例70 4-(N-甲基-N-(3-(N,N-二丁基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-76)和4-(N-甲基-N-(3-(N-丁基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-77)的制备
参照G-70的合成方法,以碘代正丁烷替换碘乙烷,制备得黄色固体状G-76、G-77样品,收率分别为14%和47%。
G-76:ESI-MS m/z:522.2[M+H]+。
1H NMR(400MHz,CDCl3)δ10.22(s,1H),8.55(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.0,1.5Hz,1H),7.28–7.24(m,1H),7.08(dd,J=8.3,1.6Hz,1H),6.86(ddd,J=8.4,7.0,1.5Hz,1H),6.70(d,J=8.6Hz,1H),6.53(dd,J=8.6,2.7Hz,1H),5.81(s,1H),3.86(s,3H),3.39(dd,J=8.3,3.5Hz,1H),3.36(s,3H),2.57–2.38(m,4H),1.98–1.81(m,2H),1.55–1.27(m,9H),1.01(d,J=6.4Hz,3H),0.95–0.89(m,9H)。
13C NMR(101MHz,CDCl3)δ173.96,162.99,157.23,154.28,146.39,141.71,130.79,129.46,127.04,122.81,119.81,117.58,116.34,116.06,110.26,95.97,62.67,55.76,50.71,44.15,33.83,30.93,29.82,26.77,23.61,22.03,20.49,14.22。
G-77:ESI-MS m/z:466.2[M+H]+。
1H NMR(400MHz,CDCl3)δ10.12(s,1H),8.55(d,J=2.6Hz,1H),7.33(ddd,J=8.5,7.0,1.5Hz,1H),7.26(dd,J=8.4,1.5Hz,1H),7.08(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.3,7.0,1.4Hz,1H),6.72(d,J=8.6Hz,1H),6.55(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.88(s,3H),3.37(s,3H),3.19(dd,J=9.6,3.9Hz,1H),2.70(dt,J=11.3,6.3Hz,1H),2.61(dt,J=11.5,6.9Hz,1H),1.80–1.37(m,7H),1.05–0.91(m,9H)。
13C NMR(101MHz,CDCl3)δ174.02,162.98,157.18,154.21,146.53,141.57,130.79,129.12,127.01,122.81,119.99,117.53,116.25,110.26,95.96,62.61,55.91,49.06,44.08,43.09,32.66,25.40,23.40,21.86,20.37,14.14。
实施例71 4-(N-甲基-N-(3-(N,N-二正庚基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-78)和4-(N-甲基-N-(3-(N-正庚基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-79)的制备
参照G-70的合成方法,以碘代正庚烷替换碘乙烷,制备得黄色固体状G-78和G-79样品,收率分别为11%和65%。
G-78:ESI-MS m/z:606.3[M+H]+。
1H NMR(400MHz,CDCl3)δ10.23(s,1H),8.56(d,J=2.7Hz,1H),7.33(ddd,J=8.4,7.1,1.5Hz,1H),7.29–7.25(m,1H),7.09(dd,J=8.2,1.5Hz,1H),6.86(ddd,J=8.3,7.0,1.4Hz,1H),6.70(d,J=8.6Hz,1H),6.52(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.86(s,3H),3.39(dd,J=8.2,3.5Hz,1H),3.36(s,3H),2.54–2.38(m,4H),1.98–1.79(m,2H),1.52(p,J=6.7Hz,4H),1.42–1.23(m,17H),1.01(d,J=6.4Hz,3H),0.93(d,J=6.4Hz,3H),0.89–0.84(m,6H)。
13C NMR(101MHz,CDCl3)δ173.99,163.01,157.23,154.27,146.37,141.70,130.79,129.42,127.04,122.80,119.81,117.58,116.33,116.03,110.18,95.97,62.64,55.74,51.01,44.15,33.85,31.97,29.39,28.75,27.33,26.77,23.60,22.76,22.04,14.24。
G-79:ESI-MS m/z:508.4[M+H]+。
1H NMR(400MHz,CDCl3)δ10.09(s,1H),8.54(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.0,1.5Hz,1H),7.27(d,J=8.2Hz,1H),7.08(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.4,7.0,1.4Hz,1H),6.71(d,J=8.7Hz,1H),6.54(dd,J=8.6,2.7Hz,1H),5.83(s,1H),3.88(s,3H),3.37(s,3H),3.22(dd,J=9.5,3.9Hz,1H),2.74–2.56(m,2H),1.84–1.64(m,4H),1.59–1.22(m,9H),1.02–0.96(m,6H),0.91–0.85(m,3H)。
13C NMR(101MHz,CDCl3)δ163.03,157.23,154.25,146.57,141.63,130.83,129.12,127.04,122.83,120.06,117.59,116.33,116.29,110.30,96.06,62.63,55.97,49.40,44.11,43.06,31.93,30.52,29.40,27.23,25.44,23.40,22.75,21.92,14.21。
实施例72 4-(N-甲基-N-(3-(N,N-二正辛基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-80)和4-(N-甲基-N-(3-(N-正辛基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-81)的制备
参照G-70的合成方法,以碘代正辛烷替换碘乙烷,制备得黄色固体状G-80和G-81样品,收率分别为10%和67%。
G-80:ESI-MS m/z:634.5[M+H]+。
1H NMR(400MHz,CDCl3)δ10.24(s,1H),8.56(d,J=2.7Hz,1H),7.33(td,J=7.6,7.1,1.5Hz,1H),7.29–7.24(m,1H),7.09(dd,J=8.4,1.4Hz,1H),6.89–6.82(m,1H),6.70(d,J=8.6Hz,1H),6.52(dd,J=8.6,2.7Hz,1H),5.81(s,1H),3.86(s,3H),3.39(dd,J=8.2,3.5Hz,1H),3.36(s,3H),2.54–2.38(m,4H),1.98–1.81(m,2H),1.51(p,J=6.9Hz,4H),1.43–1.17(m,21H),1.01(d,J=6.4Hz,3H),0.93(d,J=6.4Hz,3H),0.86(t,J=6.6Hz,6H)。
13C NMR(101MHz,CDCl3)δ173.99,163.02,157.23,154.26,146.37,141.70,130.79,129.42,127.04,122.81,119.80,117.58,116.33,116.03,110.18,95.96,62.64,51.02,44.15,33.85,31.97,29.82,29.69,29.43,28.75,27.37,26.77,23.60,22.79,22.04,14.23。
G-81:ESI-MS m/z:522.3[M+H]+。
1H NMR(400MHz,CDCl3)δ10.10(s,1H),8.55(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.0,1.5Hz,1H),7.27(dd,J=8.3,1.3Hz,1H),7.08(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.4,7.0,1.5Hz,1H),6.71(d,J=8.7Hz,1H),6.54(dd,J=8.6,2.7Hz,1H),5.83(s,1H),3.88(s,3H),3.36(s,3H),3.20(dd,J=9.6,3.9Hz,1H),2.74–2.55(m,2H),1.84–1.65(m,2H),1.59–1.18(m,13H),1.03–0.94(m,6H),0.92–0.82(m,3H)。
13C NMR(101MHz,CDCl3)δ163.02,157.22,154.25,146.56,141.64,130.82,129.15,127.04,122.83,120.03,117.59,116.31,116.29,110.28,96.07,62.64,55.98,49.43,44.11,43.10,31.96,30.58,29.71,29.40,27.29,25.45,23.42,22.78,21.90,14.23。
实施例73 4-(N-甲基-N-(3-(N-对甲基苯磺酰基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-82)
在氩气保护下,将化合物G-35和DIPEA溶解于DMF中,加入对甲基苯磺酰氯,室温搅拌48小时至反应完全,加少许水终止反应,将反应液分散于乙酸乙酯和水中,萃取,所得有机层用饱和氯化钠洗涤,再经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体,收率72%。
ESI-MS m/z:586.0[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.74(s,1H),8.33(d,J=2.6Hz,1H),7.80(d,J=8.2Hz,2H),7.34(t,J=7.7Hz,1H),7.30–7.24(m,3H),7.03(d,J=8.2Hz,1H),6.89(t,J=7.6Hz,1H),6.71(d,J=8.7Hz,1H),6.58(dd,J=8.6,2.6Hz,1H),5.85(s,1H),5.57–5.42(m,1H),3.88(s,3H),3.86–3.81(m,1H),3.35(s,3H),2.36(s,3H),1.73–1.63(m,1H),1.60–1.47(m,2H),0.84(d,J=6.3Hz,3H),0.65(d,J=6.2Hz,3H)。
13C NMR(101MHz,CDCl3)δ169.91,163.05,157.15,154.20,146.43,144.15,141.48,136.30,130.93,129.84,128.51,127.50,126.90,122.94,120.73,117.61,116.57,116.14,110.50,96.11,56.58,56.27,44.10,42.10,24.58,22.99,21.67,21.28。
实施例74 4-(N-甲基-N-(3-(N-苯甲酰基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-83)
在氩气保护下,将化合物G-35和DIPEA溶解于DMF中,加入苯甲酰氯,室温搅拌48小时至反应完全,加少许水终止反应,将反应液分散于乙酸乙酯和水中,萃取,所得有机层用饱和氯化钠洗涤,再经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体,收率85%。
ESI-MS m/z:536.0[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.41(d,J=2.6Hz,1H),7.88–7.81(m,2H),7.56–7.49(m,1H),7.45(td,J=7.6,1.8Hz,2H),7.31(ddd,J=8.6,7.0,1.6Hz,1H),7.24(dt,J=8.4,1.8Hz,1H),7.02(dt,J=8.3,1.5Hz,1H),6.98–6.90(m,1H),6.85(ddd,J=8.4,7.0,1.5Hz,1H),6.71(dd,J=8.7,1.3Hz,1H),6.59(ddd,J=8.6,2.8,1.2Hz,1H),5.81(s,1H),4.89(td,J=8.4,5.5Hz,1H),3.85(s,3H),3.33(s,3H),1.95–1.74(m,3H),1.05–0.96(m,6H)。
13C NMR(101MHz,CDCl3)δ170.65,167.79,163.00,157.12,154.18,146.36,141.51,133.58,132.10,130.89,128.76,127.24,126.90,122.92,120.66,117.56,116.83,116.12,110.51,96.04,56.17,53.20,44.09,40.95,25.08,23.09,22.22。
实施例75 4-(N-甲基-N-(3-(N-乙酰基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-84)
在氩气保护下,将化合物G-35和吡啶溶解于DCM中,加入乙酸酐,0℃搅拌2小时至反应完全,加少许水终止反应,将反应液分散于乙酸乙酯和水中,萃取,所得有机层依次用水、1mol·L-1HCl和饱和氯化钠洗涤,再经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体,收率98%。
ESI-MS m/z:474.0[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.60(s,1H),8.40(d,J=2.7Hz,1H),7.33(td,J=7.7,7.0,1.5Hz,1H),7.25(dd,J=8.3,1.4Hz,1H),7.02(dd,J=8.2,1.5Hz,1H),6.90–6.83(m,1H),6.72(d,J=8.7Hz,1H),6.60(dd,J=8.6,2.7Hz,1H),6.56–6.49(m,1H),5.82(s,1H),4.64(td,J=8.4,5.5Hz,1H),3.88(s,3H),3.34(s,3H),2.07(s,3H),1.86–1.57(m,3H),1.02–0.92(m,6H)。
13C NMR(101MHz,CDCl3)δ170.79,170.69,163.05,157.14,154.16,146.37,141.44,130.90,128.77,126.89,122.93,120.63,117.55,116.81,116.10,110.51,95.87,56.16,52.82,44.10,40.66,24.90,23.11,22.99,22.21。
实施例76 4-(N-甲基-N-(3-(N-丙酰基-L-亮氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-85)
参照G-84的制备方法,将丙酸酐替换乙酸酐,得黄色固体,收率99%。
ESI-MS m/z:488.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.62(d,J=4.3Hz,1H),8.40(d,J=2.8Hz,1H),7.36–7.30(m,1H),7.25(d,J=8.0Hz,1H),7.02(d,J=8.2Hz,1H),6.87(t,J=7.8Hz,1H),6.72(dd,J=8.7,1.5Hz,1H),6.59(dt,J=8.5,2.1Hz,1H),6.52–6.35(m,1H),5.81(s,1H),4.65(td,J=8.4,5.5Hz,1H),3.87(s,3H),3.34(s,3H),2.32(q,J=7.6Hz,2H),1.89–1.59(m,3H),1.20(t,J=7.6Hz,3H),1.03–0.92(m,6H)。
13C NMR(101MHz,CDCl3)δ174.48,170.77,163.03,157.13,154.14,146.35,141.43,130.89,128.79,126.90,122.92,120.57,117.52,116.78,116.08,110.47,95.82,56.12,52.68,44.08,40.68,29.53,24.93,23.01,22.13,9.90。
实施例77 4-(N-甲基-N-(3-(N,N-二乙基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-86)和4-(N-甲基-N-(3-(N-乙基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-87)的制备
在氩气保护下,将G-41溶解于DMF中,加入无水碳酸钾和碘乙烷,室温搅拌48小时至反应完全,将反应液倒入乙酸乙酯中,依次用水、饱和氯化钠洗涤,有机层经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体状G-86、G-87样品,收率分别为14%和28%。
G-86:ESI-MS m/z:484.1[M+H]+。
1H NMR(400MHz,CDCl3)δ10.24(s,1H),8.48(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.1,1.5Hz,1H),7.27(dd,J=8.2,1.5Hz,1H),7.08(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.4,7.0,1.5Hz,1H),6.72(d,J=8.6Hz,1H),6.55(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.88(s,3H),3.63(dd,J=8.4,3.6Hz,1H),3.36(s,3H),2.90(ddd,J=13.0,7.6,5.4Hz,1H),2.80–2.47(m,5H),2.29–2.17(m,1H),2.14(s,3H),1.89–1.76(m,1H),1.16(t,J=7.1Hz,6H)。
13C NMR(101MHz,CDCl3)δ173.31,162.98,157.21,154.27,146.53,141.69,130.83,129.20,127.00,122.85,120.03,117.59,116.30,116.20,110.40,96.06,62.77,55.98,44.76,44.16,33.43,24.40,15.51,14.26。
G-87:ESI-MS m/z:456.1[M+H]+。
1H NMR(400MHz,CDCl3)δ10.05(s,1H),8.50(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.0,1.5Hz,1H),7.27(d,J=8.1Hz,1H),7.07(dd,J=8.3,1.5Hz,1H),6.88(ddd,J=8.4,7.0,1.5Hz,1H),6.73(d,J=8.7Hz,1H),6.57(dd,J=8.6,2.7Hz,1H),5.83(s,1H),3.89(s,3H),3.41–3.38(m,1H),3.37(s,3H),2.82–2.72(m,1H),2.72–2.63(m,3H),2.24–2.15(m,1H),2.14(s,3H),2.03–1.85(m,1H),1.19(t,J=7.1Hz,3H)。
13C NMR(101MHz,CDCl3)δ172.57,162.97,157.17,154.23,146.61,141.61,130.83,128.85,126.97,122.83,120.29,117.58,116.39,116.23,110.41,96.07,62.93,56.08,44.12,43.37,32.57,30.98,15.63,15.47。
实施例78 4-(N-甲基-N-(3-(N,N-二丙基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-88)和4-(N-甲基-N-(3-(N-丙基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-89)的制备
参照G-86的合成方法,以碘代正丙烷替换碘乙烷,制备得黄色固体状G-88、G-89样品,收率分别为11%和28%。
G-88:ESI-MS m/z:534.2[M+Na]+。
1H NMR(600MHz,CDCl3)δ10.16(s,1H),8.51(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.1,1.5Hz,1H),7.27(dd,J=8.2,1.3Hz,1H),7.08(dd,J=8.4,1.6Hz,1H),6.87(ddd,J=8.5,7.2,1.4Hz,1H),6.71(d,J=8.6Hz,1H),6.55(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.85(s,3H),3.59(dd,J=8.5,3.3Hz,1H),3.36(s,3H),2.91(ddd,J=12.9,7.4,5.2Hz,1H),2.72(dt,J=12.7,7.6Hz,1H),2.52–2.41(m,4H),2.29–2.20(m,1H),2.14(s,3H),1.86–1.77(m,1H),1.63–1.50(m,4H),0.95(t,J=7.4Hz,6H)。
13C NMR(151MHz,CDCl3)δ173.22,162.97,157.24,154.31,146.42,141.73,130.83,129.29,127.01,122.85,119.96,117.60,116.34,116.11,110.40,96.13,63.40,55.82,53.23,44.14,33.56,24.00,21.88,15.49,11.80。
G-89:ESI-MS m/z:492.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ10.08(s,1H),8.52(s,1H),7.33(t,J=7.6Hz,1H),7.30–7.23(m,1H),7.08(d,J=8.3Hz,1H),6.88(t,J=7.7Hz,1H),6.72(dd,J=8.7,1.6Hz,1H),6.56(d,J=8.9Hz,1H),5.83(s,1H),3.88(s,3H),3.41–3.29(m,4H),2.72(dd,J=11.8,6.2Hz,1H),2.66(t,J=7.4Hz,2H),2.63–2.53(m,1H),2.25–2.13(m,1H),2.16–2.11(m,3H),1.99–1.85(m,1H),1.64–1.50(m,2H),1.01(t,J=7.4Hz,3H)。
13C NMR(101MHz,CDCl3)δ172.80,162.95,157.18,154.25,146.56,141.62,130.82,128.93,126.99,122.83,120.20,117.58,116.31,116.25,110.36,96.10,63.18,55.96,50.93,44.11,32.66,31.06,23.61,15.51,11.76。
实施例79 4-(N-甲基-N-(3-(N-异丙基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-90)
参照G-86的合成方法,以碘代异丙烷替换碘乙烷,制备得黄色固体,收率为15%。
ESI-MS m/z:470.1[M+H]+。
1H NMR(600MHz,CDCl3)δ10.24(s,1H),8.50(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.1,1.6Hz,1H),7.27(dd,J=8.4,1.4Hz,1H),7.07(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.4,7.1,1.4Hz,1H),6.72(d,J=8.6Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.89(s,3H),3.41(dd,J=8.2,4.5Hz,1H),3.37(s,3H),2.88–2.80(m,1H),2.68–2.61(m,2H),2.24–2.15(m,1H),2.14(s,3H),1.90–1.82(m,1H),1.17–1.11(m,6H)。
13C NMR(151MHz,CDCl3)δ173.35,162.94,157.20,154.27,146.66,141.65,130.82,128.94,126.99,122.82,120.18,117.58,116.28,110.42,96.13,60.78,56.03,48.83,44.09,33.21,31.04,23.72,23.01,15.44。
实施例80 4-(N-甲基-N-(3-(N-异丁基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-91)
参照G-86的合成方法,以碘代异丁烷替换碘乙烷,制备得黄色固体,收率为29%。
ESI-MS m/z:484.1[M+H]+。
1H NMR(600MHz,CDCl3)δ10.09(s,1H),8.54(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.1,1.5Hz,1H),7.28–7.24(m,1H),7.08(dd,J=8.3,1.5Hz,1H),6.88(ddd,J=8.4,7.1,1.4Hz,1H),6.72(d,J=8.6Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.86(s,3H),3.37(s,3H),3.31(dd,J=7.8,4.8Hz,1H),2.66(t,J=7.3Hz,2H),2.60(dd,J=11.3,5.7Hz,1H),2.39(dd,J=11.3,7.5Hz,1H),2.19(dtd,J=14.7,7.5,4.9Hz,1H),2.14(s,3H),1.93(dq,J=14.5,7.2Hz,1H),1.82–1.73(m,1H),1.04(d,J=6.6Hz,3H),0.98(d,J=6.6Hz,3H)。
13C NMR(151MHz,CDCl3)δ172.80,162.95,157.21,154.28,146.53,141.64,130.83,128.99,127.00,122.83,120.17,117.59,116.28,110.34,96.16,63.42,57.19,55.82,44.11,32.64,31.11,29.05,20.69,20.55,15.54。
实施例81 4-(N-甲基-N-(3-(N,N-二丁基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-92)和4-(N-甲基-N-(3-(N-丁基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-93)的制备
参照G-86的合成方法,以碘代正丁烷替换碘乙烷,制备得黄色固体状G-92、G-93样品,收率分别为12%和41%。
G-92:ESI-MS m/z:562.3[M+Na]+。
1H NMR(600MHz,CDCl3)δ10.14(s,1H),8.50(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.1,1.5Hz,1H),7.29–7.24(m,1H),7.08(dd,J=8.2,1.5Hz,1H),6.87(ddd,J=8.4,7.1,1.4Hz,1H),6.72(d,J=8.6Hz,1H),6.55(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.87(s,3H),3.60(dd,J=8.7,3.3Hz,1H),3.36(s,3H),2.91(ddd,J=12.9,7.4,5.3Hz,1H),2.72(ddd,J=13.2,8.4,7.1Hz,1H),2.57–2.43(m,4H),2.28–2.19(m,1H),2.14(s,3H),1.86–1.75(m,1H),1.57–1.48(m,4H),1.45–1.29(m,4H),0.93(t,J=7.3Hz,6H)。
13C NMR(151MHz,CDCl3)δ173.24,162.98,157.24,154.30,146.42,141.73,130.83,129.29,127.01,122.83,119.95,117.60,116.34,116.11,110.36,96.10,63.24,55.78,50.92,44.13,33.57,30.93,23.89,20.46,15.49,14.18。
G-93:ESI-MS m/z:506.1[M+Na]+。
1H NMR(400MHz,CDCl3)δ10.08(s,1H),8.52(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.0,1.5Hz,1H),7.30–7.23(m,1H),7.07(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.4,7.1,1.5Hz,1H),6.72(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.83(s,1H),3.88(s,3H),3.37(s,3H),3.33(dd,J=7.8,4.9Hz,1H),2.79–2.57(m,4H),2.23–2.15(m,1H),2.14(s,3H),1.98–1.86(m,1H),1.59–1.36(m,4H),0.95(t,J=7.2Hz,3H)。
13C NMR(101MHz,CDCl3)δ172.82,162.96,157.18,154.25,146.55,141.62,130.83,128.93,126.99,122.83,120.21,117.59,116.31,116.26,110.35,96.11,63.26,55.95,48.84,44.12,32.66,31.07,20.38,15.52,14.16。
实施例82 4-(N-甲基-N-(3-(N,N-二正庚基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-94)和4-(N-甲基-N-(3-(N-正庚基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-95)的制备
参照G-86的合成方法,以碘代正庚烷替换碘乙烷,制备得黄色固体状G-94和G-95样品,收率分别为12%和40%。
G-94:ESI-MS m/z:624.3[M+H]+。
1H NMR(600MHz,CDCl3)δ10.14(s,1H),8.52(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.0,1.5Hz,1H),7.27(dd,J=7.9,1.3Hz,1H),7.08(dd,J=8.3,1.5Hz,1H),6.86(ddd,J=8.4,7.0,1.4Hz,1H),6.71(d,J=8.7Hz,1H),6.54(dd,J=8.7,2.7Hz,1H),5.82(s,1H),3.86(s,3H),3.60(dd,J=8.6,3.3Hz,1H),3.36(s,3H),2.94–2.87(m,1H),2.75–2.68(m,1H),2.54–2.41(m,4H),2.27–2.18(m,1H),2.14(s,3H),1.85–1.75(m,1H),1.54(p,J=7.2Hz,4H),1.42–1.19(m,16H),0.86(t,J=6.9Hz,6H)。
13C NMR(151MHz,CDCl3)δ173.28,162.98,157.26,154.32,146.41,141.76,130.83,129.29,127.02,122.82,119.95,117.63,116.37,116.10,110.30,96.18,63.24,55.80,51.26,44.15,33.60,31.97,29.38,28.79,27.32,23.93,22.76,15.51,14.23。
G-95:ESI-MS m/z:526.2[M+H]+。
1H NMR(600MHz,CDCl3)δ10.03(s,1H),8.51(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.1,1.5Hz,1H),7.27(dd,J=8.2,1.2Hz,1H),7.07(d,J=1.5Hz,1H),6.87(ddd,J=8.4,7.1,1.3Hz,1H),6.72(d,J=8.7Hz,1H),6.57(dd,J=8.6,2.7Hz,1H),5.83(s,1H),3.88(s,3H),3.38–3.33(m,4H),2.76–2.69(m,1H),2.68–2.58(m,3H),2.23–2.15(m,1H),2.14(s,3H),2.00–1.89(m,1H),1.61–1.50(m,2H),1.44–1.21(m,8H),0.88(t,J=6.8Hz,3H)。
13C NMR(151MHz,CDCl3)δ172.62,162.97,157.23,154.30,146.61,141.69,130.85,128.94,127.00,122.84,120.26,117.63,116.41,116.31,110.42,96.22,63.23,56.02,49.15,44.12,32.59,31.92,31.06,30.47,29.37,27.21,22.75,15.53,14.20。
实施例83 4-(N-甲基-N-(3-(N,N-二正辛基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-96)和4-(N-甲基-N-(3-(N-正辛基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素(G-97)的制备
参照G-86的合成方法,以碘代正辛烷替换碘乙烷,制备得黄色固体状G-96和G-97样品,收率分别为12%和42%。
G-96:ESI-MS m/z:674.3[M+Na]+。
1H NMR(600MHz,CDCl3)δ10.14(s,1H),8.52(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.1,1.6Hz,1H),7.27(dd,J=8.3,1.3Hz,1H),7.08(dd,J=8.3,1.5Hz,1H),6.86(ddd,J=8.4,7.1,1.4Hz,1H),6.71(d,J=8.6Hz,1H),6.54(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.86(s,3H),3.60(dd,J=8.5,3.3Hz,1H),3.36(s,3H),2.90(ddd,J=12.9,7.4,5.3Hz,1H),2.72(ddd,J=13.1,8.3,7.1Hz,1H),2.55–2.40(m,4H),2.28–2.18(m,1H),2.14(s,3H),1.85–1.75(m,1H),1.53(p,J=7.1Hz,4H),1.41–1.21(m,20H),0.86(t,J=7.0Hz,6H)。
13C NMR(151MHz,CDCl3)δ173.27,162.98,157.25,154.32,146.40,141.76,130.83,129.29,127.02,122.83,119.94,117.62,116.36,116.09,110.30,96.17,63.25,55.80,51.27,44.15,33.60,31.97,29.68,29.43,28.79,27.36,23.92,22.79,15.51,14.22。
G-97:ESI-MS m/z:540.3[M+H]+。
1H NMR(600MHz,CDCl3)δ10.05(s,1H),8.52(d,J=2.7Hz,1H),7.33(ddd,J=8.6,7.1,1.5Hz,1H),7.27(dd,J=8.3,1.3Hz,1H),7.08(dd,J=8.2,1.6Hz,1H),6.87(ddd,J=8.4,7.0,1.4Hz,1H),6.72(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.83(s,1H),3.88(s,3H),3.37(s,3H),3.34(dd,J=7.8,4.9Hz,1H),2.72(dt,J=11.5,6.7Hz,1H),2.66(t,J=7.3Hz,2H),2.61(dt,J=11.3,7.1Hz,1H),2.22–2.14(m,1H),2.14(s,3H),1.97–1.88(m,1H),1.58–1.50(m,2H),1.44–1.23(m,10H),0.88(t,J=6.9Hz,3H)。
13C NMR(151MHz,CDCl3)δ172.75,162.97,157.22,154.29,146.60,141.68,130.84,128.95,127.00,122.83,120.23,117.61,116.38,116.30,110.40,96.19,63.25,56.00,49.17,44.11,32.64,31.95,31.08,30.52,29.68,29.38,27.27,22.76,15.53,14.20。
实施例84 4-(N-甲基-N-(3-(N-对甲基苯磺酰基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-98)
在氩气保护下,将化合物G-41和DIPEA溶解于DMF中,加入对甲基苯磺酰氯,室温搅拌48小时至反应完全,加少许水终止反应,将反应液分散于乙酸乙酯和水中,萃取,所得有机层用饱和氯化钠洗涤,再经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体,收率78%。
ESI-MS m/z:604.0[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.30(d,J=2.7Hz,1H),7.85–7.77(m,2H),7.35(ddd,J=10.4,5.6,2.0Hz,1H),7.30(d,J=8.2Hz,2H),7.27(dd,J=8.3,1.3Hz,1H),7.02(dd,J=8.3,1.5Hz,1H),6.94–6.85(m,1H),6.73(d,J=8.7Hz,1H),6.61(dd,J=8.6,2.7Hz,1H),6.13–6.07(m,1H),5.84(s,1H),4.15–4.07(m,1H),3.89(s,3H),3.35(s,3H),2.48–2.38(m,2H),2.39(s,3H),2.08–1.92(m,5H)。
13C NMR(101MHz,CDCl3)δ168.83,163.01,157.14,154.24,146.55,144.25,141.51,136.49,130.97,129.98,128.35,127.46,126.88,122.96,120.96,117.65,116.67,116.14,110.61,96.22,57.08,56.28,44.13,30.80,30.11,21.71,15.15。
实施例85 4-(N-甲基-N-(3-(N-苯甲酰基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-99)
在氩气保护下,将化合物G-41和DIPEA溶解于DMF中,加入苯甲酰氯,室温搅拌48小时至反应完全,加少许水终止反应,将反应液分散于乙酸乙酯和水中,萃取,所得有机层用饱和氯化钠洗涤,再经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体,收率85%。
ESI-MS m/z:554.2[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.38(d,J=2.7Hz,1H),7.90–7.84(m,2H),7.57–7.51(m,1H),7.50–7.43(m,2H),7.35–7.30(m,1H),7.30–7.22(m,1H),7.03(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.3,7.1,1.4Hz,1H),6.73(d,J=8.7Hz,1H),6.62(dd,J=8.7,2.7Hz,1H),5.83(s,1H),5.05(q,J=7.1Hz,1H),3.85(s,3H),3.35(s,3H),2.77(dt,J=13.5,6.8Hz,1H),2.67(dt,J=13.8,7.1Hz,1H),2.37–2.20(m,2H),2.17(s,3H)。
13C NMR(101MHz,CDCl3)δ169.58,167.59,162.96,157.15,154.24,146.43,141.60,133.50,132.21,130.93,128.83,128.54,127.26,126.88,122.95,120.88,117.63,116.95,116.16,110.63,96.29,56.17,53.65,44.13,30.94,30.41,15.29。
实施例86 4-(N-甲基-N-(3-(N-乙酰基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-100)
在氩气保护下,将化合物G-41和吡啶溶解于DCM中,加入乙酸酐,0℃搅拌2小时至反应完全,加少许水终止反应,将反应液分散于乙酸乙酯和水中,萃取,所得有机层依次用水、1mol·L-1HCl和饱和氯化钠洗涤,再经无水硫酸镁干燥,浓缩,所得粗品经硅胶柱层析纯化,得黄色固体,收率98%。
ESI-MS m/z:492.1[M+Na]+。
1H NMR(600MHz,CDCl3)δ8.64(s,1H),8.36(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.1,1.5Hz,1H),7.29–7.24(m,1H),7.03(dd,J=8.3,1.5Hz,1H),6.88(ddd,J=8.3,7.1,1.4Hz,1H),6.74(d,J=8.6Hz,1H),6.63(dd,J=8.7,2.7Hz,1H),6.61–6.57(m,1H),5.83(s,1H),4.81(q,J=7.2Hz,1H),3.88(s,3H),3.35(s,3H),2.70–2.64(m,1H),2.62–2.56(m,1H),2.23–2.16(m,1H),2.14(s,3H),2.11–2.04(m,4H)。
13C NMR(151MHz,CDCl3)δ170.60,169.63,162.99,157.17,154.25,146.46,141.56,130.95,128.57,126.88,122.95,120.85,117.63,116.96,116.17,110.65,96.21,56.20,53.17,44.13,31.08,30.33,23.25,15.27。
实施例87 4-(N-甲基-N-(3-(N-丙酰基-L-蛋氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-101)
参照G-100的制备方法,将丙酸酐替换乙酸酐,得黄色固体,收率99%。
ESI-MS m/z:506.1[M+Na]+。
1H NMR(600MHz,CDCl3)δ8.66(s,1H),8.36(d,J=2.7Hz,1H),7.33(ddd,J=8.5,7.1,1.5Hz,1H),7.26(dd,J=8.3,1.3Hz,1H),7.03(dd,J=8.3,1.5Hz,1H),6.88(ddd,J=8.3,7.1,1.3Hz,1H),6.73(d,J=8.7Hz,1H),6.62(dd,J=8.6,2.7Hz,1H),6.60–6.54(m,1H),5.83(s,1H),4.82(q,J=7.2Hz,1H),3.87(s,3H),3.35(s,3H),2.68(dt,J=13.6,6.8Hz,1H),2.59(dt,J=13.7,7.2Hz,1H),2.32(qd,J=7.6,1.7Hz,2H),2.25–2.16(m,1H),2.14(s,3H),2.13–2.04(m,1H),1.20(t,J=7.6Hz,3H)。
13C NMR(151MHz,CDCl3)δ174.32,169.73,162.97,157.17,154.24,146.45,141.56,130.93,128.59,126.88,122.94,120.80,117.61,116.94,116.17,110.63,96.18,56.16,53.08,44.11,31.02,30.35,29.64,15.25,9.84。
实施例88 4-(N-甲基-N-(3-(N-Boc-L-天冬氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-102)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-天冬氨酸,得黄色固体,收率46%。
ESI-MS m/z:534.2[M+Na]+。
1H NMR(400MHz,CDCl3)δ9.02(s,1H),8.41(s,1H),7.36–7.32(m,1H),7.31(d,J=1.2Hz,1H),7.29–7.24(m,1H),6.98(d,J=8.2Hz,1H),6.87(t,J=7.6Hz,1H),6.69(d,J=8.7Hz,1H),6.55(d,J=8.2Hz,1H),6.01(d,J=8.7Hz,1H),5.86(s,1H),4.81–4.65(m,1H),3.85(s,3H),3.32(s,3H),3.18(dd,J=17.1,2.4Hz,1H),2.82(dd,J=17.3,4.6Hz,1H),1.50(s,9H)。
实施例89 4-(N-甲基-N-(3-L-天冬氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-103)
参照G-23的制备方法,得黄色固体,收率73%。
ESI-MS m/z:434.1[M+Na]+。
1H NMR(500MHz,CD3OD)δ8.40(s,1H),8.13(d,J=1.8Hz,1H),7.45(t,J=7.7Hz,1H),7.32(d,J=8.3Hz,1H),7.11(d,J=8.2Hz,1H),7.06(d,J=8.7Hz,1H),7.00–6.96(m,1H),6.94(t,J=7.7Hz,1H),5.88(s,1H),4.44–4.35(m,1H),3.95(s,3H),3.43(s,3H),2.84(dd,J=17.1,6.0Hz,1H),2.71(dd,J=16.7,6.9Hz,1H)。
13C NMR(126MHz,CD3OD)δ174.48,167.61,163.87,157.74,153.90,148.05,140.98,131.03,127.85,126.71,122.77,121.61,118.20,117.00,115.79,111.30,93.84,55.27,51.28,43.16。
实施例90 4-(N-甲基-N-(3-(N-Boc-L-谷氨酰氨基)-4-甲氧苯基)-氨基)香豆素的制备(G-104)
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-Boc-L-谷氨酸,得黄色固体,收率79%。
ESI-MS m/z:549.2[M+Na]+。
1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.40(d,J=1.9Hz,1H),7.35–7.29(m,1H),7.03(d,J=7.7Hz,1H),6.87(t,J=7.5Hz,1H),6.70(d,J=8.5Hz,1H),6.60(d,J=7.8Hz,1H),5.85(s,1H),3.82(s,3H),3.34(s,3H),2.66–2.46(m,2H),2.35(s,9H),2.32–2.22(m,1H)。
13C NMR(101MHz,CDCl3)δ176.81,170.26,163.13,157.13,156.12,154.09,146.41,141.41,130.84,126.80,122.85,120.72,117.54,116.90,116.04,110.47,95.91,77.27,55.97,44.03,28.28,21.47,14.20。
实施例91 4-(N-甲基-N-(3-L-谷氨酰氨基-4-甲氧苯基)-氨基)香豆素的制备(G-105)
参照G-23的制备方法,得黄色固体,收率74%。
ESI-MS m/z:449.2[M+Na]+。1H NMR(400MHz,CDCl3)δ8.21(s,1H),7.18–7.11(m,1H),7.09(d,J=8.1Hz,1H),6.92(d,J=8.0Hz,1H),6.71(t,J=7.2Hz,1H),6.59(d,J=8.8Hz,1H),6.53(d,J=8.4Hz,1H),5.66(s,1H),3.66(s,3H),3.65–3.61(m,1H),3.15(s,3H),2.36–2.21(m,2H),2.15–1.99(m,1H),1.70–1.55(m,1H)。
13C NMR(101MHz,CDCl3)δ180.62,173.43,162.72,157.02,153.88,146.83,141.09,130.80,128.35,126.58,122.76,120.52,117.34,116.75,115.90,110.67,95.67,55.84,55.04,43.87,34.22,30.61。
实施例92本发明化合物G-107的制备
合成路线如下,参照G-22和G-23的制备方法:
G-106(C25H29N3O6):1H NMR(400MHz,CDCl3)δ8.43(s,1H),7.86(s,1H),7.36–7.31(m,1H),7.27(d,J=8.6Hz,1H),7.04(d,J=8.1Hz,1H),6.87(t,J=7.6Hz,1H),6.72(d,J=8.6Hz,1H),6.59(dd,J=8.7,2.2Hz,1H),5.84(s,1H),3.87(s,3H),3.50(q,J=5.9Hz,2H),3.36(s,3H),2.65(t,J=5.6Hz,2H),1.80(s,1H),1.44(s,9H)。
G-107(C20H21N3O4):1H NMR(400MHz,CD3OD)δ7.98(d,J=2.6Hz,1H),7.35–7.29(m,1H),7.18(dd,J=8.3,1.0Hz,1H),7.00(dd,J=8.3,1.4Hz,1H),6.92(d,J=8.7Hz,1H),6.82(ddd,J=7.0,3.3,1.2Hz,2H),5.73(d,J=7.7Hz,1H),3.81(s,3H),3.30(d,J=6.4Hz,3H),3.25(s,2H),3.02(t,J=6.3Hz,2H),2.66(t,J=6.3Hz,2H)。少一个H,可能在MeOH溶剂残留峰(3.21)或水峰(4.73)里。
实施例93本发明化合物G-108和G-109的制备
合成路线如下,参照G-22的制备方法:
G-108(C28H35N3O6):1H NMR(400MHz,CDCl3)δ8.58(s,1H),8.46(d,J=1.8Hz,1H),7.33(t,J=7.1Hz,1H),7.27(d,J=6.6Hz,1H),7.05(d,J=7.2Hz,1H),6.87(t,J=7.5Hz,1H),6.71(d,J=8.5Hz,1H),6.57(d,J=7.6Hz,1H),5.83(s,1H),4.90(s,1H),4.28(s,1H),3.87(s,3H),3.36(s,3H),1.77(s,3H)(亚甲基上的两个H可能被包含在里边,实为2H),1.47(s,9H),0.99(dd,J=6.2,5.2Hz,6H)。
G-109(C23H27N3O4):1H NMR(400MHz,CDCl3)δ10.01(s,1H),8.54(d,J=2.7Hz,1H),7.32(ddd,J=8.4,7.1,1.5Hz,1H),7.28–7.24(m,1H),7.06(dd,J=8.3,1.3Hz,1H),6.85(ddd,J=8.4,7.1,1.4Hz,1H),6.72(d,J=8.7Hz,1H),6.56(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.89(s,3H),3.61–3.51(m,1H),3.36(s,3H),1.88–1.72(m,2H),1.53–1.41(m,1H),0.99(dt,J=12.8,6.4Hz,6H)。亚甲基上的两个H可能被包含在1.88–1.72(m,5H)的宽峰里;还少了NH2的两个H。
实施例94本发明化合物G-110和G-111的制备
合成路线如下,制备方法同实施例6:
G-110(C30H31N3O6):1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),7.95(s,1H),7.60(s,1H),7.50–7.38(m,3H),7.37–7.24(m,4H),6.97(td,J=15.4,8.5Hz,3H),6.87(d,J=7.5Hz,1H),5.83(s,1H),5.54(s,1H),3.81(s,3H),3.28(d,J=6.3Hz,3H),1.39(s,9H)。
G-111(C25H23N3O4):1H NMR(400MHz,DMSO-d6)δ8.16(d,J=2.7Hz,1H),7.41(ddd,J=13.0,7.6,4.6Hz,3H),7.29(ddd,J=14.3,11.9,7.1Hz,4H),7.04(d,J=8.8Hz,1H),7.00–6.92(m,2H),6.85(dd,J=8.7,2.7Hz,1H),5.82(s,1H),4.52(s,1H),3.90(s,3H),3.28(s,3H)。
实施例95本发明化合物G-112和G-113的制备
合成路线如下,参照G-22的制备方法:
G-112(C25H29N3O6):1H NMR(400MHz,CDCl3)δ8.64(s,1H),8.46(d,J=2.5Hz,1H),7.36–7.30(m,1H),7.30–7.24(m,1H),7.05(dd,J=8.2,1.2Hz,1H),6.87(t,J=7.6Hz,1H),6.71(d,J=8.6Hz,1H),6.58(dd,J=8.6,2.4Hz,1H),5.83(s,1H),4.98(s,1H),4.35(s,1H),3.86(s,3H),3.35(s,3H),1.48(s,9H),1.46(s,3H)。
G-113(C20H21N3O4):1H NMR(400MHz,CDCl3)δ9.94(s,1H),8.52(d,J=2.7Hz,1H),7.35–7.29(m,1H),7.28–7.24(m,1H),7.06(dd,J=8.3,1.3Hz,1H),6.85(ddd,J=8.3,7.1,1.4Hz,1H),6.72(d,J=8.7Hz,1H),6.57(dd,J=8.6,2.7Hz,1H),5.82(s,1H),3.89(s,3H),3.71(q,J=7.0Hz,1H),3.36(s,3H),2.04(s,2H),1.48(d,J=7.0Hz,3H)。
实施例96本发明化合物G-114的制备
参照G-22的制备方法,将N-Boc-L-脯氨酸替换为N-(N-苄氧羰基-甘氨酰基)-L-脯氨酸,得黄色粉末样品,收率93%。
G-114(C32H32N4O7):1H NMR(600MHz,Chloroform-d)δ9.09(s,1H),8.39(d,J=2.7Hz,1H),7.38–7.29(m,6H),7.25(dd,J=8.4,1.8Hz,1H),7.03(dd,J=8.2,1.6Hz,1H),6.86(t,J=7.8Hz,1H),6.70(d,J=8.6Hz,1H),6.57(dd,J=8.6,2.7Hz,1H),5.81(s,1H),5.77(s,1H),5.13(s,2H),4.74(dd,J=8.1,2.3Hz,1H),4.11(dd,J=17.4,4.6Hz,1H),4.05(dd,J=17.5,4.6Hz,1H),3.84(s,3H),3.66–3.56(m,1H),3.54–3.43(m,1H),3.33(s,3H),2.50–2.43(m,1H),2.27–2.16(m,1H),2.12–2.06(m,1H),2.02–1.94(m,1H)。
13C NMR(151MHz,CDCl3)δ168.98,168.50,162.82,157.05,156.27,154.16,146.41,141.43,136.34,130.76,129.02,128.54,128.20,128.08,126.87,122.80,120.49,117.46,116.86,116.13,110.52,95.97,67.00,61.14,56.12,46.41,43.99,43.44,27.54,24.93。
实施例97本发明化合物G-115的制备
参照实施例2中M06的制备方法,将氯乙酰氯替换为4-氯丁酰氯,得黄色粉末样品,收率93%。
G-115(C21H21ClN2O4):1H NMR(600MHz,Chloroform-d)δ8.46(d,J=2.7Hz,1H),7.93(s,1H),7.34(ddd,J=8.6,7.1,1.5Hz,1H),7.27(dd,J=8.4,1.3Hz,1H),7.05(dd,J=8.3,1.5Hz,1H),6.87(ddd,J=8.4,7.1,1.3Hz,1H),6.74(d,J=8.6Hz,1H),6.60(dd,J=8.6,2.7Hz,1H),5.83(s,1H),3.90(s,3H),3.69(t,J=6.2Hz,2H),3.36(s,3H),2.65(t,J=7.1Hz,2H),2.22(p,J=6.7Hz,2H)。
以下通过试验例证明本发明的有益效果。
试验例1本发明目标化合物对肿瘤细胞增殖的抑制作用
1、试剂和材料
人结肠癌细胞系HCT116、人肺癌细胞系A549、紫杉醇耐药人肺腺癌细胞系A549T、人卵巢癌细胞系A2780S、紫杉醇耐药人卵巢癌细胞A2780T、人乳腺癌细胞系MCF-7、宫颈癌细胞系Hela购买于ATCC并按照相应的操作规范进行保种;RPMI-1640培养基,购自Gibco;胎牛血清(FBS),购自兰州民海生物工程有限公司。
2、实验方法
2.1 MTT细胞增殖实验
收集对数期细胞,将细胞铺于96孔板中,待细胞贴壁后加药处理;将细胞放置于含有5%二氧化碳的37℃恒温培养箱内进行培养。24h后,在每孔中加入200μL MTT溶液(配制成5mg/ml),继续培养4h;吸去孔内的液体,加入150μL DMSO,机械振荡5分钟使沉淀物溶解。最后取出96孔板,将其置于酶标仪上,震荡15秒,然后在570nm(630nm校准)下测量吸光值,结果统计分析得出抑制率或IC50值。实验结果见表1~3。
2.2抑制耐药肿瘤株的活性测试
耐药性是困扰抗肿瘤制剂发挥疗效的一个重要因素。肿瘤细胞一旦产生耐药性,那么药物的抗肿瘤活性就会显著下降。耐药性是研究抗肿瘤制剂必须要克服的问题。本实验从上述合成的目标化合物中选出了G-41、G-35、G-33、G-27、G-31五个化合物进行了耐药肿瘤细胞的抑制试验。分别选择卵巢癌细胞株A2780S(敏感株)和A2780/T(紫杉醇耐受)、腺癌人类肺细胞株A549(敏感株)和A549T(紫杉醇耐受)。化合物对肿瘤细胞株的耐受指数(Drug resistant index=(IC50 of drug resistant cancer cell)/(IC50 of parentalcancer cell))是指化合物对肿瘤细胞耐药株IC50与敏感株IC50的比值,耐受指数小,说明该化合物能够更好的克服耐药性问题。具体实验数据见表4。
3、试验结果
3.1本发明目标化合物抑制肿瘤细胞增殖的试验结果
本实验测试的化合物结构通式如下:
表1本发明部分化合物抑制肿瘤细胞增殖的IC50
表2本发明部分目标化合物对肿瘤细胞的抑制率
表3本发明部分目标化合物对肿瘤细胞的抑制率
3.2本发明目标化合物抑制耐药肿瘤株的活性测试结果
表4本发明部分化合物抑制耐药肿瘤株的IC50
化合物G-41对A2780S(敏感株)和A2780/T(紫杉醇耐受)耐受指数为76.5,对腺癌人类肺细胞株A549(敏感株)和A549T(紫杉醇耐受)耐受指数为6.2,G-35对A2780S(敏感株)和A2780/T(紫杉醇耐受)耐受指数为38.5,对腺癌人类肺细胞株A549(敏感株)和A549T(紫杉醇耐受)耐受指数为7.0,G-33对A2780S(敏感株)和A2780/T(紫杉醇耐受)耐受指数为18.2,对腺癌人类肺细胞株A549(敏感株)和A549T(紫杉醇耐受)耐受指数为3.61,G-27对A2780S(敏感株)和A2780/T(紫杉醇耐受)耐受指数为21.45,对腺癌人类肺细胞株A549(敏感株)和A549T(紫杉醇耐受)耐受指数为1.99,G-31对A2780S(敏感株)和A2780/T(紫杉醇耐受)耐受指数为50.9,对腺癌人类肺细胞株A549(敏感株)和A549T(紫杉醇耐受)耐受指数为6.7,这些化合物的耐受指数均优于对照药物长春碱(vinblastine)、紫杉醇(paclitaxel)及秋水仙碱(colchicine)。
从以上实验结果可以看出,本发明化合物在多种肿瘤细胞株(如结肠癌HCT116、乳腺癌MCF-7、卵巢癌A2780S、肺癌A549、宫颈癌Hela)中均能发挥明显的抑制细胞增殖的作用,而且,对耐药肿瘤细胞也有显著的抑制效果。
试验例2本发明目标化合物的溶解度实验
1、试验方法
(1)取10mL的塑料离心管,配置含乙醇10%、20%、50%的水溶液5mL,并另取一支离心管,加入5mL超纯水。往以上离心管内分别加入5mg的原料药,37℃超声半小时,肉眼判断药物是否完全溶解。
(2)配置含乙醇10%、10%吐温-80的水溶液10mL,分别加入待测药物50到100毫克,37℃超声半小时,肉眼判断药物是否完全溶解。
(3)测定各待测目标化合物溶在氯化钠注射液、pH4.0缓冲溶液、0.1%甲酸水中的溶解度,以及相对于M05在个溶剂中溶解度的倍数。
2、试验结果
2.1溶解度实验初测结果
参照常用药物体内实验溶解样品的方法进行溶解度的的初测,结果目标化合物G-41、G-35、G-31相比M05在100%乙醇、50%乙醇+50%水、20%乙醇+80%水、10%乙醇+90%水中的溶解度均有较为明显的提高,具体实验结果见表5、表6。
表5溶解度初测结果
M05 | G-41 | G-35 | G-31 | |
100%乙醇 | 未溶清 | 溶清 | 溶清 | 溶清 |
50%乙醇+50%水 | 未溶清 | 溶清 | 溶清 | 溶清 |
20%乙醇+80%水 | 未溶清 | 溶清 | 未溶清 | 溶清 |
10%乙醇+90%水 | 未溶清 | 溶清 | 未溶清 | 溶清 |
注:完全溶清的浓度为2mg/mL。
表6高浓度溶解实验
10%吐温+10%乙醇+80%水 | 浓度mg/mL | pH | |
G-41 | 溶清 | 10 | 7 |
G-35 | 溶清 | 10 | 7 |
G-31 | 溶清 | 5 | 6-7 |
2.2本发明目标化合物在各溶剂中的溶解度测定
表7本发明目标化合物在各溶剂中的溶解度
本试验例的实验结果表明,本发明在氨基上引入取代基(R1和/或R2)后,所得化合物的水溶性较M05显著提升,有利于提高化合物在动物体内的生物利用度以及药效的发挥,同时也更适合于开发成制剂。
试验例3体内抗肿瘤实验
1、试验方法
42只5-6周龄的雌性Balb/C裸鼠,饲养一周待其适应环境后,在每只裸鼠的右侧肩部皮下以107个细胞每只的量植入C26肿瘤细胞。待肿瘤体积达到100mm3时,将小鼠随机分为七组每组六只动物,一组是空白对照组,一组是紫杉醇阳性对照组,其余各组为实验组分别给药G-41、G-35、G-33、G-27、G-31。空白对照组给生理盐水,隔天给药,合计给药6次,给药方式为静脉注射;紫杉醇阳性对照组按30mg/kg给药,每周给药一次,合计给药两次,给药方式为静脉注射;G-41、G-35、G-33、G-27、G-31组10mg/kg给药,隔天给药,合计给药6次,给药方式为静脉注射。每隔两天记录小鼠的体重,并计算肿瘤的体积,计算公式如下:V=π/6×A2×B,V=肿瘤体积(mm3),A=肿瘤宽度(mm),B=肿瘤长度(mm)。通过抑瘤率来评价化合物的抗肿瘤活性,计算公式如下:抑瘤率=(1-治疗小组的肿瘤重量/对照小组的肿瘤重量)×100%。
2、试验结果
表10实验小鼠平均瘤重及体重
从表10以及图1~4中可以看出,G-33、G-27、G-35、G-41、G-31对瘤块生长的抑制作用明显强于紫杉醇对照和空白对照,且实验组动物体重未出现明显减轻,体重降低都控制在6%以内,说明化合物G-33、G-27、G-35、G-41、G-31对C26肿瘤细胞移植Balb/c小鼠具有治愈效果明显,毒性低的特点。
Claims (17)
2.如权利要求1所述的化合物,其特征是:R8和R9为甲基。
6.如权利要求5所述的化合物,其特征是:当R1与R2、R2与R3均不成环时,满足以下至少一项:
R1、R2独立选自H、未取代的C1~C17烷基、羟基取代的C1~C17烷基、6~14元芳基取代的C1~C17烷基、叔丁氧羰基、苄氧羰基、C1~C17烷酰基、6~14元芳酰基或6~14元芳基磺酰基;
优选地,R1、R2独立选自H、未取代的C1~C8烷基、羟基取代的C1~C8烷基、苯环上的氢任选被取代或未取代的苯基取代的C1~C8烷基、叔丁氧羰基、苄氧羰基、C1~C8烷酰基、苯环上的氢任选被取代或未取代的苯甲酰基或苯环上的氢任选被取代或未取代的苯磺酰基,所述苯环上的氢任选被取代或未取代的苯甲酰基或苯环上的氢任选被取代或未取代的苯磺酰基中的取代基为C1~C4烷基;
更优选地,R1、R2独立选自H、未取代的C1~C8烷基、羟基取代的C2烷基、苄基、叔丁氧羰基、苄氧羰基、乙酰基、丙酰基、戊酰基、苯酰基或甲苯磺酰基;
R3选自H、未取代的C1~C6烷基、羟基取代的C1~C6烷基、-SCH3取代的C1~C6烷基、-C(=O)NH2取代的C1~C6烷基、6~14元芳亚甲基或6~14元芳基;
优选地,R3选自H、未取代的C1~C6烷基、羟基取代的C1~C6烷基、-SCH3取代的C1~C6烷基、-C(=O)NH2取代的C1~C6烷基、苯环上的氢任选被羟基取代或未取代的苄基或苯环上的氢任选被羟基取代或未取代的苯基;
更优选地,R3选自H、未取代的C1~C4烷基、羟基取代的C1~C2烷基、-SCH3取代的C2烷基、-C(=O)NH2取代的C2烷基、苯基、苄基、4-羟基苯甲基。
8.如权利要求5所述的化合物,其特征是:当R2与R3相连形成脂环时,所述脂环为5元脂环,R1选自H、烷基、烷氧羰基、烷酰基、芳酰基或芳基磺酰基;
优选地,当R2与R3相连形成脂环时,所述的5元脂环含有1个杂原子,所述杂原子为氮、氧或硫;
更优选地,当R2与R3相连形成脂环时,所述5元脂环为未取代或羟基取代的5元氮杂脂环,R1选自H、叔丁氧羰基或烷酰基;
优选的,当R2与R3相连形成脂环时,R1选自H、未取代的C1~C17烷基、羟基取代的C1~C17烷基、6~14元芳基取代的C1~C17烷基、叔丁氧羰基、苄氧羰基、C1~C17烷酰基、6~14元芳酰基或6~14元芳基磺酰基;
更优选地,当R2与R3相连形成脂环时,R1选自H、未取代的C1~C8烷基、羟基取代的C1~C8烷基、苯环上的氢任选被取代或未取代的苯基取代的C1~C8烷基、叔丁氧羰基、苄氧羰基、未取代或氨基取代的C1~C8烷酰基、苯环上的氢任选被取代或未取代的苯甲酰基或苯环上的氢任选被取代或未取代的苯磺酰基,所述苯环上的氢任选被取代或未取代的苯甲酰基或苯环上的氢任选被取代或未取代的苯磺酰基中的取代基为C1~C4烷基;
再优选地,当R2与R3相连形成脂环时,R1选自H、未取代的C1~C8烷基、羟基取代的C2烷基、苄基、叔丁氧羰基、苄氧羰基、未取代或氨基取代的乙酰基、丙酰基、戊酰基、苯酰基或甲苯磺酰基;
14.权利要求1~13任意一项所述化合物、其立体异构体、化合物或其立体异构体药学上可接受的盐在制备抗肿瘤的药物中的用途;优选地,所述的肿瘤为耐药肿瘤。
15.如权利要求14所述的用途,其特征是:所述的药物是治疗和/或预防结肠癌、乳腺癌、卵巢癌、肺癌或宫颈癌的药物;优选地,所述的肺癌为肺腺癌。
16.抗肿瘤的药物组合物,其特征是:以权利要求1~13任意一项所述化合物、其立体异构体、化合物或其立体异构体药学上可接受的盐为活性成分,加入药学上接受的辅料或者辅助性成分制备而成的制剂;优选地,所述的制剂为注射剂;优选地,所述的肿瘤为耐药肿瘤。
17.如权利要求16所述的药物组合物,其特征是:所述的制剂是治疗和/或预防结肠癌、乳腺癌、卵巢癌、肺癌或宫颈癌的制剂;优选地,所述的肺癌为肺腺癌。
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