CN110526854A - 一种ɑ,β-不饱和酮衍生物、制备方法及作为药物的用途 - Google Patents
一种ɑ,β-不饱和酮衍生物、制备方法及作为药物的用途 Download PDFInfo
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- CN110526854A CN110526854A CN201910679937.9A CN201910679937A CN110526854A CN 110526854 A CN110526854 A CN 110526854A CN 201910679937 A CN201910679937 A CN 201910679937A CN 110526854 A CN110526854 A CN 110526854A
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- China
- Prior art keywords
- ketone
- methyl
- propyl
- alkene
- trimethoxyphenyl
- Prior art date
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- Granted
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- 150000002576 ketones Chemical class 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title abstract description 37
- 229940079593 drug Drugs 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 86
- -1 mono-substituted methoxyl group Chemical group 0.000 claims description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 35
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 14
- PZOUSPYUWWUPPK-UHFFFAOYSA-N 4-methyl-1h-indole Chemical compound CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 13
- 210000004881 tumor cell Anatomy 0.000 claims description 9
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
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- 239000012453 solvate Substances 0.000 claims description 8
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- 239000000203 mixture Substances 0.000 claims description 7
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- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
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- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
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- 231100000782 microtubule inhibitor Toxicity 0.000 claims description 3
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- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- YPKBCLZFIYBSHK-UHFFFAOYSA-N 5-methylindole Chemical compound CC1=CC=C2NC=CC2=C1 YPKBCLZFIYBSHK-UHFFFAOYSA-N 0.000 claims description 2
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- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
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- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- DOTMOQHOJINYBL-UHFFFAOYSA-N molecular nitrogen;molecular oxygen Chemical compound N#N.O=O DOTMOQHOJINYBL-UHFFFAOYSA-N 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
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- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 claims description 2
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Classifications
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- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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Abstract
本发明涉及医药技术领域,提出一种ɑ,β‑不饱和酮衍生物及其制备方法,结构通式如Ⅰ所示,各取代基定义见说明书,本发明的化合物可以靶向微管蛋白,对多种肿瘤亲代和耐药株均有较强的抑制作用,可以制备用于治疗恶性肿瘤及与分化增殖相关疾病的药物。
Description
技术领域
本发明涉及医药技术领域,具体涉及一类微管靶向抗肿瘤活性的ɑ,β-不饱和酮衍生物及其制备方法与应用。
背景技术
当前,癌症已经成为一种严重威胁人类健康生命的疾病。目前临床上治疗恶性肿瘤仍主要采用化疗的方法,但一半以上的肿瘤对传统化疗药物已产生显著耐药。据美国癌症协会估计,90%以上肿瘤患者死于不同程度的耐药,肿瘤耐药已经成为临床化疗失败的主要原因。因此,开发一种选择性靶向多药耐药的新型抗肿瘤化疗药物已经成为迫切需要。
近年来,微管靶向制剂已经成为抗肿瘤药物研发的一个重要部分。微管是由α,β微管蛋白组成的动态细胞骨架,它们在各种细胞功能中起着重要作用,包括有丝***。微管在细胞周期的不同阶段表现出不同的动态行为,抑制微管动力学,阻滞细胞周期,诱导细胞凋亡,是肿瘤细胞中的重要治疗靶标。紫杉醇、长春碱等微管蛋白抑制剂已广泛用于治疗多种癌症。然而,他们显示出治疗窗窄、选择性差以及多药耐药性问题,通常是由于p-糖蛋白或多药耐药相关蛋白的高表达。因此,开发一种新型靶向微管、选择性好、低毒的小分子仍有很大需求(Pharm Res(2012)29:2943–2971)。
查尔酮衍生物是类黄酮中一类重要的化合物,分子结构简单,以1,3-二苯基丙烯酮为基本骨架,具有广泛的生物学活性,如抗肿瘤、抗菌、抗炎、抗结核等。新型吲哚查尔酮是本发明人前期研究发现的一类新型查尔酮衍生物,可使其抗肿瘤活性显著提高,进一步地对抗肿瘤作用机制研究,发现该类查尔酮衍生物作用于β-微管蛋白,有效诱导肿瘤细胞凋亡,阻滞肿瘤细胞周期于G2/M 期;其中,代表化合物α-甲基取代的吲哚查尔酮表现出优异的抑制亲代肿瘤细胞和多药耐药肿瘤细胞生长活性(Mol.Pharmaceutics 2018,15,3892-3900)。
发明内容
本发明的目的是提供一类微管靶向抗肿瘤活性的ɑ,β-不饱和酮衍生物;本发明的另一目的是提供该类ɑ,β-不饱和酮衍生物的制备方法;本发明的第三目的是提供该类ɑ,β-不饱和酮衍生物的应用。
为了实现上述目的,本发明提出一种ɑ,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物。
还有必要提出一种所述的通式(I)的化合物在制备微管抑制剂中的应用。
还有必要提出所述的通式(I)的化合物在***中的应用,包括对肿瘤细胞的杀伤作用,以及在治疗具有多药耐药的肿瘤疾病中的应用。
本发明的第一个方面提供了一种ɑ,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物,结构如通式Ⅰ所示:
其中A、B分别选自饱和环,芳环及芳杂环,饱和环或芳环及芳杂环并环;
R1分别选自氢、1~7个相同或不同C1-C10烷氧基;
R2分别选自氢、1~7个相同或不同C1-C10烷基、C1-C10烷氧基、卤素、氮氢元素组成的取代基、碳氢氧元素组成的取代基、氮氧元素组成的取代基;
R3分别选自氢、C1-C10烷基;以及与A组成多元环的-(CH2)n-,(n=1~10);
优选的,其中A、B分别选自饱和环,芳环及芳杂环,饱和环或芳环及芳杂环并环;
R1分别选自氢、A上不同位置取代的三甲氧基、二甲氧基、单甲氧基、
R2分别选自氢、B上不同位置单取代的甲氧基、甲基、氟、氯、溴、硝基、胺基、羧基、
R3分别选自氢、甲基、乙基、以及与A组成多元环的-(CH2)n-,(n=1~10);
优选的,
A选自
B选自
R1分别选自氢、A上不同位置取代的三甲氧基、二甲氧基、单甲氧基、
R2分别选自氢、B上不同位置单取代的甲氧基、甲基、氟、氯、溴、硝基、胺基、羧基、
R3分别选自氢、甲基、乙基、以及与A组成六元环的-CH2CH2-。
优选的,所述的药学上可接受的盐包括通式Ⅰ化合物与下列酸形成的酸加成盐:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸。
优选的,所述的ɑ,β-不饱和酮衍生物选自以下结构中的一种:
(E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(1)、
(E)-2-甲基-3-(5-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(2)、
(E)-2-甲基-3-(6-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(3)、
(E)-2-甲基-3-(7-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(4)、
(E)-3-(苯并[b]噻吩-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1- 酮(5)、
(E)-3-(5-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1- 酮(6)、
(E)-3-(6-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1- 酮(7)、
(E)-3-(5-氯-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1- 酮(8)、
(E)-3-(5-溴-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1- 酮(9)、
(E)-1-(3,5-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮(10)、
(E)-3-(1H-吲哚-3-基)-1-(5-甲氧基吡啶-3-基)-2-甲基丙-2-烯-1-酮(11)、
(E)-3-(6-甲氧基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2- 烯-1-酮(12)、
(E)-2-甲基-3-(5-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(13)、
(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(14)、
(E)-2-甲基-3-(7-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(15)、
(E)-3-(6-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(16)、
(E)-2-((1H-吲哚-3-基)亚甲基)-1-(3,4,5-三甲氧基苯基)丁-1-酮(17)、
(E)-1-(3,4-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮(18)、
(E)-3-(1H-吲哚-3-基)-1-(3-甲氧基苯基)-2-甲基丙-2-烯-1-酮(19)、
(E)-3-(1H-吲哚-3-基)-2-甲基-1-苯基丙-2-烯-1-酮(20)、
(E)-3-(1H-吲哚-3-基)-1-苯基丙-2-烯-1-酮(21)、
(E)-2-甲基-3-(1H-吡咯并[2,3-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙 -2-烯-1-酮(22)、
(E)-2-甲基-3-(1H-吡咯并[3,2-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙 -2-烯-1-酮(23)、
(E)-2-甲基-3-(1H-吡咯并[3,2-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(24)、
(E)-2-甲基-3-(1H-吡咯并[2,3-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙 -2-烯-1-酮(25)、
(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸甲酯(26)、
(E)-3-(1H-吲哚-3-基)-1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)-2- 甲基丙-2-烯-1-酮(27)、
(E)-3-(咪唑并[1,2-a]吡啶-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2- 烯-1-酮(28)、
(E)-2-甲基-3-(吡唑并[1,5-a]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2- 烯-1-酮(29)、
(E)-2-((1H-吲哚-3-基)亚甲基)-5-甲氧基-3,4-二氢萘-1(2H)-酮 (30)、
(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸(31)、
(E)-2-甲基-3-(1H-吡唑-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(32)、
(E)-2-甲基-3-(1H-吡咯-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(33)、
(E)-2-甲基-3-(喹啉-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(34)、
(E)-3-(1H-吲哚-2-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(35)、
(E)-2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯(36)、
(E)-3-(7-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(37)、
(E)-3-(5-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(38)、
本发明的第二个方面提供了上述结构通式(Ⅰ)所示化合物在***疾病中的应用。
本发明的第三个方面提供了所述的应用,具体是作为微管抑制剂抗肿瘤药物对肿瘤细胞的杀伤作用。所述的肿瘤为HCT-116(结肠癌细胞)、HCT-116/OXA (耐药结肠癌细胞)。
本发明的第三个方面提供了该类ɑ,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物的制备方法。
本发明中,“卤素”是指氟、氯、溴或碘代;“烷基”是指直链或支链的烷基;“芳杂基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系,环状体系是芳香性的,如吡咯基、吡唑基、咪唑基、吲哚基、喹啉基、苯并噻吩基、吡咯并吡啶基等;“杂环基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系,如哌嗪基、哌啶基、吡咯烷基、吡唑烷基等。
由于采用上述技术方案,本发明的有益效果体现在以下几方面:
本发明的ɑ,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物具有较好的抑制肿瘤细胞增殖的活性,可以有效抑制结肠癌、肺癌、白血病等常见肿瘤细胞以及耐药肿瘤细胞的增殖;本发明合成简单,未涉及繁琐步骤,合成成本低。
具体实施方式
本发明所用试剂和原料均市售可得或可按文献方法制备。
下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。所有原料未注明合成方法的均购自探索平台、阿拉丁、 Sigma-Aldrich等厂家,均为分析纯。
实施例1:(E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基) 丙-2-烯-1-酮(1)的制备
步骤a:1-(3,4,5-三甲氧基苯基)丙-1-醇的合成。
在0℃下,将3,4,5-三甲氧基苯甲醛(2g,10.19mmol)加入反应容器内,真空处理后加入THF(20mL)和乙基溴化镁(15mL),在无氧条件下反应4h,TLC 监测,用水和乙酸乙酯稀释,并用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,旋干有机相,剩余粗品通过硅胶柱色谱纯化(洗脱剂:乙酸乙酯/正己烷=1:4),得化合物1-(3,4,5-三甲氧基苯基)丙-1-醇2.13g,收率94%。
步骤b:1-(3,4,5-三甲氧基苯基)丙-1-酮的合成。
在室温下,将1-(3,4,5-三甲氧基苯基)丙-1-醇(746.6mg,3.30mmol)溶于CH2Cl2(10mL),加入PCC(1068mg,4.96mmol),N2保护下反应,TLC点板监测,然后用水稀释,CH2Cl2萃取,并用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,旋干有机相,剩余粗品通过硅胶柱色谱纯化(洗脱剂:石油醚/乙酸乙酯=5:1)得化合物1-(3,4,5-三甲氧基苯基)丙-1-酮690mg,收率93.2%。
步骤c:(E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基) 丙-2-烯-1-酮的合成。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(448mg,2mmol)溶于哌啶(0.1 mL)的甲苯(6mL)溶液中,加入4-甲基-1H-吲哚-3-甲醛(156.8mg,0.8mmol), 130℃反应4h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(1)230mg, 收率51.3%。1H NMR(300MHz,CDCl3)δ8.69(s,1H),7.97(s,1H),7.60(d,1H,J= 1.2Hz),7.26-7.29(m,1H),7.10-7.16(m,1H),6.89-6.95(m,3H),3.89-3.91(m,9H), 2.47(s,3H),2.29(s,3H).MS(ESI):m/z[M+H]+:366.17。
4-甲基-1H-吲哚-3-甲醛等原材料产品可在生物厂家直接购买得到,后续原材料获得途径也是已知的。
化合物2-4的制备参照实施例1。在步骤c中,制备化合物2、3、4时,将“4-甲基-1H-吲哚-3-甲醛”分别替换为“5-甲基-1H-吲哚-3-甲醛”、“6-甲基-1H- 吲哚-3-甲醛”、“7-甲基-1H-吲哚-3-甲醛”即可,且用量不变。
实施例2:(E)-3-(苯并[b]噻吩-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙 -2-烯-1-酮(5)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(448mg,2mmol)与苯并[b]噻吩-3-甲醛(162.2mg,1mmol)溶于乙醇(8mL)溶液中,室温搅拌30min,然后加入氢氧化钠(3mL)至反应完全,用CH2Cl2萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物 (E)-3-(苯并[b]噻吩-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮206.1 mg,收率56%。1H NMR(300MHz,CDCl3)δ7.91(s,1H),7.70(d,2H,J=13.2Hz), 7.44(d,3H,J=14.1Hz),7.09(s,2H),3.91-3.96(m,9H),2.35(s,3H).MS(ESI):m/z [M+H]+:369.12.
实施例3:(E)-3-(5-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基) 丙-2-烯-1-酮(6)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与5-氟-1H- 吲哚-3-甲醛(81.6mg,0.5mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL), 95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-3-(5- 氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮94.1mg,产率 51%1H NMR(300MHz,CDCl3)δ8.62(s,1H),7.67(s,1H),7.54(s,1H),7.36(dd, 1H,J=4.5,8.7Hz),7.20-7.26(m,1H),7.02(s,3H),3.90-3.96(m,9H),2.31(s,3H). MS(ESI):m/z[M+H]+:370.14。
化合物7-8的制备参照实施例3。即:生产化合物7、8时,分别用“6-氟-1H- 吲哚-3-甲醛”、“5-氯-1H-吲哚-3-甲醛”替代“5-氟-1H-吲哚-3-甲醛”即可实现,用量相同。
实施例4:(E)-3-(5-溴-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基) 丙-2-烯-1-酮(9)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(448mg,2mmol)溶于PhCH3(6 mL)、哌啶(0.12mL)中,加入5-溴-1H-吲哚-3-甲醛(149.2mg,0.66mmol),110℃反应4h,旋干有机相,剩余粗品经乙醇重结晶得化合物(E)-3-(5-溴-1H-吲哚 -3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮154.7mg,收率为54%。1H NMR(300MHz,CDCl3)δ8.61(s,1H),7.70(s,1H),7.62(s,1H),7.53(s,1H), 7.33-7.38(m,2H),7.03(s,2H),3.91-3.97(m,9H),2.30(s,3H)。
实施例5:(E)-1-(3,5-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯 -1-酮(10)的制备
参照实施例1制备中间体1-(3,5-二甲氧基苯基)丙-1-酮。
将中间体1-(3,5-二甲氧基苯基)丙-1-酮(200mg,1.03mmol)与1H-吲哚 -3-甲醛(49.8mg,0.323mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL), 95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-1-(3,5- 二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮56.1mg,产率51%。1H NMR(300MHz,CDCl3)δ8.73(s,1H),7.70(s,1H),7.63(s,1H),7.56(d,1H,J=7.8 Hz),7.43(d,1H,J=7.8Hz),7.16-7.21(m,1H,),6.86(s,3H),6.64(s,1H),3.83(s,6H), 2.31(s,3H).MS(ESI):m/z[M+H]+:322.14。
实施例6:(E)-3-(1H-吲哚-3-基)-1-(5-甲氧基吡啶-3-基)-2-甲基丙-2- 烯-1-酮(11)的制备
参照实施例1制备中间体1-(5-甲氧基吡啶-3-基)丙-1-酮。
将中间体1-(5-甲氧基吡啶-3-基)丙-1-酮(200mg,1.21mmol)与1H-吲哚 -3-甲醛(58.5mg,0.403mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL), 95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-3-(1H- 吲哚-3-基)-1-(5-甲氧基吡啶-3-基)-2-甲基丙-2-烯-1-酮54.3mg,产率46%。1H NMR(300MHz,CDCl3)δ8.93(s,1H),8.51(d,2H,J=18.0Hz),7.67(s,2H),7.53 (d,2H,J=9.0Hz),7.44(d,1H,J=9.0Hz),7.30(s,1H),7.15-7.20(m,1H),3.93(s,3H), 2.32(s,3H).MS(ESI):m/z[M+H]+:293.13。
实施例7:(E)-3-(6-甲氧基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(12)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与6-甲氧基-1H-吲哚-3-甲醛(87.5mg,0.5mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3 mL),95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E) -3-(6-甲氧基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮120 mg,产率63%。1H NMR(600MHz,CDCl3)δ8.47(s,1H),7.62(s,1H),7.52(d,1H, J=2.4Hz),7.45(s,1H),7.43(s,1H),7.02(s,1H),6.91(d,1H,J=2.4Hz),6.85-6.86 (dd,1H,J=2.4,9.0Hz),3.95(s,3H),3.89(s,6H),3.86(s,3H),2.30(d,3H,J=0.6Hz). MS(ESI):m/z[M+H]+:382.16。
化合物26、31的制备参照实施例7。即:与实施例7相同的投料比例相同的反应条件,“1-(3,4,5-三甲氧基苯基)丙-1-酮”与“3-甲酰基-1H-吲哚-6-羧酸甲酯”反应得到化合物26;“1-(3,4,5-三甲氧基苯基)丙-1-酮”与“3-甲酰基-1H- 吲哚-6-羧酸”得到化合物31。
实施例8:(E)-2-甲基-3-(5-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基) 丙-2-烯-1-酮(13)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与5-硝基-1H- 吲哚-3-甲醛(102.9mg,0.5mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL), 95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-2-甲基-3-(5-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮84.5mg,产率41%。1H NMR(300MHz,DMSO-d6)δ12.50(s,1H),8.49(s,1H),8.07-8.13(d, 2H),7.65(d,2H,J=9.0Hz),7.04(s,2H),3.78-3.84(m,9H),2.23(s,3H).13C NMR (150MHz,DMSO-d6)δ162.66,159.45,156.50,149.49,146.64,138.11,137.52, 134.69,133.86,128.68,128.47,128.24,123.98,121.33,120.19,117.82,116.06, 114.97,74.44,67.77,46.02.MS(ESI):m/z[M+H]+:367.17。
化合物14-15的制备参照实施例8。即:生产化合物14、15时,分别用“6- 硝基-1H-吲哚-3-甲醛”、“7-硝基-1H-吲哚-3-甲醛”替代“5-硝基-1H-吲哚-3-甲醛”即可实现,用量相同。
实施例9:(E)-3-(6-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基) 丙-2-烯-1-酮(16)的制备
参照实施例8制备(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮。
将(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2- 烯-1-酮(100mg,0.25mmol)溶于乙醇/水(5:1)中,加入NH4Cl(53.9mg,1mmol),搅拌下加入铁粉(56mg,1mmol),升温至55℃,TLC点板监测至反应完全。用硅藻土过滤,CH2Cl2萃取,并用饱和氯化钠洗涤,无水硫酸钠干燥,过滤,旋干有机相,得到目标化合物(E)-3-(6-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮56.6mg,收率62%。1H NMR(300MHz,CDCl3)δ11.35(s, 1H),7.54(s,2H),7.08(d,1H,J=3.0Hz),6.92(s,2H),6.60(d,2H,J=3.0Hz), 6.47-6.48(m,1H),4.89(s,1H),3.77-3.80(m,9H),2.16(s,3H).MS(ESI):m/z[M+H]+: 367.16。
化合物37-38的制备参照实施例9。即:与实施例9相同的投料比例相同的反应条件,“(E)-2-甲基-3-(7-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙 -2-烯-1-酮”与“NH4Cl、铁粉”反应得到化合物37;“(E)-2-甲基-3-(5-硝基-1H- 吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮”与“NH4Cl、铁粉”反应得到化合物38。
实例10:(E)-2-((1H-吲哚-3-基)亚甲基)-1-(3,4,5-三甲氧基苯基)丁 -1-酮(17)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丁-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丁-1-酮(200mg,0.84mmol)与1H-吲哚-3-甲醛(40.6mg,0.28mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL), 95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-2- ((1H-吲哚-3-基)亚甲基)-1-(3,4,5-三甲氧基苯基)丁-1-酮43.9mg,产率43%。1H NMR(300MHz,CDCl3)δ8.60(s,1H),7.64(s,1H),7.54-7.57(m,2H),7.44(d,1H,J =8.1Hz),7.30(s,1H),7.16-7.21(m,1H),7.03(s,2H),3.89-3.95(m,9H),2.83(d,2H, J=7.5Hz),1.59(s,3H).MS(ESI):m/z[M+H]+:366.17。
实例11:(E)-1-(3,4-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1- 酮(18)的制备
参照实施例1制备中间体1-(3,4-二甲氧基苯基)丙-1-酮。
将中间体1-(3,4-二甲氧基苯基)丙-1-酮(200mg,1.03mmol)与1H-吲哚-3-甲醛(49.82mg,0.34mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL), 95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-1-(3,4- 二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮57.4mg,产率52%。1H NMR(300MHz,CDCl3)δ8.72(s,1H),7.57-7.62(m,3H),7.40-7.45(m,3H),7.30(s, 1H),7.16-7.21(m,1H),6.93(d,1H,J=8.1Hz),3.96(d,6H,J=13.2Hz),2.32(s,3H). MS(ESI):m/z[M+H]+:322.14。
实例12:(E)-3-(1H-吲哚-3-基)-1-(3-甲氧基苯基)-2-甲基丙-2-烯-1-酮(19)的制备
参照实施例1制备中间体1-(3-甲氧基苯基)丙-1-酮。
将中间体1-(3-甲氧基苯基)丙-1-酮(200mg,1.22mmol)与1H-吲哚-3- 甲醛(58.94mg,0.41mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL),95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-1-(E)-3- (1H-吲哚-3-基)-1-(3-甲氧基苯基)-2-甲基丙-2-烯-1-酮54.4mg,产率46%。1H NMR(300MHz,CDCl3)δ8.72(s,1H),7.65(d,2H,J=12.3Hz),7.53(d,1H,J= 7.8Hz),7.36-7.44(m,2H),7.26-7.31(m,3H,J=15.0Hz),7.08-7.20(m,2H),3.86(s, 3H),2.31(s,3H).MS(ESI):m/z[M+H]+:292.13。
实例13:(E)-3-(1H-吲哚-3-基)-2-甲基-1-苯基丙-2-烯-1-酮(20)的制备
参照实施例1制备中间体苯丙酮。
将中间体苯丙酮(200mg,1.49mmol)与1H-吲哚-3-甲醛(72.12mg,0.50 mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL),95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-3-(1H-吲哚-3-基)-2-甲基 -1-苯基丙-2-烯-1-酮74.0mg,产率57%。1HNMR(600MHz,CDCl3)δ8.76(s,1H), 7.73-7.75(m,2H),7.62-7.64(m,2H),7.55-7.57(m,1H),7.47-7.52(m,3H),7.42(d, 1H,J=7.8Hz),7.25-7.28(m,1H),7.15-7.18(m,1H),2.33(s,3H).MS(ESI):m/z [M+H]+:262.12。
实例14:(E)-3-(1H-吲哚-3-基)-1-苯基丙-2-烯-1-酮(21)的制备
将苯乙酮(200mg,1.66mmol)与1H-吲哚-3-甲醛(72.12mg,0.55mmol) 溶于乙醇(5mL)溶液中,加入哌啶(0.3mL),95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-3-(1H-吲哚-3-基)-1-苯基丙-2-烯 -1-酮75.5mg,产率55%。1H NMR(300MHz,CDCl3)δ8.54(s,1H),8.03-8.14(m, 4H),7.45-7.63(m,6H),7.31-7.34(m,2H).MS(ESI):m/z[M+H]+:248.11。
实施例15:(E)-2-甲基-3-(1H-吡咯并[2,3-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(22)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(448mg,2mmol)溶于甲苯(6 mL)、哌啶(0.12mL)中,加入1H-吡咯并[2,3-b]吡啶-3-甲醛(97.32mg,0.66mmol),110℃反应4h,过滤,经乙醇重结晶得化合物(E)-2-甲基-3-(1H-吡咯并[2,3-b] 吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮96.2mg,收率为41%。
化合物23-25的制备参照实施例15。即:与实施例15相同的投料比例相同的反应条件,“1-(3,4,5-三甲氧基苯基)丙-1-酮”与“1H-吡咯并[3,2-c]吡啶-3- 甲醛”反应得到化合物23;“1-(3,4,5-三甲氧基苯基)丙-1-酮”与“1H-吡咯并[3,2-b] 吡啶-3-甲醛”反应得到化合物24;“1-(3,4,5-三甲氧基苯基)丙-1-酮”与“1H- 吡咯并[2,3-c]吡啶-3-甲醛”反应得到化合物25。
实施例16:(E)-3-(1H-吲哚-3-基)-1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基丙-2-烯-1-酮(27)的制备
参照实施例1制备中间体1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)丙 -1-酮。
将中间体1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)丙-1-酮(200mg,0.96mmol)与1H-吲哚-3-甲醛(46.48mg,0.32mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL),95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-3-(1H-吲哚-3-基)-1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基) -2-甲基丙-2-烯-1-酮54.8mg,产率51%。1HNMR(300MHz,CDCl3)δ8.66(s,1H), 7.59-7.62(m,3H),7.44(d,1H,J=7.8Hz),7.28-7.31(m,1H),7.17-7.22(m,1H),7.06 (s,1H),6.99(s,1H),6.09(s,2H),3.93(s,3H),2.30(s,3H).MS(ESI):m/z [M+H]+:336.12。
实施例17:(E)-3-(咪唑并[1,2-a]吡啶-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(28)的制备
参照实施例1制备中间体1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)丙 -1-酮。
将中间体1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)丙-1-酮(200mg,0.89mmol)与1,8a二氢咪唑并[1,2-a]吡啶-3-甲醛(44.05mg,0.30mmol)溶于乙醇 (5mL)溶液中,加入哌啶(0.3mL),95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-3-(咪唑并[1,2-a]吡啶-3-基)-2-甲基-1-(3,4,5- 三甲氧基苯基)丙-2-烯-1-酮53.7mg,产率51%。1H NMR(300MHz,CDCl3)δ8.09(s,1H),7.99(d,1H,J=6.6Hz),7.74(d,1H,J=9.0Hz),7.32-7.38(m,2H),7.26 (s,1H),6.93-6.99(m,2H),3.89-3.95(m,9H),2.39(s,3H).MS(ESI):m/z [M+H]+:353.15。
化合物29的制备参照实施例17。即:与实施例17相同的投料比例相同的反应条件,“1-(3,4,5-三甲氧基苯基)丙-1-酮”与“吡唑并[1,5-a]吡啶-3-甲醛”反应得到化合物29。
实施例18:(E)-2-((1H-吲哚-3-基)亚甲基)-5-甲氧基-3,4-二氢萘-1(2H) -酮(30)的制备
将5-甲氧基-3,4-二氢萘-1(2H)-酮(200mg,1.13mmol)与1H-吲哚-3-甲醛(54.92mg,0.38mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL),95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-2-((1H-吲哚-3-基)亚甲基)-5-甲氧基-3,4-二氢萘-1(2H)-酮(30)59.7mg,产率52%。1H NMR(300MHz,CDCl3)δ8.55(s,1H),8.25(s,1H),7.89(d,1H,J=7.5Hz),7.78 (d,1H,J=7.8Hz),7.55(s,1H),7.43(d,2H,J=7.5Hz),7.30-7.35(m,2H),7.04(d,1H, J=8.1Hz),3.89(s,3H)2.97-3.13(m,4H).MS(ESI):m/z[M+H]+:304.13。
实施例19:(E)-2-甲基-3-(1H-吡唑-3-基)-1-(3,4,5-三甲氧基苯基)丙-2- 烯-1-酮(32)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与1H-吡唑 -3-甲醛(48.0mg,0.5mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL),95℃搅拌48h,旋干,经乙醇重结晶得到目标化合物(E)-2-甲基-3-(1H-吡唑-3-基) -1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮66.4mg,产率44%。1H NMR(300MHz,CDCl3) δ8.11(s,1H),7.66(s,1H),7.18(s,1H),6.98(s,2H),6.63(s,1H),3.88-3.92(m,9H), 2.34(s,3H)。
实施例20:(E)-2-甲基-3-(1H-吡咯-3-基)-1-(3,4,5-三甲氧基苯基)丙-2- 烯-1-酮(33)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与1H-吡咯 -3-甲醛(47.5mg,0.5mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL),95℃搅拌48h,旋干,经乙醇重结晶得到目标化合物(E)-2-甲基-3-(1H-吡咯-3-基) -1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮64.5mg,产率43%。1H NMR(300MHz,CDCl3) δ8.56(s,1H),7.23(s,1H),7.09(s,1H),6.88-6.92(m,3H),6.52(s,1H),3.88-3.96 (m,9H),2.25(s,3H)。
实施例21:(E)-2-甲基-3-(喹啉-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯 -1-酮(34)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(448mg,2mmol)与喹啉-3-甲醛(47.5mg,1mmol)溶于乙醇(8mL)中,室温搅拌30min,然后加入氢氧化钠(3mL)至反应完全,用CH2Cl2萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,旋干有机相,经乙醇重结晶得到目标化合物(E)-2-甲基-3-(喹啉-3- 基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮85.1mg,收率47%。1H NMR(300MHz, CDCl3)δ8.97(s,1H),8.29(s,1H),8.18-8.21(m,1H),7.90(d,1H,J=8.1Hz), 7.78-7.83(m,1H,),7.61-7.66(m,1H),7.28(s,1H),7.07(s,2H),3.91-3.95(m,9H), 2.38(s,3H).MS(ESI):m/z[M+H]+:364.15。
实施例22:(E)-3-(1H-吲哚-2-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2- 烯-1-酮(35)的制备
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与1H-吲哚 -2-甲醛(72.5mg,0.5mmol)溶于乙醇(5mL)溶液中,加入哌啶(0.3mL),95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E)-3-(1H- 吲哚-2-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮82.5mg,产率47%。1H NMR(300MHz,CDCl3)δ8.30(s,1H),7.66(d,1H,J=7.2Hz),7.38(s,2H),7.20 (s,2H),6.97(s,2H),6.89(s,1H),3.89-3.94(m,9H),2.43(s,3H)。
实施例23:(E)-2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯(36)的制备
合成路线如下:
步骤a:4-((叔丁基二甲基硅烷基)氧基)-3,5-二甲氧基苯甲醛的合成。
将4-羟基-3,5-二甲氧基苯甲醛(10g,54.89mmol)和咪唑(14.95g,219.6 mmol)溶于DMF(100mL)中,在0℃下加入TBSCl(16.55g,109.8mmol),TLC 监测至反应完全,用水猝灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,旋干有机相,剩余粗品通过硅胶柱色谱纯化(洗脱剂:石油醚/ 乙酸乙酯=10:1),得化合物4-((叔丁基二甲基硅烷基)氧基)-3,5-二甲氧基苯甲醛11.37g,收率70%。
步骤b、c参照实施例1中的步骤a、b。
步骤d:1-(4-羟基-3,5-二甲氧基苯基)丙-1-酮的合成。
将1-(4-((叔丁基二甲基硅烷基)氧基)-3,5-二甲氧基苯基)丙-1-酮 (2.32g,7.15mmol)溶于THF(30mL),在0℃下加入TBAF(7.5mL),N2保护下反应2h,TLC监测至反应完全,用水猝灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,旋干有机相,剩余粗品通过硅胶柱色谱纯化(洗脱剂:石油醚/乙酸乙酯=1:1),得化合物1-(4-羟基-3,5-二甲氧基苯基)丙-1- 酮1.34g,收率89%。
步骤e:2-(2,6-二甲氧基-4-丙酰基苯氧基)乙酸乙酯的合成。
将1-(4-羟基-3,5-二甲氧基苯基)丙-1-酮(266mg,1.27mmol)、碳酸钾(351.9 mg,2.55mmol)、2-溴乙酸乙酯(425.1mg,2.55mmol)溶于DMF(6mL)中, TLC监测至反应完全,用水猝灭,乙酸乙酯萃取,氯化钠洗涤,无水硫酸钠干燥,通过硅胶柱色谱纯化(洗脱剂:石油醚/乙酸乙酯=10:1),得化合物2-(2,6-二甲氧基-4-丙酰基苯氧基)乙酸乙酯296.2mg,收率79%。
步骤f:(E)-2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯的合成。
将中间体2-(2,6-二甲氧基-4-丙酰基苯氧基)乙酸乙酯(460mg,1.55mmol) 与1H-吲哚-3-甲醛(75.1mg,0.5mmol)溶于乙醇(10mL)溶液中,加入哌啶(0.6 mL),95℃搅拌48h,旋干有机相,剩余粗品经乙醇重结晶得到目标化合物(E) -2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯100.7 mg,收率46%。1H NMR(300MHz,CDCl3)δ8.61(s,1H),7.66(s,2H),7.57(s,1H), 7.43(s,1H),7.21(s,2H),7.01(s,1H),4.70-4.74(m,2H),4.30(d,2H,J=7.2Hz), 3.87-3.90(m,6H),2.31(s,3H),1.25(s,3H)。
实施例24:本发明化合物的体外抗肿瘤活性测试
采用了CellTiter-Blue法,测试了本发明合成化合物和部分中间体的体外抗肿瘤活性。
实验方法:HCT-116(结肠癌细胞)、HCT-116/OXA(耐药结肠癌细胞),用 RPMI+10%FBS+1%双抗培养。
样品液配制:用DMSO溶解,配成浓度为50μM的母液。然后用含1%DMSO 的培养基稀释(三倍或五倍稀释),最终配成系列梯度浓度溶液。
96孔板每孔加4000-8000个细胞,置于37℃、5%CO2培养箱内孵育24小时后,分别加入样品液和对照品液,200μL/孔,37℃作用72小时。每孔加入的 CellTiter-Blue(荧光蓝细胞活性试剂盒)溶液20μL,作用0.5-1小时后用全自动酶标仪(生产厂商LabsystemsDragon)测570/590nm OD值,计算半数抑制浓度 IC50。
使用GraphPad Prism软件分析处理数据,最终测得化合物IC50值。
根据以上的体外抗肿瘤活性测试方法对本发明的化合物进行体外抗肿瘤活性研究:
选取了2种肿瘤细胞株研究目标化合物的体外抗肿瘤活性:HCT-116(结肠癌细胞)、HCT-116/OXA(耐药结肠癌细胞)。选用CellTiter-Blue法进行活性测试,结果显示,化合物对结肠癌及其耐药细胞株均表现出较好的抗肿瘤活性,尤其对耐药白血病细胞表现出更好的抗肿瘤活性。其中活性最好的衍生物主要有2个:化合物6和7,IC50值都在10nM以下。但是苯环上无甲氧基取代的化合物活性显著降低,如化合物20和21;吲哚环上的溴取代、羧基取代后,活性也显著降低,如化合物9、31。
表1.目标化合物对结肠癌(HCT-116)及耐药结肠癌(HCT-116/OXA)细胞的IC50值
综上,因此本发明化合物及其盐类可以用于制备抗抗肿瘤药物。
以上已对本发明创造的较佳实施例进行了具体说明,但本发明创造并不限于所述实施例,熟悉本领域的技术人员在不违背本发明创造精神的前提下还可作出种种的等同的变型或替换,这些等同的变型或替换均包含在本申请权利要求所限定的范围内。
Claims (7)
1.一类ɑ,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物,其特征在于结构如通式Ⅰ所示:
其中A、B分别选自饱和环,芳环及芳杂环,饱和环或芳环及芳杂环并环;
R1分别选自氢、1~7个相同或不同C1-C10烷氧基;
R2分别选自氢、1~7个相同或不同C1-C10烷基、C1-C10烷氧基、卤素、氮氢元素组成的取代基、碳氢氧元素组成的取代基、氮氧元素组成的取代基;
R3分别选自氢、C1-C10烷基;以及与A组成多元环的-(CH2)n-,(n=1~10)。
2.如权利要求1所述的一类ɑ,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物,其特征在于:
其中A、B分别选自饱和环,芳环及芳杂环,饱和环或芳环及芳杂环并环;
R1分别选自氢、A上不同位置取代的三甲氧基、二甲氧基、单甲氧基、
R2分别选自氢、B上不同位置单取代的甲氧基、甲基、氟、氯、溴、硝基、胺基、羧基、
R3分别选自氢、甲基、乙基、以及与A组成多元环的-(CH2)n-,(n=1~10)。
3.如权利要求1所述的一类ɑ,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物,其特征在于:
A选自
B选自
R1分别选自氢、A上不同位置取代的三甲氧基、二甲氧基、单甲氧基、
R2分别选自氢、B上不同位置单取代的甲氧基、甲基、氟、氯、溴、硝基、胺基、羧基、
R3分别选自氢、甲基、乙基、以及与A组成六元环的-CH2CH2-。
4.如权利要求3的ɑ,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物,其特征在于:所述结构通式(Ⅰ)所示化合物,其药学上可接受的盐包括通式I化合物与下列酸形成的酸加成盐:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸。
5.根据权利要求4所述的ɑ,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物,其特征在于:所述的ɑ,β-不饱和酮衍生物选自以下结构中的一种:
(E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(1)、
(E)-2-甲基-3-(5-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(2)、
(E)-2-甲基-3-(6-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(3)、
(E)-2-甲基-3-(7-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(4)、
(E)-3-(苯并[b]噻吩-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(5)、
(E)-3-(5-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(6)、
(E)-3-(6-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(7)、
(E)-3-(5-氯-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(8)、
(E)-3-(5-溴-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(9)、
(E)-1-(3,5-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮(10)、
(E)-3-(1H-吲哚-3-基)-1-(5-甲氧基吡啶-3-基)-2-甲基丙-2-烯-1-酮(11)、
(E)-3-(6-甲氧基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(12)、
(E)-2-甲基-3-(5-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(13)、
(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(14)、
(E)-2-甲基-3-(7-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(15)、
(E)-3-(6-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(16)、
(E)-2-((1H-吲哚-3-基)亚甲基)-1-(3,4,5-三甲氧基苯基)丁-1-酮(17)、
(E)-1-(3,4-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮(18)、
(E)-3-(1H-吲哚-3-基)-1-(3-甲氧基苯基)-2-甲基丙-2-烯-1-酮(19)、
(E)-3-(1H-吲哚-3-基)-2-甲基-1-苯基丙-2-烯-1-酮(20)、
(E)-3-(1H-吲哚-3-基)-1-苯基丙-2-烯-1-酮(21)、
(E)-2-甲基-3-(1H-吡咯并[2,3-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(22)、
(E)-2-甲基-3-(1H-吡咯并[3,2-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(23)、
(E)-2-甲基-3-(1H-吡咯并[3,2-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(24)、
(E)-2-甲基-3-(1H-吡咯并[2,3-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(25)、
(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸甲酯(26)、
(E)-3-(1H-吲哚-3-基)-1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基丙-2-烯-1-酮(27)、
(E)-3-(咪唑并[1,2-a]吡啶-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(28)、
(E)-2-甲基-3-(吡唑并[1,5-a]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(29)、
(E)-2-((1H-吲哚-3-基)亚甲基)-5-甲氧基-3,4-二氢萘-1(2H)-酮(30)、
(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸(31)、
(E)-2-甲基-3-(1H-吡唑-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(32)、
(E)-2-甲基-3-(1H-吡咯-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(33)、
(E)-2-甲基-3-(喹啉-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(34)、
(E)-3-(1H-吲哚-2-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(35)、
(E)-2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯(36)、
(E)-3-(7-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(37)、
(E)-3-(5-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(38)。
6.如权利要求1所述的通式(I)的化合物在制备微管抑制剂中的应用。
7.如权利要求1所述的通式(I)的化合物在***中的应用,包括对肿瘤细胞的杀伤作用,以及在治疗具有多药耐药的肿瘤疾病中的应用。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995014003A1 (fr) * | 1993-11-17 | 1995-05-26 | Kyowa Hakko Kogyo Co., Ltd. | Derive de propenone |
CN1172476A (zh) * | 1995-12-01 | 1998-02-04 | 协和发酵工业株式会社 | 丙烯酮衍生物 |
US5952355A (en) * | 1993-11-17 | 1999-09-14 | Kyowa Hakko Kogyo Co., Ltd. | Propenone derivatives |
CN101288402A (zh) * | 2008-06-18 | 2008-10-22 | 四川大学 | 氮杂查尔酮类化合物作为农用杀菌剂的新用途 |
CN109535068A (zh) * | 2018-12-26 | 2019-03-29 | 中国药科大学 | 吡啶取代查尔酮类化合物或其可药用的盐及其制备方法和用途 |
-
2019
- 2019-07-26 CN CN201910679937.9A patent/CN110526854B/zh active Active
-
2020
- 2020-07-13 WO PCT/CN2020/101590 patent/WO2021017795A1/zh active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995014003A1 (fr) * | 1993-11-17 | 1995-05-26 | Kyowa Hakko Kogyo Co., Ltd. | Derive de propenone |
US5952355A (en) * | 1993-11-17 | 1999-09-14 | Kyowa Hakko Kogyo Co., Ltd. | Propenone derivatives |
CN1172476A (zh) * | 1995-12-01 | 1998-02-04 | 协和发酵工业株式会社 | 丙烯酮衍生物 |
CN101288402A (zh) * | 2008-06-18 | 2008-10-22 | 四川大学 | 氮杂查尔酮类化合物作为农用杀菌剂的新用途 |
CN109535068A (zh) * | 2018-12-26 | 2019-03-29 | 中国药科大学 | 吡啶取代查尔酮类化合物或其可药用的盐及其制备方法和用途 |
Non-Patent Citations (2)
Title |
---|
JUN YAN等: "Synthesis, Evaluation, and Mechanism Study of Novel Indole-Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo" * |
YASUAKI TATSUMI等: "Enhancement of in vivo Antitumor Activity of a Novel Antimitotic 1-Phenylpropenone Derivative, AM-132, by Tumor Necrosis Factor-α or Interleukin-6" * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11731939B1 (en) | 2023-03-07 | 2023-08-22 | King Faisal University | Indole-based chalcone compounds as antibacterial agents |
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