CN114206904A - 选择性bcrp/abcg2转运蛋白抑制剂作为消除抗癌药物耐药性的药物 - Google Patents
选择性bcrp/abcg2转运蛋白抑制剂作为消除抗癌药物耐药性的药物 Download PDFInfo
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- CN114206904A CN114206904A CN202080053589.5A CN202080053589A CN114206904A CN 114206904 A CN114206904 A CN 114206904A CN 202080053589 A CN202080053589 A CN 202080053589A CN 114206904 A CN114206904 A CN 114206904A
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- oxo
- oxy
- chromene
- bromophenyl
- carbonylamino
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/66—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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Abstract
Description
本发明涉及新化合物、其生产方法及其作为BCRP/ABCG2抑制剂的用途。
这些新的有机化合物均属于同一化学家族,这一同一化学家族源自天然化合物:色酮。
他们的主要目的是选择性地抑制BCRP蛋白(乳腺癌耐药蛋白),也称为ABCG2,它涉及肿瘤对抗癌剂的多药耐药现象。BCRP充当外排泵并在肿瘤细胞膜中过度表达。这些化合物充当BCRP/ABCG2的选择性、非细胞毒性抑制剂。
最后,与参考化合物Ko143相比,这些化合物具有更好的抑制活性和更好的选择性,并且细胞毒性更小,同时具有更简单的有机合成。在临床上,这些化合物可以作为佐剂与抗癌药物联合使用,以增强后者的作用并抵消肿瘤对根除它们的治疗的抵抗力。
据世界卫生组织称,癌症是世界上第二大死因,每年造成近960万人死亡。2010年该疾病的年度治疗费用估计达到11,600亿美元。目前,根据癌症的阶段和类型,治疗癌症的主要策略有3种:1)手术、2)放疗和3)化疗。应该注意的是,这些策略可以相互补充使用,以补充治疗的整体有效性。
然而,在化疗中,重复使用相同的抗癌剂会导致肿瘤细胞以保护性和防御性的方式对其产生反应。不幸的是,这也会导致肿瘤对多种抗癌药物不敏感,使化疗无效并增加对患者的伤害。肿瘤细胞建立的防御之一包括跨膜蛋白,称为ATP结合盒(ABC)转运蛋白在细胞膜中的过度表达。(Borst,P.;Elferink,R.O.Mammalian ABC Transporters in Healthand Disease.Annu.Rev.Biochem.2002,71(1),537-592.Linton,K.J.Structure andFunction of ABC Transporters.Physiology 2007,22(2),122-130.Sharom,F.J.ABCMultidrug Transporters:Structure,Function and Role in Chemoresistance.Pharmacogenomics 2008,9(1),105-127.)。
已明确确定该超家族中48种跨膜蛋白中的3种在化疗失败中起主要作用:P-gp/ABCB1、MRP1/ABCC1和BCRP/ABCG2(Leslie,E.M.;Deeley,R.G.;Cole,S.P.C.MultidrugResistance Proteins:Role of P-Glycoprotein,MRP1,MRP2,and BCRP(ABCG2)in TissueDefense.Toxicol.Appl.Pharmacol.2005,204(3),216-237.Eckford,P.D.W.;Sharom,F.J.ABC Efflux Pump-Based Resistance to Chemotherapy Drugs.Chem.Rev.2009,109(7),2989-3011.)。
它们允许运输多种化合物,并且天然存在于我们体内的大多数细胞膜和生理屏障中。因此,它们在健康人中的生理作用是防御和保护细胞器和组织免受外源性和/或异型生物质的侵害。然而,已经表明这些ABC转运蛋白极大地改变了活性成分的吸收、分布、代谢和消除。(Sharom,F.J.ABC Multidrug Transporters:Structure,Function and Role in Chemoresistance.Pharmacogenomics 2008,9(1),105-127.)
总之,这些功能使这三种转运蛋白成为寻找可行的治疗解决方案来抑制化学抗性问题过程中的有效的、新颖的和主要的治疗靶点。(Bugde,P.;Biswas,R.;Merien,F.;Lu,J.;Liu,D.-X.;Chen,M.;Zhou,S.;Li,Y.The Therapeutic Potential of Targeting ABCTransporters to Combat Multi-Drug Resistance.Expert Opin.Ther.Targets 2017,21(5),511-530.)
Ko143是一种多环有机分子,包含3个不对称中心,目前在研究中用作BCRP的参考抑制剂。然而,其优化的5步合成很繁琐,总产率为5%,并且对3个不对称中心的控制仍然是一个限制参数(Li,Y.;Hayman,E.;Plesescu,M.;Prakash,S.R.Synthesis of Potent BCRPInhibitor-Ko143.Tetrahedron Lett.2008,49(9),1480-1483.)
尽管该化合物的活性良好(50%抑制浓度,IC50=0.09μM±0.01),但其溶解度相对较低,影响了其生物利用度。临床研究表明,Ko143通过其叔丁酯的水解迅速代谢(60分钟),产生一种无活性的代谢物。(Liu,K.;Zhu,J.;Huang,Y.;Li,C.;Lu,J.;Sachar,M.;Li,S.;Ma,X.Metabolism of KO143,an ABCG2inhibitor.Drug Metab.Pharmacokinet.2017,32(4),193-200.)因此停止了临床研究。最后,该化合物在开始时对BCRP具有选择性,最终发现对ABCG2没有选择性(Weidner,L.D.;Zoghbi,S.S.;Lu,S.;Shukla,S.;Ambudkar,S.V.;Pike,V.W.;Mulder,J.;Gottesman,M.M.;Innis,R.B.;Hall,M.D.The Inhibitor Ko143 IsNot Specific for ABCG2.J.Pharmacol.Exp.Ther.2015,354(3),384-393.Allen,J.D.;van Loevezijn,A.;Lakhai,J.M.;van der Valk,M.;van Tellingen,O.;Reid,G.;Schellens,J.H.M.;Koomen,G.-J.;Schinkel,A.H.Potent and Specific Inhibition ofthe Breast Cancer Resistance Protein Multidrug Transporter in Vitro and inMouse Intestine by a Novel Analogue of Fumitremorgin C.Mol.Cancer Ther.2002,1(6),417.)
本申请人过去开发了一种称为MBL-II-141的抑制剂,该抑制剂是选择性的、无毒的并且在临床前模型中具有良好的活性。(Honorat,M.;Guitton,J.;Gauthier,C.;Bouard,C.;Lecerf-Schmidt,F.;Peres,B.;Terreux,R.;Gervot,H.;Rioufol,C.;Boumendjel,A.;et al.MBL-II-141,a Chromone Derivative,Enhances Irinotecan(CPT-11)AnticancerEfficiency in ABCG2-Positive Xenografts.Oncotarget 2014,5(23),11957-11970.Hénin,E.;Honorat,M.;Guitton,J.;Di Pietro,A.;Payen,L.;Tod,M.PharmacokineticInteractions in Mice between Irinotecan and MBL-II-141,an ABCG2 Inhibitor:Irinotecan MBLI-II-141Interaction.Biopharm.Drug Dispos.2017.Valdameri,G.;Genoux-Bastide,E.;Peres,B.;Gauthier,C.;Guitton,J.;Terreux,R.;Winnischofer,S.M.B.;Rocha,M.E.M.;Boumendjel,A.;Di Pietro,A.Substituted Chromones as HighlyPotent Nontoxic Inhibitors,Specific for the Breast Cancer ResistanceProtein.J.Med.Chem.2012,55(2),966-970.Lecerf-Schmidt,F.;Peres,B.;Valdameri,G.;Gauthier,C.;Winter,E.;Payen,L.;Di Pietro,A.;Boumendjel,A.ABCG2:RecentDiscovery of Potent and Highly Selective Inhibitors.Future Med.Chem.2013,5(9),1037-1045.Winter,E.;Lecerf-Schmidt,F.;Gozzi,G.;Peres,B.;Lightbody,M.;Gauthier,C.;Ozvegy-Laczka,C.;Szakacs,G.;Sarkadi,B.;Creczynski-Pasa,T.B.;etal.Structure-Activity Relationships of Chromone Derivatives toward theMechanism of Interaction with and Inhibition of Breast Cancer ResistanceProtein ABCG2.J.Med.Chem.2013,56(24),9849-9860.Pires,A.do R.A.;Lecerf-Schmidt,F.;Guragossian,N.;Pazinato,J.;Gozzi,G.J.;Winter,E.;Valdameri,G.;Veale,A.;Boumendjel,A.;Di Pietro,A.;et al.New,Highly Potent and Non-Toxic,Chromone Inhibitors of the Human Breast Cancer Resistance ProteinABCG2.Eur.J.Med.Chem.2016,122,291-301.)。现已发现,在这份最新出版物中用作合成中间体的化合物是乳腺癌多药耐药蛋白(乳腺癌耐药蛋白BCRP/ABCG2)的抑制剂。
由于市场上缺乏快速更新的抗癌剂,化学耐药性问题日益增多。为了应对缺乏新的抗癌药物,将自己的重心着眼于耐药问题的根源是一种可行且经济的解决方案。事实上,抑制肿瘤细胞保护和保护自己的能力可以保留当前抗癌药物的功效并限制其有效剂量,这反过来又限制了它们的副作用以及患者和社会的总体化疗成本。此外,找到比MBL-II-141和Ko143更有效的新化合物将会是一件非常有趣的事情。
本发明涉及式(I)所示化合物:
[化学式1]
或其药学上可接受的对映异构体、盐或溶剂化物,或其混合物,
其中:
环A未取代或在2、3、4、5位被F;Cl;Br;I;OR的一或二个取代;
其中R=Me、Et、Pr、i-Pr、n-Bu;O-CH2-(O-CH2CH2)n-O-CH3,其中n=3,4,5,6,Z是
[化学式2]
Y=-OH;-OMe;-OEt;-OPr;-NH2;-NHMe;-N(Me)2;-N(Me)OCH3;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH-CH(R3)-COR2,其中R2选自:
-OH;-OMe;-OEt;-OPr;-NH2;-NHMe;-N(Me)2;-N(Me)OCH3;3-(5-甲氧基)吲哚基;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH(CH2)2-3-((5-甲氧基)吲哚基)
[化学式3]
[化学式4]
[化学式5]
[化学式6]
[化学式7]
除了在环A的4位同时具有Br的化合物,R1=CH(CH3)2或CH2CH(CH3)2或CH(CH3)CH2CH3,Z=
[化学式8]
特别地,环A可以在2、3、4、5位被1个或2个Br取代并且Y=-OH;-OMe;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH-CH(R3)-COR2、R1、R2和R3如上所定义。
在一个具体实施例中,Y是-NH-(CH2)2-(3-吲哚基)或-NH(CH2)2-3-((5-羟基)吲哚基),条件是:
[化学式9]
[化学式10]
[化学式11]
具体而言,根据本发明的化合物可选自:
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-亮氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-缬氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸酯;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸酯;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-色氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-色氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-D-色氨酸;
(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸;
(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸;
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸;
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-D-色氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-缬氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-亮氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-缬氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-亮氨酸;
(S)-5-((2-溴苯基)氧基)-N-(1-((2-(5-羟基-1H-吲哚-3-基)乙基)氨基)-1-氧代-3-苯丙烷-2-基)-4-氧代-4H-色烯-2-甲酰胺;
(S)-N-(1-((2-(1H-吲哚-3-基)乙基)氨基)-1-氧代-3-苯丙烷-2-基)-5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-甲酰胺;和
le(R)-N-(1-((2-(1H-吲哚-3-基)乙基)氨基)-3-(1H-吲哚-3-基)-1-氧丙烷-2-基)-5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-甲酰胺。
本发明还涉及获得根据本发明所述的化合物的方法,其特征在于,其包括以下步骤:
(a)式所示的烷基化化合物
[化学式12]
[化学式13]
得到式14所示的中间体
[化学式14]
(b)步骤(a)中获得的中间体,在0℃-50℃的温度下,在四氢呋喃(THF)/乙醇(1:1)的混合物中,与式15所示的草酸二乙酯反应
[化学式15]
得到式16所示的中间体
[化学式16]
(c)步骤(b)中获得的中间体在50℃温度下,在酸性或碱性介质中,在THF/乙醇/水溶剂(3:1:1.5)中通过酯官能团的水解反应进行反应,以获得式17所示的中间体
[化学式17]
(d)步骤(c)中获得的中间体,在室温下,在无水DMF中形成酰胺键,与式18所示的偶联化合物反应
[化学式18]
本发明还涉及式(I)所示的化合物:
[化学式19]
或其药学上可接受的对映异构体、盐或溶剂化物,或其混合物,
其中:
环A未取代或在2、3、4、5位被F;Cl;Br;I;OR的一或二个取代;其中R=Me、Et、Pr、i-Pr、n-Bu;O-CH2-(O-CH2CH2)n-O-CH3,其中n=3,4,5,6,
Z是
[化学式20]
或-CH2-,
Y=-OH;-OMe;-OEt;-OPr;-NH2;-NHMe;-N(Me)2;-N(Me)OCH3;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH-CH(R3)-COR2,其中R2选自:
-OH;-OMe;-OEt;-OPr;-NH2;-NHMe;-N(Me)2;-N(Me)OCH3;3-(5-甲氧基)吲哚基;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH(CH2)2-3-((5-甲氧基)吲哚基)
[化学式21]
[化学式22]
[化学式23]
[化学式24]
[化学式25]
用于抑制乳腺癌的多药耐药蛋白(乳腺癌耐药蛋白BCRP/ABCG2)。
抑制乳腺癌的多药耐药蛋白(乳腺癌耐药蛋白BCRP/ABCG2),除了在乳腺癌治疗中发挥作用外,还可能使肿瘤细胞重新致敏并增强需要通过生理膜或屏障(例如血脑或胃肠道屏障)以显示其治疗活性的药物的药物代动力学和功效。
特别地,环A可以在2、3、4、5位被1个或2个Br取代并且Y=-OH;-OMe;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH-CH(R3)-COR2、R1、R2和R3如上所定义。
在一个具体实施例中,Y是-NH-(CH2)2-(3-吲哚基)或-NH(CH2)2-3-((5-羟基)吲哚基),条件是:
[化学式26]
[化学式27]
[化学式28]
用于抑制根据本发明所述的乳腺癌多药耐药蛋白(乳腺癌耐药蛋白BCRP/ABCG2)的化合物可选自:
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-亮氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-缬氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸酯;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸酯;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-色氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-色氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-D-色氨酸;
(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异亮氨酸;
(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸;
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸;
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-D-色氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-缬氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-亮氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-缬氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-亮氨酸;
(S)-5-((2-溴苯基)氧基)-N-(1-((2-(5-羟基-1H-吲哚-3-基)乙基)氨基)-1-氧代-3-苯丙烷-2-基)-4-氧代-4H-色烯-2-甲酰胺;
(S)-N-(1-((2-(1H-吲哚-3-基)乙基)氨基)-1-氧代-3-苯丙烷-2-基)-5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-甲酰胺,以及
(R)-N-(1-((2-(1H-吲哚-3-基)乙基)氨基)-3-(1H-吲哚-3-基)-1-氧丙烷-2-基)-5-((4-溴代苯)氧基)-4-氧代-4H-色烯-2-甲酰胺。
本发明还涉及一种药物组合物,其包含:
至少一种药学上可接受的活性剂;和
至少一种如上所定义的化合物。
具体而言,药学上可接受的活性剂可选自抗癌剂、肠道抗炎剂、低胆固醇剂、抗血脂异常剂和激酶抑制剂。
例如,可使用磺胺水杨酸作为肠道抗炎剂,可使用阿托伐他汀作为低胆固醇剂,可使用瑞舒伐他汀作为抗血脂剂,可使用甲磺酸伊马替尼作为抗癌剂或激酶抑制剂。
这些化合物可通过存在天然氨基酸或与色酮单元相连的天然氨基酸的对映体来区分,由商业2,6-二羟基苯乙酮1(方案1)分四步合成,总收率在13%到41%之间。分三个标准步骤获得中间体2:烷基化、Kostaneki反应和皂化,总收率为45%。例如,当天然氨基酸或天然氨基酸的对映体结合到色酮单元时,在偶联剂的协助下,促进反应并限制反应物的当量数量,最后一步通过偶联反应,例如通过肽偶联进行。
这些试剂价格低廉,通常用于实验室。此外,这些反应不太耗能,通过沉淀或再结晶对产品进行纯化,限制了所用有机溶剂的体积,因此也限制了废物的体积。最后,以纯形式分离化合物,并通过各种分析技术(NMR、质谱、X射线衍射)确定和验证其结构。应该注意的是,X射线衍射证实商业氨基酸的不对称中心不存在外消旋作用。
方案1:本发明BCRP抑制剂的合成途径。
[化学式29]
以下示例说明本发明而不限制其范围。
在这些实施例中:
在Bruker Avance-400 400MHz仪器(400MHz)或Bruker Avance-500 500MHz仪器(500MHz)上记录NMR谱。
相对于用作内标的Me4Si,报告了化学位移(δ),单位为ppm。
电喷雾电离(ESI)质谱是由格勒诺布尔大学的分析部门在Waters Xevo G2-S Q-TOF仪器上用纳米喷雾输入获得的。精确质量以m/z为单位。
使用安捷伦1100系列系统,使用二极管阵列检测器和C18反相柱(Nucleosil C18,Macherey-Nagel,5mm粒径,125mm x 3mm)在45℃下进行HPLC分析,使用由A:水和0.1%三氟乙酸(TFA)以及B:甲醇(MeOH)和0.1%TFA组成的流动相,在14min、1mL/min、10μL进样条件下,在254nm检测到,A:B梯度在85:15到0:100之间。
在Büchi B540熔点上获得以摄氏度(℃)表示的熔点(m.p.)。
在默克F-254硅胶板(0.25mm厚)上进行薄层色谱(TLC)法。
除非另有说明,否则试剂从商业来源(Alpha Aesar、Sigma Aldrich和TCI)获得,使用时无需进一步纯化。
实施例1至20
系列1
[化学式30]
注:在以下协议中,“分子数+a”指溴位于芳环位置2时,“分子数+b”指溴位于芳环位置4时。
一般程序A:
向丙酮(6mL/mmol)中的2,6-二羟基苯乙酮1(1当量)溶液中同时加入K2CO3(3当量)和之前均化在一起的四正丁基溴化铵(0.4当量)。
溶液回流30-60分钟,然后向丙酮(15mL/mmol)中逐滴加入相应的溴苯溴(1当量)。
然后将溶液回流4-5小时,并通过TLC(乙酸乙酯/环己烷3:7)进行监测。将溶液倒入水中并用乙酸乙酯萃取。收集有机相并用水和盐水冲洗,然后经硫酸镁干燥,过滤并在真空下蒸发。
一般程序B:
向2(1当量)无水四氢呋喃(10mL/mmol)溶液中加入乙醇酸钠溶液,乙醇酸钠溶液是由钠(6当量)在0℃和惰性气氛下在无水乙醇(15mL/mmol)中原位生成的。
在室温下将溶液搅拌30分钟,并向溶液中逐滴加入草酸二乙酯(4当量)。然后将溶液加热至50℃直至沉淀,然后回流2小时。通过TLC(环己烷/乙酸乙酯1:1)监测反应。
然后向溶液中加入几滴浓盐酸(37%),直到形成的沉淀物变成白色为止。
溶液回流1小时,然后冷却至室温。真空浓缩后,将溶液倒入水中并用乙酸乙酯萃取。收集有机相并用水和盐水冲洗,然后经硫酸镁干燥,过滤并在真空下蒸发。
一般操作程序C:
向THF(25mL/mmol)和乙醇(8mL/mmol)中的3(1当量)溶液中加入K2CO3(1.3当量)水溶液(12mL/mmol)。
将溶液加热至50℃持续4小时,并通过TLC(乙酸乙酯/环己烷1:1)进行监测。溶液在真空下浓缩,然后将溶液倒入碱性水中(K2CO3 20%),并用乙酸乙酯洗涤。碱性水相用浓盐酸(37%)酸化,并用乙酸乙酯萃取。
然后收集有机相,用水和盐水冲洗,然后经硫酸镁干燥、过滤和蒸发。
一般操作程序D:
向无水二甲基甲酰胺(DMF)(20mL/mmol)的羧酸衍生物4(1当量)溶液中加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基胺四氟硼酸盐(TBTU)(2当量)。在室温下将溶液搅拌30分钟。
接着,向先前的溶液中小心翼翼地加入含有N,N-二异丙基乙胺(DIEA)(4当量)的DMF(10mL/mmol)中的氨基酸衍生物(2当量)溶液。反应在室温下搅拌12或24小时,并通过TLC(乙酸乙酯/环己烷1:1)进行监测。该溶液在真空下浓缩,然后倒入酸化水中(1M HCl)并用乙酸乙酯萃取。
收集有机相并用NaHCO3溶液(20%)、水和盐水洗涤,然后经硫酸镁干燥,过滤并在真空下浓缩。
一般操作模式E:
向酯衍生物5(1当量)在THF(25mL/mmol)和甲醇(10mL/mmol)中的溶液中加入LiOH(1.5当量)在H2O(10mL/mmol)中的溶液。反应在室温下搅拌2小时,并通过TLC(乙酸乙酯/环己烷1:1)进行监测。
将溶液倒入碱化水中(20%NaHCO3)并用乙酸乙酯洗涤。水相用浓盐酸(37%)酸化,用乙酸乙酯萃取。
然后收集有机相并用盐水冲洗,然后经硫酸镁干燥,过滤并在真空下浓缩。
实施例1
1-(2-((2-溴苯基)氧基)-6-羟基苯基)乙烷-1-酮(2a)的制备
[化学式31]
根据一般程序A从1(1.500g,9.86mmol)开始制备粗产物,并通过在甲醇或乙酸乙酯中重结晶纯化该粗产物,得到2a(2.583g,82%)。C15H13BrO3。
1H NMR(400MHz,DMSO)δ11.69(s,1H),7.71(dd,J=8.0,1.1Hz,1H),7.61(dd,J=7.6,1.6Hz,1H),7.46(td,J=7.5,1,2Hz,1H),7.39-7.29(m,2H),6.67(dd,J=8.4,0.5Hz,1H),6.56(dd,J=8.3,0.7Hz,1H),5.19(s,2H),2.47(s,3H)。
13C NMR(101MHz,DMSO)δ203.38,159.60,157.95,135.31,133.90,132.72,130.64,130.41,128.00,123.04,114.62,109.83,103.19,70.02,32.86
m.p.:75.5-77.4℃.
MS(ESI)m/z 321(79Br),323(81Br)[M+H]+,319(79Br),321(81Br)[M-H]+.
实施例2
1-(2-((4-溴苯基)氧基)-6-羟基苯基)乙烷-1-酮(2b)的制备
[化学式32]
根据一般程序A从1(1.500g,9.86mmol)开始制备粗产物,并通过在乙酸乙酯中重结晶纯化该粗产物,得到2b(2.321,73%)。C15H13BrO3。
1H NMR(400MHz,DMSO)δ11.64(s,1H),7.62-7.58(m,2H),7.45-7.41(m,2H),7.30(t,J=8.3Hz,1H),6.62(dd,J=8.4,0.5Hz,1H),6.52(dd,J=8.3,0.7Hz,1H),5.14(s,2H),2.48(s,3H)
13C NMR(101MHz,DMSO)δ203.43,159.52,157.94,135.96,133.77,131.41,129.98,121.15,114.75,109.63,103.41,69.30,33.04
m.p.:114.8-116.8℃。
MS(ESI)m/z 320(79Br),322(81Br)[M]+。
实施例3
5-((2-溴苯基)氧基)-4-氧基-4H-色烯-2-羧酸乙酯(3a)的制备
[化学式33]
根据一般程序B从2a(2.583g,8.04mmol)开始制备粗产物,并通过在甲醇或乙酸乙酯中重结晶纯化该粗产物,得到3a(2.478,76%)。C19H15BrO5。
1H NMR(400MHz,DMSO)δ8.11(dd,J=7.7,1.4Hz,1H),7.79(t,J=8.4Hz,1H),7.68(dd,J=8.0,1.0Hz,1H),7.51(td,J=7.6,1.1Hz,1H),7,33(td,J=7.8,1.7Hz,1H),7.30-7.25(m,1H),7.18-7.13(m,1H),6.79(s,1H),5.23(s,2H),4.40(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)
13C NMR(101MHz,DMSO)δ176.40,172.49,160.01,158.25,157.43,150.24,135.70,135.44,132.17,129.57,129.12,127.85,121.05,115.43,114.62,110.78,108.85,69.72,62.61,13.87
m.p.:155.3-157.1℃。
MS(ESI)m/z 403(79Br),405(81Br)[M-H]+。
实施例4
乙基5-((4-溴苯基)氧基)-4-氧基-4H-色烯-2-羧酸(3b)的制备
[化学式34]
根据一般程序B从2b(1.718g,5.35mmol)开始制备粗产物,并通过在甲醇或乙酸乙酯中重结晶纯化该粗产物,得到3b(1.516,70%)。C19H15BrO5。
1H NMR(400MHz,DMSO)δ7.74(t,J=8.4Hz,1H),7.64-7.56(m,4H),7.25-7.21(m,1H),7.13-7.08(m,1H),6.77(s,1H),5.24(s,2H),4.38(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H)。
13C NMR(101MHz,DMSO)δ176.39,160.01,157.70,157.23,150.19,136.23,135.29,131.21,128.90,120.61,115.43,114.68,110.54,109.02,69.22,62.59,13.87
m.p.:148.0-149.4℃。
MS(ESI)m/z 402(79Br),404(81Br)[M]+。
实施例5
5-((2-溴苯基)氧基)-4-氧基-4H-色烯-2-羧酸(4a)的制备
[化学式35]
根据一般程序C从3a(1.000g,2.48mmol)开始制备粗产物,通过在甲醇中研磨提纯,并用乙醚洗涤,得到4a(0.777,84%)。所需产物也可通过在甲醇中再结晶获得结晶。C17H11BrO5。
1H NMR(400MHz,DMSO)δ8.14(dd,J=7.7,1.1Hz,1H),7.77(t,J=8.4Hz,1H),7.68(dd,J=8.0,0.9Hz,1H),7.51(td,J=7,6,0.9Hz,1H),7.32(td,J=7.8,1.5Hz,1H),7.26(d,J=8.1Hz,1H),7.13(d,J=8.3Hz,1H),6.74(s,1H),5.23(s,2H)。
13C NMR(101MHz,DMSO)δ176.70,161.44,157.42,157.36,151.31,135.75,135.24,132.13,129.52,129.13,127.82,121.01,115.17,114.63,110.80,108.71,69.71
m.p.:244.3℃。
MS(ESI)m/z 373(79Br),375(81Br)[M-H]-。
实施例6
5-((4-溴苯基)氧基)-4-氧基-4H-色烯-2-羧酸(4b)的制备
[化学式36]
根据一般程序C从3b(1.586g,3.93mmol)开始制备粗产物,通过在甲醇中研磨提纯,并用乙醚洗涤,得到4b(1.259,85%)。所需产品可在甲醇中结晶,得到白色晶体。C17H11BrO5。
1H NMR(400MHz,DMSO)δ7.76(t,J=8.4Hz,1H),7.66-7.59(m,4H),7.24(dd,J=8.4,0.7Hz,1H),7.14-7.10(m,1H),6.76(s,1H),5.27(s,2H)
13C NMR(101MHz,DMSO)δ176.69,161.44,157.69,157.35,151.15,136.27,135.14,131.20,128.89,120.58,115.21,114.69,110.58,108.93,69.23
m.p.:204.6-205.3℃。
MS(ESI)m/z 374(79Br),376(81Br)[M]+。
实施例7
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异亮氨酸(5a)的制
备
[化学式37]
根据一般程序D从4a(511mg,1.36mmol)和异亮氨酸甲酯盐酸盐(0.485g,2.72mmol)开始制备粗产物,并通过在甲醇中重结晶纯化该粗产物,得到5a(0.352g,51%)。C24H24BrNO6。
1H NMR(400MHz,DMSO)δ9.23(d,J=7.7Hz,1H),8.14(d,J=7.4Hz,1H),7.82(t,J=8.4Hz,1H),7.69(d,J=7.9Hz,1H),7.52(t,J=7.4Hz,1H),7.40(d,J=8.4Hz,1H),7.33(t,J=7.3Hz,1H),7.17(d,J=8.3Hz,1H),6.74(s,1H),5.25(s,2H),4.39(t,J=7.7Hz,1H),3.70(s,3H),2.10-1.99(m,1H),1.60-1.48(m,J=11.6,5.8Hz,1H),1.33-1.23(m,1H),0.97-0.86(m,6H)
13C NMR(101MHz,DMSO)δ176.44,171.41,159.61,157.38,157.05,152.97,135.76,135.11,132.17,129.56,129.14,127.85,121.04,114.49,112.75,111.09,108.81,69.70,57.26,51.90,35.48,25.09,15.37,10.77
m.p.:123.1-125.7℃.
HRMS(ESI/QTOF):
计算C24H25BrNO6(M+H+):502.0865,
发现:502.0860。
纯度(HPLC)>95%。
实施例8
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异亮氨酸(5b)的制
备
[化学式38]
根据一般程序D从4b(300mg,0.80mmol)和L-异亮氨酸甲酯盐酸盐(290mg,1.60mmol)开始制备粗产物,并通过在甲醇中重结晶纯化该粗产物,得到5b(318mg,79%)。C24H24BrNO6。
1H NMR(400MHz,DMSO)δ9.17(d,J=7.9Hz,1H),7.77(t,J=8.4Hz,1H),7.64-7.56(m,4H),7.34(dd,J=8.5,0.7Hz,1H),7.12(d,J=8.1Hz,1H),6.70(s,1H),5.25(s,2H),4.37(t,J=7.7Hz,1H),3.68(s,3H),2.07-1.96(m,1H),1.58-1.45(m,1H),1.32-1.19(m,1H),0.95-0.84(m,6H)
13C NMR(101MHz,DMSO)δ176.41,171.40,159.62,157.63,157.04,152.91,136.29,134.95,131.21,128.92,120.59,114.54,112.73,110.86,108.99,69.19,57.24,51.88,35.48,25.09,15.37,10.77
实施例9
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-亮氨酸(5c)的制备
[化学式39]
根据一般程序D从4a(500mg,1.33mmol)和L-亮氨酸甲酯盐酸盐(0.483g,2.66mmol)开始制备粗产物,并通过在甲醇中重结晶纯化该粗产物,得到5c(234mg,35%)。C24H24BrNO6。
1H NMR(400MHz,CDCl3)δ8.13(d,J=7.4Hz,1H),7.57(t,J=8.3Hz,1H),7.48(d,J=7.9Hz,1H),7.38(t,J=7.5Hz,1H),7.18-7,05(m,3H),6.98(s,1H),6.90(d,J=8.3Hz,1H),5.18(s,2H),4.82-4.73(m,1H),3.74(s,3H),1.80-1.60(m,3H),0.99-0.87(m,6H)。
13C NMR(101MHz,CDCl3)δ177.52,172.93,159.05,158.46,157.33,152.34,135.55,134.74,132.10,129.07,128.79,128.12,120.82,115.42,114.21,110.63,108.66,70.38,52.73,51.14,41.81,25.02,22.82,22.05
m.p.:60.3-60.4℃.
HRMS(ESI/QTOF):
计算C24H25BrNO6(M+H+):502.0865,
发现:502.0865。
纯度(HPLC)>98%。
实施例10
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-缬氨酸(5d)的制备
[化学式40]
根据一般程序D从4a(0.200g,0.53mmol)和L-缬氨酸甲酯盐酸盐(0.179g,1.07mmol)开始制备粗产物,并通过在甲醇中重结晶纯化该粗产物,得到5d(0.126g,48%)。C23H22BrNO6。
1H NMR(400MHz,DMSO)δ9.20(d,J=7.8Hz,1H),8.12(d,J=7.4Hz,1H),7.82(t,J=8.4Hz,1H),7.69(d,J=7.8Hz,1H),7.51(t,J=7.5Hz,1H),7.39(d,J=8.4Hz,1H),7.33(t,J=7.4Hz,1H),7.16(d,J=8.3Hz,1H),6.74(s,1H),5.24(s,2H),4.33(t,J=7.7Hz,1H),3.70(s,3H),2.32-2.19(m,1H),1.06-0.92(m,6H)
13C NMR(101MHz,DMSO)δ176.42,171.34,159.69,157.41,157.07,153.03,135.76,135.09,132.17,129.57,129.18,127.84,121.07,114.53,112.74,111.10,108.88,69.76,58.56,51.90,29.46,19.04,18.95
m.p.:127.0-128.2℃.
HRMS(ESI/QTOF):
计算C23H23BrNO6(M+H+):488.0709,
发现:488.0719。
纯度(HPLC)>98%。
实施例11
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸甲酯(5e)
的制备
[化学式41]
根据一般程序D从4a(0.194g,0.52mmol)和L-苯丙氨酸甲酯盐酸盐(0.223g,1.04mmol)开始制备粗产物,并通过在乙醚和环己烷中沉淀纯化粗产物,得到5e(0.187g,70%)。C27H22BrNO6。
1H NMR(400MHz,DMSO)δ9.47(s,1H),8.13(dd,J=7.7,1.5Hz,1H),7.82(t,J=8.4Hz,1H),7.68(dd,J=8.0,1.1Hz,1H),7.51(td,J=7.6,1.1Hz,1H),7.35-7.27(m,6H),7.25-7.19(m,1H),7.16(d,J=8.0Hz,1H),6.64(s,1H),5.24(s,2H),4.77-4.71(m,1H),3.69(s,3H),3.26(dd,J=13.8,5.4Hz,1H),3.21-3.13(m,1H)。
13C NMR(101MHz,DMSO)δ176.33,171.26,159.21,157.42,156.95,152.77,137.22,135.74,135.24,132.15,129.54,129.11,129.06,128.31,127.84,126.62,121.01,114.43,112.57,110.82,108.85,69.69,54.13,52.20,35.93,30.67
m.p.:145.5-147.5℃.
HRMS(ESI/QTOF):
计算C27H23BrNO6(M+H+):536.0709,
发现:536.0711。
纯度(HPLC)>97%。
实施例12
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸甲酯(5f)
的制备
[化学式42]
根据一般程序D从4b(0.472g,1.26mmol)和L-苯丙氨酸甲酯盐酸盐(0.453g,2.52mmol)开始制备粗产物,并通过在甲醇中重结晶纯化该粗产物,得到5f(0.551g,90%)。C27H22BrNO6。
1H NMR(400MHz,DMSO)δ9.43(d,J=7.9Hz,1H),7.79(t,J=8.4Hz,1H),7.68-7.54(m,4H),7.30(d,J=12.6Hz,5H),7.23(d,J=6.1Hz,1H),7.13(d,J=8.3Hz,1H),6.63(s,1H),5.26(s,2H),4.73(dd,J=13.5,9.1Hz,1H),3.68(s,3H),3.26(dd,J=13.8,5.2Hz,1H),3.16(dd,J=13.6,10.3Hz,1H)。
13C NMR(101MHz,DMSO)δ176.31,171.22,159.22,157.68,156.94,152.71,137.20,136.26,135.08,131.20,129.05,128.91,128.31,126.62,120.59,114.50,112.56,110.60,109.06,69.21,54.10,52.20,35.93
分解点:153.1℃。
HRMS(ESI/QTOF):
计算C27H23BrNO6(M+H+):536.0709,
发现:536.0704。
纯度(HPLC)>96%。
实施例13
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-色氨酸甲酯(5g)的
制备
[化学式43]
根据一般程序D从4a(0.100g,0.27mmol)和L-色氨酸甲酯盐酸盐(0.136g,0.53mmol)开始制备粗产物,并通过在甲醇中重结晶纯化该粗产物,得到5g(0.043g,28%)。C29H23BrN2O6。
1H NMR(400MHz,DMSO)δ10.89(s,2H),9.36(d,J=7.8Hz,2H),8.12(d,J=7.7Hz,2H),7.83(t,J=8.4Hz,2H),7.69(dd,J=8.0,0.9Hz,2H),7.62(d,J=7.8Hz,2H),7.51(td,J=7.5,0.9Hz,2H),7.39-7.28(m,6H),7.25(d,J=2.2Hz,2H),7.17(d,J=8.3Hz,2H),7.07(td,J=7.7,0.9Hz,2H),6.98(t,J=7.4Hz,2H),6.65(s,2H),5.24(s,4H),4.80-4.70(m,2H),3.69(s,7H)
13C NMR(101MHz,DMSO)δ176.36,171.52,159.18,157.43,156.95,152.81,136.09,135.74,135.21,132.17,129.57,129.15,127.85,127.03,123.79,121.05,121.02,118.44,118.04,114.43,112.55,111.48,110.83,109.47,108.89,69.73,53.80,52.19,26.38水峰以下有两个质子信号。
m.p.:250-252.8℃。
HRMS(ESI/QTOF):
计算C29H24BrN2O6(M+H+):575.0818,
发现:575.0821。
纯度(HPLC)>99%。
实施例14
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-色氨酸甲酯(5h)的
制备
[化学式44]
根据一般程序D从4b(0.100g,0.27mmol)和L-色氨酸甲酯盐酸盐(0.136g,0.533mmol)开始制备粗产物,并通过在甲醇中重结晶纯化该粗产物,得到5h(0.126g,82%)。C29H23BrN2O6。
1H NMR(400MHz,DMSO)δ10.90(s,1H),9.34(d,J=7.8Hz,1H),7.79(t,J=8.4Hz,1H),7.69-7.52(m,5H),7.35(d,J=8.1Hz,1H),7.29(d,J=8.1Hz,1H)7.25(d,J=2.2Hz,1H),7.12(d,J=8.3Hz,1H),7.10-7.03(m,1H),7.02-6.94(m,1H),6.63(s,1H),5.25(s,2H),4.80-4.69(m,1H),3.68(s,3H)
13C NMR(101MHz,DMSO)δ176.34,171.50,159.19,157.67,156.92,152.76,136.25,136.10,135.04,131.20,128.92,127.03,123.78,121.02,120.59,118.44,118.04,114.48,112.54,111.48,110.61,109.47,109.06,69.23,53.79,52.18,26.39水峰下的两个质子信号。
m.p.:235.3-236.2℃.
HRMS(ESI/QTOF):
计算C29H24BrN2O6(M+H+):575.0818,
发现:575.0807。
纯度(HPLC)>99%。
实施例15
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-D-色氨酸甲酯(5i)的
制备
[化学式45]
根据一般程序D从4b(0.300g,0.80mmol)和D-色氨酸甲酯盐酸盐(0.408g,1.60mmol)开始制备粗产物,并通过在乙酸乙酯和环己烷中沉淀纯化该粗产物,得到5i(0.375g,81%)。C29H23BrN2O6。
1H NMR(400MHz,DMSO)δ10.90(s,1H),9.34(d,J=7.8Hz,1H),7.79(t,J=8.4Hz,1H),7.66-7.57(m,5H),7.35(d,J=8.1Hz,1H),7.29(d,J=8.3Hz,1H),7.25(d,J=2.1Hz,1H)7.12(d,J=8.3Hz,1H),7.07(t,J=7.2Hz,1H),6.98(t,J=7.4Hz,1H),6.63(s,1H),5.25(s,2H),4.79-4.70(m,1H),3.69(s,3H),3.43-3.38(m,1H),3.33-3.27(m,1H)
13C NMR(101MHz,DMSO)δ176.33,171.51,159.18,157.67,156.93,152.75,136.26,136.10,135.04,131.20,128.91,127.03,123.78,121.01,120.59,118.43,118.04,114.48,112.54,111.48,110.60,109.47,109.04,69.21,53.79,52.18,26.38
m.p.:236.2-237.9℃.
HRMS(ESI/QTOF):
计算C29H24BrN2O6(M+H+):575.0818,
发现:575.0822.
纯度(HPLC)>99%.
实施例16
(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异亮氨酸(6a)的制备
[化学式46]
根据一般程序E从5a(0.256g,0.51mmol)开始制备粗产物,并通过在甲醇中重结晶纯化该粗产物,得到6a(0.114g,46%)。C23H22BrNO6。
1H NMR(400MHz,DMSO)δ8.99(d,J=8.1Hz,1H),8.14(d,J=7.5Hz,1H),7.82(t,J=8.4Hz,1H),7,69(dd,J=7.9,0.8Hz,1H),7.52(td,J=7.6,0.8Hz,1H),7.41(d,J=8.2Hz,1H),7.33(td,J=7.8,1.5Hz,1H),7.17(d,J=8.2Hz,1H),6.73(s,1H),5.25(s,2H),4.39-4.31(m,1H),2.08-1.98(m,1H),1.61-1.48(m,1H),1.35-1.23(m,1H),0.97(d,J=6.8Hz,3H),0.90(t,J=7.4Hz,3H).
13C NMR(101MHz,DMSO)δ176.46,172.23,159.43,157.39,157.06,153.18,135.76,135.07,132.16,129.57,129.16,127.84,121.06,114.49,112.64,111.12,108.84,69.73,57.21,35.62,25.04,15.52,10.96
m.p.:242.8-243.7℃。
HRMS(ESI/QTOF):
计算C23H23BrNO6(M+H+):488.0709,
发现:488.0712.
纯度(HPLC)>98%.
实施例17
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基)-L-异亮氨酸(6b)的制备
[化学式47]
根据一般程序E从5b(671mg,0.51mmol)开始制备粗产物,并通过在甲醇中重结晶该粗产物,得到6b(419mg,64%)。C23H22BrNO6。
1H NMR(400MHz,DMSO)δ12.91(s,1H),8.98(d,J=8.1Hz,1H),7.78(t,J=8.4Hz,1H),7.67-7.57(m,4H),7.37(dd,J=8.5,0.6Hz,1H),7.13(d,J=8.2Hz,1H)6.72(s,1H),5.26(s,2H),4.40-4.29(m,1H),2.07-1.96(m,1H),1.61-1.45(m,1H),1.38-1.20(m,1H),0.96(d,J=6.8Hz,3H),0.90(t,J=7.4Hz,3H).(ERO1-94)
13C NMR(101MHz,DMSO)δ176.44,172.23,159.44,157.63,157.04,153.12,136.28,134.91,131.20,128.93,120.59,114.54,112.63,110.89,108.99,69.21,57.19,35.63,25.04,15.52,10.96
p.f.:230,1-230,4℃.
HRMS(ESI/QTOF):
计算C23H23BrNO6(M+H+):488.0709,
发现:488.0715.
纯度(HPLC)>98%.
实施例18
(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸(6c)的制备
[化学式48]
根据一般程序E从5e(0.320g,0.60mmol)开始制备粗产物,并通过在甲醇中重结晶纯化该粗产物,得到6c(0.210g,67%)。C26H20BrNO6。
1H NMR(400MHz,DMSO)δ9.29(d,J=8.2Hz,2H),8.11(dd,J=7.6,1.0Hz,2H),7.82(t,J=8.4Hz,2H),7.68(dd,J=7.9,0.8Hz,2H),7.50(td,J=7.6,0.9Hz,2H),7.37-7.25(m,11H),7.24-7.10(m,4H),6.63(s,2H),5.23(s,4H),4.72-4.58(m,2H),3.14(dd,J=13.8,10.3Hz,5H)在水信号下的一个峰。
13C NMR(101MHz,DMSO)δ176.37,172.20,159.04,157.44,156.96,153.00,137.72,135.73,135.20,132.16,129.57,129.17,129.02,128.25,127.83,126.47,121.06,114.45,112.43,110.85,108.91,69.75,54.18,36.01
p.f.:240.4-241.7℃.
HRMS(ESI/QTOF):
计算C26H21BrNO6(M+H+):522.0552,
发现:522.0558
实施例19
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸(6d)的制备
[化学式49]
根据一般程序E从5f(0.551g,1.03mmol)开始制备粗产物,并通过在甲醇中重结晶纯化该粗产物,得到6d(0.446g,83%)。C26H20BrNO6。
1H NMR(400MHz,DMSO)δ8.51(d,J=6.8Hz,1H),7.72(t,J=8.4Hz,1H),7.66-7.57(m,4H),7.24-7.16(m,5H),7.16-7,07(m,2H),6.62(s,1H),5.24(s,2H),4.24(dd,J=11.0,5.9Hz,1H),3.26(dd,J=13.5,4.6Hz,1H),3.11(dd,J=13.5,6.8Hz,1H)(ERO1-71)
13C NMR(101MHz,DMSO)δ176.35,172.19,159.11,157.67,156.94,152.89,137.66,136.26,135.06,131.20,129.02,128.91,128.27,126.50,120.58,114.47,112.44,110.62,109.04,69.21,54.08,35.94
分解点:231.5℃.
HRMS(ESI/QTOF):
计算C26H21BrNO6(M+H+):522.0552,
发现:522.0559。
纯度(HPLC)>95%。
实施例20
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-D-色氨酸(6e)的制备
[化学式50]
根据一般程序E从5i(0.250g,0.27mmol)开始制备粗产物,并通过在乙酸乙酯和环己烷中沉淀纯化该粗产物,得到6e(0.158g,66%)。C28H21BrN2O6。
1H NMR(400MHz,DMSO)δ10.87(d,J=1.4Hz,1H),9.18(d,J=8.1Hz,1H),7.79(t,J=8.4Hz,1H),7.69-7.56(m,5H),7.34(d,J=8.1Hz,1H)J=8.2Hz,1H),7.24(d,J=2.2Hz,1H),7.13(d,J=8.3Hz,1H),7.10-7.04(m,1H),7.01-6.95(m,1H),6.63(s,1H),5.25(s,2H),4.73-4.65(m,1H)水峰下的两个信号。
13C NMR(101MHz,DMSO)δ176.37,172.52,159.06,157.66,156.92,152.92,136.26,136.08,135.04,131.20,128.91,127.09,123.66,120.98,120.58,118.39,118.16,114.44,112.42,111.43,110.59,109.93,109.00,69.18,53.73,26.37水峰下的两个质子信号。
m.p.:185.5-186.7℃.
HRMS(ESI/QTOF):
计算C28H22BrN2O6(M+H+):561.0661,
发现:561.0672。
纯度(HPLC)>99%。
实施例21-27
系列2
[化学式51]
注:在以下协议中,“分子数+a”指溴位于芳环位置2时,“分子数+b”指溴位于芳环位置4时。
注:与系列1至步骤e的合成方案相同。仅允许进入化合物7的步骤f不同。
一般操作程序F:
向羧酸衍生物6(1当量)在无水DMF(20mL/mmol)中的溶液中加入TBTU(1.5当量或2当量)。在室温下将溶液搅拌30分钟。因此,向先前的溶液中小心加入含有DIEA(5当量)的DMF(10mL/mmol)中的氨基酸衍生物(1.5或2当量)溶液。反应在室温下搅拌24小时,并通过TLC(环己烷/乙酸乙酯3:2)进行监测。将溶液倒入酸化水中(1M HCl)并用乙酸乙酯萃取。收集有机相并用20%NaHCO3溶液和盐水洗涤,然后经硫酸镁干燥,过滤并在真空中蒸发。
实施例21
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异亮氨酸-L-缬氨
酸甲酯(7a)的制备
[化学式52]
根据一般程序F从6a(0.091g,0.19mmol)、L-缬氨酸甲酯(0.064g,0.38mmol)开始制备粗产物,并通过在乙酸乙酯和少量环己烷中沉淀纯化该粗产物,然后用乙醚洗涤以提供7a(0.042g,37%)。C29H33BrN2O7。
1H NMR(400MHz,DMSO)δ8.79(d,J=8.4Hz,0.5H),8.60-8.50(m,1H),8.45(d,J=7.2Hz,0.5H),8.13(d,J=7.5Hz,1H),7.81(t,J=8.0Hz,1H),7.69(d,J=7.8Hz,1H),7.52(t,J=7.3Hz,1H),7.40(d,J=8.1Hz,1H),7.33(t,J=7.3Hz,1H),7.16(d,J=8,4Hz,1H),6.72(d,J=5.0Hz,1H),5.25(s,2H),4.73-4.65(m,0.5H),4.54-4.45(m,0.5H),4.27-4.21(m,0.5H),4.21-4,14(m,0.5H),3.65(d,J=4.7Hz,3H),2.13-1.92(m,2H),1.64-1.47(m,1H),1.28-1.14(m,1H),1.04-0.70(m,12H)。
13C NMR(101MHz,DMSO)δ172.31,171.91,171.88,157.84,157.83,157.82,157.51,157.49,157.46,157.43,157.42,153.69,153.67,153.65,135.92,132.79,130.34,129.78,128.33,121.94,114.74,114.72,114.70,114.66,112.89,112.87,112.69,111.52,111.46,109.48,109.46,109.37,109.35,70.33,70.31,58.31,58.30,58.21,58.05,58.02,57.96,52.33,52.26,52.23,52.21,36.32,30.00,25.02,19.31,19.17,19.13,18.66,18.59,15.29,15.28,10.85。
HRMS(ESI/QTOF):
计算C29H34BrN2O7(M+H+):601.1549,
发现:601.1533。
实施例22
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-亮
氨酸(7b)的制备
[化学式53]
根据一般程序F从6a(0.082mg,0.16mmol)、L-亮氨酸甲酯(0.061g,0.32mmol)开始制备粗产物,并通过在乙酸乙酯和少量环己烷中沉淀纯化该粗产物,然后用乙醚洗涤得到7b(0.030g,31%)。C30H35BrN2O7。
1H NMR(400MHz,DMSO)δ8.79(d,J=8.8Hz,0.5H),8.64(d,J=7.6Hz,1H),8.56(d,J=7.7Hz,0.5H),8.13(d,J=7.6Hz,1H),7.81(t,J=8.2Hz,1H),7.69(d,J=8.0Hz,1H),7.52(t,J=7.5Hz,1H),7.40(dd,J=8.3,4.4Hz,1H),7.33(t,J=7,5Hz,1H),7.16(d,J=8.1Hz,1H),6.73(d,J=7.3Hz,1H),5.25(s,2H),4.64-4.56(m,0.5H),4.41(t,J=8.7Hz,1H),4,37-4.27(m,0.5H),3.63(s,1H),2.05-1.92(m,1H),1.74-1.43(m,4H),1.27-1.13(m,1H),0.98-0.81(m,12H))。
13C NMR(126MHz,DMSO)δ177.64,174.72,173.46,173.29,171.55,171.48,159.81,159.64,157.82,157.41,153.65,153.63,135.89,135.84,132.77,130.31,129.75,128.32,121.89,114.67,112.93,112.88,111.50,109.43,70.31,58.05,57.49,52.53,52.42,52.32,51.52,51.02,50.90,41.57,40.89,37.32,36.39,25.92,24.96,24.70,24.64,23.10,23.01,22.99,21.82,21.57,21.44,21.23,15.31,14.95,11.64,10.85。
HRMS(ESI/QTOF):
计算C30H36BrN2O7(M+H+):615.1690,
发现:615.1684。
实施例23
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-缬
氨酸甲酯(7c)的制备
[化学式54]
根据一般程序F从6a(0.123g,0.25mmol)、L-缬氨酸甲酯(0.084g,0.50mmol)开始制备粗产物,并在乙醚中通过研磨纯化该粗产物,得到7c(0.061g,41%)。C29H33BrN2O7。
1H NMR(400MHz,DMSO)δ8.76(d,J=8.6Hz,0.5H),8.54(d,J=9.4Hz,1H),8.43(d,J=7.5Hz,0.5H),7.76(t,J=8,3Hz,1H),7.60(q,J=8.6Hz,4H),7.35(d,J=8.2Hz,1H),7.11(d,J=8.3Hz,1H),6.69(d,J=5.4Hz,1H)2H),4.67(dd,J=8.8,6.9Hz,0.5H),4.48(t,J=8.8Hz,0.5H),4.22(dd,J=7.9,6.9Hz,0.5H),4.15(t,J=7.0Hz,0,5H),3.63(d,J=4.9Hz,3H),2.12-1.90(m,2H),1.59-1.36(m,1H),1.25-1.11(m,1H),0.99-0.81(m,12H)。
13C NMR(101MHz,DMSO)δ176.43,171.93,171.64,170.88,170.67,159.10,158.94,157.64,157.01,153.21,136.29,134.90,131.19,128.91,120.58,114.52,112.61,112.54,110.83,109.00,69.21,57.66,57.42,57.24,56.72,51.72,51.53,37.09,35.99,29.85,29.58,25.65,24.62,19.02,18.84,18.35,18.20,14.95,14.58,11.37,10.55。
HRMS(ESI/QTOF):
计算C29H34BrN2O7(M+H+):601.1549,
发现:601.1545。
实施例24
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-亮
氨酸(7d)的制备
[化学式55]
根据一般程序F从6b(0.123g,0.25mmol)、L-亮氨酸甲酯(0.091mg,0.50mmol)开始制备粗产物,并在乙醚中通过研磨进行纯化该粗产物,得到7d(0.052g,34%)。C30H35BrN2O7。
1H NMR(400MHz,DMSO)δ8.76(d,J=8.7Hz,0.5H),8.62(d,J=7.8Hz,0.5H),8.54(dd,J=8.0,4.5Hz,1H),7.76(t,J=8.2Hz,1H),7.66-7.56(m,4H),7.35(dd,J=8.4,4.2Hz,1H),7.11(d,J=8.2Hz,1H),6.70(d,J=7.5Hz,1H),5.25(s,2H),4.58(dd,J=8.6,6.5Hz,0.5H),4.39(t,J=8.6Hz,0.5H),4.36-4.24(m,1H),3.62(d,J=2.3Hz,3H),2.03-1.89(m,1H),1.70-1.55(m,2H),1.55-1.45(m,2H),1.24-1.10(m,1H),0.96-0.79(m,12H)。
13C NMR 176.43,172.81,172.60,170.56,170.42,159.14,158.95,157.63,157.01,153.19,136.28,134.90,131.19,128.91,120.57,114.51,112.62,112.54,110.84,109.00,69.20,57.29,56.64,51.86,51.71,50.39,50.23,36.98,36.00,25.59,24.56,24.23,24.18,22.78,22.66,21.28,20.90,14.99,14.62,10.54。
HRMS(ESI/QTOF):
计算C30H36BrN2O7(M+H+):615.1690,
发现:615.1690。
实施例25
(S)-5-((2-溴苯基)氧基)-N-(1-((2-(5-羟基-1H-吲哚-3-基)乙基)氨基)-1-氧
代-3-苯丙烷-2-基)-4-氧代-4H-色烯-2-甲酰胺的制备(第7)
[化学式56]
根据一般程序F从6c(0.127mg,0.24mmol)、5-羟色胺盐酸盐(0.103mg,0.48mmol)开始制备粗产物,并通过在甲醇中研磨纯化该粗产物,然后用乙醚洗涤得到7e(0.063g,38%)。C36H30BrN3O6。
1H NMR(400MHz,DMSO)δ10.49(d,J=1.6Hz,1H),9.11(d,J=8.4Hz,1H),8.61(s,1H),8.31(t,J=5.5Hz,1H),8.10(dd,J=7.7,0,8Hz,1H),7.79(t,J=8.4Hz,1H),7.65(dd,J=8.0,0.7Hz,1H),7.48(td,J=7.6,0.7Hz,1H),7.37-7.23(m,6H),7.18(t,J=7.2Hz,1H),7.12(d,J=8.6Hz,2H),7.04(d,J=2.1Hz,1H),6.86(d,J=2.1Hz,1H),6.63(s,1H),6.60(dd,J=8.6,2.2Hz,1H),5.21(s,2H),4.73-4.65(m,1H),3.34-3.26(m,1H),3.17(dd,J=13.7,4.5Hz,1H),3.05(dd,J=13.6,10.2Hz,1H),2.73(t,J=7.5Hz,2H)。
13C NMR(101MHz,DMSO)δ176.46,170.03,158.99,157.41,156.99,153.19,150.16,137.88,135.74,135.14,132.15,130.81,129.55,129.15,128.14,127.83,126.38,123.13,121.06,114.44,112.36,111.65,111.27,110.93,110.64,108.83,102.20,69.74,54.91,37.11,25.14.31C+2EQ 3C丢失。
HRMS(ESI/QTOF):
计算C36H31BrN3O6(M+H+):680.1396,
发现:680.1392。
实施例26
(S)-N-(1-((2-(1H-吲哚-3-基)乙基)氨基)-1-氧代-3-苯丙烷-2-基)-5-((4-溴
苯基)氧基)-4-氧代-4H-色烯-2-甲酰胺(7f)的制备
[化学式57]
根据一般程序F从6d(0.090g,0.17mmol)、盐酸色胺(0.067g,0.34mmol)开始制备粗产物,并通过在乙酸乙酯和少量环己烷中研磨纯化该粗产物,然后用乙醚洗涤得到7f(0.014g,12%)。C36H30BrN3O5。
1H NMR(400MHz,CDCl3)δ8.20(s,1H),7.68(d,J=7.7Hz,1H),7.57(t,J=8.4Hz,1H),7.54-7.44(m,5H),7,32-7.15(m,6H),7.12-7.06(m,2H),7.06-7.01(m,1H),6.89(s,1H),6.85(d,J=8.2Hz,1H),6.80(s,1H),5.99-5.91(m,1H),5.19(s,2H),4.72(dd,J=13.5,7.7Hz,1H),3.53(dd,J=11.8,5.9Hz,2H),3.20(dd,J=13.4,5.6Hz,1H),3.06(dd,J=13.3,8.4Hz,1H),2.88(dt,J=13.1,6.4Hz,1H),2.84-2.73(m,1H)。
13C NMR(101MHz,CDCl3)δ177.67,170.09,159.03,158.55,157.39,152.34,136.50,136.16,135.38,134.72,131.87,129.44,128.91,128.45,127.44,127.17,122.32,122.19,121.84,119.59,118.58,115.56,113.88,112.34,111.42,110.84,109.06,70.35,60.54,55.24,39.94,38.96,29.82,25.00,21.18,14.33.36C,而不是32。
HRMS(ESI/QTOF):
计算C36H31BrN3O5(M+H+):664.1447,
发现:664.1432。
实施例27
(R)-N-(1-((2-(1H-吲哚-3-基)乙基)氨基)-3-(1H-吲哚-3-基)-1-氧丙烷-2-
基)-5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-甲酰胺(7g)的制备
[化学式58]
根据一般程序F从6e(0.069g,0.13mmol)、盐酸色胺(0.048g,0.25mmol)开始制备粗产物,并通过在乙醚中研磨纯化该粗产物,得到7g(0.051mg,59%)。C38H31BrN4O5。
1H NMR(400MHz,DMSO)δ10.83(s,2H),8.98(d,J=8.2Hz,1H),8.34(t,J=5.3Hz,1H),7.78(t,J=8,4Hz,1H),7.70(d,J=7.7Hz,1H),7.60(q,J=8.6Hz,1H),7.55(d,J=7.8Hz,1H),7.36-7.26(m,3H),7.18(dd,J=31.1,0.9Hz,2H),7.11(d,J=8.4Hz,1H),7.08-7.01(m,2H),7.00-6.92(m,2H),6.61(s,1H),5.24(s,2H),4.72-4.63(m,1H),3.30-3.14(m,2H),2.82(t,J=7.3Hz,2H).水峰下的两个信号。
13C NMR(101MHz,DMSO)δ176.46,170.44,158.90,157.64,156.94,153.16,136.27,136.19,136.04,134.99,131.20,128.90,127.24,127.15,123.76,122.67,120.89,120.88,120.58,118.53,118.21,114.43,112.31,111.66,111.33,110.67,110.08,108.95,69.17,54.44,27.38,25.02.32C+2EQ 4C丢失。
HRMS(ESI/QTOF):
计算:C38H31BrN4O5(M+H+):703.1556,
发现:703.1553.
实施例28至36
系列3
[化学式59]
注:在以下协议中,“分子数+a”指溴位于芳环2和4位置时,“分子数+b”指溴位于芳环3和5位置时。
一般操作模式A:
2,5-二羟基苯乙酮3(1当量)在丙酮(11mL/mmol)中溶解。然后将K2CO3(3当量)和四正丁基溴化铵(TBAB)(1.5当量)混合在一起,称重并添加到溶液中。将所得悬浮液回流30分钟,并加入二溴-1-(溴甲基)苯(1当量)丙酮溶液(4mL/mmol)。悬浮液回流30分钟,然后在真空下浓缩。通过TLC(环己烷/乙酸乙酯7:3)监测反应。
将反应混合物倒入乙酸乙酯和酸化水(1M HCl)中。用乙酸乙酯萃取水层(3次),然后用酸化水(1M HCl)和盐水洗涤合并的有机层(1次)。合并的有机层经MgSO4干燥,过滤并在真空下蒸发。最后,在高真空下干燥粗产物。
一般程序B:
将钠(6当量)溶解在冷无水乙醇(3mL/mmol)中,以得到新鲜的乙醇酸钠溶液。将该溶液滴入干燥THF(与乙醇体积相同)中4(1当量)的冷(0℃)溶液中。然后向溶液中加入草酸二乙酯(4当量),并在室温下搅拌30分钟。将所得溶液加热至50℃,并通过TLC(环己烷/乙酸乙酯3:2)进行监测。反应中间产物在反应过程中发生沉淀。
4小时后,向溶液中滴加37%盐酸,直到沉淀物变白。变色后反应回流1.5小时。然后蒸发反应混合物并倒入乙酸乙酯和酸化水(1M HCl)。用乙酸乙酯萃取水层(3次),直到颜色改变。用酸化水(1M HCl)和盐水洗涤合并的有机层(一次),并在蒸发之前经MgSO4干燥。
一般操作程序C:
将K2CO3(1.3当量)水溶液(15mL/mmol)添加到5(1当量)THF(30mL/mmol)和乙醇(乙醇)(10mL/mmol)溶液中。将所得溶液加热至50℃并搅拌1.5小时。通过TLC(环己烷/乙酸乙酯7:3)监测反应。将反应混合物浓缩并倒入二氯甲烷和酸化水(1M HCl)中。
为了增加所需产物在有机层中的溶解度,加入几滴甲醇。用二氯甲烷萃取水层(3次),并用酸化水(1M HCl)和盐水洗涤合并的有机层(一次)。然后经MgSO4干燥合并的有机层,过滤并蒸发。
实施例28
2,4-二溴-1-(溴甲基)苯(2)的制备
[化学式60]
将2,4-二溴甲苯1(1000g,4,00mmol)和新纯化的N-溴代丁二酰亚胺(NBS)(0925g,5,20mmol)在惰性气氛下溶解于12mL 1,2-二氯乙烷中。将溶液回流10分钟,并添加偶氮二异丁腈(AIBN)(0.328g,2.00mmol)。将所得悬浮液搅拌并回流6小时。通过TLC(100%环己烷)监测反应。然后蒸发反应混合物,并加入冷的1:1环己烷/二氯甲烷溶液以沉淀副产物(白色固体)。过滤和蒸发后,直接使用粗产物2(1.476g,4.49mmol),无需纯化。C7H5Br3
实施例29
1-(2-((2,4-二溴苯基)氧基)-6-羟基苯基)乙烷-1-酮(4a)的制备
[化学式61]
根据一般程序A从2(1.315g,4.00mmol)和3(1.000g,4.00mmol)开始制备粗产物。用1:1环己烷/二氯甲烷溶液沉淀粗产物,然后在异丙醇中重结晶,得到4a(0.793g,50%)。C15H12Br2O3。
1H NMR(400MHz,DMSO)δ11.64(s,1H),7.95(d,J=1.8Hz,1H),7.66(dd,J=8.2,1.8Hz,1H),7.54(d,J=8,2Hz,1H),7.32(t,J=8.3Hz,1H),6.62(d,J=8.3Hz,1H),6.55(d,J=8.2Hz,1H),5.13(s,2H),2.45(s,3H)。
13C NMR(101MHz,DMSO)δ203.27,159.54,157.71,134.92,134.60,133.83,132.06,131.01,123.92,122.19,114.68,109.93,103.16,69.38,32.88
HRMS(ESI/LTQ阱质谱):
计算C15H11O3Br2(M-H+):396.9080,
发现:96.9082。
实施例30
1-(2-((3,5-二溴苯基)氧基)-6-羟基苯基)乙烷-1-酮(4b)的制备
[化学式62]
根据一般程序A从1,3-二溴-5-(溴甲基)苯(1.315g,4.00mmol)和3(1.000g,4.00mmol)开始制备粗产物。通过在乙醚中研磨纯化该粗产物,得到4b(1.103g,70%)。C15H12O3Br2。
1H NMR(400MHz,DMSO)δ11.53(s,1H),7.79(s,1H),7.69(d,J=1.5Hz,2H),7.29(t,J=8.3Hz,1H),6.58(d,J=8.3Hz,1H),6.54(d,J=8.2Hz,1H),5.17(s,2H),2.53-2.46(m,5H)
13C NMR(101MHz,DMSO)δ203.16,158.98,157.30,141.43,133.41,132.81,129.45,122.49,115.30,109.78,103.40,68.24,32.91
HRMS(ESI/LTQ阱质谱):
计算C15H11O3Br2(M-H+):396.9080,
发现:396.9078。
实施例31
5-((2,4-二溴苯基)氧基)-4-氧代-4H-色烯-2-羧酸乙酯(5a)的制备
[化学式63]
根据一般程序B从4a(0.435g,1.09mmol)和草酸二乙酯(0.636g,4.35mmol)开始制备粗产物。所得油在高真空下固化,添加并加热异丙醇。
过滤所得悬浮液,将糊状产物溶解在二氯甲烷中,蒸发后获得白色固体。所需产物5a(0.144g,27%)。C19H14O5Br2。
1H NMR(400MHz,DMSO)δ8.08(d,J=8.3Hz,1H),7.94(d,J=1.9Hz,1H),7.80(t,J=8.4Hz,1H),7.74(dd,J=8.3,1.9Hz,1H),7.29(d,J=8.5Hz,1H),7.15(d,J=8.3Hz,1H),6.81(s,1H),5.19(s,2H),4.40(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H)
13C NMR(101MHz,DMSO)δ176.44,159.99,157.23,157.22,150.30,135.46,135.43,134.04,130.85,130.60,121.82,121.29,115.42,114.59,110.90,108.90,69.29,62.62,13.87
HRMS(ESI/LTQ阱质谱):
计算C19H15O5Br2(M+H+):480.9281,
发现:480.9271。
实施例32
乙基5-((3,5-二溴苯基)氧基)-4-氧代-4H-色烯-2-羧酸乙酯(5b)的制备
[化学式64]
根据一般程序B从4b(1.103g,2.76mmol)和草酸二乙酯(1.612g,14.03mmol)开始制备粗产物。通过在乙醚中研磨纯化该粗产物,得到5b(0.785g,59%)。C19H14Br2O5。
1H NMR(400MHz,DMSO)δ7.91(d,J=1.6Hz,2H),7.81-7.74(m,2H),7.26(d,J=8.1Hz,1H),7,08(d,J=8.3Hz,1H),6.83(s,1H),5.27(s,2H),4.38(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H)。
13C NMR(101MHz,DMSO)δ176.55,159.99,157.32,157.22,150.28,141.68,135.40,132.26,128.38,122.44,115.46,114.62,110.82,108.83,68.21,62.60,13.86
HRMS(ESI/LTQ阱质谱):
计算C19H15Br2O5(M+H+):480.9281,
发现:480.9274。
实施例33
5-((2,4-二溴苯基)氧基)-4-氧代-4H-色烯-2-羧酸(6a)的制备
[化学式65]
根据一般程序C从5a(0.144g,0.30mmol)开始制备粗产物,并通过在1:1乙醚/二氯甲烷中研磨纯化该粗产物,得到6a(0.074g,55%)。C17H10Br2O5。
1H NMR(400MHz,DMSO)δ8.07(d,J=8.3Hz,1H),7.90(d,J=1.9Hz,1H),7.76(t,J=8.4Hz,1H),7,70(dd,J=8.3,1.9Hz,1H),7.24(d,J=8.3Hz,1H),7.10(d,J=8.3Hz,1H),6.75(s,1H),5.15(s,2H)。
13C NMR(101MHz,DMSO)δ176.72,161.42,157.30,157.17,151.21,135.46,135.28,133.97,130.81,130.55,121.71,121.23,115.20,114.54,110.90,108.69,69.23,64.89
HRMS(ESI/LTQ阱质谱):
计算C17H11Br2O5(M+H+):454.8948,
发现:454.8937。
实施例34
5-((3,5-二溴苯基)氧基)-4-氧代-4H-色烯-2-羧酸(6b)的制备
[化学式66]
根据一般程序C从5b(0.785g,1.63mmol)开始制备粗产物,并通过在1:1乙醚/二氯甲烷中研磨纯化该粗产物,得到6b(0.493g,67%)。C17H10Br2O5。
1H NMR(400MHz,DMSO)δ7.91(s,2H),7.82-7.72(m,2H),7.24(d,J=8.4Hz,1H),7.06(d,J=8.3Hz,1H),6.79(s,1H),5.27(s,2H)
13C NMR(101MHz,DMSO)δ176.82,161.44,157.31,157.29,151.21,141.70,135.23,132.22,128.34,122.42,115.23,114.58,110.83,108.67,68.19
HRMS(ESI/LTQ阱质谱):
计算C17H11Br2O5(M+H+):454.8948,
发现:454.8941。
实施例35
5-(2,4-二溴苯基)氧基)-N-(2-(5-甲氧基-1H-吲哚-3-基)乙基)-4-氧代-4H-色
烯-2-甲酰胺(7a)的制备
[化学式67]
将6a(0.074g,0.16mmol)溶解于2mL无水DMF中。随后,向溶液中依次添加DIEA(0.084g,0.65mmol)和TBTU(0.105g,0.33mmol)。完全溶解后,添加5-甲氧基色胺(0.074g,0.33mmol),并在室温下搅拌所得溶液24小时。通过TLC(环己烷/乙酸乙酯1:4)监测反应。
将反应混合物倒入酸化水(1M HCl)中并用二氯甲烷萃取(3次)。收集有机相并用酸化水(1M HCl)、碱化水(10%NaOH)和盐水洗涤(一次),然后经MgSO4干燥、过滤和蒸发。所得油用几滴乙醚沉淀。
过滤后,使用12g硅胶柱纯化粗产物,并将环己烷/二氯甲烷4:1至100%二氯甲烷作为洗脱剂。第一个产物洗脱后,使用9:1二氯甲烷/甲醇获得所需产物。所需产物7a(0.006g,5.6%)为固体。C28H22Br2N2O5
1H NMR(500MHz,CDCl3)δ8.12(d,J=8.4Hz,1H),8.00(s,1H),7.72(d,J=1.9Hz,1H),7.60-7.55(m,2H),7.31(d,J=8.8Hz,1H),7.10(dd,J=9.8,2.3Hz,2H),7.05(s,1H),6.95-6.89(m,3H),6.85(dd,J=8.4,0.5Hz,1H),5.16(s,2H),3.84-3.78(m,5H),3.11(t,J=6.6Hz,2H)
13C NMR(126MHz,CDCl3)δ177.59,159.14,158.11,157.22,154.32,152.90,134.78,134.48,134.36,131.54,131.28,130.13,127.80,122.96,121.80,121.15,115.29,113.68,112.63,112.36,112.17,110.59,108.41,100.40,69.86,55.84,40.52,24.94
HRMS(ESI/LTQ阱质谱):
计算C28H23Br2N2O5(M+H+):626.9948,
发现:626.9929。
实施例36
((3,5-二溴苯基)氧基)-N-(2-(5-甲氧基-1H-吲哚-3-基)乙基)-4-氧代-4H-色
烯-2-甲酰胺(7b)的制备
[化学式68]
将6b(0.100g,0.22mmol)溶解于无水DMF(10mL)中并搅拌直至完全溶解。然后向溶液中加入(1H-苯并三唑-1-基氧基)(三-1-吡咯烷基)六氟磷酸膦(PyBOP)偶联剂(0.195g,0.44mmol),然后添加DIEA(0.114g,0.88mmol)。溶液在室温下搅拌1小时。颜色发生了变化。
然后加入5-甲氧基色胺(0.100g,0.44mmol),并在室温下搅拌溶液2天。在环己烷/乙酸乙酯1:1薄层色谱中无变化的情况下,向溶液中加入双(2-氧代-1,3-恶唑烷-3-基)氯化膦(BOP-Cl)(0.112g,0.44mmol)。2天后,1:1环己烷/乙酸乙酯薄层色谱显示产物形成。
蒸发反应混合物并倒入乙酸乙酯中。用碱化水(饱和K2CO3),然后用酸化水(1MHCl)和盐水洗涤有机相(3次)。有机层经MgSO4干燥并蒸发以获得棕色固体。
使用干燥样品和洗脱液(例如100%二氯甲烷,然后是2.4:0.1二氯甲烷/甲醇)通过硅胶柱色谱法纯化固体。将5mL的馏分在通风柜中保存过夜,以沉淀所需产物。过滤后,获得所需产物7b(0.007g,6.6%)。C28H22O5N2Br2
1H NMR(400MHz,DMSO)δ10.71(s,1H),9.23(t,J=5.8Hz,1H),7.94(d,J=1.3Hz,2H),7.85-7.79(m,2H),7.30(d,J=8.4Hz,1H),7.24(d,J=8.7Hz,1H),7.19(d,J=2.1Hz,1H),7.12-7.06(m,2H),6.76-6.70(m,2H),5.30(s,2H),3.75(s,3H),3.58(dd,J=14.2,6.6Hz,2H),2.97(t,J=7.4Hz,2H)
13C NMR(126MHz,DMSO)δ177.14,159.37,157.83,157.49,154.21,153.51,142.26,135.54,132.78,131.88,128.94,128.03,123.91,122.94,114.95,112.57,112.53,111.72,111.56,111.36,109.32,100.65,68.76,55.81,25.35
HRMS(ESI/LTQ阱质谱):
计算C28H23O5N2Br2(M+H+):626.9948,
发现:26.9937。
实施例37
生物学评价
材料
高葡萄糖DMEM(Dulbecco/Vogt改良Eagle's最低培养基)和GlutaMAXTM(Gibco)以及胎牛血清(FBS,GE Healthcare Hyclone)购自Fisher Scientific。青霉素/链霉素(10000U/10mg/ml)、G418、胰蛋白酶和Dulbecco磷酸盐缓冲盐水(DPBS)购自Sigma-Aldrich(法国),以及米托蒽醌(MX)、罗丹明123(R123)、钙黄绿素AM(cAM)和3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化铵(MTT)。所有商业产品的纯度都是最高的。
化合物
所有色酮衍生物溶解在二甲基亚砜(DMSO)中,然后在高糖DMEM中稀释。储备溶液储存在-20℃下,并在使用前加热至25℃。
细胞系与培养物
如前所述生成ABCB1转染NIH/3T3、ABCC1转染Flp-In 293和ABCG2转染HEK293细胞及其空质粒对应物(Borst,P.;Elferink,R.O.Mammalian ABC Transporters in Healthand Disease.Annu.Rev.Biochem.2002,71(1),537-592)。
具体而言,使用藻红蛋白偶联5D3抗体(Santa Cruz Biotech)作为内源性表达报告基因,在荧光激活细胞分选(FACS)后选择ABCG2转染的HEK293单克隆细胞系。
在37℃、含5%CO2的潮湿空气中,细胞在添加10%热灭活胎牛血清(FBS)和1%青霉素/链霉素的GlutaMAXTM的高葡萄糖DMEM中生长和维持。此外,将200μg/mL潮霉素B、90ng/mL秋水仙碱或750μg/mL G418分别添加到生长培养基中,作为NIH/3T3,Flp-In293或HEK293转染的细胞的选择剂。
细胞毒性试验
如以下文献所述,使用比色MTT法测定化合物的细胞毒性(Linton,K.J.Structureand Function of ABC Transporters.Physiology 2007,22(2),122-130.Sharom,F.J.ABCMultidrug Transporters:Structure,Function and Role in Chemoresistance.Pharmacogenomics 2008,9(1),105-127)。
简单地说,细胞以1×105个细胞/孔的密度接种在96孔板中,总生长培养基体积为100μL,并培养过夜。然后,向每个孔中加入100μL新鲜培养基,该培养基含有浓度增加的待测化合物(溶解在浓度范围为0、2和20μM的DMSO中),同时将DMSO对照固定在0.5%(v/v)。培养72小时后,向每个孔中添加22μL PBS中的MTT染料(5mg/mL),并在37℃下将培养板再培养4小时。移除培养基并干燥后,用200μLDMSO/乙醇(1:1,v/v)溶解甲染料晶体。以570nm和690nm为参考波长,采用分光光度法测定吸光度。每种化合物对所有细胞系中细胞活力的影响计算为试验培养基孔和对照培养基孔之间吸光度的差异。
根据本发明所述的化合物的细胞毒性结果如表1所示。
因此,根据本发明所述的化合物具有非常低的细胞毒性或无细胞毒性。
耐多药相关药物外排抑制试验
将细胞接种在密度为5x104个细胞/孔的96孔板中,并在200μL培养基中培养过夜。然后将生长培养基改为含有化合物的新鲜培养基,并在最终浓度为0.5%(v/v)DMSO的条件下,在4μM MX存在下作为BCRP介导流出的荧光探针。在37℃下培养30分钟后,移除培养基,用100μL Dulbecco磷酸盐缓冲盐水(DPBS)清洗细胞,然后在25μL胰蛋白酶介导下在37℃下分离细胞5分钟。最后,用175μL DPBS冰镇和2%牛血清白蛋白(BSA)中和胰蛋白酶,并小心地重新悬浮细胞。作为一种选择性试验,使用0.5μM R123或0.2μM cAM作为各自的荧光底物而不是MX,对P-gp和MRP1介导的外排进行相同的实验。
使用MacsQUANT VRB分析仪流式细胞仪(Miltenyi Biotec)测量细胞内荧光,至少记录5000个事件。MX在635nm处激发,荧光发射记录在655-730nm窗口中,R123和cAM在488nm处激发,并记录在525/50nm滤光片中。化合物抑制率由以下方程式估算:
[数学式1]
其中,G2FA是表达与荧光底物和试验化合物孵育的流出泵的细胞中累积荧光团的荧光发射(a.u.)。G2FBG是转染ABCG2(无底物或试验化合物)的细胞中产生的背景荧光发射(a.u.)。G2S是仅与底物孵育的表达外排泵的细胞中累积荧光团的荧光发射(a.u.)。HEKFA是与底物和试验化合物一起孵育的对照细胞中累积荧光团的荧光发射(a.u.)。HEKFBG是在对照细胞(无底物或试验化合物)中产生的背景荧光发射(a.u.)。所有值均以655-730nm滤光片(635nm激发)中的几何平均荧光发射(a.u.)形式给出,其中在5000次事件中测量得到。试验一式三份进行。
色酮作为ABCG2抑制剂的活性
[表2]
上表显示化合物显示出良好的IC50值。特别是,系列1中的化合物5d、系列2中的化合物7a和7b以及系列III中的化合物7a显示出比MBL-II-141抑制剂和参考抑制剂Ko143更好的结果。
BCRP与P-gp和MRP1的色酮选择性
[表3]
Claims (11)
1.一种式(I)所示化合物:
[化学式69]
或其药学上可接受的对映异构体、盐或溶剂化物,或其混合物,
其中:
环A未取代或在2、3、4、5位被F;Cl;Br;OR中的一或二个取代;其中R=Me、Et、Pr、i-Pr、n-Bu;O-CH2-(O-CH2CH2)n-O-CH3,其中n=3,4,5,6,
Z是
[化学式70]
Y=-OH;-OMe;-OEt;-OPr;-NH2;-NHMe;-N(Me)2;-N(Me)OCH3;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH-CH(R3)-COR2,
其中R2选自:
-OH;-OMe;-OEt;-OPr;-NH2;-NHMe;-N(Me)2;-N(Me)OCH3;3-(5-甲氧基)吲哚基;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH(CH2)2-3-((5-甲氧基)吲哚基)
[化学式71]
在式(I)中,Y的取代基-NH-CH(R3)-COR2的R3独立地选自:H或
[化学式72]
[化学式73]
[化学式74]
[化学式75]
除了在环A的4位同时具有Br的化合物,R1=CH(CH3)2或CH2CH(CH3)2或CH(CH3)CH2CH3,Z=
[化学式76]
Y=-OH或-OMe。
2.根据权利要求1所述的化合物,其特征在于,环A在2、3、4、5位被1个或2个Br取代并且Y=-OH;-OMe;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH-CH(R3)-COR2、R1、R2和R3如权利要求1所述。
4.根据权利要求1至3中任一项所述的化合物,其特征在于,选自:
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-亮氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-缬氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸酯;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸酯;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-色氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-色氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-D-色氨酸;
(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异亮氨酸;
(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸;
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸;
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-D-色氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-缬氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-亮氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-缬氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-亮氨酸;
(S)-5-((2-溴苯基)氧基)-N-(1-((2-(5-羟基-1H-吲哚-3-基)乙基)氨基)-1-氧代-3-苯丙烷-2-基)-4-氧代-4H-色烯-2-甲酰胺;
(S)-N-(1-((2-(1H-吲哚-3-基)乙基)氨基)-1-氧代-3-苯丙烷-2-基)-5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-甲酰胺;和
(R)-N-(1-((2-(1H-吲哚-3-基)乙基)氨基)-3-(1H-吲哚-3-基)-1-氧丙烷-2-基)-5-((4-溴代苯)氧基)-4-氧代-4H-色烯-2-甲酰胺。
5.一种获得如权利要求1至4中任一项所述化合物的方法,其特征在于,其包含以下步骤:
(a)式所示的烷基化化合物
[化学式80]
其中,环A如权利要求1所述,X为选自F、Cl、Br和I的卤素,在丙酮中,在丙酮的回流温度下,与式所示2,6-二羟基苯乙酮反应,
[化学式81]
得到式82所示的中间体
[化学式82]
(b)步骤(a)中获得的中间体,在0℃-50℃的温度下,在四氢呋喃(THF)/乙醇(1:1)的混合物中,与式83所示的草酸二乙酯反应
[化学式83]
得到式84所示的中间体
[化学式84]
(c)步骤(b)中获得的中间体在50℃温度下,在酸性或碱性介质中,在THF/乙醇/水溶剂(3:1:1.5)中通过酯官能团的水解反应进行反应,以获得式85所示的中间体
[化学式85]
(d)步骤(c)中获得的中间体,在室温下,在无水DMF中形成酰胺键,与式86所示的偶联化合物反应
[化学式86]
R1、Z和Y如权利要求1所定义,得到式(I)所示化合物。
6.一种式(I)所示化合物:
[化学式87]
或其药学上可接受的对映异构体、盐或溶剂化物,或其混合物,
其中:
环A未取代或在2、3、4、5位被F;Cl;Br;I;OR中的一或二个取代;其中R=Me、Et、Pr、i-Pr、n-Bu;O-CH2-(O-CH2CH2)n-O-CH3,其中n=3,4,5,6,
Z是
[化学式88]
Y=-OH;-OMe;-OEt;-OPr;-NH2;-NHMe;-N(Me)2;-N(Me)OCH3;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH-CH(R3)-COR2,
其中R2选自:
-OH;-OMe;-OEt;-OPr;-NH2;-NHMe;-N(Me)2;-N(Me)OCH3;3-(5-甲氧基)吲哚基;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH(CH2)2-3-((5-甲氧基)吲哚基)
[化学式89]
在式(I)中,Y的取代基-NH-CH(R3)-COR2的R3独立地选自:H或
[化学式90]
[化学式91]
[化学式92]
[化学式93]
用于抑制乳腺癌的多药耐药蛋白(乳腺癌耐药蛋白BCRP/ABCG2)。
7.根据权利要求6所述的供使用的化合物,其特征在于,环A在2、3、4、5位被1个或2个Br取代并且Y=-OH;-OMe;-NH-(CH2)2-(3-吲哚基);-NH(CH2)2-3-((5-羟基)吲哚基);-NH-CH(R3)-COR2、R1、R2和R3如权利要求6所定义。
9.根据权利要求6至8中任一项所述的供使用的化合物,其特征在于,选自:
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-亮氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-缬氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸酯;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸酯;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-色氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-色氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-D-色氨酸;
(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸;
(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸;
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-苯丙氨酸;
(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-D-色氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-缬氨酸;
甲基(5-((2-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-亮氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异异亮氨酸-L-缬氨酸;
甲基(5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-羰基氨基)-L-异亮氨酸-L-亮氨酸;
(S)-5-((2-溴苯基)氧基)-N-(1-((2-(5-羟基-1H-吲哚-3-基)乙基)氨基)-1-氧代-3-苯丙烷-2-基)-4-氧代-4H-色烯-2-甲酰胺;
(S)-N-(1-((2-(1H-吲哚-3-基)乙基)氨基)-1-氧代-3-苯丙烷-2-基)-5-((4-溴苯基)氧基)-4-氧代-4H-色烯-2-甲酰胺,以及
(R)-N-(1-((2-(1H-吲哚-3-基)乙基)氨基)-3-(1H-吲哚-3-基)-1-氧丙烷-2-基)-5-((4-溴代苯)氧基)-4-氧代-4H-色烯-2-甲酰胺。
10.一种药物组合物,包含:
至少一种医药上可接受的活性剂;和
如权利要求1至4中任一项所述的至少一种化合物。
11.根据权利要求10所述的药物组合物,其特征在于,所述药学上可接受的活性剂选自抗癌剂、肠道抗炎剂、低胆固醇剂、抗血脂异常剂及激酶抑制剂。
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US20220267289A1 (en) | 2022-08-25 |
JP2022541334A (ja) | 2022-09-22 |
FR3099156B1 (fr) | 2022-01-28 |
CA3148804A1 (fr) | 2021-01-28 |
WO2021014229A1 (fr) | 2021-01-28 |
EP4003969A1 (fr) | 2022-06-01 |
FR3099156A1 (fr) | 2021-01-29 |
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