CN110016052B - N-去乙基舒尼替尼的磷酰胺衍生物及其制备方法 - Google Patents
N-去乙基舒尼替尼的磷酰胺衍生物及其制备方法 Download PDFInfo
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- CN110016052B CN110016052B CN201811351118.3A CN201811351118A CN110016052B CN 110016052 B CN110016052 B CN 110016052B CN 201811351118 A CN201811351118 A CN 201811351118A CN 110016052 B CN110016052 B CN 110016052B
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Abstract
本发明涉及一种通式(I)所示的N‑去乙基舒尼替尼的磷酰胺衍生物、其立体异构体或药学上可以接受的盐、其制备方法以及含有它们的药物组合物以及在制备多靶点受体酪氨酸激酶抑制剂药物中的用途。
Description
技术领域
本发明涉及一种N-去乙基舒尼替尼的磷酰胺衍生物、其制备方法及其应用。具体的说,本发明涉及一种通式(I)所示的N-去乙基舒尼替尼的磷酰胺衍生物、其立体异构体或药学上可以接受的盐、其制备方法以及含有它们的药物组合物以及在制备多靶点受体酪氨酸激酶抑制剂药物中的用途。
背景技术
索坦/Sutent(苹果酸舒尼替尼胶囊,Sunitinib Malate Capsules),是由辉瑞公司生产的一种口服的小分子多靶点受体酪氨酸激酶抑制剂。该药上市十几年来,基于大量临床研究证据,已被多个国家和地区的医学指南推荐作为晚期肾细胞癌的一线治疗药物(如美国、加拿大、欧洲、中国等)。该药在中国的适应症为:(1)甲磺酸伊马替尼治疗失败或不能耐受的胃肠间质瘤 (GIST);(2)不能手术的晚期肾细胞癌(RCC);(3)不可切除的、转移性高分化进展期胰腺神经内分泌瘤(pNET)成年患者。在国内晚期肾细胞癌的治疗方面,由于其起效迅速、耐受性良好,能够快速控制肿瘤症状、与其他靶向药物相比具有较高的临床有效率、能够有效的控制肿瘤的进展,已得到泌尿外科医生和肿瘤内科医生的普遍认可。此外,索坦在肝癌上的临床研究也进入到三期,并体现出显著的效果。
索坦的主要成分是舒尼替尼苹果酸盐,舒尼替尼是一个小分子,化学名称是(Z)-N-(2-(二乙基氨基)乙基)-5-[(5-氟-2-氧代-1,2-二氢-3H-吲哚-3-亚基)甲基]-2,4-二甲基-3-氨甲酰-1H-吡咯。舒尼替尼能抑制多种受体酪氨酸激酶(RTKs),其中有些涉及肿瘤生长,病理性血管生成和癌症转移进展。通过评价舒尼替尼对各种各样激酶(>80种激酶)的抑制活性,该化合物被鉴定为血小板衍生生长因子受体(PDGFRα和PDGFRβ)、血管内皮生长因子受体(VEGFR1、VEGFR2和 VEGFR3),干细胞因子受体(KIT)、FMS样酪氨酸激酶受体3(FLT3)、集落刺激因子受体类型 1(CSF-1R)和神经胶质细胞系衍生神经营养因子受体(RET)的抑制剂。
在辉瑞向FDA提交的关于索坦的《Pharmacology Review》(以下简称报告)中提到舒尼替尼有8个代谢产物。而且在生化和细胞分析中,这些主要代谢物表现出与舒尼替尼比较相似的效力。N-去乙基舒尼替尼即是其中的一个代谢产物,报告中提到它对多个受体的酪氨酸激酶 (RTKs)、血管内皮生长因子受体(VEGFR-2)、血小板生长因子受体α与β(PDGFR-α与-β) 以及KIT等的抑制活性与舒尼替尼相近。并且在药代动力学相关数据(比如:Cmax、Tmax、T1/2,AUC0-∞等)中,N-去乙基舒尼替尼大部分与舒尼替尼相当,甚至在某些方面,N-去乙基舒尼替尼还要优于舒尼替尼。N-去乙基舒尼替尼作为舒尼替尼的活性代谢产物,在舒尼替尼抑制肿瘤血管生成和抗肿瘤细胞生长的过程中发挥着重大的作用。
本发明发现磷酰胺的引入可以通过磷酰胺基团改变药物的物理化学性质,如药物的性状、稳定性、脂溶性、P-gp底物性质等,进而改变体内吸收代谢分布的特征。磷酰修饰的药物进入体内后,在体内水解酶作用下水解释放出原药。通过控制磷酰胺药物水解速率可以延长药物体内的存在时间,也可以通过水解酶的分布等特点达到提高药物对靶部位的特异性作用给药的目的。
特别是,利用该前药技术可以显著地提高N-去乙基舒尼替尼的的肝靶向性,提高其在肝组织中的药物浓度,更有利于其发挥其在肝癌中治疗效果。同时这种靶向性能有望降低给药剂量,降低药物在血液中的浓度,从而有利于降低其毒副作用。
本发明提供一种新颖的N-去乙基舒尼替尼的磷酰胺衍生物,并发现此类结构的化合物表现出优异的效果和作用。可以显著地提高N-去乙基舒尼替尼的的肝靶向性,提高其在肝组织中的药物浓度。可以提高口服生物利用度、减少给药剂量和频率、提高病人使用顺应性、减少食物影响、减少药物对胃肠道刺激、降低毒副作用、提高安全性、延长半衰期、延长作用时间等优点。
发明内容
本发明提供一种通式(I)所示的化合物及其立体异构体或其药学上可接受的盐,其中:
R1a或R2a各自独立的选自H、C1-6烷基或者天然或可药用的氨基酸侧链;
R1b或R2b各自独立的选自C1-6烷基;
X和Y各自独立的选自O、N或者不存在;
R3和R4各自独立的选自不存在、C1-4烷基、C3-6环烷基、-C(=O)-或者苯环基,所述的烷基、环烷基或者苯环基可任选进一步被0至4个选自F、Cl、Br、I、氰基、氨基、羧基、-C1-4烷基或-O-C1-4烷基的取代基所取代;
n选自0、1或者2。
本发明优先方案,一种通式(I)所示的化合物及其立体异构体或其药学上可接受的盐,其中:
R1a或R2a各自独立的选自H、C1-6烷基或者天然或可药用的氨基酸侧链,所述氨基酸优选丙氨酸;
R1b或R2b各自独立的选自C1-6烷基,优选甲基、乙基、丙基或异丙基;
R3选自不存在、C1-4烷基、C3-6环烷基或者-C(=O)-,优选-C(=O)-,所述的烷基或环烷基可任选进一步被0至4个选自F、Cl、Br、-O-C1-4烷基的取代基所所取代,优选被0至4个-O-C1-4烷基所取代,更优选被0-1个甲氧基所取代;
R4选自C1-4烷基、C3-6环烷基或苯环基,优选C1-4烷基或者苯环基,更优选苯环基,所述的烷基、环烷基或者苯环基可任选进一步被0至4个选自F、Cl、Br、-O-C1-4烷基的取代基所取代,更优选被0-1个甲氧基所取代;
n选自0或者1。
本发明还提供一种一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1-5中任一项所述的化合物及其立体异构体或药学上可以接受的盐,以及药学上可接受的载体或者赋形剂。
本发明还提供通式(I)所述的化合物、其立体异构体或其药学上可以接受的盐,在制备多靶点受体酪氨酸激酶抑制剂药物中的应用。
定义说明:
本发明所述基团和化合物中所涉及的元素碳、氢、氧、氮或卤素均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的元素碳、氢、氧或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“氨基”是指-NH2,可以是取代的或未取代的,当被取代时,取代基优选为1至3个,独立地选自烷基、烯基、炔基、烷氧基、烷巯基、羰基、氨基、烷基氨基、烷基酰氨基、杂环烷基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、羟基烷基、羧酸或羧酸酯。
“天然或可药用氨基酸”:蛋白质分子的基本骨架是氨基酸序列,组成蛋白质的基本氨基酸有20种,这20种基本氨基酸是生物进行蛋白后期修饰的基础,此外,在这些基本氨基酸的基础上,生物还会合成羟脯氨酸、羟赖氨酸等衍生出来的氨基酸类型,这些由生物合成的氨基酸统称为“天然氨基酸”;用人工方法合成的就是“非天然氨基酸”。“可药用氨基酸”是指在药学上可接受的天然或非天然氨基酸。
“氨基酸的侧链”是指共价连接至D或L-氨基酸结构并且可表示为CH(COOH)(NH2)-R 的部分。例如,在丙氨酸CH(COOH)(NH2)(CH3)的情况下,氨基酸(R)的侧链是-CH3。
本发明的“=O”为本领域通常习惯用法,是指以双键相连的氧原子,譬如羰基中与碳原子相连的双键氧原子。
“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐,包括无机酸和碱、有机酸和碱的盐。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物,其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。
本发明具体合成方法
I-A与三氯氧磷(或甲氧基甲基二氯化磷)反应,再与氨基酸酯反应得到通式I-B的化合物。通式I-B中间体与三光气反应之后,再与N-去乙基舒尼替尼反应得到通式(I)的化合物。
具体实施方式
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(BrukerAvanceIII400和BrukerAvance300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5 mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域己知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
氯气氛是指反应瓶连接一个约1L容积的氯气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空,充入氢气,反复操作3次。
实施例中无特殊说明,反应在氮气氛下进行。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温。
室温为最适宜的反应温度,为20℃~30℃。
本发明所用试剂的缩写:
EDCI:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;
HOBt:1-羟基苯并三唑;
THF:四氢呋喃;
DIPEA:二异丙基乙基胺;
Et3N:三乙基胺;
DMF:N,N-二甲基甲酰胺。
中间体1:N-[2-(乙基氨基)乙基]-5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H- 吡咯-3-甲酰胺(中间体1)
N-[2-(ethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyr role-3-carboxamide
氮气保护下,将5-[(Z)-(5-氟-2-氧代-二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-甲酸 (15g,49.95mmol)和四氢呋喃(300mL)加入反应瓶中,搅拌下得黄色悬浮液;搅拌下依次加入N-乙基乙二胺(5.28g,59.94mmol)、EDCI(11.63g,74.93mmol)和HOBt(8.10g, 59.94mmol),加完后室温搅拌反应20h。加入二氯甲烷(100mL)搅拌10min,过滤;滤饼加入甲醇(100mL)搅拌打浆2h,过滤;滤饼加入二氯甲烷(100mL)搅拌打浆2h,过滤,滤饼45℃真空干燥,得N-[2-(乙基氨基)乙基]-5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4- 二甲基-1H-吡咯-3-甲酰胺(中间体1),黄色固体13.12g,收率:70.91%。
MS m/z(ESI):371.2[M+H]+
1H NMR(400MHz,d6-DMSO)δ13.74(s,1H),10.93(s,1H),9.02(s,1H),7.91(t,1H),7.84– 7.60(m,2H),7.03–6.76(m,2H),3.69–3.46(m,2H),3.17–2.89(m,4H),2.50–2.43(m,6H), 1.23(t,3H).
实施例1:异丙基(2S)-2-[[[4-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代-二氢吲哚-3-亚基)甲基]二甲基 -1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯 (化合物1)
isopropyl
(2S)-2-[[[4-[[ethyl-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3 -carbonyl]amino]ethyl]carbamoyl]oxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propano ate
第一步:异丙基(2S)-2-[[[4-(羟甲基)苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(1A)
isopropyl
(2S)-2-[[[4-(hydroxymethyl)phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate
氮气保护下,将二氯甲烷(90mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷(8.96 g,55mmol),冷却至-30℃。加入L-丙氨酸异丙酯盐酸盐(9.22g,55mmol),缓慢滴入三乙胺(11.11g,110mmol)和二氯甲烷(5mL)的混合溶液,加完后-30℃反应30min。然后依次加入4-羟基苄醇(6.21g,50mmol)和三乙胺(5.05g,50mmol)加完后升至室温搅拌反应4h,然后加入水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到异丙基 (2S)-2-[[[4-(羟甲基)苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(1A),淡黄色透明油状物6.12g,收率:33.66%。
MS m/z(ESI):346.2[M+H]+
1H NMR(400MHz,CDCl3)δ7.39–7.08(m,4H),5.11–4.90(m,1H),4.68–4.50(m,2H),4.16–4.00(m,1H),3.85–3.54(m,3H),3.49–3.34(m,3H),2.87(br,1H),1.33–1.17(m,9H).
第二步:异丙基(2S)-2-[[[4-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代-二氢吲哚-3-亚基)甲基]二甲基 -1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯 (化合物1)
氮气保护下,将四氢呋喃(10mL)加入反应瓶中,加入异丙基(2S)-2-[[[4-(羟甲基)苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(1A,1.24g,3.6mmol)和二异丙基乙基胺(0.47g,3.6 mmol),冷却至0℃。滴入三光气(0.53g,1.8mmol)的四氢呋喃(3mL)溶液,加完后0℃反应30min。然后加入N-[2-(乙基氨基)乙基]-5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-甲酰胺(中间体1,1.11g,3mmol)的N’N-二甲基甲酰胺(10mL)溶液和二异丙基乙基胺(0.47g,3.6mmol),加完后升至室温搅拌反应5h,然后加入乙酸乙酯(100mL) 和水(100mL),搅拌5min,静置分层。有机层用饱和氯化钠溶液(100mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)10/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar80preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物1溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到异丙基(2S)-2-[[[4-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代-二氢吲哚-3- 亚基)甲基]二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物1),黄色固体0.42g,收率:18.90%。
MS m/z(ESI):742.3[M+H]+
1H NMR(400MHz,CDCl3)δ13.40(s,1H),8.77(d,1H),7.33–7.23(m,3H),7.23–7.11(m, 3H),6.87–6.71(m,2H),6.54(d,1H),5.18–4.88(m,3H),4.19–4.02(m,1H),3.88–3.69(m,2H), 3.66–3.47(m,4H),3.44–3.29(m,5H),2.48–2.29(m,6H),2.06(br,1H),1.36–1.29(m,3H), 1.25–1.20(m,6H),1.19–1.11(m,3H).
实施例2:异丙基(2S)-2-[[[5-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代-二氢吲哚-3-亚基)甲基]二甲基 -1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]-2-甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物2)
isopropyl
(2S)-2-[[[5-[[ethyl-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3 -carbonyl]amino]ethyl]carbamoyl]oxymethyl]-2-methoxy-phenoxy]-(methoxymethyl)phosphoryl]am ino]propanoate
第一步:异丙基(2S)-2-[[[5-(羟甲基)-2-甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯 (2A)
isopropyl
(2S)-2-[[[5-(hydroxymethyl)-2-methoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate
氮气保护下,将二氯甲烷(90mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷(8.96 g,55mmol),冷却至-30℃。加入L-丙氨酸异丙酯盐酸盐(9.22g,55mmol),缓慢滴入三乙胺(11.11g,110mmol)和二氯甲烷(5mL)的混合溶液,加完后-30℃反应30min。然后依次加入4-甲氧基-3-羟基苄醇(7.50g,50mmol)和三乙胺(5.05g,50mmol)加完后升至室温搅拌反应4h,然后加入水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到异丙基(2S)-2-[[[5-(羟甲基)-2-甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(2A),淡黄色透明油状物6.51g,收率:35.64%。
MS m/z(ESI):376.1[M+H]+
1H NMR(400MHz,CDCl3)δ7.33–7.25(m,1H),7.20–7.05(m,1H),6.95–6.84(m,1H),5.06–4.90(m,1H),4.59–4.49(m,2H),4.09–3.98(m,1H),3.91–3.75(m,6H),3.53–3.44(m,3H),3.27(br,1H),1.41–1.17(m,9H).
第二步:异丙基(2S)-2-[[[5-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代-二氢吲哚-3-亚基)甲基]二甲基 -1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]-2-甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物2)
氮气保护下,将四氢呋喃(10mL)加入反应瓶中,加入异丙基(2S)-2-[[[5-(羟甲基)-2-甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(2A,2.25g,6mmol)和二异丙基乙基胺(0.78 g,6mmol),冷却至0℃。滴入三光气(0.89g,3mmol)的四氢呋喃(5mL)溶液,加完后 0℃反应30min。然后加入N-[2-(乙基氨基)乙基]-5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4- 二甲基-1H-吡咯-3-甲酰胺(中间体1,1.85g,5mmol)的N’N-二甲基甲酰胺(20mL)溶液和二异丙基乙基胺(0.78g,6mmol),加完后升至室温搅拌反应5h,然后加入乙酸乙酯(100 mL)和水(100mL),搅拌5min,静置分层。有机层用饱和氯化钠溶液(100mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)10/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar80preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL /min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物2溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到异丙基(2S)-2-[[[5-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代-二氢吲哚-3-亚基)甲基]二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]-2-甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物2),黄色固体1.12g,收率:29.05%。
1H NMR(400MHz,CDCl3)δ13.34(s,1H),8.94(s,1H),7.58–7.31(m,1H),7.27–7.19(m, 1H),7.19–7.03(m,2H),6.97–6.54(m,4H),5.14–4.84(m,3H),4.13–3.99(m,1H),3.92–3.76 (m,5H),3.64–3.30(m,9H),2.43(d,1H),2.35(d,6H),1.30–1.16(m,12H).
实施例3:乙基(2S)-2-[[[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]-[4-[[乙基-[2-[[5-[(Z) -(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]苯氧基]磷酰基]氨基]丙酸乙酯(化合物3)
Ethyl(2S)-2-[[[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]-[4-[[ethyl-[2-[[5-[(Z)-(5-fluoro-2-o xo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl]amino]ethyl]carbamoyl]oxymeth yl]phenoxy]phosphoryl]amino]propanoate
第一步:乙基(2S)-2-[[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]-[4(羟甲基)苯氧基] 磷酰基]氨基]丙酸乙酯(3A)
Ethyl(2S)-2-[[[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]-[4-(hydroxymethyl)phenoxy]phosp horyl]amino]propanoate
无水无氧处理,氮气保护,将3-羟基苄醇(5.0g,40.3mmol)加入到反应瓶中,加入二氯甲烷(40mL),降温至-78℃,加入三氯氧磷(6.30g,41.1mmol)。将三乙胺(4.88g,48.36mmol) 用四氢呋喃(10mL)稀释,于1分钟内缓慢滴加到反应中,加完保持温度反应30分钟。加入L-丙氨酸乙酯盐酸盐(13.0g,84.6mmol)和三乙胺(17.51g,173.5mmol),升温至室温下反应2小时。然后加入水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到乙基(2S) -2-[[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]-[4(羟甲基)苯氧基]磷酰基]氨基]丙酸乙酯(3A),淡黄色透明油状物4.10g,收率:25.3%。
第二步:
乙基(2S)-2-[[[[(1S)-2-乙氧基-1-甲基-2-氧代-乙基]氨基]-[4-[[乙基-[2-[[5-[(Z)-(5- 氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基] 苯氧基]磷酰基]氨基]丙酸乙酯(化合物3)
Ethyl(2S)-2-[[[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]-[4-[[ethyl-[2-[[5-[(Z)-(5-fluoro-2-o xo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl]amino]ethyl]carbamoyl]oxymeth yl]phenoxy]phosphoryl]amino]propanoate
氮气保护下,将四氢呋喃(10mL)加入反应瓶中,加入乙基(2S)-2-[[[(1S)-2-乙氧基 -1-甲基-2-氧代-乙基]氨基]-[4(羟甲基)苯氧基]磷酰基]氨基]丙酸乙酯(3A)(1.41g,2.84mmol) 和二异丙基乙基胺(0.35g,2.84mmol),冷却至0℃。加入三光气(0.36g,1.22mmol)加完后0℃反应30min。然后加入N-[2-(乙基氨基)乙基]-5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-甲酰胺(中间体1,1.00g,2.7mmol)的N’N-二甲基甲酰胺(20mL) 溶液和二异丙基乙基胺(0.7g,5.7mmol),加完后升至室温搅拌反应5h,然后加入乙酸乙酯(100mL)和水(100mL),搅拌5min,静置分层。有机层用饱和氯化钠溶液(100mL×2) 洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇= (v/v)10/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物2 溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到乙基(2S)-2-[[[[(1S)-2-乙氧基-1-甲基-2- 氧代-乙基]氨基]-[4-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H- 吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]苯氧基]磷酰基]氨基]丙酸乙酯(化合物3),橙红色固体0.68g,收率:32%。
MS m/z(ESI):400.3[M+2H]/2+
1H NMR(400MHz,d6-DMSO)δ13.74–13.60(m,1H),10.89–10.81(m,1H),7.79–7.58(m, 3H),7.38–7.25(m,2H),7.22–7.08(m,2H),6.99–6.77(m,2H),5.29–5.11(m,2H),5.03(s,2H), 4.07(m,4H),3.92–3.73(m,2H),3.43–3.33(m,4H),2.41(d,6H),1.28–1.03(m,17H).
实施例4:异丙基(2S)-2-[[[4-[[乙基-[2-[[5[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4- 二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]苯氧基]-[[(1S)-2-异丙氧基-1-甲基 -2-氧代-乙基]氨基]磷酰基]氨基]丙酸乙酯(化合物4)
Isopropyl(2S)-2-[[[4-[[ethyl-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethy l-1H-pyrrole-3-carbonyl]amino]ethyl]carbamoyl]oxymethyl]phenoxy]-[[(1S)-2-isopropoxy-1-methyl -2-oxo-ethyl]amino]phosphoryl]amino]propanoate
第一步:异丙基(2S)-2-[[[4-(羟甲基)苯氧基]-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基] 氨基]磷酰基]氨基]丙酸乙酯(4A)
Isopropyl(2S)-2-[[[4-(hydroxymethyl)phenoxy]-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]ami no]phosphoryl]amino]propanoate
无水无氧处理,氮气保护,将3-羟基苄醇(5.0g,40.3mmol)加入到反应瓶中,加入二氯甲烷(40mL),降温至-78℃,加入三氯氧磷(6.30g,41.1mmol)。将三乙胺(4.88g,48.36mmol) 用四氢呋喃(10mL)稀释,于1分钟内缓慢滴加到反应中,加完保持温度反应30分钟。加入L-丙氨酸异丙酯盐酸盐(13.5g,84.6mmol)和三乙胺(17.51g,173.5mmol),升温至室温下反应2小时。然后加入水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到异丙基(2S) -2-[[[4-(羟甲基)苯氧基]-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸乙酯(4A),淡黄色透明油状物4.50g,收率:26.3%。
第二步:异丙基(2S)-2-[[[4-[[乙基-[2-[[5[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4- 二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]苯氧基]-[[(1S)-2-异丙氧基-1-甲基 -2-氧代-乙基]氨基]磷酰基]氨基]丙酸乙酯(化合物4)
Isopropyl(2S)-2-[[[4-[[ethyl-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethy l-1H-pyrrole-3-carbonyl]amino]ethyl]carbamoyl]oxymethyl]phenoxy]-[[(1S)-2-isopropoxy-1-methyl -2-oxo-ethyl]amino]phosphoryl]amino]propanoate
氮气保护下,将四氢呋喃(10mL)加入反应瓶中,加入异丙基(2S)-2-[[[4-(羟甲基) 苯氧基]-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸乙酯(4A)(0.976g, 2.26mmol)和二异丙基乙基胺(0.28g,2.16mmol),冷却至0℃。加入三光气(0.26g,0.86 mmol)加完后0℃反应30min。然后加入N-[2-(乙基氨基)乙基]-5-[(Z)-(5-氟-2-氧代二氢吲哚-3- 亚基)甲基]-2,4-二甲基-1H-吡咯-3-甲酰胺(中间体1,0.80g,2.16mmol)的N’N-二甲基甲酰胺(20mL)溶液和二异丙基乙基胺(0.56g,4.3mmol),加完后升至室温搅拌反应5h,然后加入乙酸乙酯(100mL)和水(100mL),搅拌5min,静置分层。有机层用饱和氯化钠溶液(100mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)10/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物2溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到异丙基(2S)-2-[[[4-[[乙基 -[2-[[5[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]苯氧基]-[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]磷酰基]氨基]丙酸乙酯(化合物4),橙红色固体0.90g,收率:50.4%。
MS m/z(ESI):414.1[M+2H]/2+
1H NMR(400MHz,d6-DMSO)δ13.68(s,1H),10.86(s,1H),7.78–7.60(m,3H),7.33(d,2H),7.15(d,2H),6.89-6.83(m,2H),5.22–5.08(m,2H),5.03(s,2H),4.95–4.77(m,2H),3.90– 3.73(m,2H),3.37-3.28(m,4H),2.42(d,6H),1.26-1.06(m,23H).
实施例5:乙基(2S)-2-[[[4-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4- 二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]苯氧基]-(甲氧基甲基)磷酰基]氨基] 丙酸乙酯(化合物5)
Ethyl(2S)-2-[[[4-[[ethyl-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H -pyrrole-3-carbonyl]amino]ethyl]carbamoyl]oxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amin o]propanoate
第一步:乙基(2S)-2-[[[4-(羟甲基)苯氧基](甲氧基甲基)氨基]丙酸乙酯(5A)
ethyl(2S)-2-[[[4-(hydroxymethyl)phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate
氮气保护下,将二氯甲烷(90mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷(6.89 g,40.3mmol),冷却至-30℃。加入L-丙氨酸乙酯盐酸盐(6.5g,40.3mmol),缓慢滴入三乙胺(10.9g,107mmol)和二氯甲烷(5mL)的混合溶液,加完后-30℃反应30min。然后依次加入4-羟基苄醇(5.0g,40.3mmol)和三乙胺(5.43g,53mmol)加完后升至室温搅拌反应4h,然后加入水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到乙基(2S)-2-[[[4-(羟甲基)苯氧基](甲氧基甲基)氨基]丙酸乙酯(5A),淡黄色透明油状物3.20g,收率:24.0%。
第二步:乙基(2S)-2-[[[4-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4- 二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]苯氧基]-(甲氧基甲基)磷酰基]氨基] 丙酸乙酯(化合物5)
Ethyl(2S)-2-[[[4-[[ethyl-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H -pyrrole-3-carbonyl]amino]ethyl]carbamoyl]oxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amin o]propanoate
氮气保护下,将四氢呋喃(10mL)加入反应瓶中,加入乙基(2S)-2-[[[4-(羟甲基)苯氧基](甲氧基甲基)氨基]丙酸乙酯(5A)(0.94g,2.84mmol)和二异丙基乙基胺(0.35g,2.7mmol),冷却至0℃。滴入三光气(0.36g,1.22mmol)的四氢呋喃(5mL)溶液,加完后0℃反应30min。然后加入N-[2-(乙基氨基)乙基]-5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-甲酰胺(中间体1,1.0g,2.7mmol)的N’N-二甲基甲酰胺(20mL)溶液和二异丙基乙基胺(0.70g,5.4mmol),加完后升至室温搅拌反应5h,然后加入乙酸乙酯(100mL)和水(100mL),搅拌5min,静置分层。有机层用饱和氯化钠溶液(100mL×2) 洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇= (v/v)10/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80preparativeSFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物2 溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到乙基(2S)-2-[[[4-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基] 苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸乙酯(化合物5),橘红色固体0.78g,收率:40%。
MS m/z(ESI):728.3[M+H]+
1H NMR(400MHz,d6-DMSO)δ13.68(s,1H),10.87(s,1H),7.77-7.65(m,3H),7.40-7.34(m, 2H),7.15(t,2H),6.98–6.80(m,2H),5.68(dd,1H),5.04(s,2H),4.09–3.69(m,5H),3.43–3.34 (m,7H),2.41(d,6H),1.23–1.06(m,11H).
实施例6:乙基(2S)-2-[[[5-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4- 二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]-2-甲氧基-苯氧基]-(甲氧基甲基) 磷酰基]氨基]丙酸乙酯(化合物6)
Ethyl(2S)-2-[[[5-[[ethyl-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H -pyrrole-3-carbonyl]amino]ethyl]carbamoyl]oxymethyl]-2-methoxy-phenoxy]-(methoxymethyl)phos phoryl]amino]propanoate
第一步:乙基(2S)-2-[[[5-(羟甲基)-2-甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基] 丙酸乙酯(6A)
Ethyl(2S)-2-[[[5-(hydroxymethyl)-2-methoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]pr opanoate
氮气保护下,将二氯甲烷(90mL)加入反应瓶中,搅拌下加入(甲氧基甲基)二氯化磷(5.6 g,30.1mmol),冷却至-30℃。加入L-丙氨酸乙酯盐酸盐(9.22g,55mmol),缓慢滴入三乙胺(9.9mL,86.5mmol)和二氯甲烷(5mL)的混合溶液,加完后-30℃反应30min。然后依次加入4-甲氧基-3-羟基苄醇(5.0g,32.4mmol)和三乙胺(5.9g,43.2mmol)加完后升至室温搅拌反应4h,然后加入水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到乙基(2S)-2-[[[5-(羟甲基)-2-甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸乙酯(6A),淡黄色透明油状物4.8g,收率:41.0%。
第二步:乙基(2S)-2-[[[5-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4- 二甲基-1H-吡咯-3-羰基]氨基]乙基]氨基甲酰基]氧基甲基]-2-甲氧基-苯氧基]-(甲氧基甲基) 磷酰基]氨基]丙酸乙酯(化合物6)
Ethyl(2S)-2-[[[5-[[ethyl-[2-[[5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H -pyrrole-3-carbonyl]amino]ethyl]carbamoyl]oxymethyl]-2-methoxy-phenoxy]-(methoxymethyl)phos phoryl]amino]propanoate
氮气保护下,将四氢呋喃(10mL)加入反应瓶中,加入乙基(2S)-2-[[[5-(羟甲基)-2- 甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸乙酯(6A)(1.83g,5.06mmol)和二异丙基乙基胺(0.9mL,4.03mmol),冷却至0℃。滴入三光气(0.60g,2.2mmol)的四氢呋喃(5mL)溶液,加完后0℃反应30min。然后加入N-[2-(乙基氨基)乙基]-5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-甲酰胺(中间体1,1.5g,4.05mmol)的N’N-二甲基甲酰胺(20mL)溶液和二异丙基乙基胺(1.05g,8.1mmol),加完后升至室温搅拌反应5h,然后加入乙酸乙酯(100mL)和水(100mL),搅拌5min,静置分层。有机层用饱和氯化钠溶液(100mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯 (二氯甲烷/甲醇=(v/v)10/1),所得粗品通过制备液相进一步分离纯化(液相制备条件:仪器:Thar 80preparative SFC;色谱柱:ChiralPak AS-20u,250×50mmI.D.;流动相:A:CO2,B:甲醇;梯度:B 35%;流量:70mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:12min;样品制备:化合物2溶解于甲醇中制得15mg/ml;注射:1.5ml/针),得到乙基(2S)-2-[[[5-[[乙基-[2-[[5-[(Z)-(5-氟-2-氧代二氢吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-羰基]氨基]乙基] 氨基甲酰基]氧基甲基]-2-甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸乙酯(化合物6),橘红色固体0.6g,收率:19.6%。
MS m/z(ESI):MS m/z(ESI):758.3[M+H]+
1H NMR(400MHz,CDCl3)δ13.40(s,1H),8.35–8.03(m,1H),7.50–7.28(m,2H),7.23–7.02(m,2H),6.91–6.78(m,3H),5.07(s,2H),4.21–4.02(m,3H),3.84(d,6H),3.66–3.51(m,4H),3.49–3.31(m,5H),2.65–2.35(m,7H),1.24–1.05(m,9H).
实施例7生物活性试验
测试例1:大鼠药代动力学实验
试验动物:雄性SD大鼠,180~220g左右,6~8周龄,购于成都达硕实验动物有限公司。动物饲养于SPF环境中,温度20-22℃,相对湿度:51-55%,12h/12h明暗光照,自由饮食饮水,适应性观察3天后开始试验。
药物配制:准确称取一定量受试化合物,DMSO溶解,加入solutol HS-15增溶,再加入生理盐水,旋涡混合即可。DMSO终浓度为5%,solutolHS-15终浓度为5%。所有受试化合物均临用前新鲜配制。
给药及检测:试验当天,9只SD大鼠按体重随机分为3组,每组3只。给药前1天禁食不禁水12~14h,给药后4h给食。大鼠分别口服给予不同受试化合物,给药体积为5mL/kg或10mL/kg。于给药前及给药后异氟烷麻醉经眼眶取血0.20ml,采血时间点选取0min,5min,15min,30min, 1h,2h,4h,6h,8h,24h,肝素抗凝,3500rpm或6000rpm,4℃离心10min,收集血浆。所有血浆样品分析前存于-80℃。采用HPLC-MS/MS对血浆样品中的前药和原型药物进行检测。
结果见表1:
表1化合物大鼠药代动力学实验结果
参数 | 化合物1 |
剂量(mg·kg<sup>-1</sup>) | 30.1 |
t<sub>1/2</sub>(h) | 3.10 |
C<sub>max</sub>(ng·mL<sup>-1</sup>) | 1356 |
AUC<sub>0-t</sub>(h·ng·mL<sup>-1</sup>) | 13266 |
F% | 36.1 |
表1中数据显示化合物1具有良好的生物利用度。
测试例2:小鼠血浆和肝脏分布实验
试验动物:性ICR小鼠,25g左右,6~8周龄。购于成都达硕实验动物有限公司。
药物配制:准确称取一定量受试化合物,DMSO溶解,加入solutol HS-15增溶,再加入生理盐水,旋涡混合即可。DMSO终浓度为5%,solutolHS-15终浓度为5%。所有受试化合物均临用前新鲜配制。
给药及检测:试验当天,9只ICR小鼠按体重随机分为3组,每组3只。给药前1天禁食不禁水12~14h,给药后4h给食。于给药前及给药后异氟烷麻醉经眼眶取血0.30ml,置于EDTAK2离心管中并放置冰浴。5000rpm,4℃离心10min,收集血浆。血浆和组织采集时间点:0.5,2,4h,放血后同时采集肝脏组织,清洗处理后1:2(m/v)加50%冰甲醇匀浆。分析检测前,所有样品存于-80℃。结果见表2。
表2:本发明化合物和N-去乙基舒尼替尼分别口服给药后在小鼠血浆和肝脏中N-去乙基舒尼替尼分布情况
表2中数据显示化合物1经吸收代谢后在小鼠体内形成的N-去乙基舒尼替尼的肝血比大幅高于口服其原型药物本身所产生的肝血比,表明化合物1具有良好的肝靶向性。
Claims (7)
2.根据权利要求1所述的化合物,或其药学上可接受的盐,其中:
R3选自-C(=O)-;
R4选自苯环基,所述的苯环基可任选进一步被0至4个选自F、Cl、Br、-O-C1-4烷基的取代基所取代;
n选自1。
3.根据权利要求2所述的化合物,或其药学上可接受的盐,其中:
R1a选自H、C1-4烷基;
R2a选自H、C1-4烷基;
X选自O,Y选自O;
R3选自-C(=O)-,R4选自苯环基,所述苯环基可进一步任选的被0至4个-O-C1-4烷基所取代。
4.根据权利要求3所述的化合物,或其药学上可接受的盐,其中:
R1a或R2a各自独立的选自C1-4烷基;
R1b或R2b各自独立的选自甲基、乙基、丙基或异丙基;
R3选自-C(=O)-,R4选自苯环基,所述的苯环基进一步被0-1个甲氧基所取代。
6.一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1-5中任一项所述的化合物或药学上可以接受的盐,以及药学上可接受的载体或者赋形剂。
7.权利要求1-5中任一项所述的化合物、或其药学上可以接受的盐,在制备多激酶抑制剂药物中的应用。
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WO2005053686A1 (en) * | 2003-11-26 | 2005-06-16 | The Scripps Research Institute | Indolinone based protein kinase inhibitors |
CN101282965A (zh) * | 2005-09-22 | 2008-10-08 | 斯克利普斯研究院 | 基于烷氧基吲哚酮的蛋白激酶抑制剂 |
CN102146095A (zh) * | 2010-02-09 | 2011-08-10 | 南通波锐生物医药有限公司 | 一种吡咯吲哚酮类化合物及其制备方法和用途 |
CN102250069A (zh) * | 2010-05-17 | 2011-11-23 | 苏州波锐生物医药科技有限公司 | 吡咯酰胺类化合物及其在制备抗恶性肿瘤药物中的用途 |
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WO2005053686A1 (en) * | 2003-11-26 | 2005-06-16 | The Scripps Research Institute | Indolinone based protein kinase inhibitors |
CN101282965A (zh) * | 2005-09-22 | 2008-10-08 | 斯克利普斯研究院 | 基于烷氧基吲哚酮的蛋白激酶抑制剂 |
CN102146095A (zh) * | 2010-02-09 | 2011-08-10 | 南通波锐生物医药有限公司 | 一种吡咯吲哚酮类化合物及其制备方法和用途 |
CN102250069A (zh) * | 2010-05-17 | 2011-11-23 | 苏州波锐生物医药科技有限公司 | 吡咯酰胺类化合物及其在制备抗恶性肿瘤药物中的用途 |
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