CN109761982B - 12n-取代胺甲酰基苦参碱衍生物及其制备方法和用途 - Google Patents
12n-取代胺甲酰基苦参碱衍生物及其制备方法和用途 Download PDFInfo
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- CN109761982B CN109761982B CN201910144441.1A CN201910144441A CN109761982B CN 109761982 B CN109761982 B CN 109761982B CN 201910144441 A CN201910144441 A CN 201910144441A CN 109761982 B CN109761982 B CN 109761982B
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Abstract
本发明提供一种12N‑取代胺甲酰基苦参碱衍生物及其制备方法和用途,该化合物的结构如式Ⅰ所示化合物,其中,R1为苯基、苄基、单杂环基、稠环基、C1‑C10烷基或C3‑C10环烷基;其中,苯基、苄基、单杂环基或稠环基各自独立地被一个或多个选自氢、卤素、C1‑C10烷基、C1‑C10烷氧基、三氟甲氧基、三氟甲基、硝基、氨基、羟基、C1‑C10烷酰氨基、氰基、C1‑C10烷硫基、C1‑C10烷氨基、C1‑C10烷氧酰基、C3‑C15环烷基、单杂环基、C1‑C10烷基磺酰基的取代基取代;R2为H、C1‑C10烷基、羟基取代的C1‑C10烷基、CH2CH2COR3、COR3、单杂环基或稠环基取代的C1‑C4烷基;R3为C1‑C10烷氧基、羟基或C1‑C10烷氨基;该化合物通过抑制COL1A1启动子的活性治疗肝纤维化,
Description
技术领域
本发明属于医药领域,具体涉及12N-取代胺甲酰基苦参碱衍生物及其制备方法和用途。
背景技术
肝纤维化是一个病理生理过程,是指由各种致病因子所致肝内结缔组织异常增生。任何肝脏损伤在肝脏修复愈合的过程中都有肝纤维化的过程,如果损伤因素长期不能去除,纤维化的过程长期持续就会发展成肝硬化。到目前为止,治疗肝纤维化的药物有限,因此,迫切需要开发新的有效的抗肝纤维化的候选药物。
肝星状细胞(hepatic stellate cell,HSC)在肝纤维化形成中起了关键作用。各种病因引起的肝损伤导致HSC激活,活化的HSC增殖加速,并合成分泌大量的细胞外基质沉积于肝脏,形成纤维化。转化生长因子β1(transforming growth factor-β,TGFβ1)与肝纤维化密切相关,是目前已知最重要的致肝纤维化的细胞因子之一。TGFβ1主要通过激活HSC和上调胶原蛋白的分泌促进肝纤维化的产生,特别是I型胶原(COL1)蛋白。由于TGFβ1通过TGFβ/Smad途径可以激活关键基因I型α1链(COL1A1)用于肝纤维化的转录,据此,申请人前期建立了基于COL1A1启动子的高通量药物筛选细胞模型,发现以苦参碱为母核,设计合成的苦参噻二唑衍生物,可通过抑制TGFβ/Smad途径抑制肝纤维化。
但是合成的大部分苦参噻二唑衍生物对COL1A1启动子的抑制率较低,因此,仍需继续寻找对COL1A1启动子具有高的抑制作用的化合物。
发明内容
本发明通过对苦参碱进行进一步的结构修饰得到一系列结构新颖且对肝纤维化具有较好抑制作用的12N-取代胺甲酰基苦参碱衍生物。
本发明具体技术方案如下:
本发明提供一种式Ⅰ所示化合物、其光学异构体、溶剂合物或其药学上可接受的盐,
其中,
R1为苯基、苄基、单杂环基、稠环基、C1-C10烷基或C3-C10环烷基;其中,苯基、苄基、单杂环基或稠环基各自独立地被一个或多个选自氢、卤素、C1-C10烷基、C1-C10烷氧基、三氟甲氧基、三氟甲基、硝基、氨基、羟基、C1-C10烷酰氨基、氰基、C1-C10烷硫基、C1-C10烷氨基、C1-C10烷氧酰基、C3-C15环烷基、单杂环基、C1-C10烷基磺酰基的取代基取代;
R2为H、C1-C10烷基、羟基取代的C1-C10烷基、CH2CH2COR3、COR3、单杂环基或稠环基取代的C1-C4烷基;
R3为C1-C10烷氧基、羟基或C1-C10烷氨基。
优选地,R1为苯基、苄基或C3-C10环烷基;其中,苯基或苄基各自独立地被一个或多个选自卤素、C1-C4烷基、C1-C4烷氧基、三氟甲氧基、三氟甲基、硝基、氨基、C1-C4烷酰氨基、氰基、C1-C4烷氨基或C1-C4烷氧酰基的取代基取代。
优选地,R1为苯基、苄基或C5-C6环烷基;其中,苯基或苄基各自独立地被一个或多个选自卤素、C1-C4烷基、C1-C4烷氧基、三氟甲氧基、三氟甲基、硝基或氨基的取代基取代。
优选地,R1为苯基;其中,苯基各自独立地被一个或多个选自Cl、Br、甲基、乙基、异丙基、正丁基、三氟甲氧基或三氟甲基的取代基取代。
优选地,R2为C1-C10烷基、羟基取代的C1-C10烷基或CH2CH2COR3;R3为C1-C4烷氧基、羟基或C1-C4烷氨基。
优选地,R2为C1-C4烷基、羟基取代的C1-C4烷基或CH2CH2COR3;优选地,R2为C3烷基;R3为C1-C4烷氧基。
优选地,式Ⅰ所示化合物选自以下化合物:
12N-4-三氟甲基苯胺甲酰基苦参丁酸甲酯盐酸盐(FAM1A)
12N-4-三氟甲基苯胺甲酰基苦参丁醇盐酸盐(FAM1B)
12N-4-三氟甲基苯胺甲酰基苦参丁烷盐酸盐(FAM1C)
12N-3-氯苯胺甲酰基苦参丁酸甲酯(FAM2A)
12N-3-氯苯胺甲酰基苦参丁醇盐酸盐(FAM2B)
12N-3-氯苯胺甲酰基苦参丁烷盐酸盐(FAM2C)
12N-4-氟苯胺甲酰基苦参丁烷盐酸盐(FAM3C)
12N-4-甲基苯胺甲酰基苦参丁烷盐酸盐(FAM4C)
12N-3,5-二氯苯胺甲酰基苦参丁烷盐酸盐(FAM5C)
12N-3-甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM6C)
12N-2,4-二氟苯胺甲酰基苦参丁烷盐酸盐(FAM7C)
12N-2,6-二异丙基苯胺甲酰基苦参丁烷盐酸盐(FAM8C)
12N-4-三氟甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM9C)
12N-3,4-二氯苯胺甲酰基苦参丁烷(FAM10C)
12N-2-甲基苯胺甲酰基苦参丁烷盐酸盐(FAM11C)
12N-3-甲基苯胺甲酰基苦参丁烷盐酸盐(FAM12C)
12N-2-三氟甲基苯胺甲酰基苦参丁烷(FAM13C)
12N-4-甲氧基苄胺甲酰基苦参丁烷盐酸盐(FAM14C)
12N-3,5-二甲基苯胺甲酰基苦参丁烷盐酸盐(FAM15C)
12N-4-乙基苯胺甲酰基苦参丁烷盐酸盐(FAM16C)
12N-4-氯苯胺甲酰基苦参丁烷盐酸盐(FAM17C)
12N-2,6-二甲基苯胺甲酰基苦参丁烷盐酸盐(FAM18C)
12N-2,4,6-三甲基苯胺甲酰基苦参丁烷(FAM19C)
12N-4-硝基苯胺甲酰基苦参丁烷盐酸盐(FAM20C)
12N-2,6-二乙基苯胺甲酰基苦参丁烷盐酸盐(FAM22C)
12N-4-丁基苯胺甲酰基苦参丁烷盐酸盐(FAM23C)
12N-4-溴苯胺甲酰基苦参丁烷(FAM24C)
12N-2-氯苯胺甲酰基苦参丁烷盐酸盐(FAM25C)
12N-3-三氟甲基苯胺甲酰基苦参丁烷盐酸盐(FAM26C)
12N-苯胺甲酰基苦参丁烷盐酸盐(FAM27C)
12N-4-甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM28C)
12N-2-甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM29C)
12N-4-异丙基苯胺甲酰基苦参丁烷盐酸盐(FAM30C)
12N-环已胺甲酰基苦参丁烷盐酸盐(FAM31C)
12N-环戊胺甲酰基苦参丁烷盐酸盐(FAM32C)。
术语解释
本发明所用术语“卤素”包括但不限于氟、氯、溴等。
本发明所用术语“烷基”是指直链或支链饱和烃基,例如C1-C10烷基、C1-C6烷基或C1-C4烷基。烷基的非限制性实施例包括甲基、乙基、丙基、异丙基、丁基等。
本发明所用术语“烷氧基”是指具有“W-O-”结构的基团,其中W为烷基,例如C1-C10烷氧基、C1-C6烷氧基或C1-C4烷氧基,烷氧基的非限制性实施例包括甲氧基、乙氧基、丙氧基、异丙氧基和叔丁氧基等。
本发明所用术语“烷酰氨基”是指具有“W-C(O)NH-”结构的基团,其中W为烷基,所述烷酰氨基可为C1-C10烷酰氨基、C1-C6烷酰氨基或C1-C4烷酰氨基等,烷酰氨基的非限制性实施例包括甲酰氨基、乙酰氨基等。
本发明所用术语“烷基磺酰基”是指具有“W-S(O)2-”结构的基团,其中W为烷基,所述烷基磺酰基可为C1-C10烷基磺酰基、C1-C6烷基磺酰基或C1-C4烷基磺酰基等,烷基磺酰基的非限制性实施例包括甲磺酰基、乙磺酰基等。
本发明所用术语“烷硫基”是指具有“W-S-”结构的基团,其中W为烷基,所述烷基磺酰基可为C1-C10烷硫基、C1-C6烷硫基或C1-C4烷硫基等,烷硫基的非限制性实施例包括甲硫基、乙硫基等
本发明所用术语“烷氨基”是指具有“W-NH-”结构的基团,其中W为烷基,所述烷基磺酰基可为C1-C10烷氨基、C1-C6烷氨基或C1-C4烷氨基等,烷氨基的非限制性实施例包括甲氨基、乙氨基、N,N-二甲氨基等;
本发明所用术语“烷氧酰基”是指具有“W-C(O)-”结构的基团,其中W为烷基,所述烷氧酰基可为C1-C10烷氧酰基、C1-C6烷氧酰基或C1-C4烷氧酰基等,烷氧酰基的非限制性实施例包括甲氧酰基、乙氧酰基等;
本发明所用术语“环烷基”是指饱和或部分饱和的环状烃基,组成环烷基的碳原子数可为3-15个,例如3-10个。具体的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基等。
本发明所用术语“单杂环基”是指构成环的原子除碳原子外,还至少含有一个选自N,O或S的杂原子,可分为五元单杂环基、六元单杂环基;单杂环基的非限制性实施包括但不限于四氢吠喃基、四氢吡喃基、四氢吡咯基、哌啶基、哌嗪基、呋喃基、吡咯基、噻吩基、异噁唑基、噁唑基、咪唑基、噻唑基、吡啶基、嘧啶基、三嗪基、吗啉基、噻重氮等;本发明的单杂化基优选:呋喃基、吡啶基、吡唑基、咪唑基、吗啉基、吡咯基、异噁唑基、噻重氮等;优选地呋喃基、吡啶基等。
本发明所用术语“稠环基”是指苯环与单杂环基或单杂环基之间构成的稠环结构,稠环基的非限制性实施包括但不限于苯并噻吩、苯并呋喃、苯并咪唑、苯并吡咯等,本发明优选苯并噻吩等。
本发明另一方面提供一种式Ⅰ所示化合物、其光学异构体、溶剂合物或其药学上可接受的盐的制备方法,该制备方法包括如下步骤:
a.将苦参碱MT进行开环反应,获得化合物2;
b.将化合物2的羧基进行保护,获得化合物3;
c.将化合物3的氨基进行保护,获得化合物4;
d.将化合物4进行还原反应,获得化合物5;
e.将化合物5的羟基进行保护,获得化合物6;
f.将化合物6进行还原反应,获得化合物7;
g.脱除化合物7的氨基保护剂,获得化合物8;
h.将化合物3或化合物8与相应的苯异氰酸酯或苯胺反应,或将化合物3与相应的苯异氰酸酯或苯胺反应得到的化合物脱除羧基保护剂,获得式Ⅰ所示的化合物,反应方程式如下:
本发明式Ⅰ化合物或其药学可接受的盐还可以以晶体存在,本发明包含式I所示的苦参碱或其药学可接受的盐的任意晶型。
本发明式I所示的苦参碱衍生物或其可接受的盐可以通过以下途径给药:胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂。
本发明另一方面提供一种式Ⅰ所示化合物或其药学可接受的盐以及药学可接受的载体或赋形剂。
本发明式I所示的苦参碱衍生物或药学可接受的盐可以药物制剂的形式给药,该药物组合物包括式I所示的苦参碱或药学可接受的盐及药学可接受的载体或辅料。
本发明的式I所示的苦参碱或药学可接受的盐可根据给药途径配成各种适宜的剂型。
当口服用药时,本发明化合物可制成任意口服可接受的制剂形式,包括但不限于片剂、胶囊、水溶液或水悬浮液。其中,片剂使用的载体一般包括乳糖和玉米淀粉,另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地,以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当皮肤局部施用时,本发明化合物可制成适当的软膏、洗剂或霜剂制剂形式,其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于:矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水;洗剂或霜剂可使用的载体包括但不限于:矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
本发明式I所示的苦参碱或药学可接受的盐还可以无菌注射制剂形式用药,包括无菌注射水或油悬浮液或无菌注射溶液,也可以是冻干形式。其中,可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,灭菌的非挥发油也可用作溶剂或悬浮介质,如单甘油酯或二甘油酯。
本发明的药物制剂包括药学上可实施的任何制剂,例如口服制剂、肠胃外给药制剂等。
本发明提供的式Ⅰ所示化合物、其光学异构体、溶剂合物或其药学上可接受的盐可用于治疗肝纤维化。
本发明式Ⅰ所示化合物可可在mRNA水平上显著抑制COL1A1,TGFβ1,ACTA2,MMP2和CTGF的表达,并且可显著抑制COL1A1、TGFβ1、α-SMA、MMP2和MMP9标志物蛋白的表达,进而抑制COL1A1启动子的活性,用于治疗肝纤维化。
附图说明
图1为式Ⅰ所示化合物对TGFβ1诱导LX-2细胞中肝纤维化主要标志物mRNA水平的影响;
图2为式Ⅰ所示化合物对肝纤维化主要标志物蛋白水平的影响,其中,8C、10C、13C、22C、23C、24C、25C分别表示化合物FAM8C、FAM10C、FAM13C、FAM22C、FAM23C、FAM24C、FAM25C,DB13表示12N-3-三氟甲基苯磺酰基苦参丁烷。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1 12N-4-三氟甲基苯胺甲酰基苦参丁酸甲酯盐酸盐(FAM1A)的制备:
a.苦参丁酸(化合物2)的制备
取100g(0.4mol)苦参碱(MT),溶于350mL氢氧化钠溶液(5mol/L)中,加热回流8h,冷却至室温,过滤,滤饼加入浓盐酸溶解并保持pH<2,减压浓缩蒸干,即得化合物2,直接用于下一步。
b.苦参丁酸甲酯盐酸盐(化合物3)的制备
向步骤a所得的化合物2中加入500mL甲醇充分溶解,过滤除去无机盐,滤液加入15mL二氯亚砜,常温搅拌6h,减压蒸干得粗品苦参丁酸甲酯盐酸盐,无水乙醇洗涤除去杂质,得化合物3,白色固体产物(120g,84.9%)。
h.12N-4-三氟甲基苯胺甲酰基苦参丁酸甲酯盐酸盐(FAM1A)的制备
取游离态化合物3(0.282g,1mmol),依次加入20mL二氯甲烷,0.243g(1.5mmol)N,N’-羰基二咪唑,0.28mL三乙胺,室温搅拌1h,加入0.242g(1.5mmol)对三氟甲基苯胺,室温搅拌3h,TLC监测反应结束,用饱和氯化铵溶液萃取两次,饱和氯化钠溶液萃取一次,无水硫酸钠干燥,蒸干用快速柱层析分离纯化得无色油状液体,加入盐酸乙醚(1mol/L)后析出白色固体,抽滤得FAM1A,白色固体(0.327g,65%)。
1H NMR(600MHz,DMSO-d6)δ10.19(s,1H),9.33(s,1H),7.67(d,J=8.5Hz,2H),7.56(d,J=8.5Hz,2H),4.07–3.99(m,1H),3.92–3.84(m,1H),3.70(dd,J=14.4,5.4Hz,1H),3.54(s,3H),3.52–3.46(m,1H),3.20(t,J=13.4Hz,2H),2.94–2.84(m,2H),2.44–2.35(m,1H),2.33–2.23(m,2H),2.09–2.01(m,2H),1.99–1.87(m,1H),1.85–1.73(m,2H),1.67–1.45(m,8H);13C NMR(151MHz,DMSO-d6)δ173.3,156.6,144.4,125.5(2),124.6,121.5,118.7(2),63.2,54.6,54.4,54.1,51.1,47.8,36.1,34.2,33.1,29.2,25.2,24.7,21.5,18.4,18.3.
实施例2 12N-4-三氟甲基苯胺甲酰基苦参丁醇盐酸盐(FAM1B)的制备
取游离态FAM1A(0.467g,1mmol),溶于20mL无水四氢呋喃,在0℃条件下缓慢加入0.041g(1.1mmol)氢化铝锂,0℃搅拌1h,TLC监测反应结束后缓慢加入1mL甲醇及0.5mL饱和氯化铵溶液淬灭反应,倾入50mL二氯甲烷,室温搅拌5min,硅藻土过滤,滤液减压浓缩得到无色油状物,用快速柱层析分离纯化得无色油状液体,加入盐酸乙醚(1mol/L)后析出白色固体,抽滤得FAM1B,白色固体(0.423g,89%)。
1H NMR(600MHz,DMSO-d6)δ10.02–9.90(m,1H),9.27(s,1H),7.68(d,J=8.5Hz,2H),7.56(d,J=8.5Hz,2H),4.34(s,1H),3.98(td,J=9.6,6.4Hz,1H),3.86–3.79(m,1H),3.68(dd,J=14.3,5.6Hz,1H),3.48(d,J=10.3Hz,1H),3.19(t,J=13.5Hz,2H),2.92–2.87(m,2H),2.10–1.72(m,6H),1.69–1.53(m,6H),1.50–1.36(m,4H),1.35–1.20(m,2H);13C NMR(151MHz,DMSO-d6)δ156.5,144.5,125.5(2),124.6,121.4,118.7(2),63.0,60.7,54.6,54.4,54.3,47.3,36.1,33.9,32.3,30.0,25.2,24.9,22.4,18.4,18.3.
实施例3 12N-4-三氟甲基苯胺甲酰基苦参丁烷盐酸盐(FAM1C)的制备
c.BOC-苦参丁酸甲酯(化合物4)的制备
取10.6g(0.03mol)化合物3,依次加入150mL二氯甲烷,12.6mL三乙胺,7.8g Boc酸酐,室温搅拌8h,TLC监测反应结束后,有机相用水萃取一次,饱和氯化铵溶液萃取两次,无水硫酸钠干燥,蒸干有机相得到化合物4,无色油状物(11.0g,96.5%)。
d.BOC-苦参丁醇(化合物5)的制备
取11g(0.029mol)化合物4溶于150mL无水四氢呋喃,在0℃条件下缓慢加入1.14g(0.03mol)氢化铝锂,0℃搅拌1h,TLC监测反应结束后,缓慢加入5mL甲醇及5mL饱和氯化铵溶液淬灭反应,倾入500mL二氯甲烷,室温搅拌5min,硅藻土过滤,滤液减压浓缩得到化合物5,无色油状物(10g,98%)。
e.对甲苯磺酸BOC-苦参丁醇酯(化合物6)的制备
取10g(0.028mol)化合物5,依次加入200mL二氯甲烷,4.78mL三乙胺,5.85g对甲苯磺酰氯,室温搅拌8h,TLC监测反应结束后有机相用饱和氯化铵溶液萃取两次,无水硫酸钠干燥,蒸干有机相得到棕色油状物,此棕色油状物以二氯甲烷/甲醇为流动相,硅胶为固定相用快速柱层析分离纯化,得到化合物6,淡黄色油状物(6.38g,45%)。
f.BOC-苦参丁烷(化合物7)的制备
取6.38g(0.013mol)化合物6,溶于100mL无水四氢呋喃,在0℃条件下缓慢加入0.76g氢化铝锂,室温搅拌1h,TLC监测反应结束后,在0℃条件下缓慢加入5mL甲醇及5mL饱和氯化铵溶液淬灭反应,倾入300mL二氯甲烷,室温搅拌5min,硅藻土过滤,滤液减压浓缩得到化合物7,黄色油状物(4.0g,91.6%)。
g.苦参丁烷(化合物8)的制备
取4.0g(0.012mol)化合物7溶于10mL1,4-二氧六环,加入10mL盐酸溶液(10mol/L),室温搅拌1h,TLC监测反应结束,滴加氢氧化钠溶液调节pH至8,减压浓缩得到淡黄色固体,甲醇溶解可溶物,过滤除去无机盐,减压浓缩除去甲醇,二氯甲烷溶解可溶物,无水硫酸钠干燥,蒸干得到淡黄色油状物粗品苦参丁烷,用乙酸乙酯重结晶,得到白色固体苦参丁烷纯品,即化合物8(2.24g,79%)。
h.12N-4-三氟甲基苯胺甲酰基苦参丁烷盐酸盐(FAM1C)的制备
取0.236g(1mmol)化合物8,依次加入20mL无水二氯甲烷,0.2g(1.05mmol)4-三氟甲基苯异氰酸酯,室温搅拌0.5h,TLC检测反应结束,蒸干用快速柱层析分离纯化得无色油状液体,加入盐酸乙醚(1mol/L)后析出白色固体,抽滤得FAM1C,白色固体(0.353g,77%)。
1H NMR(600MHz,DMSO-d6)δ9.93(s,1H),9.25(s,1H),7.67(d,J=8.6Hz,2H),7.57(d,J=8.6Hz,2H),3.99(td,J=9.5,5.7Hz,1H),3.82(dd,J=14.3,11.4Hz,1H),3.64(dd,J=14.3,5.7Hz,1H),3.51–3.44(m,1H),3.23–3.15(m,2H),2.93–2.85(m,2H),2.31–2.25(m,1H),2.11–1.87(m,3H),1.87–1.71(m,2H),1.70–1.58(m,4H),1.58–1.53(m,1H),1.49–1.41(m,1H),1.39–1.14(m,4H),0.83(t,J=7.0Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.4,144.5,125.5(2),124.7,121.5,118.7(2),63.0,54.6,54.3,54.2,47.1,36.2,33.8,30.0,28.1,25.2,25.0,22.1,18.4,18.3,14.0.
实施例4 12N-3-氯苯胺甲酰基苦参丁酸甲酯(FAM2A)的制备
参照实施例1,将化合物3和3-氯苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM2C,白色固体(0.35g,81%)。
1H NMR(600MHz,DMSO-d6)δ8.67(s,1H),7.62(t,J=2.1Hz,1H),7.37–7.33(m,1H),7.21(t,J=8.1Hz,1H),6.95–6.90(m,1H),3.79–3.73(m,1H),3.56(s,3H),3.41(dd,J=13.7,6.3Hz,1H),2.69–2.61(m,2H),2.36–2.23(m,2H),1.98(t,J=3.1Hz,1H),1.94–1.86(m,1H),1.83–1.63(m,6H),1.59–1.24(m,10H);13C NMR(151MHz,DMSO-d6)δ173.3,155.7,14269,132.7,129.8,120.7,118.5,117.4,62.9,59.6,56.3,54.1,51.1,46.7,38.4,34.9,33.2,30.5,28.1,27.8,21.6,20.7,20.6.
实施例5 12N-3-氯苯胺甲酰基苦参丁醇盐酸盐(FAM2B)的制备
参照实施例2,将FAM2A用氢化铝锂还原,纯化后得FAM2B,白色固体(0.344g,78%)。
1H NMR(600MHz,DMSO-d6)δ9.74(s,1H),9.00(s,1H),7.66(t,J=2.1Hz,1H),7.38(dd,J=8.1,2.1Hz,1H),7.24(t,J=8.1Hz,1H),6.96(dd,J=8.1,2.1Hz,1H),4.33(s,1H),3.94(td,J=9.3,5.8Hz,1H),3.77(dd,J=14.3,11.4Hz,1H),3.61(dd,J=14.3,5.8Hz,1H),3.49–3.43(m,1H),3.37–3.33(m,2H),3.19(t,J=14.7Hz,2H),2.94–2.83(m,2H),2.29–2.24(m,1H),2.11–2.05(m,1H),1.98–1.89(m,2H),1.85–1.71(m,2H),1.68–1.54(m,5H),1.50–1.37(m,3H),1.33–1.19(m,2H);13C NMR(151MHz,DMSO-d6)δ156.5,142.2,132.75,129.9,121.1,118.6,117.5,63.0,60.7,54.6,54.3,54.1,46.8,36.1,33.6,32.3,30.3,25.2,25.1,22.4,18.4(2).
实施例6 12N-3-氯苯胺甲酰基苦参丁烷盐酸盐(FAM2C)的制备
参照实施例3,将化合物8和3-氯苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM2C,白色固体(0.277g,65%)。
1H NMR(600MHz,DMSO-d6)δ9.89(s,1H),9.04(s,1H),7.65(t,J=2.1Hz,1H),7.37(dd,J=8.4,2.0Hz,1H),7.23(t,J=8.1Hz,1H),6.98–6.93(m,1H),3.96(td,J=9.6,5.8Hz,1H),3.80(dd,J=14.3,11.5Hz,1H),3.62(dd,J=14.3,5.8Hz,1H),3.49–3.43(m,1H),3.23–3.14(m,2H),2.92–2.85(m,2H),2.30–2.24(m,1H),2.10–2.03(m,1H),2.01–1.89(m,2H),1.85–1.70(m,2H),1.67–1.60(m,3H),1.59–1.53(m,2H),1.47–1.40(m,1H),1.37–1.18(m,4H),0.84(t,J=7.1Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.6,142.2,132.7,129.9,121.1,118.5,117.4,63.0,54.6,54.3,54.2,47.1,36.1,33.7,30.0,28.1,25.2,25.0,22.1,18.4,18.3,14.0.
实施例7 12N-4-氟苯胺甲酰基苦参丁烷盐酸盐(FAM3C)的制备
取化合物8(0.236g,1mmol),依次加入20mL二氯甲烷,0.243g(1.5mmol)N,N’-羰基二咪唑,0.21mL三乙胺,室温搅拌1h,加入0.167g 4-氟苯胺(1.5mmol),室温搅拌3h,TLC监测反应结束,用饱和氯化铵溶液萃取两次,饱和氯化钠溶液萃取一次,无水硫酸钠干燥,蒸干用快速柱层析分离纯化得无色油状液体,加入盐酸乙醚(1mol/L)后析出白色固体,即得FAM3C(0.282g,69%)。
1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.82(s,1H),7.46(dd,J=8.8,5.0Hz,2H),7.06(t,J=8.8Hz,2H),3.93(q,J=8.4Hz,1H),3.80–3.69(m,1H),3.57(dd,J=14.3,6.1Hz,1H),3.45(d,J=10.2Hz,1H),3.19(t,J=10.9Hz,2H),2.88(q,J=11.4Hz,2H),2.28–2.21(m,1H),2.10(d,J=9.0Hz,1H),1.95–1.59(m,9H),1.44–1.22(m,5H),0.84(t,J=6.8Hz,3H);13C NMR(101MHz,DMSO)δ157.2,156.8,136.9,121.1,121.0,114.9,114.6,62.9,54.6,54.3,53.9,46.4,36.1,33.3,30.4,28.1,25.3,25.2,22.1,18.4,18.3,14.1.
实施例8 12N-4-甲基苯胺甲酰基苦参丁烷盐酸盐(FAM4C)的制备
参照实施例3,将化合物8和对甲基苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM4C,白色固体(0.275g,68%)。
1H NMR(600MHz,DMSO-d6)δ9.91(s,1H),8.71(s,1H),7.32(d,J=8.1Hz,2H),7.02(d,J=8.1Hz,2H),3.92(td,J=9.4,5.7Hz,1H),3.80–3.74(m,1H),3.59(dd,J=14.3,5.7Hz,1H),3.49–3.43(m,1H),3.18(t,J=13.9Hz,2H),2.91–2.83(m,2H),2.30–2.25(m,1H),2.21(s,3H),2.06–1.87(m,3H),1.85–1.70(m,2H),1.68–1.53(m,5H),1.47–1.38(m,1H),1.36–1.17(m,4H),0.83(t,J=6.9Hz,3H);13C NMR(151MHz,DMSO-d6)δ157.0,138.0,130.3,128.7(2),119.4(2),63.1,54.6,54.4,54.1,47.2,36.1,33.7,30.0,28.1,25.3,25.0,22.1,20.3,18.4,18.4,14.1.
实施例9 12N-3,5-二氯苯胺甲酰基苦参丁烷盐酸盐(FAM5C)的制备
参照实施例3,将化合物8和3,5-二氯苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM5C,白色固体(0.336g,73%)。
1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),9.22(s,1H),7.60(s,2H),7.09(s,1H),3.98(td,J=9.3,5.6Hz,1H),3.79(dd,J=14.2,11.4Hz,1H),3.63(dd,J=14.2,5.9Hz,1H),3.50–3.41(m,1H),3.19(t,J=10.9Hz,2H),2.89(q,J=11.4Hz,2H),2.29–2.22(m,1H),2.09(dd,J=10.9,5.6Hz,1H),2.00–1.54(m,9H),1.49–1.38(m,1H),1.36–1.17(m,4H),0.83(t,J=6.9Hz,3H);13C NMR(101MHz,DMSO)δ156.2,143.3,133.6(2),120.4,117.0(2),62.9,54.6,54.3,54.2,46.8,36.1,33.6,30.1,28.0,25.2,25.0,22.1,18.4(2),14.0.
实施例10 12N-3-甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM6C)的制备
参照实施例7,将化合物8和3-甲氧基苯胺,蒸干用快速柱层析分离纯化得FAM6C,白色固体(0.323g,77%)。
1H NMR(600MHz,DMSO-d6)δ9.90(s,1H),8.80(s,1H),7.15(s,1H),7.11(t,J=8.1Hz,1H),7.02(d,J=8.1Hz,1H),6.50(d,J=8.1Hz,1H),3.93(td,J=9.5,5.7Hz,1H),3.78(dd,J=14.3,11.5Hz,1H),3.70(s,3H),3.63–3.57(m,1H),3.49–3.43(m,1H),3.19(t,J=14.1Hz,2H),2.91–2.85(m,2H),2.32–2.26(m,1H),2.06–1.82(m,4H),1.77–1.55(m,6H),1.48–1.39(m,1H),1.38–1.30(m,1H),1.28–1.18(m,3H),0.84(t,J=6.9Hz,3H);13CNMR(151MHz,DMSO-d6)δ159.4,156.8,141.8,129.0,111.4,107.0,104.8,63.1,54.9,54.6,54.4,54.1,47.2,36.0,33.7,30.0,28.1,25.3,25.0,22.1,18.4,18.3,14.1.
实施例11 12N-2,4-二氟苯胺甲酰基苦参丁烷盐酸盐(FAM7C)的制备
参照实施例7,将化合物8和2,4-二氟苯胺,蒸干用快速柱层析分离纯化得FAM7C,白色固体(0.338g,79%)。
1H NMR(600MHz,DMSO-d6)δ10.05(s,1H),8.56(s,1H),7.40(td,J=9.0,6.2Hz,1H),7.21(ddd,J=11.3,9.0,2.9Hz,1H),7.00(td,J=9.0,2.9Hz,1H),3.96–3.89(m,1H),3.77(dd,J=14.4,11.5Hz,1H),3.63(dd,J=14.4,5.5Hz,1H),3.52–3.46(m,1H),3.19(t,J=12.3Hz,2H),2.93–2.84(m,2H),2.25–2.18(m,1H),2.14–2.07(m,1H),2.03–1.89(m,2H),1.84–1.79(m,1H),1.77–1.61(m,4H),1.59–1.55(m,1H),1.45–1.39(m,1H),1.38–1.30(m,1H),1.29–1.19(m,3H),0.85(t,J=6.7Hz,3H);13C NMR(151MHz,DMSO-d6)δ158.4,157.0,155.4,127.3,124.1,110.7,103.9,63.1,54.6,54.6,54.4,47.4,36.3,33.7,29.9,28.1,25.3,24.8,22.1,18.4,18.4,14.1.
实施例12 12N-2,6-二异丙基苯胺甲酰基苦参丁烷盐酸盐(FAM8C)的制备
参照实施例3,将化合物8和2,6-二异丙基苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM8C,白色固体(0.371g,78%)。
1H NMR(600MHz,DMSO-d6)δ10.50(s,1H),8.05(s,1H),7.20(t,J=7.7Hz,1H),7.13(d,J=7.7Hz,1H),7.09(d,J=7.7Hz,1H),3.90–3.79(m,3H),3.59–3.55(m,1H),3.23(t,J=9.3Hz,2H),3.19–3.14(m,1H),3.09–3.03(m,1H),2.92–2.85(m,2H),2.25(d,J=10.5Hz,1H),2.12(q,J=10.5,9.3Hz,1H),2.05–2.00(m,1H),1.99–1.89(m,1H),1.85(d,J=14.4Hz,1H),1.79–1.56(m,6H),1.55–1.47(m,1H),1.42–1.31(m,3H),1.27–1.19(m,2H),1.15(d,J=6.8Hz,3H),1.13–1.08(m,8H),0.87(t,J=6.7Hz,3H);13C NMR(151MHz,DMSO-d6)δ158.5,146.9,146.1,133.4,126.9,122.9,122.3,64.0,55.0,54.8,54.6,49.5,36.2,35.5,28.8,28.2(2),27.7,25.1,24.1,23.7,23.6,23.5,23.0,22.4,18.6,18.2,14.2.
实施例13 12N-4-三氟甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM9C)的制备
参照实施例3,将化合物8和4-三氟甲氧基苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM9C,白色固体(0.247g,52%)。
1H NMR(600MHz,DMSO-d6)δ9.94(s,1H),9.06(s,1H),7.56(d,J=9.0Hz,2H),7.22(d,J=9.0Hz,2H),3.96(td,J=9.6,5.7Hz,1H),3.81(dd,J=14.3,11.5Hz,1H),3.63(dd,J=14.3,5.7Hz,1H),3.50–3.44(m,1H),3.19(t,J=13.8Hz,3H),2.93–2.84(m,3H),2.30–2.24(m,1H),2.03–1.89(m,2H),1.86–1.70(m,2H),1.66–1.53(m,5H),1.47–1.40(m,1H),1.38–1.29(m,1H),1.29–1.16(m,3H),0.83(t,J=6.9Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.7,142.4,140.0,121.2(2),120.5,120.3(2),63.1,54.6,54.3,54.2,47.2,36.1,33.8,30.0,28.1,25.3,24.9,22.1,18.4,18.3,14.0.
实施例14 12N-3,4-二氯苯胺甲酰基苦参丁烷(FAM10C)的制备
参照实施例3,将化合物8和3,4-二氯苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM10C,白色固体(0.343g,81%)。
1H NMR(600MHz,DMSO-d6)δ8.72(s,1H),7.80(d,J=2.3Hz,1H),7.46–7.38(m,2H),3.80–3.73(m,1H),3.54(dd,J=13.6,9.7Hz,1H),3.37(dd,J=13.6,6.5Hz,1H),2.68–2.61(m,2H),1.97(t,J=3.3Hz,1H),1.89–1.81(m,1H),1.80–1.74(m,4H),1.72–1.47(m,4H),1.43–1.18(m,9H),0.84(t,J=7.0Hz,3H);13C NMR(151MHz,DMSO-d6)δ155.4,141.4,130.5,130.0,122.3,120.1,119.0,62.8,56.3,56.2,54.2,46.2,38.5,34.7,31.2,28.2,28.1,28.0,22.2,20.7,20.7,14.0.
实施例15 12N-2-甲基苯胺甲酰基苦参丁烷盐酸盐(FAM11C)的制备
参照实施例7,将化合物8和2-甲基苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM11C,白色固体(0.279g,69%)。
1H NMR(600MHz,DMSO-d6)δ9.84(s,1H),8.22(s,1H),7.21(d,J=7.5Hz,1H),7.16(d,J=7.5Hz,1H),7.11(t,J=7.5Hz,1H),7.02(t,J=7.5Hz,1H),3.89(td,J=9.5,5.8Hz,1H),3.75(dd,J=14.3,11.6Hz,1H),3.63(dd,J=14.3,5.8Hz,1H),3.48(dt,J=10.4,3.5Hz,1H),3.43–3.34(m,1H),3.20(t,J=11.6Hz,2H),2.93–2.84(m,2H),2.25–2.20(m,1H),2.17(s,3H),2.02–1.87(m,2H),1.82(d,J=13.8Hz,1H),1.75–1.55(m,6H),1.48–1.40(m,1H),1.38–1.32(m,1H),1.30–1.21(m,3H),0.86(t,J=6.6Hz,3H);13C NMR(151MHz,DMSO-d6)δ157.3,137.8,132.6,130.0,125.8,125.7,124.4,63.3,54.6,54.5,54.4,47.6,36.3,33.9,29.9,28.2,25.3,24.9,22.2,18.5,18.4,18.1,14.1.
实施例16 12N-3-甲基苯胺甲酰基苦参丁烷盐酸盐(FAM12C)的制备
参照实施例7,将化合物8和3-甲基苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM12C,白色固体(0.29g,72%)。
1H NMR(600MHz,DMSO-d6)δ10.09(s,1H),8.77(s,1H),7.30(s,1H),7.22(d,J=7.5Hz,1H),7.08(t,J=7.5Hz,1H),6.73(d,J=7.5Hz,1H),3.93(td,J=9.7,5.5Hz,1H),3.80(dd,J=14.5,11.6Hz,1H),3.62(dd,J=14.5,5.5Hz,1H),3.50–3.44(m,1H),3.18(t,J=14.0Hz,2H),2.92–2.82(m,2H),2.34–2.28(m,1H),2.23(s,3H),2.04–1.89(m,3H),1.86–1.81(m,1H),1.81–1.71(m,1H),1.68–1.53(m,5H),1.47–1.38(m,1H),1.37–1.28(m,1H),1.28–1.14(m,3H),0.84(t,J=6.9Hz,3H);13C NMR(151MHz,DMSO-d6)δ157.0,140.5,137.3,128.1,122.2,119.7,116.3,63.3,54.6,54.4,54.3,47.8,36.0,34.0,29.8,28.2,25.3,24.8,22.1,21.2,18.4,18.3,14.1.
实施例17 12N-2-三氟甲基苯胺甲酰基苦参丁烷(FAM13C)的制备
参照实施例7,将化合物8和2-三氟甲基苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM13C,白色固体(0.305g,72%)。
1H NMR(600MHz,Chloroform-d)δ8.04(d,J=8.4Hz,1H),7.53(d,J=7.9Hz,1H),7.48(t,J=7.9Hz,1H),7.07(t,J=7.9Hz,1H),6.84(s,1H),3.81–3.73(m,2H),3.29–3.22(m,1H),2.74(t,J=14.1Hz,2H),2.06(s,1H),1.92–1.81(m,5H),1.74–1.66(m,2H),1.61–1.56(m,2H),1.55–1.47(m,3H),1.48–1.27(m,10H),0.88(t,J=6.9Hz,4H);13C NMR(151MHz,cdcl3)δ155.6,137.9,132.8,125.9,124.7,123.5,122.2,118.6,63.3,56.9,56.7,55.8,45.7,39.7,35.2,32.5,28.9,28.3,22.9,21.4,21.3,18.6,14.2.
实施例18 12N-4-甲氧基苄胺甲酰基苦参丁烷盐酸盐(FAM14C)的制备
参照实施例7,将化合物8和4-甲氧基苄胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM14C,白色固体(0.383g,88%)。
1H NMR(600MHz,DMSO-d6)δ9.66(s,1H),7.17(d,J=8.2Hz,2H),6.84(d,J=8.2Hz,2H),4.15(s,2H),3.82(td,J=9.2,5.9Hz,1H),3.60(dd,J=14.2,11.2Hz,1H),3.48–3.38(m,2H),3.16(t,J=12.9Hz,2H),2.85(dt,J=12.9,9.5Hz,2H),2.14–2.08(m,1H),2.01–1.83(m,4H),1.80–1.74(m,1H),1.73–1.49(m,7H),1.40–1.12(m,6H),0.83(t,J=7.0Hz,3H);13C NMR(151MHz,DMSO-d6)δ159.1,157.9,133.1,128.2(2),113.4(2),63.1,55.0,54.6,54.3,54.2,45.9,42.6,36.3,33.0,30.6,28.2,25.3,25.2,22.2,18.4,18.4,14.1.
实施例19 12N-3,5-二甲基苯胺甲酰基苦参丁烷盐酸盐(FAM15C)的制备
参照实施例3,将化合物8和3,5-二甲基苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM15C,白色固体(0.235g,56%)。
1H NMR(600MHz,DMSO-d6)δ9.95(s,1H),8.65(s,1H),7.07(s,2H),6.56(s,1H),3.91(td,J=9.5,5.6Hz,1H),3.77(dd,J=14.4,11.5Hz,1H),3.59(dd,J=14.4,5.6Hz,1H),3.46(dt,J=10.6,3.5Hz,1H),3.18(t,J=14.0Hz,2H),2.92–2.84(m,2H),2.32–2.27(m,1H),2.19(s,6H),2.05–1.95(m,2H),1.94–1.88(m,1H),1.83(d,J=13.8Hz,1H),1.78–1.70(m,1H),1.67–1.51(m,5H),1.46–1.39(m,1H),1.36–1.16(m,4H),0.84(t,J=7.0Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.9,140.4,137.1(2),123.1,116.9(2),63.2,54.6,54.4,54.2,47.5,36.0,33.8,29.9,28.2,25.3,24.9,22.1,21.1(2),18.4,18.3,14.1.
实施例20 12N-4-乙基苯胺甲酰基苦参丁烷盐酸盐(FAM16C)的制备
参照实施例7,将化合物8和4-乙基苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM16C,白色固体(0.327g,78%)。
1H NMR(600MHz,DMSO-d6)δ9.86(s,1H),8.53(s,1H),7.11(d,J=8.2Hz,2H),6.82(d,J=8.2Hz,2H),3.70(td,J=9.7,5.6Hz,1H),3.57(dd,J=14.4,11.6Hz,1H),3.40(dd,J=14.4,5.6Hz,1H),3.28–3.22(m,1H),2.95(t,J=14.1Hz,2H),2.70–2.61(m,2H),2.31–2.25(m,3H),2.10–2.04(m,1H),1.82–1.74(m,2H),1.73–1.65(m,1H),1.61(d,J=13.8Hz,1H),1.57–1.49(m,1H),1.45–1.29(m,5H),1.23–1.16(m,1H),1.14–1.07(m,1H),1.05–0.95(m,3H),0.90(t,J=7.6Hz,3H),0.61(t,J=6.9Hz,3H);13C NMR(151MHz,DMSO-d6)δ157.1,138.2,136.9,127.5(2),119.4(2),63.3,54.6,54.4,54.3,47.7,36.0,34.0,29.8,28.2,27.5,25.3,24.8,22.1,18.4,18.3,15.9,14.1.
实施例21 12N-4-氯苯胺甲酰基苦参丁烷盐酸盐(FAM17C)的制备
参照实施例3,将化合物8和4-氯苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM17C,白色固体(0.298g,70%)。
1H NMR(600MHz,DMSO-d6)δ9.96(s,1H),8.99(s,1H),7.50(d,J=8.6Hz,2H),7.26(d,J=8.6Hz,2H),3.96(td,J=9.5,5.8Hz,1H),3.80(dd,J=14.3,11.4Hz,1H),3.63(dd,J=14.3,5.7Hz,1H),3.46(dt,J=10.3,3.5Hz,1H),3.21–3.15(m,2H),2.93–2.83(m,2H),2.30–2.23(m,1H),2.08–2.03(m,1H),2.03–1.87(m,2H),1.85–1.71(m,2H),1.67–1.53(m,5H),1.48–1.39(m,1H),1.36–1.16(m,4H),0.83(t,J=7.0Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.7,139.7,128.1(2),125.1,120.7(2),63.1,54.6,54.3,54.2,47.2,36.1,33.8,30.0,28.1,25.2,24.9,22.1,18.4,18.3,14.0.
实施例22 12N-2,6-二甲基苯胺甲酰基苦参丁烷盐酸盐(FAM18C)的制备
参照实施例3,将化合物8和2,6-二甲基苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM18C,白色固体(0.281g,67%)。
1H NMR(600MHz,DMSO-d6)δ10.03(s,1H),8.05(s,1H),7.05–7.00(m,3H),3.82(td,J=10.1,5.2Hz,1H),3.76(t,J=8.5Hz,2H),3.51(dt,J=10.5,3.4Hz,1H),3.22(t,J=10.1Hz,2H),2.94–2.85(m,2H),2.27–2.22(m,1H),2.16(s,6H),2.10–2.01(m,1H),1.96–1.86(m,1H),1.83(d,J=14.0Hz,1H),1.75–1.59(m,6H),1.53(tt,J=14.0,4.2Hz,1H),1.44–1.33(m,3H),1.29–1.20(m,2H),0.86(t,J=6.7Hz,3H);13C NMR(151MHz,DMSO-d6)δ157.1,136.2,135.7(2),127.6(2),125.8,63.7,54.7,54.5,54.4,48.2,36.2,34.4,29.4,28.2,25.2,24.5,22.2,18.5,18.3,18.2(2),14.2.
实施例23 12N-2,4,6-三甲基苯胺甲酰基苦参丁烷(FAM19C)的制备
参照实施例3,将化合物8和2,4,6-三甲基苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM19C,白色固体(0.238g,60%)。
1H NMR(600MHz,DMSO-d6)δ7.50(s,1H),6.82(s,2H),3.74–3.67(m,1H),3.63(dd,J=13.8,8.7Hz,1H),3.36–3.32(m,1H),2.63(dd,J=12.4,8.7Hz,2H),2.20(s,3H),2.09(s,6H),1.97(s,1H),1.86–1.65(m,8H),1.52(d,J=13.2Hz,1H),1.43–1.23(m,9H),0.86(t,J=6.6Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.2,135.7(2),134.5,134.2,128.0(2),63.0,56.5,56.4,56.354.0,39.2,34.8,31.4,28.7,28.5,27.9,22.4,20.8,20.7,20.5,18.0(2),14.2.
实施例24 12N-4-硝基苯胺甲酰基苦参丁烷盐酸盐(FAM20C)的制备
参照实施例3,将化合物8和4-硝基苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM20C,白色固体(0.27g,62%)。
1H NMR(600MHz,DMSO-d6)δ9.48(s,1H),8.16(d,J=9.2Hz,2H),7.72(d,J=9.2Hz,2H),3.98(td,J=9.0,5.9Hz,1H),3.80–3.73(m,1H),3.60(dd,J=14.1,6.3Hz,1H),3.45(dd,J=9.2,5.1Hz,1H),3.20(t,J=12.9Hz,2H),2.90(q,J=11.5Hz,2H),2.27–2.21(m,1H),2.17–2.10(m,1H),1.97–1.84(m,2H),1.82(d,J=13.6Hz,1H),1.74–1.56(m,6H),1.52–1.43(m,1H),1.37–1.15(m,5H),0.83(t,J=7.1Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.0,147.5,140.7,124.7(2),118.2(2),62.9,54.6,54.3,54.2,47.0,36.2,33.9,30.0,28.0,25.2,25.0,22.1,18.4,18.3,14.0.
实施例25 12N-2,6-二乙基苯胺甲酰基苦参丁烷盐酸盐(FAM22C)的制备
参照实施例7,将化合物8和2,6-二乙基苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM22C,白色固体(0.362g,81%)。
1H NMR(600MHz,DMSO-d6)δ10.49(d,J=9.9Hz,1H),8.02(s,1H),7.08(t,J=7.5Hz,1H),7.02(d,J=7.5Hz,2H),3.83(dt,J=12.2,8.8Hz,3H),3.52(dt,J=10.3,3.3Hz,1H),3.20–3.14(m,2H),2.89–2.81(m,2H),2.54–2.42(m,4H),2.22(dd,J=11.3,4.0Hz,1H),2.12–1.99(m,2H),1.95–1.86(m,1H),1.80(d,J=14.0Hz,1H),1.74–1.64(m,2H),1.63–1.53(m,3H),1.51–1.43(m,1H),1.35–1.29(m,3H),1.22–1.15(m,2H),1.07(t,J=7.6Hz,6H),0.83(t,J=6.4Hz,3H);13C NMR(151MHz,DMSO-d6)δ158.1,142.1,134.9(2),126.7,126.0(2),63.9,55.0,54.8,54.6,49.4,36.3,35.4,28.9,28.3,25.2,24.2,22.3,18.6(2),18.2,18.1,14.7(2),14.2.
实施例26 12N-4-丁基苯胺甲酰基苦参丁烷盐酸盐(FAM23C)的制备
参照实施例7,将化合物8和4-丁基苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM23C,白色固体(0.335g,75%)。
1H NMR(600MHz,DMSO-d6)δ9.96(s,1H),8.75(s,1H),7.34(d,J=8.1Hz,2H),7.03(d,J=8.1Hz,2H),3.92(td,J=9.6,5.7Hz,1H),3.78(dd,J=14.3,11.5Hz,1H),3.61(dd,J=14.3,5.7Hz,1H),3.50–3.44(m,1H),3.19(t,J=13.9Hz,2H),2.92–2.85(m,2H),2.48(t,J=7.8Hz,2H),2.32–2.27(m,1H),2.07–1.96(m,2H),1.95–1.87(m,1H),1.83(d,J=13.6Hz,1H),1.75(ddd,J=17.2,8.6,3.7Hz,1H),1.67–1.47(m,7H),1.46–1.40(m,1H),1.37–1.18(m,6H),0.88(t,J=7.4Hz,3H),0.84(t,J=6.9Hz,3H);13C NMR(151MHz,DMSO-d6)δ157.0,138.2,135.5,128.1(2),119.3(2),63.2,54.6,54.4,54.2,47.5,36.0,34.2,33.8,33.4,30.0,28.2,25.3,24.9,22.2,21.7,18.4,18.3,14.1,13.8.
实施例27 12N-4-溴苯胺甲酰基苦参丁烷(FAM24C)的制备
参照实施例3,将化合物8和4-溴苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM24C,白色固体(0.303g,70%)。
1H NMR(600MHz,Dichloromethane-d2)δ7.35(d,J=8.5Hz,2H),7.26(d,J=8.5Hz,2H),6.58(s,1H),3.81(dt,J=8.8,6.1Hz,1H),3.61(dd,J=12.9,9.1Hz,1H),3.26(dd,J=12.9,7.1Hz,1H),2.73(t,J=11.0Hz,2H),2.05(s,1H),1.89–1.82(m,3H),1.79–1.73(m,4H),1.69–1.61(m,1H),1.58–1.37(m,7H),1.37–1.22(m,4H),0.88(t,J=6.7Hz,3H);13CNMR(151MHz,cd2cl2)δ156.0,139.9,132.0(2),121.5(2),114.7,63.5,57.2(2),55.3,45.8,39.9,35.2,33.4,29.2,29.1,29.0,23.4,21.9,21.6,14.5.
实施例28 12N-2-氯苯胺甲酰基苦参丁烷盐酸盐(FAM25C)的制备
参照实施例7,将化合物8和2-氯苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM25C,白色固体(0.281g,66%)。
1H NMR(600MHz,DMSO-d6)δ10.10(s,1H),8.45(s,1H),7.47(d,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),7.27(t,J=7.7Hz,1H),7.13(t,J=7.7Hz,1H),3.93(td,J=9.7,5.6Hz,1H),3.79(dd,J=14.4,11.6Hz,1H),3.68(dd,J=14.4,5.6Hz,1H),3.53–3.47(m,1H),3.20(t,J=11.8Hz,2H),2.92–2.84(m,2H),2.05–1.98(m,1H),1.96–1.53(m,10H),1.46–1.40(m,1H),1.36–1.22(m,4H),0.85(t,J=6.7Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.7,136.6,129.3,128.1,127.2,127.0,125.5,63.2,54.7,54.7,54.4,47.7,36.4,33.9,29.9,28.2,25.3,24.8,22.2,18.5,18.4,14.1.
实施例29 12N-3-三氟甲基苯胺甲酰基苦参丁烷盐酸盐(FAM26C)的制备
参照实施例7,将化合物8和3-三氟甲基苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM26C,白色固体(0.395g,86%)。
1H NMR(600MHz,DMSO-d6)δ9.91(s,1H),9.19(s,1H),7.95(s,1H),7.71(d,J=7.9Hz,1H),7.45(t,J=7.9Hz,1H),7.25(d,J=7.9Hz,1H),3.98(td,J=9.5,5.8Hz,1H),3.82(dd,J=14.3,11.5Hz,1H),3.65(dd,J=14.3,5.8Hz,1H),3.50–3.44(m,1H),3.19(t,J=13.6Hz,2H),2.93–2.84(m,2H),2.31–2.25(m,1H),2.12–2.06(m,1H),2.02–1.88(m,2H),1.83(d,J=13.8Hz,1H),1.81–1.71(m,1H),1.68–1.53(m,5H),1.49–1.40(m,1H),1.38–1.29(m,1H),1.29–1.16(m,3H),0.83(t,J=7.0Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.6,141.5,129.4,129.1,124.3,122.6,117.7,115.1,63.0,54.6,54.3,54.2,47.0,36.1,33.7,30.1,28.1,25.2,25.0,22.1,18.4,18.3,14.0.
实施例30 12N-苯胺甲酰基苦参丁烷盐酸盐(FAM27C)的制备
参照实施例3,将化合物8和苯基异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM27C,白色固体(0.231g,59%)。
1H NMR(600MHz,DMSO-d6)δ9.46(s,1H),8.75(s,1H),7.45(d,J=7.7Hz,2H),7.22(t,J=7.7Hz,2H),6.92(t,J=7.7Hz,1H),3.95–3.88(m,1H),3.72(t,J=12.7Hz,1H),3.56(dd,J=14.4,6.2Hz,1H),3.45(d,J=10.3Hz,1H),3.19(t,J=13.7Hz,2H),2.93–2.84(m,2H),2.28–2.23(m,1H),2.12–2.07(m,1H),1.95–1.87(m,2H),1.82(d,J=13.5Hz,1H),1.75–1.55(m,5H),1.49–1.42(m,1H),1.36–1.18(m,4H),0.84(t,J=7.0Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.7,140.5,128.3(2),121.7,119.3(2),62.9,54.6,54.3,53.8,46.2,36.1,33.2,30.5,28.1,25.3,22.1,18.5,18.4,15.2,14.0.
实施例31 12N-4-甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM28C)的制备
参照实施例3,将化合物8和4-甲氧基苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM28C,白色固体(0.333g,79%)。
1H NMR(600MHz,DMSO-d6)δ9.99(s,1H),8.67(s,1H),7.34(d,J=8.7Hz,2H),6.80(d,J=8.7Hz,2H),3.92(td,J=9.4,5.6Hz,1H),3.77(dd,J=14.3,11.5Hz,1H),3.69(s,3H),3.61(dd,J=14.3,5.6Hz,1H),3.49–3.43(m,1H),3.17(t,J=13.9Hz,2H),2.92–2.82(m,2H),2.30–2.25(m,1H),2.06–1.87(m,3H),1.85–1.71(m,2H),1.69–1.52(m,5H),1.46–1.37(m,1H),1.37–1.16(m,4H),0.83(t,J=6.8Hz,3H);13C NMR(151MHz,DMSO-d6)δ157.2,154.3,133.6,121.1(2),113.5(2),63.2,55.2,54.6,54.4,54.2,47.3,36.1,33.7,30.0,28.2,25.3,24.9,22.1,18.4,18.3,14.1.
实施例32 12N-2-甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM29C)的制备
参照实施例7,将化合物8和2-甲氧基苯胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM29C,白色固体(0.337g,80%)。
1H NMR(600MHz,DMSO-d6)δ9.96(s,1H),7.79(s,1H),7.60(d,J=8.3Hz,1H),7.02–6.96(m,2H),6.88–6.83(m,1H),3.92(td,J=9.4,5.7Hz,1H),3.79(s,3H),3.73(dd,J=14.2,11.4Hz,1H),3.62(dd,J=14.2,5.7Hz,1H),3.51–3.45(m,1H),3.36(s,1H),3.19(t,J=12.9Hz,2H),2.93–2.84(m,2H),2.26–2.21(m,1H),2.16–2.10(m,1H),2.00–1.86(m,2H),1.82(d,J=13.8Hz,1H),1.75–1.54(m,6H),1.46(td,J=8.5,4.8Hz,1H),1.36–1.31(m,1H),1.29–1.23(m,3H),0.85(t,J=6.7Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.7,150.1,128.6,123.4,122.3,120.2,111.0,63.1,55.7,54.6,54.5,54.4,47.2,36.3,33.6,30.2,28.1,25.2,25.0,22.1,18.4,18.3,14.1.
实施例33 12N-4-异丙基苯胺甲酰基苦参丁烷盐酸盐(FAM30C)的制备
参照实施例3,将化合物8和4-异丙基苯异氰酸酯反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM30C,白色固体(0.377g,87%)。
1H NMR(600MHz,DMSO-d6)δ10.00(s,1H),8.75(s,1H),7.34(d,J=8.1Hz,2H),7.07(d,J=8.1Hz,2H),3.92(td,J=9.6,5.6Hz,1H),3.82–3.75(m,1H),3.61(dd,J=14.4,5.6Hz,1H),3.50–3.44(m,1H),3.18(t,J=14.1Hz,2H),2.93–2.84(m,2H),2.84–2.77(m,1H),2.33–2.27(m,1H),2.05–1.95(m,2H),1.95–1.86(m,1H),1.83(d,J=13.8Hz,1H),1.81–1.71(m,1H),1.67–1.51(m,5H),1.47–1.38(m,1H),1.37–1.28(m,1H),1.27–1.13(m,9H),0.84(t,J=6.9Hz,3H);13C NMR(151MHz,DMSO-d6)δ157.1,141.6,138.3,126.0(2),119.3(2),63.2,54.6,54.4,54.2,47.5,36.0,33.9,32.8,29.9,28.2,25.3,24.9,24.1,24.0,22.1,18.4,18.3,14.1.
实施例34 12N-环已胺甲酰基苦参丁烷盐酸盐(FAM31C)的制备
参照实施例7,将化合物8和环已胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM31C,白色固体(0.314g,79%)。
1H NMR(600MHz,DMSO-d6)δ9.98(s,1H),6.45(s,1H),3.79(td,J=9.6,5.5Hz,1H),3.60(t,J=13.0Hz,1H),3.44(dd,J=14.0,5.5Hz,2H),3.39–3.32(m,1H),3.15(t,J=14.0Hz,2H),2.89–2.80(m,2H),2.19–2.14(m,1H),2.00–1.91(m,2H),1.87(dd,J=13.5,4.1Hz,1H),1.79–1.49(m,11H),1.40–1.02(m,11H),0.83(t,J=7.0Hz,3H);13C NMR(151MHz,DMSO)δ158.4,63.3,54.6,54.4,48.8,47.2,36.0,33.3,33.1,32.8(2),30.0,28.2,25.4,25.3,25.0(2),24.8,22.2,18.4,18.4,14.1.
实施例35 12N-环戊胺甲酰基苦参丁烷盐酸盐(FAM32C)的制备
参照实施例7,将化合物8和环戊胺反应,TLC检测反应结束,蒸干用快速柱层析分离纯化得FAM32C,白色固体(0.337g,88%)。
1H NMR(600MHz,DMSO-d6)δ9.72(s,1H),6.40(s,1H),3.87(p,J=6.8Hz,1H),3.77(td,J=9.3,5.9Hz,1H),3.57(dd,J=14.1,11.3Hz,1H),3.45–3.36(m,2H),3.15(t,J=14.1Hz,2H),2.84(td,J=12.5,9.3Hz,2H),2.17–2.12(m,1H),1.98–1.82(m,3H),1.79–1.69(m,4H),1.66–1.13(m,16H),0.84(t,J=7.1Hz,3H);13C NMR(151MHz,DMSO)δ159.0,63.2,54.6,54.4,54.1,51.6,46.5,36.1,33.0,32.6,32.3(2),30.3,28.2,25.3,25.1,23.5(2),22.2,18.4,14.1.
试验例1式Ⅰ所示化合物在mRNA及蛋白水平上抑制TGFβ1诱导LX-2细胞中肝纤维化主要标志物试验
1.1TGFβ1诱导LX-2细胞,在含10%胎牛血清的DMEM(Gibco)培养基,37℃,5%CO2条件下培养LX2细胞。按照每孔1×105个细胞铺于6孔板,培养24小时后使用真空泵去除6孔板内原有的培养基并加入不含10%胎牛血清的DMEM(Gibco)培养基。饥饿培养24h后,加TGF-β1(2ng/ml)诱导,同时加入浓度梯度的化合物,浓度为20μM,并且设置对照组(不加入TGF-β1诱导)和TGF-β1诱导组(仅加入TGF-β1诱导)。
1.2继续培养24小时后,弃去培养基,按照AZfreshTM总RNA小量/微量提取试剂盒说明书操作步骤提取LX-2细胞总RNA。按照Roche Transcriptor First Strand cDNASynthesis Kit说明书操作步骤将LX-2总RNA逆转录为cDNA。将所得的cDNA、无菌水、RocheFastStart Universal Probe Master(Rox)以及ABI TaqMan probes(COL1A1、TGFβ1、ACTA2、MMP2、CTGF)配制成20μl反应体系,使用ABI 7500Fast Real-Time PCR System进行检测。结果如图1所示。
从图中可以看出,本发明提供的式Ⅰ所示化合物可在mRNA水平上显著抑制COL1A1,TGFβ1,ACTA2,MMP2和CTGF的表达。
1.3TGFβ1诱导后,继续培养24小时后,6孔板中每孔中加入1ml Beyotime Western及IP细胞裂解液(含1%Cocktail蛋白酶抑制剂)提取蛋白,并用BCA法测定蛋白浓度。以每孔25μg/20μl上样,经电泳、转膜、5%脱脂牛奶封闭、抗体孵育后,使用Tanon5200全自动化学发光图像分析系统获得所需蛋白条带。结果如图2所示。
从图中可以看出,本发明提供的式Ⅰ所示化合物可显著抑制COL1A1、TGFβ1、α-SMA、MMP2和MMP9标志物蛋白的表达。
试验例2基于COL1A1启动子药物筛选试验
1.1质粒转染,将LX-2细胞按照1×107个细胞铺于10cm细胞培养皿,培养24小时后使用真空泵去除培养皿内原有的培养基并加入不含10%胎牛血清的DMEM(Gibco)培养基并转入质粒(pGL4.17-COL1A1P)。转染6h后使用真空泵去除培养皿内原有的培养基并加入含10%胎牛血清的DMEM(Gibco)培养基继续培养18h。将转染入质粒的LX-2细胞消化并以每孔1.5×104铺于96孔细胞培养板,培养24h使其贴壁。
1.2向96孔细胞培养板中加入1μl含化合物的DMSO溶液,浓度分别为40μM、80μM,每浓度设置三个复孔;向对照组中加入1μl DMSO溶液,作用24h。按照Bright-GloTMLuciferaseAssay System说明书操作步骤,24h后弃培养基,加入含10%胎牛血清的DMEM(Gibco)培养基50μl/孔。加入荧光素酶底物50μl/孔,2min后进行检测,计算IC50和相对荧光素酶活性(%),结果见表1。
表1 COL1A1启动子药物筛选试验结果
NT表示未检测。
从表中可以看出,本发明提供的式Ⅰ所示化合物可显著抑制COL1A1启动子的活性。
试验例3细胞毒性测试试验
细胞毒性由MTT法评估。将HepG2细胞以6×103个细胞/孔的密度接种于96孔板并用各浓度药物处理细胞。37℃,5%CO2孵育24小时后,每孔加入20μL的MTT(5mg/mL)溶液,在37℃,5%CO2下继续孵育4小时。随后,用150μL DMSO替换培养上清液以溶解结晶,使用酶标仪测量570nm处的吸光度,计算CC50和CC50与IC50的比值CC50/IC50,结果见表2。
试验例4小鼠急性毒性试验
取昆明小鼠(19-21g)随机分组,每组雌雄各三只,给药前禁食5小时,纯净水配置样品,分别给予800mg/kg,400mg/kg,200mg/kg剂量的药品,对照组给予同剂量的生理盐水,观察七天,记录小鼠死亡情况,结果见表2。
试验例5初步药代动力学试验
取健康雄性SD大鼠(200-250g),每组3只,分别口服给药25mg/kg,给药溶液为给药前一小时配置。给药后按规定时间点(0.25h、0.5h、1h、1.5h、2h、4h、6h、24h)经颈静脉插管取全血约0.3ml,置含有K3EDTA为抗凝剂的离心管中,全血样品采出后离心分离血浆。血浆样品经有机处理后采用液相色谱-质谱联用测定药品血药浓度,计算药代动力学参数,结果见表2,除样品分析期间,血浆样品收集后置于-20℃保存。
表2细胞毒性、小鼠急性毒性及初步药代动力学试验结果
NT表示未检测。
从表中可以看出,本发明提供的式Ⅰ所示化合物对HepG2细胞具有细胞毒性,且在小鼠急性毒性试验中,小鼠死亡率低,表明本发明提供的化合物安全性较高,且具有很好的药代动力学特性。
Claims (7)
2.如权利要求1所述的式Ⅰ所示化合物、或其药学上可接受的盐,其中,
R1为苯基;其中,苯基各自独立地被一个或多个选自Cl、Br、甲基、乙基、异丙基、正丁基、三氟甲氧基或三氟甲基的取代基取代。
3.如权利要求1所述的式Ⅰ所示化合物、或其药学上可接受的盐,其中,
R2为C3烷基。
4.如权利要求1所述的式Ⅰ所示化合物、或其药学上可接受的盐,其中,式Ⅰ所示化合物选自以下化合物:
12N-4-三氟甲基苯胺甲酰基苦参丁酸甲酯盐酸盐(FAM1A)
12N-4-三氟甲基苯胺甲酰基苦参丁醇盐酸盐(FAM1B)
12N-4-三氟甲基苯胺甲酰基苦参丁烷盐酸盐(FAM1C)
12N-3-氯苯胺甲酰基苦参丁酸甲酯(FAM2A)
12N-3-氯苯胺甲酰基苦参丁醇盐酸盐(FAM2B)
12N-3-氯苯胺甲酰基苦参丁烷盐酸盐(FAM2C)
12N-4-氟苯胺甲酰基苦参丁烷盐酸盐(FAM3C)
12N-4-甲基苯胺甲酰基苦参丁烷盐酸盐(FAM4C)
12N-3,5-二氯苯胺甲酰基苦参丁烷盐酸盐(FAM5C)
12N-3-甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM6C)
12N-2,4-二氟苯胺甲酰基苦参丁烷盐酸盐(FAM7C)
12N-2,6-二异丙基苯胺甲酰基苦参丁烷盐酸盐(FAM8C)
12N-4-三氟甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM9C)
12N-3,4-二氯苯胺甲酰基苦参丁烷(FAM10C)
12N-2-甲基苯胺甲酰基苦参丁烷盐酸盐(FAM11C)
12N-3-甲基苯胺甲酰基苦参丁烷盐酸盐(FAM12C)
12N-2-三氟甲基苯胺甲酰基苦参丁烷(FAM13C)
12N-4-甲氧基苄胺甲酰基苦参丁烷盐酸盐(FAM14C)
12N-3,5-二甲基苯胺甲酰基苦参丁烷盐酸盐(FAM15C)
12N-4-乙基苯胺甲酰基苦参丁烷盐酸盐(FAM16C)
12N-4-氯苯胺甲酰基苦参丁烷盐酸盐(FAM17C)
12N-2,6-二甲基苯胺甲酰基苦参丁烷盐酸盐(FAM18C)
12N-2,4,6-三甲基苯胺甲酰基苦参丁烷(FAM19C)
12N-4-硝基苯胺甲酰基苦参丁烷盐酸盐(FAM20C)
12N-2,6-二乙基苯胺甲酰基苦参丁烷盐酸盐(FAM22C)
12N-4-丁基苯胺甲酰基苦参丁烷盐酸盐(FAM23C)
12N-4-溴苯胺甲酰基苦参丁烷(FAM24C)
12N-2-氯苯胺甲酰基苦参丁烷盐酸盐(FAM25C)
12N-3-三氟甲基苯胺甲酰基苦参丁烷盐酸盐(FAM26C)
12N-苯胺甲酰基苦参丁烷盐酸盐(FAM27C)
12N-4-甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM28C)
12N-2-甲氧基苯胺甲酰基苦参丁烷盐酸盐(FAM29C)
12N-4-异丙基苯胺甲酰基苦参丁烷盐酸盐(FAM30C)
12N-环已胺甲酰基苦参丁烷盐酸盐(FAM31C)
12N-环戊胺甲酰基苦参丁烷盐酸盐(FAM32C)。
6.药物组合物,包括权利要求1-4任一项所述的式Ⅰ所示化合物、或其药学上可接受的盐以及药学可接受的载体或赋形剂。
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