CN113209066A - 氨基-芳基-苯甲酰胺化合物及其使用方法 - Google Patents
氨基-芳基-苯甲酰胺化合物及其使用方法 Download PDFInfo
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- CN113209066A CN113209066A CN202110468648.1A CN202110468648A CN113209066A CN 113209066 A CN113209066 A CN 113209066A CN 202110468648 A CN202110468648 A CN 202110468648A CN 113209066 A CN113209066 A CN 113209066A
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Abstract
公开了用于治疗和/或降低非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)的方法。所述方法使用活性氨基‑芳基‑苯甲酰胺化合物及其制备方法。
Description
本申请是申请人于2018年05月07日提交的、申请号为201810427371.6 的、发明名称为“氨基-芳基-苯甲酰胺化合物及其使用方法”的发明专利申请的 分案申请。
技术领域
本发明涉及氨基-芳基-苯甲酰胺化合物及其制备方法。本发明还涉 及使用此类组合物治疗和/或降低非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)和非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)。
背景技术
非酒精性脂肪性肝病(NAFLD)是世界上最常见的慢性肝病,并且由 于与肥胖和胰岛素抗性密切相关,其发病率正在增加。NAFLD代表一系列肝脏 疾病,其包括:单纯性脂肪变性(>5%的肝细胞中的甘油三酯(TAG)浸润)、脂肪 浸润伴随炎症、以及肝细胞气球样变性(hepatocellular ballooning degeneration) (非酒精性脂肪性肝炎,NASH),进展为肝纤维化并最终导致肝硬化(Hardy et al.,2016Annual Reviews of Pathology)。在那些NAFLD患者中,大约25%将进 展为更为严重的NASH形式,该NASH形式是一个主要的健康问题,因为其与 心血管死亡率的增加、2型糖尿病及末期肝脏疾病(包括纤维化、肝硬化和肝细 胞癌(HCC))的重大风险密切相关(Targher et al.,2010NEJM)。5-25%的NASH 患者将在7年内形成为肝硬化,并且4-27%的NASH患者最终将形成为肝癌。 确实,NASH与超过10倍增加的肝脏相关死亡风险以及加倍的心血管风险相 关(Ekstedt et al.,2006Hepatology)。
在美国,30-40%的成年人患有非酒精性脂肪性肝病(Spengler and Loomba,2015Mayo Clinic Proceedings),并且可能因为患有肥胖的美国人数量增 加,该状况的流行性正在增加(National Digestive Diseases Information Clearinghouse,NIDDK)。一份运用超声和肝生检方法的最近前瞻性分组研究提 示在无症状中年人患者中的NAFLD流行性为46.0%,并且NASH流行性为12.2%(Williams et al.,2011Gastroenterology)。随着由于慢性病毒性肝炎引起的 肝硬化的发生率减少,认为NAFLD/NASH将成为全球肝移植的主要指征 (Charlton et al.,2011Gastroenterology)。
直到最近,连续“二次打击学说(two-hit hypothesis)”一直被广泛接 受以解释NAFLD/NASH的发病机理。确实,各种生物化学和免疫过程的联合 作用(“多重平行打击”)归因于NAFLD/NASH的形成。序贯地,肝脂肪变性 (hepatic steatosis)由早期应激应答所诱导,通过所述早期应激应答,脂毒性游离 脂肪酸(free fatty acid,FFA)分成相对稳定的TA G储存。当缓解肝脏中脂肪酸 的有害影响的适应机制不堪重负,导致活性氧类别(reactive oxygen species,ROS) 的产生、ER应激和细胞功能障碍时产生脂肪毒性。随后,细胞损伤触发免疫介 导的肝细胞损伤和细胞死亡途径的混合。一旦这些持续,肝星状细胞(HSC)被活 化,导致胶原蛋白沉积和肝纤维发生(hepatic fibrogenesis)(Hardy et al.,2016Annual Reviews of Pathology)。最终,这些事件引起可导致肝衰竭和HCC 的肝硬化(Richardson et al.,2007Gastroenterology)。
NAFLD/NASH治疗的主要关注点在于逆转肝脏脂肪变性以及降低 进展为晚期纤维化、肝硬化及其后遗症,包括HCC、代谢疾病和心血管疾病。 目前,尚无批准的NAFLD/NASH药理疗法。唯一治疗选项是与改变生活方式 相关的重量减轻。然而,此类治疗方法需要大量的义务,并且顺从性可以是困 难的。因此,迫切需要研发针对此破坏性人疾病的新型且有效的治疗剂。本发 明解决了该需求。
发明内容
本公开提供了在受试者中治疗非酒精性脂肪性肝病(NAFLD)的方 法,所述方法包括向所述受试者施用治疗有效量的化合物或其前药、治疗活性 代谢物、水合物、溶剂化物,或药学上可接受的盐,所述化合物选自由式I、式 II、式III、式IV的化合物组成的组,
其中,式I为:
其中R1为卤素,R2为亚砜基(sulfoxide group),且R3和R4独立 地为氢或低链烷基;
其中,式II为:
且式III为:
其中,
R1为-CHCHR5;-CHCHCO2R5;-CHCHCONHR5;-苯基;-苯基- R5;-CCR5;-CC-CH2R5;-OR5;-SR5;或-NHR5;
R2为-C6H4-R6;-OC6H4-R6;-SC6H4-R6;-NHC6H4-R6;-OC1-6烷 基-C6H4-R6;-NHC1-6烷基-C6H4-R6;哌嗪-R6;或吡啶-R6;
R3为H;-C1-6烷基,任选地用-OH、-NH2、苯基,或卤素取代; -CO-吡啶;-CO-CH2CH2NH2;或-CO-C1-6烷基,任选地用-OH或-NH2取代;
R4为H;-OCH3;-哌啶;-哌啶-CONH2;-吡啶;-吡咯;-噻吩;- C1-6烷基,任选地用-OH取代;-吡啶;-哌啶;-吡咯;-噻吩;或-苯基,任选 地用卤素或羟基取代;
或者,R3和R4一起形成尿嘧啶;
R5为卤素;-COOH;C1-6环烷基;-CH2C6H5;-CH2CH2C6H5;- CH2CH2C6H4-F;CH2C6H4-COOH;-CH2C6H4-OH;-CH2-呋喃;-Si(CH2)3;- CH2CO2CH3;-CH2CO2(CH2)2CH3;或-CH2CO2C6H4-Cl;或者
-C1-10烷基,任选地用卤素或-OH取代;或者
-C1-10环烷基,任选地用卤素或-OH取代;或者
-苯基,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、 -NHCOMe、-NHCO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代; 或者
-吡啶,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、-NHCOMe、-NHCO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代; 或者
-吡咯,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、 -NHCOMe、-NHCO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取 代;
R6为SO2NH2;-OPO(OH)2;-NH2;-NHCONH2;-NHCOCH3;- NHCSCH3;-NHCSCH2CH3;-NHCS(CH2)2CH3;四唑;-SO2NH(CH2)2CH3;- NHC(NH)NH2;-NHCSNH2;-NHCSCH2OH;三唑;氧代咪唑(oxoimidazol);- SO2NHCH2CH2OH;-NHCONH-C1-6烷基;或-NHCONH-吡啶;并且其中式IV 为:
其中R1选自表1中所列的基团;
表1
式IV,R1选项
其中R2选自表2中所列的基团;
表2
式IV,R2选项
其中R3选自表3中所列的基团;
表3
式IV,R3选项
其中R4选自表4中所列的基团;
表4
式IV,R4选项
在本发明的进一步的实施方案中,所述NAFLD包含选自下组的病 患:脂肪浸润加炎症(fatty infiltration plus inflammation)、非酒精性脂肪性肝炎(nonalcoholicsteatohepatitis,NASH)、肝纤维化(liver fibrosis)、肝硬化(cirrhosis), 及其组合。
在本发明的进一步的实施方案中,以约1mg/kg至约100mg/kg受试 者体重/天的剂量施用所述化合物。
在本发明的进一步的实施方案中,每天一次施用所述化合物。
在本发明的进一步的实施方案中,R1为氯化物。
在本发明的进一步的实施方案中,R2为SO2NH2。
在本发明的进一步的实施方案中,R3为氢。
在本发明的进一步的实施方案中,R4为氢。
在本发明的进一步的实施方案中,所述方法包括使用式I的化合物, 或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐。
在本发明的进一步的实施方案中,所述方法包括使用式II的化合 物,或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐。
在本发明的进一步的实施方案中,所述方法包括使用式III的化合 物,或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐。
在本发明的进一步的实施方案中,所述方法包括使用式IV的化合 物,或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐。
在本发明的进一步的实施方案中,所述方法包括使用选自下组: HPN-011 01-01133;HPN-01201-01224;HPN-01301-01322;HPN-01401-01430; HPN-01501-01506;HPN-01513-01520;HPN-01525-01527;HPN-01529-01534; HPN-01601-01630及其前药、治疗活性代谢物、水合物、溶剂化物,或药学上 可接受的盐。
本发明的一个实施方案是式I、式II、式III、式IV的化合物或其 前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐,其用于在 受试者中治疗非酒精性脂肪性肝病(NAFLD)。在某些实施方案中,治疗的疾病 为受试者中的非酒精性脂肪性肝病(NAFLD)。
本发明的一个实施方案是用于治疗NAFLD的试剂盒,所述试剂盒 包含式I、式II、式III、式IV的化合物或其前药、治疗活性代谢物、水合物、 溶剂化物,或药学上可接受的盐,以及用于将所述化合物施用至受试者的说明 书,所述受试者患有或有风险患有NAFLD或相关病患,如脂肪沉积相关炎症、 非酒精性脂肪性肝炎(NASH)、肝纤维化、肝硬化,或其组合。
本发明的一个实施方案为式III、式IV的化合物或其前药、治疗活 性代谢物、水合物、溶剂化物,或药学上可接受的盐,其中所述化合物不是式 II。
本发明的一个实施方案为药物组合物,其包含式III、式IV的化合 物或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐,其 中所述化合物不是式II。
本发明的一个实施方案为式III、式IV的化合物或其前药、治疗活 性代谢物、水合物、溶剂化物,或药学上可接受的盐或本公开的药物组合物在 制备用于治疗患有或有风险患有NAFLD或相关病患,如脂肪沉积相关炎症、 非酒精性脂肪性肝炎(NASH)、肝纤维化、肝硬化,或其组合的药物中的用途, 其中所述化合物不是式II。
附图说明
图1:式I,2-氨基-3,5-二芳基苯甲酰胺的通用结构。
图2:式II,HPN-01的结构。
图3:式III。
图4:式IV。
图5A-5D:HPN-01对肝细胞脂肪脂滴(lipid droplet,LD)生源 (biogenesis)的影响。在缺乏或存在400μM油酸(其触发LD形成)下,用各种量 的HPN-01处理肝癌(Heptoma)细胞系Huh7细胞24小时,之后用Zeiss共焦显 微镜荧光下观察胞内LD内容物。图5A)缺乏(上图)和存在(下图)油酸下,未处 理(DMSO)和HPN-01处理细胞的荧光分析。使用BODIPY 493/50对细胞的LD 内容物染色并显示为绿色。蓝色指示细胞核。图5B)存在和缺乏油酸下处理的 和未处理的(DMSO)细胞的LD大小。图5C)缺乏油酸下,处理的和未处理的 (DMSO)细胞的平均荧光强度。图5D)存在油酸下,处理的和未处理的(DMSO) 细胞的平均荧光强度。
图6:HPN-01处理对培养的肝细胞中LD生源的抑制效果(IC50= 0.25μM)。显示了与1mM胰岛素预先温育的未处理的或HPN-01处理的Huh7 细胞的分光光度吸光度。使用油红O染色LD内容物,并通过确定OD 540nm 下的分光光度计吸光度测量。
图7:HPN-01处理对分化3T3-L1细胞中分泌的小鼠脂联素 (adiponectin)水平的影响(IC50=0.32μM)。
图8:用HPN-01处理后对各种脂肪生成基因mRNA水平的抑制。 图显示了来自用DMSO(表示为1.0,灰色阴影)或HPN-01(黑/白阴影)处理的细 胞的mRNA的相对水平。固醇调节元件结合蛋白1(SREBP-1);固醇调节元件 结合蛋白2(SREBP-2);脂肪酸合酶(FASN);硬脂酰-CoA-去饱和酶(SCD1); 乙酰CoA羧化酶(ACC);非常长链脂肪酸延长脂肪酸延长酶6(Elongation of very long chain fatty acids fatty acid elongase 6,ELOVL6);低密度脂受体(Low density liporeceptor,LDLR);脂肪酸去饱和酶1(FADS1);二酰基甘油O-酰基转 移酶1(DGAT1);二酰基甘油O-酰基转移酶2(DGAT2)。
图9:HPN-01对培养的原代人肝细胞中SREBP-1(肝脏葡萄糖代谢 和脂肪酸合成主调节物)和SREBP-2(细胞中的胆固醇稳态的主调节物)的影响。 IC50=1.71μM(SREBP-1)和3.43μM(SREBP-2)。
图10A和10B:通过HPN-01抑制肝细胞生长。CC50=54.3μ M(Huh7细胞,图10A)和77.2μM(原代人肝细胞,图10B)。
图11:HPN-01对高脂肪膳食诱导的NAFLD/NASH小鼠的体内影 响的研究设计。
图12A和12B:HPN-01处理对小鼠中肥胖和内脏脂肪积累的影响。 图12A)正常饮食(normal chow diet)喂养的未处理的小鼠(NCD;圆圈)、高脂肪 膳食喂养的未处理的小鼠(NFD载体;方框),以及高脂肪膳食喂养的处理小鼠 (HFD HPN-01;三角形)中的体重变化显示了HPN-01处理逆转了HFD触发的 肥胖。图12B)处死后小鼠内部器官的检查显示了HPN-01显著缓解了内脏脂肪 积累(图12B)。
图13A和13B:HPN-01处理对HFD诱导的肝脂肪变性的影响。小 鼠根据图11所示的实验概要喂养。然后,将小鼠实施安乐死,并且对肝脏切片 进行显微镜评估。图13A)来自小鼠的肝脏组织切片的苏木精和曙红(H&E)染色。 图13B)用油红O染色的小鼠肝脏组织切片。
图14A和14B:HPN-01处理对HFD诱导的肝脏甘油三酯(图14A) 和糖原(图14B)水平的影响。
图15A-15C:HPN-01处理对HFD诱导的肝脏胆固醇、SREBP-1的 表达,和脂肪酸合成的影响。检查了来自根据图11所示的研究概要喂养的小鼠 的肝脏的胆固醇(图15A)、SREBP-1表达(图15B)和脂肪酸合成(图15C)的水平。
图16A和16B:HPN-01处理对血浆胆固醇和甘油三酯水平的影响。 从根据图11所示的研究概要喂养的小鼠获得血液,并且确定血浆胆固醇和甘 油三酯水平。图16A)高脂肪膳食(HFD)喂养的未处理和处理的小鼠中血浆胆固 醇水平。图16B)高脂肪膳食(HFD)喂养的未处理和处理的小鼠中血浆甘油三酯 水平。
图17:HPN-01处理对小鼠肝脏中细胞因子表达的影响。检查了来 自根据图11所示的研究概要喂养的小鼠的肝脏的ICAM1(CD54)、IL-1B、IL- 8、MCP-1、THF-α和LIF的水平。HPN-01处理抑制了肝炎性细胞因子表达。
图18A和18B:HPN-01处理对alpha平滑肌肌动蛋白(α–SMA) 和1型胶原alpha 1(COL1α1)mRNA表达水平的影响。对来自根据图11所示 的研究概要喂养的小鼠的肝脏检查α–SMA mRNA和COL1α1mRNA的表达。 图18A)正常膳食喂养的小鼠(NCD)中,以及高脂肪膳食(HFD)喂养的未处理的 (载体)和处理的(HPN-01)小鼠中α–SMA的表达水平。图18B)正常膳食(NCD) 喂养的小鼠中,以及高脂肪膳食(HFD)喂养的未处理的(载体)和处理的(HPN-01)小鼠中COL1α1的表达水平。
图19:HPN-01处理对各种肝脂肪因子水平的影响。对来自根据图 11所示的研究概要喂养的小鼠的肝脏检查整合蛋白alpha 2(ITGA2)、凝集素样 氧化LDL受体(LOX)、金属蛋白酶-1组织抑制剂(tissue inhibitor of metalloproteinase-1,TIMP1)、胰岛素样生长因子结合蛋白-1(IGFBP1)、胰岛素 样生长因子结合蛋白-2(IGFBP2)、胰岛素样生长因子结合蛋白-3(IGFBP3)、胰岛 素样生长因子结合蛋白-5(IGFBP5)、胰岛素样生长因子结合蛋白-6(IGFBP6),以 及成纤维细胞生长因子-21(FGF-21)的mRNA水平。
图20:HPN-01的红外光谱图。
图21:HPN-01的紫外线光谱图(甲醇)。
图22:HPN-01的紫外线光谱图(0.1mol/L盐酸溶液)。
图23:HPN-01的紫外线光谱图(0.1mol/L氢氧化钠溶液)。
图24:HPN-01的粉末X射线衍射模式。
图25:HPN-01的差分热分析(Differential thermal analysis)。
图26:HPN-01的高分辨率质谱法。
图27:研究设计,用以对链脲佐菌素(streptozotocin,STZ)和高脂肪 膳食诱导的(nSTZ+HFD)NASH小鼠测试体内HPN-01功效。
图28A和28B:HPN-01对nSTZ+HFD NASH小鼠体重和每日食物 摄入的影响。图28A)正常饮食喂养的未处理的小鼠中(未处理;灰色圆圈)、高 脂肪膳食喂养的载体处理的小鼠中(载体;黑色方框)、高脂肪膳食喂养的替米 沙坦(telmisartan)处理的小鼠中(替米沙坦;灰色上部箭头三角形)、高脂肪膳食 喂养的低剂量HPN-01处理的小鼠中(HPN-01 5mpk;灰色下部箭头三角形),以 及高剂量HPN-01处理的小鼠中(HPN-01 15mpk;黑色菱形)中体重变化。图28B) 每个研究组所记录的每日和积累的食物摄入。
图29:未处理的和HPN-01处理的nSTZ+HFD NASH小鼠中禁食 血糖水平。在药物施用的开始(第1天)和结束(第22天)测量血糖水平。
图30A和30B:HPN-01处理对未处理的和处理的小鼠中血清丙氨 酸转氨酶(ALT)和血清天冬氨酸转氨酶(AST)水平的影响。图30A)未处理的、载 体处理的、替米沙坦处理的,和HPN-01处理的小鼠中血清ALT水平。图30B) 未处理的和处理的小鼠中血清AST水平。图30A)未处理的、载体处理的、替 米沙坦处理的,和HPN-01处理的小鼠中血清ALT水平。
图31A和31B:HPN-01处理对nSTZ+HFD NASH小鼠中血清总胆 固醇(TC)和血清甘油三酯(TG)水平的影响。图31A)未处理的、载体处理的、替 米沙坦处理的,和HPN-01处理的小鼠中血清TC浓度。图31B)未处理的、载 体处理的、替米沙坦处理的,和HPN-01处理的小鼠中血清TG浓度。
图32A和32B:HPN-01处理对nSTZ+HFD NASH小鼠肝脏总胆固 醇(TC)和肝脏甘油三酯(TG)水平的影响。图32A)未处理的、载体处理的、替米 沙坦处理的,和HPN-01处理的小鼠中肝脏TC浓度。图32B)未处理的、载体 处理的、替米沙坦处理的,和HPN-01处理的小鼠中肝脏TG浓度。
图33A和33B:HPN-01处理对小鼠肝脏中炎症细胞因子表达水平 的影响。图33A)未处理的、载体处理的、替米沙坦处理的,和HPN-01处理的 小鼠的肝脏中相对TNF-αmRNA水平。图33B)未处理的、载体处理的、替米 沙坦处理的,和HPN-01处理的小鼠的肝脏中相对MCP-1mRNA水平。
图34A-C:HPN-01处理对各种纤维化标志物表达水平的影响。图 34A)未处理的、载体处理的、替米沙坦处理的,和HPN-01处理的小鼠的肝脏 中转化生长因子beta 1(TGF-β1)mRNA的相对水平。图34B)未处理的、载体处 理的、替米沙坦处理的,和HPN-01处理的小鼠的肝脏中1型胶原 alpha1(COL1A1)mRNA的相对水平。图34C)未处理的、载体处理的、替米沙坦处理的,和HPN-01处理的小鼠的肝脏中金属蛋白酶-1(metalloproteinase-1,TIMP1)mRNA的相对水平。
图35A-D:HPN-01处理对NAFLD活性评分的影响。根据苏木精 和曙红(H&E)染色以及油红O染色,在显微镜下观察来自图27中研究概要的 各组的肝脏组织。进行了包括NAFLD活性、肝脂肪变性(图35B)、气球样变性 (ballooning)(图35C)和炎症(图35D)在内的多种NAFLD/NASH病理标志的评 估。
图36:HPN-01变体的结构。
具体实施方式
本发明涉及一种治疗非酒精性脂肪性肝疾病(NAFLD)的新方法。更 具体地,本发明涉及一种通过施用本文公开的发明的2-氨基-二芳基苯甲酰胺 (2-amino-arylbenzamide)化合物治疗NFALD的方法。它也涉及治疗NAFLD相 关病患,如脂肪沉积相关炎症、非酒精性脂肪性肝炎(NASH)、肝纤维化、肝硬 化及其组合。
在进一步描述本发明之前,应当理解本发明不限于所描述的特定实 施方案,当然因此可以变化。还应当理解,本文使用的术语仅用于描述特定实 施方案的目的,并且不旨在是限制性的,因为本发明的范围将仅由权利要求书 限制。
必须注意的是,如本文和所附权利要求书中所使用的,除非上下文 另有明确规定,单数形式“一个”、“一种”和“该/所述”包括复数指示物。 例如,化合物指的是一个/种或多个/种化合物分子。因此,术语“一个”、“一 种”、“一个/种或多个/种”以及“至少一个/种”可以互换使用。类似地,术 语“包含”/“含有”和“具有”可以互换使用。还应注意的是,权利要求可以 撰写为排除任何可选元素。因此,本声明旨在充当前置基础,用于与权利要求 要素的叙述结合使用诸如“唯一”、“仅仅”等的排他性术语或者使用“负” 限制。
本文讨论的出版物仅提供其在本申请的提交日期之前的公开。本文 中的任何内容都不得解释为承认凭借现有发明,本发明没有资格早于此类出版 物。此外,提供的公开日期可能与实际公开日期不同,这可能需要独立确认。 本文提及的所有出版物通过引用并入本文,用于公开和描述与被引用的出版物 有关的方法和/或材料。
除非另有定义,本文中使用的所有技术和科学术语都与本发明所属 领域的普通技术人员通常理解的含义相同。尽管与本文所描述的任何方法和材 料相似或等同的任何方法和材料也可以应用在本发明的实践或测试中,现在描 述了优选的方法和材料。与本文公开的各种实施方案共同的以下术语和短语定 义如下:
术语“个体”、“受试者”和“患者”在本领域中是公认的,并且 在本文中可互换使用,是指易于形成NAFLD和相关病患的任何动物。实例包 括但不限于人类和其他灵长类,包括非人类灵长类动物,如黑猩猩和其他猿和 猴物种;农场动物如牛、棉羊、猪、海豹、山羊和马;家养哺乳动物如狗和猫; 实验室动物,包括啮齿动物,如小鼠、大鼠和豚鼠;禽类,包括家养、野生和 猎鸟,如鸡、火鸡和其它鹑鸡类禽类、鸭、鹅等。术语个体、受试者和患者自 身不表示特定的年龄、性别、种族等。因此,本公开意图涵盖任何年龄的个体 (无论是雄性或雌性),并包括但不限于老年,成年,儿童,幼儿(babies),婴儿 (infants)和幼童(toddlers)。
如本文所用,本文公开的化合物,或其衍生物,或盐的治疗有效量 意指当施用至受试者时足以对受试者治疗NAFLD或相关病患(如NASH)的量。 受试者中NAFLD和相关症状的治疗/处理等包括以下的一种或多种:
1.预防下列各项的形成或降低形成下列各项的风险:NAFLD和/或 相关病患,诸如脂肪沉积相关炎症(fatty deposit-related inflammation)、非酒精性 脂肪性肝炎(NASH)、肝纤维化、肝硬化及其组合。如本文所用,短语预防形成 等,以及降低形成风险等意指施用本文公开的化合物或其衍生物或盐导致 NAFLD和相关病患(如NASH)的临床症状不能在受试者中形成。治疗前,受试 者可以但不需要表现出一种或多种形成NAFLD和相关病患(如NASH)的风险 因素;
2.抑制NAFLD或相关病患(如NASH)。如本文所用,术语抑制,阻 止等意指在已经诊断为患有NAFLD或相关病患的受试者中停止NAFLD或相 关病患,如脂肪沉积相关性炎症、非酒精性脂肪性肝炎(NASH)、肝纤维化、肝 硬化及其组合的临床症状的进一步形成;以及,
3.减少NAFLD或相关病患如NASH。如本文所用,术语减少、逆 转、缓解等意指施用本文公开的化合物,或其衍生物或盐在诊断患有NAFLD 或相关病患(如脂肪沉积相关炎症、非酒精性脂肪性肝炎(NASH)、肝纤维化、肝 硬化及其组合)的个体中引起NAFLD或相关病患(如NASH)的临床症状的数目、 频率、持续时间,或严重性的减少或停止。
本领域技术人员应当理解,本文公开的化合物或其衍生物或盐的 “治疗有效量”可以针对特定受试者而变化,这取决于受试者的整体健康和身 体状况,NAFLD及其相关病患如NASH的程度,受试者的性别,和受试者的 年龄等。还应当理解,基于可以经由常规试验测定的因素,如上文公开的因素, “治疗有效量”可以落入宽范围内,所述常规试验的方法是本领域技术人员已 知的。
如本文所用,本发明的式I的化合物指具有下文和图1所示结构的 化学化合物:
其中R1为卤素(如氯),R2为亚砜基(如SO2NH2),且R3和R4独 立地为氢或低链烷基。式I的化合物的优选的实例为化合物,其中R1=Cl、R2 =SO2NH2、R3=H以及R4=H,其在本文中也称为HPN-01,并且示于以下和 图2中,并且在此称为式II:
作为进一步的例子,式I的第二个化合物为具有式II结构的化合 物,但其中用其它原子(如碘)取代氯原子。制备此类化合物的方法在本文中说 明并且基于本文的教导在本领域的技术范围内。同样在本发明的范围内的是式 I和式II化合物的前药、治疗活性代谢物、水合物、溶剂化物,和药学上可接 受的盐的用途。如本文所用,前药是指对受试者施用后代谢为施用化合物的药 理学活性形式的化合物。前药的使用和制备是本领域技术人员已知的。
如本文所用,本发明的式III指具有如下和图3中所示结构的化学 化合物,
其中:
R1为-CHCHR5;-CHCHCO2R5;-CHCHCONHR5;-苯基;-苯基- R5;-CCR5;-CC-CH2R5;-OR5;-SR5;或-NHR5;
R2为-C6H4-R6;-OC6H4-R6;-SC6H4-R6;-NHC6H4-R6;-OC1-6烷 基-C6H4-R6;-NHC1-6烷基-C6H4-R6;哌嗪-R6;或吡啶-R6;
R3为H;-C1-6烷基,任选地用-OH、-NH2、苯基,或卤素取代; -CO-吡啶;-CO-CH2CH2NH2;或-CO-C1-6烷基,任选地用-OH或-NH2取代;
R4为H;-OCH3;-哌啶;-哌啶-CONH2;-吡啶;-吡咯;-噻吩;- C1-6烷基,任选地用-OH取代;-吡啶;-哌啶;-吡咯;-噻吩;或-苯基,任选 地用卤素或羟基取代;
或者,R3和R4一起形成尿嘧啶;
R5为卤素;-COOH;C1-6环烷基;-CH2C6H5;-CH2CH2C6H5;- CH2CH2C6H4-F;CH2C6H4-COOH;-CH2C6H4-OH;-CH2-呋喃;-Si(CH2)3;- CH2CO2CH3;-CH2CO2(CH2)2CH3;或-CH2CO2C6H4-Cl;或者
-C1-10烷基,任选地用卤素或-OH取代;或者
-C1-10环烷基,任选地用卤素或-OH取代;或者
-苯基,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、 -NHCOMe、-NHCO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代; 或者
-吡啶,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、 -NHCOMe、-NHCO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代; 或者
-吡咯,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、 -NHCOMe、-NHCO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代;
R6为SO2NH2;-OPO(OH)2;-NH2;-NHCONH2;-NHCOCH3;- NHCSCH3;-NHCSCH2CH3;-NHCS(CH2)2CH3;四唑;-SO2NH(CH2)2CH3;- NHC(NH)NH2;-NHCSNH2;-NHCSCH2OH;三唑;氧代咪唑(oxoimidazol);- SO2NHCH2CH2OH;-NHCONH-C1-6烷基;或-NHCONH-吡啶。
在各种实施方案中,本发明的式III指具有以上所示结构的化学化 合物,其中所述结构不包括式II,或备选不包括式I。
如本文所用,本发明的式IV指具有如下和图4中所示结构的化学 化合物:
其中R1选自表1中所列的基团;R2选自表2中所列的基团;R3 选自表3中所列的基团;并且R4选自表4中所列的基团。
表1
式IV,R1选项
表2
式IV,R2选项
表3
式IV,R3选项
表4
式IV,R4选项
在各种实施方案中,本发明的式IV指具有如上所示结构的化学化 合物,其中所述结构不包括式II,或备选不包括式I。
式III的优选实施方案在本文中称为HPN-01101-01133;HPN- 01201-01224;HPN-01301-01322;HPN-01401-01430;HPN-01501-01506;HPN- 01513-01520;HPN-01525-01527;HPN-01529-01534;HPN-01601-01630,如以 下实施例中描述的。本文阐述了制备式III化合物的方法并且基于本文的教导 在本领域的技术范围内。在本发明的范围内还包括式III化合物的前药、治疗活 性代谢物、水合物、溶剂化物,和药学上可接受的盐。
本发明化合物还包括式I、式II、式III和式IV化合物的立体异构 体、对映异构体或非对映异构体。
用在本发明方法中的化合物可以配制成包括载体的组合物。如本文 所用,“载体”包括药学上可接受的载体、赋形剂或稳定剂,其在使用的剂量 和浓度对暴露于其的细胞或哺乳动物无毒。“药学上可接受的载体”是不妨碍 本发明化合物的生物活性有效性的赋形剂。生理上可接受的载体通常是水性pH 缓冲溶液。生理上可接受的载体的例子包括缓冲液,诸如:磷酸盐、柠檬酸盐 和其它有机酸、汉克斯溶液(Hanks’solution)、林格氏溶液(Ringer’s solution) 或生理盐水缓冲液;抗氧化剂,包括抗坏血酸;低分子量(少于约10个残基)多 肽;蛋白质,如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,如聚乙烯吡 咯烷酮;氨基酸,如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸;单糖、 二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂如EDTA;糖醇 如甘露醇或山梨糖醇;成盐抗衡离子如钠;和/或非离子表面活性剂,例如,聚 乙二醇(PEG)和。
其它试剂,如调味剂(flavoring agent)、着色剂(coloring agent)、甜味 剂(sweetening agent)和/或增稠剂也可以加入本发明的组合物。
本发明的组合物可以以任何合适的形式配制,并且在很大程度上形 式可以由预期的施用模式来确定。组合物可以是固体,半固体或液体形式。对 于实施发明的方法有用的形式的例子包括但不限于片剂、胶囊、粉剂、糖锭剂 (troche)、锭剂(lozenges)、混悬剂(suspensions)、凝胶、糊剂、浆液(slurries)、 液体组合物软凝胶胶囊和糖浆剂。优选地,组合物以适于施用精确剂量的单位 剂型生产。
在本发明方法中施用于受试者的剂量可以是适用于治疗、预防、抑 制和/或减少NAFLD或相关病患的任何剂量。结合本公开的内容,本领域技术 人员能够鉴定与所选择的配制剂和递送方法相适合的剂量。在具体的实施方案 中,剂量在0.01mg/kg至约100mg/kg的范围内。
本发明的化合物和组合物可以通过适合于所治疗的受试者的任何 途径施用。此类施用途径包括但不限于注射(包括静脉内,腹膜内,肌内和皮下 注射)、口服施用、经粘膜施用、透皮施用、局部施用(topical administration)、 鼻腔施用,眼部施用或通过栓剂施用。
本发明的一个实施方案是在受试者中治疗治疗非酒精性脂肪性肝 病(NAFLD)的方法,所述方法包括向受试者施用治疗有效量的式I、式II、式 III、式IV的化合物,或其前药、治疗活性代谢物、水合物、溶剂化物,或药学 上可接受的盐。在某些实施方案中,所述受试者有形成NAFLD的风险。在某 些实施方案中,所述受试者表现出NAFLD的形式,其包括脂肪沉积相关的炎 症、非酒精性脂肪性肝炎(NASH)、肝纤维化、肝硬化或其组合。
在某些实施方案中,化合物作为包含药学上可接受的载体的组合物 施用。在某些实施方案中,在24小时时段内施用化合物一次。在某些实施方案 中,在24小时时段内施用化合物超过一次。在某些实施方案中,化合物每1小 时、每2小时、每3小时、每4小时、每6小时,或每12小时施用。在某些实 施方案中。连续施用化合物。
本发明的进一步的实施方案为式I、式II、式III、式IV的化合物, 或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐,其用 于治疗受试者中非酒精性脂肪性肝病(NAFLD)。
本发明的一个实施方案为用于治疗NAFLD或相关病患(如脂肪沉 积相关炎症、非酒精性脂肪性肝炎(NASH)、肝纤维化、肝硬化,或其组合)的试 剂盒,所述试剂盒包含式I、式II、式III、式IV的化合物,或其前药、治疗活 性代谢物、水合物、溶剂化物,或药学上可接受的盐,以及用于将所述化合物 施用至受试者的说明书,所述受试者患有或有风险患有NAFLD或相关病患, 如脂肪沉积相关炎症、非酒精性脂肪性肝炎(NASH)、肝纤维化、肝硬化,或其 组合,其中化合物、其衍生物或其盐的配制剂适于施用至受试者,用于施用至 患有或相关病患(如脂肪沉积相关炎症、非酒精性脂肪性肝炎(NASH)、肝纤维 化、肝硬化,或其组合)的受试者。
本发明的其它实施方案包括式I、式II、式III、式IV的化合物或 其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐。或者, 本发明包括式III、式IV的化合物或其前药、治疗活性代谢物、水合物、溶剂 化物,或药学上可接受的盐,其中化合物不是式II,并且备选不是式I。进一步 的实施方案包括药物组合物,其包含式I、式II、式III、式IV的化合物或其前 药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐以及药学上可 接受的载体。或者,本发明包括药物组合物,其包含,式III、式IV的化合物 或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐以及药 学上可接受的载体,其中所述化合物不是式II,并且或者不是式I。
本发明进一步的实施方案包括制备本发明化合物的方法,如以下实 施例中描述。此类方法包括例如,如实施例1中描述的化合物II(式II)的合成; 以及如实施例18中描述的HPN 01101–HPN-01133的合成;如实施例19中描 述的HPN 01201–HPN 01224的合成;如实施例20中描述的HPN 01301–HPN 01311和HPN 01321–HPN-01322的合成;如实施例21中描述的HPN 01312– HPN-01320的合成;如实施例22中描述的HPN 01401–HPN 01430的合成; 如实施例23中描述的HPN 01501–HPN-01506;HPN 01513–HPN-01520;HPN 01525–HPN-01527;HPN01529–HPN-01534的合成;以及如实施例24中描述 的HPN 01602–HPN-01630的合成。
应当理解,为了清楚起见,描述在分开的实施方案的背景中的本发 明的某些特征也可以在单个实施方案中组合提供。相反,为了简洁起见,描述 在单个实施方案的背景中的本发明的各种特征也可以分开提供或以任何合适 的子组合提供。本发明具体涵盖了实施方案的所有组合并在本文中公开,就像 每个组合都被单独和明确地公开一样。此外,本发明也具体涵盖了所有子组合 并且在本文公开,就像每个子组合都在本文中被单独和明确地公开一样。
通过以下非限制性实施例说明本发明。本领域普通技术人员将理解, 可以获得具有取决于所使用的测量条件的测量误差的粉末X射线衍射模式。特 别地,通常已知X射线粉末衍射模式中的强度可随所采用的测量条件而波动。 应当进一步理解,相对强度也可以随实验条件而变化,并因此不应该考虑确切 的强度等级。因此,衍射图中的峰的相对强度不一定是PXRD模式的限制,因 为例如由于结晶杂质,峰值强度可以从样品到样品变化。此外,常规粉末X射 线粉末衍射模式的衍射角的测量误差通常为约5%或以下,并且应考虑到这种 程度的测量误差属于前述衍射角。此外,每个峰的角度可以变化约+/-0.1度, 或约+/-0.05度。由于校准的差异、设置以及从仪器到仪器以及从操作员到操作 员的其他变化,整个模式或大部分模式峰也可能偏移约+/-0.1度至约+/-0.2度。 报告了图、实施例和本文其他地方中的所有报告的PXRD峰,误差约为±0.3度 2-θ。除非另有说明,否则所有衍射图均在约室温(约24℃至约25℃)下获得。 应当理解,本发明的晶体结构不限于提供与本文公开的附图中所示的X射线粉 末衍射模式完全相同的X射线衍射模式的晶体结构。提供与附图中公开的粉末 X射线衍射模式基本相同的粉末X射线衍射模式的任何晶体结构都在本发明的 范围内。确定X射线粉末衍射模式的实质身份的能力在本领域普通技术人员的 范围内。然而,本领域技术人员应注意,在DSC[或TGA]测量中,根据加热速 率,晶体形状和纯度,样品制备和其他测量参数,实际测量的起始和峰值温度 有一定程度的变化性。
实施例
实施例1:脂肪变性抑制物的鉴定与合成
针对肝细胞进行小分子文库的高通量筛选以鉴定拥有有力的抗脂 肪变性活性的化合物。该筛选导致鉴定了化合物,称为HPN-01。HPN-01(化学 式:C19H16ClN3O3S),是2-氨基-3,5-二芳基苯甲酰胺(CAS:928655-63-4),一般 结构在图1中显示。HPN-01的特定结构(在此称为化合物II)在图2中显示。化 合物II是2-氨基-3-(对磺酰胺基苯基)-5-(对氯苯基)苯甲酰胺(2-amino-3-(p- sulfonamidophenyl)-5-(p-chlorophenyl)benzamide)。
使用如下方案制备化合物II:
1.室温下在反应釜中将起始原料1500g 2-氨基-5-碘代苯甲酸(2- amino-5-iodobenzoic acid)溶解于2L的DMF中,并且分批加入3733g三光气 (triphosgene)并升温搅拌2~2.5h。通过HPLC监控反应直到结束。在35-40℃ 下受控的温度下滴加8500ml的氨水。氨水添加后在相同的温度下在搅拌的情 况下继续再反应0.5-1h,然后当通过HPLC测量反应完成时,在减压下浓缩。 残余物滴入20L水中并且搅拌2-3h,之后让它静置,然后过滤、洗涤和干燥。 从上述反应中得到1275g的2-氨基-5-碘代苯甲酰胺,具有85%总收率。如由HPLC测量,纯度为99.6%。
2.向反应釜中依次添加600g 2-氨基-5-碘代苯甲酰胺、6000ml二恶 烷(Dioxane)、2400ml水、600g碳酸钾、393g对氯苯硼酸(P-chlorobenzene boronic acid),和6g PdCl2(PPh3)2,并在85-87℃在回流下加热4-5小时。过滤回收 PdCl2(PPh3)2。弃去上面的含水层,并且在减压下浓缩有机层。残余物滴入水20L 中,持续搅拌下用稀盐酸将pH调节至7。过滤、洗涤和干燥后,得到粗产品, 将该粗产品添加到无水乙醇和四氢呋喃(2:1,v/v)混合溶剂,加热至回流,滴加 等体积异丙醚,然后搅拌、过滤、异丙醚洗涤,然后干燥得2-氨基-5-(对氯苯基) 苯甲酰胺601g。如由HPLC测量,纯度为96.21%。
3.向反应釜中加入258.2g 2-氨基-5-(对氯苯基)苯甲酰胺、200mL乙 酸和1100mL二氯甲烷。在15-20℃的控制的温度下,分批添加222.9g NBS并 在室温下搅拌1-2h。接着过滤,用二氯甲烷和碳酸钾溶液洗涤,用水洗涤,然 后干燥,产生232.0g 2-氨基-3-溴代-5-(对氯苯基)苯甲酰胺,具有90%总收率。 如由HPLC测量,纯度为95.4%。
4向反应釜中添加2700g醋酸钾,2250g硼酸,11g PdCl2(dppf)2, 2000g对溴苯磺酰胺,和13500mL二恶烷,搅拌并加热至85~87℃并且反应4- 5h。通过过滤回收PdCl2(dppf)2。过滤液在减压下浓缩,并且然后添加6000mL 异丙醚并搅拌1-2h,然后过滤,异丙醚洗涤并干燥。从反应中获得116g对磺酰 胺苯基硼酸频哪醇酯(P-sulfonamide phenylboronicacidpinacol ester),具有64.8 %总收率。如由HPLC测量,纯度为96.8%。
5.向反应釜中连续添加500g 2-氨基-3-溴代-5-(对氯苯基)苯甲酰胺, 480g对磺酰胺基苯硼酸频那醇酯,425g碳酸钾,6g PdCl2(PPh3)2,3000ml二恶 烷,和1200ml水,并在回流下加热至85-87℃达3-4h直到完全反应。 通过过滤回收三苯基膦二氯化钯(triphenylphosphine dichloride palladium),并且 除去上部含水层。向浓缩的有机层添加2000mL乙醇并搅拌回流1h,接着过滤, 乙醇冲洗并干燥。从反应获得757g 2-氨基-3-(对磺酰胺基苯基)-5-(对氯苯基)苯 甲酰胺,纯度为82.6%。
6.HPN-01的纯化。向精制釜(refined kettle)中添加1000g 2-氨基-3- (对磺酰胺基苯基)-5-(对氯苯基)苯甲酰胺粗产物和20L丙酮,搅拌并加热至回 流。滤去不溶物,并且用活性炭回流脱色过滤液0.5h。然后滤去活性炭,并且 在减压下浓缩过滤液至微混浊,并且接着在50-60℃搅拌下滴入4-6L水。通过 在室温下搅拌获得晶体沉淀,过滤,用丙酮:水=1:1(v/v)混合溶剂洗涤,然后 干燥。获得了880g HPN-01,具有88%总产率。如由HPLC测量,纯度为99.2 %。
实施例2:HPN-01处理对肝细胞脂肪脂滴(LD)生源的影响
用各种量的HPN-01在缺少或存在400μM油酸下处理肝癌细胞系 Huh7达24小时,并且在Zeiss共焦荧光显微镜下观察。示于图5A-D中的该分 析的结果显示,HPN-01处理以剂量依赖的方式显著地抑制了Huh7细胞中LD 形成(无油酸预处理的情况下IC50=0.46μM,以及用油酸刺激的情况下0.27μM)。 在Zeiss共焦荧光显微镜下观察到LD内容物(用BODIPY493/503染色,绿色)。 图5A蓝指示细胞核。图5B LD大小。图5C平均荧光强度。使用ZEN软件通 过对在每个处理条件下对300个细胞计数来测量值。
实施例3:HPN-01处理对肝细胞中LD形成的影响。
模拟处理或用1mM胰岛素预处理肝细胞Huh7,并且随后用指示量 的HPN-01处理。24h后,使用油红O染色LD内容物,并通过确定OD 540nm 下的分光光度计吸光度测量(IC50=0.25μM)。这些分析的结果在图6中显示。 这些分析的结果证明,HPN-01在肝细胞中以剂量依赖的方式抑制LD形成。
实施例4:HPN-01处理对小鼠3T3-L1细胞中脂联素水平的影响。
用各种浓度的HNP-01处理分化的小鼠3T3-L1细胞,并且通过 ELISA测量分泌的脂联素水平。示于图7中的结果证明,HPN-01在肝细胞中 以剂量依赖的方式降低分泌的脂联素的量(IC50=0.32μM)。
实施例5:HPN-01对肝细胞中从头脂肪生成(lipogenesis)的影响。
用1μM HPN-01处理Huh7细胞24h,并且通过实时qPCR定量各 种关键脂肪生成酶(lipogenic enzyme)的mRNA表达水平。示于图8中的结果证 明,HPN-01处理显著抑制肝细胞中的从头脂肪生成。抑制倍数如下:SREBP- 1:2.98±0.23;SREBP-2:4.01±0.31;FASN:3.87±0.23;SCD1:4.63±0.48; ACC:4.12±0.34;ELOVL6:2.84±0.22;LDLR:3.02±0.11;FADS1:3.06± 0.17;DGAT1:1.72±0.27;DGAT2:3.77±0.45。
实施例6:HPN-01对原代人肝细胞中SREBP-1和SREBP-2表达的 影响。
用各种浓度的HPN-01处理培养的原代人肝细胞,并且随后确定 SREBP-1(肝脏糖代谢和脂肪酸合成的主调控物)和SREBP-2(细胞内胆固醇稳态 的主调控物)的表达水平。图9中显示了该分析的结果。结果证明,HPN-01处 理以剂量依赖的方式降低SREBP-1和SREBP-2的表达(IC50分别为=1.71μM 和3.43μM)。
实施例7:HPN-01的细胞毒性。
在存在各种浓度的HPN-01下培养Huh7和原代人肝细胞,并且测 量细胞生长的抑制。示于图10A和10B中的该分析的结果显示,将杀死一半处 理的细胞的细胞毒性浓度(CC50)对于Huh7细胞为54.3μM(图10A),以及对于 原代人肝细胞为77.2μM(图10B)。
实施例8:HPN-01对高脂肪膳食诱导的NAFLD/NASH小鼠的作用
将8周龄的C57BL/6小鼠分为测试组和对照组。用正常饮食(NCD) 喂养对照组小鼠24周。进一步将测试组分为预防组和治疗组。在预防组中,用 高脂肪膳食(HFD)喂养小鼠并且同时用25mg/kg的HPN-01或载体每日治疗16 周,之后,对小鼠实施安乐死并评价NAFLD/NASH形成。在治疗组中,用HFD 喂养小鼠12周以刺激NAFLD/NASH的形成,并且然后每日用25mg/kg的HPN- 01或载体再处理12周。然后对小鼠安乐死并评估NAFLD/NASH的存在。该 研究设计示于图11。
该研究的结果显示,未处理的小鼠中HFD触发的肥胖(图12A)和内 脏脂肪积累(图12B,中间图)。另外,HFD喂养的未处理小鼠具有NAFLD/NASH 特征性的增大的肝脏、深橙色颜色(图12B,中间图)。与此相反,在接受HPN- 01处理的HFD喂养的小鼠中,体重增加(图12A)和脂肪沉积是显著缓解的。肝 脏的大小和颜色(图12B,右图)与正常小鼠非常类似(图12B,左图)。
然后对肝脏切片分析了肝脏疾病的存在。肝脏组织切片的苏木精和 曙红(H&E)染色(图13A)显示,载体治疗组中HFD喂养小鼠中存在大量的空泡 (vacuole)(LD)沉积和明显的炎性细胞浸润。然而,在预防和治疗组两者中,LD 沉积和炎性炎症显著减少,提示了HPN-01治疗显著逆转了HFD介导的肝脂肪 变性。通过肝脏组织切片的油红O染色(Oil-red-Ostaining)确认了H&E染色结 果(图13B)。
实施例9:HPN-01对肝脏甘油三酯、糖原和胆固醇水平的影响。
为确定HPN-01对来自实施例8中研究的小鼠肝脏中各种脂肪相关 分子的影响,分离并制备肝组织,并且测量肝甘油三酯和糖原的水平。该分析 的结果示于图14A和14B中。
高脂肪膳食在仅接受载体的小鼠中诱导了肝细胞内的甘油三酯的 积累(图14A)和葡萄糖合成(图14B)。在预防组和治疗组两者中,HPN-01治疗 显著降低了HFD诱导的肝脏甘油三酯(图14A)和糖原(图14B)含量的升高。发 现用HPN-01治疗的HFD喂养小鼠中,甘油三酯水平在预防组中为67.2± 28.3mg/g,并且在治疗组中为75.5±19.8mg/g,相比较而言,用载体处理的HFD 喂养小鼠中,在预防组中为193.7±32.5mg/g以及在治疗组中为241.2± 27.4mg/g。发现用HPN-01治疗的HFD喂养小鼠中,糖原水平在预防组中为8.4 ±1.6μg/mg,并且在治疗组中为13.3±3.5μg/mg,相比较而言,用载体处理的 HFD喂养小鼠中,在预防组中为19.5±4.9μg/mg以及在治疗组中为26.0±3.1 μg/mg。因此,HPN-01治疗显著降低了HFD诱导的肝脏甘油三酯(图14A)和 糖原(图14B)含量(其分别是脂肪合成和葡萄糖代谢的最重要指标)的升高。
来自实施例8研究的小鼠的肝脏也用于分析它们胆固醇、SREBP- 1,和脂肪酸合成的水平。该分析(其结果示于图15A-15C)显示出NPH-01治疗 显著降低了HFD诱导的肝脏胆固醇(图15A)、SREBP-1(图15B)和脂肪酸合成 (图15C)的升高。与仅接受载体的HFD喂养的小鼠中7.5±0.7mg每g组织相 比,用HPN-01治疗的HFD喂养的小鼠中肝脏胆固醇水平是3.9±1.1mg每g 组织,降低了约1.92倍(图15A)。同样,当与仅接受载体的HFD喂养的小鼠相 比时,用HPN-01治疗的HFD喂养的小鼠中SREBP-1表达是0.52±0.06,降低 了约48%(图15B)。最后,与仅接受载体的HFD喂养的小鼠中42.0± 8.3DPMs/mg相比,用HPN-01治疗的HFD喂养的小鼠中脂肪酸合成是13.2± 2.8DPMs/mg,降低了约3.18倍(图15C)。
实施例10:HPN-01对血浆胆固醇和甘油三酯水平的影响。
在从实施例8中描述的研究中的小鼠采集的血液中确定了血浆胆 固醇和甘油三酯水平。该分析的结果示于图16A和16B中。结果显示,HPN- 01治疗大大降低了HFD介导的血浆胆固醇水平(图16A)和甘油三酯水平(图 16B)的升高。与仅接受载体的载体处理的HFD喂养的小鼠中118.1±23.3mg/相 比,接受HPN-01的HFD喂养的小鼠中血浆胆固醇水平为43.0±15.5mg/dL, 降低了2.75倍。同样,与接受仅载体的HFD喂养的小鼠中的58.4±11.7mg/dL相比,接受HPN-01的HFD喂养的小鼠中血浆甘油三酯水平为31.2±4.5mg/dL, 降低了1.87倍。
实施例11:HPN-01对肝炎性细胞因子的影响。
分析了来自实施例8的研究中的小鼠的肝脏组织的炎性细胞因子 的表达水平。示于图15中的结果证明,HFD喂养显著诱导了ICAM1(CD54)、 IL-1B、IL-8、MCP-1、THF-α和LIF的表达。另外,结果显示了该诱导通过HPN- 01处理而显著消除。
实施例12:HPN-01对纤维化标志物的肝表达的影响。
分析了来自实施例8的研究中的小鼠的肝脏组织的牵涉形成纤维 化瘢痕形成的肝分子的表达水平。图18A显示了正常饮食(NCD)喂养的小鼠中, 和接受载体或HPN-01的HFD喂养的小鼠中α-平滑肌肌动蛋白(α–SMA)的 mRNA水平。图18B显示了正常饮食(NCD)喂养的小鼠中,和接受载体或HPN- 01的HFD喂养的小鼠中COL1A1的mRNA水平。
然后,分析了肝脏组织以确定各种原纤维化细胞因子(profibrotic cytokines)的水平,该分析(其结果示于图19中)显示了HPN-01处理显著地抑制 了由HFD喂养诱导的ITGA2、LOX、TIMP1、IGFBP1、IGFBP2、IGFBP3、 IGFBP5、IGFBP6和FGF-21。在HPN-01的存在下,TIMP2(纤维化抑制物)的 表达水平是增加的。
实施例13:HPN-01红外光谱。
使用以下仪器和条件产生HPN-01的红外光谱图:
仪器型号:Nicolet NEXUS 670红外分光光度计
测试条件:KBr压片法(KBr tableting press method)
测试结果:HPN-01红外吸收图谱上在约3464.0cm-1、3440.7cm-1、 3350.3cm-1、3270.4cm-1、1654.7cm-1、1619.2cm-1、1574.7cm-1、1326.8cm-1、 1158.3cm-1处发现吸收峰。(图20)。
实施例14:HPN-01紫外光谱
使用以下仪器和条件产生HPN-01的紫外光谱图:
仪器型号:岛津(Shimadzu)UV-2600紫外分光光度计
测试条件:(1)甲醇;(2)0.1mol/L盐酸溶液;(3)0.1mol/L氢氧化钠 溶液
测试结果:HPN-01紫外图谱上在(1)甲醇:202.80λmax(nm)、240.90 λmax(nm)、290.20λmax(nm)和359.90λmax(nm)处发现吸收峰;(2)0.1mol/L 盐酸溶液:201.90λmax(nm)和243.70λmax(nm)处发现吸收峰;(3)0.1mol/L氢 氧化钠溶液:215.10λmax(nm)、241.95λmax(nm)、277.00λmax(nm)和337.00 λmax(nm)处发现吸收峰。(图21、22、23)。
实施例15:HPN-01粉末X-射线衍射模式。
使用以下仪器和条件产生HPN-01的粉末X-射线衍射模式:
仪器型号:Rigaku-D/max-rB粉末X-射线衍射仪。
测试条件:铜耙(Copper rake)Kα1,工作电压:40KV/40mA,步长 (step length):0.02,扫描速度:4.0度/分。
测试结果:以度2Θ和晶面间距(interplanar spacing)(d值)表示的X- 射线粉末衍射在约5.01(17.62)、8.50(10.39)、11.57(7.65)、15.23(5.81)、17.07(5.19)、 20.15(4.40)、21.89(4.06)、22.90(3.88)、24.96(3.56)、28 91(3.09)和31.52(2.84)处 产生峰。HPN-01粉末X-射线衍射显示本产物为结晶性粉末。(图24)。
实施例16:HPN-01差热分析
使用以下仪器和条件进行HPN-01的差热分析。
仪器型号:DSC Q2000差示扫描热量仪。
测试条件:加热速率:10.0℃/min;温度范围:30-250℃;吹扫气 (Purge gas):氮气.
测试结果:HPN-01DSC在约275.37℃熔融分解(melt decomposition) 处吸收热量传递(heat transfer)。(图25)
实施例17:HPN-01元素组成
使用以下仪器和条件进行HPN-01的元素组成分析:
仪器型号:Q-Tofmicro LC/MS。
测试条件示于图26。
测试结果:使用高分辨质谱法来确定HPN-01化合物的元素组成。 使用质谱电喷雾电离(ESI)负离子检测法获得[M-H]_400峰,并且使用高分辨质 谱法将[M-H]_400峰的组成确定为C19H15ClN3O3S,从而证明了HPN-01的元 素组成为C19H15ClN3O3S。(表5,图26)。
表5.HPN-01高分辨质谱数据列表
实施例18:HPN-01衍生物的合成
根据以下过程来合成HPN-01的新的衍生物:
步骤1.化合物B的合成:
将1.3克(g)的化合物A(5mmol)和0.9克的N-溴代琥珀酰亚胺(NBS) (5.25mmol)溶于100毫升冰醋酸中并在室温下搅拌1小时。反应完成后,将反 应溶液部分浓缩并倒入冰水中并剧烈搅拌。收集固体、干燥,并进行硅胶柱色 谱纯化,从而分离出化合物B。分离的化合物B的分析显示其具有以下特征: 产率:90%;1H NMR:(300MHz,DMSO-d6)δ:6.77(s,2H),7.42(s,1H),7.71- 7.77(dd,1H),7.79-7.86(dd,1H),8.02ppm(s,1H);MS(m/z):341.87(M+1)+。
步骤2.化合物C的合成:
将1.2g的由步骤1得到的化合物B(3mmol),取代的烯烃(alkene) (3.3mmol),0.03克乙酸钯(II)(Pd(OAc)2)(3%)和0.8毫升三乙醇胺(TEA)(6mmol) 添加到50mL的无水二甲基甲酰胺(DMF),并且将混合物在600w于110℃微波 加热下搅拌90min。停止反应,并将溶液倒入200mL冰水中并连续搅拌。收集 沉淀的固体,干燥并进行硅胶柱色谱纯化,从而分离出化合物C。化合物C的 产率为55-83%。
步骤3.HPN-01系列化合物的合成:
将10mmol的化合物C(获得自步骤2)、4.2g的化合物D(15mmol)、 0.35g的双(三苯基膦)二氯化钯(II)(PdCl2(PPh3)2)(5%),以及2.8g碳酸钾 (20mmol)的混合物溶解于50mL二恶烷和20mL水中。在氮气保护下使反应在 80℃下进行30小时。反应完成后,将所得溶液倒入冰水中并剧烈搅拌。收集固 体,干燥,并进行硅胶柱色谱纯化,得到化合物HPN-01101至HPN-01133。这 些化合物各自的结构信息如下:
HPN-01101:(E)-2-氨基-5-苯乙烯基-4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
((E)-2-amino-5-styryl-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:53%;1H NMR:(300MHz,CDCl3)δ:3.92(s,3H,CH3-O),4.55(d, 2H,J=6.0Hz,CH2-Ar),5.92(s,1H,NH),6.86(d,1H,J=2.4Hz,Ar-H),6.99-7.05 (m,3H,Ar-H),7.32(d,1H,J=15.3Hz,O=C-CH=C),7.28-7.34(m,2H,Ar-H), 7.54(d,1H,J=15.3Hz,O=C-C=CH),8.04(s,1H,O-CH=C),8.16ppm(d,1H,J =9.0Hz,Ar-H);13C NMR(75MHz,CDCl3)δ:43.53,55.32,100.10,114.49, 115.88,116.59,119.48,123.08,126.18,129.99,133.54,143.15,149.46,155.87, 160.48,165.11,175.88;HRMS(m/z):354.11(M+1)+
HPN-01102:(E)-2-氨基-5-(3-氯苯乙烯基)-4'-氨磺酰-[1,1'-联苯]-3-甲 酰胺
((E)-2-amino-5-(3-chlorostyryl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:57%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 6.95(d,2H),7.16(s,1H),7.34-7.50(m,5H),7.88-7.92(dd,4H),8.07(d,1H).HRMS (m/z):428.9(M+1)+
HPN-01103:(E)-2-氨基-5-(3-溴苯乙烯基)-4'-氨磺酰-[1,1'-联苯]-3-甲 酰胺
((E)-2-amino-5-(3-bromostyryl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:59%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 6.95(d,2H),7.16(s,1H),7.34(d,1H),7.45-7.50(d,3H),7.66(m,2H),7.88-7.92 (dd,4H),8.07(d,1H).HRMS(m/z):473.36(M+1)+
HPN-01104:(E)-2-氨基-5-(3-氟苯乙烯基)-4'-氨磺酰-[1,1'-联苯]-3-甲 酰胺
(E)-2-amino-5-(3-fluorostyryl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:63%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 6.95(d,2H),7.08-7.16(m,3H),7.31(m,1H),7.49-7.50(m,3H),7.88-7.92(dd,4H), 8.07(d,1H).HRMS(m/z):412.45(M+1)+
HPN-01105:(E)-4-(2-(6-氨基-5-氨基甲酰-4'-氨磺酰-[1,1'-联苯]-3-基) 乙烯基)苯基乙酸
((E)-4-(2-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3- yl)vinyl)phenyl acetate)
产率:50%;1H NMR:(300MHz,CDCl3)δ:2.31(s,3H),5.02(s,2H), 6.90-6.95(dd,2H),7.23(s,1H),7.33-7.39(t,3H),7.74(d,2H),7.88-7.90(d,6H), 8.17(d,1H).HRMS(m/z):452.5(M+1)+
HPN-01106:(E)-5-(4-乙酰胺基苯乙烯)-2-氨基-4'-氨磺酰-[1,1'-联 苯]-3-甲酰胺
((E)-5-(4-acetamidostyryl)-2-amino-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:73%;1H NMR:(300MHz,CDCl3)δ:2.06(s,3H),5.02(s,2H), 6.90-6.95(dd,2H),7.23(s,1H),7.39(s,1H),7.80-7.90(m,8H),8.03(d,2H),8.17 (d,2H),10.16(s,1H).HRMS(m/z):451.51(M+1)+
HPN-01107:(E)-2-氨基-5-(4-氯苯乙烯)-4'-氨磺酰-[1,1'-联苯]-3-甲酰 胺
((E)-2-amino-5-(4-chlorostyryl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:46%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 6.95(d,2H),7.16(s,1H),7.49-7.50(t,3H),7.80-7.92(m,6H),8.07(d,1H).HRMS (m/z):428.9(M+1)+
HPN-01108:(E)-2-氨基-5-(2-氯苯乙烯)-4'-氨磺酰-[1,1'-联苯]-3-甲酰 胺
((E)-2-amino-5-(2-chlorostyryl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamidee)
产率:51%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 6.78(d,1H),7.16-7.33(m,4H),7.44-7.50(m,4H),8.07(d,1H).HRMS(m/z):428.9 (M+1)+
HPN-01109:(E)-2-氨基-5-(4-溴苯乙烯)-4'-氨磺酰-[1,1'-联苯]-3-甲酰 胺
((E)-2-amino-5-(4-bromostyryl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:53%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 6.95(d,2H),7.16(s,1H),7.50-7.60(t,4H),7.73(d,2H),7.88-7.92(dd,4H),8.07 (d,1H),7.88-7.92(dd,4H),8.07(s,1H),9.72(t,1H).HRMS(m/z):473.35(M+1)+
HPN-01110:(E)-3-(2-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基) 乙烯基)苯基乙酸
((E)-3-(2-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3- yl)vinyl)phenyl acetate)
产率:73%;1H NMR:(300MHz,CDCl3)δ:2.31(s,3H),5.02(s,2H), 6.95(s,2H),7.15-7.23(m,4H),7.53(t,1H),7.67(d,1H),7.88-7.90(d,6H),8.17(d, 1H).HRMS(m/z):452.5(M+1)+
HPN-01111:(E)-3-(2-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基) 乙烯基)苯基丁酸
((E)-3-(2-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3- yl)vinyl)phenyl butyrate)
产率:67%;1H NMR:(300MHz,CDCl3)δ:0.90(t,3h),1.73(m,2H), 2.0(s,2H),2.40(dd,2H),6.27(s,2H),6.95(d,2H),7.16(s,1H),7.45.7.50(m,4H), 7.72(d,2H),.HRMS(m/z):482.56(M+1)+
HPN-01112:(E)-2-氨基-5-(3-丁酰氨基苯乙烯)-4'-氨磺酰-[1,1'-联 苯]-3-甲酰胺
((E)-2-amino-5-(3-butyramidostyryl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:51%;1H NMR:(300MHz,CDCl3)δ:0.98(t,3H),1.79(m,2H), 2.32(t,2H),5.02(s,2H),6.95(s,2H),7.23(s,2H),7.36-7.39(m,3H),7.56(m,1H), 7.64(s,1H),7.88-7.90(d,6H),8.17(d,1H),10.0(s,1H).HRMS(m/z):479.57(M +1)+
HPN-01113:(E)-3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙烯 酸
((E)-3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)acrylicacid
产率:53%;1H NMR:(300MHz,CDCl3)δ:6.36(d,1H,J=15.9Hz, O=C-CH=C),6.87(s,2H,NH2-Ar),7.36(s,1H,NH2-C=O),7.40-7.42(m,3H,S- NH2,6-ArH),7.44(d,1H,J=15.9Hz,O=C-C=CH),7.59(d,2H,J=7.8Hz,S- ArH),7.89(d,2H,J=7.8Hz,S-ArH),8.00(s,1H,4-Ar-H),8.04(s,1H,NH2-C=O), 12.06ppm(s,1H,COOH);MS(m/z):362.08(M+1)+
HPN-01114:甲基(E)-3-(6-氨基-4'-(氨基-(亚甲基)亚磺酰)-5-氨甲酰- [1,1'-联苯]-3-基)丙烯酸
(methyl(E)-3-(6-amino-4'-(amino-(methylene)sulfinyl)-5-carbamoyl- [1,1'-biphenyl]-3-yl)acrylate)
产率:52%;1H NMR:(300MHz,DMSO-d6)δ:3.68(s,3H,CH3-O), 6.47(d,1H,J=15.9Hz,O=C-CH=C),6.92(s,2H,NH2-Ar),7.37(s,1H,NH2-C=O), 7.43(s,2H,S-NH2),7.48(s,1H,6-ArH),7.51(d,1H,J=15.9Hz,O=C-C=CH), 7.59(d,2H,J=7.8Hz,S-ArH),7.51(d,2H,J=8.1Hz,S-ArH),8.00-8.03ppm(m, 2H,4-Ar-H,NH2-C=O);MS(m/z):376.09(M+1)+;
HPN-01115:乙基(E)-3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基) 丙烯酸
(ethyl(E)-3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3- yl)acrylate)
产率:36%;1H NMR:(300MHz,DMSO-d6)δ:1.21-1.25(t,3H,CH3), 4.11-4.18(q,2H,CH2),6.46(d,1H,J=15.9Hz,O=C-CH=C),6.92(s,2H,NH2- Ar),7.36(s,1H,NH2-C=O),7.43(s,2H,S-NH2),7.47(s,1H,6-ArH),7.50(d,1H, J=15.9Hz,O=C-C=CH),7.59(d,2H,J=7.8Hz,S-ArH),7.89(d,2H,J=8.4Hz, S-ArH),8.03-8.04ppm(m,2H,4-Ar-H,NH2-C=O);13C NMR(75MHz,DMSO-d6) δ:14.23,59.89,113.74,114.52,114.82,121.10,121.58,126.49,129.83,133.55, 135.32,141.63,143.10,143.55,144.49,147.85,148.92,171.06,171.31ppm;MS (m/z):390.11(M+1)+;
HPN-01116:异丙基(E)-3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3- 基)丙烯酸
(isopropyl(E)-3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)acrylate)
产率:46%;1H NMR:(300MHz,DMSO-d6)δ:1.22(d,6H,J=6.3Hz, CH3),4.94-5.02(m,1H,CH),6.44(d,1H,J=15.9Hz,O=C-CH=C),6.94(s,2H, NH2-Ar),7.37(s,1H,NH2-C=O),7.44(s,2H,S-NH2),7.46(s,1H,6-ArH),7.48(d, 1H,J=15.9Hz,O=C-C=CH),7.59(d,2H,J=8.1Hz,S-ArH),7.88(d,2H,J=8.4 Hz,S-ArH),8.04-8.05ppm(m,2H,4-Ar-H,NH2-C=O);MS(m/z):404.12(M+1)+;
HPN-01117:丁基(E)-3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基) 丙烯酸
(butyl(E)-3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3- yl)acrylate)
产率:83%;1H NMR:(300MHz,CDCl3)δ:2.83-2.87(m,2H,CH2-Ar) 3.60-3.66(m,2H,CH2-N),3.92(s,3H,CH3-O),5.70(s,1H,NH),6.86(d,1H,J= 2.1Hz,Ar-H),6.99-7.03(m,3H,Ar-H),7.15-7.20(m,2H,Ar-H),7.27(d,1H,J= 15.0Hz,O=C-CH=C),7.45(d,1H,J=15.0Hz,O=C-C=CH),8.03(s,1H,O-CH=C), 8.15ppm(d,1H,J=8.7Hz,Ar-H);13C NMR(75MHz,DMSO-d6)δ:35.30,40.75, 55.40,100.11,114.99,115.13,116.45,119.03,123.35,127.54,131.00,135.53.53, 141,156.32,158.44,161.78,166.32,177.83ppm;HRMS(m/z):368.13(M+1)+;
HPN-01118:庚基(E)-3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基) 丙烯酸
(heptyl(E)-3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3- yl)acrylate)
产率:39%;1H NMR:(300MHz,DMSO-d6)δ:0.83-0.86(t,3H,CH3), 1.25-1.34(m,8H,CH2),1.58-1.62(m,CH2-C-O),4.07-4.11(t,2H,CH2-O),6.46(d, 1H,J=15.9Hz,O=C-CH=C),6.93(s,2H,NH2-Ar),7.38(s,1H,NH2-C=O),7.44 (s,2H,S-NH2),7.47(s,1H,6-ArH),7.49(d,1H,J=15.9Hz,O=C-C=CH),7.59(d, 2H,J=8.4Hz,S-ArH),7.88(d,2H,J=8.4Hz,S-ArH),8.00-8.03ppm(m,2H,4- Ar-H,NH2-C=O);MS(m/z):460.19(M+1)+;
HPN-01119:癸基(E)-3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基) 丙烯酸
decyl(E)-3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3- yl)acrylate
产率:44%;1H NMR:(300MHz,CDCl3)δ:1.39-1.43(t,3H,CH3-CH2), 3.93(s,3H,CH3-O),4.04(dd,2H,J1=6.9Hz,J2=6.9Hz,CH2-CH3),6.86-6.89(m, 2H,Ar-H),7.02(dd,2H,J1=2.1Hz,J2=2.1Hz,Ar-H),7.36(d,1H,J=15.3Hz, O=C-CH=C),7.40(s,1H,Ar-H),7.52(d,J=15.0Hz,Ar-H),7.70(d,1H,J=15.3 Hz,O=C-C=CH),8.07(s,1H,O-CH=C),8.19ppm(d,1H,J=9.0Hz,Ar-H);13C NMR(75MHz,CDCl3)δ:15.10,56.71,57.15 100.95,115.45,116.61,122.84, 126.88,129.11,134.55,158.94,159.16,165.64,166.56,177.26ppm;HRMS(m/z): 366.13(M+1)+;
HPN-01120:苯甲基(E)-3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3- 基)丙烯酸
benzyl(E)-3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3- yl)acrylate
产率:31%;1H NMR:(300MHz,DMSO-d6)δ:5.18(s,2H,CH2-Ph), 6.53(d,1H,J=15.9Hz,O=C-CH=C),6.95(s,2H,NH2-Ar),7.30-7.35(m,5H,NH2- C=O,S-NH2,ArH),7.38-7.44(m,4H,ArH),7.49(d,1H,J=15.9Hz,O=C-C=CH), 7.55(d,2H,J=8.4Hz,S-ArH),7.89(d,2H,J=8.4Hz,S-ArH),8.02-8.04ppm(m, 2H,4-Ar-H,NH2-C=O);MS(m/z):452.12(M+1)+;
HPN-01121:(E)-4-(3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基) 丙烯酰胺基)苯甲酸
(E)-4-(3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3- yl)acrylamido)benzoic acid
产率:23%;1H NMR:(300MHz,CDCl3)δ:3.47(d,4H,J=4.2Hz), 3.83(s,4H,J=5.4Hz),3.92(s,3H),6.55(d,1H,J=2.1Hz),6.86(m,2H),6.97(d, 1H,J=2.4Hz),7.00(d,1H,J=2.4Hz),7.38(d,1H,J=1.8Hz),8.14(m,3H),8.23 ppm(d,1H,J=9Hz).MS(m/z):481.5(M+1)+;
HPN-01122:(E)-2-氨基-5-(3-((4-羟基苯基)氨基)-3-氧代丙-1-烯-1- 基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
(E)-2-amino-5-(3-((4-hydroxyphenyl)amino)-3-oxoprop-1-en-1-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:30%;1H NMR:(300MHz,DMSO-d6)δ:6.57(d,1H,J=15.6 Hz,O=C-CH=C),6.68(d,2H,J=8.7Hz,Ar-H),6.73(s,2H,Ar-NH2),7.37-7.47 (m,5H,NH2-C=O,O=C-C=CH,Ar-H),7.44(s,2H,NH2-S),7.62(d,2H,J=8.4Hz, Ar-H),7.88(s,1H,Ar-H),7.91(d,2H,J=8.4Hz,Ar-H),8.03(s,1H,NH2-C=O), 9.17(s,1H,OH),9.73ppm(s,1H,NH);MS(m/z):453.12(M+1)+;
HPN-01123:苯乙基(E)-3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3- 基)丙烯酸
phenethyl(E)-3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)acrylate
产率:37%;1H NMR:(300MHz,DMSO-d6)δ:2.92-2.96(t,2H,CH2- Ph),4.30-4.34(t,2H,CH2-O),6.44(d,1H,J=15.6Hz,O=C-CH=C),6.94(s,2H, NH2-Ar),7.26(s,1H,NH2-C=O),7.28(s,2H,S-NH2),7.30-7.47(m,6H,ArH),7.49 (d,1H,J=15.9Hz,O=C-C=CH),7.59(d,2H,J=8.4Hz,S-ArH),7.89(d,2H,J= 8.1Hz,S-ArH),8.02-8.05ppm(m,2H,4-Ar-H,NH2-C=O);MS(m/z):466.14(M+ 1)+;
HPN-01124:呋喃-2-基甲基(E)-3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'- 联苯]-3-基)丙烯酸
furan-2-ylmethyl(E)-3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)acrylate
产率:80%;1H NMR:(300MHz,CDCl3)δ:2.91-2.96(m,2H,CH2-Ar), 3.63-3.69(m,2H,CH2-N),3.92(s,3H,CH3-O),5.72(s,1H,NH),6.86(d,1H,J= 2.4Hz,Ar-H),7.00-7.11(m,3H,Ar-H),7.19-7.25(m,2H,Ar-H),7.28(d,1H,J= 15.3Hz,O=C-CH=C),7.45(d,1H,J=15.0Hz,O=C-C=CH),8.03(s,1H,O-CH=C), 8.16ppm(d,1H,J=9.0Hz,Ar-H);13C NMR(75MHz,CDCl3)δ:35.26,40.75, 55.38,100.10,114.75,115.23,116.88,119.04,121.87,124.98,127.61,127.95, 132.80,141.17,149.04,158.00,163.76,166.90,177.70ppm;HRMS(m/z):368.13 (M+1)+;
HPN-01125:(E)-2-氨基-5-(3-氧代-3-(苯基氨基)丙-1-烯-1-基)-4'-氨 磺酰-[1,1'-联苯]-3-甲酰胺
(E)-2-amino-5-(3-oxo-3-(phenylamino)prop-1-en-1-yl)-4'-sulfamoyl- [1,1'-biphenyl]-3-carboxamide
产率:76%;1H NMR:(300MHz,CDCl3)δ:3.93(s,3H,CH3-O),4.58 (d,1H,J=6.0Hz,CH2-Ar),6.03(s,1H,NH),6.74(s,1H,Ar-H),6.87(d,1H,J= 2.4Hz,Ar-H),6.94-7.00(m,2H,Ar-H),7.09(d,1H,J=7.5Hz,Ar-H),7.28-7.36 (m,2H,Ar-H,O=C-CH=C),7.58(d,1H,J=15.0Hz,O=C-C=CH),8.05(s,1H,O- CH=C),8.16ppm(d,1H,J=9.0Hz,Ar-H);13C NMR(75MHz,CDCl3)δ:44.53, 55.32,100.10,113.43,116.33,118.96,119.83,120.32,122.58,127.07,127.76, 140.43,143.32,149.99,160.22,162.48,163.02,165.89,175.88ppm;HRMS(m/z): 354.11(M+1)+;
HPN-01126:(E)-2-氨基-5-(3-氧代-3-(对甲苯基氨基)丙-1-烯-1-基)- 4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
(E)-2-amino-5-(3-oxo-3-(p-tolylamino)prop-1-en-1-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:57%;1H NMR:(300MHz,DMSO-d6)δ:2.24(s,3H,CH3),6.62 (d,1H,J=15.6Hz,O=C-CH=C),6.75(s,2H,Ar-NH2),7.11(d,2H,J=8.4Hz,Ar- H),7.37(s,2H,NH2-C=O),7.43(s,2H,NH2-S),7.45(d,1H,J=15.3Hz,O=C- C=CH),7.55(d,2H,J=8.4Hz,Ar-H),7.64(d,2H,J=8.1Hz,Ar-H),7.90-7.94(q, 3H,Ar-H),8.02(s,1H,Ar-H),9.88ppm(s,1H,NH);13C NMR(75MHz,DMSO- d6)δ:20.39,114.87,118.06,118.98,121.57,126.24,126.93,129.05,129.49,129.79, 131.75,131.89,136.96,139.51,141.68,143.10,147.93,163.80,170.95ppm;MS (m/z):451.14(M+1)+;
HPN-01127:(E)-2-氨基-5-(3-氧代-3-(间甲苯氨基)丙-1-烯-1-基)-4'- 氨磺酰-[1,1'-联苯]-3-甲酰胺
(E)-2-amino-5-(3-oxo-3-(m-tolylamino)prop-1-en-1-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:36%;1H NMR:(300MHz,DMSO-d6)δ:2.27(s,3H,CH3),6.61 (d,1H,J=15.6Hz,O=C-CH=C),6.76(s,2H,Ar-NH2),6.82(d,2H,J=9Hz,Ar- H),7.08-7.20(m,3H,NH2-C=O,O=C-C=CH),7.39-7.51(m,5H,NH2-S,Ar-H), 7.63(d,1H,J=8.7Hz,Ar-H),7.88-7.94(m,3H,Ar-H),8.01(s,1H,NH2-C=O), 9.89ppm(s,1H,NH);MS(m/z):451.14(M+1)+;
HPN-01128:(E)-2-氨基-5-(3-((4-甲氧苯基)氨基)-3-氧代丙-1-烯-1- 基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
(E)-2-amino-5-(3-((4-methoxyphenyl)amino)-3-oxoprop-1-en-1-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:69%;1H NMR:(300MHz,CDCl3)δ:3.32(s,3H,CH3),3.94(s, 3H,CH3-O),6.89(d,1H,J=2.4Hz,Ar-H),7.02-7.06(dd,1H,J1=2.4Hz,J2=2.4 Hz,Ar-H),7.11(d,1H,J=6.9Hz,Ar-H),7.19-7.28(m,2H,Ar-H),7.41(d,1H,J =15.0Hz,O=C-CH=C),7.77(d,1H,J=15.3Hz,O=C-C=CH),8.04-8.07(m,1H, Ar-H),8.09(s,1H,O-CH=C),δ8.20ppm(d,1H,J=9.0Hz,Ar-H);13C NMR(75 MHz,CDCl3)δ:18.33,55.85,100.20,114.05,114.45,116.84,118.06,121.76, 125.09,127.57,128.74,129.26,130.86,131.94,133.62,140.95,148.55,157.78, 164.26,167.86,172.17;HRMS(m/z):336.12(M+1)+;
HPN-01129:(E)-2-氨基-5-(3-((4-乙氧苯基)氨基)-3-氧代丙-1-烯-1- 基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
(E)-2-amino-5-(3-((4-ethoxyphenyl)amino)-3-oxoprop-1-en-1-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:43%;1H NMR:(300MHz,DMSO-d6)δ:1.27-1.32(t,3H,CH3), 3.94-5.01(q,2H,CH2),6.57(d,1H,J=15.6Hz,O=C-CH=C),6.74(s,2H,Ar-NH2), 6.85(d,2H,J=9Hz,Ar-H),7.38(s,2H,NH2-C=O),7.41(d,1H,J=15.6Hz,O=C- C=CH),7.43(s,2H,NH2-S),7.55(d,2H,J=9Hz,Ar-H),7.62(d,2H,J=8.4Hz, Ar-H),7.89(s,1H,Ar-H),7.90(d,2H,J=8.7Hz,Ar-H),8.03(s,1H,NH2-C=O), 9.83ppm(s,1H,NH);MS(m/z):481.15(M+1)+;
HPN-01130:(E)-2-氨基-5-(3-((4-氯苯基)氨基)-3-氧代丙-1-烯-1-基)- 4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
((E)-2-amino-5-(3-((4-chlorophenyl)amino)-3-oxoprop-1-en-1-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:46%;1H NMR:(300MHz,DMSO-d6)δ:6.59(d,1H,J=15.6 Hz,O=C-CH=C),6.79(s,2H,Ar-NH2),7.34-7.39(m,4H,Ar-H,NH2-C=O),7.44(s, 2H,NH2-S),7.46(d,1H,J=15.6Hz,O=C-C=CH),7.62(d,2H,J=8.4Hz,Ar-H), 7.69(d,2H,J=9Hz,Ar-H),7.91-7.94(m,3H,S-ArH,4-Ar-H),8.03(s,1H,NH2- C=O),10.12ppm(s,1H,NH);MS(m/z):472.08(M+1)+;
HPN-01131:(E)-2-氨基-5-(3-(苯甲基氨基)-3-氧代丙-1-烯-1-基)-4'- 氨磺酰-[1,1'-联苯]-3-甲酰胺
((E)-2-amino-5-(3-(benzylamino)-3-oxoprop-1-en-1-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:38%;1H NMR:(300MHz,DMSO-d6)δ:4.37(t,2H,CH2-N), 6.48(d,1H,J=15.9Hz,O=C-CH=C),7.23-7.34(m,7H,NH2-Ar,NH2-C=O,S-NH2, ArH),7.38-7.42(3H,Ar-H,O=C-C=CH),7.60(d,2H,J=8.4Hz,S-ArH),7.85-7.93 (m,3H,S-ArH,4-Ar-H),8.02(s,1H,NH2-C=O),8.38ppm(s,1H,NH-C=O);MS (m/z):451.14(M+1)+;
HPN-01132:(E)-2-氨基-5-(3-((4-氟苯乙基)氨基)-3-氧代丙-1-烯-1- 基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
((E)-2-amino-5-(3-((4-fluorophenethyl)amino)-3-oxoprop-1-en-1-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率54%;1H NMR:(300MHz,CDCl3)δ:2.33(s,3H,CH3),3.93(s, 3H,CH3-O),6.87(d,1H,J=2.1Hz,Ar-H),7.01-7.04(dd,2H,J1=2.4Hz,J2=2.4 Hz,Ar-H),7.15(d,1H,J=8.1Hz,Ar-H),7.37(d,1H,J=15.0Hz,O=C-CH=C), 7.50(d,2H,J=8.4Hz,Ar-H),7.69(d,1H,J=15.0Hz,O=C-C=CH),8.07(s,1H, O-CH=C),8.19ppm(d,1H,J=9.0Hz,Ar-H);13CNMR(75MHz,CDCl3)δ:21.36, 55.88,100.24,115.07,118.02,119.10,121.64,122.84,127.31,128.96,133.23, 135.94,141.52,150.65,157.14,164.01,164.34,176.54;HRMS(m/z):336.12(M+ 1)+;
HPN-01133:(E)-2-氨基-5-(3-(环己基氨基)-3-氧代丙-1-烯-1-基)-4'- 氨磺酰-[1,1'-联苯]-3-甲酰胺
(E)-2-amino-5-(3-(cyclohexylamino)-3-oxoprop-1-en-1-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:54%;1H NMR:(300MHz,CDCl3)δ:3.93(s,3H,CH3-O),6.89 (d,1H,J=2.1Hz,Ar-H),7.03-7.08(m,2H,Ar-H),7.27-7.31(m,1H,Ar-H),7.38 (s,1H,Ar-H)7.41(d,1H,J=15.0Hz,O=C-CH=C),7.76(d,1H,J=15.0Hz,O=C- C=CH),7.80(s,1H,Ar-H),8.10(s,1H,O-CH=C),8.19ppm(d,1H,J=9.0Hz,Ar- H);13C NMR(75MHz,CDCl3)δ:55.64,100.10,114.65,117.48,119.54,121.24, 122.51,124.48,127.44,129.07,132.71,141.61,149.69,157.45,164.15,167.15, 175.50ppm;HRMS(m/z):357.06(M+1)+;
实施例19:HPN-01衍生物的HPN-012系列的合成
使用以下合成过程来获得HPN-01衍生物的第二系列:
步骤1.化合物E的合成:
将12g的化合物B(3mmol),取代的炔烃(3.3mmol),0.03g PdCl2(Ph3P)2(3%)和0.8mL N,N-二异丙基乙胺(DIEA)(6mmol)添加到50mL的 无水四氢呋喃(THF),并且将混合物在600w于130℃的微波加热下搅拌30min。 停止反应,并将产生的溶液倒入200mL冰水中并连续搅拌。收集沉淀的固体, 干燥并进行硅胶柱色谱纯化,从而分离出化合物E。化合物E的产率为30-95 %。
步骤2.HPN-012系列化合物的合成:
将化合物E(10mmol)、4.2g化合物D(15mmol)、0.35g PdCl2(PPh3)2(5 %),以及2.8g碳酸钾(20mmol)的混合物溶解于50mL二恶烷和20mL水中。 在氮气保护下使反应混合物在80℃下温育30小时。反应完成后,将所得溶液 倒入冰水中并剧烈搅拌。收集固体,干燥,并进行硅胶柱色谱,产生化合物HPN- 01201至HPN-01224。化合物HPN-01201至HPN-01224的结构信息如下:
HPN-01201:2-氨基-5-(3-羟基丙-1-炔基)-4'-氨磺酰联苯-3-甲酰胺
(2-amino-5-(3-hydroxyprop-1-ynyl)-4'-sulfamoylbiphenyl-3-carboxamide)
产率:60%;1H NMR:(300MHz,CDCl3)δ:2.26(s,3H),2.34(s,3H), 3.93(s,3H),6.89(m,1H),7.04(m,2H),7.12(d,1H,J=13.2Hz),7.39(d,1H,J= 15Hz),7.75(d,1H,J=14.7Hz),7.87(s,1H),8.08(s,1H),8.19ppm(d,1H,J= 8.7Hz);MS(m/z):346.37(M+1)+;
HPN-01202:2-氨基-5-(苯基乙炔基)-4'-氨磺酰联苯-3-甲酰胺
(2-amino-5-(phenylethynyl)-4'-sulfamoylbiphenyl-3-carboxamide)
产率:38%;1H NMR:(300MHz,DMSO-d6)δ:6.72(s,2H,NH2-Ar), 7.26(d,1H,J=1.8Hz,NH2-C=O),7.36-7.42(m,3H,ArH),7.43(s,2H,S-NH2), 7.46-7.50(m,2H,ArH),7.61(d,2H,J=8.4Hz,S-ArH),7.62(s,1H,4-Ar-H),7.86 (d,1H,J=1.8Hz,NH2-C=O),7.90(d,2H,J=8.4Hz,S-ArH),8.05ppm(s,1H,6- Ar-H);MS(m/z):410.44(M+1)+;
HPN-01203:2-氨基-5-((4-氟苯基)乙炔基)-4'-氨磺酰联苯-3-甲酰胺
(2-amino-5-((4-fluorophenyl)ethynyl)-4'-sulfamoylbipheny l-3-carboxamide)
产率:48%;1H NMR:(300MHz,CDCl3)δ:3.93(s,3H),6.88(d,1H,J =2.4Hz),7.02(m,3H),7.39(m,2H),7.57(d,1H,J=1.5Hz),7.79(d,1H,J=1.8 Hz),8.09(s,1H),8.20ppm(d,1H,J=9Hz);MS(m/z):392.10(M+1)+;
HPN-01204:2-氨基-5-((4-甲氧基苯基)乙炔基)-4'-氨磺酰联苯-3-甲 酰胺
(2-amino-5-((4-methoxy phenyl)ethynyl)-4'-sulfamoyl biphenyl-3-carboxamide)
产率:60%;1H NMR:(300MHz,CDCl3)δ:2.26(s,3H),2.34(s,3H), 3.93(s,3H),6.89(m,1H),7.04(m,2H),7.12(d,1H,J=13.2Hz),7.39(d,1H,J= 15Hz),7.75(d,1H,J=14.7Hz),7.87(s,1H),8.08(s,1H),8.19ppm(d,1H,J= 8.7Hz);MS(m/z):422.47(M+1)+;
HPN-01205:2-氨基-5-((4-氯苯基)乙炔基)-4'-氨磺酰-[1,1'-联苯]-3-甲 酰胺
(2-amino-5-((4-chlorophenyl)ethynyl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:55%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.45-7.53(m,6H),7.68(s,1H),7.88-7.92(dd,4H),8.14(d,1H);MS(m/z):426.89 (M+1)+;
HPN-01206:2-氨基-5-((3-氯苯基)乙炔基)-4'-氨磺酰-[1,1'-联苯]-3-甲 酰胺
(2-amino-5-((3-chlorophenyl)ethynyl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:57%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.48-7.56(m,6H),7.88(s,1H),7.88-7.92(dd,4H),8.14(d,1H);MS(m/z):471.34 (M+1)+;
HPN-01207:2-氨基-5-((4-溴苯基)乙炔基)-4'-氨磺酰-[1,1'-联苯]-3-甲 酰胺
(2-amino-5-((4-bromophenyl)ethynyl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率43%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.48-7.56(m,6H),7.88(s,1H),7.88-7.92(dd,4H),8.14(d,1H);MS(m/z):471.34 (M+1)+;
HPN-01208:2-氨基-5-((3-溴苯基)乙炔基)-4'-氨磺酰-[1,1'-联苯]-3-甲 酰胺
(2-amino-5-((3-bromophenyl)ethynyl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:45%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.30(t,1H),7.50-7.53(dd,4H),7.68(d,1H),7.83-7.92(m,5H),8.14(d,1H);MS (m/z):471.34(M+1)+;
HPN-01209:2-氨基-4'-氨磺酰-5-((三甲基硅烷基)乙炔基)-[1,1'-联 苯]-3-甲酰胺
(2-amino-4'-sulfamoyl-5-((trimethylsilyl)ethynyl)-[1,1'-biphenyl]-3-carboxamide)
产率:56%;1H NMR:(300MHz,CDCl3)δ:0.88(t,9H),6.27(s,2H), 7.50(s,2H),7.64(d,2H),7.88-7.92(dd,4H),8.10(d,1H);MS(m/z):388.53(M+ 1)+;
HPN-01210:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基2-氯苯甲酸
(3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl-2-chlorobenzoate)
产率:55%;1H NMR:(300MHz,CDCl3)δ:4.99-5.02(d,4H),7.23(s, 2H),7.39-7.41(m,2H),7.69(m,1H),7.86-7.95(m,8H),8.34(d,1H);MS(m/z): 484.92(M+1)+;
HPN-01211:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基2-溴苯甲酸
(3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl2-bromobenzoate)
产率:47%;1H NMR:(300MHz,CDCl3)δ:4.99-5.02(d,4H),7.23(s, 2H),7.47(m,1H),7.63-7.65(m,2H),7.86-7.90(m,8H),8.34(d,1H);MS(m/z): 529.38(M+1)+;
HPN-01212:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基2-甲基苯甲酸
(3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl 2-methylbenzoate)
产率:50%;1H NMR:(300MHz,CDCl3)δ:2.53(s,3H),4.99-5.02(d, 4H),7.16-7.28(m,5H),7.72(m,1H),7.86-7.90(m,8H),8.34(d,1H);MS(m/z): 464.51(M+1)+;
HPN-01213:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基2-氟苯甲酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl 2-fluorobenzoate
产率:69%;1H NMR:(300MHz,CDCl3)δ:4.99-5.02(d,4H),7.30- 7.31(m,2H),7.47(m,1H),7.86-7.99(m,8H),8.34(d,1H);MS(m/z):468.41(M+ 1)+;
HPN-01214:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基4-甲基苯甲酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl-4-methylbenzoate
产率65%;1H NMR:(300MHz,CDCl3)δ:2.41(s,3H),4,99-5.02(d, 3H),7.20-7.23(t,4H),7.86-7.90(m,8H),8.34(d,1H);MS(m/z):464.51(M+1)+;
HPN-01215:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基3-甲基苯甲酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl 3-methylbenzoate
产率:57%;1H NMR:(300MHz,CDCl3)δ:2.43(s,3H),4,99-5.02(d, 3H),7.23-7.27(dd,4H),7.86-7.90(m,8H),8.34(d,1H);MS(m/z):464.51(M+ 1)+;
HPN-01216:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-yl)丙-2-炔- 1-基3-甲氧基苯甲酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl 3-methoxybenzoate
产率:68%;1H NMR:(300MHz,CDCl3)δ:3.77(s,3H),4.99-5.02(d, 3H),7.15-7.23(m,3H),7.51(s,1H),7.64-7.67(m,2H),7.86-7.90(m,8H),8.34(d, 1H);MS(m/z):480.51(M+1)+;
HPN-01217:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基2-甲氧基苯甲酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl-2-methoxybenzoate
产率:62%;1H NMR:(300MHz,CDCl3)δ:3.90(s,3H),4.99-5.02(d, 3H),7.18-7.23(m,3H),7.53-7.56(m,2H),7.86-7.90(m,8H),8.34(d,1H);MS (m/z):480.51(M+1)+;
HPN-01218:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基4-甲氧基苯甲酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl-4-methoxybenzoate
产率:63%;1H NMR:(300MHz,CDCl3)δ:3.81(s,3H),4.99-5.02(d, 3H),6.85(d,2H),7.23(s,2H),7.94-7.90(m,9H),8.34(d,1H);MS(m/z):480.51 (M+1)+;
HPN-01219:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基3-羟基苯甲酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl-3-hydroxybenzoate
产率:67%;1H NMR:(300MHz,CDCl3)δ:4.99-5.02(d,4H),7.16(t, 3H),7.36(d,1h)7.47-7.65(m,2H),8.34(d,1H),9.45(s,1H),7.86-7.90(m,8H), 8.34(d,1H)9.45(s,1H);MS(m/z):466.48(M+1)+;
HPN-01220:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基4-羟基苯甲酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl-4-hydroxybenzoate
产率:60%;1H NMR:(300MHz,CDCl3)δ:4.99-5.02(d,4H),6.81(d, 2H),7.23(s,2H),7.77(s,2H)7.86-7.90(m,8H),8.34(d,1H),9.68(s,1H);MS (m/z):466.48(M+1)+;
HPN-01221:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基吡啶甲酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl picolinate
产率:70%;1H NMR:(300MHz,CDCl3)δ:4.99-5.02(d,4H),7.23(s, 2H),7.86-7.90(m,8H),8.34(d,1H),8.29-8.34(t,2H),8.89(d,1H);MS(m/z): 451.47(M+1)+;
HPN-01222:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基1H-吡咯-2-羧酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl 1H-pyrrole-2-carboxylate
产率:50%;1H NMR:(300MHz,CDCl3)δ:4.99-5.02(d,4H),8.28 (t,1H),7.23-7.30(t,4H),8.34(d,1H),11.30(s,1H);MS(m/z):439.46(M+1)+;
HPN-01223:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基乙酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl acetate
产率:55%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),2.31(s,3H), 4.82(s,2H),6.27(s,2H),7.50(s,2H),7.64(d,2H),7.88-7.92(dd,4H),8.10(d,1H); MS(m/z):388.41(M+1)+;
HPN-01224:3-(6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)丙-2-炔 -1-基丁酸
3-(6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)prop-2-yn-1-yl butyrate
产率:45%;1H NMR:(300MHz,CDCl3)δ:0.90(t,3H),1.79(M,2H), 2.0(s,2H),2.32(t,2H),4.82(s,2H),6.27(s,2H),7.50(s,2H),7.64(d,2H),7.88- 7.92(dd,4H),8.10(d,1H);MS(m/z):416.46(M+1)+;
实施例20:HPN-01衍生物的HPN-013系列的合成
使用以下合成过程来生产HPN-01衍生物的第三系列:
该合成的细节如下:
步骤1.化合物F的合成:
将1.2g的化合物B(3mmol),取代的苯基硼酸/取代的环烷基硼酸/ 取代的杂芳基硼酸(3.3mmol),0.3g PdCl2(Ph3P)2(3%),和1.95g碳酸铯(CsCO3) (6mmol)添加到50mL的THF/水混合的溶剂(THF:H2O=30mL:20mL)并在氮气 保护下加热回流24小时。停止反应,并将溶液倒入200mL冰水中并连续搅拌。 收集沉淀的固体,干燥并进行硅胶柱色谱纯化,从而分离出化合物F。化合物 F的产率为20-75%。
步骤2.HPN-013系列化合物的合成:
将10mmol的化合物F、4.2g的化合物D(15mmol)、0.35g的 PdCl2(PPh3)2(5%),以及2.8g碳酸钾(20mmol)的混合物溶解于50mL二恶烷和 20mL水的混合物中,并且在氮气保护下在80℃下温育反应混合物30小时。反 应完成后,将反应溶液倒入冰水中并剧烈搅拌。收集固体,干燥,并进行硅胶 柱色谱纯化,导致分离化合物HPN-01301至HPN-01311,HPN-01321,和HPN- 01322。这些化合物各自的结构信息如下:
HPN-01301:甲基4'-氨基-5'-氨甲酰-4”-氨磺酰-[1,1':3',1”-三联苯 基]-4-羧酸
methyl 4'-amino-5'-carbamoyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-4-carboxylate
产率:61%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),3.89(s,3H), 6.27(s,2H),7.5(s,2H),7.70~7.75(m,3H),7.88-7.94(m,6H),8.31(s,1H);MS (m/z):426.46(M+1)+;
HPN-01302:乙基4'-氨基-5'-氨甲酰-4”-氨磺酰-[1,1':3',1”-三联苯 基]-4-羧酸
ethyl 4'-amino-5'-carbamoyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-4-carboxylate
产率:60%;1H NMR:(300MHz,CDCl3)δ:1.29(t,3H),2.0(s,2H), 4.30(dd,2H),6.27(s,2H),7.50(s,2H),7.70-7.75(t,3H),7.88-7.94(m,6H),8.31 (s,1H);MS(m/z):440.48(M+1)+;
HPN-01303:异丙基4'-氨基-5'-氨甲酰-4”-氨磺酰-[1,1':3',1”-三联 苯基]-4-羧酸
isopropyl 4'-amino-5'-carbamoyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-4- carboxylate
产率57%;1H NMR:(300MHz,CDCl3)δ:1.32(d,6H),2.0(s,2H),5.24 (m,1H),6.27(s,2H),7.70-7.75(t,3H),7.88-7.96(m,6H),8.31(s,1H);MS(m/z): 454.51(M+1)+;
HPN-01304:4'-氨基-5'-氨甲酰-4”-氨磺酰-[1,1':3',1”-三联苯基]-4- 基乙酸
4'-amino-5'-carbamoyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-4-ylacetate
产率:64%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),2.28(s,3H), 6.27(s,2H),7.15(d,2H),7.50(s,2H),7.70-7.76(t,3H),7.88-7.92(dd,4H),8.31 (s,1H);MS(m/z):426.46(M+1)+;
HPN-01305:4'-氨基-5'-氨甲酰-4”-氨磺酰-[1,1':3',1”-三联苯基]-4- 基丙酸
4'-amino-5'-carbamoyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-4-ylpropionate
产率71%;1H NMR:(300MHz,CDCl3)δ:1.09(t,3H),2.0(s,2H), 2.27(dd,2H),6.27(s,2H),7.15(d,2H),7.50(s,2H),7.70-7.76(t,3H),7.88-7.92 (dd,4H),8.31(s,1H);MS(m/z):455.48(M+1)+;
HPN-01306:4'-氨基-5'-氨甲酰-4”-氨磺酰-[1,1':3',1”-三联苯基]-4- 基丁酸
4'-amino-5'-carbamoyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-4-ylbutyrate
产率:65%;1H NMR:(300MHz,CDCl3)δ:0.90(t,3H),1.67(m,2H), 2.0(s,2H),2.59(t,2H),6.27(s,2H),7.15(d,2H),7.50(s,2H),7.70-7.76(t,3H), 7.88-7.92(dd,4H),8.31(s,1H);MS(m/z):454.51(M+1)+;
HPN-01307:2-氨基-5-(6-氯吡啶-3-基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰 胺
2-amino-5-(6-chloropyridin-3-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:66%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(S,2H), 7.36(d,1H),7.50(s,2H),7.70(s,1H),7.88-7.92(dd,4H),8.26-8.31(dd,2H),9.01 (s,1H);MS(m/z):403.85(M+1)+;
HPN-01308:2-氨基-5-(5-氯吡啶-2-基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰 胺
2-amino-5-(5-chloropyridin-2-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:68%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.50(s,2H),7.58(d,3H),7.88-7.92(dd,4H),8.16-8.21(t,2H),8.49(s,1H),8.82 (s,1H);MS(m/z):403.85(M+1)+;
HPN-01309:2-氨基-5-(4-氯-1H-吡咯-2-基)-4'-氨磺酰-[1,1'-联苯]-3- 甲酰胺
2-amino-5-(4-chloro-1H-pyrrol-2-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率77%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),5.0(s,1H),6.27 (s,2H),6.40(s,6.40),6.95(s,1H),7.50(s,2H),7.70(s,1H),7.88-7.92(dd,4H), 8.31(s,1H);MS(m/z):391.84(M+1)+;
HPN-01310:2-氨基-5-(5-氯-1H-吡咯-3-基)-4'-氨磺酰-[1,1'-联苯]-3- 甲酰胺
(2-amino-5-(5-chloro-1H-pyrrol-3-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide)
产率:55%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),5.0(s,1H),6.27 (s,2H),6.40(s,1H),6.95(s,1H),7.50(s.2H),7.70(,s,1H),7.88-7.92(dd,4H), 8.31(s,1H),,7.70(,s,1H),7.88-7.92(dd,4H),8.31(s,1H);MS(m/z):391.84(M +1)+;
HPN-01311:2-氨基-5-(5-溴-1H-吡咯-3-基)-4'-氨磺酰-[1,1'-联苯]-3- 甲酰胺
2-amino-5-(5-bromo-1H-pyrrol-3-yl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率61%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),5.0(s,1H),6.27 (s,2H),6.40(s,1H),6.95(s,1H),7.50(s.2H),7.70(s,1H),7.88-7.92(dd,4H),8.31 (s,1H);MS(m/z):436.29(M+1)+;
HPN-01321:2-氨基-5-(3-溴环戊基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
2-amino-5-(3-bromocyclopentyl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:59%;1H NMR:(300MHz,CDCl3)δ:1.93(m,4H),1.68-3.45(m, 10H),2.79(m,1H),3.45(m,1H),6.27(s,2H),7.50(m,2H),7.86-7.92(m,5H);MS (m/z):439.34(M+1)+;
HPN-01322:2-氨基-5-(4-溴环己基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
2-amino-5-(4-bromocyclohexyl)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:70%;1H NMR:(300MHz,CDCl3)δ:1.61-1.86(m,4H),1.61- 2.02(m,6H),2,72(m,5H),3.38(m,1H),6.27(s,2H),7.50-7.72(t,3H),7.86-7.92 (m,5H);MS(m/z):453.37(M+1)+;
实施例21:另外的HPN-013系列化合物的合成
使用以下过程来合成另外的HPN-013系列化合物:
合成的细节如下:
步骤1.化合物G的合成:
将1.2g化合物B(3mmol),取代的苯胺/取代的苯酚/取代的苯硫酚 (3.3mmol),和0.5g K2CO3(3.3mmol)添加到DMF并在氮气保护下在室温下反 应16小时。停止反应,并将溶液倒入200mL冰水中。收集沉淀的固体,干燥 并进行硅胶柱色谱,从而分离出化合物G。化合物G的产率为68至79%。
步骤2.HPN-013系列化合物的合成:
将10mmol的化合物G,4.2g的化合物D(15mmol)、0.35g的 PdCl2(PPh3)2(5%),以及2.8g碳酸钾(20mmol)的混合物溶解于50mL二恶烷和 20mL水中,并且在氮气保护下在80℃下温育反应混合物30小时。反应完成 后,将反应溶液倒入冰水中并剧烈搅拌。收集固体,干燥,并进行硅胶柱色谱 纯化,得到化合物HPN-01312至HPN-01320。这些化合物各自的结构信息如 下:
HPN-01312:2-氨基-5-((4-氯苯基)氨基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰 胺
2-amino-5-((4-chlorophenyl)amino)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:77%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),4.0(s,1H),6.27 (s,2H),6.80(d,2H),7.24(d,2H),7.50(s,2H),7.66(d,2H),7.88-7.92(dd,4H); MS(m/z):417.88(M+1)+;
HPN-01313:2-氨基-5-(4-氯苯氧基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
2-amino-5-(4-chlorophenoxy)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:65%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.44-7.57(m,8H),7.88-7.92(dd,4H);MS(m/z):418.87(M+1)+;
HPN-01314:2-氨基-5-((4-氯苯基)硫代)-4'-氨磺酰-[1,1'-联苯]-3-甲酰 胺
2-amino-5-((4-chlorophenyl)thio)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:64%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.27-7.50(t,6H),7.42-7.50(d,2H),7.76(d,2H),7.88-7.92(dd,4H);MS(m/z): 434.93(M+1)+;
HPN-01315:2-氨基-5-((3-氯苯基)氨基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰 胺
2-amino-5-((3-chlorophenyl)amino)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:54%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),4.0(s,1H),6.27 (s,2H),6.81-6.89(m,3H),7.14(t,1H),7.50-7.51(d,3H),7.88-7.92(dd,4H);MS (m/z):417.88(M+1)+;
HPN-01316:2-氨基-5-(3-氯苯氧基)-4'-氨磺酰-[1,1'-联苯]-3-甲酰胺
2-amino-5-(3-chlorophenoxy)-4'-sulfamoyl-[1,1'-biphenyl]-3-carboxamide
产率:45%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.02(m,1H),7.21(m,1H)7.34-7.35(m,2H),7.44-7.51(m,5H),7.88-7.92(dd,4H); MS(m/z):418.87(M+1)+;
HPN-01317:3-((6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)氨基)苯 甲酸
3-((6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)amino)benzoic acid
产率:65%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),4.0(s,1H),6.27 (s,2H),6.80(d,2H),6.89(d,2H),7.27(m,1H),7.41-7.57(m,4H),7.88-7.97(m, 5H),11.0(s,1H);MS(m/z):427.45(M+1)+;
HPN-01318:3-((6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)氧)苯甲 酸
3-((6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)oxy)
benzoic acid
产率:69%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.44-7.51(m,5H),7.88-7.93(m,7H),11.0(s,1H);MS(m/z):428.43(M+1)+;
HPN-01319:甲基3-((6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)氨 基)苯甲酸
methyl 3-((6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)amino)benzoate
产率:55%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),3.89(s,4H), 4.0(s,1H),6.27(s,2H),6.80(d,2H)6.89(d,2H),7.11(t,1H),7.31(m,2H),7.41- 7.50(m,3H),7.84-7.92(m,8H);MS(m/z):441.47(M+1)+;
HPN-01320:甲基3-((6-氨基-5-氨甲酰-4'-氨磺酰-[1,1'-联苯]-3-基)氧) 苯甲酸
methyl 3-((6-amino-5-carbamoyl-4'-sulfamoyl-[1,1'-biphenyl]-3-yl)oxy)benzoate
产率:57%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),3.89(s,4H), 6.27(s,2H),7.35(m,2H)7.44-7.51(m,5H),7.75-7.92(m,6H);MS(m/z):442.46 (M+1)+;
实施例22:HPN-014系列化合物的合成
使用以下过程合成另外的HPN-01衍生物:
该合成的细节如下:
将12g的化合物B(3mmol),0.553g对氯苯基硼酸(3.3mmol), 0.03gPdCl2(Ph3P)2(3%)和1.95g CsCO3(6mmol)添加到THF/水混合溶剂 (THF:H2O=30mL:20mL)中,并在氮气保护下加热回流24小时。停止反应,并 将反应溶液倒入200mL冰水中并连续搅拌。收集沉淀的固体,干燥并进行硅胶 柱色谱,从而分离出化合物H。化合物H的产率为78%。
步骤2.HPN-01406化合物的合成:
将3.25g化合物H(10mmol),3.93g 4-四甲基二氧杂硼酰脲(4-tetramethyldioxaborolyl urea)(15mmol),0.35g PdCl2(PPh3)2(5%)以及2.8g碳酸 钾(20mmol)的混合物溶解于50mL二恶烷和20mL水的混合物中,并且在氮气 保护下在80℃下温育所述混合物30小时。反应完成后,将所得溶液倒入冰水 中并剧烈搅拌。收集固体,干燥,并进行硅胶柱色谱,分离出化合物HPN-01406。 化合物HPN-01406的产率为4%。该化合物的结构信息如下:1H NMR:(300 MHz,CDCl3)δ:6.0(s,3H),6.27(s,2H),7.50-7.55(t,4H),7.70-7.77(m,4H),7.87 (d,4H),8.10(d,2H),8.31(s,1H);MS(m/z):381.83(M+1)+。
步骤3.化合物J的合成:
化合物B(1.2g,3mmol),对溴苯硼酸(0.66g,3.3mmol),PdCl2(Ph3P)2 (0.03g,3%)和CsCO3(1.95g,6mmol)加入到THF和水的混合溶剂(THF:H2O =30mL:20mL)中,氮气保护下加热至回流反应24小时,停止反应,将反应液 倒入冰水混合物中(200mL),并不断搅拌,有固体析出,收集固体,烘干。 硅胶柱层析分离,得到化合物J,收率69%。
步骤4.化合物HPN-01401的合成:
化合物J(3.67g,10mmol),化合物4-羟基苯磺酰胺(2.6g,15mmol) 和碳酸钾(2.8g,20mmol)溶解在DMF(50mL)中,氮气保护下,60℃反应24小 时。反应结束后,反应液倒入冰水混合液中,剧烈搅拌。收集固体,烘干。硅 胶柱层析纯化。得到化合物HPN-01401,收率75%,1H NMR:(300MHz,CDCl3) δ:2.0(s,2H),6.27(s,2H),7.35(d,2H),7.50-7.55(m,5H),7.71(d,2H),8.07-8.10 (t,3H);MS(m/z):418.87(M+1)+。
分别使用步骤2和步骤4合成HPN-014系列化合物。HPN-014系 列化合物的结构信息如下:
HPN-01402:4-氨基-4'-氯-5-((4-氨磺酰苯基)氨基)-[1,1'-联苯]-3-甲酰 胺
4-amino-4'-chloro-5-((4-sulfamoylphenyl)amino)-[1,1'-biphenyl]-3-carboxamide
产率:51%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),4.0(s,1H),6.27 (s,2H),6.89(s,1H),7.24(d,2H),7.50-7.61(m,6H),8.10(d,2H);MS(m/z):417.88 (M+1)+;
HPN-01403:4-氨基-4'-氯-5-((4-氨磺酰苯基)硫代)-[1,1'-联苯]-3-甲酰 胺
4-amino-4'-chloro-5-((4-sulfamoylphenyl)thio)-[1,1'-biphenyl]-3-carboxamide
产率:44%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.50-7.55(m,5H),7.66-7.69(dd,4H),8.09-8.10(t,3H);MS(m/z):434.93(M+1)+;
HPN-01404:4-氨基-4'-溴-5-((4-氨磺酰苯基)氨基)-[1,1'-联苯]-3-甲酰 胺
4-amino-4'-bromo-5-((4-sulfamoylphenyl)amino)-[1,1'-biphenyl]-3-carboxamide
产率:50%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),4.0(s,1H),6.27 (s,2H),6.89(s,1H),7.24(d,2H),7.50-7.71(m,9H);MS(m/z):462.33(M+1)+;
HPN-01405:6'-氨基-5'-氨甲酰-4”-氯-[1,1':3',1”-三联苯基]-4-基二 氢磷酸
6'-amino-5'-carbamoyl-4”-chloro-[1,1':3',1”-terphenyl]-4-yldihydrogen phosphate
产率:45%;1H NMR:(300MHz,CDCl3)δ:6.27(s,2H),7.01(d,2H), 7.507.70(m,8H),8.10(d,2H),8.31(s,1H);MS(m/z):419.77(M+1)+;
HPN-01407:4”-乙酰氨基-4'-氨基-4-氯-[1,1':3',1”-三联苯基]-5'-甲 酰胺
4”-acetamido-4'-amino-4-chloro-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:45%;1H NMR:(300MHz,CDCl3)δ:2.04(s,3H),6.27(s,2H), 7.23(s,1H),7.50-7.55(t,4H),7.70-7.77(m,4H),7.87(d,4H),8.10(d,2H),8.31(s, 1H);MS(m/z):380.84(M+1)+;
HPN-01408:4'-氨基-4-氯-4”-丙酰胺基-[1,1':3',1”-三联苯基]-5'-甲 酰胺
4'-amino-4-chloro-4”-propionamido-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:38%;1H NMR:(300MHz,CDCl3)δ:1.02(dd,3H),2.45(dd,2H), 6.27(s,2H),7.23(s,1H),7.50-7.55(t,4H),7.70-7.87(m,6H),8.10(d,2H),8.31(s, 1H);MS(m/z):394.87(M+1)+;
HPN-01409:4'-氨基-4”-丁酰氨基-4-氯-[1,1':3',1”-三联苯基]-5'-甲 酰胺
4'-amino-4”-butyramido-4-chloro-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:47%;1H NMR:(300MHz,CDCl3)δ:0.90(t,3H),1.78(m,2H), 2.39(t,2H),6.27(s,2H),7.23(s,1H),7.50-7.55(t,4H),7.70-7.87(m,6H),8.10(d, 2H),8.31(s,1H);MS(m/z):408.89(M+1)+;
HPN-01410:5-(3-(2H-四唑-5-基)苯氧基)-4-氨基-4'-氯-[1,1'-联苯]-3- 甲酰胺
5-(3-(2H-tetrazol-5-yl)phenoxy)-4-amino-4'-chloro-[1,1'-biphenyl]-3-carboxamide
产率:50%;1H NMR:(300MHz,CDCl3)δ:6.27(s,2H),7.10(m,1H), 7.47-7.55(m,6H),8.0(m,4H),8.07-8.10(m,3H);MS(m/z):407.83(M+1)+;
HPN-01411:4-氨基-4'-氯-5-(3-(N-丙基氨磺酰)苯氧基)-[1,1'-联苯]- 3-甲酰胺
4-amino-4'-chloro-5-(3-(N-propylsulfamoyl)phenoxy)-[1,1'-biphenyl]-3-carboxamide
产率:57%;1H NMR:(300MHz,CDCl3)δ:0.90(t,3H),1.60(m,2H), 3.38(t,2H),6.27(s,2H),7.14(d,1H),7.50-7.55(m,4H),7.69-7.71(t,4H),8.07- 8.10(,m,3H);MS(m/z):460.95(M+1)+;
HPN-01412:4-氨基-4'-氯-5-(3-氨磺酰苯氧基)-[1,1'-联苯]-3-甲酰胺
4-amino-4'-chloro-5-(3-sulfamoylphenoxy)-[1,1'-biphenyl]-3-carboxamide
产率:48%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.14(d,1H),7.50-7.55(m,5H),7.69-7.71(t,4H),8.07-8.10(m,3H);MS(m/z): 418.87(M+1)+;
HPN-01413:4-氨基-4'-氯-5-((3-氨磺酰苯基)氨基)-[1,1'-联苯]-3-甲酰 胺
4-amino-4'-chloro-5-((3-sulfamoylphenyl)amino)-[1,1'-biphenyl]-3-carboxamide
产率:47%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),4,0(s,1H), 6.27(s,2H),6.89(s,1H),7.12(s,2H),7.22(d,2H),7.48-7.63(m,6H),7.71(d,1H), 8.10(d,2H);MS(m/z):417.88(M+1)+;
HPN-01414:4-氨基-4'-氯-5-((3-氨磺酰苯基)硫代)-[1,1'-联苯]-3-甲酰 胺
4-amino-4'-chloro-5-((3-sulfamoylphenyl)thio)-[1,1'-biphenyl]-3-carboxamide
产率:37%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 7.41-7.60(m,8H),7.87(s,1H),8.09-8.10(t,3H);MS(m/z):434.93(M+1)+;
HPN-01415:4-氨基-4'-溴-5-(3-氨磺酰苯氧基)-[1,1'-联苯]-3-甲酰胺
4-amino-4'-bromo-5-(3-sulfamoylphenoxy)-[1,1'-biphenyl]-3-carboxamide
产率:56%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),6.27(s,2H), 6.89(s,1H),7.12(s,2H),7.22(s,2H),7.48-7.66(m,8H);MS(m/z):463.32(M+ 1)+;
HPN-014016:6'-氨基-4”-溴-5'-氨甲酰-[1,1':3',1”-三联苯基]-4-基二 氢磷酸
6'-amino-4”-bromo-5'-carbamoyl-[1,1':3',1”-terphenyl]-4-yl dihydrogenphosphate
产率:49%;1H NMR:(300MHz,CDCl3)δ:6.27(s,2H),7.01(d,2H), 7.53-7.70(m,7H),8.31(s,1H);MS(m/z):464.22(M+1)+;
HPN-01417:4'-氨基-4-chloro-4”-胍基-[1,1':3',1”-三联苯基]-5'-甲酰 胺
4'-amino-4-chloro-4”-guanidino-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:67%;1H NMR:(300MHz,CDCl3)δ:4.0(s,1H),6.27(s,1H), 6.69(d,2H),7.50-7.55(m,6H),8.10(d,2H),8.31(d,1H),8.56(s,2H);MS(m/z): 380.84(M+1)+;
HPN-01418:4'-氨基-4-氯-4”-硫脲基-[1,1':3',1”-三联苯基]-5'-甲酰 胺
4'-amino-4-chloro-4”-thioureido-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:59%;1H NMR:(300MHz,CDCl3)δ:4.0(s,1H),6.27(s,1H), 6.69(d,2H),7.50-7.55(m,6H),8.10(d,2H),8.31(d,1H),8.56(s,2H);MS(m/z): 397.89(M+1)+;
HPN-01419:4'-氨基-4-氯-4”-(2-羟基乙酰氨基)-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4'-amino-4-chloro-4”-(2-hydroxyacetamido)-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:56%;1H NMR:(300MHz,CDCl3)δ:3.65(s,1H),4.47(s,2H), 6.27(s,2H),7.23(s,1H),7.50-7.55(t,4H),7.70-7.87(m,5H),8.10(d,2H),8.31(d, 1H);MS(m/z):396.84(M+1)+;
HPN-01420:4'-氨基-4-氯-4”-(2-氧代-2,5-二氢-1H-咪唑-1-基)- [1,1':3',1”-三联苯基]-5'-甲酰胺
4'-amino-4-chloro-4”-(2-oxo-2,5-dihydro-1H-imidazol-1-yl)-[1,1':3',1”- terphenyl]-5'-carboxamide
产率:68%;1H NMR:(300MHz,CDCl3)δ:3.02(d,2H),6.27(s,2H), 7.50-7.55(m,6H),7.70-7.77(m,3H),7,87(m,5H),8.10(d,2H),8.31(d,1H);MS (m/z):405.85(M+1)+;
HPN-01421:4'-氨基-4-氯-4”-(1H-1,2,3-三唑-4-基)-[1,1':3',1”-三联 苯基]-5'-甲酰胺
4'-amino-4-chloro-4”-(1H-1,2,3-triazol-4-yl)-[1,1':3',1”-terphenyl]-5'- carboxamide
产率:58%;1H NMR:(300MHz,CDCl3)δ:6.27(s,2H),7.25(d,2H), 7.50-7.55(m,4H),7.70-7.75(d,2H),8.10(d,2H),8.30-8.31(d,3H),12.0(s,1H); MS(m/z):390.84(M+1)+;
HPN-01422:4-氨基-4'-氯-5-(3-(N-(2-羟乙基)氨磺酰)苯氧基)-[1,1'-联 苯]-3-甲酰胺
(4-amino-4'-chloro-5-(3-(N-(2-hydroxyethyl)sulfamoyl)phenoxy)-[1,1'-biphenyl]-3-carboxamide)
产率:58%;1H NMR:(300MHz,CDCl3)δ:3.44-3.49(m,4H),3.65(s, 1H),6.27(s,2H),7.14(s,1H),7.50-7.58(m,6H),7.69-7.71(m,3H),8.07-8.10(t, 3H);MS(m/z):462.92(M+1)+;
HPN-01423:4-氨基-4'-氯-5-(4-氨磺酰苯乙氧基)-[1,1'-联苯]-3-甲酰 胺
4-amino-4'-chloro-5-(4-sulfamoylphenethoxy)-[1,1'-biphenyl]-3-carboxamide
产率:48%;1H NMR:(300MHz,CDCl3)δ:3.11(t,2H),4.27(t,2H), 6.62(s,2H),7.23(s,2H),7,5~7.61(m,2H),6.62(d,2H),7.77(d,2H),7.90(s,2H), 8.10-8.13(m,3H),MS(m/z):446.92(M+1)+;
HPN-01424:4-氨基-4'-氯-5-((4-氨磺酰苯甲基)氧)-[1,1'-联苯]-3-甲酰 胺
4-amino-4'-chloro-5-((4-sulfamoylbenzyl)oxy)-[1,1'-biphenyl]-3-carboxamide
产率:52%;1H NMR:(300MHz,CDCl3)δ:5.16(s,2H),6.62(s,2H), 7.23(s,2H),7.39(d,1H),7.53(d,2H),7.62(d,2H),7.76(d,2H),7.90(s,2H), 8.10~8.13(m,3H),MS(m/z):432.89(M+1)+;
HPN-01425:4-氨基-4'-氯-5-((4-氨磺酰苯乙基)氨基)-[1,1'-联苯]-3-甲 酰胺
4-amino-4'-chloro-5-((4-sulfamoylphenethyl)amino)-[1,1'-biphenyl]-3-carboxamide
产率:55%;1H NMR:(300MHz,CDCl3)δ:2.93(t,2H),3.40(t,2H), 4.80(s,2H),6.79(s,2H),6.86(d,1H),7.23(s,2H),7.45(d,2H),7.62(d,2H), 7.79~7.87(m,3H),7.90(s,2H),8.10(d,2H),MS(m/z):445.93(M+1)+;
HPN-01426:4-氨基-4'-氯-5-((4-氨磺酰苯甲基)氨基)-[1,1'-联苯]-3-甲 酰胺
4-amino-4'-chloro-5-((4-sulfamoylbenzyl)amino)-[1,1'-biphenyl]-3-carboxamide
产率:47%;1H NMR:(300MHz,CDCl3)δ:4.32(s,2H),4.82(s,2H), 6.81(s,1H),6.86(d,1H),7.23(s,2H),7.53~7.62(m,4H),7.76~7.80(m,3H),7.93 (s,2H),8.10(d,2H),MS(m/z):431.91(M+1)+;
HPN-01427:4-氨基-4'-氯-5-(4-氨磺酰哌嗪-1-基)-[1,1'-联苯]-3-甲酰 胺
4-amino-4'-chloro-5-(4-sulfamoylpiperazin-1-yl)-[1,1'-biphenyl]-3-carboxamide
产率:53%;1H NMR:(300MHz,CDCl3)δ:2.58(t,4H),3.19(t,4H), 4.82(s,2H),5.5(s,2H),6.92(d,1H),7.62(d,2H),7.80(d,1H),7.90(s,2H),8.12 (d,2H),MS(m/z):410.89(M+1)+;
HPN-01428:4-氨基-4'-氯-5-(5-氨磺酰吡啶-2-基)-[1,1'-联苯]-3-甲酰 胺
4-amino-4'-chloro-5-(5-sulfamoylpyridin-2-yl)-[1,1'-biphenyl]-3-carboxamide
产率:51%;1H NMR:(300MHz,CDCl3)δ:6.62(s,2H),7.55(s,2H), 7.66(d,2H),7.90(s,2H),8.1~8.2(m,4H),8.43(d,1H),8.55(d,1H),8.72(d,1H), MS(m/z):403.85(M+1)+;;
HPN-01429:4'-氨基-4-氯-4”-(3-(吡啶-3-基)脲基)-[1,1':3',1”-三联 苯基]-5'-甲酰胺
4'-amino-4-chloro-4”-(3-(pyridin-3-yl)ureido)-[1,1':3',1”-terphenyl]-5'- carboxamide
产率:49%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),7.4(m,1H), 7.76~7.85(m,4H),7,95~8.03(m,4H),8.10~8.15(m,1H),8.33(m,3H),8.55(d, 1H),8.93(s,1H),9.30(s,1H),MS(m/z):458.92(M+1)+;
HPN-01430:4'-氨基-4-氯-4”-(3-异丙基脲基)-[1,1':3',1”-三联苯基]- 5'-甲酰胺
(4'-amino-4-chloro-4”-(3-isopropylureido)-[1,1':3',1”-terphenyl]-5'-carboxamide)
产率:68%;1H NMR:(300MHz,CDCl3)δ:1.20(d,6H),4.18(m,1H), 5.02(s,2H),6.51(s,1H),7.62(d,2H),7.80(d,2H),7.90(s,2H),8.10(m,3H),8.26 (s,1H),8.55(d,1H),MS(m/z):423.91(M+1)+;
实施例23:HPN-015系列化合物的合成
使用以下过程合成另外的HPN-01衍生物:
合成的细节如下:
步骤1.化合物L和M的合成:
将10mmol的化合物H'或J',15mmol取代的4-四甲基二氧杂硼 烷酮(4-tetramethyldioxaborolidine),0.35g PdCl2(PPh3)2(5%)和2.8g碳酸钾 (20mmol)溶于80mL二恶烷和30mL水的混合物中,并在氮气保护下在80℃下 反应30小时。反应完成后,将所得溶液倒入冰水中并剧烈搅拌。收集固体,干 燥,并进行硅胶柱色谱,分离化合物L和M。化合物L和M的产率为65-70 %。
步骤2.HPN-015系列化合物的合成
10mmol的化合物L和M(10mmol),溶于50mL乙腈的15mmol取 代的烷基羧酸,8.8gBOP(20mmol)和3.87g DIEA(30mmol)在氮气保护下在30℃ 下反应30小时。反应完成后,将所得溶液倒入冰水中并用20mL乙烷基乙酸萃 取三次,并且依次用酸水、碱水,和饱和盐水洗涤有机相。通过硅胶柱色谱法 纯化分离HPN-015系列化合物。HPN-015系列化合物的结构信息如下:
HPN-01501:4'-乙酰氨基-4-氯-4”-氨磺酰-[1,1':',”-三联苯基]-5'-甲 酰胺
4'-acetamido-4-chloro-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:68%;1H NMR:(300MHz,CDCl3)δ:2.0-2.04(d,5H),7.23(s, 1H),7.50-7.55(t,4H),7.88-7.93(m,5H),8.10(d,2H),8.54(s,1H);MS(m/z):444.9 (M+1)+;
HPN-01502:4-氯-4'-(2-羟基乙酰氨基)-4”-氨磺酰-[1,1':3',1”-三联 苯基]-5'-甲酰胺
4-chloro-4'-(2-hydroxyacetamido)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:65%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),3.65(s.1H),4.47 (s,2H),7.23s,1H),7.50-7.55(t,4H),7.88-7.93(m,5H),8.10(d,2H),8.54(s,1H); MS(m/z):460.9(M+1)+;
HPN-01503:4-氯-4'-(环丙甲酰)-4”-氨磺酰-[1,1':3',1”-三联苯基]- 5'-甲酰胺
4-chloro-4'-(cyclopropanecarboxamido)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:71%;1H NMR:(300MHz,CDCl3)δ:0.73-0.98(dd,4H)1.16(m, 1H),2.0(s,2H),7.23(s,1H),7.50-7.55(t,4H),7.88-7.93(m,5H),8.10(d,2H),8.54 (s,1H);MS(m/z):470.94(M+1)+;
HPN-01504:4'-(2-氨基乙酰氨基)-4-氯-4”-氨磺酰-[1,1':3',1”-三联 苯基]-5'-甲酰胺
4'-(2-aminoacetamido)-4-chloro-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'- carboxamide
产率:57%;1H NMR:(300MHz,CDCl3)δ:1.53(s,2H),2.0(s,2H), 3.85(s,2H),7.23(s,1H),7.50-7.55(t,4H),7.88-7.93(m,5H)8.10(d,2H),8.54(s, 1H);MS(m/z):459.92(M+1)+;
HPN-01505:4'-乙酰氨基-4-氯-4”-脲基-[1,1':3',1”-三联苯基]-5'-甲 酰胺
4'-acetamido-4-chloro-4”-ureido-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:50%;1H NMR:(300MHz,CDCl3)δ:4.0(s,1H),6.0(s,3H),7.50- 7.55(t,4H)7.77-7.93(m,5H),8.10(d,2H),8.54(s,1H),8.70(s,1H);MS(m/z): 408.83(M+1)+;
HPN-01506:4-氯-4'-(2-羟基乙酰氨基)-4”-脲基-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4-chloro-4'-(2-hydroxyacetamido)-4”-ureido-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:77%;1H NMR:(300MHz,CDCl3)δ:3.65(s,1H),4.47(s,2H), 6.0(d,3H),7.23(s,1H),7.50-7.55(t,4H),7.77-7.93(m,5H),8.10(d,2H),8.54(s, 1H);MS(m/z):439.86M+1)+;
HPN-01513:4-溴-4'-(3-羟基丙酰胺)-4”-氨磺酰-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4-bromo-4'-(3-hydroxypropanamido)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:69%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),2.42(t,2H),3.65 (s,1H),3.91(t,2H),7.23(s,1H),7.50-7.53(t,4H)7.66(d,2H),7.88-7.93(m,6H), 8.54(s,1H);MS(m/z):519.38(M+1)+;
HPN-01514:4'-(3-氨基丙酰胺)-4-溴-4”-氨磺酰-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4'-(3-aminopropanamido)-4-bromo-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:47%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),2.71(t,2H), 3.03(t,2H)5.11(s,2H),7.23(s,1H),7.50-7.53(t,4H)7.66(d,2H),7.88-7.93(m, 6H),8.54(s,1H);MS(m/z):518.4(M+1)+;
HPN-01515:4'-丁酰氨基-4-氯-4”-氨磺酰-[1,1':3',1”-三联苯基]-5'- 甲酰胺
4'-butyramido-4-chloro-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:39%;1H NMR:(300MHz,CDCl3)δ:0.90(t,3H),1.78(m,2H), 2.0(s,2H),2.39(t,2H),7.23(s,1H),7.50-7.55(t,4H)7.88-7.93(m,6H),8.10(d, 2H),8.54(s,1H);MS(m/z):488.96(M+1)+;
HPN-01516:4-氯-4'-(3-羟基丙酰胺)-4”-氨磺酰-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4-chloro-4'-(3-hydroxypropanamido)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:53%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),2.42(t,2H), 3.65(s,1H),3.91(t,2H),7.23(s,1H),7.50-7.55(t,4H),7.88-7.93(m,6H),8.10(d, 2H),8.54(s,1H);MS(m/z):474.93(M+1)+;
HPN-01517:4'-(3-氨基丙酰胺)-4-氯-4”-氨磺酰-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4'-(3-aminopropanamido)-4-chloro-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:58%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),2.71(t,2H), 3.03(t,2H)5.11(s,2H),7.50-7.55(t,4H),7.88-7.93(m,6H),,8.10(d,2H),8.54(s, 1H);MS(m/z):473.94(M+1)+;
HPN-01518:4'-(2-氨基乙酰氨基)-4-氯-4”-脲基-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4'-(2-aminoacetamido)-4-chloro-4”-ureido-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:67%;1H NMR:(300MHz,CDCl3)δ:1.53(s,2H),3.85(s,2H), 6.0(d,3H),7.23(s.1H),7.50-7.55(t,4H),8.10(d,2H),8.54(s,1H);MS (m/z):454.88(M+1)+;
HPN-01519:4'-丁酰氨基-4-氯-4”-脲基-[1,1':3',1”-三联苯基]-5'-甲 酰胺
4'-butyramido-4-chloro-4”-ureido-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:47%;1H NMR:(300MHz,CDCl3)δ:0.90(t,3H),1.78(m,2H), 2.0(s,2H),2.39(t,2H),6.0(s,3H),7.23(s,1H),7.50-7.55(t,4H),7.77-7.93(m, 6H)8.10(d,2H),8.54(s,1H);MS(m/z):451.92(M+1)+;
HPN-01520:4-氯-4'-(3-羟基丙酰胺)-4”-脲基-[1,1':3',1”-三联苯基]- 5'-甲酰胺
4-chloro-4'-(3-hydroxypropanamido)-4”-ureido-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:77%;1H NMR:(300MHz,CDCl3)δ:2.42(t,2H),3.65(s,1H), 3.91(s,1H),7.50-7.55(t,4H),7.77-7.93(m,6H),8.10(d,2H),8.54(s,1H);MS (m/z):453.89(M+1)+;
HPN-01525:4-溴-4'-(环丙烷甲酰胺基)-4”-氨磺酰-[1,1':3',1”-三联 苯基]-5'-甲酰胺
4-bromo-4'-(cyclopropanecarboxamido)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:57%;1H NMR:(300MHz,CDCl3)δ:0.73-0.98(dd,4H)1.16(m, 1H),2.0(s,2H),7.23(s,1H),7.50-7.53(t,4H),7.66(d,2H),7.88-7.93(m,6H),8.54 (s,1H);MS(m/z):515.39(M+1)+;
HPN-01526:4-溴-5'-氨甲酰-4”-脲基-[1,1':3',1”-三联苯基]-4'-基3- 氨基丙酸
4-bromo-5'-carbamoyl-4”-ureido-[1,1':3',1”-terphenyl]-4'-yl 3-aminopropanoate
产率:55%;1H NMR:(300MHz,CDCl3)δ:2.63(t,2H),2.92(t,2H), 5.11(s,2H),6.0(s,3H),7.50-7.53(t,4H),7.66(d,2H),7.77-7.92(m,6H),8.53(s, 1H);MS(m/z):498.34(M+1)+;
HPN-01527:4'-(2-氨基乙酰氨基)-4-溴-4”-氨磺酰-[1,1':3',1”-三联 苯基]-5'-甲酰胺
4'-(2-aminoacetamido)-4-bromo-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:49%;1H NMR:(300MHz,CDCl3)δ:1.53(s,2H),2.0(s,2H), 3.85(s,2H),7.23(s,1H),7.50-7.53(t,4H),7.66(d,2H),7.88-7.93(m,6H),8.54(s, 1H);MS(m/z):504.37(M+1)+;
HPN-01529:N-(5'-氨甲酰-4-氯-4”-氨磺酰-[1,1':3',1”-三联苯基]-4'- 基)烟酰胺
N-(5'-carbamoyl-4-chloro-4”-sulfamoyl-[1,1':3',1”-terphenyl]-4'- yl)nicotinamide
产率:68%;1H NMR:(300MHz,CDCl3)δ:7.23(s,2H),7.59~7.62(m, 3H),7.88~7.91(m,6H),8.10(d,2H),8.28~8.30(m,2H),8.76~8.80(m,2H),9.14 (s,1H),10.10(s,2H),MS(m/z):507.96(M+1)+;
HPN-01530:4'-(3-氨基丙甲酰)-4-氯-4”-氨磺酰-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4'-(3-aminopropanamido)-4-chloro-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:48%;1H NMR:(300MHz,CDCl3)δ:1.5(s,2H),2.71(t,2H), 3.02(t,2H),7.23(s,2H),7.62(d,2H),7.88~7.92(m,6H),8.10(d,2H),8.29(d,1H), 8.80(s,1H),10.10(s,2H),MS(m/z):473.94(M+1)+;
HPN-01531:4-氯-4'-((2-羟乙基)氨基)-4”-氨磺酰-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4-chloro-4'-((2-hydroxyethyl)amino)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:52%;1H NMR:(300MHz,CDCl3)δ:3.55(t,2H),3.67(t,2H), 4.92(s,1H),7.22(s,2H),7.62(d,2H),7.88~7.92(m,6H),8.10(d,2H),8.29(d, 1H),8.80(s,1H),10.10(s,1H),MS(m/z):446.92(M+1)+;
HPN-01532:4-氯-4'-((3-氯苯甲基)氨基)-4”-氨磺酰-[1,1':3',1”-三联 苯基]-5'-甲酰胺
4-chloro-4'-((3-chlorobenzyl)amino)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:50%;1H NMR:(300MHz,CDCl3)δ:4.32(s,2H),7.88(s,1H), 7.23(m,2H),7.35(d,2H),7.43(d,1H),7.62(d,2H),7.88~7.92(m,6H),8.10(m, 3H),8.60(d,1H),MS(m/z):527.43(M+1)+;
HPN-01533:4'-(丁基氨基)-4-氯-4”-氨磺酰-[1,1':3',1”-三联苯基]- 5'-甲酰胺
4'-(butylamino)-4-chloro-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:57%;1H NMR:(300MHz,CDCl3)δ:0.89(t,3H),1.32(m,2H), 1.47(m,2H),3.30(t,2H),7.88(s,1H),7.23(s,2H),7.62(d,2H),7.88~7.92(m, 6H),8.12(m,3H),8.66(d,1H),MS(m/z):458.97(M+1)+;
HPN-01534:4-氯-4'-(苯乙基氨基)-4”-氨磺酰-[1,1':3',1”-三联苯基]- 5'-甲酰胺
4-chloro-4'-(phenethylamino)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:43%;1H NMR:(300MHz,CDCl3)δ:2.93(t,2H),3.40(t,2H), 7.88(s,1H),7.23~7.26(m,7H),7.62(d,2H),7.88~7.92(m,6H),8.12(m,3H),8.66 (d,1H),MS(m/z):507.02(M+1)+;
实施例24:HPN-016系列化合物的合成。
使用以下方法合成另外的HPN-01衍生物:
合成的详情如下:
步骤1.化合物O的合成:
在氮气保护下,使3.6g化合物N(10mmol),溶于50mL乙腈的 10mmol取代的脂族胺,8.8g BOP(20mmol)和3.87g DIEA(30mmol)在室温下反 应30小时。反应完成后,将反应溶液倒入冰水中,用20mL乙酸乙酯萃取三 次。将有机相依次用酸水,碱性水(basic water)和饱和盐水洗涤,并且通过硅胶 柱层析法得到化合物O。化合物O的产率为88~94%。
步骤2.化合物P的合成:
将3mmol化合物,3.3mmol取代的苯基硼酸,0.03g PdCl2(Ph3P)2(3 %)和1.95gCsCO3(6mmol)加入到THF/水混合的溶剂(THF:H2O=30mL:20mL)中 加入0.03mmol,并在氮气保护下加热回流24小时。停止反应,并将反应溶液 倒入200ml冰水中并连续搅拌。收集沉淀的固体,干燥,并进行硅胶柱层析, 从而分离出化合物P。化合物P的产率为75%。
步骤3.化合物Q的合成:
将5mmol化合物P和0.9克NBS(5.25mmol)溶于100mL冰醋酸中 并在室温下搅拌1小时。反应完成后,将反应溶液部分浓缩并倒入冰水中并剧 烈搅拌。收集固体,干燥并进行硅胶柱层析分离,从而分离出化合物Q。化合 物Q的产率>90%。
步骤4.合成HPN-01601:
将10mmol化合物Q,4.2g化合物D(15mmol),0.35g PdCl2(PPh3)2(5%) 和2.8g碳酸钾(20mmol)溶于50mL二恶烷和20mL水的混合物中。在氮气保护下, 在80℃下进行反应30小时。反应完成后,将反应溶液倒入冰水中并剧烈搅拌。 收集固体,干燥并进行硅胶柱层析分离,从而分离出化合物HPN-01601。化合 物HPN-01601的产率为75%。该化合物的结构信息如下:1H NMR:(300MHz, CDCl3)δ:2.0(s,2H),2.85(s,3H),6.27(s,2H),7.55-7.61(t,3H),7.70(d,2H),7.88- 7.92(dd,4H),8.10(d,2H),8.31(d,1H);MS(m/z):416.89(M+1)+;
步骤5.化合物R的合成
将0.7g化合物2-氟-4-碘苯胺(2-fluoro-4-iodoaniline)(3mmol), 3.3mmol取代的苯基硼酸,0.03g PdCl2(Ph3P)2(3%)和1.95g CsCO3(6mmol)加 入到THF/水混合溶剂(THF:H2O=30mL:20mL)中并在氮气保护下加热回流24 小时。停止反应,将反应溶液倒入200mL冰水中并搅拌。收集沉淀的固体,干 燥,并进行硅胶柱层析分离,从而分离出化合物R。化合物R的产率为65%。
步骤6.化合物S的合成
将2mmol化合物R和2mmol取代的哌嗪溶于20mL乙腈中。加入 0.4gTEA(4mmol),并在室温下搅拌反应物16小时。将反应物倒入冰水中并用 20mL乙酸乙基萃取三次。纯化的化合物S具有的产率为80%。
步骤7.化合物T的合成:
将2mmol化合物T和0.45g NBS(2.6mmol)溶于50mL冰醋酸中并 在室温下搅拌1小时。反应完成后,将反应溶液部分浓缩并倒入冰水中并剧烈 搅拌。收集固体,干燥并进行硅胶柱层析分离,从而分离出化合物Q。化合物 Q的产率>90%。
步骤8.化合物HPN-01621的合成:
将1mmol化合物T,0.4g化合物D(1.5mmol),0.04g PdCl2(PPh3)2(5 %)和0.3g碳酸钾(2mmol)溶于5mL二恶烷(dioxane)和2mL水的混合物中并在 氮气保护下在80℃下反应24小时。反应完成后,将反应溶液倒入冰水中并剧 烈搅拌。收集固体,并进行硅胶柱层析,从而分离出化合物HPN-01621。化合 物HPN-01621的产率为45%。该化合物的结构信息如下:1H NMR:(300MHz, CDCl3)δ:1.91-2.0(d,3H),2.78(t,4H),3.46(t,4H),6.27(s,2H),6.79(d,2H),7.55 (d,2H),7.88-7.92(dd,4H),8.10(d,2H);MS(m/z):443.96(M+1)+;
步骤9.化合物U的合成:
在低温下将2mmol化合物H&J和0.2g三光气(triphosgene) (0.7mmol)溶于15mL二氯甲烷中。缓慢加入0.5g TEA(5mmol),并将混合物在 室温下搅拌16小时。反应完成后,将反应溶液部分浓缩并倒入冰水中并剧烈搅 拌。收集固体,干燥,并进行硅胶柱层析分离,从而分离出化合物U。化合物 U的产率为44%。
步骤10.化合物HPN-01609的合成:
将1mmol化合物U,0.4克化合物D(1.5mmol),0.04克PdCl2(PPh3)2(5 %)和0.3克碳酸钾(2mmol)溶于5mL二恶烷和2mL水的混合物中,在氮气保护 下在80℃反应24小时。反应完成后,将反应溶液倒入冰水中并剧烈搅拌。收 集固体,干燥并进行硅胶柱层析分离,从而分离出化合物HPN-01609。化合物 HPN-01609的产率为45%。该化合物的结构信息如下:1HNMR:(300MHz, CDCl3)δ:2.0(s,2H),7.88(s,4H),7.55(d,2H),7.88-7.93(m,5H),8.10(d,2H), 8.54(d,1H),10.0(s,1H);MS(m/z):428.86(M+1)+;根据以上步骤,完成了一系 列化合物的合成,结构信息总结如下:
HPN-01602:4'-氨基-4-溴-N-甲基-4”-氨磺酰-[1,1':3',1”-三联苯基]- 5'-甲酰胺
4'-amino-4-bromo-N-methyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:53%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),2.85(s,3H), 6.27(s,2H),7.3-7.70(m,7H)7.88-7.92(dd,4H),8.31(d,1H);MS(m/z):461.34(M +1)+;
HPN-01603:4'-氨基-4-氯-N-丙基-4”-氨磺酰-[1,1':3',1”-三联苯基]- 5'-甲酰胺
4'-amino-4-chloro-N-propyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:58%;1H NMR:(300MHz,CDCl3)δ:0.90(t,3H),1.64(m,2H), 2.0(s,2H),3.42(t,2H),6.27(s,2H),7.55(d,2H),7.70(d1H),8.10-8.03(t,3H), 8.31(d,1H);MS(m/z):444.95(M+1)+;
HPN-01604:4'-氨基-4-溴-N-丙基-4”-氨磺酰-[1,1':3',1”-三联苯基]- 5'-甲酰胺
4'-amino-4-bromo-N-propyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:66%;1H NMR:(300MHz,CDCl3)δ:0.90(t,3H),1.64(m,2H), 2.0(s,2H),3.42(t,2H),6.27(s,2H),7.53(d,2H),7.70-7.66(t,3H),7.88-7.92(dd, 4H),8.03(s,1H),8.31(d,1H);MS(m/z):489.4(M+1)+;
HPN-01605:4'-氨基-4-氯-N-环丙基-4”-氨磺酰-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4'-amino-4-chloro-N-cyclopropyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:64%;1H NMR:(300MHz,CDCl3)δ:1H-NMR:0.61-0.86(m,4H), 2.0(s,2H),2.75(m,1H),6.27(s,2H),7.55(d,2H),7.70(d,1H),7.88-7.92(dd, 4H)8.10(d,2H),8.31(d,1H);MS(m/z):442.93(M+1)+;
HPN-01606:4'-氨基-4-溴-N-环丙基-4”-氨磺酰-[1,1':3',1”-三联苯 基]-5'-甲酰胺
4'-amino-4-bromo-N-cyclopropyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:54%;1H NMR:(300MHz,CDCl3)δ:0.61-0.86(m,4H),2.0(s, 2H),2.75(m,1H),6.27(s,2H),7.53(d,2H),7.66-7.70(t,3H),7.88-7.92(dd,4H), 8.03(s,1H),8.31(d,1H);MS(m/z):487.38(M+1)+;
HPN-01607:4'-氨基-4-氯-N-(2-羟基乙基)-4”-氨磺酰-[1,1':3',1”-三 联苯基]-5'-甲酰胺
4'-amino-4-chloro-N-(2-hydroxyethyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:55%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),3.30(t,2H), 3.65(t,3H),6.27(s,2H),7.55(d,2H),7.70(d,1H),7.88-7.92(dd,4H)8.10(d,2H), 8.31(d,1H);MS(m/z):446.92(M+1)+;
HPN-01608:4'-氨基-4-溴-N-(2-羟基乙基)-4”-氨磺酰-[1,1':3',1”-三 联苯基]-5'-甲酰胺
4'-amino-4-bromo-N-(2-hydroxyethyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:54%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),3.30(t,2H), 3.65(t,3H),6.27(s,2H),7.53(d,2H),7.66-7.70(t,3H),7.88-7.92(dd,4H),8.03 (s,1H),8.31(d,1H);MS(m/z):491.37(M+1)+;
HPN-01610:4-(6-(4-溴苯基)-2,4-二氧代-1,2,3,4-四氢喹唑啉-8-基)苯 磺酰胺4-(6-(4-bromophenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-8-yl)benzenesulfonamide
产率:51%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),7.88(s.4H),7.53 (d,2H)7.66(d,2H),7.88-7.92(dd,4H),8.54(d,1H),10.0(s,1H);MS(m/z):473.31 (M+1)+;
HPN-01611:4'-氨基-4-氯-N-苯基-4”-氨磺酰-[1,1':3',1”-三联苯基]- 5'-甲酰胺
4'-amino-4-chloro-N-phenyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:54%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),7.07(m,1H), 7.23-7.32(dd,4H),7.70(m,2H),8.10-8.04(m,3H),8.55(d,1H),10.32(s,1H),; MS(m/z):478.96(M+1)+;
HPN-01612:4'-氨基-4-溴-N-苯基-4”-氨磺酰-[1,1':3',1”-三联苯基]- 5'-甲酰胺
4'-amino-4-bromo-N-phenyl-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:67%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),7.07(m,1H), 7.23-7.32(dd,4H),7.65(dd,4H),7.88(s,4H),8.04(d,1H),8.55(s,1H)10.32(s, 1H);MS(m/z):523.42(M+1)+;
HPN-01613 4'-氨基-4-氯-N-(3-氟苯基)-4”-氨磺酰-[1,':3',1”-三联苯 基]-5'-甲酰胺
4'-amino-4-chloro-N-(3-fluorophenyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:54%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),6.96(t,1H), 7.23(s,1H),7.40(t,1H),7.56-7.62(M,3H),7.88(s,4H),8.04-8.10(dd,3H)8.55 (d,1H),10.32(s,1H);MS(m/z):496.95(M+1)+;
HPN-01614:4'-氨基-4-溴-N-(3-氟苯基)-4”-氨磺酰-[1,1':3',1”-三联 苯基]-5'-甲酰胺
4'-amino-4-bromo-N-(3-fluorophenyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:64%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),6.96(t,1H), 7.23(s,1H),7.40(t,1H),7.65-7.72(M,5H),7.88(s,4H),8.04(d,1H)8.55(d,1H), 10.32(s,1H);MS(m/z):541.41(M+1)+;
HPN-01615:4'-氨基-4-氯-N-(3,4-二氟苯基)-4”-氨磺酰-[1,1':3',1”- 三联苯基]-5'-甲酰胺
4'-amino-4-chloro-N-(3,4-difluorophenyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:54%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),7.23(s,2H), 7.37(t,1H),7.58-7.62(dd,3H),7.73(d,1H),7.80-8.10(t,3H),8.55(d,1H),10.32 (s,1H);MS(m/z):514.94(M+1)+;
HPN-01616:4'-氨基-4-溴-N-(3,4-二氟苯基)-4”-氨磺酰-[1,1':3',1”- 三联苯基]-5'-甲酰胺
4'-amino-4-bromo-N-(3,4-difluorophenyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:64%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),7.23(s,2H), 7.37(t,1H)7.73(m,6H),7.88(s,4H)8.04(d,1H),8.55(d,1H),10.32(s,1H);MS (m/z):559.4(M+1)+;
HPN-01617:4'-氨基-4-氯-N-(3,4-二羟基苯基)-4”-氨磺酰-[1,1':3',1” -三联苯基]-5'-甲酰胺
4'-amino-4-chloro-N-(3,4-dihydroxyphenyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:54%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),5.35(d,2H), 6.27(s,2H),6.76(d,1H),7.01(d,1H),7.15(d,2H),7.45-7.63(m,6H),8.10(d,2H), 8.31(d,1H),9.15(s,1H);MS(m/z):510.96(M+1)+;
HPN-01618:4'-氨基-4-溴-N-(3,4-二羟基苯基)-4”-氨磺酰-[1,1':3',1” -三联苯基]-5'-甲酰胺
4'-amino-4-bromo-N-(3,4-dihydroxyphenyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide
产率:59%;1H NMR:(300MHz,CDCl3)δ:2.0(s,2H),5.35(d,2H), 6.27(s,2H),6.76(d,1H),7.01(d,1H),7.15(d,2H),7.45-7.53(dd,4H)7.63-7.66 (dd,4H),8.10(d,2H),8.31(d,1H),9.15(s,1H);MS(m/z):555.41(M+1)+;
HPN-01619:4'-氨基-4-氯-N-(3-甲氧基苯基)-4”-氨磺酰-[1,1':3',1” -三联苯基]-5'-甲酰胺
(4'-amino-4-chloro-N-(3-methoxyphenyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide)
产率:54%;1H NMR:(300MHz,CDCl3)δ:3.74(s,3H),5.02(s,2H), 6.67(d,1H),7.20-7.23(dd,4H),7.47(d,1H),7.62(d,2H),7.88(s,4H),8.04-8.10 (dd,3H),8.55(d,1H),10.32(s,1H);MS(m/z):508.99(M+1)+;
HPN-01620:4'-氨基-4-溴-N-(3-甲氧基苯基)-4”-氨磺酰-[1,1':3',1” -三联苯基]-5'-甲酰胺
(4'-amino-4-bromo-N-(3-methoxyphenyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide)
产率:57%;1H NMR:(300MHz,CDCl3)δ:3.74(s,3H),5.02(s,2H), 6.67(d,1H),7.20-7.23(dd,4H),7.47(d,1H),7.65(s,4H),7.88(s,4H),8.04(d, 1H),8.55(d,1H),10.32(s,1H);MS(m/z):553.44(M+1)+;
HPN-01622:6'-氨基-4'-溴-5'-(哌嗪-1-基)-[1,1':3',1”-三联苯基]- 4-磺酰胺
(6'-amino-4”-bromo-5'-(piperazin-1-yl)-[1,1':3',1”-terphenyl]-4-sulfonamide)
产率:54%;1H NMR:(300MHz,CDCl3)δ:1.91-2.0(d,3H),2.78(t, 4H),3.46(t,4H),6.27(s,2H)6.79(d,2H),7.53(d,2H),7.66(d,2H),7.88-7.92(dd, 4H);MS(m/z):488.41(M+1)+;
HPN-01623:4-(4'-氨基-4-氯-4”-氨磺酰-[1,1':3',1”-三联苯基]-5'-基) 哌嗪-1-甲酰胺
(4-(4'-amino-4-chloro-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'- yl)piperazine-1-carboxamide)
产率:54%;1H NMR:(300MHz,CDCl3)δ:3.29(t,4H),3.52(t,4H), 5.02(s,2H),6.20(s,2H),6.77(s,1H),7.13(s,1H),7.23(s,2H),7.62(d,2H)7.88 (s,4H),8.10(d,.2H);MS(m/z):586.99(M+1)+;
HPN-01624:4-(4'-氨基-4-溴-4”-氨磺酰-[1,1':3',1”-三联苯基]-5'-基) 哌嗪-1-甲酰胺
(4-(4'-amino-4-bromo-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'- yl)piperazine-1-carboxamide)
产率:66%;1H NMR:(300MHz,CDCl3)δ:2.78(t,4H),3.46(t,4H), 5.02(s,2H),6.77(s,1H),7.13(s,1H),7.23(s,2H),7.65(s,4H),7.88(s,4H);MS (m/z):488.42(M+1)+;
HPN-01625:4'-氨基-4-氯-N-(吡啶-3-基)-4”-氨磺酰-[1,1':3',1”-三联 苯基]-5'-甲酰胺
(4'-amino-4-chloro-N-(pyrid in-3-yl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide)
产率:57%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),7.23(s,2H), 7.40(d,1H),7.62(d,2H),7.88(d,4H),8.10~8.17(m,4H),8.33(d,1H),8.55(d, 1H),8.93(d,1H),10.33(s,1H),MS(m/z):479.95(M+1)+;
HPN-01626:4'-氨基-4-氯-N-(1H-吡咯-2-yl)-4”-氨磺酰-[1,1':3',1”- 三联苯基]-5'-甲酰胺
(4'-amino-4-chloro-N-(1H-pyrrol-2-yl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide)
产率:58%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),6.25(d,1H), 6.38(d,1H),6.95(d,1H),7.23(s,2H),7.62(d,2H),7.88(d,4H),8.10~8.12(m, 3H),8.55(d,1H),11.17(s,1H),12.00(s,1H),MS(m/z):467.94(M+1)+;
HPN-01627:4'-氨基-4-氯-4”-氨磺酰-N-(噻吩-3-基)-[1,1':3',1”-三联 苯基]-5'-甲酰胺
(4'-amino-4-chloro-4”-sulfamoyl-N-(thiophen-3-yl)-[1,1':3',1”-terphenyl]-5'-carboxamide)
产率:53%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),6.43(d,1H), 7.23(s,2H),7.48(d,1H),7.59~7.62(m,3H),7.88(d,4H),8.10~8.12(m,3H),8.55 (d,1H),10.21(s,1H),MS(m/z):484.99(M+1)+;
HPN-01628:4'-氨基-4-氯-N-(1H-吡咯-3-yl)-4”-氨磺酰-[1,1':3',1” -三联苯基]-5'-甲酰胺
(4'-amino-4-chloro-N-(1H-pyrrol-3-yl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide)
产率:48%;1H NMR:(300MHz,CDCl3)δ:5.02(s,2H),6.23(d,1H), 6.86(d,1H),7.23(s,2H),7.62(d,2H),7.88(d,4H),8.10~8.12(m,3H),8.55(d, 1H),9.05(s,1H),10.21(s,1H),MS(m/z):467.94(M+1)+;
HPN-01629:N-((1H-吡咯-2-基)甲基)-4'-氨基-4-氯-4”-氨磺酰-[1,1':3', 1”-三联苯基]-5'-甲酰胺
(N-((1H-pyrrol-2-yl)methyl)-4'-amino-4-chloro-4”-sulfamoyl-[1,1':3',1” -terphenyl]-5'-carboxamide)
产率:55%;1H NMR:(300MHz,CDCl3)δ:4.32(s,2H),5.02(s,2H), 5.88(d,1H),6.11(d,1H),6.64(d,1H),7.23(s,2H),7.62(d,2H),7.88(d,4H), 8.10~8.12(m,3H),8.55(d,1H),8.77(s,1H),11.86(s,1H),MS(m/z):481.97(M+ 1)+;
HPN-01630 4'-氨基-4-氯-N-(吡啶-3-基甲基)-4”-氨磺酰-[1,1':3',1” -三联苯基]-5'-甲酰胺
(4'-amino-4-chloro-N-(pyridin-3-ylmethyl)-4”-sulfamoyl-[1,1':3',1”-terphenyl]-5'-carboxamide)
产率:68%;1H NMR:(300MHz,CDCl3)δ:4.47(s,2H),5.02(s,2H), 7.23(s,2H),7.37(d,1H),7.62(d,2H),7.88(m,5H),8.05~8.10(m,3H),8.37(d, 1H),8.58~8.60(m,2H),8.73(s,1H),MS(m/z):493.98(M+1)+;
实施例25:HPN-01变体对肝细胞中脂肪脂滴(LD)形成的影响。
使用实施例3中概述的程序测试了从上述合成方法获得的每种 HPN-01衍生物抑制肝细胞中LD形成的能力。该分析的结果显示在下表6(第 二栏)中。
实施例26:HPN-01变体对原代人肝细胞中SREBP-1和SREBP-2 表达的影响。
使用实施例6中概述的程序测试了从上述合成方法获得的每种 HPN-01衍生物抑制原代肝细胞中的SREBP-1和SREBP-2mRNA表达的能力。 该分析的结果显示在表6(第三和第四栏)中。
表6
HPN-01变体的抑制作用
实施例27:HPN-01对链脲佐菌素(STZ)和高脂肪膳食诱导的NASH 小鼠的效力
测试了HPN-01对诱导产生NASH的小鼠中各种物理和生物化学 参数的影响。总体研究设计如图27所示。简而言之,将新生C57/BL6J小鼠分 成5组,每组8只动物。一组(未处理)在整个研究期间以正常饮食喂食,并且 没有接受任何种类的药物治疗。将其余四组在第2,3和4天注射含有90μg链 脲佐菌素(STZ)的载体(载体由40%PEG400:10%CremophorEL:50%水组成), 并从第4周到第9周喂以高脂肪膳食(HFD)以在肝脏中建立NASH标志。接受 STZ的组之一(载体组)没有得到任何进一步的药物治疗。其余三组在第6周开 始口服施用替米沙坦或口服施用HPN-01并持续3周。以10mpk(mg/kg体重)的 剂量,每天一次(QD)口服施用替米沙坦;将这组作为阳性对照。以较低(5mpk) 或较高(15mpk)的剂量每天两次(BID)口服施用HPN-01。图28A显示了以下小 鼠的体重变化:喂食正常饮食的未处理小鼠(未处理;灰色圆圈),喂食高脂肪膳 食的经载体处理的小鼠(载体;黑方块),喂食高脂肪膳食的经替米沙坦处理的 小鼠(替米沙坦;灰色上箭头三角形),喂食高脂肪膳食的经低剂量HPN-01处理 的小鼠(HPN-01 5mpk;灰色下箭头三角形)和喂养高脂肪膳食的经高剂量HPN-01处理的小鼠(HPN-01 15mpk;黑色菱形)。图28B显示了针对每个研究组记录 的每日积累的食物摄入。结果显示用HPN-01处理对nSTZ+HFD NASH小鼠体 重或每日食物摄入没有影响。
在研究结束时,将动物禁食过夜,并且测量禁食血糖水平并与研究 第1天获得的禁食葡萄糖水平比较。图29显示用HPN-01处理对nSTZ+HFD NASH小鼠禁食血糖水平没有影响。
然后将小鼠实施安乐死,并通过心脏穿刺抽取全血。制备血清并储 存在-80℃下以用于丙氨酸氨基转移酶(ALT),天冬氨酸氨基转移酶(AST),甘油 三酯(TG)和总胆固醇(TC)的检测。分离肝脏并记录肝脏重量。在-80℃保存肝组 织以用于TG,TC检测,各种炎症和纤维化标志物的测量以及病理学研究。
血清丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)水平分 别显示于图30A和30B中。数据显示HPN-01以剂量依赖性方式显著逆转 nSTZ+HFDNASH小鼠中血清ALT(图30A)和AST(图30B)水平的升高。
图31A和31B分别显示了nSTZ+HFD NASH小鼠中的血清总胆固 醇(TC)和甘油三酯(TG)水平。数据显示HPN-01以剂量依赖性方式显著消除 NASH小鼠中血清TC(图31A)和TG(图31B)水平的增加。
图32A和32B分别显示了来自nSTZ+HFD NASH小鼠肝脏的总胆 固醇(TC)和甘油三酯(TG)水平。数据显示HPN-01施用以剂量依赖性方式显著 逆转肝脏TC(图32A)和TG(图32B)水平的升高。
图33A和33B分别显示了如上所述处理的小鼠肝脏中TNF-α和 MCP-1mRNA的水平。数据显示HPN-01处理以剂量依赖性方式显著抑制TNF- α(图33A)和MCP1(图33B)两者。同样,图34A-34C显示HPN-01处理以剂量 依赖性方式降低了转化生长因子β1(TGF-β1)(图34A),胶原蛋白1型α 1(COL1A1)(图34B)和金属蛋白酶-1的组织抑制剂(TIMP-1)(图34C)的水平。
在苏木精(Hematoxylin)和曙红(H&E)染色和油红O染色后,在显微 镜下观察来自图27所示研究的各组的肝组织,并测定NAFLD活性评分。结果 如图35A所示。还测定了另外的NAFLD/NASH病理评分,包括肝脂肪变性评 分(图35B),气球样变性(ballooning)评分(图35C)和炎症评分(图35D)。
虽然已经结合具体实施方案和实施例描述了本发明,但是对于本领 域普通技术人员而言考虑到所述技术和本公开应该是显而易见的是,具体公开 的材料和方法的等同物也将适用于本发明;并且此类等同物包括在所附权利要 求书中。
Claims (23)
1.一种化合物或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐在制备治疗非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)的药物中的应用,所述化合物选自由式I、式III、式IV的化合物组成的组,其中,
式I为:
其中R1为卤素,R2为亚砜基,R3和R4独立地为氢或低链烷烃;其中,
式III为:
其中,
R1为-CHCHR5;-CHCHCO2R5;-CHCHCONHR5;-苯基;-苯基-R5;-CCR5;-CC-CH2R5;-OR5;-SR5;或-NHR5;
R2为-C6H4-R6;-OC6H4-R6;-SC6H4-R6;-NHC6H4-R6;-OC1-6烷基-C6H4-R6;-NHC1-6烷基-C6H4-R6;哌嗪-R6;或吡啶-R6;
R3是H;-C1-6烷基,任选地用-OH、-NH2、苯基,或卤素取代;-CO-吡啶;--CO-CH2CH2NH2;或-CO-C1-6烷基,任选地用-OH或-NH2取代;
R4为H;-OCH3;-哌啶;-哌啶-CO NH2;-吡啶;-吡咯;-噻吩;-C1-6烷基,任选地用-OH取代;-吡啶;-哌啶;-吡咯;-噻吩;或-苯基,任选地用卤素或羟基取代;
或者,R3和R4一起形成尿嘧啶;
R5为卤素;-COOH;C1-6环烷基;-CH2C6H5;-CH2CH2C6H5;-CH2CH2C6H4-F;-CH2C6H4-COOH;-CH2C6H4-OH;-CH2呋喃;-Si(CH2)3;-CH2CO2 CH3;-CH2CO2(CH2)2CH3,或-CH2CO2 C6H4-Cl;或者
-C1-10烷基,任选地用卤素或-OH取代;或者
-C1-10环烷基,任选地用卤素或-OH取代;或者
-苯基,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、-NHCOMe、-NH CO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代;或者
-吡啶,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、-NHCOMe、-NH CO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代;或者
-吡咯,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、-NHCOMe、-NH CO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代;
R6为SO2NH2;-OPO(OH)2;-NH2;-NHCONH2;-NHCOCH3;-NHCSCH2CH3;-NHCS(CH2)2CH3;四唑;-SO2NH(CH2)2CH3;-NHC(NH)NH2;-NHCSNH2;-NHCSCH2OH;-三唑;-氧代咪唑(oxoimidazol);-SO2NHCH2CH2OH;-NHCONH-C1-6烷基;或-NHCONH-吡啶;其中
式IV为:
其中:R1选自表1中所列的基团;R2选自表2中所列的基团;R3选自表3中所列的基团;并且R4选自表4中所列的基团;
表1
式IV,R1选项
表2,
式IV,R2选项
表3,
式IV,R3选项
表4
式IV,R4选项
2.如权利要求1所述的应用,其特征在于,所述NAFLD包括对脂肪浸润加炎症(fattyinfiltration plus inflammation)、非酒精性脂肪性肝炎(nonalcoholicstratohepatitis,NASH)、肝纤维化(liver fibrosis)、肝硬化(cirrhosis),及其组合。
3.如权利要求1所述的应用,其特征在于,所述化合物是式I的化合物或其前药、治疗活性代谢物、水合物、溶剂化物(solvate),或药学上可接受的盐。
4.如权利要求3所述的应用,其特征在于,其中R1为氯化物。
5.如权利要求3所述的应用,其特征在于,其中R2为SO2NH2。
6.如权利要求3所述的应用,其特征在于,其中R3为氢。
7.如权利要求3所述的应用,其特征在于,其中R4为氢。
8.如权利要求1所述的应用,其特征在于,所述化合物是式Ⅲ的化合物或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐。
9.如权利要求1所述的应用,其特征在于,所述化合物是式Ⅳ的化合物或其前药、治疗活性代谢物、水合物、溶剂化物(solvate),或药学上可接受的盐。
10.如权利要求8所述的应用,其特征在于,其中R1为-OR5;-SR5;或-NHR5。
11.如权利要求8所述的应用,其特征在于,其中R2为-C6H4-R6。
12.如权利要求8所述的应用,其特征在于,其中R3为氢。
13.如权利要求8所述的应用,其特征在于,其中R4为氢。
14.如权利要求8所述的应用,其特征在于,其中R5为-苯基,任选地用-COOH取代。
15.如权利要求8所述的应用,其特征在于,其中R6为SO2NH2。
19.如权利要求9所述的应用,其特征在于,其中R4为H。
20.如权利要求1-19任一项所述的应用,其中所述化合物选自下组:HPN-01101-01133;HPN-01201-01224;HPN-01301-01322;HPN-01401-01430;HPN-01501-01506;HPN-01513-01520;HPN-01525-01527;HPN-01529-01534;HPN-01601-01630或其前药、治疗活性代谢物、水合物、溶剂化物(solvate),或药学上可接受的盐。
21.治疗NAFLD的试剂盒,其中包含治疗有效量的式I、式III、式IV的化合物或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐,以及用于将所述化合物施用至受试者的说明书,所述受试者患有或有风险患有NAFLD或相关病患,如脂肪沉积相关炎症、非酒精性脂肪性肝炎(NASH)、肝纤维化、肝硬化(cirrhosis),或其组合,其中,
式I为:
其中R1为卤素,R2为亚砜基,R3和R4独立地为氢或低链烷烃;其中,
式III为:
其中,
R1为-CHCHR5;-CHCHCO2R5;-CHCHCONHR5;-苯基;-苯基-R5;-CCR5;-CC-CH2R5;-OR5;-SR5;或-NHR5;
R2为-C6H4-R6;-OC6H4-R6;-SC6H4-R6;-NHC6H4-R6;-OC1-6烷基-C6H4-R6;-NHC1-6烷基-C6H4-R6;哌嗪-R6;或吡啶-R6;
R3是H;-C1-6烷基,任选地用-OH、-NH2、苯基,或卤素取代;-CO-吡啶;--CO-CH2CH2NH2;或–CO-C1-6烷基,任选地用-OH或-NH2取代;
R4为H;-OCH3;-哌啶;-哌啶-CO NH2;-吡啶;-吡咯;-噻吩;-C1-6烷基,任选地用-OH取代;-吡啶;-哌啶;-吡咯;-噻吩;或–苯基,任选地用卤素或羟基取代;
或者,R3和R4一起形成尿嘧啶;
R5为卤素;-COOH;C1-6环烷基;-CH2C6H5;-CH2CH2C6H5;-CH2CH2C6H4-F;-CH2C6H4-COOH;-CH2C6H4-OH;-CH2呋喃;-Si(CH2)3;-CH2CO2 CH3;-CH2CO2(CH2)2CH3,或-CH2CO2 C6H4-Cl;或者
-C1-10烷基,任选地用卤素或-OH取代;或者
-C1-10环烷基,任选地用卤素或-OH取代;或者
-苯基,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、-NHCOMe、-NH CO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2–C1-4烷基取代;或者
-吡啶,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、-NHCOMe、-NH CO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2–C1-4烷基取代;或者
-吡咯,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、-NHCOMe、-NH CO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2–C1-4烷基取代;
R6为SO2NH2;-OPO(OH)2;-NH2;-NHCONH2;-NHCOCH3;-NHCSCH2CH3;-NHCS(CH2)2CH3;四唑;-SO2NH(CH2)2CH3;-NHC(NH)NH2;-NHCSNH2;-NHCSCH2OH;-三唑;-氧代咪唑(oxoimidazol);-SO2NHCH2CH2OH;-NHCONH-C1-6烷基;或-NHCONH-吡啶;其中
式IV为:
其中:R1选自表1中所列的基团;R2选自表2中所列的基团;R3选自表3中所列的基团;并且R4选自表4中所列的基团;
表1
式IV,R1选项
表2,
式IV,R2选项
表3,
式IV,R3选项
表4
式IV,R4选项
22.式III、式IV化合物或其前药、治疗活性代谢物、水合物、溶剂化物,或药学上可接受的盐,其中,
式III为:
其中,
R1为-CHCHR5;-CHCHCO2R5;-CHCHCONHR5;-苯基;-苯基-R5;-CCR5;-CC-CH2R5;-OR5;-SR5;或-NHR5;
R2为-C6H4-R6;-OC6H4-R6;-SC6H4-R6;-NHC6H4-R6;-OC1-6烷基-C6H4-R6;-NHC1-6烷基-C6H4-R6;哌嗪-R6;或吡啶-R6;
R3是H;-C1-6烷基,任选地用-OH、-NH2、苯基,或卤素取代;-CO-吡啶;--CO-CH2CH2NH2;或-CO-C1-6烷基,任选地用-OH或-NH2取代;
R4为H;-OCH3;-哌啶;-哌啶-CO NH2;-吡啶;-吡咯;-噻吩;-C1-6烷基,任选地用-OH取代;-吡啶;-哌啶;-吡咯;-噻吩;或-苯基,任选地用卤素或羟基取代;
或者,R3和R4一起形成尿嘧啶;
R5为卤素;-COOH;C1-6环烷基;-CH2C6H5;-CH2CH2C6H5;-CH2CH2C6H4-F;-CH2C6H4-COOH;-CH2C6H4-OH;-CH2呋喃;-Si(CH2)3;-CH2CO2 CH3;-CH2CO2(CH2)2CH3,或-CH2CO2 C6H4-Cl;或者
-C1-10烷基,任选地用卤素或-OH取代;或者
-C1-10环烷基,任选地用卤素或-OH取代;或者
-苯基,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、-NHCOMe、-NH CO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代;或者
-吡啶,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、-NHCOMe、-NH CO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代;或者
-吡咯,任选地用卤素、-OH,-CH3、-C1-10烷基、OCO-C1-4烷基、-NHCOMe、-NH CO(CH2)2CH3、-COOH、-OC1-10烷基、或-CO2-C1-4烷基取代;
R6为SO2NH2;-OPO(OH)2;-NH2;-NHCONH2;-NHCOCH3;-NHCSCH2CH3;-NHCS(CH2)2CH3;四唑;-SO2NH(CH2)2CH3;-NHC(NH)NH2;-NHCSNH2;-NHCSCH2OH;-三唑;-氧代咪唑(oxoimidazol);-SO2NHCH2CH2OH;-NHCONH-C1-6烷基;或-NHCONH-吡啶;其中
式IV为:
其中:R1选自表1中所列的基团;R2选自表2中所列的基团;R3选自表3中所列的基团;并且R4选自表4中所列的基团;
表1
式IV,R1选项
表2,
式IV,R2选项
表3,
式IV,R3选项
表4
式IV,R4选项
23.药用组合物,其包含权利要求22所述的化合物和药学上可接受的赋形剂。
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