CN105037305B - 5‑羟基‑2’‑硝基橙酮或5‑羟基‑4’‑硝基橙酮衍生物及其应用 - Google Patents
5‑羟基‑2’‑硝基橙酮或5‑羟基‑4’‑硝基橙酮衍生物及其应用 Download PDFInfo
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- CN105037305B CN105037305B CN201510062046.0A CN201510062046A CN105037305B CN 105037305 B CN105037305 B CN 105037305B CN 201510062046 A CN201510062046 A CN 201510062046A CN 105037305 B CN105037305 B CN 105037305B
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- Prior art keywords
- nitro
- hydroxy
- pharmaceutically acceptable
- compound
- aurone
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类5‑羟基‑2’‑硝基橙酮或5‑羟基‑4’‑硝基橙酮衍生物及其应用，该衍生物为式(I)所示的化合物、异构体或其药学上可接受的盐。本发明化合物对内皮细胞和肿瘤细胞A549、Bel‑74021和MCF‑7具有优异的抑制活性，对肿瘤细胞A549迁移能力和侵袭能力具有较佳的抑制作用。
Description
技术领域
本发明属于药物化学领域，具体涉及5-羟基-2’-硝基橙酮和5-羟基-4’-硝基橙酮衍生物、立体异构体、顺反异构体、或其药学上可接受的盐的制备和药学上的应用。这些化合物具有抑制血管生成作用、杀伤癌细胞或抑制癌细胞增殖等作用，所以这些化合物可以用来治疗和预防肿瘤、类风湿性关节炎、糖尿病和肥胖症及其它代谢性疾病、心血管病变、生殖系统疾病，免疫性疾病、炎症、包括老年痴呆症和Parkinson症及其它神经障碍类疾病。
背景技术
许多植物包括大米、麦子以及许多中药材中存在大量橙酮类化合物，这些化合物除了可能对于保证营养物质发挥作用外也具有一定预防和治疗疾病的效果。
肿瘤细胞增殖是肿瘤消耗机体营养的关键，使用杀伤癌细胞的药物或者抑制癌细胞增殖的药物均是控制肿瘤生长的有效手段。血管生成是肿瘤恶化的关键步骤，因此抑制血管生成可能预防肿瘤发生以及抑制肿瘤生长，所以血管生成作用的抑制剂是现代抗肿瘤药物的重要成员。由于类风湿性关节炎的恶化过程中血管生成同样起着重要作用，因此血管生成作用的抑制剂可以是治疗类风湿性关节炎的药物。但是现有的抑制肿瘤细胞生长或抑制血管新生的药物多数具有单一性作用，即不能同时具有既能抑制肿瘤细胞增殖又能抑制血管新生作用。
发明内容
本发明的目的是在现有技术的基础上，提供一类具有相应活性的5-羟基-2’-硝基橙酮和5-羟基-4’-硝基橙酮衍生物、立体异构体、顺反异构体、或其药学上可接受的盐。
本发明的另一个目的是提供一种上述化合物在制药方面的用途。
本发明的目的可以通过以下措施达到：
式(I)所示的化合物、异构体或其药学上可接受的盐，
其中，
R1、R2、R3、R4、R5、R6或R7分别独立地选自氢、羟基、巯基、卤素、氰基、硝基、三氟甲基、C1～6烷基、C1～6卤代烷基、C1～6酰基、C1～6羧酸基、C1～6酰胺基、取代或非取代的C3～6环烷基、取代或非取代的C1～6烷氧基、取代或非取代的C1～6烷硫基、取代或非取代的C2～6羧酸酯、取代或非取代的氨基、取代或非取代的磺酰基、取代或非取代的C2～6烯烃基、取代或非取代的C3～6环烯烃基、取代或非取代的C3～6杂环基、取代或非取代的芳香基、取代或非取代的芳香烷基；所述取代基选自羟基、巯基、卤素、氰基、硝基、三氟甲基、C1～6烷基、C1～6卤代烷基、C1～6烷氧基、C1～6烷硫基或C2～6烯烃基；
或者R1～R3或R4～R7中相邻的两个基团与所在的环状基团共同构成萘、蒽、菲、喹啉、异喹啉、苯并吡喃、苯并吡喃酮、苯并呋喃、苯并噻吩、吲哚、嘌呤或喋啶基团。
本发明中的R1～R7是指R1、R2、R3、R4、R5、R6和R7。R1～R3和R4～R7也具有相似含义。
本发明中的R1、R2、R3、R4、R5、R6、R7可以在相应苯环的任意空位上。
本发明中式(I)苯环上的硝基可以在苯环的任意空位上，一种优选方案是硝基在邻位或对位，即硝基在2’-位或4’-位。
在一种优选方案中，R1～R3分别独立地选自氢或C1～3烷基，R4～R7分别独立地选自氢、羟基、卤素、硝基或C1～3烷基。
在另一种优选方案中，R1～R3分别独立地选自氢；R4～R7分别独立地选自氢、羟基或硝基。
在一种优选方案中，本发明的化合物、异构体或其药学上可接受的盐中化合物可选自下式化合物：
本发明公开了一种药物组合物，其以本发明所述的化合物、异构体或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的载体组成。
制备方法
各种取代的呋喃酮在冰醋酸中在浓盐酸催化下与相应的取代醛反应得到相应的橙酮化合物(I)。
定义
构成本发明的一部分是药学上可接受的溶剂化物，可以使结晶水合物或者是与其它溶剂结晶物，如乙醇等。
构成本发明的一部分是药学上可接受的盐：
如果本发明化合物为碱性的，则适当的“药学上可接受的盐”包括本发明化合物和无机酸或有机酸反应形成的本发明化合物的常规无毒盐。例如，包括得自无机酸例如盐酸、氢溴酸、硫酸、磷酸、硝酸等的盐，也包括得自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等的盐。
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”是指本发明化合物通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在和合成的取代胺、环状胺及碱性离子交换树脂。例如精氨酸、甜菜碱、咖啡因、胆碱、二乙胺、2－二乙基氨基乙醇、2－二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N－乙基吗啉、N－乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
本发明所述化合物可具有不对称中心、手性轴及手性面，且存在的外消旋物、外消旋物混合物及单一非对映体和所有可能的同分异构体及其混合物包括旋光异构体均包括在本发明内。另外，本发明公开的化合物可以互变异构体存在，且两种互变异构形式都包括在本发明的范围内，即使仅描述了其中一种互变异构结构。例如，任何要求保护的下列化合物A都理解为包括互变异构结构B，且反之亦然，同样包括其混合物。
本发明存在双键顺反异构体时，以单一异构体存在，或者是顺式异构体和反式异构体的混合物，即使仅描述了其中一种异构结构。
本发明所用术语“烃基”意指包括C1-C18烷基、C2-C18烯基、C2-C18炔基、芳基、芳烷基、杂芳基、杂芳烷基、杂环基、杂环烷基。自取代基划入环系统的线表示所指的键可连接到任何能取代的环的原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。
术语“任意取代”要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和方法自可以获得的原料可以合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。
本发明所用术语“烷基”意指包括具有特定碳原子数目的支链的、直链的或环状的饱和脂肪烃基。“C1-C18烷基”中“C1-C18”的定义包括以直链或支链排列的具有1、2、3、4、5、6、7、8～18个碳原子主链的基团。例如，“C1-C18烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。
术语“烯基”指直链、支链或环状的，主链含有12～18个碳原子及至少一个碳-碳双键的非芳香烃基。因此，“C12-C18烯基”指主链具有12～18个碳原子的烯基。烯基包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基等。烯基的直链、支链或环状部分可含有双键且如果指明了取代的烯基则此部分可被取代。
术语“炔基”指直链、支链或环状的，主链含有12～18个碳原子及至少一个碳碳三键的非芳香烃基。因此，“C12-C18炔基”指具有12～18个碳原子的炔基。炔基包括乙炔基、丙炔基、丁炔基、3-甲基丁炔基等。炔基的直链、支链或环状部分可含有三键且如果指明了取代的炔基则此部分可被取代。
术语“芳基”是指环中多达3-10个原子的任何稳定的单环或每个环中多达3-10个原子双环碳环，其中至少一个环为芳香环。芳基的实例包括苯基、萘基、蒽基及联苯基。
术语“芳烷基”包括其中上述“烷基”被上述“芳基”取代的基团。芳烷基的实例包括苄基、苯乙基、萘基亚甲基、蒽基亚甲基。
术语“杂芳基”代表环中多达3-10个原子的稳定的单环或每个环中多达3-10个原子双环碳环，其中至少一个环为芳香环且含有1-4个选自O、N和S的杂原子。本定义范围内的杂芳基包括但不限于吖啶基、咔唑基、噌啉基、喹噁啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基。
术语“杂芳烷基”包括其中上述“烷基”被上述“杂芳基”取代的基团。杂芳基的实例包括呋喃亚甲基、吡啶乙基、吡咯亚甲基。
术语“杂环基”是指含有1-4个选自O、N和S等杂原子的3-12元芳香性或非芳香性杂环，且包括双环基团。“杂环基”因此包括上面提及的杂芳基，也包括其二氢化及四氢化类似物。“杂环基”进一步的实例包括但不限于苯并咪唑基、苯并呋喃基、苯并吡喃基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并噁唑基、咔唑基、咔啉基、噌啉基、呋喃基、咪唑基、二氢吲哚基、吲哚基，吲唑基、异苯并呋喃基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、噁二唑基、噁唑基、噁唑啉、异噁唑啉、氧杂环丁烷基(oxetanyl)、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶并吡啶基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹噁啉基、四氢吡喃基、四唑基、四唑并吡啶基、噻二唑基、噻唑基、噻吩基、三唑基、氮杂环丁烷基、l,4－二噁烷基、氮杂环庚烷基(hexallydroazepinyl)、哌嗪基、哌啶基、吡啶－2－酮基、吡咯烷基、吗啉基、硫代吗啉基(thiomorpholinyl)、二氢苯并咪唑基、二氢苯并呋喃基、二氢苯并噻吩基、二氢苯并噁唑基、二氢呋喃基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、亚甲基二氧基苯甲酰基、四氢呋喃基和四氢噻吩基及其N-氧化物。杂环取代基的连接可通过碳原子或通过杂原子实现。
术语“环状”表明环中含有3多个碳或者其它原子的环状化合物。
术语“多环”包括其中形成至少2个环的结构，这些环之中至少有两个环之间有1个共同原子的螺环或至少2个共同的原子的并(合)环或桥(跨)环结构。典型的结构如金刚烷、降冰片、降冰片烯、蒎烷、(异)樟烷、蒈烷等的基本结构。这些环上可以含有或不含取代基的结构，这些多环结构可以杂多环。
术语“杂环基”包括其中上述“烷基”被上述“杂环基”取代的基团。杂环基实例包括咪唑亚甲基、吡咯烷乙基、四唑亚甲基。
术语“卤素”意指包括氟、氯、溴和碘。
术语“单独”是指独立应用的变量在应用于应用之间独立变化。
本发明所述穿心莲内酯衍生物可以被配制为药用组合物，按照多种合适选择的给予方式给患者用药，这些途径包括全身例如口服或胃肠外，通过静脉内、肌肉、透皮或皮下等。
优选的穿心莲内酯衍生物的给药方式是口服，但需根据化合物的具体物理和化学特点和稳定性的不同，以及治疗目的的差异决定使用的用药剂型和给药方式，包括但不限于缓释可控的用药方式。
本发明的另一需要解决的技术问题是提供上述5-羟基-2’-硝基橙酮和5-羟基-4’-硝基橙酮衍生物、立体异构体、顺反异构体、或其药学上可接受的盐在医药中的应用。
本发明的5-羟基-2’-硝基橙酮和5-羟基-4’-硝基橙酮衍生物、异构体或其盐可应用于预防和治疗血管新生相关的疾病，如肿瘤、类风湿性关节炎等。
本发明的5-羟基-2’-硝基橙酮和5-羟基-4’-硝基橙酮衍生物、异构体或其盐可应用于直接杀伤癌细胞或抑制癌细胞增殖从而预防和治疗肿瘤。
本发明的化合物、异构体或其药学上可接受的盐可应用于制备治疗或预防疾病药物，其中所述疾病选自肿瘤、胆固醇或血脂代谢异常、糖尿病、肥胖症、心血管病变、生殖系统疾病，免疫性疾病、炎症、老年痴呆症、Parkinson症或神经障碍类疾病。
本发明提供的化合物可以具有一定的抗肿瘤细胞增殖活性同时具有抑制内皮细胞增殖活性，可能具有较广泛用途。本发明中以非小细胞肺癌细胞株A549、该癌细胞珠Bel-7402和乳腺癌细胞株MCF-7为模型，测试了本申请化合物对癌细胞的杀伤作用或抑制癌细胞增殖效果，结果显示本发明化合物对内皮细胞(HUVEC)和肿瘤细胞A549、Bel-74021和MCF-7具有优异的抑制活性，对肿瘤细胞A549迁移能力和侵袭能力具有较佳的抑制作用。
附图说明
图1是本发明化合物(式II)对肿瘤细胞A549迁移能力抑制效果图(左侧)和侵袭能力抑制效果图(右侧)。
具体实施方式
实施例1：制备例
取1.0mmol的5-羟基呋喃酮与1.2mmol相应的醛在10ml冰醋酸中和4滴浓盐酸催化下，在室温搅拌3-10小时，TLC跟踪反应进程。反应结束后将反应混合物倒入冰水中，析出的固体水洗后重结晶得到目标产物。
化合物II-V的1H NMR数据和熔点
化合物II
熔点：﹥250℃。1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.35-8.28(m,2H),8.24-8.16(m,2H),7.41(d,J＝8.9Hz,1H),7.25(dd,J＝8.8,2.7Hz,1H),7.05(d,J＝2.8Hz,1H),7.00(s,1H).
化合物III
熔点：207.3-208.8℃。1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.23(dd,J＝7.8,1.4Hz,1H),8.13(dd,J＝8.2,1.3Hz,1H),7.92-7.82(m,1H),7.69(ddd,J＝8.7,7.4,1.4Hz,1H),7.36(d,J＝8.8Hz,1H),7.24(dd,J＝8.8,2.7Hz,1H),7.09(s,1H),7.05(d,J＝2.8Hz,1H).
化合物IV
熔点：﹥250℃。1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.83(d,J＝2.4Hz,1H),8.64(dd,J＝8.6,2.3Hz,1H),8.45(d,J＝8.8Hz,1H),7.35(d,J＝8.9Hz,1H),7.25(dd,J＝8.8,2.7Hz,1H),7.12(s,1H),7.06(d,J＝2.6Hz,1H).
化合物V
熔点：240.1-243.3℃。1H NMR(400MHz,DMSO-d6)δ9.93(d,J＝26.7Hz,1H),7.98(d,J＝8.7Hz,1H),7.73(d,J＝1.8Hz,1H),7.52(dd,J＝8.7,1.8Hz,1H),7.38(d,J＝8.8Hz,1H),7.25(dd,J＝8.8,2.7Hz,1H),7.05(t,J＝2.6Hz,1H),6.85(s,1H).
实施例2：化合物II-V对内皮细胞(HUVEC)和肿瘤细胞A549、Bel-74021和MCF-7的抑制活性
在96孔板中，按1000个HUVEC/孔、1500个MCF-7或BEL-7402/孔、2000个A549/孔接种在190μL培养基中，培养24小时后，加入10μL空白或不同药物浓度的测试药物，每个浓度有3组平行空，培养72小时后细胞用MTT试剂处理，然后测定OD600，计算IC50。
实施例3：
细胞迁移实验使用普通的Transwell膜(8μm pore)，细胞侵袭试验是用Matrigel(60μL x 250μg)包被的Transwell膜(8μm pore)。A549细胞首先在无血清状态下饥饿24小时，然后以2万个A549细胞(200μL)/孔接种在Transwell中，Transwell再放入含有600μL培养基(添加10％FBS)中的24孔板槽中，在A549细胞中加入0.08μM的化合物II，继续培养24小时。除去留在Transwell上层的细胞后Transwell先用甲醇固定，再用结晶紫染色，在放大200倍的显微镜下计算10个以上区域的细胞数，计算迁移率。
化合物II对肿瘤细胞A549迁移能力和侵袭能力的抑制作用结果见图1。
Claims (6)
1.式(I)所示的化合物或其药学上可接受的盐，
其中，R4选自氢、羟基或硝基；式(I)苯环上的硝基在邻位或对位。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其中化合物选自：
3.一种药物组合物，其特征在于其以权利要求1或2所述的化合物或其药学上可接受的盐为活性成分，辅以药学上可接受的载体组成。
4.一种药物组合物，其特征在于其以权利要求1或2所述的化合物或其药学上可接受的盐为主要活性成分，辅以药学上可接受的载体。
5.权利要求1或2所述的化合物或其药学上可接受的盐在制备用于预防或治疗血管新生相关疾病药物方面的用途。
6.权利要求1或2所述的化合物或其药学上可接受的盐在制备治疗或预防疾病药物中的应用，其中所述疾病选自肿瘤。
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| US20050288519A1 (en) * | 2002-08-19 | 2005-12-29 | Wolfgang Magerlein | 5-Nitrobenzofurans |
| CN101570524A (zh) * | 2009-06-16 | 2009-11-04 | 南京工业大学 | 取代的穿心莲内酯衍生物及其制备方法和用途 |
| CN102603685A (zh) * | 2011-01-19 | 2012-07-25 | 中国药科大学 | 类黄酮脂肪酸酯衍生物、其制备方法和医药用途 |
| CN102964322A (zh) * | 2012-12-12 | 2013-03-13 | 中国药科大学 | 异黄酮或类黄酮脂肪醚类衍生物、其制备方法和医药用途 |
| CN103864734A (zh) * | 2012-12-07 | 2014-06-18 | 天津科技大学 | 一种新颖的4,6-二羟基-3(2h)-苯并呋喃酮类衍生物的合成及应用 |
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| US20050288519A1 (en) * | 2002-08-19 | 2005-12-29 | Wolfgang Magerlein | 5-Nitrobenzofurans |
| CN101570524A (zh) * | 2009-06-16 | 2009-11-04 | 南京工业大学 | 取代的穿心莲内酯衍生物及其制备方法和用途 |
| CN102603685A (zh) * | 2011-01-19 | 2012-07-25 | 中国药科大学 | 类黄酮脂肪酸酯衍生物、其制备方法和医药用途 |
| CN103864734A (zh) * | 2012-12-07 | 2014-06-18 | 天津科技大学 | 一种新颖的4,6-二羟基-3(2h)-苯并呋喃酮类衍生物的合成及应用 |
| CN102964322A (zh) * | 2012-12-12 | 2013-03-13 | 中国药科大学 | 异黄酮或类黄酮脂肪醚类衍生物、其制备方法和医药用途 |
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