CN108148097B - 含有吡啶的苯并咪唑类化合物钴配合物及其应用 - Google Patents
含有吡啶的苯并咪唑类化合物钴配合物及其应用 Download PDFInfo
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- CN108148097B CN108148097B CN201810186455.5A CN201810186455A CN108148097B CN 108148097 B CN108148097 B CN 108148097B CN 201810186455 A CN201810186455 A CN 201810186455A CN 108148097 B CN108148097 B CN 108148097B
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- alkoxy
- compound
- cobalt
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/06—Cobalt compounds
- C07F15/065—Cobalt compounds without a metal-carbon linkage
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及新型钴配合物——含有吡啶的苯并咪唑类化合物钴配合物,含有这些配合物的组合物,及其在制备抗肿瘤药物中的应用。本发明的化合物结构如下式(I)所示:其中,R选自H,C1‑C6烷氧基,卤代C1‑C6烷氧基,羟基,氨基,硝基,氰基;R1选自H,C1‑C6烷基,C1‑C6烷氧基,卤代C1‑C6烷氧基,羟基,氨基,硝基,氰基;R2选自H,取代或未取代的C1‑C6烷基、C1‑C6烷氧基;所述的取代基为C1‑C6烷氧基、卤代C1‑C6烷氧基;R3选自H,C1‑C6烷基,C1‑C6烷氧基。本发明的钴配合物及其组合物可以用于制备抗肿瘤药物。
Description
技术领域
本发明涉及新型钴配合物——含有吡啶的苯并咪唑类化合物钴配合物,含有这些配合物的组合物,及其在制备抗肿瘤药物中的应用。
背景技术
恶性肿瘤是世界公认的对人类健康危害最严重的疾病之一,其危害性仅次于心血管疾病。因此,加强肿瘤治疗的研究,提高现有各种治疗手段的效果,降低癌症死亡率,减少复发率,改善癌症患者的生活质量,具有重要的社会效益和巨大的经济效益。在肿瘤治疗中,化疗是当前肿瘤治疗的重要方法之一。在众多化疗药物中,铂族化合物是一类抗肿瘤作用较强、抗肿瘤谱较广的药物。自1967年Rosenberg等人发现顺铂(cisplatin)具有抗肿瘤活性以来,顺铂作为一种高效的抗肿瘤药物,被广泛地用于治疗多种癌症,例如睾丸癌、卵巢癌、子***、膀胱癌、肺癌以及头颈癌等(Wong E,Giandomenico CM.Current statusof platinum-based antitumor drugs.Chem Rev,1999,99(9):2451-2466.)。随后,一系列铂族化合物例如卡铂(carboplatin)、奈达铂(nedaplatin)、奥沙利铂(oxaliplatin)、乐铂(lobaplatin)、环铂(cycloplatin)作为抗肿瘤金属药物在临床上已成功使用(Abu-SurrahAS,Kettunen M.Platinum group antitumor chemistry:design and development ofnew anticancer drugs complementary to cisplatin.Curr Med Chem,2006,13(11):1337-57.),但由于铂族化合物的毒性与耐药性等问题,研发新型的过渡金属配合物抗肿瘤药物也越来越引起广泛关注。
与此同时,钴作为生物学必需的微量元素,存在于生物体内金属蛋白和金属酶的活性部位,在生物体内参与维持正常的生理机能,对造血***和中枢神经***的发育、骨骼和***的形成以及皮肤色素的沉积等过程具有重要作用,同时在生机体内氧化还原体系中有着独特的催化作用,对衰老和癌症及其相关联的内源性氧化剂所致DNA损伤发挥着关键作用(王飞利,常艳玲,安丽容等.非铂类金属抗癌化合物的研究进展.化学研究与应用,2003,15(5):612-616.),且钴的毒性比非必须微量元素如铂的毒性要小,因此钴金属配合物有望保持铂族化合物的抗肿瘤活性同时又具有低毒性的特点。
钴是普遍存在于所有动物体内的微量元素,主要以维生素B12的形式发挥着作用。钴在生物体内几个重要的生理过程中有着不可或缺的作用,例如,对于机体自身红细胞的形成,DNA的合成和调节及正常的脑神经功能的维持,维生素B12参与脂肪酸和氨基酸的代谢(Catherine R M,Kogularamanan S.Advances in cobalt complexes as anticanceragents.Dalton Trans,2015,44:13796–13808.)。钴作为人体内必须的微量元素且比非必需金属(如铂)对人体毒性更小,因此钴金属配合物有望保持铂族化合物的抗肿瘤活性同时又具有低毒性的特点。
本发明在合成一些含有吡啶基团的苯并咪唑类化合物基础上,以此为配体,合成出一系列含有吡啶基团的苯并咪唑类化合物钴配合物,这些配合物具有显著的抗肿瘤活性,有望成为新型抗癌治疗的候选药物。
发明内容
本发明所解决的技术问题是提供一种如式I所示的钴配合物、其前体药物和药物活性代谢物以及其药学上可接受的盐,并提供了其在制备抗肿瘤药物中的应用。
本发明的化合物结构如下式(I)所示:
其中,
R选自H,C1-C6烷氧基,卤代C1-C6烷氧基,羟基,氨基,硝基,氰基;
R1选自H,C1-C6烷基,C1-C6烷氧基,卤代C1-C6烷氧基,羟基,氨基,硝基,氰基;
R2选自H,取代或未取代的C1-C6烷基、C1-C6烷氧基;所述的取代基为C1-C6烷氧基、卤代C1-C6烷氧基;
R3选自H,C1-C6烷基,C1-C6烷氧基。
优选地,
R选自H,C1-C4烷氧基,卤代C1-C4烷氧基;
R1选自H,C1-C4烷基,C1-C4烷氧基;
R2选自H,取代或未取代的C1-C4烷基、C1-C4烷氧基,所述取代基为C1-C4烷氧基、卤代C1-C4烷氧基;
R3选自H,C1-C4烷基,C1-C4烷氧基。
进一步地,
R选自H,甲氧基,二氟甲氧基;
R1选自H,甲基,甲氧基;
R2选自H,甲基,甲氧基,2-甲氧基乙氧基,3-甲氧基丙氧基,2,2,2-三氟乙氧基;
R3选自H,甲基,甲氧基。
“药学上可接受的盐”指保留了式I化合物的生物效力和性质,并与合适的非毒性有机酸或无机酸或有机碱或无机碱形成的常规酸加成盐或碱加成盐。酸加成盐包括盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、磷酸盐、硫酸盐、高氯酸盐、硫氰酸盐、硫酸氢盐、过硫酸盐、硼酸盐、甲酸盐、乙酸盐、丙酸盐、戊酸盐、新戊酸盐、己酸盐、庚酸盐、辛酸盐、异辛酸盐、十一烷酸盐、月桂酸盐、棕榈酸盐、硬脂酸盐、油酸盐、环丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、己二酸盐、壬二酸盐、丙烯酸盐、草莓盐、巴豆酸盐、惕格酸盐、衣康酸盐、山梨酸盐、肉桂酸盐、乙醇酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、亚酒石酸盐、扁桃酸盐、二苯乙醇酸盐、托品酸盐、抗坏血酸盐、葡萄糖酸盐、葡庚糖酸盐、葡萄糖二酸盐、甘露糖酸盐、乳糖酸盐、苯甲酸盐、酞酸盐、对酞酸盐、糠酸盐、烟酸盐、异烟酸盐、水杨酸盐、乙酰水杨酸盐、酪酸盐、没食子酸盐、咖啡酸盐、阿魏酸盐、苦味酸盐、樟脑酸盐、樟脑磺酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、苯磺酸盐、对甲苯磺酸盐、对氨基苯磺酸盐、氨基磺酸盐、牛磺酸盐、2-羟基乙磺酸盐、甘氨酸盐、丙氨酸盐、缬氨酸盐、亮氨酸盐、异亮氨酸盐、苯丙氨酸盐、色氨酸盐、酪氨酸盐、天冬氨酸盐、天冬酰胺盐、谷氨酸盐、赖氨酸盐、谷氨酰胺盐、甲硫氨酸盐、丝氨酸盐、苏氨酸盐、半胱氨酸盐、脯氨酸盐、组氨酸盐、精氨酸盐、依地酸盐、丙酮酸盐、α-酮戊二酸盐、藻酸盐、环戊烷丙酸盐、3-苯基丙酸盐、3-环己基丙酸、2-萘甲酸盐、2-萘磺酸盐、双羟萘酸盐、月桂基硫酸盐、甘油磷酸盐、月桂基硫酸盐、果胶脂酸盐等。碱加成盐包括铵盐,碱金属盐,例如钠和钾盐,碱土金属盐,例如钙和镁盐,有机碱的盐,例如二环己胺盐,N-甲基-D-葡糖胺盐等,而且,碱性含氮基团可以用这样的试剂季铵化,例如低级烷基卤化物,如甲基,乙基,丙基和丁基的氯、溴和碘化物;硫酸二烷基酯,如硫酸二甲酯,二乙酯,二丁酯和二戊酯;长链卤化物,如癸基,月桂基,肉豆蔻基和硬脂酰基的氯、溴和碘化物;芳烷基卤化物,如苄基和苯乙基的溴化物等。优选用于生成酸加成盐的酸包括盐酸、对甲苯磺酸、甲磺酸、顺丁烯二酸、苹果酸、苦味酸、柠檬酸、对氨基苯磺酸。
“药学上可接受的”如药学上可接受地载体、赋形剂、前体药物等,指药理学上可接受的、并对给药具体化合物的患者基本上无毒性。
“药学活性代谢物”指药学上可接受并有效的式I化合物的代谢产物。
本发明也涉及其药用组合物,该组合物含有式I或其立体异构体或其药学上适用的酸加成盐以及药学上适用的载体。
化合物的某些晶体形式可以以多晶体形式存在,亦纳入本发明之内。另外,一些化合物可与水形成溶剂合物(即水合物)或普通有机溶剂形成溶剂合物,并且这样的溶剂合物也纳入本发明的范围之内。
本发明包括在其范围内的本发明化合物的前药。一般,这样的前药将是在体内易于转化为需要的化合物的、本化合物的官能性衍生物。因此,在本发明的治疗方法中,术语“给予”将包含用具体公开的化合物,或用没有具体公开但在给予患者后在其体内转化为指定化合物的化合物,治疗多种已描述的疾患。
如下反应流程概括了制备本发明化合物的制备步骤。
反应流程
本发明还涉及钴与含有吡啶的苯并咪唑类化合物的配合物作为抗肿瘤药物用肿瘤治疗。
使用的治疗方法和剂量
本文描述的待治疗的各种疾病和病症是本领域技术人员熟知的和清楚的。也应理解本领域技术人员可以用治疗有效量的化合物治疗目前正为疾病或病症而痛苦的患者,或者通过预防性的治疗为疾病或病症而痛苦的患者从而影响有关的疾病和病症。
本文使用的术语“患者”是指患有肿瘤的温血动物,例如哺乳动物。应理解豚鼠、狗、猫、大鼠、小鼠马、牛、羊和人是在本术语含义范围内的动物的实例。
这里使用的术语“治疗有效量”是指对控制与肿瘤有关的疾病和病症有效的量。术语“控制”是用来指所有可以减缓、中断、阻止或停止本文描述的疾病和病症的发展的过程,而未必是需要完全消除全部的疾病和病症的症状。
治疗有效量可以通过主治诊断医师作为本领域技术人员使用常规的技术和观察类似情况下得到的结果容易地确定。在确定治疗有效量的剂量过程中,主治诊断医师考虑许多因素,包括但不限于:哺乳动物的种类;其大小、年龄和大体的健康情况;涉及的具体疾病;疾病的程度或复杂情况或严重程度;个体患者的反应;给药的特定化合物;给药方式;给药的制剂的生物利用率特性;选择的配药方案;伴随的药物治疗的使用及其他相关的情况。
化合物的治疗有效量预计从大约0.001毫克每公斤体重每天(mg/kg/天)至大约100mg/kg/天不等。优选的量可以由本领域技术人员确定。
在有效治疗患有上述的疾病和病症的患者时,此类化合物可以以使化合物生物可利用的任何形式或方式按治疗有效量给药,包括口服、吸入和肠胃外的路径。例如,化合物可以通过口服、吸入气雾剂或干燥粉、皮下注射、肌内注射、静脉注射、透皮给药、鼻内给药、直肠给药、局部给药等等方式给药。口服或吸入给药通常优选用于治疗呼吸***疾病,例如哮喘。配制配方的本领域技术人员可以根据选择的化合物的具体特性,要治疗的疾病或病症的情况,疾病或病症的阶段及其他相关的情况容易地选择恰当的给药形式和方式。
本发明的化合物可以单独给药或与药学上可接受的载体或赋形剂结合以药物组合物的形式给药,载体或赋形剂的比例和性质由选择的化合物的溶解度和化学性质,选择的给药途径,和标准制药准则确定。本发明的化合物虽然本身是有效的,但可以以其药学上可接受的盐例如酸加成盐或碱加成盐的形式配制配方和给药,这是为了稳定、方便结晶、提高溶解度等等目的。
本发明提供了含有治疗有效量的化合物与一种或多种药学上可接受的载体或赋形剂混合或以其他方式结合的药物组合物。
药物组合物按药物领域众所周知的方法制备。可以作为活性成分的运载体或介质的载体或赋形剂可以是固体、半固体或液体原料。合适的载体或赋形剂是本领域众所周知的。可使药物组合物适于口服、吸入、肠胃外使用或局部使用,可以以片剂、胶囊、气雾剂、吸入剂、栓剂、溶液、悬浮液等等形式给患者用药。
本发明的化合物可以例如与一种惰性稀释剂或与一种可食用的载体口服给药.它们可以包在胶囊中或压成药片。为了口服治疗给药,化合物可以与赋形剂混合,并以片剂、锭剂、胶囊、酏剂、悬浮液、糖浆、糯米纸囊剂、咀嚼胶等等形式使用。这些制剂应该含有至少4%的本发明化合物,即活性成分,但是可以根据具体形式而变化,在单元重量的4%至大约70%之间方便地变化。存在于组合物的化合物的量应可以得到合适的剂量。本发明优选的组合物和制剂可以由本领域技术人员确定。
片剂、丸剂、胶囊、锭剂等等可以还含有一种或多种下列的助剂:粘合剂例如微晶纤维素、黄着树胶或明胶;赋形剂例如淀粉或乳糖,崩解剂例如海藻酸、Primogel、玉米淀粉等等;润滑剂例如硬脂酸镁或Sterotex;助流剂例如胶体二氧化硅;并可以加入甜味剂例如蔗糖或糖精或调味剂例如薄荷、水杨酸甲酯或橙子香料。当药剂单位形式是胶囊时,除了含有上述类型的原料之外,可以含有液体载体例如聚乙二醇或脂肪油。其它的药剂单位形式可以含有修饰药剂单位物理形式的其它的不同的原料,例如作为涂层。这样,片剂或丸剂可以涂有糖、片胶或其它的肠溶衣试剂.糖浆除了含有本化合物,可以含有蔗糖作为甜味剂和一定的防腐剂、染料和着色剂和食用香料。制备这些不同的组合物使用的材料应该是药学纯的和使用量下是无毒的。
为了肠胃外治疗给药,本发明的化合物可以加入到一种溶液或悬浮液中。这些制剂应该含有至少0.1%的本发明化合物,但是可以在制剂重量的0.1和大约50%之间改变。存在于这种组合物中的化合物的量应当可以得到合适的剂量。优选的组合物和制荆能够由本领域技术人员确定。
本发明的化合物也可以通过吸入,例如用气雾剂或干燥粉给药。可以用一种液化的或压缩的气体或用一种分配本发明化合物或其配方的合适的泵送***释放。通过吸入化合物给药的配方可以以单相、双相的或三相的***输送。对于用化合物的气雾剂给药,许多***是可用的。干粉配方是通过将化合物制粒或碾磨至合适的粒径制备的,或者是通过混合已制粒的或碾磨的化合物与合适的载体例如乳糖等等制备的。通过吸入的释放***包括必要的容器、活化剂、阀门、亚容器等等。优选的通过吸入给药的气雾剂和干粉配方能够由本领域技术人员确定。
本发明的化合物还可以局部给药,这样做时裁体适当地含有溶液、软膏或者凝胶基剂。基剂例如可以舍有一种或多种下列物质:矿脂、羊毛脂、聚乙二醇、蜂蜡、矿物油、例如水和醇的稀释剂,和乳化剂和稳定剂.局部配方含钙化合物或其药学上可接受的盐的浓度可以从约0.1到约10%w/v(重量每单位体积)。
该溶液或者悬浮液还可以含有一种或多种下列助剂:无菌稀释剂例如注射用水,盐水溶液,固定油类,聚乙二醇,甘油,丙二醇或者其它的合成溶剂;抗菌剂例如苄醇或者羟苯甲酸甲酯;抗氧化剂例如维生素C或者亚硫酸氢钠;鳌合剂例如乙二胺四乙酸;缓冲剂例如醋酸盐、柠檬酸盐或者磷酸盐和调节渗透压的试剂例如氯化钠或者葡萄糖。肠胃外制剂可以装在玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。
附图说明
图1为配合物ZZ-13的分子结构图;
图2为配合物ZZ-14的分子结构图。
具体实施方式
实施例1:二氯{2-[(4-甲氧基-3,5-甲基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴(ZZ-01)的制备
将CoCl2·6H2O(1.0mmol)溶解于10mL无水乙醇中,在室温条件下,向其中滴加2-[(3,5-二甲基-4-甲氧基-2-吡啶基)]甲硫基]-1H-苯并咪唑(1.0mmol)的10mL甲醇溶液,加热回流,TLC检测,反应4h完毕后,旋蒸除去溶剂,得亮蓝色固体即为二氯{2-[(4-甲氧基-3,5-甲基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴0.39g。产率86.0%。HRMS(m/z):426.973684([M-H]-);IR(KBr):υ3438.3,3154.1,2975.5,2928.9,1650.2,1631.5,1595.8,1478.1,1434.7,1412.1,1273.6,1221.4,1089.5,994.0,746.4。
实施例2:二氯{2-[(3,4-二甲氧基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴(ZZ-02)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率85.7%。HRMS(m/z):428.951775([M-H]-);IR(KBr):υ3433.3,2925.3,2169.5,1650.8,1631.6,1599.9,1496.7,1409.1,1308.3,1273.8,1069.1,1007.8,833.1。
实施例3:二氯{2-{[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴(ZZ-03)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率81.8%。HRMS(m/z):480.945169([M-H]-);IR(KBr):υ3374.0,3151.8,3092.6,2983.4,2916.7,2169.5,1630.8,1599.7,1485.3,1444.9,1418.4,1308.5,1262.1,1173.1,1106.2,1007.5,970.6,832.5,742.5。
实施例4:二氯{2-{[3-甲基-4-(3-甲氧基丙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴(ZZ-04)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率88.2%。HRMS(m/z):470.998721([M-H]-);IR(KBr):υ3430.6,3143.5,3106.6,2926.4,1650.5,1631.9,1599.1,1415.7,1302.0,1273.7,1093.6,1005.8,832.9,759.8。
实施例5:二氯{5-甲氧基-2-[(3,5-二甲基-4-甲氧基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴(ZZ-05)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率88.8%。HRMS(m/z):456.983130([M-H]-);IR(KBr):υ3435.8,3177.4,2948.2,2169.5,1632.4,1632.4,1596.2,1493.6,1477.1,1414.4,1273.3,1154.6,1089.0,1009.0,849.2,812.8,789.7。
实施例6:二氯{5-甲氧基-2-[(3,4-二甲氧基-2-吡啶基甲硫基-κN]-1H-苯并咪唑-κN3}合钴(ZZ-06)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率87.6%。HRMS(m/z):458.962015([M-H]-);IR(KBr):υ3413.8,3170.2,2934.6,2169.5,1632.6,1632.6,1599.1,1499.1,1457.6,1429.6,1310.7,1276.0,1160.8,1072.0,1011.0,1024.9,834.4。
实施例7:二氯{5-甲氧基-2-{[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴(ZZ-07)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率82.0%。HRMS(m/z):510.955244([M-H]-);IR(KBr):υ3443.5,2957.3,2169.5,1634.6,1599.5,1486.5,1454.6,1417.9,1263.3,1162.7,1113.3,1008.8,1030.9,978.6,833.1,848.9。
实施例8:二氯{5-甲氧基-2-{[3-甲基-4-(3-甲氧基丙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴(ZZ-08)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率89.0%。HRMS(m/z):501.008048([M-H]-);IR(KBr):υ3434.4,3185.3,2934.3,2169.6,1633.0,1597.4,485.7,1439.4,1410.2,1306.2,1274.2,1156.8,1091.4,1027.8,1009.6,832.0,703.1。
实施例9:二氯{5-二氟甲氧基-2-[(3,5-二甲基-4-甲氧基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴(ZZ-09)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率83.1%。HRMS(m/z):492.965050([M-H]-);IR(KBr):υ3430.9,2930.0,2169.5,1696.4,1631.4,1631.4,1598.1,1479.4,1407.9,1271.0,1169.6,1125.4,1106.5,1042.5,832.9。
实施例10:二氯{5-二氟甲氧基-2-[(3,4-二甲氧基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴(ZZ-10)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率80.6%。HRMS(m/z):494.943678([M-H]-);IR(KBr):υ3422.2,3084.2,2948.6,2604.8,2169.6,1855.7,1631.2,1601.5,1587.3,1499.5,1456.3,1407.0,1316.2,1172.0,1133.0,1071.9,1037.2,1005.1,931.0,838.9。
实施例11:二氯{5-二氟甲氧基-2-{[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴(ZZ-11)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率78.4%。HRMS(m/z):546.937144([M-H]-);IR(KBr):υ3425.3,2951.8,2169.5,1649.9,1631.5,1599.4,1482.6,1412.2,1412.2,1263.9,1171.7,1107.4,1039.2,972.3,833.3。
实施例12:二氯{5-二氟甲氧基-2-{[3-甲基-4-(3-甲氧基丙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴(ZZ-12)的制备
参考实施例1的制备方法,得到亮蓝色固体,产率78.4%。HRMS(m/z):459.957116([M-H]-);IR(KBr):υ3431.3,3182.8,2934.6,2169.6,1633.6,1598.0,1486.7,1460.3,1440.0,1412.0,1305.8,1175.01,1098.3,1037.9,835.2,648.9。
实施例13:二氯{2-{[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴水合物(ZZ-13)的制备
取5mg左右二氯{2-{[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴,完全溶解与5mL甲醇中,然后加入不同量的水,同时配出不同比例的甲醇与水混合溶液。其中甲醇作为良溶剂,水作为不良溶剂。将配好的不同比例的混合溶液分别置于之前用铬酸溶液浸洗干净并干燥,内壁光滑的不同个小锥形瓶中,瓶口用塑封膜封口后,扎上几个小口,便于瓶内溶剂缓慢挥发。将小锥形瓶置于安静,避光,平稳的地方静置培养,得到亮蓝色晶体。在高倍显微镜下,挑选规则透明的单晶颗粒,在Rigaku MSC X光晶体衍射仪上收集其晶体衍射数据,并用SHELXL及SHELXS程序解析出其晶体结构,其晶胞参数见表1,其晶体结构见图1。
表1.配合物ZZ-13的晶体结构参数
实施例14:二氯{5-甲氧基-2-[(3,4-二甲氧基-2-吡啶基甲硫基-κN]-1H-苯并咪唑-κN3}合钴甲醇溶剂化物(ZZ-14)的制备
参考实施例13的制备方法,得到二氯{5-甲氧基-2-[(3,4-二甲氧基-2-吡啶基甲硫基-κN]-1H-苯并咪唑-κN3}合钴亮蓝色晶体。在高倍显微镜下,挑选规则透明的单晶颗粒,在Rigaku MSC X光晶体衍射仪上收集其晶体衍射数据,并用SHELXL及SHELXS程序解析出其晶体结构,其晶胞参数见表2,其晶体结构见图2。
表2.配合物ZZ-14的晶体结构参数
实施例15:受试化合物对人肝癌细胞HepG2、人结肠癌细胞SW480及人正常肝细胞HL7702增殖的抑制活性
(1)实验材料
细胞株:HepG2人肝癌细胞,SW480人结肠癌细胞,HL7702人正常癌细胞;10%新生牛血清(FBS);96孔板,;Dulbecco氏改进的Eagle培养基(DMEM)。
受试化合物:L-01~L-16,C-01~C-16共32个化合物,,以DMSO溶解为50mM保存于-20℃待用,DMSO在培养液中的终浓度低于0.1%。
MTT实验:以PBS溶解为5mg/mL,保存于-20℃。
(2)实验方法
采用MTT法(Mosmann T.Rapid colorimetric assay for cellular growth andsurvival:application to proliferation and cytotoxicity assays.J ImmunolMethods.1983,65(1-2):55-63.)对受试化合物进行抗肿瘤活性测定。
取HepG2(肝癌)、SW480(人结肠癌)和HL7702(人正常肝细胞)在细胞Eagle培养基(DMEM)上进行培养。该培养基是Dulbecco氏改进的,包含10%小牛血清(FBS),SW480细胞株及HepG2细胞株。每个化合物给药终浓度为50uM及25uM,每个浓度3个平行孔。当细胞增殖至80~90%时使其合并随后进行不超过20代的传代培养,然后在下一步处置前使它们适应环境达到24h。将这些细胞置于96孔板上(8×104/mL),然后在含有5%CO2的湿润环境中培养过夜并控温在37℃。在37℃继续培养24h后,各孔分别加人MTT(5mg/ml)溶液,轻轻震荡培养板,放回培养箱内再孵育4h,然后吸尽上清液,于各孔中加DMSO100μL,置震荡器上震荡5~10min使MTT完全溶解,用酶标光度计(TECAN SPECTRA,Wetzlar,德国)测出每孔中波长为490nm的吸光值(OD值),以下列公式计算抑制率(见表3)。
抑制率=(1-药物组OD值/对照组OD值)×100%
实验采用顺铂为阳性对照药,顺铂对人肝癌细胞(HepG2)和人结肠癌细胞(SW480)增殖抑制的IC50分别为6.6±1.0μmol/L和15±2.7μmol/L。
实验结果表明,受试的钴配合物对人肝癌细胞HepG2的增殖均有不同的抑制作用,并呈现量效关系,仅有少数受试的钴配合物对人结肠癌细胞SW480的增殖有抑制作用,受试的部分钴配合物对人肝癌细胞HepG2的增殖抑制作用均强于对人结肠癌细胞SW480的增殖抑制作用,而受试的钴配合物对对人正常肝细胞HL7702的增殖几乎没有抑制作用。
表3.受试化合物对各种细胞增殖的抑制作用
药物组合物
实施例16:片剂配方
活性化合物25-1000mg,淀粉45mg,微晶纤维素35mg,聚乙烯吡咯烷酮(为10%水溶液)4mL,羧甲基纤维素钠4.5mg,硬脂酸镁0.5mg,滑石1mg。
实施例17:悬浮剂配方
活性化合物0.1-1000mg,羧甲基纤维素钠50mg,糖浆1.25mg,苯甲酸钠0.1mg,矫味剂适量,着色剂适量,加纯水至5mL。
实施例18:气溶胶配方
活性化合物0.25mg,乙醇25-75mL,抛射剂22(氯二氟甲烷)70mg。
实施例19:栓剂配方
活性化合物250mg,饱和脂肪酸甘油酯类2000mL。
实施例20:可注射制剂配方
活性化合物50mg,等渗盐溶液1000mL。
实施例21:软膏配方
微粉化活性化合物0.025g,液体石蜡10g,加软白蜡至100g。
实施例22:软膏配方
活性化合物0.025g,丙二醇5g,脱水山梨醇倍半油酸酯5g,液体石蜡10g,加软白蜡至100g。
实施例23:水包油霜剂配方
活性化合物0.025g,十六醇5g,单硬脂酸甘油酯5g,液体石蜡10g,Ce tomacrogol1 000 2g,柠檬酸0.1g,柠檬酸钠0.2g,丙二醇35g,加水至100g。
实施例24:水包油霜剂配方
微粉化活性化合物0.025g,软白蜡15g,液体石蜡5g,十六醇5g,Sorbimacrogolstearate 2g,脱水山梨醇单硬脂酸酯0.5g,山梨酸0.2g,柠檬酸0.1g,柠檬酸钠0.2g,加水至100g。
实施例25:油包水霜剂配方
活性化合物0.025g,软白蜡35g,液体石蜡5g,脱水山梨醉倍半油酸酯5g,山梨酸0.2g,柠檬酸0.1g,柠檬酸钠0.2g,加水至100g。
实施例26:洗剂配方
活性化合物0.25g,异丙醇0.5mL,羧基乙烯基聚合物3mg,NaOH适量,加水至1g。
实施例27:注射用悬浮液配方
活性化合物0.05-10mg,羧甲基纤维素钠7mg,NaCl 7mg,聚氧乙烯(20)脱水山梨醇单油酸酯0.5mg,苯甲醇8mg,加无菌水至1mL。
实施例28:用于口腔和鼻吸入的气雾剂配方
活性化合物0.1%w/w,脱水山梨醇三油酸酯0.7%w/w,三氯氟甲烷24.8%w/w,二氯四氟乙烷24.8%w/w,二氯二氟甲烷49.6%w/w。
实施例29:雾化溶液配方
活性化合物7mg,丙二醇5mg,加水至10g。
实施例30:用于吸入的粉剂配方
用下述成份的混合物填充明质胶囊,微粉化活性化合物0.1mg,乳糖20mg,借助于吸入装置吸入该粉末。
实施例31:用于吸入的粉剂配方
球化的粉剂装入多剂粉末吸入器,每剂含有微粉化活性化合物0.1mg。
实施例32:用于吸入的粉剂配方
将球化的粉剂装入多剂粉末吸入器,每剂含有微粉化活性化合物0.1mg,微粉化乳糖1mg。
实施例33:胶囊剂配方
活性化合物1.0小糖球321mg,Aquacoat ECD 30 6.6mg,乙酰柠檬酸三丁酯0.5mg,吐温-80 0.1mg,Eudragit L 100-55 17.5mg,柠檬酸三乙酯1.8mg,滑石粉8.8mg,消泡剂MMS 0.lmg。
实施例34:胶囊剂苗体配方
活性化合物2.0mg,小糖球305mg,Aquocoat ECD 30 5.0mg,乙酰柠檬三丁酯0.4mg,吐温-80 0.14mg,Eudragit NE30 D 12.6mg,Eudragit S 100 12.6mg,滑石粉0.l6mg。
实施例35:灌肠剂配方
活性化合物00.2mg,羧甲基纤维素钠25mg,乙二胺四乙酸二钠0.5mg,对羟基苯甲酸甲酯0.8mg,对羟基苯甲酸丙酯0.2mg,氯化钠7mg,柠檬酸1.8mg,吐温-80 0.01mg,加纯水至1mL。
实施例36:含有脂质体的配方配方
A.滴注配方的制备
在一玻璃管中混合合成的二棕榈酰基卵磷脂(45mg),二肉豆蔻酰基卵磷脂(7mg),二棕榈酰基磷脂酰甘油(1mg)和活性化合物(5mg),将所有组份溶解在氯仿中,用N2蒸发掉大部分溶剂,然后减压,由此,在玻璃管表面形成脂质薄膜.在该脂质中加入水溶液(0.9%NaCl),在高于脂质的转相温度下形成脂质体,所得悬液含有大小范围为极小囊泡至2μm的脂质体。
B.吸入用配方的制备
按实施例A制备脂质体,其中的水溶液含有10%乳糖,乳糖与脂质之比为7:3。将该脂质体悬液用干冰冷冻,并且进行冷冻干燥,将干燥产物微粉化,所得颗粒的质均空气动力学直径(MMAD)约为2μm。
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其他形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
Claims (19)
2.权利要求1所述的化合物,其药学上可接受的盐,其中,
R选自H,C1-C4烷氧基,卤代C1-C4烷氧基。
3.权利要求1所述的化合物,其药学上可接受的盐,其中,
R选自H,甲氧基,二氟甲氧基。
4.权利要求1-3任何一项所述的化合物,其药学上可接受的盐,其中,
R1选自H,C1-C4烷基,C1-C4烷氧基。
5.权利要求1-3任何一项所述的化合物,其药学上可接受的盐,其中,
R1选自H,甲基,甲氧基。
6.权利要求1-3任何一项所述的化合物,其药学上可接受的盐,其中,
R2选自H,取代或未取代的C1-C4烷基、C1-C4烷氧基,所述取代基为C1-C4烷氧基、卤代C1-C4烷氧基。
7.权利要求1-3任何一项所述的化合物,其药学上可接受的盐,其中,
R2为H,甲基,甲氧基,2-甲氧基乙氧基,3-甲氧基丙氧基,2,2,2-三氟乙氧基。
8.权利要求4所述的化合物,其药学上可接受的盐,其中,
R2选自H,取代或未取代的C1-C4烷基、C1-C4烷氧基,所述取代基为C1-C4烷氧基、卤代C1-C4烷氧基。
9.权利要求5所述的化合物,其药学上可接受的盐,其中,
R2选自H,取代或未取代的C1-C4烷基、C1-C4烷氧基,所述取代基为C1-C4烷氧基、卤代C1-C4烷氧基。
10.权利要求1、2、3、8或9任何一项所述的化合物,其药学上可接受的盐,其中,
R3选自H,C1-C4烷基,C1-C4烷氧基。
11.权利要求4所述的化合物,其药学上可接受的盐,其中,
R3选自H,C1-C4烷基,C1-C4烷氧基。
12.权利要求5所述的化合物,其药学上可接受的盐,其中,
R3选自H,C1-C4烷基,C1-C4烷氧基。
13.权利要求6所述的化合物,其药学上可接受的盐,其中,
R3选自H,C1-C4烷基,C1-C4烷氧基。
14.权利要求7所述的化合物,其药学上可接受的盐,其中,
R3选自H,C1-C4烷基,C1-C4烷氧基。
15.权利要求1所述的化合物,其药学上可接受的盐,选自:
二氯{2-[(4-甲氧基-3,5-甲基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴;
二氯{2-[(3,4-二甲氧基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴;
二氯{2-{[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴;
二氯{2-{[3-甲基-4-(3-甲氧基丙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴;
二氯{5-甲氧基-2-[(3,5-二甲基-4-甲氧基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴;
二氯{5-甲氧基-2-[(3,4-二甲氧基-2-吡啶基甲硫基-κN]-1H-苯并咪唑-κN3}合钴;
二氯{5-甲氧基-2-{[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴;
二氯{5-甲氧基-2-{[3-甲基-4-(3-甲氧基丙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴;
二氯{5-二氟甲氧基-2-[(3,5-二甲基-4-甲氧基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴;
二氯{5-二氟甲氧基-2-[(3,4-二甲氧基-2-吡啶基)甲硫基-κN]-1H-苯并咪唑-κN3}合钴;
二氯{5-二氟甲氧基-2-{[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴;
二氯{5-二氟甲氧基-2-{[3-甲基-4-(3-甲氧基丙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴;
二氯{2-{[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲硫基-κN}-1H-苯并咪唑-κN3}合钴水合物;
二氯{5-甲氧基-2-[(3,4-二甲氧基-2-吡啶基甲硫基-κN]-1H-苯并咪唑-κN3}合钴甲醇溶剂化物。
16.一种药物组合物,包括作为活性成分的权利要求1-15中任何一项的化合物及其药学上可接受的盐和药学上可接受的载体或赋形剂。
18.权利要求1-15任何一项所述的化合物、其药学上可接受的盐或权利要求16所述的药物组合物在制备***药物中的应用。
19.根据权利要求18所述的应用,其特征在于:所述的肿瘤为肝癌、结肠癌或直肠癌。
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