CN1532198A - 季白屈菜碱衍生物 - Google Patents
季白屈菜碱衍生物 Download PDFInfo
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- CN1532198A CN1532198A CNA031373550A CN03137355A CN1532198A CN 1532198 A CN1532198 A CN 1532198A CN A031373550 A CNA031373550 A CN A031373550A CN 03137355 A CN03137355 A CN 03137355A CN 1532198 A CN1532198 A CN 1532198A
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- alkaloid
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- water
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Abstract
本发明涉及在工艺处理中可获得的生物碱反应产物,其中生物碱与烷基化剂进行反应,优选噻替派,此后通过用水或适当的水性溶剂进行洗涤以从反应混合物中除去未反应的烷基化剂和其它水溶性化合物,此后用强酸对反应混合物进行处理,优选盐酸(HCl),以沉淀反应产物中的水溶性盐。该沉淀的反应产物包括至少一种季生物碱衍生物并且适用于作为预防或治疗应用的药物,特别是用于治疗免疫或代谢功能障碍、以及癌症。
Description
本发明所属技术领域
本发明属于药物开发和卫生保健领域并涉及生物碱白屈菜碱及其衍生物,其中白屈菜碱分子中的氮是季氮。本发明进一步涉及制备这类化合物的方法、含有这类化合物的组合物、及其在治疗各种疾病和身体不适中的应用。
背景技术
生物碱白屈菜碱和含有白屈菜碱的组合物在本技术领域是熟知的,如白屈菜碱或某些白屈菜碱衍生物在治疗各种身体不适和疾病中的治疗应用,包括代谢功能障碍和肿瘤。
DE2028330和US3865830披露了噻替派-异喹啉加合物的制备,即通过将罂栗科植物白屈菜(Chelidonium majus L.)中选择的生物碱与三(1-吖丙啶基)硫化膦在有机溶剂中反应来制备。
AT354644和AT377988描述了通过与抑癌剂磷化合物反应来制备生物碱磷衍生物的方法,该抑癌剂磷化合物是通过转化成它们的盐以水溶性形式加以提供。该披露方法的缺点是,反应产物向水溶性盐的转化是不完全的并且反应产物的主要部分仍然是非水溶性的。
US5981512披露了应用披露于AT377988和AT354644中的物质来治疗辐照损伤。
在所述专利中描述的化合物具有不同的细胞生长抑制和抑癌活性。生物碱的混合物,特别是罂栗科植物白屈菜的全部生物碱的混合物,已证明在治疗上特别有前景,其药理活性在对癌症治疗的一些研究中已得到证明。在反应完成后,从合成混合物中除去未反应的试剂。因为三(1-吖丙啶基)硫化膦(在下文也称作“噻替派”)可溶于有机溶剂,如苯、乙醚或氯仿,因而在前述的方法提出,通过用乙醚洗涤反应产物以从合成混合物中除去未反应的三(1-吖丙啶基)硫化膦。
前述的制备有药理活性白屈菜碱衍生物的方法,一般都需要用易燃或甚至爆炸性有机溶剂来提纯最终产物,然而现在发现用水性溶剂也可以,甚至可更好地完成该提纯过程。
发明简述
在一个方面,本发明涉及用适当的烷基化剂来制备生物碱的反应产物,特别是白屈菜碱、氧化白屈菜碱或甲氧基白屈菜碱的反应产物的新方法,在完成烷基化反应后,该方法涉及至少一个用水性溶剂的洗涤步骤,优选用水。
该方法还包括将生物碱衍生物转化成水溶性盐的步骤,以制成具有低毒性和广谱治疗活性的可注射药物制剂。
在另一个方面,本发明涉及水溶性反应产物,例如,包括白屈菜碱衍生物,其中在生物碱分子中起初的叔氮已转化为季氮,并且其中季氮的第四配体是低级烷基,优选甲基或乙基或取代的甲基或乙基,如硫化三磷残基(thiotepa residue)。在优选具体实施例中,该季白屈菜碱衍生物具有某种特性以致于选择性地蓄积在靶组织中,特别是在癌性组织中。
在另一个方面,本发明涉及药物组合物,其含有至少一种季生物碱,特别是季白屈菜碱,根据本发明的方法可获得这种衍生物。
本发明进一步涉及包含季生物碱衍生物的反应产物作为治疗药物的应用,以及所述衍生物来制造治疗各种疾病或身体不适的药物组合物的应用。
附图简要说明
图1所示为高效液相色谱(HPLC)图,表现罂栗科植物白屈菜根部的特征性的全部生物碱组成。
图2所示为根据实施例1的制剂的HPLC指纹图谱。
图3所示为选择的适用于作为试剂的磷衍生物。
图4所示为反应产物U-KRS的核磁共振谱。
图5所示为反应产物U-KRS的紫外光谱。
图6所示为白屈菜碱氢氯化物(chelidonine hydrochloride)的紫外光谱。
图7所示为反应产物U-KRS的质谱的第一部分。
图8所示为在更高的分辨率下反应产物U-KRS的质谱的第二部分。
图9所示为白屈菜碱氢氯化物(Chelidonin hydrochloride)的质谱。
发明详述
根据本发明的方法包括在有机溶剂中生物碱或生物碱的混合物与烷基化剂进行反应,优选用自身具有治疗活性烷基化剂,如含有至少一个氮丙啶基的细胞毒素磷酰胺或磷酸衍生物,然后用水洗涤反应产物。该用水或等效水性溶剂(例如弱盐溶液)进行的洗涤步骤尤其促进其后的不良水溶性或水不溶性反应产物(即季生物碱衍生物)向水溶性化合物(例如盐)的转化步骤。优选地,假如烷基化剂是细胞毒素物质,它也是水溶性的或至少与水接触后分解成水溶性成分,从而通过用水进行的洗涤步骤从反应混合物中基本除去未反应的烷基化剂或其部分。
用水进行的洗涤步骤会相当程度上简化制备过程,因为不再需要采取复杂的安全预防措施(其是由于纯有机溶剂如二甲醚的爆炸危险),从而使得该过程容易扩大进行。而且,在反应混合物中存在的不理想的水溶性成分可由此与反应产物分离开并除去。意想不到的是,还发现该洗涤步骤以某种方式对反应产物的结构和组成具有正影响,以致其后产物变为水溶性形式的转化步骤的效率与用纯有机溶剂进行洗涤的过程相比增加达10至15倍,因而显著提高所希望的最终产物的产率。
本方法可用于,例如,生物碱与含描述于AT377988的权利要求1中化合物的抑癌磷的烷基化反应,示于本应用图3中的磷化合物特别适合,而具有氮丙啶基的磷化合物最适合。
如在本文所使用的术语白屈菜碱也同样适用于选自由白屈菜碱、氧化白屈菜碱、以及甲氧基白屈菜碱组成的组的任一成员,除非另有说明或可从描述中绝对地推论出来。
根据本发明,适当的有机溶剂为任何试剂,在其中供反应用的生物碱是可溶的。例如,该生物碱可以溶解于促进或有助于烷基化反应的有机溶剂,这样的有机溶剂选自由一氯甲烷、二氯甲烷、三氯甲烷、一氯乙烷、二氯乙烷、和三氯乙烷组成的组。
生物碱的烷基化反应在升高的温度下进行,优选在溶剂的沸点。
在用水洗涤之后,生成的反应产物被转化成水溶性形式。这可以根据在AT377988和AT354644中描述的方法进行,即通过转化为水溶性盐,特别是转化为氢氯化物,例如借助于通过液体或气体形式(如HCl气体)的强酸,或把HCl溶液加入经洗涤的反应产物的有机溶液,在其期间或之后氢氯化物则沉淀下来。通过这种酸性处理大多数烷基化剂似乎可以从中间反应化合物(在生物碱和烷基化剂之间形成)分离出来,留下改性的生物碱衍生物,其中起初的叔氮原子已转化为季氮,其中氢基(hydrogen residue)或来自烷基化剂的残基结合于季氮作为第四配体,优选地,该残基选自由甲基、乙基、和三(1-吖丙啶基)硫化膦残基组成的组,或选自部分三(1-吖丙啶基)硫化膦。为获得更好的理解,以下化学式(I)说明本发明的典型的季生物碱反应产物,以白屈菜碱作为例子加以说明:
R1=甲基、乙基、三(1-吖丙啶基)硫化膦、甲基-R2、乙基-R2,R2是部分三(1-吖丙啶基)硫化膦
一种沉淀的反应产物(根据本发明)的元素分析(见实施例3)表明,不受理论限制,至少部分烷基化剂或烷基化剂的分解化合物,其在终止烷基化(例如季化反应)后通过反应混合物的酸性处理而获得,可在一定程度上封留在沉淀物的晶体中或以某种方式有力地附着于晶体,从而经受住有机溶剂(如乙醚和二氯甲烷)洗涤对沉淀物的纯化作用。不过可以证明,甚至在存在这类伴随物质的条件下,反应产物仍然完全起作用。
反应产物的水溶性盐适合以注射溶液的剂型应用。
在本发明的具体实施例中,该反应采用三(1-吖丙啶基)硫化膦(CAS No.52-24-4)进行,其在药典中也称作噻替派。另外的同义词是:噻替哌(ledertepa)、噻替哌(Onco thiotepa)、三胺硫磷(TESPA)、噻替哌(tespamine)、硫替派(thiophosphamide)、硫代-四乙烯戊胺(thio-TEPA)、三亚乙基硫代磷酰胺(thiotriethylenephosphoramide)、噻替派(tifosyl)、三吖丙啶基硫化膦(triaziridinylphosphine sulphide)、N,N′,N″-三-1,2-联二甲基磷硫炔三酰胺(N,N′,N″-tri-1,2-ethanediylphosphorothioine triamide)、N,N′,N″-三-1,2-联二甲基硫代磷酰胺(N,N′,N″-tri-1,2-ethanediylthiophosphoramide)、三-(亚乙基氨基)硫代磷酰胺(tri-(ethyleneimino)thiophosphoramide)、N,N′,N″-三乙烯硫代磷酰胺(N,N′,N″-triethylenethiophosphoramide)、三乙烯硫代磷酰三胺(triethylenethiophosphorotriamide)、间三乙烯硫代磷酰胺(m-triethylenethiophosphoramide)、间三(氮丙啶-1-基)硫化膦(m-tris(aziridin-1-yl)phosphine sulphide)、三乙烯硫代磷酰胺(triethylenethiophosphoramide)、三(1-吖丙啶基)硫化膦(tris(1-aziridinyl)phosphine sulphor)、三(亚乙基氨基)硫代磷酸盐(tris(ethyleneimino)thiophosphate)、噻替哌(TSPA)、以及噻替哌(WR45312)。
在本发明的另一个具体实施例中,有机溶剂中的生物碱的提取液,可选地罂栗科植物白屈菜的全部生物碱的提取液,与三(1-吖丙啶基)硫化膦(噻替派)进行反应,然后生成的反应产物,可选地作为化合物的混合物存在,用水洗涤至少一次。因为噻替派在水中分解,因而在反应后过量存在的噻替派的未转化残留物可通过这种方法从有机相中除去。优选地,含有中间反应产物(即在烷基化剂和生物碱之间形成的化合物)的有机溶液被洗涤数次,每次用水饱和。特别优选地,重复洗涤直到多余的高毒性噻替派从反应产物中被完全除去。
此外,某些水溶性毒性生物碱,导致药用中的不良反应并且甚至可引起肝硬变,可用水相从合成混合物中将其除去或使其浓度降低。通过艾姆斯试验,表明该具体实施例的反应产物(根据本发明制备)并不是致突变的物质。
当从罂栗科植物白屈菜的全部生物碱提取液开始反应时,最终反应产物是生物碱的混合物,包括噻替派与生物碱的较高分子量反应产物,以及噻替派的降解产物。作为合成过程的结果,生物碱的溶解度会变化。该反应产物包括约60%至70%未反应白屈菜属生物碱和约30%至40%三(1-吖丙啶基)硫化膦的反应产物的混合物。
叔生物碱是获自罂栗科植物白屈菜的生物碱提取液的起始成分的主要部分。例如,下述叔生物碱可作为合成混合物中的起始成分:白屈菜碱、前鸦片碱(protopin)、人血草碱(stylopin)、别隐品碱(allocryptopin)、α-高白屈菜碱、白屈菜定、白屈菜明、L-鹰爪豆碱(L-sparteine)、白屈菜默碱、二氢血根碱、氧化血根碱(oxysanguarine)、氧化白屈菜碱、以及甲氧基白屈菜碱。
在终止烷基化反应后,未反应的季生物碱(例如小檗碱)通过用水进行的洗涤步骤基本上从反应混合物中除去,而未反应的水不溶性生物碱和烷基化生物碱反应产物则仍留在有机溶剂中。取决于用于烷基化反应的有机溶剂和/或烷基化剂的特性,生成的中间反应产物可包括连接噻替派的化合物,其中一个噻替派分子连接于一个、两个或三个白屈菜碱、氧化白屈菜碱、或甲氧基白屈菜碱分子。此外,它可以包括烷基化生物碱衍生物,其中生物碱分子(例如,白屈菜碱、氧化白屈菜碱、或甲氧基白屈菜碱分子)通过其季氮连接于短直链烷基,特别是连接于甲基或乙基。在终止烷基化反应后,在反应混合物中仍存在很多的烷基化反应化合物。
根据本发明,自罂栗科植物白屈菜的全部生物碱与噻替派的反应获得的反应产物比从类似过程获得的反应产物显示出更广谱(better spectrum)的治疗活性,在该类似过程中洗涤步骤采用有机溶剂(例如,乙醚)进行。至少某些在本发明的反应产物中存在的化合物,特别是季白屈菜碱衍生物,选择性地蓄积在癌组织中并通过细胞凋亡消灭癌细胞,但与大多数已知的细胞抑制剂相反,并没有攻击健康细胞。这导致用这种制剂治疗具有良好的耐受性,并且使其对于个体的治疗甚至预防疾病具有普遍的适用性,该个体由于,例如,遗传分布,其癌症易患性的风险增高。其应用简单并且在治疗剂量上没有显著的不良反应。
自罂栗科植物白屈菜的全部生物碱与噻替派的反应获得的反应产物在代谢调节上显示出生物活性,不但适用于预防和治疗代谢性疾病,如骨质疏松症,而且适用于预防和治疗:风湿疾病、过敏反应、病毒感染、癫痫、多发性硬化、瘢痕、皮肤瘤、术后伤口、和辐照损伤。
罂栗科植物白屈菜的干燥根部的提取液可用作合成的原材料。根部比叶或茎具有更高含量的生物碱。
最近意外地发现,当以市售的白屈菜碱、氧化白屈菜碱、或甲氧基白屈菜碱作为唯一的生物碱来源时,根据本发明的方法获得的反应产物(见实施例3,上文)表现出的治疗质量和活性,至少可与来自全部白屈菜属生物碱的烷基化反应的产物(根据实施例1)相当。
通常的药物赋形剂(特别是用于溶液,例如注射溶液或输液剂,或用于软膏)、浓缩基质或悬浮基质,适用于含有根据本发明制备的反应产物的药物。
提供下述实施例以进一步说明本发明。
实施例1
A)生物碱的提取:
a.将25g生物碱盐混合物悬浮于水中并转移到分离漏斗。加入100ml二氯甲烷后,摇动分离漏斗。然后分开有机相并过滤进入玻璃瓶。
b.将1N NaOH(pH值8-9)加入水相中直到出现混浊。加入100ml二氯甲烷后,摇动混合物。然后分开有机相并与来自步骤a的二氯甲烷相合并。重复该过程,例如3次。过滤有机相并合并。
c.通过加入NaOH将水相的pH值调节到10。加入二氯甲烷后,摇动混合物。然后分开有机相,过滤并与其他有机相混合。现在用NaOH将水相的pH值调节到13并用二氯甲烷反复抽提。
d.蒸发合并的有机相,得到油性的棕色物质。
B)与三(1-吖丙啶基)硫化膦进行反应:
将生物碱残基溶解于二氯甲烷,然后加入三(1-吖丙啶基)硫化膦。该混合物在80℃回流2小时。冷却到室温后,澄清反应混合物。然后进行过滤并在分离漏斗中用250ml水洗涤滤液数次,例如3次或更多次。
C)与HCl反应
将经洗涤的溶液转移到玻璃烧杯,搅拌并用HCl气体饱和,氢氯化物络合物则沉淀下来。过滤出沉淀产物,用乙醚洗涤,干燥,然后溶解于水中。
依据实施例1获得的反应产物,测定了其对大鼠的半致死剂量值(LD50 value)为485mg/kg。对小鼠和大鼠的研究表明,依据本发明的产物调节胸腺的激素调节,并在胸腺已除去的动物中诱导具有胸腺素样活性的物质的合成。这种效应是剂量依赖的。该制剂增加外周血中T淋巴细胞的数目达50%(治疗前为4.04±0.43×109/1,治疗后为6.24±0.73×109/1),调节对渗透抗原的体液免疫应答和脾细胞中的自然杀伤细胞活性(198.20±17.69%,对照组为71.50±9.10%),以及在动物实验中增强白细胞的干扰素释放潜能。临床观察证实了动物实验的结果。因而,在癌症患者中也观察到免疫参数的改善。
制剂(来自实施例1)的约5mg制剂/70kg体重的剂量可用于预防和免疫用途。对癌症治疗,优选给予5mg制剂/20kg体重。
实施例2:HPLC指纹图谱
测定是通过离子对反相层析法以梯度方式来完成的,并利用DAD检测器在285nm波长处测量。同时,对参照生物碱进行层析测定。此外,进行HPLC-MSD分析,表明除了生物碱的峰值之外没有其他峰值。图1和图2的HPLC图是基于下述实验数据获得:
层析法参数:
柱:LiChrospher 60RP选B,5μm,125×24mm内径
洗脱液:A)200ml(乙腈)+800ml(水)+1.5g(己磺酸(hexanesulphonic acid))+0.3ml(85%磷酸)
B)900ml(乙腈)+100ml(水)+1.5g(已磺酸)+0.3ml(85%磷酸)
梯度:5分钟同溶剂地(isocratically)100%A;
在24分钟内达到40%B
在1分钟内达到100%B
5分钟100%B;
用100%A平衡5分钟
检测:在285nm处的紫外线
洗脱物流率:1ml/分钟,35分钟后停止。
注射容积:10μl
样品制备:
反应前的提取液(图1):用超声波将25mg生物碱溶解于40ml甲醇中,补足到50ml并用膜滤器过滤。
反应产物(图2):把反应产物转化为氢氯化盐(hydrochloridesalt),溶解于水中浓度为1mg/ml,并将pH值调节在2.5和6.5之间。
实施例3
依据实施例1所描述的条件将市售的纯化白屈菜碱(Sigma)与三(1-吖丙啶基)硫化膦(=噻替派)进行反应。终止烷基化反应后,进行后续的洗涤步骤和利用HCl气体的转化步骤,对最终产物进一步处理如下:
把340g经HCl处理的水溶性反应产物溶解于水中,浓缩接近饱和将其放置在8℃的冰箱中。几小时后,发生自发沉淀,然后收集到264mg沉淀物(在下文称作U-KRS)。该沉淀物包括轻微淡黄色吸湿晶体,其具有相当窄的熔点205-207℃(表明它是相当好的结晶产物),在用366nm处的紫外光辐照后呈现浅蓝色荧光。也可见痕量的黄色、橙色、和红色荧光带。该产物在进行薄层层析时并不移动而是留在起点位置(Rf=0),只有痕量荧光带(traces),其至少移动至Rf>0.1。从核磁共振(NMR)谱(图4)可以清楚看到U-KRS含有芳环,其与包含在白屈菜碱分子中的芳环相似。紫外光谱(图5)在148、155、160、205、230、和282nm处呈现最大吸收,与白屈菜碱的紫外光谱非常相似(图6),唯一不同点在于:U-KRS的峰值在230nm处,而白屈菜碱的峰值则在240nm处。这表明在U-KRS中的氮是季氮,而在白屈菜碱中的氮则是叔氮。
进一步的分析详图可从图7和图8(U-KRS)以及图9(白屈菜碱)中的质谱图以及来自U-KRS的元素分析结果得到,其揭示物质的下述组成(表1):
表1:以总质量的百分比计U-KRS的元素组成
元素 | 总质量的百分比 |
C | 45.7045.05 |
H | 5.84 |
N | 6.566.37 |
O | 22.2519.6 |
P | 3.273.27 |
S | 2.783.06 |
Cl | 17.29 |
下述实施例显示化合物U-KRS(其结果来自于实施例3所描述的步骤)的各种应用。
实施例4
用抗肿瘤药物U-KRS选择性抑制体外细胞生长
材料和方法
在含有8%CO2的增湿空气的条件下,在37-37.5℃的洛氏瓶(Roux bottles)中,进行细胞培养。用0.01%胰蛋白酶和0.2%乙二胺四乙酸(EDTA)的磷酸盐缓冲液除去汇合培养物,然后以1∶5至1∶25的比率分开。
通过胶原酶处理,从脐静脉分离人内皮细胞。内皮细胞的培养基是M199并补充以15%热失活(heat inactivated)胎牛血清、200μg/ml内皮细胞生长因子和90μg/ml肝素。
荧光显微术
细胞生长在35mm的培养皿中并用100μg/ml U-KRS温育30-60分钟。吸出培养基,细胞用PBS洗两次。将盖玻片安放在细胞上并用装备有氩激光源的共聚焦激光扫描显微镜激发荧光。在光电倍增管中检测发射光。利用MRC600图像处理软件将信号在视频监测器上成像。
结果
1.在20-40μg/ml U-KRS的范围内,内皮细胞生长约55%受到抑制的量被测定。这种浓度可杀死人类骨肉瘤细胞系。两种细胞类型的杂交表明和正常细胞具有几乎相同的敏感性。
2.由于其自身荧光,可对U-KRS进行细胞内检测。激光扫描显微镜显示在恶性细胞中有U-KRS的高吸收。
实施例5
U-KRS作为抗癌剂-氧消耗量
材料和方法
小鼠的体内实验。对2至5个对照8日龄动物腹腔内注射50μl艾氏小鼠腹水瘤悬液,新鲜腹水瘤悬液取自发育成熟的供体动物。对照组未进一步治疗。在肿瘤植入后,试验组立即在腹部区域注射10mg U-KRS/kg动物体重。
结果
植入腹水瘤的小鼠,在腹腔内或皮下注射U-KRS后,比未用其他方法治疗的植入动物表现出更长的生存时间。
在体外用电极测量了腹水瘤悬液的氧消耗,在加入U-KRS后氧消耗短暂增加,然而接着是迅速下降,其不同于未与U-KRS混合治疗的对照悬液组。
实施例6
在啮齿目动物中用U-KRS改善吗啡的抗伤害作用
材料和方法
动物:实验是用雄性Albino Swiss小鼠和雄性Wistar大鼠进行。
治疗:腹腔内注射U-KRS,剂量从20mg/kg(对小鼠)和25mg/kg(对大鼠)开始。
实验步骤:在每个实验中,四组动物注射以1)安慰剂,2)吗啡,3)U-KRS,4)U-KRS和吗啡。
结果:
结果表明,同时注射U-KRS和吗啡可改善麻醉性止痛药的作用。它们在大鼠的闪尾疼痛测试(tail-flick test)中产生抗伤害性作用,明显表现在潜伏期的增加。
本结果表明,在所描述的测试中,与吗啡同时注射的U-KRS改变了实验动物对伤害性反应的敏感性。本结果提示U-KRS可与癌症中使用的止痛药相互作用。
实施例7
通过衍生物U-KRS诱导恶性细胞的双模态程序化细胞死亡
材料和方法
采用K562红白血病(erythroleukaemia)细胞系,U-KRS是以纯结晶形式产生并溶解于水中,浓度为1.2mg/ml。
利用碘化丙啶(propidium iodide)和流式细胞仪分析了在暴露于各种浓度的U-KRS的条件下K562细胞的DNA含量。
结果
该研究的结果表明,U-KRS诱导双模态程序化细胞死亡,首先是细胞凋亡,由奎尼丁敏感Ca2+依赖性K+通道介导;第二种模态是水疱(blister)细胞死亡,其通过阻止微管形成并因此诱导多倍体来介导。
实施例8
在恶性细胞中U-KRS对DNA、RNA、和蛋白质合成的影响
材料和方法
将3H标记的胸苷(0.5μCi,在20μl培养基中)、尿苷(0.5μCi,在20μl培养基中)、和亮氨酸(1.0μCi,在20μl培养基中)放置于具有不同U-KRS浓度的四孔中2至4小时。在此之前,下述细胞系在96微量浓度测定加样孔中于37℃生长24小时:豚鼠(麦地那龙猪)肝细胞(guinea pig hepatocytes)、C1L肝细胞、人类扁桃体细胞、鼠淋巴瘤、鼠骨髓瘤、Yoshida细胞、两种海拉细胞株EsB-、EB、淋巴瘤、ZAC/1、P815。
WiDr细胞以稍微不同的方案温育6和24小时,U-KRS浓度为1、4、8、和14μg/ml。
结果
荧光测定表明,U-KRS对癌细胞核的元件比对其他癌细胞区域具有更强的亲和力。荧光现象可清楚表明,在肿瘤和转移区域U-KRS有强有力和快速的亲和力。在用治疗剂量的正常细胞中未见毒性效应,该剂量对至今为止试验的癌细胞系具有100%的生长抑制效应。
实施例9
U-KRS对人类异种移植物的影响
材料和方法
肿瘤细胞是取自人类肿瘤异种移植物,然后逐次移植进入裸小鼠中。这些细胞是用于体外的成集落检定。肿瘤细胞在不同浓度的药物U-KRS下连续温育至少1周。这是用6种不同的类型来完成,并对每个肿瘤评价(scored)集落形成。报道的药物效应为T/C百分数(试验/对照)。
结果
许多不同种类的肿瘤对U-KRS是敏感的,与用U-KRS试验的种类有关。杀肿瘤效应似乎依赖于免疫器官(immune apparatus)的再生能力,它的刺激和调节可用U-KRS来完成。
实施例10
U-KRS对人类恶性细胞系的影响
材料和方法
采用了四种不同的恶性细胞系:1)小鼠肉瘤;2)雌性乳腺癌;3)人类结肠癌;4)人类黑色素瘤。
将U-KRS和PP9AA02衍生物加入培养基。
辐照后,在每个载玻片上涂200个细胞,温育1周,然后染色并计数。
结果
这里提供的结果表明,U-KRS和PP9AA02衍生物作为细胞毒素物质协同地作用于人类恶性细胞系。
实施例11
在人类表皮样癌(Epidermoid Carcinoma)细胞系中由U-KRS诱导的G2/M停止和细胞凋亡
材料和方法
原代的人类角质细胞是分离自新生皮肤标本。对表皮层进行胰蛋白酶消化并离心收集单细胞悬液。
结果
U-KRS以剂量依赖方式抑制细胞周期的进展。
在A431和ME180细胞中,U-KRS治疗可影响细胞周期分布和诱导细胞凋亡。
在用U-KRS治疗后,细胞周期蛋白CDKs和CDK抑制剂p27的表达会发生变化。
实施例12
U-KRS的抗转移效应及其对患有黑色素瘤B-16小鼠的氧和能量代谢的影响
材料和方法
该实验是用133 C57B/6雄性小鼠进行。将转移黑素瘤B-16移植到每只小鼠的右胫肌(shin muscle)。在肿瘤移植后第10天,将该动物分成两组。第一组将U-KRS注射到眼的静脉窦,剂量为1mg/kg,容积为0.05ml,注射5次,每两天一次。第二组用相同的方式将无菌生理溶液注射到静脉窦。
结果
该研究表明,第一次静脉注射U-KRS后一天,肌组织中的氧状态指数(indices of the oxygen regime)明显改善。在吸氧期间pO2水平的比率增加到最大值,而在停止吸氧后pO2水平的比率则从最大值降低到最初的水平。在实验组的动物中,注射制剂后一天,肝线粒体的氧化磷酸化的某些指标也获得改善。众所周知,在恶性化过程中,氧和代谢受到抑制。在注射5次U-KRS的小鼠中,这类抑制较不明显。在对照组动物中,肌组织中的氧压水平和氧气输送到肌组织的速率在统计学上增高。总结获得的资料,可以得到下述结论:在患有B/16黑素瘤的小鼠中,U-KRS改善了氧向组织的输送以及抑制恶性化过程对有机体生物能的破坏效应。
随后的实施例说明U-KRS的免疫调节和代谢调节性能,其使得U-KRS特别适用于治疗变态反应、病毒性疾病(HIV、甲型肝炎、乙型肝炎、和丙型肝炎、大肠杆菌(E.coli)、流感)、骨质疏松症、多关节炎、银屑病、和其他疾病、或身体不适。
实施例13
用U-KRS增强巨噬细胞的肿瘤杀伤(破坏癌细胞)活性
材料和方法
在实验室通过近亲交配来维持BALB/c小鼠的纯种。通过皮下注射将肿瘤D1 DMBA/3常规移植于BALB/c小鼠。植入5天后该肿瘤变得明显。
在皮下肿瘤植入5天后开始用U-KRS进行体内治疗。采用3种注射途径,即静脉、腹腔内、和皮下注射。所有3种实验组,每组至少10只小鼠,接受在0.15ml PBS中的5.0μU-KRS。该剂量的选择是基于初步实验结果。
结果
在经治疗的小鼠中,肿瘤生长的速率显著降低。接受U-KRS治疗的小鼠没有显示出药物相关的有害的副反应。
实施例14
在体外U-KRS对正常人类淋巴细胞表型的效应
材料和方法
本研究是针对淋巴细胞进行的,该淋巴细胞是分离自10个健康志愿者的外周血。细胞通过Ficoll-Paque密度梯度离心进行分离。通过0.1%台盼蓝染色测定细胞的活力,其活力为95%。
利用单克隆抗体通过免疫荧光技术对总的T细胞、辅助性T细胞、和抑制性T细胞对各淋巴细胞亚群进行定量分析。然后,细胞用FITC/偶联的兔F/ab/2片断抗小鼠IgG进行处理,用PBS冲洗,然后利用聚乙烯醇和甘油制作标本。在对照制剂中,采用PBS或正常小鼠血清而不是单克隆抗体。
结果
本研究表明U-KRS可能对T细胞亚群有直接影响,这证实了早期的观察结果,即在癌症患者中U-KRS可能是细胞免疫的良好的免疫刺激剂。
实施例15
U-KRS对人类外周血单核细胞的促分裂性能
材料和方法
外周血单核细胞。该血液用等量的PBS(含有1mM EDTA,pH值7.5)进行稀释,在Histopaque 1077中分层。试管在2000转/分的条件下离心30分钟。收集含有淋巴细胞的界面层并用RPMI组织培养液洗3次。
结果
研究发现,甚至用U-KRS对细胞进行短期的预处理也能对植物血凝素(PHA)刺激的有丝分裂产生有效的协同效应,这导致比仅采用PHA处理具有显著更高的细胞刺激指数。而且,还发现,为使U-KRS发挥其促有丝分裂效应,细胞的短期PHA处理是必要的。
本研究表明,在用U-KRS治疗的恶性肿瘤的晚期(advancedstage)患者的循环淋巴细胞显著增加。
实施例16
在体内用U-KRS调节免疫效应物细胞溶细胞活性和肿瘤生长抑制
材料和方法
肿瘤细胞:肥大细胞瘤P815和AKR白血病AKIL细胞系在DMEM培养基中培养,补充以9.0%的含有青霉素和链霉素的胎牛血清。
结果
本体外研究说明,U-KRS是有效的生物反应调节剂,使异源免疫小鼠的脾淋巴细胞的裂解活性增加达48倍。通过在细胞介导的裂解检定培养基(lysis assay medium)中加入U-KRS,经IL-2治疗的脾细胞和腹膜渗出物淋巴细胞的裂解活性也明显增加。
该结果包括结合U-KRS也增强脾淋巴细胞的溶细胞活性的结果表明,在体内观察到的U-KRS的治疗效应是通过刺激免疫效应细胞溶细胞活性介导的。
实施例17
在体外和体内U-KRS对免疫血参数的影响
材料和方法
96只Wistar大鼠用于本研究。雄性和雌性大鼠的初始年龄均为16周。
用3H胸苷(#Hthymidine)试验,测定U-KRS和PHA对T淋巴细胞的刺激指数,其中剂量是从0.01至20μg/ml。
结果
U-KRS刺激造血和免疫系统的不同亚类(subsets)。在这个实验中,诱导网织红细胞增多作为刺激某些干细胞或一般激活红细胞生成系统的可能的体征。因为不能证明绝对白细胞计数的变化,因而可以假定,在这个实验中通过U-KRS的作用仅强调节了性能,例如不同亚类的迁移(dislocation)。
与在这些实验中获得的指标相当的结果也在体外实验中观察到,包括癌细胞的凋亡。
实施例18
在小鼠中U-KRS对卵白蛋白抗原性和抗卵白蛋白IgE抗体应答的抑制效应
材料和方法
在BALB/c和F1(BALB/c×C57BI/6J)小鼠中测试了U-KRS抑制卵白蛋白诱导的致敏的能力。把U-KRS引入小鼠中,其中U-KRS在与抗原(卵白蛋白)和佐剂(明矾)的混合物中,其抑制小鼠的致敏,反映在较低的抗OA IgE抗体反应和降低抗原诱导的来自肥大细胞的组胺释放,该肥大细胞是由致敏小鼠的腹腔分离的。在对大鼠的异源被动皮肤过敏(PCA)反应中测试了在过敏反应中U-KRS对卵白蛋白(OA)抗原性的影响。
结果
结果表明,将U-KRS掺入制备的OA混合物中,降低了OA与大鼠体内抗内源性OA的抗-OA IgE抗体的反应能力,该抗体在异源PCA反应中固定在大鼠肥大细胞的表面。该结果表明,OA的U-KRS预处理可影响其抗原性和与抗内源性IgE分子的抗-OA IgE抗体的反应能力。
实施例19
用U-KRS进行的治疗对早期骨质疏松症的作用
材料和方法
给雌性大鼠腹腔内注射U-KRS,隔天注射6个月,剂量为30mg/kg,该雌性大鼠患有卵巢切除术诱导的早期骨质疏松症。在外科手术后第二天开始注射U-KRS。在用U-KRS长期治疗结束时,测定每只大鼠的两个肱骨的强度并测量大鼠股骨的某些参数。
结果
结果表明,通过U-KRS的6个月治疗可预防肱骨机械强度的下降和卵巢切除术引起的股骨的一些变化。
实施例20
U-KRS制剂对流感病毒以及大肠杆菌和金黄色葡萄球菌(S.aureus)的影响
材料和方法
APR8/HON1/34株的流感病毒在10日龄的鸡胚(hen embryos)中培养;
大肠杆菌来自目前的临床材料,并采用金黄色葡萄球菌的209P株。系列290614的U-KRS制剂。
结果
本研究证实,U-KRS制剂在被感染的大生物体中具有抗感染作用。这种影响的施加是通过刺激宿主免疫系统中的由于微生物感染引起继发破坏某些元件,或者作用于微生物感染的细胞。
实施例21
U-KRS抗流感病毒的生物学活性
材料和方法
A型病毒,Port-Chalmers 1/73培养,抗原H3N2变种。每个胚胎以1、10、和100半数卵感染剂量(EID50)注射病毒。U-KRS被重新溶解在汉克斯溶液中。
结果
已证实,U-KRS对感染过程的发展具有阻碍作用。
实施例22
U-KRS对辐照效应的作用
材料和方法
16/20g体重的CBA/J雄性小鼠。
对小鼠进行短期全身γ辐照,剂量范围从6.0Gy至7.5Gy。利用CEGO装置进行长期辐照,累积剂量为8.75Gy。
腹腔内注射U-KRS,剂量为0.1、1.4和12mg/kg体重。
结果
在CBA/J小鼠中,利用0.1至12mg/kg的药物剂量研究了U-KRS改善辐照效应的能力。研究发现,在5.00至7Gy的辐照剂量下U-KRS增加了小鼠的存活率50-60%,而在7.5Gy的剂量下没有影响。改变药物剂量并不影响辐照的结果。
本研究的主要实验结果表明,U-KRS能改善预防和治疗剂量的辐照对小鼠的影响。
实施例23
U-KRS抵抗电离辐射的效应
材料和方法
Brest癌、结肠直肠腺癌(colorectal adenocarcinomas)、恶性胶质细胞瘤(glioblastoma)、和胰腺癌细胞系。U-KRS制剂。
在从0.2μG/ml的浓度范围测试了U-KRS对细胞存活的影响。暴露时间是1、3和24小时,其后用磷酸盐缓冲液洗细胞,然后加入新鲜的培养基。
结果
U-KRS处理导致促克隆形成的细胞存活的不同的时间和剂量依赖性下降。所有测试的四种人类肿瘤细胞系对U-KRS表现出不同的敏感性,当与人类成纤维细胞共同孵育24小时的肿瘤细胞比较时,促克隆形成的细胞存活则具有高达100倍的降低。
Claims (25)
1.生物碱反应产物,包括至少一种通过一种或多种生物碱与烷基化剂反应获得的生物碱衍生物,其中在所述衍生物中起始的叔氮是以季氮形式存在,氢基或来自所述烷基化剂的残基与其结合作为第四配体,优选地所述残基选自由甲基、乙基、和三(1-吖丙啶基)硫化膦残基组成的组,或选自部分三(1-吖丙啶基)硫化膦。
2.根据权利要求1所述的生物碱反应产物,其中至少一种生物碱衍生物是以水溶性盐的形式存在,优选以氢氯化物的形式存在。
3.根据权利要求1或2所述的生物碱反应产物,其中所述生物碱至少是一种存在于罂栗科植物白屈菜药草中的生物碱,优选几种或所有罂栗科植物白屈菜的生物碱的混合物。
4.根据权利要求1至3任一权项所述的生物碱反应产物,其中所述生物碱是选自由白屈菜碱、前鸦片碱、人血草碱、别隐品碱、高白屈菜碱、血根碱、白屈菜定、白屈菜明、L-鹰爪豆碱、和氧化白屈菜碱组成的组。
5.根据权利要求1至4任一权项所述的生物碱反应产物,其中所述白屈菜碱、氧化白屈菜碱、或甲氧基白屈菜碱是作为唯一的生物碱来源存在。
6.根据权利要求1至5任一权项所述的生物碱反应产物,其中所述产物进一步包括至少一种化合物,其选自由未反应的叔生物碱、未反应的烷基化剂、和所述烷基化剂的分解产物组成的组。
7.根据权利要求1至6任一权项所述的生物碱反应产物,其中所述产物进一步用至少一种分析显示来表征,其选自由图4的核磁共振谱、图5的紫外光谱、图7和8的质谱、和表1的元素分析组成的组。
8.根据权利要求1至7任一权项所述的生物碱反应产物,用在权利要求11至22任一权项中所定义的方法获得。
10.根据权利要求9所述的白屈菜碱衍生物,是水溶性形式,优选是与强酸形成的盐,最好是氢氯化物的形式。
11.制备根据权利要求1中所定义的生物碱反应产物的方法,包括:
a)提供包括有机溶剂和至少一种在其化学结构中有叔氮的生物碱以及烷基化剂的反应混合物,并在有所述有机溶剂的情况下通过所述至少一种生物碱与所述烷基化剂的反应进行烷基化反应,从而便于形成至少一种反应产物,其中烷基化发生在所述生物碱叔氮从而将所述叔氮转化成季氮;
b)在终止所述反应后,所述生成的反应混合物至少用水性溶剂或水洗涤一次,以除去在所述反应混合物中存在的水溶性化合物;以及
c)用气体或液体形式的强酸处理所述经洗涤的反应混合物,优选用气体氯化氢或氯化氢溶液,从而将至少一种残存的反应产物转化成水溶性形式,特别是水溶性盐。
12.根据权利要求11所述的方法,其中在步骤c)中用酸进行所述处理期间或之后反应产物沉淀,此后所述沉淀物从所述有机溶剂分离,然后可选地优选用有机溶剂进一步提纯。
13.根据权利要求11或12所述的方法,其中所述烷基化反应是在升高的温度进行,特别是在所述溶剂的沸点。
14.根据权利要求11至13任一权项所述的方法,其中至少一种生物碱被用作生物碱来源,其存在于罂栗科植物白屈菜药草中,优选几种或所有罂栗科植物白屈菜的生物碱的混合物。
15.根据权利要求11至14任一权项所述的方法,其中所述生物碱是选自由白屈菜碱、前鸦片碱、人血草碱、别隐品碱、高白屈菜碱、血根碱、白屈菜定、白屈菜明、L-鹰爪豆碱、和氧化白屈菜碱组成的组。
16.根据权利要求11至15任一权项所述的方法,其中白屈菜碱、氧化白屈菜碱、或甲氧基白屈菜碱被用作唯一的生物碱来源。
17.根据权利要求11至16任一权项所述的方法,其中所述烷基化剂是生理活性剂,优选细胞毒素剂。
18.根据权利要求11至17任一权项所述的方法,其中所述烷基化剂是水溶性的或与水接触后分解成水溶性成分。
19.根据权利要求11至18任一权项所述的方法,其中所述有机溶剂促进或有助于所述烷基化反应并且优选地选自由一氯甲烷、二氯甲烷、三氯甲烷、一氯乙烷、二氯乙烷和三氯乙烷组成的组。
20.根据权利要求11至19任一权项所述的方法,其中所述烷基化剂是三(1-吖丙啶基)硫化膦(CAS 52-24-4)。
21.根据权利要求11至20任一权项所述的方法,其中所述反应产物包括至少一种选自由白屈菜碱、氧化白屈菜碱、和甲氧基白屈菜碱组成的组的化合物,其中所述化合物具有季氮原子,氢基或来自所述烷基化剂的残基与其结合作为第四配体,优选地所述残基选自由甲基、乙基、和三(1-吖丙啶基)硫化膦残基组成的组。
22.根据权利要求11至21的任一权项所述的方法,其中三(1-吖丙啶基)硫化膦用作所述烷基化剂,而其中所述残基是所述烷基化剂的一部分,可选地由于用酸进行的所述处理而形成的分解产物。
23.根据权利要求1至10任一权项中所定义的反应产物作为药物或药剂的应用。
24.根据权利要求1至10任一权项中所定义的反应产物制备药物组合物的应用,用于预防或治疗疾病或身体不适,所述疾病或身体不适选自由病毒感染、癌症、免疫功能障碍、代谢功能障碍、和辐照损伤组成的组。
25.根据权利要求24所述的应用,其中所述疾病是选自由过敏反应、骨质疏松症、皮肤瘤、流感病毒感染、风湿疾病、瘢痕、术后伤口、癫痫、和多发性硬化组成的组。
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Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03006015A EP1459753A1 (en) | 2003-03-18 | 2003-03-18 | Quaternary chelidonine and alkaloid derivatives, process for their preparation and their use in the manufacture of medicaments |
EP03006015.6 | 2003-03-18 |
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CN1532198A true CN1532198A (zh) | 2004-09-29 |
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CNA031373550A Pending CN1532198A (zh) | 2003-03-18 | 2003-06-19 | 季白屈菜碱衍生物 |
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US (1) | US7795434B2 (zh) |
EP (2) | EP1459753A1 (zh) |
JP (1) | JP5303719B2 (zh) |
KR (1) | KR101020680B1 (zh) |
CN (1) | CN1532198A (zh) |
AR (1) | AR043629A1 (zh) |
AT (1) | ATE469651T1 (zh) |
AU (1) | AU2004222661B2 (zh) |
BR (1) | BRPI0408386A (zh) |
CA (1) | CA2517769C (zh) |
CL (2) | CL2004000552A1 (zh) |
CY (1) | CY1112598T1 (zh) |
DE (1) | DE602004027496D1 (zh) |
DK (1) | DK1644012T3 (zh) |
EA (1) | EA009049B1 (zh) |
ES (1) | ES2346216T3 (zh) |
GE (1) | GEP20084501B (zh) |
GT (1) | GT200400046A (zh) |
HR (1) | HRP20050987B1 (zh) |
IL (1) | IL170505A (zh) |
MA (1) | MA27833A1 (zh) |
MX (1) | MXPA05009919A (zh) |
MY (1) | MY141779A (zh) |
NO (1) | NO333672B1 (zh) |
NZ (1) | NZ542151A (zh) |
PA (1) | PA8598201A1 (zh) |
PE (1) | PE20050351A1 (zh) |
PL (1) | PL1644012T3 (zh) |
PT (1) | PT1644012E (zh) |
SG (1) | SG158748A1 (zh) |
SI (1) | SI1644012T1 (zh) |
TN (1) | TNSN05230A1 (zh) |
TW (1) | TWI347939B (zh) |
UA (1) | UA89353C2 (zh) |
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Cited By (1)
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WO2021073603A1 (en) * | 2019-10-17 | 2021-04-22 | Chengdu Anticancer Bioscience, Ltd. | Benzophenanthridine alkaloids and their methods of use |
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ITMI20080284A1 (it) * | 2008-02-22 | 2009-08-23 | Indena Spa | Agenti antitumorali a struttura benzofenantridinica e formulazioni che li contengono |
US8835506B2 (en) | 2008-06-05 | 2014-09-16 | Stc.Unm | Methods and related compositions for the treatment of cancer |
CN102552264A (zh) * | 2012-02-28 | 2012-07-11 | 苏州大学 | 血根碱在制备电离辐射防护剂中的应用 |
CN113372355B (zh) * | 2021-05-13 | 2023-02-17 | 山东大学 | 六氢苯并菲啶类生物碱及其制备方法和应用 |
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SU368254A1 (ru) | 1969-06-16 | 1973-01-26 | А. И. Потопальский , В. М. Новицкий Львовский государственный медицинский институт | Способ получения соединений тиофосфамида с алкалоидами чистотела большого |
US3865830A (en) | 1969-06-16 | 1975-02-11 | Nikolai Mikhailovich Turkevich | Thiophosphamide derivatives of isoquinoline alkaloids, method of producing and application thereof |
AT354644B (de) | 1975-12-19 | 1980-01-25 | Nowicky Wassili | Verfahren zur herstellung von neuen salzen von alkaloidderivaten von thiophosphorsaeure |
AT377988B (de) | 1976-06-28 | 1985-05-28 | Nowicky Wassili | Verfahren zur herstellung von neuen phosphorderivaten von alkaloiden |
DE3128018A1 (de) | 1981-07-13 | 1983-04-07 | Wassyl 1060 Wien Nowicky | "verfahren zum diagnostizieren und fuer die therapeutische behandlung von tumoren und/oder infektioesen krankheiten verschiedenster art unter praeparativem einsatz von alkaloid-verbindungen bzw. deren salze" |
US4970212A (en) | 1982-05-18 | 1990-11-13 | Nowicky Wassili | Method of treating human illnesses which compromise the ability to mount an effective immunological response |
AT407833B (de) * | 1995-06-01 | 2001-06-25 | Nowicky Wassyl Dr | Mittel zur behandlung von strahlenschäden |
AT408719B (de) | 2000-03-22 | 2002-02-25 | Nowicky Wassili | Mittel zur behandlung von hepatitis c |
CH695417A5 (de) | 2001-11-15 | 2006-05-15 | Ddr Wassyl Nowicky Dipl Ing | Verfahren zur Umsetzung von Alkaloiden. |
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- 2004-03-12 DE DE602004027496T patent/DE602004027496D1/de not_active Expired - Lifetime
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WO2021073603A1 (en) * | 2019-10-17 | 2021-04-22 | Chengdu Anticancer Bioscience, Ltd. | Benzophenanthridine alkaloids and their methods of use |
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