CN1976698A - 包含2-甲基-噻唑烷-2,4-二羧酸的复合制剂 - Google Patents
包含2-甲基-噻唑烷-2,4-二羧酸的复合制剂 Download PDFInfo
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- CN1976698A CN1976698A CNA2005800186921A CN200580018692A CN1976698A CN 1976698 A CN1976698 A CN 1976698A CN A2005800186921 A CNA2005800186921 A CN A2005800186921A CN 200580018692 A CN200580018692 A CN 200580018692A CN 1976698 A CN1976698 A CN 1976698A
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- carcinoma
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- thiazolidine
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Abstract
本发明涉及2-甲基-噻唑烷-2,4-二羧酸和/或其生理学上可耐受的盐和至少一种细胞毒素的和/或细胞抑制的化合物的复合制剂以及这些复合制剂在治疗癌症上的用途。
Description
技术领域
本发明涉及2-甲基-噻唑烷-2,4-二羧酸和/或其生理学上可耐受的盐和至少一种抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物的复合制剂。本发明进一步涉及这些复合制剂在治疗癌症上的用途以及通过2-甲基-噻唑烷-2,4-二羧酸的额外添加抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物功效的增加。
背景技术
2-甲基-噻唑烷-2,4-二羧酸的合成是在DE-OS 21 16 629中已知的。EP0 969 834 B1公开了2-甲基-噻唑烷-2,4-二羧酸作为粘液溶解剂的用途,EP98 916 809公开了2-甲基-噻唑烷-2,4-二羧酸和扑热息痛的一种复合制剂,以及EP 01 915 023讨论了2-甲基-噻唑烷-2,4-二羧酸在感染疾病,特别是HIV治疗上的用途。
欧洲专利EP 1 255 538 B1公开了2-甲基-噻唑烷-2,4-二羧酸在治疗和预防癌症上的用途。在这个专利中,2-甲基-噻唑烷-2,4-二羧酸在制备为防止和/或减少不希望的细胞抑制物副作用的药物上的用途也被公开了。
细胞抑制物代表那些阻止或者相当地耽搁起始以及妨碍或者扰乱核周期和/或细胞液分裂(有丝分裂或者细胞浆移动)的物质。它们干扰DNA的复制或者翻译或者DNA载体结构的构成和分裂,并且导致分裂不稳定染色体失常或者抑制纺锤体的构成和扰乱纺锤体的作用(并且几乎总是诱变体)。从广义上说,细胞抑制物也代表那些扰乱和阻止核蛋白合成或者纺锤体作用所必需能量的供应的物质。通常,根据其作用模式它们分类为抗代谢物,烷化剂,细胞抑制的活性抗体以及有丝分裂抑制物(Roche Lexikon Medizin,4.Edition;Urban & Fischer Verlag,München 1984/1987/1993/1999)。
帕尼特西(Taxol)也许是被研究的最好的细胞抑制物之一。
EP 1 255 538 B1公开了2-甲基-噻唑烷-2,4-二羧酸在减少细胞抑制物不希望的副作用上的用途。因此,EP 1 255 538 B1为减少细胞抑制物不希望的副作用的问题提供了一个办法。
发明内容
然而,本发明的目的是为了增加效应,也就是说细胞抑制物的功效和/或活性。
这个目的是通过独立专利权利要求的技术教学解决的。本发明的优势体现在从属专利权利要求,发明说明以及实例中。
令人惊奇地,结果表明,上述细胞抑制物的功效可以通过2-甲基-噻唑烷-2,4-二羧酸的添加得到提高。
因此,本发明涉及包含2-甲基-噻唑烷-2,4-二羧酸和/或其生理学上可耐受的盐和至少一种抗血管原性的和/或细胞毒素的和/或细胞抑制的活性化合物的复合制剂。
2-甲基-噻唑烷-2,4-二羧酸是一种带有两个固相中心的化学化合物,其中R-构象在位置4时是特别优先的。固相中心在位置2时没有优先的构象。
术语“2-甲基-噻唑烷-2,4-二羧酸”是假设源于非对映体的化合物(2R,4R)-2-甲基-噻唑烷-2,4-二羧酸,(2S,4R)-2-甲基-噻唑烷-2,4-二羧酸以及(2RS,4R)-2-甲基-噻唑烷-2,4-二羧酸。如果是(2RS,4R)-2-甲基-噻唑烷-2,4-二羧酸,(2R,4R)-2-甲基-噻唑烷-2,4-二羧酸和(2S,4R)-2-甲基-噻唑烷-2,4-二羧酸的摩尔比范围是从90∶10到10∶90,其中优先的(2R,4R)-2-甲基-噻唑烷-2,4-二羧酸的百分率是占优势的。
进一步地,术语“2-甲基-噻唑烷-2,4-二羧酸”是理解为不仅包含游离酸也包含生理学上可耐受的盐。因此,化合物2-甲基-噻唑烷-2,4-二羧酸和其对映异构体,非对映异构体或者其对映异构体的和/或非对映异构体的混合物可以作为游离酸和/或生理学上可耐受的盐的形式来使用。这些盐的适合的例子包含酸性添加盐和碱性金属盐。因此,碱性金属盐可以被使用,例如钠盐,钾盐,锂盐,镁盐,钙盐和/或烷基铵盐。作为可形成酸附加盐的酸,以下的可以被提及:硫磺酸,磺酸,磷酸,硝酸,亚硝酸,高氯酸,氢溴酸,氢氯酸,蚁酸,乙酸,丙酸,琥珀酸,草酸,葡糖酸(glyconic acid,dextronic acid),乳酸,苹果酸,酒石酸,丙醇二酸(hydroxymalonic acid,hydroxypropionic diacid),延胡酸,柠檬酸,抗坏血酸维生素C,马来酸,丙二酸,丁酮二酸,丙酮酸,苯乙酸,(o,m,p)-甲苯酸,苯酸,p-氨基苯酸,p-水杨酸,水杨酸,p-对氨基水杨酸,甲磺酸,乙磺酸,羟基乙磺酸,乙烯乙磺酸,p-甲苯乙磺酸,萘基乙磺酸,萘基胺乙磺酸,磺胺酸,樟脑乙磺酸,中国酸(canine acid),o-甲基扁桃酸,氢基-苯磺酸,苦味酸(2,4,6-trinitrophenol),己二酸和D-o-甲苯基酒石酸。氨基酸也可以被用作盐的构成,例如甘胺酸,丙胺酸,纈胺酸,亮胺酸,异亮胺酸,丝胺酸,苏胺酸,苯丙胺酸,酪胺酸,色胺酸,赖胺酸,精胺酸,组胺酸,天冬胺酸,谷胺酸,天冬酰胺,谷胺酰胺,半胱胺酸,甲硫胺酸和脯胺酸,其中氨基酸甲硫胺酸,色胺酸,赖氨酸和精胺酸是优先的。
一种包含2-甲基-噻唑烷-2,4-二羧酸的复合制剂,也就是说,2-甲基-噻唑烷-2,4-二羧酸的至少一个对映异构体或者非对映异构体作为游离酸或者盐以及至少一种抗血管原性的和/或至少一种细胞毒素的化合物和/或至少一种细胞抑制的化合物,在一种药物形式中不必须包含两种活性剂。
明显地,包含2-甲基-噻唑烷-2,4-二羧酸和抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物一起的药物形式可以被供应。然而,优先的制剂是包含两种独立药物形式的复合制剂,也就是一种为了2-甲基-噻唑烷-2,4-二羧酸以及另一种为了至少一种抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物。这样是有好处的,因为两种活性剂可以同时地被应用,但两种化合物使用的剂量以及两种化合物应用的特殊的时间可以是变化的。进一步的好处是,在添加抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物之前,同时或者之后应用只引起低副作用的化合物2-甲基-噻唑烷-2,4-二羧酸。在添加抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物之前可以代表6小时,12小时,18小时,24小时,30小时,36小时,42小时,48小时,54小时或者60小时之前。术语“同时地”理解为涉及两种情况,两种活性剂的添加是以一种单一形式以及一种活性剂的添加拖延至一个小时。在添加抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物之后可以是6小时,12小时,18小时,24小时,30小时,36小时,42小时,48小时,54小时或者60小时之后。优先的是,2-甲基-噻唑烷-2,4-二羧酸的添加在添加抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物之后并且特别优先实在24小时或者48小时之后。
因而,复合制剂优先地包含一种药物形式,它包含2-甲基-噻唑烷-2,4-二羧酸和/或其生理学上可耐受的盐以及至少一种其它药物形式,它包含抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物
除此之外,接下来的物质可以被用作抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物,也就是说,具有抗血管原性的和/或细胞毒素的和/或细胞抑制的特性的化学化合物:它包含烷化剂,具有细胞抑制特征的抗生素,抗代谢物,微管抑制剂和拓扑异构酶抑制剂,包含铂的化合物以及其它细胞抑制物(细胞抑制的和/或细胞毒素的活性剂)例如天冬酰胺酶,视黄醛,生物碱,足叶草毒素,紫杉醇和米替福新。
根据发明,2-甲基-噻唑烷-2,4-二羧酸和/或其生理学上可耐受的盐以及其它肿瘤治疗剂例如激素,免疫调节剂,单克隆抗体,信号转导子(信号转导分子)和细胞活素的结合也是可以运用的。
烷化剂的例子是,主要是氮芥,癌得星(cytoxan),曲洛磷胺,异环磷酰胺(Ifex),美法仑(Alkeran),盐酸氮芥(Mustargen),瘤可宁(Leukeran),白消安(Myleran),噻替派,卡氯芥,顺铂(Platinol),洛莫司汀,氮烯咪胺,甲苄肼,替莫唑胺,曲奥舒凡,雌莫司汀和尼莫司汀。
具有细胞抑制特征的抗生素的例子有柔红霉素以及脂质柔红霉素(Daunomycin,Cerubidine),阿霉素(adriamycin)以及脂质阿霉素,放线菌素,丝裂霉素C,博来霉素(Blenoxane),表柔比星(4-epi-adriamycin),伊达比星(Idamycin),放线菌素(Actinomycin D,Cosmegen),丝裂蒽醌(Novantrone),丝裂霉素C(Mitomycin),普卡霉素(Mithracin),安吖啶和放线菌素D。
甲氨蝶呤(MTX,Mexate),5-氟尿嘧啶(Fluoracil,5-FU),6-硫鸟嘌呤(Thioguanine,6-TG),6-巯基嘌呤,氟达拉滨(Fludara),氟尿苷(FUDR),克拉曲滨,喷司他丁,吉西他滨(Gemzar),阿糖胞苷(cytarabine),硫唑嘌呤,雷替曲噻,卡培他滨(Xeloda),阿糖胞苷(cytosine arabinoside),脱氧柯福霉素(Pentostatin,Nipent),硫鸟嘌呤和巯基嘌呤(6-MP,Purinethol)可以作为抗代谢物(抗代谢活性的物质)的例子。
生物碱和足叶草毒素类别中的例子是长春新碱,长春碱,长春地辛,依托泊苷以及替尼泊苷。进一步地,根据发明,包含铂的化合物可以被使用。作为包含铂的化合物可以是例如顺铂,佳铂帝和奥沙利铂。作为微管抑制剂是例如生物碱如长春花碱(长春新碱,长春碱,长春地辛,长春瑞宾)。在拓扑异构酶抑制剂中是例如依托泊苷(VP-16,Etopophos,VePesid)和替尼泊苷(VM-26,Vumon)以及在喜树碱中是例如拓扑替康(Hycamtin)和伊立替康(Camptosar)以及在亚硝基脲化合物中是卡氯芥(BCNU),洛莫司汀(CCNU)和链脲菌素(Zanosar)。可能的拓扑异构酶抑制剂是比如依托泊苷,替尼泊苷,喜树碱,拓扑替康和伊立替康。
帕尼特西和多西他赛是紫杉醇类别化合物的例子以及在其它细胞抑制活性剂(其它细胞抑制物)中是例如羟基脲(hydroxyurea),伊马替尼,米替福新,安吖啶,拓扑替康(topoisomerase-I inhibitor),喷司他丁,视黄醛,维他命A酸和门冬酰胺酶。单克隆抗体类别化合物的代表主要是曲妥珠单抗(也被已知为Herceptin),阿来组单抗(也被已知为MabCampath)和利妥昔单抗(也被已知为MabThera)。
根据发明,激素例如糖皮质激素(prednisone),氢化可的松,地塞米松(Decadron),雌激素[磷雌酚,雌莫司汀(Emcyt),三对甲氧苯氯乙烯(TACE),乙烯雌酚(DES)],芳香酶抑制物[安美达锭(Arimidex),LHRH(布舍瑞林,戈舍瑞林,亮丙瑞林,曲普瑞林),氟他胺(Eulexing),比卡鲁胺(Casodex),亮脯利特(Lupron),醋酸性瑞林(Zoladex),醋酸环丙孕酮,孕酮(Medoxyprogesterone acetate[(Depo-provera)],乙酸甲地孕酮(Megacel),它莫西芬,托瑞米芬,氨鲁米特,福美斯坦,依西美坦,来曲唑和阿那曲唑也可以被利用。在免疫调节剂,细胞活素,抗体和信号转导子类别中是白介素-2,干扰素-α,红细胞生成素,G-CSF,曲妥珠单抗(Herceptin),利妥昔单抗(MabThera),吉非替尼(Iressa),替伊莫单抗(Zevalin),左旋咪唑以及类维生素A。根据发明,进一步的可以被利用的活性物质是门冬酰胺酶(Elspar),培门冬酶(Oncaspar),羟基脲(Hydrea,Mylocel),甲苄肼(Matulane)和甲磺酸伊马替尼(Gleevec)。
更进一步地,复合剂以及在此描述的复合剂的使用是优先的,其中这些复合剂包含与2-甲基-噻唑烷-2,4-二羧酸和/或2-甲基-噻唑烷-2,4-二羧酸的盐以及一种抗血管原性的活性物质结合的一种细胞抑制物。
在抗血管原性的活性物质中主要是那些干扰或者阻碍血管形成的物质。因而,抗血管原性活性物质是特别地那些药物活性物质,它们干扰或者阻碍内皮细胞形成血管中的排列,移动,增殖和组织。抗血管原性物被特别称为抗血管原性的前提是,如果它们的抗血管原性特征是通过至少一个测试过程证明的,例如CAM测试。
抗血管原性的活性物质是比如根据它们的行动模式分类的并且也被称为血管生成抑制物和调节物。根据发明,以下根据行动模式分类的抗血管原性的活性物质可以被使用:
1.基质分解的抑制物(MMP抑制物:Neovastat,胞浆素抑制物);
2.内皮细胞增殖抑制物
-VEGF抑制物 bevamizumab,阿瓦斯丁,angiozyme
-PDGF抑制物 gleevec
-Plasminogene/胶原质XVIII抑制物:血管内皮抑制素,血管生成抑制剂
-抗血管的物质: combrestatin
-整联蛋白抑制剂: vitaxin
3.上游调节剂 (曲妥珠单抗,尔比得舒)
4.具未知模式的物质
-钙通道阻滞药: carboxyamido thiazole;
-COX-2-抑制物: 西乐葆;
-含氧量低的物质: 替拉扎明;
-NFkB调节剂
-镇静剂
在抗血管原性的物质中,特别是抗有丝分裂行为的物质,紫杉醇(帕尼特西,帕尼特西的衍生物(Taxol))和长春花碱(长春新碱,长春碱),阿霉素(adriamycin),阿霉素(doxorubicin),伊达比星,5-氟尿嘧啶,依托泊苷,精蛋白,甲氨蝶呤,依曲替酯,地塞米松以及镇静剂(Contergan,化学公式:(±)-N-(2,6-二氧代-3-哌啶基)phtalamide)。
因而,2-甲基-噻唑烷-2,4-二羧酸与一种抗血管原性物和一种活性物的复合剂是优先的。这个活性物质选自下组:它包含氮芥,癌得星,曲洛磷胺,异环磷酰胺,美法仑,瘤可宁,白消安,噻替派,卡氯芥,洛莫司汀,氮烯咪胺,甲苄肼,替莫唑胺,曲奥舒凡,雌莫司汀,尼莫司汀,柔红霉素以及脂质柔红霉素,阿霉素(adriamycin)以及脂质阿霉素,放线菌素,丝裂霉素C,博来霉素,表柔比星(4-表阿霉素),伊达比星,放线菌素,丝裂蒽醌,普卡霉素,放线菌素D,甲氨蝶呤,5-氟尿嘧啶,6-硫鸟嘌呤,6-巯基嘌呤,氟达拉滨,克拉曲滨,喷司他丁,吉西他滨,阿糖胞苷(cytarabine),硫唑嘌呤,雷替曲噻,卡培他滨,阿糖胞苷(cytosine arabinoside),硫鸟嘌呤,巯基嘌呤,长春新碱,长春碱,长春地辛,顺铂,佳铂帝,奥沙利铂,长春花碱,长春瑞宾,依托泊苷,替尼泊苷,喜树碱,拓扑替康,伊立替康,帕尼特西,多西他赛,羟基脲(hydroxyurea),伊马替尼,米替福新,安吖啶,拓扑替康(拓扑异构酶-1抑制剂),喷司他丁,视黄醛,维他命A酸,门冬酰胺酶,曲妥珠单抗,阿来组单抗,利妥昔单抗,糖皮质激素(泼尼松),雌激素(磷雌酚,雌莫司汀),LHRH(布舍瑞林,戈舍瑞林,亮丙瑞林,曲普瑞林),氟他胺,醋酸环丙氯地孕酮,它莫西芬,托瑞米芬,氨鲁米特,福美斯坦,依西美坦,来曲唑,阿那曲唑,白介素-2,干扰素-α,红细胞生成素,G-CSF,曲妥珠单抗(Herceptin),利妥昔单抗(MabThera),吉非替尼(Iressa),替伊莫单抗(Zevalin),左旋咪唑,其中顺铂,替莫唑胺和长春新碱是特别优先的。
在这个三重复合剂中,优先的抗血管原性物是帕尼特西。接下来的三重复合剂特别优先:2-甲基-噻唑烷-2,4-二羧酸与帕尼特西和顺铂,2-甲基-噻唑烷-2,4-二羧酸与帕尼特西和替莫唑胺,2-甲基-噻唑烷-2,4-二羧酸与帕尼特西和长春新碱。
特别优先的是2-甲基-噻唑烷-2,4-二羧酸和/或2-甲基-噻唑烷-2,4-二羧酸的盐与顺铂,替莫唑胺和/或长春新碱的结合。
根据发明的复合制剂以及包含2-甲基-噻唑烷-2,4-二羧酸的药物形式和包含至少一种抗血管原性的和/或细胞毒素的和/或细胞抑制物的药物形式可能进一步包含至少一种生理学上耐受的载体,衍生物,辅助剂和/或溶剂。
根据发明的复合制剂以及根据发明的复合制剂的药物形式是通过传统制药习惯利用传统固体或者液体载体或者稀释剂以及根据希望的用药方式和适宜的剂量使用通常制药辅助剂来制备的。这样的药物形式是例如药片,衣被药片,涂层药片,糖衣药片,胶囊,微粒胶囊,微粒药球和药球,药丸,药粒,粉末,干混粉末,溶液,分散液,悬浮液,栓剂,悬浮剂,凝胶,药膏,糖浆或者缓慢释放制剂或者吸入溶液以及吸入粉末。其次,根据发明的制药成分包含药物形式例如用于控制的和/或连续的活性剂释放的层片以及微粒包装作为特殊药物模式。
这样的成分是例如适合于吸入的或者静脉内的,腹膜内的,肌肉内的,皮下的,口的,直肠的,经过皮肤的(transdermal),局部的,皮层内的,胃内的,皮内的,叶鞘内的,鼻内的,颊内的,经肤的(percutaneous)或者下舌的用药方式。
特别具有优势的用药方式是口的和局部的用药,注射以及吸入。
相应的药片可以通过例如混合根据发明可利用的药物成分和/或其盐,并具有辅助剂例如惰性稀释剂比如葡萄糖,糖,山梨醇,甘露醇,聚乙烯吡咯烷酮,分解质比如玉米淀粉或者褐藻酸,连接剂例如淀粉或者白明胶,滑润剂比如硬脂酸镁或者滑石和/或用于达到缓慢释放效果的佐剂例如聚羧乙烯,羧甲基纤维素,纤维醋法酯或者聚乙烯乙酸酯。药片可以包含许多涂层。
相应地,糖衣药片可以通过包被核心制备,这类似于制备药片使用传统上用于糖衣的物质,例如聚乙烯吡咯烷酮或者虫漆,阿拉伯树胶,滑石,二氧化钛或者糖。因此,衣被也可以包含许多涂层,其中,如果是药片上述的辅助剂可以使用。
具有根据发明的活性剂的溶液或者悬浮液可以进一步地包含动剂例如糖精,环己烷氨基磺酸酯或者糖以及增香剂例如香草醛或者橘提取物。它们可以进一步包含悬浮剂例如羧甲基纤维素钠或者防腐剂例如p-羟基苯甲酸甲酯。包含活性成分的胶囊可以被生产,例如,通过混合活性物与惰性载体比如乳糖或者山梨醇并且将其包装在白明胶胶囊中。
适合的栓剂可以被生产,例如通过与相应物质例如中性脂肪或者聚乙二烯及其衍生物的混合。
这样的药物形式是例如适合于吸入的或者静脉内的,腹膜内的,肌肉内的,皮下的,口的,直肠的,经过皮肤的(transdermal),局部的,皮层内的,胃内的,皮内的,叶鞘内的,鼻内的,颊内的,经肤的(percutaneous)或者下舌的用药方式。
作为药理上可接受的载体可以使用例如乳糖,淀粉,山梨醇,蔗糖,硬脂酸镁,磷酸二钙,硫酸钙,滑石,甘露醇,酒精以及类似物。粉末以及药片可以包含从5到95%这样的载体。
此外,淀粉,白明胶,天然糖,天然的和合成的橡胶例如阿拉伯树胶或者瓜尔豆胶,海藻酸钠,羧甲基纤维素,聚乙二烯以及蜡可以作为连接剂使用。作为滑润剂可以使用硼酸,苯甲酸钠,乙酸钠,氯化钠以及类似物。
进一步地,分解质,染色剂,增味剂和/或连接剂可以天加入药物成分中。
液体形式包含液体,悬浮液,喷剂和乳剂例如以水或者水-丙二醇为基础的用于肠胃外注射的注射剂。
对于栓剂的制备,低熔点的蜡,脂肪酯和甘油酯是优先使用的。
胶囊是例如用甲基纤维素,聚乙烯醇或者变性的白明胶或者淀粉制成的。
可以作为分解质使用的是:淀粉,羧甲基淀粉钠,天然的及合成的橡胶例如刺槐豆胶,刺梧桐树胶,瓜尔豆胶,黄芪胶和琼脂以及纤维素衍生物例如甲基纤维素,羧甲基纤维素钠,微晶纤维素以及藻酸盐,粘土和膨润土。这些成分可以在重量百分比从2到30%的范围内使用。
糖,玉米脂肪,米或者马铃薯,天然橡胶例如阿拉伯树胶,白明胶,黄芪胶,褐藻酸,海藻酸钠,藻酸胺钙,甲基纤维素,羧甲基纤维素钠,羟丙基甲基纤维素,聚乙烯吡咯烷酮以及无机化合物例如镁铝硅酸可以作为连接剂添加。连接剂可以在重量百分比从1到30%的范围内添加。
作为滑润剂可以使用的是:硬脂酸盐例如硬脂酸镁,硬脂酸钙,硬脂酸钾,硬脂酸,高熔点蜡以及水溶滑润剂例如氯化钠,苯甲酸钠,乙酸钠,油酸钠,聚乙二烯和氨基酸例如亮胺酸。这些润滑剂可以在重量百分比从0.05到15%的范围内添加。
根据发明的复合制剂特别使用于癌症的治疗。它不限制于特别的癌瘤,肿瘤或者癌症类型。迹象是特别根据使用的抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物类型,也就是说,在癌症种类中这些抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物至今作为单一物质使用。
根据发明,复合制剂可以使用在以下肿瘤以及癌症类型中:急性的和慢性的骨髓性白血病,急性的和慢性的淋巴性白血病,肛门癌,星细胞瘤,基细胞癌,小细胞和非小细胞支气管癌,伯基特氏淋巴瘤,CUP-综合病症,小肠肿瘤,子宫内膜癌,室鼓膜瘤,Ewing氏肉瘤,胆囊和胆道癌,成胶质细胞瘤,毛细胞白血病,脑肿瘤(神经胶质瘤),脑转移瘤,睪丸癌症,何杰金病,脑下垂体肿瘤,类癌,卡波济肉瘤,喉癌,胚组织瘤,骨癌,头和颈肿瘤,大肠癌,颅咽管瘤,在嘴附近和嘴唇上的癌,肝细胞癌,肝癌转移,眼睑肿瘤,胃癌,恶性黑素瘤,乳房癌,髓母细胞瘤,脑膜瘤,蕈状肉芽肿,神经鞘瘤,肾细胞癌,非霍金淋巴瘤,小突神经瘤,食管癌,骨肉瘤,卵巢癌,胰腺癌,阴茎癌,浆细胞瘤,前列腺癌,直肠癌,眼癌,甲状腺癌,脊髓癌,胸腺瘤,输卵管癌,眼肿瘤,尿道癌,泌尿道上皮癌,外阴癌,疣症状,软组织肿瘤,威尔斯氏肿瘤,子宫颈癌和舌癌。
具体实施方式
实例1:
进行2-甲基-噻唑烷-2,4-二羧酸和N-乙酰半胱氨酸的细胞毒在人肿瘤细胞株的体外测试。
使用的物质:
2-甲基-噻唑烷-2,4-二羧酸(MTDC),由Trommsdorff GmbH & Co.KG,Alsdorf(MTDC:40mg/ml在蒸馏去离子水中),
N-乙酰半胱氨酸40mg/ml在水中,
替莫唑胺5mg/ml在DMSO中。
细胞培养:
细胞保持在培养介质RPMI 1640(Sigma,Munich)及10%FCS(Sigma,Munich),50ml的细胞培养瓶(Greiner),37℃以及含5%CO2的空气中,并且每周移入新的培养瓶一到两次。
使用的细胞株:
神经胶质瘤细胞 H4
膀胱癌细胞 EJ
细胞毒测试:
通过分散2×106个肿瘤细胞在96孔培养盘(Greiner)上制备出单层肿瘤细胞。在培养了24小时之后,培养介质被换作含有测试化合物的介质。所有的测试都进行四次。
72小时后,活细胞数通过与结晶紫染色确定。
为此,培养盘里每个洞里的介质被排除,培养盘用PBS溶液洗两次,细胞用含1%多聚甲醛的PBS溶液固定,室温干燥15分钟。接着,细胞用PBS溶液冲洗并且室温干燥。然后,细胞在水中用1%的结晶紫染色两分钟,在用水冲洗之后理想密度是利用ELISA分光计在595nm测试。四次平行测试的平均值和平均值的标准偏差都被测定。
结果:
在人神经胶质瘤细胞H4中,2-甲基-噻唑烷-2,4-二羧酸具有显著的细胞毒效应。IC50值发现为9.66μg/ml。N-乙酰半胱氨酸达到相对高的浓度,仍然没有效果。
进一步地,膀胱癌细胞株EJ的生长并没有受到2-甲基-噻唑烷-2,4-二羧酸的影响。
然而,如果2-甲基-噻唑烷-2,4-二羧酸与细胞抑制的替莫唑胺一起使用,相比较于有2-甲基-噻唑烷-2,4-二羧酸时用替莫唑胺的测试,EJ细胞对于替莫唑胺有显著增加的敏感性。替莫唑胺单独使用时IC50值为1053.36μg/ml。在2-甲基-噻唑烷-2,4-二羧酸含量为200μg/ml的情况下,IC50值降低为96.58μg/ml。
相对的,在N-乙酰半胱氨酸含量为1000μg/ml的情况下,替莫唑胺没有增加对于EJ细胞的影响(替莫唑胺单独使用时IC50值:1053.36μg/ml;在N-乙酰半胱氨酸含量为1000μg/ml的情况下,替莫唑胺的IC50值为:903.24μg/ml)。
相比较与单个细胞抑制物的使用以及通过N-乙酰半胱氨酸的细胞抑制的或细胞毒素的或抗细胞原性物的使用时,效应没有影响或者只有低程度的影响,这些测试数据证明了未预料的细胞抑制物与2-甲基-噻唑烷-2,4-二羧酸结合时的效应增长。
实例2
使用的物质:
2-甲基-噻唑烷-2,4-二羧酸的钠盐(MTDC-Na)(Trommsdorff GmbH &Co.KG Arzneimittel);
·顺铂(从Alfa可以买到);
·替莫唑胺(从Essex Pharma可以买到);
·长春新碱(从Medac可以买到)。
以下储液被使用:
·MTDC-Na 40mg/ml(溶解在蒸馏水),
·顺铂,0.5mg/ml(溶解在蒸馏水),
·替莫唑胺,5mg/ml(溶解在DMSO),
·长春新碱1mg/ml(溶解在蒸馏水)。
以下细胞株杯检验:
·神经胶质瘤H4
·膀胱癌EJ
·前列腺癌DU145
细胞培养:
细胞被保持在培养溶液RPMI1640(Sigma,Munich),及10%FCS(Sigma,Munich),50ml的细胞培养瓶(Greiner),37℃以及含5%CO2的空气中。
细胞毒测试:
通过分散2×106个肿瘤细胞在96孔培养盘(Greiner)上制备出单层肿瘤细胞。
在培养了30(t=0)小时之后,培养介质被换作含有抗癌物制剂的介质。
在培养了24(t=+24h)小时之后,抗癌物被排除并且换为培养介质。
当现在的培养介质被换作包含MTDC-Na的新鲜培养介质时,MTDC-Na被加入。
所有的测试进行三次。
抗癌制剂的以下浓度被使用:
·替莫唑胺的浓度为0-1000μg/ml,
·长春新碱的浓度为0-200ng/ml,
·顺铂的浓度为0-25μg/ml。
在培养126小时后,细胞被收集并且活细胞的数量通过与结晶紫染色确定。
为此,培养介质被排除,培养孔盘用PBS溶液洗两次并且接着细胞用含1%多聚甲醛的PBS溶液室温固定15分钟。然后,培养盘用PBS溶液冲洗两次并且室温干燥。细胞在水中用1%的结晶紫染色两分钟。
在用水冲洗之后理想密度是利用ELISA-指示仪在595nm测试。三次测试系列的平均值和平均值的标准偏差都被测定。
IC50值的测定是通过标定活性剂浓度比理想浓度。
结果显示在表1中:
表1:在与其它细胞毒素的和/或细胞抑制的化合物结合时,MTDC-Na的细胞毒活性的增加
细胞株 | 细胞毒素的和/或细胞抑制的化合物 | 活性的增加IC50值的降低 |
前列腺癌DU 145 | 顺铂/MTDC-Na(1000μg/ml) | 2-倍(fold) |
前列腺癌DU 145 | 长春新碱/MTDC-Na(1000μg/ml) | 2.7-倍 |
膀胱癌EJ | 顺铂/MTDC-Na(1000μg/ml) | 10-倍 |
膀胱癌EJ | 替莫唑胺/MTDC-Na(1000μg/ml) | 67-倍 |
膀胱癌EJ | 长春新碱/MTDC-Na(1000μg/ml) | 6-倍 |
膀胱癌EJ | 长春新碱/MTDC-Na(1000μg/ml) | 4.8-倍 |
神经胶质瘤H4 | 顺铂/MTDC-Na(200μg/ml) | 4-倍 |
神经胶质瘤H4 | 替莫唑胺/MTDC-Na(200μg/ml) | 15-倍 |
Claims (11)
1、一种复合制剂,其特征在于,包含2-甲基-噻唑烷-2,4-二羧酸和/或其生理学上可耐受的盐和至少一种细胞毒素的和/或细胞抑制的化合物。
2、根据权利要求1所述的复合制剂,其特征在于所述复合制剂包含一种药物形式,所述药物形式包含2-甲基-噻唑烷-2,4-二羧酸和/或其生理学上可耐受的盐,以及至少一种其它药物形式,所述其它药物形式包含至少一种抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物。
3、根据权利要求1或者2所述的复合制剂,其特征在于,进一步包含至少一种生理学上可耐受的载体,添加剂,辅助剂和/或溶剂。
4、根据权利要求1至3中任一项所述的复合制剂,其特征在于,其中所述抗血管原性的和/或细胞毒素的和/或细胞抑制的化合物是选自于烷化剂(alkylating agent),具有细胞抑制特征的抗生素(antibotic),抗代谢物(antimetabolite),微管抑制剂(microtubule inhibitor),拓扑异构酶抑制剂(topoisomerase inhibitor),包含铂的化合物,生物碱(alkaloid),足叶草毒素(podophyllotoxin),紫杉醇(taxane),激素(hermone),免疫调节剂(immunomodulator),单克隆抗体(monoclonal antibodies),信号转导子(signaltransductor)(信号转导分子)和细胞活素(cytokine)所组成的族群。
5、根据权利要求4所述的复合制剂,其特征在于,其中所述烷化剂,所述具有细胞抑制特征的抗生素,所述抗代谢物,所述微管抑制剂,所述拓扑异构酶抑制剂,所述包含铂的化合物,所述生物碱,所述足叶草毒素,所述紫杉醇,所述激素,所述免疫调节剂,所述单克隆抗体,所述信号转导子(信号转导分子)和所述细胞活素是选自于氮芥(chlorethamine),癌得星(cyclophosphamide),曲洛磷胺(trofosfamide),异环磷酰胺(ifosfamide),美法仑(melphalan),瘤可宁(chlorambucil),白消安(busulfan),噻替派(thiotepa),卡氯芥(carmustine),洛莫司汀(lomustine),氮烯咪胺(dacarbazine),甲苄肼(procarbazine),替莫唑胺(temozolomide),曲奥舒凡(treosulfan),雌莫司汀(estramustine),尼莫司汀(nimustine),柔红霉素(daunorubicin)以及脂质柔红霉素,阿霉素(doxorubicin),阿霉素(adriamycin)以及脂质阿霉素,放线菌素(dactinomycin),丝裂霉素C(mitomycin C),博来霉素(bleomycin),表柔比星(epriubicin)(4-表阿霉素(4-epi-adriamycin)),伊达比星(idarubicin),放线菌素(dactinomycin),丝裂蒽醌(mitoxantrone),丝裂霉素C(mitomycin C),普卡霉素(plicamycin),安吖啶(amsacrine),放线菌素D(actinomycin D),甲氨蝶呤(methotrexate),5-氟尿嘧啶(5-fluorouracil),6-硫鸟嘌呤(6-thioguanine),6-巯基嘌呤(6-mercaptopurine),氟达拉滨(fludarabine),克拉曲滨(cladribine),喷司他丁(pentostatin),吉西他滨(gemcitabine),阿糖胞苷(cytarabine),硫唑嘌呤(azathioprine),雷替曲噻(raltitrexed),卡培他滨(capecitabine),阿糖胞苷(cytosine arabinoside),硫鸟嘌呤(thioguanine),巯基嘌呤(mercaptopurine),长春新碱(vincristine),长春碱(vinblastine),长春地辛(vindesine),依托泊苷(etoposide),替尼泊苷(teniposide),顺铂(cisplatin),佳铂帝(carboplatin),奥沙利铂(oxaliplatin),长春花碱(vinca alkaloids),长春瑞宾(vinorelbine),依托泊苷(etoposide),替尼泊苷(teiposide),喜树碱(camptothecin),拓扑替康(topotecan),伊立替康(irinotecan),帕尼特西(paclitaxel),多西他赛(docetaxel),羟基脲(hydroxycarbamide)(hydroxyurea),伊马替尼(imatinib),米替福新(miltefosine),安吖啶(amsacrine),拓扑替康(拓扑异构酶-1(topoisomerase-1)抑制剂),喷司他丁(pentostatin),视黄醛(bexarotene),维他命A酸(tretinoin),门冬酰胺酶(asparaginase),曲妥珠单抗(trastuzumab),阿来组单抗(alemtuzumab),利妥昔单抗(rituximab),糖皮质激素(glucocorticoids)(泼尼松(prednisone)),雌激素(estrogens)(磷雌酚(fosfestrol),雌莫司汀(estramustine)),促黄体激素释放激素(LHRH)(布舍瑞林(buserelin),戈舍瑞林(goserelin),亮丙瑞林(leuprorelin),曲普瑞林(triptorelin)),氟他胺(flutamide),醋酸环丙氯地孕酮(cyproterone acetate),它莫西芬(tamoxifen),托瑞米芬(toremifen),氨鲁米特(aminoglutethimide),福美斯坦(formestane),依西美坦(exemestane),来曲唑(letrozole),阿那曲唑(anastrozole),白介素-2(interleukin-2),干扰素-α(interferon-α),红细胞生成素(erythropoietin),粒细胞集落刺激因子(G-CSF),曲妥珠单抗(trastuzumab),利妥昔单抗(rituximab),吉非替尼(gefitinib),替伊莫单抗(ibritumomab),左旋咪唑(levamisole)以及类维生素A(retinoids)所组成的族群。
6、根据权利要求5所述的复合制剂,其特征在于,其中所述烷化剂,所述具有细胞抑制特征的抗生素,所述抗代谢物,所述微管抑制剂,所述拓扑异构酶抑制剂,所述包含铂的化合物,所述生物碱,所述足叶草毒素,所述紫杉醇,所述激素,所述免疫调节剂,所述单克隆抗体,所述信号转导子(信号转导分子)和所述细胞活素是选自于顺铂,替莫唑胺和长春新碱所组成的族群。
7、一种根据权利要求1至5中任一项所述的复合制剂的用途,其特征在于,是用于肿瘤和癌症的预防和/或治疗。
8、根据权利要求7所述的根据权利要求1至5中任一项所述的复合制剂的用途,其特征在于,其中有关的所述肿瘤和所述癌症是急性的和慢性的骨髓性白血病(myeloid leukemia),急性的和慢性的淋巴性白血病(lymphatic leukemia),肛门癌(anal carcinoma),星细胞瘤(astrocytoma),基细胞癌(basal cell carcinoma),小细胞和非小细胞支气管癌(cell bronchialcarcinoma),伯基特氏淋巴瘤(Burkitt’s lymphoma),CUP-综合病症(CUP-syndrome),小肠肿瘤(small intestine tumors),子宫内膜癌(endometrialcarcinoma),室鼓膜瘤(ependymoma),Ewing氏肉瘤(Ewing’s tumors),胆囊和胆道癌(gall bladder and bile duct carcinoma),成胶质细胞瘤(glioblastoma),毛细胞白血病(hairy cell leukemia),脑肿瘤(brain tumors)(神经胶质瘤(gliomas)),脑转移瘤(brain metastases),睾丸癌症(testicle cancer),何杰金病(Hodgkin’s disease),脑下垂体肿瘤(hypophysis tumors),类癌(carcinoids),卡波济肉瘤(Kaposi’s sarcoma),喉癌(laryngeal cancer),胚组织瘤(germ celltumor),骨癌(bone cancer),头和颈肿瘤(head and neck tumors),大肠癌(coloncarcinoma),颅咽管瘤(craniopharyngiomas),在嘴附近和嘴唇上的癌,肝细胞癌(liver cell carcinoma),肝癌转移(liver metastases),眼睑肿瘤(eyelidtumor),胃癌(stomach cancer),恶性黑素瘤(malignant melanoma),乳房癌(breast carcinoma),髓母细胞瘤(medulloblastomas),脑膜瘤(meningiomas),蕈状肉芽肿(mycosis fungoides),神经鞘瘤(neurinoma),肾细胞癌(renal cellcarcinoma),非霍金淋巴瘤(Non-Hodgkin’s lymphomas),小突神经瘤(oligodendroglioma),食管癌(esophageal carcinoma),骨肉瘤(osteosarcoma),卵巢癌(ovarian carcinoma),胰腺癌(pancreatic carcinoma),阴茎癌(penilecarcinoma),浆细胞瘤(plasmocytoma),前列腺癌(prostate carcinoma),直肠癌(rectal carcinoma),眼癌(retinoblastoma),甲状腺癌(thyroid carcinoma),脊髓癌(spinalioma),胸腺瘤(thymoma),输卵管癌(tube carcinoma),眼肿瘤(eyetumors),尿道癌(urethral cancer),泌尿道上皮癌(urothelial carcinoma),外阴癌(vulva carcinoma),疣症状(wart appearance),软组织肿瘤(soft tissuetumors),威尔斯氏肿瘤(Wilm’s tumor),子宫颈癌(cervical carcinoma)和舌癌(tongue ancer)。
9、一种2-甲基-噻唑烷-2,4-二羧酸和/或生理学上可耐受的盐的用途,其特征在于,是用于增加细胞抑制物的功效。
10、根据权利要求9所述的2-甲基-噻唑烷-2,4-二羧酸和/或生理学上可耐受的盐的用途,其特征在于,其中细胞抑制物是选自于烷化剂,具有细胞抑制特征的抗生素,抗代谢物,微管抑制剂,拓扑异构酶抑制剂,包含铂的化合物,生物碱,足叶草毒素,紫杉醇,激素,免疫调节剂,单克隆抗体,信号转导子(信号转导分子)和细胞活素所组成的族群。
11、根据权利要求10所述的2-甲基-噻唑烷-2,4-二羧酸和/或生理学上可耐受的盐的用途,其特征在于,其中它包含烷化剂,具有细胞抑制特征的抗生素,抗代谢物,微管抑制剂,拓扑异构酶抑制剂,包含铂的化合物,生物碱,足叶草毒素,紫杉醇,激素,免疫调节剂,单克隆抗体,信号转导子(信号转导分子)和细胞活素选自下组,它包含氮芥,癌得星,曲洛磷胺,异环磷酰胺,美法仑,瘤可宁,白消安,噻替派,卡氯芥,洛莫司汀,氮烯咪胺,甲苄肼,替莫唑胺,曲奥舒凡,雌莫司汀,尼莫司汀,柔红霉素以及脂质柔红霉素,阿霉素以及脂质阿霉素,放线菌素,丝裂霉素C,博来霉素,表柔比星(4-表阿霉素),伊达比星,放线菌素,丝裂蒽醌,普卡霉素,安吖啶,放线菌素D,甲氨蝶呤,5-氟尿嘧啶,6-硫鸟嘌呤,6-巯基嘌呤,氟达拉滨,克拉曲滨,喷司他丁,吉西他滨,阿糖胞苷,硫唑嘌呤,雷替曲噻,卡培他滨,阿糖胞苷,硫鸟嘌呤,巯基嘌呤,长春新碱,长春碱,长春地辛,依托泊苷,替尼泊苷,顺铂,佳铂帝,奥沙利铂,长春花碱,长春瑞宾,替尼泊苷,喜树碱,拓扑替康,伊立替康,帕尼特西,多西他赛,羟基脲,伊马替尼,米替福新,安吖啶,拓扑替康(拓扑异构酶-1抑制剂),喷司他丁,视黄醛,维他命A酸,门冬酰胺酶,曲妥珠单抗,阿来组单抗,利妥昔单抗,糖皮质激素(泼尼松),雌激素(磷雌酚,雌莫司汀),促黄体激素释放激素(布舍瑞林,戈舍瑞林,亮丙瑞林,曲普瑞林),氟他胺,醋酸环丙氯地孕酮,它莫西芬,托瑞米芬,氨鲁米特,福美斯坦,依西美坦,来曲唑,阿那曲唑,白介素-2,干扰素-α,红细胞生成素,粒细胞集落刺激因子,曲妥珠单抗,利妥昔单抗,吉非替尼,替伊莫单抗,左旋咪唑以及类维生素A。
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US6596712B2 (en) * | 1996-04-26 | 2003-07-22 | Genaera Corporation | Treatment of carcinomas using squalamine in combination with other anti-cancer agents or modalities |
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