CN1128949A - 蛋白下垂诱导组合物 - Google Patents
蛋白下垂诱导组合物 Download PDFInfo
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- CN1128949A CN1128949A CN95190477A CN95190477A CN1128949A CN 1128949 A CN1128949 A CN 1128949A CN 95190477 A CN95190477 A CN 95190477A CN 95190477 A CN95190477 A CN 95190477A CN 1128949 A CN1128949 A CN 1128949A
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- cell
- sagging
- albumen
- deriv
- apoptosis inducer
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Abstract
本发明提供了一种蛋白下垂诱导组合物，含有药理学有效量的作为活性成分的至少一种选自下式(1)其中R为氢原子或低级烷基，所表示的菲衍生物及其盐的物质，和药用可接受的无毒的载体。
本发明的蛋白下垂诱导组合物具有诱导和促进蛋白下垂的能力，由于具有该能力，它有效地用于医药领域中，例如作为抗癌剂，自体免疫病和肝病如肝炎和肝硬变的治疗剂，肿瘤转移的抑制剂等。
Description
技术领域
本发明涉及一种新的蛋白下垂(apotosis)诱导组合物。
本发明的公开
本发明的蛋白下垂诱导组合物包含作为一种活性成份的至少一种选自下式(1)所表示的菲衍生物及其盐的物质其中R为氢原子或低级烷基(下文称作化合物(1))。
以上化合物(1)及其生产过程已公开在例如，日本公开特许公报第211035/1992号和第1746/1994号中。该化合物作为白细胞介素-1抑制剂的用途也是已知的。
本发明的发明入对化合物(1)进行了进一步研究，并且发现该化合物具有由该化合物所述已知作用难以预知的蛋白下垂诱导(诱导或促进)活性。
同时，已知细胞死亡包含两类机理。其一是传统类型的细胞死亡，称为坏死。坏死在形态学上的特征在于，线粒体显著膨胀，细胞质和细胞核交替膨胀，然后细胞破坏和自溶以后。它的发生是被动的或偶然的。组织坏死一般是由，例如，细胞体损伤或化学毒素引起的。
另一类细胞死亡称为蛋白下垂(程序细胞死亡)[Kerr，J.F.R.和Wyllie，A.H.，Br.J.Cancer，265.239(1972)]。已知蛋白下垂能在各种生理条件下发生。蛋白下垂(apotosis)的特征为相邻细胞失去接触，细胞质浓缩，与核酸内切酶活性有关的染色体凝聚并固缩，以及细胞核分裂。也可观察到微绒毛从细胞表面消失和细胞表面(细胞表面上的绒毛膜结构：膜泡)变光滑。也可进一步观察到由于核酸内切酶活化，细胞核体的DNA单元断裂成180-200个碱基大小的DNA片段。下垂蛋白体细胞的最终碎片被相邻细胞吞噬。这是Duvall和Wyllie[Duvall，E.和Wyllie，A.H.，Immunology Today，7(4)，115-119(1986)；Science，245，301-305(1989)]讨论的机理。Wyllie进一步报道了糖肾上腺皮质激素诱导的胸腺细胞的蛋白下垂与细胞内核酸内切酶活化有关[Wyllie，A.H.，Nature，284，555-556(1986)]。可通过琼脂糖凝胶电泳容易地证实核酸内切酶活性引起的蛋白下垂细胞内的DNA断裂为低聚核苷酸。
上述的蛋白下垂可被认为是在组织的发育、分化、转化过程中所见的前序细胞的死亡[Wyllie，A.H.，等Int.Rev.Cytol，68，251-306(1980)]。
胸腺细胞中钙离子体的钙浓度或cAMP浓度的提高促进以上述蛋白下垂为特性的DNA断裂[Wyllie，A.H.，等J.Pathol.，142，67-77(1984)]，并且因此钙离子和/或cAMP可能与蛋白下垂的机理有关。作为目前报道的一个实例可提到由视黄酸或钙离子体诱导分化的HL-60细胞的蛋白下垂[Martin，S.J.，等，J.Immunol.，145，1859-1867(1990)；Martin，S.J.，等，Clin.Exp.Immunol.，79，448-453(1990)]。
据报道，蛋白下垂不仅是在胚胎发生过程中的细胞的生理死亡和活细胞周期中普通细胞的生理死亡(例如，肝脏、肾上腺皮质和前列腺细胞)中发生，同时也受糖肾上腺皮质激素治疗、细胞毒性T细胞造成的细胞损伤、激素依赖组织的萎缩、辐射、NK细胞、杀伤细胞、肿瘤坏死因子(TNF)、淋巴毒素(LT)、其他细胞激活素等的诱导。[Wyllie，A.H.，等，Int.Rev.Cytol.，68，251(1980)；Duvall，E.和Wyllie，A.H.，Immunology Today，7，115-119(1986)；Sellins，K.S.，等，J.Immunol.，139，3199(1987)：Yamada，T.，等，Int.J.Radiat.Biol.，53，65(1988)；Wyllie，A.H.，Nature，284.555(980)；Schmid，D.S.，等，Proc.Natl.Acad.Sci.USA，83，1881-1885(1986)；John，C.，等，J.Imunol.，129(4)，1782-1787(1982)；Howell，D.M.，等，J.Immunol.，140，689-692(1988)；Gillian，B.，等，Eur.J.Immunol.，17，689-693(1987)]。
另外，某些抗体也会引发蛋白下垂，例如抗-CD3、抗-APO-I和抗-Fas抗体[Trauth，B.C.，等，Science，245，301-305(1989)：Smith，C，A.，等，Nature，337，181-184(1989)；Tadakuma，T.等，Eur.J.Immunol.，20，779(1990)]并且，Nakamura等由恶性肿瘤的自发消退进一步证实了诱导的蛋白下垂[Nakamura，Y.，等，Ri nsho Hifuka(Jpn，J.Clin，Dermatol.)，35(4)，289-295(1981)]。
有报道描述了亚胺环己酮(一种蛋白合成抑制剂)对急性白血病细胞，抗菲霉菌素(actinomycin)D(一种RNA合成抑制剂)对小肠腺细胞和两者共对HL-60细胞的蛋白下垂的诱导作用[Matin，S.J.，等，J.Immunol.，145，1859-1867(1990)]。
近年来，已用抗-Apo-I抗体的癌症治疗尝试进行与蛋白下垂有关的治疗。在脑脊髓综合症(MDS)，(胚细胞成长活化的RAEB和RAEB的转化(RAEB-t)中)，鬼臼乙叉甙和阿桑比星是蛋白下垂促进剂，能够抑制胚细胞成长，[Shibuya，T.，J.Clinical andExperimental Medicine，160(5)，319-323(1992)]。
Murakami等报道了约半数以上表达抗红细胞自体抗体的反基因小白鼠证明是因失去自体耐受力造成的自体免疫病，这是由于普通小白鼠体内产生细胞反应的自体抗体抗原诱导蛋白下垂而引起消除自体抗体细胞能力的缺乏[Murakami，M.等，Nature，357，77-80(1992)]
Watanabe-Fukunaga等指出，对于MRL lpr/lpr小白鼠，有关蛋白下垂的Fas分子异常，并且自体反应T细胞的被动选择(蛋白下垂)机制在胸腺中不能正常起作用。结果产生了自体免疫病[Watanabe-Fukunaga，R.，等，Nature，356，314-317(1992)]。
另一方面，已知在肝脏中，分裂素诱导肝细胞成长而产生增生状态，该状态通过肝细胞的衰退和死亡(即蛋白下垂)从而恢复正常[Kerr，J.F.，等，Br.J.Cancer，26，239-257(1972)]。
考虑到在从慢性肝炎转变为肝硬变，进一步发展成肝癌的过程中，蛋白下垂处于受控状态下，因此细胞毒性T细胞可诱发肝细胞发炎，然后是纤维变性，引起肝硬变的加重，因此，促进蛋白下垂可以抑制肝炎从而进一步预防肝硬变。
本发明提供了一种蛋白下垂诱导组合物，包含作为活性组分的药理学有效量的至少一种选自式(1)的化合物及其盐的物质，和无毒的药用可接受的载体。
本发明的蛋白下垂诱导组合物具有诱导或促进蛋白下垂的能力，由于具有该能力，它在医药领域中是有效的，如上文所述例如可作为抗癌剂，用作自体免疫病和肝病如肝炎和肝硬变的治疗剂，肿瘤转移的抑制剂等等。
表示化合物(1)的式(1)中，低级烷基包括直链或支链的C1-5的烷基，如甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、己基等。
在适于用作活性成分的化合物(1)中，具有酸性基团的化合物易于与碱性化合物转化成药用可接受的盐类。这些盐可与自由化合物一样用作活性成份。上述的碱性化合物的例子如碱金属或碱土金属的氢氧化物，碳酸盐或氢化物，如氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠、碳酸钾、碳酸氢钠、氢化钠等。也可用作形成盐的碱性化合物为有机胺类，如甲胺、乙胺、异丙胺、吗啉、哌嗪、哌啶、3，4-二甲氧基苯乙胺等。与碱性化合物成盐的反应可采用常用的方式，例如，上述的公开物中描述的方法。
本发明的活性成份化合物当然也包括立体异构体和光学异构体。
本发明中作为蛋白下垂诱导组合物活性成份的化合物(1)及其盐以常用药物制剂的形式来使用。采用常用的填充剂、增量剂、粘合剂、保湿剂、崩解剂、表面活性剂、润滑剂和作为无毒载体的类似的稀释剂或赋形剂来制备此类制剂。该药物制剂可根据治疗目的来选择剂量形式，其典型实例为片剂，丸剂，粉剂，溶液剂，悬浮剂，乳剂，颗粒剂，胶囊剂，栓剂，注射剂(溶液，悬浮液等)，滴眼剂等。
可采用本领域所熟知的各种载体来制造片剂，因此例如可采用赋形剂如乳糖、蔗糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸，粘合剂如水、乙醇、丙醇、单糖浆、葡萄糖溶液、淀粉溶液，明胶溶液、羧甲基纤维素、紫胶、甲基纤维素、磷酸钾和聚乙烯吡咯烷酮，崩解剂如干淀粉、藻酸钠、粉状琼脂、粉状昆布糖、碳酸氢钠、碳酸钙、聚氧乙烯脱水山梨醇脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘油酯、淀粉和乳糖，崩解抑制剂如蔗糖、三硬脂酸甘油酯、可可脂和氢化油，吸收促进剂如季铵碱和十二烷基硫酸钠，润湿剂或湿润剂如甘油和淀粉，吸附剂如淀粉、乳糖、高岭土、膨润土和硅胶，润滑剂如精制滑石粉、硬脂酸盐、粉状硼酸和聚乙二醇。如必要，可用常用的包衣材料对片剂包衣，例如糖衣片、明胶衣片、肠溶衣片、薄膜衣片或双层衣或多层衣片。
可采用本领域所熟知的各种载体来制造丸剂。例如可采用赋形剂如葡萄糖、乳糖、淀粉、可可脂、硬化植物油、高岭土和滑石粉，粘合剂如粉状阿拉伯树胶、粉状黄蓍胶、明胶和乙醇，崩解剂如昆布糖和琼脂。
可采用本领域所熟知的各种载体来制造栓剂。例如，上述的聚乙二醇、可可脂、高级醇、高级醇酯、明胶和半合成甘油酯。
制备注射剂时，优选灭菌的和与血液具有等渗性的溶液或悬浮液，并且在制备如溶液，乳液或悬浮液剂型时，可采用本领域常用的所有稀释剂。例如可提及的，水、乙醇、丙二醇、乙氧化异硬脂酵、聚氧异硬脂醇和聚氧乙烯脱水山梨醇脂肪酸酯。这样，该药物制剂还可含有足量的氯化钠、葡萄糖或甘油成为等渗性溶液。可加入常用的增溶剂，缓冲剂，减痛剂，等。
另外，如必要，本发明的蛋白下垂诱导组合物可含有着色剂、防腐剂、增香剂、芳香剂、甜味剂等以及其它药物。
前述的本发明药物组合物中活性成分化合物的比例并非关键，但可在一宽范围内适当选取。而通常，该比例建议选择在组合物重量的1-70％的范围内，优选为1-30％(重量比)。
前述药物制剂的给药途径并非关键，但应根据剂型、患者的年龄、性别和其它因素以及所治疗的病症的严重程度进行选择。这样，例如，给患者的剂型为片剂、丸剂、溶液剂、悬浮剂、乳剂、颗粒剂或胶囊剂，则该制剂以口服给药。注射溶液为静脉给药，可单独给药或混有含葡萄糖、氨基酸等的常用非肠道输注液。如必要，该制剂可经肌内、皮内、皮下或腹膜内途径给药。栓剂为直肠给药。滴眼剂当然应滴入眼睛。
而上述药物制剂的剂量根据给药方法，患者的年龄、性别和其它背景因素，病症的严重程度等来进行适当选择，通常建议每千克体重每天给于约0.1至约1000mg的活性成分，即化合物(1)。每个剂量单元所含的活性成份的量为约1至600mg。
本发明的蛋白下垂诱导组合物可根据其蛋白下垂的诱导或促进活性用于各种疾病，并且预期对治疗这些疾病在药理上有效。这些疾病包括，例如，癌症，AIDS、ARS(与AIDS有关的综合症)，ATL(成熟T细胞性白血病)，毛状细胞性白血病，脊髓病(HAM/TSP)，呼吸疾病(HAB/HABA)，关节病(HAAP)，眼色素层炎(HAU)，其它与HTLVI有关的疾病，自体免疫病如SLE(系统性红斑狼疮)，胶原疾病如类风湿性关节炎(RA)，溃疡性结肠炎，斯耶格伦综合症，初期胆肝硬变，自发性血小板减少性紫瘢(ITP)，自体免疫溶血性贫血，maysthenia grayis，(桥本)淋巴瘤性甲状腺肿，和胰岛素依赖性(1型)糖尿病。本发明的蛋白下垂诱导组合物也可用于各种血小板减少症的并发疾病，例如脊髓发育不良综合症，周期性血小板减少症，再生障碍性贫血，自发性血小板减少症，播散性血管内凝血，等。本发明的组合物还可进一步用于各种其它疾病包括各类肝炎(如C、A、B和F类型)，进行性脑变性，阿尔茨海默型早老性痴呆，心肌炎，ARDS(成人呼吸窘迫综合症)，传染症，肝硬变，前列腺肥大，子宫肌瘤，支气管哮喘，动脉硬化，各种先天性畸形，肾炎，老年性白内障，慢性疲劳综合症和肌营养不良。
本发明的蛋白下垂诱导组合物，例如作为抗癌组合物给药时，能诱导和促进癌细胞的蛋白下垂从而产生抗癌效果。这样，如不考虑剂型和/或给药途径，本发明的组合物可与一种或多种已知作为癌症化疗剂和/或放射疗法的抗癌剂联合使用。本发明能产生良好抗癌效果的活性成份化合物还能显著促进其它并用抗癌剂的效果而产生协同作用。因此，在采用较常用剂量小得多的配合抗癌剂剂量时，也能得到满意的抗癌效果，由此将配合抗癌剂的不良效果减至最小。这里所提到的化疗剂例如，5-氟尿嘧啶(5-FU：Kyowa Hakko Kogyo)，丝裂霉素C(Kyowa Hakko Kogyo)，呋喃氟尿嘧啶(FT-207；Taiho Pharmaceutical)，安道生(Shionogi & Co.)和色霉素A3(Takeda Chemical Industries)。
本发明的蛋白下垂诱导组合物用于治疗血小板减少症时，能抑制患者体内胚细胞的繁殖，例如，MDS中如RAEB或RAEB-t，从而造成成熟细胞的增殖。
本发明的蛋白下垂诱导组合物能够诱导或促进蛋白下垂，从而对患有药物诱导性肝炎或病毒性肝炎的患者进行治疗，并且能预防肝细胞纤维变性。
附图的简要描述
附图1显示由药理试验实施例1中描述的蛋白下垂诱导效能试验所获得的结果。
附图2表示由药理试验实施例1中描述的蛋白下垂诱导效能试验所获得的结果。
附图3表示由药理试验实施例1中描述的蛋白下垂诱导效能试验所获得的结果。
本发明的最佳实施方式
以下给出的制剂实施例说明了本发明的蛋白下垂诱导组合物的制备方法，并且以下也描述了本发明的蛋白下垂诱导组合物的活性成份的药理试验结果。
式(A)所表示的化合物用作活性成份化合物之一(以下称作“化合物A”)。
制剂实施例1
化合物A 150gAvicel(注册商标，Asahi Chemical Industry Co.，Ltd.) 40g玉米淀粉 30g硬脂酸镁 2g羟丙基甲基纤维素 10g聚乙二醇6000 3g蓖麻油 40g甲醇 40g
将上述的活性成份化合物，Avicel，玉米淀粉和硬脂酸镁共同混合和研细，并且将所得混合物用糖衣药丸R10mm的冲压机直接压模。将所得片剂用含有羟丙基甲基纤维素，聚乙二醇6000，蓖麻油和甲醇的薄膜衣组合物进行包衣，得到薄膜衣片剂。
制剂实施例2
3，4，4a，5，8，9，10，10a-八氢-1，4 a-二甲 150.0g基-7-(1-甲基乙基)-5，8-二氧-2-菲羧酸枸橼酸 1.0g乳糖 33.5g磷酸二钙 70.0gPluronic F-68 30.0g十二烷基硫酸钠 15.0g聚乙烯吡咯烷酮 15.0g聚乙二醇(Carbowax 1500) 4.5g聚乙二醇(Carbowax 6000) 45.0g玉米淀粉 30.0g干十二烷基硫酸钠 3.0g干硬脂酸镁 3.0g乙醇 适量
将上述的活性成份化合物，枸橼酸、乳糖、磷酸二钙、PluronicF-68和十二烷基硫酸钠混合。通过60号筛网选择颗粒尺寸，之后该混台物用含有聚乙烯吡咯烷酮、Carbowax 1500和Carbowax 5000的乙醇溶液进行湿法制粒。如必要，可加乙醇至使粉末成为糊状团。然后加入玉米淀粉，继续混合，直至形成均匀颗粒。使该混合物通过10号筛网，摊于盘中并且在烘箱中干燥12至14小时，温度保持在100℃。干燥颗粒经16号筛网过筛，然后加入干十二烷基硫酸钠和干硬脂酸镁，混合后，将该混合物用压片机压制成所需的形状，从而得到片心。
以上片心经涂层处理，加入滑石粉的撒粉以防止吸湿，然后产生包衣内层，反复多次进行涂层包衣足以满足内服使用。该片再包另一层内包衣和一层抛光包衣。包着色衣至所需颜色。经干燥得到包衣片。
下文所述的为对本发明的活性成份化合物进行的药理试验。
药理试验实施例1
蛋白下垂诱导效能试验(1)本试验根据文献[Nicoletti等，J.Immunological Methods，139，271-279(1991)]中所述的方法进行。
在补充有10％胚胎腓肠血清的RPMI-1640介质中，调节HL-60细胞的浓度为5×104个细胞/毫升。将作为试验化合物的化合物(A)加到该细胞悬浮体中使其浓度为10μg/ml。将该混合系统放入温度为37℃的六孔板(Costar)的孔内培养，1、2或3天(试验组)。作为对照，仅将溶剂加入类似的细胞悬浮体中，并将该混合物以同样方式培养(对照组)。培养完毕后回收细胞，并将1×108细胞转入聚乙烯试管中，在200xg下离心5分钟以得到团块。
使上述所得的团块再悬浮于0.25ml的缓冲剂[0.1％枸橼酸钠中50mg/ml propidium的碘化物(PI，Sigma，PBS中100μg/ml)＋0.1％Triton X-100(Katayama Kagaku)]中。将该试管于4℃置暗处过夜。
第二天，通过血细胞流量计数器(Profile II，Coulter出品)测定单个核的PI萤光。流动速率定在约200细胞核/秒，并且每个样品分析至少104个细胞核。
直方图分析排除了萤光强度低的细胞碎片。然后计算出所显示的含量不少于2N的细胞核与所显示的含量不多于2N的细胞核之比。认为所显示的含量不多于2N的细胞核为发生蛋白下垂细胞的细胞核，并且认为所显示的含量不多于2N的细胞核的比例为断裂的DNA，并作为蛋白下垂诱导活性的指标。
所得的结果显示在附图1中。
在附图1中，所绘的纵坐标为培养期(天)，所绘的横坐标为蛋白下垂细胞(％)。黑色柱形表示试验组，白色柱形表示对照组。
附图1显示了本发明的活性成份化合物所产生的蛋白下垂诱导作用和促进作用。
上述试验中应用的人类早幼粒细胞白血病细胞系(HL-60)是由Robet Gallo等建立的人类白血病细胞系，并且其典型特性在文献[Gallo，R.C.，等，Blood，54，713(1979)]中有描述。该细胞系在美国类型培养中心(ATCC)保藏，ATCC入藏号为CCL-240号。(2)用从人类Burkitt淋巴组织瘤获得的Daudi细胞(ATCC CCL-213号)和从人类急性成淋巴细胞白血病获得的MOLT-4细胞(ATCCCRL-1582号)代替用于试验(1)的HL-60细胞，以与试验(1)相同的方式进行试验。其结果显示在附图2和附图3中，结构与附图(1)相同。
类似附图1，附图2和3显示了本发明的活性成份化合物所产生的蛋白下垂诱导作用和促进作用。(3)通过MTT方法[J.Immunol.Methods，65，55(1983)]可证实浓度为10μg/ml的本发明的活性成份可抑制上述三类细胞的增殖。
在工业领域中使用的可能性：
本发明的蛋白下垂诱导组合物具有诱导和促进蛋白下垂的能力，由于具有该能力，它有效地用于医药领域中，可作为抗癌剂，自体免疫病和肝病如肝炎和肝硬变的治疗剂，肿瘤转移的抑制剂等。
Claims (2)
1.一种蛋白下垂诱导组合物，含有作为活性成分的药理学有效量的至少一种选自下式(1)
其中R为氢原子或低级烷基，所表示的菲衍生物及其盐的物质，和药用可接受的无毒的载体。
2.权利要求1的蛋白下垂诱导组合物，它用作治疗癌症的抗癌组合物。
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| JP2009001569A (ja) * | 1996-04-12 | 2009-01-08 | Hayashibara Biochem Lab Inc | アポトーシス調節剤 |
| IT1307786B1 (it) | 1999-07-22 | 2001-11-19 | Bracco Spa | Analoghi di ceramidi, processo per la loro preparazione e loro usocome antitumorali. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2069281T3 (es) * | 1990-03-06 | 1995-05-01 | Otsuka Pharma Co Ltd | Derivado de fenantreno. |
| JPH06263688A (ja) * | 1991-09-04 | 1994-09-20 | Otsuka Pharmaceut Factory Inc | フェナンスレン誘導体 |
-
1995
- 1995-04-11 WO PCT/JP1995/000709 patent/WO1995028154A1/ja not_active Application Discontinuation
- 1995-04-11 AU AU21486/95A patent/AU2148695A/en not_active Abandoned
- 1995-04-11 KR KR1019950705621A patent/KR960703010A/ko not_active Application Discontinuation
- 1995-04-11 CN CN95190477A patent/CN1128949A/zh active Pending
- 1995-04-11 EP EP95914560A patent/EP0714658A1/en not_active Withdrawn
- 1995-04-11 CA CA002165062A patent/CA2165062A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR960703010A (ko) | 1996-06-19 |
| WO1995028154A1 (fr) | 1995-10-26 |
| CA2165062A1 (en) | 1995-10-15 |
| EP0714658A1 (en) | 1996-06-05 |
| AU2148695A (en) | 1995-11-10 |
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