CN1171739A - 奈必洛尔作为抗动脉粥样化剂的用途 - Google Patents
奈必洛尔作为抗动脉粥样化剂的用途 Download PDFInfo
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- CN1171739A CN1171739A CN95197149A CN95197149A CN1171739A CN 1171739 A CN1171739 A CN 1171739A CN 95197149 A CN95197149 A CN 95197149A CN 95197149 A CN95197149 A CN 95197149A CN 1171739 A CN1171739 A CN 1171739A
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Abstract
本发明涉及α,α′-亚氨基双(亚甲基)-双[2-苯并二氢吡喃甲醇]衍生物在制备用于治疗或预防人患或易于患与氧化应激有关的血管和神经系统的退化疾病和退化状态的药物方面的用途。
Description
本发明是关于α,α′-亚氨基-双(亚甲基)-双〔2-苯并二氢吡喃甲醇〕衍生物在制备用于治疗或预防人患有与氧化应激有关的血管和神经系统的老化或退化疾病的药物中的用途。
α,α′-亚氨基双(亚甲基)双-〔2-苯并二氢吡喃甲醇〕衍生物在EP-0,145,067中作为高血压治疗方面有治疗潜力的β-1阻滞剂而被公开。奈必洛尔,为(RSSS)和(SRRR)α,α′-亚氨基双(亚甲基)双〔6-氟-2-苯并二氢吡喃甲醇〕的外消旋体混合物,在其中作为商品名公开。奈必洛尔具体公开在EP-0,334,429中。其中(SRRR)对映体为有效的和有选择性的β-1阻滞剂,而(RSSS)对映体不是有效的β-1阻滞剂,但是为一系列抗高血压剂如阿替洛尔,萘心安(propanolol),哌唑嗪,肼屈嗪的增效剂,以及有趣地也是其本身的对映体(SRRR)的增效剂。在此期间,随后的研究显示奈必洛尔的几种有益的血液动力效应,这种效应不同于其它的β-1阻滞剂,例如它急剧地降压自发的高血压大鼠的血压,减少外周血管的阻力,增加麻醉狗心博容量,这些效应也可大部分地归应于(RSSS)对映体。
现在实验表明,α,α′-亚氨基双(亚甲基)双〔2-苯并二氢吡喃甲醇〕衍生物体外和体内均具有有效的抗氧化剂活性。显然,这是继卡维地洛及其代谢产物在体外和体内显示抗氧化剂性质后的第二组β-1阻滞剂。与此不同,α,α′-亚氨基双(亚甲基)双〔2-苯并二氢吡喃甲醇〕衍生物显得更有效力。从其抗氧化剂的观点出发,α,α′-亚氨基(亚甲基)双〔2-苯并二氢吡喃甲醇〕衍生物在对待由氧化应激引起的血管和神经系统的退化疾病和老化方面具有治疗用途。
因此,本发明涉及α,α′-亚氨基双(亚甲基)双〔2-苯并二氢吡喃甲醇〕衍生物,所述的衍生物与可药用的酸加成的盐,立体化学异构体形式及所述衍生物、盐和立体异构体的任意混合物在制备用于治疗或预防与氧化应激有关的血管和神经系统的老化和退化疾病的药物中的应用,所述的衍生物具有(1)的化学式。其中R1和R3分别代表氟、羟基或氢,R2和R4分别代表氢或羟基,“星号”均表示立体中心。
本发明也涉及治疗患有与氧化应激有关的血管和神经系统的老化和退化疾病之患者的方法,该方法系通过给予所述的病人一定量的α,α′-亚氨基双(亚甲基)双〔2-苯并二氢吡喃甲醇〕衍生物来有效地改善、阻止、延迟或减轻此过程和/或所述的老化和退化疾病的过程和/或效应。
化合物,其中R1和R3代表羟基,R2和R4代表氢,被认为是由R1和R3代表氟的相应化合物中形成的主要代谢产物,但是最近发现不是如此。然而这些伪代谢产物确实具有有效的抗氧化剂活性。
本发明的具体化合物包括:(RSSS)和(SRRR)α,α′-亚氨基双(亚甲基)双〔6-氟-2-苯并二氢吡喃甲醇〕,该化合物的外消旋体混合物被称为奈必洛尔,其各个对映体,(RSSS)和.(SRRR)α,α′-亚氨基(亚甲基)双〔6-羟基-2-苯并二氢吡喃甲醇〕;〔(RSSS)+(RSRR)+(SRSS)+(SRRR)α〔〔〔2-苯并二氢吡喃-2-基)-2-羟乙基〕氨基〕-甲基〕-6-羟基-2-苯并二氢吡喃-甲醇乙二酸(1∶1);〔(SRSR)+(SRRS)+(RSSR)〕-α,α′-亚氨基双(亚甲基)双〔6-羟基-2-苯并二氢吡喃甲醇〕和〔(RRSR)+(RRRS)+(SSSR)+(SSRS)〕-α-〔〔〔2-苯并二氢吡喃-2-基)-2-羟乙基〕氨基〕甲基〕-6-羟基-2-苯并二氢吡喃-甲醇乙二酸(1∶1)。
式(I)的化合物可以按EP-0,145,067和EP-0,334,429描述的方法来制备。因为它们具有碱性,通过用适当酸处理这些化合物而转化成与可药用酸加成的盐的形式。适当的酸包括,例如无机酸如氢卤酸即盐酸或氢溴酸;硫酸;硝酸;磷酸和类似的酸;或有机酸,例如醋酸,丙酸、羟乙酸,乳酸,丙酮酸,草酸,丙二酸,琥珀酸,马来酸,富马酸,苹果酸,酒石酸,柠檬酸,甲磺酸,乙磺酸,苯磺酸,对甲苯磺酸,环己烷氨基磺酸,水杨酸,对氨基水杨酸,双羟萘酸以及类似的酸。上文使用的术语加成的盐也包括式(1)的化合物和其盐能形成溶剂化物。这种溶剂化物为例如水合物,乙醇化物及其类似物。奈必洛尔的优选酸加成的盐是盐酸盐。不可药用的盐在式(1)化合物和含有这类化合物的组合物的制备中可以是有用的。
氧化应激指特别是与组织中内源性强氧化剂的作用、特别是有害作用相关的现象。内源性强氧化剂如超氧化物(O2 -),过氧化氢(H2O2),氢氧根(HO)。组织可以是中枢的,周围的或髓质的,特别是属于血管系统,神经系统,肾,胰腺,甲状旁腺,和性腺的。氧化损伤组织细胞归因于脂质过氧化作用,这种作用导致细胞膜的完整性和功能的改变。由自由基产生的氧对内皮造成的损伤,当今一般被认为是动脉粥样硬化和相关血管疾病开始和进行中的关键步骤。
治疗措施包括给予改善,阻止,延迟或减轻血管和神经系统退化疾病的过程和/或效应有效量的式(1)化合物。预防措施包括给予预防或延缓老化或血管和神经系统退化疾病的发生和发展有效量的化合物。
α,α′-亚氨基双(亚甲基)双〔2-苯并二氢吡喃甲醇〕衍生物的抗氧化活性可通过其体外清除自由基(羟基,超氧化物和氮氧化物基)并因此防止这些基团介导的脂质过氧化作用及细胞毒性的能力来证明。在神经元细胞的培养物中,它们能有效地代替已知的内源性抗氧剂维生素E(α-生育酚)。这类化合物还通过清除超氧化物(O2 -)模拟超氧化物岐化酶(SOD)的作用。式(1)化合物的不同立体异构体的抗氧化剂活性是类似的。式(1)化合物的抗氧化剂活性与存在的羟基数目成比例。
特别有趣的发现是其中R1-4至少一个代表羟基的化合物在体外毫摩尔范围内以剂量-依赖性方式抑制氧化了的人的低密度脂蛋白(OX-LDL)的形成。氧化了的LDL(OX-LDL)参与动脉粥样硬化形成以及氧化膜脂的形成。图1表示OX-LDL形成过程中显示的阶段。图2表示在对照环境中和在活性药物存在下体外OX-LDL形成。因为羟基化是奈必洛尔代谢中的一个重要的酶反应过程。鉴于该化合物的羟基类似物的抗氧化作用,可以预见在体内对抗氧化损伤方面奈必洛尔应具有重要的保护作用。
体内试验中一个意外的观察证实了这一点,试验动物用奈必洛尔长期地治疗,结果在对照动物中能见到的血管系统的正常老化在试验动物中被抑制,即治疗动物的老化过程明显地被推迟。
与氧化应激有关的并且被认为易于用式(1)化合物治疗的血管和神经系统的疾病是血管系统的正常的和病理的变性,如动脉粥样化形成,动脉粥样化病(血管内壁脂质变性),动脉硬化,动脉粥样硬化,与高血压、高脂蛋白血症相关的血管肥大和衰老引起的正常血管变性;性腺和胰腺的血管病理;甲状旁腺的反应性增生;慢性肾病;肿瘤病;和炎性疾病。
进一步地,式(1)化合物在预防或治疗神经系统神经元丧失方向,尤其是与氧化损伤有关的周围神经系统方面也有治疗价值,例如血栓栓塞性中风,脑中风,出血性中风,脑缺血,脑血管痉挛,脑老化,脑或脊髓创伤,心博停止,动脉低血压,心或肺外科,严重低血糖,缺氧症,低氧,产期窒息;以及在氧化代谢过程中起作用的减轻神经变性症方面也有治疗价值,例如享廷顿舞蹈病,阿尔茨海默病,老年性痴呆,皮克病,科尔萨科夫精神病,橄榄体脑桥小脑萎缩,肌萎缩性外侧硬化症,帕金森氏病,唐氏综合症,戊二酸血症,癫痫,惊厥状态,多梗塞性痴呆,病毒感染诱导的神经退化,例如神经-AIDS,包括痴呆,识别困难,与HIV感染有关的神经和肌病,狂犬病,麻疹和破伤风。
动脉粥样化形成是一个复杂的过程,其特征是存在于动脉壁巨噬细胞中的胆固醇累积。巨噬细胞经过清除剂受体吸收OX-LDL,与正常LDL受体相反,清除剂受体不受细胞胆固醇含量的调节。缺乏调节机制导致细胞胆固醇积聚和泡沫-细胞形成。OX-LDL已在体内接近动脉粥样硬化损伤的区域被发现(关于此观点可见Jackson,R.L.等(1993),Medicinal Research Reviews13,161-162)。LDL氧化包括脂质过氧化,醛的形成,蛋白质破碎以及维生素E有关的LDL颗粒的消耗。抗OX-LDL的自动抗体已在人体内确证,它们的滴度是颈动脉动脉粥样硬化进程中的独立预言者(Salonen J.T.等(1992),The Lancet 339,No 8798,883-7)。而且,LDL氧化的敏感度与冠状动脉粥样硬化的严重性有关(Regnstrm,J.等(1992),The Lancet 339,No 8803,1183-1186)。任何抗氧化剂性质归因于心血管保护药,除了它的其它药理性质以外,这种抗氧化剂性质增强其对预防动脉粥样硬化进展的治疗作用。
下文实施例1的数据证明:奈必洛尔的羟基类似物对人的LDL具有影响深远的抗氧化效应。体外使用的浓度高(2μm),但与体内情况比较不成比例。确实,维生素E和已知的抗氧化剂以及降脂血剂普鲁布考(hipolipidemic agent probucol)在数星期内(over a timecourse spanning Weeks)被结合到LDL颗粒的脂质相中(Reaven,P.D.等(1992),Artheriosclerosis and Thrombosis,12.No 3,318-324;Kagan,V.E.等(1992),J.Lip.Res.,33,385-397)实施例1的短期实验没有模拟体内情况。药物在LDL颗粒的水相和脂质相之间的分布有可能没有达到平衡,因此这些脂溶性药物的抗氧化能力被低估了,正如参考化合物维生素E需要极高的浓度一样(图2)。定性地,奈必洛尔羟基类似物和维生素E的作用相类似。两者均延缓LDL的氧化,这种氧化仅仅在存在于测定系统的抗氧化剂消耗后才开始。
本发明适合于作为药物的式(1)化合物的药物组合物包括本领域技术人员熟知的一种或多种赋形剂或载体。通过适当地选择一种或多种这些赋形剂或载体,使药物组合物适合于口服,直肠给药,阴道给药,局部给药,非肠道给药(包括肌肉,皮下和静脉)或植入给药,或以一种适合于吸入的形式给药。合适时,制剂常以单剂量形式存在。将这些成分制备成制剂的方法是本领域的技术人员熟知的,其特征在于活性成分和赋形剂相互密切地混合。整个过程包括活性化合物与液相载体或分散得很好的固相载体或固-液载体两者产生密切的混合,如果必要,把产品制成所需要的剂型。
为了口服给药,药物组合物可被制成固体单剂形式,如片剂与胶囊剂,这采用药剂上能被接受的的赋形剂通过常规方法来制备。这些赋形剂如粘合剂(如预凝胶淀粉,聚乙烯吡咯烷酮或羟丙基甲基纤维素);填充剂如乳糖,微晶纤维素或磷酸钙),润滑剂(如硬脂酸镁,滑石粉或二氧化硅);崩解剂(如马铃薯淀粉、淀粉羟乙酸钠);或润湿剂(如十二烷基硫酸钠)。片剂可以用本领域技术人员熟知的方法包衣。
口服的液体制剂可以采取,例如溶液剂,糖浆剂或混悬剂的形式,或者制成一种干燥产品,服用前以水或其它合适的赋形剂溶解药物。这样的液体制剂可用常规方法以药剂上能被接受的添加剂来制备,这些添加剂如悬浮剂(如山梨醇糖浆,甲基纤维素或氢化食用脂肪);乳化剂(如卵磷脂或阿拉伯胶);非水赋形剂(如杏仁油,油脂或乙醇);防腐剂(如对羟基苯甲酸甲酯或丙酯或山梨酸)。
为了口腔局部给药,药物组合物可以采用常规方法制成的颊下或舌下片的形式,滴剂或锭剂形式。
为了皮肤局部给药,本发明的化合物可被制成霜剂,胶剂,油膏或洗剂,或透皮吸收贴。这样的组合物例如可以用水或油性基法,添加适当的增稠剂,胶剂,乳化剂,稳定剂,分散剂,悬浮剂,和/或着色剂来制备。
式(1)化合物也可被制成储存剂型,这种长时间起作用的剂型,可以通过植入方法(例如皮下或肌肉)或通过肌肉注射来给药。例如,化合物可以用合适的多聚体或疏水材料(如在可接受油中的乳液)或离子交换树脂,或微溶性衍生物,例如微溶性盐做成合适的剂型。
式(1)化合物可被做成非肠道给药的剂型而通过注射(通常为静脉注射,肌肉注射或皮下注射)来给药,例如快速静脉注射或连续静脉滴注。注射剂可以是单剂量的形式,如安瓿,或加防腐剂的多剂量的容器形式。该组合物可以是油或水性赋形剂的悬浮液,溶液或乳剂的形式,可以含有成形剂,如悬浮剂,稳定剂和/或分散剂。替代地,活性成分可以是粉末状剂型,用合适的赋形剂如无菌无热源的水配制。
式(1)化合物也可被制成直肠给药组合物,例如含有常规栓剂基质如可可油或其它甘油脂的栓剂或滞溜灌肠。
式(1)化合物可用鼻腔来给药,例如作为液体喷雾剂,或作为粉末或滴剂的形式。
式(1)化合物可通过吸入给药,为此药物通常以气溶胶喷雾的形式借助适当的喷射剂从压力装置或喷雾器中释放出来,所用的喷射剂如二氯二氟甲烷,三氯氟甲烷,二氯四氟乙烷,1,1,1,2-四氢乙烷,二氧化碳,或其它合适的气体。在加压的气溶胶中,单位剂量可以通过阀的计量释放而确定。吸入器中使用的凝胶筒和容器可以按含有本发明的化合物的适当的粉末基质如乳糖或淀粉的粉状混合物的要求制造。上述任何药物组合物可以按与控制释放剂型有关的常规方法进行。
为了增加式(1)化合物的生物利用度,配入合适的环糊精较为有利。合适的环糊精有:α-,β-γ,-环糊精或酯或其混合酯,其中一个或多个环糊精的无水葡萄糖单元的羟基用C1-6烷基,特别是甲基,乙基或异丙基;羟基C1-6烷基,特别是羟乙基,羟丙基或羟丁基;羧基C1-6烷基,特别是羧甲基或羧乙基;C1-6烷羰基,特别是乙酰基;C1-6烷氧羰基-C1-6烷基或羧基-C1-6烷氧基C1-6烷基,特别是羧甲氧基丙基或羧乙氧基丙基;C1-6烷基羰氧基C1-6烷基,特别是2-乙酰氧基丙基来取代。尤其值得注意的作为复合剂和/或加溶剂的是β-CD,2,6-二甲基-β-CD,2-羟乙基-β-CD,2-羟乙基-γ-CD,2-羟丙基-γ-CD和(2-羧基-甲氧基)丙基-β-CD,特别是2-羟丙基-β-CD(2-Hp-β-CD)。用于本发明组合物中最优选的环糊精衍生物是2-羟丙基-β-环糊精,其平均摩尔取代(M.S)在0.35-0.5(质谱测得)范围内,含有不到1.5%的未取代的β-环糊精。通过NMR或IR测得的M.S值的最优选范围是0.55-0.75。
药物组合物可以仅由式(1)化合物和环糊精或环糊精衍生物组成。这个固体形式常可通过水溶液的冷冻干燥,或其沉淀的方法制备,这种形式对用水、盐水或环糊精的水溶液的重新配制,或与非药物固体(特别是食物)结合特别有用。
优选地,本发明药物组合物适合于口服给药。
药物组合物可以分剂量单位,尤其是单位剂量形式存在。常规单剂量制剂含有活性成分的量为0.1-100mg。式(1)化合物在治疗中所需的日剂量将不仅随被选定的特定化合物而改变,而且将随给药途径、被治疗的疾病的性质,病人的年龄、体重和病人的状况而改变,同时还与伴过医生自行处理谨慎有关。然而,合适的剂量范围一般每天约为0.1-20mg,合适的预防日剂量一般在相同的范围内。
需要的剂量常可以单剂量或作适当间隔的分剂量给药。例如每天2次、3次、4次或更细分的剂量。奈必洛尔的日剂量能以单剂量(o.d)给药,因为这样的生活制度在24小时内产生有效的血浆水平。由于随着抗氧化剂效率的增加形成活性代谢产物,奈必洛尔抗动脉粥样硬化的效力将由于重复或长期给药而增加直至达到稳定状态。
式(1)化合物也可与其它降血压剂或其它治疗剂,例如降血脂剂(hypolipaemics),降脂血剂(hypolipidemics),降胆固醇剂,ACAT抑制剂或抗氧化剂联合使用。本发明在进一步的方面提供含有如本文定义的组合物与另一个活性治疗剂,特别是另一个降血压剂,或降血脂剂,降脂血剂,降胆固醇剂,ACAT抑制剂或抗氧化剂的联合使用。这种联合使用可以分开给药,例如同时地,或连续地按上述任何一种途径,或者这种联用也可以一种药剂的形式使用。这样,本发明的进一步方面包括:一种药剂产品包括(a)式(1)化合物和(b)上文定义的另一种治疗剂,这种药剂产品以一种联合制剂,同时,分开、或顺序地用于治疗或预防人类衰老或与氧化应激有关的血管或神经系统的衰老或退化的疾病。这样一种产品可以含有药盒,它包括含有式(1)化合物的药物组合物的容器,和包含第二个治疗剂的药物组合物的另一容器。这个具有两种活性成分的分开的组合物的产品的优点是:每个组分的适当的量,给药的时间和顺序能根据病人的机能状况来选择。
用于上文所定义的联合使用的合适治疗剂包括,例如降血压剂,尤其是β-1阻滞剂如阿替洛尔、塞利洛尔、萘心安;降血脂剂,例如用于降低低密度脂蛋白(LDL)或胆固醇的药物,如HMG CoA还原酶抑制剂如洛伐他汀,氟伐他汀,普伐他汀,昔伐司汀及其类似物;吉非贝齐;Zaragozic acid;或抗氧化剂如普罗布考,维生素E(α-生育酚),或尤其是上面提及的几个生理性质相关的化合物,例如卡维地洛,维拉帕米,地尔硫,维生素C(抗坏血酸或其盐)。
当式(1)化合物被用于与第二个治疗剂联合使用的时候,每个化合物的剂量可以与化合物单独使用时不同(有改变)。因此,当式(1)化合物与第二个治疗剂合用时,每个化合物会与该化合物单独使用时相同或更多的是低于它。合适的剂量很容易被本领域的技术人员作出评价。
实施例1:人的LDL的体外氧化。
将人的静脉血收集在EDTA(2.68mM的最后浓度)中。通过离心分离血浆。加入NaBr(37.3mg/ml),溶解(最后密度1.03g/ml)。装入离心管使达到其最大容量的2/3,进一步装入1.036g/ml的NaBr溶液,然后在50Ti转子(Beckmann)45,000rpm离心18小时。离心后,倾去漂浮的脂蛋白。将剩下的溶液调节到1.055g/ml的密度。装入离心管,按上述方法重复离心。离心后,将漂浮的LDL在含有127mM NaCl,8mMNa2HPO4,2H2O,2.7mM KCl和1.47mM KH2PO4的PH为7.4的缓冲液中透析。透析以后,将LDL通过一个Millipore滤器(0.45μm)过滤,测定蛋白的含量。将经Millipore滤器滤过的透析缓冲液制备成25μm/ml的稀释液。在Pharmacia Ultraspec III比色计上测定氧化情况。在234nm处记录生成的共轭二烯。向Eppendorf管中加入2μl的药物或溶剂(DMSO),过后加入1ml的LDL(25μg/ml),轻轻地混合这些物质,在13000g离心1分钟。将溶液移入37℃恒温的比色计的Quartz比色杯中,平衡后,添加CuSO4(最后浓度10μm)使氧化反应开始。实验期间内每3分钟测定吸收。在234nm处的吸收分为三期:滞后期,增长期和分解期(图1)。滞后期被定义为增长期吸收曲线与基线的截距。氧化速率被定义为斜度的正切。Tmax被定义为增长期和分解期之间达到最大吸收所需的时间。tmax吸收减去t0吸收为形成二烯总量的指示。为了检验测定的重现性,制备参考LDL样品,保存在4℃氮气流的暗处。这个参考样品包含在每个氧化实验中。LDL是从23个受试者分离出来的。血浆胆固醇范围为156-278mg/dl(平均213mg/dl),三硝酸甘油脂的范围为47-328mg/dl(平均191mg/dl)磷脂的范围为178-327mg/dl(平均231mg/dl)。
图2表示奈必洛尔的2-羟基类似物的抗氧化作用:〔(RSSS)+(RSRR)+(SRSS)+(SRRR)〕-α-〔〔〔2-苯并二氢吡喃-2-基)-羟乙基〕氨基〕-甲基〕-6-羟基-2-苯并二氢吡喃-甲醇乙二酸(1∶1),和〔(SRSR)+(SRRS)+(RSSR)〕-α,α′-亚氨基双(亚甲基)双〔6-羟基-2-苯并二氢吡喃-甲醇〕。Tmax,和滞后时间两者均增加,氧化速率降低。在体外,奈必洛尔没有抗氧化作用。作为参考化合物的维生素E在浓度低于10μM时没有显示任何抗氧化剂作用(结果未显示)。在我们的实验条件下20μM维生素E的tmax接近于2μM奈必洛尔的羟基代谢产物的tmax。氧化速率,开始时的吸收和二烯总量不受维生素E的影响。总之,奈必洛尔的羟基代谢产物在体外对人的LDL具有抗氧化作用。因此奈必洛尔在体外对动脉粥样硬化,炎症,癌症引起的氧化损伤具有重要的保护作用。实施例2:奈必洛尔体内抗动脉粥样化作用。
为证实奈必洛尔对与衰老有关的血管病理学是否有作用。给许多大鼠口服奈必洛尔,其24个月内的剂量为0(仅为载体),2.5,10和40mg/kg。作为载体,使用2-羟丙基-β-环糊精以改善奈必洛尔的生物利用度。在2年的研究中,每个剂量组有50只雄鼠和雌鼠。不接受奈必洛尔的50只雄鼠和雌鼠对照组也包括在此研究中。将试验动物作尸体解剖,并观察组织学的非瘤形成的改变。有关血管退化或老化的组织学特征具体作如下观察:
—腹部间皮瘤,胰腺和睾丸的血管病理学,
—甲状旁腺的病灶和扩散增生,和
—肾的组织学,特别是许多嗜碱染色的小管是慢性肾病和矿化作用的证据。
组织学观察如下在0-3间评分:
—0:无组织学变化
—1:轻微组织学变化
—2:中等组织学变化
—3:严重组织学变化
计算每个观察的平均得分。用Mann-Whitney U检测(双尾概率)分析观察得到的评估结果,来统计比较治疗组和对照组之间在统计学上显著性差异。这些评估结果归纳于下表。通过Mann-Whitney U双尾检测计算出显著性:*p<0.05 **p<0.01 ***p<0.001表1
实施例3
剂量组(mg/kg) | |||||
组织学变化 | 对照 | 载体 | 2.5 | 10 | 40 |
雄性 | |||||
腹部间皮瘤:血管病变肾:嗜碱(染色)小管慢性病胰腺:血管病变甲状旁腺:弥散性增生病灶增生睾丸血管病变 | 2.500.101.680.300.180.160.52 | -0.121.400.180.140.080.48 | -0.181.32*0.040.080.040.20* | -0.181.24*0.02*0.150.02*0.08** | 0.00*0.60***0.66***0.00***0.02*0.00**0.02*** |
雌性 | |||||
肾:嗜碱(染色)小管慢性疾病矿化作用(parenchum/pelvis)胰腺血管病变 | 0.041.040.960.12 | 0.140.760.740.04 | 0.180.880.840.04 | 0.18*0.920.64*0.02 | 0.42***0.780.14***0.00* |
初级的胚胎海马培养物基本上按以前文献描述的方法来制备(Pauwel等;Van Aschouw,H.P.,Peeters,L,Moeremars,M.,Leysen,J.E.(1992)用沙贝鲁唑长期处理以保护培养的大鼠脑神经元免受兴奋性氨基酸的神经毒素的作用。Synapse,12:271-280)。对胚胎期17天的大鼠形成的海马进行解剖,并于0.05%胰蛋白酶,0.1mg/ml DNase I的DMEM(Dulbecco Modified EagleMedium)中离解。加入热-失活的马血清(HS)到浓度为4%,将细胞离心,用DMEM洗涤,重新悬浮于含有10%HS的DMEM/Ham′sF12(3∶1)中。将细胞以4×105个细胞/cm2的密度放在预涂多聚L-溶血素(0.001%)的多孔-24板中。培养1天,介质变成化学上被定义的CDM-R12介质(DMEM-HEPES/Ham′s F12(3∶1),该介质含有0.26%牛血清,30nM硒酸钠,3nM 3,3′5三碘代醚-L-甲状腺原氨酸,0.35μM视黄质(维生素A),0.3μM视黄质乙酸盐,2.3μmDL-α-生育酚,2.1μM DL-α-生育酚乙酸盐,3.6μM亚麻酸,3.6μM亚油酸,0.125%人铁传递蛋白,20nM孕(甾)酮,57.7nM皮质甾酮,49U/I胰岛素,0.4μM维生素H,10μM L-肉碱,83μMD(+)半乳糖,3.3μM谷胱甘肽,10μM乙醇胺,0.1mM腐胺;Romijn,H.J.,Van Huizen,F.,Wolters,P.S.(1984)。正在进行一种改进的无血清的,用于长期培养大脑皮层组织的化学上定义的介质,Neurosci Behav.Rev.,8:301-334)。培养物的急性的和延长的预处理基本上按以前文献描述的方法(Pauwels等,1992)。将药物溶解和稀释成10%或1%羟丙基-β-环糊精以使急性和慢性暴露的溶剂的最后浓度分别为0.1%和0.01%。在下面例子中使用的化合物A为〔(RRSR)+(RRRS)+(SSSR)+(SSRS)〕-α-〔〔〔2-(苯并二氢吡喃-2-基-)-2-羟基-乙基〕氨基〕甲基〕-6羟基-2-苯并二氢吡喃-甲醇乙二酸(1∶1)。
对于急性处理,将药物或溶剂加到培养7天的培养物中,20分钟以后,介质用200μl化学上定义为DMEM介质(与CDM-R12介质的组成相同,但没有Ham′s F12)(对照)或含有氧化应激触发剂的化学上定义为DMEM介质代替。使用的氧化应激触发剂为1mM硝普钠(SNP,一种氧化氮基产生的化合物)或7.5-10mM二乙基二硫代氨基甲酸盐(DDTC,一种超氧化物岐化酶的抑制剂)和试验化合物。
对于延长预处理实验,将药物(浓度范围0.1nM-10μM)加到培养1天和4天的无血清介质中。第7天,将培养物用DMEM洗一次,用0.2ml化学上定义为DMEM的介质于37℃孵化2小时。洗涤该细胞,介质用0.2ml化学上定义为DMEM介质(对照)或含有氧化应激触发剂的化学上定义为DMEM介质代替(见上文)。
对于急性实验和延长预处理实验,细胞外和细胞内LDH(脱氢乳糖酶)的活性用EPOS的5060分析仪在340nm进行比色测定,该测定系根据Bergmeyer方法(Bergmeyer,H.U.(1974)Biochemical reagent.In.Methocd of Enzymatic Analysis H.U.Bergmeyer,edsAcademic Press,New York,2nd Ed.,pp 480-242)。细胞在1ml水中溶解后测得的培养物介质中的细胞外LDH活性和细胞浆LDH活性被用于计算总LDH活性和LDH释放百分率。神经元保护百分率归诸于LDH抑制释放百分率。氧化应激触发剂诱导的LDH释放被定义为0%保护,LDH释放的基础(对照)水平被定义为100%保护。
对于维生素E排除实验,如上获得初级培养。但在第1天,在存在或不存在试验化合物的情况下,改变培养物中的介质来从化学上定义有(对照)或缺乏DL-α-生育酚(维生素E)和DL-α-生育酚乙酸酯的LDM-R12介质。当维生素E从培养介质中除去时,第4天体外观察到严重的细胞死亡。添加化合物能够挽救培养物。培养物的存活率籍助于细胞浆LDH的活性来测定。%维生素E的互补作用归诸于%细胞浆的LDH,当LDH水平像含有培养物的VitE中观察到的LDH水平一样高时被定为100%,当LDH水平像排除VitE的培养物中观察到的LDH水平一样低时被定为0%。VitE互补作用的EC50值指使培养物恢复到在VitE增补介质中生长的培养物所观察到的存活的50%存活率所需要的化合物的浓度。每个化合物的7个浓度均重复试验三次,表中指出独立实验号和计算的平均EC50值±SD。表2:维生素E互补试验:奈必洛尔衍生物的作用,筛选数据。表3:维生素E互补试验:化合物A的效力。表4:奈必洛尔化合物A和卡维地洛对抗氧化氮和超氧化物基而在体外对神经元的保护作用。
体外初级神经元培养物的生存取决于培养基中抗氧化剂VitE的存在。当排除VitE的介质用于培养物的生长时,存活率下降到对照组的±20%。具有抗氧化性质的化合物能补充维生素E的缺乏,因此当将这些化合物加到培养基中时,能挽救缺乏VitE的培养物。在初级神经元培养物的VitE排除试验中,几个奈必洛尔衍生物在10-7M和10-6M浓度下试验。化合物A,奈必洛尔,1-奈必洛尔和d-奈必洛尔在某种程度上都能挽救排除VitE的介质的存活率(表2)。
化合物A是最有效的化合物:在排除VitE的介质中,完全挽救初级神经元生长的浓度为10-6M(见表2)。培养物被挽救达到对照组(对照组培养物生长的介质含有4.4μM VitE)的50%时的化合物A的浓度为126±88nM(表3)。
用超氧化物岐化酶抑制剂DDTC和氧化氮供体SNP处理培养物导致游离基(O2 -和NO-)介导的神经毒性。当触发剂添加期间和添加以前的短时间内(急性处理)或当触发剂添加前的6天(延长预处理)时,具有抗氧化性质的化合物能保护培养物免除自由基介导的神经毒性。从表3可以清楚地看到奈必洛尔和化合物A在一个或其它的处理范例中能授予神经元保护培养物对抗DDTC或SNP。至今对处理-神经元保护的依赖关系的机理尚不知道,尽管见到了奈必洛尔和化合物A对抗SNP和DDTC的部分保护作用,然而未见卡维地洛的保护作用,这使奈必洛尔和化合物A在这方面成为占优势的药物。表2:维生素E互补作用试验:奈必洛尔衍生物的作用,筛选数据
化合物 | 浓度(M) | %维生素E互补(试验号) |
化合物A奈必洛尔(RSSS,SRRR)1-奈必洛尔(SRRR)d-奈必洛尔(RSSS) | 10-710-610-710-610-710-610-710-6 | 27±28(16)85±21(16)29±29(15)29±28(15)22±20(13)24±26(13)12±17(7)19±22(7) |
神经元的初级海马培养物在生存因素VitE缺乏的情况下生长而导致严重的细胞死亡。当培养期间给予奈必洛尔衍生物时,培养物在某种程度上能被挽救。100%维生素E的互补作用指与含有细胞培养物的VitE无关的培养物的存活率。表3:维生素E互补作用试验:羟基-奈必洛尔的效力
化合物 | 平均EC50±SD(剂量应答数) |
化合物A | 126±88nM(5) |
神经元的初级海马培养物在生存因素VitE缺乏的情况下生长,导致严重的细胞死亡。当培养期间给羟基奈必洛尔时,培养物能被挽救。像测量细胞浆的LDH的活性一样,EC50值指培养物被挽救50%时的浓度。表4:体外奈必洛尔、化合物A和卡维地洛对抗氧化氮和超氧化物基的神
经保护作用
%神经保护,平均±SD(独立培养物的号) | |||||
化合物 | 触发剂 | 延长处理 | 急性处理 | ||
10-7M | 10-6M | 10-7M | 10-6M | ||
奈必洛尔(RSSS,SRRR)化合物A卡维地洛 | DDTCSNPDDTCSNPDDTCSNP | NA(2)26±13(2)NA(2)39±13(2)NA(2)NA(1) | 37±23(2)36±18(3)NA(2)38(1)NA(2)NA(1) | 32±28(5)NA(2)35±32(5)NA(2)NA(1)NA(1) | 29±16(7)NA(2)30±28(6)NA(2)NA(4)NA(1) |
神经元的初级海马培养物在CDM-R12介质中生长7天。试验化合物可以在培养1天和4天(延长预处理)或培养7天(急性处理)给予。在7天给予氧化应激触发剂,基于LDH释放的抑制作用计算神经保护率。NA表示无活性,例如得分<25%的神经保护表示无活性。实施例4
通过某些细胞中摄取的胱氨酸的谷氨酸盐的竞争性抑制导致谷胱甘肽的消除和氧化应激的发生。这种氧化应激模型被描述为神经胶质的C6神经胶质瘤细胞(Kato等,1992,因C6神经胶质瘤细胞中谷氨酸盐的毒性涉及胱氨酸摄取的抑制而导致谷胱甘肽清除的机理。Neurosci·48:903-914)和神经元细胞系N 18 RE 105(Murphy等,1989,在神经元细胞系中谷氨酸盐毒性涉及到导致氧化应激的胱氨酸运输的抑制(Neuro 2:1547-1558)。细胞培养物:C6神经胶质细胞系(America Type CultureCollecction,CCL 107)在补充2或4mM谷氨酰胺,1mM丙酮酸盐和5%或10% 热灭活的胎儿腓肠血清的DMEM中孵化。培养物在空气/5-10%CO2,水饱和的大气中维持37℃。谷胱甘肽清除和药物作为抗氧化剂的评价:
实验进行时,将培养物放置在有30,000-50,000个细胞/厘米2的24孔培养皿中(用于毒性和脂质过氧化物的测量)或在有136,000个细胞/厘米2的96孔培养皿中(为测定GSH)8-24小时后,将培养物转入最终浓度为10mM的缺乏或存在胱氨酸摄取抑制剂谷氨酸盐的培养基中。为了测试用于氧化应激抑制的药物,将该药物和谷氨酸一起加入(最后的溶剂浓度为0.01%羟丙基β-环糊精,0.1%DMSO)。在6-8小时后测量细胞内的谷胱甘肽水平,14-20小时后测量脂质过氧化物,48小时后根据Bergmeyer和Bernt方法(用丙酮酸盐和NADH的UV测定。In:Methods of Enzymatic Analysis,1974,H.U.Bergmeyer ed. Acad Press,New York,2nd Ed.,pp 574-579)用LDH测定分析毒性和保护作用。C6神经胶质瘤细胞培养物中GSH含量的测定:
GSH水平基本上按Vandeputte等人描述的微量法进行分析,在洗涤和匀质化方法上作了改进(用微量滴度培养皿测定培养物/分离细胞中总的谷胱甘肽和谷胱甘肽二硫化物的含量:实施新的小型化的实验研究。1994.Cell Biol.Toxicol 10:415-421)。细胞(在96孔培养皿中)用PBS洗涤,在含有1.3%5-磺基水杨酸的50μl 10mM HCl中匀质化,将匀质化物在4℃ 1200×g离心10分钟。将40μl的上清液转移到96孔培养皿的1个孔中,并加入200μl试剂(1mM 5,5′-二硫代双(2-硝基苯甲酸),0.34mM NADPH和6.3mM EDTA于pH7.4的143mM磷酸缓冲液)。在室温下平衡5分钟后,添加40μl谷胱甘肽还原酶(8.5IV/ml 143mM磷酸盐缓冲液,6.3mM EDTA pH 7.4),反应即开始。随后NADPH用Multiskan MCC/340(实验室系统)在414nm氧化5分钟,计算每分钟吸收(DA)的变化。根据标准曲线范围0.2-2nM,从每次测试商用GSH(DA/分/浓度)推算出谷胱甘肽的量。细胞内过氧化物的荧光测量:细胞内过氧化物的形成是用6-羧基-2′,7′-二氯二氢荧光素二乙酸盐,二(乙酰甲酯)(C-DCDHF,分子探针)检出的。将C-DCDHF以10mM浓度溶解于DMSO中,贮存在-70℃的氮气条件下。培养物暴露到谷胱甘肽清除剂后,细胞在37℃负荷10μM C-DCDHF 1小时。吸出介质,将PBS加到细胞中,在Cytofluar II微量培养皿读数器(Perseptive Bio-Systems)上读数。用485/530滤光片选择激发和发射波长。结果以相对荧光单位/μg蛋白表示。结果:用10mM谷氨酸盐处理C6神经胶质瘤细胞培养物6小时或更长时间导致细胞内谷胱甘肽水平的急剧下降(表5)。谷胱甘肽的降低导致氧化应激,正如表5指出的,毒性细胞内过氧化物以±6倍地增加(表5)。16-18小时后最终地发生细胞死亡。该毒性不包括细胞外毒性,因为细胞浆LDH的释放(细胞毒性指数)不能被NMDA拮抗剂MK801(数据未显示)保护。在我们的培养条件下C6神经胶质瘤细胞培养物中的基础LDH释放为总LDH的2.7±0.3%(平均±SD,n=2),用10mM谷氨酸盐处理48小时后,LDH的释放为总LDH的93.2±1.3%。奈必洛尔和化合物A以高效力保护这些培养物免遭细胞死亡。(表6)。奈必洛尔和化合物A的保护的IC50值大约为9nM。这种保护作用不是由于谷胱甘肽水平的恢复(表5),大约谷胱甘肽的一半在健康对照细胞中仍能见到,提出这两个化合物的保护作用是介导氧化应激的GSH清除干扰的结果。细胞内过氧化物的评价表明:奈必洛尔和化合物A两者在过氧化作用中抑制谷氨酸盐介导的增加(表5)。结论:体外试验清楚地表明:奈必洛尔和化合物A作为有效的抗氧化剂作用于细胞培养物;它们保护细胞免遭氧化应激介导的细胞死亡,因为这些化合物抑制氧化应激介导的毒性细胞内过氧化物的增加。表5:C6神经胶质瘤细胞中谷胱甘肽清除介导的细胞内过氧化作用的抑
制
表6:C6神经胶质瘤细胞中谷胱甘肽清除介导的氧化应激(毒性)的抑
化合物 | GSH浓度pmol/孔(平均±SD,6) | 细胞内过氧化物相对荧光单位/μg蛋白(平均±SD,n) |
溶剂谷氨酸盐,10mM+化合物A, 1μM+奈必洛尔, 1μM | 90±9296±26301±12301±12 | 86±16(12)525±57(12)137±8(3)155±13(3) |
制
化合物 | 保护IC50,nM(平均±SD,n=3) |
化合物A奈必洛尔 | 8.6±0.29.1±0.1 |
Claims (16)
2.根据权利要求1的应用,其中被治疗的疾病包括血管系统退化的病理学形式,如动脉粥样化形成,动脉粥样化病,动脉粥样硬化,动脉硬化,与高血压有关的血管肥大,高脂蛋白血症,或因老化造成的正常血管退化;性腺和胰腺的血管病理学;甲状旁腺的反应性增生;慢性肾病;肿瘤疾病;和炎性疾病。
3.根据权利要求1的应用,其中式(1)化合物为奈必洛尔。
4.根据权利要求3的应用,其中式(1)化合物用于制备适合于口服的药物组合物。
5.根据权利要求4的应用,其中奈必洛尔的日剂量范围是0.1-20mg。
6.根据权利要求5的应用,其中日剂量是单次给药。
7.一种药物组合物,它含有可药用的载体和有效量的作为活性成分的权利要求1定义的式(1)化合物与有效量的降血压剂、降血脂剂、降脂血剂、降胆固醇剂、ACAT抑制剂或抗氧化剂。
8.根据权利要求7的组合物,其中式(1)的化合物是奈必洛尔。
9.根据权利要求8的组合物,其适合于口服给药。
10.一种产品,它含有式(1)化合物和选自降血压剂、降血脂剂、降脂血剂、降胆固醇剂、ACAT抑制剂或抗氧化剂的另一类治疗剂,作为联合制剂同时、分开或连续地用于治疗或预防人类患者与氧化应激有关的血管和神经系统的老化和退化疾病。
12.根据权利要求11的方法,其中被治疗的疾病涉及血管系统退化的病理形式,如动脉粥样化形成,动脉粥样化病,动脉硬化,动脉粥样硬化,与高血压有关的血管肥大,高脂蛋白血症,或老化引起的正常血管退化;性腺和胰腺的血管病理学;甲状旁腺的反应性增生;慢性肾病;肿瘤疾病;和炎症性疾病。
13.根据权利要求11的方法,其中式(1)化合物是奈必洛尔。
14.根据权利要求13的方法,其中式(1)化合物被用于制备适合于口服的药物组合物。
15.根据权利要求14的方法,其中奈必洛尔的日剂量范围是0.1-20mg。
16.根据权利要求15的方法,其中日剂量以单次给药。
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EP0801564B1 (en) | 2002-03-27 |
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FI972793A0 (fi) | 1997-06-27 |
CA2207333C (en) | 2006-10-17 |
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