CN103269585B - 治疗弹性蛋白酶相关病症的超硫酸化双糖 - Google Patents
治疗弹性蛋白酶相关病症的超硫酸化双糖 Download PDFInfo
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Abstract
本文公开了式I超硫酸化双糖和其它超硫酸化双糖用于治疗与人嗜中性粒细胞弹性蛋白酶失衡相关的疾病或病状。适用于制备这些化合物的双糖和/或中间体由肝素来制备。用式I化合物治疗的疾病和病状包括慢性阻塞性肺病症(COPD)和囊性纤维化(CF)。所述制剂以气溶胶制剂形式或以干粉方式或经由雾化来递送至肺。口服形式也是合适的。
Description
发明领域
本发明涉及如以下进一步描述的式I超硫酸化双糖化合物以及如本文公开的其它超硫酸化双糖在治疗与白细胞弹性蛋白酶相关的疾病或病状中的用途。具体地说,本发明涉及改善肺功能(气管粘液速度)和/或治疗/减轻疾病或病状如慢性阻塞性肺病(COPD)和/或囊性纤维化(CF)的式I化合物制剂。COPD已经被描述为“安静的杀手”,因为其进展较慢以及其经常在病程早期未得到治疗的事实。肺气肿和慢性支气管炎是COPD的子类型。在肺气肿中,肺泡的壁在结构上被损坏,最终减小用于气体交换和肺活量的表面积。慢性支气管炎的特征在于过量粘液产生并且随着疾病进展出现气流限制。患有COPD的患者具有显著气流限制并且最终失去充分地给血液充氧的能力。COPD是全世界的主要死因并且COPD相关的死亡率正在上升。New England J.of Med.2010年9月16日。逐渐丧失肺功能,COPD的标志,不能由当前可利用疗法来预防。因此,迫切需要用于此疾病的药物或有效治疗。
弹性蛋白酶通常从如巨噬细胞和嗜中性粒细胞的白细胞中释放并且促成在COPD中引起的显著结构破坏。人嗜中性粒细胞弹性蛋白酶(HNE)已知为非常有效的蛋白酶,其可降解结缔组织的大分子组分如弹性蛋白、诱导粘液分泌过多并且导致疾病例如COPD、CF和如类风湿性关节炎的其它炎症性病症,或与所述疾病或病症相关联。也已知弹性蛋白酶可结合至如Mac-1的粘附分子,其调控或参与嗜中性粒细胞粘附和迁移。另外,弹性蛋白酶可裂解细胞间粘附分子1(ICAM-1),其为Mac-1的配体。因此,包括类固醇的当前可利用疗法所不可改变的COPD患者肺中的弹性蛋白酶负载增加产生了对于弹性蛋白酶抑制剂和/或其它药物疗法的需要,所述抑制剂和/或疗法可降低COPD、CF和其它这类疾病中的升高水平的弹性蛋白酶的影响。对于COPD来说,所述疾病当前用以下来治疗:吸入的抗胆碱能支气管扩张剂(异丙托溴铵(ipratropium bromide)、噻托溴铵(tiotropium))或吸入的β激动剂(沙丁胺醇(albuterol)、沙美特罗(salmeterol)或福莫特罗(formoterol))或这些药剂与类固醇 或甲基黄嘌呤(茶碱)的组合。对于CF来说, 当前疗法包括DNASE、吸入的抗生素(例如妥布霉素(tobramycin)),抗炎症剂(例如高剂量布洛芬(ibuprofen))以及COPD的以上治疗。显著需要新的疗法,其可有效地治疗和/或减轻这些疾病。
发明背景
许多专利和科学出版物都公开或涉及发现HNE抑制剂的尝试,所述抑制剂有效地治疗慢性或遗传性肺病症,所述病症通常具有与弹性蛋白酶的强大和破坏性效果相关联的严重症状。在被称为弹性蛋白酶抑制剂的药物种类之中,肝素或其衍生物是显著兴趣的焦点。肝素可在体外和体内极有效地抵御HNE。这种效力和相对活性显然归因于肝素分子结构的具体化学性质。这些性质包括质量、链长、硫酸化程度、电荷密度、特定硫酸化和艾杜糖醛酸(iduronic acid)含量。也已知肝素可影响白细胞与血管内皮相互作用并且其除了是弹性蛋白酶的抑制剂以外还影响弹性蛋白酶的释放。也已知肝素具有抗凝活性,因此本发明人以及多个其它科学家已经发现包括来自肝素的较短寡糖的肝素类似物或其衍生物,其具有抗炎症活性而不具有抗凝性质。
以前的发现已经提出对于肝素片段的弹性蛋白酶抑制活性来说,需要至少12-14个糖的链长。其它论文已经提出需要最小分子量(M)为2000-3000的肝素部分以便抑制弹性蛋白酶。超硫酸化肝素(6.3kD)已经相对于其弹性蛋白酶抑制活性来予以研究。在与评估肝素对于粘附活性的效果相关的研究中,发现4-14个糖的肝素馏份对于嗜中性粒细胞与已经用IL-1β刺激的内皮细胞的粘附作用没有效果。肝素寡糖抑制弹性蛋白酶释放遵循类似模式。具有4、6或8个糖的肝素寡糖只在高浓度下具有标称效果并且随着分子量降低,抑制活性丧失。本发明人已经意外地发现式I的短长度、低分子量多硫酸化双糖治疗或减轻人嗜中性粒细胞弹性蛋白酶的效果,并且因此适用作治疗与升高弹性蛋白酶活性或弹性蛋白酶/抗弹性蛋白酶活性失衡相关联的病状或疾病的药物。
美国专利号7,056,898('898专利)公开并要求保护某些超硫酸化双糖和使用其治疗某些炎性病症的方法。所述‘898专利具体描述了所要求保护的化合物治疗包括哮喘和哮喘相关病理学的肺炎症,如过敏反应或炎性疾病或病状。所述专利中公开的化合物被描述为能够预防、逆转和/或减轻哮喘和哮喘相关病理学的症状,尤其是哮喘患者在抗原刺激后的晚期反应。
美国临时61/266,361公开某些制剂相对于在不含所要求保护的添加剂的情形下口服递送的相同化合物来说,可增强吸收/生物利用度/效力,所述制剂包含本文所述的超硫酸化双糖和选自由以下组成的组的递送剂:药学上可接受的天然或合成聚合物以及其它先前已用于改进较大化合物(例如,分子量大于4,500道尔顿(dalton)(平均分子量)的那些化合物)的递送的其它媒介物。
发明概述
本发明涉及包含式I化合物和其药学上可接受的盐以及适合于吸入的媒介物的药物制剂,
其中R1、R2、R3、R4、R5和R6独立地选自由H、SO3H或PO3H2组成的组,并且条件是R1-R6中的至少两个选自SO3H或PO3H2。本发明进一步涉及具有式I化合物的制剂,其中R1-R6中的至少三个选自SO3H或PO3H2。本发明进一步涉及具有式I化合物的制剂,其中R1-R6中的至少四个选自SO3H或PO3H2。本发明进一步涉及具有式I化合物的制剂,其中R1-R6中的至少五个选自SO3H或PO3H2。本发明优选涉及式I化合物和其药学上可接受的盐,其中R1-R6都选自SO3H。本发明也涉及具有式I化合物的制剂,其中R1-R6独立地选自SO3H或PO3H2。本发明进一步包含式I化合物的前药、衍生物、活性代谢物、部分电离和完全电离的衍生物和其立体异构体。构成本发明双糖的单体可为D或L异构体,且环绕碳环的羟基部分或其硫酸化或磷酸化形式(或其中间体)在任一特定立体中心处可具有α或β标记。单糖部分间的连接氧原子也可为α或β氧原子。本发明化合物的分子量通常小于1,000道尔顿。本发明也涉及具有两个六员环的多硫酸化双糖在治疗弹性蛋白酶相关病症中的用途。
最优选实施方案涉及含有R1-R6选自SO3H的式I化合物和其药学上可接受的盐的气溶胶/可雾化制剂。本发明也涉及用于治疗弹性蛋白酶相关病症的具有如上文定义的变量的式I化合物的口服制剂。
本发明也涵盖治疗需要治疗的生物体的弹性蛋白酶相关病状的方法,其包括施用药学有效量的化合物,所述化合物包含式I化合物
和其药学上可接受的盐,其中R1-R6独立地选自SO3H、PO3H2或H,并且条件是R1-R6中的至少两个是SO3H或PO3。
附图简述
在以下附图中描述本发明。
图1示出吸入的超硫酸化双糖对于HNE诱导的气管粘液速度(TMV)降低的效果。
图2展示相等剂量的双糖钠对于HNE诱导作用的效果。
图3示出超硫酸化双糖还可逆转HNE的效果。
图4示出卡波姆制剂中的口服超硫酸化双糖对于HNE诱导的TMV降低的正性效果。
详细描述
本发明涉及适合于递送至需要这种治疗的患者的肺的药物制剂和其用途,其中所述制剂包含式I化合物和其药学上可接受的盐
其中R1、R2、R3、R4、R5和R6独立地选自由H、SO3H或PO3H2组成的组,并且条件是R1-R6中的至少两个选自SO3H或PO3H2。
本发明也涉及适合于递送至需要这种治疗的患者的肺的药物制剂,其包含
(i)式I化合物和其药学上可接受的盐
其中R1、R4和R5独立地选自H、SO3H或PO3H2且R2、R3和R6独立地选自SO3H或PO3H2。
本发明也涉及适合于递送至需要这种治疗的患者的肺的药物制剂,其包含
(i)式I化合物和其药学上可接受的盐
其中R2和R6独立地选自H、SO3H或PO3H2并且R1、R3、R4和R5独立地选自SO3H或PO3H2。
本发明涉及适合于递送至需要这种治疗的患者的肺的药物制剂,其包含
(i)式I化合物和其药学上可接受的盐
其中R1、R2和R6独立地选自H、SO3H或PO3H2并且R3、R4和R5独立地选自SO3H或PO3H2。
在另一个实施方案中,本发明涉及适合于递送至需要这种治疗的患者的肺的药物制剂,其包含(i)式II化合物
和其药学上可接受的盐,其中R1、R2、R4、R5和R6独立地选自由SO3H或PO3H2组成的组。
在一个优选实施方案中,本发明涉及适合于递送至需要这种治疗的患者的肺的药物制剂,其包含(i)式II化合物和其药学上可接受的盐
其中R1和R4是SO3H并且R2、R5和R6独立地选自H、SO3H或PO3H2。
在另一个优选实施方案中,本发明涉及适合于递送至需要这种治疗的患者的肺的药物制剂,其包含(i)式II化合物和其药学上可接受的盐
其中R1是SO3H,R2是H并且R4、R5和R6独立地选自SO3H或PO3H2。
本发明还涉及适合于递送至需要这种治疗的患者的肺的液体或固体剂型,其包含式I化合物或II和其药学上可接受的盐,其中R1-R6如上文定义。
本发明也涵盖治疗或减轻与弹性蛋白酶或弹性蛋白酶/抗弹性蛋白酶失衡相关联的病状的方法,其包括施用(i)药学有效量的制剂,所述制剂包含式I化合物
和其药学上可接受的盐,其中R1-R6独立地选自SO3H、PO3H2或H并且条件是R1-R6中的至少两个是SO3H或PO3H2。
本发明优选地涉及可雾化、干粉或气溶胶药物制剂,其包含式I化合物,其中R1、R2、R3、R4、R5和R6选自表1中以化合物1-14展示的变量。
表1
在一优选实施方案中,制剂中的化合物选自上文表1中所示式I化合物的金属盐,其中羧酸基团发生电离且双糖周围的每一硫酸根基团都发生电离以形成金属盐,其中金属选自(例如)钠。此外,包含胺盐的其它盐可在羧酸根或硫酸根位置处形成。最优选化合物是呈化合物14的钠盐(化合物14a)的完全电离形式。
本发明化合物可如本文实施例中所述从(例如)肝素获得。尽管所用具体方法利用猪肝素,但可以使用来自任何哺乳动物的肝素来制备本发明化合物。此外,化合物可以合成方式获得。也可利用各种其它多糖作为用于所述双糖的源材料,包括但不限于硫酸肝素、硫酸皮肤素、硫酸软骨素、多硫酸戊聚糖酯和其它葡糖氨基聚糖和粘多糖。
化合物通常可通过包括以下的方法制备:(1)将肝素钠溶于水中并将pH值调节为弱酸性(约pH 6),(2)使用亚硝酸钠(NaNO2)水溶液处理此溶液以形成亚硝酸从而将肝素解聚(并对(例如)IdoA(2S)GlcNS(6S)脱氨基以形成IdoA(2S)-aMan),(3)将解聚的肝素溶液碱化至pH值为约7,(4)稀释解聚的肝素溶液,(5)过滤所述溶液以收集并富集小于3kDa(3000道尔顿)的肝素寡糖,(6)碱化含有小于3kDA的解聚肝素的过滤的溶液,(7)使用硼氢化钠(NaBH4)处理此碱化溶液以将在酸化和解聚肝素之后形成的醛羰基还原成醇;(8)使用浓酸处理还原产物,然后将pH值调节为约7,(9)使用尺寸排除色谱法进一步分馏所获得的还原寡聚物,以获得双糖铵盐,使用阳离子交换树脂进一步处理所述双糖铵盐以形成钠盐,进一步分馏所述钠盐以获得如下作为主要组分的钠盐形式的式I化合物:其中R1是H,R2是H,R3是SO3 -,R4是SO3 -,R5是H且R6是H,并且羧基(CO2H)是CO2 -Na+;和如下作为次要组分的式I化合物:其中R1是H,R2是H,R3是SO3 -,R4是SO3 -,R5是SO3 -且R6是H,并且羧基(CO2H)是CO2 -Na+,和(10)使用硫酸盐源(例如(CH3)3NSO3)在适宜条件下处理所得双糖以形成用于本发明制剂中的超硫酸化双糖。
不受限于本发明,应理解,肝素和其它碳水化合物或络合的碳水化合物是在具有设定或绝对立体化学的环上存在羟基以及硫酸根基团或羧酸基团的手性分子。肝素中最常见的双糖单元是(例如)IdoA(2S)-GlcNS(6S),其为2-O硫酸化艾杜糖醛酸和6-O硫酸化葡糖胺。
通常应理解,产生用于本发明制剂中的寡糖和双糖的多糖来源将在极大程度上决定碳水化合物环周围的手性中心的绝对立体化学。通过上文所概述的方法以化学方式或通过任何已知方式来添加其它硫酸根基团以得到最具活性的部分(超硫酸化双糖和其盐),将所述最具活性的部分进一步纯化以形成药学级双糖,将所述药学级双糖进一步与赋形剂一起进行配制以便形成适合于递送至需要治疗的患者的肺的制剂。以上展示为多硫酸化衍生物的分子可有效治疗弹性蛋白酶相关病症。这种多硫酸化衍生物具有超过三个以上展示的硫酸根基团。
可使用核磁共振成像和/或其它已知的结构鉴定方法来确定从解聚肝素(源自其任何已知来源)或其它所选多糖获得的分子的化学结构。在化合物是以合成方式或半合成方式制得的情况下,本领域技术人员可使用标准有机化学技术并利用本领域一般技术人员已知的保护基团来保护所需的羟基部分。
然后将如上所述的式I化合物(或其混合物)与气溶胶赋形剂或可雾化赋形剂一起调配以形成本发明制剂。赋形剂选自由以下组成的组:任何已知或发现的吸入剂、推进剂和/或适合于递送至患者的肺的其它添加剂。本文描述的这些制剂和/或活性成分还可与用于COPD、其亚疾病、CF或其它弹性蛋白酶相关病状的已知治疗剂一起递送或与所述治疗剂组合与或与其组合使用。对于COPD来说,所述疾病当前用以下来治疗:吸入的抗胆碱能支气管扩张剂(异丙托溴铵、噻托溴铵)或吸入的β激动剂(沙丁胺醇、沙美特罗或福莫特罗)或这些药剂与类固醇(Advair、Symbicort)或甲基黄嘌呤(茶碱)的组合。对于CF来说,当前疗法包括DNASE、吸入的抗生素(例如妥布霉素(tobramycin)),抗炎症剂(例如高剂量布洛芬(ibuprofen))以及COPD的以上疗法。根据患者和医师处方,本发明和用于指明疾病的任何一种以上治疗剂的组合可用于治疗患者。类固醇通常对于COPD患者是无效的,因此对于例如要求保护的多硫酸化双糖制剂的疗法存在巨大需求。
可通过任何适宜已知方式将本发明制剂递送至患者或其它生物体。添加到制剂中的添加剂和添加剂类型相对于活性成分和其它赋形剂的百分比是基于所需制剂的类型来计算。举例来说,在气溶胶制剂中,合适推进剂以及水溶液可用于在例如吸入器的合适递送装置中递送药物。
本发明的组合物进一步包含适合于气溶胶递送部件或可雾化部件的药学上可接受的赋形剂。
式I和式II化合物可如上所述形成药学上可接受的盐。金属盐包括(例如)具有Na、K、Ca、Ng或Ba或Al、Zn、Cu、Zr、Ti、Bi、Mn或Os的盐,或通过使式I或式II化合物与如氨基酸等有机碱或任何胺进行反应而形成的盐。优选的盐是钠盐。
因此,本发明的优选制剂包括表1中展示的那些化合物并且其为超硫酸化双糖并且进一步包含选自例如可雾化水溶液的递送剂。优选活性成分呈钠盐形式,其中钠置换式I中的羧氢原子。
这些制剂适用于治疗与升高或异常水平的人嗜中性粒细胞弹性蛋白酶相关的那些病状,例如COPD、囊性纤维化等。
囊性纤维化的特征在于在患者肺中产生异常粘稠的粘液,导致病原菌的慢性感染。细菌菌落引起炎症细胞的流入,从而进一步导致炎症细胞因子(IL-6和IL-8)升高。这导致CF患者中的感染和炎症的反复循环并且导致发病和死亡。在CF患者中,溶解粘液并且允许从肺中清除粘液并且也具有抗炎症和抗弹性蛋白酶活性的药物有助于减轻或治疗此疾病。虽然肝素已经用于在较小临床试验(六个患者)中治疗CF患者,并且在较稀的痰和其它临床参数方面取得一些成功,但是没有批准使用此药物来治疗CF或其它弹性蛋白酶相关病状,例如肺气肿或COPD。
本文所用的术语“治疗或减轻症状”意指与未被治疗的个体症状或个体相比,可减少、预防和/或逆转已施用本发明制剂的个体的症状。
已发现,本发明制剂可有效地用于预测在人以及其它动物中的用途的动物研究中。本文描述的特定动物研究证明所述制剂适用于改善或刺激全肺粘膜纤毛清除(MCC)。气管粘液速度(TMV)作为绵羊中的MCC的标记来加以测量。TMV模型在各种相对病状下用作模拟响应的测量手段,所述响应在例如受损个体和用药物治疗的受损个体中观察到。嗜中性粒细胞弹性蛋白酶在动物模型(绵羊)中用作诱导粘膜纤毛功能异常的试剂并且作为在绵羊中抑制MCC长达8小时的试剂。然后,式I化合物在弹性蛋白酶治疗动物中用作增加TMV并且恢复MCC的药物。
在研究中使用的绵羊在人道护理下来治疗。绵羊在整个研究中有意识并且在用局部麻醉剂处理动物之后执行器械操作。为了研究式I化合物的效果,绵羊在用麻醉剂(鼻部通道中的2%利多卡因(lidocaine))局部治疗之后经鼻插入气管内导管(7.5cm直径)。导管的管头正好放置在声带下方以便允许最大程度地暴露气管表面区域。除了在药物递送期期间以外,管头在整个研究期内放气以便将导管对于TMV的影响减少到最低限度。将吸入的空气加温并且加湿。
TMV活体内通过总体上在公布Chest,128卷/5,2005年11月,第3742-3749页中描述的方法来测量。TMV在体内通过X线摄影技术来测量,所述技术使用五个至10个不透射线的特氟隆/三氧化二铋圆盘,所述圆盘为1mm直径、0.8mm厚度和1.8mg重量。圆盘经由连接至连续压缩空气来源(3-4L/min)的改进抽吸导管来吹入至气管中。导管保留于气管内管中并且不与气管表面接触。个别圆盘的头部-轴向速度记录于图像放大器单元的录象磁带上。个别圆盘速度通过测量在1min观察期期间每个圆盘行进的距离来计算。对于每次运作,然后计算所有个别圆盘速度的平均值。用于研究的绵羊穿戴含有已知长度的不透射线的参考标记物的项圈,所述标记物作为校正荧光检查单元固有的放大误差的标准。
HNE从Elastin Product Company(Owensville,MO)获得。储备溶液根据制造商规范来制备。使用产生具有约1.1微米MMAD的小液滴的Raindrop Nebulizer(NellcorPuritan-Bennett,Carlsbad,CA)气溶胶递送系统来向绵羊施用规定量的HNE。雾化器连接至剂量计,其由电磁阀和20磅/平方英寸(psi)的压缩空气来源组成。雾化器的输出连接至T形接头,其一个末端连接至Harvard呼吸器(Harvard Apparatus Inc.,Holliston MA)。呼吸器设定于1:1的吸气/呼气比率和每分钟二十次呼吸的速率下。在呼吸器的呼吸循环开始时将电磁阀启动一秒。500ml的正常呼吸量用于递送试剂。在本发明中,可使用将式I化合物递送至患者的肺的任何合适部件。气溶胶递送部件、可雾化递送部件和推进剂和/或吸入剂装置部件在在本领域中为已知的并且可用于本文。本文利用的化合物优选地以干粉形式使用,其然后在递送至患者的当天使用无菌容器和去离子水或其它合适溶剂/递送系统制备成溶液。在一些装置中,式I化合物的干粉可用于将药物递送至患者而不需要增溶剂或溶液。
本发明制剂也可取决于所治疗的特定疾病或病状,与其它适宜药剂或活性成分组合施用。本发明涉及治疗COPD的方法,其包括向有需要的生物体施用治疗有效量的式I或II化合物,其中R1-R6如本文定义(即,具有至少两个硫酸根基团)。额外活性成分可呈组合疗法形式或呈具有至少两种活性成分的单一剂量单位形式施用,其中第一活性成分是式I或式II化合物(其中R1-R6如本文所定义),且第二活性成分选自用作第一线疗法以治疗CF、COPD或任何弹性蛋白酶相关病状或病症所继发的任何病状的任何药物或药剂。此类药剂包括消炎药、白三烯拮抗剂或调节剂、抗胆碱能药、肥大细胞稳定剂、皮质类固醇、免疫调节剂、β-肾上腺素能激动剂(短效和长效)、甲基黄嘌呤、和用于治疗所述病症的其它一般种类或特异性药物,包括但不限于孟鲁司特钠、沙丁胺醇(albuterol)、左旋沙丁胺醇(levoalbuterol)、沙美特罗(salmeterol)、福莫特罗(formoterol)、丙酸氟替卡松(fluticasone propionate)、布地奈德(budesonide)、西替利嗪(ceterizine)、氯雷他定(loratadine)、地氯雷他定(desloratadine)、茶碱、异丙托铵(ipratropium)、色甘酸(cromolyn)、奈多罗米(nedocromil)、倍氯米松(beclomethasone)、氟尼缩松(flunisolide)、莫米松(mometasone)、曲安西龙(triaminoclone)、泼尼松龙(prednisoline)、泼尼松(prednisone)、扎鲁司特(zafirlukast)、齐留通(zileuton)或奥马鲁钠(omalziunab)。
下列实施例意图进一步说明本发明的某些实施方案且并不加以限制。
实施例1-超硫酸化双糖的制备
通过首先解聚肝素钠来制备本发明制剂中所用的化合物。用于制备活性药物物质的起始材料是(例如)猪肠粘膜肝素(1至4个连接的葡糖胺与糖醛酸残基的多分散硫酸化共聚物)。活性药物物质(ADS)(如本文所述的超硫酸化双糖)在绵羊模型中显示抗过敏性活性。ADS的制备通常如下:
1)对猪肝素实施受控的亚硝酸解聚;
2)使用NaBH4将末端醛基团还原成醇;
3)实施尺寸排除色谱法(SEC)以制备经过分离的双糖的铵盐;
4)使双糖铵盐与三氧化硫吡啶络合物进行反应以得到超硫酸化双糖;
5)实施SEC,随后阳离子交换钠盐以提供最终产物
以此方式制得的优选产物是具有6个硫酸根基团的钠盐形式的超硫酸化双糖,如下文所示(化合物14a)
化合物14a的溶解度大于0.5g/mL。下列程序描述制备本文所述化合物的许多可能方式中的一种。在室温下,将250g可商购的猪肝素-Na(从可商购的来源获得,包括(例如)SPL of Waunakee,Wisconsin)添加至含有3升水的烧杯中并搅拌成浆液,此时再添加2升水以完全溶解肝素盐。
然后将肝素溶液中的pH值调节至约pH 6(5.98)。向此溶液中添加17.25g NaNO2(0.25mmol,J.T.Baker,ACS级)以对肝素实施受控的亚硝酸解聚。继续搅拌10分钟,同时在约23℃的温度下缓慢添加约35.1ml 37%HCl以使pH值达到约3(3.00)。在2小时时间(120分钟)内监测溶液的温度和pH,同时温度降至20℃并且pH降至pH 2.16。然后通过缓慢添加约23ml 50%NaOH以将pH值调节至6.75来将溶液骤冷以提供解聚的肝素溶液。
使用dtH2O将上文获得的解聚的肝素溶液稀释至最终体积为8升,且过滤(Millipore(Bedford,Mass.),Pellicon 2,3k PLBC-C,面积为0.5m2(Cassett:目录号P2PLBCC 05),(截断分子量为3kDa))以收集并富集尺寸小于3kDa(3000道尔顿)的肝素寡糖(即,渗透物由小于3000道尔顿的那些寡糖组成)。使用20M溶液对大于3000道尔顿的滞留物实施亚硝酸的第二解聚处理以进一步开始分解肝素。使用相同类型过滤器(截断分子量为3,000道尔顿)对所述经过二次处理的寡糖制剂实施超滤后,将所得渗透物(分子量小于3kDa)添加至来自第一超滤的渗透物中,并且然后通过反渗透来浓缩整个批料以将最终体积降至2.5升。然后将此批料冻干。
将冻干的寡糖制剂(50g)溶于1升纯化水中,然后在冰浴中冷却至2-10℃。将NaHCO3(21g)添加至冷却的寡糖溶液中且搅拌制剂直至完全溶解为止。制备存于400mL0.01M NaOH溶液中的硼氢化钠(NaBH4)的0.5M溶液,且经过60分钟时间缓慢添加至冷却的寡糖/NaHCO3溶液中。通过NaBH4处理0.5M溶液以将在5员环上形成的醛(在脱胺后形成)还原成醇部分。将反应制剂在2-10℃下搅拌3小时,然后使用浓HCl骤冷至pH 4.0。然后使用NaOH将溶液的pH值调节至6.75且最后通过反渗透浓缩至最小体积,然后冻干以提供经过还原的寡糖。然后通过尺寸排除色谱(SEC)使用Bio-Rad Biogel P6树脂(使用0.2M NH4HCO3洗脱)对尺寸小于3kDa的经过还原寡糖制剂实施分馏以将寡核混合物分馏并收集双糖铵盐。通过咔唑分析来分析收集的馏份,Abs530对馏份数的分布图可提供所收集馏份的曲线。汇集曲线上的相似馏份,然后冻干以得到铵盐形式的经过分离的馏份并去除NH4HCO3。使用AmberliteIR 120 Plus阳离子交换树脂(可商购自Sigma-Aldrich)实施阳离子交换以将铵盐转化成钠盐形式。从馏份获得两种双糖且鉴别其为化合物A(85wt%)和B(3-5wt%):
化合物A:
化合物B:
将含有上述化合物A和B的馏份进一步处理以形成超硫酸化双糖。利用两种非限制性方法。在方法1中,根据制造商说明书经由与Dowex 500WX200酸性树脂(可商购自Sigma-Aldrich)进行反应来酸化含有2.5克双糖且存于50mL水中的上述馏份的溶液。使用四丁基氢氧化铵来中和酸性滤液,且冻干溶液以获得絮状固体形式的四丁基铵(Bu4N+)盐。然后,在氩下将无水DMF(50mL)添加至双糖铵盐与(CH3)3NSO3(5.22克)的混合物中。将反应混合物在50℃下加热48小时。然后,将溶液冷却至室温。添加100ml存于乙醇中的乙酸钠饱和溶液,且在室温下将混合物搅拌20分钟,使用2.5L水稀释,然后经由500道尔顿(也即,0.5kDa)膜过滤。冻干滞留物(即,大于0.5kDa);再混悬于0.2M NH4HCO3溶液中,在Bio-Rad Biogel P6树脂(Bio-Rad,Hercules,CA)上根据制造商说明书实施色谱并使用0.2M NH4HCO3洗脱以获得超硫酸化双糖的NH4 +盐(3.5克)。根据制造商说明书经由与Amberlite IR 120Plus阳离子交换树脂(可商购自Sigma-Aldrich)进行反应将此盐部分(2.4克)转化成Na+盐形式,从而提供示于表1中且如下文化合物14a所示的化合物14的钠盐:
化合物14a:
同样根据方法2来制备此化合物。在方法2中,将0.5克含有化合物A和B的馏份与3克存于15mL DMF中的(CH3)3NSO3的混合物在氩和60℃下加热48小时。然后,将反应混合物冷却至室温,使用20mL 10%乙酸钠水溶液稀释,并在室温下搅拌20分钟,添加100mL乙醇,且在高真空下浓缩反应混合物以获得固体残余物。将残余物溶于500mL水中并通过500道尔顿膜过滤(使用H2O洗涤(3x))。将含有超硫酸化14a产物的钠盐滞留物冻干成灰白色固体。
实施例2-
为了说明根据本发明的制剂治疗并且减轻弹性蛋白酶相关疾病和病状,包括但不限于列举本文的具体疾病和病状的有效性,申请人提供以下实施例:
动物制剂
用于在此项研究中的所有程序由负责确保人道使用实验动物的西奈山医疗中心动物研究委员会(Mount Sinai Medical Center Animal Research Committee)来审查并且批准。
将成年绵羊以直立位置约束在专用身体挽具手推车中。将动物头部固定,并且在以2%利多卡因诱导鼻部通道的局部麻醉之后,动物经鼻插入标准气管内(ET)导管(7.5mm直径、Mallinckrodt,St.Louis,MO)。光学纤维气管镜用于引导ET导管并且验证其在气管中的位置。导管的管头正好放置在声带下方以便允许最大程度地暴露气管表面区域。为了将由气管内导管管头充气造成的TMV可能影响减少到最低限度,除了在将化合物雾化期期间以外,在整个研究中将管头放气。另外,为了减轻长时间插管的影响,使用BennettHumidifier(Puritan-Bennett;Lenexa,KS)将吸入的空气加温并且加湿。在插管之后,允许动物静止约20分钟,然后开始研究。动物在整个研究中清醒并且警觉。
TMV测量
TMV在体内通过利用Siremobile 2000荧光镜(Siemens)的荧光检查技术来测量。将五至七个不透射线的特氟隆/三氧化二铋圆盘(1mm直径,0.8mm厚度,和1.8mg重量)吹入动物气管的中间部分。连接至3至4L/min的连续压缩空气来源的导管用于经由气管内导管来将圆盘递送至气管表面。导管只在圆盘吹入期间保持于气管内导管内并且不与气管表面接触。一旦圆盘递送至气管上,每个个别圆盘的头部-轴向速度记录于与荧光镜串联的便携式图像放大器单元的录象磁带上。速度通过测量在1min观察期期间每个圆盘行进的距离来计算。对于每次运作,计算所有个别圆盘速度的平均值。含有已知长度的不透射线的参考标记物的项圈固定于绵羊脖子周围并且用作校正荧光检查单元固有的放大率影响的标准。
气溶胶递送系统
所有试剂使用产生具有约1.1微米MMAD的小液滴的Raindrop Nebulizer(NellcorPuritan-Bennett,Carlsbad,CA)来雾化。雾化器连接至剂量计系统,其由电磁阀和20磅/平方英寸(psi)的压缩空气来源组成。雾化器的输出连接至T形接头,其一个末端连接至Harvard呼吸器(Harvard Apparatus Inc.,Holliston MA)。呼吸器设定于1:1的吸气/呼气比率和每分钟20次呼吸的速率下。在呼吸器的吸气循环开始时将电磁阀启动一秒。500ml的正常呼吸量用于递送试剂。
试剂
人嗜中性粒细胞弹性蛋白酶(HNE)从Elastin Products Corporation,Inc.(Owenville,MO)获得。储备溶液根据制造商规范来制备。从储备物制备含有1190mU活性酶的6.8微升的等分试样并且存储于-80℃下。在实验当天,HNE溶解于3mL磷酸盐缓冲盐水溶液中,并且使用如上所述的气溶胶递送系统向绵羊施用总量。
双糖钠和超硫酸化双糖以干粉形式来提供。在实验当天制备新调制的溶液。无菌容器用于将化合物称重并且将总共3.0mL去离子水添加至容器。一旦化合物完全溶解,通过气溶胶使用所描述的系统将溶液施用至动物。所有试剂雾化至干(约10-12分钟)。
呈胶囊形式的口服剂型使用1:2比率的活性成分与卡波姆(15mg活性物质/30mgs卡波姆)来制备。如图4展示来利用的剂量是各自15mg的两个胶囊。类似于卡波姆的其它合适赋形剂还可用于口服制剂中。
方案
方案1:用双糖钠和超硫酸化双糖预治疗对于HNE诱导的TMV减少的效果:在获得初始基线TMV测量之后,动物在单独场合用双糖钠(10mg、30mg或100mg)或超硫酸化双糖(10mg、30mg或100mg)来治疗。在30分钟之后,然后绵羊用雾化HNE来激发。在HNE施用之后15min、30min和45min,然后历时长达6小时每小时获得TMV的测量结果。
方案2:超硫酸化双糖对于逆转HNE诱导的TMV减少的效果:在获得基线TMV测量结果之后,绵羊用雾化HNE来激发。然后在施用HNE之后前四个小时每小时获得TMV测量结果。在4h TMV测量之后,立即将绵羊用10mg、30mg或100mg超硫酸化双糖来治疗。每小时直至HNE后8h获得连续TMV测量结果。
方案3:口服超硫酸化双糖对于HNE诱导的TMV减少的效果:动物用每12小时施用的两个剂量的口服超硫酸化双糖(14a)(具有30mg卡波姆的各自15mg的2个胶囊,其中活性物质的总剂量等于30mg)来治疗。最后一个剂量在用HNE来进行气溶胶激发之前90分钟施用。获得基线和气雾化HNE激发之后15分钟的TMV测量结果,然后如上所述长达激发之后六个小时连续获得TMV测量结果。
结果:
图1示出吸入的超硫酸化双糖(化合物14a)对于HNE诱导的TMV减少的效果。单独HNE将TMV减少至基线的~60%。用吸入的超硫酸化双糖预治疗导致针对此HNE诱导的TMV减少的剂量依赖性防护。比较之下,图2展示等效剂量的2’,6硫酸氢盐双糖钠(通过用氧化氮进行的肝素化学解聚而产生)对于HNE诱导作用的效果。与超硫酸化双糖相比,10mg和30mg剂量的2’,6-硫酸氢盐双糖钠都不提供针对HNE诱导的响应的保护。因此,超硫酸化双糖(例如具有超过2个硫酸根)展示针对HNE诱导的效果进行防护方面的增加的效力。用于此比较实施例中的2’,6-硫酸氢盐双糖钠展示为式I化合物的相同化合物,其中羟基代替硫酸根基团(即,R1、R2、R5和R6是H并且R3和R4是硫酸根并且具有羧酸根阴离子的钠盐)。
图3示出超硫酸化双糖还可逆转HNE的效果。在此项研究中,10mg剂量的超硫酸化双糖是无效的,但是使用30mg和100mg超硫酸化双糖观察到HNE诱导的响应的显著逆转。这些发现指示超硫酸化双糖可治疗性以及预防性使用(如图1中观察到)以便抗击HNE诱导的TMV减少。
在图1-图3呈现的研究中,动物数据明显展示要求保护的化合物是与人嗜中性粒细胞弹性蛋白酶相关的疾病或病状的有效调节剂。在一个优选实施方案中,要求保护的式I化合物和其盐呈多硫酸化盐形式并且递送至需要其治疗的患者的肺。
尽管本文已参照其具体的实施方案详尽描述了所要求保护的发明,但本领域一般技术人员应了解,可对所要求保护的发明作出各种改变和修改,此并不背离本发明的精神和范围。因此,举例来说,本领域技术人员应在最多使用常规实验的情形下了解或能够确定所要求保护的发明中并未明确描述的诸多实施方案。所述实施方案属于本发明范围内。
本发明进一步涉及一种用任何多硫酸化双糖来治疗弹性蛋白酶相关病症的方法,所述多硫酸化双糖包括来自肝素的那些双糖并且具有六-六环结构并且条件是至少三个硫酸根基团存在于所述部分上。这些化合物描述于例如美国专利公布US20030087875;5,690,910;6,193,957和7056898中,其全部通过引用并入。以下展示的N-硫酸化双糖单元和包括其异构体的其多硫酸化形式也种有效治疗弹性蛋白酶相关病症:
因此,术语“超硫酸化双糖”是指在双糖核心分子上具有至少两个硫酸根部分的任何双糖部分并且条件是这些分子不包含式I化合物中的R1、R2、R5和R6为H并且R3和R4为硫酸根(SO3 -M+)的钠双糖。此术语也包括来自肝素并且具有低分子量(例如约1,000道尔顿或少)的任何多硫酸化双糖和其任何多硫酸化衍生物或化学/酶修饰形式并且条件是所述部分具有至少两个硫酸根基团。酶处理提供如以上展示的6,6双糖。用NO来化学解聚提供6,5环状结构。优选修饰或衍生物具有至少三个硫酸根部分。最优选部分具有所有羟基置换为硫酸根基团并且任何N基团经过N-硫酸化。
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Claims (7)
1.药物制剂在制备逆转具有嗜中性粒细胞弹性蛋白酶的患者的弹性蛋白酶诱导的气管粘液速度(TMV)降低的药物中的用途,其中所述药物制剂适合于递送至患者的肺,其包含式I化合物或其药学上可接受的盐
其中R1、R2、R3、R4、R5和R6独立地选自由SO3H或PO3H2组成的组。
2.一种干粉药物制剂在制备增加具有嗜中性粒细胞弹性蛋白酶的患者气管粘液速度的药物中的用途,其包括
(i)式I化合物或其药学上可接受的盐
其中R1、R2、R3、R4、R5和R6独立地选自由SO3H或PO3H2组成的组。
3.一种可雾化药物制剂在制备增加具有嗜中性粒细胞弹性蛋白酶的患者气管粘液速度的药物中的用途,其包含(i)式II化合物
或其药学上可接受的盐,其中R1、R2、R4、R5和R6独立地选自由SO3H或PO3H2组成的组,以及
(ii)递送剂。
4.一种气溶胶、干粉或可雾化制剂在制备增加具有嗜中性粒细胞弹性蛋白酶的患者气管粘液速度的药物中的用途,其包含选自具有如下R1-R6的式I化合物
或其药学上可接受的盐。
5.一种组合在制备用于增加气管粘液速度及改善患者肺功能的药物中的用途,所述组合包括根据权利要求1所述的式I化合物和选自以下的至少一种额外活性成分:消炎药、抗胆碱能药、肥大细胞稳定剂、免疫调节剂、短效和长效β-肾上腺素能激动剂、甲基黄嘌呤和抗组胺。
6.根据权利要求5所述的用途,其中所述消炎药选自白三烯拮抗剂或调节剂、皮质类固醇。
7.根据权利要求5所述的用途,其中所述至少一种额外活性成分选自孟鲁司特钠(montelukast sodium)、沙丁胺醇(albuterol)、左旋沙丁胺醇(levoalbuterol)、沙美特罗(salmeterol)、福莫特罗(formoterol)、丙酸氟替卡松(fluticasone propionate)、布地奈德(budesonide)、西替利嗪(ceterizine)、氯雷他定(loratadine)、地氯雷他定(desloratadine)、茶碱、异丙托铵(ipratropium)、色甘酸(cromolyn)、奈多罗米(nedocromil)、倍氯米松(beclomethasone)、氟尼缩松(flunisolide)、莫米松(mometasone)、曲安西龙(triaminoclone)、泼尼松龙(prednisoline)、泼尼松(prednisone)、扎鲁司特(zafirlukast)、齐留通(zileuton)或奥马鲁钠(omalziunab)。
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US5977080A (en) * | 1995-08-23 | 1999-11-02 | The Regents Of The University Of California | Sulfated disaccharide inhibitors of selectins, methods for synthesis and therapeutic use |
CN1092049C (zh) * | 1997-08-04 | 2002-10-09 | 巴克·诺顿药物有限公司 | 治疗后期过敏反应和炎性疾病的组合物及其用途 |
US20030087875A1 (en) * | 2001-04-16 | 2003-05-08 | Tahir Ahmed | Hypersulfated disaccharides and methods of using the same for the treatment of inflammations |
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CN102711463A (zh) * | 2009-12-03 | 2012-10-03 | Opko健康公司 | 超硫酸化双糖制剂 |
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US5539123A (en) * | 1994-08-26 | 1996-07-23 | University Of Kentucky Research Foundation | Low molecular weight thiocarbamates as inhibitors of elastase, uses and method of synthesis |
ES2167251B1 (es) * | 2000-07-13 | 2003-09-16 | Bioiberica | Nuevos disacaridos con accion antiartrosica. |
EP1488819A1 (en) * | 2003-06-16 | 2004-12-22 | Rijksuniversiteit te Groningen | Dry powder inhaler and method for pulmonary inhalation of dry powder |
US20090215717A1 (en) * | 2004-08-05 | 2009-08-27 | Ivax Drug Research Institute Ltd. | Sulfated oligosaccharides |
EP1778709B1 (en) * | 2004-08-05 | 2008-05-28 | IVAX Drug Research Institute Ltd | Polysulfated glycosides and salts thereof |
ES2364683B1 (es) * | 2009-12-29 | 2012-08-08 | Bioibérica S.A. | Disacáridos sulfatados para el tratamiento de enfermedades neurodegenerativas y/o neurovasculares. |
AR081747A1 (es) * | 2010-03-31 | 2012-10-17 | Opko Health Inc | Composicion farmaceutica de glucopiranosidos hipersulfatados |
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2011
- 2011-10-27 EP EP11837085.7A patent/EP2632259A4/en not_active Withdrawn
- 2011-10-27 RU RU2013116520/15A patent/RU2013116520A/ru not_active Application Discontinuation
- 2011-10-27 MX MX2013004575A patent/MX2013004575A/es not_active Application Discontinuation
- 2011-10-27 CN CN201180052056.6A patent/CN103269585B/zh not_active Expired - Fee Related
- 2011-10-27 KR KR1020137011776A patent/KR20130132792A/ko not_active Application Discontinuation
- 2011-10-27 CA CA2814951A patent/CA2814951A1/en not_active Abandoned
- 2011-10-27 JP JP2013536825A patent/JP2014500863A/ja active Pending
- 2011-10-27 US US13/880,875 patent/US20130203695A1/en not_active Abandoned
- 2011-10-27 WO PCT/US2011/058085 patent/WO2012058424A1/en active Application Filing
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2015
- 2015-06-16 US US14/741,254 patent/US20150283157A1/en not_active Abandoned
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US5690910A (en) * | 1995-08-18 | 1997-11-25 | Baker Norton Pharmaceuticals, Inc. | Method for treating asthma |
US5977080A (en) * | 1995-08-23 | 1999-11-02 | The Regents Of The University Of California | Sulfated disaccharide inhibitors of selectins, methods for synthesis and therapeutic use |
CN1092049C (zh) * | 1997-08-04 | 2002-10-09 | 巴克·诺顿药物有限公司 | 治疗后期过敏反应和炎性疾病的组合物及其用途 |
US20030087875A1 (en) * | 2001-04-16 | 2003-05-08 | Tahir Ahmed | Hypersulfated disaccharides and methods of using the same for the treatment of inflammations |
WO2005075490A2 (en) * | 2004-02-03 | 2005-08-18 | Ivax Corporation | Synthesis of polysulfated uronic acid glycosides |
CN102711463A (zh) * | 2009-12-03 | 2012-10-03 | Opko健康公司 | 超硫酸化双糖制剂 |
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EP2632259A4 (en) | 2015-04-29 |
JP2014500863A (ja) | 2014-01-16 |
RU2013116520A (ru) | 2014-12-10 |
EP2632259A1 (en) | 2013-09-04 |
CA2814951A1 (en) | 2012-05-03 |
MX2013004575A (es) | 2013-05-17 |
CN103269585A (zh) | 2013-08-28 |
US20130203695A1 (en) | 2013-08-08 |
KR20130132792A (ko) | 2013-12-05 |
US20150283157A1 (en) | 2015-10-08 |
WO2012058424A1 (en) | 2012-05-03 |
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