CN106456646B - 用于治疗或预防肾结石症的可可碱或其衍生物 - Google Patents
用于治疗或预防肾结石症的可可碱或其衍生物 Download PDFInfo
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Abstract
本发明涉及可可碱或其衍生物作为尿酸结晶抑制剂的用途，以便预防尿中的尿酸晶体形成，并且因此预防肾结石症或特别地尿酸肾结石症。
Description
技术领域
本发明涉及可可碱或其衍生物作为尿酸结晶抑制剂的用途，以避免尿中的尿酸晶体形成，并且因此避免尿酸肾结石症。
背景技术
目前已知尿酸肾结石症的根本问题在于5.5以下的尿pH值的或多或少的持久存在。与这种物质的排泄联系的尿酸的尿过饱和是重要的，但几乎不存在其中它已证实是尿石症发展中的决定因素的情况。直观地，看起来很可能尿酸结晶抑制剂的存在必须是相关的，因为在具有相同尿pH值和尿酸浓度的个体中，一些个体形成尿酸肾结石，并且其他个体不形成。然而，尽管潜在尿酸结晶抑制剂的一些体外研究已得到执行，所述体外研究已显示皂苷、糖胺聚糖和糖蛋白显示出抑制尿酸结晶的惊人能力，但不存在关于这个主题的已知临床研究。
目前，尿酸肾结石症的预防治疗基于饮食措施的实现，以减少尿中的尿酸水平且依次又增加尿pH水平。这就是为何推荐减少动物蛋白质(红肉、海鲜、油性鱼、内脏等)和酒精饮料的过度消耗，且增加水果(主要是柑橘类水果)和蔬菜以及碳酸饮料的消耗。目前用于治疗尿酸肾结石症的唯一药学药物是作为尿碱化剂的柠檬酸盐，并且在其中检测到高尿酸血症的那些情况下，血浆中的尿酸合成通过别嘌呤醇或非布司他的经口施用而减少，以便抑制黄嘌呤氧化酶，所述黄嘌呤氧化酶负责尿酸的合成(Grases F等人，Urol.Int.1999；62(4):201-4；Ngo TC等人，Rev.Urol.2007；9(1):17-27)。
因此，可用于治疗尿酸肾结石症的治疗武器库仍是非常有限的，促使在提供对这种病理学的新解决方案的新治疗策略的兴趣。
发明内容
本发明的目的在于基于新的和有力的尿酸结晶抑制剂的发现，呈现用于治疗尿酸肾结石症的新产物。这种产物是黄嘌呤衍生物，其中第3和7位通过含有一至六个碳原子的烷基的直链或支链进行修饰；链可为彼此等同或不同的-例如，其中R1和R2基团作为甲基，称为可可碱的二甲基黄嘌呤。
可可碱(C7H8N4O2，化学名称3,7-二甲基黄嘌呤或3,7-二氢-3,7-二甲基-1H-嘌呤-2,6-二酮)是来自甲基黄嘌呤家族的生物碱，所述甲基黄嘌呤家族还包括茶碱和咖啡因。与咖啡因含有的三个基团相比较，可可碱具有两个甲基。
因此，本发明的主要方面涉及具有通式(I)的化合物或其药学可接受的盐中的任一种用于产生用于治疗和/或预防肾结石症，优选尿酸肾结石症的组合物的用途，
其中R1和R2相同或不同，并且代表烷基(C1-C6)。
本发明中的术语“烷基”指线性或分支饱和烃链，所述线性或分支饱和烃链具有1-6个碳原子，例如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、仲丁基、正戊基、正己基等，更优选1-3个碳原子，且更优选地，它是甲基。
在一个优选实施例中，R1是烷基(C1-C3)，更优选地，R1是甲基。
在另一个优选实施例中，R2是烷基(C1-C3)，更优选地，R2是甲基。
在一个更优选的实施例中，R1和R2均为甲基。
考虑到本发明已证实具有通式(I)的化合物是尿酸结晶抑制剂，在另一个优选实施例中，如先前描述的，具有通式(I)的化合物用于产生预期减少患者的风险且改善患者的健康状态的组合物，所述患者患有与尿酸结晶相关的疾病，例如尿酸肾结石症。
可可碱以相当高的浓度在巧克力中发现。含有最低限度34％直到最大限度98％可可的50g一片的黑巧克力或苦巧克力可含有平均378mg可可碱。这个巧克力量明显是安全的并且可被食用，而无任何类型的副作用。超过1000mg的剂量已安全用于临床试验中，而无继发效应或毒性作用，尽管它可引起轻微胃不适。必须食用大量可可才使得可可碱对人具有任何有害作用。尽管可可碱在人中不引起有害效应，但它对于一些驯养动物包括犬和猫是高度毒性的。在动物中低剂量的可可碱可引起心律失常、抽搐甚至死亡。
因此，在一个优选实施例中，本发明涉及具有式(I)的化合物更优选可可碱的制剂用于在治疗或预防肾结石症，优选尿酸肾结石症的组合物(药物组合物或营养组合物、功能性食品或食物补充剂)中使用的用途。使用的剂量在100mg/天直到380mg/天之间变动。
术语“肾结石症”、“尿石症”或“肾结石”指通过肾或尿道(尿管、膀胱)内的结石或石头的存在引起的病症。肾结石由通常在尿中发现的物质(钙盐、尿酸、半胱氨酸等)组成，所述物质出于不同原因已变得浓缩且沉淀出，形成不同大小的碎片。
术语“尿酸晶体”或“尿酸结石”包括所有这些过程或状况，其涉及/诱导该物质涉及其中的尿中的沉淀固体形成。
在一个优选实施例中，组合物是药物组合物或营养组合物或功能性食品。
具有式(I)的化合物且特别是可可碱可以固体形式(包括颗粒剂、粉末或栓剂)或液体形式(例如溶液、悬浮液或乳状液)施用。它可以这种方式施用或甚至在经历操作例如灭菌或者防腐剂、稳定剂或乳化剂的添加后施用。
具有式(I)的化合物且特别是可可碱的施用可与一种或多种化合物组合，所述一种或多种化合物有助于其通过所选施用途径的吸收。它因此可与乳糖、蔗糖、滑石、硬脂酸镁、纤维素、钙盐、明胶、脂肪酸以及其他类似物质一起施用。
可用于所述组合物中的药学可接受的佐剂和媒介物是本领域的专家已知的且常用于制备治疗组合物的佐剂和媒介物。
对于治疗用途，如果具有式(I)的化合物且特别是可可碱以药学可接受的形式或是基本上纯的，即它具有药学可接受的水平的纯度，排除正常药学添加剂，例如稀释剂和载体，并且不含在正常剂量水平下视为毒性的任何材料，则是优选的。关于活性物质的纯度水平优选在50％以上，更优选在70％以上，并且再更优选在90％以上。在一个优选实施例中，具有式(I)的化合物或者其盐或溶剂化物的水平在95％以上。
在说明书和权利要求书自始至终，单词“包含”及其变化不预期排除其他技术特征、添加剂、组分或步骤。对于本领域的专家，本发明的其他目的、优点和特征部分起于说明书且部分起于本发明的实践。下述实例和附图通过举例说明提供且不预期是本发明的限制。
附图说明
图1.在不同可可碱浓度下，在pH＝4.67的合成尿中的尿酸(400mg/l)结晶的动力学曲线。吸光度(在550nm处)针对时间(以分钟表示)进行标绘。
图2.对于不同pH值和可可碱浓度，关于在合成尿中的400mg/l尿酸溶液的诱导期(以分钟表示)的图示。
图3.在不存在可可碱的情况下(A)以及在20mg/l(B)和40mg/l(C)可可碱的存在下，在pH＝4.67的合成尿中获得的，使用扫描电子显微镜检查观察到的尿酸晶体。
图4.由合成尿溶液和尿酸溶液(各自通过具有不同流速的蠕动泵驱动)、T形连接和含有尿酸结石的室组成的所使用系统的流程图。
图5.当在不同浓度的可可碱的存在下经历合成尿的恒定流动48小时，在体外冲击波碎石术后获得的，来自单个患者的肾尿酸结石碎片的体外质量中的增加百分比(伴随标准差条)。
图6.与合成尿接触已增长的肾尿酸结石碎片的扫描电子显微镜图像，所述合成尿不含可可碱(A)和含有20mg/l可可碱(B)。
具体实施方式
浊度计用于获得关于在不同pH和可可碱浓度下，对应于合成尿(类似于尿的平均组合物)中的400mg/l尿酸溶液的尿酸结晶的动力学曲线。图1显示了关于以pH＝4.67的尿酸(不含可可碱)以及关于具有10mg/l、20mg/l和40mg/l添加的可可碱的相同尿酸浓度的动力学曲线。如可见的，诱导时间(当晶体开始出现的时间)随着可可碱浓度增加而显著地增加，指示这种物质充当尿酸成核抑制剂。
诱导时间因此对于不同pH和不同可可碱浓度在合成尿中的400mg/l尿酸进行计算(表2)。如由图2中的曲线可见的，诱导时间随着可可碱浓度增加而增加。另外，抑制效应对于增加的尿pH显著得多。
表1.对于以不同pH和可可碱浓度的合成尿中的400mg/l尿酸溶液的诱导时间(和标准差(SD))。
在比浊法实验期间生成的沉淀物进行真空过滤，允许晶体干燥并且随后在扫描电子显微镜下检查它们，以察看在不同可可碱浓度下形成的晶体之间是否存在任何形态差异。图3显示了在不含可可碱以及具有20mg/l和40mg/l可可碱、以pH＝4.67的合成尿中的400mg/l溶液中生成的晶体。如可见的，随着可可碱浓度增加，尿酸晶体的形态变得窄得多且更细长。这指示抑制剂作用于晶体的侧面，阻止在该区域中的生长。因此，除了是尿酸成核的抑制剂之外，它还充当晶体生长的抑制剂。
执行的最后实验是关于可可碱作为尿酸晶体生长的抑制剂的作用的研究。为了实现这点，使用如图4中所示的流动系统，将来自相同患者的尿酸结石的碎片(通过体外冲击波碎石术获得)置于具有400mg/l尿酸和不同浓度的可可碱的合成尿的流动中。该系统具有两个蠕动泵。其中之一抽泵以pH＝3.00的不含尿酸的合成尿(4-A)。另一个抽泵以pH＝10.70的2g/l尿酸溶液(4-B)。两种溶液的温度在37℃下进行调节(5)。对于研究可可碱效应的时期，它溶解于合成尿溶液中。这些溶液(合成尿和尿酸)在T形连接(3)中混合，以产生以pH 5.40或约pH 5.40的具有400mg/l尿酸的合成尿。蠕动泵具有不同流速，因为最终合成尿必须具有400mg/l尿酸，并且总日体积必须为750ml，这是经过肾的平均尿体积。
起因于尿酸和合成尿溶液混合的溶液经过含有已知重量的尿酸结石的室(2)；该室位于以37℃的烘箱内(1)。流动系统维持48小时。在该时间结束时，结石在烘箱中干燥且再次称重。随后计算质量中的增加％。
图5显示了与可可碱浓度有关的质量中的增加百分比。总共5个结石用于每个可可碱浓度。如可见的，随着可可碱浓度增加，结石碎片的质量％下降，其中质量增加在20mg/l可可碱时事实上为零。
使用扫描电子显微镜检查来检查总共两个碎片，以便察看在结石暴露于流动过程后，是否存在与可可碱浓度相关的结石之间的任何形态学差异(图6)。可见当不存在抑制剂时，已在结石表面上生长的碎片大于可可碱存在时。
所有先前实验均证实可可碱抑制尿酸晶体成核和生长的高能力，具有在肾结石症的治疗和预防中的潜在应用。
Claims (3)
1.具有通式(I)的化合物或其药学可接受的盐中的任一种用于制造用于治疗和/或预防肾结石症的药物组合物的用途，
其中R1和R2是甲基，其中所述肾结石症是尿酸肾结石症。
2.根据权利要求1所述的用途，其中所述具有通式(I)的化合物以100mg/天至380mg/天适合于其施用的剂量存在。
3.根据权利要求1-2中任一项所述的用途，其中除所述具有通式(I)的化合物之外，所述药物组合物含有乳糖、蔗糖、滑石、硬脂酸镁、纤维素、钙盐、明胶或脂肪酸。
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