CN111447933A - 曲前列环素的糖苷衍生物 - Google Patents
曲前列环素的糖苷衍生物 Download PDFInfo
- Publication number
- CN111447933A CN111447933A CN201880079687.9A CN201880079687A CN111447933A CN 111447933 A CN111447933 A CN 111447933A CN 201880079687 A CN201880079687 A CN 201880079687A CN 111447933 A CN111447933 A CN 111447933A
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- CN
- China
- Prior art keywords
- treprostinil
- derivative
- group
- minutes
- glycoside
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 Glycoside derivatives of treprostinil Chemical class 0.000 title claims abstract description 60
- 229930182470 glycoside Natural products 0.000 title claims abstract description 40
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- 150000002338 glycosides Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 235000000346 sugar Nutrition 0.000 claims description 16
- 239000008103 glucose Substances 0.000 claims description 13
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
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- 125000006239 protecting group Chemical group 0.000 claims description 9
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 8
- 125000003147 glycosyl group Chemical group 0.000 claims description 8
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Abstract
本发明涉及药学产品领域,具体涉及曲前列环素的糖苷衍生物。糖苷曲前列环素衍生物可以用于治疗对于采用曲前列环素的治疗有响应的任何病况,包括肺高压,例如肺动脉高压。
Description
技术领域
本发明涉及药学产品领域,具体涉及糖苷曲前列环素和制备其的方法。
背景技术
曲前列环素(Treprostinil)是用于治疗肺动脉高压的血管扩张剂。曲前列环素属于前列环素(PGI2)族类似物,并以瑞莫杜林(Remodulin)(输注)、Orenitram(口服)和Tyvaso(吸入)的名称销售。
瑞莫杜林通过连续皮下或静脉内输注施用。根据制造商,输注速率起初应为1.25ng/kg/min。如果患者不能耐受该剂量,则输注速率可降低至0.625ng/kg/min。
生物利用度接近100%,并且在人类生物体中的生物学半衰期为4.4至4.6小时[1]。曲前列环素经肝脏代谢,尿排泄量为79%(其中4%为未经代谢的曲前列环素,64%经鉴定为代谢产物)和粪便中13%。
US 2015/166503A1描述了曲前列环素衍生物。
WO 2016/205202A1和US 9,394,227B1涉及具有提高的系统利用度的曲前列环素衍生物。
WO 2005/007081A2描述了具有提高的口服利用度的曲前列环素衍生物。
迄今为止,仍然需要将曲前列环素通过患者必须始终佩戴的输液泵以连续皮下输注或连续静脉内输注的方式来施用。曲前列环素的皮下输注往往疼痛到患者无法忍受这种疼痛的程度,因此将施用方式改为静脉输注。然而,已经报道了静脉内使用瑞莫杜林令败血症的风险增加。由于皮下输注与疼痛有关,因此需要开发一种前列环素激动剂或类似物,其可以通过皮下施用来进行施用,但疼痛度降低。尽管吸入曲前列环素更为方便,并且没有常与皮下输注曲前列环素关联的剧烈疼痛,但吸入法被认为效果更差,因此处方较不常见。
因此,仍然存在给患者提供功效更好和/或更为舒适的曲前列环素治疗的需求。
发明内容
因此,本发明的一个目的在于提供曲前列环素的改进前药。该目的通过本发明的主题来实现。
根据本发明,提供了通式I的曲前列环素的糖苷衍生物,
其中,R1、R2和R3彼此独立地为H或糖基,且其中R1、R2和R3中的至少一个不是H。
在一个实施方式中,糖苷衍生物具有如上所述的通式,其中R1和R2是H且R3是糖基。
本发明的另一个实施方式涉及本文所述的曲前列环素衍生物,其中所述糖基是环式单糖、二糖、低聚糖、氨基糖或糖醇。
在本发明的一个实施方式中,所述单糖是吡喃糖苷或呋喃糖苷。
在本发明的一个实施方式中,所述糖基选自:己醛糖如阿洛糖、阿卓糖、葡萄糖、甘露糖、古洛糖、艾杜糖、半乳糖和塔罗糖,己酮糖如阿洛酮糖、果糖、山梨糖和塔格糖,戊醛糖如核糖、阿拉伯糖、木糖和来苏糖,戊酮糖如核酮糖和木酮糖,或己糖胺如半乳糖胺、葡萄糖胺、甘露糖胺、神经胺酸、胞壁胺酸(muramine acid)和N-乙酰葡萄糖胺。
在本发明的一个实施方式中,所述吡喃糖苷是葡萄糖或半乳糖。
本发明的另一个实施方式涉及本文所述的曲前列环素衍生物,其中所述曲前列环素衍生物的血浆半衰期为至少60分钟,特别是70分钟、80分钟、90分钟,特别是100分钟±20分钟。
本发明的另一个实施方式涉及本文所述的曲前列环素衍生物,其中,在20h±5h时所述曲前列环素衍生物在血浆中被切割至少50%,特别是至少60%、70%、80%,更特别是至少90%。
本发明的另一个实施方式涉及本文所述的曲前列环素衍生物,其中,与未经修饰的曲前列环素相比,所述曲前列环素衍生物具有减少的对IP、EP2和/或EP受体的受体结合亲和力。具体地,相对于未经修饰的曲前列环素对受体的结合亲和力而言,所述受体结合为至少2倍,特别是5倍、10倍、15倍,更特别是约20倍。
本发明的一个实施方式涉及包含本文所述的曲前列环素的糖苷衍生物的组合物。
本发明的一个实施方式涉及包含本文所述的曲前列环素的糖苷衍生物的药物组合物。
本发明的另一个实施方式涉及本文所述的药物组合物,其中所述曲前列环素衍生物选自:
本发明的一个实施方式涉及制备式I的化合物的方法,所述方法包括以下反应步骤:
其中,PG是保护基,
并且
R1、R2和R3如本文中所定义。
在本发明的一个实施方式中,R1、R2或R3中的一个表示H,且因此可用于连接保护基。在以下反应步骤中,未被保护的残基被糖基化。其后将糖苷的保护基去除。因此,在终产品中,R1、R2和/或R3被糖基化。
本发明的另一个实施方式涉及本文所述的方法,其中所述保护基是(但不限于):苄基醚(取代甲醚、取代乙醚、取代苯甲醚、各种甲硅烷基醚)、酯(乙酸酯、取代乙酸酯、苯甲酸酯、碳酸酯、磺酸酯)、环式缩醛(acetale)、来自酮和醛的缩醛)。
可以优选的是这样的保护基:在室温下对分子有最高的可能保护,将再次分离,而不会被产物干扰并且pH没有明显变化。苄基醚的使用是本文的一个具体实施方案,其易于合成且易于通过异源催化水合裂解。
针对曲前列环素的酸官能的保护基可以是酯(例如苄酯)、酰胺和酰肼。
本发明的一个实施方式涉及式II的中间体化合物:
其中Bn是苄基部分。
附图说明
图1绘出曲前列环素的校准曲线。
图2示出曲前列环素在人血浆中和水中的水解。
图3展示了游离曲前列环素的洗脱曲线。
图4示出曲前列环素半乳糖苷在人血浆中孵育后的游离曲前列环素的浓度。
图5:血浆中的曲前列环素葡萄糖苷。
图6:血浆中的曲前列环素葡萄糖苷水解。
图7:瞬时表达IP受体的HEK293细胞中的曲前列环素和曲前列环素葡萄糖苷浓度响应曲线(n=3次独立实验)。
图8:瞬时表达EP2受体的HEK293细胞中的曲前列环素和曲前列环素葡萄糖苷浓度响应曲线(n=4次独立实验)。
图9:瞬时表达EP4受体的HEK293细胞中的曲前列环素和曲前列环素葡萄糖苷浓度响应曲线(n=3次独立实验)。
具体实施方式
曲前列环素是前列环素(PGI2)的合成类似物,指示用于治疗肺动脉高压(PAH)。曲前列环素的主要药理学作用机理是对肺及全身性动脉血管床进行直接扩张并且抑制血小板聚集。
前药是药物的修饰形式,其在活化时形成药物。因此,前药设计是药物发现的重要部分。前药相对于母药可以提供许多优势,例如增加的溶解性、增强的稳定性、提高的生物利用率、减少的副作用和/或更好的选择性。前药设计的关键步骤是引入将能以高效和/或受控的方式将前药转化为活性物质以满足给定的医疗应用的需求的活化机理。前药活化可以通过酶介导的水解过程来实现。
越来越多的证据显示,糖苷能够充当前药并且具有直接的治疗效果。糖苷前药可以能够实现提高的药物生物利用率或提高的药物药代动力学,包括更多的位点特异性或组织特异性的药物递送、在血浆中更一致的药物水平,以及药物的持续或延迟释放。
糖苷是其中的糖部分与另一官能团经糖苷键键合的分子。糖苷在活生物体中发挥许多重要作用。
如本文所用,术语“前药”是指在施用后必须通过代谢过程经过化学转化才能成为活性药理试剂的化合物。
曲前列环素糖苷由两个结构特征组成:糖(糖苷基(glycon))和曲前列环素部分(糖苷配基(aglycon))。术语“曲前列环素糖苷前药”或“曲前列环素糖苷”可互换使用,且一般性地指代曲前列环素的糖苷。曲前列环素糖苷前药经过糖苷键水解(典型地,通过糖苷酶的作用)以释放活性曲前列环素。
如本文所用,术语“糖苷基(glycon)”是指糖苷的糖部分。经保护的糖苷基是其中羟基被保护基(例如被苄基部分)保护的糖部分。
此外根据本发明,曲前列环素糖苷前药在糖苷键水解时转化以提供活性曲前列环素药物。因此,本发明已证明,具有疏水性糖苷配基部分的糖苷在血浆中经历葡萄糖水解,从而产生疏水性的曲前列环素化合物。
如本文所用,“糖基(carbohydrate)”是指多羟基醛或多羟基酮及其衍生物。最简单的糖基是单糖,单糖是添加有许多羟基(通常在除官能团以外的每个碳上有一个羟基)的小的直链醛和酮。单糖的实例包括赤藓糖、阿拉伯糖、阿洛糖、阿卓糖、葡萄糖、甘露糖、苏阿糖、木糖、古洛糖、艾杜糖、半乳糖、塔罗糖、己醛糖、果糖、己酮糖、核糖和戊醛糖。其它糖基由单糖单元构成,包括二糖、低聚糖或多糖,这取决于单糖单元的数目。二糖由通过共价糖苷键连接的两个单糖单元构成。二糖的实例有蔗糖、乳糖和麦芽糖。低聚糖和多糖由通过糖苷键键合在一起的单糖单元的更长链构成。低聚糖通常含有3至9个单糖单元,而多糖含有大于10个单糖单元。
在本发明的一个方面,糖基是糖,特别是己糖或戊糖,并且可以是醛糖或酮糖。糖可以是D或L系列的成员,并且可以包括氨基糖、脱氧糖以及它们的糖醛酸衍生物。
氨基糖是其中羟基被氨基替代的糖分子。合适的氨基糖例如己糖胺、半乳糖胺、葡萄糖胺、甘露糖胺、神经胺酸、胞壁酸、N-乙酰葡萄糖胺,特别是D-葡萄糖胺(2-氨基-2-脱氧-D-葡萄糖)或D-半乳糖胺(2-氨基-2-脱氧-D-半乳糖)、糖醇。
在其中糖基是己糖的本发明实施方式中,己糖选自由葡萄糖、半乳糖和甘露糖组成的组,合适的戊糖糖类包括阿拉伯糖、果糖和核糖。
曲前列环素的化学结构拥有两个羟基,其可以被利用来通过糖苷连接而形成糖苷。在本发明的某些实施方式中,一个羟基与糖部分缀合。在本发明的某些实施方式中,两个羟基均与糖部分缀合。在本发明的某些实施方式中,糖部分是相同的部分或具有不同的结构。
作为O-糖苷的曲前列环素糖苷衍生物可以例如经化学或酶合成来获得。
在O-糖苷的化学合成中,糖基供体与糖基受体中的游离羟基反应(通常在某些促进剂的存在下)而得到所需的糖苷。在本发明的一个实施方式中,提供了一种制备曲前列环素糖苷的方法,其包括将曲前列环素与一种或多种糖基供体反应(可选地在某些促进剂的存在下)以得到所需的曲前列环素糖苷衍生物。
根据本发明,提供了一种制备曲前列环素糖苷的方法,其包括在一种或多种糖基转移酶的存在下将曲前列环素与一种或多种糖供体一同孵育。
另外的实施方式涉及药物组合物,所述药物组合物包含本文所述的一种或多种曲前列环素衍生物、或其药学可接受的盐、溶剂化物、水合物或多晶型体以及一种或多种药学可接受的赋形剂或载剂。组合物可以任选地含有另外的治疗剂。
适当的制剂可能取决于各种因素,例如所选择的施用途径。包含糖苷曲前列环素衍生物的药物组合物的潜在施用途径包括但不限于口服、肠胃外(包括皮内、皮下、肌内、血管内、静脉内、动脉内、髓内和鞘内)、腔内、腹膜内和局部(包括皮肤/皮表、透皮、粘膜、透粘膜、鼻内[例如,通过鼻喷雾或滴鼻剂]、眼内(例如,通过滴眼剂)、肺部(例如,通过吸入)、颊部、舌下、直肠和阴道)。局部制剂可以设计来产生局部或系统性的治疗效果。由于曲前列环素的糖酐衍生物之故,预期皮下施用疼痛感更弱。
举例而言,适用于口服施用的糖苷基曲前列环素衍生物制剂可以呈现为例如胶囊(包括推合胶囊和软胶囊)、扁囊剂和片剂;粉末或颗粒;大丸剂、冲剂或糊剂。例如,推合胶囊(push-fit capsule)可以含有与例如填料(例如,乳糖)、粘合剂(例如,淀粉)和润滑剂(例如,滑石或硬脂酸镁)以及任选的稳定剂共混的糖苷基曲前列环素衍生物。对于软胶囊,糖苷基曲前列环素衍生物可以溶解或悬浮在合适的液体(例如,脂肪油、液体石蜡或液体聚乙二醇)中,并且可以添加稳定剂。
本文所述的糖苷基曲前列环素衍生物可以在体内转化为曲前列环素,且因此可以充当曲前列环素的前药。在某些实施方式中,糖苷基曲前列环素衍生物在肝中被快速且基本完全地转化成曲前列环素(例如,至少约70%、80%、90%或95%转化)。
糖苷基曲前列环素衍生物可以与另外的治疗剂联合使用以治疗对采用前列环素或曲前列环素的治疗有响应的任何病况。
用于治疗例如肺高压的糖苷基曲前列环素衍生物的治疗有销量和施用频率可能取决于各种因素,包括肺高压的类型、病况的严重程度、施用模式、受试者的年龄、体重、一般健康状况、性别和饮食、以及该受试者对治疗的响应,并且可以由治疗医师来确定。在某些实施方式中,糖苷基曲前列环素衍生物的每日有效剂量为约0.1mg至100mg、0.1mg至50mg、0.5mg至50mg、0.5mg至25mg、0.5mg至10mg、1mg至10mg或1mg至5mg,或如治疗医师所认为适当的量,其可以以单次剂量或分开的剂量进行施用。在其它实施方式中,糖苷基曲前列环素衍生物的每日有效剂量为约0.001mg/kg体重至2mg/kg体重、0.005mg/kg体重至1mg/kg体重、0.01mg/kg体重至0.5mg/kg体重或0.01mg/kg体重至0.1mg/kg体重,或如治疗医师所认为适当的量。
实施例
阐述以下的实施例是为了辅助对发明的理解,而并非意图也不应该被解释为以任何方式对发明范围的限制。实施例不包括对常规方法的详细描述;这些方法是本领域普通技术人员所公知的。
实施例1.血浆样品中的曲前列环素的测定
通常通过HPLC-MS来从血样中测定曲前列环素[2,3]。为了测定血浆样品中的曲前列环素,开发了一种等度(isocratic)稳健HPLC方法,其允许采用仅一个步骤的样品制备来对血浆中的游离曲前列环素进行测定。
HPLC方法和设备:
泵: BESTA HD-2 400
柱箱: -
检测器: 紫外可见Beckmann 163可变波长检测器
阀: Rheodyne 7125
柱: RP,Nucleosil 120 3C18,直径4mm,前柱4cm,柱8cm
样品环: 20μL
检测波长: 277nm
进给速率: 0.6mL/min
流动相: 68.5mL乙腈,120mL水,10mL甲酸铵,0.2mL HCOOH
梯度: 无;等度条件;洗脱曲线如图3所示。
校准
通过HPLC采用上文限定的设定来产生针对曲前列环素的绝对浓度的校准曲线。曲前列环素的校准曲线如图1所示。直线方程为:y=4178.3x–1.717
实施例2.曲前列环素糖苷的水解
为了确定曲前列环素的糖苷衍生物的糖苷键在血浆样品中是否通过酶促方式切割。
自健康成人(男性,MW 58周岁,n=2)取静脉血并离心(r=12cm,3000rpm,10min)。随后,将如此制备的血浆储存于-20℃。
将4mg曲前列环素糖苷供给至10cm试管内。随后,添加4mL融化的血浆,产生1mg/mL的浓度。然后将试管略微振摇并立即取样(0.5mL)。将血浆样品用3mL无水乙醇稀释,并使血浆蛋白质沉淀。因此,催化反应立刻停止。将经稀释的样品离心(r=12cm,3000rpm,10min),然后将上清液直接注入HPLC。游离曲前列环素在约23分钟出现,且对曲线下的面积进行积分。
平行且同时地,采用水代替血浆执行相同的过程以获得对血浆基质的对比。为了排除反应介质中的酸水解,将曲前列环素糖苷在缓冲溶液(Sorensen pH 7)中孵育,这是因为半乳糖苷由于合成步骤的原因而略具酸性(约pH 6)。
现将所有制备物(血浆、水和缓冲液中的曲前列环素糖苷)在干燥烘箱中于37℃孵育。分别在0、30、90、180、270和1200分钟后取样,并通过上文所述的方法测定游离曲前列环素。
实施例3.曲前列环素葡萄糖苷
结果如表1中所示。曲前列环素葡萄糖苷的血浆半衰期为约100分钟。这意味着在100分钟后约50%曲前列环素葡萄糖苷被水解。20小时后,将糖苷定量切割。曲前列环素葡萄糖苷的64%质量分数为曲前列环素,因此检测到了所使用的曲前列环素的约90%。这隐含表明了包含曲前列环素葡萄糖苷的样品中约90%的曲前列环素葡萄糖苷是可被切割的。
表1.曲前列环素-半乳糖苷的水解
(1)直接来自离心后的上清液的曲前列环素峰的面积
(2)转化后的孵育的反应样品中的游离曲前列环素mg/mL
曲前列环素的摩尔质量为390.5g/mol,且曲前列环素葡萄糖苷为约552.7g/mol。因此,该糖苷的约33%(w/w)为葡萄糖。反应混合物中的曲前列环素葡萄糖苷的重量为1mg/mL血浆,这得到0.33mg葡萄糖和0.67mg曲前列环素(仅在理论上,杂质或水未考虑在内)。在孵育20小时后,游离曲前列环素的浓度为约0.54mg/mL血浆。这意味着起始材料由大约90%可切割曲前列环素葡萄糖苷组成(假设糖苷被定量水解)。
血浆中和水中的游离曲前列环素的浓度曲线如图2所示。反应基本遵循Michaelis-Menten模型,这清楚地指示酶促反应。对于曲前列环素葡萄糖苷,前稳态期据估计为约30分钟。在约10小时达到游离曲前列环素的平衡。
游离曲前列环素的洗脱曲线在图3中示出。曲前列环素展示出保留时间为23分钟。线条1反映出0min孵育时间后的测量,线条2为30min后,线条3为90min后,线条4为180min后,且线条5为1200min后。曲前列环素葡萄糖的峰出现在8min处(线条1)并随时间消失且在1200min后不再能检测到。
实施例4.曲前列环素半乳糖苷
由于曲前列环素半乳糖苷的合成过程所致,基质在水中略微有酸性(pH 6)。因此,除了血浆和水孵育混合物之外,还另外进行了在缓冲溶液(例如可以使用pH 7的Sorensen缓冲液)中的孵育。
结果如表2所示。虽然在24小时的时长中在水中未达到半乳糖苷的半衰期,但血浆中的曲前列环素半乳糖苷显示出约90分钟的半衰期。这意味着在上文所述的条件下90分钟后50%的半乳糖苷被切割。20小时后,半乳糖苷被定量地切割为曲前列环素和半乳糖。
由于制造过程之故,本方法中使用的曲前列环素半乳糖苷含有约5%至6%的未结合的曲前列环素。游离曲前列环素物质的这一量也可借助于HPLC被检测到,并从测定值中扣除。表2中示出的值是减去了起始材料中所含的游离曲前列环素的量的测定值。
表2:曲前列环素-半乳糖苷的水解
(1)直接来自离心后的上清液的曲前列环素峰的面积
(2)转化后的孵育的反应样品中的游离曲前列环素mg/mL:每种孵育混合物(血浆、水和缓冲液)含有1mg/mL曲前列环素-半乳糖苷,其中x mg曲前列环素在对应的时间单位被释放。
曲前列环素的摩尔质量为390.5g/mol,且曲前列环素半乳糖苷为约552.7g/mol。因此,该糖苷的约33%(w/w)为半乳糖。反应混合物中的曲前列环素半乳糖苷的重量为1mg/mL血浆,这得到0.33mg半乳糖和0.67mg曲前列环素。在孵育20小时后,游离曲前列环素的浓度为约0.304mg/mL血浆。这意味着起始材料由约50%可切割曲前列环素半乳糖苷组成。这与供应商的说明书一致,剩余50%包括半乳糖(40%)、游离曲前列环素(5%-6%)和不明残留(4%-5%)。
血浆、缓冲液和水中通过曲前列环素半乳糖苷水解的游离曲前列环素的浓度曲线如图4所示。约6至8小时后曲前列环素半乳糖苷在血浆中被定量水解。
实施例5.血浆中的曲前列环素葡萄糖苷
曲前列环素-葡萄糖苷在曲前列环素的羧基-OH基团处具有糖苷,将其在人血浆和变性血浆(蛋白被乙醇96%变性)中孵育。20小时孵育时间后,人血浆中53%的曲前列环素-葡萄糖苷被水解。相比之下,20小时后在变性血浆中仅检测到4%的水解的曲前列环素-葡萄糖苷。结果示于图5和图6。
实施例5.酸基团的苄酯保护
将1.1g曲前列环素钠盐悬浮在50ml乙腈中。向悬浮液添加1.3g Cs2CO3和1.4g苄溴并在回流下搅拌直到TLC中检测不到起始材料。然后将悬浮液过滤并用二氯甲烷洗涤。蒸发溶剂,并将残留物重新溶解于50mL二氯甲烷中,用50mL 2%NaHCO3溶液洗涤3次,1×50mL盐水。然后在硫酸钠上干燥,过滤并蒸发以产生黄色浆液。将浆液重新溶解于二氯甲烷中,施加至硅胶柱并用THF洗脱。将含有产物的级分蒸发并获得作为无色浆液的1.3g曲前列环素苄酯。
实施例6.酯基的糖基化
将1.0g曲前列环素苄酯悬浮在20mL无水THF中,并向曲前列环素苄酯溶液中添加0.1mL三氟甲磺酸三甲基甲硅烷酯(TMSOTf)。然后在室温缓慢添加3g TCA-葡萄糖在20g无水THF中的溶液。将反应用0.5mL三甲胺终止,并蒸发以得到黄色浆液。将浆液施加于硅胶柱上进行快速柱色谱。将含产物的级分浓缩。蒸发基本纯的产物以得到1.5g糖苷基曲前列环素,为无色浆液。
实施例7.保护基的去除
制备1.5g的受保护的曲前列环素葡萄糖苷在50mL甲醇/THF 1:1中的溶液,并向该溶液添加0.5g Pd/C 10%(干)。蒸发所得混合物并用氢气吹扫。然后将反应混合物在1bar氢气下搅拌直至所有苄基被切割。然后将反应混合物以硅藻土过滤并用水清洗。蒸发溶剂以产生所需曲前列环素二糖苷。
实施例8.瞬时表达了前列环素I2受体(IP)或前列环素E2受体2(EP2)或前列环素E2受体4(EP4)的HEK293细胞中曲前列环素或曲前列环素-葡萄糖苷诱导的cAMP累积
方法:
第0天:将9百万HEK293细胞接种至15cm培养皿以用于各实验(对于各培养皿:20mlDMEM培养基+10%FCS)。
第1天:将细胞用空载体或编码IP或EP2或EP4受体的质粒转染。
转染规程:对于每个15cm培养皿,向1ml(终体积)JetPRIME转染缓冲液中添加10μgDNA和20μl JetPRIME转染试剂,并在室温孵育10min。其后,将该混合物逐滴地添加到细胞中(转染后4小时将培养基换为新鲜培养基以降低毒性)。
第2天:将细胞用PBS洗涤,胰蛋白酶化,接种至6孔板(0.7百万细胞/孔)并与[3H]-腺嘌呤(1μCi/ml)预孵育12至16小时。
第3天:在测定缓冲液(HEPES 10mM,NaCl 120mM,KCl 3mM,CaCl2 2mM,MgCl2 2mM,葡萄糖20mM,RO-20-1724,100μM pH 7.3)中用曲前列环素或曲前列环素-葡萄糖苷(在R3位具有葡萄糖苷)在室温刺激细胞30分钟(总是包含未经刺激的对照),然后用2.5%高氯酸(PCA)在冰上裂解30分钟。中和PCA提取物(采用KOH)并使用DOWEX和氧化铝柱通过连续色谱将[3H]-cAMP与其他核苷酸分离,并最终使用闪烁计数器以CPM(每分钟计数)测定放射活性。
瞬时表达IP受体的HEK293细胞中的曲前列环素和曲前列环素-葡萄糖苷(在R3位具有葡萄糖苷)浓度响应曲线(n=3次独立实验)如图7所示。曲前列环素的EC 50值为0.8065,在R3具有葡萄糖苷的曲前列环素-葡萄糖苷的EC50为9.277。
瞬时表达EP2受体的HEK293细胞中的曲前列环素和曲前列环素-葡萄糖苷(在R3位具有葡萄糖苷)浓度响应曲线(n=4次独立实验)如图8所示。曲前列环素的EC50值为3.103,曲前列环素-葡萄糖苷的EC50为56.57。
瞬时表达EP4受体的HEK293细胞中的曲前列环素和曲前列环素-葡萄糖苷(在R3位具有葡萄糖苷)浓度响应曲线(n=次3独立实验)如图9所示。曲前列环素的EC50值为0.2801,曲前列环素-葡萄糖苷的EC50为5.016。
结果:有利的是,本发明的曲前列环素-葡萄糖苷对于IP、EP2和EP4受体具有降低的亲和力,但仍导致类似的cAMP增加。因此,预期曲前列环素-葡萄糖苷的皮下施用的疼痛感更弱。
Claims (14)
2.如权利要求1所述的曲前列环素衍生物,其中,所述糖基是单糖、二糖、低聚糖、氨基糖或糖醇。
3.如权利要求2所述的曲前列环素衍生物,其中,所述单糖是吡喃糖苷或呋喃糖苷。
4.如权利要求2所述的曲前列环素衍生物,其中,所述糖基选自:己醛糖如阿洛糖、阿卓糖、葡萄糖、甘露糖、古洛糖、艾杜糖、半乳糖和塔罗糖,己酮糖如阿洛酮糖、果糖、山梨糖和塔格糖,戊醛糖如核糖、阿拉伯糖、木糖和来苏糖,戊酮糖如核酮糖和木酮糖,或己糖胺如半乳糖胺、葡萄糖胺、甘露糖胺、神经胺酸、胞壁胺酸(muramine acid)和N-乙酰葡萄糖胺。
5.如权利要求4所述的曲前列环素衍生物,其中,吡喃糖苷是葡萄糖或半乳糖。
6.如权利要求1至5中任一项所述的曲前列环素衍生物,其中,所述曲前列环素衍生物的血浆半衰期为至少60分钟,特别是70分钟、80分钟、90分钟,特别是100分钟±20分钟。
7.如权利要求1至5中任一项所述的曲前列环素衍生物,其中,在20h±5h时所述曲前列环素衍生物在血浆中被切割至少50%,特别是至少60%、70%、80%,更特别是至少90%。
8.包含权利要求1至7中任一项所述的曲前列环素的糖苷衍生物的组合物。
9.包含权利要求1至7中任一项所述的曲前列环素的糖苷衍生物的药物组合物。
12.如权利要求11所述的方法,其中,所述保护基是:苄基,苯甲基,选自由取代甲醚、取代乙醚、取代苯甲醚、各种甲硅烷基醚组成的组的醚,选自由乙酸酯、取代乙酸酯、苯甲酸酯、碳酸酯、磺酸酯组成的组的酯,环式缩醛,酮的缩醛,酯,酰胺,酰肼,苄酯。
13.如权利要求11或12所述的方法,其中,所述糖苷是吡喃糖苷,特别是葡萄糖或半乳糖。
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EP17207329.8A EP3498283A1 (en) | 2017-12-14 | 2017-12-14 | Glycosidic derivatives of treprostinil |
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PCT/EP2018/084779 WO2019115702A1 (en) | 2017-12-14 | 2018-12-13 | Glycosidic derivatives of treprostinil |
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JP2003523935A (ja) | 1999-03-31 | 2003-08-12 | ユナイテッド セラピューティクス コーポレイション | 末梢血管疾患と肺高血圧症を治療するためのプロスタグランジン化合物、組成物および方法 |
US20030108512A1 (en) | 2001-12-10 | 2003-06-12 | Robert Shorr | Modified prostaglandin compounds and analogs thereof, compositions containing the same useful for the treatment of cancer |
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ES2612510T3 (es) | 2011-02-07 | 2017-05-17 | Scipharm Sàrl | Composición novedosa para el tratamiento de fibrosis quística |
CN103857413A (zh) | 2011-08-12 | 2014-06-11 | 阿森迪斯药物股份有限公司 | 载体连接的曲罗尼尔前药 |
HUE034485T2 (en) | 2012-06-15 | 2018-02-28 | Scipharm Sarl | Process for the preparation of treprostinil and its derivatives |
US20150315114A1 (en) | 2012-12-07 | 2015-11-05 | Cayman Chemical Company Incorporated | Methods of Synthesizing a Prostacyclin Analog |
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US9505737B2 (en) * | 2013-01-11 | 2016-11-29 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
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US9394227B1 (en) * | 2015-06-17 | 2016-07-19 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
US9643911B2 (en) * | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
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CA3085398A1 (en) | 2019-06-20 |
SG11202005360TA (en) | 2020-07-29 |
US20210087216A1 (en) | 2021-03-25 |
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