CN101716167B - 一类饱和胺类化合物在制备外周血造血干细胞动员药物中的应用 - Google Patents
一类饱和胺类化合物在制备外周血造血干细胞动员药物中的应用 Download PDFInfo
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Abstract
本发明提供了一类饱和胺类化合物的新用途，即其在制备外周血造血干细胞动员药物中的应用。实验证明，该化合物(代号TA01)能够有效的动员骨髓中的造血干细胞，是一类新型的造血干细胞动员剂。本发明将在外周血造血干细胞动员药物的研究和开发中发挥重要作用，应用前景广阔。
Description
技术领域
本发明涉及化合物的新用途，特别是涉及一类饱和胺类化合物(代号TA01)在制备外周血造血干细胞动员药物中的应用。
背景技术
成人骨髓是血细胞再生的场所，也是形成血管的内皮祖细胞，能分化为脂肪细胞、软骨细胞及成骨细胞的间充质干细胞等，是干细胞或祖细胞的储存场所。早期的研究显示，化疗康复的患者外周血中造血祖细胞增加，因此认识到造血干细胞和造血祖细胞可从骨髓诱导出来，称之为“干细胞动员”，这些被动员的细胞可以聚集，也可以再返回骨髓行使其造血功能。诱导入血的造血细胞可用于移植。新的干细胞的诱导分离相关研究结果显示，造血干细胞的定量、定性研究及其潜在的作用和外周血造血干细胞移植的疗效是目前研究的热点。
粒细胞集落刺激因子(G-CSF)对外周血干细胞的诱导作用
多种因子均可通过不同的作用诱导外周血干细胞移出，提示在这条导致干细胞移出的通路上具有多种调节机制。多种因子的协同和联合作用下，可以诱导一定性质和(或)数量的干细胞移植。G-CSF是临床干细胞移植的主要诱导剂，其对外周血干细胞的诱导作用比骨髓和脐带血干细胞强，而且使中性粒细胞和血小板恢复更快，需要输注的血小板更少，淋巴细胞重建更快，相关的炎症发生率及病死率更低。与G-CSF相比，应用化学方法诱导外周血干细胞移植(PBSC)后血细胞计数的恢复时间更长，发热等并发症及需要输血的量更多。而且经化学方法摄取的外周血干细胞在进行同种异体移植时已失去活性。PBSC的采集避免了骨髓采集的侵入性操作及常规麻醉相关的风险。为适合移植的配对及HLA的配型，已可以清除其中的1～3种成分，而且可以保证明其单倍同一性。基于G-CSF的干细胞移植耐受性好，尽管偶有脾破裂发生。大部分供者可以完成足够移植干细胞的采集。虽然尚无明确成功移植的PBSC最低移植量的阀值，但输注的CD34+细胞数低于2×106/kg可能与移植失败有关。较高的CD34+细胞剂量可能产生急性或慢性移植物抗宿主病的发生率增加的消极作用，却可能产生整体患者生存率增加的积极作用。细胞亚型，尤其是T细胞及CD14+单核细胞，可影响移植效果。PBSC质量和数量的变化均可明显影响移植的效果。
25％的患者，尤其是淋巴瘤患者、多发性骨髓、急性白血病以及10％-20％的正常人，G-CSF对干细胞的动员作用较差，需要扩大清除成分的范围。此外，这种动员无力还发生在广泛治疗的癌症患者、遗传缺陷如Fanconi贫血患者。新近的研究PBSC动员及自身移植治疗恢复期再生障碍性贫血的结果显示，应用G-CSF收集PBSC只在小部分患者中可行，在供者和患者中，G-CSF的动员作用存在很大的个体差异。扩大同种异体移植的应用，尤其是接受配对移植物移植的重症患者、接受具有耐受原的器官移植患者、非致命性遗传缺陷病患者，需要更大剂量的动员干细胞来克服HLA障碍而获得持久的干细胞植入，促进白细胞活性恢复，减少移植物抗宿主病的发生。到目前，造血干细胞移植已成为治疗白血病的主要手段之一。然而，昂贵的治疗费用使许多白血病患者丧失了生的希望。我国每年新增白血病患者四五万人，加上历年累计的患者，全国有近百万名白血病患者需要接受造血干细胞移植治疗，接受造血干细胞移植通常需要花费30万元，这对于普通家庭来说无异于天文数字。目前临床上通过G-CSF的作用使造血干/祖胞从骨髓进入外周血，采集与患者有一定血缘关系的人的造血干细胞，这是人们通常的采集干细胞的做法。然而，通过此种方法采集造血干细胞进行干细胞移植，其操作起来程序相当繁杂，为了达到移植所需要的量必须采用外科手术。这是由于G-CSF是通过间接的作用实现造血干/祖细胞的动员的，首先诱使一种金属蛋白酶的释放来干扰CXCR4/SDF-1的相互作用，从而导致干细胞的释放。干细胞供者不得不进行4-6天的药物注射，而医院不同部门、人员之间的协调也都是必须的。
虽然G-CSF已成功应用，但要获得明显的临床突破还有大量的问题需要解决，特别是干细胞剂量，不同患者的最适诱导及个体差异，需清除的成分，最佳动员时间及移植成分控制等。
骨髓作为成人干细胞的贮存场所有助于组织修复，问题是动员药物是否可以动员除HSC外的其它干细胞，是否有新的药物可特异的动员成人干细胞。
已知的饱和胺类化合物已收录于小分子化合物库中，它是氢键的受体，通过氢键和特殊空间位点与蛋白和碳水化合物作用，属于一类新型医药中间体(Rozenbaum W，Antimoniotungstate(HPA-23)treatment of three patients with AIDS and one withprodrome，Lancet，1985，1：450-451)，其已知的用途有可以介入HIV病毒进入T细胞、炎症、类风湿关节炎、哮喘和血管损伤等方面的作用。
发明内容
本发明提供了一类饱和胺类化合物TA01的新用途，即在制备外周血造血干细胞动员药物中的应用。
所述化合物TA01具有式I所示的分子式：
其中，R1＝H、CH3、CH2CH3，R2＝H、CH3、CH2CH3；优选R1＝R2＝CH3。
本发明的药物可采用注射剂的剂型。
所述注射剂的溶剂的选择是多种多样的，如pH7.5-8.5的TE缓冲液、生理盐水、PBS或灭菌蒸馏水等，优选为pH7.5-8.5的TE缓冲液。
需要的时候，在上述药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、吸收促进剂、表面活性剂等。
上述药物的用量一般为5mg/kg体重/day，疗程一般为1-2天。剂量和疗程都可根据实际情况调整。
本发明提供了饱和胺类化合物TA01的新用途，即在制备外周血造血干细胞动员药物中的应用。实验证明，该化合物能够有效的动员骨髓中的造血干细胞，是一类新型的造血干细胞动员剂。TA01能动员较大剂量的造血干细胞，采集PBSC比较方便，采集时无需麻醉，也无需多部位穿刺骨髓抽髓引起的痛苦；对于部分侵犯骨髓的患者和多发性骨髓瘤的患者，由于骨质破坏或肿瘤细胞浸润骨髓，及骨盆局部放疗等原因无法采集骨髓时，可采集PBSC；移植后造血功能恢复快，移植后感染、出血等并发症少，减少了抗生素和成分输血的应用，降低了移植相关死亡率，缩短了住院时间，节减了费用；与骨髓相比，外周血中肿瘤细胞混入的少。本发明将在外周血造血干细胞动员药物的研究和开发中发挥重要作用，应用前景广阔。
下面结合具体实施例对本发明做进一步详细说明。
附图说明
图1为TA01合成过程示意图
图2为TA01能提高小鼠外周血中CD34+细胞含量的检测结果
图3为TA01能提高小鼠外周血中WBC含量的检测结果
图4为TA01能提高小鼠外周血中单个核所产生的CFU数，也能提高小鼠外周血中单个核所产生的CFU-GM数的检测结果
图5为注射TA01动员的外周血中单个核能提高照射致死剂量小鼠存活率的检测结果
具体实施方式
下述实施例中所用方法如无特别说明均为常规方法。
实施例1、TA01的合成
如图1所示流程，用本发明的方法合成TA01。参考文献①梅光泉，β，β′，β″-三氨基三乙基胺合成方法的改进，赣南师范学院学报，2002，3：55-56，②Kimura E等，Cleavage of amino acid esters and peptides with hydroxoaque(2，2′，2″-triaminotriethylamine)cobalt(III)ion，Inorg.Chem，1970，9(5)：1187)。具体方包括以下步骤：
邻苯二甲酰亚胺钾的合成(I)
在装有1600ml无水乙醇的圆底烧瓶中，加入80.0g邻苯二甲酰胺，加热回流0.5h，仅有少量的原料未溶；用倾析法将此热溶液倒入30.5g氢氧化钾混合液中(30ml水和90ml乙醇)，立即生成白色沉淀，冷却后过滤，回收乙醇，产品用200ml丙酮洗涤，得产品98.0g，产率合98.0％。
N-β-溴乙基邻苯二甲酰亚胺的合成(II)
在装配有搅拌器及回流冷凝管的圆底烧瓶中放入150g邻苯二甲酰亚胺钾，450g1，2-二溴乙烷，将混合物置于油浴，加热12h，保持油浴温度在180～190℃，然后再改用冷凝管将过量的1，2-二溴乙烷减压蒸出，回收得到约290g。在上面粗制的N-β-溴乙基邻苯二甲酰亚胺和KBr的混合物中，加入30ml乙醇，回流0.5h，直到黑色油状物完全溶解为止。混合液趁热过滤，并用少量热乙醇洗涤KBr沉淀，合并滤液，减压蒸尽乙醇。
将上述干燥的剩余物加入500ml CS2溶剂中回流15～20min，趁热过滤，在减压下蒸去CS2，得到浅褐色晶体131.0g，产率63.6％，熔点78～80℃.
β，β′，β″-三邻苯二甲酰亚胺基三乙基胺的合成(III)
将46.0g产物(II)加热溶化，维持在140～150℃，通入过量干燥NH3，反应5～8h，往混合物中加入450ml乙醇，加热回流0.5h，过滤，沉淀用热乙醇洗，再经少量水洗涤，用冰乙酸重结晶，得白色晶体25.2g产率78.0％，溶点为187.5℃。
β，β′，β″-三氨基三乙基胺盐酸的合成(IV)
往20.0g产物(III)中滴加50ml浓HCL，温度控制在150℃左右，反应2h，浓缩至原体积的一半左右，滤去邻苯二甲酸沉淀，用4倍热乙醇处理滤液，静置一昼夜，析出白色晶体8.0g产率为84.0％，熔点283℃。
β，β′，β″-三氨基三乙基胺的合成(V)
取6.0g产物(IV)与2.6gKOH混合均匀(摩尔比为1∶2)，不断振荡，加入少许K2CO3吸收水，胺则从水相中分出，可以闻到浓烈的刺鼻臭味，塞紧容器。一昼夜后过滤，在分液漏斗中收集两层滤液，胺处于淡黄色溶液的上层，减压蒸馏，得一清晰透明的液体，液体再经金属钠干燥后减压蒸馏，收集135℃/9mm Hg馏分，得到无色稠液体，产品重1.6g，产率为47.2％。
三(2-(二甲氨基)乙基)胺的合成(VI)
化合物V进行甲基化反应，得到化合物VI。
合成的饱和胺类化合物为三(2-(二甲氨基)乙基)胺，以下实验均以此化合物为例。当然，该化合物也可用其它已公开文献介绍的方法合成。
同样，式I表示的其它化合物可按已公开文献方法合成，或参照以上合成操作改变相应基团后合成，本发明不再一一详述。
实施例2、TA01能提高小鼠外周血中CD34+细胞的含量
9只雄性C57小鼠(购自中国人民解放军军事医学科学院实验动物中心)，随机分成三组，DMSO(购自北化)组3只，G-CSF(购自厦门特宝生物工程股份有限公司)组3只，TA01组3只，每只小鼠按5mg/kg体重计算注射量，注射剂的溶剂为pH7.5-8.5的TE缓冲液。皮下注射4h后，剪尾取100μL血液，按1∶10的比例加入红细胞裂解液(购自晶美生物工程有限公司)，混匀，室温静置10-15min，1500rpm/min离心6min，弃去上清，加入1％的血清(购自Hyclone公司)100ul，吹打混匀，加入0.75ul一抗(Purified anti-mouse CD34，购自Biolegend公司，超净台中操作)，混匀，室温孵育1-2h。补含有1％血清的PBS至1.5ml，1500rpm/min离心5min，弃去上清，加入1％的血清100ul，吹打混匀，加入2ul二抗(羊抗小鼠，FITC标记，购自北京中杉金桥生物技术有限公司)，混匀，室温孵育30min。补含有1％血清的PBS至1.5ml，1500rpm/min离心5min，弃去上清，加入1％的血清500ul，吹打混匀，流式细胞仪检测CD34+细胞的百分数。从结果中(如图2所示)可以看出，较DMSO组和G-CSF组，TA01能提高小鼠外周血中CD34+细胞的含量。
实施例3、TA01能提高小鼠外周血中白细胞(WBC)的含量
9只雄性C57小鼠，随机分成三组，DMSO组3只，G-CSF组3只，TA01组3只，每只小鼠按5mg/kg体重计算注射量，注射剂的溶剂为pH7.5-8.5的TE缓冲液。皮下注射4h后，剪尾取10μL血液，加入2mL血细胞稀释液(购自济南博莱生物技术有限公司)，细胞分析仪检测WBC的含量。从结果中(如图3所示，*表示与DMSO组相比有显著性差异)可以看出，较DMSO组和G-CSF组，TA01能提高小鼠外周血中WBC的含量。
实施例4、TA01能提高小鼠外周血中单个核所产生的CFU数，也能提高小鼠外周血中单个核所产生的CFU-GM(粒单系造血组细胞集落)数
9只雄性C57小鼠，随机分成三组，DMSO组3只，G-CSF组3只，TA01组3只，每只小鼠按5mg/kg体重计算注射量，注射剂的溶剂为pH7.5-8.5的TE缓冲液。皮下注射4h后，摘眼球取血，10ml离心管事先用肝素(购自天津灏洋生物制品科技有限责任公司)清洗一遍，混匀后，补PBS(购自Hyclone公司)至5ml，混匀。小鼠淋巴细胞分离液(购自天津灏洋生物制品科技有限责任公司)预先分装成5ml/管(超净台中操作)，将与PBS混匀的血液轻轻的注入分离液的上层，2000rpm/min离心20min。将中间白白的一层细胞吸入10ml离心管中，补PBS至10ml，混匀，1500rpm/min离心5min，弃去上层PBS，补PBS至10ml，混匀，1500rpm/min离心5min，弃去上层PBS，补PBS至1ml，混匀，细胞计数器计数。计算每毫升血液中单个核的数量，并将之与500μL半固体培养基(配方为0.9％甲基纤维素，15％胎牛血清，100U/ml青霉素/链霉素，1mM丙酮酸钠，2mM谷氨酰胺，2mM PFHM II，200μg/ml转铁蛋白，1％BSA，0.45mM MTG，30％IMDM，50ng/ml SCF，10ng/ml TPO，10ng/ml IL-3，10ng/ml IL-11，10ng/ml GM-CSF，3U/ml EPO)，混匀，37℃、5％CO2培养箱中培养7天，对总CFU和CFU-GM进行计数。从结果(如图4所示，*表示与DMSO组相比有显著性差异)可以看出，较DMSO组和G-CSF组，TA01能提高小鼠外周血中单个核所产生的CFU数，也能提高小鼠外周血中单个核所产生的CFU-GM数。
实施例5、注射TA01动员的外周血中单个核能提高照射致死剂量小鼠的存活率9只雄性C57小鼠，随机分成三组，用60Co γ射线进行全身照射，剂量率2.72Gy/min，照射量7.0Gy。9只雄性C57小鼠，随机分成三组，DMSO组3只，G-CSF组3只，TA01组3只，每只小鼠按5mg/kg体重计算注射量，注射剂的溶剂为pH7.5-8.5的TE缓冲液。皮下注射4h后，摘眼球取血，10ml离心管事先用肝素清洗一遍，混匀后，补PBS至5ml，混匀。小鼠淋巴细胞分离液(购自天津灏洋生物制品科技有限责任公司)预先分装成5ml/管(超净台中操作)，将与PBS混匀的血液轻轻的注入分离液的上层，2000rpm/min离心20min。将中间白白的一层细胞吸入10ml离心管中，补PBS至10ml，混匀，1500rpm/min离心5min，弃去上层PBS，补PBS至10ml，混匀，1500rpm/min离心5min，弃去上层PBS，补PBS至0.5ml，混匀。将得到的单个核细胞尾静脉注射至经致死剂量照射的小鼠体内，观察小鼠在30天内的存活数量。从结果(如图5所示)可以看出，较DMSO组和G-CSF组，注射TA01动员的外周血中单个核能提高照射致死剂量小鼠的存活率。
以上实验以三(2-(二甲氨基)乙基)胺为例，验证了式I表示的化合物能有效动员骨髓中的造血干细胞。本发明用同样方法也验证了式I表示的其它化合物也具有类似效果，这里不再一一详述实验过程。
Claims (4)
1.式I所示饱和胺类化合物在制备外周血造血干细胞动员药物中的应用，
其中，R1＝H、CH3或CH2CH3，R2＝H、CH3或CH2CH3。
2.根据权利要求1所述的应用，其特征在于：所述饱和胺类化合物式中，R1＝R2＝CH3，命名为三(2-(二甲氨基)乙基)胺。
3.根据权利要求1或2所述的应用，其特征在于：所述药物的剂型为注射剂。
4.根据权利要求3所述的应用，其特征在于：所述注射剂的溶剂为pH 7.5-8.5的TE缓冲液、生理盐水、PBS或灭菌蒸馏水。
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| CN101716167A CN101716167A (zh) | 2010-06-02 |
| CN101716167B true CN101716167B (zh) | 2011-12-28 |
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| US (1) | US20120322886A1 (zh) |
| EP (1) | EP2510926B1 (zh) |
| JP (1) | JP5667640B2 (zh) |
| CN (1) | CN101716167B (zh) |
| WO (1) | WO2011069336A1 (zh) |
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| CN101716167B (zh) * | 2009-12-08 | 2011-12-28 | 中国人民解放军军事医学科学院野战输血研究所 | 一类饱和胺类化合物在制备外周血造血干细胞动员药物中的应用 |
| CN102389408B (zh) * | 2011-10-20 | 2013-07-24 | 中国人民解放军军事医学科学院野战输血研究所 | 一种饱和胺类化合物在制备治疗缺血性疾病的药物中的应用 |
| CN103110613B (zh) * | 2013-01-25 | 2014-10-22 | 中国人民解放军军事医学科学院野战输血研究所 | 饱和胺类化合物在制备抗辐射损伤药物中的应用 |
| WO2017172976A1 (en) * | 2016-03-29 | 2017-10-05 | The Regents Of The University Of California | Methods for promoting oligodendrocyte regeneration and remyelination |
| US20220257796A1 (en) | 2019-07-02 | 2022-08-18 | Fred Hutchinson Cancer Research Center | Recombinant ad35 vectors and related gene therapy improvements |
| CN114891746A (zh) * | 2021-12-21 | 2022-08-12 | 青岛今墨堂生物技术有限公司 | 一种犬全血造血干细胞的制备方法 |
| EP4476331A2 (en) | 2022-02-07 | 2024-12-18 | Ensoma, Inc. | Inhibitor-resistant mgmt modifications and modification of mgmt-encoding nucleic acids |
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| US3767763A (en) * | 1971-11-26 | 1973-10-23 | Exxon Research Engineering Co | Separation of sodium compounds |
| BR9914465A (pt) * | 1998-09-29 | 2001-10-09 | Gamida Cell Ltd | Métodos para controlar a proliferação e a diferenciação de células-tronco e células progenitoras e uma composição farmacêutica para induzir a diferenciação em uma população de células |
| KR20040020075A (ko) * | 2001-07-31 | 2004-03-06 | 아노르메드 인코포레이티드 | 선조/줄기 세포를 가동시키는 방법 |
| CA2612227C (en) * | 2005-06-14 | 2014-04-22 | Taigen Biotechnology Co., Ltd. | Pyrimidine compounds |
| CN101716167B (zh) * | 2009-12-08 | 2011-12-28 | 中国人民解放军军事医学科学院野战输血研究所 | 一类饱和胺类化合物在制备外周血造血干细胞动员药物中的应用 |
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- 2010-12-08 EP EP10835373.1A patent/EP2510926B1/en not_active Not-in-force
- 2010-12-08 WO PCT/CN2010/001986 patent/WO2011069336A1/zh not_active Ceased
- 2010-12-08 JP JP2012542340A patent/JP5667640B2/ja not_active Expired - Fee Related
Also Published As
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| JP5667640B2 (ja) | 2015-02-12 |
| EP2510926B1 (en) | 2018-03-28 |
| JP2013512932A (ja) | 2013-04-18 |
| WO2011069336A1 (zh) | 2011-06-16 |
| US20120322886A1 (en) | 2012-12-20 |
| EP2510926A1 (en) | 2012-10-17 |
| EP2510926A4 (en) | 2013-08-21 |
| CN101716167A (zh) | 2010-06-02 |
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