CN115192580A - 一种化合物在制备靶向ErbB2突变体的抑制药物中的应用 - Google Patents
一种化合物在制备靶向ErbB2突变体的抑制药物中的应用 Download PDFInfo
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- CN115192580A CN115192580A CN202210356800.1A CN202210356800A CN115192580A CN 115192580 A CN115192580 A CN 115192580A CN 202210356800 A CN202210356800 A CN 202210356800A CN 115192580 A CN115192580 A CN 115192580A
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Abstract
本发明公开了一种含有化学式1所示结构的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或、其晶型的应用,特别是在制备靶向ErbB2突变体的抑制药物中的应用。本发明所提供的化合物对ErbB2突变体具有抑制活性,能够有效抑制ErbB2突变肿瘤细胞的增殖。
Description
技术领域
本发明涉及生物医药领域,具体涉及一种化合物在制备靶向ErbB2突变体的抑制药物中的应用。
背景技术
ErbB2基因扩增/蛋白过表达(称为ErbB2阳性)为ErbB2活化的常见机制,过去20年的研究已经确认,ErbB2蛋白的过表达,无论是通过基因扩增还是通过转录失活,其经常与各种实体肿瘤的致癌有关。在临床上,ErbB2阳性的肿瘤如:乳腺癌、胃癌、食道癌、卵巢癌、子宫内膜癌、结直肠癌、肺癌等,其中,在乳腺癌、胃癌瘤中,ErbB2的表达量相对更高。ErbB2作为一种致癌的驱动因子,是乳腺癌和胃癌中公认的治疗靶点。
随着人类对癌症基因组图谱的不断认识,ErbB2的周期性体细胞突变已经被识别出,通常发生在没有基因扩增的情况下。与BRAF或KRAS等其他突变致癌基因不同,没有单一突变等位基因占主导地位,突变的精确分布因肿瘤类型而异(Nature,2018,554(7691):189-194.)。ErbB2突变在几种肿瘤类型中以低频率发生,特别是在乳腺癌(3%)、结肠癌(2-3%)和肺癌(2-3%)中。其他的人类肿瘤类型也被报道含有ErbB2突变,包括头颈部癌症,膀胱癌,胃癌,卵巢癌,肝癌(Oncotarget,2018,9(11):9741-9750)。另外,有报道称一些ErbB2阳性的患者会对抗ErbB2治疗有耐药性。
多种耐药机制表明,ErbB2的突变是一个关键的机制。ErbB2的突变激活可由三种体细胞分子改变引起:激酶域的插入和错义突变、细胞外域的错义突变、或细胞外域的缺失突变,从而导致ErbB2的截断形式(J Clin Oncol,2020)。或许部分由于缺乏有效的靶向治疗的原因,与其他致癌驱动因素相比,ErbB2突变的预后更差。
肺癌是最常被诊断的癌症之一,以ErbB2突变为致癌驱动因素,在非小细胞肺癌(NSCLC)中发生率为2-3%,在EGFR/ALK/ROS1三阴性NSCLC中则可达6.7%(BMC Cancer2016;16:828)。虽然ErbB2突变在肺腺癌中是一种罕见的突变,但是鉴于肺腺癌的庞大基数,仍然有着潜在的临床意义。有文献报道,患有ErbB2突变型的肺癌患者治疗过程中脑转移的发生率高于KRAS突变型患者(28%vs.8%),且有高于EGFR突变型患者的趋势(28%vs.16%)(Cancer,2019Aug 30.)。
CN109422755A公开了能够有效抑制未突变的ErbB2的一类化合物,但由于ErbB2突变导致其结构改变,从而使ErbB2突变体对ErbB2抑制剂产生耐药性,因此急需一种靶向ErbB2突变体的有效抑制剂。
发明内容
本发明所要解决的技术问题是为克服现有技术中缺乏靶向ErbB2突变体的有效抑制剂的缺陷,提供一种化合物在制备靶向ErbB2突变体的抑制药物中的应用。
本发明所提供的技术方案之一为:一种含有化学式1所示结构的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或、其晶型在制备靶向ErbB2突变体抑制药物中的应用;
其中,R1为卤素或C1-C6烷烃;
n为1或2;
G为N或C-CN。
某一实施方案中,所述含有化学式1所示结构的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或、其晶型中,
R1为卤素或C1-C6烷烃;
n为1或2;
G为N或C-CN。
某一实施方案中,所述含有化学式1所示结构的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或、其晶型中,
R1为卤素或C1-C6烷烃;
n为1或2;
G为N或C-CN。
本发明所提供的技术方案之一为:一种含有化学式1所示结构的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或、其晶型在制备治疗或预防ErbB2突变体相关疾病的药物中的应用;
其中,R1为卤素或C1-C6烷烃;
n为1或2;
G为N或C-CN。
某一实施方案中,所述含有化学式1所示结构的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或、其晶型中;
R1为卤素或C1-C6烷烃;
n为1或2;
G为N或C-CN。
某一实施方案中,所述含有化学式1所示结构的化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物、或、其晶型中,
R1为卤素或C1-C6烷烃;
n为1或2;
G为N或C-CN。
本发明所述化学式1中,R1为卤素时,所述卤素较佳地为Cl;R1为C1-C6烷烃时,所述C1-C6烷烃较佳地为甲基。
此外,在本发明一实施方案中,
所述含有化学式1所示结构的化合物优选为选自(R,Z)-N-(4-((4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)-2-氟-3-(1-甲基吡咯-2-基)丙烯酰胺、拉帕替尼、妥卡替尼、吡咯替尼、来那替尼、
本发明所述ErbB2突变体的突变类型较佳地包含D769H、D769Y、R896C、V777L、G766>VC和A775_G776insYVMA中的一种或多种。
在本发明一较佳实施方案中,所述ErbB2突变类型为D769H、D769Y、R896C、V777L、G766>VC或A775_G776insYVMA,所述含有化学式1所示结构的化合物为(R,Z)-N-(4-((4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)-2-氟-3-(1-甲基吡咯-2-基)丙烯酰胺。
在本发明另一较佳实施方案中,所述ErbB2突变体类型为D769H、D769Y、R896C、V777L或A775_G776insYVMA,所述含有化学式1所示结构的化合物为拉帕替尼。
在本发明另一较佳实施方案中,所述ErbB2突变体类型为D769H、D769Y、R896C或V777L,所述含有化学式1所示结构的化合物为妥卡替尼。
在本发明另一较佳实施方案中,所述ErbB2突变体类型为D769H、D769Y、R896C或V777L,所述含有化学式1所示结构的化合物为吡咯替尼。
在本发明另一较佳实施方案中,所述ErbB2突变体类型为D769H、D769Y、R896C或V777L,所述含有化学式1所示结构的化合物为来那替尼。
在本发明某一实施方案中,所述的rbB2突变体类型为D769H、D769Y、R896C或V777L,所述的含有化学式1所示结构的化合物为以下结构中的任一种:
本发明所述ErbB2突变相关疾病较佳地为ErbB2突变型癌症;
所述ErbB2突变型癌症优选包含乳腺癌、结肠癌、头颈部癌症、膀胱癌、胃癌、卵巢癌、肝癌或肺癌;
所述肺癌进一步优选为非小细胞肺癌。
本发明所述治疗较佳地为抑制肿瘤转移和/或增长,所述抑制肿瘤增长包含抑制原发肿瘤和已转移肿瘤的增长,所述已转移肿瘤优选为脑转移肿瘤。
本发明所述的药物较佳地还包括药学上可接受的载体。
本发明所述含有化学式1所示结构的化合物较佳地为所述药物的唯一活性成分,或者,与其他ErbB2突变抑制剂或治疗癌症的药物共同作为活性成分。
本发明所述的药物中所述含有化学式1所示结构的化合物的含量较佳地为达到治疗有效量的含量。
本发明中,化合物(R,Z)-N-(4-((4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)-2-氟-3-(1-甲基吡咯-2-基)丙烯酰胺表示为化合物I:
如本发明所用,术语“卤素”是指周期系ⅦA族元素。
如本发明所用,术语“烷烃”是指分子中的碳原子都以碳碳单键相连,其余的价键都与氢结合而成的化合物。
如本发明所用,术语“治疗”可用于表示治疗性和预防性的治疗。在此,预防可用于表示个体的病理状况或疾病被缓解或减轻。术语“治疗”包括用于治疗包括人类在内的哺乳动物中的疾病的应用或任何形式的给药。另外,该术语包括抑制或减慢疾病或疾病的进展。包括恢复或修复功能受损或丧失的含义,以使疾病得到部分缓解或完全缓解;刺激低效的流程;或缓解严重性疾病。
如本发明所用,术语“治疗有效量”或“药物有效量”是指足以预防或治疗所讨论疾病的化合物或组合物的量,其足以以合理的益处/风险比治疗疾病,且适用于医疗并不会造成不良影响。可以根据包括患者的健康状况、疾病的严重程度、药物活性、患者对药物的敏感性、给药方式、给药时间、给药途径和排泄率、治疗持续时间、制剂或同时施用的药物以及本领域众所周知的医疗领域内的其他因素确定有效量的水平。在本发明一较佳实施方案中,化合物I治疗有效量为10-40mg/kg,例如10、15、20、25、30、35、或40mg/kg。
在此,药学上可接受的载体可以是任何载体,只要该载体是适合递送给患者的无毒物质即可。可以包含蒸馏水、酒精、脂肪、蜡和惰性固体作为载体,也可以包含药学上可接受的佐剂(缓冲剂、分散剂)。
具体地,通过包含除活性成分之外的药学上可接受的载体,可以使用本领域已知的常规方法根据其给药途径将药物组合物制备成制剂。在此,术语“药学上可接受的”是指载体的毒性不超过所施用(处方的)的对象所能适应的量,同时不抑制活性成分的活性。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明所提供的化合物,对ErbB2突变体具有抑制活性,能够有效抑制ErbB2突变肿瘤细胞的增殖。在一较佳实施例中,本发明所提供的化合物,尤其是化合物I,对于ErbB2突变在NCI-H1781和Ba/F3细胞株上的增殖具有较好的抑制活性,且在B细胞淋巴瘤细胞系Ba/F3 ErbB2 A775_G776insYVMA细胞小鼠异体移植模型中,能够有效抑制肿瘤的增长。显示出该类化合物潜在的临床应用价值。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
化合物I的制备
化合物I:[(R,Z)-N-(4-((4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)-2-氟-3-(1-甲基吡咯-2-基)丙烯酰胺]的制备
步骤A:7-乙氧基-6-硝基喹唑啉-4-醇的制备:将7-氟-6-硝基喹唑啉-4-醇(4000mg,19.13mmol)溶于四氢呋喃(20ml)中,冰水浴冷至0度下,缓慢将乙醇钠(4000mg,58.78mmol)的无水乙醇(20ml)溶液滴至反应液中,逐渐升至室温,搅拌16个小时。冰水浴下,用乙酸将反应液中PH值调至5-6,过滤,真空干燥得浅黄色固体4000mg,并直接用于下一步反应。
步骤B:4-氯-7-乙氧基-6-硝基喹唑啉的制备:将7-乙氧基-6-硝基喹唑啉-4-醇(4000mg,17.01mmol)溶于三氯氧磷(50ml)中,搅拌下加热回流4个小时。然后将反应液减压浓缩干,将残余物溶于二氯甲烷(500ml)中,依次用水(500ml)、饱和食盐水(500ml)洗涤,无水硫酸钠干燥2个小时,减压浓缩得淡黄色固体4000mg,收率92.7%,并直接用于下一步反应。
步骤C:N-(4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)-7-乙氧基-6-硝基喹唑啉-4-胺的制备:将4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯胺(250mg,1.04mmol)、4-氯-7-乙氧基-6-硝基喹唑啉(400mg,1.58mmol)、碳酸钾(290mg,2.10mmol)混合于N,N-二甲基甲酰胺(10mL)中,室温搅拌。过滤,向滤液中加入二氯甲烷(100ml)和水(100ml),分出有机层,依次用水(100ml)、饱和食盐水(100ml)洗涤,无水硫酸钠干燥。过滤,减压浓缩得黄色固体590mg,并直接用于下一步反应。
步骤D:N4-(4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)-7-乙氧基喹唑啉-4,6-二胺的制备:将N-(4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)-7-乙氧基-6-硝基喹唑啉-4-胺(590mg,1.29mmol)溶于甲醇(20ml)中,加入雷尼镍,氩气置换三次,通入氢气,室温搅拌2个小时。硅藻土过滤,减压浓缩得固体330mg,并直接用于下一步反应。
步骤E:二乙基(2-((4-((4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)氨基)-1-氟-2-氧代乙基)膦的制备:将7-乙氧基N4-[3-甲基-4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)苯基]喹唑啉-4,6-二胺(1.15g,2.69mmol)和2-二乙氧基磷酰基-2-氟-乙酸(691mg,3.22mmol)加入到20mL吡啶中,在0度下滴加1.5mL三氯氧磷,并反应1.5小时。碳酸氢钠水溶液淬灭反应,减压浓缩得到残余物,加入二氯甲烷和水,弃去有机相。水相用二氯甲烷萃取(60mLx3),合并有机相,无水硫酸钠干燥。减压浓缩得到粗品,经柱层析分离纯化得到黄色固体920mg,收率55%。
步骤F:(R,Z/E)-2-(3-((4-((4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)氨基)-2-氟-3-氧代丙-1-烯-1-基)吡咯烷-1-羧酸叔丁酯的制备:将氢氧化钠(359mg,8.97mmol)溶于混合溶剂乙醇18mL和水1.8mL中,加入二乙基(2-((4-((4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)氨基)-1-氟-2-氧代乙基)膦(700mg,1.12mmol),溶液澄清后,0度下加入(2R)-2-甲酰基吡咯烷-1-羧酸叔丁酯(447mg,2.24mmol),反应液升到室温,搅拌3小时。加入氯化铵水溶液,减压浓缩掉有机溶剂,剩余物用二氯甲烷(60mLx3)萃取,合并有机相,无水硫酸钠干燥。减压浓缩得到粗品,经柱层析分离纯化得到黄色固体混合物565mg,收率75%。
步骤G:(R,Z)-N-(4-((4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)-2-氟-3-(1-甲基吡咯-2-基)丙烯酰胺的制备:将(R,Z/E)-2-(3-((4-((4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)氨基)-2-氟-3-氧代丙-1-烯-1-基)吡咯烷-1-羧酸叔丁酯混合物(540mg,0.81mmol)溶解于16mL二氯甲烷中,加入4mL三氟乙酸,室温搅拌3小时。减压浓缩,所得残余物溶解于20mL甲醇中,加入37%甲醛水溶液1mL,室温搅拌1.5小时,缓慢加入醋酸硼氢化钠(1g,4.69mmol),反应液室温搅拌16小时。减压浓缩得到残余物,加入二氯甲烷和碳酸氢钠水溶液,弃去有机相,水相用二氯甲烷(80mLx3)萃取,合并有机相,无水硫酸钠干燥。过滤,减压浓缩得到残余物,经柱层析分离纯化得到粗品,再经过SFC分离纯化得到目标化合物134mg,收率28%。
以下实施例中化合物2-化合物7、化合物10-化合物15、化合物17已在WO2019042409A1中公开,按照该专利申请中记载的制备方法获得;化合物8、化合物9和化合物16已在WO2017148391A1中公开,按照该专利申请中记载的制备方法获得。拉帕替尼、妥卡替尼、吡咯替尼、来那替尼通过商业购买。
实施例1.ErbB2突变体抑制测试
该测试所用试剂材料及测试过程由Reaction Biology Corporation提供并完成。具体步骤为:
1、化合物配制:受试化合物和对照化合物(星形孢菌素/Staurosporine)均溶解于DMSO;
2、酶反应测试条件:受试化合物孵育时间为20分钟,ATP的浓度为10μM,酶反应时间为2小时;
3、酶反应实验步骤
酶反应缓冲液为20mM HEPES(pH 7.5),10mM MgCl2,2mM MnCl2,1mM EGTA,0.01%Brij35,0.02mg/ml BSA,0.1mM Na3VO4,2mM DTT,1%DMSO。
酶反应步骤为:
(1)将各个酶反应所需底物分别溶解于新鲜制备的酶反应缓冲液中;
(2)将各个酶分别加入以上底物溶液中,混匀;
(3)将受试化合物以相应浓度分别加入酶-底物混合溶液中,室温孵育20分钟;
(4)分别加入33P-ATP(终浓度0.01μCi/μl)启动酶反应,室温孵育2小时;
(5)酶反应溶液加在P81离子交换纸上(Whatman#3698-915);
(6)用0.75%磷酸清洗;
(7)对纸上的放射性磷酸化底物进行读数。
4、数据分析:
激酶活性%=(受试化合物样本激酶剩余活性/溶媒对照样本(DMSO)激酶活性)*100%。
根据不同化合物浓度下的激酶活性%拟合计算化合物的IC50。
表1
其中对照化合物为星形孢菌素(Staurosporine),其为一种有效、非选择性蛋白激酶抑制剂,是一个凋亡诱导剂,其作用在于证明实验系统有效。
拉帕替尼、妥卡替尼、吡咯替尼、来那替尼与化合物Ⅰ均含有如化学式1所示结构,其结构分别如下所示:
结果:拉帕替尼、妥卡替尼、吡咯替尼、来那替尼及化学式1对ErbB2突变体均具有抑制性能,其中化学式1中多数化合物的抑制性能均高于拉帕替尼、妥卡替尼、吡咯替尼和来那替尼。
实施例2.ErbB2突变细胞抑制测试
表2
培养细胞,收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力,确保细胞活力在90%以上。体外培养后,获得2×106个细胞。将细胞悬液以1×103个/孔的量分别添加至96孔板中(90μL/孔),置于37℃、5%CO2、95%湿度条件下培养过夜。配制10倍药物溶液,检测最高浓度为10μM,3倍稀释为9个浓度,在接种有细胞的96孔板中每孔加入10μL药物溶液,每个药物浓度设置三个复孔。将已加药的96孔板中的细胞置于37℃、5%CO2、95%湿度条件下继续培养72小时,之后进行CTG分析。
表3
结果:拉帕替尼及化合物Ⅰ在上述2个突变细胞株(这两个突变在肺癌中有出现)上具有较好的抑制细胞增殖的活性。
实施例3.NPSG小鼠异体转移模型中的药效测试
NPSG小鼠(上海吉辉实验动物饲养有限公司,合格证:No.20170012006783),雄性,右侧肩部皮下接种Ba/F3 ErbB2 A775_G776insYVMA细胞(体外培养,获得9×107细胞),当平均肿瘤体积达到130mm3时,依据肿瘤体积和体重随机分为6组,每组10只,随即开始给药。给药后,小鼠每周2次测量体重及肿瘤体积,连续给药至实验Day13。在实验Day14,对各组进行药后采集操作。
表4实验中的各组小鼠平均肿瘤体积数据
注:数据为平均值±标准误差;对照组为不施用任何化合物的组。
结论:通过数据表明,在B细胞淋巴瘤细胞系Ba/F3 ErbB2 A775_G776insYVMA细胞小鼠异体移植模型上连续给予13天实验中,吡咯替尼和来那替尼在20mg/kg剂量下呈现中等药效;化合物Ⅰ在10mg/kg、20mg/kg、40mg/kg剂量下均呈现强药效,其中化合物Ⅰ40mg/kg抑瘤效果最强,与其余各受试药组均呈现统计学差异(p值均小于0.01)。各受试药组动物在试验期间无明显体重下降,无死亡。
Claims (14)
8.如权利要求1~7任一项所述的应用,其特征在于,所述ErbB2突变体的突变类型包含D769H、D769Y、R896C、V777L、G766>VC和A775_G776insYVMA中的一种或多种。
9.如权利要求8所述的应用,其特征在于,所述ErbB2突变类型为D769H、D769Y、R896C、V777L、G766>VC或A775_G776insYVMA,所述含有化学式1所示结构的化合物为(R,Z)-N-(4-((4-([1,2,4]三唑并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)-2-氟-3-(1-甲基吡咯-2-基)丙烯酰胺;
或,所述ErbB2突变体类型为D769H、D769Y、R896C、V777L或A775_G776insYVMA,所述含有化学式1所示结构的化合物为拉帕替尼;
或,所述ErbB2突变体类型为D769H、D769Y、R896C或V777L,所述含有化学式1所示结构的化合物为妥卡替尼;
或,所述ErbB2突变体类型为D769H、D769Y、R896C或V777L,所述含有化学式1所示结构的化合物为吡咯替尼;
或,所述ErbB2突变体类型为D769H、D769Y、R896C或V777L,所述含有化学式1所示结构的化合物为来那替尼;
或,所述的rbB2突变体类型为D769H、D769Y、R896C或V777L,所述的含有化学式1所示结构的化合物为以下结构中的任一种:
10.如权利要求4~6任一项所述的应用,其特征在于,所述ErbB2突变相关疾病为ErbB2突变型癌症;
所述ErbB2突变型癌症优选包含乳腺癌、结肠癌、头颈部癌症、膀胱癌、胃癌、卵巢癌、肝癌或肺癌;
所述肺癌进一步优选为非小细胞肺癌。
11.如权利要求4~6任一项所述的应用,其特征在于,所述治疗为抑制肿瘤转移和/或增长。
12.如权利要求1~11任一项所述的应用,其特征在于,所述的药物还包括药学上可接受的载体。
13.如权利要求1~11任一项所述的应用,其特征在于,所述含有化学式1所示结构的化合物为所述药物的唯一活性成分,或者,与其他ErbB2突变抑制剂或治疗癌症的药物共同作为活性成分。
14.如权利要求1~11任一项所述的应用,其特征在于,所述的药物中所述含有化学式1所示结构的化合物的含量为达到治疗有效量的含量。
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