CN102653522B - ω-羧基取代的二苯基硫脲类化合物及其制备方法和用途 - Google Patents
ω-羧基取代的二苯基硫脲类化合物及其制备方法和用途 Download PDFInfo
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- CN102653522B CN102653522B CN201210109081.XA CN201210109081A CN102653522B CN 102653522 B CN102653522 B CN 102653522B CN 201210109081 A CN201210109081 A CN 201210109081A CN 102653522 B CN102653522 B CN 102653522B
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- Prior art keywords
- thioureido
- carboxamide
- thiophenyl
- pyridine
- phenylthio
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Abstract
本发明涉及一种如式I所示的ω-羧基取代的二苯基硫脲衍生物、其药学上可接受的盐、所述衍生物的溶剂合物、或者所述盐的溶剂合物,其为有效的酪氨酸激酶抑制剂。本发明还涉及所述ω-羧基取代的二苯基硫脲衍生物的制备方法,含有所述ω-羧基取代的二苯基硫脲衍生物、其药学上可接受的盐、所述衍生物的溶剂合物、或者所述盐的溶剂合物的药物组合物,以及所述ω-羧基取代的二苯基硫脲衍生物、其药学上可接受的盐、所述衍生物的溶剂合物、或者所述盐的溶剂合物在制备用于治疗或辅助治疗哺乳动物(包括人类)中由酪氨酸激酶介导的肿瘤或酪氨酸激酶驱动的肿瘤细胞的增殖和迁移的药物的用途。
Description
技术领域
本发明属于医药化工领域,主要涉及一类ω-羧基取代的二苯基硫脲类衍生物及其药学上可接受的盐。本发明还涉及所述ω-羧基取代的二苯基硫脲类衍生物的制备方法、一种药物组合物及用途。
背景技术
肿瘤是严重威胁人类生命和生活质量的主要疾病之一,据世界卫生组织(WHO)统计,全世界每年死于肿瘤的患者约690万。由于生存环境和生活习性的改变,在不良环境和一些不利因素的作用下,肿瘤的发病率和死亡率近年呈逐步上升趋势。
近年来,人们致力于抑制细胞信号转导途径研究以开发新型靶点的抗肿瘤药物。信号转导抑制剂下调肿瘤的生存和增殖信号,促进细胞凋亡,与传统的细胞毒作用的抗肿瘤药物相比,具有选择性较高、毒副作用较小的优点。目前已有十多种信号转导抑制剂应用于临床治疗肿瘤,主要为酪氨酸激酶抑制剂类抗肿瘤药物。其中作为多靶点的二芳基脲类结构类型化合物的开发比较成熟,如拜耳公司开发的已上市的多靶点酪氨酸激酶抑制剂sorafeinib等。
小分子酪氨酸激酶抑制剂作为新的靶向抗肿瘤药物,副作用轻微,有良好的耐受性,为肿瘤的治疗和预防打开了一扇新窗口。虽然目前已经上市的有10多个小分子酪氨酸激酶抑制剂,但仍然需要发现一些较之现有的酪氨酸激酶抑制剂具有更好的体内活性和/或改良的药理学特性的药物分子。因此开发新的改进的或更高效的酪氨酸激酶抑制剂,更深入地了解该类药物与已知靶蛋白之间的关系以及其发挥抗肿瘤作用的机理对抗肿瘤新药的发现和肿瘤临床治疗具有重要的指导意义。
发明内容
在研究各类酪氨酸激酶晶体结构的基础上,我们设计了一类ω-羧基芳基取代的二苯基硫脲类化合物,并与多个靶标结构具有良好的匹配模式,经体外细胞株筛选,所设计的化合物具有较好的抗肿瘤活性。
本发明提供了式I所示的可用于制备治疗细胞增殖性疾病(如肿瘤)药物的二苯基硫脲类衍生物及其药学上可接受的盐。
式I
其中,
R1选自H,C1-C8的烷基,卤素,-CF3,-OCF3、-NO2,-CN,R2O-,-SO2NH2,-NHSO2R3,-NR4R5,-CONR6R7,-COOR8,R9CO-以及它们的二取代或三取代的组合,其中R2,R3,R4,R5,R6,R7,R8,R9分别为H或C1-C8的烃基;
L选自-NHR10、-NHOR11、-NR12R13、其中R10,R11,R12,R13分别为H或C1-C8的烷基;其中L不为-NHCH3;
n从1到4。
本文所用的术语“卤素”是指氟,氯,溴或碘。优选的卤素基团为氟,氯或溴。
本文所用的术语“卤代烷基”是指被本文所定义的卤素单或多取代的如本文所定义的烷基。“卤代烷基”的实例包括但不限于-CF3,-CHF2,-CH2CCl3等。
本文所用的术语“卤代烷氧基”是指被本文所定义的卤素单或多取代的如本文所定义的烷氧基。“卤代烷基”的实例包括但不限于-OCF3,-OCHF2,-OCH2CCl3等。
上述的药学上可接受的盐选自:盐酸盐、硫酸盐、硫酸氢盐、甲磺酸盐、对甲苯磺酸盐、苯磺酸盐、富马酸盐、马来酸盐、苹果酸盐,或者这些盐的溶剂合物,例如水合物。
在本发明的一个实施方案中,所述二苯基硫脲类衍生物选自下列的化合物:
4-{4-[3-[4-氯苯基]硫脲基]-苯硫基}-N-苄基吡啶-2-甲酰胺(JY-Z01);
4-{4-[3-[3-三氟甲基苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷(JY-Z02);
4-{4-[3-[3-三氟甲基苯基]硫脲基]-苯硫基}-N-苄基吡啶-2-甲酰胺(JY-Z03);
4-{4-[3-[3,4-二氟苯基]硫脲基]-苯硫基}-N-苄基吡啶-2-甲酰胺(JY-Z04);
4-{4-[3-(4-氟苯基)硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷;(JY-Z05);
4-{4-[3-[3-(三氟甲基)-4-氯苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷(JY-Z06);
4-{4-[3-[4-氯苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷(JY-Z07);
4-{4-[3-[3,4-二氟苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷(JY-Z08);
4-{4-[3-(4-三氟甲氧基苯基)硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷(JY-Z09);
4-{4-[3-(3-三氟甲基苯基)硫脲基]-苯硫基}-N-环己基吡啶-2-甲酰胺(JY-Z10);
4-{4-[3-(3-三氟甲基-4-氯苯基)硫脲基]-苯硫基}-N-环己基吡啶-2-甲酰胺(JY-Z11);
4-{4-[3-(3,4-二氟苯基)硫脲基]-苯硫基}-N-环己基吡啶-2-甲酰胺(JY-Z12);
4-{4-[3-(4-氯苯基)硫脲基]-苯硫基}-N-环己基吡啶-2-甲酰胺(JY-Z13);
4-{4-[3-(3-三氟甲基苯基)硫脲基]-苯硫基}-N-环丙基吡啶-2-甲酰胺(JY-Z14);
4-{4-[3-(3-三氟甲基-4-氯苯基)硫脲基]-苯硫基}-N-环丙基吡啶-2-甲酰胺(JY-Z15);
4-{4-[3-(3,4-二氟苯基)硫脲基]-苯硫基}-N-环丙基吡啶-2-甲酰胺(JY-Z16);
4-{4-[3-(3-三氟甲基-4-氯苯基)硫脲基]-苯硫基}-N-乙基吡啶-2-甲酰胺(JY-Z17);
4-{4-[3-[3,4-二氟苯基]硫脲基]-苯硫基}-N-乙基吡啶-2-甲酰胺(JY-Z18);
4-{4-[3-[2,4-二氯苯基]硫脲基]-苯硫基}-N-苄基吡啶-2-甲酰胺(JY-Z19);
4-{4-[3-[4-甲氧苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷(JY-Z20)。
本发明另一个方面涉及上述的ω-羧基取代的二苯基硫脲衍生物的制备方法,包括如下步骤:
1)化合物(II)在三乙烯二胺(缩写为TED)存在下,与二硫化碳反应生成中间体(III),中间体(III)与双(三氯甲基)碳酸酯(缩写为BTC)反应制得中间体(IV):
2)2-吡啶甲酸与氯化亚砜反应得到4-氯-2-吡啶甲酰氯(或其盐酸盐),所得4-氯-2-吡啶甲酰氯与甲醇发生酯化反应生成4-氯-2-吡啶甲酸甲酯(或其盐酸盐),4-氯-2-吡啶甲酸甲酯与伯胺或仲胺及其衍生物(HL)反应得到相应的吡啶甲酰胺类化合物中间体(V):
3)中间体(V)与对氨基苯硫酚在强碱作用下缩合得到中间体(VI):
4)化合物(IV)与化合物(VI)在适当有机溶剂中反应得到式I所示的化合物,该化合物与相应酸反应得到式I所示化合物的相应酸盐。
其中R1、L、n分别如前所述;
所述强碱可以选自NaH,KH,CH3ONa,EtONa,t-BuOK,i-PrONa,NaOH,KOH中的一种或多种。
本发明涉及一种药物组合物,其包含上述的ω-羧基取代的二苯基硫脲类衍生物、其药学上可接受的盐,以及任选的一种或多种药学上可接受的载体和/或辅料。
本发明涉及上述的二苯基硫脲衍生物、其药学上可接受的盐在制备酪氨酸激酶抑制剂治疗细胞增殖性疾病(如肿瘤)药物的用途。
本发明涉及上述的二苯基硫脲衍生物、其药学上可接受的盐在制备用于治疗和/或预防哺乳动物与受体酪氨酸激酶相关的细胞增殖性疾病(如肿瘤)的药物中的用途。具体地,所述哺乳动物为人类。
本发明的还涉及上述的二苯基硫脲衍生物、其药学上可接受的盐在制备用于治疗或辅助治疗和/或预防哺乳动物由受体酪氨酸激酶介导的肿瘤或由受体酪氨酸激酶驱动的肿瘤细胞增殖和迁移的药物中的用途。具体地,所述哺乳动物为人类。
根据本发明,完全可以预期本发明化合物可用于治疗VEGFR或PDGFR等酪氨酸激酶敏感癌症,如VEGFR、PDGFR高表达及VEGF驱动的肿瘤,包括实体肿瘤如胆管、骨、膀胱、脑/中枢神经系统、乳房、结直肠、子宫内膜、胃、头和颈、肝、肺、神经元、食道、卵巢、胰腺、前列腺、肾脏、皮肤、睾丸、甲状腺、子宫和外阴等的癌症,和非实体肿瘤如白血病、多发性骨髓瘤或淋巴瘤等。本发明所述的衍生物能够调节蛋白激酶的活性,可以用于蛋白激酶相关性细胞功能障碍的预防和治疗,从而本发明的化合物还可以用于预防和治疗涉及异常蛋白激酶活性的功能障碍。
本发明涉及的一种治疗和/或预防哺乳动物中与酪氨酸激酶相关的疾病的用途,通过施用有效量的本发明的ω-羧基取代的二苯基硫脲衍生物、其药学上可接受的盐,或者本发明所述的药物组合物实现。
本发明的另一个方面涉及用于治疗或辅助治疗和/或预防哺乳动物(包括人)中由酪氨酸激酶介导的肿瘤或由酪氨酸激酶驱动的肿瘤细胞增殖和迁移的用途,该用途通过施用有效量的本发明的ω-羧基取代的二苯基硫脲衍生物、其药学上可接受的盐,或者本发明的药物组合物。
本发明的还一个方面涉及一种治疗和/或预防哺乳动物(包括人)的肿瘤或癌症的方法,所述方法包括给有需要的哺乳动物施用有效量的本发明的ω-羧基取代的二苯基硫脲衍生物、其药学上可接受的盐、或者本发明的药物组合物。所述的肿瘤或癌症包括VEGFR或PDGFR酪氨酸激酶敏感癌症,如VEGFR、PDGFR高表达及VEGF驱动的肿瘤,包括实体肿瘤如胆管、骨、膀胱、脑/中枢神经系统、乳房、结直肠、子宫内膜、胃、头和颈、肝、肺(尤其是非小细胞肺癌)、神经元、食道、卵巢、胰腺、前列腺、肾脏、皮肤、睾丸、甲状腺、子宫和外阴等的癌症,和非实体肿瘤如白血病、多发性骨髓瘤或淋巴瘤等。
本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这些文献所表达的含义与本发明不一致时,以本发明的表述为准。此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。
术语“卤素”或“卤代”是指氟、氯、溴和碘。
本发明中,当提及时,所采用的术语“烃基”包括烷基、烯基和炔基。
本发明中,当提及时,所采用的术语“烷基”、“烯基”和“炔基”具有本领域公知的一般含义,它们是直链或支链的烃基基团,例如但不限于甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、烯丙基、丙烯基、丙炔基等,并且所述的“烷基”、“烯基”和“炔基”可以统称为“烃基”或“链烃基”。
在本发明合成式I化合物的方法中,反应所用的各种原材料是本领域技术人员根据现有技术可以制备得到的,或者是可以通过文献公知的方法制得的,或者是可以通过商业购得的。以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以作适当改变的。或者,本领域技术人员也可以根据本发明第二方面方法合成本发明未具体列举的其它式I化合物。
本发明的式I化合物可以与其它活性成分组合使用,只要它不产生其他不利作用,例如过敏反应。
本发明式I所示的活性化合物可作为单独的抗癌药物使用,或者可以与一种或多种其他抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时、顺次或隔开给药来实现。
本文所用的术语“组合物”意指包括包含指定量的各指定成分的产品,以及直接或间接从指定量的各指定成分的组合产生的任何产品。
本发明的化合物可以以衍生自无机酸或有机酸的药学上可接受的盐的形式使用。词语“药学上可接受的盐”指在可靠的医学判断范围内,适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等,且与合理的效果/风险比相称的盐。药学上可接受的盐是本领域公知的。例如,S.M.Berge,etal.,J.PharmaceuticalSciences,1977,66:1中对药学上可接受的盐进行了详细描述。所述盐可通过使本发明化合物的游离碱官能团与合适的有机酸反应,在本发明化合物的最终分离和纯化过程中原位制备或者单独制备。代表性的酸加成盐包括但不限于乙酸盐、己二酸盐、海藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硫酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(异硫代硫酸盐,isothionate)、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、苹果酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一烷酸盐。同样,碱性含氮基团可用以下物质季铵化:低级烷基卤化物如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;硫酸二烷基酯如硫酸二甲酯、二乙酯、二丁酯和二戊酯;长链卤化物如癸基、十二烷基、十四烷基和十八烷基的氯化物、溴化物和碘化物;芳基烷基卤化物如苄基溴和苯乙基溴及其他。
本发明式I所示化合物还包括其异构体、消旋体、对映体、非对映体、对映体富集物、溶剂合物、和酯。上述化合物还可以是前药或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。一般来说,对于本发明的目的,与药学可接受的溶剂如水、乙醇等的溶剂合物形式与非溶剂合物形式相当。
可改变本发明药物组合物中各活性成分的实际剂量水平,以便所得的活性化合物量能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据具体化合物的活性、给药途径、所治疗病况的严重程度以及患者的病况和既往病史来选定。但是,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。
当用于上述治疗和/或预防或其他治疗和/或预防时,治疗和/或预防有效量的一种本发明化合物可以以纯形式应用,或者以药学可接受的酯或前药形式(在存在这些形式的情况下)应用。或者,所述化合物可以以含有该目的化合物与一种或多种药物可接受赋形剂的药物组合物给药。“治疗和/或预防有效量的本发明化合物”指以适用于任何医学治疗和/或预防的合理效果/风险比治疗障碍的足够量的化合物。但应认识到,本发明化合物和组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的障碍和该障碍的严重程度;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体化合物的给药时间、给药途径和排泄率;治疗持续时间;与所采用的具体化合物组合使用或同时使用的药物;及医疗领域公知的类似因素。例如,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。一般说来,本发明式I化合物用于哺乳动物特别是人的剂量可以介于0.001~1000mg/kg体重/天,例如介于0.01~100mg/kg体重/天,例如介于0.01~10mg/kg体重/天。
运用本领域技术人员熟悉的药物载体可以制备成含有效剂量的本发明化合物的药物组合物。因此本发明还提供包含与一种或多种无毒药物可接受载体配制在一起的本发明化合物的药物组合物。所述药物组合物可特别专门配制成以固体或液体形式供口服给药、供胃肠外注射或供直肠给药。
所述的药物组合物可配制成许多剂型,便于给药,例如,口服制剂(如片剂、胶囊剂、溶液或混悬液);可注射的制剂(如可注射的溶液或混悬液,或者是可注射的干燥粉末,在注射前加入注射水可立即使用)。所述的药物组合物中载体包括:口服制剂使用的粘合剂(如淀粉,通常是玉米、小麦或米淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮),稀释剂(如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素,和/或甘油),润滑剂(如二氧化硅、滑石、硬脂酸或其盐,通常是硬脂酸镁或硬脂酸钙,和/或聚乙二醇),以及如果需要,还含有崩解剂,如淀粉、琼脂、海藻酸或其盐,通常是藻酸钠,和/或泡腾混合物,助溶剂、稳定剂、悬浮剂、无色素、矫味剂等,可注射的制剂使用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可以将其配制成肠衣片剂。
更具体地说,本发明的药物组合物可通过口服、直肠、胃肠外、阴道内、腹膜内、局部(如通过散剂、软膏剂或滴剂)、口颊给予人类和其他哺乳动物,或者作为口腔喷雾剂或鼻腔喷雾剂给予。本文所用术语“胃肠外”指包括静脉内、肌肉内、腹膜内、胸骨内、皮下和关节内注射和输液的给药方式。
适合于胃肠外注射的组合物可包括生理上可接受的无菌含水或非水溶液剂、分散剂、混悬剂或乳剂,及供重构成无菌可注射溶液剂或分散剂的无菌散剂。合适的含水或非水载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、植物油(如橄榄油)、可注射有机酯如油酸乙酯及它们的合适混合物。
这些组合物也可含有辅料,如防腐剂、湿润剂、乳化剂和分散剂。通过各种抗细菌剂和抗真菌剂,例如尼泊金酯类、三氯叔丁醇、苯酚、山梨酸等,可确保防止微生物的作用。还期望包括等渗剂,例如糖类、氯化钠等。通过使用能延迟吸收的物质,例如单硬脂酸铝和明胶,可达到可注射药物形式的延长吸收。
混悬剂中除活性化合物外还可含有悬浮剂,例如乙氧基化异十八醇、聚氧乙烯山梨醇和聚氧乙烯失水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶或者这些物质的混合物等。
在一些情况下,为延长药物的作用,期望减慢皮下或肌内注射药物的吸收。这可通过使用水溶性差的晶体或无定形物质的液体混悬剂来实现。这样,药物的吸收速度取决于其溶解速度,而溶解速度又可取决于晶体大小和晶型。或者,胃肠外给药的药物形式的延迟吸收通过将该药物溶解于或悬浮于油媒介物中来实现。
可注射贮库制剂形式可通过在生物可降解聚合物如聚丙交酯-聚乙交酯(polylactide-polyglycolide)中形成药物的微胶囊基质来制备。可根据药物与聚合物之比和所采用的具体聚合物的性质,对药物释放速度加以控制。其他生物可降解聚合物的实例包括聚原酸酯类(poly(orthoesters))和聚酐类(poly(anhydrides))。可注射贮库制剂也可通过将药物包埋于能与身体组织相容的脂质体或微乳中来制备。
可注射制剂可通过用滤菌器过滤或通过掺入无菌固体组合物形式的灭菌剂来灭菌,所述固体组合物可在临用前溶解或分散于无菌水或其他无菌可注射介质中。
本发明化合物或其组合物可用口服方法或非胃肠道给药方式。口服给药可以是片剂、胶囊剂、包衣剂,肠道外用药制剂有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟悉的方法制备的。为了制造片剂、胶囊剂、包衣剂所用的辅料是常规用的辅料,例如淀粉、明胶、阿拉伯胶,硅石,聚乙二醇,液体剂型所用的溶剂如水、乙醇、丙二醇、植物油(如玉米油、花生油、橄榄油等)。含有本发明化合物的制剂中还有其它辅料,例如表面活性剂,润滑剂,崩解剂,防腐剂,矫味剂和色素等。在片剂、胶囊剂、包衣剂、注射剂和栓剂中含有本发明式I化合物的剂量是以单元剂型中存在的化合物量计算的。在单元剂型中本发明式I化合物一般含量为1-5000mg,优选的单元剂型含有10-500mg,更优选的单元剂型含有20-300mg。具体地说,本发明可以提供的供口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在此类固体剂型中,活性化合物可与至少一种惰性的药物可接受赋形剂或载体如柠檬酸钠或磷酸二钙和/或以下物质混合:a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸;b)粘合剂如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯树胶;c)保湿剂如甘油;d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶液阻滞剂如石蜡;f)吸收加速剂如季铵化合物;g)湿润剂如鲸蜡醇和甘油单硬脂酸酯;h)吸附剂如高岭土和膨润土以及i)润滑剂如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠和它们的混合物。在胶囊剂、片剂和丸剂的情况下,所述剂型中也可包含缓冲剂。
相似类型的固体组合物使用赋形剂例如乳糖及高分子量聚乙二醇等,也可用作软胶囊和硬胶囊中的填充物。
片剂、糖衣丸剂(dragees)、胶囊剂、丸剂和颗粒剂的固体剂型可与包衣和壳料如肠溶衣材和医药制剂领域公知的其他衣材一起制备。这些固体剂型可任选含有遮光剂,且其组成还可使其只是或优先地在肠道的某个部位任选以延迟方式释放活性成分。可以使用的包埋组合物的实例包括高分子物质和蜡类。如果适合,活性化合物也可与一种或多种上述赋形剂配成微囊形式。
供口服给药的液体剂型包括药学可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂。液体剂型除含有活性化合物外还可含有本领域常用的惰性稀释剂,例如水或其他溶剂,增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇(tetrahydrofurfurylalcohol)、聚乙二醇和脱水山梨糖醇的脂肪酸酯及它们的混合物。口服组合物除包含惰性稀释剂外还可包含辅料,例如湿润剂、乳化剂和悬浮剂、甜味剂、矫味剂和香味剂。
供直肠或阴道给药的组合物优选是栓剂。栓剂可通过将本发明化合物与合适的非刺激性赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合来制备,它们在室温下为固体,但在体温下则为液体,因此可在直肠腔或阴道腔内熔化而释放出活性化合物。
本发明的化合物及其组合物还考虑用于局部给药。供局部给予本发明化合物的剂量形式包括散剂、喷雾剂、软膏剂和吸入剂。在无菌条件下将活性化合物与药学可接受的载体和任何所需的防腐剂、缓冲剂或推进剂混合。眼用制剂、眼软膏剂、散剂和溶液剂也被考虑在本发明范围内。
本发明化合物也可以脂质体形式给药。如本领域所公知,脂质体通常用磷脂或其他脂类物质制得。脂质体由分散于含水介质中的单层或多层水化液晶所形成。任何能够形成脂质体的无毒、生理上可接受和可代谢的脂质均可使用。脂质体形式的本发明组合物除含有本发明化合物外,还可含有稳定剂、防腐剂、赋形剂等。优选的脂类是天然和合成的磷脂和磷脂酰胆碱(卵磷脂)。
本发明人还惊奇地发现,式I所示的部分ω-羧基取代的二苯基硫脲衍生物在大鼠动脉环的试验和细胞毒性试验中证实具有较好的抑制血管新生和较低的细胞毒性。从裸鼠移植瘤试验中也发现这些化合物具有较好的体内活性,且部分化合物对肿瘤的抑制作用与阳性对照sorafeinib相当或优于阳性对照。此外,根据动物的死亡率分析,部分活性较好的化合物显示出比阳性对照sorafeinib更小的毒性。具体地说,本发明的化合物可用于预防或治疗VEGFR或PDGFR等酪氨酸激酶敏感癌症,如VEGFR、PDGFR高表达及VEGF驱动的肿瘤,包括实体肿瘤如胆管、骨、膀胱、脑/中枢神经系统、乳房、结直肠、子宫内膜、胃、头和颈、肝、肺、神经元、食道、卵巢、胰腺、前列腺、肾脏、皮肤、睾丸、甲状腺、子宫和外阴等的癌症,和非实体肿瘤如白血病、多发性骨髓瘤或淋巴瘤等。
具体实施方式
为进一步说明本发明,结合以下实施例具体说明:
下面通过具体的制备实施例和生物学试验例进一步说明本发明,但是,应当理解为,这些实施例和试验例仅仅是用于更详细具体地说明之用,而不应理解为用于以任何形式限制本发明。
本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的,但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚,在下文中,如果未特别说明,本发明所用材料和操作方法是本领域公知的。
在本发明中,除非另外说明,其中:(i)温度以摄氏度(℃)表示,操作在室温或环境温度下进行,所述室温是指15-25℃;(ii)有机溶剂用无水硫酸钠或无水硫酸镁干燥,溶剂的去除使用旋转蒸发仪减压蒸馏,浴温不高于70℃;(iii)反应过程用薄层色谱(TLC)跟踪;(iv)终产物具有满意的氢核磁共振谱(1H-NMR)和质谱(MS)数据。
实施例1
4-{4-[3-[4-氯苯基]硫脲基]-苯硫基}-N-苄基吡啶-2-甲酰胺(JY-Z01);
1).4-氯苯异硫氰酸酯的合成:
在100ml三口烧瓶中加入4-氯苯胺(5g,0.039mol)、三乙烯二胺(13.18g,0.117mol)和40ml甲苯,室温搅拌溶解。然后30min内滴加二硫化碳(9.0g,0.118mol),滴完后于15-25℃保温反应12h.反应结束后,抽滤,滤饼用15ml甲苯淋洗一次,烘干,得到淡黄色粉末状4-氯苯胺基二硫代甲酸盐。将所得的4-氯苯胺基二硫代甲酸盐悬浮于50mL氯仿中,开动搅拌,冷却至0℃。慢慢滴加溶有BTC(6.0g,0.021mol)的50ml氯仿,滴完后,冰浴(0-2℃)反应1.5h,然后室温(25-30℃)反应2h,升温至回流,保温1.5-2h。反应结束后,冷却至室温,抽滤除去不溶物,滤液减压蒸馏,先回收溶剂,然后得到4-氯苯基异硫氰酸酯粗品。经柱层析(硅胶G,纯石油醚洗脱)纯化,得到淡黄色针状晶体5.64g,熔点43-45℃,含量:99.7%(GC),收率:85.2%。
2).N-苄基-4-氯-2-吡啶甲酰胺的合成:
将50ml氯化亚砜加入150ml的反应瓶中,在不断搅拌下慢慢加入2-吡啶甲酸(15g,0.122mol),升温回流反应10h。降至室温,减压回收未反应的氯化亚砜,然后加入80ml甲苯,减压蒸馏回收甲苯,得到棕黄色油状物。加入40ml甲醇,在25-30℃保温反应2h,抽滤,中和,干燥,得到浅黄色4-氯-2-吡啶甲酸甲酯固体16.4g,收率78.5%,mp:52-54℃,含量98.8%(HPLC)。
将4-氯-2-吡啶甲酸甲酯(6g,0.035mol)溶于20ml甲醇中,搅拌下形成浅黄色悬浊液。在室温(15-25℃)下滴加苄胺的THF溶液(11.24g,0.105mol),滴加完毕,在室温下反应8h。减压回收溶剂,残余物加入150ml乙酸乙酯,搅拌均匀后过滤,滤液用饱和食盐水洗涤、无水硫酸钠干燥,减压浓缩、结晶、过滤、洗涤、干燥,得到浅黄色固体7.36g,收率85.3%,mp:78-82℃,含量97.8%(HPLC)。
3).4-(2-(N-苄基氨基甲酰基)-4-吡啶硫基)苯胺的合成:
将4-氨基苯硫酚(2.03g,0.016mol)加入DMF(40ml)中,接着加入叔丁醇钾(5.15g,0.045mol),室温搅拌2h,后加入K2CO3(1.35g,9.8mmol),然后加入N-苄基-4-氯-2-吡啶甲酰胺(4g,0.016mol),升温至70-75℃,保温反应10h。将反应混合物降至室温,加入150ml乙酸乙酯和150ml的饱和食盐水,水相用乙酸乙酯150ml提取三次,合并有机相,用饱和食盐水洗涤3次,无水硫酸钠干燥,减压浓缩至干,真空干燥,得到浅棕色固体,乙醇重结晶,得到浅黄色固体3.62g,收率67.5%,mp:122-124℃,含量98.6%(HPLC)。4)4-{4-[3-[4-氯苯基]硫脲基]-苯硫基}-N-苄基吡啶-2-甲酰胺的合成:
将4-(2-(N-苄基氨基甲酰基)-4-吡啶硫基)苯胺(1.3g,3.88mmol)加入100ml三口反应瓶中,加CH2Cl210ml搅拌溶解,冰浴降温至0℃,缓慢滴加4-氯苯异硫氰酸酯(0.66g,3.88mmol)的CH2Cl2溶液10ml,0℃反应约2h,撤去冰浴后室温反应约20h。然后向反应体系加入石油醚约60ml,搅拌,抽滤,洗涤,干燥,得淡黄色粉末状固体1.49g,收率75.8%,HPLC测含量98.2%,mp:100-104℃。1H-NMR(600MHz,DMSO-d6)4.436(d,J=6.6Hz,2H,-CH2Ph),7.226(dd,J=6.0,2.4Hz,1H,pyridine),7.280-7.309(m,5H,aryl),7.408(d,J=9.0Hz,2H,aryl),7.538(d,J=8.4Hz,2H,aryl),7.575-7.596(m,3H),,7.746(d,J=9.0Hz,2H,aryl),8.442(d,J=6.0Hz,1H,pyridine),9.330(t,J=6.6Hz,1H,-CONH),10.191(s,1H,-NHCS-),10.247(s,1H,-NHCS-),ESI-MSm/z505.2((M+H)+);
实施例2
4-{4-[3-[3-三氟甲基苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷(JY-Z02)1).3-三氟甲基苯异硫氰酸酯的合成:
在100ml三口烧瓶中加入3-三氟甲基苯胺(6.5g,0.04mol)、三乙烯二胺(13.4g,0.12mol)和40ml甲苯,室温搅拌溶解。然后1h内滴加二硫化碳(7.5ml,0.12mol),滴完后于25-30℃保温反应10h,反应结束后,抽滤,滤饼用10ml甲苯淋洗,烘干,得到粉末状3-三氟甲基苯胺基二硫代甲酸盐。将所得的3-三氟甲基苯胺基二硫代甲酸盐悬浮于70mL氯仿中,开动搅拌冷至0℃。慢慢滴加溶有BTC(4.8g,16.2mmol)的20ml氯仿,滴完后,冰浴(0-2℃)反应1h,然后室温反应1h,后加热至回流,保温1.5-2h。反应结束后,冷却至室温,抽滤除去不溶物,滤液减压蒸馏,回收溶剂,残余物经减压分馏得到淡黄色透明液体6.05g,含量98.64%(GC),收率:74.4%。
2)4-氯-吡啶-2-甲酰基-N-吡咯烷的合成:
4-氯-2-吡啶甲酸甲酯的合成实施例1。得到浅黄色固体16.4g,收率78.5%,mp:52-54℃,含量98.8%(HPLC)。
将4-氯-2-吡啶甲酸甲酯(10g,58.3mmol)加入到20ml甲醇中,搅拌下形成浅黄色悬浊液。在0℃下滴加四氢吡咯的THF溶液(12.0g,0.17mol),滴加完毕,在室温下反应4h。反应结束后减压蒸除溶剂,残余物加入100ml乙酸乙酯,搅拌均匀后过滤,滤液用饱和食盐水洗涤、无水硫酸钠干燥,减压蒸出溶剂,得到4-氯-吡啶-2-甲酰基-N-吡咯烷的浅黄色油状液体10.7g,收率87.1%,含量98.2%。
3).4-(2-(N-吡咯烷基甲酰基)-4-吡啶硫基)苯胺的合成:
将4-氨基苯硫酚(3.21g,25.7mmol)加入DMF(40ml)中,加入叔丁醇钾(2.88g,25.7mmol),搅拌1.5h,加入K2CO3(2.2g,15.9mmol),加入4-氯-吡啶-2-甲酰基-N-吡咯烷(5.4g,25.7mmol)的DMF溶液20ml,升温至70-75℃,保温反应12h。将反应混合物降至室温,加入150ml乙酸乙酯和150ml的饱和食盐水,水相用乙酸乙酯150ml提取三次,合并有机相,用饱和食盐水洗涤3次,无水硫酸钠干燥,减压浓缩至干,真空干燥,得到黄色固体4-(2-(N-吡咯烷基甲酰基)-4-吡啶硫基)苯胺6.19g,收率80.4%,mp:171-173℃,含量98.1%(HPLC)。
4).4-{4-[3-[3-三氟甲基苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷(JY-Z02):
将4-(2-(N-吡咯烷基甲酰基)-4-吡啶硫基)苯胺(1.2g,4.01mmol)加入100ml三口反应瓶中,加CH2Cl220ml搅拌溶解,冰浴降温至0-5℃,缓慢滴加入3-三氟甲基苯异硫氰酸酯(0.82g,4.01mmol)的CH2Cl2溶液10ml,0-5℃以下反应约1.5h,撤去冰浴后室温(15-25℃)反应约12h,然后在30-32℃恒温反应16h,向反应体系加入石油醚约60ml,搅拌,抽滤,洗涤,干燥得淡黄色粉末状固体1.47g,收率72.7%,HPLC测含量97.8%,mp:178-180℃。1H-NMR(600MHz,DMSO-d6)1.808(t,J=6.6Hz,4H,CH2CH2),3.439(t,J=6.6Hz,2H,CH2),3.550(t,J=6.6Hz,2H,CH2),7.147(dd,J=5.4,1.8Hz,1H,pyridine),7.246(d,J=1.8Hz,1H,pyridine),7.492(d,J=7.8Hz,1H,aryl),7.571-7.609(m,3H,aryl),7.725(d,J=8.4Hz,2H,aryl),7.779(d,J=7.8Hz,1H,aryl),7.961(s,1H,aryl),8.398(d,J=5.4Hz,1H,pyridine),10.267(s,1H,-NHCS-),10.328(s,1H,-NHCS-).ESI-MSm/z503.0((M+H)+)
实施例3:
4-{4-[3-[3-三氟甲基苯基]硫脲基]-苯硫基}-N-苄基吡啶-2-甲酰胺(JY-Z03)
1).3-三氟甲基苯异硫氰酸酯的合成
合成方法同实施例2
2).N-苄基-4-氯-2-吡啶甲酰胺的合成
合成方法同实施例1
3).4-(2-(N-苄基氨基甲酰基)-4-吡啶硫基)苯胺的合成
合成方法同实施例1
4)4-{4-[3-[3-三氟甲基苯基]硫脲基]-苯硫基}-N-苄基吡啶-2-甲酰胺(JY-Z03)的合成
将4-(2-(N-苄基氨基甲酰基)-4-吡啶硫基)苯胺(1.3g,3.88mmol)加入100ml三口反应瓶中,加CH2Cl210ml搅拌溶解,冰浴降温至0℃,缓慢滴加3-三氟甲基苯异硫氰酸酯(0.79g,3.88mmol)的CH2Cl2溶液10ml,0℃反应约2h,撤去冰浴后室温反应约18h。然后向反应体系加入石油醚约60ml,搅拌,抽滤,洗涤,干燥,得淡灰色粉末状固体1.59g,收率76.3%,HPLC测含量98.1%,mp:117-120℃。1H-NMR(DMSO-d6)4.437(d,J=6.0Hz,2H,-CH2Ph),7.225(dd,J=6.0,2.4Hz,1H,pyridine),7.277-7.309(m,5H,aryl),7.492(d,J=7.8Hz,1H,aryl),7.573-7.606(m,4H),7.735(d,J=9.0Hz,2H,aryl),7.775(d,J=7.8Hz,1H,aryl),7.962(s,1H,aryl),8.446(d,J=5.4Hz,1H,pyridine),9.332(t,J=6.6Hz,1H,-CONH),10.270(s,1H,-NHCS-),10.325(s,1H,-NHCS-).ESI-MSm/z539.3((M+H)+)
与实施例1类似的方法可以得到以下化合物
生物学实验
材料
细胞株:人乳腺癌细胞株MDA-MB-231、人结肠癌细胞株HCT-116,均购自中国科学院典型培养物保藏委员会细胞库。仪器:CO2培养箱(Forma3110,USA),超净工作台(BCN-1360,哈尔滨东联),酶标仪(BioRad550,USA),倒置显微镜(Nikon),细胞培养瓶(Costar,USA),96孔细胞培养板(Costar,USA)。
软件:MicrosoftExcel7.0统计分析软件;MicrocalOrigin6.0数据处理软件。方法
药物及试剂配制:RPMI1640培养基一袋加水一升,补加2克碳酸氢钠,10万单位青霉素和100mg链霉素,调节pH值至7.4,用0.22μm除菌滤膜过滤除菌。90ml培养基加灭活新生牛血清10ml即为完全培养液。胰蛋白酶用D-hanks缓冲液配成0.25%溶液,过滤除菌后4℃保存备用。
准确称取二苯硫脲衍生物100mg,加到灭菌的1.5ml离心管中,加入DMSO1ml,配成100mg/ml原液,-20℃冷冻保存。临用前融化后取适量以完全培养液稀释成相应浓度备用。
细胞培养及传代:所有细胞均贴壁培养于含10ml完全培养液细胞培养瓶中,于37℃、5%CO2、饱合湿度下培养。细胞长满瓶底后用灭菌D-hanks液洗两次,加0.25%胰蛋白酶消化细胞2min,倒掉胰蛋白酶,待轻摇细胞能完全脱落后,加完全培养液30ml后,用移液管吹散细胞,分装于3个新的细胞培养瓶中,继续培养。
药物处理:取刚刚长满的细胞一瓶,胰蛋白酶消化后收集细胞,用移液管吹打均匀,取两滴细胞悬液台盼蓝染色,于显微镜下计数活细胞数目,用完全培养液调整细胞数目至1×105个细胞/ml。于96孔细胞培养板中每孔加入100μl细胞悬液,将培养板置于CO2培养箱中培养12h,取出培养板后于每孔中补加100μl含不同浓度二苯硫脲衍生物的完全培养液,药物终浓度分别为4×10-6,2×10-5,1×10-4mol/L,实验重复3次,每次实验3个副孔进行初筛。复筛时以初筛结果为基础,选取药物终浓度分别为4×10-6,2×10-5,1×10-4mol/L,实验重复3次,每次实验3个副孔进行复筛。另设3孔细胞加入不含药完全培养液作阴性对照孔,3孔细胞加入含索拉菲尼的完全培养液作阳性对照,索拉菲尼终浓度为10-4mol/L。
加完药后培养板于微孔板振荡器上振荡混匀,置于CO2培养箱中继续培养48h。取出培养板,不除去培养液,每孔加入50%(质量/体积)的三氯乙酸(TCA)50μl固定细胞。TCA的终浓度为10%,轻轻地加在每孔液面上,静置5min后在4℃冰箱中放置1小时,培养板各孔用去离子水冲洗沉淀5遍,以去除TCA。甩干,空气干燥至无湿迹。每孔加入4mg/mlSRB100μl,室温放置15min,弃去各孔内液体后用1%乙酸冲洗5次,空气中干燥后加入150μl/孔的Tris溶液,酶标仪540nm波长测定吸光度值。
根据各孔OD值计算药物对细胞增殖的抑制率:
抑制率=[(A540对照孔-A540给药孔)/A540对照孔]×100%;实验重复3次,根据各浓度抑制率用Graphpad软件计算半数抑制浓度IC50。
实验数据采用SAS9.0anova过程进行分析,结果以平均值±标准差表示。P<0.05被认为有统计学意义。
结论及分析:
下表为部分样品对体外不同肿瘤细胞的半数抑制浓度IC50(对照品为sorafenib)
hct116 | MDA-MB-231 | |
IC50(uM) | IC50(uM) | |
JY-Z01 | >100 | >100 |
JY-Z02 | 29.5±2.1 | >100 |
JY-Z03 | 91.5±2.9 | >100 |
JY-Z04 | >100 | >100 |
JY-Z05 | 29.25±2.5 | >100 |
JY-Z06 | 5.95±0.6 | 85±3.2 |
JY-Z07 | 24.58±0.8 | >100 |
JY-Z08 | 24.75±1.7 | 79.28±0.59 |
JY-Z09 | 8.85±1.0 | >100 |
JY-Z10 | 3.27±0.3 | 93.26±0.33 |
JY-Z11 | 2.1±0.7 | 88.75±0.36 |
JY-Z12 | 3.1±0.2 | >100 |
JY-Z13 | 15.8±1.7 | 98.73±0.66 |
JY-Z14 | 50.5±3.5 | >100 |
JY-Z15 | 22.0±2.8 | 52.8±3.2 |
JY-Z16 | 38.5±3.5 | >100 |
JY-Z17 | 8.85±0.2 | 46±2.1 |
JY-Z18 | 34.5±2.1 | 23.84±0.25 |
JY-Z19 | >100 | >100 |
JY-Z20 | 88.05±0.83 | >100 |
sorafenib | 7.75±1.05 | 11.66±0.86 |
结论
从上述体外试验结果可以看出,本发明所述通式(I)的二苯硫脲类化合物对人乳腺癌细胞株MDA-MB-231、人结肠癌细胞株HCT-116具有一定的抑制作用。
以上所述的实施例仅仅是对本发明的优选实施方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通工程技术人员对本发明的技术方案作出的各种变形和改进,均应落入本发明的权利要求书确定的保护范围内。
Claims (2)
1.一类ω-羧基取代的二苯基硫脲衍生物在制备治疗人乳腺癌、人结肠癌的药物中的应用,其特征在于:所述二苯基硫脲衍生物选自下列的化合物:
4-{4-[3-[3-三氟甲基苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷;
4-{4-[3-[3-三氟甲基苯基]硫脲基]-苯硫基}-N-苄基吡啶-2-甲酰胺;
4-{4-[3-(4-氟苯基)硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷;
4-{4-[3-[3-(三氟甲基)-4-氯苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷;
4-{4-[3-[4-氯苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷;
4-{4-[3-[3,4-二氟苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷;
4-{4-[3-(4-三氟甲氧基苯基)硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷;
4-{4-[3-(3-三氟甲基苯基)硫脲基]-苯硫基}-N-环己基吡啶-2-甲酰胺;
4-{4-[3-(3-三氟甲基-4-氯苯基)硫脲基]-苯硫基}-N-环己基吡啶-2-甲酰胺;
4-{4-[3-(3,4-二氟苯基)硫脲基]-苯硫基}-N-环己基吡啶-2-甲酰胺;
4-{4-[3-(4-氯苯基)硫脲基]-苯硫基}-N-环己基吡啶-2-甲酰胺;
4-{4-[3-(3-三氟甲基苯基)硫脲基]-苯硫基}-N-环丙基吡啶-2-甲酰胺;
4-{4-[3-(3-三氟甲基-4-氯苯基)硫脲基]-苯硫基}-N-环丙基吡啶-2-甲酰胺;
4-{4-[3-(3,4-二氟苯基)硫脲基]-苯硫基}-N-环丙基吡啶-2-甲酰胺;
4-{4-[3-(3-三氟甲基-4-氯苯基)硫脲基]-苯硫基}-N-乙基吡啶-2-甲酰胺;
4-{4-[3-[3,4-二氟苯基]硫脲基]-苯硫基}-N-乙基吡啶-2-甲酰胺;
4-{4-[3-[4-甲氧苯基]硫脲基]-苯硫基}-吡啶-2-甲酰基-N-吡咯烷。
2.一种药物组合物,其包含权利要求1所述的二苯基硫脲类衍生物、其药学上可接受的盐,以及药学上可接受的载体和/或辅料。
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