CN101863901A - 2-(取代苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-取代-乙酰胺、其制备方法和用途 - Google Patents
2-(取代苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-取代-乙酰胺、其制备方法和用途 Download PDFInfo
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- CN101863901A CN101863901A CN 201010212474 CN201010212474A CN101863901A CN 101863901 A CN101863901 A CN 101863901A CN 201010212474 CN201010212474 CN 201010212474 CN 201010212474 A CN201010212474 A CN 201010212474A CN 101863901 A CN101863901 A CN 101863901A
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- pyridines
- tetramethylene sulfide
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Abstract
本发明属于抗恶性肿瘤药物技术领域,提供具有通式I结构的2-(取代苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-取代-乙酰胺及其药学上可接受的盐,其中R为氢,C1-C3直链或支链烷基;R1,R2为氢,C1-C3直链或支链烷基,卤素,卤代甲基,C1-C3烷氧基。本发明还涉及上述化合物的制备方法,并同时公开了以该化合物或其药学上可接受的盐作为活性有效成分的药物组合物,以及它们在作为抗恶性肿瘤药物方面的应用。
Description
技术领域
本发明属于医药技术领域,更确切地说,是涉及一类具有抗恶性肿瘤作用的2-(取代苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-取代-乙酰胺及其制备方法。
背景技术
癌症是人类健康的最主要杀手之一,其死亡率在我国居前位,在世界排第二位。据世界卫生组织统计,2007年全球癌症死亡人数达790万(约占所有死亡人数的13%),肺癌、胃癌、肝癌、结肠癌和乳癌是每年大多数癌症死亡的罪魁祸首。近年来,由于城市空气污染、体重超重或肥胖、酒精烟草的滥用等癌症危险因素日趋严重,导致癌症的发病率逐年上升。在发展中国家,随着传染病死亡和儿童死亡率的降低,更多人民寿命的延长,癌症的负担也随之增加。药物治疗是癌症的主要治疗手段之一,抗癌药物的寻找一直是科学家们研究的热门领域。目前临床上用于抗癌的药物有数百种,有效地延长了癌症患者的生命或提高了癌症患者的生存质量,但大多数药物为细胞毒药物,选择性不高,在消灭肿瘤细胞的同时对正常细胞也有严重损伤,引起强烈的毒副反应,并且存在耐药性问题。另外,现有化学药物对多数实体瘤的治疗效果并不理想。因此,寻找新型抗癌药物任重而道远。
发明内容
本发明的一个目的在于,公开了一类2-(取代苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-取代-乙酰胺化合物及其药用盐。
本发明的另一个目的在于,公开了以一类2-(取代苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-取代-乙酰胺化合物及其药用盐为主要活性成分的药物组合物。
本发明的再一个目的在于,公开了一类2-(取代苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-取代-乙酰胺化合物及其药用盐的制备方法。
本发明还有一个目的在于,公开了一类2-(取代苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-取代-乙酰胺化合物及其药用盐,作为抗恶性肿瘤药物方面的应用,特别是在用于制备治疗肺癌、乳腺癌、肝癌、胃癌药物方面的用途。
本发明具体涉及通式I结构的化合物及其药学上可接受的盐:
其中:
R为氢,C1-C3直链或支链烷基;
R1,R2为氢,C1-C3直链或支链烷基,卤素,卤代甲基,C1-C3烷氧基。
本发明所述的C1-C3直链或支链烷基具体代表甲基,乙基,丙基,异丙基;卤素代表氟,氯;卤代甲基代表三氟甲基;C1-C3烷氧基代表甲氧基,乙氧基,丙氧基,异丙氧基,等。
本发明涉及的具有式I结构的化合物,其中部分化合物为:
I-12-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-甲氧基乙酰胺;
I-22-(2-氟-4-甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-乙氧基乙酰胺;
I-32-(2,3-二氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-羟基乙酰胺;
I-42-苯基-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-甲氧基乙酰胺;
I-52-(3-三氟甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-乙氧基乙酰胺;
I-62-(4-甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-羟基乙酰胺;
I-72-(4-甲氧基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-甲氧基乙酰胺;
I-82-(2-氟-6-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-乙氧基乙酰胺。
本发明中的具有式I结构的化合物或其药学上可接受的盐系指:本发明化合物与无机酸、有机酸所成的盐。其中特别优选的盐是:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、丙酸盐、丁酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、马来酸盐、苯甲酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、富马酸盐、牛磺酸盐、葡萄糖酸盐、氨基酸盐,等等。
式I化合物的制备路线:
化合物(1)与烷氧基胺(2)在脂肪醇中,在碳酸钾/乙酸胺存在下,25℃~80℃反应制得I。其中脂肪醇为甲醇、乙醇、丙醇、异丙醇、丁醇等,反应时间30min~10h,以薄层层析法(TLC)检测反应终点。
将反应制得各种中间体或所得产物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种,滴加无机酸或有机酸的溶液,制成药学上可接受的盐。
具体是将各种化合物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种,于冰水浴下滴加盐酸乙醚溶液至pH=2,制成盐酸盐;或将各种化合物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种,加入等摩尔酒石酸,加热搅拌得其酒石酸盐;抑或将各种化合物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种,于冰水浴下滴加浓硫酸溶液至pH=3,制成硫酸盐,等等。
此类化合物对于治疗人类恶性肿瘤是有效的。尽管本发明的化合物可以不经任何配制直接给药,但所述的各种化合物优选以药物制剂的形式使用,给药途径可以是非肠道途径(如静脉、肌肉给药)及口服给药。
本发明化合物的药物组合物制备如下:使用标准和常规的技术,使本发明化合物与制剂学上可接受的固体或液体载体结合,以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成微粒或微球。固体剂型包括片剂、分散颗粒、胶囊、缓释片、缓释微丸等等。固体载体可以是至少一种物质,其可以充当稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、粘合剂、崩解剂以及包裹剂。惰性固体载体包括磷酸镁、硬脂酸镁、滑粉糖、乳糖、果胶、丙二醇、聚山梨酯80、糊精、淀粉、明胶、纤维素类物质例如甲基纤维素、微晶纤维素、低熔点石蜡、聚乙二醇、甘露醇、可可脂等。液体剂型包括溶剂、悬浮液例如注射剂、粉剂等等。
药物组合物以及单元剂型中含有的活性成份(本发明化合物)的量可以根据患者的病情、医生诊断的情况特定地加以应用,所用的化合物的量或浓度在一个较宽的范围内调节。通常,活性化合物的量范围为组合物的0.5%~90%(重量),另一优选的范围为0.5%~70%。
本发明的具有式I结构的化合物或其药学上可接受的盐,在体外、体内对肿瘤有明显的抑制作用。
体外的抗肿瘤作用
(1)实验方法:
采用经典的细胞毒活性体外检测法MTT法,检测发明化合物对体外培养的人肿瘤细胞的细胞增殖毒性。
(2)实验材料:
实验样品:发明化合物(由发明人自制提供)。实验时样品以DMSO助溶,无血清DMEM培养基稀释到所需浓度,部分样品溶液呈悬浮状。
主要试剂:MTT,Amresco公司分装,批号:04M0904。完全DMEM培养基,Gibco公司产品,批号:1290007。小牛血清,兰州民海生物,批号:20060509。胰蛋白酶,Amresco公司分装,批号:016B0604;氟尿嘧啶注射液,0.25g/10mL(支),批号:0512022,天津金耀氨基酸有限公司。
实验仪器:超净工作台,苏州净化设备厂;CO2培养箱,Thermo公司,型号:HERA Cell150;倒置显微镜,Carl Zeiss公司,型号:Axiovert 200;酶联免疫检测仪,TECAN公司,型号:Sunrise;离心机,Kerdro公司,型号:Heraeus。
细胞株:肺癌A-549细胞、肝癌SMMC-7721细胞、乳腺癌MCF-7细胞、胃腺癌SGC-7901细胞,均购自中国科学院上海细胞研究所。
(3)实验步骤:
细胞培养:肿瘤细胞接种在含10%小牛血清,100IU/mL青霉素G钠盐及100ug/mL硫酸链霉素的DMEM培养液中,置于37℃、100%相对湿度、含5%CO2的培养箱中,传代3次后备用。
MTT法测定:取对数生长期的细胞,经0.25%胰蛋白酶消化后(悬浮细胞无须消化),悬浮于含10%小牛血清的DMEM培养液中,用玻璃滴管轻轻吹打成单细胞悬液,显微镜下用血细胞记数板记数活细胞。96孔培养板每孔接种细胞悬液90μL(细胞浓度调整为6~10×104个/mL),在37℃、100%相对湿度、含5%C02、95%空气的培养箱培养24h后,每孔加10μL药液(终浓度设为:40μg/mL、20μg/mL、10μg/mL、5μg/mL和2.5μg/mL五个浓度)。另外,每个浓度设阴性对照(等浓度DMSO)及空白本底(不加细胞),各组均设6个复孔。再连续培养24h,然后每孔加入5mg/mL的MTT溶液10μL,继续培养4h后,仔细吸去上清液(悬浮细胞,需要先离心,再吸去上清)。每孔加入100μL DMSO,置微量振荡器震荡5min以使结晶完全溶解,酶标仪492nm单波长比色,测定0D值。以下述方法计算细胞生长抑制率作为评价指标。
抑制率(%)=[1-(实验组0D均值-空白组0D均值)/(对照组0均值-空白组0D均值)]×100%。根据细胞生长抑制率,以直线回归方法计算IC50值。
(4)实验结果见下表:
对体外培养的肿瘤细胞的IC50(μg/mL)
(5)结论:
根据上述体外试验结果,我们可以看出具有式I结构的化合物对上述4种人类肿瘤细胞具有较强的抑制作用。
体内的抗肿瘤作用
(1)实验材料:
样品:I-1由发明人自制提供。
细胞株:肝癌H22细胞,购自中国科学院上海细胞研究所。
仪器:PB303-N型千分之一电子天平,梅特勒-托利多公司生产。
动物:昆明种小鼠,SPF级,雌雄各半,体重18-22g,购于中国医学科学院放射医学研究所,合格证号:SCXK(津)2005-0001。
(2)实验方法:
取腹腔接种瘤株9天,肿瘤生长良好,腹部膨隆明显的荷瘤小鼠,无菌操作下吸取腹水,按1∶3生理盐水稀释配成癌细胞混悬液,于所有实验小鼠右前肢腋部皮下接种(0.2mL/鼠),所有操作在30min内完成。次日将接种瘤液小鼠按体重随机分组,即荷瘤对照组,I-1组(100mg/kg、50mg/kg)。各给药组均腹腔注射给药,每日一次,对照组给予同体积生理盐水。小鼠连续给药10天,末次给药24h后,脱颈椎处死,剥离肿瘤,称取瘤重,计算各组小鼠瘤重平均值及抑制率。
抑制率=[(对照组平均瘤重-实验组平均瘤重)/对照组平均瘤重]×100%
(3)结果:
(4)结论:
从上述动物体内试验结果可以看出,I-1对H22荷瘤小鼠的肿瘤生长具有一定的抑制作用。
具体实施方式
下面结合实施例对本发明做进一步地说明,实施例仅为解释性的,决不意味着它以任何方式限制本发明的范围。所述的化合物经高效液相色谱(HPLC),薄层色谱(TLC)进行检测。随后可以采用诸如红外光谱(IR),核磁共振谱(1H NMR,13C NMR),质谱(MS)等更进一步确证其结构。
参考实施例:
本发明所用的起始原料,参考文献US 5,036,156A1(Bouisset et al.)的方法合成,产物的结构经红外光谱,核磁共振氢谱,质谱,元素分析确证。
反应通式如下:
实施例1:2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-甲氧基乙酰胺(化合物I-1)
在反应瓶中加入1a 3.39g(0.011mol),无水乙醇50mL,碳酸钾3.04g(0.022mol),醋酸铵0.85g(0.011mol),加入甲氧胺盐酸盐1.25g(0.011mol),50℃下搅拌。3h后,过滤,然后减压蒸尽溶媒,蒸毕,向残余物中加入50mL蒸馏水和30mL二氯甲烷,充分搅拌,分出有机层,水层用3×30mL二氯甲烷提取,合并有机层,用无水硫酸钠充分干燥。减压蒸尽二氯甲烷,柱色谱分离,得白色固体2.8g(HPLC:99.1%),m.p.139.0℃~139.3℃。Rf=0.36[单点,展开剂:v(二氯甲烷)∶v(甲醇)=5∶1]。
实施例2:2-(2-氟-4-甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-乙氧基乙酰胺(化合物I-2)
参照实施例1的方法,用乙氧胺盐酸盐代替甲氧胺盐酸盐,与1b反应,得白色固体产物3.1g(HPLC:98.8%)。Rf=0.39[单点,展开剂:v(二氯甲烷)∶v(甲醇)=5∶1]。
实施例3:2-(2,3-二氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-羟基乙酰胺(化合物I-3)
在反应瓶中加入1c 3.76g(0.011mol),无水甲醇40mL,碳酸钾3.04g(0.022mol),醋酸铵0.85g(0.011mol),加入盐酸羟胺0.36g(0.011mol),65℃下搅拌。2h后,过滤,然后减压蒸尽溶媒,蒸毕,向残余物中加入50mL蒸馏水和30mL三氯甲烷,充分搅拌,分出有机层,水层用3×30mL三氯甲烷提取,合并有机层,用无水硫酸钠充分干燥。减压蒸尽三氯甲烷,柱色谱分离,得白色固体3.2g(HPLC:99.6%)。Rf=0.30[单点,展开剂:v(二氯甲烷)∶v(甲醇)=5∶1]。
实施例4:2-苯基-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-甲氧基乙酰胺(化合物I-4)
参照实施例3的方法,用甲氧胺盐酸盐代替盐酸羟胺,与1d反应,得白色固体产物2.7g(HPLC:99.3%)。Rf=0.44[单点,展开剂:v(二氯甲烷)∶v(甲醇)=5∶1]。
实施例5:2-(3-三氟甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-乙氧基乙酰胺(化合物I-5)
在反应瓶中加入1e 3.75g(0.011mol),异丙醇30mL,碳酸钾3.04g(0.022mol),醋酸铵0.85g(0.011mol),加入乙氧胺盐酸盐0.67g(0.011mol),80℃下搅拌。30min后,过滤,然后减压蒸尽溶媒,蒸毕,向残余物中加入50mL蒸馏水和30mL二氯甲烷,充分搅拌,分出有机层,水层用3×30mL二氯甲烷提取,合并有机层,用无水硫酸钠充分干燥。减压蒸尽二氯甲烷,柱色谱分离,得白色固体3.5g(HPLC:99.2%)。Rf=0.34[单点,展开剂∶v(二氯甲烷)∶v(甲醇)=5∶1]。
实施例6:2-(4-甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-羟基乙酰胺(化合物I-6)
参照实施例5的方法,用盐酸羟胺代替乙氧胺盐酸盐,与1f反应,得白色固体产物2.8g(HPLC:99.5%)。Rf=0.37[单点,展开剂:v(二氯甲烷)∶v(甲醇)=5∶1]。
实施例7:2-(4-甲氧基苯基)-2-(4,5,6,7-四氧嗥吩并[3,2-c]吡啶-5(4H)-基)-N-甲氧基乙酰胺(化合物I-7)
参照实施例5的方法,用甲氧胺盐酸盐与1g反应,得白色固体产物3.3g(HPLC:99.8%)。Rf=0.47[单点,展开剂:v(二氯甲烷)∶v(甲醇)=5∶1]。
实施例8:2-(2-氟-6-氯苯基)-2-(4,5,6,7-四氢嗥吩并[3,2-c]吡啶-5(4H)-基)-N-乙氧基乙酰胺(化合物I-8)
参照实施例5的方法,用乙氧胺盐酸盐与1h反应,得白色固体产物3.5g(HPLC:98.9%)。Rf=0.49[单点,展开剂:v(二氯甲烷)∶v(甲醇)=5∶1]。
实施例9:
化合物I-1成盐酸盐:取I-1固体产物2.0g,溶于10mL无水乙醚。冰水浴冷却至0℃,滴加25%盐酸乙醚溶液至pH为2,继续于冰水浴下搅拌约1h。过滤,得白色固体。
实施例10:
化合物I-4成酒石酸盐:取I-4固体产物2.0g,溶于15mL无水乙醇。加热至回流后加入等摩尔酒石酸,继续于回流下搅拌反应约3h。反应完毕,于室温下静置24h。过滤,得白色固体。
实施例11:
化合物I-7成硫酸盐:取I-7固体产物2.0g,溶于20mL无水甲醇。冰水浴冷却至5℃,滴加浓硫酸溶液至pH为3,继续于冰水浴下搅拌约2h。过滤,得白色固体。
为了更充分地说明本发明的2-(取代苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-取代-乙酰胺的药物组合物,下面提供下列制剂实施例,所述实施例仅用于说明,而不是用于限制本发明的范围。所述制剂可以使用本发明化合物中的任何活性化合物及其盐。
实施例12:
用下述成分制备硬明胶胶囊:
用量/囊
化合物 I-275mg
预胶化淀粉 100mg
泊洛沙姆 4mg
羧甲基淀粉钠 10mg
硬脂酸镁 20mg
10%聚维酮乙醇溶液 适量
制备工艺:将原辅料预先干燥,过100目筛备用。按处方量将上述成分混匀,过60目筛三次,加适量10%聚维酮乙醇(95%)溶液制软材,过18目筛制粒,40℃干燥,过16目筛整粒,填充入硬明胶胶囊中。
实施例13:
用下述成分制备片剂:
用量/片
化合物I-4的酒石酸盐 75mg
淀粉 45mg
微晶纤维素 40mg
羧甲基淀粉钠盐 4.5mg
硬脂酸镁 1mg
滑石粉 1mg
泊洛沙姆 3mg
制备工艺:将原辅料预先干燥,过100目筛备用。先将处方量的辅料充分混匀。将原料药以递增稀释法加到辅料中,每次加时充分混匀2-3次,保证药与辅料充分混匀,过20目筛,在55℃通风烘箱中干燥2h,干颗粒过16目筛整理,测定中间体含量,混合均匀,在压片机上压片。
实施例14:
注射液的制备:
化合物I-1的盐酸盐 45mg
丙二醇 100mg
聚山梨酯80 适量
蒸馏水 300mL
制备方法:取活性成分加入到已溶解山梨醇和丙二醇的注射用水中,加入药用碱调节pH值至4~8使其溶解。加入活性炭,搅拌吸附30min,除炭、精滤、灌封、灭菌。
实施例15:
注射用冻干粉的制备:
化合物I-7的硫酸盐 50mg
药用碱 0.1-7.0%
甘露醇 55-80%
制备方法:取活性成分加入注射用水,用药用碱调节pH值至4~8使其溶解。再加入甘露醇,按注射剂的要求进行高压灭菌,加入活性炭,采用微孔滤膜过滤,滤液进行分装,采用冷冻干燥法,制得疏松块状物,封口,即得。
Claims (9)
2.如权利要求1中所述的式I化合物,其中C1-C3直链或支链烷基代表甲基,乙基,丙基,异丙基;卤素代表氟,氯;卤代甲基代表三氟甲基;C1-C3烷氧基代表甲氧基,乙氧基,丙氧基,异丙氧基。
3.如权利要求1中所述的式I化合物,优选以下化合物:
I-12-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-甲氧基乙酰胺;
I-22-(2-氟-4-甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-乙氧基乙酰胺;
I-32-(2,3-二氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-羟基乙酰胺;
I-42-苯基-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-甲氧基乙酰胺;
I-52-(3-三氟甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-乙氧基乙酰胺;
I-62-(4-甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-羟基乙酰胺;
I-72-(4-甲氧基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-甲氧基乙酰胺;
I-82-(2-氟-6-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)-N-乙氧基乙酰胺。
4.如权利要求1所述的化合物,其药学上可接受的盐指:化合物与无机酸、有机酸所成的盐。
5.如权利要求4所述的式I化合物药学上可接受的盐优选:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、丙酸盐、丁酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、马来酸盐、苯甲酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、富马酸盐、牛磺酸盐、葡萄糖酸盐、氨基酸盐。
7.一种抗恶性肿瘤的药物组合物,它包含治疗有效量的式I化合物或其盐及一种或多种药用赋形剂。
8.权利要求1~5中式I化合物及其盐在用于制备抗恶性肿瘤药物方面的应用。
9.如权利要求8所述的应用,在用于制备治疗肺癌、肝癌、乳腺癌、胃癌药物方面的用途。
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CN101962388A (zh) * | 2010-10-14 | 2011-02-02 | 天津药物研究院 | 乙酰胺衍生物及其制备方法和用途 |
CN101974016A (zh) * | 2010-10-14 | 2011-02-16 | 天津药物研究院 | 酰胺类化合物及其制备方法和用途 |
CN102358742A (zh) * | 2011-08-24 | 2012-02-22 | 天津药物研究院 | 具有抗肿瘤活性的噻唑类化合物 |
JP2016512512A (ja) * | 2013-03-14 | 2016-04-28 | シーエイチディーアイ ファウンデーション,インコーポレーテッド | ヒストンデアセチラーゼ阻害剤及びその組成物と使用方法 |
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CN1683373A (zh) * | 2005-02-23 | 2005-10-19 | 天津药物研究院 | 噻吩并吡啶取代的乙酰肼衍生物 |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101962388A (zh) * | 2010-10-14 | 2011-02-02 | 天津药物研究院 | 乙酰胺衍生物及其制备方法和用途 |
CN101974016A (zh) * | 2010-10-14 | 2011-02-16 | 天津药物研究院 | 酰胺类化合物及其制备方法和用途 |
CN102358742A (zh) * | 2011-08-24 | 2012-02-22 | 天津药物研究院 | 具有抗肿瘤活性的噻唑类化合物 |
CN102358742B (zh) * | 2011-08-24 | 2014-04-09 | 天津药物研究院 | 具有抗肿瘤活性的噻唑类化合物 |
JP2016512512A (ja) * | 2013-03-14 | 2016-04-28 | シーエイチディーアイ ファウンデーション,インコーポレーテッド | ヒストンデアセチラーゼ阻害剤及びその組成物と使用方法 |
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