CN100348580C - 紫杉醇增强化合物 - Google Patents
紫杉醇增强化合物 Download PDFInfo
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- CN100348580C CN100348580C CNB028177339A CN02817733A CN100348580C CN 100348580 C CN100348580 C CN 100348580C CN B028177339 A CNB028177339 A CN B028177339A CN 02817733 A CN02817733 A CN 02817733A CN 100348580 C CN100348580 C CN 100348580C
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- Prior art keywords
- methyl
- nhr
- replacement
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- phenyl
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Abstract
本发明公开了由结构式(I)表示的化合物;Y是共价键,次苯基或是取代或未取代的直链烃基。另外,Y和与其相连的两侧的>C=Z一起构成取代或未取代的芳香基团。优选地,Y是共价键或-C(R7R8)-。R1和R2独立地是芳基或取代的芳基,R3和R4独立地是-H,脂族基,取代的脂族基,芳基或取代的芳基。R5-R6独立地是-H,脂族基,取代的脂族基,芳基或取代的芳基。R7和R8分别独立地是-H,脂族基或取代的脂族基,或者R7是-H,R8是取代的或未取代的芳基,或者R7和R8一起构成C2-C6取代或未取代的亚烷基。Z是=O或者=S。本发明也公开了包含本发明的化合物和药学可接受的载体或稀释剂的药物组合物。本发明还公开了通过将结构式(I)的化合物与紫杉醇或紫杉醇类似物联合给患者施用以治疗癌症患者的方法。
Description
相关申请
本申请要求2001年7月10日申请的美国临时申请No.60/304252和2002年3月6日的美国临时申请No.60361946的权利。通过在此引述将这两个申请的全文引入本文。
发明背景
目前有许多新药可供肿瘤学家在治疗癌症患者的时候使用。通常,肿瘤对联合施用抗癌药物的治疗比单独或顺序施用抗癌药物的治疗更敏感。这种治疗方法的一个好处就在于抗癌药物会产生协同作用,这是因为肿瘤细胞同时被多种药物以多种作用方式攻击。因此,应当可以通过联合给药更快地减小肿瘤。联合化学疗法的另一个优点就是肿瘤更有希望被彻底根除,而且更不会对治疗患者所用的抗癌药物产生抗性。
联合化学疗法有一个严重的局限性,就是抗癌药物通常都具有严重的副作用,甚至是在单独给药的时候。例如,众所周知的抗癌药物紫杉醇可以引起中性白细胞减少,神经病,粘膜炎,贫血,血小板减少,心搏徐缓,腹泻,恶心。更糟的是,联合用药会加剧抗癌药物的毒性。因此,一些特定的药物通常是不联合用药的,同时给药的那些抗癌药物具有的联合毒性副作用严重限制了联合用药的剂量。联合用药的剂量通常是不足以达到所希望的协同作用的。因此,迫切需要寻找能增强抗癌药物的肿瘤攻击效果,又不增加其副作用的药物。
发明概述
现已发现某些双[硫代-酰肼胺]化合物可以显著增加紫杉醇的抗癌活性。例如,化合物(1)与紫杉醇(Paclitaxel(帕尼特西))联合用药治疗用人乳腺癌细胞系MDA-435在裸鼠中诱发的肿瘤。24天后,每天给予5mg/kg紫杉醇和25mg/kg化合物(1)的小鼠比仅给予5mg/kg紫杉醇或仅给予25mg/kg化合物(1)的小鼠的肿瘤体积减小了5倍(实施例13)。结果如图1所示。化合物(1)的结构如下所示:
化合物(1)
而且也发现这些双[硫代-酰肼胺]化合物的副作用极低。例如,用紫杉醇和化合物(1)治疗的小鼠在治疗期间体重几乎没有降低(见图2)。基于这些结果,在此公开可以增强紫杉醇抗癌活性的新的化合物,包含这些化合物的药物组合物,以及治疗癌症患者的方法。
本发明的一个实施方案是由结构式(I)表示的化合物:
Y是共价键,次苯基或取代或未取代的直链烃基。另外,Y和与其相连的两侧的>C=Z一起构成取代或未取代的芳基。优选地,Y是共价键或-C(R7R8)-。
R1和R2独立地是芳基或取代的芳基,R3和R4独立地是-H,脂族基,取代的脂族基,芳基或取代的芳基。
R5-R6独立地是-H,脂族基,取代的脂族基,芳基或取代的芳基。
R7和R8独立地是-H,脂族基或取代的脂族基,或者R7是-H,R8是取代的或未取代的芳基,或者,R7和R8一起构成C2-C6取代或未取代的亚烷基。
Z是=O或=S。
一方面,当Y是-C(R7R8)-,R3和R4都是苯基,R5-R8都是-H的时候,结构式(I)所示的化合物中R1和R2不都是苯基。
本发明的另一个实施方案是包含药学可接受的载体或稀释剂和结构式(I)所示的化合物的药物组合物。优选地,该药物组合物包含有效浓度的该化合物。
本发明的另一个实施方案是治疗癌患者的方法。该方法包括给患者施用有效量的紫杉醇或紫杉醇类似物,以及有效量的结构式(I)所示的化合物。
所公开的化合物可以增强紫杉醇和紫杉醇类似物的抗癌活性。另外,这些化合物的毒性副作用极低。所以,当紫杉醇或其类似物与本发明的化合物联合用药的时候,甚至当用量达到紫杉醇的最大耐受量时,都可以增强其药效。因此使用本发明的化合物进行的联合疗法有望为使用紫杉醇进行治疗的癌症患者提供更有效的临床效果。通过将本发明的化合物与紫杉醇一同给药,还有可能达到与使用更大剂量的紫杉醇相同的治疗效果,同时减少了副作用,提高了患者的生活质量。
附图描述
通过下面本发明的详细描述和具体实施方案可以清楚看到本发明的发明目的、特点和优点,这些通过附图也可以看到,附图中相同的参考标记在不同不同部分的意义都相同。附图并不是按比例绘制,仅用于阐述本发明的原理。
图1显示了分别用载体;化合物(1)(25mg/kg);帕尼特西(15mg/kg);或化合物(1)(25mg/kg)和帕尼特西(15mg/kg)治疗的裸鼠的平均肿瘤体积(以ml计)随时间(以天计)的变化。肿瘤是由人乳腺癌细胞系MDA-435诱发的。
图2显示了分别用载体;化合物(1)(25mg/kg);帕尼特西(15mg/kg);或化合物(1)(25mg/kg)和帕尼特西(15mg/kg)治疗的裸鼠的体重百分比随时间的变化。小鼠的肿瘤是由人乳腺癌细胞系MDA-435诱发的。
图3是紫杉醇(帕尼特西)的结构
图4是泰索帝(Docetaxol)的结构
图5-25均是紫杉醇类似物的结构。
图26是包括聚合物骨架和紫杉醇类似物基团的聚合物。该聚合物是所示的三个单体的三元共聚物。
发明详述
在第一个优选的实施方案中,结构式(I)中的Y和与其相连的两侧的>C=Z一起构成取代或未取代的亚芳基,该化合物由结构式(II)表示:
结构式(II)中的R1-R6如结构式(I)中所述。Ar是取代的或未取代的亚芳基。优选地,Ar是含有氮原子的亚杂芳基。示例如下:
环A为取代的或未取代的。
在第二个优选的实施方案中,结构式(I)中的Y是共价键或者取代或未取代的直链烃基。R7和R8如结构式(I)中所述。优选地,Y是共价键,-C(R7R8)-,-(CH2CH2)-,反-(CH=CH)-,顺-(CH=CH)-,-(CC)-或者1,4-次苯基。更优选地,Y是共价键或-C(R7R8)-。
在第三个优选的实施方案中,结构式(I)中的Y是共价键或者-C(R7R8)-,该化合物由结构式(III)表示:
R1-R8如结构式(I)中所述。Y’是共价键或者-C(R7R8)-。优选地,R7和R8都是甲基;R7和R8一起构成丙烯或丁烯;或者R7是-H,R8是低级烷基(优选地是甲基),噻吩基,苯基,苄基,或氨基。
在更优选的实施方案中,结构式(III)中的R5-R8是-H,该化合物由结构式(IV)表示:
结构式(IV)中的R1-R4如结构式(I)中所述。Y”是共价键或-CH2-。
在由结构式(IV)表示的化合物的第一个例子中,R3和R4都是取代或未取代的脂族基,优选地都是取代或未取代的低级烷基,更优选地都是甲基或乙基。当结构式(IV)中的R3和R4都是取代或未取代的脂族基的时候,R1和R2优选都是取代或未取代的芳基(例如取代的或未取代的杂芳基或者取代或未取代的苯基,或者至少一个非脂族基的基团取代的苯基)。
在由结构式(IV)表示的化合物的第二个例子中,R3和R4都是取代或未取代的杂芳基。当结构式(IV)中的R3和R4都是取代或未取代的杂芳基的时候,R1和R2优选都是:1)取代或未取代的苯基;或者2)取代或未取代的杂芳基
在由结构式(IV)表示的化合物的第三个例子中,R3和R4都是取代或未取代的苯基(例如被至少一个非脂族基的基团取代的苯基)。当结构式(IV)中的R3和R4都是取代或未取代的苯基的时候,R1和R2优选都是:1)取代或未取代的苯基;或者2)取代或未取代的杂芳基。
在由结构式(IV)表示的化合物的第四个例子中,R1和R2都是取代或未取代的芳基(例如取代的或未取代的杂芳基,取代的或未取代的苯基,或者被至少一个非脂族基的取代基取代的苯基)。更优选地,R3和R4都是甲基,其余的可变基团如上所述。
在第四个优选的实施方案中,本发明的化合物由结构式(III)表示,其中至少R1-R4其中之一是杂芳基,取代的杂芳基或被至少一个非脂族基的取代基取代的苯基。优选地,R5-R8都是-H。
下面是由结构式(IV)表示的化合物的一些示例:R1和R2都是苯基,R3和R4都是o-CH3-苯基;R1和R2都是o-CH3C(O)O-苯基,R3和R4都是苯基;R1和R2都是苯基,R3和R4都是甲基;R1和R2都是苯基,R3和R4都是乙基;R1和R2都是苯基,R3和R4都是正丙基;R1和R2都是p-苯腈基(p-cyanophenyl),R3和R4都是甲基;R1和R2都是p-硝基苯基,R3和R4都是甲基;R1和R2都是2,5-二甲氧基苯基,R3和R4都是甲基;R1和R2都是苯基,R3和R4都是正丁基;R1和R2都是p-氯苯基,R3和R4都是甲基;R1和R2都是3-硝基苯基,R3和R4都是甲基;R1和R2都是3-苯腈基,R3和R4都是甲基;R1和R2都是3-氟苯基,R3和R4都是甲基;R1和R2都是2-呋喃,R3和R4都是苯基;
R1和R2都是2-甲氧基苯基,R3和R4都是甲基;R1和R2都是3-甲氧基苯基,R3和R4都是甲基;R1和R2都是2,3-二甲氧基苯基,R3和R4都是甲基;R1和R2都是2-甲氧基-5-氯苯基,R3和R4都是乙基;R1和R2都是2,5-二氟苯基,R3和R4都是甲基;R1和R2都是2,5-二氟苯基,R3和R4都是甲基;R1和R2都是2,5-二甲基苯基,R3和R4都是甲基;
R1和R2都是2-甲氧基-5-氯苯基,R3和R4都是甲基;R1和R2都是3,6-二甲氧基苯基,R3和R4都是甲基;R1和R2都是苯基,R3和R4都是2-乙基苯基;R1和R2都是2-甲基-5-吡啶基,R3和R4都是甲基;或者R1是苯基;R2是2,5-二甲氧基苯基,R3和R4都是甲基。
在第五个优选的实施方案中,结构式(I)中的Y是-C(R7R8)-,R5和R6都是-H。当Y是共价键或-CR7R8-,并且R5和R6都是-H的时候,本发明的化合物由结构式(V)表示:
R1-R4,R7和R8如结构式(I)中所述,Y’是共价键或-C(R7R8)-。R7和R8可以相同也可以不同。优选地,R7和R8都是甲基;R7和R8一起构成丙烯或丁烯;或者R7是-H而R8是低级烷基(优选是甲基),噻吩基,苯基或苄基。
在由结构式(V)表示的化合物的一个例子中,R1和R2都是芳基或取代的芳基,R3和R4都是低级烷基或取代的低级烷基;优选地,R1和R2都是芳基或取代的芳基,R3和R4都是甲基或乙基,R7是-H,R8是-H或甲基。在由结构式(V)表示的化合物的另一个例子中,R1和R2都苯基或取代的苯基,R3和R4都是甲基,乙基,苯基或噻吩基,优选地,R7和R8一起组成丙烯或丁烯。在由结构式(V)表示的化合物的另一个例子中,Y’是共价键或-CR7R8-;R1和R2都是取代或未取代的芳基;R3和R4都是-H,甲基或乙基;R7是-H,R8是-H或甲基。
下面是由结构式(V)表示的化合物的一些示例:R1和R2都是苯基;R3和R4都是甲基;R7是-H,R8是乙基;R1和R2都是苯基;R3和R4都是苯基;R7和R8都是甲基;R1和R2都是2-噻吩基;R3和R4都是苯基;R7和R8都是甲基;R1和R2都是4-苯腈基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是苯基;R3和R4都是甲基;R7是-H;R8是苄基;R1和R2都是苯基;R3和R4都是甲基;R7是-H;R8是乙基;R1和R2都是苯基;R3和R4都是乙基;R7是-H;R8是正丁基;R1和R2都是2,5-二甲氧基苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是苯基;R3和R4都是甲基;R7是-H,R8是异丙基;R1和R2都是3-硝基苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是4-氯苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是苯基;R3和R4都是甲基;R7是-H,R8是3-噻吩基;R1和R2都是苯基;R3和R4都是甲基;R7和R8一起是丙烯;R1和R2都是2,3-二甲氧基苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是2-氯-5-甲氧基苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是2,5-二氟苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是2,5-二氯苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是2,6-二氯苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是2,6-二甲氧基苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是2,5-二甲基苯基;R3和R4都是甲基;R7是-H,R8是甲基;R1和R2都是2,5-二甲氧基苯基;R3和R4都是乙基;R7是-H,R8是甲基;R1和R2都是2,5-二乙氧基苯基;R3和R4都是甲基;R7是-H,R8是甲基。
在第六个优选的实施方案中,结构式(I)中的Y是共价键或-CH2-。当Y是共价键或-CH2-的时候,本发明的化合物由结构式(VI)表示:
结构式(VI)中的R1-R6如结构式(I)中所述。R5和R6可以相同也可以不同。Y”是共价键或-CH2-。
在由结构式(VI)表示的化合物的一个例子中,R5和R6都是低级烷基(优选地是甲基)或是苯基。当R5和R6都是低级烷基或苯基的时候,R1和R2优选地都是苯基或取代的苯基,R3和R4优选地都是低级烷基。
下面是本发明所述的化合物的一些示例:R1和R2都是苯基,R3和R4都是苯基,R5和R6都是甲基,R7和R8都是-H;R1和R2都是苯基,R3和R4都是苯基,R5和R6都是正己基,R7和R8都是-H;R1和R2都是苯基,R3和R4都是甲基,R5和R6都是甲基,R7和R8都是-H;R1和R2都是苯基,R3和R4都是甲基,R5和R6都是甲基,R7是-H,R8是甲基;R1和R2都是苯基,R3和R4都是-H,R5和R6都是苯基,R7是-H,R8是甲基;R1和R2都是4-氯苯基,R3和R4都是甲基,R5和R6都是甲基,R7和R8都是-H。
在结构式(I)-(VI)中,R1和R2是相同的或者不同的;和/或R3和R4是相同的或是不同的。优选地,R1和R2是相同的,R3和R4是相同的。
“直链烃基”是烯基,即,-(CH2)x-,其中一个或多个(优选一个)亚甲基可选择地被连接基团取代。x是正整数(例如在1至大约10之间),优选地在1到大约6之间,更优选地是1或2。“连接基团”指取代直链烃基中的亚甲基的功能基团。适合的连接基团的实例包括酮(-C(O)-),烯烃,炔,次苯基,醚(-O-),硫醚(-S-),或者胺[-N(Ra)]-,其中Ra定义见后。优选的连接基团是-C(R7R8)-,其中R7和R8定义如前所述。适合的烯基和烃基的取代基是不显著影响反应发生的那些。R7和R8是优选的烯基或烃基的取代基。
脂族基是直链的,支链的或者非芳香族的环烃,其是完全饱和的或者包括一或多个不饱和单位。通常,直链或支链基团含有1到大约20个碳原子,优选地含有1到大约10个,环脂族基团含有3到大约10个碳原子,优选地含有3到大约8个。脂族基优选地是直链或直链烷基,例如甲基,乙基,正丙基,异丙基,正丁基,仲丁基,叔丁基,戊基,己基,戊基或辛基,或是有3到约8个碳原子的环烷基。C1-C20的直链或直链烷基或者C3-C8的环烷基也可以称作“低级烷基”。
芳香基团包括碳环形的芳香基团例如苯基,萘基和蒽基,和杂芳基例如咪唑基,噻吩基,呋喃基,吡啶基,嘧啶基,吡喃基,吡唑基,吡咯基,吡嗪基,噻唑,呃唑基和四唑。
芳香基团也包括融合的多环芳香环系统,其中碳环芳香环或杂芳环与一个或多个其它杂芳环相融合。实例包括苯噻嗯基,苯并呋喃基,吲哚,喹啉,苯并噻唑,苯并唑,苯并咪唑,喹啉,异喹啉和异氮杂茚基。
术语“亚芳基”指与相邻位置以两个其它键相连的芳基。例如,1,4-次苯基的结构如下所示:
亚芳基的取代基同下述芳基的取代基。
非芳香族的杂环是指非芳香族的碳环,其环中包括一个或多个杂原子例如氮,氧或硫。该环可以是五元,六元,七元或八元环。实例包括四氢呋喃,四氢苯硫基,吗啉代,硫吗啉代,吡咯烷基,哌嗪基,哌啶基和噻唑烷基。
术语“低级烷氧基”,“低级酰基”,“(低级烷氧基)甲基”和“(低级烷基)硫甲基”分别指-O-(低级烷基),-C(O)-(低级烷基),-CH2-O-(低级烷基)和-CH2-S-(低级烷基)。术语“取代的低级烷氧基”和“取代的低级酰基”分别是指-O-(取代的低级烷基),-C(O)-(取代的低级烷基)。
脂族基,非芳香族的杂环,苄基或芳基(碳环的和杂芳基的)的适合的取代基是那些不会显著影响所述化合物对紫杉醇及其类似物的抗癌活性的增强的基团。当化合物被取代基取代了以后其对抗癌活性的增强减小了50%以上时,就认为该取代基是显著影响了所述化合物对抗癌活性的增强。合适的取代基的实例包括-OH,卤素(-Br,-Cl,-I和-F),-ORa,-O-CORa,-CORa,-CN,-NO2,-COOH,-SO3H,-NH2,-NHRa,-N(RaRb),-COORa,-CHO,-CONH2,-CONHRa,-CON(RaRb),-NHCORa,-NRCORa,-NHCONH2,-NHCO NRaH,-NHCON(RaRb),-NRcCONH2,-NRcCONRaH,-NRcCON(RaRb),-C(=NH)-NH2,-C(=NH)-NHRa,-C(=NH)-N(RaRb),-C(=NRc) -NH2,-C(=NRc)-NHRa,-C(=NRc)-N(RaRb),-NH-C(=NH)-NH2,-NH-C(=NH)-NHRa,-NH-C(=NH)-N(RaRb),-NH-C(=NRc)-NH2,-NH-C(=NRc)-NHRa,-NH-C(=NRc)-N(RaRb),-NRd-C(=NH)-NH2,-NRd-C(=NH)-NHRa,-NRd-C(=NH)-N(RaRb),-NRd-C(=NRc)-NH2,-NRd-C(=NRc)-NHRa,-NRd-C(=NRc)-N(RaRb),-NHNH2,-NHNHRa,-SO2NH2,-SO2NHRa,-SO2NRaRb,-CH=CHRa,-CH=CRaRb,-CRc=CRaRb,-CRc=CHRa,-CRc=CRaRb,-CCRa,-SH,-SOkRa(k是0,1或2)和-NH-C(=NH)-NH2。Ra-Rd分别独立地是脂族基,取代的脂族基,苄基,取代的苄基,芳基或取代的芳基,优选地是烷基,苄基或芳基。另外,-NRaRd,一起构成取代的或未取代的非芳香族的杂环基团。非芳香族的杂环基团,苄基或芳基也可以有脂族基或取代的脂族基作为取代基。取代的脂族基也可以有非芳香族的杂环,取代的非芳香族的杂环,苄基,取代的苄基,芳基或取代的芳基作为取代基。取代的脂族基,非芳香族的杂环基团,取代的芳基或者取代的苄基可以有多于一个的取代基。
本发明还包括所述化合物的药学可接受的盐。本发明的化合物具有足够的酸性和碱性或同时具有二者功能的基团,因此可以和任何无机碱,无机和有机酸反应生成盐。通常用于生成酸加成盐的是无机酸例如盐酸,氢溴酸,氢碘酸,硫酸,磷酸以及类似的无机酸,和有机酸如p-甲苯亚磺酸,甲磺酸,草酸,p-溴苯基-硫酸,碳酸,琥珀酸,柠檬酸,苯甲酸,乙酸乙基类似的有机酸。盐的实例包括硫酸盐,焦硫酸盐,硫酸氢盐,亚硫酸盐,亚亚硫酸氢盐,磷酸盐,一氢磷酸盐,二氢磷酸盐,偏磷酸盐,焦磷酸盐,氯化物,溴化物,碘化物,乙酸盐,丙酸盐,癸酸盐,辛酸盐,丙烯酸盐,甲酸盐,异丁酸盐,己酸盐,庚酸盐,丙炔酸盐,草酸盐,丙二酸盐,琥珀酸盐,辛二酸盐,癸二酸盐,延胡索酸盐,马来酸盐,丁炔-1,4-二酯,己炔-1,6-二酯,苯甲酸盐,氯苯甲酸盐,甲基苯甲酸盐,二硝基苯甲酸盐,羟基苯甲酸盐,甲氧基苯甲酸盐,邻苯二甲酰盐,磺酸盐,二甲苯磺酸盐,苯乙酸盐,苯丙酸盐,苯丁酸盐,柠檬酸盐,乳酸盐,-羟基丁酸盐,羟乙酸盐,酒石酸盐,甲基磺酸盐,丙基磺酸盐,萘-1-磺酸盐,萘-2-磺酸盐,扁桃酸盐和类似的盐。
碱加成盐包括衍生于无机碱例如铵或碱或碱土金属的氢氧化物,碳酸盐,碳酸氢盐以及类似的无机碱的盐。可用于制备本发明的盐的碱包括氢氧化钠,氢氧化钾,氢氧化铵,碳酸钾以及类似的碱。
紫杉醇,也即“帕尼特西”,是一类著名的抗癌药物,可以抑制微管生成。已知许多紫杉醇的类似物,包括泰索帝,其结构如图4所示。泰索帝也叫做“Docetaxol”。其它紫杉醇类似物的结构如图5-25所示。这些化合物都有一个基本的紫杉烷骨架作为共有的结构特征,都能够通过抑制微管增殖从而抑制G2-M期的细胞。因此,从图5-25可以明显看出,可以用许多取代基修饰紫杉烷骨架,而不影响其生物学功能。而且紫杉醇类似物中的0个,1个或全部环己烷环在指定位置上都可以有一个双键。为清楚起见,基本的紫杉烷骨架如下结构式(VII)所示:
在结构式(VII)所表示的紫杉烷骨架中没有显示环己烷环中的双键。应当理解,基本紫杉烷骨架可以包括一个或全部环己烷环中的0个或1个双键,如图5-25和下面的结构式(VIII)和(IX)所示的那样。结构式(VII)中也没有显示某些碳原子,这是为了表明紫杉醇类似物中经常发生结构变化的位点。例如,紫杉烷骨架中仅仅有氧原子的部位表示这些位置通常是羟基,酰基,烷氧基或其它包含氧的取代基。应当理解紫杉烷骨架上的这些取代基和其它取代基都不影响其增强抗癌活性和抑制微管生成的活性。因此,这里将术语“紫杉醇类似物”定义为具有基本紫杉醇骨架并能促进微管分解的化合物。
特别地,这里所述的紫杉醇类似物由结构式(VIII)或(IX)表示:
R10是低级烷基,取代的低级烷基,苯基,取代的苯基,-SR19,-NHR19或-OR19。
R11是低级烷基,取代的低级烷基,芳基或取代的芳基。
R12是-H,-OH,低级烷基,取代的低级烷基,低级烷氧基,取代的低级烷氧基,-O-C(O)-(低级烷基),-O-C(O)-(取代的低级烷基),-O-CH2-O-(低级烷基)-S-CH2-O-(低级烷基)。
R13是-H,-CH3,或者,与R14一起是-CH2-。
R14是-H,-OH,低级烷氧基,-O-C(O)-(低级烷基),取代的低级烷氧基,-O-C(O)-(取代的低级烷基),-O-CH2-O-P(O)(OH)2,-O-CH2-O-(低级烷基),-O-CH2-S-(低级烷基),或者与R20一起是双键。
R15是-H,低级酰基,低级烷基,取代的低级烷基,烷氧基甲基,烷基硫代甲基,-OC(O)-O(低级烷基),-OC(O)-O(取代的低级烷基),-OC(O)-NH(低级烷基)或-OC(O)-NH(取代的低级烷基)。
R16是苯基或取代的苯基。
R17是-H,低级酰基,取代的低级酰基,低级烷基,取代的低级烷基,(低级烷氧基)甲基或者(低级烷基)硫甲基。
R18是-H,-CH3,或者,与R17以及和R17和R18相连接的碳原子一起,构成五元或六元的非芳香族的杂环。
R19是低级烷基,取代的低级烷基,苯基,取代的苯基。
R20是-H或卤素。
R21是-H,低级烷基,取代的低级烷基,低级酰基或取代的低级酰基。
优选地,结构式(VIII)和(IX)中的可变位点如下定义:R10是苯基,叔丁氧基,-S-CH2-CH-(CH3)2,-S-CH(CH3)3,-S-(CH2)3CH3,-O-CH(CH3)3,-NH-CH(CH3)3,-CH=C(CH3)2或对氯苯基;R11是苯基,(CH3)2CHCH2-,-2-呋喃,环丙基或对甲苯甲酰;R12是-H,-OH,CH3CO-或-(CH2)2-N-吗啉代;R13是甲基,或者R13和R14一起是-CH2-;
R14是-H,-CH2SCH3或-CH2-O-P(O)(OH)2;R15是CH3CO-;
R16是苯基;R17是-H,或者R17和R18一起是-O-CO-O-;
R18是-H;R20是-H或-F;R21是-H,-C(O)-CHBr-(CH2)13-CH3或者-C(O)-(CH2)14-CH3,-C(O)-CH2-CH(OH)-COOH,-C(O)-CH2-O-C(O)-CH2CH(NH2)-CONH2,-C(O)-CH2-O-CH2CH2OCH3或者-C(O)-O-C(O)-CH2CH3。
紫杉醇类似物也可以与药学可接受的多聚物例如聚丙烯酰胺相连接。图26给出了这种类型的多聚物的一个实例。这里所用的术语“紫杉醇类似物”也包括这样的多聚物。
本发明的化合物是紫杉醇和紫杉醇类似物的抗癌活性的增强物,当紫杉醇或其类似物与所述化合物联合给药的活性比单独给药活性大时,认为该化合物可以增强紫杉醇及其类似物的抗癌活性。活性提高的程度取决于化合物的施用量。本发明的化合物可以与紫杉醇及其类似物联合给药治疗癌症患者。所述癌症包括结肠癌,胰癌,黑色素瘤,肾癌,肉瘤,乳腺癌,卵巢癌,肺癌,胃癌,膀胱癌和宫颈癌。
“患者”可以是哺乳动物,优选是人,但是也可以是兽医治疗的动物,例如宠物(例如狗,猫等),家畜(例如牛,羊,猪,马等)以及实验用动物(例如大鼠,小鼠,豚鼠等)。
为了增加紫杉醇及其类似物的抗癌活性,将有效量的本发明的化合物与有效量的紫杉醇或其类似物一起给患者施用。对于紫杉醇或其类似物,“有效量”是指通常能达到抗癌效果的量。对于本发明的化合物,“有效量”是指当与紫杉醇或其类似物联合施用时能获得比紫杉醇或其类似物单独施用更好的效果的量。该化合物与紫杉醇(或紫杉醇类似物)可以作为同一个药物组合物的组分一起施用,或者也可以分别作为独立的药物组合物的成分一起施用。当作为独立的药物组合物施用的时候,本发明的化合物和紫杉醇(或紫杉醇类似物)可以同时或分次给药,以保持该化合物的增强效果。
给患者施用的化合物和紫杉醇(或紫杉醇类似物)的量应视疾病的类型或病情的严重程度以及患者的特点例如一般健康状况,年龄,性别,体重和药物耐受力而定。也取决于癌症的严重程度和类型。技术人员应当能够根据这些因素和其它因素确定合适的剂量。众所周知,紫杉醇及其类似物的有效剂量一般是大约每天1mg/mm2至大约每天1000mg/mm2,优选地是大约每天10mg/mm2至大约每天500mg/mm2。本发明的化合物的有效量一般是大约每天1mg/mm2至大约每天10grams/mm2,优选地是大约每天10mg/mm2至大约每天5grams/mm2。
本发明的化合物可以以任何适当的形式给药,包括,例如,口服胶囊,悬液或片剂或经肠道外给药。肠道外给药包括,例如,全身给药如肌肉内,静脉内,皮下,或腹膜内注射。该化合物可以通过口服(例如通过饮食),局部地,通过吸入(例如支气管内,鼻内,口腔吸入或鼻内点滴),或者通过直肠给药,这取决于要治疗的癌症的类型。口服和肠道外给药是优选的给药方式。紫杉醇和其类似物的适当的给药方式是本领域公知的,包括和本发明的化合物一样的肠道外给药。紫杉醇和其类似物的适当的给药方式是众所周知的,包括其它肠道外给药和口服给药。
本发明的化合物可以和药学可接受的载体一起组成药物组合物用于治疗癌症。该化合物的配方根据给药方式(例如溶液,乳剂,胶囊)的不同而不同。合适的药学载体应当包括不与该化合物反应的惰性成分。可以使用标准的药物处方设计,例如《雷明蹲药物科学》(Remington’s Pharmaceutical Sciences,MackPublishing Company,Easton,PA)中所述的。肠道外给药的合适的药物载体包括,例如无菌水,生理盐水,抑菌盐水(包含约0.9%mg/ml的苯甲醇),磷酸盐缓冲液,Hank’s溶液,Ringer’s乳酸盐等。将组合物包入胶囊的方法(例如在外面包裹一层硬的明胶或环葡聚糖)是本领域公知的(Baker,et al.,“ControlledRelease of Biological Active Agents”,John Wiley and Sons,1986)。紫杉醇和其类似物的配方是本领域所公知的。
本发明的化合物可以依据实施例1-12的方法制备,也可以依据2001年7月10日提交的名为“紫杉醇增强物的合成”的,申请号为60/304318的共同未决的美国临时申请中描述的方法制备。通过在此引述将该申请全文引入本文。
下述实施例旨在说明本发明,而并非以任何方式限制本发明。
实施例
实施例1
硫代苯甲酸N-甲基酰肼的制备:将现有技术(Acta Chem.Scand.1961,1087-1096)做少许改进即可制得产率为88%的硫代苯甲酸N-甲基酰肼;1H NMR(CDCl3)δ 3.3(s,3H),6.0(s,2H),7.3-7.4(m,5H);计算ESMS(C8H10N2S):166.1;实测:167.1(M+H)+。
实施例2
硫代苯甲酸N-甲基酰肼的制备:将溴苯(1.6g,10mmol)加入到25ml含有镁粉(0.3g,12.5mmol)的无水THF溶液中,回流2小时。冷却后,在0℃将澄清的反应溶液加入到二硫化碳(1ml,16.8mmol)中,室温搅拌30分钟。然后将得到的混合物在0℃加入到甲基酰肼(1.6ml,30mmol)中,再搅拌2小时。然后向此溶液中加入水(15ml),用EtOAc(30ml×3)提取。将此有机溶剂浓缩至最小体积,进行硅胶柱层析(洗脱液:1∶3-1∶1乙酸乙酯∶己烷)得到硫代苯甲酸N1-甲基酰肼(0.72g,总产率:48%)。1H NMR(CDCl3)δ3.3(s,3H),6.0(s,2H),7.3-7.4(m,5H);计算ESMS(C8H10N2S):166.1;实测:1 67.1(M+H)+。
实施例3
2,5-二甲氧基硫代苯甲酸N-甲基酰肼的制备:DCC(4.5g,21.8mmol)部分加入到冰浴冷却的2,5-二甲氧基苯甲酸(3.6g,20mol),甲基肼(1.2ml,23mmol)和DMAP(30mg,cat.)的CH2Cl2(60ml)溶液中。于室温将反应混合物搅拌过夜。-20摄氏度冷却1小时,然后过滤。使CH2Cl2溶液蒸发,将残余物真空干燥。得到的粗产物溶解于甲苯(50ml)中。向此溶液中加入Lawesson试剂(5.8g,14mmol)。将该混合物回流40分钟,冷却至室温,直接进行硅胶柱层析(洗脱液:含有25%至35%乙酸乙酯的己烷),得到2,5-二甲氧基硫代苯甲酸N-甲基肼(3.7g,产率:82%)的乳白色固体。1H NMR(300MHz,CDCl3):δ6.88-6.80(m,3H),5.46(s,2H),3.84(s,3H),3.82(s,3H),3.28(s,3H)。
实施例4
N-丙二酰-双[N’-苯基-N’-(硫代乙酰)酰肼]的制备:在0℃向搅拌过的硫代苯甲酸N-甲基肼(0.166g,10mmol),HOBt·H2O(0.15g,11mol)和丙二酸(0.052g,5mmol)的DMF(2ml)溶液中加入DCC(0.22g,10.7mmol)。得到的悬液在0摄氏度搅拌1小时,在室温搅拌3小时。滤出沉淀物,用EtOAc(3×15ml)洗涤。将过滤液和洗涤液混合,相继用H2O(2×20ml),5%柠檬酸(20ml),H2O(20ml),饱和NaHCO3(20ml)和盐水(20ml)洗涤。用Na2SO4干燥后,减压除去溶剂,得到黄色固体的粗产物,然后用加热的EtOAc洗涤。得到0.16g(产率80%)纯产物黄色粉末。Rf0.3(己烷/EtOAc 1∶1 v/v);1H NMR(CDCl3)δ3.1-3.8(m,6H),3.4(s,2H),7.1-7.45(m,10H),9.5-10.5(m,1H)ppm;计算ESMS(C19H20N4O2S2):400.1;实测399.1(M-H)+。
N-(2-甲基丙二酰-双{N’-甲基-N’-[(2,5-二甲氧基)硫代苯甲酰] 酰肼}的制备:
在0摄氏度边搅拌边将DCC(4g,19mmol)加入到2,5-二甲氧基硫代苯甲酸N-甲基肼(3.7g,16.4mmol)和2-甲基丙二酸(2g,17mmol)的DMF(20ml)溶液中。反应混合物于室温搅拌1小时。-20℃冷却1小时,然后过滤。滤液用EtOAc(300ml)稀释,用水(50ml×3)洗涤,用Na2SO4干燥。将EtOAc溶液浓缩至最小体积,进行硅胶柱层析(洗脱液:1∶4至2∶1,乙酸乙酯∶己烷),得到标题化合物(3.5g,80%)的黄色粉末。1H NMR(CDCl3)δ10.12-9.14(2H),7.12-6.81(m,6H),4.01-3.78(m,6H),3.75-3.22(m,6H),2.82-2.62(m,1H),1.12-0.11(m,3H);计算ESMS(C24H30N4O6S2):534.16;实测535.1(M+H)。
实施例5
N-丙二酰-双[N’-甲基-N’-(硫代苯甲酰)酰肼]的制备:在0摄氏度边搅拌边向硫代苯甲酸N-甲基肼(10g)溶液中相继加入三乙胺(8.5ml)和丙二酰二氯(3.05ml)。将反应混合物搅拌10分钟,用水(3×50ml)洗涤,用硫酸钠干燥,然后浓缩。用二氯甲烷(35ml)再结晶纯化得到淡黄色晶体产物(9.0g,75%),与实施例6中得到的产物相同。
实施例6
N-丙二酰-双[N’-甲基-N’-(硫代苯甲酰)酰肼]的制备:将搅拌后的硫代苯甲酸N-甲基肼(1.66g,10mmol)和丙二酸二苯酯(1.30g,5.08mmol)的无水THF溶液(100ml)加热回流72小时。减压除去挥发组分。将粗产物用硅胶柱层析纯化,洗脱液为己烷和EtOAc的混合物(4∶1 v/v到1∶1 v/v梯度)。得到1.07g(51%产率)的N-丙二酰-双[N’-甲基-N’-(硫代苯甲酰)酰肼]纯产物黄色粉末。该化合物的物理性质与实施例5中得到的产物相同。
实施例7
将硫代苯甲酸N-甲基肼(1.0g,6mmol),单-叔丁基丙二酸(1.0ml,6mmol),HOBt·H2O(0.98g,7.2mmol),和DCC(1.34g,6.5mmol)在DMF中的浆液(5ml)在0摄氏度搅拌3小时,然后在室温搅拌3小时。滤出沉淀物,用EtOAc(3×20ml)洗涤。将过滤液和洗涤液混合,相继用H2O(2×20ml),5%柠檬酸(20ml),H2O(20ml),饱和NaHCO3(20ml)和盐水(20ml)洗涤。用Na2SO4干燥后,减压除去溶剂,得到固体粗产物,用Et2O洗涤。得到0.94g(产率51%)N’-甲基-N’-硫代苯甲酰-肼基羰基)-乙酸叔丁酯的纯产物黄色粉末。1H NMR(CDCl3)δ1.6-1.7(ds,9H),3.1-4.1(m,5H),7.3-7.7(m,5H),9.7-10.3(ds,1H)ppm;计算ESMS(C15H20N2O3S):308;实测:307(M-H)+。
将N’-甲基-N’-硫代苯甲酰-肼基羰基)-乙酸叔丁酯(0.19g,0.6mmol)和TFA(0.12ml,1.6mmol)的无水DCM溶液(10ml)在10-15摄氏度搅拌12小时(用TLC监测反应)。真空干燥后,加入DMF(3ml),然后加入DCC(0.13g,0.6mmol),HOBt·H2O(93mg,0.7mmol)和硫代-2,5-二甲氧基苯甲酸N-甲基肼(0.13g,0.57mmol)。将得到的溶液在0摄氏度搅拌半小时,然后在室温搅拌3小时。滤出沉淀物,用EtOAc(3×10ml)洗涤。将过滤液和洗涤液混合,然后相继用H2O(2×10ml),5%柠檬酸(10ml),H2O(10ml),饱和NaHCO3(20ml)和盐水(20ml)洗涤。用Na2SO4干燥后,减压除去溶剂,得到油状粗产物,用SGC纯化(4∶1己烷/EA至2∶1 EtOAc/己烷)。得到0.14g(产率53%)纯产物的黄色粉末。1H NMR(CDCl3)δ3.1-3.9(m,18H),6.7-7.4(m,9H)ppm;计算ESMS(C21H24N4O4S2):460.1;实测:461.1(M+H)+。
实施例8
N-丙二酰-双[N’-苯基-N’-(硫代苯甲酰)酰肼]的制备
苯肼(30ml)和乙基丙二酸(于二甲苯中)(150ml)的混合物加热回流过夜。将反应冷却到室温。过滤收集沉淀,用乙醇清洗,得到N-丙二酰-双(N’-苯肼)的白色固体(14g)。酰肼(3.4g)悬于乙酸酐(30ml)中,冰浴冷却。逐滴加入高氯酸(57%水溶液,3ml)。反应混合物首先变成清液,然后迅速凝固。室温放置1h,加入乙醚(50ml)。得到的浆液过滤后用乙醚洗涤(2×00ml),得到白色固体的高氯酸盐(5.7g)。将此高氯酸盐加入丙酮中,5分钟之后形成浆液,加入Na2S(0.6M水溶液,90ml)中,室温搅拌,30分钟后用HCl(c)将反应酸化生成黄色浆液。过滤收集固体,用水(20ml)和乙醚(2×25ml)洗涤,得到乳白色固体N-丙二酰-双[N’-苯基-N’-(硫代苯甲酰)酰肼](3.6g)。1H NMR(CDCl3):δ7.2(m,20H);3.5(br s,2H).C29H24N4O2S2的计算MS:524.13;实测:525.1(M+H)。
实施例9
N-丙二酰-双[N’-甲基-N’-(硫代苯甲酰)酰肼]的制备
向搅拌后的N-丙二酰-双[N’-苯基-N’-(硫代苯甲酰)酰肼](180mg,0.34mmol),MeOH(22ml)和三苯基膦(200mg,0.64mmol)的无水THF溶液(10ml)中逐滴加入DEAD(0.12ml)的THF溶液(3ml)。将得到的橙色溶液在室温搅拌12小时。除去挥发性组分后,用SGC(3∶1己烷/EtOAc)纯化粗产物得到98mg(产率52%)标题化合物的浆液。1H NMR(CDCl3):δ3.3-4.5(m,8H),7.1-7.8(m,20H)ppm;的计算ESMS(C31H28N4O2S2):552;实测:551(M-H)+。
实施例10
将搅拌后的N-丙二酰-双[N’-苯基-N’-(硫代乙酰)酰肼)(0.1g,0.25mmol)和Lawesson试剂(0.15g,0.37mmol)在无水苯(20ml)中的混合物加热回流1小时。待冷却到室温后,将混合物通过硅胶层过滤,用THF(2×15ml)洗涤。混合过滤液和洗涤液,并减压浓缩。在硅胶柱上进行冲洗式柱层析(己烷至4∶1己烷/EtOAc至2∶1己烷/EtOAc),得到N-双硫代丙二酰-双[N’-苯基-N’-(硫代乙酰)酰肼)的透明浆液(16mg,15%)。1H NMR(CDCl3)δ3.80-3.95(m,8H),7.02-7.30(m,10H)。计算ESMS(C19H20N4S2):432.06;实测:433.0(M+H)+。
实施例11
通过前述步骤制备下述化合物。分析数据列举于下。
1H NMR(CDCl3)δ3.1-3.8(m,6H),3.4(s,2H),7.1-7.45(m,10H),9.5-10.5(m,1H)ppm;计算ESMS(C19H20N4O2S2):400.1;实测:399.1(M-H)+。
1H NMR(CDCl3)δ1.0-1.35(m,6H),3.0-4.3(m,6H),7.05-7.40(m,10H),9.1-10.1(m,2H);计算ESMS(C21H24N4O2S2):428.8;实测:427(M-H)+。C21H24N4O2S2(428.13)的分析计算值:C,58.85;H,5.64;N,13.07;S,14.96。实测:C,58.73;H,5.62;N,12.97;S,14.96。
1H NMR(CDCl3)δ 0..7-1.0(m,6H),1.4-1.9(m,4H),3.1-4.2(m,6H),7.1-7.4(m,10H),8.9-10.2(m,2H)ppm;ESMS(C23H28N4O2S2):456.1;实测:455.1(M-H)+。
mp141-143℃;1H NMR(CDCl3)δ0.6-1.05(m,6H),1.1-1.9(m,8H),3.0-4.2(m,6H),7.0-7.35(m,10H),8.9-11(ms,2H);ESMS(C25H32N4O2S2):484.2;实测:483.1(M-H)+。C25H32N4O2S2(484.2)的分析计算值:C,61.95;H,6.65;N,11.56;S,13.23。实测:C,61.98;H,6.52;N,11.26;S,13.16。
1H NMR(DMSO-d6)0.4-0.9(dd,3H,J=7),2.7(q,1H),3.1-3.6(m,6H),7.1-7.5(m,10H),10.9(br,2H)ppm;ESMS(C20H22N4O2S2):414;实测:413(M-H)+。
1H NMR(CDCl3)0.5(t,3H,J=7),1.1-1.6(m,2H),2.7(t,1H,J=7),3.1-3.3(m,6H),7.0-7.3(m,10H),10.25(s,2H)ppm;MS(C21H24N4O2S2):428.1;实测:427.1(M-H)+。
1H NMR(CDCl3)0.5(d,6H,J=7),0.9-1.2(m,1 H),3.0-4.1(m,7H),7.1-7.4(m,10H),10.3(s,2H)ppm;ESMS(C22H26N4O2S2):442.1;实测:441.1(M-H)+。
1H NMR(CDCl3)0.4-1.3(m,5H),1.5-1.8(m,2H),3.0-3.7(m,6H),7.1-7.5(m,10H),11(s,2H)ppm;MS(C23H28N4O2S2):456.1;实测:455.1(M-H)+。
1H NMR(CDCl3)2.1(d,2H,J=7),2.9(t,1H,J=7),3.1-3.5(m,6H),6.8-7.4(m,15H),11(s,2H)ppm;MS(C26H26N4O2S2):490.1;实测:489.1(M-H)+。
1H NMR(CDCl3)0.4(d,3H,J=7),1.0-1.4(m,6H),2.75(q,1H),3.0-4.3(m,4H),7.1-7.4(m,10H),10.6(s,2H);计算ESMS(C22H26N4O2S2):442.1;实测:441.1(M-H)+。C22H26N4O2S2(442.15)的分析计算值:C,59.70;H,5.92;N,12.66;S,14.49。实测:C,59.64;H,5.92;N,12.59;S,14.47。
1H NMR(DMSO-d6)3.20(br,2H),7.1-7.6(m,20H),11.5(s,2H)ppm;计算ESMS(C29H24N4O2S2):524.1;实测:523.1(M-H)+。
1H NMR(CDCl3)3.0-4.3(m,14H),6.6-7.5(m,8H),10.4(s,2H)ppm;计算ESMS(C21H24N4O2S2):460.2;实测:461.2(M+H)+。
1H NMR(CDCl3)2.65-3.60(m,8H),7.2-7.4(m,8H),11.1(br,2H);计算ESMS(C19H18Cl2N4O2S2):468.0;实测:467.9(M-H)+。
1H NMR(CDCl3)0.4(d,3H,J=7),2.7(q,1H,J=7),3.0-3.8(m,6H),7.2-8.2(m,8H),10.5-10.7(ms,2H)ppm;计算ESMS(C20H20N4O2S2):482.0;实测:481.0(M-H)+。
1H NMR(CDCl3)2.9-3.8(m,6H),7.3-7.7(m,4H),8.0-8.3(m,4H),10.9(s,2H);计算ESMS(C10H18N6O6S2):490.0;实测:489.0(M-H)+。
1H NMR(CDCl3)3.1-3.9(m,14H),6.7-7.8(m,8H),9.0-10(m,2H)ppm;计算ESMS(C21H24N4O4S2):460.1;实测:459.1(M-H)+。
(SBR-11-5032):1H NMR(CDCl3)3.0-3.9(m,14H),6.7-7.3(m,8H),9.0-10(m,2H)ppm;计算ESMS(C21H24N4O4S2):460.1;实测:459.1(M-H)+。
1H NMR(丙酮-d6)3.5(s,2H),6.45(d,2H,J=5),6.9(d,2H,J=5),7.2-7.6(m,12H),10.6(s,2H)ppm;计算ESMS(C25H20N4O4S2):504.1;实测:503.1(M-H)+。
1H NMR(DMSO-d6)2.60(s,6H),3.05(s,6H),3.40(s,2H),7.15-7.50(m,8H)ppm;计算ESMS(C27H24N6O4S2):630.1;实测:629.1(M-H)+。
1H NMR(CDCl3)10.06-8.82(2H),7.16-6.81(m,6H),4.01-3.81(m,6H),3.78-3.11(m,6H),2.81-2.58(m,2H);计算ESMS(C23H28N4O6S2):520.15;实测:521(M+H)。
1H NMR(CDCl3)10.38-9.01(2H),7.12-6.82(m,6H),3.92-3.78(m,12H),3.75-3.06(m,6H),2.61-2.51(m,2H);计算ESMS(C23H28N4O6S2):520.15;实测:521(M+H)。
1H NMR(CDCl3)9.45-8.63(2H),7.18-6.81(m,6H),4.01-3.80(m,6H),3.78-3.24(m,6H),2.62-2.50(m,1H),1.74-0.11(m,3H);计算ESMS(C24H30N4O6S2):534.16;实测:535(M+H)。
1H NMR(CDCl3)10.19-8.61(2H),7.26-6.52(m,6H),3.81-3.08(m,8H),3.01-2.88(m,12H).计算ESMS(C23H30N6O2S2):486.19;实测:487(M+H)。
1H NMR(CDCl3)9.92-8.80(2H),7.41-6.72(m,6H),4.01-3.81(m,6H),3.80-3.15(m,6H),2.76-2.42(m,2H);计算ESMS(C21H22Cl2N4O4S2):528.05;实测:529(M+H)。
1H NMR(CDCl3)10.21-9.02(2H),7.60-6.81(m,6H),4.14-3.88(m,6H),3.87-3.18(m,6H),2.84-2.65(m,1H),1.10-0.16(m,3H);计算ESMS(C22H24Cl2N4O4S2):542.06;实测:543(M+H)。
1H NMR(CDCl3)10.02-9.20(2H),7.63-7.01(m,6H),4.21-3.22(m,6H),1.88-1.36(m,2H);计算ESMS(C19H16F4N4O2S2):472.07;实测:473(M+H)。
1H NMR(CDCl3)7.93-7.61(2H),7.40-6.92(m,6H),3.98-3.41(m,6H),2.19-0.93(m,4H);计算ESMS(C20H18F4N4O2S2):486.08;实测:487(M+H)。
1H NMR(CDCl3)10.12-9.21(2H),7.67-7.23(m,6H),3.94-3.22(m,6H),2.01-1.21(m,2H);计算ESMS(C19H16Cl4N4O2S2):535.95;实测:537(M+H)。
1H NMR(CDCl3)7.78-7.23(2H),4.56-3.10(m,6H),2.34-1.12(m,4H);计算ESMS(C20H18Cl4N4O2S2):549.96;实测:551(M+H)。
1H NMR(CDCl3)9.92-9.01(2H),7.38-7.15(m,3H),6.66-6.51(m,3H),3.98-3.75(m,12H),3.72-3.21(m,6H),2.01-0.42(m,4H);计算ESMS(C24H30N4O6S2):534.16;实测:535(M+H)。
1H NMR(CDCl3)10.51-9.82(2H),7.42-6.80(m,6H),3.92-3.04(m,6H),2.60-1.21(m,14H);计算ESMS(C23H28N4O2S2):456.17;实测:457(M+H)。
1H NMR(CDCl3)10.51-9.82(2H),7.11-6.89(m,6H),3.81-3.02(m,6H),2.40-1.02(m,16H);计算ESMS(C24H30N4O2S2):470.18;实测:471(M+H)。
1H NMR(CDCl3)9.86-8.42(2H),7.01-6.6(m,6H),4.18-3.51(m,16H),3.22-2.26(2H),1.40-1.04(m,6H);计算ESMS(C25H32N4O6S2):548.18;实测:547(M-H)。
1H NMR(CDCl3)9.99-8.41(2H),7.01-6.68(m,6H),4.18-3.56(m,16H),1.40-0.02(m,10H);计算ESMS(C26H34N4O6S2):562.19;实测:561(M-H)。
1H NMR(CDCl3)10.12-8.82(2H),7.03-6.62(m,6H),4.21-3.87(m,8H),3.84-3.01(m,6H),2.71-2.42(m,2H),1.56-1.21(m,12H);计算ESMS(C27H36N4O6S2):576.21;实测:577(M+H)。
1H NMR(CDCl3)9.81-8.79(2H),7.01-6.64(m,6H),4.21-3.81(m,8H),3.80-3.22(m,6H),1.54-1.20(m,13H),1.01-0.16(m,3H);计算ESMS(C28H38N4O6S2):590.22;实测:591(M+H)。
1H NMR(DMSO-d6)8.25(d,J=8.1Hz,4H),7.50(d,J=8.1Hz,4H),3.7-3.3(m,8H);C19H18N6O6S2的计算ESMS:490.1;实测:489.0(M-H)。
1H NMR(CDCl3):10.25(m,2H),7.7-7.4(m,8H),3.7(m,2H),3.35(m,6H);C21H18N6O2S2的计算ESMS:450.1;实测:449.0(M-H)。
1H NMR(CDCl3):8.2(s,2H),7.7-7.5(m,4H),3.7-3.4(m,8H),2.9-2.8(m,6H);C19H22N6O2S2的计算ESMS:430.1;实测:431.1(M+H)。
1H NMR(CDCl3):10.0-9.2(m,2H),7.9-7.45(m,8H),4.0-3.4(m,8H);C21H18N6O2S2的计算ESMS:450.1;实测:451.0(M+H)。
1H NMR(CDCl3):10.1-9.4(2H),7.5-7.2(m,8H),3.9-3.3(m,8H);C19H18N4O2S2的计算ESMS:436.1;实测:437.1(M+H)。
1H NMR(CDCl3)3.3(s,2H),3.6(s,6H),5.25(s,4H),7.05-7.3(m,16H),7.6(s,2H),7.9(d,2H,J=6),10.56(s,2H)ppm;计算ESMS(C37H34N6O2S2):658.2;实测:659.2(M+H)+。
1H NMR(DMSO)11.98(2H),7.44-7.12(m,10H),3.69-3.14(s,6H);计算ESMS(C18H18N4O2S2):386.09;实测:387.1(M+H)。
1H NMR(CHCl3)9.48-8.55(2H),7.56-7.20(m,10H),3.80-3.31(m,6H),2.88-2.22(m,4H);计算ESMS(C20H22N4O2S2):414.12;实测:415.1(M+H)。
1H NMR(300MHz,CDCl3)10.21-9.91(m,2H),8.06-7.32(m,14H),3.91-3.56(m,6H);计算ESMS(C24H22N4O2S2):462.12;实测:463(M+H)。
1H NMR(300MHz,DMSO-d6)11.60-11.40(m,2H),7.48-6.46(m,12H),3.64-3.30(m,6H);计算ESMS(C20H20N4O2S2):412.10;实测:413(M+H)。
1H NMR(300MHz,CDCl3)7.58-7.20(m,12H),3.68-3.20(m,6H);计算ESMS(C20H20N4O2S2):412.10;实测:413(M+H)。
1H NMR(300MHz,CDCl3)9.65-8.70(2H),8.01-7.21(m,14H),3.84-3.40(m,6H);计算ESMS(C24H22N4O2S2):462.12;实测:463(M+H)。
1H NMR(CDCl3):7.2(m,18H);3.5(br s,2H);2.4(br s,6H).C31H28N4O2S2的计算MS:552.2;实测:553.2(M+H)。
1H NMR(CDCl3):7.5(br s,18H),3.4(br s,2H),2.45(s,6H).C33H28N4O6S2的计算ESMS:640.1;实测:641.1(M+H)。
1H NMR(CDCl3-D2O):7.45-7.15(m,20H),1.6(br s,6H).C31H28N4O2S2的计算ESMS:552.2;实测:553.2(M+H)。
1H NMR(DMSO-d6):11.3(s,2H),7.75(d,J=6.0Hz,2H),7.4-7.5(m,12H);6.9(m,2H);C27H24N4O2S4的计算ESMS:564.1;实测:565.2(M+H)。
1H NMR(300MHz,CDCl3):10.18-8.60(m,2H),7.26-6.46(m,8H),3.80-3.02(m,6H),3.00-2.80(m,12H).1.78-1.56(m,2H);计算ESMS(C23H30N4O2S2):486.19;实测:487(M+H)。
1H NMR(300MHz,DMSO):10.90-10.81(m,2H),7.50-7.21(m,10H),3.78-3.36(m,6H),2.64-0.50(m,10H).计算ESMS(C20H28N4O2S2):456.17;实测:457(M+H)。
1H NMR(300MHz,CDCl3):10.00-9.71(m,2H),7.72-7.21(m,8H),3.80-3.26(m,6H).计算ESMS(C20H16N6O2S2):436.08;实测:437(M+H)。
1H NMR(300MHz,CDCl3):10.60-9.41(m,2H),7.15-6.23(m,6H),3.89-3.28(m,6H),3.76(S,12H).计算ESMS(C22H28N4O6S2):506.13;实测:507(M+H)。
1H NMR(300MHz,DMSO):7.40-7.12(m,10H),3.70-2.80(m,6H),1.84-0.72(m,16H).计算ESMS(C26H34N4O2S2):498.21;实测:499(M+H)。
1H NMR(300MHz,CDCl3):10.42-9.53(m,2H),7.55-6.87(m,8H),3.99-3.28(m,6H),计算ESMS(C18H10N4F2O2S2):422.07;实测:423(M+H)。
1H NMR(300MHz,DMSO):12.08(br.10H),8.27-7.24(m,8H),3.70-3.15(m,6H).计算ESMS(C18H16N6O6S2):476.06;实测:477(M+H)。
1H NMR(300MHz,CDCl3):10.12-9.83(m,2H),7.15-6.63(m,6H),3.99-2.91(m,6H),计算ESMS(C22H26N4O6S2):506.13;实测:507(M+H)。
1H NMR(300MHz,DMSO):11.12-10.54(m,2H),8.27-7.18(m,10H),4.26-3.72(m,2H),3.37-3.18(m,2H).计算ESMS(C17H16N4O2S2):372.07;实测:371(M+H)。
1H NMR(300MHz,DMSO):11.52(br,2H),7.95-7.33(m,10H),3.42-3.22(m,6H),2.48(m,2H).计算ESMS(C23H20N4O2S4):512.05;实测:513(M+H)。
1H NMR(300MHz,CDCl3):7.81-7.28(m,8H),3.82(s,6H).计算ESMS(C22H18N4O2S4):498.03;实测:499(M+H)。
1H NMR(300MHz,CDCl3):10.02-9.11(m,2H),8.16-7.28(m,8H),3.99-3.08(m,6H),2.90-1.20(m,2H).计算ESMS(C23H24N4O6S2):516.11;实测:517(M+H)。
1H NMR(300MHz,DMSO):7.99(m,8H),8.16-7.28(m,8H),3.80-3.14(m,6H),1.80-1.21(m,2H).计算ESMS(C21H20N4O6S2):488.08;实测:487(M+H)。
1H NMR(300MHz,CDCl3):10.82-10.55(m,2H),7.91-7.29(m,10H),3.64-3.11(m,6H),1.90-1.40(m,2H).计算ESMS(C19H20N4O2S2):400.19;实测:399(M-H)。
实施例12-化合物(1)在体内增强帕尼特西的抗癌活性
体内抗癌研究的一般步骤
对小鼠肿瘤用肿瘤生长抑制检测研究新的化合物在体内的抗癌增强效果。通过向小鼠侧腹部皮下注射肿瘤细胞悬液植入肿瘤细胞。待肿瘤生长成(体积为约100mm3)后就可以用实验用化合物和帕尼特西进行肿瘤治疗。化合物和帕尼特西通过四种方式给药,并在给药部位对动物进行多次注射。每周进行两次肿瘤检测。在检测过程中,每天对动物身上出现的危险标志,包括体重的降低,进行检测。
步骤
用50%DMEM/Dulbecco改进的Eagle培养基(高葡萄糖),50%RPMI 1640,10%FBS/牛胎血清(经杂交瘤检测;过滤灭菌),1%L-谷氨酰胺,1%青霉素-链霉素,1%MEM丙酮酸钠和1%MEM非基本氨基酸制备补充培养基。FBS得自Sigma Chemical Co.,其它试剂都得自Invitrogen Life Technologies,USA。将补充培养基加热至37℃,取50ml加入175cm2的组织培养瓶中。
检测所用细胞是来自美国典型培养物保藏中心的MDA-435人乳腺癌细胞。取一小瓶液氮冷冻的MDA-435细胞,立即放入37℃水浴中,轻旋直至解冻。冷冻瓶用70%乙醇洗涤,立即将细胞用吸管转至175cm2含补充培养基的组织培养瓶中。细胞培育过夜,隔天倾去培养基,换以新鲜的补充培养液。培育至培养瓶中细胞有90%汇合。大约需要5-7天。
用10ml无菌室温磷酸盐缓冲液(PBS)洗涤培养瓶。向培养瓶中的细胞加入5ml温育的胰蛋白酶-EDTA(Invitrogen)使其胰蛋白酶化。然后37℃培育细胞2-3分钟直至细胞开始从培养瓶表面解离。向培养瓶中加入等体积的补充培养基(5ml)。将所有细胞收集在一个50ml的试管中,20℃1000rpm离心5分钟。吸去上清,细胞沉淀重悬于10ml补充培养基中,计数。1-3百万个细胞/培养瓶接入5-7个组织培养瓶(175cm2)中。每个培养瓶中有50ml补充培养基。培养细胞直至培养瓶中细胞有90%汇合。重复转接细胞直至有足够的细胞进行肿瘤移植。
上述胰蛋白酶化和离心步骤之后,吸取上清并将细胞沉淀重悬于10ml无菌PBS中,进行细胞计数。细胞离心并用适当体积的无菌PBS重悬,以注射适当数目的细胞进行肿瘤移植。对于MDA-435,100百万个细胞重悬于2.0ml无菌PBS中,使终浓度达到50百万个细胞/ml,每个小鼠注射0.1ml即5百万个细胞。
小鼠(CD-1 nu/nu)得自Charles River实验室:术语:Crl:CD-1-nuBR,年龄:6-8周。小鼠在进行实验之前允许适应1周。
MDA-435肿瘤细胞悬液移植入雌性CD-1 nu/nu小鼠的脂肪体中。此脂肪体在小鼠的侧腹部的内脏处。肿瘤细胞经皮下移植到位于髋骨(骨盆)和股骨(大腿骨)交界处的腹部的右边四分之一处的脂肪体中。用27G(1/2英寸)的针管注射0.1ml无菌PBS中含有的5百万个MDA-435细胞。移植后2-3周可发生MDA-435肿瘤。
将所述化合物以需要的浓度溶解于细胞培养级的DMSO(二甲亚砜)中以制备化合物储液。该DMSO的储液在超声水浴中进行超声处理,直至所有粉末溶解。
配方溶剂如下制备:首先在50-60℃水浴中加热100%Cremophore RH40直至其溶解,澄清以制备20%CremophoreRH40(聚氧乙烯40氢化蓖麻油,得自BASF公司)的水溶液。将10ml 100%Cremophore RH40等分放入含有40ml无菌水的圆锥形离心管中(Cremophore RH40以1∶5的比例稀释)。将20%Cremophore RH40溶液重新加热,直至其再次变得澄清,将试管颠倒几次混匀。此20%Cremophore RH40溶液室温贮存,可贮存3个月。
化合物给药的计量溶液的制备:化合物储液以1∶10的比例用20%Cremophore RH40稀释。:1)将100mg/ml的化合物储液用1.8ml的20%Cremophore RH40水溶液稀释,得到2.0ml的10mg/ml的化合物(1)的计量溶液;2)将0.1ml的化合物1的DMSO储液(50mg/ml)和0.1ml的帕尼特西的DMSO储液(10mg/ml)混合,然后用1.8ml的20%Cremophore RH40水溶液稀释,得到含有2.0ml的1mg/ml帕尼特西(得自Sigma Chemical Co.)和5mg/ml化合物(1)的计量溶液。最终的计量溶液的组分是10%DMSO,18%Cremophore RH40和72%水。
将剂量溶液(计量体积:0.01ml/gram=10ml/kg)给有MDA-435人乳腺癌肿瘤的小鼠进行静脉注射。
实验方法
组 药物治疗 (剂量)
1 只用载体
2 帕尼特西 (15mg/kg)
3 化合物(1) (25mg/kg)
4 帕尼特西 (15mg/kg)+化合物(1)(25mg/kg)
5 帕尼特西 (15mg/kg)+化合物(1)(50mg/kg)
剂量安排:一共三周,每周3次(周一,周三,周五),每组5只小鼠
结果
图1显示了化合物(1)增强帕尼特西(紫杉醇)的抗肿瘤活性的效果。从图1中可以看到,化合物(1)显著增强了帕尼特西对于裸鼠中人乳腺癌肿瘤MDA-435的抗肿瘤活性。图2显示了化合物(1)和帕尼特西对于有MDA-435人乳腺癌肿瘤的裸鼠的体重的影响。从图2中可以看出,化合物(1)显著增强了帕尼特西的抗肿瘤活性,而没有增加其毒性。
实施例13-化合物(1)和(2)在体内增强帕尼特西的抗癌活性
化合物(2)
实施例12中的实验方法都可用于检测化合物(1)和(2)增强帕尼特西对于小鼠的抗癌活性的能力,其中做如下修改。
实验方法
组 药物治疗 (剂量)
1 只用载体
2 帕尼特西 (2mg/kg)
3 帕尼特西 (5mg/kg)
4 化合物(1) (80mg/kg)
5 化合物(2) (80mg/kg)
6 帕尼特西 (2mg/kg)+化合物(1)(80mg/kg)
7 帕尼特西 (5mg/kg)+化合物(1)(80mg/kg)
8 帕尼特西 (2mg/kg)+化合物(2)(80mg/kg)
9 帕尼特西 (5mg/kg)+化合物(2)(80mg/kg)
剂量安排:一共三周,每周3次(周一,周三,周五),每组5只小鼠。
结果
组 第23天的平均肿瘤体积(mm3) 肿瘤生长百分率
1 301.3 100
2 259.8 86
3 164.8 55
4 270.0 90
5 305.8 101
6 193.3 64
7 106.2 35
8 148.4 49
9 60.6 20
化合物(1)和(2)用2mg/kg和5mg/kg都显著增加了帕尼特西的抗肿瘤活性,而没有增加其毒性。
实施例14-化合物(1)在体内增强了帕尼特西的抗癌活性。
实施例12中的实验方法都可用于检测化合物(1)和(2)增强帕尼特西对于小鼠的抗癌活性的能力,其中做如下修改。
实验方法
组 药物治疗 (剂量)
1 只用载体
2 帕尼特西 (10mg/kg)
3 化合物(1) (50mg/kg)
4 帕尼特西 (10mg/kg)+化合物(1)(25mg/kg)
剂量安排:
一共三周,每周3次(周一,周三,周五),每组5只小鼠。
结果
组 平均肿瘤体积[mm3] 第48天的肿瘤生长抑制百分率
1 752.2 -
2 105.4 86%
3 754.9 0%
4 0.59 >99.9%
使用10mg/kg帕尼特西时可以观察到显著的抗肿瘤活性。但是,在药物治疗(1-20天)终止后,肿瘤开始生长,到第43天长到105mm3。另一方面,用帕尼特西(10mg/kg)加上化合物(1)(25mg/kg)治疗的平均肿瘤体积只有0.59mm3,肿瘤生长的抑制达到99.9%以上。
实施例15-化合物(3)-(5)在体内增强帕尼特西的抗癌活性
化合物(3)
化合物(4)
化合物(5)
实施例12中的实验方法都可用于检测化合物(1)和(2)增强帕尼特西对于小鼠的抗癌活性的能力,其中做如下修改。
实验方法
组 药物治疗 (剂量)
1 只用载体
2 帕尼特西 (5mg/kg)
3 帕尼特西 (5mg/kg)+化合物(3)(50mg/kg)
4 帕尼特西 (5mg/kg)+化合物(4)(100mg/kg)
5 帕尼特西 (5mg/kg)+化合物(5)(100mg/kg)
剂量安排:
一共三周,每周3次(周一,周三,周五),每组5只小鼠。
结果
组 第27天的平均肿瘤生长抑制百分率
2 19
3 76
4 66
5 79
化合物(3)-(5)已证明可以显著增强紫杉醇的抗肿瘤活性。
本发明是通过优选实施方式来描述,本领域技术人员应当理解,在不脱离本发明权利要求书所定义的范围的情况下,可以在形式上和细节上有各种变化。
Claims (33)
1.由下述结构式表示的化合物:
或者其药学可接受的盐,其中:
Y是共价键,次苯基或取代或未取代的直链C1-C10的亚烷基,或者,Y和与其相连的两侧的>C=Z一起构成取代或未取代的芳香族基团;
R1和R2独立地是芳基或取代的芳基;
R3和R4独立地是-H,脂族基,取代的脂族基,芳基或取代的芳基;
R5-R6独立地是-H,脂族基,取代的脂族基,芳基或取代的芳基;
Z是=O或=S;
其中,每个脂族基独立地是C1-C20直链或支链烃基或C3-C10环状非芳香族烃基,是完全饱和的或含有一个或多个不饱和单位;
每个芳基或芳香族基团独立地选自苯基,萘基,蒽基,咪唑基,噻吩基,呋喃基,吡啶基,嘧啶基,吡喃基,吡唑基,吡咯基,吡嗪基,噻唑,呃唑基,四唑,苯噻嗯基,苯并呋喃基,吲哚,喹啉,苯并噻唑,苯并唑,苯并咪唑,喹啉,异喹啉,和异氮杂茚基;
其中,环状非芳香族烃基包括非芳香族杂环,每个非芳香族杂环是5到8元非芳香族碳环,在环上包括一个或多个N,O,或S原子;
取代芳基的取代基独立地选自-OH,-Br,-Cl,-I和-F,-ORa,-O-CORa,-CORa,-CN,-NO2,-COOH,-SO3H,-NH2,-NHRa,-N(RaRb),-COORa,-CHO,-CONH2,-CONHRa,-CON(RaRb),-NHCORa,-NRCORa,-NHCONH2,-NHCONRaH,-NHCON(RaRb),-NRcCONH2,-NRcCONRaH,-NRcCON(RaRb),-C(=NH)-NH2,-C(=NH)-NHRa,-C(=NH)-N(RaRb),-C(=NRc)-NH2,-C(=NRc)-NHRa,-C(=NRc)-N(RaRb),-NH-C(=NH)-NH2,-NH-C(=NH)-NHRa,-NH-C(=NH)-N(RaRb),-NH-C(=NRc)-NH2,-NH-C(=NRc)-NHRa,-NH-C(=NRc)-N(RaRb),-NRd-C(=NH)-NH2,-NRd-C(=NH)-NHRa,-NRd-C(=NH)-N(RaRb),-NRd-C(=NRc)-NH2,-NRd-C(=NRc)-NHRa,-NRd-C(=NRc)-N(RaRb),-NHNH2,-NHNHRa,-SO2NH2,-SO2NHRa,-SO2NRaRb,-CH=CHRa,-CH=CRaRb,-CRc=CRaRb,-CRc=CHRa,-CRc=CRaRb,-CCRa,-SH,-SOkRa和-NH-C(=NH)-NH2以及脂族基团;并且
取代C1-C10的亚烷基或脂族基团的取代基独立地选自-OH,-Br,-C1,-I,-F,-ORa,-O-CORa,-CORa,-CN,-NO2,-COOH,-SO3H,-NH2,-NHRa,-N(RaRb),-COORa,-CHO,-CONH2,-CONHRa,-CON(RaRb),-NHCORa,-NRCORa,-NHCONH2,-NHCONRaH,-NHCON(RaRb),-NRcCONH2,-NRcCONRaH,-NRcCON(RaRb),-C(=NH)-NH2,-C(=NH)-NHRa,-C(=NH)-N(RaRb),-C(=NRc)-NH2,-C(=NRc)-NHRa,-C(=NRc)-N(RaRb),-NH-C(=NH)-NH2,-NH-C(=NH)-NHRa,-NH-C(=NH)-N(RaRb),-NH-C(=NRc)-NH2,-NH-C(=NRc)-NHRa,-NH-C(=NRc)-N(RaRb),-NRd-C(=NH)-NH2,-NRd-C(=NH)-NHRa,-NRd-C(=NH)-N(RaRb),-NRd-C(=NRc)-NH2,-NRd-C(=NRc)-NHRa,-NRd-C(=NRc)-N(RaRb),-NHNH2,-NHNHRa,-SO2NH2,-SO2NHRa,-SO2NRaRb,-CH=CHRa,-CH=CRaRb,-CRc=CRaRb,-CRc=CHRa,-CRc=CRaRb,-CCRa,-SH,-SOkRa,-NH-C(-NH)-NH2,非芳香族杂环,苄基,以及芳基;并且
Ra-Rd分别独立地是烷基,苄基或芳基基团;或者,-N(RaRd)一起构成非芳香族的杂环基团;
K是0,1或2;
其前提是,当Y是-CH2-,R3和R4都是苯基,R5-R6都是-H的时候,R1和R2不都是苯基。
5.权利要求4的化合物,其中R1和R2都是芳基或取代的芳基,R3和R4都是C1-C20烷基或取代的C1-C20烷基,所述取代基的定义如权利要求1所述。
6.权利要求5的化合物,其中R1和R2都是苯基或取代的苯基,R3和R4都是甲基,乙基,苯基或噻吩基,所述取代基的定义如权利要求1所述。
7.权利要求6的化合物,其中R7和R8都是甲基,或者R7和R8一起是亚丙基或亚丁基,或者,R7是-H,R8是C1-C20烷基,噻吩基,苯基或苄基。
9.权利要求8的化合物,其中R1和R2均是选择性地被一个或多个下列基团取代的苯基:-OH,-Br,-Cl,-I,-F,-ORa,-O-CORa,-CORa,-CN,-NO2,-COOH,-SO3H,-NH2,-NHRa,-N(RaRb),-COORa,-CHO,-CONH2,-CONHRa,-CON(RaRb),-NHCORa,-NRCORa,-NHCONH2,-NHCONRaH,-NHCON(RaRb),-NRcCONH2,-NRcCONRaH,-NRcCON(RaRb),-C(=NH)-NH2,-C(=NH)-NHRa,-C(=NH)-N(RaRb),-C(=NRc)-NH2,-C(=NRc)-NHRa,-C(=NRc)-N(RaRb),-NH-C(=NH)-NH2,-NH-C(=NH)-NHRa,-NH-C(=NH)-N(RaRb),-NH-C(=NRc)-NH2,-NH-C(=NRc)-NHRa,-NH-C(=NRc)-N(RaRb),-NRd-C(=NH)-NH2,-NRd-C(=NH)-NHRa,-NRd-C(=NH)-N(RaRb),-NRd-C(=NRc)-NH2,-NRd-C(=NRc)-NHRa,-NRd-C(=NRc)-N(RaRb),-NHNH2,-NHNHRa,-SO2NH2,-SO2NHRa,-SO2NRaRb,-CH=CHRa,-CH=CRaRb,-CRc=CRaRb,-CRc=CHRa,-CRc=CRaRb,-CCRa,-SH,-SRa,-S(O)Ra,-S(O)2Ra,其中Ra-Rd分别独立地是烷基,苄基,或芳香族基团,或者,-N(RaRd),一起构成非芳香族的杂环基团。
11.权利要求10的化合物,其中R5和R6均是C1-C20烷基或苯基。
12.权利要求1的化合物,其中化合物由下述结构式表示:
或其药学可接受的盐,其中:
a)R1和R2均是苯基;R3和R4均是甲基;R7和R8均是-H;
b)R1和R2均是苯基;R3和R4均是乙基;R7和R8均是-H;
c)R1和R2均是4-苯腈基;R3和R4均是甲基;R7是甲基;R8是-H;
d)R1和R2均是4-甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
e)R1和R2均是苯基;R3和R4均是甲基;R7是甲基;R8是-H;
f)R1和R2均是苯基;R3和R4均是乙基;R7是甲基;R8是-H;
g)R1和R2均是4-苯腈基;R3和R4均是甲基;R7和R8均是-H;
h)R1和R2均是2,5-二甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
i)R1和R2均是2,5-二甲氧基苯基;R3和R4均是甲基;R7是甲基;R8是-H;
j)R1和R2均是3-苯腈基;R3和R4均是甲基;R7和R8均是-H;
k)R1和R2均是3-氟苯基;R3和R4均是甲基;R7和R8均是-H;
l)R1和R2均是4-氯苯基;R3和R4均是甲基;R7是甲基;R8是-H;
m)R1和R2均是2-二甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
n)R1和R2均是3-甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
o)R1和R2均是2,3-二甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
p)R1和R2均是2,3-二甲氧基苯基;R3和R4均是甲基;R7是甲基;R8是-H;
q)R1和R2均是2,5-二氟苯基;R3和R4均是甲基;R7和R8均是-H;
r)R1和R2均是2,5-二氟苯基;R3和R4均是甲基;R7是甲基;R8是-H;
s)R1和R2均是2,5-二氯苯基;R3和R4均是甲基;R7和R8均是-H;
t)R1和R2均是2,5-二甲基苯基;R3和R4均是甲基;R7和R8均是-H;
u)R1和R2均是2,5-二甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
v)R1和R2均是2,5-二甲氧基苯基;R3和R4均是甲基;R7是甲基;R8是-H。
13.权利要求12的化合物,其中R1和R2均是苯基;R3和R4均是甲基;R7和R8均是-H。
14.一种药物组合物,包含药学可接受的载体或稀释剂和由下述结构式表示的化合物
或其药学可接受的盐,其中:
Y是共价键,次苯基或取代或未取代的直链C1-C10的亚烷基,或者,Y和与其相连的两侧的>C=Z一起构成取代或未取代的芳香基团;
R1和R2独立地是芳基或取代的芳基;
R3和R4独立地是-H,脂族基,取代的脂族基,芳基或取代的芳基;
R5-R6独立地是-H,脂族基,取代的脂族基,芳基或取代的芳基;
Z是=O或=S;
其中,每个脂族基独立地是C1-C20直链或支链烃基或C3-C10环状非芳香族烃基,是完全饱和的或含有一个或多个不饱和单位;
每个芳基或芳香族基团独立地选自苯基,萘基,蒽基,咪唑基,噻吩基,呋喃基,吡啶基,嘧啶基,吡喃基,吡唑基,吡咯基,吡嗪基,噻唑,呃唑基,四唑,苯噻嗯基,苯并呋喃基,吲哚,喹啉,苯并噻唑,苯并唑,苯并咪唑,喹啉,异喹啉,和异氮杂茚基;
其中,环状非芳香族烃基包括非芳香族杂环,每个非芳香族杂环是5到8元非芳香族碳环,在环上包括一个或多个N,O,或S原子;
取代芳基的取代基独立地选自-OH,-Br,-Cl,-I和-F,-ORa,-O-CORa,-CORa,-CN,-NO2,-COOH,-SO3H,-NH2,-NHRa,-N(RaRb),-COORa,-CHO,-CONH2,-CONHRa,-CON(RaRb),-NHCORa,-NRCORa,-NHCONH2,-NHCONRaH,-NHCON(RaRb),-NRcCONH2,-NRcCONRaH,-NRcCON(RaRb),-C(=NH)-NH2,-C(=NH)-NHRa,-C(=NH)-N(RaRb),-C(=NRc)-NH2,-C(=NRc)-NHRa,-C(=NRc)-N(RaRb),-NH-C(=NH)-NH2,-NH-C(=NH)-NHRa,-NH-C(=NH)-N(RaRb),-NH-C(=NRc)-NH2,-NH-C(=NRc)-NHRa,-NH-C(=NRc)-N(RaRb),-NRd-C(=NH)-NH2,-NRd-C(=NH)-NHRa,-NRd-C(=NH)-N(RaRb),-NRd-C(=NRc)-NH2,-NRd-C(=NRc)-NHRa,-NRd-C(=NRc)-N(RaRb),-NHNH2,-NHNHRa,-SO2NH2,-SO2NHRa,-SO2NRaRb,-CH=CHRa,-CH=CRaRb,-CRc=CRaRb,-CRc=CHRa,-CRc=CRaRb,-CCRa,-SH,-SOkRa和-NH-C(=NH)-NH2以及脂族基团;并且
取代C1-C10的亚烷基或脂族基团的取代基独立地选自-OH,-Br,-C1,-I,-F,-ORa,-O-CORa,-CORa,-CN,-NO2,-COOH,-SO3H,-NH2,-NHRa,-N(RaRb),-COORa,-CHO,-CONH2,-CONHRa,-CON(RaRb),-NHCORa,-NRCORa,-NHCONH2,-NHCONRaH,-NHCON(RaRb),-NRcCONH2,-NRcCONRaH,-NRcCON(RaRb),-C(=NH)-NH2,-C(=NH)-NHRa,-C(=NH)-N(RaRb),-C(=NRc)-NH2,-C(=NRc)-NHRa,-C(=NRc)-N(RaRb),-NH-C(=NH)-NH2,-NH-C(=NH)-NHRa,-NH-C(=NH)-N(RaRb),-NH-C(=NRc)-NH2,-NH-C(=NRc)-NHRa,-NH-C(=NRc)-N(RaRb),-NRd-C(=NH)-NH2,-NRd-C(=NH)-NHRa,-NRd-C(=NH)-N(RaRb),-NRd-C(=NRc)-NH2,-NRd-C(=NRc)-NHRa,-NRd-C(=NRc)-N(RaRb),-NHNH2,-NHNHRa,-SO2NH2,-SO2NHRa,-SO2NRaRb,-CH=CHRa,-CH=CRaRb,-CRc=CRaRb,-CRc=CHRa,-CRc=CRaRb,-CCRa,-SH,-SOkRa,-NH-C(-NH)-NH2,非芳香族杂环,苄基以及芳基;并且
Ra-Rd分别独立地是烷基,苄基或芳香基基团;或者,-N(RaRd)一起构成非芳香族的杂环基团;
其中,K是0,1或2。
17.权利要求16的药物组合物,其中R1和R2均是苯基或取代的苯基;R3和R4是甲基,乙基,苯基或噻吩基;以及,R7和R8均是甲基;R7和R8一起是亚丙基或亚丁基;或者,R7是-H,R8是C1-C20烷基,噻吩基,苯基或苄基,所述取代基的定义如权利要求14所述。
19.权利要求18的药物组合物,其中R1和R2均是选择性地被一个或多个下列基团取代的苯基:-OH,-Br,-Cl,-I,-F,-ORa,-O-CORa,-CORa,-CN,-NO2,-COOH,-SO3H,-NH2,-NHRa,-N(RaRb),-COORa,-CHO,-CONH2,-CONHRa,-CON(RaRb),-NHCORa,-NRCORa,-NHCONH2,-NHCONRaH,-NHCON(RaRb),-NRcCONH2,-NRcCONRaH,-NRcCON(RaRb),-C(=NH)-NH2,-C(=NH)-NHRa,-C(=NH)-N(RaRb),-C(=NRc)-NH2,-C(=NRc)-NHRa,-C(=NRc)-N(RaRb),-NH-C(=NH)-NH2,-NH-C(=NH)-NHRa,-NH-C(=NH)-N(RaRb),-NH-C(=NRc)-NH2,-NH-C(=NRc)-NHRa,-NH-C(=NRc)-N(RaRb),-NRd-C(=NH)-NH2,-NRd-C(=NH)-NHRa,-NRd-C(=NH)-N(RaRb),-NRd-C(=NRc)-NH2,-NRd-C(=NRc)-NHRa,-NRd-C(=NRc)-N(RaRb),-NHNH2,-NHNHRa, -SO2NH2,-SO2NHRa,-SO2NRaRb,-CH=CHRa,-CH=CRaRb,-CRc=CRaRb,-CRc=CHRa,-CRc=CRaRb,-CCRa,-SH,-SRa,-S(O)Ra,-S(O)2Ra,其中Ra-Rd分别独立地是烷基,苄基,或芳香族基团,或者,-N(RaRd),一起构成非芳香族的杂环基团。
20.权利要求14的药物组合物,其中化合物由下述结构式表示:
或其药学可接受的盐,其中:
a)R1和R2均是苯基;R3和R4均是苯基;R7和R8均是-H;
b)R1和R2均是苯基;R3和R4均是乙基;R7和R8均是-H;
c)R1和R2均是4-苯腈基;R3和R4均是甲基;R7是甲基;R8是-H;
d)R1和R2均是4-甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
e)R1和R2均是苯基;R3和R4均是甲基;R7是甲基;R8是-H;
f)R1和R2均是苯基;R3和R4均是乙基;R7是甲基;R8是-H;
g)R1和R2均是4-苯腈基;R3和R4均是甲基;R7和R8均是-H;
h)R1和R2均是2,5-二甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
i)R1和R2均是2,5-二甲氧基苯基;R3和R4均是甲基;R7是甲基;R8是-H;
j)R1和R2均是3-苯腈基;R3和R4均是甲基;R7和R8均是-H;
k)R1和R2均是3-氟苯基;R3和R4均是甲基;R7和R8均是-H;
l)R1和R2均是4-氯苯基;R3和R4均是甲基;R7是甲基;R8是-H;
m)R1和R2均是2-二甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
n)R1和R2均是3-甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
o)R1和R2均是2,3-二甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
p)R1和R2均是2,3-二甲氧基苯基;R3和R4均是甲基;R7是甲基;R8是-H;
q)R1和R2均是2,5-二氟苯基;R3和R4均是甲基;R7和R8均是-H;
r)R1和R2均是2,5-二氟苯基;R3和R4均是甲基;R7是甲基;R8是-H;
s)R1和R2均是2,5-二氯苯基;R3和R4均是甲基;R7和R8均是-H;
t)R1和R2均是2,5-二甲基苯基;R3和R4均是甲基;R7和R8均是-H;
u)R1和R2均是2,5-二甲氧基苯基;R3和R4均是甲基;R7和R8均是-H;
v)R1和R2均是苯基;R3和R4均是甲基;R7和R8均是-H;
w)R1和R2均是2,5-二甲氧基苯基;R3和R4均是甲基;R7是甲基;R8是-H。
21.权利要求20的药物组合物,其中R1和R2均是苯基;R3和R4均是甲基;R7和R8均是-H。
22.由下述结构式表示的化合物在制备与紫杉醇或紫杉醇类似物共同治疗癌症的药物中的应用:
或者其药学可接受的盐,其中:
Y是共价键,次苯基或取代或未取代的直链C1-C10的亚烷基;或者,Y和与其相连的两侧的>C=Z一起构成取代或未取代的芳香族基团;
R1和R2独立地是芳基或取代的芳基;
R3和R4独立地是-H,脂族基,取代的脂族基,芳基或取代的芳基;
R5-R6独立地是-H,脂族基,取代的脂族基,芳基或取代的芳基;
Z是=O或=S;
其中,每个脂族基独立地是C1-C20直链或支链烃基或C3-C10环状非芳香族烃基,是完全饱和的或含有一个或多个不饱和单位;
每个芳基或芳香族基团独立地选自苯基,萘基,蒽基,咪唑基,噻吩基,呋喃基,吡啶基,嘧啶基,吡喃基,吡唑基,吡咯基,吡嗪基,噻唑,呃唑基,四唑,苯噻嗯基,苯并呋喃基,吲哚,喹啉,苯并噻唑,苯并唑,苯并咪唑,喹啉,异喹啉,和异氮杂茚基;
其中,环状非芳香族烃基包括非芳香族杂环,每个非芳香族杂环是5到8元非芳香族碳环,在环上包括一个或多个N,O,或S原子;
取代芳基的取代基独立地选自-OH,-Br,-Cl,-I和-F,-ORa,-O-CORa,-CORa,-CN,-NO2,-COOH,-SO3H,-NH2,-NHRa,-N(RaRb),-COORa,-CHO,-CONH2,-CONHRa,-CON(RaRb),-NHCORa,-NRCORa,-NHCONH2,-NHCONRaH,-NHCON(RaRb),-NRcCONH2,-NRcCONRaH,-NRcCON(RaRb),-C(=NH)-NH2,-C(=NH)-NHRa,-C(=NH)-N(RaRb),-C(=NRc)-NH2,-C(=NRc)-NHRa,-C(=NRc)-N(RaRb),-NH-C(=NH)-NH2,-NH-C(=NH)-NHRa,-NH-C(=NH)-N(RaRb),-NH-C(=NRc)-NH2,-NH-C(=NRc)-NHRa,-NH-C(=NRc)-N(RaRb),-NRd-C(=NH)-NH2,-NRd-C(=NH)-NHRa,-NRd-C(=NH)-N(RaRb),-NRd-C(=NRc)-NH2,-NRd-C(=NRc)-NHRa,-NRd-C(=NRc)-N(RaRb),-NHNH2,-NHNHRa,-SO2NH2,-SO2NHRa,-SO2NRaRb,-CH=CHRa,-CH=CRaRb,-CRc=CRaRb,-CRc=CHRa,-CRc=CRaRb,-CCRa,-SH,-SOkRa和-NH-C(=NH)-NH2以及脂族基团;并且
取代C1-C10的亚烷基或脂族基基团的取代基独立地选自-OH,-Br,-C1,-I,-F,-ORa,-O-CORa,-CORa,-CN,-NO2,-COOH,-SO3H,-NH2,-NHRa,-N(RaRb),-COORa,-CHO,-CONH2,-CONHRa,-CON(RaRb),-NHCORa,-NRCORa,-NHCONH2,-NHCONRaH,-NHCON(RaRb),-NRcCONH2,-NRcCONRaH,-NRcCON(RaRb),-C(=NH)-NH2,-C(=NH)-NHRa,-C(=NH)-N(RaRb),-C(=NRc)-NH2,-C(=NRc)-NHRa,-C(=NRc)-N(RaRb),-NH-C(=NH)-NH2,-NH-C(=NH)-NHRa,-NH-C(=NH)-N(RaRb),-NH-C(=NRc)-NH2,-NH-C(=NRc)-NHRa,-NH-C(=NRc)-N(RaRb),-NRd-C(=NH)-NH2,-NRd-C(=NH)-NHRa,-NRd-C(=NH)-N(RaRb),-NRd-C(=NRc)-NH2,-NRd-C(=NRc)-NHRa,-NRd-C(=NRc)-N(RaRb),-NHNH2,-NHNHRa,-SO2NH2,-SO2NHRa,-SO2NRaRb,-CH=CHRa,-CH=CRaRb,-CRc=CRaRb,-CRc=CHRa,-CRc=CRaRb,-CCRa,-SH,,非芳香族杂环,苄基,以及芳基;并且Ra-Rd分别独立地是烷基,苄基或芳香基基团;或者,-N(RaRd)一起构成非芳香族的杂环基团;
其中,K是0,1或2。
23.权利要求22的应用,其中所述化合物由下述结构式表示:
其中Y’是共价键或者-CR7R8-,R7和R8分别独立地是-H,脂族基或取代的脂族基,或者R7是-H,R8是取代或未取代的芳基,或者R7和R8一起是C2-C6的取代的或未取代的亚烷基,所述取代基团的定义如权利要求22所述。
24.权利要求22的应用,其中所述紫杉醇类似物由选自下组的结构式表示:
或
其中:
R10是C1-C20烷基,取代的C1-C20烷基,苯基,取代的苯基,-SR19,-NHR19或-OR19;
R11是C1-C20烷基,取代的C1-C20烷基,芳基或取代的芳基;
R12是-H,-OH,C1-C20烷基,取代的C1-C20烷基,C1-C20烷氧基,取代的C1-C20烷氧基,-O-C(O)-(C1-C20烷基),-O-C(O)-(取代的C1-C20烷基),-O-CH2-O-(C1-C20烷基)-S-CH2-O-(C1-C20烷基);
R13是-H,-CH3,或者,与R14一起是-CH2-;
R14是-H,-OH,C1-C20烷氧基,-O-C(O)-(C1-C20烷基),取代的C1-C20烷氧基,-O-C(O)-(取代的C1-C20烷基),-O-CH2-O-P(O)(OH)2,-O-CH2-O-(C1-C20烷基),-O-CH2-S-(C1-C20烷基),或者与R20一起是双键;
R15是-H,C1-C20酰基,C1-C20烷基,取代的C1-C20烷基,烷氧基甲基,烷基硫代甲基,-OC(O)-O(C1-C20烷基),-OC(O)-O(取代的C1-C20烷基),-OC(O)-NH(C1-C20烷基)或-OC(O)-NH(取代的C1-C20烷基);
R16是苯基或取代的苯基;
R17是-H,C1-C20酰基,取代的C1-C20酰基,C1-C20烷基,取代的C1-C20烷基,(C1-C20烷氧基)甲基或者(C1-C20烷基)硫甲基;
R18是-H,-CH3,或者,与R17以及和R17和R18相连接的碳原子一起,构成五元或六元的非芳香族的杂环;
R19是C1-C20烷基,取代的C1-C20烷基,苯基,取代的苯基;
R20是-H或卤素;
R21是-H,C1-C20烷基,取代的C1-C20烷基,C1-C20酰基或取代的C1-C20酰基;
所述取代的基的定义如权利要求22所述。
25.权利要求24的应用,其中:
R10是苯基,叔丁氧基,-S-CH2-CH-(CH3)2,-S-CH(CH3)3,-S-(CH2)3CH3,-O-CH(CH3)3,-NH-CH(CH3)3,-CH=C(CH3)2或对氯苯基;
R11是苯基,(CH3)2CHCH2-,-2-呋喃基,环丙基或对甲苯甲酰;
R12是-H,-OH,CH3CO-或-(CH2)2-N-吗啉代;
R13是甲基,或者R13和R14一起是-CH2-;
R14是-H,-CH2SCH3或-CH2-O-P(O)(OH)2;
R15是CH3CO-;
R16是苯基;
R17是-H,或者R17和R18一起是-O-CO-O-;
R18是-H;
R20是-H或-F;
R21是-H,-C(O)-CHBr-(CH2)13-CH3或者-C(O)-(CH2)14-CH3,-C(O)-CH2-CH(OH)-COOH,-C(O)-CH2-O-C(O)-CH2CH(NH2)-CONH2,-C(O)-CH2-O-CH2CH2OCH3或者-C(O)-O-C(O)-CH2CH3。
29.权利要求28的应用,其中R1和R2均是芳基或取代的芳基,R3和R4均是C1-C20烷基或取代的C1-C20烷基,所述取代基的定义如权利要求22所述。
31.权利要求30的应用,其中R1和R2均是选择性地被一个或多个下列基团取代的苯基:-OH,-Br,-Cl,-I,-F,-ORa,-O-CORa,-CORa,-CN,-NO2,-COOH,-SO3H,-NH2,-NHRa,-N(RaRb),-COORa,-CHO,-CONH2,-CONHRa,-CON(RaRb),-NHCORa,-NRCORa,-NHCONH2,-NHCONRaH,-NHCON(RaRb),-NRcCONH2,-NRcCONRaH,-NRcCON(RaRb),-C(=NH)-NH2,-C(=NH)-NHRa,-C(=NH)-N(RaRb),-C(=NRc)-NH2,-C(=NRc)-NHRa,-C(=NRc)-N(RaRb),-NH-C(=NH)-NH2,-NH-C(=NH)-NHRa,-NH-C(=NH)-N(RaRb),-NH-C(=NRc)-NH2,-NH-C(=NRc)-NHRa,-NH-C(=NRc)-N(RaRb),-NRd-C(=NH)-NH2,-NRd-C(=NH)-NHRa,-NRd-C(=NH)-N(RaRb),-NRd-C(=NRc)-NH2,-NRd-C(=NRc)-NHRa,-NRd-C(=NRc)-N(RaRb),-NHNH2,-NHNHRa,-SO2NH2,-SO2NHRa,-SO2NRaRb,-CH=CHRa,-CH=CRaRb,-CRc=CRaRb,-CRc=CHRa,-CRc=CRaRb,-CCRa,-SH,-SRa,-S(O)Ra,-S(O)2Ra,其中Ra-Rd分别独立地是烷基,苄基,芳香基团,或者,-N(RaRd),一起构成非芳香族的杂环基团。
32.权利要求22的应用,其中R1和R2均是苯基;R3和R4均是甲基;R5和R6均是-H;Z是-O;Y是-CH2-。
33.权利要求22的应用,其中所述的癌症是结肠癌,胰癌,黑色素瘤,肾癌,肉瘤,乳腺癌,卵巢癌,肺癌,胃癌,膀胱癌和宫颈癌。
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Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI297335B (en) | 2001-07-10 | 2008-06-01 | Synta Pharmaceuticals Corp | Taxol enhancer compounds |
TWI252847B (en) * | 2001-07-10 | 2006-04-11 | Synta Pharmaceuticals Corp | Synthesis of taxol enhancers |
US6924312B2 (en) | 2001-07-10 | 2005-08-02 | Synta Pharmaceuticals Corp. | Taxol enhancer compounds |
TWI332943B (en) | 2001-07-10 | 2010-11-11 | Synta Pharmaceuticals Corp | Taxol enhancer compounds |
TWI330079B (en) * | 2003-01-15 | 2010-09-11 | Synta Pharmaceuticals Corp | Treatment for cancers |
AU2006228035B2 (en) * | 2003-01-15 | 2010-02-18 | Synta Pharmaceuticals Corp. | Bis (thio-hydrazide amide) compounds for treating multi-drug resistant cancer |
JP5362986B2 (ja) | 2004-06-23 | 2013-12-11 | シンタ ファーマスーティカルズ コーポレイション | 癌治療のためのビス(チオ‐ヒドラジドアミド)塩 |
WO2006033913A2 (en) * | 2004-09-16 | 2006-03-30 | Synta Pharmaceuticals Corp. | Bis (thio-hydrazide amides) for treament of hyperplasia |
US8148426B2 (en) | 2004-11-19 | 2012-04-03 | Synta Pharmaceuticals Corp. | Bis(thio-hydrazide amides) for increasing Hsp70 expression |
WO2006062732A2 (en) * | 2004-11-19 | 2006-06-15 | Synta Pharmaceuticals Corp. | Compounds acting at the centrosome |
CA2603314A1 (en) * | 2005-04-15 | 2006-10-26 | Synta Pharmaceuticals Corp. | Methods of increasing natural killer cell activity for therapy |
JP2008536875A (ja) | 2005-04-15 | 2008-09-11 | シンタ ファーマシューティカルズ コーポレーション | ビス(チオヒドラジド)アミド化合物による併用癌療法 |
BRPI0611262A2 (pt) * | 2005-05-16 | 2010-08-24 | Synta Pharmaceuticals Corp | mÉtodos de preparaÇço de um di-sal de bis (tio-hidrazida amida) |
AU2006279891B2 (en) * | 2005-08-16 | 2010-03-11 | Synta Pharmaceuticals Corp. | Bis(thio-hydrazide amide) formulation |
TW200804307A (en) * | 2005-10-27 | 2008-01-16 | Synta Pharmaceuticals Corp | Process for preparing mesylate salts of IL-12 inhibitory compounds |
SG174087A1 (en) | 2006-08-21 | 2011-09-29 | Synta Pharmaceuticals Corp | Compounds for treating proliferative disorders |
WO2008024299A2 (en) * | 2006-08-21 | 2008-02-28 | Synta Pharmaceuticals Corp. | Combination with bis(thiohydrazide amides) for treating cancer |
JP2010501563A (ja) * | 2006-08-21 | 2010-01-21 | シンタ ファーマシューティカルズ コーポレーション | 増殖性障害を治療するための化合物 |
US8497272B2 (en) | 2006-08-21 | 2013-07-30 | Synta Pharmaceuticals Corp. | Compounds for treating proliferative disorders |
AU2007288336B2 (en) * | 2006-08-21 | 2011-04-21 | Synta Pharmaceuticals Corp. | Bis(thiohydrazide amides) for use in preventing or delaying the recurrence of melanoma |
WO2008024305A2 (en) * | 2006-08-21 | 2008-02-28 | Synta Pharmaceuticals Corp. | Bis (thiohydrazide amides) for treating melanoma |
EP2076254A2 (en) | 2006-08-31 | 2009-07-08 | Synta Pharmaceuticals Corporation | Combination with bis(thiohydrazide amides) for treating cancer |
WO2008033300A2 (en) * | 2006-09-11 | 2008-03-20 | Synta Pharmaceuticals Corp. | Bis (thiohydrazide amides) formulation |
US9498528B2 (en) * | 2006-09-13 | 2016-11-22 | Genzyme Corporation | Treatment of multiple sclerosis (MS) |
WO2008033494A2 (en) * | 2006-09-15 | 2008-03-20 | Synta Pharmaceuticals Corp. | Purification of bis(thiohydrazide amides) |
WO2008082579A1 (en) * | 2007-01-03 | 2008-07-10 | Synta Pharmaceuticals Corp. | Method for treating cancer |
US8093425B2 (en) * | 2007-04-30 | 2012-01-10 | Synta Pharmaceuticals Corp. | Compounds for treating proliferative disorders |
TW200922550A (en) | 2007-08-07 | 2009-06-01 | Synta Pharmaceuticals Corp | Compounds for treating proliferative disorders |
US8618170B2 (en) * | 2007-11-09 | 2013-12-31 | Synta Pharmaceuticals Corp. | Oral formulations of bis(thiohydrazide amides) |
TW200940050A (en) * | 2007-11-28 | 2009-10-01 | Synta Pharmaceuticals Corp | Polymorphs of N-malonyl-bis(N'-methyl-N'-thiobenzoylhydrazide) |
WO2009073148A2 (en) * | 2007-11-28 | 2009-06-11 | Synta Pharmaceuticals Corp. | Polymorphs of n-malonyl-bis(n'-methyl-n'-thiobenzoylhydrazide) |
WO2009105257A1 (en) * | 2008-02-21 | 2009-08-27 | Synta Pharmaceuticals Corp. | Compounds for treating proliferative disorders |
WO2009123704A2 (en) * | 2008-03-31 | 2009-10-08 | Synta Pharmaceuticals Corp. | Process for preparing bis(thiohydrazide amides) |
AU2009308502B2 (en) | 2008-10-22 | 2013-08-01 | Synta Pharmaceuticals Corp. | Transition metal complexes of bis[thiohydrazide amide] compounds |
CN102256949B (zh) * | 2008-10-22 | 2014-09-24 | 辛塔医药品有限公司 | 双[硫代酰肼酰胺]化合物的过渡金属络合物 |
US8525776B2 (en) * | 2008-10-27 | 2013-09-03 | Lenovo (Singapore) Pte. Ltd | Techniques for controlling operation of a device with a virtual touchscreen |
WO2010065512A2 (en) | 2008-12-01 | 2010-06-10 | Synta Pharmaceuticals Corp. | Compounds for treating proliferative disorders |
WO2011069159A2 (en) | 2009-12-04 | 2011-06-09 | Synta Pharmaceuticals Corp. | Bis[thiohydrazide amide] compounds for treating leukemia |
US8815945B2 (en) | 2010-04-20 | 2014-08-26 | Masazumi Nagai | Use of bis [thiohydrazide amide] compounds such as elesclomol for treating cancers |
CA2854186A1 (en) | 2011-11-10 | 2013-05-16 | Jim SANG | Administration of a bis(thiohydrazide amide) compound for treating cancers |
US20130149392A1 (en) * | 2011-12-12 | 2013-06-13 | Synta Pharmaceuticals Corp. | Method of treating non-small cell lung cancer with bis-(thiohydrazide)amide compounds |
WO2013103795A1 (en) | 2012-01-05 | 2013-07-11 | The Board Of Trustees Of The Leland Stanford Junior University | Bis (thiohydrazide amide) compounds for treating cancers |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994010995A1 (fr) * | 1992-11-10 | 1994-05-26 | Rhone-Poulenc Rorer S.A. | Compositions antitumorales contenant des derives du taxane |
Family Cites Families (82)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US304318A (en) | 1884-09-02 | Inlet-pipe for water-works | ||
US304252A (en) | 1884-08-26 | Gael behee | ||
US361946A (en) | 1887-04-26 | Watch arbor and pivot | ||
US3357956A (en) | 1965-03-30 | 1967-12-12 | Du Pont | Polymeric 1, 3, 4-thiadiazoles and the process for their preparation |
FR2097737A5 (en) | 1970-07-14 | 1972-03-03 | Berlin Chemie Veb | Virustatic 4-substd 1-acylthiosemicarbazides -from carboxylic acid - hydrazide and isothiocyanates or from carboxylic acid chloride and 4- |
DE2037257A1 (en) | 1970-07-28 | 1972-02-03 | Farbwerke Hoechst AG, vorm. Meister Lucius & Brüning, 6000 Frankfurt | Poly-(5-amino-1,3,4-thiadiazol-2-yl) derivs prepn - intermediates for drug and polymer prodn |
GB1272920A (en) | 1971-03-15 | 1972-05-03 | Berlin Chemie Veb | New thiosemicarbazides |
US4012360A (en) * | 1973-12-03 | 1977-03-15 | Ciba-Geigy Corporation | Bis-salicyloyl-dicarboxylic acid dihydrazides as stabilizers for polyolefines |
JPS5091056A (zh) * | 1973-12-17 | 1975-07-21 | ||
US4822777A (en) | 1987-02-27 | 1989-04-18 | Liposome Technology, Inc. | Amphotericin B/cholesterol sulfate composition |
JP2767241B2 (ja) | 1987-04-15 | 1998-06-18 | ロ−ム アンド ハ−ス コンパニ− | 殺虫性のn−(場合により置換された)−n′−置換−n,n′−ジ置換ヒドラジン |
US6013836A (en) * | 1992-02-28 | 2000-01-11 | Rohm And Haas Company | Insecticidal N'-substituted-N,N'-disubstitutedhydrazines |
DK0693924T4 (da) | 1993-02-22 | 2008-08-04 | Abraxis Bioscience Inc | Fremgangsmåde til (in vivo) levering af biologiske materialer og sammensætninger, der er egnede dertil |
US6753006B1 (en) | 1993-02-22 | 2004-06-22 | American Bioscience, Inc. | Paclitaxel-containing formulations |
US5665382A (en) | 1993-02-22 | 1997-09-09 | Vivorx Pharmaceuticals, Inc. | Methods for the preparation of pharmaceutically active agents for in vivo delivery |
US6096331A (en) | 1993-02-22 | 2000-08-01 | Vivorx Pharmaceuticals, Inc. | Methods and compositions useful for administration of chemotherapeutic agents |
US6537579B1 (en) | 1993-02-22 | 2003-03-25 | American Bioscience, Inc. | Compositions and methods for administration of pharmacologically active compounds |
US6749868B1 (en) | 1993-02-22 | 2004-06-15 | American Bioscience, Inc. | Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof |
US5439686A (en) | 1993-02-22 | 1995-08-08 | Vivorx Pharmaceuticals, Inc. | Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor |
US5916596A (en) | 1993-02-22 | 1999-06-29 | Vivorx Pharmaceuticals, Inc. | Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof |
US5840746A (en) | 1993-06-24 | 1998-11-24 | Merck Frosst Canada, Inc. | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases |
US5523325A (en) | 1993-09-09 | 1996-06-04 | Jacobson; Richard M. | Amidrazones and their use as pesticides |
KR970703306A (ko) | 1994-06-03 | 1997-07-03 | 슈타르크, 카르크 | 카르바모일 카르복실산 히드라지드 및 진균류에 대한 이들의 용도(Carbamoyl Carboxylic Acid Hydrazides and Their Use Against Fungi) |
ATE184613T1 (de) * | 1995-09-22 | 1999-10-15 | Novo Nordisk As | Varianten des grünen fluoreszenzproteins, gfp |
US5739686A (en) | 1996-04-30 | 1998-04-14 | Naughton; Michael J. | Electrically insulating cantilever magnetometer with mutually isolated and integrated thermometry, background elimination and null detection |
KR980008219A (ko) | 1996-07-16 | 1998-04-30 | 김상응 | 안정화된 주사제용 약제학적 조성물 |
ATE243993T1 (de) * | 1997-04-18 | 2003-07-15 | Janssen Pharmaceutica Nv | Verwendung von 5ht3 antagonisten zum fördern der darmspülung |
US6235787B1 (en) * | 1997-06-30 | 2001-05-22 | Hoffmann-La Roche Inc. | Hydrazine derivatives |
GB9727524D0 (en) * | 1997-12-31 | 1998-02-25 | Pharmacia & Upjohn Spa | Synergistic antitumor composition containing a biologically active ureido compound |
JP3099880B2 (ja) * | 1998-08-12 | 2000-10-16 | 日本電気株式会社 | 半導体スイッチ及びスイッチ回路 |
TW479053B (en) * | 1998-10-19 | 2002-03-11 | Agro Kanesho Co Ltd | Hydrazineoxoacetamide derivatives and pesticides |
ES2161594B1 (es) * | 1998-12-17 | 2003-04-01 | Servier Lab | Nuevos derivados de la hidrazida, su procedimiento de preparacion y las composiciones farmaceuticas que los contienen. |
JP3908876B2 (ja) * | 1999-07-23 | 2007-04-25 | 日東電工株式会社 | 粘着テープ用基材フィルム及び粘着テープまたはシート |
US6322303B1 (en) * | 2000-05-12 | 2001-11-27 | David M. John | Dunnage bag and method of making same |
EP1164126A1 (de) * | 2000-06-16 | 2001-12-19 | Basf Aktiengesellschaft | Salicylsäurehydrazid-Derivate, Verfahren und Zwischenprodukte zu ihrer Herstellung, sie enthaltende Mittel und ihre Verwendung zur Bekämpfung von Schadpilzen |
US6365745B1 (en) * | 2000-07-14 | 2002-04-02 | Sumika Fine Chemicals Co., Ltd. | Method for producing hydrazine derivative |
MXPA03006666A (es) * | 2001-01-25 | 2004-05-31 | Guilford Pharm Inc | Compuestos de union de ciclofilina carbociclicos trisubstituidos y su uso. |
CA2445967A1 (en) | 2001-05-01 | 2002-11-07 | Abbott Laboratories | Compositions comprising lopinavir and methods for enhancing the bioavailability of pharmaceutical agents |
WO2002094259A1 (en) | 2001-05-03 | 2002-11-28 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Compounds that inhibit hsp90 and stimulate hsp70 and hsp40, useful in the prevention or treatment of diseases associated with protein aggregation and amyloid formation |
US6602907B1 (en) * | 2001-06-08 | 2003-08-05 | University Of Central Florida | Treatment of breast cancer |
TWI332943B (en) * | 2001-07-10 | 2010-11-11 | Synta Pharmaceuticals Corp | Taxol enhancer compounds |
TWI297335B (en) | 2001-07-10 | 2008-06-01 | Synta Pharmaceuticals Corp | Taxol enhancer compounds |
TWI252847B (en) | 2001-07-10 | 2006-04-11 | Synta Pharmaceuticals Corp | Synthesis of taxol enhancers |
US6924312B2 (en) * | 2001-07-10 | 2005-08-02 | Synta Pharmaceuticals Corp. | Taxol enhancer compounds |
ES2330927T3 (es) | 2001-11-28 | 2009-12-17 | Ipsen Pharma | Derivados de 5-sulfanil-4h-1,2,4-triazoles para tratar trastornos asociados a la somatostatina. |
TW200408407A (en) | 2001-11-30 | 2004-06-01 | Dana Farber Cancer Inst Inc | Methods and compositions for modulating the immune system and uses thereof |
AU2006228035B2 (en) | 2003-01-15 | 2010-02-18 | Synta Pharmaceuticals Corp. | Bis (thio-hydrazide amide) compounds for treating multi-drug resistant cancer |
TWI330079B (en) | 2003-01-15 | 2010-09-11 | Synta Pharmaceuticals Corp | Treatment for cancers |
ES2393483T3 (es) | 2003-02-11 | 2012-12-21 | Vernalis (R&D) Limited | Compuestos de isoxazol como inhibidores de las proteínas de choque térmico |
KR100575251B1 (ko) | 2003-03-03 | 2006-05-02 | 재단법인서울대학교산학협력재단 | p38/JTV-1을 유효성분으로 하는 암 치료용 약학적조성물 및 암 치료용 약학적 조성물의 스크리닝 방법 |
EP1493445A1 (en) | 2003-07-04 | 2005-01-05 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Inhibition of stress-induced ligand-dependent EGFR activation |
AR045595A1 (es) | 2003-09-04 | 2005-11-02 | Vertex Pharma | Composiciones utiles como inhibidores de proteinas quinasas |
KR100544347B1 (ko) | 2003-12-11 | 2006-01-23 | 한국생명공학연구원 | 디아릴이소옥사졸계 화합물을 유효성분으로 함유하는 암 예방 및 치료용 약학적 조성물 |
WO2005097758A1 (en) | 2004-03-26 | 2005-10-20 | Amphora Discovery Corporation | Certain triazole-based compounds, compositions, and uses thereof |
JP5362986B2 (ja) * | 2004-06-23 | 2013-12-11 | シンタ ファーマスーティカルズ コーポレイション | 癌治療のためのビス(チオ‐ヒドラジドアミド)塩 |
US7385085B2 (en) | 2004-07-09 | 2008-06-10 | Elan Pharmaceuticals, Inc. | Oxime derivative substituted hydroxyethylamine aspartyl protease inhibitors |
WO2006033913A2 (en) | 2004-09-16 | 2006-03-30 | Synta Pharmaceuticals Corp. | Bis (thio-hydrazide amides) for treament of hyperplasia |
WO2006062732A2 (en) | 2004-11-19 | 2006-06-15 | Synta Pharmaceuticals Corp. | Compounds acting at the centrosome |
US8148426B2 (en) | 2004-11-19 | 2012-04-03 | Synta Pharmaceuticals Corp. | Bis(thio-hydrazide amides) for increasing Hsp70 expression |
JP5123671B2 (ja) | 2005-02-17 | 2013-01-23 | シンタ ファーマシューティカルズ コーポレーション | 増殖性疾患の治療のための化合物 |
WO2006113493A2 (en) | 2005-04-15 | 2006-10-26 | Synta Pharmaceuticals Corp. | Methods of determining cancer prognosis via natural killer cell activity |
CA2603314A1 (en) | 2005-04-15 | 2006-10-26 | Synta Pharmaceuticals Corp. | Methods of increasing natural killer cell activity for therapy |
JP2008536875A (ja) | 2005-04-15 | 2008-09-11 | シンタ ファーマシューティカルズ コーポレーション | ビス(チオヒドラジド)アミド化合物による併用癌療法 |
BRPI0611262A2 (pt) | 2005-05-16 | 2010-08-24 | Synta Pharmaceuticals Corp | mÉtodos de preparaÇço de um di-sal de bis (tio-hidrazida amida) |
AU2006279891B2 (en) | 2005-08-16 | 2010-03-11 | Synta Pharmaceuticals Corp. | Bis(thio-hydrazide amide) formulation |
CA2653222A1 (en) | 2006-05-25 | 2007-12-06 | Synta Pharmaceuticals Corp. | Triazole compounds that modulate hsp90 activity |
SG174087A1 (en) | 2006-08-21 | 2011-09-29 | Synta Pharmaceuticals Corp | Compounds for treating proliferative disorders |
WO2008024299A2 (en) | 2006-08-21 | 2008-02-28 | Synta Pharmaceuticals Corp. | Combination with bis(thiohydrazide amides) for treating cancer |
AU2007288336B2 (en) | 2006-08-21 | 2011-04-21 | Synta Pharmaceuticals Corp. | Bis(thiohydrazide amides) for use in preventing or delaying the recurrence of melanoma |
US8497272B2 (en) | 2006-08-21 | 2013-07-30 | Synta Pharmaceuticals Corp. | Compounds for treating proliferative disorders |
WO2008024305A2 (en) | 2006-08-21 | 2008-02-28 | Synta Pharmaceuticals Corp. | Bis (thiohydrazide amides) for treating melanoma |
WO2008024298A1 (en) | 2006-08-21 | 2008-02-28 | Synta Pharmaceuticals Corp. | Bis(thiohydrazide amides) for inhibiting angiogenesis |
EP2076254A2 (en) | 2006-08-31 | 2009-07-08 | Synta Pharmaceuticals Corporation | Combination with bis(thiohydrazide amides) for treating cancer |
WO2008033300A2 (en) | 2006-09-11 | 2008-03-20 | Synta Pharmaceuticals Corp. | Bis (thiohydrazide amides) formulation |
EP2059250A2 (en) | 2006-09-14 | 2009-05-20 | Synta Pharmaceuticals Corporation | Compounds for the treatment of angiogenesis |
WO2008033494A2 (en) | 2006-09-15 | 2008-03-20 | Synta Pharmaceuticals Corp. | Purification of bis(thiohydrazide amides) |
WO2008082579A1 (en) | 2007-01-03 | 2008-07-10 | Synta Pharmaceuticals Corp. | Method for treating cancer |
US8093425B2 (en) | 2007-04-30 | 2012-01-10 | Synta Pharmaceuticals Corp. | Compounds for treating proliferative disorders |
TW200922550A (en) | 2007-08-07 | 2009-06-01 | Synta Pharmaceuticals Corp | Compounds for treating proliferative disorders |
US8618170B2 (en) | 2007-11-09 | 2013-12-31 | Synta Pharmaceuticals Corp. | Oral formulations of bis(thiohydrazide amides) |
TW200940050A (en) | 2007-11-28 | 2009-10-01 | Synta Pharmaceuticals Corp | Polymorphs of N-malonyl-bis(N'-methyl-N'-thiobenzoylhydrazide) |
WO2009073148A2 (en) | 2007-11-28 | 2009-06-11 | Synta Pharmaceuticals Corp. | Polymorphs of n-malonyl-bis(n'-methyl-n'-thiobenzoylhydrazide) |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994010995A1 (fr) * | 1992-11-10 | 1994-05-26 | Rhone-Poulenc Rorer S.A. | Compositions antitumorales contenant des derives du taxane |
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