CN101018551A - 卟啉衍生物及其在光子活化疗法中的用途 - Google Patents
卟啉衍生物及其在光子活化疗法中的用途 Download PDFInfo
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Abstract
本发明涉及式(I)化合物在制备通过光子活化疗法用于细胞死亡的药物组合物中的用途以及所述化合物在预防和/或治疗癌症中的用途。
Description
本发明提供了用于光子活化疗法的改进的化合物及其在杀死靶细胞(如肿瘤)中的作用。本发明的手段和方法能够使光子活化疗法对临床应用而言最优化。
在癌症的治疗中使用了许多不同的双峰疗法(bimodal therapies)。这些疗法通常需要两步,其中首先给患者施用无药物活性的物质并使之在体内到达其靶位。其次,无活性物质被活化为杀死靶细胞的毒性形式。本领域已知的这种双峰疗法包括光动力疗法(PDT)、硼中子俘获疗法(BNCT)和放射增敏。这些双峰疗法的使用提供了优于常规放射疗法的优点,在常规放射疗法中,疗法的生物效应扩散至整个受辐射区域,并需要高的辐射剂量以产生破坏性的电离径迹来引起期望的生物效应。
光子活化疗法是放射增敏的一种形式。它通常采用在靶细胞蓄积的药学上惰性的物质。通过采用X-射线照射靶细胞和周围的组织使该物质在体内被活化。
对于采用光子活化疗法来治疗脑肿瘤而言,已经研发了钆替沙林(gadolinium teaxfrin)。采用全脑辐射来活化物质并监视患者的神经学进展。用电离辐射对钆替沙林进行活化产生了一种对细胞和细胞器有高度损害性的短寿命的细胞毒性基团。因此,在本领域需要有一种可以采用而且对周围细胞和组织的所不期望的损害最小的光子活化疗法用物质。
先前在药物中已经使用过卟啉。这些化合物对哺乳动物的肿瘤组织表现出高亲和力并已经用于PDT。然而,卟啉在临床上的用途由于活化卟啉所需的可见光的穿透性差而受到限制。
本发明提供了卟啉衍生物,所述卟啉衍生物可通过电离辐射在体内被活化以提供一种稳定长寿命的基团。卤代卟啉在它们的构象及光物理学和化学性质方面显示出变化。例如,在吡咯环上被八个溴原子取代的内消旋四苯基卟啉产生了550mv的氧化电位位移。认为这种氧化电位的增加使卤代卟啉对抗氧化降解的稳定性增强,从而允许其用于光子活化疗法。这些卟啉可用作催化剂或非线性吸收物质。此类稳定长寿命基团的产生降低了活化物质所需的有损害的辐射的量。还可以以比其它技术(如BNCT)所需浓度的更低的浓度来提供该物质。本发明化合物的使用提供了许多体内方面的优点,因为它们显示出低的全身毒性、对肿瘤的高选择性以及从血液中的快速清除。此外,卤代卟啉在与X-射线联合时展示了改进的效力,并对肿瘤组织显示出选择性。
因此,本发明第一个方面提供了式(I)化合物在制备通过光子活化疗法用于细胞死亡的药物组合物中的用途;
其中R1各自独立地选自氢、任选被取代的C1-8烷基、任选被取代的C2-8链烯基、卤素、SO3R4、=O或NO2,其中取代基选自一个或多个C1-6烷基、R5、=O、OR5、CO2R5、CONR6R6,并且各取代基可进一步被一个或多个CO2R5或OR5取代;
其中R2各自独立地选自氢、任选被取代的C1-8烷基、任选被取代的C2-8链烯基、卤素、SO3R4、NO2,其中取代基选自一个或多个C1-6烷基、R5、=O、OR5、CO2R5、CONR6R6,并且各取代基可进一步被一个或多个CO2R5或OR5取代;
其中C1-8烷基可任选被一个或多个O、CO2或NR7间隔;
其中R1和R2可共同形成六元环,其中所述的环可以是完全饱和的、部分饱和的或不饱和的,并任选被一个或多个=O、卤素、SO3R4、NO2、C1-6烷基或CO2R5取代;
其中R3各自独立地为氢、卤素、C1-20烷基、C2-20链烯基、C2-20炔基、C1-6卤代烷基、C3-12芳基或C3-12杂芳基、C1-20烷氧基、C2-20链烯氧基、C2-20炔氧基、C3-12芳氧基、C3-12杂芳氧基;其中所述烷基、烷氧基、链烯基、链烯氧基、炔基、炔氧基、芳基、芳氧基、杂芳基和杂芳氧基任选被一个或多个C1-6烷基、芳基、R5、OR5、NR6 2、SO3R4、NO2、卤素、CO2R5或B(OR6)2取代,并且各取代基可进一步被一个或多个卤素、C1-6烷基取代;
其中R2和R3或者R1和R3可共同形成五元环,其中所述的环可以是完全饱和的、部分饱和的或不饱和的,并任选被一个或多个=O、C1-8烷基或CO2R5取代;
其中一个或多个R1、R2或R3为选自F、Cl、Br、I、NO2的吸电子基,优选为Br;
其中R4为氢或C1-6烷基;R5为氢或C1-6烷基、C6-12芳基、任选被取代的碳硼烷、生物相容的聚合物或抗衡离子如Na或K,所述烷基或芳基任选被NR6 2、NO2、C1-4烷基或C6-12芳基取代;R6为氢或C1-6烷基,R7为氢或任选被CO2R5取代的C1-6烷基;且
M为金属或氢,优选选自V、Ga、Mn、Fe、Ru、Tc、Cr、Pt、Co、Ni、Cu、Zn、Ge、In、Sn、Y、Au、Ba、W、Gd、Pb或Pt。在第一个方面优选的特征中,金属为Au或Pb或者是在X-射线辐射下产生电子雨(shower of electrons)的任意其它金属。所述电子雨的产生增加了本发明化合物的效力。
在第一个方面优选的特征中,一个或多个R1基团为吸电子基,如卤素或NO2,优选选自F、Cl、Br或I的卤素,更优选Br或Cl,最优选Br。更优选R1基团中的2、3或4个为卤素。本领域技术人员可以理解R1可为任意吸电子基,其中R1基团优选提供与卤素基团相同程度的电负性。
在第一个方面其它优选的特征中,一个或多个R2基团为吸电子基,优选选自F、Cl、Br或I的卤素,更优选Br或Cl,最优选Br。更优选R2基团中的2、3或4个为卤素。
在第一个方面其它优选的特征中,一个或多个R3基团为吸电子基,优选选自F、Cl、Br或I的卤素,更优选Br或Cl,最优选Br。更优选R3基团中的2、3或4个为卤素。
在第一个方面优选的特征中,一个或多个R1基团和一个或多个R2基团为吸电子基,优选选自F、Cl、Br或I的卤素,更优选Br或Cl,最优选Br。更优选R1基团中的2、3或4个和R2基团中的2、3或4个为卤素。
在第一个方面更优选的特征中,本发明的化合物被4、5、6、7、8、9或10个卤素原子取代,优选被8个卤素原子取代,其中所述的卤素原子优选是Br。
对于本发明的目的,烷基涉及1至20个碳原子、优选1至8个碳原子、更优选1至6个碳原子、最优选1至4个碳原子的直链和支链烷基两者,包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基。术语烷基还包括环烷基,包括但不限于环丙基、环丁基、CH2-环丙基、CH2-环丁基。
卤代烷基涉及被一个或多个卤素原子取代的优选具有1至8个碳原子、优选1至4个碳原子的烷基,例如CH2CH2Br、CF3或CCl3。
术语“链烯基”指2至20个碳原子、优选2至8个、更优选2-6个碳原子、最优选2-4个碳原子的直链或支链链烯基,含有一条或多条碳-碳双键,包括但不限于乙烯基、正丙-1-烯基、正丙-2-烯基、异丙烯基等。“炔基”指2至20个碳原子、优选2至8个碳原子、更优选2-6个碳原子、最优选2-4个碳原子的直链或支链炔基,包括但不限于乙炔基、2-甲基乙炔基。本发明的烷基、链烯基和/或炔基可以包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子。
“芳基”指芳香族3至12元烃,优选5或6元烃,含有一个环或稠合于一个或多个饱和或不饱和环上,包括但不限于苯基、萘基、蒽基或菲基。
“杂芳基”指芳香族3-12元芳基,优选5或6元烃,含有一个或多个选自N、O或S的杂原子并且含有一个环或稠合于一个或多个饱和或不饱和环上。杂芳基可以是完全饱和的、部分饱和的或不饱和的。芳基或杂芳基的实例包括但不限于苯基、吖啶、苯并咪唑、苯并呋喃、苯并噻吩、苯并唑、苯并噻唑、咔唑、噌啉、二氧芑、二烷、二氧戊烷、二噻烷、二噻嗪、二噻唑、二硫戊环、呋喃、咪唑、咪唑啉、咪唑烷、吲哚、二氢吲哚、吲嗪、吲唑、异吲哚、异喹啉、异唑、异噻唑、吗啉、萘啶、唑、二唑、噻唑、噻唑烷、嗪、二嗪、吩嗪、吩噻嗪、吩嗪、酞嗪、哌嗪、哌啶、蝶啶、嘌呤、吡喃、吡嗪、吡唑、吡唑啉、吡唑烷、哒嗪、吡啶、嘧啶、吡咯、吡咯烷、吡咯啉、喹啉、喹喔啉、喹唑啉、喹嗪、四氢呋喃、四嗪、四唑、噻吩、噻二嗪、噻二唑、噻三唑、噻嗪、噻唑、硫吗啉、硫萘、噻喃、三嗪、三唑或三噻烷。
卤素指F、Cl、Br或I,优选Br或Cl。
在第一个方面优选的特征中,基团R5为生物相容的聚合物。生物相容聚合物的存在使本发明化合物的物理和化学性质出现变化。例如,这种生物相容聚合物的存在可增强水溶性、增强肿瘤靶向、降低毒性,例如通过降低和/或阻止血细胞和/或血小板的干扰或通过降低化合物在肝脏、脾脏、骨髓和/或肺中的蓄积来产生这些变化。这种生物相容聚合物的实例包括如下聚合物中的一种或多种:N-(2-羟丙基)异丁烯酰胺(HPMA共聚物)-侧链、聚乙二醇(PEG)、乙二醇共聚物、多糖如糊精、葡聚糖、壳聚糖(N-琥珀酰壳聚糖)、羧甲基壳多糖、羧甲基支链淀粉、海藻酸盐、聚(氨基酸)、聚[N-(2-羟基乙基)-L-谷氨酰胺](PHEG)、β-聚(2-羟基乙基天冬酰胺)(PHEA)、聚(谷氨酸)、聚(天冬氨酸)、聚赖氨酸(聚(L-赖氨酸))、聚酯、聚(α或β-苹果酸)、交替聚合物、PEG-赖氨酸、嵌段共聚物、聚(乙二醇-天冬氨酸)、苯乙烯和马来酸酐的共聚物、聚半乳糖醛酸、羟基烷基(甲基)丙烯酸酯如N-苯基吡咯烷酮的共聚物、聚(L-谷氨酸和羟基乙基-L-谷氨酰胺)、聚(α-苹果酸)、聚天冬氨酸-PEG共聚物、聚-L-赖氨酸、聚乙烯亚胺的共聚物、聚(α-L-谷氨酸)(PGA)、生物可降解的二酰氨基-二胺聚合物或类固醇如雌二醇或胆固醇。R5还可为任选被一个或多个C1-4烷基、OH、NH2或卤素取代的碳硼烷。
本领域技术人员可以理解,本发明的化合物可用一种或多种生物相容的聚合物进行衍生化并且本发明囊括这种衍生化的化合物。这种衍生化可在带有官能团部分的式I化合物的任意位置发生。此类部分的实例包括-CO2H、OH、Br、-CH=CH-、C=O、NH2等。
在第一个方面更优选的特征中:
R1为C1-4烷基且更优选甲基,或者为卤素且更优选Br,
R2为任选被CO2R5取代的C1-4烷基,或者为卤素且更优选Br,且
R3为C6-12芳基且优选苯基,任选被CO2R5或OR5取代,或者为卤素且优选Br,
其中R5优选为如上文定义的生物相容的聚合物。
提供本发明第一个方面的化合物用于癌症的预防和/或治疗,优选其中癌症为实体瘤和/或转移瘤。提供本发明的化合物用于淋巴瘤和皮肤癌的预防和/或治疗。肿瘤可以是皮肤癌(如恶性黑素瘤,包括鳞状细胞癌、梅克尔细胞癌和基底细胞癌)、肺癌、头与颈癌、骨癌、前列腺癌、结肠癌、子宫颈癌、乳癌、脑癌、肝癌或胰腺癌。化合物还可与外科手术联合使用来帮助缩小肿瘤的尺寸及降低正常组织的损失。
将本发明的化合物提供给需要其的受治疗者。受治疗者可以是哺乳动物,包括人类或家畜,例如宠物、动物园动物或农场动物。所述化合物尤其可用于治疗动物如猫、狗、马、牛、猪、山羊、绵羊、鸟、灵长类动物、象或大猫。
本发明不限于通过光子活化疗法对癌症进行治疗,但是可用于需要光子活化疗法的任意方法中用于组织死亡。对于本发明的目的,术语“细胞死亡”还包括组织死亡。可受益于光子活化疗法的病症的实例包括非恶性疾病、非转移性良性肿瘤、子宫平滑肌瘤、关节炎、乳腺瘤、menohrragina、良性前列腺增生和选择性心脏结构的破坏或凝块。光子活化疗法还可用于以下情况:其中组织死亡优于诸如外科手术、光动力疗法、低温外科手术、热激光消融和蒸发的操作。另外,还提供本发明的化合物用于其它疾病的治疗,例如心血管疾病(如动脉粥样硬化斑块)、年龄相关性黄斑变性紊乱。
对于本发明的目的,“细胞死亡”包括细胞的破坏和损害或损伤。术语“细胞死亡”包括细胞清除(cell ablation),但对于本发明的目的而言,在PAT之后肿瘤组织或细胞不需要从体内移除。细胞损伤可以是永久的或暂时的。
本发明的第二个方面提供了式(I)化合物,
其中R1各自独立地选自氢、任选被取代的C1-8烷基、任选被取代的C2-8链烯基、卤素、SO3R4、NO2、=O,其中取代基选自一个或多个C1-6烷基、R5、=O、OR5、CO2R5、CONR6R6,并且各取代基可进一步被一个或多个CO2R5或OR5取代;
其中R2各自独立地选自氢、任选被取代的C1-8烷基、任选被取代的C2-6链烯基、卤素、SO3R4、NO2,其中取代基选自一个或多个C1-6烷基、R5、=O、OR5、CO2R5、CONR6R6,并且各取代基可进一步被一个或多个CO2R5或OR5取代;其中C1-8烷基可任选被一个或多个O、CO2或NR7间隔;
其中R1和R2可共同形成六元环,其中所述的环可以是完全饱和的、部分饱和的或不饱和的,并任选被一个或多个=O、C1-6烷基、卤素、SO3R4、NO2或CO2R5取代;
其中R3各自独立地为氢、卤素、C1-6烷基、C1-6卤代烷基、NO2、C3-12芳基、C3-12杂芳基、C1-6烷氧基、C3-12芳氧基或C3-12杂芳氧基;其中烷基、烷氧基、芳基、芳氧基、杂芳基和杂芳氧基任选被一个或多个C1-6烷基、R5、C3-12芳基、OR5、NR6、SO3R4、卤素、CO2R5、B(OR6)2取代,并且各取代基可进一步被一个或多个卤素或C1-6烷基取代;
其中R2和R3或者R1和R3可共同形成五元环,其中所述的环可以是完全饱和的、部分饱和的或不饱和的,并任选被一个或多个=O、C1-8烷基或CO2R5取代;
其中一个或多个R1、R2或R3为选自F、Cl、Br、I、NO2的吸电子基,优选为Br;
其中R4为氢或C1-6烷基;R5为氢或C1-6烷基或任选被取代的碳硼烷、生物相容的聚合物或抗衡离子如Na或K;R6为氢或C1-6烷基;R7为氢或任选被CO2R5取代的C1-6烷基;且
M为金属或氢,优选选自V、Mn、Fe、Ru、Tc、Cr、Pt、Co、Ni、Cu、Zn、Ge、In、Sn、Y、Au、Ba、W、Gd、Pb或Pt,条件是当R1和R2均为溴或均为氯时,R3不为氢或被F、Br、CO2Me、CO2Et、CH3、CF3、Cl或NO2取代的苯基;
当R1和R2为溴或氯时,R3不为被F、Br、CO2Me、CO2Et、CH3、CF3、Cl或NO2取代的苯基;
当R1和R2均为氢时,R3不是Cl、Br、F、CF3或被Cl或F取代的苯基;
当R1是氢且R3是苯基时,R2不是NO2、Cl或CH2OH;
当R2是氢且R1是NO2时,R3不是被甲基取代的苯基;
当R2是氢且R1是F时,R3不是氢;并且
当R1和R2均为乙基时,R3不是NO2。
在第二个方面优选的特征中,一个或多个R1基团为吸电子基,优选选自F、Cl、Br或I的卤素,更优选Br或Cl,最优选Br。更优选R1基团中的2、3或4个为卤素。
在第二个方面其它优选的特征中,一个或多个R2基团为吸电子基,优选选自F、Cl、Br或I的卤素,更优选Br或Cl,最优选Br。更优选R2基团中的2、3或4个为卤素。
在第二个方面其它优选的特征中,一个或多个R3基团为吸电子基,优选选自F、Cl、Br或I的卤素,更优选Br或Cl,最优选Br。更优选R3基团中的2、3或4个为卤素。
在第二个方面优选的特征中,一个或多个R1基团和一个或多个R2基团为吸电子基,优选选自F、Cl、Br或I的卤素,更优选Br或Cl,最优选Br。更优选R1基团中的2、3或4个和R2基团中的2、3或4个为卤素。
本发明第一个和第二个方面优选的化合物为:
本发明优选的其它化合物包括
或
其中R为任选被OH、NH2、MeO或CO2Me取代的苯基;或苄基,或吡啶基,或(CH2)17CH3或氢,或类固醇。
或
其中n为1至20,优选2至15,更优选2、3、4、5、6、7、8、9、10、11、12或13;
或
其中R13为(CH2)5CH3、(CH2)5CH2OH或雌二醇;
或
其中R14为Br、氢、甲基或N(CH3)2,R15为H或OMe,且R16为甲基;
或
其中X为CH2、O、OCH2或不存在;
或
或
其中R15为4-(1-甲基-o-碳硼烷基甲基),其中碳硼烷基=carboranyl。
如上文说明的优选化合物还可与金属组合提供,其中金属可以是V、Ga、Mn、Fe、Ru、Tc、Cr、Pt、Co、Ni、Cu、Zn、Ge、In、Sn、Y、Au、Ba、W、Gd、Pb、Al或Pt,优选Au、Zn、Fe、Cr、Sn、Ni、Pt、V、Al、Co、Mn、Cu或Pd。
本发明的第三个方面提供了药物组合物,所述的药物组合物包含如本发明第二个方面定义的化合物和可药用赋形剂。
式(I)化合物可依据已知的方法配制来生产药学上有用的组合物,由此式(I)化合物与可药用载体合并成混合物。如果可被接受者耐受,则所得组合物是可药用的。适宜载体的实例是本领域技术人员已知的,其在Remingtons’Pharmaceutical Sciences(Maack出版公司,伊斯顿PA)中有描述。
本发明的第四个方面涉及通过光子活化疗法用于细胞清除的如本发明第二个方面定义的式(I)化合物。
本发明第五个方面提供了式(I)化合物的制备方法,所述方法包括卟啉化合物的卤化。可用于制备式(I)化合物的试剂的实例包括溴化试剂如分子溴和N-溴代琥珀酰亚胺(NBS)。氯化试剂包括N-氯代琥珀酰亚胺。
本发明的第六个方面提供了通过光子活化疗法进行的细胞死亡方法,所述方法包括向需要其的受治疗者施用如本发明第一个方面定义的式(I)化合物。
式(I)化合物的剂量将根据诸如以下的因素而变化:患者的年龄、体重、身高、性别、医疗条件和既往医疗史,以及待治疗病症的位置和严重性,本发明化合物在靶位沉积的程度和速率,结合物内化的程度和速率,以及式(I)化合物的清除率。
施用于接受者的式(I)化合物的剂量必须导致治疗上可接受的量;即,在给予X-射线时它的存在必须足以引起细胞损害或死亡。
肿瘤块内的药物剂量需要足以引起细胞杀伤。为了达到这个目的,施用的剂量在0.1mg/kg至100mg/kg范围内,优选1mg-50mg/kg,更优选5mg/kg-25mg/kg。化合物在肿瘤组织内理想地均匀分布。化合物对肿瘤:周围组织的选择性比例在最小500∶1、优选100∶1、更优选20∶1至1∶1的范围内。肿瘤组织中化合物的量等于0.1微克/克至200微克/克肿瘤组织中的化合物。这些容易还原的卟啉(或带有吸电子基的卟啉)可与电离辐射一起使用。电离辐射可从外源(如常规放射疗法线性加速剂、重离子束如碳离子、伽玛刀、电子束、质子束、快中子束)来照射进入,或通过常规放射性种子如铱-192种子、钯-103种子或碘-125种子、镭-226、铯-137、钴-60、金-198、锶-90、钇-90体内应用于肿瘤块内(近程放射治疗)。
本发明的化合物可与质子疗法、质子疗法、反质子疗法、介子疗法、放射-免疫疗法、电子束疗法以及常规放射疗法一起使用。
药物物质可在给予放射之前向患者施用。通常在给予放射之前10-180分钟至48-96小时的范围内给药。药物可以每日或以规律或不规律的间隔给予以在肿瘤块内维持治疗有效量,所述间隔为5至21天,优选7至10天。例如,每天给予常规放射剂量,每周5天,持续4-6周。所述化合物还可用于称为连续超加速放射治疗(Continuous Hyper AcceleratedRadiotherapy,CHART)的常规放射疗法的变体,例如约39份1.2Gy-1.5Gy的放射分割剂量可在11天时间内递送。化合物还可与强度调控放射疗法(IMRT)一起使用。IMRT是一种在给定的区域上以不同的放射剂量将X-射线精确传递到其靶点的技术。
对于本发明的目的,给药方式是超静脉(ultravenous)、经口、腹膜内、粘膜、经皮、阴道或口服施用的方式。
对于本发明的目的而言有用的X-射线的总剂量约为0.1Gy至200Gy,优选1Gy至120Gy,更优选15Gy至100Gy。分割的X-射线剂量为0.1至10Gy,优选0.5Gy至3Gy,更优选0.5Gy至2Gy。分割的总数为1至100,优选1至70,更优选1至40。放射给予1至100天,优选1至70天,更优选1至40天。
该化合物对常规放射疗法、加速超分割放射疗法和强度调控放射疗法尤其有用。
优选的电离源为X-射线。对于本发明的目的而言有用的X-射线具有大约10千电子伏特至1000兆电子伏特的能量,优选的范围为100千电子伏特至50兆电子伏特,更优选的范围为1兆电子伏特至20兆电子伏特。
现在将参考下文的一个或多个非限制性实施例来解释说明本发明。
实施例
5,10,15,20-四苯基-21H,23H-卟吩的溴化
历经20分钟将溴(1.55ml,30mmol)在CCl4(20ml)中的溶液逐滴加入到搅拌的5,10,15,20-四苯基-21H,23H-卟吩(600mg,0.976mmol)在CCl4(80ml)中的溶液中,将所得混合物搅拌1小时。混合物用二氯甲烷(100ml)稀释并用10%焦亚硫酸钠水溶液(100ml)洗涤。收集有机层,用盐水洗涤,干燥(MgSO4)并蒸发溶剂。
受抑制的细胞增殖
在采用动物和人肿瘤细胞系培养物(人乳腺肿瘤细胞系(MCF-7,ZR-75-1)、鼠雄激素响应性Shionogi乳腺癌(SC115)细胞系、人结肠肿瘤细胞系HT29和SW480)的体外细胞培养中,采用化合物作为预处理以进行细胞增殖的抑制。暗毒性(dark toxicity)和X-射线+药物化合物表明卤代化合物被活化并显著降低细胞增殖,如标准IC50评分所测定的那样。剂量递增研究提供了用于X-射线+药物研究中所需的药物剂量的指示。采用通常等于25Gy、35Gy、45Gy(相当于分割的50-70Gy)的X-射线放射的单次剂量和分割剂量。以1-2Gy分割剂量历经2-5天进行分割剂量研究。增殖的减少为100%至10%,通常可观察到85%-95%的抑制。
治疗效果的实验性评估需要在卤代化合物的存在下对肿瘤动物进行局部辐射。给药方案和给药后辐射开始的时间选择取决于先前的药物动力学和生物分布研究。该评估由对肿瘤体积的变化进行定量、肿瘤消融和长期存活的发生率组成。通过对比的方式,并使RBE/CBE因子能够计算,给出了X-射线和单独热光束的分级剂量。
体内研究:采用如人异种移植物肿瘤神经胶质瘤U343、前列腺癌pc-3、头与颈鳞状细胞癌-咽htb-43 fadu、乳腺癌htb-19、雌激素非依赖型转移乳腺癌、人结肠癌t-84、肺鳞状细胞癌mri-h-165,在标准啮齿类动物肿瘤模型中进行这些研究。
采用重16-22g的Balb/c小鼠中的鼠乳房肉瘤EMT6肿瘤模型来证明生物分布和化合物活性。肿瘤直径可达7-9mm。化合物经静脉内或腹膜内给予,例如以在盐水中的5%聚氧乙烯蓖麻油或3%乙醇和3%PEG 800的溶液或5%聚氧乙烯蓖麻油和3%乙醇的溶液形式给予。所用药物浓度为50-100mg/ml。肿瘤可接受单次或多次放射,所述放射开始于给药后2小时、12小时、24小时和48小时。平均剂量速率为每分钟100-200cGy。于放射前后测量肿瘤尺寸。采用25、35和45Gy剂量的单次分割剂量。
采用标准技术在受辐射的正常组织和肿瘤上进行标准组织病理学分析。动物用10%缓冲的福尔马林盐水灌流-固定。
用概率分析来评价采用不同终末点的剂量-响应数据;从拟合曲线中得到ED50和TCP50值。将这些值用于计算RBE/CBE因子的值。在所有研究中采用适当的对照组。在治疗实验中,采用Kaplan-Meier方法分析放射后相对于时间的存活百分数。将各试验组的存活时间进行分级和排序,通过非参数统计技术Wilcoxin 2-Sample Test进行比较。
结果:以上实验表明,本发明的化合物在肿瘤块中蓄积并历经1-2天从血液中清除。仅照射X-射线后产生约30%肿瘤消除(tumor free),同时用卤代化合物+X-射线放射治疗在40-100天后产生40%至>90%的肿瘤消除。肿瘤消除的数量和/或肿瘤控制的水平是化合物效力和所用X-射线剂量的函数。
患者治疗:将化合物用于对所有接受放射疗法的患者进行预治疗。在放射疗法(常规放射疗法或CHART或IMRT)的过程之前向患者给药并根据需要直到放射疗法过程结束时结束。常规放射疗法将历经4-6周、每周5天、以约2Gy的分割剂量、采用标准4-10兆电子伏特放射疗法线性加速剂传递50Gy-60Gy的X-射线剂量。如果使用CHART,则放射治疗过程持续11天,在治疗期间以1.2-1.5Gy的分割剂量每天传递50-60Gy的总剂量,每天平均3.5份剂量。使用以上药物化合物的结果是显著增强了治疗结果。改善在单独放射治疗之上20-80%或更多的区域内。
图1说明了施用本发明化合物的作用(以%肿瘤消除表示)。
Claims (24)
1.式(I)化合物在制备通过光子活化疗法用于细胞死亡的药物组合物中的用途;
其中R1各自独立地选自氢、任选被取代的C1-8烷基、任选被取代的C2-8链烯基、卤素、SO3R4、=O或NO2,其中取代基选自一个或多个C1-6烷基、R5、=O、OR5、CO2R5、CONR6R6,并且各取代基可进一步被一个或多个CO2R5或OR5取代;
其中R2各自独立地选自氢、任选被取代的C1-8烷基、任选被取代的C2-8链烯基、卤素、SO3R4、NO2,其中取代基选自一个或多个C1-6烷基、R5、=O、OR5、CO2R5、CONR6R6,并且各取代基可进一步被一个或多个CO2R5或OR5取代;
其中R1和R2可共同形成六元环,其中所述的环可以是完全饱和的、部分饱和的或不饱和的,并任选被一个或多个=O、卤素、SO3R4、NO2、C1-6烷基或CO2R5取代;
其中R3各自独立地为氢、卤素、C1-20烷基、C2-20链烯基、C2-20炔基、C1-6卤代烷基、C3-12芳基或C3-12杂芳基、C1-20烷氧基、C2-20链烯氧基、C2-20炔氧基、C3-12芳氧基、C3-12杂芳氧基;其中所述烷基、烷氧基、链烯基、链烯氧基、炔基、炔氧基、芳基、芳氧基、杂芳基和杂芳氧基任选被一个或多个C1-6烷基、芳基、R5、OR5、NR6 2、SO3R4、NO2、卤素、CO2R5或B(OR6)2取代,并且各取代基可进一步被一个或多个卤素、C1-6烷基取代;
其中R2和R3或者R1和R3可共同形成五元环,其中所述的环可以是完全饱和的、部分饱和的或不饱和的,并任选被一个或多个=O、C1-8烷基或CO2R5取代;
其中R4为氢或C1-6烷基;R5为氢或C1-6烷基、C6-12芳基、任选被取代的碳硼烷、生物相容的聚合物或抗衡离子如Na或K,所述烷基或芳基任选被NR6 2、NO2、C1-4烷基或C6-12芳基取代;R6为氢或C1-6烷基,R7为氢或任选被CO2R5取代的C1-6烷基;
M为金属或氢,优选选自V、Mn、Fe、Ru、Tc、Cr、Pt、Co、Ni、Cu、Zn、Ge、In、Sn、Y、Au、Ba、W、Gd、Pb或Pt;
其中一个或多个R1、R2或R3为选自F、Cl、Br、I、NO2的吸电子基,优选Br。
2.如权利要求1所要求的用途,其中一个或多个R1基团为F、Cl、Br或I。
3.如权利要求1或2所要求的用途,其中一个或多个R2基团为F、Cl、Br或I。
4.如权利要求1至3中任意一项所要求的用途,其中一个或多个R3基团为F、Cl、Br或I。
5.如权利要求1至中任意一项所要求的用途,用于预防和/或治疗癌症。
6.如权利要求5所要求的用途,其中所述的癌症为实体瘤和/或转移瘤。
7.如权利要求5或权利要求6所要求的用途,用于预防和/或治疗淋巴瘤、皮肤癌、肺癌、头和/或颈癌、骨癌、前列腺癌、结肠癌、子宫颈癌、乳癌、脑癌、肝癌或胰腺癌。
8.如权利要求7所要求的用途,其中皮肤癌为恶性黑素瘤,包括鳞状细胞癌、梅克尔细胞癌或基底细胞癌。
9.如权利要求1至8任意一项所要求的用途,用于哺乳动物。
10.如权利要求1至5任意一项所要求的用途,用于预防和/或治疗非转移良性肿瘤、子宫平滑肌瘤、关节炎、乳腺瘤、menohrragina、良性前列腺增生和选择性心脏结构的破坏、凝块、动脉粥样硬化斑块或年龄相关性黄斑变性紊乱。
11.式(I)化合物
其中R1各自独立地选自氢、任选被取代的C1-8烷基、任选被取代的C2-8链烯基、卤素、SO3R4、NO2、=O,其中取代基选自一个或多个C1-6烷基、R5、=O、OR5、CO2R5、CONR6R6,并且各取代基可进一步被一个或多个CO2R5或OR5取代;
其中R2各自独立地选自氢、任选被取代的C1-8烷基、任选被取代的C2-8链烯基、卤素、SO3R4、NO2,其中取代基选自一个或多个C1-6烷基、R5、=O、OR5、CO2R5、CONR6R6,并且各取代基可进一步被一个或多个CO2R5或OR5取代;其中C1-8烷基可任选被一个或多个O、CO2或NR7间隔;
其中R1和R2可共同形成六元环,其中所述的环可以是完全饱和的、部分饱和的或不饱和的,并任选被一个或多个=O、C1-6烷基、卤素、SO2R4、NO2或CO2R5取代;
其中R3各自独立地为氢、卤素、C1-6烷基、C1-6卤代烷基、NO2、C3-12芳基、C3-12杂芳基、C1-6烷氧基、C3-12芳氧基或C3-12杂芳氧基;其中烷基、烷氧基、芳基、芳氧基、杂芳基和杂芳氧基任选被一个或多个C1-6烷基、R5、C3-12芳基、OR5、NR6、SO3R4、卤素、CO2R5、B(OR6)2取代,并且各取代基可进一步被一个或多个卤素或C1-6烷基取代;
其中R2和R3或者R1和R3可共同形成五元环,其中所述的环可以是完全饱和的、部分饱和的或不饱和的,并任选被一个或多个=O、C1-8烷基或CO2R5取代;
其中一个或多个R1、R2或R3为选自F、Cl、Br、I、NO2的吸电子基,优选Br;
其中R4为氢或C1-6烷基;R5为氢或C1-6烷基或任选被取代的碳硼烷、生物相容的聚合物或抗衡离子如Na或K;R6为氢或C1-6烷基;R7为氢或任选被CO2R5取代的C1-6烷基;
M为金属或氢,优选选自V、Mn、Fe、Ru、Tc、Cr、Pt、Co、Ni、Cu、Zn、Ge、In、Sn、Y、Au、Ba、W、Gd、Pb或Pt,
条件是,
当R1和R2均为溴或均为氯时,R3不是氢或被F、Br、CO2Me、CO2H、CH3、CF3、Cl或NO2取代的苯基;
当R1和R2为溴或氯时,R3不是被F、Br、CO2Me、CO2H、CH3、CF3、Cl或NO2取代的苯基;
当R1和R2均为氢时,R3不是Cl、Br、F、CF3或被Cl或F取代的苯基;
当R1是氢且R3是苯基时,R2不是NO2、Cl或CH2OH;
当R2是氢且R1是NO2时,R3不是被甲基取代的苯基;
当R2是氢且R1是F时,R3不是氢,并且
当R1和R2均为乙基时,R3不是NO2。
16.如权利要求11所要求的化合物,
其中R13为(CH2)5CH3、(CH2)5CH2OH或雌二醇。
20.如权利要求11至19任意一项所要求的化合物,所述化合物另外包含一个或多个V、Mn、Fe、Ru、Tc、Cr、Pt、Co、Ni、Cu、Zn、Ge、In、Sn、Y、Au、Ba、W、Gd、Ga、Pb、Al或Pt。
21.药物组合物,含有如权利要求11至20任意一项所定义的化合物和可药用赋形剂。
22.通过光子活化疗法用于细胞死亡的如权利要求11至20所定义的式(I)化合物或如权利要求21所要求的组合物。
23.如权利要求11至20任意一项所要求的式(I)化合物的制备方法,所述方法包括卟啉化合物的卤化。
24.通过光子活化疗法导致细胞死亡的方法,所述方法包括向需要其的受治疗者施用权利要求1至5任意一项所定义的式(I)化合物。
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Cited By (3)
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CN102499924A (zh) * | 2011-11-23 | 2012-06-20 | 中国医学科学院生物医学工程研究所 | 二乙撑三胺五乙酸或乙二胺四乙酸或胺三乙酸修饰卟啉的用途 |
CN105503918A (zh) * | 2015-12-08 | 2016-04-20 | 南京林业大学 | 一种含二氧杂戊硼基卟啉锌配合物及其制备方法 |
CN109679110A (zh) * | 2018-12-25 | 2019-04-26 | 北京科技大学 | 一种基于菌绿素的纳米金属-有机框架光敏剂及制备方法 |
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AU2005261561A1 (en) | 2006-01-19 |
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BRPI0513278A (pt) | 2008-05-06 |
ZA200701175B (en) | 2008-11-26 |
WO2006005924A1 (en) | 2006-01-19 |
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KR20070054636A (ko) | 2007-05-29 |
GB0415663D0 (en) | 2004-08-18 |
GB0702696D0 (en) | 2007-03-21 |
GB2433070A (en) | 2007-06-13 |
JP2008506675A (ja) | 2008-03-06 |
US7816518B2 (en) | 2010-10-19 |
CA2573609A1 (en) | 2006-01-19 |
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