CN107072970B - 用于治疗癌症和其他增殖性疾病的新的辣椒平类似物 - Google Patents
用于治疗癌症和其他增殖性疾病的新的辣椒平类似物 Download PDFInfo
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Abstract
本公开内容一般地涉及辣椒平衍生物及其使用方法。在一些方面,本公开内容涉及使用辣椒平衍生物来治疗癌症或其他过度增殖性疾病。在本公开内容的一些方面中,本公开内容提供了可用于治疗癌症的辣椒平衍生物。所述化合物可用于治疗的这些癌症包括但不限于乳腺癌、子宫颈癌、口腔癌、头癌、颈癌或前列腺癌。在一些方面,通过将所述化合物直接注射到肿瘤(特别是口腔肿瘤)中,所述化合物可用于治疗肿瘤。在另一些方面,所述化合物全身施用。本公开内容的化合物还可用于治疗与所述化合物所施用之肿瘤相关的疼痛。
Description
背景技术
本申请要求2014年8月29日提交的美国临时申请序列号62/043,750的优先权,其全部内容通过引用并入本文。
I.技术领域
本公开内容一般地涉及新的辣椒平(capsazepine)衍生物、其在药物组合物中的用途、使用该化合物治疗疾病的方法。
II.相关技术的描述
晚期口腔癌具有70%的死亡率,该死亡率30年来没有变化。此外,报道这些患者最严重的症状是与无法手术的口腔癌相关的疼痛,并且没有有效缓解这种疼痛的可用药物。在头颈部具有无法手术之肿瘤的患者随着肿瘤继续生长以及侵袭关键结构而经历剧烈疼痛。阿片类药物是用于控制疼痛和提供姑息治疗的主要药物,然而,这些患者很快对这些药物产生耐受性,导致很少有甚至没有疼痛控制和非常缓慢而痛苦的死亡。随着这些肿瘤的生长,它们经常侵袭神经血管结构,导致剧烈疼痛,并且它们经常使颈动脉破裂导致死亡。减小肿瘤体积和TRPV1通道的堵塞不仅防止侵袭关键结构,而且提供更好的生活质量,并且证明可用于接受治疗的患者和临终患者的姑息治疗。口腔癌患者的肿瘤是可及的并且经常无法手术,因为它们侵袭或接近头颈部中的关键结构。许多口腔癌患者死于颈动脉的肿瘤侵袭。这没有为这种患者群体留下治疗选择。施用辣椒平(尤其是将辣椒平直接注射到这些肿瘤中)导致肿瘤体积减小,并可防止神经束和关键结构(例如颈动脉)的肿瘤侵袭(WO2014/089067)。治疗这些癌症和其他癌症的另外的化合物的开发代表一个重要的临床挑战。
发明内容
根据本公开内容,提供了治疗癌症的方法,其包括向有此需要的患者施用治疗有效量的下式化合物或者其可药用盐或互变异构体:
其中X1为O或S;R1为-NR3R4,其中R3为氢、烷基(C≤12)、经取代烷基(C≤12);且R4为芳烷基(C≤12)或经取代芳烷基(C≤12);或者
其中R5和R5′各自独立地为氢、或烷基(C≤12)、烯基(C≤12)、炔基(C≤12)、芳基(C≤12)、芳烷基(C≤12)或这些基团中任一种的经取代形式;n为0、1、2、3、4、5或6;R6为氢、卤素、氨基、氰基、羟基、巯基、硝基、或磺基、或烷基(C≤12)、芳基(C≤12)、烷氧基(C≤12)、烷基氨基(C≤12)、二烷基氨基(C≤2)、烷基磺酰基氨基(C≤12)、烷基磺酰基(C≤12),或这些基团中任一种的经取代形式;并且z为0、1、2、3、4或5;R2为烯基(C512)、芳烷基(C≤12)、或这些基团中任一种的经取代形式;或下式的化合物:
前提是所述化合物不是下式的化合物:
在一些实施方案中,X1为O。在另一些实施方案中,X1为S。在一些实施方案中,R1为-NR3R4,其中:R3为氢、烷基(C≤12)、经取代的烷基(C≤12);且R4为芳烷基(C≤12)或经取代芳烷基(C≤12)。在一些实施方案中,R3为氢。在另一些实施方案中,R3为烷基(C≤12)。在一些实施方案中,R3为烷基(C≤6)。在一些实施方案中,R3为甲基。在一些实施方案中,R4为芳烷基(C≤12)。在一些实施方案中,R4为苄基或2-苯乙基。在一些实施方案中,R4为经取代的芳烷基(C≤12)。在一些实施方案中,R4为3,4-二羟基苄基、4-氯苄基、4-氟苄基、2,4-二氯苄基、3,4-二甲氧基苄基、2-(3,4-二羟基苯基)乙基、2-(4-氯苯基)乙基、2-(4-氟苯基)乙基、2-(2,4-二氯苯基)乙基或2-(二甲氧基苯基)乙基。在另一些实施方案中,R1为其中:R5和R5′各自独立地为氢、烷基(C≤12)、烯基(C≤12)、炔基(C≤12)、芳基(C≤12)、芳烷基(C≤12)或这些基团中任一种的经取代形式;n为0、1、2、3、4、5或6;R6为氢、卤素、氨基、氰基、羟基、巯基、硝基或磺基,或烷基(C≤12)、芳基(C≤12)、烷氧基(C≤12)、烷基氨基(C≤12)、二烷基氨基(C≤12)、烷基磺酰基氨基(C≤12)、烷基磺酰基(C≤12)或这些基团中任一种的经取代形式;并且z为0、1、2、3、4或5。在一些实施方案中,R5为氢。在另一些实施方案中,R5为烷基(C≤12)。在一些实施方案中,R5为烷基(C≤8)。在一些实施方案中,R5为异丙基。在一些实施方案中,R5′为氢。在另一些实施方案中,R5′为烷基(C≤6)。在一些实施方案中,R5′为甲基。在另一些实施方案中,R5为芳基(C≤12)。在一些实施方案中,R5为苯基。在一些实施方案中,n为0、1、2、3或4。在一些实施方案中,n为1、2或3。在一些实施方案中,n为1。在另一些实施方案中,n为2。在另一些实施方案中,n为3。在一些实施方案中,R6为氢、卤素、氨基、羟基或烷基(C≤12)、烷氧基(C≤12)、烷基氨基(C≤12)、二烷基氨基(C≤12),或这些基团中任一种的经取代形式。在一些实施方案中,R6为羟基。在另一些实施方案中,R6为卤素。在另一些实施方案中,R6为烷氧基(C≤12)。在一些实施方案中,R6为烷氧基(C≤8)。在一些实施方案中,R6为甲氧基。在一些实施方案中,z为0、1、2或3。在一些实施方案中,z为1或2。在一些实施方案中,z为1。在另一些实施方案中,z为2。在一些实施方案中,R2为烯基(C≤12)。在一些实施方案中,R2为烯基(C≤8)。在一些实施方案中,R2为2-丙烯基。在另一些实施方案中,R2为芳烷基(C≤12)。在一些实施方案中,R2为芳烷基(C≤8)。在一些实施方案中,R2为苄基或2-苯乙基。在另一些实施方案中,R2为经取代的芳烷基(C≤12)。在一些实施方案中,R2为经取代的芳烷基(C≤8)。在一些实施方案中,R2为3,4-二羟基苄基、4-氯苄基、4-氟苄基、2,4-二氯苄基、3,4-二甲氧基苄基、2-(3,4-二羟基苯基)乙基、2-(4-氯苯基)乙基、2-(4-氟苯基)乙基、2-(2,4-二氯苯基)乙基或2-(二甲氧基苯基)乙基。在一些实施方案中,该式进一步限定为:
或者其可药用盐或互变异构体。在一些实施方案中,所述癌症是上皮癌(carcinoma)、肉瘤、淋巴瘤、白血病、黑素瘤、间皮瘤、多发性骨髓瘤或精原细胞瘤。在一些实施方案中,所述癌症是膀胱癌、血癌、骨癌、脑癌、乳腺癌、中枢神经系统癌、子宫颈癌、结肠癌、子宫内膜癌、食管癌、胆囊癌、胃肠道癌、外生殖器癌、泌尿生殖道癌、头癌、肾癌、喉癌、肝癌、肺癌、肌肉组织癌、颈癌、口腔癌或鼻黏膜癌、卵巢癌、胰腺癌、前列腺癌、皮肤癌、脾癌、小肠癌、大肠癌、胃癌、睾丸癌或甲状腺癌。在一些实施方案中,所述癌症是乳腺癌、前列腺癌、子宫颈癌、头癌、肺癌、颈癌、口腔癌或鼻黏膜癌或实体瘤。在一些实施方案中,所述癌症是头癌、颈癌或口腔癌或鼻黏膜癌。在另一些实施方案中,所述癌症是乳腺癌、前列腺癌、子宫颈癌或肺癌。在一些实施方案中,所述癌症是无法手术的。在一些实施方案中,所述无法手术的癌症在用所述化合物治疗后变得可手术。在一些实施方案中,所述癌症是口腔鳞状细胞癌。在一些实施方案中,所述癌症是实体瘤。在一些实施方案中,所述方法包括将所述化合物直接注射到肿瘤中。在一些实施方案中,所述化合物配制成可注射溶液。在一些实施方案中,所述方法包括全身施用化合物。在一些实施方案中,所述化合物配制成用于经口或静脉内施用。在一些实施方案中,所述方法还包括减轻疼痛。在一些实施方案中,所述方法还包含第二治疗剂。在一些实施方案中,所述第二治疗剂是手术、放射治疗、免疫治疗、遗传治疗或第二化学治疗化合物。在一些实施方案中,第二治疗剂是二甲双胍。在一些实施方案中,化合物降低肿瘤大小,使得肿瘤变得可切除。
在另一方面,本公开内容提供了降低肿瘤大小的方法,其包括向有此需要的患者施用治疗有效量的下列化合物或者其可药用盐或互变异构体:
其中X1为O或S;R1为-NR3R4,其中R3为氢、烷基(C≤12)、经取代的烷基(C≤12);且R4为芳烷基(C≤12)或经取代芳烷基(C≤12);或者
其中R5为氢或烷基(C≤12)、烯基(C≤12)、炔基(C≤12)、芳基(C≤12)、芳烷基(C≤12)或这些基团中任一种的经取代形式;n为0、1、2、3、4、5或6;R6为氢、卤素、氨基、氰基、羟基、巯基、硝基或磺基,或烷基(C≤12)、芳基(C≤12)、烷氧基(C≤12)、烷基氨基(C≤12)、二烷基氨基(C≤12)、烷基磺酰基氨基(C≤12)、烷基磺酰基(C≤12)或这些基团中任一种的经取代形式;并且z为0、1、2、3、4或5;R2为烯基(C≤12)、芳烷基(C≤12)或这些基团中任一种的取代基;或下式的化合物:
前提是所述化合物不是下式的化合物:
在另一方面,本公开内容提供了下式的化合物:
其中X2为O或S;R7为-CH(CH3)2、芳基(C≤12)或经取代的芳基(C≤12);R8是-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3、-S(O)2NH2、烷基(C≤12)或经取代的烷基(C≤12)。y为0、1、2、3、4、5、6、7、8或9;R9为烯基(C≤12)、芳基(C≤12)、芳烷基(C≤12)或这些基团中任一种的经取代形式;且R10为氢、烷基(C≤12)或经取代的烷基(C≤12);或者其可药用盐或互变异构体。在一些实施方案中,X2为S。在一些实施方案中,R7为芳基(C≤12)或经取代的芳基(C≤12)。在一些实施方案中,R10为烷基(C≤6)或经取代的烷基(C≤6)。在一些实施方案中,y为0、1、2、3或4。在一些实施方案中,R9为烯基(C≤12)或经取代的烯基(C≤12)。在一些实施方案中,R9为芳烷基(C≤12)或经取代的芳烷基(C≤12)。在一些实施方案中,该式进一步定义为:
或者其可药用盐或互变异构体。在一些实施方案中,所述化合物是:
或者其可药用盐或互变异构体。
在又一方面,本公开内容提供了下式的化合物:
或者其可药用盐或互变异构体。
在另一方面,本公开内容提供了包含可药用赋形剂和本公开内容之化合物的药物组合物。
从下面的详细描述中,本公开内容的其他目的、特征和优点将变得明显。然而,应理解,虽然指示了本公开内容的具体实施方案,但是详细描述和具体实施例仅以示例说明的方式给出,因为对于本领域技术人员而言,根据该详细描述,在本公开内容的精神和范围内的各种改变和修改是明显的。注意,仅仅因为特定的化合物归属于一个特定的通式并不意味着它不能还属于另一种通式。
附图说明
以下附图形成本说明书的一部分,并且被包括在内以进一步说明本公开内容的某些方面。通过参考这些附图之一结合本文给出的具体实施方案的详细描述可以更好地理解本公开内容。
图1-细胞生存力作为新的辣椒平类似物之浓度的函数的图。
图2-与载剂相比,当用CIDD 99或CIDD 118处理24小时,HSC3、MDA231、PC3和H460细胞系的细胞生存力图。辣椒平对这些细胞系的抑制显示为水平虚线。***p<0.001
图3-与辣椒平和载剂相比,用5、10和30μM的CIDD 99、108、109、111、114或118处理24小时之SCC4细胞的细胞生存力图。**p<0.05和***p<0.001。
图4-与载剂对照相比,在10天期间,在用40μg(1μg/μl)的CIDD24或辣椒平处理后,SCC4异种移植物的肿瘤体积%变化的图,n=每组5只。*p<0.05;**p<0.01,***p<0.001。CIDD 24还示出CIDD 24和辣椒平之间的统计学显著性差异(#=p<0.05)。
图5-当用辣椒平、CIDD 99和CIDD 118以10μM处理24小时时HSC3细胞的细胞生存力图。将10mM的N-乙酰半胱氨酸添加到细胞中,观察到的细胞生长抑制被逆转。*p<0.05和***p<0.001。
图6-每隔一天用80μg(1μg/μl)的CIDD24、CIDDI11处理或载剂对照处理14天的小鼠异种移植物中SCC4肿瘤体积(mm3)的图,n=每组5只。与载剂相比,*p<0.05;**p<0.01和***p<0.001。
具体实施方式
在本公开内容的一些方面中,本公开内容提供可用于治疗癌症的辣椒平衍生物。所述化合物可用于治疗的这些癌症包括但不限于:乳腺癌、子宫颈癌、口腔癌、头癌、颈癌或前列腺癌。在一些方面,通过将所述化合物直接注射到肿瘤中,所述化合物可用于治疗肿瘤,特别是口腔肿瘤。在另一些方面,化合物全身施用。本公开内容的化合物还可用于治疗与所述化合物所施用之肿瘤相关的疼痛。在一些实施方案中,与辣椒平相比,本公开内容的化合物更具治疗活性或具有至少一种有利的治疗性质。下面详细地描述本公开内容的这些和其他方面。
I.定义
当在化学基团的情况下使用时:“氢”是指-H;“羟基”是指-OH;“氧代”是指=O;“羰基”是指-C(=O)-;“羧基”是指-C(=O)OH(也写作-COOH或-CO2H);“卤代”独立地是指-F、-CI、-Br或-I;“氨基”是指-NH2;“羟氨基”是指-NHOH;“硝基”是指-NO2;亚氨基是指=NH;“氰基”是指-CN;“异氰酸酯”是指-N=C=O;“叠氮基”是指-N3;在一价的情况下,“磷酸酯”是指-OP(O)(OH)2或其去质子化形式;在二价的情况下,“磷酸酯”是指-OP(O)(OH)O-或其去质子化形式;“巯基”是指-SH;以及“硫代”是指=S;“磺酰酯”是指-S(O)2-;以及“亚磺酰基”是指-S(O)-。
在化学式的情况下,符号“-”表示单键,“=”表示双键,“≡”表示三键。符号“----”表示任选的键,如果存在的话则为单键或双键。符号表示单键或双键。因此,例如,式包括并且应了解,没有一个这样的环原子形成多于一个双键的一部分。此外,注意,当连接一个或两个立体原子时,共价键符号“-”并不表示任何优选的立体化学。相反,其涵盖所有的立体异构体及其混合物。当与键垂直交叉绘制时(例如,对于甲基的),符号表示该基团的连接点。注意,连接点通常仅对于较大的基团以这种方式指示以帮助读者明确地识别连接点。符号表示单键,其中与楔形物的较厚端连接的基团“离开页面”。符号表示单键,其中与楔形物的较厚端连接的基团“进入页面”。符号表示单键,其中双键周围的几何形状(例如,E或Z)未限定。因此,指示两种选择以及其组合。在本申请中示出的结构的原子上任何未限定的化合价都隐含地表示与该原子键合的氢原子。碳原子上的粗点表示连接到该碳上的氢被定向于纸平面之外。
当环系统上基团“R”被描述为“浮动基团(floating group)”时,例如,在下式中:
则R可取代与任何环原子连接的任何氢原子,包括所描绘的、隐含的或明确限定的氢,只要形成稳定的结构即可。当在稠环系统上的基团“R”被描述为“浮动基团”时,例如在下式中:
则除非另有说明,否则R可替换与稠环之一的任一环原子连接的任一氢原子,只要形成稳定的结构即可。可替换的氢包括所描绘的氢(例如,上式中与氮连接的氢)、隐含的氢(例如,上式未示出但理解为存在的氢)、明确限定的氢和任选的其存在取决于环原子之特性氢(例如,当X等于-CH-时,与基团X连接的氢),只要形成稳定的结构即可。在所示的实例中,R可以位于稠环体系的5元环或6元环上。在上式中,紧随在括号中的“R”基团之后的下标“y”表示数字变量。除非另有规定,否则该变量可以为0、1、2或任何大于2的整数,其仅受环或环系统的可替换氢原子的最大数目限制。
对于下面的基团和类别,基团中碳原子数如下所示:“Cn”限定在该基团/类别中碳原子的确切数目(n)。“C≤n”限定可在基团/类别中的碳原子的最大数目(n),其中对于所讨论的基团,最小数目尽可能小,例如,应理解,在基团“烯基(C≤8)”或类别“烯烃(C≤8)”中最小碳原子数目为两个。“烷氧基(C≤10)”表示具有1至10个碳原子的烷氧基。“膦(C≤10)”表示具有0至10个碳原子的膦基。“Cn-n”限定基团中碳原子的最小数目(n)和最大数目(n′)。因此,“烷基(C2-10)”表示具有2至10个碳原子的那些烷基。通常,碳原子数标识(carbon numberindicator)在其修饰的基团之后,用括号括起来,并且全部写在下标中;然而,该标识也可能在该基团之前,或者不带括号,而不代表任何意义上的变化。因此,术语“C5烯烃”,“C5-烯烃”,“烯烃(C5)”和“烯烃C5”都是同义的。
除非以下另有说明,否则本文使用的术语“饱和的”是指如此修饰的化合物或基团不具有碳-碳双键和碳-碳三键。在饱和基团的经取代形式的情况下,可存在一个或更多个碳氧双键或碳氮双键。当存在这样的键时,则不排除可能作为酮-烯醇互变异构或亚胺/烯胺互变异构的一部分出现的碳-碳双键。
当在没有“经取代的”修饰语的情况下使用时,术语“脂族”表示如此修饰的化合物/基团是无环或环状但非芳族的烃化合物或基团。在脂族化合物/基团中,碳原子可以以直链、支链或非芳族环(脂环族)连接在一起。脂肪族化合物/基团可以是饱和的,其通过单键(烷烃/烷基)连接,或不饱和的,与一个或更多个双键(烯烃/烯基)或一个或更能多个三键(炔烃/炔基)连接。
当在没有“经取代的”修饰语的情况下使用时,术语“烷基”是指具有碳原子作为连接点,直链或支链的无环结构,并且不含碳和氢以外的原子的单价饱和脂族基团。基团-CH3(Me)、-CH2CH3(Et)、-CH2CH2CH3(n-Pr或丙基)、-CH(CH3)2(i-Pr,iPr或异丙基)、-CH2CH2CH2CH3(n-Bu)、-CH(CH3)CH2CH3(仲丁基)、-CH2CH(CH3)2(异丁基)、-C(CH3)3(叔丁基、t-butyl、t-Bu或tBu)和-CH2C(CH3)3(新戊基)是烷基的非限制性实例。当不使用“经取代的”修饰语时,术语“烷二基”是指二价饱和脂族基团,具有一个或两个饱和碳原子作为连接点,直链或支链的无环结构,不含碳-碳双键或三键,并且不含除碳和氢之外的原子。基团-CH2-(亚甲基)、-CH2CH2-、-CH2C(CH3)2CH2-和-CH2CH2CH2-是烷二基的非限制性实例。当在没有“经取代的”修饰语的情况下使用时,术语“亚烷基”是指二价基团=CRR′,其中R和R′独立地为氢或烷基。亚烷基的非限制性实例包括:=CH2、=CH(CH2CH3)和=C(CH3)2。“烷烃”是指化合物H-R,其中R是烷基,正如上文所定义的该术语。当这些术语中的任何一个与“经取代的”修饰语一起使用时,一个或更多个氢原子已被-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3或-S(O)2NH2独立地取代。以下基团是经取代的烷基的非限制性实例:-CH2OH、-CH2Cl、-CF3、-CH2CN、-CH2C(O)OH、-CH2C(O)OCH3、-CH2C(O)NH2、-CH2C(O)CH3,-CH2OCH3、-CH2OC(O)CH3、-CH2NH2、-CH2N(CH3)2和-CH2CH2Cl。术语“卤代烷基”是经取代的烷基的子集,其中氢原子替换被限制为卤素(即-F、-Cl、-Br或-I),使得除碳、氢和卤素之外不存在其他原子。基团-CH2Cl是卤代烷基的非限制性实例。术语“氟代烷基”是经取代的烷基的子集,其中氢原子替换被限制为氟,使得除碳、氢和氟之外不存在其他原子。基团-CH2F、-CF3和-CH2CF3是氟代烷基的非限制性实例。
当在没有“经取代的”修饰语的情况下使用时,术语“环烷基”是指这样的单价饱和脂族基团,其具有碳原子作为连接点(所述碳原子形成一个或更多个非芳族环结构的一部分),不含碳-碳双键或三键并且不含除碳和氢以外的原子。非限制性实例包括:-CH(CH2)2(环丙基)、环丁基、环戊基或环己基(Cy)。当在没有“经取代的”修饰语的情况下使用时,术语“环烷二基”是指具有两个碳原子作为连接点的二价饱和脂族基团,其不含碳-碳双键或三键,并且不含除碳和氢以外的原子。基团是环烷二基的非限制性实例。“环烷烃”是指化合物H-R,其中R是上文所定义的环烷基。当这些术语中的任何一个与“经取代的”修饰语一起使用时,一个或更多个氢原子已被-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3或-S(O)2NH2独立地替换。
当在没有“经取代的”修饰语的情况下使用时,术语“烯基”是指这样的单价不饱和脂族基团,其具有碳原子作为连接点、直链或支链的无环结构、至少一个非芳族碳-碳双键、不含碳-碳三键、不合碳和氢之外的原子的。非限制性实例包括:-CH=CH2(乙烯基)、-CH=CHCH3、-CH=CHCH2CH3、-CH2CH=CH2(烯丙基)、-CH2CH=CHCH3和-CH=CHCH=CH2。当在没有“经取代的”修饰语的情况下使用时,术语“烯二基”是指二价不饱和脂族基团,其具有两个碳原子作为连接点、直链或支链的、线性或支化的无环结构、至少一个非芳族碳-碳双键、不含碳-碳三键并且不含除碳和氢以外的原子的。基团-CH=CH-、-CH=C(CH3)CH2-、-CH=CHCH2-和-CH2CH=CHCH2-是烯二基的非限制性实例。注意到,尽管烯二基是脂族的,但是一旦在两端连接,不排除该基团形成芳族结构的一部分。术语“烯(alkene)”或“烯烃(olefin)”是同义的,并且是指具有式H-R的化合物,其中R是烯基,正如上文所定义的该术语。“末端烯烃(terminal alkene)”是指仅具有一个碳-碳双键的烯烃,其中该键在分子的一端形成乙烯基。当这些术语中的任何一个与“经取代的”修饰语一起使用时,一个或更多个氢原子已被-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3或者-S(O)2NH2独立地替换。基团-CH=CHF、-CH=CHCl和-CH=CHBr是经取代的烯基的非限制性实例。
当在没有“经取代的”修饰语的情况下使用时,术语“炔基”是指这样的单价不饱和脂族基团,其具有碳原子作为连接点、直链或支链的无环结构、至少一个碳-碳三键并且不含除碳和氢之外的其他原子。如本文使用的术语炔基不排除存在一个或更多个非芳族碳-碳双键。基团-C≡CH、-C≡CCH3和-CH2C≡CCH3是炔基的非限制性实例。“炔烃”是指化合物H-R,其中R是炔基。当这些术语中的任何一个与“经取代的”修饰语一起使用时,一个或更多个氢原子已被-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3或-S(O)2NH2独立地替换。
当在没有“经取代的”修饰语的情况下使用时,术语“芳基”是指具有芳族碳原子作为连接点的单价不饱和芳族基团,所述碳原子形成一个或更多个六元芳族环结构的一部分,其中环原子都是碳,并且其中该基团不合除碳和氢以外的原子。如果存在多于一个环,那么这些环可以是稠合的或未稠合的。如本文使用的术语不排除存在与第一芳族环或存在的任何另外芳族环连接的一个或更多个烷基或芳烷基(碳原子数限制允许)。芳基的非限制性实例包括苯基(Ph)、甲基苯基、(二甲基)苯基、C6H4CH2CH3(乙基苯基)、萘基和衍生自联苯的单价基团。当在没有“经取代的”修饰语的情况下使用时,术语“芳二基(arenediyl)”是指具有两个芳族碳原子作为连接点的二价芳族基团,所述碳原子形成一个或更多个六元芳族环结构的一部分,其中环原子都是碳,并且其中所述一价基团不包含除碳和氢以外的原子。如本文使用的术语不排除存在与第一芳族环或存在的任何另外的芳族环连接的一个或更多个烷基、芳基或芳烷基(碳原子数限制允许)。如果存在多于一个环,那么这些环可以是稠合的或不稠合的。未稠合的环可通过以下一种或更多种方式连接:共价键、烷二基或烯二基(碳原子数限制允许)。芳二基的非限制性实例包括:
“芳烃”是指化合物H-R,其中R是芳基,正如上文所定义的该术语。苯和甲苯是芳烃的非限制性实例。当这些术语中的任何一个与“经取代的”修饰语一起使用时,一个或更多个氢原子已被-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3或-S(O)2NH2独立地替换。
当在没有“经取代的”修饰语的情况下使用时,术语“芳烷基”是指单价基团-烷二基-芳基,其中术语烷二基和芳基各自以与上述提供的定义一致的方式使用。非限制性实例是:苯基甲基(苄基,Bn)和2-苯基-乙基。当术语“芳烷基”与“经取代的”修饰语一起使用时,来自烷二基和/或芳基的一个或更多个氢原子被-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3或-S(O)2NH2独立地替换。经取代的芳烷基的非限制性实例是:(3-氯苯基)-甲基和2-氯-2-苯基-乙-1-基。
当在没有“经取代的”修饰语的情况下使用时,术语“杂芳基”是指具有芳族碳原子或氮原子作为连接点的一价芳族基团,所述碳原子或氮原子形成一个或更多个芳族环结构的一部分,其中在至少一个环原子是氮、氧或硫,并且其中杂芳基由不包含碳、氢、芳族氮、芳族氧和芳族硫之外的其他原子。如果存在多于一个环,那么这些环可以是稠合的或未稠合的。如本文使用的该术语不排除存在与芳族环或芳族环系统连接的一个或更多个烷基、芳基和/或芳烷基(碳原子数限制允许)。杂芳基的非限制性实例包括呋喃基、咪唑基、吲哚基、吲唑基(Im)、异恶唑基、甲基吡啶基、恶唑基、苯基吡啶基、吡啶基、吡咯基、嘧啶基、吡嗪基、喹啉基、喹唑啉基、喹喔啉基、三嗪基、四唑基、噻唑基、噻吩基和三唑基。术语“N-杂芳基”是指具有氮原子作为连接点的杂芳基。“杂芳烃”是指化合物H-R,其中R是杂芳基。吡啶和喹啉是杂芳烃的非限制性实例。当这些术语与“经取代的”修饰语一起使用时,一个或更多个氢原子已被-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3或-S(O)2NH2独立地替换。
当在没有“经取代的”修饰语的情况下使用时,术语“杂环烷基”是指具有碳原子或氮原子作为连接点的一价非芳族基团,所述碳原子或氮原子形成一个或更多个非芳族环的一部分结构,其中至少一个环原子是氮、氧或硫,并且其中杂环烷基不包含碳、氢、氮、氧和硫原子之外的原子。如果存在多于一个环,那么这些环可以是稠合的或未稠合的。如本文使用的术语不排除存在与环或环系统连接的一个或更多个烷基(碳原子数限制允许)。此外,该术语不排除在环或环系统中存在一个或更多个双键,前提条件是所得基团仍为非芳族。杂环烷基的非限制性实例包括吖丙啶基、氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、四氢呋喃基、四氢噻吩基、四氢吡喃基、吡喃基、环氧乙烷基和氧杂环丁烷基(oxetanyl)。术语“N-杂环烷基”是指具有氮原子作为连接点的杂环烷基。当这些术语与“经取代的”修饰语一起使用时,一个或更多个氢原子已被被-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3、-S(O)或-C(O)OC(CH3)3(叔丁氧基羰基,BOC)独立地替换。
当在没有“经取代的”修饰语的情况下使用时,术语“酰基”是指基团-C(O)R,其中R为氢、烷基、环烷基、烯基、芳基、芳烷基或杂芳基,正如上文所定义的这些术语。基团-CHO、-C(O)CH3(乙酰基,Ac)、-C(O)CH2CH3、-C(O)CH2CH2CH3、-C(O)CH(CH3)2、-C(O)CH2)2、-C(O)C6H5、-C(O)C6H4CH3、-C(O)CH2C6H5、-C(O)(咪唑基)是酰基的非限制性实例。“硫代酰基”以类似的方式定义,不同之处在于基团-C(O)R的氧原子已被替换为硫原子,即-C(S)R。术语“醛”对应于如上所定义的烷烃,其中至少一个氢原子被替换为-CHO基。当这些术语中的任何一个与“经取代的”修饰语一起使用时,一个或更多个氢原子(包括与羰基或硫代羰基的碳原子直接连接的氢原子,如果有的话)已经被-OH、-F、-Cl、-Br、-I、-NH2、-SH、-OCH3、-OCH2CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-OC(O)CH3或者-S(O)NH2独立地替换。基团-C(O)CH2CF3、-CO2H(羧基)、-CO2CH3(甲基羧基)、-CO2CH2CH3、-C(O)NH2(氨基甲酰基)和-CON(CH3)2是经取代酰基的非限制性实例。
当在没有“经取代的”修饰语的情况下使用时,术语“烷氧基”是指基团-OR,其中R为烷基,正如上文所定义的该术语。非限制性实例包括:-OCH3(甲氧基)、-OCH2CH3(乙氧基)、-OCH2CH2CH3、-OCH(CH3)2(异丙氧基)、-OC(CH3)3(叔丁氧基)、-OCH(CH2)2、-O-环戊基和-O-环己基。当在没有“经取代的”修饰语的情况下使用时,术语“环烷氧基”、“烯氧基”、“炔氧基”、“芳氧基”、“芳烷氧基”、“杂芳基氧基”、“杂环烷氧基”和“酰氧基”是指定义为-OR的基团,其中R分别为环烷基、烯基、炔基、芳基、芳烷基、杂芳基、杂环烷基和酰基。当在没有“经取代的”修饰语的情况下使用时,术语“烷硫基”和“酰硫基”是指基团-SR,其中R分别是烷基和酰基。术语“醇”对应于如上定义的烷烃,其中至少一个氢原子已替换为羟基。术语“醚”对应于如上定义的烷烃,其中至少一个氢原子已替换为烷氧基。当这些术语中的任何一个与“经取代的”修饰语一起使用时,一个或更多个氢原子已被-OH、-F、-Cl、-Br、-I、-NH2、-NO2、-CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3或者-S(O)NH2独立地替换。
当在没有“经取代的”修饰语的情况下使用时,术语“烷基氨基”是指基团-NHR,其中R为烷基,正如上文所定义的该术语。非限制性实例包括:-NHCH3和-NHCH2CH3。当在没有“经取代的”修饰语的情况下使用时,术语“二烷基氨基”是指基团-NRR′,其中R和R′可以是相同或不同的烷基,或者R和R′可一起表示烷二基。二烷基氨基的非限制性实例包括:-N(CH3)2、-N(CH3)(CH2CH3)和N-吡咯烷基。当在没有“经取代的”修饰语的情况下使用时,术语“环烷基氨基”、“烯基氨基”、“炔基氨基”、“芳基氨基”、“芳烷基氨基”、“杂芳基氨基”、“杂环烷基氨基”,“烷氧基氨基”和“烷基磺酰基氨基”是指定义为-NHR的基团,其中R分别为环烷基、烯基、炔基、芳基、芳烷基、杂芳基、杂环烷基、烷氧基和烷基磺酰基。芳基氨基的非限制性实例是-NHC6H5。当在没有“经取代的”修饰语的情况下使用时,术语“酰胺基”(酰基氨基)是指基团-NHR,其中R为酰基,正如上文所定义的该术语。酰氨基的非限制性实例是-NHC(O)CH3。当在没有“经取代的”修饰语的情况下使用时,术语“烷基亚氨基”是指二价基团=NR,其中R为烷基,正如上文所定义的该术语。当这些术语中的任何一个与“经取代的”修饰语一起使用时,与碳原子连接的一个或更多个氢原子已被-OH、-F、-Cl、-Br、-I、-NH2、-NO2、CO2H、-CO2CH3、-CN、-SH、-OCH3、-OCH2CH3、-C(O)CH3、-NHCH3、-NHCH2CH3、-N(CH3)2、-C(O)NH2、-OC(O)CH3或者-S(O)2NH2独立地替换。基团-NHC(O)OCH3和-NHC(O)NHCH3是经取代的酰氨基的非限制性实例。
当与权利要求书和/或说明书中的术语“包含”一起使用时,使用单词“一个”或“一种”可以意味着“一个/种”,但是它也符合“一个/种或更多个/种”、“至少一个/种”、“一个/种或多于一个/种”的含义。
贯穿本申请中,术语“约”用于表示值包括用于确定值或研究对象之间存在的变化之方法、装置的误差的固有变化。
术语“包含”,“具有”和“包括”是开放式连结动词。这些动词的一种或更多种的形式或时态,例如“包含(comprises)”,“包含(comprising)”,“具有(has)”,“具有(having)”,“包括(includes)”和“包括(including)”也是开放式的。例如,“包含”、“具有”或“包括”一个或更多个步骤的任何方法不限于仅具有那些一个或更多个步骤并且还包括其他未列出的步骤。
在说明书和/或权利要求书中使用的术语“有效的”意指足以实现期望的、预期的或想要的结果。当在用化合物治疗患者或对象的情况下使用时,“有效量”、“治疗有效量”或“药学有效量”意指当向对象或患者施用以治疗疾病时,足以实现疾病的这种治疗的化合物的量。
如本文使用的术语“IC50”是指为所获得的最大反应之50%的抑制剂量。这种定量测量表明抑制给定的生物、生化或化学过程(或过程的组分,即酶、细胞、细胞受体或微生物)的一半需要多少特定药物或其他物质(抑制剂)。在一些实施方案中,IC50为与测定条件、实验时间、细胞铺板或其他反应条件相比的相对值。
第一化合物的“异构体”是其中每个分子含有与第一化合物相同的组成原子的独立化合物,但是三维中这些原子的构型不同。
如本文使用的术语“患者”或“对象”是指活的哺乳动物生物体,例如人、猴、马、牛、绵羊、山羊、狗、猫、小鼠、大鼠、豚鼠或其转基因物种。在某些实施方案中,患者或对象是灵长类动物。人对象的非限制性实例是成年人、青少年、婴儿和胎儿。
本文中通常使用的“可药用的”是指在合理的医学判断范围内适用于与人和动物的组织、器官和/或体液接触而无过度的毒性、刺激性、过敏反应的与合理的利益/风险比相称的其他问题或并发症的那些化合物、材料、组合物和/或剂型。
“可药用盐”是指本公开内容的化合物的盐,其是如上定义的可药用的并且具有所需的药理学活性。这些盐包括与无机酸形成的酸加成盐,例如盐酸、氢溴酸、硫酸、硝酸、磷酸等;或与有机酸形成的酸加成盐,例如1,2-乙二磺酸、2-羟基乙磺酸、2-萘磺酸、3-苯基丙酸、4,4′亚甲基双(3羟基-2-烯-1-羧酸)、4-甲基双环[2.2.2]辛二烯-1-羧酸、乙酸、脂族单羧酸和二羧酸、脂族硫酸、芳香族硫酸、苯磺酸、苯甲酸、樟脑磺酸、碳酸、肉桂酸、柠檬酸、环戊烷丙酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、庚酸、己酸、羟基萘甲酸、乳酸、月桂基硫酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘康酸、o-(4羟基苯甲酰基)苯甲酸、草酸、对氯苯磺酸、苯基取代的链烷酸、丙酸、对甲苯磺酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、酒石酸、叔丁基乙酸、三甲基乙酸等。可药用盐还包括当存在酸性质子时能够与无机或有机碱反应形成的碱加成盐。可接受的无机碱包括氢氧化钠、碳酸钠、氢氧化钾、氢氧化铝和氢氧化钙。可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。应认识到,构成本公开内容的任何盐的一部分的特定阴离子或阳离子不是关键的,只要该盐作为整体在药理学上是可接受的即可。可药用盐及其制备和使用方法的另外的实例列于Handbook of Pharmaceutical Salts:Properties,and Use(P.H.Stahl&C.G.Wermuth编辑,Verlag Helvetica Chimica Acta,2002)中。
本文使用的术语“可药用载体”是指参与运载或运输化学试剂的可药用材料、组合物或载剂,例如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。
“预防”或“防止”包括:(1)在可能处于疾病风险和/或易患疾病但尚未经历或显示疾病的任何或所有病理或症状的对象或患者中抑制疾病的发作,和/或(2)在可能处于疾病风险和/或易患疾病但尚未经历或显示疾病的任何或全部病理或症状的对象或患者中减缓疾病之病理或症状的发作。
“立体异构体”或“光学异构体”是给定化合物的异构体,其中相同的原子与相同的其他原子键合,但是三维中这些原子的构型不同。“对映异构体”是给定化合物的立体异构体,其是彼此的镜像,如左手和右手。“非对映异构体”是非对映体的给定化合物的立体异构体。手性分子含有手性中心,也称为立构中心或立体中心,它是具有基团的分子中的使得任何两个基团的互换导致立体异构体的任何一点,而不必是原子。在有机化合物中,手性中心通常是碳、磷或硫原子,但是其他原子也可能是有机化合物和无机化合物中的立体中心。分子可具有多个立体中心,得到许多立体异构体。在立体异构现象是由于四面体立体中心(例如,四面体碳)的化合物中,假设可能的立体异构体的总数不超过2n,其中n是四面体立体中心的数目。具有对称性的分子通常具有少于最大可能数量的立体异构体。将对映异构体的50∶50混合物称为外消旋混合物。或者,对映异构体的混合物可以是对映异构体富集的,使得一种对映体以大于50%的量存在。通常,使用本领域已知的技术可拆分或分离对映异构体和/或非对映异构体。预期对于立体化学尚未定义的任何立体中心或手性轴,立体中心或手性轴可以以其R式、S式或作为R和S式的混合物存在,包括外消旋和非外消旋混合物。如本文使用短语“基本上不含其他立体异构体”是指组合物含有≤15%、更优选≤10%、甚至更优选≤5%或最优选≤1%的其他立体异构体。
“治疗”包括(1)在经历或显示疾病的病理或症状的对象或患者中抑制疾病(例如阻止病理或症状的进一步发展),(2)在经历或显示疾病的病理或症状的个体或患者中改善疾病(例如逆转病理或症状),和/或(3)在经历或显示疾病的病理或症状的个体或患者中实现疾病的任何可测量的降低。
上述定义代替通过引用并入本文的任何参考文献中的任何冲突定义。然而,定义某些术语的事实不应被视为指示任何未定义的术语是不明确的。相反,据信用来描述本公开内容所有术语明确使得本领域普通技术人员可以理解本公开内容的范围和实践。
II.本公开内容的化合物
在本公开内容中,描述了尝试合成新的辣椒平抗癌剂。本公开内容中描述的新的辣椒平衍生物可根据下面实施例部分所述的方法制备。这些方法可使用本领域技术人员应用的有机化学的原理和技术来进一步改进和优化。这些原理和技术例如在March’sAdvanced Organic Chemistry:Reactions,Mechanisms,and Structure(2007)中教导,其通过引用并入本文。在一些实施方案中,本公开内容包含如表1所述的式的化合物。表1:本公开内容的化合物
本公开内容中描述的新的辣椒平衍生物可含有一个或更多个不对称取代的碳原子或氮原子,并且可以以光学活性或外消旋形式分离。因此,除非明确指明具体的立体化学或异构形式,否则指示所有手性、非对映异构体、外消旋形式、差向异构形式和所有几何异构形式的结构。新的辣椒平衍生物可作为外消旋物和外消旋混合物、单一对映体、非对映体混合物和单独的非对映异构体存在。在一些实施方案中,获得单一非对映异构体。本公开内容的手性中心可具有S或R构型。
此外,构成本公开内容的新的辣椒平衍生物的原子旨在包括这些原子的所有同位素形式。如本文使用的同位素包括具有相同原子序数但质量数不同的那些原子。作为一般实例而非限制,氢的同位素包括氚和氘,碳的同位素包括13C和14C。类似地,构想本公开内容的化合物的一个或更多个碳原子可被硅原子替换。此外,构想新的辣椒平衍生物的一个或更多个氧原子可被硫或硒原子替换。
新的辣椒平衍生物还可具有如下优点,与用于本文所述的适应症的现有技术已知的化合物相比,其可以更有效、毒性更低、作用时间更长、更有效、产生更小的副作用、更易于吸收和/或具有更好的药物动力学特征(例如,更高的口服生物利用度和/或较低的清除率)和/或具有其他有用的药理学、物理或化学优点。
本公开内容的化合物还可以以前药形式存在。因为已知前药增加药物的许多期望的特性(例如溶解性、生物利用度、制造等),所以在本公开内容的某些方法中使用的化合物可以以前药形式递送(如果需要的话)。因此,本公开内容构想本公开内容之化合物的前药以及递送前药的方法。可通过对化合物中的功能官能团进行修饰的方式来制备本公开内容中采用的化合物的前药,从而以常规操作或体内切割修饰得到母体化合物。因此,前药包括例如本文所述的化合物,其中羟基、氨基或羧基与任何基团键合,当前药被施用于对象时,分别切割以形成羟基、氨基或羧酸。
应认识到,形成本公开内容的任何盐的一部分的特定阴离子或阳离子不是关键的,只要该盐作为整体在药理学上是可接受的即可。可药用盐的另一些实例及其制备和使用方法在Handbook of Pharmaceutical Salts:Properties,and Use(2002)中提出,其通过引用并入本文。
III.过度增殖性疾病
尽管过度增殖性疾病可能与导致细胞开始不可控制地繁殖的任何疾病有关,但癌症是常见的例子。癌症的关键因素之一是细胞的正常凋亡周期被中断,因此导致细胞凋亡的药剂是用于治疗这些疾病的重要治疗剂。在本公开内容中,已经显示新的辣椒平衍生物导致细胞凋亡,因此可以潜在地用于治疗多种类型的癌细胞系。因此,新的辣椒平衍生物可用于有效治地治疗癌症,例如口腔肿瘤、头部或颈部肿瘤、乳腺癌、子宫颈癌或前列腺癌等。在多个方面中,构想本公开内容的化合物可用于治疗几乎任何恶性肿瘤(malignancy)。
根据实施方案可用本公开内容的辣椒平衍生物治疗的癌细胞包括但不限于来自以下的细胞:膀胱、血液、骨、骨髓、脑、乳腺、结肠、食道、胃肠、牙龈、头、肾、肝、肺、鼻咽、颈、口腔、卵巢、前列腺、皮肤、胃、胰腺、睾丸、舌头、子宫颈或子宫。此外,癌症可能具体为以下组织学类型,但是不限于此:恶性赘生物;上皮癌;未分化的上皮癌;巨细胞和梭状细胞癌;小细胞癌;乳头状癌(papillary carcinoma);鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌(pilomatrix carcinoma);移行细胞癌;乳头状移行细胞癌;腺癌;恶性胃泌素瘤;肝胆癌(cholangiocarcinoma);肝细胞癌;联合肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤性息肉中的腺瘤;腺癌,家族性结肠息肉病;实体癌;恶性类癌肿瘤;分支肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸性癌;嗜酸性腺癌;嗜碱性癌;透明细胞腺癌;颗粒细胞癌;滤泡腺癌;乳头状和滤泡性腺癌;非包囊硬化性癌(nonencapsulating sclerosing carcinoma);肾上腺皮质癌;子宫内膜癌;皮肤附属器癌;顶浆分泌腺癌(apocrine adenocarcinoma);皮脂腺癌;盯聍腺癌(ceruminous adenocarcinoma);粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌(papillary serous cystadenocarcinoma);黏液性囊腺癌;黏液性腺癌;印戒细胞癌;浸润性导管癌;髓质癌;小叶癌;炎性癌;乳腺的佩吉特病;腺泡细胞癌;腺鳞癌;腺癌伴鳞状化生(denocarcinoma w/squamous metaplasia);恶性胸腺瘤;恶性卵巢间质瘤;恶性卵泡膜细胞瘤(thecoma);恶性颗粒细胞瘤;恶性卵睾丸母细胞瘤(androblastoma);塞托利细胞癌;恶性莱迪希细胞瘤;恶性脂质细胞瘤;恶性副神经节瘤;恶性乳腺外副神经节瘤;嗜铬细胞瘤;肾小球肉瘤;恶性黑素瘤;无色素性黑素瘤;浅表扩散性黑素瘤;巨型色素痣中的恶性黑素瘤;上皮样细胞黑素瘤;恶性蓝色痣;肉瘤;纤维肉瘤;恶性纤维组织细胞瘤;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;肺泡横纹肌肉瘤;间质肉瘤;恶性混合瘤;苗勒氏混合瘤;肾母细胞瘤;肝母细胞瘤;癌肉瘤;恶性间质瘤;恶性布伦纳瘤;恶性叶状瘤(phyllodes tumor);滑膜肉瘤;恶性间皮瘤;无性细胞瘤;胚胎癌;恶性畸胎瘤;恶性卵巢甲状腺瘤;绒毛膜癌;恶性中肾瘤;血管肉瘤;恶性血管内皮瘤;卡波西肉瘤;恶性血管外皮细胞瘤;淋巴管肉瘤;骨肉瘤;皮质旁骨肉瘤(juxtacortical osteosarcoma);软骨肉瘤;恶性成软骨细胞瘤;间充质软骨肉瘤(mesenchymal chondrosarcoma);骨巨细胞瘤;尤文氏肉瘤;恶性牙肉瘤(odontosarcoma);成釉细胞性牙肉瘤;恶性成釉细胞瘤;成釉细胞纤维肉瘤;恶性松果体瘤;脊索瘤;恶性胶质瘤;室管膜瘤;星形细胞瘤;原生质型星形细胞瘤;纤维性星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突胶质细胞瘤;少突胶质母细胞瘤;原始神经外胚层瘤;小脑肉瘤;神经节细胞瘤;神经母细胞瘤;视网膜母细胞瘤;嗅神经源性肿瘤(olfactory neurogenic tumor);恶性脑膜瘤;神经纤维肉瘤;恶性神经鞘瘤;恶性颗粒细胞瘤;恶性淋巴瘤;霍奇金病;副肉芽肿霍奇金病;小淋巴细胞恶性淋巴瘤;大细胞弥漫性恶性淋巴瘤;滤泡恶性淋巴瘤;蕈样真菌病(mycosis fungoides);其他指定的非霍奇金淋巴瘤;恶性组织细胞增生症;多发性骨髓瘤;肥大细胞肉瘤;免疫增生小肠疾病;白血病;淋巴性白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;骨髓性白血病;嗜碱性白血病;嗜酸粒细胞白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;骨髓肉瘤以及毛细胞白血病。在某些方面,肿瘤可包括骨肉瘤、血管肉瘤、横纹肌肉瘤、平滑肌肉瘤、尤文肉瘤、胶质母细胞瘤、神经母细胞瘤或白血病。
IV.药物制剂和施用途径
为了向需要这种治疗的哺乳动物施用,治疗有效量的新的辣椒平衍生物通常与适合所指示的施用途径的一种或更多种赋形剂组合。新的辣椒平衍生物可与乳糖、蔗糖、淀粉粉末、链烷酸的纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠盐和钙盐、明胶、阿拉伯胶、藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇混合,并进行压片或包封以方便施用。或者,新的辣椒平衍生物可溶于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苄醇、氯化钠和/或各种缓冲液中。另一些赋形剂和施用方式在制药领域中是广泛已知的。
可用于本公开内容的药物组合物可进行常规的药物操作,例如灭菌和/或可包含常规的药物载体和赋形剂,例如防腐剂、稳定剂、润湿剂、乳化剂、缓冲剂等。
新的辣椒平衍生物可通过各种方法施用,例如经口或通过注射(例如皮下、肿瘤内、静脉内、腹膜内等)。根据施用途径,新的辣椒平衍生物可包封在材料中以保护化合物免受酸和其他可能使化合物失活的天然条件的作用。它们也可通过疾病或伤口部位的连续灌注/输注来施用。
为了通过肠胃外施用以外的方式施用治疗化合物,可能需要用防止其失活的材料来涂覆新的辣椒平衍生物,或将新的辣椒平衍生物与防止其失活的材料共同施用。例如,治疗性化合物可以以合适的载体,例如脂质体或稀释剂的方式向患者施用。可药用稀释剂包括盐水和缓冲水溶液。脂质体包括水包油包水CGF乳剂以及常规的脂质体。
新的辣椒平衍生物也可经肠胃外、腹膜内、脊柱内或脑内施用。分散体可在甘油、液体聚乙二醇及其混合物中以及在油中制备。在通常的储存和使用条件下,这些制剂可含有防止微生物生长的防腐剂。
还设想适用于可注射用途的药物组合物包括无菌水溶液(水溶性的情况下)或分散体和用于临时制备无菌可注射溶液或分散体的无菌粉末。在所有情况下,组合物必须是无菌的,并且必须是达到易于注射的程度的流体。在制造和储存的条件下必须是稳定的,并且必须防止例如细菌和真菌等微生物的污染作用。载体可以是含有例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等),其合适的混合物和植物油的溶剂或分散介质。例如,通过使用例如卵磷脂的涂层,通过在分散体的情况下维持所需的粒径和通过使用表面活性剂可以维持合适的流动性。防止微生物的作用可通过各种抗细菌剂和抗真菌剂,例如,对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞等来实现。在许多情况下,优选在组合物中包含等张剂,例如糖、氯化钠或多元醇例如甘露糖醇和山梨糖醇。可注射组合物的延长吸收可通过在组合物中包含延迟吸收的试剂,例如单硬脂酸铝或明胶来实现。
无菌可注射溶液可根据需要通过将所需量的新辣椒平衍生与上述所列成分的一种或组合物一起并入合适的溶剂中(如果需要,之后通过过滤灭菌)来制备。通常,通过将治疗化合物和来自上述列举的所需的其他成分一起并入含有碱性分散介质的无菌载体来制备分散体。在用于制备无菌注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥,其产生活性成分(即,治疗化合物)加上来自其先前无菌过滤溶液的任何另外的所需成分的粉末。
新的辣椒平衍生物可以例如与惰性稀释剂或可被吸收的可食用载体一起经口施用。治疗化合物和其他成分也可封闭在硬壳或软壳明胶胶囊中,压制成片剂,或直接掺入对象的饮食中。对于口服治疗性施用,新的辣椒平衍生物可与赋形剂一起使用并可以以可摄入片剂、口含片、锭剂、胶囊剂、酏剂、混悬剂、糖浆剂、糯米纸囊剂(wafer)等形式使用。当然,治疗化合物在组合物和制剂中的百分比可以变化。新辣椒平衍生物在这些治疗有用的组合物中的量是使得将获得合适的剂量。
以剂量单位形式配制肠胃外组合物对于方便施用和剂量均匀是特别有利的。本文所用的剂量单位形式是指作为适合于待治疗对象之单位剂量的物理上离散的单位;每个单位含有预定量的新的辣椒平衍生物,经计算其与所需的药物载体结合产生所期望的治疗效果。本公开内容的剂量单位形式的规格由以下因素决定并直接取决于以下因素(a)本公开内容中描述的新的辣椒平衍生物的独特特征和要实现的具体治疗效果(b)用于治疗患者中选择的病症的这样的治疗化合物在配药领域中的固有限制。
治疗化合物也可局部地向皮肤、眼睛或黏膜施用。或者,如果需要向肺局部递送,则治疗化合物可通过吸入干粉或气雾剂施用。
在本公开内容中描述的新的辣椒平衍生物以足以治疗与患者病症相关的病症的治疗有效剂量施用。例如,可在动物模型系统中评价新的辣椒平衍生物的效力,所述动物模型系统可预测人疾病治疗的效力,例如在实施例和附图中示出的模型系统。
在一些实施方案中,施用于对象的本公开内容的新的辣椒平衍生物或包含本发明新的辣椒平衍生物之组合物的实际剂量由身体和生理因素例如年龄、性别、体重、病症的严重性、所治疗的疾病的类型、先前或同时的治疗干预、对象的特发病和施用途径确定。本领域技术人员可使用这些因素来确定适当的剂量。负责施用的专业人员通常将确定组合物中活性成分的浓度和个体对象的合适剂量。在任何并发症的情况下,个体医生可以调整剂量。
有效量通常为约2mg/kg至约50mg/kg,每天施用一个或更多个剂量,持续一天或数天(取决于施用模式的疗程和上述讨论的因素)。在一些具体实施方案中,该量小于5,000mg/天,范围为100mg至4500mg/天。
在一些实施方案中,有效量小于10mg/kg/天、小于100mg/kg/天、小于250mg/kg/天、小于100mg/kg/天、小于50mg/kg/天、小于25mg/kg/天或小于10mg/kg/天。或者,在一些实施方案中,所述范围为1mg/kg/天至200mg/kg/天。
在另一些非限制性实例中,剂量还可包含每次施用约10mg/kg/体重、约100mg/kg/体重、约10g/kg/体重、约5g/kg/体重,或更多,以及其中可推导的任何范围。在本文所列数量的可推导范围的非限制性实例中,基于上述数量,可施用约1mg/kg/体重至约100mg/kg/体重,约5g/kg/体重至约10g/kg/体重范围等。
在某些实施方案中,本公开内容的药物组合物可包含例如至少约0.1%的本公开内容中所述的新的辣椒平衍生物。在另一些实施方案中,例如,本公开内容的化合物可占单位重量的约0.25%至约75%,或约25%至约60%,或约1%至约10%,以及其中可导出的任何范围。
构想单剂量或多剂量的药剂。用于递送多个剂量的所需时间间隔可由本领域普通技术人员仅使用常规实验来确定。作为示例,对象可以每天以约12小时的间隔施用两个剂量。在一些实施方案中,每天施用一次药剂。
新的辣椒平衍生物可以以常规时间表施用。如本文所使用的,常规时间表是指预定的指定时间段。常规时间表可包括相同或长度不同的时间段,只要时间表是预定的即刻。例如,常规时间表可包括一天两次、每两天、每三天、每四天、每五天、每六天、每周、每月或其间任意设定的天数、周数施用。或者,预定的常规时间表可包括在第一周每天两次施用,随后几个月每天施用等等。在另一些实施方案中,本公开内容提供了可经口服用的药剂,其时间选择依赖或不依赖于食物摄入。因此,例如,可以每天早上和/或每天晚上服用药剂,而不管对象何时吃的饭或将要吃饭。在另一些实施方案中,将本公开内容作为膳食补充剂。在一些实施方案中,新的辣椒平衍生物作为预防措施在肿瘤出现之前服用。在另一些实施方案中,新的辣椒平衍生物被视为治疗选择,用作抗增殖剂。
V.联合治疗
除了用作单一治疗之外,本公开内容中描述的新的辣椒平衍生物也可用于联合治疗中。有效的联合治疗可使用包含两种药剂的单一组合物或药物制剂,或同时施用的两种不同的组合物或制剂来实现,其中一种组合物包含新的辣椒平衍生物,另一种包含第二种药剂。其他治疗方式可在施用新的辣椒平衍生物之前施用、与其同时施用或在其之后施用。使用新的辣椒平衍生物的治疗可在施用其他药剂之前或之后间隔数分钟至数周。在其他药物和新的辣椒平衍生物分别施用的实施方案中,通常将确保在每次递送时间之间的有效时期没有过期,使得每种药剂仍然能够发挥有利的组合效果。在这种情况下,预期通常在彼此的约12至24小时内,更优选彼此约6至12小时内施用新辣椒平衍生物和其他治疗剂,仅约12小时的延迟时间是最优选的。在某些情况下,可能需要显著延长治疗时间段,然而,在各施用之间延迟数天(2、3、4、5、6或7)到数周(1、2、3、4、5、6、7或8)。
还可以想到,将需要不止一次施用新辣椒平衍生物或其他药物。在这一点上,可采用各种组合。作为说明,在新辣椒平衍生物为“A”而另一种药剂为“B”的情况下,基于3和4次总施用的以下排列是示例性的:
同样构想其他组合。可用于本公开内容的药理学试剂的非限制性实例包括已知在癌症或过度增殖性病症或疾病的治疗中有益的任何药理学试剂。在一些实施方案中,构想了新辣椒平衍生物与癌靶向免疫治疗、放射治疗、化学治疗或手术的组合。还构想了新的辣椒平衍生物与一种以上的上述方法的组合,包括一种以上特异性治疗类型。在一些实施方案中,构想免疫治疗是靶向HER2/neu的单克隆抗体,诸如曲妥珠单抗或类似抗体。在另一些实施方案中,免疫治疗可以是另一些靶向癌症的抗体,例如阿仑单抗(alemtuzumab)贝伐单抗西妥昔单抗和帕尼单抗或缀合的抗体,例如替伊莫单抗(ibritumomab tiuxetan)托西莫单抗(tositumomab)brentuximab vedotin曲妥珠单抗-emtansine偶联物(ado-trastuzumab emtansine)(KadcylaTM)或地尼白介素-毒素连接物(denileukin dititox)以及靶向免疫细胞的抗体例如伊匹单抗(ipilimumab)tremelimumab、抗PD-1、抗4-1-BB、抗GITR、抗TIM3、抗LAG-3、抗TIGIT、抗CTLA-4或抗-LIGHT。此外,在一些实施方案中,新的辣椒素衍生物可与吉非替尼、TAE684、tivantinib或这些药物的组合一起施用。此外,在一些实施方案中,设想新的辣椒平衍生物用于与基于树突状细胞的免疫治疗例如Sipuleucel T或过继性T细胞免疫治疗的组合治疗。
此外,构想新的辣椒平衍生物与化学治疗剂组合使用,例如吉非替尼、TAE684、tivantinib、蒽环类、紫杉烷类、甲氨蝶呤、米托蒽醌、雌莫司汀、多柔比星、依托泊苷、长春花碱、卡铂、长春瑞滨、5-氟尿嘧啶、顺铂、托泊替康、异环磷酰胺、环磷酰胺、表柔比星、吉西他滨、长春瑞滨、伊立替康、依托泊苷、长春花碱、培美曲塞(pemetrexed)、美法仑(melphalan)、卡培他滨、奥沙利铂、BRAF抑制剂和TGF-β抑制剂。在一些实施方案中、组合治疗被设计为靶向癌症,例如上述那些。在优选的实施方案中,所设计的组合治疗针对的癌症是颈癌、口腔癌或头癌、乳腺癌、肺癌、前列腺癌、子宫颈癌或其他上皮来源的实体瘤。
1.化学治疗
在一些实施方案中,本公开内容的辣椒平衍生物可与一种或更多种另外的化学治疗结合使用。术语“化学治疗”是指使用药物治疗癌症。“化学治疗剂”用于表示在癌症治疗中施用的化合物或组合物。这些药剂或药物通过其在细胞内的活动模式进行分类,例如,是否影响细胞周期和在什么阶段影响细胞周期。或者,可以基于其直接交联DNA、插入DNA或通过影响核酸合成来诱导染色体和有丝分裂畸变的能力来表征药剂。大多数化学治疗剂分为以下几类:烷化剂、抗代谢物、抗肿瘤抗生素、有丝分裂抑制剂和亚硝基脲类。
化学治疗剂的实例包括烷化剂例如噻替派和环磷酰胺;烷基磺酸盐例如白消安、胺丙磺酯和哌泊舒凡;氮丙啶类例如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺类(ethylenimines)和甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(trietylenephosphoramide)、三乙撑硫代磷酰胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(camptothecin)(包括合成类似物拓扑替康(topotecan))、苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);隐藻素类(cryptophycins)(特别是隐藻素1和隐藻素8);多拉司他丁(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;sarcodictyin;海绵抑素(spongistatin);氮芥类(nitrogen mustards),诸如氯丁酸氮芥(chlorambucil)、萘氮芥、胆磷酰胺(cholophosphamide)、雌氮芥(estramustine)、异磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸甲氧氮芥(mechlorethamine oxidehydrochloride)、美法仑、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、松龙苯芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);硝基脲类(nitrosureas),诸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimustine);抗生素类,诸如烯二炔类(enediyne)抗生素(如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ψI1;达内霉素(dynemicin),包括达内霉素A;二膦酸盐类(bisphosphonate),诸如氯膦酸盐(clodronate);埃斯波霉素(esperamicin);以及新抑癌菌素(neocarzinostatin)生色团和相关色蛋白烯二炔类抗生素生色团、阿克拉霉素(aclacinomysins)、放线菌素、氨茴霉素(authramycin)、氮丝氨酸(azaserine)、博来霉素、放线菌素C(cactinomycin)、carabicin、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-二氮-5-氧-L-正亮氨酸、多柔比星(doxorubicin)(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯代多柔比星和脱氧多柔比星)、表柔比星、依索比星(esorubicin)、依达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素诸如丝裂霉素C、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycin)、培来霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲霉素(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物类,诸如甲氨喋呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、甲氨喋呤、蝶酰三谷氨酸(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、多西氟尿啶(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素类,诸如卡鲁睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、表硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺类,诸如氨鲁米特(aminoglutethimide)、曼托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸;醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基酮戊酸(aminolevulinic acid);恩尿嘧啶(eniluracil);氨苯吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);defofamine;地美可辛(demecolcine);地吖醌(diaziquone);elformithine;醋酸羟吡咔唑(elliptinium acetate);埃博霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟脲;香菇多糖(lentinan);氯尼达明(lonidamine);美登木素生物碱类(maytansinoids),诸如美登素(maytansine)和安丝菌素(ansamitocin));米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼(procarbazine);PSK多糖复合物;雷佐生(razoxane);根霉素(rhizoxin);西索菲兰(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2’,2”-三氯三乙胺;单端孢菌素类(trichothecene)(尤其是T-2毒素、verracurin A、杆孢菌素A(roridin A)和蛇形菌素(anguidine));47inblast;长春地辛(vindcsine);达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺;噻替哌;类紫杉醇(taxoids),如紫杉醇(paclitaxel)和多西他塞(doxetaxel);苯丁酸氮芥(chloranbucil);吉西他滨;6-硫鸟嘌呤;巯基嘌呤;甲氨喋呤;铂配位复合物,诸如顺铂、奥沙利铂和卡铂;长春碱(vinblastine);铂;依托泊苷(VP-16);异磷酰胺;米托蒽醌;长春新碱;长春瑞宾;诺安托(novantrone);替尼泊甙(teniposide);依达曲沙;柔红霉素;氨基蝶呤;希罗达(xeloda);伊拜膦酸盐(ibandronate);伊立替康(例如,CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类维生素A例如视黄酸;卡培他滨;顺铂(CDDP)、卡铂、丙卡巴肼、二氯甲基二乙胺、环磷酰胺、喜树碱、异环磷酰胺、美法仑、苯丁酸氮芥、白消安、亚硝酸脲、更生霉素、柔红霉素、多柔比星、博来霉素、plicomycin、丝裂霉素、依托泊苷(VP16)、他莫昔芬、雷洛昔芬、雌激素受体结合剂、紫杉酚、紫杉醇、多西他赛、吉西他滨、诺维本、法呢基蛋白转染酶抑制剂、反铂,5-氟尿嘧啶、长春新碱、长春花碱和甲氨蝶呤,以及以上任一的可药用盐、酸或衍生物。
2.放射治疗
在一些实施方案中,本公开内容的辣椒平衍生物可与放射治疗结合使用。放射治疗也称为放疗,即用电离辐射治疗癌症和其他疾病。电离辐射沉积能量,这通过损坏正在治疗的区域中的细胞的遗传物质使得这些细胞不可能继续生长来损伤或破坏细胞。不受理论约束,放射治疗可提高肿瘤细胞中活性氧类的量。在一些实施方案中,本公开内容的化合物和放射治疗的组合治疗可增强活性氧类的产生,从而增强治疗的抗肿瘤效果。尽管辐射损害癌细胞和正常细胞二者,但是后者能够修复自己并正常运作。
根据本公开内容使用的放射治疗可包括但不限于使用γ-射线、X-射线和/或向肿瘤细胞定向递送放射性同位素。还考虑了其他形式的DNA损伤因素,例如微波和UV辐照。最有可能所有这些因素对DNA、DNA的前体、DNA的复制和修复以及染色体的组装和维持引起广泛的损害。X射线的剂量范围为从以50至200伦琴每日剂量持续一段长的时间(3至4周)到2000至6000伦琴的单剂量。放射性同位素的剂量范围变化很大,取决于同位素的半衰期、放射辐射的强度和类型以及赘生性细胞的摄取。
放射治疗可能包括使用放射性标记的抗体将辐射剂量直接递送至癌症部位(放射免疫治疗)。抗体是由身体响应于抗原(由免疫系统识别为外源的物质)的存在而生成的高度特异性蛋白质。一些肿瘤细胞含有触发产生肿瘤特异性抗体的特异性抗原。大量的这些抗体可在实验室中制备并附着于放射性物质(称为放射性标记过程)。一旦注射到体内,抗体就会主动寻找癌细胞,其将被辐射的细胞杀伤(细胞毒性)作用破坏。这种方法可将对健康细胞的辐射损伤的风险降至最低。
适形放疗使用与正常的放射治疗相同的放射治疗仪、线性加速器,但是金属块被放置在x射线束的路径中以改变其形状从而匹配癌症的形状。这确保了向肿瘤给予更高的辐射剂量。健康的周围细胞和附近的结构接受较低剂量的辐射,因此降低了副作用的可能性。已经开发了称为多叶准直器的装置并且可用作金属块的替代品。多叶准直器由固定在线性加速器上的多个金属片组成。可以调整各层,使得放射治疗束可成形为治疗区域,而不需要金属块。放射治疗仪的精确定位对于适形放疗非常重要,可以在每次治疗开始时使用特殊的扫描机检查内脏的位置。
高分辨率强度调制的放射治疗也使用多叶准直器。在该治疗期间,在给予处理的同时移动多叶准直器的层。该方法很可能实现治疗束的更精确的成形,并且使放射治疗剂量在整个治疗区域上是恒定的。
尽管研究表明,适形放射治疗和强度调制放射治疗可降低放射治疗的副作用,但精确地对治疗区域进行成形有可能会阻止刚好在治疗区域外的微观癌细胞被破坏。这意味着使用这些专门的放射治疗技术,未来癌症复发的风险可能会更高。
科学家们也在寻找提高放射治疗效果的方法。正在研究两种类型的研究中药物对经受辐射的细胞的影响。放射增敏剂使肿瘤细胞更容易被破坏,放射防护剂保护正常组织免受辐射的影响。也正在研究使用热量的过热在使组织对辐射敏感方面的有效性。
3.免疫治疗
在一些实施方案中,本公开内容的辣椒平衍生物可与一种或更多种另外的免疫治疗结合使用。在癌症治疗的情况下,免疫治疗通常依赖于使用免疫效应细胞和分子来靶向和破坏癌细胞。曲妥珠单抗(HerceptinTM)是一个这样的例子。免疫效应物可以是例如对肿瘤细胞表面上的一些标志物特异的抗体。单独的抗体可充当治疗的效应物,或者可募集其他细胞以实际影响细胞杀伤。抗体还可与药物或毒素(化学治疗剂、放射性核素、蓖麻毒素A链、霍乱毒素、百日咳毒素等)缀合,并且仅充当靶向剂。或者,效应物可以是携带表面分子的淋巴细胞,其直接或间接地与肿瘤细胞靶相互作用。各种效应细胞包括细胞毒性T细胞和NK细胞。治疗方式,即直接的细胞毒性活性和抑制或减少ErbB2的组合将在治疗ErbB2过度表达的癌症中提供治疗益处。
在免疫治疗的一个方面中,肿瘤细胞必须具有适合靶向的一些标志物,即不存在于大多数其他细胞上的标志物。存在许多肿瘤标志物,并且这些肿瘤标志物中的任何一种可能适合于在本公开内容的情况下的靶向。常见的肿瘤标志物包括癌胚抗原、前列腺特异性抗原、泌尿道肿瘤相关抗原(urinary tumor associated antigen)、胎儿抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸路易斯抗原、MucA、MucB、PLAP、雌激素受体、层粘连蛋白受体和p155。免疫治疗的另一个方面是将抗癌作用与免疫刺激作用相结合。还存在免疫刺激分子,其包括:细胞因子例如IL-2、IL-4、IL-6、IL-10、IL-12、GM-CSF、γ-IFN,趋化因子例如MIP-1、MCP-1、IL-8和生长因子例如FLT3配体。结合免疫刺激分子,无论作为蛋白质还是与肿瘤抑制剂组合使用基因递送都已经显示出增强抗肿瘤作用(Ju等,2000)。此外,可使用针对任何这些化合物的抗体来靶向本文讨论的抗癌剂。
目前正在研究或正在使用的免疫治疗的实例是免疫佐剂,例如牛结核分枝杆菌(Mycobacterium bovis)、恶性疟原虫(Plasmodium falciparum)、二硝基氯苯和芳族化合物(美国专利5,801,005和5,739,169;Hui和Hashimoto,1998;Christodoulides等,1998),细胞因子治疗,例如,干扰素α,β和γ;IL-1、GM-CSF和TNF(Bukowski等,1998;Davidson等,1998;Hellstrand等,1998),基因治疗,例如TNF、IL-1、IL-2、p53(Qin等,1998;Austin-Ward和Villaseca,1998;美国专利5,830,880和5,846,945)和单克隆抗体,例如,抗神经节苷脂GM2、抗HER-2、抗p185(Pietras等,1998;Hanibuchi等1998年;美国专利5,824,311)。构想可使用本文所述的基因沉默治疗进行一种或更多种抗癌治疗。
在主动免疫治疗中,通常与不同的细菌佐剂一起施用抗原肽、多肽或蛋白质、或者自体或同种异体肿瘤细胞组合物或“疫苗”(Ravindranath和Morton,1991;Morton等,1992;Mitchell等,1993)。
在过继性免疫治疗中,患者的循环淋巴细胞或肿瘤浸润的淋巴细胞在体外被分离,被淋巴因子例如IL-2激活或用肿瘤坏死基因转导并被重新施用(Rosenberg等,1988;1989)。
4.手术
在一些实施方案中,本公开内容的辣椒平衍生物可以与手术结合使用。大约60%的癌症患者将接受某种类型的手术,包括预防性、诊断性或分期、治疗性和缓解性手术。治疗性手术是可与其他治疗(例如本公开内容的治疗、化学治疗、放射治疗、激素治疗、基因治疗、免疫治疗和/或替代治疗)结合使用的一种癌症治疗。
治疗性手术包括其中全部或部分癌组织被物理去除、切除和/或破坏的切除术。肿瘤切除术是指物理去除肿瘤的至少一部分。除肿瘤切除术外,手术治疗包括激光手术、冷冻手术,电外科手术和显微控制的手术(莫氏手术(Mohs’surgery))。进一步构想本公开内容可以与移除浅表癌、癌前病变(precancer)或附带量的正常组织结合使用。
在切除部分或全部癌细胞、组织或肿瘤后,可在体内形成腔。治疗可通过灌注、直接注射或在该区域局部施用附加的抗癌治疗来完成。可重复这种治疗,例如每1、2、3、4、5、6或7天,或每1、2、3、4周和5周或每1、2、3、4、5、6、7、8、9、10、11或12个月。这些治疗也可以是不同的剂量。
5.其他试剂
构想其他试剂可与本公开内容一起使用。这些另外的试剂包括免疫调节剂,影响细胞表面受体上调和GAP连接的试剂、细胞抑制剂和分化剂、细胞粘附抑制剂、增加过度增殖细胞对凋亡诱导剂的敏感性的试剂或其他生物制剂。免疫调节剂包括肿瘤坏死因子;干扰素α、β和γ;IL-2和其他细胞因子;F42K和其他细胞因子类似物;或MIP-1、MIP-1β、MCP-1、RANTES和其他趋化因子。进一步构想细胞表面受体或其配体如Fas/Fas配体、DR4或DR5/TRAIL(Apo-2配体)的上调将通过建立对过度增殖细胞起作用的自分泌或旁分泌来增强本公开内容的凋亡诱导能力。通过提高GAP连接数来增加细胞间信号传导将增加对相邻过度增殖细胞群的抗过度增殖作用。在另一些实施方案中,细胞生长抑制剂或分化剂可与本公开内容结合使用以改善治疗的抗增殖效力。构想细胞粘附抑制剂以改善本公开内容的效力。细胞粘附抑制剂的实例是粘着斑激酶(focal adhesion kinase,FAKs)抑制剂和洛伐他汀。进一步构想可与本公开内容结合使用提高过度增殖细胞对细胞凋亡的敏感性的其他试剂,例如抗体c225以改善治疗效力。
在引入细胞毒性化学治疗药物后,癌症治疗方面取得了许多进展。然而,化学治疗的后果之一是耐药表型的形成/获得和多重耐药性的形成。耐药性的形成仍然是治疗这种肿瘤的主要障碍,因此,显然需要例如基因治疗的替代方法。
与化学治疗、放射治疗或生物治疗结合使用的另一种治疗形式包括过热,其是将患者组织暴露于高温(高至106°F)的过程。外部或内部加热装置可能涉及局部、区域或全身过热的应用。局部应用涉及向小面积(例如肿瘤)施加热量。可以从身体外部的装置的以靶向肿瘤的高频波在外部产生热量。内部热量可能涉及无菌探针,包括薄的加热线或填充有温水、植入的微波天线或射频电极的中空管。
患者的器官或肢体被加热用于区域治疗,其使用产生高能量的装置(例如磁体)来实现。或者,可将患者的一些血液取出并加热,之后再灌注到将被内部加热的区域中。在癌症遍及全身的情况下也可实施全身加热。为此,可以使用温水毯、热蜡、感应线圈和热室。
技术人员参考“Remington′s Pharmaceutical Sciences”第15版,第33章,特别是第624-652页。剂量必然会根据所治疗的对象的状况而发生一些变化。无论如何,负责的施用人员将决定个体对象的适当剂量。此外,对于人施用,制剂应符合FDA生物制品局标准要求的无菌性、致热原性、一般安全性和纯度标准。
还应指出,可证明任何上述治疗本身在治疗癌症中是有用的。
VI.实施例
包括以下实施例以示出本公开内容的优选实施方案。本领域技术人员应理解,以下实施例中公开的技术表示发明人发现的在实践本发明中运行良好的技术,因此可被认为构成其实践的优选模式。然而,根据本公开内容的教导,本领域技术人员应理解,在不脱离本公开的精神和范围的情况下,可以在所公开的具体实施方案中进行许多改变,并且仍然获得同样或相似的结果。
实施例1-结果
1.辣椒平类似物的合成
式I化合物或其可药用盐可根据本文所述的反应方案制备。除非另有说明,否则公式如上文和权利要求中所定义。
在二氯甲烷中的三氟乙酸的存在下,在室温至150℃的温度下用适当经取代的醛或酮处理胺1,产生所需的环化化合物2。该转化的替代条件还包括使用微波辐照。用于该转化的其他合适条件包括使用路易斯酸例如四异丙基醇钛、四氯化钛、三氟化硼乙醚络合物(boron trifluoride etherate)和相关的路易斯酸。在叔胺碱例如三乙胺和二氯甲烷的存在下,在室温至80℃的温度下,用适当经取代的异氰酸酯或硫代异氰酸酯处理化合物2,产生所需的脲(X=O)或硫脲(X=S)化合物3。可以从相应的胺和硫代羰基二咪唑制备适当经取代的异氰酸酯或硫代异氰酸酯试剂。
方案1:尿素或硫脲化合物的合成
其中Q为氢、羟基、卤素、烷基(C≤12)、经取代的烷基(C≤12)、烷氧基(C≤12)或经取代的烷氧基(C≤12);X为O或S;R1为烯基(C≤12)、芳基(C≤12)、芳烷基(C≤12)或这些基团中任一种的经取代形式;R2和R3各自独立地为氢、烷基(C≤12)、经取代的烷基(C≤12)、芳基(C≤12)或经取代的芳基(C≤12);R4和R5各自独立地为氢、共价键、烷二基(C≤6)或经取代的烷二基(C≤6)。
6,7-二甲氧基-1-苯基-1,2,3,4-四氢异喹啉(2)
将2-(3,4-二甲氧基苯基)乙-1-胺(1)(1.69ml,10mmol)、苯甲醛(1.22ml,12mmol)、TFA(6.13ml,80mmol)和甲苯(10ml)的混合物放入微波小瓶并在140C辐照2小时。完全反应后,残余物用冷水和1N NaOH处理,然后用DCM萃取。将有机层干燥并浓缩以得到粗制棕色固体,进行SiO2快速色谱(洗脱液:10%MeOH/DCM)以得到为棕色油状物的所需产物(2),产率73%。
(m/z:270.2)1H NMR(400mHz,CD3OD):δ7.45-7.38(m,3H),7.33-7.30(m,2H),6.83(s,1H),6.31(s,1H),5.43(s,1H),3.84(s,3H),3.58(s,3H),3.40-3.33(m,1H),3.27-3.24(m,1H),3.15-3.07(m,1H)3.02-2.96(m,1H);13C NMR(400mHz,CD3OD):δ149.2,148.3,139.9,129.8,129.1,129.0,126.3,125.9,111.9,111.3,60.2,40.3,26.3.
向含有6,7-二甲氧基-1-苯基-1,2,3,4-四氢异喹啉(2)(500mg,1.8mmol)的烧瓶中添加HBr(在H2O中48%)(9ml),将反应物在回流下搅拌12小时。在完全转化成所需产物后,将溶液真空浓缩以定量产率得到为棕色固体的6,7-二羟基-1-苯基-1,2,3,4-四氢异喹啉-2-溴化物(3)。该物质不经进一步纯化就用于随后的反应。
(m/z:242.2)1H NMR(400mHz,CD3OD):δ7.50-7.48(m,3H),δ7.47-7.38(m,2H),6.70(s,1H),6.20(s,1H),5.60(s,1H),3.52-3.44(m,2H),3.19-3.04(m,1H)3.02-3.00(m,1H);13C NMR(400mHz,CD3OD):δ147.2,145.9,138.1,130.9,130.3,124.4,123.3,116.0,115.3,61.0,41.5,25.6.
N-(4-氯苯乙基)-6,7-二羟基-1-苯基-3,4-二氢异喹啉-2(1H)-硫代甲酰胺(4)
向搅拌的6,7-二羟基-1-苯基-1,2,3,4-四氢异喹啉-2-溴化物(3)(100mg,0.4mmol)的DMF溶液中添加TEA(0.13ml,1.2mmol)并将所得溶液在室温下搅拌15分钟。向其中添加2-(4-氯苯乙基)异硫氰酸酯(0.078ml,0.48mmol),并在室温下搅拌1小时。完全反应后,将溶液真空浓缩。将剩余的有机残余物在EtOAc中稀释并用H2O和盐水洗涤数次。将有机层真空浓缩,将粗物质进行SiO2快速色谱(洗脱液:10%MeOH/DCM),以26%的产率提供所需产物(4)。
(m/z:439.1)1HNMR(400mHz,CDCl3):δ7.243-7.193(m,5H),δ7.125-7.065(m,4H),6.901(br,1H),6.697(s,1H),6.629(s,1H),5.544(t,J=5.4Hz,1H),3.943(q,J=5.6Hz,2H),3.673(br,2H),2.903(td,J=Hz,2H),2.672-2.577(m,2H);13C NMR(400mHz,CDCl3):δ181.3,143.7,142.2,140.7,137.3,132.6,130.3,129.0,128.7,128.3,127.6,127.4,126.9,115.2,114.8,62.2,47.0,44.1,34.7、27.2.
表2:化合物的特征数据
2.辣椒素类似物的生物学分析
在使用OSCC细胞系(HSC3和SCC4)、乳腺癌细胞系MDA231和前列腺癌细胞系PC3的细胞增殖测定中,用新型辣椒平类似物处理在24小时处理后诱导细胞增殖的显著降低(p<0.001)。这种降低可在图1中看到。其他的细胞系数据可在图2和图3中看到。
在用OSCC细胞系SCC4接种的无胸腺裸鼠中产生的OSCC异种移植物中进行体内测试。每隔一天用40μg类似物CIDD24、CIDD25或辣椒平处理SCC4肿瘤,持续两周(图4)。与载剂对照相比,CIDD24处理在经处理的小鼠中导致肿瘤生长降低80%(p<0.01)。与载剂对照相比,CIDD25导致肿瘤生长降低50%,这与母体化合物辣椒平相当(p<0.001,图4)。小鼠的体重没有减轻,每次处理后和整个两周处理期间恢复正常运动功能。没有观察到对非恶性相邻组织的不良反应。没有发现红斑、肿胀或溃疡。图3和图4分别示出了9种类似物的细胞增殖测定的图示和用CIDD24和CIDD25处理的具有SCC4异种移植物的体内试验数据。
进行研究以了解这些化合物的作用机制。当细胞也用抗氧化剂N-乙酰基-L-半胱氨酸处理时,观察到效果被逆转。不受理论约束,这些效应的逆转表明这些类似物通过产生活性氧类(reactive oxygen species,ROS)导致细胞死亡。用类似物处理后细胞周期停滞的流式细胞术分析表明癌细胞在指示凋亡的subG1期积累。该逆转在图5中示出。
为比较CIDD24和CIDD111在每隔一天用80μg的辣椒平类似物处理两周的SCC4肿瘤中的效力进行的额外的体内测试示于图6中。与载剂对照相比,CIDD24和CIDD111都导致显著降低了肿瘤生长(<0.001)。此外,没有观察到不良反应。尽管CIDD111比CIDD24稍微有效,但在这些条件下效力没有显著性差异。
3.方法和材料
细胞系。OSCC细胞系、SCC4、SCC25和HSC3均来源于人舌OSCC。SCC4和SCC25细胞获自ATCC(Rockville,MD)。HSC3细胞由Brian Schmidt博士(纽约大学)提供(Saghafi等,2011)。乳腺癌细胞(MDA231)、前列腺癌细胞(PC3)和非小细胞肺癌细胞(H460)获自ATCC(Rockville,MD)。在37℃下,将细胞保持在5%CO2下含有10%FBS的DMEM(Gibco,Carlsbad,CA)中。永生化角化细胞(OKF6-TERT2;Harvard Medical School Cell Culture CoreCollection,Cambridge,MA)用作对照上皮细胞。
活性氧类(ROS)测定。使用2,7-二氯二氢荧光素二乙酸酯(DCF-DA;Sigma-Aldrich,St.Louis,MO)通过流式细胞术检查OSCC细胞系中的ROS水平。将细胞(3×105)接种在12孔板中,并在37℃下用DCF-DA孵育30分钟,然后使用含有和不含10mM NAC的无酚介质用30μM适当的辣椒平衍生物或辣椒平处理。处理的细胞在37℃下孵育1小时,收获,洗涤两次,并通过FACS进行分析。
动物。所有研究均获得了UTHSCSA研究所动物保护和使用委员会的批准。在无病原体条件下,在层流空气柜中使用6周龄的雌性无胸腺裸鼠(Harlan,Indianapolis,IN)。他们在受控的温度和湿度下提供12小时光/黑暗的时间表,食物和水自由获取。在研究开始之前,小鼠适应一周。
OSCC小鼠异种移植模型。在小鼠的右胁皮下注射在0.1ml无菌PBS中的2×106SCC4细胞。接种后4周,肿瘤生长至150mm3平均体积。将小鼠分为两组,n=每组5只,接受以下处理作为肿瘤内注射:A组,载剂对照组;B组,辣椒平或辣椒平衍生物(类似物)处理。每隔一天重复处理,持续总计14天。
OSCC异种移植模型中辣椒平类似物的体内效应分析。将辣椒平和新的辣椒平类似物原液(20μg/μL,100%乙醇)在无菌盐水中稀释至5%乙醇,产生终浓度为1μg/μL。SCC4异种移植物每隔一天接受肿瘤内注射40μg的CIDD24或40μg的辣椒平(图4)持续两周。在第二次研究中,SCC4异种移植物每隔一天注射80μg的CIDD24或80μg的CIDD111,持续两周(图5)。对照异种移植物接受肿瘤内注射载剂对照(5%乙醇在无菌盐水中)。每天监测小鼠肿瘤生长(使用数字卡尺)、恶病质和体重减轻。处理24小时后监测体温。通过椭圆形公式计算肿瘤体积:1/2(长×宽2)(Jensen等,2008)。
统计分析。使用GraphPad Prism4(San Diego,California)进行统计学分析。实验一式三份进行,结果表示为平均值±SD,除指定之外。通过单因素方差分析和Bonferroni事后检验(n=4)分析细胞生存力的细胞毒性测定。使用重复测量值的方差分析进行肿瘤生长的统计学分析,并进行Bonferroni事后检验(n=5)。P值小于0.05被认为具有统计学显著性。
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根据本公开内容的教导,可以制备和实施本文公开和要求保护的所有化合物、制剂和/或方法而无需过度实验。虽然已经根据一些优选实施方案描述了本公开内容的化合物、制剂和方法,但是对于本领域技术人员明显的是,在不脱离本公开内容的理念、精神和范围的情况下可以对本文描述的化合物、制剂和方法,以及方法的步骤或方法的步骤顺序进行变化。更具体地,化学和生理学二者相关的某些试剂明显可代替本文所述的试剂而将获得相同或相似的结果。对于本领域技术人员明显的是所有这些类似的替代和修改均被认为在由所附权利要求限定的本公开内容的精神、范围和概念内。
VII.参考文献
以下参考文献通过引用具体地并入本文,程度达到为本文所阐述的那些提供示例性程序或其他补充性细节。
Handbook of Pharmaceutical Salts:Properties,and Use,(Stahl和Wermuth编辑),Verlag Helvetica Chimica Acta,2002.
Jensen,等,BMC Med.Imaging,8:16,2008
March’s Advanced Organic Chemistry:Reactions,Mechanisms,andStructure,2007.
Saghafi,等,Neurosci.Lett.,488:247-251,2011.
WO 2014/089067
Claims (24)
2.药物组合物,其包含可药用赋形剂和根据权利要求1所述的化合物。
3.治疗有效量的权利要求1所述的化合物或者其可药用盐或互变异构体在制备用于治疗癌症之药物中的用途。
4.根据权利要求3所述的用途,其中所述癌症是上皮癌、肉瘤、淋巴瘤、白血病、黑素瘤、间皮瘤或者精原细胞瘤。
5.根据权利要求4所述的用途,其中所述癌症是多发性骨髓瘤。
6.根据权利要求3所述的用途,其中所述癌症是膀胱癌、血癌、骨癌、脑癌、乳腺癌、中枢神经系统癌、子宫颈癌、结肠癌、子宫内膜癌、食管癌、胆囊癌、肾癌、喉癌、肝癌、肺癌、肌肉组织癌、口腔癌或鼻黏膜癌、卵巢癌、胰腺癌、前列腺癌、皮肤癌、脾癌、小肠癌、胃癌、睾丸癌或甲状腺癌。
7.根据权利要求3所述的用途,其中所述癌症是泌尿生殖道癌。
8.根据权利要求3所述的用途,其中所述癌症是外生殖器癌。
9.根据权利要求3所述的用途,其中所述癌症是胃肠道癌。
10.根据权利要求3所述的用途,其中所述癌症是大肠癌。
11.权利要求3所述的用途,其中所述癌症是头癌或颈癌。
12.权利要求3所述的用途,其中所述癌症是无法手术的。
13.权利要求12所述的用途,其中所述无法手术的癌症在使用所述化合物后变得可手术。
14.权利要求3所述的用途,其中所述癌症是口腔鳞状细胞癌。
15.根据权利要求3所述的用途,其中所述癌症是实体瘤。
16.根据权利要求13所述的用途,其中所述使用包括将所述化合物直接注射到肿瘤中。
17.权利要求16所述的用途,其中所述化合物配制成可注射溶液。
18.根据权利要求13所述的用途,其中所述使用包括全身施用所述化合物。
19.权利要求18所述的用途,其中所述化合物配制成用于经口或静脉内施用。
20.根据权利要求3至15中任一项所述的用途,其中所述治疗还包括减轻疼痛。
21.根据权利要求3至15中任一项所述的用途,其中所述治疗还包括施用第二治疗方案。
22.权利要求21所述的用途,其中所述第二治疗方案是手术、放射治疗、免疫治疗、基因治疗或第二化学治疗化合物。
23.权利要求22所述的用途,其中所述第二治疗方案包含二甲双胍。
24.根据权利要求3至15中任一项所述的用途,其中所述化合物降低肿瘤大小,使得所述肿瘤变得可切除。
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CA3107453A1 (en) * | 2018-07-23 | 2020-01-30 | Ohio State Innovation Foundation | Derivatives of papaverine that are effective hypoxic tumor radiosensitizers |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101421257A (zh) * | 2006-03-21 | 2009-04-29 | 欧洲分子生物学实验室 | 阻断细胞复制的试剂以及它们在抑制病理状态中的用途 |
CN102958914A (zh) * | 2010-07-05 | 2013-03-06 | 埃科特莱茵药品有限公司 | 1-苯基取代的杂环衍生物及其作为前列腺素d2受体调节剂的用途 |
WO2014089067A2 (en) * | 2012-12-03 | 2014-06-12 | The Board Of Regents Of The University Of Texas System | Use of capsazepine and analogs thereof to treat cancer |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5824311A (en) | 1987-11-30 | 1998-10-20 | Trustees Of The University Of Pennsylvania | Treatment of tumors with monoclonal antibodies against oncogene antigens |
US5846945A (en) | 1993-02-16 | 1998-12-08 | Onyx Pharmaceuticals, Inc. | Cytopathic viruses for therapy and prophylaxis of neoplasia |
US5801005A (en) | 1993-03-17 | 1998-09-01 | University Of Washington | Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated |
CA2143143A1 (en) | 1994-03-08 | 1995-09-09 | Toshihiko Tanaka | 3-phenylpyrrolidine derivatives |
GB9506466D0 (en) | 1994-08-26 | 1995-05-17 | Prolifix Ltd | Cell cycle regulated repressor and dna element |
US5637619A (en) | 1995-07-05 | 1997-06-10 | Yale University | Antitumor 2-aminocarbonyl-1, 2-bis(methylsulfonyl)-1-(substituted)hydrazines |
US5739169A (en) | 1996-05-31 | 1998-04-14 | Procept, Incorporated | Aromatic compounds for inhibiting immune response |
US5981521A (en) | 1998-11-13 | 1999-11-09 | Abbott Laboratories | Tetrahydroisoquinoline derivatives as LHRH antagonists |
JP2002540086A (ja) * | 1999-03-19 | 2002-11-26 | パーカー ヒューズ インスティテュート | チオ尿素および尿素液相コンビナトリアルライブラリ、合成およびアポトーシス誘導 |
AU6909300A (en) | 1999-08-20 | 2001-03-19 | Merck & Co., Inc. | Substituted ureas as cell adhesion inhibitors |
US20050070570A1 (en) | 2003-06-18 | 2005-03-31 | 4Sc Ag | Novel potassium channels modulators |
US20050165004A1 (en) | 2004-01-22 | 2005-07-28 | Staffan Skogvall | Bronchorelaxing compounds |
WO2007011290A1 (en) | 2005-07-18 | 2007-01-25 | Respiratorius Ab | Bronchorelaxing agents based on indol- and isoquinoline derivatives |
KR100712667B1 (ko) | 2006-04-11 | 2007-05-02 | 재단법인서울대학교산학협력재단 | 신규한 디아자 헤테로고리 유도체 및 그의 고체상 제조방법 |
WO2008130321A2 (en) | 2007-04-23 | 2008-10-30 | Astrazeneca Ab | Novel n-tetrahydronaphtalene or 5-heterocyclyl-chromane or 8-heterocyclyl-tetrahydronaphtalene derivatives for the treatment of pain |
WO2009073203A1 (en) | 2007-12-04 | 2009-06-11 | Amgen Inc. | Trp-m8 receptor ligands and their use in treatments |
WO2010114824A1 (en) | 2009-03-30 | 2010-10-07 | Transtech Pharma Inc | Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof |
CN101791312B (zh) | 2010-03-31 | 2012-01-04 | 中国药科大学 | 一类四氢异喹啉衍生物的用途 |
TW201238950A (en) | 2010-11-15 | 2012-10-01 | Abbott Lab | NAMPT and rock inhibitors |
TWI532742B (zh) | 2011-02-28 | 2016-05-11 | 艾伯維有限公司 | 激酶之三環抑制劑 |
EP2684468A4 (en) | 2011-03-07 | 2014-08-27 | Ajinomoto Kk | EXTENDER OF SALTY TASTE |
ES2392915B1 (es) * | 2011-06-03 | 2013-09-13 | Univ Sevilla | Compuestos bioactivos polifenolicos conteniendo azufre o selenio y sus usos |
CN106588965A (zh) | 2015-10-15 | 2017-04-26 | 北京大学 | 脲拟肽硼酸化合物及其药物组合物、制备方法和用途 |
-
2015
- 2015-08-25 EP EP19159216.1A patent/EP3549582A3/en active Pending
- 2015-08-25 WO PCT/US2015/046784 patent/WO2016033105A1/en active Application Filing
- 2015-08-25 EP EP15836811.8A patent/EP3185860A4/en not_active Withdrawn
- 2015-08-25 US US15/505,260 patent/US10457676B2/en active Active
- 2015-08-25 CN CN201580058701.3A patent/CN107072970B/zh active Active
-
2019
- 2019-09-06 US US16/563,131 patent/US20200024276A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101421257A (zh) * | 2006-03-21 | 2009-04-29 | 欧洲分子生物学实验室 | 阻断细胞复制的试剂以及它们在抑制病理状态中的用途 |
CN102958914A (zh) * | 2010-07-05 | 2013-03-06 | 埃科特莱茵药品有限公司 | 1-苯基取代的杂环衍生物及其作为前列腺素d2受体调节剂的用途 |
WO2014089067A2 (en) * | 2012-12-03 | 2014-06-12 | The Board Of Regents Of The University Of Texas System | Use of capsazepine and analogs thereof to treat cancer |
Non-Patent Citations (1)
Title |
---|
One-Pot α-Amidosulfone-Mediated Variation of the Pictet-Spengler Tetrahydroisoquinoline Synthesis, Suitable for Amide-Type Substrates;Francico J. Arroyo et al.;《Eur. J. Org. Chem.》;20140801;第26卷;5720-5727 * |
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US20170275280A1 (en) | 2017-09-28 |
EP3185860A4 (en) | 2018-08-29 |
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