CN107050458A - 用于治疗肿瘤的药物联合制剂 - Google Patents
用于治疗肿瘤的药物联合制剂 Download PDFInfo
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- CN107050458A CN107050458A CN201611061998.1A CN201611061998A CN107050458A CN 107050458 A CN107050458 A CN 107050458A CN 201611061998 A CN201611061998 A CN 201611061998A CN 107050458 A CN107050458 A CN 107050458A
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Landscapes
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Abstract
本申请公开了药物联合制剂，其包含：(a)抗‑肿瘤剂和(b)由式(I)表示的脂肪酸衍生物。本发明的联合制剂用于哺乳动物受试者中肿瘤的治疗。本申请也提供用于治疗损伤、尤其是胃肠道损伤包括由抗‑肿瘤剂诱导的粘膜炎的组合物和方法，其包含式(I)的脂肪酸衍生物。
Description
本申请是申请日为2010年9月16日的申请号为201080041097.0的题为“用于治疗肿瘤的药物联合制剂”的发明专利申请的分案申请。
技术领域
本发明涉及抗-肿瘤剂和脂肪酸衍生物的药物联合制剂，其用于治疗哺乳动物受试者中的肿瘤。本发明也涉及用于治疗哺乳动物受试者中的肿瘤的方法。本发明进一步涉及用于治疗损伤，尤其是胃肠道损伤，包括粘膜炎如由抗-肿瘤剂诱导的口炎的组合物和方法。
背景技术
肿瘤病在整个世界被认为是严重和常常威胁生命的状况。这些肿瘤病一直且持续为全世界研究努力的主题，所述努力是针对在患有该病的患者的治疗中有效的治疗剂的鉴定。
存在治疗肿瘤病的许多抗-肿瘤剂。例如，5-氟尿嘧啶(以下称为"5-FU")是具有嘧啶类似物结构的抗代谢物，其用作肿瘤病治疗中的药物。其主要应用是在胃肠道癌症如胃癌、结肠癌、直肠癌和胰腺癌中。其它应用例如在肝癌、乳腺癌、子宫癌和卵巢癌中。化疗剂5-FU主要充当胸苷酸合酶抑制剂。胸苷酸合酶抑制剂包括5-FU、卡培他滨、替加氟、卡莫氟、氟尿苷等等。已知替加氟在活体中激活时释放5-FU。已知5-FU具有严重的问题，即5-FU在活体中的延长存在引起消化器官如口腔和肠中的损伤。接受单独5-FU连续静脉输注的患者常常经历那些损伤。
顺铂、顺氯氨铂或II顺氯氨铂(II)(CDDP)是基于铂的化疗药物，其用于治疗各种类型的癌症，包括睾丸肿瘤、膀胱癌、前列腺癌、卵巢癌、非小细胞肺癌、食道癌、宫颈癌、胃癌、骨肉瘤、淋巴瘤和生殖细胞肿瘤。其为抗-癌症药物类的第一成员，所述药物现在也包括卡铂、奈达铂和奥沙利铂。这些铂复合物在体内反应、与DNA结合并引起DNA交联，这最终触发凋亡(程序性细胞死亡)。
一般地，这些抗-肿瘤剂的严重的副作用限制剂量逐步增加并防止实现更好的治疗效果。
为了改进治疗效果，提出了多种药物的一些联合制剂，所述药物具有不同的机制和不同的副作用。但是，仍强烈期望更有效的药物和治疗方法以使癌症患者的存活时间得以进一步延长以及使癌症患者的QOL得以改进。
前列腺素类(下文称为PG(s))是脂肪酸衍生物，为有机羧酸类的成员，其包含在人或其它哺乳动物的组织或器官中，并且展示出宽范围的生理活性。天然发现的PGs(初级PGs)一般地具有式(A)中示出的前列腺烷酸骨架:
另一方面，初级PGs的一些合成类似物具有修饰的骨架。初级PGs根据5元环部分的结构分类为PGAs、PGBs、PGCs、PGDs、PGEs、PGFs、PGGs、PGHs、PGIs和PGJs，并通过碳链部分的不饱和键的数目和位置进一步分类为下列3种类型:
下标1：13,14-不饱和-15-OH
下标2：5,6-和13,14-二不饱和-15-OH
下标3：5,6-、13,14-和17,18-三不饱和-15-OH。
进一步地，根据9-位的羟基的构型，PGFs分类为α型(羟基是α-构型的)和β型(羟基是β-构型的)。
已知PGs具有各种药理和生理学活性，例如血管舒张，诱导炎症，血小板聚集，刺激子宫肌肉，刺激肠肌肉，抗-溃疡效果等。
一些15-酮基(即，在15-位具有氧代代替羟基)-PGs和13，14-二氢(即，在13和14-位之间具有单键)-15-酮基-PGs是已知为通过初级PGs代谢过程中酶的作用天然产生的物质的脂肪酸衍生物。
授予Ueno等人的美国专利申请公开号2006/0281818描述，特定的前列腺素化合物对TJs中的构象变化具有显著效果，其引起胃肠道粘膜屏障功能的恢复。
发明内容
本发明的一个目标是提供用于通过减少由抗-肿瘤剂诱导的毒性副作用而实现针对肿瘤的更好治疗效果的方法或药物。
本发明的另一目标是提供用于治疗由抗-肿瘤剂诱导的疾病或状况的方法或药物。
本发明的又一目标是提供用于治疗粘膜炎的方法或药物。
本发明涉及药物联合制剂，其包含:
(a)药学上有效量的抗-肿瘤剂，选自烷化剂、抗代谢物、抗生素、植物碱、分子靶向药物、激素、铂复合物、反义物(antisense)、抗体和RNAi，和
(b)药学上有效量的由式(I)表示的脂肪酸衍生物:
其中L、M和N是氢、羟基、卤素、低级烷基、羟基(低级)烷基、低级烷酰基氧基或氧代，其中L和M中的至少一个是不同于氢的基团，并且5元环可具有至少一个双键；
A是–CH3、或-CH2OH、-COCH2OH、-COOH或其官能衍生物；
B是单键、-CH2-CH2-、-CH＝CH-、-C≡C-、-CH2-CH2-CH2-、-CH＝CH-CH2-、-CH2-CH＝CH-、-C≡C-CH2-或-CH2-C≡C-；
Z是
或单键
其中R4和R5是氢、羟基、卤素、低级烷基、低级烷氧基或羟基(低级)烷基，其中R4和R5不同时是羟基和低级烷氧基；
R1是饱和或不饱和的二价低级或中级脂族烃残基，其是未取代的或被卤素、烷基、羟基、氧代、芳基或杂环基取代，并且脂族烃中的至少一个碳原子任选地被氧、氮或硫替换；并且Ra是饱和或不饱和的低级或中级脂族烃残基，其是未取代的或被卤素、氧代、羟基、低级烷基、低级烷氧基、低级烷酰基氧基、环(低级)烷基、环(低级)烷基氧基、芳基、芳基氧基、杂环基或杂环-氧基基团取代；低级烷氧基；低级烷酰基氧基；环(低级)烷基；环(低级)烷基氧基；芳基；芳基氧基；杂环基；杂环-氧基基团。
通过联合抗-肿瘤剂和式(I)的脂肪酸衍生物，抗-肿瘤剂的效果得以增高和/或抗-肿瘤剂的副作用得以充分抑制。
在本发明的另一方面，提供了药物组合物，其包含:
(a)药学上有效量的抗-肿瘤剂，选自烷化剂、抗代谢物、抗生素、植物碱、分子靶向药物、激素、铂复合物、反义物、抗体和RNAi，和
(b)药学上有效量的由式(I)表示的脂肪酸衍生物，其与药学上适当的赋形剂结合。
根据本发明，包含两种组分的组合物可以包含组分(a)和(b)二者的单一剂量单位配制，或以单独包含组分(a)和(b)的单独剂量单位配制。
进一步地，本发明提供用于治疗肿瘤的方法，其包括向需要其的受试者施用下列的联合制剂：
(a)药学上有效量的抗-肿瘤剂，选自烷化剂、抗代谢物、抗生素、植物碱、分子靶向药物、激素、铂复合物、反义物、抗体和RNAi，和
(b)药学上有效量的由式(I)表示的脂肪酸衍生物。
根据本发明，组分(a)和(b)可同时地、分开地或顺序地施用。
而且，本发明提供用于治疗哺乳动物受试者中的毒性副作用如胃肠道损伤、包括由抗-肿瘤剂诱导的粘膜炎的组合物，其包含药学上有效量的由式(I)表示的脂肪酸衍生物，其中待治疗的受试者正接受选自烷化剂、抗代谢物、抗生素、植物碱、分子靶向药物、激素、铂复合物、反义物、抗体和RNAi的抗-肿瘤剂。
更进一步地，本发明也提供用于治疗哺乳动物受试者中的粘膜炎如口炎的组合物，其包含药学上有效量的由式(I)表示的脂肪酸衍生物。
具体实施方案
(a)抗-肿瘤剂
本发明中提到的抗-肿瘤剂选自烷化剂、抗代谢物、抗生素、植物碱、分子靶向药物、激素、铂复合物、反义物、抗体和RNAi。
抗-肿瘤剂的例子是烷化剂，如环磷酰胺和白消安(buslfan)；抗代谢物如甲氨蝶呤、6-巯嘌呤(6-MP)、硫唑嘌呤、氟尿嘧啶(5-FU)、替加氟和胞嘧啶阿糖核苷(ara-C)；抗生素如博来霉素、丝裂霉素C、柔红霉素、阿霉素和放线菌素D；植物碱如长春新碱、长春碱、长春地辛、紫杉醇、多西紫杉醇、依托泊甙和伊立替康；分子靶向药物如伊马替尼、吉非替尼、埃罗替尼、索拉非尼、舒尼替尼、曲妥珠单抗、利妥昔单抗、吉姆单抗-奥佐米星、贝伐单抗和西妥昔单抗；激素如泼尼松龙、二乙基己烯雌酚和他莫昔芬；铂复合物如顺铂、卡铂和奥沙利铂；反义物如bcl-2反义物如G3139、hsp27反义物如OGX427、XIAP反义物如AEG35156、PKC-α反义物如LY900003、缺氧-诱导因子反义物如EZN-2968；抗体如CD20抗体如利妥昔单抗、Her2抗体如曲妥珠单抗、VEGF抗体如贝伐珠单抗、EGFR抗体如西妥昔单抗；RNAi如RNAi靶向核糖核苷酸还原酶如CALAA-01。抗-肿瘤剂的优选的例子包括5-FU、替加氟和顺铂。
(b)脂肪酸衍生物
本文应用的脂肪酸衍生物的命名法基于上式(A)中表示的前列腺烷酸的编号系统。
式(A)示出C-20碳原子的基本骨架，但本发明不限于具有相同数目碳原子的那些。在式(A)中，构成PG化合物基本骨架的碳原子编号起始于羧酸(编号1)，并且α-链中的碳原子朝向5元环编号为2至7，环中的碳原子是8至12，并且ω-链中的碳原子是13至20。当α-链中碳原子数目降低时，起始于位置2按顺序删除编号；并且当α-链中碳原子数目增加时，将化合物命名为取代化合物，具有在位置2的各自取代基代替羧基(C-1)。类似地，当ω-链中碳原子数目降低时，起始于位置20按顺序删除编号；并且当ω-链中碳原子数目增加时，将超出位置20的碳原子命名为取代基。化合物的立体化学与上式(A)的立体化学相同，除非另外指定。
一般地，术语PGD、PGE和PGF中的每一个表示在位置9和/或11具有羟基基团的PG化合物，但在本说明书中，这些术语也包括在位置9和/或11具有不同于羟基基团的取代基的那些。将这种化合物称为9-脱羟基-9-取代的-PG化合物或11-脱羟基-11-取代的-PG化合物。具有氢代替羟基基团的PG化合物简单地命名为9-或11-脱氧基-PG化合物。
如上述，PG化合物的命名法基于前列腺烷酸骨架。但是，在化合物具有与前列腺素类似的部分结构的情况下，可应用缩写"PG"。因此，将α-链延长2个碳原子、即α-链中具有9个碳原子的PG化合物命名为2-脱羧基-2-(2-羧基乙基)-PG化合物。类似地，将α-链中具有11个碳原子的PG化合物命名为2-脱羧基-2-(4-羧基丁基)-PG化合物。进一步，将ω-链延长2个碳原子、即ω-链中具有10个碳原子的PG化合物命名为20-乙基-PG化合物。但是，这些化合物可也根据IUPAC命名法命名。
类似物(包括取代的衍生物)或衍生物的例子包括其α-链末端的羧基被酯化的PG化合物；其α-链延长的化合物；其生理学可接受的盐；在2-3位置具有双键或在位置5-6具有三键的化合物，在位置3、5、6、16、17、18、19和/或20具有一个或多个取代基的化合物；和在位置9和/或11具有低级烷基或羟基(低级)烷基基团代替羟基的化合物。
根据本发明，在位置3、17、18和/或19的优选的取代基包括具有1-4个碳原子的烷基，尤其是甲基和乙基。在位置16的优选的取代基包括低级烷基如甲基和乙基、羟基、卤素原子如氯和氟、和芳基氧基如三氟甲基苯氧基。在位置17的优选的取代基包括低级烷基如甲基和乙基、羟基、卤素原子如氯和氟、芳基氧基如三氟甲基苯氧基。在位置20的优选的取代基包括饱和或不饱和的低级烷基如C1-4烷基、低级烷氧基如C1-4烷氧基、和低级烷氧基烷基如C1-4烷氧基-C1-4烷基。在位置5的优选的取代基包括卤素原子如氯和氟。在位置6的优选的取代基包括形成羰基的氧代基团。在位置9和/或11具有羟基、低级烷基或羟基(低级)烷基取代基的PGs的立体化学可为α、β或其混合物。
进一步地，上述类似物或衍生物可为在ω-链末端具有烷氧基、环烷基、环烷基氧基、苯氧基或苯基基团的化合物，其中该链短于初级PGs。
用在本发明中的脂肪酸衍生物由式(I)表示:
其中L、M和N是氢、羟基、卤素、低级烷基、羟基(低级)烷基、低级烷酰基氧基或氧代，其中L和M中的至少一个是不同于氢的基团，并且5元环可具有至少一个双键；
A是–CH3、或-CH2OH、-COCH2OH、-COOH或其官能衍生物；
B是单键、-CH2-CH2-、-CH＝CH-、-C≡C-、-CH2-CH2-CH2-、-CH＝CH-CH2-、-CH2-CH＝CH-、-C≡C-CH2-或-CH2-C≡C-；
Z是
或单键
其中R4和R5是氢、羟基、卤素、低级烷基、低级烷氧基或羟基(低级)烷基，其中R4和R5不同时是羟基和低级烷氧基；
R1是饱和或不饱和的二价低级或中级脂族烃残基，其是未取代的或被卤素、烷基、羟基、氧代、芳基或杂环基取代，并且脂族烃中的至少一个碳原子任选地被氧、氮或硫替换；并且Ra是饱和或不饱和的低级或中级脂族烃残基，其是未取代的或被卤素、氧代、羟基、低级烷基、低级烷氧基、低级烷酰基氧基、环(低级)烷基、环(低级)烷基氧基、芳基、芳基氧基、杂环基或杂环-氧基基团取代；低级烷氧基；低级烷酰基氧基；环(低级)烷基；环(低级)烷基氧基；芳基；芳基氧基；杂环基；杂环-氧基基团。
用在本发明中的优选的化合物由式(II)表示:
其中L和M是氢原子、羟基、卤素、低级烷基、羟基(低级)烷基、低级烷酰基氧基或氧代，其中L和M中的至少一个是不同于氢的基团，并且5元环可具有一个或多个双键；
A是–CH3、或-CH2OH、-COCH2OH、-COOH或其官能衍生物；
B是单键、-CH2-CH2-、-CH＝CH-、-C≡C-、-CH2-CH2-CH2-、-CH＝CH-CH2-、-CH2-CH＝CH-、-C≡C-CH2-或-CH2-C≡C-；
Z是
或单键
其中R4和R5是氢、羟基、卤素、低级烷基、低级烷氧基或羟基(低级)烷基，其中R4和R5不同时是羟基和低级烷氧基；
X1和X2是氢、低级烷基或卤素；
R1是饱和或不饱和的二价低级或中级脂族烃残基，其是未取代的或被卤素、烷基、羟基、氧代、芳基或杂环基取代，并且脂族烃中的至少一个碳原子任选地被氧、氮或硫替换；
R2是单键或低级亚烷基；并且
R3是低级烷基、低级烷氧基、低级烷酰基氧基、环(低级)烷基、环(低级)烷基氧基、芳基、芳基氧基、杂环基或杂环-氧基基团。
在上式中，用于R1和Ra定义中的术语"不饱和"意图包括单独地、分开地或连续地存在于主和/或侧链的碳原子之间的至少一个或多个双键和/或三键。根据通常的命名法，两个连续位置间的不饱和键通过指明两个位置中的较低编号表示，并且两个远端位置之间的不饱和键通过指明两个位置表示。
术语"低级或中级脂族烃"指具有1至14个碳原子(对于侧链优选1至3个碳原子)和优选地1至10、尤其是1至8个碳原子的直链或支链烃基。
术语"卤素原子"涵盖氟、氯、溴和碘。
整个说明书中的术语"低级"意图包括具有1至6个碳原子的基团，除非另外指定。
术语"低级烷基"指含有1至6个碳原子的直链或支链饱和烃基，且包括例如，甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基和已基。
术语"低级亚烷基"指含有1至6个碳原子的直链或支链二价饱和烃基，且包括例如，亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚叔丁基、亚戊基和亚已基。
术语"低级烷氧基"指低级烷基-O-基团，其中低级烷基如上限定。
术语"羟基(低级)烷基"指取代以至少一个羟基基团的如上限定的低级烷基，如羟基甲基、1-羟基乙基、2-羟基乙基和1-甲基-1-羟基乙基。
术语"低级烷酰基氧基"指由式RCO-O-表示的基团，其中RCO-是如上限定的低级烷基基团的氧化形成的酰基基团，如乙酰基。
术语"环(低级)烷基"指通过如上限定但含有三个或更多个碳原子的低级烷基基团的环化形成的环状基团，并且包括例如，环丙基、环丁基、环戊基和环已基。
术语"环(低级)烷基氧基"指环(低级)烷基-O-基团，其中环(低级)烷基如上限定。
术语"芳基"可包括未取代的或取代的芳烃环(优选地单环基团)，例如，苯基、甲苯基、二甲苯基。取代基的例子是卤素原子和卤代(低级)烷基，其中卤素原子和低级烷基如上限定。
术语"芳基氧基"指由式ArO-表示的基团，其中Ar是如上限定的芳基。
术语"杂环基"可包括单环至三环，优选地单环杂环基，其为5至14、优选地5至10元环，具有任选地取代的碳原子和1至4、优选地1至3个选自氮原子、氧原子和硫原子1或2种杂原子。杂环基的例子包括呋喃基、噻吩基、吡咯基、唑基、异唑基、噻唑基、异噻唑基、咪唑基、吡唑基、呋咱基、吡喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、2-吡咯啉基、吡咯烷基、2-咪唑啉基、咪唑烷基、2-吡唑啉基、吡唑烷基、哌啶子基(piperidino)、哌嗪基、吗啉代、吲哚基、苯并噻吩基、喹啉基、异喹啉基、嘌呤基、喹唑啉基、咔唑基、吖啶基、菲啶基、苯并咪唑基、苯并咪唑啉基、苯并噻唑基、吩噻嗪基。该情况下的取代基的例子包括卤素和卤素取代的低级烷基基团，其中卤素原子和低级烷基基团如上述。
术语"杂环-氧基基团"意味着由式HcO-表示的基团，其中Hc是如上述的杂环基。
术语"官能衍生物"包括盐(优选地药学上可接受的盐)、醚、酯和酰胺。
适当的"药学上可接受的盐"包括常规应用的无毒性盐，例如与无机碱的盐如碱金属盐(如钠盐和钾盐)、碱土金属盐(如钙盐和镁盐)、铵盐；或与有机碱的盐，例如胺盐(如甲胺盐，二甲胺盐，环已胺盐，苄胺盐，哌啶盐，乙二胺盐，乙醇胺盐，二乙醇胺盐，三乙醇胺盐，三(羟基甲基氨基)乙烷盐，单甲基-单乙醇胺盐，普鲁卡因盐和咖啡因盐)，碱性氨基酸盐(如精氨酸盐和赖氨酸盐)，四烷基铵盐等。这些盐可通过常规方法制备，例如由对应的酸和碱或通过盐交换。
醚的例子包括烷基醚，例如，低级烷基醚如甲醚，乙醚，丙醚，异丙醚，丁醚，异丁醚，叔丁醚，戊醚和1-环丙基乙基醚；和中级或高级烷基醚如辛醚，二乙基已基醚，月桂醚和鲸蜡醚；不饱和醚如油基醚和亚麻醚；低级烯基醚如乙烯醚，烯丙醚；低级炔基醚如乙炔醚和丙炔醚；羟基(低级)烷基醚如羟基乙基醚和羟基异丙基醚；低级烷氧基(低级)烷基醚如甲氧基甲基醚和1-甲氧基乙基醚；任选地取代的芳基醚如苯基醚，甲苯磺酰基醚，叔丁基苯基醚，水杨醚，3，4-二-甲氧基苯基醚和苯甲酰氨基苯基醚；和芳基(低级)烷基醚如二苯醚，三苯甲醚和二苯甲醚。
酯的例子包括脂肪族酯，例如，低级烷基酯如甲酯，乙酯，丙酯，异丙酯，丁酯，异丁酯，叔丁酯，戊酯和1-环丙基乙基酯；低级烯基酯如乙烯酯和烯丙酯；低级炔基酯如乙炔酯和丙炔酯；羟基(低级)烷基酯如羟基乙基酯；低级烷氧基(低级)烷基酯如甲氧基甲基酯和1-甲氧基乙基酯；和任选地取代的芳基酯如，例如，苯酯，甲苯酯，叔丁基苯基酯，水杨酯，3，4-二-甲氧基苯基酯和苯甲酰氨基苯基酯；和芳基(低级)烷基酯如苄酯，三苯甲酯和二苯甲酯。
A的酰胺意味着由式–CONR'R"表示的基团，其中R'和R"的每一个是氢、低级烷基、芳基、烷基-或芳基-磺酰基、低级烯基和低级炔基，并且包括例如低级烷基酰胺如甲基酰胺、乙基酰胺、二甲基酰胺和二乙基酰胺；芳基酰胺如苯胺和甲苯胺；和烷基-或芳基-磺酰基酰胺如甲磺酰基酰胺、乙磺酰基-酰胺和甲苯磺酰基酰胺。
L和M的优选的例子包括氢、羟基和氧代，并且尤其地，M是羟基或氢并且L是氧代。
A的优选的例子是–COOH，其药学上可接受的盐，其酯或酰胺。
X1和X2的优选的例子都是卤素原子，并且更优选地，氟原子，即所谓的16，16-二氟类型。
优选的R1是含有1-10个碳原子、优选地6-10个碳原子的烃残基。进一步地，脂族烃中的至少一个碳原子任选地被氧、氮或硫替换。
R1的例子包括，例如，下列基团:
-CH2-CH2-CH2-CH2-CH2-CH2-，
-CH2-CH＝CH-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-CH＝CH-，
-CH2-C≡C-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-O-CH2-，
-CH2-CH＝CH-CH2-O-CH2-，
-CH2-C≡C-CH2-O-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-，
-CH2-CH＝CH-CH2-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH＝CH-，
-CH2-C≡C-CH2-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-，
-CH2-CH2-CH2-CH2-CH(CH3)-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-，
-CH2-CH＝CH-CH2-CH2-CH2-CH2-CH2-，
-CH2-CH2-CH2-CH2-CH2-CH2-CH＝CH-，
-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-，和
-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-。
优选的Ra是含有1-10个碳原子、更优选地1-8个碳原子的烃。Ra可具有一个或两个具有一个碳原子的侧链。
优选的化合物包括式(I)中的Ra被卤素取代和/或Z是C＝O，或式(II)中的X1和X2中的一个被卤素取代和/或Z是C＝O。
优选的实施方案的例子是(-)-7-[(2R，4aR，5R，7aR)-2-(1，1-二氟戊基)-2-羟基-6-氧代八氢环戊[b]吡喃-5-基]庚酸，(-)-7-{(2R，4aR，5R，7aR)-2-[(3S)-1，1-二氟-3-甲基戊基]-2-羟基-6-氧代八氢环戊[b]吡喃-5-基}庚酸和(-)-7-[(1R，2R)-2-(4，4-二氟-3-氧代辛基)-5-氧代环戊基]庚酸或其官能衍生物。
上式(I)和(II)中环和α-和/或ω链的构型可与初级PGs相同或不同。但是，本发明也包括具有初级型构型的化合物和具有非初级型构型的化合物的混合物。
在本发明中，二氢位于13和14之间和酮基(＝O)位于15位置的脂肪酸衍生物可通过位置11的羟基和位置15的酮基之间形成半缩醛而处于酮基-半缩醛平衡。
例如，已揭示当X1和X2都是卤素原子、尤其是氟原子时，化合物含有互变异构体，为双环化合物。
如果这种所述互变异构体存在，两种互变异构体的比例随分子其余部分的结构或存在的取代基的种类而改变。有时一种异构体可相比于另一异构体占优势地存在。但是，应理解本发明包括两种异构体。
进一步地，用在本发明中的脂肪酸衍生物包括双环化合物和其类似物或衍生物。
双环化合物由式表示(III)
其中，A是–CH3、或-CH2OH、-COCH2OH、-COOH或其官能衍生物；
X1'和X2'是氢、低级烷基或卤素；
Y是
其中R4'和R5'是氢、羟基、卤素、低级烷基、低级烷氧基或羟基(低级)烷基，其中R4'和R5'不同时为羟基和低级烷氧基。
R1是饱和或不饱和的二价低级或中级脂族烃残基，其是未取代的或被卤素、烷基、羟基、氧代、芳基或杂环基取代，并且脂族烃中的至少一个碳原子任选地被氧、氮或硫替换；并且
R2'是：饱和或不饱和的低级或中级脂族烃残基，其是未取代的或被卤素、氧代、羟基、低级烷基、低级烷氧基、低级烷酰基氧基、环(低级)烷基、环(低级)烷基氧基、芳基、芳基氧基、杂环基或杂环-氧基基团取代；低级烷氧基；低级烷酰基氧基；环(低级)烷基；环(低级)烷基氧基；芳基；芳基氧基；杂环基；杂环-氧基基团。
R3'是氢、低级烷基、环(低级)烷基、芳基或杂环基。
而且，虽然用在本发明中的化合物不论是否存在异构体都可通过基于酮基-类型的式或名称表示，应指出这种结构或名称不意图排除半缩醛型化合物。
在本发明中，任何异构体如个别互变异构体、其混合物、或光学异构体、其混合物、外消旋混合物和其它立体异构体都可用于相同目的。
用在本发明中的一些化合物可通过美国专利号5,073,569、5,166,174、5,221,763、5,212,324、5,739,161和6,242,485(这些引用的参考文献通过引用并入本文)中公开的方法制备。
药学上适当的赋形剂
根据本发明，联合制剂的每一组分可以任何形式一起或单独地配制以得到药物组合物。因此，药学上适当的赋形剂可取决于期望的组合物形式进行选择。根据本发明，"药学上适当的赋形剂"意味着惰性物质，其适用于该形式，并与本发明的活性成分组合。
例如，本发明用于口服施用的固体组合物可包括片剂、胶囊、丸剂、散剂、颗粒剂等。在这种固体组合物中，一种或多种活性成分可与至少一种失活稀释剂混合，例如，乳糖、甘露醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、硅酸铝镁等。根据通常的操作，组合物可含有不同于失活稀释剂的添加剂，例如，润滑剂如硬脂酸镁；崩解剂如纤维性葡萄糖酸钙；稳定剂如环糊精，例如，α，β-或γ-环糊精；醚化环糊精如二甲基-α-，二甲基-β-，三甲基-β-，或羟丙基-β-环糊精；分支环糊精如葡糖基-，麦芽糖基-环糊精；甲酰化环糊精，含硫环糊精；磷脂等。当应用上述环糊精时，有时可形成应用环糊精的包合物以增强稳定性。可选地，有时可应用磷脂以形成脂质体，引起增强的稳定性。
片剂或丸剂可按需要包被有可溶于胃或肠的薄膜，如糖、明胶、羟丙基纤维素或羟丙基甲基纤维素邻苯二甲酸酯。进一步地，它们可与可吸收物质如明胶形成为胶囊。优选地，将组合物以软明胶胶囊配制，其带有脂肪酸衍生物和中级链脂肪酸甘油三酯的液体内容物。用在本发明中的中级链脂肪酸甘油三酯的例子包括具有6-14个碳原子并可具有支链的饱和或不饱和脂肪酸的甘油三酯。优选的脂肪酸是直链饱和脂肪酸，例如己酸(C6)、辛酸(C8)、癸酸(C10)、月桂酸(C12)和肉豆蔻酸(C14)。此外，两种或更多种中级链脂肪酸甘油三酯可联合应用。进一步适当的赋形剂在WO01/27099中公开。
用于口服施用的液体组合物可为药学上可接受的乳液、溶液、悬浮液、糖浆或酏剂，以及一般地应用的失活稀释剂。除失活稀释剂外，这种组合物还可含有佐剂如润滑剂和悬浮剂、甜味剂、矫味剂、防腐剂、增溶剂、抗氧化剂等。添加剂的细节可选自药物领域中任何通用教科书中描述的那些。这种液体组合物可直接封在软胶囊中。根据本发明用于肠胃外施用的溶液，例如，栓剂、灌肠剂等包括无菌水性或非水性溶液、悬浮液、乳液、洗涤剂等。水性溶液和悬浮液包括，例如，蒸馏水、生理盐水和林格氏溶液。
非水性溶液和悬浮液包括，例如，丙二醇、聚乙二醇、脂肪酸甘油三酯、和植物油如橄榄油、醇如乙醇、聚山梨醇酯等。这种组合物可含有佐剂如防腐剂、湿润剂、乳化剂、分散剂、抗氧化剂等。
用于肠胃外施用的本发明注射组合物的例子包括无菌水性或非水性溶液、悬浮液和乳液。用于水性溶液或悬浮液的稀释剂可包括，例如，注射用蒸馏水、生理盐水和林格氏溶液。
用于溶液和悬浮液的非水性稀释剂可包括，例如，丙二醇、聚乙二醇、植物油如橄榄油、醇如乙醇和聚山梨醇酯。组合物可进一步包括添加剂如防腐剂、湿润剂、乳化剂、分散剂等。它们可如下灭菌：通过例如细菌保留滤器过滤，与灭菌剂混合，或借助气体或放射性同位素辐射灭菌。注射组合物可也提供为灭菌粉末组合物，其在使用前待溶解于灭菌溶剂中用于注射。
本发明的组合物可处于喷雾组合物形式，其可根据已知方法制备。
本发明的组合物可处于鼻内制剂形式。鼻内制剂的例子可为包含一种或多种活性成分的水性或油性溶液、悬浮液或乳液。对于通过吸入施用活性成分而言，本发明的组合物可处于可以提供气雾剂的悬浮液、溶液或乳液形式，或处于适于干粉吸入的散剂形式。用于吸入施用的组合物可进一步包括常规应用的抛射剂。
外部制剂的例子包括用在皮肤病学和耳鼻喉学中的所有外部制备物，其包括软膏剂、乳膏剂、液体、洗剂、贴剂和喷雾剂。
本发明的组合物的另一形式是栓剂或阴道栓(pessary)，其可通过将活性成分混合入常规基质如在体温软化的可可脂而制备，并且具有适当软化温度的非离子表面活性剂可用于改进吸收性。
根据本发明的方法，本发明的组合物可以通过口服或肠胃外施用方式全身性或局部施用，包括栓剂，灌肠剂等。可施用单一或多个组合物以实现期望的剂量。
本文应用的表述“施用联合制剂"或"联合制剂被施用"意味着将两种组分以单一实体或剂量形式同时地施用给受试者，或将两种组分作为单独实体同时地或顺序地施用给患者而无特定的时间限制，其中这种施用在体内提供治疗有效水平的两种组分，优选在同时。
根据本发明，哺乳动物受试者中的肿瘤可通过施用本发明的联合制剂由本发明治疗。哺乳动物受试者可为任何受试者，包括人患者。组合物可全身性或局部应用。通常，化合物可通过口服施用、鼻内施用、吸入施用、静脉内注射(包括输注)、皮下注射、直肠内施用、阴道内施用、透皮施用而施用，以及其可为包括液体、软膏剂、糊剂或贴剂等的外部制剂。
每一组分的剂量可取决于动物品系、年龄、体重、待治疗症状、期望的治疗效果、施用途径、治疗时期等变化。满意的效果可以通过每日全身性施用1-4次或连续施用联合制剂获得。联合制剂的组分(a)的量可为例如，对于替加氟约0.1至约100mg/kg/日，优选地约0.5至约30mg/kg/日；对于5-FU 0.1至约100mg/kg/日，优选地约10至约40mg/kg/日；对于顺铂0.1至100mg/kg/日，优选地5至30mg/kg/日。组分(b)或式(I)的脂肪酸衍生物的量可为约0.00001-500mg/kg每日，更优选地0.001-1000μg/kg每日，并且尤其是0.01-100μg/kg每日。基于组合物总量，式(I)的脂肪酸衍生物的局部制剂可为0.000001-10.0％，更优选地0.00001-5.0％重量。
本发明的联合制剂可以以每日单一剂量或以每日2至4个分开剂量施用。当以注射溶液形式用于例如静脉内注射时，必要时可用生理盐水或注射葡萄糖溶液稀释的组合物可以在5分钟或更长时间逐步施用给成人受试者。当处于栓剂形式时，以6至12小时间隔、每日一次或两次、通过插入直肠将组合物施用给成人受试者。
进一步地，由抗-肿瘤剂在哺乳动物受试者中诱导的损伤可通过施用包含式(I)脂肪酸衍生物的组合物治疗。在该实施方案中，包含式(I)脂肪酸衍生物的组合物可以上文论述的相同方式制备和施用。
本文应用的术语"的治疗"或"治疗"包括任何方式的控制，如预防、护理、状况缓解、状况减轻和进程遏制。
待由本发明联合制剂治疗的肿瘤类型不受限制，并且可为例如，头颈癌，胃肠道癌症如食道癌、胃癌、结肠癌、直肠癌(大肠癌)和胰腺癌、肝癌、胆囊/胆管癌，肺癌，乳腺癌，膀胱癌，前列腺癌，子宫癌，咽癌，肾癌，卵巢癌等。特别地，可以对胃肠道癌症预期显著效果。
根据本发明，作为活性成分的抗-肿瘤剂的抗肿瘤效果可以显著加强，而不特别增加其毒性。
此外，根据本发明，脂肪酸衍生物用于降低或预防毒性副作用，尤其是抗-肿瘤剂诱导的胃肠道损伤。抗-肿瘤剂诱导的胃肠道损伤可为粘膜炎如口炎，肠炎，胃肠道溃疡，胰腺炎，肝和胆障碍。
本发明的药物组合物可进一步含有其它药物成分，只要它们不与本发明目的相抵触。
下面将参考实验例说明本发明的进一步细节，但是其不意图限制本发明。
实验例1
化合物A针对5-FU诱导的毒性的效果
方法
1周适应期(acclimatization period)后，开始实验(第0日)。从第0日至第4日，每日一次口服施用化合物A((-)-7-{(2R，4aR，5R，7aR)-2-[(3S)-1，1-二氟-3-甲基戊基]-2-羟基-6-氧代八氢环戊[b]吡喃-5-基}庚酸)(3，10，30μg/kg)或载体，共5日(时间表1)。
在其它给药时间表组中，从第4日至第6日，每日一次口服施用化合物A(30μg/kg)(时间表2)。
从第1日至第4日，每日一次腹膜内施用5-FU(50mg/kg)，共4日。在第1、2、3和4日，在施用化合物A或载体后立即施用5-FU。在实验期间(第0-7日)，每日对动物称重。在第7日，通过异氟烷麻醉动物。切取回肠并将其固定在10％甲醛液中。制备石蜡包埋切片并用H&E染色进行组织损伤的组织病理学评价。根据下列标准对组织损伤分级:
0.无改变，
1:少量，
2:轻度的，
3:中等的，
4:重度的
应用组织损伤总分数评价每一化合物的效果。
结果
每一治疗组的总分数在下表中示出。10或30μg/kg的化合物降低总分数，不论给药时间表如何。这表明化合物A对毒性是有效的，尤其是胃肠道毒性如5-FU诱导的粘膜炎。
实验例2
化合物A对口炎的效果
方法
应用雄性叙利亚金色仓鼠(5周龄)。1周适应期后，对仓鼠腹膜内施用60mg/kg 5-氟尿嘧啶(5-FU)(第1日)。在第2日再次重复5-FU施用。在第4日，通过用18号针的尖端进行浅表刮擦，在麻醉下对仓鼠的颊囊粘膜层进行机械性刺激，以产生暂时性红斑。在第8日和第10日，进行相同的刮擦程序并进行5-FU施用。从第1日至第14日，将24μg/位点剂量的化合物A或载体局部应用于颊囊。在治疗期间，对颊囊粘膜层进行肉眼观察并且根据下列标准对颊损害评分(口炎分数):
0:正常粘膜层
1:观察到红斑
2:观察到严重的红斑
3:观察到一个或多个位置的严重的红斑和溃疡形成。溃疡的累积尺寸牵涉～25％的颊囊粘膜层。假膜形成是明显的。
4:观察到严重的红斑和溃疡形成。溃疡的累积尺寸牵涉约一半颊囊粘膜层。丧失粘膜柔韧性(pliability)。
5:扩散性、广泛性溃疡。丧失粘膜柔韧性。颊囊仅可从口中部分地提取。
应用每个治疗组的分数均值评价口炎的严重性。
结果
相比于载体对照组，化合物A改进通过5-FU治疗加剧的口炎。
*p<0.05，与载体对照组相比(斯氏t检验)。
Claims (10)
1.药物联合制剂，其包含:
(a)药学上有效量的抗-肿瘤剂，其选自烷化剂、抗代谢物、抗生素、植物碱、分子靶向药物、激素、铂复合物、反义物、抗体和RNAi，和
(b)药学上有效量的由式(I)表示的脂肪酸衍生物:
其中L、M和N是氢、羟基、卤素、低级烷基、羟基(低级)烷基、低级烷酰基氧基或氧代，其中L和M中的至少一个是不同于氢的基团，并且5元环可具有至少一个双键；
A是–CH3、或-CH2OH、-COCH2OH、-COOH或其官能衍生物；
B是单键、-CH2-CH2-、-CH=CH-、-C≡C-、-CH2-CH2-CH2-、-CH=CH-CH2-、-CH2-CH=CH-、-C≡C-CH2-或-CH2-C≡C-；
Z是
或单键
其中R4和R5是氢、羟基、卤素、低级烷基、低级烷氧基或羟基(低级)烷基，其中R4和R5不同时是羟基和低级烷氧基；
R1是饱和或不饱和的二价低级或中级脂族烃残基，其是未取代的或被卤素、烷基、羟基、氧代、芳基或杂环基取代，并且所述脂族烃中的至少一个碳原子任选地被氧、氮或硫替换；并且
Ra是：饱和或不饱和的低级或中级脂族烃残基，其是未取代的或被卤素、氧代、羟基、低级烷基、低级烷氧基、低级烷酰基氧基、环(低级)烷基、环(低级)烷基氧基、芳基、芳基氧基、杂环基或杂环-氧基基团取代；低级烷氧基；低级烷酰基氧基；环(低级)烷基；环(低级)烷基氧基；芳基；芳基氧基；杂环基；杂环-氧基基团。
2.权利要求1所述的联合制剂，其中Ra被单或二卤素取代。
3.权利要求1所述的联合制剂，其中Z是C=O。
4.权利要求1所述的联合制剂，其中B是-CH2-CH2-，Ra被单或二卤素取代。
5.权利要求1所述的联合制剂，其中B是-CH2-CH2-并且Z是C=O。
6.权利要求1所述的联合制剂，其中B是-CH2-CH2-、Z是C=O并且Ra被单或二卤素取代。
7.权利要求1所述的联合制剂，其中B是-CH2-CH2-并且Ra被单或二氟取代。
8.权利要求1所述的联合制剂，其中Z是C=O并且Ra被单或二氟取代。
9.权利要求1所述的联合制剂，其中B是-CH2-CH2-、Z是C=O并且Ra被单或二氟取代。
10.权利要求1所述的联合制剂，其中L是氧代、M是氢或羟基、N是氢、B是–CH2-CH2-并且Ra被单或二卤素取代。
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| US20150272961A1 (en) | 2015-10-01 |
| EP2477632A1 (en) | 2012-07-25 |
| KR101760963B1 (ko) | 2017-07-24 |
| WO2011034210A1 (en) | 2011-03-24 |
| JP2013504520A (ja) | 2013-02-07 |
| AR078182A1 (es) | 2011-10-19 |
| JP5891168B2 (ja) | 2016-03-22 |
| CN102481302A (zh) | 2012-05-30 |
| AU2010296307B2 (en) | 2016-02-11 |
| RU2577700C2 (ru) | 2016-03-20 |
| SG179153A1 (en) | 2012-04-27 |
| JP2016056191A (ja) | 2016-04-21 |
| AU2010296307A1 (en) | 2012-04-05 |
| TW201116277A (en) | 2011-05-16 |
| NZ598618A (en) | 2014-10-31 |
| IL218392A (en) | 2016-05-31 |
| SG10201405467PA (en) | 2014-10-30 |
| BR112012005896A2 (pt) | 2016-03-15 |
| MX2012003188A (es) | 2012-04-30 |
| US20170079986A1 (en) | 2017-03-23 |
| US20110064748A1 (en) | 2011-03-17 |
| IL218392A0 (en) | 2012-04-30 |
| CA2772314A1 (en) | 2011-03-24 |
| EP2477632A4 (en) | 2013-06-12 |
| ZA201201894B (en) | 2012-11-28 |
| KR20120081139A (ko) | 2012-07-18 |
| US9084815B2 (en) | 2015-07-21 |
| RU2012114771A (ru) | 2013-10-27 |
| TWI535436B (zh) | 2016-06-01 |
| RU2016103415A (ru) | 2018-11-22 |
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Application publication date: 20170818 |