CN101222925A - 嘧啶基氨基苯甲酰胺和mTOR激酶抑制剂的组合产品 - Google Patents
嘧啶基氨基苯甲酰胺和mTOR激酶抑制剂的组合产品 Download PDFInfo
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Abstract
本发明提供了药物组合产品以及使用该组合产品治疗或预防增殖性疾病的方法,所述药物组合产品包含:a)嘧啶基氨基苯甲酰胺化合物,和b)mTOR激酶抑制剂。
Description
本发明涉及包含嘧啶基氨基苯甲酰胺化合物和mTOR抑制剂的药物组合产品和该组合产品例如在增殖性疾病中的用途,所述增殖性疾病例如为肿瘤、骨髓瘤、白血病、银屑病、再狭窄、硬皮症(sclerodermitis)和纤维化。
尽管对于增殖性疾病病人而言有多种治疗选择,但有效和安全的抗增殖药物以及它们在联合治疗中的优先用途仍是合乎需要的。
发明概要
目前已发现,例如下面所述的包含至少一种嘧啶基氨基苯甲酰胺化合物和mTOR抑制剂的组合产品对增殖性疾病具有有益作用,所述增殖性疾病例如为肿瘤、骨髓瘤、白血病、银屑病、再狭窄、硬皮症和纤维化。
发明详述
本发明涉及式I嘧啶基氨基苯甲酰胺化合物和其N-氧化物或药学上可接受的盐在制备治疗激酶依赖性疾病的药物组合产品中的用途:
其中
R1代表氢、低级烷基、低级烷氧基-低级烷基、酰氧基-低级烷基、羧基-低级烷基、低级烷氧羰基低级烷基或苯基-低级烷基;
R2代表氢;低级烷基,任选被一个或多个相同或不同的R3基团所取代;环烷基;苯基环烷基;杂环基;芳基基团;或包含0、1、2或3个环氮原子和0或1个氧原子和0或1个硫原子的单环或双环杂芳基基团,每种情况下该杂芳基基团为未取代的或者单或多取代的;
且R3代表羟基、低级烷氧基、酰氧基、羧基、低级烷氧羰基、氨基甲酰基、N-单取代或N,N-二取代的氨基甲酰基、氨基、单或二取代的氨基、环烷基、杂环基、芳基基团或包含0、1、2或3个环氮原子和0或1个氧原子和0或1个硫原子的单环或双环杂芳基基团,每种情况下该杂芳基基团为未取代的或者单或多取代的;
或者其中R1和R2共同代表含有4、5或6个碳原子的亚烷基,该亚烷基任选被下列基团所取代,所述基团为低级烷基、环烷基、杂环基、苯基、羟基、低级烷氧基、氨基、单或二取代的氨基、氧代、吡啶基、吡嗪基或嘧啶基;含有4或5个碳原子的苯基亚烷基(benzlkylene);含有1个氧原子和3或4个碳原子的氧杂亚烷基;或含有1个氮原子和3或4个碳原子的氮杂亚烷基,其中氮原子是未取代的或被下列基团取代的,所述基团为低级烷基、苯基-低级烷基、低级烷氧羰基-低级烷基、羧基-低级烷基、氨基甲酰基-低级烷基、N-单取代或N,N-二取代的氨基甲酰基-低级烷基、环烷基、低级烷氧羰基、羧基、苯基、取代的苯基、吡啶基、嘧啶基或吡嗪基;
R4代表氢、低级烷基或卤素。
除非另外说明,在上下文中使用的一般术语在本发明的文中优选具有的下述意义:
前缀“低级”指最多至并包括7个、尤其是最多至并包括4个碳原子的基团,该基团为线性的或是具有单个或多个分支的支链的。
当化合物、盐等用复数形式表示时,认为其也同样指代一种化合物、盐等。
任何不对称碳原子可能以(R)-、(S)-或(R,S)-构型存在,优选以(R)-或(S)-构型存在。因此化合物可以以异构体的混合物或纯的异构体存在,优选为对映体纯的非对映异构体。
本发明还涉及式I化合物的可能存在的互变异构体。
低级烷基优选为从1至7并包括1和7、优选从1至4并包括1和4的烷基,并且可以为线性或支链的;优选地,低级烷基为丁基,如正丁基、仲丁基、异丁基、叔丁基;丙基,如正丙基或异丙基;乙基;或甲基。低级烷基优选为甲基、丙基或叔丁基。
低级酰基优选为甲酰基或低级烷羰基,特别是乙酰基。
芳基基团为通过位于该基团芳香环碳原子上的键键合至分子的芳香基。在一个优选实施方案中,芳基为包含6到14个碳原子的芳族基团,尤其是苯基、萘基、四氢萘基、芴基或菲基,并且是未取代的或被一个或多个(优选最多至三个,尤其是一个或两个)取代基取代的,所述取代基尤其选自:氨基、单或二取代的氨基、卤素、低级烷基、取代的低级烷基、低级烯基、低级炔基、苯基、羟基、醚化或酯化的羟基、硝基、氰基、羧基、酯化的羧基、烷酰基、苯甲酰基、氨基甲酰基、N-单取代或N,N-二取代的氨基甲酰基、脒基、胍基、脲基、巯基、磺基、低级烷硫基、苯硫基、苯基-低级烷硫基、低级烷基苯硫基、低级烷基亚磺酰基、苯基亚磺酰基、苯基-低级烷基亚磺酰基、低级烷基苯基亚磺酰基、低级烷基磺酰基、苯基磺酰基、苯基-低级烷基磺酰基、低级烷基苯基磺酰基、卤素-低级烷基巯基、卤素-低级烷基磺酰基,尤其为例如三氟甲磺酰基、二羟基硼基(-B(OH)2)、杂环基、单环或双环杂芳基基团以及键合在环上相邻C原子上的低级亚烷基二氧基,如亚甲二氧基。芳基更优选为苯基、萘基或四氢萘基,每种情况下它们为未取代的或者独立地被一个或两个取代基取代,所述取代基选自卤素,特别是氟、氯或溴;羟基;被以下基团醚化的羟基,所述基团例如为如甲基的低级烷基、如三氟甲基的卤素-低级烷基或苯基;键合在相邻的两个C原子上的低级亚烷基二氧基,如亚甲二氧基;低级烷基,如甲基或丙基;卤素-低级烷基,如三氟甲基;羟基-低级烷基,如羟甲基或2-羟基-2-丙基;低级烷氧基-低级烷基,如甲氧甲基或2-甲氧基乙基;低级烷氧羰基-低级烷基,如甲氧羰基甲基;低级炔基,如1-丙炔基;酯化的羧基,特别是低级烷氧羰基,如甲氧羰基、正丙氧羰基或异丙氧羰基;N-单取代的氨基甲酰基,特别是低级烷基单取代的氨基甲酰基,所述低级烷基例如为甲基、正丙基或异丙基;氨基;低级烷基氨基,如甲氨基;二低级烷基氨基,如二甲氨基或二乙氨基;低级亚烷基-氨基,如吡咯烷基(pyrrolidino)或哌啶子基;低级氧杂亚烷基-氨基,如吗啉代;低级氮杂亚烷基-氨基,如哌嗪基(piperazino);酰氨基,如乙酰氨基或苯甲酰氨基;低级烷基磺酰基,如甲磺酰基;氨磺酰基;或苯磺酰基。
环烷基基团优选为环丙基、环戊基、环己基或环庚基,并可以是未取代或被一个或多个(尤其一个或两个)取代基取代的,所述取代基选自上面对芳基取代基所定义的基团,最优选低级烷基,如甲基;低级烷氧基,如甲氧基或乙氧基;或羟基;另外还可以被氧代基团取代或与苯并环稠合,如苯并环戊基或苯并环己基。
取代的烷基如上面所定义的烷基,尤其是低级烷基,优选甲基;当可能存在一个或多个(尤其是最多至三个)取代基时,取代基主要选自卤素(尤其是氟)、氨基、N-低级烷基氨基、N,N-二低级烷基氨基、N-低级烷酰基氨基、羟基、氰基、羧基、低级烷氧羰基和苯基-低级烷氧羰基。三氟甲基是特别优选的。
单或二取代氨基尤其是被一个或两个基团取代的氨基,所述基团相互独立地选自低级烷基,如甲基;羟基-低级烷基,如2-羟基乙基;低级烷氧基低级烷基,如甲氧基乙基;苯基-低级烷基,如苄基或2-苯基乙基;低级烷酰基,如乙酰基;苯甲酰基;取代的苯甲酰基,其中苯基尤其被一个或多个(优选一个或两个)取代基所取代,所述取代基选自硝基、氨基、卤素、N-低级烷基氨基、N,N-二低级烷基氨基、羟基、氰基、羧基、低级烷氧羰基、低级烷酰基和氨基甲酰基;以及苯基-低级烷氧羰基,其中苯基为未取代的或尤其被一个或多个(优选一个或两个)取代基取代的,所述取代基选自硝基、氨基、卤素、N-代级烷基氨基、N,N-二低级烷基氨基、羟基、氰基、羧基、低级烷氧羰基、低级烷酰基和氨基甲酰基;并优选为N-低级烷基氨基,如N-甲基氨基;羟基-低级烷基氨基,如2-羟基乙基氨基或2-羟基丙基;低级烷氧基低级烷基,如甲氧基乙基;苯基-低级烷基氨基,如苄基氨基;N,N-二低级烷基氨基;N-苯基-低级烷基-N-低级烷基氨基;N,N-二低级烷基苯基氨基;低级烷酰基氨基,如乙酰基氨基;或选自苯甲酰基氨基和苯基-低级烷氧羰基氨基的取代基,其中每种情况下苯基为未取代的或尤其被硝基或氨基取代的,或被下列基团取代的:卤素、氨基、N-低级烷基氨基、N,N-二低级烷基氨基、羟基、氰基、羧基、低级烷氧羰基、低级烷酰基、氨基甲酰基或氨基羰基氨基。二取代的氨基还有低级亚烷基-氨基,如吡咯烷基、2-氧代吡咯烷基或哌啶子基;低级氧杂亚烷基-氨基,如吗啉代,或低级氮杂亚烷基-氨基,如哌嗪基或N-取代的哌嗪基,如N-甲基哌嗪基或N-甲氧基羰基哌嗪基。
卤素尤其为氟、氯、溴或碘,尤其为氟、氯或溴。
醚化的羟基尤其为C8-C20烷氧基,如正癸氧基;低级烷氧基(优选),如甲氧基、乙氧基、异丙氧基或叔丁氧基;苯基-低级烷氧基,如苄氧基、苯氧基;卤素-低级烷氧基,如三氟甲氧基、2,2,2-三氟乙氧基或1,1,2,2-四氟乙氧基;或被包含一个或两个氮原子的单或双环杂芳基取代的低级烷氧基,优选被下列基团取代的低级烷氧基,所述基团为咪唑基,如1H-咪唑-1-基;吡咯基;苯并咪唑基,如1-苯并咪唑基;吡啶基,尤其为2-、3-或4-吡啶基;嘧啶基,尤其为2-嘧啶基;吡嗪基;异喹啉基,尤其为3-异喹啉基;喹啉基;吲哚基;或噻唑基。
酯化的羟基尤其为低级烷酰氧基;苯甲酰氧基;低级烷氧羰基氧基,如叔丁氧羰基氧基;或苯基-低级烷氧羰基氧基,如苄氧羰基氧基。
酯化的羧基尤其为低级烷氧羰基,如叔丁氧羰基、异丙氧羰基、甲氧羰基或乙氧羰基;苯基-低级烷氧羰基;或苯氧羰基。
烷酰基主要为烷基羰基,尤其为低级烷酰基,如乙酰基。
N-单或N,N-二取代的氨基甲酰基尤其为被一个或两个取代基取代的,所述取代基独立选自低级烷基、苯基-低级烷基和羟基-低级烷基或低级亚烷基、氧杂-低级亚烷基或末端氮原子上任选取代的氮杂-低级亚烷基。
包含0、1、2或3个环氮原子和0或1个氧原子和0或1个硫原子的单环或双环杂芳基基团(在每种情况下是未被取代的或被单或多取代的)指将杂芳基键合到式I分子的剩余部分的环是不饱和的杂环基团,优选这样的环,其中在键合的环内,且还任选在任何捏合(annealed)环中,至少有一个碳原子被选自氮、氧和硫原子的杂原子取代;其中键合环优选5到12环原子,更优选5或6个原子;并且它可以是未取代的或被一个或多个(尤其一个或两个)取代基取代的,取代基选自如上述定义的芳基的取代基,最优选低级烷基,如甲基;低级烷氧基,如甲氧基或乙氧基;或羟基。优选地,单环或双环杂芳基基团选自:2H-吡咯基、吡咯基、咪唑基、苯并咪唑基、吡唑基、吲唑基、嘌呤基、吡啶基、吡嗪基、嘧啶基、哒嗪基、4H-喹嗪基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹喔啉基、喹唑啉基、喹啉基(quinnolinyl)、蝶啶基、吲嗪基、3H-吲哚基、吲哚基、异吲哚基、唑基、异唑基、噻唑基、异噻唑基、三唑基、四唑基、呋咱基(furazanyl)、苯并[d]吡唑基、噻吩基和呋喃基。更优选选自下列基团的单环或双环杂芳基:吡咯基;咪唑基,如1H-咪唑-1-基;苯并咪唑基,如1-苯并咪唑基;吲唑基,尤其为5-吲唑基;吡啶基,尤其为2-、3-或4-吡啶基;嘧啶基,尤其为2-嘧啶基;吡嗪基;异喹啉基,尤其为3-异喹啉基;喹啉基,尤其为4-或8-喹啉基;吲哚基,尤其为3-吲哚基;噻唑基;苯并[d]吡唑基、噻吩基和呋喃基。在本发明一个优选实施方案中,吡啶基氮原子的邻位被羟基取代,因此至少部分以相应的互变异构体吡啶-(1H)2-酮的形式存在。在另一个优选实施方案中,嘧啶基在2位和4位被羟基取代,因此以几个互变异构体形式存在,如嘧啶-(1H,3H)2,4-二酮。
杂环基尤其为含有一个或两个选自氮、氧和硫原子的杂原子的5、6或7元杂环体系,该杂环体系可以是不饱和的或完全或部分饱和的,而且为未取代的或被下列基团取代的,所述基团尤其为低级烷基,如甲基;苯基-低级烷基,如苄基;氧代;或杂芳基,如2-哌嗪基;杂环基尤其为2-或3-吡咯烷基、2-氧代-5-吡咯烷基、哌啶基、N-苄基-4-哌啶基、N-低级烷基-4-哌啶基、N-低级烷基-哌啶基、吗啉基(如2-或3-吗啉基)、2-氧代-1H-氮杂-3-基、2-四氢呋喃基或2-甲基-1,3-二氧戊环-2-基。
盐尤其是式I化合物的药学上可接受的的盐。
由含有一个碱性氮原子的式I化合物(优选与有机或无机酸)形成所述盐,例如为酸加成盐,尤其是药学上可接受的盐。适当的无机酸例如为如盐酸的氢卤酸、硫酸或磷酸。适当的有机酸例如为羧酸、膦酸、磺酸或氨基磺酸,例如乙酸、丙酸、辛酸、癸酸、十二烷酸、羟基乙酸、乳酸、富马酸、琥珀酸、脂肪酸、庚二酸、辛二酸、壬二酸、苹果酸、酒石酸、柠檬酸、氨基酸,如谷氨酸或天冬氨酸、马来酸、羟基马来酸、甲基马来酸、环己烷甲酸、金刚烷甲酸、苯甲酸、水杨酸、4-氨基水杨酸、邻苯二甲酸、苯乙酸、苦杏仁酸、肉桂酸、甲磺酸或乙磺酸、2-羟基乙磺酸、乙烷-1,2-二磺酸、苯磺酸、2-萘磺酸、1,5-萘-二磺酸、2-,3-或4-甲基苯磺酸、甲硫酸、乙硫酸、十二烷基硫酸、N-环己基氨基磺酸、N-甲基、N-乙基或N-丙基氨基磺酸或其他有机质子酸,如抗坏血酸。
在负电荷基团的存在下,如羧基或磺基,还可以与碱生成盐,如金属或铵盐,如碱金属或碱土金属盐,例如钠盐、钾盐、镁盐或钙盐;或与氨或适当的有机胺形成的铵盐,所述有机胺如为叔单胺,如三乙胺或三(2-羟基乙基)胺;或杂环碱,如N-乙基-哌啶或N,N’-二甲基哌嗪。
当碱性基团和酸性基团同时出现在相同分子中时,式I的化合物还可以形成内盐。
为了分离或纯化的目的,也可以使用药学上不可接受的盐,例如苦味酸盐或高氯酸盐。对于治疗用途而言,只有药学上可接受的盐或游离化合物可被使用(当以药物制剂形式施用时),因此,所述药学上可接受的盐或游离化合物是优选的。
考虑到游离形式和盐形式的新化合物之间的密切关系,所述盐包括例如在纯化或鉴定新型化合物中可用作中间体的盐,上文或下文中的游离化合物的任何称谓都应当理解为也指相应的盐,如适当和适宜的。
式I范围内的化合物和它们的制备方法公开在在2004年1月15日公开的WO 04/005281中,将其在此引入本申请中作为参考。优选的化合物为4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-N-[5-(4-甲基-1H-咪唑-1-基)-3-(三氟甲基)苯基]苯甲酰胺。
本发明的组合产品包括作用于(target)、降低或抑制丝氨酸/苏氨酸mTOR激酶的活性/功能的化合物。这类化合物将被称为“mTOR抑制剂”,包含但不限于这些作用于/抑制mTOR激酶家族成员的化合物、蛋白质或抗体,如RAD、雷帕霉素(西罗莫司)及其衍生物/类似物,如依维莫司或RAD001。西罗莫司还称为雷帕鸣,依维莫司或RAD001还称为CERTICAN。其他作用于/抑制mTOR激酶家族成员的化合物、蛋白质或抗体包括CCI-779、ABT578、SAR543和子囊霉素(FK506的乙基类似物)。还包括Ariad公司的AP23573和AP23841。
适当的mTOR抑制剂包括如:
I.雷帕霉素,其是由吸水链霉菌(Streptomyces hygroscopicus)产生的免疫抑制性内酰胺大环内酯。
II.雷帕霉素衍生物如:
a.取代的雷帕霉素,如40-O-取代的雷帕霉素,如以下文献中所述的:US 5258389、WO 94/09010、WO 92/05179、US 5118677、US 5118678、US 5100883、US 5151413、US 5120842、WO 93/11130、WO 94/02136、WO94/02485和WO 95/14023,将所有上述文献在此引入作为参考。
b.16-O-取代的雷帕霉素,如在WO 94/02136、WO 95/16691和WO 96/41807中所述,将上述文献的内容在此引入作为参考。
c.32-氢化的雷帕霉素,如在WO 96/41807和US 5256790中所述的,将上述文献在此引入作为参考。
d.优选的雷帕霉素衍生物为式I化合物
其中
R1为甲基或C3-6炔基,
R2为H或-CH2-CH2-OH、3-羟基-2-(羟甲基)-2-甲基-丙酰基或四唑基,且X=O、(H,H)或(H,OH)
前提是当X=O及R1为甲基时,R2不是H,
或其前药,当R2为-CH2-CH2-OH时,如其生理条件下可水解的醚。
式I的化合物公开在例如WO 94/09010、WO 95/16691或WO 96/41807中,将其在此引入作为参考。它们可以如这些文献所公开进行制备或用类似于这些文献中所述的方法制备。
优选的化合物为32-去氧雷帕霉素、16-戊-2-炔氧基-32-去氧雷帕霉素、16-戊-2-炔氧基-32(S)-二氢-雷帕霉素、16-戊-2-炔氧基-32(S)-二氢-40-O-(2-羟乙基)-雷帕霉素并更优选40-O-(2-羟乙基)-雷帕霉素,如在WO 94/09010的实施例8中所公开的。
特别优选的式I雷帕霉素衍生物为40-O-(2-羟乙基)-雷帕霉素、40-[3-羟基-2-(羟甲基)-2-甲基丙酸酯]-雷帕霉素(也叫做CCI779)、40-表-(四唑基)-雷帕霉素(也称为ABT578)、32-去氧雷帕霉素、16-戊-2-炔氧基-32(S)-二氢-雷帕霉素或TAFA-93。
f.雷帕霉素衍生物还包括所谓的雷帕霉素衍生物(rapalogs),如在WO 98/02441和WO 01/14387中所公开的,如AP23573、AP23464或AP23841。
根据观察的活性,如在WO 94/09010,WO 95/16691或WO 96/41807中所描述的与如巨菲蛋白-12(也称为FK-506结合蛋白或FKBP-12)结合的活性,已发现雷帕霉素和其衍生物是有效的,如作为免疫抑制剂,如在急性同种异体移植排斥治疗中。
III.子囊霉素,其为FK506的乙基类似物。
在上述给出引用的专利申请文献的各种情况下,所述专利申请中与化合物有关的主题均在此引入本申请中作为参考。同样也包含上面所公开化合物的药学上可接受的盐、相应的外消旋体、非对映异构体、对映异构体、互变异构体以及相应的晶体变型(如果存在的话),例如其中公开的溶剂化物、水合物和多晶型。本发明的组合产品中作为活性成分的化合物可根据引用文献中所描述分别进行制备和给药。有超过两种单独活性成分的组合产品也在本发明的范围内,即本发明范围内的药物组合产品可包含三种或更多种活性成分。
根据本发明的具体发现,提供了
1.药物组合产品,该药物组合产品包含:
a)式(I)嘧啶基氨基苯甲酰胺化合物;和
b)至少一种mTOR抑制剂。
2.治疗或预防有其需要的患者中的增殖性疾病的方法,该方法包括将治疗有效量的式(I)嘧啶基氨基苯甲酰胺化合物和mTOR抑制剂(例如如上所述的)联合给药(例如同时或依次)至上述患者。
增殖性疾病的例子包括,例如肿瘤、白血病、银屑病、再狭窄、硬皮症和纤维化。特别优选治疗白血病,如CML和对伊马替尼(Gleevec或STI571)耐受的白血病。
3.如上述1)下所定义的药物组合产品,该药物组合产品例如在上述2)下所定义的方法中使用。
4.如上述1)下所定义的药物组合产品,该药物组合产品用于制备在上述2)下所定义的方法中使用的药物。
本发明的组合产品在如以上指定的方法中的有效性,可在动物实验方法和临床中得到证实,例如根据下文描述的方法。
A.组合治疗
适当的临床研究例如为在患有增殖性疾病的患者中进行的标签公开、剂量按比例增加的研究。具体来讲,这类研究可证实本发明的组合产品中活性成分的协同作用。对银屑病或多发性硬化症的有益作用可通过这些研究的结果直接确定,这对本领域技术人员来说是公知的。这些研究特别适于比较使用活性成分的单一疗法的效果和使用本发明组合产品的效果。优选地,药物a)的剂量逐步增加至达到最大耐受剂量,而药物b)按固定剂量给药。或者,药物a)按照固定剂量给药,药物b)的剂量按逐步增加。每位病人每日或间隔服用药物a)。例如,12、18或24周后,通过每6周进行症状评分可在这类试验中确定治疗效果。
与仅用本发明组合产品中的一种药学活性成分的单一疗法相比,本发明的药学组合产品的给药不仅产生有利的作用,例如关于减轻症状、延缓进展或抑制症状的,例如协同治疗作用,而且还产生了令人惊奇的有利作用,例如较少的副作用、生活质量改善或发病率降低。
另外的益处为本发明的组合产品可使用较低的剂量的活性成分,例如,不仅所需剂量通常更小,而且应用频率也更少,这可减小副作用的发生率或严重程度。这符合接受治疗的患者的愿望和要求。
如文中所用,术语“联合给药”或“组合给药”等指包括将所选的治疗药物给药至单个患者,并且还将包括治疗方案,其中药物并不必须以相同的给药途径或在相同时间给药。
本发明的一个目的是提供药物组合物,该药物组合物包含对治疗或预防增殖性疾病有共同治疗效果的一定量的本发明的组合产品。在本组合产品中,药物a)和药物b)可以一起、先后或分开装在一个组合的单位剂型中或在两个单独的单位剂型中给药。单位剂型也可以是固定的组合产品。
根据本发明,药物(a)和药物(b)分开给药或在固定组合产品中(即其包含至少两种组合搭档(a)和(b)的单独的盖仑组合物)给药的药物组合物,可按照本身已知的方法制备,并且它们适于肠内,例如口服或直肠,或胃肠外给药至例如哺乳动物(温血动物),包括人类,该药物组合物包含至少一种治疗有效量的药理学活性组合产品搭档自身(例如上述的),或与一种或多种药学上可接受的载体或稀释剂(尤其是适于肠内或胃肠外使用的)组合。
适当的药物组合物包含例如约0.1%至约99.9%、优选约1%至约60%的活性成分。
用于肠内或胃肠外给药的联合治疗的药物制剂例如为在单位剂型中药物制剂,例如糖衣片剂、片剂、胶囊或栓剂或安瓿。如果没有另外指出,这些剂型用本身为已知的方法制备,例如,通过常规的混合、制粒、包糖衣、溶解或冻干处理。应当理解,包含在每种剂型的单独剂量中的组合产品搭档的单位含量不需要其自身构成有效量,因为必需的有效量可通过给药多个剂量单位而达到。
具体地讲,治疗有效量的本发明的组合产品的每种组合产品搭档可同时或以任意次序依次给药,并且所述组分可分开或作为固定组合产品给药。例如,根据本发明,预防或治疗增殖性疾病的方法可包括(i)给药游离或药学上可接受的盐形式的第一种药物(a),和(ii)给药游离或药学上可接受的盐形式的药物(b),给药是同时或按照任意次序依次,以共同的治疗有效量,优选协同有效量,例如以相应于文中所述的量每日或间隔进行的。本发明组合产品的单个组合产品搭档可在治疗期间的不同时间分开给药,或以分开的或单独的组合产品形式同时给药。此外,术语给药也包括使用组合产品搭档的前药,该前药在体内转化为所述组合产品搭档。因此,本发明应被理解为包含所有上述的同时或交替治疗方案,并且术语“给药”将根据上述理解。
在本发明的组合产品中使用的每种组合产品搭档的有效剂量可根据使用的具体化合物或药物组合物、给药方式、治疗的疾病、治疗疾病的严重程度而变化。因此,本发明的组合产品的剂量方案是根据多种因素选择的,所述因素包括给药途径、患者的肾脏和肝脏功能。具备普通技能的临床医生或医师可容易地确定并开具减轻、抵消或阻止疾病进展的所需的单个活性成分的有效量。达到产生疗效而不出现毒性的活性成分浓度范围内的最佳精度,需要基于活性成分至靶位点的有效性的动力学的方案确定。
药物(a)或(b)的日剂量当然将取决于多种因素,例如所选的化合物、治疗的具体疾病以及希望达到的效果。但是,一般而言,如下给药可达到满意的结果:药物(a)以约每日0.03至5mg/kg的日剂量给药,特别是每日0.1至5mg/kg,例如每日0.1至2.5mg/kg,作为单剂量或以分剂量给药。药物(a)和药物(b)可以通过任何常规途径给药,尤其为肠内给药,例如口服,例如以片剂、胶囊、饮用溶液形式;或胃肠外给药,例如以注射溶液或混悬液的形式。口服给药的适当单位剂型包含约0.02至50mg活性成分,通常为0.1至30mg,例如,药物(a)或(b),以及一种或多种药学上可接受的稀释剂或载体。
药物(b)可以以0.5至1000mg的日剂量给药至人类。口服给药的适当单位剂型包含约0.1至500mg活性成分以及一种或多种药学上可接受的稀释剂或载体。
与仅使用本发明组合产品中所用的一种药物活性成分的单一疗法相比,本发明的药学组合产品的给药不仅可产生有益作用,例如,协同治疗作用,所述作用例如是与抑制血液学干细胞不受调节的增殖或减缓白血病(例如CML或AML)的进展或肿瘤的生长有关的,而且还可产生令人惊奇的有益作用,例如,较少的副作用、生活质量改善或发病率降低。
另外的益处是,可使用较低剂量的本发明组合产品的活性成分,例如,不仅所需的剂量更小,而且应用频率减少,或者可以用以减少副作用的发生率。这符合被治疗的患者的愿望和要求。
B.治疗的疾病
术语“增殖性疾病”包括但不限于肿瘤、银屑病、再狭窄、硬皮症和纤维化。
术语“血液学恶性肿瘤”特别是指白血病,尤其是表达Bcr-Abl、c-Kit或Flt-3的白血病,并且包括但不限于慢性髓细胞性白血病(CML)和急性淋巴细胞性白血病(ALL),尤其是费城染色体阳性的急性淋巴细胞性白血病(Ph+ALL)以及STI571耐受的白血病和表达伊马替尼耐受的Bcr-abl突变的细胞,例如Bcr-AblT3151。
术语“实体瘤疾病”尤其指卵巢癌、乳腺癌、结肠和普遍的胃肠道癌、子宫颈癌、肺癌,例如,小细胞肺癌和非小细胞肺癌、头颈癌、膀胱癌、前列腺癌或卡波西氏(Kaposi)肉瘤。
根据本发明的组合产品可抑制上述的蛋白激酶活性,尤其是上下文中所提到的酪氨酸蛋白激酶,因此它们可用于治疗蛋白激酶依赖性疾病。蛋白激酶依赖性疾病尤其是增殖性疾病,优选良性或尤其为恶性肿瘤(例如肾癌、肝痛、肾上腺癌、膀胱癌、乳腺癌、胃癌、卵巢癌、结肠癌、直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌或甲状腺癌、肉瘤、胶质母细胞瘤和多种头颈肿瘤以及白血病)。它们能使肿瘤退行,预防肿瘤转移灶的形成以及(也可是微小转移灶)转移灶的生长。另外,它们还能用于表皮增殖过度(例如银屑病)、前列腺增生,以及用于治疗瘤,尤其是具有上皮特征的,例如,乳腺癌。还可以使用本发明的组合产品治疗免疫系统疾病(与几个或尤其与单个酪氨酸蛋白激酶有关的);此外,本发明的组合产品也可用于治疗中枢或外周神经系统疾病,其中涉及由至少一种酪氨酸蛋白激酶(尤其是从特别提到的酪氨酸蛋白激酶中选出的)参与的信号转导。
在慢性髓细胞性白血病(CML)中,造血干细胞(HSCs)中相互平衡的染色体易位产生Bcr-Abl杂合基因。后者编码癌基因Bcr-Abl融合蛋白。而ABL编码一种紧密调节的蛋白酪氨酸激酶,其在调节细胞增殖、粘附、凋亡中起根本作用,Bcr-Abl融合基因编码组成性激活的激酶,其转化HSCs,产生显示使克隆增殖失调、对骨髓间质粘附能力降低、对突变刺激的凋亡响应下降的表型,这使其逐渐累积更多的恶性转化。产生的粒细胞不能发展为成熟淋巴细胞,并被释放至循环中,导致成熟细胞缺乏,对感染的敏感性增强。对Bcr-Abl的ATP竞争性抑制剂已进行了描述,其可抑制激活促有丝分裂和抗凋亡的途径的激酶(例如P-3激酶和STAT5),导致Bcr-Abl表型细胞死亡,从而提供抗CML的有效治疗。因此,本发明的组合产品尤其适于治疗与其过度表达有关的疾病,尤其为白血病,例如白血病,例如CML或ALL。
Claims (10)
1.药物组合产品,该药物组合产品包含:
a)式(I)嘧啶基氨基苯甲酰胺化合物,和
b)至少一种mTOR抑制剂。
2.治疗或预防有其需要的患者中的增殖性疾病方法,该方法包括将治疗有效量的至少一种mTOR抑制剂和式(I)嘧啶基氨基苯甲酰胺化合物联合给药,例如同时或依次,至上述患者。
3.根据权利要求1的药物组合产品,该药物组合产品在根据权利要求2的方法中使用。
4.根据权利要求1的药物组合产品,该药物组合产品用于制备在根据权利要求2的方法中使用的药物。
5.根据权利要求1的药物组合产品,其中药物a)为4-甲基-3-[[4-(3-吡啶基)-2嘧啶基]氨基]-N-[5-(4-甲基-1H-咪唑-1-基)-3-(三氟甲基)苯基]苯甲酰胺。
6.治疗白血病的方法,该方法包括将mTOR抑制剂和式(I)嘧啶基氨基苯甲酰胺化合物的组合产品给药。
7.治疗白血病的方法,该方法包括将mTOR抑制剂和4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-N-[5-(4-甲基-1H-咪唑-1-基)-3-(三氟甲基)苯基]苯甲酰胺的组合产品给药。
8.根据权利要求7的方法,其中mTOR抑制剂选自RAD雷帕霉素(西罗莫司)及其衍生物/类似物,例如依维莫司或RAD001、CCI-779、ABT578、SAR543、子囊霉素(FK506的乙基类似物)、AP23573和AP23841。
9.根据权利要求1的药物组合物在制备治疗或预防增殖性疾病的药物中的用途。
10.根据权利要求1的药物组合物在治疗或预防增殖性疾病中的用途。
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KR102432999B1 (ko) | 2018-08-29 | 2022-08-17 | 고려대학교 산학협력단 | 마이크로파 조사를 이용한 체외 아밀로이드 응집체 합성방법 |
CN110613848A (zh) * | 2019-10-29 | 2019-12-27 | 西安交通大学医学院第二附属医院 | Tipe1作为靶点在制备防治银屑病的药物中的应用 |
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PT98990A (pt) | 1990-09-19 | 1992-08-31 | American Home Prod | Processo para a preparacao de esteres de acidos carboxilicos de rapamicina |
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US5100883A (en) | 1991-04-08 | 1992-03-31 | American Home Products Corporation | Fluorinated esters of rapamycin |
US5118678A (en) | 1991-04-17 | 1992-06-02 | American Home Products Corporation | Carbamates of rapamycin |
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US5151413A (en) | 1991-11-06 | 1992-09-29 | American Home Products Corporation | Rapamycin acetals as immunosuppressant and antifungal agents |
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US5256790A (en) | 1992-08-13 | 1993-10-26 | American Home Products Corporation | 27-hydroxyrapamycin and derivatives thereof |
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US5258389A (en) | 1992-11-09 | 1993-11-02 | Merck & Co., Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives |
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US20060094674A1 (en) * | 2002-07-05 | 2006-05-04 | Neel Benjamin G | Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms |
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AU2006271650A1 (en) | 2007-01-25 |
KR20080041206A (ko) | 2008-05-09 |
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RU2443418C2 (ru) | 2012-02-27 |
AU2006271650B2 (en) | 2011-01-06 |
WO2007010012A3 (en) | 2007-07-05 |
EP2253320A1 (en) | 2010-11-24 |
KR20130087058A (ko) | 2013-08-05 |
US20080200486A1 (en) | 2008-08-21 |
CA2615254C (en) | 2013-09-24 |
JP2009501765A (ja) | 2009-01-22 |
AU2006271650B8 (en) | 2011-02-10 |
CA2615254A1 (en) | 2007-01-25 |
WO2007010012A2 (en) | 2007-01-25 |
EP1909794A2 (en) | 2008-04-16 |
KR20120079163A (ko) | 2012-07-11 |
MX2008000897A (es) | 2008-03-18 |
BRPI0613692A2 (pt) | 2011-01-25 |
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