CN108314663B - 芴、蒽、呫吨、二苯并环庚酮和吖啶的衍生物及其用途 - Google Patents
芴、蒽、呫吨、二苯并环庚酮和吖啶的衍生物及其用途 Download PDFInfo
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- CN108314663B CN108314663B CN201810249295.4A CN201810249295A CN108314663B CN 108314663 B CN108314663 B CN 108314663B CN 201810249295 A CN201810249295 A CN 201810249295A CN 108314663 B CN108314663 B CN 108314663B
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- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 title abstract description 14
- BMVWCPGVLSILMU-UHFFFAOYSA-N 5,6-dihydrodibenzo[2,1-b:2',1'-f][7]annulen-11-one Chemical compound C1CC2=CC=CC=C2C(=O)C2=CC=CC=C21 BMVWCPGVLSILMU-UHFFFAOYSA-N 0.000 title abstract description 7
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Abstract
本发明涉及芴、蒽、呫吨、二苯并环庚酮和吖啶的衍生物及其用途。特别地,本文公开化学剂如芴、蒽、呫吨、二苯并环庚酮和吖啶和类似杂环结构的二磺酰胺衍生物,包括其盐,所述化学剂可用作抗癌和抗肿瘤剂,特别是当此类化学剂调控Wnt/β‑联蛋白信号途径的活性和减少细胞如癌细胞中β‑联蛋白水平时,或者当化学剂调控包括癌细胞在内的细胞系统中的基因表达水平时,可用作抗癌和抗肿瘤剂,还公开制备此类化学剂的方法,以及含有此类化学剂作为活性成分的药用组合物和用这些药用组合物作为治疗剂的方法。
Description
本申请是申请号为200880023589.X,申请日为2008年5月9日,发明名称为“芴、蒽、呫吨、二苯并环庚酮和吖啶的衍生物及其用途”的发明专利申请的分案申请。
本申请要求2007年5月10日提交的美国临时申请60/928,592和2007年10月15日提交的60/999,153的优先权,其公开通过引用完全结合到本文中。
技术领域
本发明涉及用于治疗癌症的新化合物及其使用方法的领域。
背景技术
Wnt/β-联蛋白信号途径被认为是癌症的主要信号途径之一,被视为许多肿瘤类型特别是结肠肿瘤的治疗干预的有效目标。
多细胞生物体的细胞具有相互识别和传递信号的能力,有时距离相当远。通过产生由一个细胞产生的信号分子然后与不同细胞上的特异性受体结合,可完成此类信号传递。此类信号途径涉及各种疾病过程,包括癌症。通过受体结合然后增加细胞内β-联蛋白的Wnt信号传递被称为经典(canonical)途径。Wnt蛋白形成高度保守的分泌信号分子家族,所述分子调节细胞与细胞相互作用,涉及癌症的发病机制。Wnt蛋白与细胞表面的Frizzled和LRP家族的受体结合。通过几种胞质中继组分,将信号转导至β-联蛋白,然后进入细胞核,与TCF形成复合物以激活Wnt靶基因的转录。
在这种途径中,Wnt多肽存在于信号细胞表面上,或由细胞释放并最终接触另一个细胞的特异性细胞表面受体。在靶细胞上的此类受体包括Frizzled/LRP受体(LRP=LDL-受体-相关蛋白),它们将信号传递至细胞内蛋白,如β-联蛋白,其通过连续降解(通常由蛋白体介导)通常保持在相当低的稳态水平。这由含有蛋白GSK-3/APC/Axin (GSK-3=糖原合成酶激酶和APC=腺瘤性结肠息肉病)的复合物控制。Wnt结合在靶细胞表面上的结果是抑制β-联蛋白降解,从而使后者蓄积,进入细胞核内,与转录调节剂结合以打开基因。
业已发现促进Wnt信号途径组成型激活的突变可导致癌症。[综述参阅Logan和Nusse,″The Wnt Signaling Pathway in Development and Disease(在发育和疾病中的Wnt信号途径),″在Ann.Rev.Cell Dev.Biol.,20:781-810(2004)中]例如,Axin2突变使个体容易患结肠癌(Lammi等,Am.J.Hum.Genet.,74:1043-50(2004))。再例如,家族性腺瘤性息肉病(FAP),一种以结肠和直肠多发息肉为特征的遗传性疾病,通常由APC(另一种Wnt信号途径蛋白)切断引起,其促进Wnt途径的畸变激活[参阅:Kinzler等,Science,253:661-665(1991)]在结肠癌及其它肿瘤类型中也已发现APC和β-联蛋白突变(综述参阅Giles等,Biochim.Biophys.Acta,1653:1-24(2003))。此外,导致功能丧失的Axin突变可见于肝细胞癌。[参阅:Satoh等,Nat.Genet.,24:245-50(2000)]因此,使Wnt信号和β-联蛋白调控中断的任何突变或其它细胞事件对于癌症的发生很重要。
因为此类致癌事件与β-联蛋白水平提高有关(即β-联蛋白水平独立于Wnt),所以重新建立这种连接或减少β-联蛋白的小的有机化合物或其它药物将有助于减轻癌性过程,可用作抗肿瘤剂。本发明提供降低肿瘤细胞中β-联蛋白水平的采用芴、蒽、呫吨、二苯并环庚酮和吖啶的二磺酰胺衍生物形式的此类药物。
本领域已知具有被芳族胺取代的磺酰胺基的结构上相关的芴和蒽衍生物(参阅如US 2004/0019042)是包含P2X3和P2X2/3的受体的抑制剂,可用于治疗和预防疾病如膀胱过度活动症、遗尿或尿痛。但是,本文显示,可制备新的结构上相关的化合物,用作Wnt/β-联蛋白途径的调节剂。已知β-联蛋白是Wnt信号途径调节剂(参阅Willert和Nusse,CurrentOpinion in Genetics and Development(遗传和发育的新观点),8:95-102(1998)。
发明内容
本发明提供干扰Wnt信号途径和减低癌细胞中β-联蛋白水平的用于治疗癌症的新化合物,及其合成方法。在具体实施方案中,这些化合物包括降低肿瘤细胞中β-联蛋白水平的芴、蒽、呫吨、二苯并环庚酮和吖啶的二磺酰胺衍生物。
本发明化合物具有式I结构:
其中n=0-2,其中当n=1时,X选自CH2、O、NRA、CO和C=NORA,其中当n=2时,X=CH2
Y=O、S、NORA或NRA
其中RA选自H、烷基、杂烷基、烯基、炔基、环烷基、-C(=O)RB、-C(=O)ORB、-C(=O)NRBRC、-C(=NRB)RC、-NRBRc、杂环烷基、芳基或多芳族、杂芳基、芳基烷基和烷基芳基
其中所述RB和Rc各自独立是H、烷基或杂烷基,
U和V各自独立选自C=O和O=S=O,其中当U是C=O时,V不是C=O,
R1、R2、R3和R4各自独立选自H、烷基、杂烷基、环烷基、芳基环烷基、烯基、炔基、芳基、杂芳基、杂环烷基,所述R1、R2和所述R3、R4可各自独立结合以形成杂环烷基,
R5和R6各自独立选自H、OH、SH、烷氧基、硫代烷氧基、烷基、卤素、CN、CF3、NO2、COORD、CONRDRE、NRDRE、NRDCORE、NRDSO2RE和NRFCONRDRE;
其中RD、RE和RF独立是H、烷基、杂烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基或杂环烷基;
其中如果X是O、Y是O且U和V都是O=S=O,则NR1R2和NR3R4不相同,其中R1和R3各自独立选自H和低级烷基,其中R2和R4各自独立选自低级烷氧基(低级烷基)、二(低级)烷基氨基(低级)烷基、卤代苄基、吗啉代(低级)烷基,或者NR1R2和NR3R4独立选自哌啶子基、吗啉代、哌嗪-1-基(piperazino)、N-苯基哌嗪-1-基、乙氨基或取代的甘氨酸,
其中当X是(CH2)2、Y是O或NOH且U和V各自是O=S=O时,则R1、R2、R3和R4无一是甲基,
其中当n=0、Y是O或NOH且U和V各自是O=S=O时,则NR1R2和NR3R4不相同,且R1、R2、R3和R4各自独立选自C1-C5烷基、C10烷基、C16烷基、C17烷基、苯基、苄基、萘基、哌嗪-1-基(piperizino)、吡啶基、吡唑基、苯并咪唑基、三唑基;或者NR1R2和NR3R4独立是哌啶子基、吗啉代或哌嗪-1-基,
其中当X是CO、Y是O且U和V各自是O=S=O时,则NR1R2和NR3R4不一样,其中R1、R2、R3和R4各自独立选自甲基、乙基、羟基-C1-C3-烷基、SH、RO、COOH、SO、NH2和苯基;NR1R2和NR3R4独立选自未被取代的哌啶子基、N-甲基哌嗪-1-基或N-甲基高哌嗪-1-基,
其中当X是C=O或C=NOH,Y是O或NOH,U和V各自是O=S=O,R1或R2其中之一和R3或R4其中之一是苯基时,则R1或R2和R3或R4中的另一个不是H或烷基,
包括其所有药学上可接受的盐、酯、酰胺、立体异构体、几何异构体、溶剂化物或前药。
在具体实施方案中,本发明化合物包括表2-13的那些化合物,所述化合物各自或以任何组合构成本发明。
本发明还提供本发明的任何化合物如表1-13的化合物的治疗组合物。
本发明还涉及改善哺乳动物癌或肿瘤转移的方法,包括给予所述哺乳动物有效量的本发明化合物。特别是表1-13化合物的用途。
定义
除非另外明确表示,否则以下术语各自具有所示含义:
“酰基”或“羰基”是羧酸脱除羟基形成的基团(即R-C(=O)-)。优选酰基包括(例如)乙酰基、甲酰基和丙酰基。
术语“碳链”包括任何烷基、烯基、炔基或杂烷基、杂烯基或杂炔基,为直链、环状或其任何组合。如果该链是连接体的一部分且该连接体包含一个或多个环作为核心主链的一部分,为了计算链长,“链”只包括组成指定环的底部或顶部(并非两者都是)的那些碳原子,当环的顶部和底部长度不等时,应当用较短的距离确定链长。如果链包含杂原子作为主链的一部分,那些原子不算碳链长的一部分。
“烷基”指具有1-15个碳原子、优选1-10个碳原子的饱和烃链。无论单独或组合使用,它都指具有1-约30个碳、更优选1-12个碳的任选取代的直链或任选取代的支链饱和烃基。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、叔戊基、戊基、己基、庚基、辛基等。
单独或组合的术语“烯基”指任选取代的直链或任选取代的支链烃基,具有一个或多个碳-碳双键且具有2-约30个碳原子,更优选2-约18个碳。烯基的实例包括乙烯基、丙烯基、丁烯基、1,3-丁二烯基等。
单独或组合的术语“炔基”指任选取代的直链或任选取代的支链烃基,具有一个或多个碳-碳三键且具有2-约30个碳原子,更优选2-约12个碳原子、2-约6个碳原子以及具有2-约4个碳原子。炔基的实例包括乙炔基、2-丙炔基、2-丁炔基、1,3-丁二炔基等。
“烯烃”是具有至少1个(优选仅1个)碳-碳双键且具有2-15个碳原子、优选2-10个、更优选2-5个碳原子的烃链。
“炔烃”是具有至少1个(优选仅1个)碳-碳三键且具有2-15个碳原子、优选2-10个、更优选2-5个碳原子的烃链。
烷基、烯烃和炔烃链(总称为“烃链”)可以是直链或支链,可以未被取代或被取代。优选支链烷基、烯烃和炔烃链具有1或2个分支,优选1个分支。优选链是烷基。烷基、烯烃和炔烃链各自可未被取代或被1-4个取代基取代;当被取代时,优选链被单-、二-或三-取代。烷基、烯烃和炔烃链各自可被卤代基、羟基、芳氧基(如苯氧基)、杂芳氧基、酰氧基(如乙酰氧基)、羧基、芳基(如苯基)、杂芳基、环烷基、杂烷基、杂环烷基、螺环、氨基、酰氨基(amido)、酰基氨基(acylamino)、酮基、硫酮基、氰基或其任何组合取代。优选烃基包括甲基、乙基、丙基、异丙基、丁基、乙烯基、烯丙基、丁烯基和exomethylenyl。
“低级烷基”是较短的烷基,如含有1-约6个碳原子的烷基。
而且,本文提到的“低级”烷基、烯烃或炔烃部分(如“低级烷基”)在烷基情况下是由1-10、优选1-8个碳原子组成的链,在烯烃和炔烃情况下是由2-10、优选2-8个碳原子组成的链。
“烷氧基”指具有烃链取代基的氧基团,其中烃链是烷基或烯基(即-O-烷基或-O-烯基)。烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、烯丙氧基等。
“芳基”是芳族烃环。芳环是单环或稠合双环的环系统。单环芳环的环中包含6个碳原子。单环芳环也称为苯环。双环芳环的环中包含8-17个碳原子,优选9-12个碳原子。双环芳环包括其中一个环是芳基且另一个环是芳基、环烷基或杂环烷基的环系统。优选双环芳环包含与5-、6-或7-元环稠合的5-、6-或7-元环。芳环可以未被取代或在环上被1-4个取代基取代。芳基可以被卤代基、氰基、硝基、羟基、羧基、氨基、酰基氨基、烷基、杂烷基、卤代烷基、苯基、芳氧基、烷氧基、杂烷氧基、氨基甲酰基、卤代烷基、亚甲基二氧基、杂芳氧基或其任何组合取代。优选芳环包括萘基、甲苯基、二甲苯基和苯基。最优选芳环基是苯基。
“芳氧基”是具有芳基取代基的氧基团(即-O-芳基)。优选芳氧基包括(例如)苯氧基、萘氧基、甲氧基苯氧基和亚甲基二氧基苯氧基。
“环烷基”指非芳族的饱和或不饱和烃环。环烷基环是单环,或是稠合、螺或桥接双环或多环的环系统。单环的环烷基环在环中包含约3-约12个碳原子,优选3-7个碳原子。双环的环烷基环在环中包含7-17个碳原子,优选7-12个碳原子。优选双环环烷基环包含与5-、6-或7-元环稠合的4-、5-、6-或7-元环。环烷基环可以未被取代或在环上被1-4个取代基取代。环烷基可被卤代基、氰基、烷基、杂烷基、卤代烷基、苯基、酮基、羟基、羧基、氨基、酰基氨基、芳氧基、杂芳氧基或其任何组合取代。优选环烷基环包括环丙基、环戊基、环己基、环庚基、环辛基和环壬基环。
术语“环烷基”还包括环状烷基,包括单环、双环、三环和高级多环烷基,其中各环状部分具有3-约12个碳原子,是3-12元环。环烷基的实例包括环丙基、环丁基、环戊基、环己基等。
术语“环炔基”指环状炔基,包括单环、双环、三环和高级多环炔基,其中各环状部分具有3-约8个碳原子。“低级炔基”指具有2-约6个碳的炔基。
“卤代基”或“卤素”是氟代基、氯代基、溴代基或碘代基。优选卤代基是氟代基、氯代基和溴代基;通常最优选氯代基和氟代基,特别是氟代基。
“卤代烷基”是被一个或多个卤代取代基取代的直链、支链或环状烃。优选C1-C12卤代烷基;更优选C1-C6卤代烷基;还更优选C1-C3卤代烷基。优选卤代取代基是氟代基和氯代基。
“杂原子”是氮、硫或氧原子。包含不止一个杂原子的基团可包含不同的杂原子。
术语“杂烷基(heteroalkyl)、杂烯基和杂炔基”包括任选取代的如上所述烷基、烯基和炔基结构,其中一个或多个骨架链原子选自非碳原子,如氧、氮、硫、磷或其组合。
“杂烷基(heteroalkyl)”是包含碳和至少一个杂原子的饱和或不饱和链,其中没有两个杂原子相邻。杂烷基链的链中包含2-15、优选2-10、更优选2-5个成员原子(碳和杂原子)。例如,烷氧基(即-O-烷基或-O-杂烷基)可包含在杂烷基中。杂烷基链可为直链或支链。优选支链杂烷基具有1或2个分支,优选1个分支。优选饱和杂烷基。不饱和杂烷基具有一个或多个碳-碳双键和/或一个或多个碳-碳三键。优选不饱和杂烷基具有1或2个双键或三键,更优选1个双键。杂烷基链可以未被取代或被1-4个取代基取代。优选取代的杂烷基被单-、二-或三-取代。杂烷基可被低级烷基、卤代烷基、卤代基、羟基、芳氧基、杂芳氧基、酰氧基、羧基、单环芳基、杂芳基、环烷基、杂烷基、杂环烷基、螺环、氨基、酰基氨基、酰氨基、酮基、硫酮基、氰基或其任何组合取代。当将一种基团描述为例如烷基衍生物如“-乙基吡啶”时,破折号“-”表示取代基的连接点。因此,“-乙基吡啶”指通过基团的乙基段连接乙基吡啶,而“乙基吡啶-”指通过吡啶环连接。
“杂芳基”是在环中包含碳原子和1-约6个杂原子的芳环。杂芳环是单环或稠合的双环环系统。单环杂芳环在环中包含约5-约9个成员原子(碳和杂原子),优选5或6个成员原子。双环杂芳环在环中包含8-17个成员原子,优选8-12个成员原子。双环杂芳环包括其中一个环是杂芳基且另一个环是芳基、杂芳基、环烷基或杂烷基、杂环烷基的环系统。优选双环杂芳基环系统包含与5-、6-或7-元环稠合的5-、6-或7-元环。杂芳环可以未被取代或在环上被1-4个取代基取代。杂芳基可被卤代基、氰基、硝基、羟基、羧基、氨基、酰基氨基、烷基、杂烷基、卤代烷基、苯基、烷氧基、芳氧基、杂芳氧基或其任何组合取代。优选杂芳环包括但不限于以下杂芳环:
稠合杂芳基可包含2-4个稠环,连接的环是杂芳环,稠环系统内的其它各环可以是芳族环、杂芳族环、脂族环或杂环族环。术语杂芳基还包括具有5-约12个骨架环原子以及具有5-约10个骨架环原子的单-杂芳基或稠合杂芳基。术语“低级杂芳基”指具有5-约10个骨架环原子的杂芳基,如吡啶基、噻吩基、嘧啶基、吡嗪基、吡咯基或呋喃基。
“杂芳氧基”是具有杂芳基取代基的氧基团(即-O-杂芳基)。优选杂芳氧基包括(例如)吡啶氧基、呋喃氧基、(噻吩)氧基、(噁唑)氧基、(噻唑)氧基、(异噁唑)氧基、嘧啶氧基、吡嗪氧基和苯并噻唑氧基。
“杂环烷基”是环内包含碳原子和1-4(优选1-3)个杂原子的饱和或不饱和环。杂环烷基环并非芳环。杂环烷基环是单环,或是稠合、桥接或螺双环的环系统。单环杂环烷基环在环中包含约3-约9个成员原子(包括碳和杂原子),优选5-7个成员原子。双环杂环烷基环在环中包含7-17个成员原子,优选7-12个成员原子。双环杂环烷基环包含约7-约17个环原子,优选7-12个环原子。双环杂环烷基环可以是稠合、螺或桥接的环系统。优选双环杂环烷基环包含与5-、6-或7-元环稠合的5-、6-或7-元环。杂环烷基环可以未被取代(即包含氢作为环原子的取代基)或被1-4个取代基取代(在碳或杂原子上或两者皆可),所述取代基选自甲基、卤代基、卤代烷基、氰基、羟基、羧基、酮基、硫酮基、氨基、酰基氨基、酰基、酰氨基、烷基(除甲基以外)、杂烷基、卤代烷基、苯基、烷氧基、芳氧基或其任何组合。优选杂环烷基上的取代基包括甲基、乙氧基、卤代基和卤代烷基。杂环烷基环可通过所述杂环烷基环的任何化学上合适的原子连接成更大结构的取代基。优选杂环烷基环包括但不限于以下杂环烷基环:
术语“元环”可包括任何环状结构,包括芳族、杂芳族、脂环族、杂环和多环的稠合环系统,如下描述。术语“元”指构成环的骨架原子数。因此,例如吡啶、吡喃和嘧啶是6-元环,吡咯、四氢呋喃和噻吩是5-元环。
单独或组合的术语“芳基”指6-约20个环原子的任选取代的芳族烃基,包括单-芳环和稠合芳环。稠合芳环基包含2-4个稠环,其中连接的环是芳环,稠环内的其他各环可以是芳族环、杂芳族环、脂环族或杂环族环。而且,术语芳基包括含有6-约12个碳原子以及含有6-约10个碳原子的单-芳环和稠合芳环。芳基的实例包括但不限于苯基、萘基、蒽基、基和苯并芘基环系统。术语“低级芳基”指具有6-约10个骨架环碳的芳基,如苯基和萘基环系统。
术语“杂环基”指含有5-约20个环原子的任选取代的饱和或不饱和非芳环基团,其中一个或多个环原子是杂原子如氧、氮、硫和磷。术语脂环基包括单-杂环和稠合杂环基。稠合杂环基可包含2-4个稠环,其中连接环是杂环,稠合杂环基内的其它各环可以是芳族、杂芳族、脂环族或杂环族。术语杂环族还包括具有5-约12个骨架环原子以及具有5-约10个骨架环原子的单-杂环族和稠合脂环族基团。杂环族的实例包括但不限于四氢呋喃基、苯二氮杂基、四氢吲唑基、二氢喹啉基等。术语“低级杂环族”指具有5-约10个骨架环原子的杂环系统,如二氢吡喃基、吡咯烷基、吲哚基、哌啶基、哌嗪基等。
单独或组合使用的术语“烷基芳基”指其中1个H原子被如上文限定的烷基代替的如上文限定的芳基,如甲苯基、二甲苯基等。
单独或组合的术语“芳基烷基”或“芳烷基”指其中1个H原子被如上文限定的芳基代替的如上文限定的烷基,如苄基、2-苯基乙基等。
术语“杂芳基烷基”指其中1个H原子被如上文限定的杂芳基代替的如上文限定的烷基,其各自可被任选取代,但其中芳基连接于较大的核心结构,烷基为末端部分。
术语“烷基杂芳基”指其中1个H原子被如上文限定的杂芳基代替的如上文限定的烷基,其各自可被任选取代,但其中烷基连接于较大的核心结构,杂芳基为末端部分。
单独或组合的术语“芳氧基”指其中术语芳基如上文限定的芳基醚基。芳氧基的实例包括苯氧基、苄氧基等。
单独或组合的术语“烷硫基”指烷硫基,烷基-S-,其中术语烷基如上文限定。
单独或组合的术语“芳硫基”指芳硫基,芳基-S-,其中术语芳基如上文限定。
术语“杂芳硫基”指基团杂芳基-S-,其中术语杂芳基如上文限定。
术语“酰基”指基团-C(O)R,其中R包括烷基、烯基、炔基、芳基、杂芳基、脂环基、杂环基、芳基烷基或杂芳基烷基,其中烷基、烯基、炔基、芳基、杂芳基、脂环基、杂环基、芳基烷基或杂芳基烷基可被任选取代。
术语“酰氧基”指酯基-OC(O)R,其中R是H、烷基、烯基、炔基、芳基、杂芳基、脂环基、杂环基、芳基烷基或杂芳基烷基,其中烷基、烯基、炔基、芳基、杂芳基、脂环基、杂环基、芳基烷基或杂芳基烷基可被任选取代。
术语“羧基酯”指-C(O)OR,其中R是烷基、芳基或芳基烷基,其中烷基、芳基和芳基烷基可被任选取代。
术语“氨甲酰基”指结构-C(O)NRR′,其中氮连接于羰基碳,R和R′各自独立选自H、烷基、芳基、杂芳基、脂环基、杂环基、芳基烷基和杂芳基烷基,其中烷基、芳基、杂芳基、脂环基、杂环基或芳基烷基可被任选取代。
术语“氧代基”指双键合的氧,以=O表示。
术语“卤素”包括F、Cl、Br和I。
使用“卤代烷基、卤代烯基、卤代炔基和卤代烷氧基”包括被一个或多个氟、氯、溴或碘或其组合取代的如上描述的烷基、烯基、炔基和烷氧基结构。
术语“全卤代烷基、全卤代烷氧基和全卤代酰基”指所有H原子都被氟、氯、溴或碘或其组合取代的如上描述的烷基、烷氧基和酰基。
术语“环烷基、芳基烷基、芳基、杂芳基、脂环基、杂环基、烷基、炔基、烯基、卤代烷基和杂烷基”包括任选取代的环烷基、芳基烷基、芳基、杂芳基、脂环基、杂环基、烷基、炔基、烯基、卤代烷基和杂烷基。
术语“烷基氨基”指基团-NHR1,其中R独立选自烷基。
术语“二烷基氨基“指基团-NRR′,其中R和R′是烷基。
术语“硫醚”指与2个原子共价结合的硫原子;所述硫的正式(formal)氧化状态是(II)。术语“硫代醚”可与术语“硫醚”互换使用。
术语“亚砜”指与3个原子共价结合的硫原子,其中至少1个原子是氧原子;所述硫原子的正式氧化状态是(IV)。
术语“砜”指与4个原子共价结合的硫原子,其中至少2个原子是氧原子;所述硫原子的正式氧化状态是(VI)。
术语“任选的”或“任选地”指接着描述的事件或状态可以但不一定发生,该描述既包括该事件或状态发生的情况也包括不发生的情况。例如,“被烷基任选单-或二-取代的芳基”指该烷基可以但不一定存在,或者可能存在1或2个烷基,该描述包括芳基被1或2个烷基取代的情况和芳基不被烷基取代的情况。
“任选取代的”基团可被取代或未被取代。“任选取代的”基团的取代基可包括但不限于独立选自以下基团或其特定亚类的一个或多个取代基:低级烷基、低级烯基、低级炔基、低级芳基、杂芳基、脂环基、杂环基、芳基烷基、杂芳基烷基、低级烷氧基、低级芳氧基、氨基、烷基氨基、二烷基氨基、二芳基烷基氨基、烷硫基、芳硫基、杂芳硫基、氧代基、氧杂基、羰基(-C(O))、羧基酯(-C(O)OR)、氨甲酰基(-C(O)NH2)、羧基、酰氧基、-H、卤代基、-CN、-NO2、-N3、-SH、-OH、-C(O)CH3、全卤代烷基、全卤代烷氧基、全卤代酰基、胍、吡啶基、噻吩、呋喃基、吲哚、吲唑、酯、酰胺、膦酸酯、膦酸、磷酸酯、磷酰胺、磺酸酯、砜、硫酸酯、磺酰胺、氨基甲酸酯、脲、硫脲和硫代酰胺、硫烷基。任选取代的基团可以未被取代(如-CH2CH3)、完全取代(如-CF2CF3)、单取代(如-CH2CH2F)或在完全取代与单取代之间的任何水平取代(如-CH2CF3)。
本发明的一些化合物可包含一个或多个手性中心,因此可存在对映体和非对映体形式。本发明的范围预计包括所有异构体本身,以及顺式和反式异构体混合物、非对映体混合物和对映体(旋光异构体)的外消旋混合物,可以用众所周知的方法分离各种形式,本发明一些实施方案的特征可以是指定对映体或非对映体的纯化或富集物。
“药理组合物”指本文所述一种或多种化合物或其药学上可接受的盐与其它化学组分(如药学上可接受的载体和/或赋形剂)的混合物。药理组合物的目的是便于将化合物给予生物体。
短语“药学上可接受的载体”用于本文指药学上可接受的材料、组合物或溶媒,如液体或固体填充剂、稀释剂、赋形剂、溶剂或包囊材料,用于将主药从一种器官或机体的一部分携带或转运至另一种器官或机体的一部分。每种载体必须“可被接受”指与制剂的其它成分相容且对患者无害。可作为药学上可接受的载体的一些材料实例包括:(1)糖,如乳糖、葡萄糖和蔗糖;(2)淀粉,如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;(4)黄蓍胶粉;(5)麦芽;(6)明胶;(7)滑石粉;(8)赋形剂,如可可豆油和栓蜡;(9)油,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇,如丙二醇;(11)多元醇,如甘油、山梨醇、甘露醇和聚乙二醇;(12)酯,如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,如氢氧化镁和氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏液;(19)乙醇;(20)磷酸盐缓冲液;和(21)用于药用制剂中的其它非毒性相容性物质。生理学上可接受的载体应当对生物体不产生明显刺激性并且不消除给予的化合物的生物活性和特性。
术语“赋形剂”指加至药理学组合物以进一步便于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖类和淀粉类型、纤维素衍生物、明胶、植物油和聚乙二醇。
用于本文时,术语“治疗作用”包括但不限于抑制(完全或部分)增殖性疾病如结肠癌的特征细胞的生长。治疗作用还可包括改善疾病的一种或多种症状(除了细胞团块的细胞生长或大小之外),可包括1)减少细胞数目;2)减小细胞大小;3)抑制(即减慢,优选停止)细胞浸润(即转移)入周围器官内;3)抑制或减慢细胞生长;和/或4)缓解与疾病如癌有关的一种或多种症状。产生此类治疗作用的本文公开化合物的任何剂量视为所述化合物的“治疗有效剂量”或“治疗有效量”。
当涉及癌症时,短语“有效量”指在转移或原发性肿瘤进展、大小或生长方面,足以产生所需效应或改善症状或体征的量。代表性的哺乳动物治疗接受者包括小鼠、大鼠、猫、狗和灵长类,包括人。对于具体患者的有效量可不同,取决于以下因素,如正在治疗的疾病、患者的全身健康状况、给药方法、途径和剂量以及副作用的严重度。优选该作用将导致定量改变至少约10%,优选至少20%、30%、50%、70%或甚至90%或更多。当组合时,有效量与组分的组合成比例,其作用不限于各组分单独使用时的作用。
“溶剂化物”是溶质(如金属蛋白酶抑制剂)和溶剂(如水)组合形成的复合物。参阅J.Honig等,The Van Nostrand Chemist′s Dictionary,p.650(1953)。
术语“旋光异构体”、“几何异构体”(如顺式和/或反式异构体)、“立体异构体”和“非对映体”具有公认含义(参阅如Hawley′s Condensed Chemical Dictionary,11thEd.)。举例说明的本发明化合物的具体被保护形式及其它衍生物预计非限制性。其它有用的保护基团、盐形式、前药等的应用在技术人员能力范围之内。
“前药”是在变为活化或完全活化的药物之前必须通过代谢过程发生化学转化的药物形式。前药在其摄入或吸收形式或给药形式时无活性,或活性较小。例如,前药可被消化系统中的细菌分解为产物,其中至少一种将活化成为药物。或者,它可通过全身例如静脉内注射给药,接着代谢为一种或多种活性分子。
用于本文时,术语“IC50”指在测量此类效应的测定中,获得最大效应50%抑制的具体测试化合物的量、浓度或剂量。在本发明的一些方法实施方案中,本发明化合物对正常细胞的“IC50”值可大于对表现增殖性疾病的细胞,如乳癌细胞的“IC50”值。该数值取决于所用测定法。
“标准”指阳性或阴性对照。阴性对照在这里指与癌细胞相反的正常对照,如具有正常细胞相关的Wnt/β-联蛋白途径活性的样品。阴性对照还可包括不含有此类途径的样品。相反,阳性对照含有优选为增殖性疾病如乳癌中所见过度表达相关量的此类途径。对照物可来自细胞或组织样品,或可包含纯化、固定等的配体(或不含配体)。在一些实施方案中,一种或多种对照物可采用诊断“测量杆(dipstick)”的形式。
“选择性靶向”指对一种类型细胞的作用超过另一种,如对于癌细胞和对于非癌细胞的情况下。
发明详述
本发明提供具有式I结构的化合物
其中n=0-2,其中当n=1时,X选自CH2、O、NRA、CO和C=NORA,其中当n=2时,X=CH2
Y=O、S、NORA或NRA,
其中RA选自H、烷基、杂烷基、烯基、炔基、环烷基、-C(=O)RB、-C(=O)ORB、-C(=O)NRBRC、-C(=NRB)RC、-NRBRC、杂环烷基、芳基或多芳族、杂芳基、芳基烷基和烷基芳基其中所述RB和Rc各自独立是H、烷基或杂烷基,
U和V各自独立选自C=O和O=S=O,其中当U是C=O时,V不是C=O,
R1、R2、R3和R4各自独立选自H、烷基、杂烷基、环烷基、芳基环烷基、烯基、炔基、芳基、杂芳基、杂环烷基,所述NR1R2和NR3R4可各自独立形成杂环烷基,
R5和R6各自独立选自H、OH、SH、烷氧基、硫代烷氧基、烷基、卤素、CN、CF3、NO2、COORD、CONRDRE、NRDRE、NRDCORE、NRDSO2RE和NRFCONRDRE;
其中RD、RE和RF独立是H、烷基、杂烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基或杂环烷基;
前提是如果X是O、Y是O且U和V都是O=S=O,则NR1R2和NR3R4不相同,其中R1和R3各自独立选自H和低级烷基,其中R2和R4各自独立选自低级烷氧基(低级烷基)、二(低级)烷基氨基(低级)烷基、卤代苄基、吗啉代(低级)烷基,或者NR1R2和NR3R4独立选自哌啶子基、吗啉代、哌嗪-1-基、N-苯基哌嗪-1-基、乙氨基或取代的甘氨酸,
如果X是(CH2)2、Y是O或NOH且U和V各自是O=S=O,则R1、R2、R3和R4不全是甲基,
如果n=0、Y是O或NOH且U和V各自是O=S=O,则NR1R2和NR3R4不相同,且R1、R2、R3和R4各自独立选自C1-C5烷基、C10烷基、C16烷基、C17烷基、苯基、苄基、萘基、哌嗪-1-基、吡啶基、吡唑基、苯并咪唑基、三唑基;或者NR1R2和NR3R4独立是哌啶子基、吗啉代或哌嗪-1-基,
如果X是CO、Y是O且U和V各自是O=S=O,则NR1R2和NR3R4不相同,其中R1、R2、R3和R4各自独立选自甲基、乙基、羟基-C1-C3-烷基、SH、RO、COOH、SO、NH2和苯基,或者其中不相同的NR1R2和NR3R4其中之一或两者是未被取代的哌啶子基、N-甲基哌嗪-1-基或N-甲基高哌嗪-1-基,
其中当X是C=O或C=NOH,Y是O或NOH,U和V各自是O=S=O,R1或R2其中之一和R3或R4其中之一是苯基时,则R1或R2和R3或R4中的另一个不是H或烷基,
包括其所有药学上可接受的盐、酯、酰胺、立体异构体、几何异构体、溶剂化物或前药。
在另一个实施方案中,本发明提供具有式II结构的化合物
其中R7和R8独立选自H和SO2NR3R4,R7或R8其中之一是氢,或式III化合物
其中R7和R8独立选自H和SO2NR3R4,其中R7和R8其中之一是氢,其中在每个所述式II和III中,其它取代基具有如式I限定的含义。
在本发明的具体实施例中,式I化合物是此类结构,其中A是NR1,或其中A是(CR1R2)m,m=1,或其中A是(CR1R2)m,m=2,R1和R2如本文其它地方限定。
在本发明的具体实施例中,式I化合物是此类结构,其中B是NR1,或其中B是(CR1R2)m,m=1,或其中B是(CR1R2)m,m=2,R1和R2如本文其它地方限定。
在本发明的其它具体实施例中,式I化合物是此类结构,其中C是NR1,或其中C是(CR1R2)m,m=1或m=2,R1和R2如本文其它地方限定。
在本发明的其它具体实施例中,式I化合物是此类结构,其中D是NR1,或其中D是(CR1R2)m,m=1或m=2,R1和R2如本文其它地方限定。
在本发明的另外的具体实施例中,式I化合物是此类结构,其中n=0,使得中间含X的环为5-元环。
在本发明的其它具体实施例中,式I化合物是此类结构,其中X是O且n=1或其中X是O且n=2。
在本发明的具体实施例中,式I化合物是此类结构,其中X是NR1,n=1,或其中X是CO且n=1,或其中X是C=NOR1,n=1,R1如本文其它地方限定。
在本发明的具体实施例中,式I化合物是此类结构,其中X是CR1R2,n=1或其中X是CR1R2,n=2,其中R1和R2如本文其它地方限定。
在本发明的具体实施例中,式I化合物是此类结构,其中Y是O,或其中Y是NR1或其中Y是NOR1,其中R1如本文其它地方限定。
在式I的一个实施方案中,当Y是O时,X不是C=O,当X是C=O时,Y不是O。在单独的实施方案中,Y是O且X是C=O。
在式I的另一个实施方案中,当E是O或NR1时,Y不是NOH或n不是1。在后者的单独实施方案中,当E是O或NR1时,n是1且Y是NOH。
在式I化合物的具体实施例中,U和V各自是O=S=O。后者的另外实施例是其中X是CH2、n=1或2且Y是O或S的化合物,或其中X是CH2、n=1或2且Y是NORA或NRA的化合物,或X是O且Y是O或S的化合物,或其中X是O且Y是NORA或NRA的化合物,或其中X是NRA且Y是O或S的化合物,或其中X是NRA且Y是NORA或NRA的化合物,或其中X是CO且Y=O的化合物,或其中X是CO且Y是NORA或NRA的化合物,或其中X是C=NORA且Y是O的化合物,或其中X是C=NORA且Y是NORA的化合物。
在式I的所有实施方案中,当X是C=O或C=NOH,Y是O或NOH,且U和V各自是O=S=O且R1或R2其中之一和R3或R4其中之一是苯基时,则R1或R2和R3或R4中的另一个不是H或烷基。因此,一种非限制性实施例是如果X是C=O,Y是NOH,U和V各自是O=S=O,R1和R4各自是苯基时,则R2不是H或烷基,R3不是H或烷基。
在式II的一个实施方案中,R1、R2、R3和R4各自独立选自H、烷基、环烷基、烯基和炔基。在另一个此类实施方案中,RA是氢,R1、R2、R3和R4各自独立选自H、烷基、环烷基、烯基和炔基。在其它此类实施方案中,NR1R2和NR3R4各自独立是6-至15-元杂环,优选杂环烷基。
在式II的具体实施方案中,R1、R2、R3和R4各自独立选自H、烷基、环烷基、烯基或炔基。在其它此类实施例中,RA是氢,R1、R2、R3和R4各自独立选自H、烷基、环烷基、烯基或炔基。在其它实施例中,NR1R2和NR3R4独立是6-至15-元杂环,优选在环中含有1个氮的杂环烷基。
在其它实施方案中,本发明化合物是以下环系统其中一种的衍生物,特别是其二磺酰胺衍生物:
此类化合物可被适当取代。
本发明还涉及包括表1-13中化合物在内的化合物的组合物,所述化合物具有式I结构,以治疗有效量存在于药学上可接受的载体中。
其中X=CH2且n=0-2;或O、NRA、CO或C=NORA且n=1Y=O、S、NORA或NRA
其中RA独立选自氢、烷基、杂烷基、烯基、炔基、环烷基、-C(=O)RB、-C(=O)ORB、-C(=O)NRBRc、-C(=NRB)RC、-NRBRC、杂环烷基、芳基或多芳族、杂芳基、芳基烷基和烷基芳基
其中所述RB和RC各自独立是H、烷基、杂烷基,
U和V各自独立选自C=O和O=S=O,如果U是C=O,V不可以是C=O,
R1、R2、R3和R4各自独立选自氢、烷基、杂烷基、环烷基、芳基环烷基、烯基、炔基、芳基、杂芳基、杂环烷基,所述NR1R2和NR3R4各自可独立形成杂环烷基,
R5和R6选自氢、羟基、巯基、烷氧基、硫代烷氧基(thioalkoxy)、烷基、卤素、CN、CF3、NO2、COORD、CONRDRE、NRDRE、NRDCORE、NRDSO2RE和NRFCONRDRE;
其中RD、RE和RF独立是氢、烷基、杂烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基和杂环烷基;
包括其所有药学上可接受的盐、酯、酰胺、立体异构体、几何异构体、溶剂化物或前药。
所述组合物的化合物还可包含多环环烷基或杂环烷基桥结构(如表所示),所述结构含有总计至多12个原子和至多4个选自N和O的杂原子。
本发明还提供本发明的任何化合物如表1-13的化合物的治疗组合物。
本发明的化合物可采用其药学上可接受的盐、酯、酰胺、立体异构体、几何异构体、溶剂化物或前药的形式。当本发明化合物是立体异构体时,可以是对映体或非对映体。当所述化合物是对映体(或包含手性中心,如手性碳原子)时,用于药用目的的化合物形式可包括对映体或外消旋体,但可优选所述对映体中的一种(例如当对映体中的一种是活化形式或比其它对映体更有活性的情况下)。当所述本发明化合物是几何异构体(如包含以顺式-或反式-构型连接取代基的碳对)时,虽然顺式-形式或反式-形式可优选药用,但顺式-和反式形式的混合物也可用于本发明的方法以达到它们具有所需药效的程度。
“药学上可接受的盐”是在任何酸性(如羧酸)基团形成的阳离子盐,或在任何碱性(如氨基)基团形成的阴离子盐。本领域已知许多此类盐,如描述于WO 87/05297(Johnston等,1987年9月11日公布,通过引用结合到本文中)。合适的酸式盐实例包括乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、乙醇酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐;棕榈酸盐(palmoate)、果胶酯酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一酸盐。其它酸如草酸虽然本身并非为药学上可接受,但可用于制备盐,所述盐可作为获得本发明化合物及其药学上可接受的酸加成盐的中间体。优选阳离子盐包括碱金属盐(如钠和钾),和碱土金属盐(如镁和钙)和有机盐。优选阴离子盐包括卤化物(如氯化物盐)、磺酸盐、羧酸盐、磷酸盐等。
含有一个或多个酸性官能团的本发明化合物能够与药学上可接受的碱形成药学上可接受的盐。术语“药学上可接受的盐”在这些情况下指本发明化合物的相对无毒性、无机和有机碱加成盐。同样这些盐可在最终分离和纯化化合物时原位制备,或者通过使游离酸形式的纯化化合物单独与合适的碱(如药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐)、与氨或与药学上可接受的有机伯、仲或叔胺反应制备。代表性碱盐或碱土盐包括锂、钠、钾、钙、镁和铝盐等。可使用的一些碱的例示性实例包括氢氧化钠、氢氧化钾、胆碱氢氧化物、碳酸钠、N+(C1-4烷基)4等。可用于形成碱加成盐的代表性有机胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。本发明还预计使本文公开的化合物的任何碱性含氮基团季铵化。通过这样季铵化可获得可溶解或分散在水或油中的产物。
技术人员熟知此类盐,技术人员能够用专业知识制备任何数目的盐。而且,应理解技术人员可能由于溶解度、稳定性、配制方便性等原因而优选一种盐而不选另一种。对此类盐的确定和优化在技术人员的技能范围内。
另一方面,本发明涉及本发明任何化合物的组合物,优选其中此类化合物以治疗有效量存在于药学上可接受的载体中。此类组合物将通常包含非毒性量(即对治疗而言为安全的量)的此类化合物。
本发明化合物的选择性实例包括但不限于表2-13的任何或所有化合物。任何和所有此类化合物因其在任何和所有本发明方法中的用途而被特别要求保护。在每种所示结构中,通过标记星号(*)的原子连接配体。例如,在表1中,核心结构的硫原子在表中R列标记星号的氮处连接所示R基团。
表1
表2
表3
表4
表5
表6
表7
表8
表9
表10
表11
表12
表13
表14
如上所述,本发明涉及本发明化合物作为药物、特别是作为用于治疗肿瘤的药物的活性成分的用途。因此本发明化合物将存在于药用组合物中,所述药用组合物含有式I或II化合物作为活性成分,与其混合的是药学上可接受的载体和赋形剂,包括本身不诱导产生对接受组合物的个体有害的抗体的任何药物,其给药可不产生过度毒性。药学上可接受的载体包括但不限于液体如水、盐水、甘油和乙醇等,包括可用于形成鼻腔及其它呼吸道喷雾剂或递药至眼部系统的载体。关于药学上可接受的载体、稀释剂及其它赋形剂的全面讨论可参阅REMINGTON′S PHARMACEUTICAL SCIENCES(Mack Pub.Co.,N.J.currentedition)。本领域技术人员熟知此类载体的用途,在本文将不再讨论。
如上所述,本发明还涉及预防或治疗与哺乳动物具体基因集合(set)表达水平改变有关的疾病的方法,包括给予所述哺乳动物有效量的本发明化合物。
本发明化合物在需要这样治疗的哺乳动物特别是人中,将具有减少肿瘤特别是原发性肿瘤大小和数量的作用。原发性肿瘤或转移细胞数量的统计学显著性改变将通常为至少约10%、优选20%、30%、50%、70%、90%或更多。
根据本发明,可将本文所述药物与本文所述疾病的其它疗法结合,如其它化疗、放疗、免疫疗法、手术治疗等。还可将本发明化合物与其它药物联合给药,如止痛药、利尿剂、抗利尿剂、抗病毒剂、抗生素、营养补充剂、贫血疗法、凝血疗法、骨疗法,以及精神病学和心理学疗法。
由临床医生(如使用本领域已知可完成治疗或预计将完成治疗的参数或因素)确定合适的治疗剂量。通常,开始的剂量比最佳剂量小一些,然后逐渐小量增加,直至获得与任何不良副作用相比而言所需或最佳的作用。
当然,给予本发明化合物以获得治疗和/或预防作用的具体剂量将由具体情况决定,包括例如给予的具体化合物、给药途径、待治疗疾病和待治疗个体。通常日剂量(单次或分次给药)将包含约0.01mg/kg-约50-100mg/kg体重的本发明活性化合物的剂量水平。优选日剂量通常将为约0.05mg/kg-约25mg/kg,最理想的是约0.1mg/kg-约10mg/kg。虽然本文没有明确叙述,但本领域技术人员用标准程序将很容易确定因素如清除率、半衰期和最大耐受剂量(MTD)。
治疗的有效量将通常使症状控制至少约10%;通常至少约20%;优选至少约30%;更优选至少约50%。或者,迁移的控制将指各种癌细胞类型的迁移或转运受影响。这样将导致例如受影响细胞的数量发生统计学显著性和可定量的改变。这可以是在一段时间或靶区域内吸引的靶细胞数减少。还可监测原发性肿瘤进展的速率、大小或生长。
另一方面,本发明涉及预防或治疗由改变的基因表达调控的疾病的方法,其中所述疾病选自癌、心血管疾病、关节炎、骨质疏松症、炎症、牙周病和皮肤病,包括给予需要这样治疗或预防的哺乳动物治疗有效量的本发明化合物。
在优选实施方案中,本发明涉及在哺乳动物中预防、治疗或改善癌或肿瘤转移的方法,包括给予所述哺乳动物有效量的本发明化合物,优选其中所述哺乳动物是人。
本发明化合物通常通过调控出现于细胞特别是哺乳动物细胞中的一个或多个基因将发挥治疗作用,所述细胞如癌细胞,优选结肠癌,最优选腺癌。因此,通过确定本发明的一种或多种化合物对基因集合的调控,可用本发明的一种或多种化合物测定或区分这样的基因集合。例如,当发现某基因集合在癌细胞比在其它正常细胞特别是与癌细胞相同组织或器官的正常细胞中上调时,可通过用本发明的一种或多种化合物接触此类基因或含有此类基因的细胞,通过其共同的被调控的特性测定基因集合(基于基因表达的改变,如转录RNA的比率或量或者由所述表达产生的多肽量的改变)。当然,此类调控的程度可与用于接触的所述一种或多种化合物的量有关。此类调控可包括所有测定基因(即该集合的基因)的表达增加,所有该集合基因的表达减少,或该集合基因中一些表达增加而其它表达减少。因此,测试化合物(用于接触基因或含有它们的细胞的化合物)不调控的基因视为非该集合成员。
因此,本发明涉及基因集合,其中所述基因集合与本发明化合物接触的结果是调控所述基因集合各成员的表达。在具体实施方案中,所述接触的结果是所述基因集合各成员的表达增加或者所述接触的结果是表达减少。在另一个优选实施方案中,基因集合存在于细胞中。此类基因集合将通常与具体疾病过程有关,如其中所有基因都由本发明化合物调控的基因集合,其中此类化合物具有具体治疗作用,如作为抗肿瘤剂。
本发明还涉及在哺乳动物中改善癌或肿瘤转移的方法,包括给予所述哺乳动物有效量的本发明化合物。特别是表1化合物的用途。在选择的实施方案中,所述癌是肉瘤或所述癌是癌瘤。本发明方法针对的具体癌包括但不限于结肠癌、腺癌、直肠癌、结直肠癌、乳癌、肺癌、卵巢癌、腺瘤性息肉病和肝细胞癌中的一种或多种。
本发明还提供根据流程1所示通用合成途径合成式I化合物的便利方法。可通过使相应的芳环系统直接氯磺酰化或通过使合适的磺酸衍生物氯化获得原料磺酰氯1。使化合物1与6或7-元环胺反应以得到仲磺酰胺2。另外可将化合物2转换为衍生物3,其有时可充当前药,所述前药具有改良的物理-化学和药理学特性如水溶性、改良的蛋白结合特性、在血浆中的稳定性、毒性等。
具体实施方式
根据流程1所示通用合成途径用相应的磺酰氯衍生物制备本文公开的大部分化合物。
流程1
以下流程和实施例预计用于举例说明,不限制在附属权利要求书中限定的本发明范围。
流程2
实施例1
2,7-二(氮杂环辛烷-1-基磺酰基)蒽-9,10-二酮(1-27)
使蒽醌-2,7-二磺酰氯(1215mg,3mmole)溶于100mL DCM中。将溶液冷却至-50℃。向该溶液内加入1mL(8mmole)七亚甲亚胺(heptamethyleneimine),接着加入1mL二异丙基乙胺。将反应混合物在室温下搅拌4小时。蒸发溶剂,将残留物用1N HCl处理,滤除,用水洗涤和干燥。使粗材料从氯仿-己烷中结晶,得到1.014g(91%)黄色化合物1-27。H1-NMR(CDCl3):8.70(2H,d,C1和C8),8.47(2H,d,C4和C5),8.22(2H,dd,C3和C6),3.22(8H,m),1.70(20H,m)。
实施例2
2,7-二(氮杂环辛烷-1-基磺酰基)蒽-9,10-二酮二肟(2-22)
将实施例1的产物(1.0g,1.706mmole)、5mL吡啶和盐酸羟胺(1.5g,21.5mmole)在95℃搅拌36小时。蒸发吡啶,将残留物用1N HCl(50mL)搅拌几分钟。将白色产物过滤收集,用水洗涤和干燥。然后用DCM-己烷使粗材料结晶,得到970mg(97%)白色化合物2-22。H1NMR(CDCl3):9.05(1H,dd),8.75(1H,dd),8.35(1H,dd),8.05(1H,dd),7.90(2H,m),3.20(8H,m),1.70(20H,m)。
实施例3
2,7-二(氮杂环辛烷-1-基磺酰基)蒽-9,10-二酮二肟二钠盐(2-22x 2Na)
将化合物2-22(620mg,1.0mmole)、35mL DCM和2.2mL 1M乙醇钠/乙醇的混合物加热搅拌,直至形成澄清溶液。向溶液内加入100mL醚,对混合物声处理5分钟。将黄色固体产物过滤收集,用醚洗涤和干燥以得到660mg(100%)标题化合物。
实施例4
9,10-二(N′-(3-(二甲基氨基)丙基)-N-乙基氨基甲亚氨酰基氧基亚氨基)-2,7-二(氮杂环辛烷-1-基磺酰基)-9,10-二氢-蒽四盐酸盐(3-18)
将化合物2-22(442mg,0.75mmole)、4mL无水氯仿和400mg EDAC在60℃搅拌1小时。将反应混合物浓缩和用HPLC层析。加入5mL 1N HCl使含有所需产物(MH+=899)的合并流分酸化并蒸发至干。使产物溶于蒸馏水中,冻干得到530mg(68%)白色标题化合物。
流程3
实施例5
9,10-二[(3-氨基丙基)氧基亚氨基]-2,7-二(氮杂环辛烷-1-基磺酰基)-9,10-二氢-蒽(3-24)
向化合物2-22x 2Na(320mg,0.5mmole)在DMSO(2mL)中的溶液内加入3-溴代丙基氨基甲酸叔丁酯(180mg,0.75mmole),将混合物在室温下搅拌1小时。将水加入反应混合物内,用乙酸乙酯提取沉淀产物。将提取物用硫酸钠干燥,蒸发,用4N HCl/二氧己环(5mL)将残留物搅拌1小时。蒸发溶剂,使残留物溶于甲醇中,用制备HPLC纯化。将含有主产物的流分用盐酸酸化和蒸发。使残留物溶于水中和冻干以得到标题化合物,为二盐酸盐(170mg,2步骤收率为44%)。MS703(MH+)。
实施例6
10-(3-氨基丙基)氧基亚氨基-9-羟基亚氨基-2,7-二(氮杂环辛烷-1-基磺酰基)-9,10-二氢-蒽(3-24)
将实施例5的第二种主产物分离为标题化合物。收率:2步骤后为20%.MS 646(MH+)。
流程4
实施例7
10-甲基-9-氧代-9,10-二氢吖啶-2,7-二磺酰二氯
将10-甲基吖啶-9(10H)-酮(4.2g,20mmole)和氯磺酸(100mL,1.5mole)的混合物回流加热5小时。然后使反应混合物浓缩,冷却至室温,小心地倒在500g冰上。将黄色沉淀产物过滤收集,用水洗涤,干燥以得到8.1g标题化合物。该材料不需纯化用于下一步。
实施例8
2,7-二(3,5-二甲基哌啶-1-基磺酰基)-10-甲基吖啶-9(10H)-酮(11-4)
向来自实施例7的10-甲基-9-氧代-9,10-二氢吖啶-2,7-二磺酰二氯(810mg,2mmole)在THF(20mL)中的溶液内加入3,5-二甲基哌啶(2mL,15mmole),将反应混合物在室温下搅拌6小时。蒸发溶剂,将残留物用1N HCl(50mL)处理和搅拌10分钟。将黄色产物过滤收集,用水和甲醇洗涤并干燥。使粗材料从氯仿-乙醇中结晶以得到900mg(80%)黄色11-4。MS 560(MH+)。
实施例9
2,7-二(3,5-二甲基哌啶-1-基磺酰基)-10-甲基吖啶-9(10H)-硫酮
将化合物11-4(560mg,1mmole)、无水甲苯(10mL)和Lawesson′s试剂(820mg,2mmole)的混合物回流4小时。蒸发除去甲苯。向残留物内加入甲醇(20mL),在室温下搅拌几分钟,将产物过滤收集和干燥以得到500mg标题化合物。MS 576(MH+)。
实施例10
2,7-二(3,5-二甲基哌啶-1-基磺酰基)-9-羟基亚氨基-10-甲基-(9H,10H)-吖啶(12-4)
向2,7-二(3,5-二甲基哌啶-1-基磺酰基)-10-甲基吖啶-9(10H)-硫酮(290mg,0,5mmole)在吡啶(5mL)中的溶液内加入盐酸羟胺(210mg,30mmole),将混合物在100℃搅拌8小时。除去溶剂,用水处理残留物以除去过量羟胺。使粗材料从甲醇-水中结晶以得到245mg(85%)标题化合物。MS 575(MH+)。
实施例11
2,7-二(3,5-二甲基哌啶-1-基磺酰基)-9-(3-二甲基氨基丙基)亚氨基-10-甲基-(9H,10H)-吖啶(12-5)
将2,7-二(3,5-二甲基哌啶-1-基磺酰基)-10-甲基吖啶-9(10H)硫酮(145mg,0.25mmole)、吡啶(5mL)和二甲氨基丙胺(0.125mL,1mmole)的混合物在100℃搅拌4小时。部份蒸发溶剂,加入甲醇使反应产物沉淀。将沉淀物过滤收集,用甲醇洗涤和干燥以得到137mg(85%)标题化合物。MS 644(MH+)。
流程5
实施例12
N2,N7-二(4-叔丁基环己基)-9,10-二氧代-9,10-二氢蒽-2,7-二磺酰胺(1-36):
使蒽醌-2,7-二磺酰氯(10g,24.7mmol)溶于200mL DCM中。将溶液冷却至-50℃。向该溶液内加入4-叔丁基环己胺(8.43g,54mmol),接着加入三乙胺(8.6ml,61.7mmol)。将反应混合物在室温下搅拌4小时。蒸发溶剂,将残留物用MeOH处理,滤除,干燥以得到15g(95%)产物(1-36),为黄色粉状物。
实施例13
N2,N7-二(4-叔丁基环己基)-N2-(3-(二甲基氨基)丙基)-9,10-二氧代-9,10-二氢蒽-2,7-二磺酰胺(13-1)和
N2,N7-二(4-叔丁基环己基)-N2,N7-二(3-(二甲基氨基)丙基)-9,10-二氧代-9,10-二氢蒽-2,7-二磺酰胺(1-70)
在氩气下向磺酰胺(1-36,6.82g,10.61mmol)在无水DMF(100ml)中的冰冷溶液内加入NaH(95.0%,697mg,27.58mmol)。将溶液搅拌5分钟,然后加入3-氯代-N,N-二甲基丙-1-胺盐酸盐(2.18g,13.8mmol)。10分钟后,将反应混合物转移至40℃预热油浴中,搅拌3天。LCMS显示存在单烷基化和二烷基化产物(比率,65∶25),以及未反应的原料。冷却后,将1NNaOH加入反应混合物内,用乙酸乙酯提取。用无水硫酸镁干燥有机相,减压蒸发滤液。将粗混合物用硅胶柱层析纯化。用40%EtOAc/己烷洗脱该柱,回收未反应的原料。单用EtOAc洗脱时获得纯的单烷基化产物(13-1,LCMS,MS 728.0(MH+)),用5%三乙胺/EtOAc作为洗脱剂时分离二烷基化产物(1-70,LCMS,MS 813.2(MH+))。将收集的流分减压蒸发至干以得到13-1(3.02g,53%)和1-70(1.10g,17%)。
流程6
实施例14
N2,N7-二(4-叔丁基环己基)-N2-(3-(二甲基氨基)丙基)-9,10-二(羟基亚氨基)-9,10-二氢蒽-2,7-二磺酰胺(6-1)
用36小时在95℃按照通用程序用单烷基化磺酰胺(13-1,2g,2.7mmol)、过量盐酸羟胺(2.7g,27.5mmol)和吡啶(50ml)制备二肟(6-1)。冷却后,将过量羟胺过滤除去,用吡啶洗涤,将滤液减压蒸发至干。向其内加入过量1N HCl水溶液,使肟沉淀,过滤以收集无色沉淀物和干燥。通过结晶或HPLC进一步纯化以得到作为无色HCl盐的肟(6-1)(1.42g,65%)。
1H NMR(400MHz,DMSO-d6)δ:13.04-13.01(m,1H),12.94-12.89(m,1H),10.48(brs,1H),9.18-9.07(m,1H),8.87-8.78(m,1H),8.40-7.78(m,4H),3.75-3.05(m,16H),2.72(s,6H),1.96-0.76(m,28H)。
实施例15
N2,N7-二(4-叔丁基环己基)-N2,N7-二(3-(二甲基氨基)丙基)-9,10-二(羟基亚氨基)-9,10-二氢蒽-2,7-二磺酰胺(2-65)
按照上文描述的通用程序,用36小时在95℃用相应的蒽醌衍生物(1-70,1g,1.23mmol)、过量盐酸羟胺(1.2g,12.3mmol)和吡啶(25ml)制备作为HCl盐的二肟(2-65)(0.710g,63%)。
1H NMR(400MHz,DMSO-d6)δ:13.09-13.07(m,1H),12.98-12.95(m,1H),9.14-9.08(m,1H),8.89-8.82(m,1H),8.35-7.92(m,4H),3.75-3.04(m,16H),2.72-0.77(m,46H)。
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