CN102203103A - 1-氨基-2-环丁基乙基硼酸衍生物 - Google Patents
1-氨基-2-环丁基乙基硼酸衍生物 Download PDFInfo
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- CN102203103A CN102203103A CN200980144074XA CN200980144074A CN102203103A CN 102203103 A CN102203103 A CN 102203103A CN 200980144074X A CN200980144074X A CN 200980144074XA CN 200980144074 A CN200980144074 A CN 200980144074A CN 102203103 A CN102203103 A CN 102203103A
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Abstract
本发明提供适用作蛋白酶体抑制剂的新颖化合物。本发明还提供包含本发明化合物的医药组合物和使用所述组合物治疗各种疾病的方法。
Description
技术领域
本发明涉及适用作蛋白酶体抑制剂的硼酸和硼酸酯化合物。本发明还提供包含本发明化合物的医药组合物和使用所述组合物治疗各种疾病的方法。
本申请案主张2008年9月29日申请的美国临时专利申请案第61/194,614号的优先权,所述申请案是以引用的方式全部并入本文中。
背景技术
硼酸和硼酸酯化合物显示了多种医药学上有用的生物活性。申维(Shenvi)等人的美国专利第4,499,082号(1985)揭示肽硼酸为某些蛋白水解酶的抑制剂。凯特纳(Kettner)和申维(Shenvi)的美国专利第5,187,157号(1993)、美国专利第5,242,904号(1993)和美国专利第5,250,720号(1993)描述一类抑制胰蛋白酶样蛋白酶的肽硼酸。克里曼(Kleeman)等人的美国专利第5,169,841号(1992)揭示抑制肾素(renin)作用的N端经修饰的肽硼酸。金德尔(Kinder)等人的美国专利第5,106,948号(1992)揭示某些硼酸化合物抑制癌细胞生长。巴霍维金(Bachovchin)等人的WO 07/0005991揭示抑制成纤维细胞活化蛋白的肽硼酸化合物。
硼酸和硼酸酯化合物特别有望作为蛋白酶体(一种负责大部分细胞内蛋白质周转的多催化蛋白酶)的抑制剂。亚当斯(Adams)等人的美国专利第5,780,454号(1998)描述适用作蛋白酶体抑制剂的肽硼酸酯和肽硼酸化合物。此参考文献也描述使用硼酸酯和硼酸化合物来降低肌肉蛋白质降解速率、降低细胞中NF-κB的活性、降低细胞中p53蛋白的降解速率、抑制细胞中细胞周期素(cyclin)的降解、抑制癌细胞的生长和抑制NF-κB依赖性细胞粘附。福莱特(Furet)等人的WO 02/096933、恰特而伊(Chatterjee)等人的WO 05/016859和伯纳迪尼(Bernadini)等人的WO 05/021558和WO 06/08660揭示其他据报导具有蛋白酶体抑制活性的硼酸酯和硼酸化合物。
奇哈诺夫(Ciechanover),细胞(Cell),79:13-21(1994)揭示蛋白酶体为泛素-蛋白酶体路径的蛋白水解组分,其中蛋白质通过与多个泛素分子结合而成为降解的目标。奇哈诺夫(Ciechanover)还揭示泛素-蛋白酶体路径在多种重要生理学过程中起着关键作用。里维特(Rivett)等人,生物化学杂志(Biochem.J.)291:1(1993)揭示蛋白酶体显示胰蛋白酶肽酶活性、胰凝乳蛋白酶肽酶活性和肽基谷氨酰基肽酶活性。20S蛋白酶体构成26S蛋白酶体的催化核心。麦克科迈奇(McCormack)等人,生物化学(Biochemistry)37:7792(1998)教示包括Suc-Leu-Leu-Val-Tyr-AMC、Z-Leu-Leu-Arg-AMC和Z-Leu-Leu-Glu-2NA在内的多种肽底物受20S蛋白酶体裂解,其中Suc为N-琥珀酰基、AMC为7-氨基4-甲基香豆素而2NA为2-萘胺。
蛋白酶体抑制代表癌症治疗的一种重要新策略。金(King)等人,科学(Science)274:1652-1659(1996)描述泛素-蛋白酶体路径在调节细胞周期、赘生生长和转移中的重要作用。作者教示在细胞周期中泛素-蛋白酶体路径使包括细胞周期素和细胞周期素依赖性激酶p21和p27KIP1在内的多种关键调节蛋白按时序降解。细胞完全经历细胞周期和进行有丝***需要这些蛋白质有序降解。
此外,泛素-蛋白酶体路径也为转录调节所需。帕洛姆贝拉(Palombella)等人,细胞(Cell),78:773(1994)教示转录因子NF-κB的活化受抑制剂蛋白质IκB的蛋白酶体介导的降解调节。NF-κB又在免疫和发炎性反应中所涉及的基因的调节中起重要作用。雷德(Read)等人,免疫学(Immunity)2:493-506(1995)教示泛素-蛋白酶体路径为诸如E-选择素(E-selectin)、ICAM-1和VCAM-1等细胞粘附分子的表达所需。泽特尔(Zetter),癌症生物学研讨会(Seminars in Cancer Biology)4:219-229(1993)教示细胞粘附分子通过引导肿瘤细胞粘附至和自血管渗出至体内的远端组织部位而参与活体内肿瘤转移和血管生成。此外,贝格(Beg)和巴尔的摩(Baltimore),科学(Science)274:782(1996)教示NF-κB为抗细胞凋亡控制因子,且抑制NF-κB活化使得细胞对环境压力和细胞毒性剂更敏感。
蛋白酶体抑制剂VELCADE(硼替佐米(bortezomib);N-2-吡嗪羰基-L-苯丙氨酸-L-亮氨酸硼酸)为首个获得官方批准的蛋白酶体抑制剂。米奇戴斯(Mitsiades)等人,当代药物目标(Current Drug Targets),7:1341(2006)回顾了促使批准硼替佐米用于治疗事先已接受至少一种疗法的多发性骨髓瘤患者的临床研究。费舍尔(Fisher)等人,临床肿瘤学杂志(J.Clin.Oncol.),30:4867描述了证实硼替佐米在患有复发性或难治性套细胞淋巴瘤的患者体内的活性的国际多中心第II期研究。伊雪伊(Ishii)等人,医学化学中的抗癌剂(Anti-Cancer Agents in Medicinal Chemistry),7:359(2007)和洛卡罗(Roccaro)等人,当代医药生物技术(Curr.Pharm.Biotech.),7:1341(2006)论述多种可能促成硼替佐米的抗肿瘤活性的分子机制。
由弗戈斯(Voges)等人,生物化学综述年鉴(Annu.Rev.Biochem.),68:1015(1999)报导的结构分析揭示20S蛋白酶体包含28个次单位,其中催化次单位β1、β2和β5分别负责肽基谷氨酰基、胰蛋白酶和胰凝乳蛋白酶肽酶活性。里维特(Rivett)等人,当代蛋白质肽科学(Curr.Protein Pept.Sci.),5:153(2004)揭示当蛋白酶体暴露于包括IFN-γ和TNF-α在内的某些细胞因子时,β1、β2和β5次单位经替代性催化次单位β1i、β2i和β5i置换,形成称为免疫蛋白酶体的蛋白酶体的变异形式。
奥尔洛瓦斯基(Orlowski),血液学(Hematology)(美国血液学教育计划协会(Am.Soc.Hematol.Educ.Program))220(2005)揭示免疫蛋白酶体也在一些来源于造血前驱细胞的细胞中组成性表达。作者提出免疫蛋白酶体特异性抑制剂可能允许针对由血液学起源产生的癌症的靶向疗法,从而可能使诸如胃肠和神经组织等正常组织免受副作用影响。
如上述参考文献所证明,蛋白酶体代表治疗性干预的一个重要目标。因此,对新颖和/或改良的蛋白酶体抑制剂仍持续存在需要。
发明内容
本发明提供作为蛋白酶体的一种或一种以上肽酶活性的有效抑制剂的化合物。这些化合物适用于活体外和活体内抑制蛋白酶体活性,且尤其适用于治疗各种细胞增生性疾病。
本发明化合物具有通式(I):
或其医药学上可接受的盐或硼酸酐,其中:
A为0、1或2;
P为氢或氨基封端部分;
Ra1为C1-6脂肪族基、C1-6氟脂肪族基、-(CH2)m-CH2-RB、-(CH2)m-CH2-NHC(=NR4)NH-Y、-(CH2)m-CH2-CON(R4)2、-(CH2)m-CH2-N(R4)CON(R4)2、-(CH2)m-CH(R6)N(R4)2、-(CH2)m-CH(R5)-OR5或-(CH2)m-CH(R5)-SR5;
各Ra2独立地为氢、C1-6脂肪族基、C1-6氟脂肪族基、-(CH2)m-CH2-Rb、-(CH2)m-CH2-NHC(=NR4)NH-Y、-(CH2)m-CH2-CON(R4)2、-(CH2)m-CH2-N(R4)CON(R4)2、-(CH2)m-CH(R6)N(R4)2、-(CH2)m-CH(R5)-OR5或-(CH2)m-CH(R5)-SR5;
各Y独立地为氢、-CN、-NO2或-S(O)2-R10;
各RB独立地为经取代或未经取代的单环或双环***;
各R4独立地为氢或经取代或未经取代的脂肪族基、芳基、杂芳基或杂环基;或同一氮原子上的两个R4连同所述氮原子一起形成经取代或未经取代的4至8元杂环基环,所述环除所述氮原子外还具有0至2个独立地选自N、O和S的环杂原子;
各R5独立地为氢或经取代或未经取代的脂肪族基、芳基、杂芳基或杂环基;
各R6独立地为经取代或未经取代的脂肪族基、芳基或杂芳基;
各R10独立地为C1-6脂肪族基、C6-10芳基或-N(R4)2;
m为0、1或2;
Z1和Z2各自独立地为羟基、烷氧基、芳氧基或芳烷氧基;或Z1和Z2一起形成衍生自硼酸络合剂的部分。
除非另外明确声明,否则术语“蛋白酶体”意指组成性蛋白酶体、免疫蛋白酶体或两者。
如本文所用的术语“脂肪族”或“脂肪族基”意谓完全饱和或含有一个或一个以上不饱和单元,但不为芳香族的经取代或未经取代的直链、分支链或环状C1-12烃。举例来说,合适脂肪族基包括经取代或未经取代的直链、分支链或环状烷基、烯基或炔基和其杂合物,诸如(环烷基)烷基、(环烯基)烷基或(环烷基)烯基。在各种实施例中,脂肪族基具有1至12、1至8、1至6、1至4或1至3个碳。
单独或作为较大部分的一部分使用的术语“烷基”、“烯基”和“炔基”是指具有1至12个碳原子的直链或分支链脂肪族基。出于本发明的目的,当将脂肪族基连接至分子剩余部分的碳原子为饱和碳原子时将使用术语“烷基”。然而,烷基可在其他碳原子处包括不饱和度。因此,烷基包括(但不限于)甲基、乙基、丙基、烯丙基、炔丙基、丁基、戊基和己基。
出于本发明的目的,当将脂肪族基连接至分子剩余部分的碳原子形成碳碳双键的一部分时将使用术语“烯基”。烯基包括(但不限于)乙烯基、1-丙烯基、1-丁烯基、1-戊烯基和1-己烯基。
出于本发明的目的,当将脂肪族基连接至分子剩余部分的碳原子形成碳碳三键的一部分时将使用术语“炔基”。炔基包括(但不限于)乙炔基、1-丙炔基、1-丁炔基、1-戊炔基和1-己炔基。
单独或作为较大部分的一部分使用的术语“环脂肪族基”是指具有3至约14个成员的饱和或部分不饱和环状脂肪族环***,其中所述脂肪族环***任选经取代。在一些实施例中,环脂肪族基为具有3-8或3-6个环碳原子的单环烃。非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环庚烯基、环辛基、环辛烯基和环辛二烯基。在一些实施例中,环脂肪族基为具有6-12、6-10或6-8个环碳原子的桥联或稠合双环烃,其中双环***中的任何个别环具有3-8个成员。
在一些实施例中,环脂肪族环上的两个相邻取代基连同其间的***环原子一起形成具有0-3个选自由O、N和S组成的群组组的环杂原子的任选经取代的稠合5至6元芳香族环或3至8元非芳香族环。因此,术语“环脂肪族基”包括与一个或一个以上芳基、杂芳基或杂环基环稠合的脂肪族环。非限制性实例包括茚满基、5,6,7,8-四氢喹喔啉基、十氢萘基或四氢萘基,其中基团或连接点在所述脂肪族环上。
单独或作为较大部分(例如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”)的一部分使用的术语“芳基”和“芳”是指包含一至三个各自任选经取代的环的C6至C14芳香族烃。芳基优选为C6-10芳基。芳基包括(但不限于)苯基、萘基和蒽基。在一些实施例中,芳基环上的两个相邻取代基连同其间的***环原子一起形成具有0-3个选自由O、N和S组成的群组的环杂原子的任选经取代的稠合5至6元芳香族环或4至8元非芳香族环。因此,如本文所用的术语“芳基”包括芳基环与一个或一个以上杂芳基、环脂肪族或杂环基环稠合的基团,其中基团或连接点在所述芳香族环上。所述稠合环***的非限制性实例包括吲哚基、异吲哚基、苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩恶嗪基、四氢喹啉基、四氢异喹啉基、芴基、茚满基、菲啶基、四氢萘基、吲哚啉基、吩恶嗪基、苯并二恶烷基和苯并间二氧杂环戊烯基。芳基可为单环、双环、三环或多环,优选为单环、双环或三环,更优选为单环或双环。术语“芳基”可与术语“芳基基团”、“芳基部分”和“芳基环”互换使用。
“芳烷基”或“芳基烷基”包含芳基与烷基共价连接,其中任一者均独立地任选经取代。芳烷基优选为C6-10芳基(C1-6)烷基、C6-10芳基(C1-4)烷基或C6-10芳基(C1-3)烷基,包括(但不限于)苯甲基、苯乙基和萘甲基。
单独或作为较大部分(例如杂芳烷基或“杂芳烷氧基”)的一部分使用的术语“杂芳基”和“杂芳”是指具有5至14个环原子,优选具有5、6、9或10个环原子;具有6、10或14个于环阵列中共享的π电子;且除碳原子外还具有一至四个杂原子的基团。术语“杂原子”是指氮、氧或硫且包括氮或硫的任何氧化形式和碱性氮的任何季铵化形式。因此,当关于杂芳基的环原子使用时,术语“氮”包括氧化型氮(如在吡啶N-氧化物中)。如下文所进一步定义,5元杂芳基的某些氮原子也可经取代。杂芳基包括(但不限于)衍生自噻吩、呋喃、吡咯、咪唑、吡唑、***、四唑、恶唑、异恶唑、恶二唑、噻唑、异噻唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪、吲嗪、萘啶、蝶啶、吡咯并吡啶、咪唑并吡啶、恶唑并吡啶、噻唑并吡啶、***并吡啶、吡咯并嘧啶、嘌呤和***并嘧啶的基团。如本文所用的短语“衍生自……的基团”意谓通过自母体杂芳香族环***移除一个氢基所产生的单价基团。可在母体杂芳基环***的任何环上的任何可取代位置处产生基团(即,杂芳基与分子剩余部分的连接点)。
在一些实施例中,杂芳基上的两个相邻取代基连同其间的***环原子一起形成具有0-3个选自由O、N和S组成的群组的环杂原子的任选经取代的稠合5至6元芳香族环或4至8元非芳香族环。因此,如本文所用的术语“杂芳基”和“杂芳”也包括一个杂芳香族环与一个或一个以上芳基、环脂肪族或杂环基环稠合的基团,其中基团或连接点在所述芳香族环上。非限制性实例包括吲哚基、异吲哚基、苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、4H-喹嗪基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩恶嗪基、四氢喹啉基、四氢异喹啉基和吡啶并[2,3-b]-1,4-恶嗪-3(4H)-酮基。杂芳基可为单环、双环、三环或多环,优选为单环、双环或三环,更优选为单环或双环。术语“杂芳基”可与术语“杂芳基环”或“杂芳基基团”互换使用,所述术语中的任一者均包括任选经取代的环。术语“杂芳烷基”是指烷基经杂芳基取代,其中所述烷基和杂芳基部分独立地任选经取代。
如本文所用的术语“芳香族环”和“芳香族环***”是指具有0-6个、优选0-4个环杂原子且具有6、10或14个于环阵列中共享的π电子的任选经取代的单环、双环或三环基团。因此,术语“芳香族环”和“芳香族环***”涵盖芳基和杂芳基两者。
如本文所用的术语“杂环”、“杂环基”、“杂环基团”和“杂环状环”可互换使用且是指稳定的3至7元单环或稠合7至10元或桥联6至10元双环杂环部分,其为饱和或部分不饱和部分且除碳原子外还具有一个或一个以上,优选一至四个如上文所定义的杂原子。当关于杂环的环原子使用时,术语“氮”包括经取代的氮。举例来说,在具有1-3个选自氧、硫或氮的杂原子的杂环基环中,氮可为N(如在3,4-二氢-2H-吡咯基中)、NH(如在吡咯烷基中)或+NR(如在N-经取代的吡咯烷基中)。杂环可以任何产生稳定结构的杂原子或碳原子与其侧基连接,且任何环原子均可任选经取代。所述饱和或部分不饱和杂环基的实例包括(但不限于)四氢呋喃基、四氢噻吩基、吡咯烷基、吡咯烷酮基、哌啶基、吡咯啉基、四氢喹啉基、四氢异喹啉基、十氢喹啉基、恶唑啶基、哌嗪基、二恶烷基、二氧戊环基、二氮杂卓基、恶氮杂卓基、噻氮杂卓基、吗啉基和奎宁环基。
在一些实施例中,杂环上的两个相邻取代基连同其间的***环原子一起形成具有0-3个选自由O、N和S组成的群组的环杂原子的任选经取代的稠合5至6元芳香族环或3至8元非芳香族环。因此,术语“杂环”、“杂环基”、“杂环基环”、“杂环基”、“杂环部分”和“杂环基团”在本文中可互换使用,且包括一个杂环基环与一个或一个以上芳基、杂芳基或环脂肪族环稠合的基团,诸如吲哚啉基、3H-吲哚基、色满基、菲啶基或四氢喹啉基,其中基团或连接点在杂环基环上。杂环基可为单环、双环、三环或多环,优选为单环、双环或三环,更优选为单环或双环。术语“杂环基烷基”是指烷基经杂环基取代,其中烷基和杂环基部分独立地任选经取代。
如本文所用的术语“部分不饱和”是指在环原子之间包括至少一个双键或三键的环部分。术语“部分不饱和”意欲涵盖具有多个不饱和位点的环,但不欲包括如本文所定义的芳基或杂芳基部分。
术语“卤脂肪族基”、“卤烷基”、“卤烯基”和“卤烷氧基”是指任选经一个或一个以上卤素原子取代的脂肪族基、烷基、烯基或烷氧基。如本文所用的术语“卤素”或“卤基”意谓F、Cl、Br或I。术语“氟脂肪族基”是指卤素为氟的卤脂肪族基,包括全氟脂肪族基。氟脂肪族基的实例包括(但不限于)氟甲基、二氟甲基、三氟甲基、2-氟乙基、2,2,2-三氟乙基、1,1,2-三氟乙基、1,2,2-三氟乙基和五氟乙基。
术语“连接基团”或“连接基”意谓连接化合物的两个部分的有机部分。连接基通常包含诸如氧或硫等原子、诸如-NH-、-CH2-、-C(O)、-C(O)NH-等单元或诸如亚烷基链等原子链。连接基的分子质量通常在约14至200的范围内,优选在14至96的范围内,长度为至多约6个原子。在一些实施例中,连接基为C1-6亚烷基链。
术语“亚烷基”是指二价烷基。“亚烷基链”为聚亚甲基,即-(CH2)x-,其中x为正整数,优选为1至6、1至4、1至3、1至2或2至3。经取代亚烷基链为一个或一个以上亚甲基氢原子经取代基置换的聚亚甲基。合适取代基包括以下关于经取代脂肪族基描述的那些取代基。亚烷基链也可于一个或一个以上位置经脂肪族基或经取代脂肪族基取代。
亚烷基链也可任选杂有官能团。当内部亚甲基单元经官能团置换时,亚烷基链“杂有”官能团。合适“杂入官能团”的非限制性实例包括-C(R*)=C(R*)-、-C≡C-、-O-、-S-、-S(O)-、-S(O)2-、-S(O)2N(R+)-、-N(R*)-、-N(R+)CO-、-N(R+)C(O)N(R+)-、-N(R+)C(=NR+)-N(R+)-、-N(R+)-C(=NR+)-、-N(R+)CO2-、-N(R+)SO2-、-N(R+)SO2N(R+)-、-OC(O)-、-OC(O)O-、-OC(O)N(R+)-、-C(O)-、-CO2-、-C(O)N(R+)-、-C(O)-C(O)-、-C(=NR+)-N(R+)-、-C(NR+)=N-、-C(=NR+)-O-、-C(OR*)=N-、-C(Ro)=N-O-或-N(R+)-N(R+)-。各R+独立为氢或任选经取代的脂肪族基、芳基、杂芳基或杂环基,或同一氮原子上的两个R+连同所述氮原子一起形成除所述氮原子外还具有0-2个选自N、O和S的环杂原子的5-8元芳香族环或非芳香族环。各R*独立地为氢或任选经取代的脂肪族基、芳基、杂芳基或杂环基。
“杂有”-O-的C3-6亚烷基链的实例包括例如-CH2OCH2-、-CH2O(CH2)2-、-CH2O(CH2)3-、-CH2O(CH2)4-、-(CH2)2OCH2-、-(CH2)2O(CH2)2-、-(CH2)2O(CH2)3-、-(CH2)3O(CH2)-、-(CH2)3O(CH2)2-和-(CH2)4O(CH2)-。“杂有”官能团的亚烷基链的其他实例包括-CH2ZCH2-、-CH2Z(CH2)2-、-CH2Z(CH2)3-、-CH2Z(CH2)4-、-(CH2)2ZCH2-、-(CH2)2Z(CH2)2-、-(CH2)2Z(CH2)3-、-(CH2)3Z(CH2)-、-(CH2)3Z(CH2)2-和-(CH2)4Z(CH2)-,其中Z为上文所列的“杂入”官能团之一。
所属领域的一般技术人员将认识到,当具有杂入基团的亚烷基链连接于官能团时,某些组合对于医药用途来说将不够稳定。类似地,T1与R2c或T2与R2d的某些组合对于医药用途来说将不够稳定。仅稳定或化学上可行的化合物在本发明的范围内。稳定或化学上可行的化合物为维持其完整性足够久以适用于治疗性或预防性投予患者的化合物。优选的是,当在低于-70℃、低于-50℃、低于-20℃、低于0℃或低于20℃的温度下,在无水分或其他化学反应性条件存在下保存至少一周时,化学结构实质上不改变。
如本文所用的“经取代”意谓所指定部分的氢基经指定取代基置换,限制条件为所述取代产生稳定或化学上可行的化合物。当关于所指定原子使用时,术语“可取代”意谓可经合适取代基的基团置换的氢基连接于所述原子。
如本文所用的短语“一个或一个以上取代基”是指等于一至基于可用键结位点的数目而可能的取代基的最大数目的取代基数目,限制条件为符合上述稳定性和化学可行性的条件。除非另有说明,否则任选经取代的基团可在基团的各可取代位置具有取代基,且所述取代基可相同或不同。
如本文所用的术语“独立地选择”意谓在单一化合物中可针对指定代号的多个实例选择相同或不同值。
芳基(包括芳烷基、芳烷氧基、芳基氧基烷基等中的芳基部分)或杂芳基(包括杂芳烷基和杂芳烷氧基等中的杂芳基部分)可含有一个或一个以上取代基。芳基或杂芳基的不饱和碳原子上的合适取代基的非限制性实例包括卤基、-NO2、-CN、-R*、-C(R*)=C(R*)2、-C≡C-R*、-OR*、-SRo、-S(O)Ro、-SO2Ro、-SO3R*、-SO2N(R+)2、-N(R+)2、-NR+C(O)R*、-NR+C(O)N(R+)2、-N(R+)C(=NR+)-N(R+)2、-N(R+)C(=NR+)-Ro、-NR+CO2Ro、-NR+SO2Ro、-NR+SO2N(R+)2、-O-C(O)R*、-O-CO2R*、-OC(O)N(R+)2、-C(O)R*、-CO2R*、-C(O)-C(O)R*、-C(O)N(R+)2、-C(O)N(R+)-OR*、-C(O)N(R+)C(=NR+)-N(R+)2、-N(R+)C(=NR+)-N(R+)-C(O)R*、-C(=NR+)-N(R+)2、-C(=NR+)-OR*、-N(R+)-N(R+)2、-C(=NR+)-N(R+)-OR*、-C(Ro)=N-OR*、-P(O)(R*)2、-P(O)(OR*)2、-O-P(O)-OR*和-P(O)(NR+)-N(R+)2,其中Ro为任选经取代的脂肪族基、芳基或杂芳基,且R+和R*如上文所定义,或两个相邻取代基连同其间的***原子一起形成具有0-3个选自由N、O和S组成的群组的环原子的5至6元不饱和或部分不饱和环。
脂肪族基或非芳香族杂环可经一个或一个以上取代基取代。脂肪族基或非芳香族杂环的饱和碳上的合适取代基的实例包括(但不限于)上文关于芳基或杂芳基的不饱和碳所列出者和以下:=O、=S、=C(R*)2、=N-N(R*)2、=N-OR*、=N-NHC(O)R*、=N-NHCO2Ro、=N-NHSO2Ro或=N-R*,其中R*和Ro各自如上文所定义。
杂芳基或非芳香族杂环的可取代氮原子上的合适取代基包括(但不限于)-R*、-N(R*)2、-C(O)R*、-CO2R*、-C(O)-C(O)R*、-C(O)CH2C(O)R*、-SO2R*、-SO2N(R*)2、-C(=S)N(R*)2、-C(=NH)-N(R*)2和-NR*SO2R*;其中各R*如上文所定义。杂芳基或非芳香族杂环的环氮原子也可经氧化形成相应N-羟基或N-氧化物化合物。这种具有氧化环氮原子的杂芳基的一非限制性实例为N-氧离子基吡啶基。
本文中使用的术语“约”意谓大约、在范围内、大致或左右。当结合数值范围使用术语“约”时,其通过使所阐明数值的界限向上或向下扩展来修订所述范围。一般来说,本文中使用术语“约”来修订数值至所述数值上方和下方10%的偏差。
如本文所用的术语“包含”意谓“包括(但不限于)”。
所属领域的技术人员将明了,本发明的某些化合物可以互变异构形式存在,化合物的所有这些互变异构形式均在本发明的范围内。除非另有说明,否则本文所述的结构也意欲包括所有几何(或构形)异构体,即(Z)和(E)双键异构体和(Z)和(E)构形异构体,以及结构的所有立体化学形式;即各不对称中心的R和S构型。因此,本发明化合物的单一立体化学异构体以及对映异构和非对映异构混合物均在本发明的范围内。当混合物中相对于另一立体异构体富含一种立体异构体时,所述混合物可含有例如至少50%、75%、90%、99%或99.5%的对映异构体过量。
除非另有说明,否则本文所述的结构也意欲包括不同之处仅在于存在一个或一个以上同位素富集原子的化合物。举例来说,除氢经氘或氚置换,或碳原子经13C-或14C-富集碳置换以外,具有本发明结构的化合物均在本发明的范围内。
在式(I)化合物中,代号P为氢或氨基封端部分。氨基封端部分的非限制性实例可见于P.G.M.武特斯(P.G.M.Wuts)和T.W.格林(T.W.Greene),有机合成中的格林保护基(Greene′s Protective Groups in Organic Synthesis)(第四版)约翰威利父子出版社(John Wiley & Sons),NJ(2007)中,且包括例如酰基、磺酰基、氧酰基和氨酰基。
在一些实施例中,P为Rc-C(O)-、Rc-O-C(O)-、Rc-N(R4c)-C(O)-、Rc-S(O)2-或Rc-N(R4c)-S(O)2-,其中Rc选自由C1-6脂肪族基、C1-6氟脂肪族基、-RD、-T1-RD和-T1-R2c组成的群组,且代号T1、RD、R2c和R4c具有下文描述的值。
代号R4c为氢、C1-4烷基、C1-4氟烷基或C6-10芳(C1-4烷基),其芳基部分经取代或未经取代。在一些实施例中,R4c为氢或C1-4烷基。在某些特定实施例中,R4c为氢。
代号T1为经0-2个独立选择的R3a或R3b取代的C1-6亚烷基链,其中亚烷基链任选杂有-C(R5)=C(R5)-、-C≡C-或-O-。各R3a独立地选自由以下组成的群组:-F、-OH、-O(C1-4烷基)、-CN、-N(R4)2、-C(O)(C1-4烷基)、-CO2H、-CO2(C1-4烷基)、-C(O)NH2和-C(O)-NH(C1-4烷基)。各R3b独立地为任选经R3a或R7取代的C1-3脂肪族基。各R7为经取代或未经取代的芳香族基。在一些实施例中,T1为C1-4亚烷基链。
代号R2c为卤基、-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-NR4CO2R6、-N(R4)SO2R6、-N(R4)SO2N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5或-C(O)N(R4)2,其中:
各R4独立地为氢或任选经取代的脂肪族基、芳基、杂芳基或杂环基;或同一氮原子上的两个R4连同氮原子一起形成除所述氮原子外还具有0-2个独立地选自N、O和S的环杂原子的任选经取代的4至8元杂环基环;
各R5独立地为氢或任选经取代的脂肪族基、芳基、杂芳基或杂环基;且
各R6独立地为任选经取代的脂肪族基、芳基或杂芳基。
代号RD为经取代或未经取代的芳香族环、杂环基环或环脂肪族环,其中任一者任选与经取代或未经取代的芳香族环、杂环基环或环脂肪族环稠合。RD中的各饱和环碳原子未经取代,或经=O、Rd或R8d取代。RD中的各不饱和环碳原子未经取代,或经Rd或R8d取代。RD中的各可取代环氮原子未经取代或经以下取代:-C(O)R5、-C(O)N(R4)2、-CO2R6、-SO2R6、-SO2N(R4)2、C1-4脂肪族基、经取代或未经取代的C6-10芳基或C6-10芳(C1-4)烷基,其芳基部分经取代或未经取代。
在一些实施例中,RD中的一或两个饱和环碳原子经=O取代;RD中的剩余可取代环碳原子经0-2个Rd和0-2个R8d取代;且RD中的各可取代环氮原子未经取代或经以下取代:-C(O)R5、-C(O)N(R4)2、-CO2R6、-SO2R6、-SO2N(R4)2、C1-4脂肪族基、经取代或未经取代的C6-10芳基或C6-10芳(C1-4)烷基,其芳基部分经取代或未经取代。各Rd独立地选自由以下组成的群组:C1-6脂肪族基、C1-6氟脂肪族基、卤基、-R1d、-R2d、-T2-R1d和-T2-R2d,其中代号T2、R1d、R2d和R8d具有下文描述的值。
T2为经0-2个独立选择的R3a或R3b取代的C1-6亚烷基链,其中亚烷基链任选杂有-C(R5)=C(R5)-、-C≡C-或-O-。代号R3a和R3b具有上文所述的值。
各R1d独立地为经取代或未经取代的芳基、杂芳基、杂环基或环脂肪族环。
各R2d独立地为-NO2、-CN、-C(R5)=C(R5)2、-C≡C-R5、-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-R6、-NR4CO2R6、-N(R4)SO2R6、-N(R4)SO2N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5、-C(O)N(R4)2、-C(O)N(R4)-OR5、-C(O)N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-N(R4)-C(O)R5或-C(=NR4)-N(R4)2。
各R8d独立地选自由以下组成的群组:C1-4脂肪族基、C1-4氟脂肪族基、卤基、-OH、-O(C1-4脂肪族基)、-NH2、-NH(C1-4脂肪族基)和-N(C1-4脂肪族基)2。
在一些实施例中,RD为选自由以下组成的群组的经取代或未经取代的单环或双环***:呋喃基、噻吩基、吡咯基、异恶唑基、恶唑基、噻唑基、异噻唑基、咪唑基、吡唑基、恶二唑基、噻二唑基、苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、苯并呋喃基、苯并噻吩基、吲哚基、苯并恶唑基、苯并异恶唑基、苯并咪唑基、吲唑基、嘌呤基、萘基、喹啉基、异喹啉基、噌啉基、喹唑啉基、喹喔啉基、酞嗪基、萘啶基、四氢喹啉基、四氢异喹啉基、四氢喹喔啉基和二氢苯并恶嗪基。在一些实施例中,RD为选自由以下组成的群组的经取代或未经取代的单环或双环***:苯基、吡啶基、嘧啶基、吡嗪基、萘基、苯并咪唑基、喹啉基、异喹啉基、喹喔啉基、四氢喹啉基、四氢异喹啉基、四氢喹喔啉基和二氢苯并恶嗪基。
在一些实施例中,RD中的一或两个饱和环碳原子经=O取代,且RD中的剩余可取代环碳原子经0-1个Rd和0-2个R8d取代,其中:
各Rd独立地选自由以下组成的群组:C1-6脂肪族基、C1-6氟脂肪族基、卤基、-R1d、-R2d、-T2-R1d和-T2-R2d;
T2为未经取代或经R3a或R3b取代的C1-3亚烷基链;
各R1d独立地为经取代或未经取代的芳基、杂芳基、杂环基或环脂肪族环;且
各R2d独立地为-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5或-C(O)N(R4)2。
在一些实施例中,代号Rd具有式-Q-RE,其中Q为-O-、-NH-或-CH2-,且RE为经取代或未经取代的芳基、杂芳基、杂环基或环脂肪族环。在一些实施例中,RE为经取代或未经取代的苯基、吡啶基、嘧啶基、吡嗪基、哌啶基、哌嗪基或吗啉基环。
在一些实施例中,P具有式Rc-C(O)-,其中Rc为C1-4烷基、C1-4氟烷基或C6-10芳(C1-4)烷基,其芳基部分经取代或未经取代。在某些所述实施例中,P选自由乙酰基、三氟乙酰基和苯乙酰基组成的群组。
在一些实施例中,P具有式RD-C(O)-,其中RD为经取代或未经取代的苯基、吡啶基、吡嗪基、嘧啶基、喹啉基或喹喔啉基。在某些实施例中,P具有式RD-C(O)-,其中RD为经0-1个Rd和0-2个R8d取代的苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喔啉基、苯并咪唑基或二氢苯并恶嗪基。在某些特定实施例中,P具有式RD-C(O)-,其中RD为经式-O-RE的取代基取代的吡啶基、吡嗪基或嘧啶基,且RE为经取代或未经取代的苯基。在某些其他特定实施例中,P具有式RD-C(O)-,其中RD为经式-O-RE的取代基取代的苯基,且RE为经取代或未经取代的吡啶基、吡嗪基或嘧啶基。
在一些其他实施例中,P具有式Rc-SO2-,其中Rc为-RD或-T1-RD,其中T1为C1-4亚烷基且RD为经0-1个Rd和0-2个R8d取代的苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喔啉基、苯并咪唑基或二氢苯并恶嗪基。在一些实施例中,P具有式RD-SO2-,其中RD为经取代或未经取代的苯基、吡啶基、吡嗪基、嘧啶基、喹啉基或喹喔啉基。在某些实施例中,P具有式RD-SO2-,其中RD为经0-1个Rd和0-2个R8d取代的苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喔啉基、苯并咪唑基或二氢苯并恶嗪基。在某些特定实施例中,P具有式RD-SO2-,其中RD为经式-O-RE的取代基取代的吡啶基、吡嗪基或嘧啶基,且RE为经取代或未经取代的苯基。在某些其他特定实施例中,P具有式RD-SO2-,其中RD为经式-O-RE的取代基取代的苯基,且RE为经取代或未经取代的吡啶基、吡嗪基或嘧啶基。
代号Ra1和各代号Ra2独立地为C1-6脂肪族基、C1-6氟脂肪族基、-(CH2)m-CH2-RB、-(CH2)m-CH2-NHC(=NR4)NH-Y、-(CH2)m-CH2-CON(R4)2、-(CH2)m-CH2-N(R4)CON(R4)2、-(CH2)m-CH(R6)N(R4)2、-(CH2)m-CH(R5)-OR5或-(CH2)m-CH(R5)-SR5,其中代号R4、R5和R6具有上文所述的值,且代号RB和m具有下文描述的值。
各RB独立地为经取代或未经取代的单环或双环***。在一些实施例中,各RB独立地为经取代或未经取代的苯基、吡啶基、吲哚基、苯并咪唑基、萘基、喹啉基、喹喔啉基或异喹啉基环。在某些实施例中,RB为经取代或未经取代的苯基环。
代号m为0、1或2。在一些实施例中,m为0或1。
在一些实施例中,Ra1和Ra2各自独立地为C1-6脂肪族基、C1-6氟脂肪族基或-(CH2)m-CH2-RB,且m为0或1。在一些所述实施例中,RB为经取代或未经取代的苯基。
在一些实施例中,Ra1为C1-6脂肪族基、-(CH2)m-CH2RB或-(CH2)m-CH(C1-4烷基)-OH。在某些实施例中,Ra1为苯甲基。在其他某些实施例中,Ra1为-CH2-CH(CH3)-OH。
在一些实施例中,Ra2为C1-6脂肪族基或-(CH2)m-CH2RB。在某些实施例中,Ra2为异丙基、苯甲基或苯乙基。
代号A为0、1或2。在一些实施例中,A为0或1。在某些实施例中,A为0。
在一些实施例中,本发明涉及特征为式(I-A)的式(I)化合物:
或其医药学上可接受的盐或硼酸酐,其中各代号P、Ra1、Ra2、A、Z1和Z2具有上文针对式(I)描述的值和优选值。
在某些实施例中,本发明涉及特征为式(I-B)的式(I)化合物:
或其医药学上可接受的盐或硼酸酐,其中各代号P、Ra1、Ra2、A、Z1和Z2具有上文针对式(I)描述的值和优选值。
在某些特定实施例中,本发明涉及特征为式(II)的式(I)化合物:
或其医药学上可接受的盐或硼酸酐,其中各代号P、Z1和Z2具有上文针对式(I)描述的值和优选值。
在一些实施例中,本发明涉及式(II)化合物,其中P具有式RD-C(O)-,其中RD为经取代或未经取代的苯基、吡啶基、吡嗪基、嘧啶基、喹啉基或喹喔啉基。在某些实施例中,P具有式RD-C(O)-,其中RD为经0-1个Rd和0-2个R8d取代的苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喔啉基、苯并咪唑基或二氢苯并恶嗪基。在某些特定实施例中,P具有式RD-C(O)-,其中RD为经式-O-RE的取代基取代的吡啶基、吡嗪基或嘧啶基,且RE为经取代或未经取代的苯基。在某些其他特定实施例中,P具有式RD-C(O)-,其中RD为经式-O-RE的取代基取代的苯基,且RE为经取代或未经取代的吡啶基、吡嗪基或嘧啶基。
在一些其他实施例中,本发明涉及式(II)化合物,其中P具有式Rc-SO2-,其中Rc为-RD或-T1-RD,其中T1为C1-4亚烷基且RD为经0-1个Rd和0-2个R8d取代的苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喔啉基、苯并咪唑基或二氢苯并恶嗪基。在一些实施例中,P具有式RD-SO2-,其中RD为经取代或未经取代的苯基、吡啶基、吡嗪基、嘧啶基、喹啉基或喹喔啉基。在某些实施例中,P具有式RD-SO2-,其中RD为经0-1个Rd和0-2个R8d取代的苯基、吡啶基、吡嗪基、嘧啶基、萘基、喹啉基、喹喔啉基、苯并咪唑基或二氢苯并恶嗪基。在某些特定实施例中,P具有式RD-SO2-,其中RD为经式-O-RE的取代基取代的吡啶基、吡嗪基或嘧啶基,且RE为经取代或未经取代的苯基。在某些其他特定实施例中,P具有式RD-SO2-,其中RD为经式-O-RE的取代基取代的苯基,且RE为经取代或未经取代的吡啶基、吡嗪基或嘧啶基。
式(I)化合物的代表性实例展示于表1中。
表1:蛋白酶体抑制剂
上表1中的化合物也可由以下化学名称鉴别:
如本文所用的术语“硼酸”是指含有-B(OH)2部分的化合物。在一些实施例中,硼酸化合物可通过硼酸部分的脱水作用形成寡聚酸酐。举例来说,辛德尔(Snyder)等人,美国化学协会期刊(J.Am.Chem.Soc.)80:3611(1958)报导寡聚芳基硼酸。
如本文所用的术语“硼酸酐”是指通过两个或两个以上硼酸化合物分子失去一个或一个以上水分子而组合形成的化合物。当与水混合时,硼酸酐化合物水合释放自由硼酸化合物。在各种实施例中,硼酸酐可包含两个、三个、四个或更多个硼酸单元,且可具有环状或线性构型。本发明肽硼酸化合物的寡聚硼酸酐的非限制性实例说明如下:
在式(1)和(2)中,代号n为0至约10的整数,优选为0、1、2、3或4。在一些实施例中,硼酸酐化合物包含式(2)的环状三聚体(“环硼氧烷”),其中n为1。代号W具有式(3):
其中代号P、Ra1和Ra2具有上文针对式(I)所述的值和优选值。
在一些实施例中,硼酸酐化合物中所存在硼酸的至少80%以单一寡聚酸酐形式存在。在一些实施例中,硼酸酐化合物中所存在硼酸的至少85%、90%、95%或99%以单一寡聚酸酐形式存在。在某些优选实施例中,硼酸酐化合物由具有式(3)的环硼氧烷组成,或基本上由具有式(3)的环硼氧烷组成。
硼酸酐化合物优选可由相应硼酸通过暴露于脱水条件(包括但不限于再结晶、冷冻干燥)、暴露于热和/或暴露于干燥剂来制备。合适再结晶溶剂的非限制性实例包括乙酸乙酯、二氯甲烷、己烷、***、乙腈、乙醇和其混合物。
在一些实施例中,Z1和Z2一起形成衍生自硼酸络合剂的部分。出于本发明的目的,术语“硼酸络合剂”是指具有至少两个官能团,且各官能团可与硼形成共价键的任何化合物。合适官能团的非限制性实例包括氨基、羟基和羧基。在一些实施例中,至少一个官能团为羟基。术语“衍生自硼酸络合剂的部分”是指通过自硼酸络合剂的两个官能团移除氢原子所形成的部分。
如本文所用的术语“硼酸酯(boronate ester/boronic ester)”可互换使用且是指含有-B(Z1)(Z2)部分的化合物,其中Z1或Z2中的至少一者为烷氧基、芳烷氧基或芳氧基;或Z1和Z2一起形成衍生自具有至少一个羟基的硼酸络合剂的部分。
在式(I)、(I-A)、(I-B)和(II)的化合物中,Z1和Z2各自独立地为羟基、烷氧基、芳氧基或芳烷氧基;或Z1和Z2一起形成衍生自硼酸络合剂的部分。在一些实施例中,Z1和Z2各自为羟基。在一些其他实施例中,Z1和Z2一起形成衍生自链或环中具有至少两个由至少两个连接原子隔开的羟基的化合物的部分,所述链或环包含碳原子且任选包含一个或一个以上可为N、S或O的杂原子,其中在各状况下与硼连接的原子为氧原子。
如本文所用的术语“具有至少两个羟基的化合物”是指具有两个或两个以上羟基的任何化合物。出于本发明的目的,两个羟基优选由至少两个连接原子,优选约2至约5个连接原子,更优选2或3个连接原子隔开。出于方便起见,术语“二羟基化合物”可用于指如上文所定义具有至少两个羟基的化合物。因此,如本文所用的术语“二羟基化合物”不欲限于仅具有两个羟基的化合物。衍生自具有至少两个羟基的化合物的部分可通过其中任意两个羟基的氧原子与硼连接。硼原子、与硼连接的氧原子和连接两个氧原子的原子优选一起形成5或6元环。
出于本发明的目的,硼酸络合剂优选为医药学上可接受的,即适于投予人类。在一些优选实施例中,硼酸络合剂为糖,如例如普拉芒顿(Plamondon)等人的WO 02/059131和古普塔(Gupta)等人的WO 02/059130中所描述。术语“糖”包括任何多羟基碳水化物部分,包括单糖、双糖、多糖、糖醇和氨基糖。在一些实施例中,糖为单糖、双糖、糖醇或氨基糖。合适糖的非限制性实例包括葡萄糖、蔗糖、果糖、海藻糖、甘露糖醇、山梨糖醇、葡糖胺和N-甲基葡糖胺。在某些实施例中,糖为甘露糖醇或山梨糖醇。因此,在糖为甘露糖醇或山梨糖醇的实施例中,Z1和Z2一起形成式C6H12O6的部分,其中两个去质子化羟基的氧原子与硼形成共价连接,从而形成硼酸酯化合物。在某些特定实施例中,Z1和Z2一起形成衍生自D-甘露糖醇的部分。
在一些其他优选实施例中,如例如伊利奥特(Elliott)等人于2009年6月16日申请的U.S.12/485,344中所述,硼酸络合剂为α-羟基羧酸或β-羟基羧酸。在一些所述实施例中,硼酸络合剂选自由以下组成的群组:乙醇酸、苹果酸、六氢扁桃酸、柠檬酸、2-羟基异丁酸、3-羟基丁酸、扁桃酸、乳酸、2-羟基-3,3-二甲基丁酸、2-羟基-3-甲基丁酸、2-羟基异己酸、β-羟基异戊酸、水杨酸、酒石酸、二苯乙醇酸、葡糖庚酸、麦芽糖酸、乳糖酸、半乳糖二酸、恩波酸(embonic acid)、1-羟基-2-萘甲酸和3-羟基-2-萘甲酸。在某些所述实施例中,硼酸络合剂为柠檬酸。
通用合成方法
式(I)化合物可通过所属领域的一般技术人员已知的方法制备。参见例如亚当斯(Adams)等人的美国专利第5,780,454号;匹克尔斯齐尔(Pickersgill)等人的国际专利公开案WO 2005/097809。本发明N-酰基-肽基硼酸化合物(P=Rc-C(O)-)的一例示性合成路径阐述于下文流程1中。
流程1:
使化合物i与N-经保护的氨基酸(ii)偶合,随后脱除N端的保护基,形成化合物iii。合适保护基(PG)的实例包括(但不限于):酰基保护基,例如甲酰基、乙酰基(Ac)、琥珀酰基(Suc)和甲氧基琥珀酰基;和氨基甲酸酯保护基,例如叔丁氧羰基(Boc)、苯甲氧羰基(Cbz)和芴基甲氧羰基(Fmoc)。肽偶合反应可通过先将化合物ii的羧酸部分转化为活化酯(例如O-(N-羟基琥珀酰亚胺)酯),随后以化合物i处理来进行。或者,可通过使羧酸与肽偶合试剂接触来现场产生活化酯。合适肽偶合试剂的实例包括(但不限于):碳化二亚胺试剂,例如二环己基碳化二亚胺(DCC)或1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺(EDC);鏻试剂,例如六氟磷酸苯并***-1-基氧基三(二甲基氨基)鏻(BOP);和脲盐试剂,例如四氟硼酸O-(1H-苯并***-1-基)-N,N,N′,N′-四甲基脲盐(TBTU)。
随后使化合物iii与羧酸(RcCO2H)偶合得到化合物iv。上述用于化合物i与化合物ii的偶合的肽偶合条件也适用于偶合化合物iii与RcCO2H。随后,脱除硼酸部分的保护基得到化合物v。优选通过在包含硼酸酯化合物iv、有机硼酸受体、低级烷醇、C5-8烃溶剂和无机酸水溶液的两相混合物中进行酯基转移反应完成脱除保护基步骤。
流程2:
或者,如流程2所示,逆转偶合反应的顺序。因此,首先使O-经保护的甘氨酸(vi)与经取代的苯甲酸(ArCO2H)偶合,随后进行酯水解以形成化合物vii。随后,如上文关于流程1所述完成与化合物i的偶合和硼酸保护基脱除,得到化合物v。
制备本发明的N-磺酰基-肽基硼酸化合物(P=Rc-S(O)2-)的一例示性合成路径阐述于下文流程3中:
流程3:
在碱(诸如二异丙基乙胺)存在下用磺酰氯处理如上文关于流程1所述制备的化合物iii得到化合物vi。随后,如上文关于流程1所述完成硼酸部分的保护基脱除,得到化合物vii。也可以类似于流程2的方式逆转制备化合物vii的反应顺序。
用途、调配物和投药
本发明提供作为蛋白酶体的有效抑制剂的化合物。可在活体外或活体内分析所述化合物抑制蛋白酶体介导的肽水解或蛋白质降解的能力。
因此,在另一方面中,本发明提供一种抑制细胞中蛋白酶体的一种或一种以上肽酶活性的方法,其包含使需要蛋白酶体抑制的细胞与本文所述的化合物或其医药学上可接受的盐、硼酸酯或硼酸酐相接触。
本发明还提供一种抑制细胞增殖的方法,其包含使需要此抑制的细胞与本文所述的化合物相接触。短语“抑制细胞增殖”用来表示与未接触抑制剂的细胞相比,本发明化合物抑制所接触细胞的细胞数目或细胞生长的能力。可通过使用细胞计数器计数细胞或通过细胞活力分析(例如MTT或WST分析)来评估细胞增殖。当细胞处于实体生长(例如实体肿瘤或器官)中时,可通过例如以卡尺测量生长,并比较接触细胞与未接触细胞的生长规模来进行细胞增殖的这种评估。
优选地,与未接触细胞的生长相比,与抑制剂接触的细胞的生长延缓至少约50%。在各种实施例中,与未接触细胞相比,接触细胞的细胞增殖受抑制达至少约75%、至少约90%或至少约95%。在一些实施例中,短语“抑制细胞增殖”包括与未接触细胞相比,接触细胞的数目减少。因此,抑制接触细胞的细胞增殖的蛋白酶体抑制剂可诱导接触细胞经历生长延缓、经历生长停滞、经历程序性细胞死亡(即细胞凋亡)或经历坏死性细胞死亡。
在另一方面中,本发明提供一种医药组合物,其包含式(I)化合物或其医药学上可接受的盐或硼酸酐,和医药学上可接受的载剂。
如果在这些组合物中使用本发明化合物的医药学上可接受的盐,那么所述盐优选衍生自无机或有机酸或碱。关于合适盐的回顾,参见例如贝尔奇(Berge)等人,医药科学杂志(J.Pharm.Sci.)66:1-19(1977)和雷明顿:医药科学和实践(Remington:The Science and Practice of Pharmacy),第20版,A.根纳罗(A.Gennaro)编,利平科特威廉姆斯和维尔金斯出版社(Lippincott Williams & Wilkins),2000。
合适酸加成盐的非限制性实例包括以下:乙酸盐、己二酸盐、海藻酸盐、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、乙烷磺酸盐、富马酸盐、葡糖庚酸盐(lucoheptanoate)、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙烷磺酸盐、乳酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟碱酸盐、草酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基-丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一烷酸盐。
合适碱加成盐包括(但不限于):铵盐;碱金属盐,诸如锂盐、钠盐和钾盐;碱土金属盐,诸如钙盐和镁盐;其他多价金属盐,诸如锌盐;与诸如二环己胺、N-甲基-D-葡糖胺、叔丁胺、乙二胺、乙醇胺和胆碱等有机碱形成的盐;以及与诸如精氨酸、赖氨酸的氨基酸形成的盐,等等。在一些实施例中,医药学上可接受的盐为式(I)硼酸化合物的碱加成盐,其中Z1和Z2均为羟基。
如本文所用的术语“医药学上可接受的载剂”是指与接受个体(优选为哺乳动物,更优选为人类)相容且适于向目标部位传递活性剂而不终止药剂活性的物质。与载剂相关的毒性或不良作用(若存在)优选与合理的活性剂预定用途的风险/效益比相称。
术语“载剂”、“助剂”或“媒剂”在本文中可互换使用,且包括适于特定所要剂型的任何和所有溶剂、稀释剂和其他液体媒剂、分散剂或分散助剂、表面活性剂、pH值调节剂、等张剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。雷明顿:医药科学和实践(Remington:The Science and Practice of Pharmacy),第20版,A.根纳罗(A.Gennaro)编,利平科特威廉姆斯和维尔金斯出版社(Lippincott Williams & Wilkins),2000揭示了用于调配医药学上可接受的组合物的各种载剂和其已知制备技术。除非任何常规载剂介质均不与本发明化合物相容,诸如因产生任何不当生物作用,或另外与医药学上可接受的组合物的任何其他组分以有害方式相互作用,否则预期其使用在本发明的范围内。可用作医药学上可接受的载剂的物质的一些实例包括(但不限于):离子交换剂;氧化铝;硬脂酸铝;卵磷脂;血清蛋白质,诸如人类血清白蛋白;缓冲物质,诸如磷酸盐、碳酸盐、氢氧化镁和氢氧化铝、甘氨酸、山梨酸或山梨酸钾;饱和植物脂肪酸的偏甘油酯混合物;水;无热原质水;盐或电解质,诸如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠和锌盐;胶态二氧化硅;三硅酸镁;聚乙烯吡咯烷酮;聚丙烯酸酯;蜡;聚乙烯-聚氧丙烯封端聚合物;羊毛脂;糖,诸如乳糖、葡萄糖、蔗糖和甘露糖醇;淀粉,诸如玉米淀粉和马铃薯淀粉;纤维素和其衍生物,诸如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;粉状黄芪胶;麦芽;明胶;滑石粉;赋形剂,诸如可可脂和栓剂蜡;油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇,诸如丙二醇和聚乙二醇;酯,诸如油酸乙酯和月桂酸乙酯;琼脂;褐藻酸;等张盐水;林格氏溶液(Ringer′s solution);醇,诸如乙醇、异丙醇、十六烷醇和甘油;环糊精,诸如羟丙基-β-环糊精和磺丁基醚-β-环糊精;润滑剂,诸如月桂基硫酸钠和硬脂酸镁;石油烃,诸如矿物油和石蜡。着色剂、释放剂、涂布剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可根据调配者的判断存在于组合物中。
本发明的医药组合物可通过所属领域中熟知的方法制造,尤其诸如常规粒化、混合、溶解、囊封、冻干或乳化方法。组合物可产生为各种形式,包括颗粒、沈淀物或微粒、粉末(包括冷冻干燥粉末、旋转干燥粉末或喷雾干燥粉末)、非晶形粉末、片剂、胶囊、糖浆、栓剂、注射剂、乳液、酏剂、悬浮液或溶液。
根据一优选实施例,本发明组合物经调配以供医药投予至哺乳动物,优选人类。本发明的所述医药组合物可经口、不经肠、通过吸入喷雾、局部、经直肠、经鼻、经颊、经***或通过植入式贮器投予。如本文所用的术语“不经肠”包括皮下、静脉内、肌肉内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。优选地,组合物经口、静脉内或皮下投予。本发明调配物可设计为短效、快速释放或长效调配物。更进一步,化合物可以局部而非全身性方式投予,诸如在肿瘤部位(例如通过注射)投予。
用于经口投药的液体剂型包括(但不限于)医药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除活性化合物外,液体剂型还可含有所属领域中常用的惰性稀释剂,诸如水或其他溶剂;增溶剂和乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、环糊精、二甲基甲酰胺;油(尤其为棉籽油、落花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油);甘油;四氢糠醇;聚乙二醇;和脱水山梨糖醇的脂肪酸酯;和其混合物。除惰性稀释剂外,口服组合物还可包括佐剂,诸如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和芳香剂。
可根据已知技术使用合适分散剂或润湿剂和悬浮剂来调配注射制剂,例如无菌注射水性或油性悬浮液。无菌注射制剂也可为不经肠可接受的无毒稀释剂或溶剂中的无菌注射溶液、悬浮液或乳液,例如为1,3-丁二醇中的溶液。可使用的可接受媒剂和溶剂包括水、林格氏溶液、U.S.P.和等张氯化钠溶液。此外,通常使用无菌不挥发性油作为溶剂或悬浮介质。因此,可使用任何温和不挥发性油,包括合成单酸甘油酯或二酸甘油酯。此外,在注射剂制备中使用脂肪酸,诸如油酸。可对注射调配物进行灭菌,例如通过细菌截留过滤器过滤,或通过并入灭菌剂,呈无菌固体组合物形式,其可在使用前溶解或分散于无菌水或其他无菌注射介质中。调配用于不经肠投药的组合物可通过快速注射或定时推注进行注射,或可通过连续输注投予。
用于经口投药的固体剂型包括胶囊、片剂、丸剂、散剂和颗粒。在这些固体剂型中,活性化合物与至少一种以下混合:医药学上可接受的惰性赋形剂或载剂,诸如柠檬酸钠或磷酸二钙;和/或a)填充剂或增量剂,诸如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸;b)粘合剂,诸如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和***胶;c)保湿剂,诸如甘油;d)崩解剂,诸如琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶解延迟剂,诸如石蜡;f)吸收促进剂,诸如季铵化合物;g)润湿剂,诸如十六烷醇和单硬脂酸甘油酯;h)吸收剂,诸如高岭土和膨润土;和i)润滑剂,诸如滑石粉、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠和其混合物。在胶囊、片剂和丸剂的情况下,剂型还可包含缓冲剂,诸如磷酸盐或碳酸盐。
也可使用相似类型的固体组合物作为使用诸如乳糖(lactose/milk sugar)以及高分子量聚乙二醇等的赋形剂的软质和硬质填充明胶胶囊中的填充剂。片剂、糖衣药丸、胶囊、丸剂和颗粒的固体剂型可用诸如肠溶衣和医药调配技术中熟知的其他包衣等包衣和壳来制备。其可任选含有遮光剂,且也可具有使其仅在或优先在肠道某一部分释放或任选以延迟方式释放活性成分的组成。可使用的包埋组合物的实例包括聚合物和蜡。也可使用相似类型的固体组合物作为使用诸如乳糖(lactose/milk sugar)以及高分子量聚乙二醇等的赋形剂的软质和硬质填充明胶胶囊中的填充剂。
活性化合物也可用一种或一种以上上述赋形剂制备为微囊封形式。片剂、糖衣药丸、胶囊、丸剂和颗粒的固体剂型可用诸如肠溶衣、释放控制包衣和医药调配技术中熟知的其他包衣等包衣和壳来制备。在这些固体剂型中,活性化合物可与至少一种诸如蔗糖、乳糖或淀粉等惰性稀释剂混合。正常实施时,这些剂型还可包含除惰性稀释剂以外的其他物质,例如压片润滑剂以及其他压片助剂,诸如硬脂酸镁和微晶纤维素。在胶囊、片剂和丸剂的情况下,这些剂型还可包含缓冲剂。其可任选含有遮光剂,且也可具有仅在或优先在肠道某一部分释放或任选以延迟方式释放活性成分的组成。可使用的包埋组合物的实例包括聚合物和蜡。
用于局部或经皮投予本发明化合物的剂型包括软膏、糊剂、乳霜、洗剂、凝胶、散剂、溶液、喷雾、吸入剂或贴片。在无菌条件下将活性组分与医药学上可接受的载剂和任何所需防腐剂或缓冲剂按要求混合。还预期眼用调配物、滴耳剂和滴眼剂处于本发明的范围内。此外,本发明涵盖使用经皮贴片,其具有提供化合物向身体的控制传递的额外优点。这些剂型可通过将化合物溶解或分散于适当介质中来制备。也可使用吸收增强剂来增加化合物穿过皮肤的流量。速率可通过提供速率控制膜或将化合物分散于聚合物基质或凝胶中来控制。
在一些实施例中,式(I)化合物是静脉内投予。在一些所述实施例中,如全文以引用的方式并入本文中的普拉芒顿(Plamondon)等人的WO 02/059131中所述,Z1和Z2一起形成衍生自硼酸络合剂的部分的式(I)化合物可制备成冻干粉末形式。在一些实施例中,冻干粉末还包含自由硼酸络合剂。优选的是,自由硼酸络合剂和式(I)化合物以约0.5∶1至约100∶1、更优选约5∶1至约100∶1范围内的摩尔比存在于混合物中。在各种实施例中,冻干粉末包含摩尔比在约10∶1至约100∶1、约20∶1至约100∶1或约40∶1至100∶1范围内的自由硼酸络合剂与相应硼酸酯。
在一些实施例中,冻干粉末包含硼酸络合剂和式(I)化合物,实质上不含其他组分。然而,组合物还可包含一种或一种以上其他医药学上可接受的赋形剂、载剂、稀释剂、填充剂、盐、缓冲剂、增积剂、稳定剂、增溶剂和所属领域中熟知的其他物质。含有这些物质的医药学上可接受的调配物的制备描述于例如雷明顿:医药科学和实践(Remington:The Science and Practice of Pharmacy),第20版,A.根纳罗(A.Gennaro)编,利平科特威廉姆斯和维尔金斯出版社(Lippincott Williams & Wilkins),2000或最新版本中。在一些实施例中,医药组合物包含式(I)化合物、增积剂和缓冲剂。
包含式(I)化合物的冻干粉末可根据描述于普拉芒顿(Plamondon)等人的WO 02/059131中的程序制备。因此,在一些实施例中,制备冻干粉末的方法包含:(a)制备包含式(I)硼酸化合物(其中Z1和Z2各自为羟基)和硼酸络合剂的水性混合物;和(b)冻干所述混合物。
冻干粉末优选通过添加适于医药投药的水性溶剂进行复原。合适复原溶剂的实例包括(但不限于)水、盐水和磷酸盐缓冲盐水(PBS)。优选以生理(0.9%)盐水复原冻干粉末。复原后,在硼酸酯化合物与相应自由硼酸化合物之间建立平衡。在一些实施例中,平衡在添加水性介质后例如10-15分钟内快速达成。平衡时存在的硼酸酯和硼酸的相对浓度取决于诸如溶液pH值、温度、硼酸络合剂的性质和冻干粉末中存在的硼酸络合剂与硼酸酯化合物的比率等参数。
本发明的医药组合物优选经调配用于投予患有蛋白酶体介导的病症或有发展所述病症的风险或经历所述病症的复发的患者。如本文所用的术语“患者”意谓动物,优选为哺乳动物,更优选为人类。本发明的优选医药组合物为调配用于经口、静脉内或皮下投药的医药组合物。然而,含有治疗有效量的本发明化合物的任何上述剂型均完全在常规试验的范围内,且因此也完全在本发明的范围内。在一些实施例中,本发明的医药组合物还可包含另一治疗剂。在一些实施例中,所述另一治疗剂为通常投予患有所治疗疾病或病状的患者的治疗剂。
“治疗有效量”意谓足以引起蛋白酶体活性或蛋白酶体介导的病症的严重程度发生可检测到的降低的量。所需蛋白酶体抑制剂的量将取决于抑制剂对于指定细胞类型的有效性和治疗所述病症所需的时间长度。还应了解,用于任何特定患者的具体剂量和治疗方案将视多种因素而定,包括所用具体化合物的活性、患者的年龄、体重、一般健康状况、性别和饮食、投药时间、***率、药物组合和治疗医师的判断,和所治疗的特定疾病的严重程度。本发明组合物中存在的其他治疗剂的量通常将不超过利用仅包含所述治疗剂作为唯一活性剂的组合物通常所投予的量。优选的是,其他治疗剂的量将在通常存在于包含所述药剂作为唯一治疗活性剂的组合物中的量的约50%至约100%范围内。
在另一方面中,本发明提供一种治疗患有蛋白酶体介导的病症或有发展所述病症的风险或经历所述病症复发的患者的方法。如本文所用的术语“蛋白酶体介导的病症”包括由蛋白酶体表达或活性增加所导致或以蛋白酶体表达或活性增加为特征,或需要蛋白酶体活性的任何病症、疾病或病状。术语“蛋白酶体介导的病症”也包括抑制蛋白酶体活性有益的任何病症、疾病或病状。
举例来说,本发明的化合物和医药组合物适用于治疗通过受蛋白酶体活性调节的蛋白质(例如NFκB、p27Kip、p21WAF/CIP1、p53)介导的病症。相关病症包括发炎性病症(例如类风湿性关节炎、发炎性肠病、哮喘、慢性阻塞性肺病(COPD)、骨关节炎、皮肤病(例如异位性皮肤炎、牛皮癣))、血管增生性病症(例如动脉粥样硬化、再狭窄)、增生性眼部病症(例如糖尿病性视网膜病)、良性增生性病症(例如血管瘤)、自体免疫性疾病(例如多发性硬化症、组织和器官排斥反应)以及感染相关性炎症(例如免疫反应)、神经退化性病症(例如阿尔茨海默氏病(Alzheimer′s disease)、帕金森氏病(Parkinson′s disease)、运动神经元疾病、神经性疼痛、三体重复病症、星形细胞瘤和酒精性肝病导致的神经退化)、缺血性损伤(例如中风)和恶质症(例如伴随各种生理和病理病况(例如神经损伤、禁食、发烧、酸中毒、HIV感染、癌症痛苦和某些内分泌病)的肌肉蛋白质分解加速)。
本发明的化合物和医药组合物尤其适用于治疗癌症。如本文所用的术语“癌症”是指一种细胞性病症,其特征为细胞增殖失控或不受调节、细胞分化减少、具有侵入周围组织的不当能力和/或在异位建立新生长的能力。术语“癌症”包括(但不限于)实体肿瘤和血液肿瘤。术语“癌症”涵盖皮肤、组织、器官、骨、软骨、血液和血管的疾病。术语“癌症”还涵盖原发性和转移性癌症。
各种蛋白酶体抑制剂之间的酶动力学(即解离半衰期)的差异可导致各种抑制剂的组织分布的差异,所述差异可导致安全性和功效曲线的差异。举例来说,在使用缓慢可逆和不可逆抑制剂时,相当大比例的分子可与红血球、血管内皮和诸如肝等充分灌注器官中的蛋白酶体(即最近区室中的最“可立即利用的”蛋白酶体)结合。这些部位可有效充当这些药剂迅速结合分子且影响实体肿瘤中的分布的“接收器(sink)”。
不希望受理论束缚,本发明者相信更迅速与蛋白酶体解离的化合物会更有效地分布至肿瘤,从而产生改良的抗肿瘤活性。在一些实施例中,本发明涉及一种治疗患有癌症的患者的方法,其包含向患者投予式(I)、(I-A)、(I-B)或(II)中任一者的化合物,其中所述化合物显示小于60分钟的解离半衰期。在一些实施例中,所述化合物显示小于10分钟的解离半衰期。
可用所揭示蛋白酶体抑制剂治疗的实体肿瘤的非限制性实例包括:胰腺癌;膀胱癌;结肠直肠癌;乳癌,包括转移性乳癌;***癌,包括雄激素依赖性***癌和雄激素非依赖性***癌;肾癌,包括例如转移性肾细胞癌;肝细胞癌;肺癌,包括例如非小细胞肺癌(NSCLC)、细支气管肺泡癌(BAC)和肺腺癌;卵巢癌,包括例如进行性上皮性或原发性腹膜性癌;子***;胃癌;食道癌;头颈癌,包括例如头颈部的鳞状细胞癌;黑色素瘤;神经内分泌癌,包括转移性神经内分泌肿瘤;脑肿瘤,包括例如神经胶质瘤、退行性寡树突神经胶细胞瘤、成人多形性成胶质细胞瘤和成人退行性星形细胞瘤;骨癌;和软组织肉瘤。
可用所揭示蛋白酶体抑制剂治疗的血液科恶性疾病的非限制性实例包括:急性骨髓性白血病(AML);慢性骨髓性白血病(CML),包括加速CML和CML急变期(CML-BP);急性成淋巴细胞性白血病(ALL);慢性成淋巴细胞性白血病(CLL);霍奇金病(Hodgkin′s disease,HD);非霍奇金淋巴瘤(non-Hodgkin′s lymphoma,NHL),包括滤泡性淋巴瘤和套细胞淋巴瘤;B细胞淋巴瘤;T细胞淋巴瘤;多发性骨髓瘤(MM);瓦尔登斯特伦巨球蛋白血症(Waldenstrom′s macroglobulinemia);骨髓发育不良综合症(MDS),包括难治性贫血(RA)、难治性贫血伴有环形铁粒幼细胞(RARS)、难治性贫血伴有胚细胞增多(RAEB)和转化中的RAEB(RAEB-T);和骨髓增生综合症。
在一些实施例中,使用本发明的化合物或组合物来治疗患有选自由多发性骨髓瘤和套细胞淋巴瘤组成的群组的癌症或有发展所述癌症的风险或经历所述癌症的复发的患者。
在一些实施例中,本发明的蛋白酶体抑制剂可结合另一治疗剂投予。另一治疗剂也可抑制蛋白酶体,或可通过不同机制起作用。在一些实施例中,另一治疗剂为通常向患有所治疗疾病或病状的患者投予的治疗剂。本发明的蛋白酶体抑制剂可与另一治疗剂以单一剂型或以分开的剂型投予。当以分开的剂型投予时,另一治疗剂可在投予本发明的蛋白酶体抑制剂之前、同时或之后投予。
在一些实施例中,式(I)的蛋白酶体抑制剂结合抗癌剂投予。如本文所用的术语“抗癌剂”是指出于治疗癌症的目的投予患有癌症的个体的任何药剂。
损伤DNA的化学治疗剂的非限制性实例包括:拓扑异构酶I抑制剂(例如伊立替康(irinotecan)、拓朴替康(topotecan)、喜树碱(camptothecin)和其类似物或代谢物,和阿霉素(doxorubicin));拓扑异构酶II抑制剂(例如依托泊苷(etoposide)、替尼泊苷(teniposide)和道诺霉素(daunorubicin));烷化剂(例如美法仑(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、硫替派(thiotepa)、异环磷酰胺(ifosfamide)、亚硝脲氮芥(carmustine)、洛莫司汀(lomustine)、司莫司汀(semustine)、链脲霉素(streptozocin)、达卡巴肼(decarbazine)、甲胺蝶呤(methotrexate)、丝裂霉素C(mitomycin C)和环磷酰胺(cyclophosphamide));DNA***剂(例如顺铂(cisplatin)、奥赛力铂(oxaliplatin)和卡铂(carboplatin));DNA***剂和自由基产生剂,诸如博莱霉素(bleomycin);和核苷模拟剂(例如5-氟尿嘧啶(5-fluorouracil)、截瘤达(capecitibine)、吉西他滨(gemcitabine)、氟达拉宾(fludarabine)、阿糖胞苷(cytarabine)、巯基嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine)、喷司他汀(pentostatin)和羟基脲(hydroxyurea))。
干扰细胞复制的化学治疗剂包括:太平洋紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)和相关类似物;长春新碱(vincristine)、长春碱(vinblastin)和相关类似物;沙立度胺(thalidomide)、来那度胺(lenalidomide)和相关类似物(例如CC-5013和CC-4047);蛋白质酪氨酸激酶抑制剂(例如甲磺酸伊玛替尼(imatinib mesylate)和吉非替尼(gefitinib));蛋白酶体抑制剂(例如硼替左米(bortezomib));NF-κB抑制剂,包括IκB激酶的抑制剂;与癌症中过度表达的蛋白质结合且从而下调细胞复制的抗体(例如曲妥珠单抗(trastuzumab)、利妥昔单抗(rituximab)、西妥昔单抗(cetuximab)和贝伐单抗(bevacizumab));和已知在癌症中上调、过度表达或活化的蛋白质或酶的其他抑制剂,其中抑制这些蛋白质或酶下调细胞复制。
具体实施方式
为更充分理解本发明,阐述以下制备和测试实例。这些实例说明如何制备或测试具体化合物,而不应以任何方式解释为限制本发明的范围。
实例
分析型LC-MS方法
LCMS条件
以Waters Symmetry 3.5μm C18 6×100mm ID管柱使用以下梯度对硼酸进行分析:
溶剂A:1%乙腈,99%水,0.1%甲酸
溶剂B:95%乙腈,5%水,0.1%甲酸
时间 | A[%] | B[%] | 流速[ml/min] |
0.0 | 95.0 | 5.0 | 1.0 |
7.5 | 0.0 | 100.0 | 1.0 |
9.8 | 0.0 | 100.0 | 1.0 |
9.8 | 95.0 | 5.0 | 1.0 |
10.0 | 95.0 | 5.0 | 1.0 |
中间物的光谱以Hewlett-Packard HP1100使用以下条件进行:
甲酸:Phenominex Luna 5μm C1850×4.6mm管柱,流速2.5mL/min,梯度为3分钟内于H2O中的含有0至100%0.1%甲酸的ACN。
乙酸铵:Phenominex Luna 5μm C18 50×4.6mm管柱,流速2.6mL/min,梯度为3分钟内于H2O中的含有0至100%10mM乙酸铵的ACN。
实例1:(1R)-2-环丁基-1-[(3aS,4S,6S)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙胺·C2HO2F3(中间物4)
步骤1:(3aS,4S,6S)-2-(二氯甲基)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧
硼戊环(中间物1)
在N2下,在-80℃至-90℃下向CH2Cl2(80mL,1.2mol)于THF(800mL)中的溶液中添加正丁基锂(于己烷中2.5M,480mL,1.2mol),且在-80℃以下搅拌反应混合物1.5小时。以整份添加B(OEt)3(200mL,1.2mol),且在-45℃至-30℃下搅拌混合物1小时。随后在低于-20℃的温度下逐滴添加HCl水溶液(5M,240mL,1.2mol),且在-20℃下搅拌所得混合物4小时。分离有机层且以Et2O(100mL×2)萃取水层。合并的有机层经无水Na2SO4干燥且浓缩得到中间物。将中间物再溶解于Et2O(800mL)中,且向所述溶液中添加蒎烷二醇(188g,1.1mol)。在室温下搅拌反应混合物过夜且随后在真空中浓缩。通过管柱色谱(石油醚∶乙酸乙酯=10∶1至1∶1)纯化残余物得到中间物1(190g,60%产率)。
步骤2:(3aS,4S,6S)-2-[(1S)-1-氯-2-环丁基乙基]-3a,5,5-三甲基六氢-4,6-亚甲基
-1,3,2-苯并二氧硼戊环(中间物2)
在N2下,向含Mg(13.60g,560mmol)的THF(650mL)中添加DIBAL(于甲苯中1M,9.1mL,9.1mmol),且在室温下搅拌混合物30分钟。随后在低于40℃下逐滴添加中间物2(40.6mL,360mmol),且在室温下搅拌反应混合物2.5小时。冷却至-78℃后,在N2保护下在-78℃下将溶液转移至中间物1(70g,0.267mol)于THF(400mL)中的溶液中,且搅拌所得混合物45分钟。随后以整份添加ZnCl2(于Et2O中1M,750mL,750mmol),使混合物升温至室温并搅拌过夜。向反应混合物中添加乙酸乙酯(800mL)和饱和NH4Cl(350mL),搅拌混合物1小时且以水(300mL)、盐水(300mL)洗涤有机层,经无水Na2SO4干燥并浓缩。通过管柱色谱(石油醚∶乙酸乙酯=20∶1至2∶1)纯化残余物得到呈无色油状的中间物2(65g,82%产率)。
步骤3:N-{(1R)-2-环丁基-1-[(3aS,4S,6S)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯
并二氧硼戊环-2-基]乙基}-1,1,1-三甲基-N-(三甲基硅烷基)硅烷胺
(中间物3)
在N2保护下,在-78℃下向LiHMDS(于THF中1M,500mL,0.5mol)于THF(500mL)中的溶液中添加中间物2(130g,0.438mol)于THF(700mL)中的溶液。使反应混合物升温至室温并搅拌过夜。通过旋转蒸发移除溶剂且以1.0L Et2O/Hex(1∶1)溶解残余物。通过硅胶(300g)垫过滤溶液并以500mL Et2O/Hex(1∶1)洗涤。浓缩溶液得到呈无色油状的中间物3(166g,90%)。
步骤4:(1R)-2-环丁基-1-[(3aS,4S,6S)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二
氧硼戊环-2-基]乙胺·C
2
HO
2
F
3
(中间物4)
在-45℃下,向中间物3(166g,0.39mol)于Et2O(1.5L)中的溶液中添加TFA(92mL,1.2mol)于Et2O(500mL)中的溶液。使混合物升温至室温且搅拌1小时。通过过滤收集沈淀物且以Et2O(200mL×3)洗涤得到呈白色固体状的中间物4(103g,71%产率)。
实例2:{(1R)-1-[((2S)-2-{[(2S)-2-(乙酰基氨基)-4-苯基丁酰基]氨基}-3-苯基丙酰基)氨基]-2-环丁基乙基}硼酸(22)
步骤1:[(1S)-1-苯甲基-2-({(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢
-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}氨基)-2-侧氧基乙基]氨基甲酸叔丁酯
向单颈圆底烧瓶中添加中间物4(496mg,1.26mmol)N-(叔丁氧羰基)-L-苯丙氨酸(0.362g,1.36mmol)、TBTU(0.640g,1.99mmol)和N,N-二甲基甲酰胺(10.0mL,0.129mol)。随后在-45℃下逐滴添加N,N-二异丙基乙胺(1.12mL,6.40mmol)。20分钟后移除冷却浴,且在室温下搅拌混合物过夜。使反应混合物在乙酸乙酯与水之间分配,随后以3×100mL水和3×100mL盐水洗涤有机层。有机层经硫酸钠干燥且在真空中移除溶剂。通过40%EA/hex中的管柱色谱纯化所得残余物得到0.55g(84%产率)呈灰白色固体状的产物。
步骤2:(2S)-2-氨基-N-{(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-
亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}-3-苯基丙酰胺·HCl
向单颈圆底烧瓶中添加[(1S)-1-苯甲基-2-({(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}氨基)-2-侧氧基乙基]氨基甲酸叔丁酯(0.550g,1.05mmol)、二氯甲烷(6.00mL,0.0936mol)和4.0M盐酸的1,4-二恶烷溶液(6.00mL,0.024mol)。在室温下搅拌混合物30分钟。在真空中移除溶剂和HCl得到0.517g(99%产率)呈白色固体状的所要产物。
步骤3:[(1S)-1-({[(1S)-1-苯甲基-2-({(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三
甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}氨基)-2-侧氧基乙基]氨基}羰
基)-3-苯基丙基]氨基甲酸叔丁酯
在室温下向单颈圆底烧瓶中相继逐滴添加(2S)-2-氨基-N-{(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}-3-苯基丙酰胺(217mg,0.511mmol)、Boc-homophe-OH(171mg,0.614mmol)、TBTU(246mg,0.767mmol)和N,N-二甲基甲酰胺(14.5mL,0.187mol),随后添加N,N-二异丙基乙胺(0.187mL,1.07mmol)。在室温下搅拌混合物过夜。在真空下自反应混合物移除DMF,且将所得残余物通过制备型TLC于40%EtOAc/己烷中纯化得到298mg(85%产率)呈白色固体状的所要产物。
步骤4:(2S)-2-氨基-N-[(1S)-1-苯甲基-2-({(1R)-2-环丁基
-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}氨
基)-2-侧氧基乙基]-4-苯基丁酰胺·HCl
向单颈圆底烧瓶中相继添加[(1S)-1-({[(1S)-1-苯甲基-2-({(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}氨基)-2-侧氧基乙基]氨基}羰基)-3-苯基丙基]氨基甲酸叔丁酯(298mg,0.000434mol)、二氯甲烷(3.0mL,0.047mol)和4.0M盐酸的1,4-二恶烷溶液(3.0mL,0.012mol)。在室温下搅拌混合物30分钟,随后在真空中移除溶剂得到0.243g(90%产率)所要产物。
步骤5:(2S)-2-(乙酰基氨基)-N-[(1S)-1-苯甲基-2-({(1R)-2-环丁基
-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}氨
基)-2-侧氧基乙基]-4-苯基丁酰胺
向20mL闪烁瓶中添加(2S)-2-氨基-N-[(1S)-1-苯甲基-2-({(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}氨基)-2-侧氧基乙基]-4-苯基丁酰胺·HCl(52.0mg,0.0836mmol)、乙腈(5.20mL,0.0996mol)、乙酸酐(8.68μL,0.092mmol)、N,N-二异丙基乙胺(36.4μL,0.209mmol)和N,N-二甲基氨基吡啶(0.0005g,0.004mmol)。搅拌混合物过夜,并过滤沈淀物且以Et2O洗涤得到0.028g(53%产率)呈白色固体状的产物。
步骤6:{(1R)-1-[((2S)-2-{[(2S)-2-(乙酰基氨基)-4-苯基丁酰基]氨基}-3-苯基丙酰
基)氨基]-2-环丁基乙基}硼酸
向单颈圆底烧瓶中添加(2S)-2-(乙酰基氨基)-N-[(1S)-1-苯甲基-2-({(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}氨基)-2-侧氧基乙基]-4-苯基丁酰胺(24.8mg,0.0395mmol)、甲醇(0.237mL,5.86mmol)、己烷(0.237mL,1.81mmol)、盐酸(0.0889mmol,0.0889mmol)和2-甲基丙基硼酸(8.65mg,0.0849mmol)。在室温下搅拌混合物过夜。通过制备型TLC于10%MeOH/CH2Cl2中纯化反应混合物得到9.90mg(51%产率)呈白色固体状的所要产物。1H NMR(CD3OD,300MHz,δ):7.32-7.12(m,10H);4.74(t,J=7.94Hz,1H);4.26(dd,J=5.49,8.55Hz,1H);3.14-3.05(m,2H);2.66-2.55(m,2H);2.48-2.41(m,1H);2.19-2.05(m,1H);2.04-1.89(m,8H);1.89-1.69(m,3H);1.58-1.36(m,3H);1.33-1.22(m,1H)。
实例3:{(1R)-1-[((2S)-2-{[(2S)-2-(乙酰基氨基)-4-苯基丁酰基]氨基}-3-苯基丙酰基)氨基]-2-环丁基乙基}硼酸的D-甘露糖醇酯
向上述产物{(1R)-1-[((2S)-2-{[(2S)-2-(乙酰基氨基)-4-苯基丁酰基]氨基}-3-苯基丙酰基)氨基]-2-环丁基乙基}硼酸(9.90mg,0.0201mmol)中添加叔丁醇(1.21mL,0.0127mol)、水(1.21mL,0.0672mol)和D-甘露糖醇(72.0mg,0.395mmol)。将溶液在-78℃下冷冻,并置于冷冻干燥机上40小时得到80.1mg(97%产率)白色粉末。
实例4:其他N-酰基-肽基硼酸化合物
通过类似于上文实例1-2中描述的程序制备下列硼酸化合物。如实例3中所述将所有化合物也转化为相应D-甘露糖醇酯。
实例5:{(1R)-2-环丁基-1-[((2S)-2-{[(6-苯氧基吡啶-3-基)磺酰基]氨基}-3-苯基丙酰基)氨基]乙基}硼酸(11)
步骤1:(2S)-N-{(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基
-1,3,2-苯并二氧硼戊环-2-基]乙基}-2-{[(6-苯氧基吡啶-3-基)磺酰基]氨基}-3-苯基丙酰胺
向20mL小瓶中添加(2S)-2-氨基-N-{(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}-3-苯基丙酰胺·HCl(46.3mg,0.109mmol)(如实例中所述制备)、THF(1.47mL)、N,N-二异丙基乙胺(47.5μL)和6-苯氧基-3-吡啶磺酰氯(32.4mg)。在室温下搅拌混合物过夜。通过制备型TLC于硅石板上使用含50%乙酸乙酯的己烷纯化产物得到35mg呈白色固体状的所要产物。
步骤2:{(1R)-2-环丁基-1-[((2S)-2-{[(6-苯氧基吡啶-3-基)磺酰基]氨基}-3-苯基丙
酰基)氨基]乙基}硼酸
向20mL小瓶中添加(2S)-N-{(1R)-2-环丁基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼戊环-2-基]乙基}-2-{[(6-苯氧基吡啶-3-基)磺酰基]氨基}-3-苯基丙酰胺(31.2mg,0.047mmol)、(2-甲基丙基)硼酸(10.4mg)、1N盐酸(0.107mmol)、甲醇(0.285mL)和己烷(0.285mL)。在室温下搅拌混合物过夜,随后分离己烷层并丢弃。在真空中移除残余溶剂,并通过制备型TLC于硅石板上使用含10%MeOH的CH2Cl2纯化产物得到18.4mg(74%产率)呈白色固体状的所要产物。1H NMR(CD3OD,300MHz,δ):8.36(s,1H);7.95-7.84(m,1H);7.52-7.39(m,2H);7.33-7.06(m,10H);6.95-6.83(m,1H);4.25-4.13(m,1H);3.09-2.94(m,1H);2.93-2.78(m,1H);2.46-2.32(m,1H);2.26-1.93(m,3H);1.92-1.71(m,2H);1.64-1.37(m,3H);1.37-1.22(m,1H)。
实例6:{(1R)-2-环丁基-1-[((2S)-2-{[(6-苯氧基吡啶-3-基)磺酰基]氨基}-3-苯基丙酰基)氨基]乙基}硼酸的D-甘露糖醇酯
向上述产物{(1R)-2-环丁基-1-[((2S)-2-{[(6-苯氧基吡啶-3-基)磺酰基]氨基}-3-苯基丙酰基)氨基]乙基}硼酸(18.4mg,0.0352mmol)中添加叔丁醇(2.12mL,0.0222mol)、水(2.12mL,0.118mol)和甘露糖醇-D(127mg,0.697mmol)。将溶液在-78℃下冷冻,并置于冷冻干燥机上40小时。获得142.6mg(97%产率)呈白色粉末状的所得{(1R)-2-环丁基-1-[((2S)-2-{[(6-苯氧基吡啶-3-基)磺酰基]氨基}-3-苯基丙酰基)氨基]乙基}硼酸·20[C6H14O6]。
实例7:其他N-磺酰基-肽基硼酸化合物
通过类似于上文实例5中描述的程序制备下列化合物。将所有化合物也转化为相应D-甘露糖醇酯。
实例8:20S蛋白酶体分析
向384孔黑色微孔滴定板中的1μL溶解于DMSO中的测试化合物中添加25μL含有人类PA28活化剂(博斯腾生化公司(Boston Biochem),最终12nM)与Ac-WLA-AMC(β5选择性底物)(最终15μM)的37℃分析缓冲液,随后添加25μL含有人类20S蛋白酶体(博斯腾生化公司(Boston Biochem),最终0.25nM)的37℃分析缓冲液。分析缓冲液由20mM HEPES、0.5mM EDTA和0.01%BSA(pH7.4)构成。随后将反应置于BMG Galaxy板读取器(37℃,激发380nm,发射460nm,增益20)上。相对于0%抑制(DMSO)和100%抑制(10μM硼替左米)对照组计算出抑制百分比。
在此分析中测试化合物1-24和29-32和化合物34-48。在此分析中,化合物1-9、11-14、16-32、34-41、43-45和48显示IC50值小于50nM。在此分析中,化合物10、15、42、46和47显示IC50值大于50nM且小于150nM。
实例9:蛋白酶体抑制动力学
包括解离常数和半衰期在内的酶动力参数通过如下对酶进程曲线进行分析来测定:
通过监测位点特异性的经荧光7-酰胺基-4-甲基香豆素(AMC)-标记的肽底物(β5,Suc-LLVY-AMC;β2,Z-VLR-AMC,和β1,Z-LLE-AMC)在不同抑制剂浓度下水解的个别进程曲线获得蛋白酶体去活化测量值。根据460nm(λex=360nm)下荧光发射的变化连续监测荧光肽的裂解并作为时间的函数绘图。所有分析在37±0.2℃下在具有2mL 50mM HEPES(pH 7.5)、0.5mM EDTA的比色杯中进行,并伴随连续搅拌。底物浓度自10至25μM(<1/2KM)不等。人类20S蛋白酶体的浓度为0.25nM且以0.01%SDS活化。描述自初始速度至稳态速度的转变的速率常数kobs通过使用时间相关性或缓慢结合抑制的等式对个别进程曲线进行非线性最小平方回归分析来估算:
其中F为荧光,vi和vs为抑制剂存在下反应的初始和稳态速度,且t为时间。由线性拟合数据的斜率获得与[I]相关的kobs的曲线图以获得kon。表观解离常数Kapp i通过与[I]相关的分数速度vs/vo的非线性最小拟合确定,其中vs为由随时间相关性或缓慢结合等式获得的稳态值且vo为无抑制剂存在下的初始速度:
解离常数Ki由表观Ki利用以下表达式计算:
解离速率koff由上述确定参数使用以下关系式以数学方法计算:
随后由koff值使用以下关系式确定半衰期:
使用此方案,确定化合物1、2、6、17、20、35、36、41、43和45的解离半衰期。化合物1、20、35、36、41、43和45显示t1/2小于10分钟。化合物2、6和17显示T1/2大于10分钟且小于60分钟。
实例10:抗增殖分析
将于100μL补充有10%胎牛血清(英杰公司(Invitrogen))的适当细胞培养基(对于HCT-116为McCoy′s 5A,英杰公司(Invitrogen))中的HCT-116(1000)或其他肿瘤细胞接种于96孔细胞培养板的孔中,并在37℃下培育过夜。添加测试化合物至孔中并将板在37℃下培育96小时。向各孔中添加MTT或WST试剂(10μL,罗氏公司(Roche)),并按制造商所述在37℃下培育4小时。对于MTT,根据制造商说明书(罗氏公司(Roche))将经代谢的染料溶解过夜。使用分光光度计(分子设备公司(Molecular Devices))在595nm(主波长)和690nm(参考波长)下(对于MTT)和在450nm下(对于WST)读取各孔的光学密度。对于MTT,自主波长的值中减去参考光学密度值。使用设定为100%的DMSO对照组的值来计算抑制百分比。
实例11:活体内肿瘤功效模型
使用1mL 263/8号针(贝克顿迪金森公司(Becton Dickinson)参考编号309625)将于100μL RPMI-1640培养基(西格玛阿尔德里希公司(Sigma-Aldrich))中的新鲜解离的HCT-116(2-5×106)、WSU-DLCL2(2-5×106)或其他肿瘤细胞无菌注射至雌性CD-1裸小鼠(5-8周龄,查理斯河(Charles River))右背侧的皮下间隙内。或者,一些异种移植模型(例如CWR22)需要肿瘤片段连续继代。在此情况下,将肿瘤组织的较小片段(约1mm3)通过13号套针(波普父子公司(Popper&Sons)7927)植入经麻醉(3-5%异氟烷(isoflourane)/氧混合物)C.B-17/SCID小鼠(5-8周龄,查理斯河(Charles River))的右背侧皮下。在接种肿瘤后第7天开始使用游标卡尺一周测量两次。使用标准程序(0.5×(长度×宽度2))计算肿瘤体积。当肿瘤达到约200mm3的体积时,将小鼠随机分成治疗组并开始接受药物治疗。基于先前自药物动力学/药效学和最大耐受剂量研究获得的结果确定每次实验的剂量和时程。对照组将接受不含任何药物的媒剂。通常,以不同剂量和时程通过静脉内(27号针)、经口(20号管饲针)或皮下(27号针)途径投予测试化合物(100-200μL)。每周两次测量肿瘤尺寸和体重,且当对照肿瘤达到约2000mm3时结束研究。
尽管前文已出于清晰性和理解的目在一定程度上详细地描述了本发明,但认为这些特定实施例仅具说明性而不具限制性。所属领域的技术人员阅读本揭示案后将了解,可在不脱离本发明真实范围下对形式和细节作出各种改变,所述真实范围将由附随权利要求书而非特定实施例界定。
本文参考的专利和科技文献确定所属领域的技术人员可获得的知识。除非另有定义,否则本文所用的所有技术和科学术语具有与本发明所属领域中的一般技术人员所通常了解相同的含义。本文引用的颁予的专利、申请案和参考文献以引用的方式并入本文中,程度仿佛特别且个别地指出各自以引用的方式并入一般。在矛盾的情况下,将以本揭示案(包括定义)为主。
Claims (16)
1.一种式(I)化合物,
或其医药学上可接受的盐或硼酸酐,其中:
A为0、1或2;
P为氢或氨基封端部分;
Ra1为C1-6脂肪族基、C1-6氟脂肪族基、-(CH2)m-CH2-RB、-(CH2)m-CH2-NHC(=NR4)NH-Y、-(CH2)m-CH2-CON(R4)2、-(CH2)m-CH2-N(R4)CON(R4)2、-(CH2)m-CH(R6)N(R4)2、-(CH2)m-CH(R5)-OR5或-(CH2)m-CH(R5)-SR5;
各Ra2独立地为氢、C1-6脂肪族基、C1-6氟脂肪族基、-(CH2)m-CH2-RB、-(CH2)m-CH2-NHC(=NR4)NH-Y、-(CH2)m-CH2-CON(R4)2、-(CH2)m-CH2-N(R4)CON(R4)2、-(CH2)m-CH(R6)N(R4)2、-(CH2)m-CH(R5)-OR5或-(CH2)m-CH(R5)-SR5;
各Y独立地为氢、-CN、-NO2或-S(O)2-R10;
各RB独立地为经取代或未经取代的单环或双环***;
各R4独立地为氢或经取代或未经取代的脂肪族基、芳基、杂芳基或杂环基;或同一氮原子上的两个R4连同所述氮原子一起形成除所述氮原子外还具有0-2个独立地选自N、O和S的环杂原子的经取代或未经取代的4至8元杂环基环;
各R5独立地为氢或经取代或未经取代的脂肪族基、芳基、杂芳基或杂环基;
各R6独立地为经取代或未经取代的脂肪族基、芳基或杂芳基;
各R10独立地为C1-6脂肪族基、C6-10芳基或-N(R4)2;
m为0、1或2;
Z1和Z2各自独立地为羟基、烷氧基、芳氧基或芳烷氧基;或Z1与Z2一起形成衍生自硼酸络合剂的部分。
2.根据权利要求1所述的化合物,其中P为Rc-C(O)-、Rc-O-C(O)-、Rc-N(R4c)-C(O)-、Rc-S(O)2-或Rc-N(R4c)-S(O)2-;
Rc选自由C1-6脂肪族基、C1-6氟脂肪族基、-RD、-T1-RD和-T1-R2c组成的群组;
T1为经0-2个独立选择的R3a或R3b取代的C1-6亚烷基链,其中所述亚烷基链任选杂有-C(R5)=C(R5)-、-C≡C-或-O-;
RD为经取代或未经取代的单环或双环***;
R2c为卤基、-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-NR4CO2R6、-N(R4)SO2R6、-N(R4)SO2N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5或-C(O)N(R4)2;
各R3a独立地选自由以下组成的群组:-F、-OH、-O(C1-4烷基)、-CN、-N(R4)2、-C(O)(C1-4烷基)、-CO2H、-CO2(C1-4烷基)、-C(O)NH2和-C(O)-NH(C1-4烷基);
各R3b独立地为经R3a或R7取代或未经取代的C1-3脂肪族基;
各R7为经取代或未经取代的芳香族基;且
R4c为氢、C1-4烷基、C1-4氟烷基或C6-10芳(C1-4烷基),其中所述C6-10芳(C1-4烷基)的芳基部分经取代或未经取代。
3.根据权利要求2所述的化合物,其特征为式(I-B):
或其医药学上可接受的盐或硼酸酐。
4.根据权利要求3所述的化合物,其中A为0。
5.根据权利要求3所述的化合物,其中Ra1和Ra2各自独立地为C1-6脂肪族基、C1-6氟脂肪族基或-(CH2)m-CH2-RB,且m为0或1。
6.根据权利要求5所述的化合物,其中RB为经取代或未经取代的苯基。
7.根据权利要求6所述的化合物,其中Ra1为-CH2-RB,且RB为苯基。
8.根据权利要求3所述的化合物,其中Ra1为-(CH2)m-CH(C1-4烷基)-OH。
9.根据权利要求3所述的化合物,其中RD在可取代环碳原子上经0-2个Rd和0-2个R8d取代;
各Rd独立地选自由以下组成的群组:C1-6脂肪族基、C1-6氟脂肪族基、卤基、-R1d、-R2d、-T2-R1d、-T2-R2d,
T2为经0-2个独立选择的R3a或R3b取代的C1-6亚烷基链,其中所述亚烷基链任选杂有-C(R5)=C(R5)-、-C≡C-或-O-;
各R1d独立地为经取代或未经取代的芳基、杂芳基、杂环基或环脂肪族环;
各R2d独立地为-NO2、-CN、-C(R5)=C(R5)2、-C≡C-R5、-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-R6、-NR4CO2R6、-N(R4)SO2R6、-N(R4)SO2N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5、-C(O)N(R4)2、-C(O)N(R4)-OR5、-C(O)N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-N(R4)-C(O)R5或-C(=NR4)-N(R4)2;
各R3a独立地选自由以下组成的群组:-F、-OH、-O(C1-4烷基)、-CN、-N(R4)2、-C(O)(C1-4烷基)、-CO2H、-CO2(C1-4烷基)、-C(O)NH2和-C(O)NH(C1-4烷基);
各R3b独立地为经R3a或R7取代或未经取代的C1-3脂肪族基,或同一个碳原子上的两个取代基R3b连同其所连接的所述碳原子一起形成3至6元环脂肪族环;
各R7独立地为经取代或未经取代的芳基或杂芳基环;
各R8d独立地选自由以下组成的群组:C1-4脂肪族基、C1-4氟脂肪族基、卤基、-OH、-O(C1-4脂肪族基)、-NH2、-NH(C1-4脂肪族基)和-N(C1-4脂肪族基)2;且
RD中的各可取代环氮原子未经取代或经以下取代:-C(O)R5、-C(O)N(R4)2、-CO2R6、-SO2R6、-SO2N(R4)2、C1-4脂肪族基、经取代或未经取代的C6-10芳基或C6-10芳(C1-4)烷基,其中所述C6-10芳(C1-4)烷基的芳基部分经取代或未经取代。
10.根据权利要求3所述的化合物,其中:
RD中的各饱和环碳原子未经取代或经=O、Rd或R8d取代;
RD中的各不饱和环碳原子未经取代或经Rd或R8d取代;
各Rd独立地选自由以下组成的群组:C1-6脂肪族基、C1-6氟脂肪族基、卤基、-R1d、-R2d、-T2-R1d、-T2-R2d,
T2为经0-2个独立选择的R3a或R3b取代的C1-6亚烷基链,其中所述亚烷基链任选杂有-C(R5)=C(R5)-、-C≡C-或-O-;
各R1d独立地为经取代或未经取代的芳基、杂芳基、杂环基或环脂肪族环;
各R2d独立地为-NO2、-CN、-C(R5)=C(R5)2、-C≡C-R5、-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-R6、-NR4CO2R6、-N(R4)SO2R6、-N(R4)SO2N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5、-C(O)N(R4)2、-C(O)N(R4)-OR5、-C(O)N(R4)C(=NR4)-N(R4)2、-N(R4)C(=NR4)-N(R4)-C(O)R5或-C(=NR4)-N(R4)2;
各R3a独立地选自由以下组成的群组:-F、-OH、-O(C1-4烷基)、-CN、-N(R4)2、-C(O)(C1-4烷基)、-CO2H、-CO2(C1-4烷基)、-C(O)NH2和-C(O)NH(C1-4烷基);
各R3b独立地为经R3a或R7取代或未经取代的C1-3脂肪族基,或同一个碳原子上的两个取代基R3b连同其所连接的所述碳原子一起形成3至6元环脂肪族环;
各R7独立地为经取代或未经取代的芳基或杂芳基环;
各R8d独立地选自由以下组成的群组:C1-4脂肪族基、C1-4氟脂肪族基、卤基、-OH、-O(C1-4脂肪族基)、-NH2、-NH(C1-4脂肪族基)和-N(C1-4脂肪族基)2;且RD中的各可取代环氮原子未经取代或经以下取代:-C(O)R5、-C(O)N(R4)2、-CO2R6、-SO2R6、-SO2N(R4)2、C1-4脂肪族基、经取代或未经取代的C6-10芳基或C6-10芳(C1-4)烷基,其中所述C6-10芳(C1-4)烷基的芳基部分经取代或未经取代。
11.根据权利要求7所述的化合物,其中RD为选自由以下组成的群组的经取代或未经取代的单环或双环***:苯基、吡啶基、嘧啶基、吡嗪基、萘基、苯并咪唑基、喹啉基、异喹啉基、喹喔啉基、四氢喹啉基、四氢异喹啉基、四氢喹喔啉基和二氢苯并恶嗪基。
12.根据权利要求7所述的化合物,其特征为式(II):
或其医药学上可接受的盐或硼酸酐,其中:
P具有式RD-SO2-或RD-C(O)-;
RD为选自由以下组成的群组的经取代或未经取代的单环或双环***:苯基、吡啶基、嘧啶基、吡嗪基、萘基、苯并咪唑基、喹啉基、异喹啉基、喹喔啉基、四氢喹啉基、四氢异喹啉基、四氢喹喔啉基和二氢苯并恶嗪基;
RD中的各饱和环碳原子未经取代或经=O、Rd或R8d取代;
RD中的各不饱和环碳原子未经取代或经Rd或R8d取代;
各Rd独立地选自由-R1d、-R2d、-T2-R1d和-T2-R2d组成的群组;
T2为未经取代或经R3a或R3b取代的C1-3亚烷基链;
各R1d独立地为经取代或未经取代的芳基、杂芳基、杂环基或环脂肪族环;
各R2d独立地为-OR5、-SR6、-S(O)R6、-SO2R6、-SO2N(R4)2、-N(R4)2、-NR4C(O)R5、-NR4C(O)N(R4)2、-O-C(O)R5、-OC(O)N(R4)2、-C(O)R5、-CO2R5或-C(O)N(R4)2;且各R8d独立地选自由以下组成的群组:C1-4脂肪族基、C1-4氟脂肪族基、卤基、-OH、-O(C1-4脂肪族基)、-NH2、-NH(C1-4脂肪族基)和-N(C1-4脂肪族基)2。
13.根据权利要求12所述的化合物,其中Rd具有式-Q-RE;
Q为-O-、-NH-或-CH2-;且
RE为经取代或未经取代的芳基、杂芳基、杂环基或环脂肪族环。
14.根据权利要求12所述的化合物,其中RD为经式-O-RE的取代基取代的苯基、吡啶基、吡嗪基或嘧啶基,且RE为经取代或未经取代的苯基、吡啶基、吡嗪基或嘧啶基。
15.一种医药组合物,其包含根据权利要求1所述的化合物和医药学上可接受的载剂。
16.一种治疗癌症的方法,其包含向需要所述治疗的患者投予根据权利要求15所述的医药组合物。
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