CN101772507A - 蛋白酶体抑制剂 - Google Patents
蛋白酶体抑制剂 Download PDFInfo
- Publication number
- CN101772507A CN101772507A CN200780100142A CN200780100142A CN101772507A CN 101772507 A CN101772507 A CN 101772507A CN 200780100142 A CN200780100142 A CN 200780100142A CN 200780100142 A CN200780100142 A CN 200780100142A CN 101772507 A CN101772507 A CN 101772507A
- Authority
- CN
- China
- Prior art keywords
- amino
- boric acid
- ethanoyl
- methyl butyl
- benzoyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 83
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 62
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- C—CHEMISTRY; METALLURGY
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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。本发明还提供含有本发明化合物的药用组合物以及使用所述组合物治疗各种疾病的方法。
Description
技术领域
本发明是关于适用作蛋白酶体抑制剂的硼酸和硼酸酯化合物。本发明还提供含有本发明化合物的药用组合物以及使用所述组合物治疗各种疾病的方法。
背景技术
硼酸和硼酸酯化合物展现各种药学上适用的生物活性。神飞(Shenvi)等人在美国专利第4,499,082号(1985年)中揭示:肽硼酸(peptide boronic acid)是某些蛋白水解酶的抑制剂。克特纳(Kettner)和神飞(Shenvi)在美国专利第5,187,157号(1993年)、美国专利第5,242,904号(1993年)和美国专利第5,250,720号(1993年)中描述了一类抑制胰蛋白酶样蛋白酶的肽硼酸。克里曼(Kleeman)等人在美国专利第5,169,841号(1992年)中揭示了抑制肾素的作用的N-末端修饰肽硼酸。肯达(Kinder)等人在美国专利第5,106,948号(1992年)中揭示了抑制癌细胞生长的某些硼酸化合物。巴乔夫钦(Bachovchin)等人在WO 07/0005991中揭示了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希望成为蛋白酶体(即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)等人在美国专利第5,780,454号(1998年)中描述了适用作蛋白酶体抑制剂的肽硼酸酯和硼酸化合物。此文献还描述了硼酸酯和硼酸化合物降低肌肉蛋白降解率、降低细胞中NF-κB的活性、降低细胞中p53蛋白的降解率、抑制细胞中的细胞周期蛋白(cyclin)降解、抑制癌细胞生长和抑制NF-κB依赖性细胞粘附的用途。孚雷(Furet)等人的WO 02/096933、查特吉(Chatterjee)等人的WO 05/016859以及布拿甸尼(Bernadini)等人的WO 05/021558和WO 06/08660中揭示了据报导具有蛋白酶体抑制活性的其它硼酸酯和硼酸化合物。
西查诺瓦(Ciechanover),细胞(Cell),79:13-21(1994)揭示:蛋白酶体是泛素-蛋白酶体途径的蛋白水解组分,在此途径中蛋白质通过与多个泛素分子结合而被靶向降解。西查诺瓦还揭示:泛素-蛋白酶体途径在各种重要生理过程中起关键作用。李维特(Rivett)等人,生物化学杂志(Biochem.J.)291:1(1993)揭示蛋白酶体展现出胰蛋白酶、胰凝乳蛋白酶和肽基谷氨酰基肽酶活性。构成26S蛋白酶体催化核心的是20S蛋白酶体。麦克马克(McCormack)等人,生物化学(Biochemistry)37:7792(1998)教示了各种肽底物被20S蛋白酶体所分解,所述底物包括Suc-Leu-Leu-Val-Tyr-AMC、Z-Leu-Leu-Arg-AMC和Z-Leu-Leu-Glu-2NA,其中Suc为N-琥珀酰基,AMC为7-氨基-4-甲基香豆素,以及2NA为2-萘胺。
蛋白酶体抑制体现了癌症治疗的一种重要新策略。金(King)等人,科学(Science)274:1652-1659(1996)描述了泛素-蛋白酶体途径在调控细胞周期、肿瘤生长和转移方面的重要作用。作者教示:在细胞周期期间许多关键调控蛋白质(包括细胞周期蛋白和细胞周期蛋白依赖性激酶p21和p27KIP1)通过泛素-蛋白酶体途径而暂时性地被降解。细胞需要这些蛋白质的有序降解以加快细胞周期并进行有丝分裂。
此外,转录调控也需要泛素-蛋白酶体途径。帕罗贝拉(Palombella)等人,细胞(Cell),78:773(1994)教示:转录因子NF-κB的活化受到蛋白酶体介导的抑制蛋白IκB降解的调控。NF-κB又对调控涉及免疫反应和炎症反应的基因起重要作用。瑞德(Read)等人,免疫(Immunity)2:493-506(1995)教示:细胞粘附分子(例如E-选择蛋白、ICAM-1和VCAM-1)的表达需要泛素-蛋白酶体途径。泽特尔(Zetter),癌生物学研究文辑(Seminars in Cancer Biology)4:219-229(1993)教示:细胞粘附分子通过引导肿瘤细胞向体内远处组织位点粘附和外渗以及从脉管系统向体内远处组织位点粘附和外渗而涉及于体内(in vivo)肿瘤转移和血管生成。此外,贝歌(Beg)和巴尔地摩(Baltimore),科学(Science)274:782(1996)教示:NF-κB是一种抗细胞凋亡控制因子,并且对NF-κB活化的抑制使细胞对环境压力和细胞毒性剂更加敏感。
蛋白酶体抑制剂(硼替佐米(bortezomib);N-2-吡嗪羰基-L-苯丙氨酸-L-亮氨酸硼酸)是首个得到监管机构批准的蛋白酶体抑制剂。米斯亚德(Mitsiades)等人,当代药物靶点(Current Drug Targets),7:1341(2006)综述了使得硼替佐米获准用于治疗已接受至少一种先前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描述了一种确认硼替佐米在复发或难治性套细胞淋巴瘤患者中的活性的国际多中心II期研究。石井(Ishii)等人,药物化学中的抗癌剂(Anti-Cancer Agents in Medicinal Chemistry),7:359(2007)和罗卡罗(Roccaro)等人,当代药物生物技术(Curr.Pharm.Biotech.),7:1341(2006)讨论了多种可促成硼替佐米抗肿瘤活性的分子机制。
由以上参考文献所证明,蛋白酶体是治疗性干预的重要靶点。因此,不断需要新颖和/或改进的蛋白酶体抑制剂。
发明内容
本发明提供作为有效蛋白酶体抑制剂的化合物。这些化合物适用于体外(in vitro)和体内(in vivo)抑制蛋白酶体活性,并且尤其适用于治疗各种细胞增殖性疾病。
本发明化合物具有通式(I):
或其药学上可接受的盐或硼酸酐,其中:
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Z2一起形成源自硼酸络合剂的部分;并且
环A选自由以下所组成的群组:
式(I)的硼酸化合物(其中Z1和Z2各自为羟基)以下列化学名称来提及。
表1.蛋白酶体抑制剂
化学名称 | |
I-1 | [(1R)-1-({[(2,3-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-2 | [(1R)-1-({[(5-氯-2-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-3 | [(1R)-1-({[(3,5-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-4 | [(1R)-1-({[(2,5-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-5 | [(1R)-1-({[(2-溴苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-6 | [(1R)-1-({[(2-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-7 | [(1R)-1-({[(2-氯-5-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-8 | [(1R)-1-({[(4-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-9 | [(1R)-1-({[(3,4-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-10 | [(1R)-1-({[(3-氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-11 | [(1R)-1-({[(2,5-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-12 | [(1R)-1-({[(3,4-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-13 | [(1R)-1-({[(3-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-14 | [(1R)-1-({[(2-氯-4-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
化学名称 | |
I-15 | [(1R)-1-({[(2,3-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-16 | [(1R)-1-({[(2-氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-17 | [(1R)-1-({[(2,4-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-18 | [(1R)-1-({[(4-氯-2-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-19 | [(1R)-1-({[(4-氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-20 | [(1R)-1-({[(2,4-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
I-21 | [(1R)-1-({[(3,5-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸 |
单独使用或作为较大部分的一部分使用的术语“烷基”是指具有1至12个碳原子的直链或支链或环状脂肪族基团。术语“烷氧基”是指-O-烷基。
单独使用或作为较大部分的一部分使用的术语“芳基”和“芳-”(例如“芳烷基”、“芳烷氧基”或“芳氧基烷基”)是指含有1至3个环的C6至C14芳香族烃,所述环各自任选经取代。优选地,芳基为C6-10芳基。芳基包括(但不限于)苯基、萘基和蒽基。“芳烷基”或“芳基烷基”含有与烷基共价连接的芳基,所述烷基或所述芳基各自独立地任选经取代。优选地,芳烷基为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。
本文中所用的术语“经取代”意指指定部分的氢基被特定取代基的基团置换,前提是取代作用导致稳定或化学上可行的化合物。合适取代基的非限制性实例包括C1-6烷基、C3-8环烷基、C1-6烷基(C3-8)环烷基、C2-8烯基、C2-8炔基、氰基、氨基、C1-6烷基氨基、二(C1-6)烷基氨基、苯甲基氨基、二苯甲基氨基、硝基、羧基、羰基(C1-6)烷氧基、三氟甲基、卤素、C1-6烷氧基、C6-10芳基、C6-10芳基(C1-6)烷基、C6-10芳基(C1-6)烷氧基、羟基、C1-6烷基硫基、C1-6烷基亚磺酰基、C1-6烷基磺酰基、C6-10芳基硫基、C6-10芳基亚磺酰基、C6-10芳基磺酰基、C6-10芳基、C1-6烷基(C6-10)芳基和卤代(C6-10)芳基。
本文中所使用的短语“一个或多个取代基”是指一定数目的取代基,其等于基于可利用的成键位点的数目有可能的一个至最大数目的取代基,前提是满足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所述基团的每个可取代位置具有取代基,并且取代基可相同或不同。本文中所使用的术语“独立地选定”意指针对单个化合物中指定代号的多种情形可以选择相同或不同的值。
术语“约”在本文中用于表示近似、大约、大致或左右。当术语“约”与数值范围联合使用时,其通过将界限扩展至所述数值以上和以下来修饰那一范围。一般来说,术语“约”在本文中用于修饰高于或低于所述值10%的数值。
本文中所使用的术语“包含”意指“包括(但不限于)”。
除非另有说明,否则本文中所示的结构意在包括区别仅在于存在一个或多个同位素富集原子的化合物。例如,除了以氘或氚置换氢原子或以13C或14C富集碳置换碳原子之外具有本发明结构的化合物在本发明的范围之内。
本文中所用的术语“硼酸”是指含有-B(OH)2部分的化合物。在一些实施例中,硼酸化合物可通过使硼酸部分脱水而形成寡聚酸酐。举例来说,斯奈德(Snyder)等人,美国化学会志(J.Am.Chem.Soc.)80:3611(1958)报导了寡聚芳基硼酸。
本文中所使用的术语“硼酸酐”是指由两个或两个以上硼酸化合物分子结合同时失去一个或多个水分子所形成的化合物。当与水混合时,硼酸酐化合物被水化而释放游离硼酸化合物。在各种实施例中,硼酸酐可含有两个、三个、四个或四个以上硼酸单元,并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非限制性实例如下所示。
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,硼酸酐化合物含有式(2)的环状三聚体(“硼氧烃三聚物(boroxine)”),其中n为1。代号W具有式(3):
其中环A具有上文关于式(I)所述的值。
在一些实施例中,硼酸酐化合物中所存在的至少80%硼酸以单寡聚酸酐形式存在。在一些实施例中,硼酸酐化合物中所存在的至少85%、90%、95%或99%硼酸以单寡聚酸酐形式存在。在某些优选实施例中,硼酸酐化合物由或基本上由具有式(3)的硼氧烃三聚物组成。
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、冻干、暴露于热和/或暴露于干燥剂)下来制备硼酸酐化合物。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、乙醚、乙腈、乙醇和其混合物。
在一些实施例中,Z1和Z2一起形成源自硼酸络合剂的部分。就本发明而言,术语“硼酸络合剂”是指任何具有至少两个官能团的化合物,所述至少两个官能团各自可与硼形成共价键。合适官能团的非限制性实例包括氨基和羟基。在一些实施例中,至少一个官能团是羟基。术语“源自硼酸络合剂的部分”是指通过从硼酸络合剂的两个官能团去除氢原子所形成的部分。
本文中所使用的术语“硼酸酯(boronate ester/boronic ester)”是指含有-B(Z1)(Z2)部分的化合物,其中Z1或Z2中至少一个是烷氧基、芳烷氧基或芳氧基;或Z1和Z2一起形成源自具有至少一个羟基的硼酸络合剂的部分。
在一些实施例中,Z1和Z2一起形成源自具有至少两个被链或环中的至少两个相连原子所隔开的羟基的化合物的部分,所述链或环含有碳原子和(任选地)可为N、S或O的一个或多个杂原子,其中在各情况下与硼相连的原子是氧原子。
本文中所使用的术语“具有至少两个羟基的化合物”是指任何具有两个或两个以上羟基的化合物。就本发明而言,两个羟基优选被至少两个相连原子、优选约2至约5个相连原子、更优选2或3个相连原子所隔开。为了方便起见,术语“二羟基化合物”可用于指代上述定义的具有至少两个羟基的化合物。因此,本文中所使用的术语“二羟基化合物”并不旨在限于仅具有两个羟基的化合物。源自具有至少两个羟基的化合物的部分可通过其羟基中任意两个羟基的氧原子与硼相连。优选地,硼原子、与硼相连的氧原子和连接两个氧原子的原子一起形成5或6元环。
就本发明而言,硼酸络合剂优选为药学上可接受的,即适合投与人类。在一些优选实施例中,硼酸络合剂是糖。术语“糖”包括任何多羟基碳水化合物部分,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、甘露醇、山梨醇、葡糖胺和N-甲基葡糖胺。在某些实施例中,糖是甘露醇或山梨醇。因此,在糖为甘露醇或山梨醇的实施例中,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Z2一起形成源自D-甘露醇的部分。
在一些实施例中,式(I)化合物如普拉蒙东(Plamondon)等人在WO 02/059131中所描述制备成冻干粉,此案的全文据此以引用的方式并入本文中。在一些实施例中,冻干粉还包含游离二羟基化合物。优选地,游离二羟基化合物与式(I)化合物以在约0.5∶1至约100∶1、更优选为约5∶1至约100∶1范围内的摩尔比存在于混合物中。在二羟基化合物为甘露醇的各种实施例中,冻干粉包含摩尔比在约10∶1至约100∶1、约20∶1至约100∶1或约40∶1至约100∶1范围内的游离甘露醇与甘露醇硼酸酯。
在一些实施例中,冻干粉包含甘露醇和式(I)化合物,大体上不含其它组分。然而,组合物可进一步含有一种或多种其它药学上可接受的赋形剂、载剂、稀释剂、填充剂、盐、缓冲剂、稳定剂、增溶剂和业界熟知的其它物质。含有这些物质的药学上可接受制剂的制备描述于(例如)雷明登氏药学的理论与实践(Remington:The Science and Practiceof Pharmacy),第20版,詹纳罗(A.Gennaro)编,利平科特·威廉斯·威尔金斯出版公司(Lippincott Williams & Wilkins),2000或最新版本中。
优选根据普拉蒙东(Plamondon)等人在WO 02/059131中描述的程序制备包含式(I)化合物的冻干粉。因此,在一些实施例中,用以制备冻干粉的方法包含:(a)制备包含肽硼酸和二羟基化合物的水性混合物;和(b)冻干所述混合物。
一般合成方法
式(I)化合物可通过所属领域技术人员已知的方法来制备。参见,例如亚当斯(Adams)等人的美国专利第5,780,454号;皮格斯吉尔(Pickersgill)等人的国际专利公开案WO 2005/097809。示范性合成途径如下面流程1中所示。
流程1:
化合物i与N受保护甘氨酸(ii)偶联,随后进行N-端脱保护,从而提供化合物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)、苄氧羰基(Cbz)和芴基甲氧羰基(Fmoc)。肽偶联反应可通过预先使化合物ii的羧酸部分转化成活化酯(例如,O-(N-羟基琥珀酰亚胺)酯),随后用化合物i处理来进行。或者,可通过使羧酸与肽偶联试剂相接触而就地产生活化酯。合适肽偶联试剂的实例包括(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-(3-二甲氨基丙基)-3-乙基碳化二亚胺(EDC);磷鎓试剂,例如苯并三唑-1-基氧基三(二甲氨基)磷鎓六氟磷酸盐(BOP);和脲鎓试剂,例如,O-(1H-苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓四氟硼酸酯(TBTU)。
随后,使化合物iii与经取代的苯甲酸(ArCO2H),偶联提供化合物iv。上述用于化合物i和ii偶联的肽偶联条件也适合于使化合物iii与ArCO2H偶联。随后,将硼酸部分脱保护获得化合物v。优选在包含硼酸酯化合物iv、有机硼酸受体(acceptor)、低碳烷醇、C5-8烃溶剂和水性无机酸的两相混合物中通过酯交换作用(transesterification)来实现脱保护步骤。
流程2:
或者,如流程2所示,可颠倒偶联反应的顺序。因而,首先使O受保护甘氨酸(vi)与经取代的苯甲酸(ArCO2H)偶联,然后发生酯水解反应,从而形成化合物vii。随后,如上文关于流程1所描述,实现与化合物i偶联和硼酸脱保护而获得化合物v。
用途、调配和投药
本发明提供作为有效蛋白酶体抑制剂的化合物。可在体外或体内测定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多种肽酶活性的方法,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,其包含使需要所述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在所接触的细胞中抑制细胞数目或细胞生长的能力。可通过使用细胞计数器来计数细胞或通过细胞存活力测定(例如,MTT或WST测定)来评估细胞增殖。在细胞呈实体生长(例如,实体肿瘤或器官)时,可通过例如使用测径器测量生长并比较被接触细胞与未接触细胞的生长的尺寸来评估细胞增殖。
优选地,与未接触细胞的生长相比,与抑制剂相接触的细胞的生长被延迟至少约50%。在各种实施例中,与未接触细胞相比,被接触细胞的细胞增殖被抑制了至少约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被接触细胞的数目减少。因此,在被接触细胞中抑制细胞增殖的蛋白酶体抑制剂可诱导被接触细胞经历生长延迟、生长停滞、程序化细胞死亡(即凋亡)或细胞坏死。
在另一方面中,本发明提供一种药用组合物,其包含式(I)化合物或其药学上可接受的盐或硼酸酐,和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药学上可接受的盐,则所述盐优选源自无机或有机酸或碱。关于合适盐的综述可参见(例如)伯格(Berge)等人,药物科学杂志(J.Pharm.Sci.)66:1-19(1977)和雷明登氏药学的理论与实践(Remington:The Scienceand Practice of Pharmacy),第20版,詹纳罗(A.Gennaro)编,利平科特·威廉斯·威尔金斯出版公司(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、天门冬氨酸盐、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、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、富马酸盐、葡庚糖酸盐(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、甲苯磺酸盐和十一酸盐。
合适碱加成盐包括(但不限于):铵盐;碱金属盐,例如锂盐、钠盐和钾盐;碱土金属盐,例如钙盐和镁盐;其它多价金属盐,例如锌盐;与有机碱形成的盐,所述有机碱例如有二环己胺、N-甲基-D-葡糖胺、叔丁胺、乙二胺、乙醇胺和胆碱;以及与氨基酸形成的盐,所述氨基酸例如有精氨酸、赖氨酸和诸如此类。在一些实施例中,药学上可接受的盐是式(I)硼酸化合物的碱加成盐,其中Z1和Z2均为羟基。
术语“药学上可接受的载剂”在本文中用于指与接受个体(优选为哺乳动物,更优选为人类)相容并适合于向目标位置传递活性剂而不会使试剂活性终止的物质。为达成活性剂的预期用途,与载剂相关的毒性或不良效应(如果存在)优选与合理的风险/益处比相当。
术语“载剂”、“佐剂”或“媒剂”在本文中可互换使用并包括适合于所要特定剂型的任意和所有溶剂、稀释剂和其它液体媒剂、分散或悬浮助剂、表面活性剂、pH调节剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂和诸如此类。雷明登氏药学的理论与实践(Remington:The Science and Practice of Pharmacy),第20版,詹纳罗(A.Gennaro)编,利平科特·威廉斯·威尔金斯出版公司(Lippincott Williams & Wilkins),2000揭示了用于调配药学上可接受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与本发明化合物不相容(例如由于产生任何不良的生物效应或不然以有害方式与药学上可接受组合物的任何其它组分发生相互作用),否则其使用均涵盖在本发明的范围内。可充当药学上可接受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(例如人血清白蛋白);缓冲物质,例如磷酸盐、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,例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠和锌盐;硅胶、三硅酸镁、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、羊毛脂;糖,例如乳糖、葡萄糖、蔗糖和甘露醇;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素和其衍生物,例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;黄蓍胶粉、麦芽、明胶、滑石、赋形剂,例如可可脂和栓剂蜡;油类,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇类,例如丙二醇和聚乙二醇;酯类,例如油酸乙酯和月桂酸乙酯;琼脂、褐藻酸、等渗盐水、林格氏溶液(Ringer′s solution);醇类,例如乙醇、异丙醇、十六醇和甘油;环糊精,例如羟丙基β-环糊精和磺丁基醚β-环糊精;润滑剂,例如月桂基硫酸钠和硬脂酸镁;石油烃,例如矿物油和矿脂(petrolatum)。依照调配者的判断,着色剂、释放剂、包衣剂、甜味剂、调味剂和加香剂、防腐剂和抗氧化剂也可存在于组合物中。
本发明的药用组合物可通过业界熟知的方法制造,例如常规制粒、混合、溶解、包囊、冻干或乳化工艺等。组合物可制为各种形式,包括颗粒剂、沉淀物或微粒、粉末(包括冷冻干燥粉末、旋转干燥粉末或喷雾干燥粉末、无定形粉末)、片剂、胶囊、糖浆、栓剂、注射剂、乳液、酏剂、悬浮液或溶液。
根据一个优选实施例,为向哺乳动物(优选人类)投药对本发明的组合物进行调配。本发明的这些药用组合物可以口服、以不经肠方式、通过吸入喷雾剂、以局部、经直肠、经鼻、经颊、经阴道方式或经由植入式储集器投与。本文中所使用的术语“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,组合物口服、静脉内或皮下投与。本发明的制剂可被设计成短效、速释或长效的。更进一步地,化合物可以局部而非全身性方式投与,例如在肿瘤位点处(例如通过注射)投与。
用于口服的液体剂型包括(但不限于)药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除活性化合物之外,液体剂型还可含有业界通常使用的惰性稀释剂,例如水或其它溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、环糊精、二甲基甲酰胺、油类(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、聚乙二醇和山梨醇酐脂肪酸酯,以及其混合物。除了惰性稀释剂外,口服组合物也可包括佐剂,例如,润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和加香剂。
可根据已知技术使用适合的分散剂或润湿剂和悬浮剂来调配可注射制剂,例如无菌可注射的水性或油质悬浮液。无菌可注射制剂还可为于无毒、不经肠可接受的稀释剂或溶剂中的无菌可注射溶液、悬浮液或乳液,例如于1,3-丁二醇中的溶液。在可接受的媒剂和溶剂中,可使用的有水、林格氏溶液、U.S.P.和等渗氯化钠溶液。此外,常规上使用无菌不挥发油作为溶剂或悬浮介质。为此,可使用任何温和的不挥发油,包括合成单甘油酯和二甘油酯。此外,在注射剂的制备中使用脂肪酸,例如油酸。可对可注射制剂进行灭菌,例如,通过经由滤菌器过滤,或通过在无菌固体组合物形式中并入杀菌剂,所述组合物可在使用前溶解于或分散于无菌水或其它无菌可注射介质中。经调配用于不经肠投药的组合物可通过团注或通过定时推注来注射,或可通过连续输注来投与。
用于口服的固体剂型包括胶囊、片剂、丸剂、粉末和颗粒剂。在这些固体剂型中,将活性化合物与至少一种惰性、药学上可接受的赋形剂或载剂(例如柠檬酸钠或磷酸二钙)和/或a)填充剂或增量剂(例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸)、b)粘合剂(例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶)、c)保湿剂(例如甘油)、d)崩解剂(例如琼脂-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)阻溶剂(例如石蜡)、f)吸收促进剂(例如季铵化合物)、g)润湿剂(例如鲸蜡醇和单硬脂酸甘油酯)、h)吸收剂(例如高岭土和膨润土)和i)润滑剂(例如滑石、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混合。在胶囊、片剂和丸剂的情况下,所述剂型还可包含缓冲剂,例如磷酸盐或碳酸盐。
还可使用赋形剂(例如,乳糖或奶糖以及高分子量聚乙二醇和诸如此类)将相似类型的固体组合物用作软填充和硬填充明胶胶囊中的填充物。片剂、糖锭剂、胶囊、丸剂和颗粒剂的固体剂型可制备为具有包衣和外壳,例如肠溶衣和药物调配技术中熟知的其它包衣。其可任选地含有遮光剂,并且还可为仅在或优先在肠道某特定部分任选地以延迟方式释放活性成分的组合物。可使用的包埋组合物的实例包括聚合物质和蜡。还可使用赋形剂(例如,乳糖或奶糖以及高分子量聚乙二醇和诸如此类)将相似类型的固体组合物用作软填充和硬填充明胶胶囊中的填充物。
活性化合物还可与一种或多种上述赋形剂一起呈微胶囊形式。片剂、糖锭剂、胶囊、丸剂和颗粒剂的固体剂型可制备为具有包衣和外壳,例如肠溶衣、控释包衣和药物调配技术中熟知的其它包衣。在这些固体剂型中,可将活性化合物与至少一种惰性稀释剂(例如蔗糖、乳糖或淀粉)混合。如在正常作业中,这些剂型还可包含除惰性稀释剂之外的其它物质,例如压片润滑剂和其它压片助剂,例如硬脂酸镁和微晶纤维素。在胶囊、片剂和丸剂的情况下,所述剂型还可包含缓冲剂。其可任选地含有遮光剂,并且还可为仅在或优先在肠道某特定部分任选地以延迟方式释放活性成分的组合物。可使用的包埋组合物的实例包括聚合物质和蜡。
用于局部或经皮投与本发明化合物的剂型包括软膏、糊剂、乳膏、洗剂、凝胶、粉末、溶液、喷雾剂、吸入剂或贴片。在无菌条件下,将活性组分与药学上可接受的载剂和任何所需的防腐剂或缓冲剂按要求混合。眼用制剂、滴耳剂和滴眼剂也涵盖于本发明的范围之内。另外,本发明还涵盖使用经皮贴片,其具有提供化合物于身体内受控传递的额外益处。这些剂型可通过使化合物溶解或分散于合适介质中而制得。也可使用吸收增强剂来增加化合物穿过皮肤的通量。可通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中来控制速率。
在一些实施例中,式(I)化合物静脉内投与。在这些实施例中,式(I)化合物(其中Z1和Z2一起形成源自硼酸络合剂的部分)可制备成上述冻干粉的形式。优选通过添加适合于药物投与的水性溶剂来复配冻干粉。合适复配溶剂的实例包括(但不限于)水、盐水和磷酸盐缓冲盐水(PBS)。优选地,使用标准(0.9%)盐水来复配冻干粉。复配后,在硼酸酯化合物与相应游离硼酸化合物之间建立平衡。在一些实施例中,在添加水性介质后很快达到平衡,例如在10-15分钟之内。平衡时所存在的硼酸酯与硼酸的相对浓度取决于诸多参数,例如溶液pH值、温度、硼酸络合剂的性质以及冻干粉中存在的硼酸络合剂与硼酸酯化合物的比率。
本发明的药用组合物优选为了投与患有蛋白酶体介导性病症或处于患上蛋白酶体介导性病症或经历蛋白酶体介导性病症复发的风险之中的患者而调配。本文中所使用的术语“患者”意指动物,优选为哺乳动物,更优选为人类。本发明的优选药用组合物是经调配用于口服投药、静脉内投药或皮下投药的那些组合物。然而,含有治疗有效量的本发明化合物的上述任一种剂型都完全在常规试验的范围之内,并因此,完全在本发明的范围之内。在一些实施例中,本发明的药用组合物可进一步含有另一治疗剂。在一些实施例中,所述另一治疗剂是通常向患有所治疗疾病或病状的患者投与的治疗剂。
“治疗有效量”意指足以引起蛋白酶体活性或蛋白酶体介导性病症严重程度可检测到的降低的量。所需蛋白酶体抑制剂的量应取决于抑制剂对给定细胞种类的有效性以及治疗所述病症所需的时间长度。还应了解,对于任何特定患者而言,具体剂量和治疗方案应取决于各种因素,包括所使用具体化合物的活性、患者的年龄、体重、总体健康情况、性别和饮食、投药时间、排泄率、药物组合、治疗医师的判断以及所治疗特定疾病的严重程度。本发明组合物中所存在的其它治疗剂的量通常应不超过就含有这一治疗剂作为唯一活性剂的组合物而言通常将投与的量。优选地,其它治疗剂的量的范围可为含有这一治疗剂作为唯一治疗活性剂的组合物中通常所存在量的约50%至约100%。
在另一方面中,本发明提供一种治疗患有蛋白酶体介导性病症或处于患上蛋白酶体介导性病症或经历蛋白酶体介导性病症复发的风险之中的患者的方法。本文中所使用的术语“蛋白酶体介导性病症”包括由蛋白酶体表达或活性的增加所引起、或特征在于蛋白酶体表达或活性的增加、或需要蛋白酶体活性的任何病症、疾病或病状。术语“蛋白酶体介导性病症”还包括对蛋白酶体活性的抑制有益处的任何病症、疾病或病状。
举例来说,本发明化合物和药用组合物适用于治疗经由受蛋白酶体活性调控的蛋白质(例如,NFκB、p27Kip、p21WAF/CIP1、p53)所介导的病症。相关病症包括炎性病症(例如,类风湿性关节炎、炎症性肠病、哮喘、慢性阻塞性肺病(COPD)、骨关节炎、皮肤病(例如,异位性皮炎、牛皮癣))、血管增殖性病症(例如,动脉粥样硬化症、再狭窄)、眼部增殖性病症(例如,糖尿病性视网膜病变)、良性增殖性病症(例如,血管瘤)、自身免疫疾病(例如,多发性硬化、组织和器官排斥反应),以及与感染相关的炎症(例如,免疫反应)、神经退行性病症(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、神经病理性疼痛、三联体重复病症(tripletrepeat disorder)、星形细胞瘤和由酒精性肝病导致的神经退化)、缺血性损伤(例如,中风)和恶病质(例如,伴随各种生理病理状态的加速肌肉蛋白降解(例如,神经损伤、绝食、发烧、酸中毒、HIV感染、癌症和某些内分泌病))。
本发明化合物和药用组合物特别适用于治疗癌症。本文中所使用的术语“癌症”是指一种细胞病症,其特征为不受控制或失调的细胞增殖、降低的细胞分化、不适当地侵袭周围组织的能力和/或在异位位点形成新的生长的能力。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”还包括原发癌和转移癌。
可用所揭示的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;乳腺癌,包括转移性乳腺癌;前列腺癌,包括雄激素依赖性前列腺癌和雄激素非依赖性前列腺癌;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)进行性上皮癌或原发性腹膜癌;子宫颈癌;胃癌;食道癌;头颈部癌,包括(例如)头颈部鳞状细胞癌;黑色素瘤;神经内分泌癌,包括转移性神经内分泌肿瘤;脑部肿瘤,包括(例如)神经胶质瘤、间变少枝胶质细胞瘤、成人多形性胶质母细胞瘤和成人间变星形细胞瘤;骨癌;和软组织肉瘤。
可用所揭示的蛋白酶体抑制剂治疗的血液恶性肿瘤的非限制性实例包括急性骨髓白血病(AML);慢性骨髓性白血病(CML),包括加速期CML和急变期CML(CML-BP);急性淋巴母细胞白血病(ALL);慢性淋巴细胞白血病(CLL);霍奇金病(Hodgkin′sdisease,HD);非霍奇金淋巴瘤(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′smacroglobulinemia);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)、难治性贫血伴有原始细胞过多(RAEB)和转变中的RAEB(RAEB-T);和骨髓增殖性综合症。
在一些实施例中,本发明化合物或组合物用于治疗患有癌症或处于患上癌症或经历癌症复发的风险之中的患者,所述癌症选自由多发性骨髓瘤和套细胞淋巴瘤组成的群组。
在一些实施例中,本发明的蛋白酶体抑制剂与另一治疗剂联合投与。所述另一治疗剂也可抑制蛋白酶体,或可以不同机制起作用。在一些实施例中,所述另一治疗剂是通常向患有所治疗疾病或病状的患者投与的治疗剂。本发明的蛋白酶体抑制剂可与另一治疗剂一起以单一剂型或以独立剂型投与。当以独立剂型投与时,所述另一治疗剂可在投与本发明的蛋白酶体抑制剂之前、同时或之后投与。
在一些实施例中,式(I)的蛋白酶体抑制剂与抗癌剂联合投与。本文中所使用的术语“抗癌剂”是指出于治疗癌症的目的向患癌症的个体投与的任何药剂。
DNA损伤化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)、拓扑替康(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,足叶乙甙(etoposide)、替尼泊甙(teniposide)和柔红霉素(daunorubicin));烷基化剂(例如,美法仑(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、噻替派(thiotepa)、异环磷酰胺(ifosfamide)、卡氮芥(carmustine)、洛莫司汀(lomustine)、司莫司汀(semustine)、链脲佐菌素(streptozocin)、氮烯咪胺(decarbazine)、甲氨蝶呤(methotrexate)、丝裂霉素C(mitomycinC)和环磷酰胺(cyclophosphamide));DNA嵌入剂(例如,顺铂(cisplatin)、奥沙利铂(oxaliplatin)和卡铂(carboplatin));DNA嵌入剂和自由基产生剂,例如博莱霉素(bleomycin);以及核苷模拟物(例如,5-氟尿嘧啶(5-fluorouracil)、卡培他滨(capecitibine)、吉西他滨(gemcitabine)、氟达拉滨(fludarabine)、阿糖胞苷(cytarabine)、巯基嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine)、喷妥司汀(pentostatin)和羟基脲(hydroxyurea))。
破坏细胞复制的化疗剂包括:紫杉醇(paclitaxel)、多西紫杉醇(docetaxel)和相关类似物;长春新碱(vincristine)、长春碱(vinblastin)和相关类似物;沙利度胺(thalidomide)、来那度胺(lenalidomide)和相关类似物(例如,CC-5013和CC-4047);蛋白酪氨酸激酶抑制剂(例如甲磺酸伊马替尼(imatinib mesylate)和吉非替尼(gefitinib));蛋白酶体抑制剂(例如,硼替佐米);NF-κB抑制剂,包括IκB激酶抑制剂;与过表达于癌症中的蛋白质结合并进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));和已知在癌症中被上调、过表达或活化的蛋白质或酶的其它抑制剂,所述抑制会下调细胞复制。
为了更充分地理解本发明,陈述以下制备实例和测试实例。这些实施例说明如何制备或测试特定化合物,但不应视为以任何方式限制本发明的范围。
具体实施方式
实例
缩写
DCM 二氯甲烷
DIEA 二异丙基乙胺
EDCI N-(3-二甲基氨基丙基)-N′-乙基碳化二亚胺盐酸盐
EtOAc 乙酸乙酯
h 小时
HPLC 高效液相色谱
TBTU o-苯并三唑-N,N,N′,N′-四甲基脲鎓四氟硼酸酯
HOBt 1-羟基苯并三唑水合物
LCMS 液相色谱质谱
min 分钟
tr 二极管阵列光谱的滞留时间
分析型LC-MS方法
使用下列梯度在Symmetry C18-3.5μm-4.6×50mm柱上进行光谱测量:
溶剂A:2%异丙醇、98%水、10mM NH4OAc
溶剂B:75%乙腈、25%甲醇、10mM NH4OAc
时间[min] | 流速[mL/min] | 溶剂B的百分比 |
0.0 | 1.0 | 5.0 |
3.5 | 1.0 | 100.0 |
4.9 | 1.0 | 100.0 |
5.0 | 1.0 | 5.0 |
实例1:[(1R)-1-({[(2,3-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸·20 D-甘露醇(I-1)的合成
步骤1:[(2,3-二氟苯甲酰基)氨基]乙酸甲酯
向2,3-二氟苯甲酸(0.190g,1.2mmol)的四氢呋喃(5mL)溶液中添加甘氨酸甲酯盐酸盐(0.150g,1.2mmol)、HOBt(0.162g,1.2mmol)、DIEA(0.209mL,1.2mmol)和EDCI(0.252g,1.3mmol)。使反应混合物搅拌过夜。用饱和碳酸氢钠溶液中止反应混合物反应,并使产物分配于DCM中。分离有机层,继而去除溶剂,得到[(2,3-二氟苯甲酰基)氨基]乙酸甲酯,其不经纯化即用于下一步骤。
步骤2:[(2,3-二氟苯甲酰基)氨基]乙酸
向[(2,3-二氟苯甲酰基)氨基]乙酸甲酯(0.250g,1.1mmol)的甲醇(7mL)溶液中添加氢氧化锂(0.053g,2.2mmol)和水(3mL)。使反应混合物搅拌过夜。混合物用水(20mL)稀释并用1N HCl(5mL)酸化。使产物于DCM/甲醇(4∶1)中分配。用硫酸钠干燥有机层,并去除溶剂,得到[(2,3-二氟苯甲酰基)氨基]乙酸,其不经纯化即用于下一步骤。
步骤3:2,3-二氟-N-[2-({(1R)-3-甲基-1-[(3aR,4R,6R,7aS)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺
向[(2,3-二氟苯甲酰基)氨基]乙酸(0.205g,0.95mmol)的二甲基甲酰胺(10mL)溶液中添加TBTU(0.337g,1.0mmol)和(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁-1-胺的三氟乙酸盐(0.362g,0.95mmol)。使混合物冷却到0℃,并滴加DIEA(0.498mL,2.9mmol)。使反应混合物升温到室温并搅拌过夜。用100mL水中止反应,并使产物分配于DCM中。用硫酸钠干燥有机层,并去除溶剂,得到2,3-二氟-N-[2-({(1R)-3-甲基-1-[(3aR,4R,6R,7aS)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺。
步骤4:[(1R)-1-({[(2,3-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸
向2,3-二氟-N-[2-({(1R)-3-甲基-1-[(3aR,4R,6R,7aS)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺(0.536g,1.2mmol)的甲醇/1N HCl(1∶1)(1.5mL)溶液中添加庚醇(1mL)和硼酸异丁酯(0.207g,2.0mmol)。使反应混合物搅拌过夜。将庚醇层分离并浓缩甲醇/HCl层。通过反相HPLC纯化粗产物,得到[(1R)-1-({[(2,3-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸。
步骤5:[(1R)-1-({[(2,3-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸·20D-甘露醇(I-1)
向[(1R)-1-({[(2,3-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(0.085g,0.26mmol)于叔丁醇(2mL)和水(5mL)中的溶液中添加D-甘露醇(0.943g,5.2mmol)。温热溶液并使之搅拌直到全部溶解。接着将溶液冷冻并通过冻干法去除溶剂,得到[(1R)-1-({[(2,3-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸·20 D-甘露醇(I-1)(0.98g,97%)。
实例2:[(1R)-1-({[(2-溴苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸·20 D-甘露醇(I-5)的合成
步骤1:[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}氨基)-2-氧代乙基]氨基甲酸叔丁酯
经15分钟向(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁-1-胺的三氟乙酸盐(4.9g,10.8mmol)、N-·-(叔丁氧羰基)甘氨酸(1.98g,11.3mmol)和TBTU(3.81g,11.9mmol)于DCM(100mL)中的混合物中滴加DIEA(5.64mL,32.4mmol)的DCM(25mL)溶液。使反应混合物搅拌过夜并浓缩。通过柱色谱纯化粗产物,得到[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}氨基)-2-氧代乙基]氨基甲酸叔丁酯(2.5g,55%)。
步骤2:2-氨基-N-{(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}乙酰胺
向[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}氨基)-2-氧代乙基]氨基甲酸叔丁酯(2.5g,5.9mmol)的DCM(15mL)溶液中添加二噁烷(5.9mL)中的4M HCl。使反应混合物搅拌2小时并浓缩,得到2-氨基-N-{(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}乙酰胺,其不经纯化即用于下一步骤。
步骤3:2-溴-N-[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺
向2-溴苯甲酸(0.124g,0.62mmol)的DCM(2.25mL)溶液中添加EDCI(0.119g,0.62mmol)、HOBt(0.084g,0.62mmol)、N-甲基吗啉(0.185mL,1.68mmol)和2-氨基-N-{(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}乙酰胺(0.2g,0.56mmol)。使反应混合物搅拌2小时并浓缩。将残余物用水稀释并用EtOAc萃取。将有机溶液合并,用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过柱色谱纯化粗产物,得到2-溴-N-[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺(0.22g,78%)。
步骤4:[(1R)-1-({[(2-溴苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸
向2-溴-N-[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氢-4,6-亚甲基-1,3,2-苯并二氧硼烷-2-基]丁基}氨基)-2-氧代乙基]苯甲酰胺(0.220g,0.44mmol)于甲醇/己烷(1∶1)(2.2mL)中的溶液中添加1N HCl(1mL,1.0mmol)和硼酸异丁酯(0.078g,0.76mmol)。将反应混合物搅拌过夜。浓缩反应混合物并通过反相HPLC纯化,得到[(1R)-1-({[(2-溴苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(0.119g,73%)。
步骤5:[(1R)-1-({[(2-溴苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸·20 D-甘露醇(I-5)
向[(1R)-1-({[(2-溴苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸(0.103g,0.28mmol)于叔丁醇(9mL)和水(15mL)中的溶液中添加D-甘露醇(1.01g,5.5mmol)。温热溶液并使之搅拌直到全部溶解。接着将溶液冷冻并通过冻干法去除溶剂,得到[(1R)-1-({[(2-溴苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸·20D-甘露醇(I-5)(0.92g,84%)。
以与实例1或2类似的方法由适当的起始物质制备下表中的化合物。
I-1 | LCMS:ES-327.3,tr=3.36min。 |
I-2 | LCMS:ES-343.2,tr=3.62min。 |
I-3 | LCMS:ES-327.3,tr=3.49min。 |
I-1 | LCMS:ES-327.3,tr=3.36min。 |
I-4 | LCMS:ES-327.2,tr=3.27min。 |
I-5 | LCMS:ES-369.2,tr=3.30min。1H NMR(300MHz,d4-MeOD)δ:7.62(dd,1H),7.28-7.50(m,3H),4.19(s,2H),2.70-2.78(m,1H),1.57-1.71(m,1H),1.26-1.40(m,2H)和0.89(d,6H)。 |
I-6 | LCMS:ES-309.1,tr=3.14min。 |
I-7 | LCMS:ES-343.2,tr=3.30min。 |
I-8 | LCMS:ES-309.3,tr=3.23min。 |
I-9 | LCMS:ES-327.3,tr=3.49min. |
I-10 | LCMS:ES-325.2,tr=3.58min。 |
I-11 | LCMS:ES-359.2,tr=3.66min。1H NMR(300MHz,d4-MeOD)δ:7.62(s,1H),7.49(d,2H),4.23(s,2H),2.74-2.82(m,1H),1.62-1.78(m,1H),1.30-1.45(m,2H)和0.95(d,6H)。 |
I-12 | LCMS:ES-359.2,tr=3.95min。 |
I-13 | LCMS:ES-309.2,tr=3.34min。 |
I-14 | LCMS:ES-343.2,tr=3.44min。 |
I-15 | LCMS:ES-359.2,tr=3.26min。 |
I-16 | LCMS:ES-325.2,tr=3.20min。 |
I-17 | LCMS:ES-327.3,tr=3.39min。 |
I-18 | LCMS:ES-343.2,tr=3.58min。 |
I-19 | LCMS:ES-325.1,tr=3.51min。 |
I-20 | LCMS:ES-359.2,tr=3.54min。 |
I-21 | LCMS:ES-359.2,tr=3.99min。 |
实例2:20S蛋白酶体分析
在37℃向384孔黑色微量滴定板中溶于DMSO的1μL测试化合物中添加25μL含有人类PA28活化子(Boston Biochem,终浓度12nM)与Ac-WLA-AMC(β5选择性底物)(终浓度15μM)的测定缓冲液,随后在37℃再添加25μL含有人类20S蛋白酶体(Boston Biochem,终浓度0.25nM)的测定缓冲液。测定缓冲液由20mM HEPES、0.5mMEDTA和0.01% BSA组成,pH值为7.4。用BMG Galaxy读板器(37℃,380nm激发,460nm发射,20增益)跟踪反应。相对于0%抑制(DMSO)和100%抑制(10μM硼替佐米)对照组计算抑制百分比。
当以此测定测试时,化合物I-1至I-21均展现IC50值小于50nM。
实例3:抗增殖测定
将100μL补充有10%胎牛血清(英杰公司(Invitrogen))的适当细胞培养基(McCoy′s5A for HCT-116,英杰公司)中的HCT-116(1000)或其它肿瘤细胞接种于96孔细胞培养板的孔中,并在37℃培育过夜。将测试化合物加入到孔内并将板在37℃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℃培育4小时。针对MTT,根据制造商说明书(罗氏公司)使所代谢的染料增溶过夜。对于MTT使用分光光度计(分子装置公司(Molecular Devices))在595nm(主波长)和690nm(参比波长)下读取各孔的光密度,对于WST则在450nm下读取各孔的光密度。对于MTT,从主波长的光密度值减去参比光密度值。使用设为100%的DMSO对照组的值来计算抑制百分比。
实例4:体内肿瘤功效模型
使用1mL 26 3/8号针(碧迪公司(Becton Dickinson)Ref#309625)将100μLRPMI-1640培养基(西格玛-奥德里奇(Sigma-Aldrich))中的新鲜分离的HCT-116(2-5×106个)或其它肿瘤细胞无菌注射至雌性CD-1裸小鼠(5-8周龄,查尔斯河公司(CharlesRiver))右背侧的皮下间隙内。或者,一些异种移植模型需要肿瘤片段的连续传代。在这些情况中,经由13号套管针(波普尔&森斯公司(Popper & Sons)7927)将肿瘤组织的小片段(约1mm3)经皮下植入到经麻醉(3-5%异氟烷/氧混合物)C.B-17/SCID小鼠(5-8周龄,查尔斯河公司)的右背侧。自接种后第7天开始,使用游标卡尺每周2次测量肿瘤。使用标准程序(0.5×(长度×宽度2))计算肿瘤体积。当肿瘤体积达到约200mm3时,将小鼠随机分为若干治疗组并开始接受药物治疗。基于先前从药物动力学/药效学和最大耐受剂量研究中获得的结果确定各实验的给药剂量和时程。对照组将接受不含任何药物的媒剂。通常,以不同剂量和时程将测试化合物(100-200μL)经由静脉(27号针)、口服(20号管饲针)或皮下(27号针)途径投与。每周两次测量肿瘤尺寸和体重,并且当对照肿瘤达到约2000mm3时终止研究。
尽管前文已出于清晰性和理解的目的相当详细地描述了本发明,但这些特定实施例应被视为说明性的而非具限制性。所属领域技术人员在阅读本揭示案后应了解,在不脱离本发明真实范围的情况下可对形式和细节作各种改变,本发明的真实范围应由随附权利要求书而非具体实施例来界定。
本文中所提及的专利和科技文献为所属领域技术人员提供了可利用的知识。除非另有定义,否则本文中所用的所有科技术语具有与本发明所属领域技术人员通常所理解相同的含义。本文中所引用的已授权专利、申请案和参考文献以引用的方式并入本文中,其引用程度就如同特定地和个别地指示将各个已授权专利、申请案和参考文献以引用的方式并入一般。在矛盾的情况下,应以本揭示案(包括定义)为准。
Claims (5)
2.根据权利要求1所述的化合物,其选自由以下所组成的群组:
[(1R)-1-({[(2,3-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(5-氯-2-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(3,5-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2,5-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2-溴苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2-氯-5-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(4-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(3,4-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(3-氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2,5-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(3,4-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(3-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2-氯-4-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2,3-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2-氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2,4-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(4-氯-2-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(4-氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2,4-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;和
[(1R)-1-({[(3,5-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
或其药学上可接受的盐或硼酸酐。
3.根据权利要求1所述的化合物,其是选自由以下所组成的群组的硼酸化合物的甘露醇酯:
[(1R)-1-({[(2,3-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(5-氯-2-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(3,5-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2,5-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2-溴苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2-氯-5-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(4-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(3,4-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(3-氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2,5-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(3,4-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(3-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2-氯-4-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2,3-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2-氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2,4-二氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(4-氯-2-氟苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(4-氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;
[(1R)-1-({[(2,4-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸;和
[(1R)-1-({[(3,5-二氯苯甲酰基)氨基]乙酰基}氨基)-3-甲基丁基]硼酸。
4.一种药用组合物,其包含根据权利要求1所述的化合物和药学上可接受的载剂。
5.一种治疗癌症的方法,其包含向需要此治疗的患者投与根据权利要求3所述的药用组合物。
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