CN106660989A - 作为MetAP‑2抑制剂的吡咯烷酮衍生物 - Google Patents
作为MetAP‑2抑制剂的吡咯烷酮衍生物 Download PDFInfo
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Abstract
权利要求1的化合物,是甲硫氨酸氨肽酶的抑制剂,并且可用于治疗肿瘤。
Description
本发明涉及选自以下的化合物:
及其可药用盐、互变异构体和立体异构体,包括其所有比率的混合物。
本发明以这样的目的为基础,即找到具有有价值的性质的新型化合物,特别是可用于制备药剂的那些。
已经发现,本发明的化合物及其盐具有非常有价值的药理性质,同时耐受性良好。
它们特别对金属蛋白酶,优选对甲硫氨酸氨肽酶(MetAP),特别对亚型MetAP-2表现出调节、调整和/或抑制作用。
它们可用作抗癌药,以及用作积极影响脂肪代谢的药剂,以及用作抗炎药。
其它羟基取代的吡咯烷酮从下列文献中获知:
WO 2011/004608 (MetAP2-抑制剂)和WO 2013/149704 (MetAP2-抑制剂);
Zeitschrift für Naturforschung, B: Chemical Sciences (1994), 49(11),1586-95;
Analytica Chimica Acta (1987), 202, 167-74;
Journal of Electroanalytical Chemistry and Interfacial Electrochemistry(1988), 239(1-2), 161-73;
Zeitschrift fuer Naturfor. B部分: Anorg. Chem. Org. Chem (1978), 33B(12),1540-6;
J. Chem. Soc. (1965), (Oct.), 5556-62;
J. Chem. Soc. (1965), (Oct.), 5551-6。
WO 01/79157描述了取代酰肼和N-烷氧基酰胺,其具有MetAP-2抑制活性并可用于抑制血管生成,特别用于治疗其发展依赖于血管生成的疾病,例如癌症。
WO 02/081415描述了可用于治疗癌症、血管瘤、增殖性视网膜病、类风湿性关节炎、动脉粥样硬化新生血管形成、牛皮癣、眼部新生血管形成和肥胖症的MetAP-2抑制剂。
WO 2008/011114描述了作为可用于治疗淋巴性白血病和淋巴瘤的血管生成抑制剂和MetAP-2抑制剂的化合物。
根据本发明的化合物的抗癌作用特别在于它们的抗血管生成作用。血管生成抑制在超过70种疾病中证实有用,例如卵巢癌(F. Spinella等人J. Cardiovasc. Pharmacol.2004, 44, 140页)、乳腺癌(A. Morabito等人Crit. Rev. Oncol./Hematol. 2004, 49,91)、前列腺癌(B. Nicholson等人Cancer Metastas. Rev. 2001, 20, 297)、糖尿病性失明、牛皮癣和黄斑变性(E. Ng等人Can. J. Ophthalmol. 2005, 23, 3706)。
蛋白酶调节许多不同的细胞过程,特别是肽和蛋白质的调整,特备是蛋白质转化、蛋白质成熟和信号肽加工、异常蛋白的分解和调节蛋白的灭活/活化。特别地,新生多肽的氨基末端修饰是最常见的调整。氨基蛋白酶是裂解肽或蛋白质的未受保护的N末端氨基酸的金属蛋白酶,所述裂解可以以共翻译(co-translatory)进行或翻译后(post-translatory)进行。。
甲硫氨酸氨肽酶(MetAP)裂解新生肽的末端甲硫氨酸,特别是如果倒数第二个氨基酸小且不带电荷(例如Gly、Ala、Ser、Thr、Val、Pro或Cys)。
在许多疾病进程中,血管生成是疾病的致病中心或对疾病的发展具有恶化作用。例如在癌症的情况下,血管生成会导致肿瘤尺寸变大并进入其它器官。血管生成起到重要作用的其它疾病是牛皮癣、关节病、动脉硬化和眼病,如糖尿病视网膜病变、年龄引发的黄斑变性、虹膜红变或新生血管性青光眼,以及炎症。因此,作为本发明的基础的化合物、包含这些化合物的组合物和所述方法可用于治疗这些疾病。
因此,给予本发明的化合物或其可药用的盐用于治疗癌症,包括实体癌,例如肺、胰腺、甲状腺、膀胱或结肠的癌,骨髓病(例如骨髓性白血病)或腺瘤(例如绒毛状结肠腺瘤)。
肿瘤还包括单核细胞白血病、脑癌、泌尿生殖系统癌、淋巴系统癌、胃癌、喉癌和肺癌(包括肺腺癌和小细胞肺癌),胰腺癌和/或乳腺癌。
本发明因此涉及作为在所述疾病的治疗和/或预防中的药剂和/或药剂活性化合物的根据本发明的化合物和根据本发明的化合物用于制备用于所述疾病的治疗和/或预防的药物的用途,以及所述疾病的治疗方法,包括向需要这种给药的患者给予一种或多种根据本发明的化合物。
可以证明,根据本发明的化合物具有抗癌作用。本发明的化合物给药于患病的患者,例如用于抑制肿瘤生长,用于减轻与淋巴增生性疾病相关的炎症、用于抑制移植排斥或由组织修复造成的神经损伤等。本化合物适用于预防或治疗目的。本文所用的术语“治疗”用于表示预防疾病和治疗已有病况。通过在产生显性疾病之前施用根据本发明的化合物,实现对增殖/存活的预防,例如用于预防肿瘤生长。或者,该化合物用于通过稳定或改善患者的临床症状来治疗持续性疾病。
宿主或患者可以属于任何哺乳动物物种,例如灵长类动物,特别是人类;啮齿动物,包括小鼠、大鼠和仓鼠;兔子;马、牛、狗、猫等。动物模型对实验研究有意义,它们为人类疾病的治疗提供模型。
可通过在体外的试验确定特定细胞对用根据本发明的化合物处理的易感性。通常将细胞培养物与根据本发明的化合物在不同的浓度下孵育一段足够长的时间,常常在约1小时至1周之间,以使活性剂诱导细胞死亡或抑制细胞增殖、细胞活力或迁移。可以使用从活组织检查样品培养得到的细胞进行体外试验。然后确定处理后残留的细胞的量。
剂量随所用的具体化合物、具体的疾病、患者状况等而不同。治疗剂量通常相当充分,以减少靶组织中的不希望的细胞群体,同时维持患者的生存能力。通常持续进行治疗直到存在相当大的细胞负载的减少,例如,至少约50%的细胞负载的减少,并且可持续治疗直到机体中基本上不再检测到不希望的细胞。
已经发现,根据本发明的化合物造成MetAP-2的特异性抑制。根据本发明的化合物优选表现出在例如本文中描述的试验中可检出的有利的生物活性。在这类试验中,根据本发明的化合物表现出并造成抑制作用,所述抑制作用经常由在合适范围、优选在微摩尔范围且更优选在纳摩尔范围的IC50值表示。
此外,根据本发明的化合物可用在某些现有癌症化疗法和放射疗法中以实现附加或协同效应和/或以恢复某些现有癌症化疗法和放射疗法的效力。
根据本发明的化合物还可用于治疗肥胖症。Henri R. Lijnen等人在Obesity,第18卷,no.12, 2241-2246 (2010)中描述了一种Met-AP2抑制剂-烟曲霉素在减少脂肪组织中的用途。
在WO 2011/085201 A1中也描述了使用Met-AP2抑制剂(烟曲霉素类型的化合物)用于治疗肥胖症。
根据本发明的化合物也可用于治疗疟疾。X. Chem等人在Chemistry & Biology,第16卷, 193-202 (2009)中描述了一种Met-AP2抑制剂-烟曲霉素在治疗疟疾中的用途。
根据本发明的化合物也可用于治疗良性前列腺肥大。
在WO 2011/085198 A1中描述了使用Met-AP2抑制剂(烟曲霉素类型的化合物)治疗良性前列腺肥大。
根据本发明的化合物还意指这些化合物的水合物和溶剂合物,以及可药用衍生物。
本发明还涉及这些化合物的旋光活性形式(立体异构体)、盐、对映体、外消旋物、非对映体以及水合物和溶剂合物。术语化合物的溶剂合物理解为由于它们的相互吸引力而形成的惰性溶剂分子加合到该化合物上。溶剂合物是例如单-或二水合物或醇化物。
术语可药用衍生物意指例如根据本发明的化合物的盐以及所谓的前药化合物。
术语前药衍生物意指已用例如烷基或酰基、糖或寡肽修饰的根据本发明的化合物,其在生物体中快速裂解产生有效的根据本发明的化合物。
这些还包括如例如在Int. J. Pharm. 115, 61-67 (1995)中所述的根据本发明的化合物的可生物降解的聚合物衍生物。
表述“有效量”表示在组织、系统、动物或人类中造成例如研究人员或医生追求或想要的生物或医疗应答的药剂或药物活性化合物的量。
此外,表述“治疗有效量”是指与没有接受这种量的相应对象相比具有下列后果的量:改进的治疗、愈合、预防或消除疾病、综合症、病况、不适、病症或副作用或减轻疾病、病况或病症的发展。
表述“治疗有效量”也包括有效提高正常生理机能的量。
本发明还涉及使用根据本发明的化合物的混合物,例如两种非对映体的混合物,例如以1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000的比率。
这些特别优选是立体异构体化合物的混合物。
根据本发明的优选的化合物选自:
及其可药用盐、互变异构体和立体异构体,包括其所有比率的混合物。
此外,根据本发明的优选的化合物选自:
及其可药用盐、互变异构体和立体异构体,包括其所有比率的混合物。
优选是“A75”、“A78”和“A79”及其可药用盐、互变异构体和立体异构体,包括其所有比率的混合物。
根据本发明的化合物及其盐按对于WO 2011/004608和WO 2013/149704的式I的化合物所述制备。
根据本发明的化合物的制备类似于WO 2011/004608中所述的式I化合物及其可药用盐、互变异构体和立体异构体进行,特征在于
a) 将式II化合物
其中R1和R3具有WO 2011/004608的权利要求1所示的含义,
和L表示Cl、Br、I或游离OH基团或反应官能性修饰的OH基团,
与式III化合物反应,
其中R2和R4具有WO 2011/004608的权利要求1所示的含义,
或者
b) 为制备WO 2011/004608的式I化合物,其中R3表示OH,
将式IV化合物氧化
其中R1、R2和R4具有WO 2011/004608的权利要求1所示的含义,
或者
c) 通过用卤素原子置换OH基团,或用N3置换卤素原子,将基团R3转化为另一基团R3,
和/或将式I的碱或酸转化为其盐之一。
此外,通过本身已知的方法,更确切地说在已知并适合所述反应的反应条件下,制备根据本发明的化合物及其制备用的原材料,所述方法如文献中(例如在标准著作中,如Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart)描述的。在此也可以使用在本文中没有更具体提及的本身已知的变型。
根据本发明的化合物和WO 2011/004608或WO 2013/149704中描述的式I化合物优选可以通过式II的化合物与式III的化合物的反应来获得。
式II和式III的化合物通常是公知的。但是,如果它们是新颖的,则可通过本身已知的方法来制备。
在式II的化合物中,L优选是指Cl、Br、I或游离的或反应性修饰的OH基团,例如活化酯、咪唑基(Imidazolide)或具有1-6个C原子的烷基磺酰基氧基(优选为甲基磺酰基氧基或三氟甲基磺酰基氧基)或具有6-10个C原子的芳基磺酰基氧基(优选为苯基-或对甲苯基磺酰基氧基)。
该反应优选在脱水剂,任选在N-羟基苯并三唑存在下完成,所述脱水机例如为碳二亚胺,如N,N'-二环己基碳二亚胺("DCCI")、1,1'-羰基二咪唑或N-3-二甲基氨基丙基-N'-乙基碳二亚胺("DAPECI"),以及丙烷磷酸酐T3P(参见Angew. Chem. 92, 129 (1980))、二苯基磷酰叠氮化物或2-乙氧基-N-乙氧基羰基-1,2-二氢喹啉;
。
该反应在惰性溶剂中进行并通常在酸结合剂,优选有机碱,如DIPEA、三乙胺、二甲基苯胺、吡啶或喹啉存在下进行。
添加碱金属-或碱土金属-氢氧化物、碳酸盐或碳酸氢盐,或碱金属或碱土金属,优选钾、钠、钙或铯的另外的弱酸盐的也会是有利的。
根据所用条件,反应时间在数分钟至14天之间,反应温度在大约-15°至150°之间,通常在40°至130°之间,特别优选在60°至110℃之间。
合适的惰性溶剂是例如烃,如己烷、石油醚、苯、甲苯或二甲苯;氯化的烃,如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇,如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,如乙醚、二异丙基醚、四氢呋喃(THF)或二氧杂环己烷;二醇醚,如乙二醇单甲基醚或乙二醇单乙基醚、乙二醇二甲基醚(二甘醇二甲醚);酮,如丙酮或丁酮;酰胺,如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,如乙腈;亚砜,如二甲亚砜(DMSO);二硫化碳;羧酸,如甲酸或乙酸;硝基化合物,如硝基甲烷或硝基苯;酯,如乙酸乙酯或所述溶剂的混合物。
特别优选的是二醇醚,如乙二醇单甲基醚、THF、二氯甲烷和/或DMF。
式I的化合物还优选通过氧化式IV的化合物获得。
优选使用过氧化氢叔丁基进行所述氧化。
根据所用条件,反应时间在数分钟至14天之间,反应温度在大约-15°至150°之间,通常在40°至130°之间,特别优选在60°至110℃之间。
作为溶剂优选的是水,其中也优选添加碱金属-或碱土金属-氢氧化物、碳酸盐或碳酸氢盐,或碱金属或碱土金属,优选钾、钠、钙或铯的另外的弱酸盐。
药用盐和其它形式
所述根据本发明的化合物可以以它们的最终非盐形式使用。另一方面,本发明还包括以根据本领域中已知的程序可衍生自各种有机和无机酸和碱的它们的可药用的盐形式使用这些化合物。根据本发明的化合物的可药用的盐形式主要通过常规方法制备。如果根据本发明的化合物含有羧基,则可以通过使该化合物与合适的碱反应产生相应的碱加成盐来形成其合适的盐之一。这样的碱是例如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;和各种有机碱,如哌啶、二乙醇胺和N-甲基谷氨酰胺。同样包括根据本发明的化合物的铝盐。在某些根据本发明的化合物的情况下,可以通过用可药用的有机和无机酸,例如卤化氢,如氯化氢、溴化氢或碘化氢、其它无机酸及其相应的盐,硫酸盐、硝酸盐或磷酸盐等和烷基-和单芳基磺酸盐,如乙磺酸盐、甲苯磺酸盐和苯磺酸盐,和其它有机酸及其相应的盐,如乙酸盐、三氟乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等处理这些化合物来形成酸加成盐。相应地,式I的化合物的可药用的酸加成盐包括下列:乙酸盐、己二酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(苯磺酸盐)、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、粘酸盐(由粘酸形成)、半乳糖醛酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴化物、氢碘化物、2-羟基乙磺酸盐、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖醛酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、甲基苯甲酸盐、磷酸一氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、双羟萘酸盐(palmoate)、果胶酯酸盐、过硫酸盐、苯基乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这并非限制。
此外,根据本发明的化合物的碱式盐包括铝-、铵-、钙-、铜-、铁(III)-、铁(II)-、锂-、镁-、锰(III)-、锰(II)-、钾-、钠和锌盐,但这无意代表限制。在上述盐中,优选铵;钠和钾的碱金属盐,以及钙和镁的碱土金属盐。衍生自可药用的有机无毒碱的根据本发明的化合物的盐包括伯胺、仲胺和叔胺、取代胺,也包括天然存在的取代胺、环胺和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、N,N'-二苄基乙二胺(苄星)、二环己基胺、二乙醇胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡糖胺、葡糖胺、组氨酸、哈胺(Hydrabamine)、异丙胺、利多卡因、赖氨酸、葡甲胺、N-甲基-D-葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟基甲基)甲基胺(氨丁三醇)的盐,但这无意代表限制。
含有碱性含氮的基团的本发明的化合物可以用如(C1-C4)烷基卤,例如甲基-、乙基-、异丙基-和叔丁基氯、-溴和-碘;二(C1-C4)烷基硫酸盐,例如二甲基-、二乙基-和二戊基硫酸盐;(C10-C18)烷基卤,例如癸基-、十二烷基-、月桂基-、十四烷基-和十八烷基氯、-溴和-碘;和芳基-(C1-C4)烷基卤,例如苄基氯和苯乙基溴之类的试剂季碱化。可以使用这样的盐制备根据本发明的水溶性和油溶性化合物。
优选的上述药用盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴化物、羟乙基磺酸盐、扁桃酸盐、葡甲胺、硝酸盐、油酸盐、膦酸盐、特戊酸盐、磷酸钠、硬脂酸盐、硫酸盐、磺基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨丁三醇,但这无意代表限制。
通过使游离碱形式与足量的所需酸接触,由此以常规方式形成盐来制备碱性的根据本发明的化合物的酸加成盐。可以通过使盐形式与碱接触并以常规方式分离游离碱来再生游离碱。游离碱形式在某些方面,在某些物理性质,如在极性溶剂中的溶解度方面不同于其相应的盐形式;但为了本发明的目的,该盐在其它方面相应于其各自的游离碱形式。
如所提到,用金属或胺,如碱金属和碱土金属或有机胺形成根据本发明的化合物的可药用的碱加成盐。优选的金属是钠、钾、镁和钙。优选的有机胺是N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡糖胺和普鲁卡因。
通过使游离酸形式与足量的所需碱接触,由此以常规方式形成盐来制备根据本发明的酸性化合物的碱加成盐。可以通过使盐形式与酸接触并以常规方式分离游离酸来再生游离酸。游离酸形式在某些方面,在某些物理性质,如在极性溶剂中的溶解度方面不同于其相应的盐形式;但为了本发明的目的,该盐在其它方面相应于其各自的游离酸形式。
如果根据本发明的化合物含有多于一个能形成这种类型的可药用的盐的基团,则本发明还包括复合盐。典型的复合盐形式包括例如,酒石酸氢盐、双乙酸盐、富马酸氢盐、二葡甲胺、二磷酸盐、二钠和三盐酸盐,但这无意代表限制。
根据上文可以看出,表述“可药用的盐”在本文中意指包含以其盐之一的形式的根据本发明的化合物的活性化合物,特别是,与之前使用的活性化合物的游离形式或该活性化合物的任何其它盐形式相比,如果这种盐形式赋予了该活性化合物改进的药代动力学性质。该活性化合物的可药用的盐形式还可首次赋予这种活性化合物之前没有的并甚至在其体内治疗效力方面对这种活性化合物的药效学可具有积极影响的所需药代动力学性质。
本发明还涉及包含至少一种根据本发明的化合物和/或其可药用衍生物、溶剂合物和立体异构体,包括它们以所有比率的混合物和任选赋形剂和/或辅助剂的药剂。
药物制剂可以以每剂量单位包含预定量的活性化合物的剂量单位形式给药。根据治疗的病况、给药方法和患者的年龄、体重和状况,这样的单位可包含例如0.5毫克至1克,优选1毫克至700毫克,特别优选5毫克至100毫克的根据本发明的化合物,或药物制剂可以以每剂量单位包含预定量的活性化合物的剂量单位形式给药。优选的剂量单位制剂是包含如上指示的日剂量或分剂量或其相应部分的活性化合物的那些。此外,可以使用制药领域中公知的方法制备这种类型的药物制剂。
可调整药物制剂经由任意合适方法给药,例如通过经口(包括口腔或舌下)、直肠、经鼻、局部(包括口腔、舌下或经皮)、阴道或肠道外(包括皮下、肌肉内、静脉内或皮内)方法。可以使用制药领域中已知的所有方法通过例如将活性化合物与一种或多种赋形剂或一种或多种辅助剂合并来制备这样的制剂。
适合口服给药的药物制剂可作为独立单位,例如胶囊或片剂;粉剂或颗粒剂;在水性或非水性液体中的溶液或混悬液;可食用泡沫或泡沫食品;或水包油液体乳剂或油包水液体乳剂给药。
因此,例如,在片剂或胶囊形式的口服给药情况下,可以将活性成分组分与口服、无毒和可药用的惰性赋形剂,例如乙醇、甘油、水等合并。通过将该化合物研碎至合适的细粒度并将其与以类似方式研碎的药物赋形剂,例如可食用的碳水化合物,例如淀粉或甘露醇混合,制备粉剂。还可能存在矫味剂、防腐剂、分散剂和染料。
通过如上所述制备粉末混合物并用其填充成形明胶壳,制造胶囊。在填充操作之前可以将助流剂和润滑剂,例如固体形式的高分散二氧化硅、滑石、硬脂酸镁、硬脂酸钙或聚乙二醇添加到该粉末混合物中。也可以添加崩解剂或增溶剂,例如琼脂、碳酸钙或碳酸钠,以改进服用胶囊后药剂的利用度。
此外,如果需要或必要,也可以将合适的粘合剂、润滑剂和崩解剂以及染料掺入该混合物中。合适的粘合剂包括淀粉、明胶、天然糖,例如葡萄糖或β-乳糖,由玉米制成的甜味剂、天然和合成橡胶,例如阿拉伯树胶、黄蓍胶或藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。这些剂型中所用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括,但不限于,淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。通过例如制备粉末混合物、粒化或干压该混合物,添加润滑剂和崩解剂并将整个混合物压制成片剂来配制片剂。通过将以合适方式粉碎的化合物与如上所述的稀释剂或基料和任选与粘合剂,例如羧甲基纤维素、藻酸盐、明胶或聚乙烯基吡咯烷酮、溶出阻滞剂,例如石蜡,吸收促进剂,例如季铵盐,和/或吸收剂,例如膨润土、高岭土或磷酸二钙混合,制备粉末混合物。可以通过用粘合剂,例如糖浆、淀粉糊、阿拉伯胶浆或纤维素-或聚合物材料的溶液润湿并将其压过筛子来粒化该粉末混合物。代替粒化,可以使粉末混合物经过压片机,以产生形状不均匀的团块,将其打碎形成颗粒。可以通过添加硬脂酸、硬脂酸盐、滑石或矿物油使颗粒涂上油脂以防止粘着到铸片模具上。然后将经涂脂的混合物压成片剂。根据本发明的化合物也可以与自由流动的惰性赋形剂合并,然后在不进行造粒或干压步骤的情况下直接压成片剂。可存在由虫胶密封层、糖或聚合物材料层和蜡制光泽层构成的透明或不透明保护层。可以将染料添加到这些包衣中以便能区分不同的剂量单位。
口服液,例如溶液、糖浆和酏剂可以以剂量单位形式制备以使所给的量包含预定量的化合物。可以通过将该化合物溶解在含合适矫味剂的水溶液中来制备糖浆,而使用无毒醇类媒介物制备酏剂。可以通过将该化合物分散在无毒媒介物中来配制混悬液。也可以加入增溶剂和乳化剂,例如乙氧基化异硬脂醇和聚氧乙烯山梨糖醇醚,防腐剂、矫味添加剂,例如薄荷油,或天然甜味剂或糖精,或其它人工甜味剂等。
如果期需,用于口服给药的剂量单位制剂可包封在微囊中。也可以以延长或延迟释放的方式制备该制剂,例如通过将微粒材料包衣或包埋于聚合物、蜡等中。
根据本发明的化合物及其盐、溶剂合物和生理功能衍生物还可以以脂质体递送体系,例如单层小囊泡、单层大囊泡和多层囊泡的形式给药。脂质体可以由各种磷脂,例如胆固醇、硬脂胺或磷脂酰胆碱形成。
根据本发明的化合物及其盐、溶剂合物和生理功能衍生物还可以使用单克隆抗体作为该化合物分子偶联于其上的独立载体递送。该化合物还可到与作为靶向药剂载体的可溶聚合物偶联。这样的聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰氨基苯酚、聚羟乙基天冬酰氨基苯酚或聚氧化乙烯聚赖氨酸,其被棕榈酰基基团取代。此外,该化合物可偶联到适合实现药剂控释的一类可生物降解的聚合物,例如聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃类、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物上。
适于经皮施用的药物制剂可以作为与接受者的表皮长期紧密接触的独立硬膏剂施用。因此,例如,可以用离子电渗疗法使活性化合物从硬膏剂中递送,如PharmaceuticalResearch, 3(6), 318 (1986)中的通用术语所述。
适合局部给药的药物化合物可配制为软膏剂、乳膏剂、混悬液、洗剂、粉剂、溶液、糊剂、凝胶、喷雾剂、气雾剂或油。
为了治疗眼睛或其它外部组织,例如口腔和皮肤,该制剂优选以局部软膏剂或乳膏剂的形式施用。在配制成软膏剂的情况下,活性化合物可以与石蜡族或水混溶性膏基一起使用。或者,活性化合物可以与水包油型乳膏基质或油包水型基质一起配制成膏剂。
适合局部施用于眼睛的药物制剂包括滴眼液,其中将活性化合物溶解或悬浮在合适的载体,特别是水性溶剂中。
适合局部施用于口腔的药物制剂包括锭剂、软锭剂和漱口液。
适合直肠给药的药物制剂可以以栓剂或灌肠剂的形式给药。
其中载体物质是固体的适合经鼻给药的药物制剂包括粒度为例如20-500微米的粗粉,其以鼻吸的方式给药,即通过经鼻腔通道从靠近鼻子的含有粉剂的容器中快速吸入。以液体作为载体物质的适合作为鼻喷雾剂或滴鼻剂给药的制剂包括在水或油中的活性成分溶液。
适合通过吸入给药的药物制剂包含可通过各种类型的含气雾剂的加压分配器、喷雾器或吹入器生成的细粒粉或雾。
适合阴道给药的药物制剂可作为子宫托、棉条、乳膏剂、凝胶、糊剂、泡沫或喷雾制剂给药。
适合肠道外给药的药物制剂包括包含抗氧化剂、缓冲剂、抑菌剂和由此使得该制剂与被治疗的受体的血液等渗的溶质的水性和非水性无菌注射液;可包含悬浮介质和增稠剂的水性和非水性无菌混悬液。该制剂可以在单剂量或多剂量容器,例如密封的安瓿和小瓶中给药并以冷冻干燥(冻干)状态储存,以便仅需在临用前加入无菌载体液体例如注射用水。按照处方制备的注射溶液和混悬液可以由无菌粉末、颗粒和片剂制备。
不言而喻的是,除上文特别提到的成分外,该制剂还可包含本领域中根据制剂的特定类型常见的其它试剂;因此,例如,适合口服的制剂可包含矫味剂。
根据本发明的化合物的治疗有效量取决于许多因素,包括例如动物的年龄和体重、需要治疗的确切病症及其严重程度、制剂的性质和给药方法,并最终由治疗医生或兽医决定。但是,用于治疗肿瘤生长,例如结肠或乳腺癌的本发明的化合物的有效量通常在0.1至100毫克/公斤受体(哺乳动物)体重/天的范围,并特别通常为1至10毫克/公斤体重/天的范围。因此,体重70公斤的成年哺乳动物每天的实际量通常在70至700毫克之间,其中这种量可作为每天单剂给药或通常以每天一系列分剂量(例如2、3、4、5或6)给药,以使总日剂量相同。可作为根据本发明的化合物本身的有效量的比例确定其盐的有效量。类似剂量被认为适用于治疗上文提到的其它疾病情况。
本发明还涉及包含至少一种根据本发明的化合物和/或其可药用盐和立体异构体,包括它们所有比率的混合物和至少一种其它药剂活性化合物的药剂。
本发明还涉及套装(试剂盒),其由下列的单独包装构成
(a) 有效量的根据本发明的化合物和/或其可药用盐和立体异构体,包括它们所有比率的混合物,
和
(b) 有效量的其它药剂活性化合物。
该套装包含合适的容器,如盒、单个瓶、袋或安瓿。该套装可例如包含分开的安瓿,每个安瓿各自含有有效量的根据本发明的化合物和/或其可药用盐和立体异构体,包括它们以所有比率的混合物,和有效量的溶解或冻干形式的其它药剂活性化合物。
本发明涉及用于治疗肿瘤、肿瘤转移、肾小球系膜细胞的增殖性疾病、血管瘤、增殖性视网膜病、类风湿性关节炎、动脉粥样硬化新生血管形成、牛皮癣、眼部新生血管形成、骨质疏松症、糖尿病和肥胖症、淋巴性白血病、淋巴瘤、疟疾和前列腺肥大的根据本发明的化合物及其可药用盐、互变异构体和立体异构体,包括它们所有比率的混合物。
用途
本化合物适合作为药物活性化合物用于哺乳动物,尤其是人类以治疗和控制疾病。这些疾病包括肿瘤细胞增殖、促进实体瘤生长的病理性新生血管形成(或血管生成)、眼中的新生血管形成(糖尿病视网膜病变、年龄引发的黄斑变性等)和炎症(牛皮癣、类风湿性关节炎等)和肾小球系膜细胞的增殖性疾病。
本发明包括根据本发明的化合物和/或其生理学可接受的盐和溶剂合物用于制备用于治疗或预防肿瘤、肿瘤病和/或肿瘤转移的药剂的用途。
所述肿瘤病优选选自:鳞状上皮、膀胱、胃、肾、头颈、食道、子宫颈、甲状腺、肠、肝、脑、前列腺、泌尿生殖道、淋巴系统、胃、喉、肺、皮肤的肿瘤,单核细胞白血病、肺腺癌、小细胞肺癌、胰腺癌、成胶质细胞瘤、乳腺癌、急性骨髓性白血病、慢性骨髓性白血病、急性淋巴性白血病、慢性淋巴性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤。
还包括根据本发明的化合物和/或其生理学可接受的盐和溶剂合物用于制备用于治疗骨质疏松症、糖尿病和肥胖症的药剂的用途。
还包括根据本发明的化合物和/或其生理学可接受的盐和溶剂合物用于制备用于治疗或预防牵涉血管生成的疾病的药剂的用途。
牵涉血管生成的这种类型的疾病是眼病,如视网膜血管新生、糖尿病视网膜病变、年龄引发的黄斑变性等。
血管生成疾病优选选自糖尿病视网膜病变、关节炎、癌、牛皮癣、卡波西肉瘤、血管瘤、心肌血管生成、动脉粥样硬化斑块新生血管、血管生成性眼病、脉络膜新生血管、晶状体后纤维增生症、黄斑变性、角膜移植排斥、虹膜红变、神经肌肉青光眼(neuroscularglaucoma)、Oster Webber综合征。
肾小球系膜细胞的增殖性疾病优选选自肾小球肾炎、糖尿病肾病、恶性肾硬化、血栓性微血管病综合征、移植排斥、肾小球病。
根据本发明的化合物和/或其生理学可接受的盐和溶剂合物用于制备用于治疗或预防炎性疾病的药剂的用途也落在本发明的范围内。这样的炎性疾病的实例包括类风湿性关节炎、牛皮癣、接触性皮炎、迟发型过敏反应等。
所述炎性疾病优选选自炎性肠病、关节炎、动脉粥样硬化、哮喘、过敏症、炎性肾病、多发性硬化、慢性阻塞性肺疾病、炎性皮肤病、牙周疾病(pardontal disease)、牛皮癣、T-细胞介导的免疫病。
所述炎性肠病优选选自溃疡性结肠炎、克罗恩病、非特异性结肠炎。
所述T-细胞介导的免疫病优选选自变应性脑脊髓炎、变应性神经炎、移植排斥、移植物抗宿主反应、心肌炎、甲状腺炎、肾炎、系统性红斑狼疮、胰岛素依赖性糖尿病。
所述关节炎病优选选自类风湿性关节炎、骨关节炎、卡普兰综合征、费尔蒂综合征、干燥综合征、强直性脊柱炎、斯蒂尔病、软骨钙质沉着病、代谢性关节炎、风湿热、莱特尔氏病、Wissler综合征。
所述炎性肾病优选选自肾小球肾炎、肾小球损伤、肾病综合征、间质性肾炎、狼疮性肾炎、肺出血性肾炎综合征、韦格纳肉芽肿、肾血管炎、IgA肾病、特发性肾小球疾病。
所述炎性皮肤病优选选自牛皮癣、特应性皮炎、接触敏感、痤疮。
还包括根据本发明的化合物和/或其可药用的盐和溶剂合物用于制备用于治疗或预防哺乳动物的疾病或病症的药剂的用途,在这种方法中,将治疗有效量的根据本发明的化合物给予需要这种治疗的生病哺乳动物。治疗量取决于具体疾病并可以由本领域技术人员不经过度努力来确定。
本发明还包括根据本发明的化合物和/或其生理学可接受的盐和溶剂合物用于制备用于治疗或预防视网膜血管形成的药剂的用途。
还包括根据本发明的化合物和/或其可药用的盐用于制备用于治疗和/或对抗哺乳动物的肿瘤引发的疾病的药剂的用途,在这种方法中,将治疗有效量的本发明的化合物给予需要这种治疗的生病哺乳动物。治疗量取决于具体疾病并可以由本领域技术人员不经过度努力来确定。
所公开的根据本发明的化合物可以与其它治疗剂,包括抗癌剂联合给药。如这里所使用的,术语“抗癌剂”涉及以治疗癌症为目的给予癌症患者的任何药剂。
上文定义的抗癌治疗可以作为单一疗法应用,或者除了本文公开的化合物之外,还可以包括常规外科手术或放射疗法或药物治疗。这样的药物治疗,例如化疗或靶向治疗,可以包括下列抗肿瘤剂的一种或多种,但优选一种:
烷基化剂
例如六甲蜜胺,苯达莫司汀,白消安,卡莫司汀,苯丁酸氮芥,氮芥(chlormethine),环磷酰胺,达卡巴嗪,异环磷酰胺,英丙舒凡, 甲苯磺酸盐, 洛莫司汀, 美法仑, 二溴甘露醇, 二溴卫矛醇, 尼莫司汀, 雷莫司汀, 替莫唑胺, 塞替派, 曲奥舒凡, 氮芥(mechloretamine), 卡波醌;
apaziquone,福莫司汀,葡磷酰胺,palifosfamide,哌泊溴烷,曲磷胺,乌拉莫司汀,TH-3024, VAL-0834;
铂化合物
例如卡铂,顺铂,依他铂,米铂(miriplatine)水合物,奥沙利铂,洛铂,奈达铂,吡铂(picoplatin),沙铂;
洛铂,奈达铂,吡铂,沙铂;
DNA改变剂
例如氨柔比星,比生群,地西他滨,米托蒽醌,丙卡巴肼,曲贝替定,氯法拉滨;
安吖啶,brostallicin,pixantrone,laromustine1,3;
拓扑异构酶抑制剂
例如依托泊苷,伊立替康,雷佐生,索布佐生,替尼泊苷,拓扑替康;
氨萘非特,贝洛替康,elliptinium乙酸盐, voreloxin;
微管调节剂
例如卡巴他赛,多西紫杉醇,艾日布林,伊沙匹隆(ixabepilone),紫杉醇,长春碱,长春新碱,长春瑞滨,长春地辛,长春氟宁;
fosbretabulin,替司他赛;
抗代谢物
例如天冬酰胺酶3,阿扎胞苷,左亚叶酸钙,卡培他滨,克拉屈滨, 阿糖胞苷, 依诺他滨, 氟尿苷, 氟达拉滨,氟尿嘧啶,吉西他滨,巯基嘌呤,甲氨蝶呤,奈拉滨,培美曲塞,普拉曲塞,硫唑嘌呤,硫鸟嘌呤,卡莫氟;
去氧氟尿苷, elacytarabine,雷替曲塞,沙帕他滨,替加氟2,3,三甲曲沙;
抗癌抗生素
例如博来霉素, 更生霉素, 多柔比星, 表柔比星, 伊达比星, 左旋咪唑, 米替福新,丝裂霉素C,罗米地辛,链脲菌素,戊柔比星,净司他丁,佐柔比星,柔红霉素,普卡霉素;
阿柔比星,培罗霉素,吡柔比星;
激素/拮抗剂
例如阿巴瑞克,阿比特龙,比卡鲁胺,布舍瑞林,卡普睾酮,氯烯雌醚,地加瑞克(degarelix),地塞米松,雌二醇,氟可龙,氟甲睾酮,氟他胺,氟维司群,戈舍瑞林,组氨瑞林,亮丙瑞林,甲地孕酮,米托坦,那法瑞林,诺龙,尼鲁米特,奥曲肽,泼尼松龙,雷洛昔芬,他莫昔芬,促甲状腺激素α,托瑞米芬,曲洛司坦,曲普瑞林,己烯雌酚;
阿佐比芬(acolbifene),达那唑,地洛瑞林,环硫雄醇,orteronel,enzalutamide1,3;
芳香酶抑制剂
例如氨鲁米特,阿那曲唑,依西美坦,法倔唑,来曲唑,睾内酯;
福美坦;
小分子激酶抑制剂
例如crizotinib,达沙替尼,厄洛替尼,伊马替尼,拉帕替尼,尼洛替尼,帕唑帕尼,regorafenib,ruxolitinib,索拉非尼,舒尼替尼,凡德他尼,vemurafenib,波舒替尼,吉非替尼,阿西替尼;
阿法替尼,alisertib,dabrafenib,dacomitinib,dinaciclib,dovitinib,enzastaurin,nintedanib,lenvatinib,linifanib,linsitinib,masitinib,米哚妥林,motesanib,来那替尼,orantinib,哌立福辛(perifosine),ponatinib,radotinib,rigosertib,tipifarnib,tivantinib,tivozanib,trametinib,pimasertib,brivanibalaninate, cediranib, apatinib4, cabozantinib S-malate1,3, ibrutinib1,3,icotinib4, buparlisib2, cipatinib4, cobimetinib1,3, idelalisib1,3, fedratinib1,XL-6474;
光敏剂
例如甲氧沙林3;
卟吩姆钠,他拉泊芬,替莫泊芬;
抗体
例如阿仑单抗,besileomab,brentuximab vedotin,西妥昔单抗,denosumab,ipilimumab,ofatumumab,帕尼单抗,利妥昔单抗,托西莫单抗,曲妥珠单抗,贝伐单抗,帕妥珠单抗2,3;
catumaxomab,elotuzumab,依帕珠单抗,farletuzumab,mogamulizumab,necitumumab,尼妥珠单抗,obinutuzumab,ocaratuzumab,oregovomab,ramucirumab,rilotumumab,siltuximab,tocilizumab,扎妥木单抗,zanolimumab,马妥珠单抗,dalotuzumab1,2,3,onartuzumab1,3, racotumomab1, tabalumab1,3, EMD-5257974, nivolumab1,3;
细胞因子
例如阿地白介素,干扰素α2,干扰素α2a3,干扰素α2b2,3;
西莫白介素,他索纳明,替西白介素,奥普瑞白介素1,3,重组干扰素β-1a4;
药物缀合物
例如地尼白介素(denileukin diftitox),替伊莫单抗,碘苄胍I123,泼尼莫司汀,曲妥珠单抗emtansine,雌莫司汀,吉姆单抗,奥佐米星,阿柏西普;
cintredekin besudotox, edotreotide, 伊替单抗奥佐米星,naptumomabestafenatox,oportuzumab monatox,锝(99mTc)阿西莫单抗1,3,vintafolide1,3;
疫苗
例如sipuleucel3; vitespen3, emepepimut-S3, oncoVAX4, rindopepimut3,troVax4, MGN-16014, MGN-17034;
其它
阿利维A酸,贝沙罗汀,硼替佐米,依维莫司,伊班膦酸,咪喹莫特,来那度胺,香菇多糖,甲酪氨酸,mifamurtide,帕米膦酸,培门冬酶,喷司他丁,sipuleucel3,西佐喃,他米巴罗汀,西罗莫司,沙利度胺,维甲酸,vismodegib,唑来膦酸,伏立诺他;
塞来昔布,西仑吉肽,entinostat,依他硝唑,ganetespib,idronoxil,iniparib,ixazomib,氯尼达明,尼莫唑,帕比司他,peretinoin,plitidepsin,pomalidomide,丙考达唑,ridaforolimus,tasquinimod,telotristat,胸腺法新,替拉扎明,tosedostat,trabedersen,乌苯美司,伐司朴达,gendicine4,溶链菌4, reolysin4, retaspimycin盐酸盐1,3, trebananib2,3, 维鲁利秦(virulizin)4, carfilzomib1,3, 内皮他丁(endostatin)4, immucothel4, belinostat3, MGN-17034;
1 Prop. INN (提议的国际非专有名称)
2 Rec. INN (推荐的国际非专有名称)
3 USAN (美国采用的名称)
4 非INN。
药理学抑制剂对肿瘤细胞的增殖/活力的作用的体外证明
1.0 背景
在本实验描述中,描述了通过活性化合物抑制肿瘤细胞增殖/肿瘤细胞活力。
在微滴定板(96孔形式)中以合适的细胞密度播种细胞并以浓度系列的形式加入受试物质。在含血清的培养基中再培养4天后,可以借助阿尔玛蓝试验系统测定肿瘤细胞增殖/肿瘤细胞活力。
2.0 实验方法
2.1 细胞培养
例如,市售可得的结肠癌细胞系、卵巢细胞系、前列腺细胞系或乳腺细胞系等。
在培养基中培养细胞。以几天的时间间隔,借助于胰蛋白酶溶液从培养皿中剥离细胞并在合适稀释度下播种在新鲜培养基中。在37℃和10% CO2下培养细胞。
2.2. 细胞播种
用多通道移液器将规定的细胞数(例如2000个细胞)/培养物/在180微升体积培养基中的孔播种在微滴定板(96孔细胞培养板)中。随后在CO2培养器(37℃和10% CO2)中培养细胞。
2.3. 受试物质的添加
将受试物质溶解在例如DMSO中并随后以相应浓度(如果需要,以稀释系列)用在细胞培养基中。可根据活性化合物的效力和所希望的浓度分布调节稀释等级。将细胞培养基以相应浓度添加到受试物质中。可以在细胞播种的同一天将受试物质添加到细胞中。为此,在每种情况下,将来自预稀释板的20微升物质溶液添加到培养物/孔中。细胞在37℃和10% CO2下再培养4天。
2.4. 显色反应的测量
在各情况下,每孔分别加入20微升AlamarBlue试剂,并将微滴定板在CO2培养器(在37℃和10% CO2下)中再孵育例如7小时。在带有荧光过滤器的读数器中在540纳米波长下测量板。可在临测量前轻轻摇动板。
3. 评估
从所有其它吸光度值中减去培养基对照物(未使用细胞和受试物质)的吸光度值。将对照物(无受试物质的细胞)设定为等于100%,并相对于其表示所有其它吸光度值(例如以对照物的%):
计算:
借助统计程序,例如RS1测定IC50值(50%抑制)。
在BrdU增殖试验(细胞检测)中测定甲硫氨酸氨肽酶2的抑制剂的增殖抑制
通过将溴脱氧尿嘧啶核苷(BrdU)加入人脐静脉内皮细胞(HUVEC, PromoCell, C-12200)中,测定增殖抑制。在37℃和5% CO2下,在含有补充剂混合物(PromoCell, C-39225)的基础培养基(PromoCell, C-22200)中培养HUVEC。在借助胰蛋白酶/EDTA剥离细胞后,测定活细胞数并在175微升总体积中以每孔1000个细胞的密度播种细胞(孔预先用补充的培养基在37℃下涂布1-2小时或用1.5%明胶在37℃下涂布0.5-2小时)。在培养24小时后,以各种浓度(例如在10倍逐步稀释中,最终浓度30 µM至0.03 nM)和25微升的体积加入受试物质。DMSO浓度恒定保持在0.3%。在培养总共48或72小时后,加入20微升溴脱氧尿嘧啶核苷(Roche, # 11647229001,在培养基中1:1000稀释,最终浓度10µM),并培养另外20至24小时。在用受试物质培养总共72或96小时后,除去培养基并进行免疫组织化学测定以检测BrdU并入(BrdU ELISA, Roche, # 11647229001)。为此,在室温下将细胞用固定剂处理30分钟,随后用过氧化物酶标记的抗-BrdU抗体(在抗体稀释缓冲液中稀释1:100)在室温下孵育60分钟。在用1倍浓缩的DPBS缓冲液(Gibco, # 14200)洗涤三次后,在TMB底物溶液中引发酶促反应。在15分钟后通过添加25微升1M硫酸溶液,停止显色。在5分钟内,通过在450 nM波长下测量进行光学密度测定。所用对照物是含有DMSO处理的细胞(100%对照)的孔或空孔(空白值)。通过使用抑制剂烟曲霉素检查和证实这一试验对甲硫氨酸氨肽酶抑制剂的敏感性。
MetAP-2活性测量
通过偶联酶反应测定MetAP-2活性。使用三肽Met-Arg-Ser (MAS)作为底物。释放的甲硫氨酸首先通过L-氨基氧化酶(AAO)转化成Metox和H2O2。在第二步骤中,借助于H2O2,过氧化物酶(POD)催化隐色染料邻联茴香胺生成邻联茴香胺ox的氧化,在450纳米下光度检出其增加。
可以作为动力学连续记录MetAP-2活性。反应图式表明,每摩尔甲硫氨酸形成1摩尔邻联茴香胺ox。因此MetAP-2酶活性可以直接计算为每时间单位的Δ吸收。可以借助邻联茴香胺ox消光系数定量MetAP-2活性(摩尔Met/时间单位)。将每时间单位的消光变化绘成图表并在该反应的视觉线性区中进行斜率计算。
该化合物的活性概括在表1中。
通过并入BrdU定量测定HUVEC增殖
HUVEC意指人脐带静脉内皮细胞。
化合物的活性概述在表2。
测定的目的/定义
在5天孵育期后使用BrdU的并入作为细胞周期活性的度量,测量HUVEC增殖。在存在或不存在受试物质的情况下孵育细胞。在孵育期的最后18-24小时期间将BrdU加入至培养基。在细胞发展通过细胞周期的S-期(DNA合成)时将BrdU并入DNA。固定细胞,和并入的BrdU的量可使用用于检测BrdU的市售ELISA定量测定。
该测定法对于MetAP2项目而被开发用于筛选受试物质,但可应用于评价影响HUVEC增殖的任何物质的作用。
试剂
EGM MV – 细胞培养基
胰蛋白酶/EDTA (0.5% / 0.53 mM溶液)
不含Ca和Mg的Dulbeccos’s PBS
细胞增殖ELISA BrdU比色
DMSO
参比化合物
Abbott参比A-832234 MSC2129790
TNP-470 MSC1902850
程序
HUVEC在EGM MV培养基中常规培养和在第3和8代之间使用。
第1天–接种细胞
吸取75 µl/孔生长培养基EGM MV (Promocell)至96孔板,H行孔只接受培养基而无细胞,用于试剂空白。
将板在37℃孵育,同时制备细胞。
按惯例用胰蛋白酶收获HUVEC:
吸出培养基,用10 ml PBS洗涤单层细胞一次,每个T75 cm2瓶加入2 ml胰蛋白酶溶液和在37℃下孵育2-5分钟以使细胞脱离。
用10 ml EGM MV从瓶冲洗细胞和转移至离心管。
以400 xg离心5分钟,重悬和计数。
调整细胞浓度至1e4个细胞/ml。
在以75 ul/孔制备的板中,吸取100 ul/孔= 1000个细胞/孔,总体积175 ul/孔。
将板在37℃下孵育过夜。
第2天–加入受试物质
一般而言,受试物质由药房以10 mM在REMP管中提供。
将受试物质预稀释在DMSO中,然后制备在细胞培养基中的工作稀释液以加入细胞板。
受试物质的浓度范围是30 µM,连续3倍稀释,6点曲线。
参比化合物 –
MSC 1902850 TNP-270 以30 nM (1:1000预稀释)开始
MSC 2129790 以300 nM (1:100预稀释)开始
参比化合物必须在DMSO中预稀释,以产生浓度曲线,其中预期的EC50落入6-点曲线的中间。参比化合物的10 mM储液在DMSO中预稀释,然后按下所述加入板中。
在DMSO中预稀释受试物质:
在96孔聚丙烯圆底板中:
行A – 放入20 µl在DMSO中的10 mM受试物质储液(或按上所述预稀释的参比化合物)。
行B-H放入20 ul DMSO。
通过从行A转移10 µl至行B连续稀释3倍,混合和转移10 µl至行C,等等至行F。
行G是100 % = 未处理,仅DMSO。这是无作用参考= 在Assay Explorer中0 %作用的值。
行H是无细胞的试剂空白,仅培养基。这是标度参考/类型抑制 = 在AssayExplorer中-100 %作用的值。
在培养基中的工作稀释液:
在96孔聚丙烯圆底板中:
放入244 µl培养基/孔
转移6 µl的DMSO稀释液至含细胞培养基的孔= 1:41,6稀释= 8-倍浓度。
转移25 µl/孔的工作稀释液至含175 µl的细胞板,= 1:8稀释。
对于在测试板中终浓度30 µM,自10 mM储液的最终稀释为1:333 (即41.6 x 8)。所有孔包含0.3% DMSO。
将板在37℃孵育直至第4天。
第4天–加入BrdU
BrdU储液是10 mM,在PBS中(1000倍储液)。
通过按1:100将其稀释在培养基中,制备100 µM的工作稀释液。各板需要2.2 ml。使用22 µl BrdU储液/2.2 ml EGM MV培养基。
吸取20 µl/孔(1:10稀释)。终浓度= 10 µM BrdU。
将板在37℃孵育18-24 hr。
第5天–固定,变性,ELISA –按试剂盒说明书进行,具有以下体积变化:
摇出培养基,轻轻在纸巾上拍打,以除去所有培养基。
加入来自试剂盒的100 ul FixDenat溶液和在室温下孵育30 min。
摇出FixDenat和轻轻在纸巾上拍打。
使板短暂空气干燥(1-2分钟),允许固定的醇蒸发。
通过在试剂盒提供的抗体稀释缓冲液中1:100稀释储液,每次新鲜制备抗-BrdU过氧化物酶缀合物工作溶液。
各板需要5 ml,使用50 µl/5 ml抗体稀释缓冲液。
抗BrdU过氧化物酶缀合物储液通过将冻干物质溶解在1.1 ml MilliQ水中制备。将储液在4℃下保存数周,在-20℃下长期保存。
加入50 ul/孔的抗-BrdU过氧化物酶缀合物和在室温下在Eppendorf板振荡器上以300 rpm孵育60-90分钟。
摇出抗体溶液,和将板用225 µl/孔洗涤溶液(试剂盒中提供,或也可使用含Ca/Mg的PBS)洗涤3次。
加入100 µl/孔底物,和在室温下孵育5-10分钟。
加入25 µl/孔1 M H2SO4 终止溶液和将板在450 nm /参比690 nm在TecanInfiniteM200中读数。
注意:
或者可使用以下底物混合物。使用100 ml/孔和50 µl 1M H2SO4 终止溶液。测量波长如上所述。
底物:每次新鲜混合
柠檬酸盐/磷酸盐缓冲液pH 5 9 ml
1 mg/ml四甲基联苯胺/DMSO 1 ml
对于各10 ml底物,临用前加入2ul 30% H202
------------------------------------------------------
0.1M柠檬酸
0.2M磷酸氢二钠
混合243 ml的柠檬酸+ 257 ml的磷酸氢二钠得到pH 5.0
用MilliQ水使体积至1000 ml
3,3´,5,5´四甲基联苯胺 Merck VWR 1.08622
板设计 – 最终浓度
所有物质按一式三份运行。
统计学方法/数据分析
参比化合物在每一次测定中运行。期望值为:
8e-10M (范围2e-10M至1e-9M)的MSC1902850A
2e-8M (范围8e-9M至6e-8M)的MSC2129790A
背景活性–空白值或标度参比= 不含细胞的孔,应该为无作用参比(未处理的细胞)值的10%或更低。
使用Assay Explorer程序分析数据。简言之,从所有值减去空白,将一式三份平均和标准化至未处理。EC50从4-参数一般S形曲线测定(Hill拟合y = (s0 - sInf) / (1 +( x / AC50)^nHill) + sInf),Assay Explorer, Symyx)。
处理的数据(EC50或如果未达到EC50则为%作用,功效)从Assay Explorer直接上载至MSRDB。
安全性考虑
受试物质具有未知的活性,应以通常的安全性预防措施操作。在所有时间应穿戴手套和实验服。当操作DMSO中的浓缩储液时,建议腈而非橡胶手套。
所有污染废物(吸头、管、板)在用合适的标签标记的细胞毒性实验室废物箱中处置(2.29728.888)。
需要的化学品、一次性用品和设备清单
溶解度测量
通过“摇瓶溶解度测量法”测定
洗脱液制备:
洗脱液A: 2毫升二乙胺, 用于合成 +
1000毫升甲醇, LiChrosolv
洗脱液B: 5克乙酸铵, 用于合成 +
5毫升甲醇, LiChrosolv +
995毫升超纯水
样品溶剂:
缓冲液:3.954克一水合磷酸二氢钠 + 6.024克氯化钠 + 950毫升超纯水,使用0.1 MNaOH或0.1 M HCl调节pH。
样品制备:
样品在37℃和450 rpm下摇振24小时。
在大约7小时后,检查样品的pH,并且如果必要,调节pH。
还检查样品是否仍过量存在。
在24小时摇振时间临结束前,再检查样品的pH值和沉淀物。
超纯水装置: MilliQ梯度, Millipore, 仪器: F3PN37462D
摇振器: TiMix control, Bühler
孵育罩: TH 15 Bühler
pH计: 766 Calimatic Knick 仪器: pH 1
pH电极: InLab 423 Mettler。
根据本发明的化合物的外消旋最终产物或外消旋中间体可以简单地并以分析规模和以制备规模通过手性HPLC或SFC柱分离。
LC-MS
柱:Chromolith RP-18e 100-3
溶剂:
A:水+ 0.05%甲酸
B:乙腈+ 0.05%甲酸
流速:2.4 ml/min
梯度:
B: 0 -> 2.8 min; 4% -> 100%
B: 2.8 -> 3.3 min; 100%
时间:3.3 min
* LC-MS:
柱:XBridge C8, 3.5 µm, 4.6 x 50 mm;溶剂A:水+ 10 Mm NH4HCO3;溶剂B:CAN;流速:1 ml/min;梯度:0 min: 5 % B, 8 min: 100 % B, 8.1 min: 100 % B, 8.5 min: 5%B, 10 min 5% B。
在上下文中,所有温度以℃表示。在下列实施例中,“常规后处理”是指:如果必要,加入水,如果必要,根据最终产物的组成,将pH调节至2至10之间的值,用乙酸乙酯或二氯甲烷萃取混合物,分离各相,有机相经硫酸钠干燥,蒸发并通过硅胶上的色谱法和/或通过结晶纯化产物。
用于制备本发明的化合物的合成图式:
a)
b)
c)
a) 路径1:将酸在酰胺偶联中转化成相应的酰胺,然后在碱性环境中使用过氧化氢叔丁基在两个羧基之间的碳上氧化以产生醇(接着通过色谱法分离对映体)。
b) 路径2:或者,已经发现,在与途径1中描述用于酰胺的相同的氧化条件下,不能氧化原料酸的乙酯。但是,这可以用氯化铈来实现。以30%获得的氯衍生物可以与醇类似地分离成对映体,然后进一步衍生化。(在此没有显示进一步的反应,但产物随之为例如"A39"、"A43"和"A61")。
c) 但是,氟化铈的使用不产生类似的氟衍生物。醇化合物与DAST(三氟化二乙基氨基硫)在二氯甲烷中的反应产生所需的氟类似物。测试证实由使用DAST氟化醇的原理考虑预计到的在不对称中心的反转。
d)
在d)中显示可如何制备N-芳基内酰胺羧酸。如果氮化合物是液体,则这一途径可容易进行。据发现,如果氮-芳基化合物不是液体,则原材料的共同熔融不是有利的。但是,如果熔融氮-芳基化合物并将二羧酸酯(Meldrum’s酸)添加到这种熔体中,则获得所需产物。
e)
e)显示用以制备N-烷芳基内酰胺羧酸的路径。
f)
f)显示为了可利用内酰胺氮上的芳基而进行的另一替代方案,其中类似的氮化合物不是液体。在此,将内酰胺氮偶联到芳基卤化物上,这一步骤优选用过渡金属化合物催化。
实施例1
合成3-羟基-1-(4-甲烷亚磺酰亚胺基-苯基)-2-氧代-吡咯烷-3-甲酸 3-氯-5-氟-苄基酰胺 (“A64”)
1.1
在0℃下将0.73 ml的30% H2O2 溶液加入至1 g 4-溴苯甲硫醚的5 ml乙酸溶液。在RT下将混合物搅拌12 h和用10% NaOH溶液后处理。水相用乙酸乙酯萃取。有机相用饱和NaCl溶液洗涤,和经Na2SO4干燥。除去溶剂,得到0.97 g粗产物,其用于下一步骤无需进一步纯化。
1.2
在0℃下将223 mg叠氮化钠滴加至900 mg 1-溴-4-甲烷亚磺酰基-苯的18 ml氯仿溶液。在0℃下将混合物搅拌12 h和加入冰水。常规后处理得到600 mg粗产物,其用于下一步骤无需进一步纯化。
1.3
将253 mg 3-羟基-2-氧代-吡咯烷-3-甲酸 3-氯-5-氟-苄基酰胺(描述于WO 2013/149704)、359 mg碳酸钾、382 mg N‘,N‘-二甲基-乙烷-1,2-二胺和330 mg碘化铜(I)连续加入来自步骤1.2的200 mg 亚磺酰亚胺(sulfoximin)的12 ml脱气二噁烷溶液。在140 ℃下在微波炉中将混合物反应2 h。混合物经硅藻土过滤,和真空除去溶剂。制备型HPLC得到55mg的“A64” (非对映体混合物);
1H NMR 400 MHz, DMSO-d6: δ [ppm] 8.79 (t, J = 6.40 Hz, 1H), 7.90-7.96 (m,4H), 7.26-7.29 (m, 1H), 7.20 (s, 1H), 7.10 (d, J = 9.60 Hz, 1H), 6.87 (s,1H), 4.35-4.41 (m, 1H), 4.20-4.27 (m, 2H), 3.90-3.93 (m, 2H), 3.04 (d, J =0.80 Hz, 3H), 2.58-2.62 (m, 1H), 2.12-2.19 (m, 1H).
实施例2
合成(S)-3-羟基-1-(1H-吲唑-5-基)-2-氧代-吡咯烷-3-甲酸 3,5-二氟-苄基酰胺(“A75”)和(R)-3-羟基-1-(1H-吲唑-5-基)-2-氧代-吡咯烷-3-甲酸 3,5-二氟-苄基酰胺
2.1
在80 ℃下将11 g 6,6-二甲基-5,7-二氧杂-螺[2.5]辛烷-4,8-二酮和7 g 5-氨基吲唑在50 ml乙腈和50 ml DMF中的溶液搅拌12 h。
除去溶剂,常规后处理得到13 g 1-(1H-吲唑-5-基)-2-氧代-吡咯烷-3-甲酸。
2.2
将15 ml 4-甲基吗啉和16 g HATU (1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐)加入8.5 g 1-(1H-吲唑-5-基)-2-氧代-吡咯烷-3-甲酸的20 ml DMF溶液。在RT下将溶液搅拌20分钟和加入至6 g 3,5-二氟苄基胺的20 ml DMF溶液。在60 ℃下将混合物搅拌2 h。除去溶剂和常规后处理得到9 g 1-(1H-吲唑-5-基)-2-氧代-吡咯烷-3-甲酸 3,5-二氟-苄基酰胺。
2.3
将15.5 g单过氧钛酸镁六水合物加入至8.5 g 1-(1H-吲唑-5-基)-2-氧代-吡咯烷-3-甲酸 3,5-二氟-苄基酰胺的50 ml DMF溶液。在60 ℃下将黄色悬浮液搅拌12 h。除去溶剂和常规后处理后,残留物通过色谱法纯化(硅胶);收率:5.1 g (S)-3-羟基-1-(1H-吲唑-5-基)-2-氧代-吡咯烷-3-甲酸 3,5-二氟-苄基酰胺(“A75”)和(R)-3-羟基-1-(1H-吲唑-5-基)-2-氧代-吡咯烷-3-甲酸 3,5-二氟-苄基酰胺的黄色油。
2.4
5.1 g对映体混合物的分离通过SF色谱法进行。
柱:ChiralPAK AS-H
洗脱液:CO2 : 甲醇 = 80 : 20
波长:220 nm
流速:100 ml/min.
收率:
1.4 g (S)-3-羟基-1-(1H-吲唑-5-基)-2-氧代-吡咯烷-3-甲酸 3,5-二氟-苄基酰胺(“A75”)
1.3 g (R)-3-羟基-1-(1H-吲唑-5-基)-2-氧代-吡咯烷-3-甲酸 3,5-二氟-苄基酰胺(“A75”);
“A75”: LC-MS 1.776 min; [M+H+] [387.1]; 1H NMR (500 MHz, DMSO-d6) δ [ppm]13.07 (s, 1H), 8.68 (t, J = 6.4 Hz, 1H), 8.09 (d, J = 10.3 Hz, 1H), 7.91 (d,J = 1.6 Hz, 1H), 7.76 (dd, J = 9.0, 2.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H),7.05 (tt, J = 9.4, 2.3 Hz, 1H), 7.03 – 6.97 (m, 2H), 6.72 (s, 1H), 4.42 (dd,J = 15.8, 6.8 Hz, 1H), 4.27 (dd, J = 15.8, 6.0 Hz, 1H), 3.96 – 3.87 (m, 2H),2.63 (ddd, J = 12.0, 6.9, 4.9 Hz, 1H), 2.16 (dt, J = 12.9, 7.5 Hz, 1H).
类似获得以下化合物:
表1
MetAP-2的抑制
根据本发明的化合物的IC50
表2
HUVEC
根据本发明的化合物的IC50
比较性数据
与现有技术化合物相比,根据本发明的化合物,例如“A75”、“A78”和“A79”显示更高的溶解度。当给予化合物时,更高的溶解度导致更高的生物利用度。
下列实施例涉及药剂:
实施例A:注射小瓶
使用2 N盐酸将100克根据本发明的活性化合物和5克磷酸氢二钠在3升重蒸馏水中的溶液调节至pH 6.5,无菌过滤,转移到注射小瓶中,在无菌条件下冻干并在无菌条件下密封。各注射小瓶含有5毫克活性化合物。
实施例B:栓剂
将20克根据本发明的活性化合物与100克大豆卵磷脂和1400克可可油的混合物熔化,倒入模具中并使其冷却。每个栓剂含有20毫克活性化合物。
实施例C:溶液
在940毫升重蒸馏水中由1克根据本发明的活性化合物、9.38克NaH2PO4 ∙ 2 H2O、28.48克Na2HPO4 ∙ 12 H2O和0.1克苯扎氯铵制备溶液。将pH调节至6.8,将该溶液配至1升并通过辐射消毒。这种溶液可以以滴眼液形式使用。
实施例D:软膏
将500毫克根据本发明的活性化合物与99.5克凡士林在无菌条件下混合。
实施例E:片剂
将1千克根据本发明的活性化合物、4千克乳糖、1.2千克马铃薯淀粉、0.2千克滑石和0.1千克硬脂酸镁的混合物以常规方式压成片剂,其方式使各片剂含有10毫克活性化合物。
实施例F:糖衣丸
与实施例E类似地压制片剂并随后以常规方式用蔗糖、马铃薯淀粉、滑石、黄蓍胶和染料的包衣料包衣。
实施例G:胶囊
将2千克根据本发明的活性化合物以常规方式引入硬明胶胶囊中,其方式使各胶囊含有20毫克该活性化合物。
实施例H:安瓿
将1千克根据本发明的活性化合物在60升重蒸馏水中的溶液无菌过滤,转移到安瓿中,在无菌条件下冻干并在无菌条件下密封。各安瓿含有10毫克活性化合物。
Claims (8)
1.选自以下的化合物
及其可药用盐、互变异构体和立体异构体,包括其所有比率的混合物。
2.权利要求1的化合物,其选自
及其可药用盐、互变异构体和立体异构体,包括其所有比率的混合物。
3.权利要求1的化合物,其选自
及其可药用盐、互变异构体和立体异构体,包括其所有比率的混合物。
4.药剂,其包含至少一种根据权利要求1的化合物和/或其可药用盐、互变异构体和立体异构体,包括它们所有比率的混合物,以及任选赋形剂和/或辅助剂。
5.权利要求1的化合物及其可药用盐、互变异构体和立体异构体,包括它们所有比率的混合物,其用于治疗肿瘤、肿瘤转移、肾小球系膜细胞的增殖性疾病、血管瘤、增殖性视网膜病、类风湿性关节炎、动脉粥样硬化新生血管形成、牛皮癣、眼部新生血管形成、骨质疏松症、糖尿病和肥胖症、淋巴性白血病、淋巴瘤、疟疾和前列腺肥大。
6.权利要求5的化合物,其中所述肿瘤病选自:鳞状上皮、膀胱、胃、肾、头颈、食道、子宫颈、甲状腺、肠、肝、脑、前列腺、泌尿生殖道、淋巴系统、胃、喉、肺、皮肤,单核细胞白血病、肺腺癌、小细胞肺癌、胰腺癌、成胶质细胞瘤、乳腺癌、急性骨髓性白血病、慢性骨髓性白血病、急性淋巴性白血病、慢性淋巴性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤。
7. 权利要求1的化合物和/或其可药用的盐,其用于治疗肿瘤,其中将治疗有效量的根据权利要求1的化合物与选自下述的化合物联合给药:1) 雌激素受体调节剂、2) 雄激素受体调节剂、3) 类维生素A受体调节剂、4) 细胞毒素剂、5) 抗增殖剂、6) 异戊烯基-蛋白转移酶抑制剂、7) HMG-CoA还原酶抑制剂、8) HIV蛋白酶抑制剂、9) 逆转录酶抑制剂和10)其它血管生成抑制剂。
8. 权利要求1的化合物和/或其可药用的盐,其用于治疗肿瘤,其中将治疗有效量的根据权利要求1的化合物与放射疗法和下述的化合物联合给药:1) 雌激素受体调节剂、2) 雄激素受体调节剂、3) 类维生素A受体调节剂、4) 细胞毒素剂、5) 抗增殖剂、6) 异戊烯基-蛋白转移酶抑制剂、7) HMG-CoA还原酶抑制剂、8) HIV蛋白酶抑制剂、9) 逆转录酶抑制剂和10) 其它血管生成抑制剂。
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CN114026069A (zh) * | 2019-07-03 | 2022-02-08 | 默克专利股份公司 | 制造(s)-3-羟基-1-(1h-吲哚-5-基)-2-氧代-吡咯烷-3-甲酸3,5-二氟-苄基酰胺的工艺 |
CN112480100A (zh) * | 2019-09-11 | 2021-03-12 | 康威(广州)生物科技有限公司 | 吡咯烷酮衍生物 |
CN112480100B (zh) * | 2019-09-11 | 2022-10-14 | 康威(广州)生物科技有限公司 | 吡咯烷酮衍生物 |
CN111728969A (zh) * | 2020-08-25 | 2020-10-02 | 北京欣颂生物科技有限公司 | 抗衰老抗氧化的化合物在制备药物或者抗衰老化妆品中的用途 |
CN111840278A (zh) * | 2020-09-12 | 2020-10-30 | 北京欣颂生物科技有限公司 | 化合物与微生素e的组合在制备抗衰老药物或者化妆品中的用途 |
CN111840278B (zh) * | 2020-09-12 | 2021-09-03 | 自然堂生物科技(广州)有限公司 | 化合物与维生素e的组合在制备抗衰老药物或者化妆品中的用途 |
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