CN110012668B - 作为MEK1/2抑制剂的吡啶并[4,3-d]嘧啶-2,4,7-三酮的衍生物 - Google Patents
作为MEK1/2抑制剂的吡啶并[4,3-d]嘧啶-2,4,7-三酮的衍生物 Download PDFInfo
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- CN110012668B CN110012668B CN201680090983.XA CN201680090983A CN110012668B CN 110012668 B CN110012668 B CN 110012668B CN 201680090983 A CN201680090983 A CN 201680090983A CN 110012668 B CN110012668 B CN 110012668B
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Abstract
本发明的目的在于创造新的MEK1、MEK2和MEK1/2抑制剂,其在长期剂量中具有较低毒性。该目的通过式1的新化合物N‑{3‑[3‑环丙基‑5‑(2‑氟‑4‑碘苯基氨基)‑6,8‑二甲基‑2,4,7‑三氧代‑3,4,6,7‑四氢‑2H‑吡啶并[4,3‑d]嘧啶‑1‑基]‑苯基}‑环丙烷甲酰胺二甲亚砜溶剂化物来实现。
Description
技术领域
本发明涉及吡啶并[4,3-d]嘧啶-2,4,7-三酮的新衍生物,即N-{3-[3- 环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H- 吡啶并[4,3-d]嘧啶-1-基]-苯基}-环丙烷甲酰胺二甲亚砜溶剂化物,其作为治疗由不良细胞增殖导致的障碍的药物,特别是作为抗肿瘤药是令人感兴趣的。更具体地,本发明涉及作为抗肿瘤药令人感兴趣的МЕK1、МЕK2和МЕK1/2抑制剂,该抑制剂可以用于治疗恶性黑色素瘤。
背景技术
存在众所周知的МЕK1、МЕK2和МЕK1/2抑制剂,其结构包括 1Н,6Н-吡啶并[4,3-d]嘧啶-2,4,7-三酮[WO2005/121142、 WO2012/088033、USA7378423],大部分高级药物是Mekinist(曲美替尼 (Trametinib)二甲亚砜,GSK1120212)[H.Abe,S.Kikuchi,K.Hayakawa 等人,ACS Med.Chem.Lett.2011,2,320-324]。GSK1120212是有效的MEK1/2抑制剂,它们表现出对C-Raf活化前的u-MEKl/2(u-MEKl: IC50=0.7nM)比对其预活化的(рр-МЕK1:IC50=14.9nM)更高的效能 [http://clincancerres.aacrjournals.org/content/17/5/989.full]。
然而,曲美替尼和Mekinist实际上不溶于рН=2至рН=8的水性介质中。曲美替尼和Mekinist也极微溶于有机溶剂,包括高极性溶剂(微溶于热的无质子溶剂)。
这就是为什么仍然需要这样化合物的原因,所述化合物可以表现出关于МЕK1、МЕK2和МЕK1/2的有利效率特性,以及在水性或有机溶剂中的高溶解度。由于改善的生物利用度,预期这些化合物更适合作为癌症治疗剂。
除此之外,尽管Mekinist具有低单剂量口服毒性(小鼠:LD50> 2000mg/kg),但在长期高剂量水平施用期间观察到严重的体重减轻或有时甚至动物死亡。因此,寻找该组较低的长期剂量毒性产品仍然非常重要。
本发明的目的在于创造新的MEK1、MEK2和MEK1/2抑制剂,其在长期剂量中具有较低毒性。
该目的通过式1的新化合物N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]- 苯基}-环丙烷甲酰胺二甲亚砜溶剂化物实现。
发明公开
申请人令人意外地发现,式1的新化合物N-{3-[3-环丙基-5-(2-氟 -4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d] 嘧啶-1-基]-苯基}-环丙烷甲酰胺二甲亚砜溶剂化物与曲美替尼对MEK1、MEK2和MEK1/2的效能相当,其在长期剂量中无毒性。
因此,式1的新化合物N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8- 二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-环丙烷甲酰胺二甲亚砜溶剂化物可以特别地用于治疗牵涉MEK1、MEK2 和MEK1/2的障碍,例如治疗癌症,包括恶性黑色素瘤。
本发明的主题为式1的N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8- 二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-环丙烷甲酰胺二甲亚砜溶剂化物。
本发明的主题还有包含式1的化合物的MEK1、MEK2和MEK1/2 抑制剂。
新的式1的化合物的优点是在有机介质中具有更高的溶解度,这可以提供更多种类的合适制剂并且能够实现更高的生物利用度和其他药代动力学参数。因此,例如,式1的化合物在二甲亚砜中的溶解度比曲美替尼的溶解度大2倍以上。在4%二甲亚砜和96%植物油的混合物中的溶解度也更高。表1中给出了式1的化合物在不同介质中与曲美替尼的溶解度相比的溶解度。
表1.式1的化合物和曲美替尼在不同介质中的溶解度
新的式1的化合物的抑制活性与曲美替尼对MEK1的抑制活性相当,实验值为IС50=8.02nM(曲美替尼的IC50=8.14nM)。
与原型(Mekinist,曲美替尼的二甲亚砜复合物)相比,显著降低的过程剂量毒性是新的式1的化合物的绝对优势。对A375人黑色素瘤异种移植模型的效率研究表明,式1的化合物以剂量依赖性方式抑制肿瘤生长并引起肿瘤消退。式1的化合物的效率与Mekinist的效率相当,式1的化合物毒性较小:Mekinist的实验性治疗导致两只动物的严重体重减轻和死亡,而式1的化合物不会导致动物死亡,即使剂量较高。
对NMRI裸雌性小鼠进行式1的化合物与Mekinist对比的抗肿瘤活性研究。在形成肿瘤后,将动物细分成组,使得该组中的平均肿瘤大小为~150mM3。用测试产品处理动物21天。在实验组中接受式1 的化合物的剂量高达并且包括3mg/kg的动物的重量与对照组中的动物没有显着差异(图1)。用10mg/kg剂量的式1的化合物治疗导致动物体重减轻,这在整个研究中从第一次施用中观察到,但与治疗开始日期相比不超过20%。然而,胃内施用3mg/kgMekinist 9天导致严重的体重减轻和两只动物的死亡,这导致需要在该组中停止治疗3天以恢复体重。
肿瘤生长动力学如图2所示。0.3mg/kg的式1的化合物的胃内施用对肿瘤生长没有影响,而在所有其他组中观察到肿瘤生长的显著抑制。此外,另外,在接受1mg/kg式1的化合物的8只动物的3只中观察到肿瘤消退,并且在分别接受3和10mg/kg式1的化合物的7/8 和8/8动物中观察到肿瘤消退。3mg/kg Mekinist的胃内施用也引起该组100%动物中的消退。
因此,式1的化合物表现出剂量依赖性肿瘤生长抑制和消退,仅在最大研究剂量下不引起动物死亡和中度降低的动物体重。
本发明的主题还有包含式1的化合物的MEK1、MEK2和MEK1/2 抑制剂。该抑制剂优选用于治疗患者的癌症,包括恶性黑色素瘤。
本发明的主题还有生产式1的化合物的方法,其包括式2的1-(3- 氨基苯基)-3-环丙基-5-{(2-氟-4-碘苯基)氨基}-6,8-二甲基吡啶并[4,3-d] 嘧啶-2,4,7(1Н,3Н,6Н)-三酮或其盐与环丙基甲酸或其活化衍生物(例如,该酸的氯代酸酐或相应活化酯或酸酐)在溶剂例如CH2Cl2、四氢呋喃、N,N二甲基甲酰胺、N,N-二甲基乙酰胺或N-甲基吡咯烷酮中的相互作用,其中通过缓慢冷却在二甲亚砜中的热饱和溶液进一步得到最终产物的结晶溶剂化物。
本发明的主题是用于制备包含式1的化合物的药物组合物和剂型的活性成分。
本发明的主题是表现出MEK1、MEK2和MEK1/2抑制剂性质并含有治疗有效量的式1的化合物作为活性成分和药学上可接受的赋形剂的药物组合物。
该药物组合物可以是适于口服使用的形式(例如,片剂,锭剂,硬或软胶囊,水性或油性悬浮液,乳液,可分散的粉末或颗粒,糖浆或酏剂),用于局部使用(例如,霜剂,软膏,凝胶,水性或油性溶液或混悬液),用于吸入(例如,细粉或液体气溶胶),用于吹入(例如,细粉) 或用于肠胃外施用(例如,用于静脉内、皮下或肌内剂量注射的无菌水性或油性溶液,或用于直肠施用的栓剂)。
该药物组合物可以使用公知的常规药物赋形剂通过常规方法获得。因此。用于口服施用的药物组合物可含有例如一种或几种着色剂,甜味剂,矫味剂和/或防腐剂。
通常,式1的化合物以5-5000mg/m2体表面积的单剂量施用于患者,即通常提供治疗有效剂量的约0.1-100mg/kg。通常单一剂型例如片剂或胶囊含有例如1-250mg活性成分。每日剂量始终根据患者、具体施用途径和治疗时病症的严重程度的不同而变化。因此,对特定患者进行治疗的医生可以确定最佳剂量。在本说明书中,术语“疗法”包括“预防”。
具有对MEK1、MEK2和MEK1/2的抑制活性的式1的化合物可用于治疗与MEK1、MEK2和MEK1/2活性相关的疾病或医学病症,例如用于治疗癌症。可能倾向于使用式1的化合物或其药学上可接受的盐和/或溶剂化物治疗的癌症类型包括(但不限于)恶性黑色素瘤。
本发明的主题还有用于治疗与MEK1、MEK2和MEK1/2相关的疾病的药物,其包含治疗有效量的式1的化合物。本发明的形式之一是预期该药物用于治疗与MEK1、MEK2和MEK1/2有关并且包括癌症的疾病。
本发明的主题还有治疗与MEK1、MEK2和MEK1/2有关的疾病的方法,包括使用如上定义的式1的化合物。本发明的形式之一是治疗与MEK1、MEK2和MEK1/2有关并且包含癌症的疾病。
根据本发明的另一方面,提出了如上述所定义的式1的化合物,其用于通过将治疗有效量的式1的化合物与药学上可接受的赋形剂混合来制备用于治疗癌症的药物。
根据本发明的另一个方面,还提出了一种在需要这种治疗的患者中获得抗癌作用的方法,该方法包括给患者施用有效量的式1的化合物。
根据本发明的另一方面,还提出了治疗患有其中MEK1/2抑制有用的疾病的人的方法;该方法包括向需要这种治疗的患者施用有效量的式1的化合物的步骤。特别地,其中MEK1、MEK2和MEK1/2抑制有用的疾病是癌症。
在本文提及的任何方面或形式中,其中癌症以一般意义指示,所述癌症可选自脑瘤(具有恶性星形神经胶质瘤和少突神经胶质瘤等的成分的神经胶质瘤),食道癌,胃癌,肝癌,胰腺癌,结肠直肠癌(结肠癌,直肠癌等),肺癌(非小细胞肺癌,小细胞肺癌,原发性和转移性鳞状细胞癌等),肾癌,乳腺癌,卵巢癌,前列腺癌,皮肤癌,神经母细胞瘤,肉瘤,骨软骨瘤,骨瘤,骨肉瘤,精原细胞瘤,性腺外肿瘤,睾丸瘤,子宫癌(宫颈癌,子宫内膜癌等),头部癌症和颈部肿瘤(上颌窦癌,喉癌,咽癌,舌癌,口腔癌等),多发性骨髓瘤,恶性淋巴瘤 (网状细胞肉瘤,淋巴肉瘤,霍奇金病等),真性红细胞增多症,白血病(急性髓性白血病,慢性髓性白血病,急性淋巴细胞白血病,慢性淋巴细胞白血病等),甲状腺肿,盆腔癌,输尿管肿瘤,膀胱肿瘤,胆囊癌,胆管癌,恶性黑色素瘤,儿童肿瘤(尤因肉瘤,Wilms肿瘤,横纹肌肉瘤,血管肉瘤,胚胎睾丸癌,神经母细胞瘤,视网膜母细胞瘤,肝母细胞瘤,肾母细胞瘤等)等。
上述癌症疾病的治疗可以用作单一疗法,或除了根据本发明的化合物之外还可以包括普通外科手术或放疗或化疗或免疫疗法。该化疗可以同时、依次或分开引入,并且可以另外包括一种或多种来自以下类别的抗肿瘤剂:抗增殖/抗癌药物及其在医学肿瘤学中使用的组合;细胞抑制剂;抗侵袭剂;生长因子抑制剂;抗血管生成剂;血管制剂;损伤内皮素受体拮抗剂;反义疗法;基因治疗方法;和免疫疗法(J)。
因此,本发明提出了一种药物组合物,其包含如上定义的式1的化合物和另外的抗肿瘤物质,用于癌症的伴随治疗。
本发明提出了一种药物组合物,其包含如上定义的式1的化合物和另外的抗肿瘤物质,用于癌症的联合治疗。
与联合疗法相关的术语“伴随治疗”应理解为同时、分开或连续施用。
本发明提出了式1的化合物和另外的抗肿瘤物质在癌症的伴随治疗中的用途。
本发明得到附图支持。
图1.研究中的药物治疗期间动物体重变化的动力学。
图2.在Mekinist和式1的化合物治疗期间异种移植物模型中 A375人黑色瘤肿瘤生长的动态1动力学。
本发明的最佳实施方式
将使用具体实施例更详细地描述本发明。提供以下实施例作为示例,而不是用于对本发明的任何限制。本领域技术人员可以容易地理解各种非关键参数,这些参数可以被改变或修改而得到基本相同的结果。
实施例1.制备N-{3-[3-环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基 -2,4,7-三氧代-3,4,6,7-四氢-2H-吡啶并[4,3-d]嘧啶-1-基]-苯基}-环丙烷甲酰胺二甲亚砜溶剂化物的方法
在环境温度下将环丙基甲酰氯(182mg,1.74mmol)加入到式2的 1-(3-氨基苯基)-3-环丙基-5-{(2-氟-4-碘苯基)氨基}-6,8-二甲基吡啶并 [4,3-d]嘧啶-2,4,7(1Н,3Н,6Н)-三酮(500mg,0.87mmol)和二异丙基乙胺 (225mg,1.74mmol)在5mL二甲基甲酰胺中的溶液中,将反应物质混合过夜。反应完成后,真空蒸发溶剂,将残余物溶于5mL二氯甲烷中,依次用碳酸氢钠饱和水溶液和氯化钠饱和水溶液洗涤。分离有机层,用无水硫酸钠干燥过夜,过滤,真空蒸发滤液。使用二氯甲烷和二氯甲烷和乙酸乙酯(1:1)的混合物作为洗脱液,通过硅胶快速色谱法分离产物。在70℃下将粗产物(250mg)溶解在1.3mL二甲亚砜中,将溶液混合1小时,然后冷却至环境温度,混合过夜。过滤沉淀物,在过滤器上用二氯甲烷洗涤,在40-50℃高真空下干燥2小时。得到N-{3-[3- 环丙基-5-(2-氟-4-碘苯基氨基)-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢-2H- 吡啶并[4,3-d]嘧啶-1-基]-苯基}-环丙烷甲酰胺二甲亚砜溶剂化物 (130mg,48%),为白色结晶粉末。
1H NMR(CDCl3,400MHz):0.79(m,2Н),0.86(m,2Н),1.05 -1.15(m,4Н),1.44(s,3Н),1.5(m,1Н),2.62(s,6H),2.74(m, 1H),3.21(s,3H),6.7(t,1H),7.03(m,1H),7.31-7.4(m,2H), 7.45(d,1H),7.53(d,1H),7.65(s,1H),7.71(s,1H),11.3(s,1H)。
实施例2.确定式1的化合物和曲美替尼原型的热力学溶解度。将 5mg研究中的化合物与1mL pH=2.0、4.0或7.0的通用缓冲液(Pion Ltd)在25℃时混合持续15分钟。使用额外量的物质直至溶液变浑浊。将小瓶与溶液一起在25℃温育24小时,同时混合,以达到饱和溶液与沉淀之间的平衡。在平衡时,通过96-孔滤板(Millipore)过滤200μL 溶液(一式两份)以分离沉淀物。使用标准校准曲线通过分光光度法测定滤液中化合物的浓度。进行物质的光学吸收光谱的测量并绘制选定波长处的校准曲线(通常相应于物质吸收最大值λmax)。通过以下等式计算滤液中物质的浓度(即溶解度):
溶解度=(ODλmax滤液—ODλmax空白)/斜率×1.67×滤液稀释度,
其中
ODλmax滤液=滤液吸光度;
ODλmax空白=不含物质的空白溶液的吸光度;
斜率=校准曲线的斜率;
1.67=滤液在乙腈中的稀释因子;
滤液稀释度=滤液在缓冲液中的稀释因子。
结果如表1中所示。
实施例3
测定。使用Z'-LYTE筛选平台(Life Technologies)测试这些物质对МЕK1激酶活性的影响。反应混合物中DMSO的浓度为1%。在 100%DMSO中,在2.4μL激酶缓冲液(50mMHEPES pH 7.5,0.01% BRIJ-35,10mM mgCl2,1mM EGTA)中稀释100nL 100倍的所研究物质,并添加至384-孔板(由Corning制造的黑色,小体积,кат.#3676) 中的5μL 2倍底物/激酶混合物(МЕK1/灭活MARK1(ERK2)/Ser/ Thr03,最终含量0.08-0.31ngМЕK1,105ng灭活MARK1(ERK2)和 2μM Ser/Thr03)中。在环境温度下将物质与激酶预温育10分钟。然后加入2.5μL的4倍ATP溶液以开始反应(反应混合物中ATP的最终浓度为100μM)。在摇床上温育30秒后,在环境温度下温育反应体系60 分钟。然后加入5μL稀释为1:1024的试剂В(LifeTechnologies),在环境温度下再温育60分钟。用在400nM的激发和在445nM和520nM 的发射测量荧光。通过如下等式计算肽底物的磷酸化程度(低发射比意味着肽被磷酸化,即激酶活性不受抑制,而高发射比意味着肽未被磷酸化,即激酶活性受到抑制)。
如下计算%磷酸化:
如下计算%抑制:
其中:
С100%=平均香豆素发射信号,100%磷酸化对照;
С0%=平均香豆素发射信号,0%磷酸化对照;
F100%=平均荧光素发射信号,100%磷酸化对照;
F0%=平均荧光素发射信号,0%磷酸化对照。
实施例4.人黑色素瘤异种移植物模型中的效能研究。本研究在ProQinase GmbHFreiburg,Breisacher Str.117,D-79106Freiburg, GERMANY进行。
在37℃下和含有95%空气和5%СO2的潮湿气氛中将А375人黑色素瘤细胞在含有DMEM培养基的小瓶中培养,在所述培养基中添加了10%FBS。在适应期后将癌细胞传代给动物。为此,使用TrypLE Express(Invitrogen)收集细胞,洗涤并悬浮在无菌PBS中至终浓度为 3×107个细胞/mL。将该细胞悬浮液皮下注射(SC)于小鼠左侧腹部(每只小鼠3×106个细胞或100μL)。
当平均肿瘤大小达到100-200mM3时,将动物细分为实验组,并开始用试验药物治疗。每天胃内施用所述产品,而对照组接受溶剂。实验产品剂量列于表2中。
表2.人黑色素瘤异种移植物模型中的效率研究中的产品剂量
组 | 物质 | 剂量mg/kg | 动物数量 |
1 | 溶剂 | 10mL/kg | 10 |
2 | Mekinist | 3.0 | 8 |
3 | 式1的化合物 | 0.1 | 8 |
4 | 式1的化合物 | 0.3 | 8 |
5 | 式1的化合物 | 1.0 | 8 |
6 | 式1的化合物 | 3.0 | 8 |
7 | 式1的化合物 | 10.0 | 8 |
关键的测量的参数:
从导入细胞的当天开始每周2次进行皮下植入肿瘤测量。通过如下等式确定肿瘤体积(mm3):
V=L×W2/2,
其中L相应于最大肿瘤直径,且W相应于最小肿瘤直径(mm)。使用滑动式卡尺进行测量。
本研究包括计算肿瘤生长抑制值:
Т/С=Vexp/Vctrl×100%,
其中:
Vctrl=对照组中的平均肿瘤体积;
Vexp=实验组中的平均肿瘤体积。
此外,监测动物健康和行为,记录致死性结果和肿瘤消退的数量:
消退率=(Vini–Vfin)/Vi×100%,
其中:
Vini=治疗开始时的起始肿瘤体积;
Vfin=治疗结束时的肿瘤体积。
每周3次进行动物体重测量。
表3. 21天治疗后的肿瘤抑制参数(Т/С)
图2显示Mekinist和式1的化合物治疗期间在异种移植物中A375 黑色素瘤肿瘤生长的动力学。
式1的化合物表现出与Mekinist效果强度相当的剂量依赖性肿瘤生长抑制和消退。然而,与Mekinist不同,式1的化合物在任何研究剂量下都不会导致动物死亡(Mekinist治疗导致显著的体重减轻和2只动物死亡),并且在最大研究剂量下仅适度地减轻了动物体重。这推定式1的化合物与Mekinist相比毒性较低,同时不会损失黑色素瘤的治疗效率。
实施例5.药物的片剂制备。混合1600mg淀粉、1600mg研磨乳糖、400mg滑石粉和1000mg式1的抑制剂,并且压制成条。将该条研磨成颗粒并且筛选14-16目筛的颗粒。将这些颗粒压制成适当形状的片剂(各500mg)。
实施例6.药物的胶囊制备。混合式1的抑制剂与乳糖(2:1)。将该粉末混合物填充入适当大小的胶囊(各600mg)。
实施例7.作为用于肌内、腹膜内或皮下注射的组合物的药物制备。混合500mg式1的抑制剂与300mg三氯叔丁醇、2mL丙二醇和 100mL注射用水。过滤该溶液并且填充在1mL安瓿中,然后密封。
工业实用性
本领域技术人员易于理解不同的非关键性参数,可以改变或变型它们以得到相同的效果。除本文所述的那些外,本发明的各种变型对于本领域技术人员而言从上述提供的描述中显而易见。
Claims (9)
3.权利要求2的药物组合物,以片剂、胶囊或置于药学上可接受的容器中的注射剂的形式使用。
4.用于治疗涉及MEK1、MEK2和MEK1/2的疾病并且包含权利要求1的化合物的药物。
5.权利要求1的化合物或权利要求2的药物组合物或权利要求4的药物在制备用于癌症预防和/或治疗的药物中的用途。
6.权利要求5的用途,其中所述癌症预防和/或治疗包括预防和/或治疗恶性黑色素瘤。
8.权利要求7的用于制备药物的方法,所述药物用于治疗恶性黑色素瘤。
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