CN109820853B - 取代的杂环化合物在制备治疗癌症药物中的用途 - Google Patents
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Abstract
本发明涉及新型合成取代的杂环化合物和含有所述化合物的药物组合物。本发明还涉及这类化合物在治疗和/或预防某些类型的癌症、疼痛、炎症、再狭窄、动脉粥样硬化、银屑病、血栓、阿尔茨海默病、与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤或功能障碍中的用途。
Description
本发明专利申请是国际申请号为PCT/US2015/014592,国际申请日为2015年2月5日,进入中国国家阶段的申请号为201580007308.1,名称为“化合物的组合物及其用途”的发明专利申请的分案申请。
相关申请的交叉引用
本申请要求于2014年2月5日提交的美国临时专利申请号61/936,267的优先权,该文的全部内容通过引用纳入本文用于所有目的。
1.技术领域
本发明涉及合成取代的杂环化合物及含有其的药物组合物,其能够抑制或拮抗蛋白激酶活性。本发明还涉及这类化合物在治疗和/或预防某些类型的癌症、搔痒、特应性皮炎、疥疮、糠疹、炎症、再狭窄、动脉粥样硬化、银屑病、血栓、阿尔茨海默病、疼痛,与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤或功能障碍,或与蛋白激酶异常活性相关的病症中的用途。
2.发明背景
Trk家族蛋白是由3种家族成员TrkA、TrkB和TrkC组成的受体酪氨酸激酶。它们以高亲和性结合至神经营养蛋白配体家族,并且介导神经营养蛋白配体家族诱导的信号转导,神经营养蛋白配体家族的模式成员是神经生长因子(NGF)、大脑来源的神经营养因子(BDNF)和神经营养蛋白3-5(NT 3-5)。另外,已经鉴定了缺少酶活性的共受体p75,其以低亲和性结合所有神经营养蛋白(NT)并且调节神经营养蛋白信号转导。已经通过小鼠中的基因破坏研究认识了Trk及其配体在中枢和外周神经系统发育期间的关键作用。具体地,TrkA-NGF相互作用显示为参与介导疼痛信号转导的某些外周神经元群的存活所需。已经显示TrkA的增加表达也与胰腺癌中疼痛水平上升相关(Zhu等,临床肿瘤学杂志(journal ofclinical oncology),17:2419-2428(1999))。也在人骨关节炎软骨细胞中观察到NGF和TrkA的表达增加(Iannone等,风湿病学(Rheumatology)41:1413-1418(2002))。
TrkA(原肌球蛋白-受体激酶A)是含胞外、跨膜和胞质激酶结构域的细胞表面受体激酶。神经营养因子的结合引发受体的寡聚化,激酶结构域中酪氨酸残基的磷酸化,和胞内信号转导通路的激活,包括Ras/MAPK级联,PI3K/AKT,和IPS-依赖性Ca2+释放。酪氨酸激酶活性是通过这类受体的信号转导的绝对要求。也已经在神经系统外的多种细胞类型上发现NGF受体。例如,也已经在人单核细胞、T和B淋巴细胞以及肥大细胞上发现TrkA。
存在多种本领域已知的抗-TrkA抗体或抗-NGF抗体的示例。例如,PCT公开号WO2006/131952、WO 2005/061540和EP 1181318公开了抗-TrkA抗体在炎性和神经性疼痛的体内动物模型中作为有效镇痛剂的用途。PCT申请号WO 01/78698、WO 2004/058184和WO2005/019266公开了NGF拮抗剂预防或治疗疼痛的用途。PCT申请WO 2004/096122描述了一种通过共同给予抗-NGF抗体和阿片样拮抗剂治疗或预防疼痛的方法。PCT申请WO 2006/137106描述了一种通过共同给予抗-TrkA抗体和阿片样拮抗剂治疗或预防疼痛的方法。另外,已经通过采用抗-NFG抗体实现显著或明显减少的由前列腺癌转移导致的骨疼痛(Sevik,MA等,疼痛学(Pain)115:128-141(2005))。
TrkA(NTRK1)中功能缺失突变导致对疼痛先天不敏感和无汗症(Nat Genet 1996;13:485-8)并且抗-NGF抗体他尼珠单抗已经证明在骨关节炎疼痛和糖尿病性神经性疼痛中在临床上是高效的(N Engl J Med 2010;363:1521-31:Arthritis Rheum 2013;65:1795-803)。另外,Trk抑制剂已经显示出在疼痛的临床前模型中出色的效力(Mol Pain 2010;6:87-100)。最近Array已经证明变构TrkA-敏感性抑制剂在疼痛模型中同样有效,其潜力在于比之后所述的泛-Trk抑制剂更安全(Array网页,2012.网址:http://wwwMrraybiopharrnaxonm/_documents/Pubbcation/PubAttachment587.pdf)(最后访问:2014年1月22)。
有一些证据表明抑制Trk可在阿尔茨海默病的治疗中有益。NGF和TrkA水平在哮喘者(哮喘)的气道中升高(哮喘杂志(J Asthma)2013;50:712-17;呼吸学(Respirology)(2009)14,60-68;和PLoS ONE 4(7):e6444.doi:10.1371/journal.pone.0006444)并且可导致炎症、反应过度和重建。也已经显示NGF和TrkA加剧了啮齿动物中卵清蛋白诱导的气道炎症(Exp Ther Pled 2013;6:1251-8)。CT327是一种已经由Creabilis在临床上针对诸如特应性皮炎、银屑病和瘙痒的疾病中慢性瘙痒评价的局部TrkA抑制剂(http://clinicaltnals.gov/show/NCT01808157)。可在美洲锥虫病治疗中采用抑制TrkA。克氏锥虫(Trypanosoma cruzi),美洲锥虫病的致病物,采用Trk来侵入人类宿主中的各种细胞类型(Infect Immun 2009;77:1368-75;Infect Immun 2011;79:4081-7)。
选择性抑制TrkA激酶活性也可用于治疗耳部疾病[Laryngoscope 2011年10月;121(10):2199-213]、肝硬化和肝细胞癌[World J Gastroenterol 2007年10月7日;13(37):4986-4995]、肺部炎性疾病[《免疫学和微生物学》(Immunology andMicrobiology),"Inflammatory Diseases-A Modern Perspective(炎性疾病-现代视角)",Amit Nagal编书,ISBN 978-953-307-444-3,2011年12月16日出版,第五章:TrkA受体在肺部炎性疾病中的作用和表达]、纤维化[J Cell Commun Signal.2010年3月;4(1):15-23.专利申请:PCT/GB2004/004795]、翼状胬肉[Int.J.Exp.Path.(2009),90,615-620]、肺病[Expert Rev Respir Med.2010年6月;4(3):395-411.]、肺部结节病[Dagnell等,Respiratory Research 2010,11:156]、膀胱功能障碍[Neurourology and Urodynamics30:1227-1241(2011);BJU International 111,372-380;J Urol.2013年8月;190(2):757-764;Neurourology and Urodynamics 33:39-45(2014)]、下泌尿道功能障碍[International Journal of Urology(2013)20,13-20]、佩吉特病[J Cutan Pathol2010:37:1150-1154]、糖尿病性肾病变[Diabetes.2012年9月,第61卷,第9期,p2280-2288.;Regulatory Peptides 135(2006)30-38]、肠易激综合征[NeurogastroenterolMolil(2013)25,e740-e754]、辐射保护[Radioiher Oncol.2012年6月;103(3):380-387]。
此外,由疾病本身或由治疗导致的疼痛在患有癌症的人中常见,虽然并非所有患有癌症的人都将经受疼痛。大约30%-50%的患有癌症的人经受疼痛,同时经过治疗,并且70%-90%的患有晚期癌症的人经受疼痛(Lesage P.和Portenoy RK.Cancer Control;Journal of the Moffitt Cancer Center 1999;6(2):136-145)某些疼痛是复杂的,随时变化的症状,其是混合机制疼痛的最终结果。其涉及多个部位处的炎性、神经性、缺血性和压迫机制(癌症疼痛和阿片耐受病理学(Pathophysiology of cancer pain and opioidtolerance)于英国疼痛协会的癌症疼痛管理(The British Pain Society's Cancer PainManagement)。英国疼痛协会网站www.britishpainsociety.org.2010年1月出版,访问:2013年1月29日)。这是一种主观、异质的经历,其受到个体遗传学、病史、情绪、预期和培养的调整。癌症疼痛综合征基于发病和持续时间被分类为急性和慢性。急性疼痛综合征有突然的、明确的发病,可鉴定的病因(例如,手术),经过交感输出(或战或逃反应)并且预期通过管理来改善。在另一方面,慢性疼痛有较不明显的发病,有延长和波动性过程,并且很大程度上由来自急性损伤的可塑性响应和中枢至敏所驱动(Fornasari D.慢性疼痛患者的疼痛机制(Pain mechanisms in patients with chronic pain).Clin Drug Investig2012;32(增刊l):45-52;Latremoliere A,Woo If CJ.中枢至敏:由中枢神经可塑性的疼痛过敏的生成物(Central sensitization:a generator of pain hypersensitivity bycentral neural plasticity).J Pain 2009;10:895-926)。其通常特征是称为穿透性疼痛的“疼痛发散”(Portenoy RK,Dhingra LK.癌症疼痛评价(Assessment of cancer pain).In:Drews RE,编.UpToDate.Waliham,MA:最新;2013)
有效的Trk抑制剂的治疗性意义可能远远超过疼痛治疗。已经鉴定TrkA多态性与精神分裂症相关(J Psychiatr Res.2009年10月;43(15):1195-9)。已经记录该受体及其信号转导通路在某些恶性肿瘤中被破坏。之前已经覆盖了Trk抑制剂在肿瘤学中的潜在应用(综述参见,Expert Opin Ther Pat.2014年7月;24(7):731-44;Nat Rev Cancer,2004:4:361-70;Clin Cancer Res,2009;15:5962-7)。TrkA和/或Trk(B/C)已经涉及以下的存活与转移:前列腺癌[Expert Opin Investig Drugs,2007;16:303-9;Prostate,2000:45:140-8]、乳腺癌[Cytokine Growth Factor Rev,2012;23;357-65]、肝细胞癌(肝癌)和肝硬化[World J Gastroenterol.2007年10月7日;13(37):4986-95:Gastroenterology.2002Jun;122(7):1978-86;Biochem Biophys Res Commun.2011年3月4日;406(1):89-95.;Digestive Diseases and Sciences,第55卷,第10期,(2010年10月),pp.2744-55,ISSN0163-2116]、肝内胆管细胞癌[World J Gastroenterol 2014年4月14日;20(14):4076-4084]、肝纤维化[Expert Rev Mol Med.;11:e7.doi:10.1017/S1462399409000994]、卵巢癌[Gynecol Oncol 2007年1月;104(1):168-75]、胰腺癌[Clin Cancer Res.,2005;1 1:440-9]、口腔癌[Dermatol Surg 2004;30:1009-1016]和口腔癌疼痛[JDent Res 91(5):447-453,2011]、皮肤癌[Am J Clin Pathol 2004;122:412-420]、宫颈癌[AfricanJournal of Biotechnology卷10(38),pp.7503-7509,2011年7月25日]、骨癌[J VetIntern Med 2008:22:1181-1188]。其他罕见癌症如先天性中胚层肾瘤、胎儿纤维肉瘤[AmJ Pathol,1998;153:1451-8]和分泌性乳腺癌[Cancer Cell,2002;347-8]携带Tel-TrkC基因重排。已经在小但是一致的乳头状甲状腺瘤的亚组中检测到TrkA的体重排(Cancer Lett2006;232:90-8;Mol Cell Endocrinol 2010:321:44-9;Genomics.1995年7月1日;28(1):15-24;Int J Cancer.1999年3月15日;80(6):842-7)。
最近在一小亚组的肺癌患者(Nat Med 2013;19:1469-72)和结直肠癌(以TPM3-TrkA融合突变)(Mol Oncol.2014年6月12日.pii:S 1574-7891(14)00125-2)中发现致癌TrkA(NTRKl)重排打开了该领域中令人激动的一条新路。来自之前没有鉴定到遗传变化的91名肺癌患者中的3名患者的肿瘤样品显示TrkA基因(NTRKl)融合的证据。这些基因融合突变是胞内致癌蛋白质,并且它们已经组成型激活的胞内TrkA激酶活性并转化成纤维细胞。已经在胶质母细胞瘤、良性幼年黑素瘤、黑色素瘤、急性髓细胞性白血病和分泌性乳腺癌中鉴定到TrkA(NTRKl)、TrkB(NTRK2)、或TrkC(NTRK3)融合(Greco A,等,Mol CellEndocrinol 2009;Alberti L,等,J Cell Physiol 2003;Mariin-Zanca D等,Nature1986;Wiesner T,等,Nat Commun 2013;Vaishnavi A等,Nat Med 2013)。这种基因重排或融合突变的鉴定可能使得患者采用层化方法,与Pfizer所有效采用的类似,使得克唑替尼能够被快速注册并批准(Drugs 2013;73:2031-51)。
事实上,最近在临床上用RXDX-101(一种泛Trk抑制剂)治疗患有TrkA-阳性代谢性结直肠癌的患者并且实现的部分响应(Ignyta,Inc.News Release.2014年5月31日.网站:http://finance.yahoo.com/news/ignyta-announces-interim-data-rxdx-190000889.html)。我们自己对公开的人癌症基因组数据库的研究揭示了许多类型的人类癌症有TrkA融合或融合突变,例如,乳腺癌(例如,来自5名患者的CAL-51、CAMA-1和其他3种人类乳腺癌细胞)、子宫内膜癌(例如,来自8名患者的RK95-2和其他7种人类癌细胞)、血癌(例如,来自4名患者的CML-TI和其他3种癌细胞)、肝癌(来自3名患者的SNU-878和其他2种癌细胞)、结直肠癌(例如,来自11名患者的SNU-C4和其他10种癌细胞)、胰腺癌(例如,来自2名患者的pane 02.13和pane 03.27)、和皮肤癌(例如,来自5名患者的LOX IMVI和其他4种癌细胞),可采用TrkA选择性抑制剂,如本发明中公开的那些或本发明的化合物来精确灭活在组成型激活的胞内致癌蛋白质,即TrkA融合突变中的胞内Trk激酶活性,并且因此用作上述类型的人类癌症的有效人类癌症治疗疗法。
Trk的酪蛋白激酶活性被认为促进细胞增殖细胞器的上调激活。单独或组合的TrkA、TrkB、或TrkC的抑制剂被认为具有针对一些最常见癌症的实用性,如脑癌、黑素瘤、多发性骨髓瘤、鳞状细胞癌、膀胱癌、胃癌、胰腺癌、乳腺癌、头部癌、颈部癌、食道癌、前列腺癌、结直肠癌、肺癌、肾癌、卵巢癌、妇科癌症、甲状腺癌,以及某些类型的血液恶性肿瘤。来他替尼(CEP-701,Cephalon),包括Flt-3和TrkA的几种酪氨酸激酶的吲哚并咔唑抑制剂,和CEP-751(泛Trk抑制剂)已经进入治疗急性骨髓性白血病(AML)、胰腺癌和多发性骨髓瘤(MM)和/或前列腺癌的二期临床试验。
特别注意的是在人类前列腺癌和胰腺导管腺癌的发展和进展中涉及NGF和TrkA受体激酶的异常表达以及急性骨髓性白血病(AML)、甲状腺癌和乳腺癌中Trk染色体重排激活和预测受体点突变在结肠癌中组成型激活的报告。除了这些激活机制以外,已经在多种肿瘤类型中报告了升高的Trk受体和配体,包括多发性骨髓瘤、黑色素瘤、神经母细胞瘤、卵巢癌和胰腺癌。已经显示神经营养蛋白及其相应的Trk受体亚型在恶性肿瘤细胞中发挥多种多效性响应,包括增强的肿瘤侵入性和趋化性、激活凋亡、刺激克隆生长、和改变细胞形态。已经在前列腺癌、乳腺癌、甲状腺癌、结肠癌、恶性黑色素瘤、肺癌、胶质母细胞瘤、胰腺类癌以及多种儿科和神经外胚层衍生肿瘤,包括胚胎性癌肉瘤、神经母细胞瘤和髓母细胞瘤中观察到这些影响。神经营养蛋白及其受体亚型已经通过涉及癌细胞和周围的实质和实体组织的自分泌或旁分泌机制参与这些癌症。总之,多个肿瘤类型中Trk信号转导的致癌性质使得Trk受体信号传导的调节成为不同恶性肿瘤中潜在有吸引力的治疗介入点。
然而,除了抗体以外,已知很少TrkA抑制剂并且非常少(如果存在)显示高的TrkA激酶选择性(包括十字孢碱衍生的TrkA抑制剂,CEP-751和CEP-701)。本领域几乎不知道(如有存在)合成有机分子或化合物已经用作枝接TrkA或NGF抑制剂或拮抗剂用于治疗或预防特定疼痛。这可能主要是由于鉴定强效并且特别有选择性的抗-TrkA或抗-NGF有机化合物的困难,尽管已经确定了NGF与TrkA受体复合的晶体结构(Nature 401:184-188(1996)&254:411(1991))。
有效的Trk抑制剂的治疗性意义可能远远超过疼痛治疗。已经记录该受体及其信号转导通路在某些恶性肿瘤中被破坏。Trk的酪蛋白激酶活性被认为促进细胞增殖细胞器的上调激活。单独或组合的TrkA、TrkB、或TrkC的抑制剂被认为具有针对一些最常见癌症的实用性,如脑癌、黑素瘤、多发性骨髓瘤、鳞状细胞癌、膀胱癌、胃癌、胰腺癌、乳腺癌、头部癌、颈部癌、食道癌、前列腺癌、结直肠癌、肺癌、肾癌、卵巢癌、妇科癌症、甲状腺癌,以及某些类型的血液恶性肿瘤。来他替尼(CEP-701,Cephalon),包括Flt-3和TrkA的几种酪氨酸激酶的吲哚并咔唑抑制剂,和CEP-751(泛Trk抑制剂)已经进入治疗急性骨髓性白血病(AML)、胰腺癌和多发性骨髓瘤(MM)和/或前列腺癌的二期临床试验。
由于与抑制TrkA相关的治疗希望,并且相对缺乏强效并有选择性的抑制剂,非常需要发现强效并有特定同种型选择性的TrkA抑制剂,尤其是可口服的活性小合成分子用于与TrkA活性相关的疾病或病症的可能治疗或预防。
3.发明内容
本发明的对象是小合成分子及其盐或溶剂合物或前药作为蛋白激酶抑制剂和/或拮抗剂,尤其是HGF受体TrkA抑制剂和/或拮抗剂在制备用于治疗和/或预防直接或间接与抑制TrkA相关的疾病的药物中的用途,疾病包括某些癌症(例如,胰腺癌、胃癌、食道癌、胃肠道癌、结直肠癌、肺(小细胞和非小细胞)癌、肝癌、肝细胞癌、肝内胆管细胞癌、脑癌或人神经母细胞瘤、胶质母细胞瘤和髓母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、黑色素瘤、恶性间皮瘤、乳腺癌、膀胱癌、卵巢癌、前列腺癌或转移癌、甲状腺癌、鳞状细胞癌、良性幼年黑素瘤、黑色素瘤、急性髓细胞性白血病、子宫内膜癌、皮肤癌、口腔癌、骨癌、黑色素瘤)、瘙痒、特应性皮炎、疥疮、糠疹、炎性肠病、炎性关节炎、哮喘、人气道疾病、呼吸道疾病、纤维化疾病、肾纤维化、肝纤维化、肝硬化、再狭窄、动脉粥样硬化、银屑病、血栓、美洲锥虫病、寄生虫病、阿尔茨海默病、疼痛(即,减少有此需要的对象的疼痛,包括急性疼痛、慢性疼痛、炎性疼痛、神经性疼痛、癌症疼痛、和全身疼痛病症)、肺部炎性疾病、肺部结节病、膀胱功能障碍或下泌尿道功能障碍、佩吉特病、糖尿病性肾病变、肠易激综合征、辐射、精神分裂症,与髓鞘形成障碍或脱髓鞘有关的疾病,病症、损伤或功能障碍,或者与蛋白激酶的异常活性有关的疾病或病症。
在一个方面中,本发明提供了小分子化合物及其盐或溶剂合物或前药作为NGF受体TrkA抑制剂和/或拮抗剂用于制备用于治疗和/或预防直接或间接与调节TrkA蛋白激酶的表达或活性或者在患有带TrkA-阳性突变、融合或融合突变的以下癌症类型的某些患者群中活性或者遗传异常的TrkA激酶活性相关的疾病的药物,其可通过现有或未来的诊断工具临床诊断,例如,胰腺癌、前列腺癌或转移癌、乳腺癌、肝细胞癌、肝内胆管细胞癌、肝癌、卵巢癌、甲状腺癌、肺(小细胞和非小细胞)癌、结直肠癌、胶质母细胞瘤、良性幼年黑素瘤、黑色素瘤、急性髓细胞性白血病、子宫内膜癌、皮肤癌、口腔癌、骨癌、黑色素瘤、胃癌、食道癌、胃肠道癌、脑癌或人神经母细胞瘤、和髓母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、恶性间皮瘤、膀胱癌、鳞状细胞癌。
在一个方面,本发明提供了结构为式(I)的化合物:
或其盐、溶剂合物、酯、或前药;
其中:
A1和A2独立地是氧或硫;
R1表示NH2或R7;
R2表示NR7或CR7R10;
R3、R5、R6和R9独立地是R7;
或者,R6和R9与它们接合的原子一起形成含有一个或多个选自氮、氧和硫的杂原子的3-6元任选取代的杂环基;
R4表示卤素、CN、NO2、CF3、-(CHR)nCOOR11、-(CHR)nSO2R11、C1-4卤代烷基、-OC1-4-卤代烷基、C2-6烷基、C2-6烯基、C2-6炔基、-(CHR)nC6-10芳基、-(CHR)nC5-8杂环、-(CHR)nC3-8环烷基、-O-C6-10芳基、-O-C5-10杂环、-(CHR)nC(O)CF3、-(CHR)nC(OH)(CF3)2、-(CH2)n卤素、-OR10、-NR11R12、-NRaCOR11、-NRaCOOR11、-NRaSO2R11、-NRaCONR11R12、-COR11、四唑、-(CHR)n四唑、-S-C1-6烷基、或–CONR11R12,其中各所述烷基、烯基、炔基、芳基、环烷基和杂环独立地任选被1至2个R8基团取代;
或者,R4和R5与它们接合的原子一起形成含有一个或多个选自氮、氧和硫的杂原子的3-6元任选取代的杂环基;
R7和R10独立地选自氢、卤素、CN、NH2、NO2、C1-4卤代烷基、-OC1-4卤代烷基、C1-6烷基、C2-6烯基、C2-6炔基、-(CHR)nC6-10芳基、-(CHR)nC5-8杂环、-(CHR)nC3-8环烷基、-O-C6-10芳基、-O-C5-10杂环、-C(O)CF3、-(CH2)n卤素、-(CHR)n-(O)n-C(=O)R8、-(CHR)n-(S)n-C(=O)R8、-ORa、-NR11R12、-NRaCOR11、-NRaCOORa、-NRaSO2R、-NRaCONR11R12、-CORa、-(CHR)nCOORa、-S-C1-6烷基、和–CONR11R12,其中各所述烷基、烯基、炔基、芳基、环烷基和杂环独立地任选被1至2个R8基团取代;
R11和R12独立地选自氢、N(Ra)C(=O)R、卤素、CN、NH2、NHRa、NO2、C1-4卤代烷基、-OC1-4卤代烷基、C1-6烷基、C2-8烯基、-S-C1-6烷基、-C(=O)-(O)n-Ra、-(CHR)n-(O)n-C(=O)R8、-(CHR)n-(S)n-C(=O)R8、-ORa、-(CHR)nC3-10环烷基、-(CHR)nC6-10芳基、-(CHR)nC5-10杂芳基、和-(CHR)nC5-10杂环,其中各所述烷基、烯基、环烷基、芳基、杂芳基和杂环独立地任选被1至2个R8基团取代,并且其中所述烷基的一个或多个碳原子可被一个或多个选自氮、氧和硫的杂原子取代;
或者,R11和R12与它们接合的原子一起形成含有一个或多个选自氮、氧和硫的杂原子的3-6元任选取代的杂环基;其中任选的取代基是R8;并且
R各自独立地表示氢、卤素、CN、NO2、NH2、或C1-6烷基;
Ra各自独立地表示氢或C1-6烷基;
R8各自独立地表示C1-6烷基、卤素、CN、NO2、NH2、NHRa、SO2R11、或NRaSO2R11;并且
n表示0-3的整数;
有以下前提:
当R2是CH2时,R4不是H或CH3;
当R2是NCH2CH2OH时,(a)R4不是H或OCH3,或者(b)R5不是OCH3;并且
当R2是N(CH3)时,R4不是H、CH3、OCH3、或F。在式(I)的一个实施方式中,R1选自氢、-(CH2)n卤素、-CN、-CH3、NH2、NHRa、和-C1-3烷基。
在式(I)的一个实施方式中,R4选自-C(O)OR11、-SO2NHC(=O)CH3、-C(CF3)(CF3)OH、-SO2NH2、-C(O)NR11R12、-CN、-CF3、-NO2、-C(O)CF3、-(CH2)n卤素、
在式(I)的一个实施方式中,R3、R5、R6和R9是氢。
在式(I)的一个实施方式中,R2选自
在另一个方面,本发明提供了结构为式(II)的化合物:
或其盐、溶剂合物、酯、或前药;
其中:
X表示N或CH;
R4表示选自-(CHR)nCOOR11、-(CHR)nSO2R11、-(CHR)nC5-8杂环、或-(CHR)nC(OH)(CF3)2的羧基生物电子等排体,其中各所述杂环独立地任选被1至2个R8基团取代;
R11独立地选自氢、C1-6烷基、NH2、NHRa、和NRaC(=O)R,其中各所述烷基独立地任选被1至2个R8基团取代,并且其中所述烷基的一个碳原子可被一个选自氮、氧、和硫的杂原子取代;
R8各自独立地表示C1-6烷基、卤素、CN、NO2、NH2、NHRa、SO2R11、或NRaSO2R11;
R各自独立地表示氢、卤素、CN、NO2、NH2、或C1-6烷基;
Ra各自独立地表示氢或C1-6烷基;并且
n表示0。
在式(II)的一个实施方式中,X表示N。
在式(II)的一个实施方式中,R4表示-COOR11,其中R11是氢。在式(II)的一个实施方式中,R4表示-COOR11,其中R11是C1-6烷基。在式(II)的一个实施方式中,R4表示–COOR11,其中R11是C1-6烷基,其中所述C1-6烷基的一个碳原子被一个氮原子取代。
在式(II)的一个实施方式中,X表示N且R4表示-COOR11,其中R11是氢。
在式(II)的另一个实施方式中,R4表示-SO2R11,其中R11是NH2或NRaC(=O)R。在式(II)的一些实施方式中,R4表示-SO2R11,其中R11是NHC(=O)R并且其中R是C1-6烷基。
在式(II)的一个实施方式中,R4表示C5杂环,其中该杂环是四唑。
在另一个方面,本发明提供了包含一种或多种上述化合物或其盐、溶剂合物、酯、前药或生理功能衍生物;和药学上可接受的载剂的药物组合物。
在另一个方面中,本发明提供了用治疗有效量的如上所述的化合物、或盐、或溶剂化物、或生理学功能性衍生物选择性抑制或拮抗NGF受体TrkA用于治疗和/或预防包括以下的某些疾病、病症、症状或状况的方法,包括癌症(例如,胰腺癌、胃癌、食管癌、胃肠癌、结肠直肠癌、肺癌、肝癌、脑癌或人神经母细胞瘤、成胶质细胞瘤和髓母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、黑色素瘤、恶性间皮细胞瘤、乳腺癌、膀胱癌、卵巢癌、前列腺癌、甲状腺癌、鳞状上皮细胞癌),搔痒、特应性皮炎、疥疮、糠疹、炎性肠病、炎性关节炎、哮喘、人气道疾病、再狭窄、动脉粥样硬化、牛皮癣、血栓、美洲锥虫病、寄生虫病、阿尔茨海默病,与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤或功能障碍,或者与蛋白激酶的异常活性有关的疾病或病症。
在另一个方面中,本发明提供了用(a)治疗有效量的如上所述的化合物,或其盐,溶剂化物,或酯,前药,或生理学功能性衍生物,与(b1)阿片样拮抗剂或至少一种通过不同于Trk拮抗剂的机制起作用的拮抗剂或(b2)现有的或已批准的抗癌药或至少一种现有的或已批准的抗癌药的联合治疗和预防以下疾病的方法:某些癌症(例如,胰腺癌、胃癌、食管癌、胃肠癌、结肠直肠癌、肺癌、肝癌、脑癌或人神经母细胞瘤、成胶质细胞瘤和髓母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、黑色素瘤、恶性间皮细胞瘤、乳腺癌、膀胱癌、卵巢癌、前列腺癌、甲状腺癌、鳞状上皮细胞癌),搔痒、特应性皮炎、疥疮、糠疹、炎性肠病、炎性关节炎、哮喘、人气道疾病、再狭窄、动脉粥样硬化、牛皮癣、血栓、美洲锥虫病、寄生虫病、阿尔茨海默病,与髓鞘形成障碍或脱髓鞘有关的疾病、病症、损伤或功能障碍,或者与蛋白激酶的异常活性有关的疾病或病症。
其他实施方式包括任意上述实施方式与一种或多种药学上可接受的赋形剂的组合。其他实施方式包括剂型,例如固体或半固体剂型,包含任意上述结晶形式、无定形形式、或组合。在其他实施方式中,包含任意上述结晶形式、无定形形式、或组合的剂型包括以下一种或多种:片剂,硬胶囊,软胶囊,粉末剂,栓剂和凝胶,或一种或多种可注射形式,经皮贴剂,可喷雾形式以及和可植入储库。
其他实施方式是利用任意上述实施方式来制备用于抑制,或者用于抑制,一种NGF受体,TrkA的剂型。其他实施方式是任意前述实施方式用治疗有效量的上述化合物、或其盐、溶剂合物或生理功能衍生物在制备用于治疗选自以下的疾病、病症或状况的剂型中的用途:疼痛(即,减少有此需要的对象的疼痛,包括急性疼痛、慢性疼痛、炎性疼痛、神经性疼痛、癌症疼痛、和全身疼痛病症)、癌症(例如,胰腺癌、前列腺癌或转移癌、乳腺癌、肝细胞癌、肝内胆管细胞癌、肝癌、卵巢癌、甲状腺癌、肺(小细胞和非小细胞)癌、结直肠癌、胶质母细胞瘤、良性幼年黑素瘤、黑色素瘤、急性髓细胞性白血病、子宫内膜癌、皮肤癌、口腔癌、骨癌、黑色素瘤、胃癌、食道癌、胃肠道癌、脑癌或人神经母细胞瘤、和髓母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、恶性间皮瘤、膀胱癌、鳞状细胞癌)、特应性皮炎、银屑病、皮肤病、瘙痒、肝纤维化、肝硬化、疥疮、糠疹、炎性肠病、炎性关节炎、哮喘、人气道疾病、美洲锥虫病、寄生虫病、阿尔茨海默病、再狭窄、动脉粥样硬化、血栓、肝硬化、肝纤维化、肺部炎性疾病、肺部结节病、膀胱功能障碍或下泌尿道功能障碍、佩吉特病、糖尿病性肾病变、肠易激综合征、辐射、精神分裂症,与髓鞘形成障碍或脱髓鞘有关的疾病、病症或损伤,或者与TrkA蛋白激酶的异常活性或TrkA(NTRK1)蛋白的融合或突变有关的疾病或病症。
另一方面,本发明提供了一种药物组合物,其包含上文所述的化合物以及药学上可接受的载剂。
在另一个方面中,本发明提供了在医学治疗和预防中使用结构为式(I)和/或式(II)的化合物的方法。
在另一个方面中,本发明提供了使用结构为式(I)和/或式(II)的化合物与(a)治疗有效量的如上所述的化合物,或其盐,溶剂化物,或酯,前药,或生理学功能性衍生物,和(b1)阿片样拮抗剂或至少一种通过不同于Trk拮抗剂的机制起作用的拮抗剂或(b2)现有的或已批准的抗癌药或化疗剂或者至少一种现有的或已批准的抗癌药联用以医学治疗和预防以下的方法:疼痛(即,减少有此需要的对象的疼痛,包括急性疼痛、慢性疼痛、炎性疼痛、神经性疼痛、癌症疼痛、和全身疼痛病症)、癌症(例如,胰腺癌、前列腺癌或转移癌、乳腺癌、肝细胞癌、肝内胆管细胞癌、肝癌、卵巢癌、甲状腺癌、肺(小细胞和非小细胞)癌、结直肠癌、胶质母细胞瘤、良性幼年黑素瘤、黑色素瘤、急性髓细胞性白血病、子宫内膜癌、皮肤癌、口腔癌、骨癌、黑色素瘤、胃癌、食道癌、胃肠道癌、脑癌或人神经母细胞瘤、和髓母细胞瘤、视网膜母细胞瘤、白血病、淋巴瘤、恶性间皮瘤、膀胱癌、鳞状细胞癌)、特应性皮炎、银屑病、皮肤病、瘙痒、肝纤维化、肝硬化、疥疮、糠疹、炎性肠病、炎性关节炎、哮喘、人气道疾病、美洲锥虫病、寄生虫病、阿尔茨海默病、再狭窄、动脉粥样硬化、血栓、肝硬化、肝纤维化、肺部炎性疾病、肺部结节病、膀胱功能障碍或下泌尿道功能障碍、佩吉特病、糖尿病性肾病变、肠易激综合征、辐射、精神分裂症,与髓鞘形成障碍或脱髓鞘有关的疾病、病症或损伤,或者与TrkA蛋白激酶的异常活性或TrkA(NTRK1)蛋白的融合或突变有关的疾病或病症。
在另一个方面中,本发明提供了制备上述结构为式(I)和/或式(II)的化合物的方法。
在另一个方面中,本发明提供了在患者中治疗与不规则TrkA活性、或TrkA蛋白或NTRK1基因的融合或突变相关的疾病、病症、症状或状况的方法,包括向该患者给予包含治疗有效量的结构为式(I)和/或式(II)的化合物的药物组合物,其中该药物组合物配制成选自下组的单位剂型:口服单位剂型(包括粉末、片剂、丸剂、粒料、胶囊、粉末剂、锭剂、颗粒剂、溶液、悬浮液、乳液、糖浆、酏剂、缓释制剂、气雾剂、喷剂和囊片)、吸入单位剂型(包括喷剂、气雾剂、吸入器、喷雾器、吸烟器和蒸发器)、胃肠道外单位剂型(包括皮内、肌内、骨内、腹膜内、静脉内、硬膜外、心内、眼内、关节内、皮下和鞘内注射单位剂型)、局部外用单位剂型(包括霜剂、凝胶、搽剂或唇膏、洗剂或油膏、滴耳液、滴眼液、皮肤贴片和阴道环)、鼻内单位剂型、栓剂单位剂型(包括阴道用、灌肠用、子宫托、和直肠用)、硬膜外单位剂型、舌下单位剂型(包括锭剂和含片)、和大脑内单位剂型。
在另一个方面中,本发明提供了治疗患者中与不规则TrkA活性,或TrkA蛋白或NTRK1基因的融合或突变相关的疾病、病症、症状或状况的方法,包括向该患者给予包含治疗有效量的结构为式(I)和/或式(II)的化合物的药物组合物,其中该药物组合物配制成包含约0.02mg化合物/kg体重至约60mg化合物/kg体重的口服单位剂型。
在另一个方面中,本发明提供了治疗患者中与不规则TrkA活性,或TrkA蛋白或NTRK1基因的融合或突变相关的疾病、病症、症状或状况的方法,包括向该患者给予包含治疗有效量的结构为式(I)和/或式(II)的化合物的药物组合物,其中该药物组合物配制成包含约0.002mg化合物/kg体重至约60mg化合物/kg体重的静脉内单位剂型。
在另一个方面中,本发明提供了治疗患者中与不规则TrkA活性,或TrkA蛋白或NTRK1基因的融合或突变相关的疾病、病症、症状或状况的方法,包括向该患者给予包含治疗有效量的结构为式(I)和/或式(II)的化合物的药物组合物,其中该药物组合物配制成包含约0.002mg化合物/kg体重至约6mg化合物/kg体重的鼻内单位剂型。
在另一个方面中,本发明提供了治疗患者中与不规则TrkA活性,或TrkA蛋白或NTRK1基因的融合或突变相关的疾病、病症、症状或状况的方法,包括向该患者给予包含治疗有效量的结构为式(I)和/或式(II)的化合物的药物组合物,其中该药物组合物配制成包含约0.001mg化合物/kg体重至约50mg化合物/kg体重的栓剂单位剂型并且包含约0.5重量%至约10重量%的活性成分。
在另一个方面中,本发明提供了治疗患者中与不规则TrkA活性,或TrkA蛋白或NTRK1基因的融合或突变相关的疾病、病症、症状或状况的方法,包括向该患者给予包含治疗有效量的结构为式(I)和/或式(II)的化合物的药物组合物,其中该药物组合物配制成选自下组的单位剂型:胃肠道外单位剂型(包括皮内、肌内、骨内、腹膜内、静脉内、硬膜外、心内、眼内、关节内、皮下和鞘内注射单位剂型)、局部单位剂型(包括霜剂、凝胶、搽剂或唇膏、洗剂或油膏、滴耳液、滴眼液、皮肤贴片和阴道环)、鼻内单位剂型、栓剂单位剂型(包括阴道用、灌肠用、子宫托、和直肠用)、硬膜外单位剂型、舌下单位剂型(包括锭剂和含片)、和大脑内单位剂型、皮内单位剂型、肌内单位剂型、腹膜内单位剂型、皮下单位剂型、硬膜外单位剂型、舌下单位剂型、和大脑内单位剂型,其中所述单位剂型包含约0.001mg化合物/kg体重至约60mg化合物/kg体重。
5.发明详述
本发明涉及新型合成小分子,其作用是Trk家族蛋白激酶成员,尤其是NGF受体,TrkA的抑制剂和/或拮抗剂。
5.1定义
除非另有说明,权利要求书和说明书中使用的术语如下文所述定义。
术语“本发明的化合物”、“本发明所述化合物”或“本发明化合物”是指由本文所示的结构式和/或任何亚通式所包括的一种或多种化合物并且包括本文公开其结构的这些一般式内的任意具体化合物。本发明的化合物可含有一个或多个手性中性和/或双键并且因此可以立体异构体,如双键异构体(即,几何异构体)、外消旋混合物、对映异构体或非对映异构体存在。因此,本文所示的化学结构包括所示化合物的所有可能对映异构体和立体异构体,包括立体异构纯形式(例如,几何纯、对映异构纯或非对映异构纯)与对映异构和立体异构混合物。本发明的化合物也可以多种互变异构形式存在。因此,本文所示的化学结构包括所示化合物的所有可能互变异构形式。化合物还包括有同位素标记的化合物,其中一个或多个原子的质量与在自然界中发现的传统的原子质量不同。对可能被纳入到化合物的同位素例子包括但不限于:2H、3H、13C、14C、15N、17O、18O等。化合物可能存在于未溶剂化和溶剂化的形式,包括水合物和N-氧化物。一般来说,化合物的盐,水合物,溶剂化物和N-氧化物的形式,都是包含在本发明的范围内。本发明的某些化合物可能存在多个结晶形式或无定形的形式。通常,在本发明所考虑的应用中所有物理形式是等同的,且这些物理形式均应在本发明范围内。
本文所用术语“生理学功能性衍生物”是指本发明化合物的任何可生理容忍的衍生物,例如,酯或前药,在给予哺乳动物(例如,人)时,直接或间接的转变成式(I)和/或式(II)的化合物或其活性代谢物。生理功能衍生物包括本发明中的化合物的前药。前药的例子可参考H.Okada等,Chem.Pharm.Bull.1994,42,57-61。这样的前药可在体内代谢成本发明中的化合物。这些前药本身可能有活性,也可能没有。
“烷基(alkyl)”本身或作为其他取代基的部分是指由从母体烷烃、烯烃或炔烃的单个碳原子去除一个氢原子衍生的饱和或不饱和支链、直链或环状单价烃自由基。术语“烷基”具体旨在包括具有任意饱和度或饱和水平的基团,即,具有排他性的碳碳单键的基团、具有一个或多个碳碳双键的基团、具有一个或多个碳碳三键的基团、以及具有碳碳单键、双键和三键混合的基团。在旨在特性饱和水平的情况中,使用表述“烷基(alkanyl)”、“烯基”和“炔基”。在一些实施方式中,烷基包括1-20个碳原子(C1-C20烷基)。在其他实施方式中,烷基包括1-10个碳原子(C1-C10烷基)。在其他实施方式中,烷基包括1-6个碳原子(C1-C6烷基)。典型的烷基包括但不限于,甲基;乙基类如乙基、乙烯基、乙炔基;丙基类如丙-1-基、丙-2-基、环丙-1-基、丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基(烯丙基)、环丙-1-烯-1-基;环丙-2-烯-1-基、丙-1-炔-1-基、丙-2-炔-1-基等;丁基类如丁-1-基、丁-2-基、2-甲基-丙-1-基、2-甲基-丙-2-基、环丁-1-基、丁-1-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-2-基、丁-1,3-二烯-1-基、丁-1,3-二烯-2-基、环丁-1-烯-1-基、环丁-1-烯-3-基、环丁-1,3-二烯-1-基、丁-1-炔-1-基、丁-1-炔-3-基、丁-3-炔-1-基等。
“烷基(alkanyl)”本身或作为其他取代基的部分是指由从母体烷烃的单个碳原子去除一个氢原子衍生的饱和支链、直链或环状烷基自由基。典型的烷基(alkanyl)包括但不限于,甲基;乙基;丙基类如丙-1-基、丙-2-基(异丙基)、环丙-1-基等;丁基类如丁-1-基、丁-2-基(仲丁基)、2-甲基-丙-1-基(异丁基)、2-甲基-丙-2-基(叔丁基)、环丁-1-基等。
“烯基”本身或作为其他取代基的部分是指由从母体烯烃的单个碳原子去除一个氢原子衍生的具有至少一个碳碳双键的不饱和支链、直链或环状烷基自由基。该基团关于双键可以是顺式或反式构象。典型的烯基包括但不限于,乙烯基;丙烯基类如丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基(烯丙基)、丙-2-烯-2-基、环丙-1-烯-1-基、环丙-2-烯-1-基;丁烯基类如丁-1-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-1-基、丁-2-烯-2-基、丁-1,3-二烯-1-基、丁-1,3-二烯-2-基、环丁-1-烯-1-基、环丁-1-烯-3-基、环丁-1,3-二烯-1-基等。
“炔基”本身或作为其他取代基的部分是指由从母体炔烃的单个碳原子去除一个氢原子衍生的具有至少一个碳碳三键的不饱和支链、直链或环状烷基自由基。典型的炔基包括但不限于,乙炔基;丙炔基类如丙-1-炔-1-基、丙-2-炔-1-基等;丁炔基类如丁-1-炔-1-基、丁-1-炔-3-基、丁-3-炔-1-基等。
“烷基二基”本身或作为其他取代基的部分是指由从母体烷烃、烯烃或炔烃的2个不同碳原子各自去除一个氢原子,或者通过从母体烷烃、烯烃或炔烃的单个碳原子去除2个氢原子衍生的饱和或不饱和支链、支链或环状二价烃基。两个单价基团中性或二价基团中心的各价态可与相同或不同的原子成键。典型的烷基二基包括但不限于甲二基;乙二基类如乙-1,1-二基、乙-1,2-二基、乙烯-1,1-二基、乙烯-1,2-二基;丙二基如丙-1,1-二基、丙-1,2-二基、丙-2,2-二基、丙-1,3-二基、环丙-1,1-二基、环丙-1,2-二基、丙-1-烯-1,1-二基、丙-1-烯-1,2-二基、丙-2-烯-1,2-二基、丙-1-烯-1,3-二基、环丙-1-烯-1,2-二基、环丙-2-烯-1,2-二基、环丙-2-烯-1,1-二基、丙-1-炔-1,3-二基等;丁二基类如丁-1,1-二基、丁-1,2-二基、丁-1,3-二基、丁-1,4-二基、丁-2,2-二基、2-甲基-丙-1,1-二基、2-甲基-丙-1,2-二基、环丁-1,1-二基、环丁-1,2-二基、环丁-1,3-二基、丁-1-烯-1,1-二基、丁-1-烯-1,2-二基、丁-1-烯-1,3-二基、丁-1-烯-1,4-二基、2-甲基-丙-1-烯-1,1-二基、2-甲基亚基-丙-1,1-二基、丁-1,3-二烯-1,1-二基、丁-1,3-二烯-1,2-二基、丁-1,3-二烯-1,3-二基、丁-1,3-二烯-1,4-二基、环丁-1-烯-1,2-二基、环丁-1-烯-1,3-二基、环丁-2-烯-1,2-二基、环丁-1,3-二烯-1,2-二基、环丁-1,3-二烯-1,3-二基、丁-1-炔-1,3-二基、丁-1-炔-1,4-二基、丁-1,3-二炔-1,4-二基等。在特定饱和水平的情况中,使用命名烷基二基(alkanyldiyl)、烯基二基和/或炔基二基。在一些实施方式中,烷基二基是(C1-C20)烷基二基、更优选(C1-C10)烷基二基、最优选(C1-C6)烷基二基。
“亚烷基”本身或作为其他取代基的部分是指由从支链母体烷烃、烯烃或炔烃的2个末端碳原子各自去除一个氢原子衍生的具有2个末端单价基团中心的支链烷基二基。典型的亚烷基包括但不限于,亚甲基;亚乙基类如桥亚乙基、亚乙烯基、亚乙炔基;亚丙基类如亚丙基(propano)、亚丙[1]烯基、亚丙[1,2]二烯基、亚丙[1]炔基等;亚丁基类如亚丁基(butano)、亚丁[1]烯基、亚丁[2]烯基、亚丁[1,3]二烯基、亚丁[1]炔基、亚丁[2]炔基、亚丁[1,3]二炔基等。在特定饱和水平的情况中,使用命名亚烷基(alkano)、亚烯基和/或亚炔基。
“酰基”本身或作为其他取代基的部分是指基团-C(O)R200,其中R200是氢、烷基、取代的烷基、芳基、取代的芳基、芳烷基、取代的芳烷基、杂烷基、取代的杂烷基、杂芳烷基或取代的杂芳烷基,如本文所定义。代表性的示例包括但不限于甲酰基、乙酰基、环己基羰基、环己基甲基羰基、苯甲酰基、苄基羰基等。
“氨基”本身或作为其他取代基的部分是指基团-NRaRb,其中Ra和Rb独立地是氢、烷基、芳基、取代的芳基、芳烷基、取代的芳烷基、杂烷基、取代的杂烷基、杂芳烷基或取代的杂芳烷基,如本文所定义,或者Ra和Rb与其结合的原子一起形成环杂烷基环。代表性示例包括但不限于-NH2、-NHCH3、-(CH3)2、-NH-苯基、-NH-CH2-苯基、吡咯烷等。
“芳基”本身或作为其他取代基的部分是指通过从本文定义的母体芳环系统的单个碳原子去除一个氢原子衍生的单价芳烃基团。典型的芳基包括但不限于,衍生自醋蒽烯(aceanthrylene)、苊烯、醋菲烯(acephenanthrylene)、蒽、柑菊环(azulene)、草屈、苯、晕苯、萤蒽、芴、并六苯、己芬、并环己二烯(hexalene)、不对称-引达省(as-indacene)、对称-引达省(s-indacene)、茚满、茚、萘、并辛苯、辛芬、并环辛二烯、卵苯、戊-2,4-二烯、并戊苯、并环戊二烯、五苯、二萘嵌苯、非那烯、菲、苉、七曜烯(pleiadene)、芘、吡蒽(pyranthrene)和玉红省(rubicene)、苯并菲、三萘等的基团。在一些实施方式中,芳基包括6-20个碳原子(C6-C20芳基)。在其他实施方式中,芳基包括6-15个碳原子(C6-C15芳基)。在其他实施方式中,芳基包括6-10个碳原子(C6-C10芳基)。
“芳烷基”本身或作为其他取代基的部分是指环烷基,其中与碳原子(一般是末端或sp3碳原子)结合的氢原子之一被本文定义的芳基取代。典型的芳烷基包括但不限于:苄基、2-苯基乙-1-基、2-苯基乙烯-1-基、2-萘基甲基、2-萘基乙-1-基、2-萘基乙烯-1-基、萘并苄基、2-萘并苯基乙-1-基等。在特定烷基部分的情况中,使用命名芳基烷基(arylalkanyl)、芳基烯基和/或芳基炔基。在一些实施方式中,芳烷基是(C6-C30)芳烷基,例如,芳烷基的烷基、烯基或炔基部分是(C1-C10)烷基并且芳基部分是(C6-C20)芳基。在其他实施方式中,芳烷基是(C6-C20)芳烷基,例如,芳烷基的烷基、烯基或炔基部分是(C1-C8)烷基并且芳基部分是(C6-C12)芳基。在其他实施方式中,芳烷基是(C6-C15)芳烷基,例如,芳烷基的烷基、烯基或炔基部分是(C1-C5)烷基并且芳基部分是(C6-C10)芳基。
“芳氧基”本身或作为其他取代基的部分是指式-O-R201的基团,其中R201是芳基、取代的芳基、芳烷基、或取代的芳烷基。
“芳氧基羰基”本身或作为其他取代基的部分是指式-C(O)-O-R201的基团,其中R201是芳基、取代的芳基、芳烷基、或取代的芳烷基。
“羧基生物电子等排体”本身或作为其他取代基的部分在本文中用于指代在生理pH下预期产生与化合物的相同位置处的羧酸部分类似的化学或生物性质的部分。在某些实施方式中,羧酸生物电子等排体是选自下组的部分:-C(O)OR11、-SO2R11、-C5-8杂环、和-C(OH)(CF3)2;R11独立地选自氢、C1-6烷基、NH2、NHRa、和NRaC(=O)R,其中各所述烷基独立地任选被取代,并且其中所述烷基的一个碳原子可被一个选自氮、氧和硫的杂原子取代;R各自独立地表示氢、卤素、CN、NO2、NH2、或C1-6烷基;Ra各自独立地表示氢或C1-6烷基。
“环烷基”或“碳环基”本身或作为其他取代基的部分是指饱和或不饱和的本文定义的环状烷基基团。在特定饱和水平的情况中,使用命名“环烷基(cycloalkanyl)”或“环烯基”。典型的环烷基包括但不限于,衍生自环丙烷、环丁烷、环戊烷、环己烷等的基团。在一些实施方式中,环烷基包括3-10个环原子(C3-C10环烷基)。在其他实施方式中,环烷基包括3-7个环原子(C3-C7环烷基)。
“环杂烷基”或“杂环基”本身或作为其他取代基的部分是指饱和或不饱和环烷基基团,其中一个或多个碳原子(和任选地任何相关氢原子)独立地被相同或不同的杂原子取代。取代碳原子的典型杂原子包括但不限于B、N、P、O、S、Si等。在特定饱和水平的情况中,使用命名“环杂烷基(cycloheteroalkanyl)”或“环杂烯基”。典型的环杂烷基包括但不限于衍生自环氧化物、环氮乙烷、硫杂丙环、咪唑烷、吗啉、哌嗪、哌啶、吡唑烷、吡咯烷、奎宁环、环戊硼烷、二氧杂环戊硼烷等的基团。在一些实施方式中,环杂烷基包括3-10个环原子(3-10元环杂烷基)。在其他实施方式中,环烷基包括5-7个环原子(5-7元环杂烷基)。
“卤素”或“卤代”本身或作为其他取代基的部分是指元素氟、氯、溴、碘、和砹中的任一种,占据元素周期表的VIIA(17)族。
环杂烷基可在杂原子,例如,氮原子处被(C1-C6)烷基取代。作为具体示例,N-甲基-咪唑烷基、N-甲基-吗啉基、N-甲基-哌嗪基、N-甲基-哌啶基、N-甲基-吡唑烷基和N-甲基-吡咯烷基包括在“环杂烷基”的定义内。环杂烷基可通过环碳原子或环杂原子接合至分子的其余部分。
“杂烷基(heteroalkyl)、杂烷基(heteroalkanyl)、杂烯基、杂烷基(heteroalkanyl)、杂烷基二基和杂亚烷基”本身或作为其他取代基的部分分别指烷基、烷基(alkanyl)、烯基、炔基、烷基二基和亚烷基,其中一个或多个碳原子(和任何相关的氢原子)各自独立地被相同或不同的杂原子基团取代。这些基团中可包括的典型杂原子基团包括但不限于-O-、-S-、-O-O-、-S-S-、-O-S-、-NR203R204-、=N-N=、-N=N-、-N=N-NR205R206、-PR207-、-P(O)2-、-POR208-、-O-P(O)2-、-SO-、-SO2-、-SnR209R210-、-BR211R212、BOR213OR214等,其中R203、R204、R205、R206、R207、R208、R209、R210、R211、R212、R213和R214独立地是氢、烷基、取代的烷基、芳基、取代的芳基、芳烷基、取代的芳烷基、环烷基、取代的环烷基、环杂烷基、取代的环杂烷基、杂烷基、取代的杂烷基、杂芳基、取代的杂芳基、杂芳烷基或取代的杂芳烷基。
“杂芳基”本身或作为其他取代基的部分是指通过从本文定义的母体杂芳环系统的单个碳原子去除一个氢原子衍生的单价杂芳基基团。典型的杂芳基包括但不限于,衍生自吖啶、β-咔啉、苯并二氢吡喃、苯并吡喃、噌啉、呋喃、咪唑、吲唑、吲哚、二氢吲哚、中氮茚、异苯并呋喃、异苯并吡喃、异吲哚、异二氢吲哚、异喹啉、异噻唑、异噁唑、萘啶、噁二唑、噁唑、萘嵌间二氮杂苯(perimidine)、菲啶、菲咯啉、吩嗪、酞嗪、蝶啶、嘌呤、吡喃、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、吡呤环、喹唑啉、喹啉、喹嗪、喹喔啉、四唑、噻二唑、噻唑、噻吩、三唑、呫吨、呋喃吡啶(furopyridine)等的基团。在一些实施方式中,杂芳基包括5-20个环原子(5-20元杂芳基)。在其他实施方式中,杂芳基包括5-10个环原子(5-10元杂芳基)。示例性的杂芳基包括衍生自呋喃、噻吩、吡咯、苯并噻吩、苯并呋喃、苯并咪唑、吲哚、吡啶、吡唑、喹啉、咪唑、噁唑、异噁唑和吡嗪的那些。
“烷芳烷基”本身或作为其他取代基的部分是指环烷基,其中与碳原子(一般是末端或sp3碳原子)结合的氢原子之一被杂芳基取代。在特定烷基部分的情况中,使用命名杂芳烷基(heteroarylalkanyl)、杂芳烯基和/或杂芳炔基。在一些实施方式中,杂芳烷基是6-21元杂芳烷基,例如,杂芳烷基的烷基、烯基或炔基部分是(C1-C6)烷基并且杂芳基部分是5-15元杂芳基。在其他实施方式中,杂芳烷基是6-13元杂芳烷基,例如,烷基、烯基或炔基部分是(C1-C3)烷基并且杂芳基部分是5-10元杂芳基。
“杂芳氧基”本身或作为其他取代基的部分是指式-O-R201的基团,其中R201是杂芳基、取代的杂芳基、杂芳烷基、或取代的杂芳烷基。
“杂芳氧基羰基”本身或作为其他取代基的部分是指式-C(O)-O-R201的基团,其中R201是杂芳基、取代的杂芳基、杂芳烷基、或取代的杂芳烷基。
“调节”是指调整、改变或变化。本文所用的调节钙离子通道包括拮抗、激动、或部分拮抗。即,本发明的化合物可用作钙离子通道活性的拮抗剂、激动剂、或部分拮抗剂。
“母体芳环系统”是指具有共轭π电子系统的不饱和环状或多环系统。“母体芳环系统”定义内具体包括稠合环系统,其中环中的一个或多个是芳环并且环中的一个或多个是饱和或不饱和的,例如,芴、茚满、茚、非那烯等。典型的母体芳基系统包括但不限于,衍生自醋蒽烯(aceanthrylene)、苊烯、醋菲烯(acephenanthrylene)、蒽、柑菊环(azulene)、草屈、苯、晕苯、萤蒽、芴、并六苯、己芬、并环己二烯(hexalene)、不对称-引达省(as-indacene)、对称-引达省(s-indacene)、茚满、茚、萘、并辛苯、辛芬、并环辛二烯、卵苯、戊-2,4-二烯、并戊苯、并环戊二烯、五苯、二萘嵌苯、非那烯、菲、苉、七曜烯(pleiadene)、芘、吡蒽(pyranthrene)和玉红省(rubicene)、苯并菲、三萘等的基团。
“母体杂芳环系统”是指母体芳环系统,其中一个或多个碳原子(和任选的任意相关氢原子)各自独立地被相同或不同的杂原子取代。取代碳原子的典型杂原子包括但不限于B、N、P、O、S、Si等。“母体杂芳环系统”定义内具体包括稠合环系统,其中环中的一个或多个是芳环并且环中的一个或多个是饱和或不饱和的,例如,苯并二噁烷、苯并呋喃、苯并二氢吡喃、苯并吡喃、吲哚、二氢吲哚、呫吨等。典型的杂芳环系统包括但不限于,衍生自吖啶、咔唑、β-咔啉、苯并二氢吡喃、苯并吡喃、噌啉、呋喃、咪唑、吲唑、吲哚、二氢吲哚、中氮茚、异苯并呋喃、异苯并吡喃、异吲哚、异二氢吲哚、异喹啉、异噻唑、异噁唑、萘啶、噁二唑、噁唑、萘嵌间二氮杂苯(perimidine)、菲啶、菲咯啉、吩嗪、酞嗪、蝶啶、嘌呤、吡喃、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、吡呤环、喹唑啉、喹啉、喹嗪、喹喔啉、四唑、噻二唑、噻唑、噻吩、三唑、呫吨等的基团。
“患者”或“对象”包括但不限于动物,例如哺乳动物。优选地,所述患者是人。
“预防”或“防止”在动词和名词时都是指降低得病或失调的风险(即至少造成这种疾病的临床症状之一不继续恶化,即使患者可能已接触到或易患疾病,但还没有体验或显示疾病症状)。
“保护基团”是指原子组,其在接合至分子中的反应性功能性基团时掩蔽、降低或组织功能性基团的反应性。保护基团的示例可发现于Green等,《有机化学中的保护性基团》(Protective Groups in Organic Chemistry),(Wiley,第二版,1991)和Harrison等,《合成有机方法纲要》(Compendium of Synthetic Organic Methods),卷1-8(John Wiley andSons,1971-1996)。代表性的氨基保护基团包括但不限于甲酰基、乙酰基、三氟乙酰基、苄基、苯氧基羰基(“CBZ”)、叔丁氧基羰基(“Boc”)、三甲基甲硅烷基(“TMS”)、2-三甲基甲硅烷基-乙磺酰基(“SES”)、三苯甲基和取代的三苯甲基、烯丙氧基羰基、9-芴基甲氧基羰基(“FMOC”)、硝基-藜芦基氧基羰基(“NVOC”)等。代表性的羟基保护基团包括但不限于,羟基被乙酰化或烷基化的那些,如苄基、和三苯甲基醚乙基烷基醚、四氢吡喃基醚、三烷基甲硅烷基醚和烯丙基醚。
“盐”指代化合物的盐,其具有母体化合物的所需药学活性。这类盐包括:(1)与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的;或与有机酸如乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、延胡索酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰)苯甲酸、肉桂酸、苦杏仁酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、4-甲基双环[2.2.2]-辛-2-烯-1-羧酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡糖酸、谷氨酸、羟基萘酸、水杨酸、硬脂酸、粘康酸等形成的酸加成盐;或(2)母体化合物中存在的酸性质子被金属离子,如碱金属离子、碱土金属离子或铝离子取代时形成的盐;或与有机碱如乙醇胺,二乙醇胺,三乙醇胺,N-甲基葡糖胺等的配位化合物。
“溶剂合物”指溶剂化后的化合物(溶剂分子或溶质分子或离子的组合物,其中溶质分子是指本发明中的化合物)或一个包含溶质离子或分子(本发明中的化合物)与一种以上的溶剂分子的总合。
“药学上可接受的”是指适合直接使用在人类和动物组织上,而不发生过分的毒性,刺激性,过敏性反应等,与合理的效益/风险比相称,并且在合理医疗判断的范围内对于目标应用而言是有效的。
“前药或软性药物”指药理活性化合物的前体,其中,该前体本身可能有也可能没有药理活性,但是,给药后,前体可通过代谢或其他方式被转换成有药理活性的化合物或药物。例如,前药或软性药物是药物的酯或醚形式。不少前药已经被不同的制药公司发现并合成。参见例如,Bundgaard,H.和Moss,J.,J.Pharm.Sci.78:122-126(1989)。因此,本领域技术人员知晓如何用常用有机合成技术来制备这些前体、前药或软性药物。
“取代的”在用于修饰具体基团时表示具体基团中的一个或多个氢原子各自独立地被相同或不同的取代基取代。可用于取代具体基团中的饱和碳原子的取代基包括但不限于-Ra、卤素、-O-、=O、-ORb、-SRb、-S-、=S、-ΝRcRc、=NRb、=N-ORb、三卤代甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、=N2、-N3、-S(O)2Rb、-S(O)2NRb、-S(O)2O-、-S(O)2ORb、-OS(O)2Rb、-OS(O)2O-、-OS(O)2ORb、-P(O)(O-)2、-P(O)(ORb)(O-)、-P(O)(ORb)(ORb)、-C(O)Rb、-C(S)Rb、-C(NRb)Rb、-C(O)O-、-C(O)ORb、-C(S)ORb、-C(O)NRcRc、-C(NRb)NRcRc、-OC(O)Rb、-OC(S)Rb、-OC(O)O-、-OC(O)ORb、-OC(S)ORb、-NRbC(O)Rb、-NRbC(S)Rb、-NRbC(O)O-、-NRbC(O)ORb、-NRbC(S)ORb、-NRbC(O)NRcRc、-NRbC(NRb)Rb和-NRbC(NRb)NRcRc,其中Ra选自烷基、取代的烷基、芳烷基、烷基二基、取代的烷基二基、芳基、取代的芳基、芳烷基、取代的芳烷基、杂烷基、取代的杂烷基、杂烷基二基、取代的杂烷基二基、杂芳基、取代的杂芳基、杂芳烷基、取代的杂芳烷基;各Rb独立地是氢或Ra;并且各Rc独立地是Rb,或者2个Rc与它们结合的氮原子一起形成环杂烷基环,其可任选地包含1-4个选自O、N和S的相同或不同的其他杂原子。作为具体示例,-NRcRc表示包括-NH2、-NH-烷基、N-吡咯烷基和N-吗啉基。
类似地,可用于取代具体基团中的不饱和碳原子的取代基包括但不限于-Ra、卤素、-O-、-ORb、-SRb、-S-、-NRcRc、三卤代甲基、-CF3、-CN、-OCN、-SCN、-NO、-NO2、-N3、-S(O)2Rb、-S(O)2O-、-S(O)2ORb、-OS(O)2Rb、-OS(O)2O-、-OS(O)2ORb、-P(O)(O-)2、-P(O)(ORb)(O-)、-P(O)(ORb)(ORb)、-C(O)Rb、-C(S)Rb、-C(NRb)Rb、-C(O)O-、-C(O)ORb、-C(S)ORb、-C(O)NRcRc、-C(NRb)NRcRc、-OC(O)Rb、-OC(S)Rb、-OC(O)O-、-OC(O)ORb、-OC(S)ORb、-NRbC(O)Rb、-NRbC(S)Rb、-NRbC(O)O-、-NRbC(O)ORb、-NRbC(S)ORb、-NRbC(O)NRcRc、-NRbC(NRb)Rb和-NRbC(NRb)NRcRc,其中Ra、Rb和Rc如之前定义。
可用于取代杂烷基和环杂烷基中的氮原子的取代基包括但不限于-Ra、-O-、-ORb、-SRb、-S-、-NRcRc、三卤代甲基、-CF3、-CN、-NO、-NO2、-S(O)2Rb、-S(O)2O-、-S(O)2ORb、-OS(O)2Rb、-OS(O)2O-、-OS(O)2ORb、-P(O)(O-)2、-P(O)(ORb)(O-)、-P(O)(ORb)(ORb)、-C(O)Rb、-C(S)Rb、-C(NRb)Rb、-C(O)ORb、-C(S)ORb、-C(O)NRcRc、-C(NRb)NRcRc、-OC(O)Rb、-OC(S)Rb、-OC(O)ORb、-OC(S)ORb、-NRbC(O)Rb、-NRbC(S)Rb、-NRbC(O)ORb、-NRbC(S)ORb、-NRbC(O)NRcRc、-NRbC(NRb)Rb和-NRbC(NRb)NRcRc,其中Ra、Rb和Rc如之前定义。
可用于取代其他具体基团的来自上述列表的取代基将对于本领域技术人员而言是显而易见的。用于取代具体基团的取代基还可被一般选自上述各种基团的相同或不同基团中的一种或多种取代。术语“任选地取代”在与具体基团联用时表示该具体基团可以是取代或未取代的。例如,任选地取代的烷基表示取代的烷基或未取代的烷基。
在一些实施方式中,疾病或病症的“处理”或“治疗”是指减轻或预防疾病或病症(即抑制、防止、保持或减轻疾病的发展或至少其临床症状之一)。在其他实施方式中,“处理”或“治疗”是指改善至少一个物理参数,也许在患者身上并不明显。在另一些实施方式中,“处理”或“治疗”是指从身体(例如,一个明显症状的稳定)或者生理(例如,一个物理参数的稳定)方面下手抑制疾病或病症,又或两者兼而有之。在又一些实施方式中,“处理”或“治疗”是指延缓疾病或病症的发生。
“治疗有效量”指给予对象用于治疗疾病时,足以实现治疗疾病的化合物的用量。“治疗有效量“将根据化合物、疾病及其严重性以及需要治疗的患者的年龄、体重等因素而变化。
“载剂”是指使用其给予化合物的稀释剂,辅药,赋形剂,或运载体。
一些参考实例及文献将在本发明中有选择性的在一些具体实例中体现并详细指出。虽然本发明将有选择性地描述某些具体实例和具体体现,但是,应该理解的是,选择性的描述不是为了限制发明于这些具体体现。相反地,所有的替换、改良和等价内容都应包括在由所附权利要求书定义的本发明的精神和范围之内。
术语“受体”是指一种分子或分子复合物,一般(虽然不必然)是蛋白质,其特异性地被一种或多种特定配体结合。该受体被成为该配体的受体。在许多情况中,配体-受体结合包括一种或多种生物响应。多肽的“调节剂”是该多肽的作用或功能的抑制剂或增强剂。类似地,信号转导通路的“调节剂”是由该信号转导通路介导的至少一种功能的抑制剂或增强剂。参照多肽如下定义调节剂的方面;然而,本领域技术人员易于理解这些定义也应用于信号转导通路。
多肽的“非选择性”调节剂是在一般用于调节特定多肽的浓度下调节同一多肽家族的其他成员的试剂。
多肽的“选择性”调节剂在一定浓度下显著调节特定多肽,在该浓度下并不显著调节同一多肽家族的其他成员。
在调节剂通过与多肽的直接相互作用发挥其作用时,该调节剂“直接作用于”该多肽。
在调节剂通过与除了多肽以外的分子相互作用发挥其作用,该相互作用导致调节多肽功能或作用时,该调节剂“间接作用于”该多肽。
多肽的“抑制剂”或“结抗体”是与没有(或存在少量)试剂的情况中所观察到的相比,通过任意机制减少多肽的任意作用或功能的试剂。多肽的抑制剂可影响:(1)多肽的表达、mRNA稳定性、蛋白质运输、修饰(例如,磷酸化)、或降解,或者(2)多肽的正常作用或功能中的一种或多种。多肽的抑制剂可以是非选择性的或选择性的。优选的抑制剂(结抗体)一般是小分子,其直接作用于靶标多肽并且对靶标多肽有选择性。
“可逆”抑制剂是其作用可逆转的抑制剂(即,不会不可逆地灭活靶标多肽的抑制剂)。
多肽的“竞争性”抑制剂是与多肽功能所需的另一组分竞争结合该多肽的抑制剂。例如,TrkA功能需要ATP和底物结合。因此,TrkA的竞争性抑制剂可通过例如在ATP或底物结合位点处结合来发挥作用。这种抑制一般可通过增加反应混合物的ATP或底物的浓度来逆转。这种抑制剂被称为分别对ATP或底物竞争性抑制TrkA。
多肽的“非竞争性”抑制剂一般在除了多肽功能所需的另一组分的结合位点以外的位点处结合多肽。这种结合不可通过增加多肽功能所需组分的浓度来逆转。
本文所用的多肽(一般是酶或受体)的“变构调节剂”是在除了靶标多肽的活性位点以外的位置处结合的调节剂,其通过诱导靶标多肽的形状变构改变来改变活性。
术语“多肽”和“蛋白质”在本文中互换使用指代氨基酸聚合物,并且除非另有限制,包括可以与天然存在的氨基酸类似的方式发挥功能的非典型氨基酸。
本文定义的术语“特异性结合”是结合伴侣(例如,2个多肽、1个多肽和核酸分子、或2个核酸分子)彼此在特定位点处的优先结合。术语“特异性结合”表明靶标分子/序列的结合优先性(例如,亲和性)是非特异性靶标分子(例如,随机生成的缺少特异性识别位点的分子)的至少2倍、更优选至少5倍、并且最优选至少10倍或20倍。
短语“有效量”和“足量”是指一种生物活性剂可以产生预期的生物活性的数量。
在提到Trk(即TrkA)拮抗剂和其他作用剂给药使用时,术语“共同给药”或“一起给药”是指拮抗剂和其他作用剂的给药使它们至少有一段生理活性时间是重叠的。因此,TrkA拮抗剂可同时给药和/或与另一作用剂顺序给药。在顺序给药中,甚至在给第二剂之前可以出现一些实质性的延迟(例如,几分钟甚至数小时或数天),只要当第二剂给药或在患者体内体现活性时,第一剂仍有生理活性。
本文中所使用的术语“减少疼痛”是指减少患者疼痛的感知水平(相对于不干预情况下)。如果患者是一个人,感觉到的疼痛程度可以通过要求他或她来描述疼痛或与其它疼痛的经历比较来评估。另外,疼痛程度可以通过测量对象对疼痛的物理反应而得到,如应力释放有关的因素或在周围神经系统或中枢神经系统神经中的疼痛转导神经的活动。疼痛程度也可以通过止痛剂的剂量来测量,止痛剂的剂量由患者回馈疼痛消失或疼痛症状消失来确定。减少疼痛另一个衡量办法是经历疼痛刺激的观察对象的阈值增加。在某些实施方式中,可以通过减少“痛觉过敏”,对有害的刺激的高度警觉来减少疼痛,这种抑制作用可以在不损害“伤害感受”和对“有害”刺激的正常敏感性的情形下实现。本文所用术语“疼痛”也指例如,急性疼痛、慢性疼痛、炎性疼痛、神经性疼痛、和全身疼痛病症。
在减少疼痛参考中,“有此需要的对象”是指预计其在不久的将来会有疼痛的动物或人,最好是人。这种动物或人可能有持续的状况造成当前的疼痛,并可能继续引起疼痛。或者,这种动物或人已经,正在或将经历一个通常有疼痛的过程或事件。慢性疼痛如糖尿病神经过敏和胶原血管疾病属于第一类的例子;牙科工作,尤其伴随有炎症或神经损伤,和毒素暴露(包括接触化疗药物)属于后一类的例子。
“炎性疼痛”是指由炎症引起的疼痛。炎性疼痛往往表现为对机械刺激(机械性痛或压痛)越来越敏感。例如,炎症性疼痛是由下列状况引起:烧伤、晒伤、关节炎、骨关节炎、结肠炎、心肌炎、皮炎、肌炎、神经炎、粘膜炎、尿道炎、膀胱炎、胃炎、肺炎、以及胶原血管疾病。
“神经性疼痛”是指导致神经损伤的状况或事件引起的疼痛。“神经病”是指疾病过程中造成神经损害。“灼性神经痛”代表神经损伤后的慢性疼痛状态。“痛觉超敏”是指一个人对正常无痛刺激,如一个温柔的触摸,感到疼痛。例如,神经性疼痛是由下列状况引起:灼痛,糖尿病,胶原血管疾病,三叉神经痛,脊髓损伤,脑干损伤,丘脑疼痛综合征,复杂区域疼痛综合征I型/反射性交感神经萎缩症组选定的条件,法布里氏综合征,小纤维病变,癌症,癌症化疗,慢性酒精中毒,中风,脓肿,脱髓鞘疾病,病毒感染,抗病毒治疗,艾滋病,和艾滋病治疗。神经性疼痛也可来自:创伤,外科手术,截肢,毒素,和化疗。
本文中所使用的术语广义“全身疼痛病症”是一种特发性疼痛综合征组(例如,纤维肌痛,肠易激综合症,及颞下颌关节紊乱),为此,致病机制目前未知的,分散的或普遍的痛苦,和表征其中一对为炎症或病变作为疼痛的直接原因诊断排除在外。
“止痛剂”是指减少疼痛的一个分子或分子组合。
“急性”和“慢性”疼痛之间的区别就是时间差:在导致这种疼痛的事件发生(如炎症或神经损伤)后,很快会感觉急性疼痛(例如,通常在大约48小时,更典型的24小时之内,大多数一般在12小时)。与此相反,在导致这种疼痛的事件发生相当长的之后,才会感觉到慢性疼痛。这种时间上的延迟至少约48小时,更典型,至少约96小时后,最通常至少约一星期后。
术语“适应不良的物质使用”是指导致使用者不良后果超过从该物质获得的任意益处的任何物质使用。以适应不良的方式使用的物质一般被身体消耗或给予身体(通常自给予),通过任何给药途径,以对身体产生使用者一般愉快经历的影响。该物质可以是单一物质(例如,可卡因)或一种类型的物质(例如,一般食物)。不良后果可包括,例如,对健康、照顾自己的能力、形成和维持人类关系的能力、和/或工作能力的不良影响。不良后果一般是明显足以使得使用者会控制、减少或终止物质使用,或者使用者的家庭成员和/或朋友会希望看到使用者控制、减少或终止物质使用。适应不良的物质使用可包括不受控制的渴求物质;物质依赖,包括心理和/或生理依赖;和适应不良的物质使用;以及以下所列的物质依赖和/或滥用的任意个体症状。
术语“神经甾体”是指有一类甾体,其天然形式由中枢或外周神经系统的细胞产生,独立于内分泌腺的类固醇生成活性。神经甾体衍生自胆固醇,并且神经甾体的示例包括3α,5α-四氢孕酮、3α,5β-四氢孕酮、和3α,5α-四氢脱氧皮质酮。例如,加那索酮和阿法沙龙。
“苯并二氮杂”是指选自下组的试剂:阿普唑仑、利眠宁、盐酸利眠宁、氯美扎酮、氯巴占、氯硝西泮、氯拉卓酸二钾、地西泮、氟哌利多、艾司唑仑、柠檬酸芬太尼、盐酸氟西泮、哈拉西泮、劳拉西泮、盐酸咪达唑仑、奥沙西泮、普拉西泮、夸西泮、替马西泮、和三唑仑。
“巴比妥盐”是指选自选自的试剂:异戊巴比妥、异戊巴比妥钠、阿普比妥、另丁巴比妥钠、环己烯巴比妥钠、甲苯巴比妥、甲巴比妥、美索比妥钠、戊巴比妥、戊巴比妥钠、苯巴比妥、苯巴比妥钠、司可巴比妥、司可巴比妥钠、他布酮、硫戊巴比妥钠、和戊硫代巴比妥钠。
本文所用术语“组合物”旨在包括含有特定量特定成分的产品,以及从特定量的特定成分组合直接或间接生成的任何产品。关于药物组合物而言,该术语目的是涵盖包括活性成分和构成载体的惰性成分的产品,以及任何直接或间接从任意两个或更多个成分组合、络合或聚集,或一个或更多成分的分解,或一个或更多成分其他类型的反应或相互作用形成的任意产品。因此,本发明的药物组合物涵盖了通过混合本发明化合物与药学上可接受的载体形成的任意组合物。“药学上可接受的”指运载体、稀释剂或者赋形剂必须与制剂中其它成分相容,且对接受者没有毒害作用。
术语“癌症”指或描述典型特征是细胞生长失控的哺乳动物的生理病症。癌症的例子包括,例如,白血病,淋巴瘤,母细胞瘤,癌和肉瘤。这类癌症的更具体示例包括慢性髓细胞性白血病、急性淋巴细胞性白血病、费城染色体阳性的急性淋巴细胞性白血病(Ph+ALL)、鳞状细胞癌、肺癌(例如,小细胞肺癌、和非小细胞肺癌)、胶质瘤、胃肠癌、肾癌、卵巢癌、肝癌(例如,肝细胞癌、纤维板层癌、胆管癌、血管肉瘤、肝毒细胞瘤、血管瘤、肝细胞腺瘤和局灶性结节状增生、以及转移性肝癌)、结直肠癌、子宫内膜癌、肾癌、前列腺癌、甲状腺癌、神经母细胞硫、胰腺癌(例如,腺癌、胰岛细胞癌、胰腺母细胞瘤、分离的肉瘤和淋巴瘤、假乳头状瘤、壶腹癌、外分泌肿瘤、神经内分泌肿瘤和内分泌肿瘤)、多形性成胶质细胞瘤、宫颈癌、胃癌、膀胱癌、肝细胞癌、乳腺癌、结肠癌、和头颈癌、胃癌、生殖细胞癌、小儿肉瘤、鼻窦自然杀伤、多发性骨髓瘤、急性髓细胞白血病(AML)、和慢性淋巴细胞白血病(CML)。
应该理解的是,本发明不限于特定的方法,试剂,化合物,成分,或生物系统,它们都可以变化。也应该理解的是,此处使用的术语只是为描述具体方面,而不是起限制作用。在本说明书和权利要求书中所用的单数形式“一个”、“一种”和“该”包括多个指示物,除非上下文中有明显的表示。因此,例如,提到的“一个化合物”包括两个或两个以上的化合物或分子,等等。
5.2化合物
在一个方面,本发明提供了结构为式(I)的化合物,
或其盐、溶剂合物、酯、或前药;
其中:
A1和A2独立地是氧或硫;
R1表示NH2或R7;
R2表示NR7或CR7R10;
R3、R5、R6、和R9独立地是R7;
或者,R6和R9与它们接合的原子一起形成含有一个或多个选自氮、氧和硫的杂原子的3-6元任选取代的杂环基;
R4表示卤素、CN、NO2、CF3、-(CHR)nCOOR11、-(CHR)nSO2R11、C1-4卤代烷基、-OC1-4-卤代烷基、C2-6烷基、C2-6烯基、C2-6炔基、-(CHR)nC6-10芳基、-(CHR)nC5-8杂环、-(CHR)nC3-8环烷基、-O-C6-10芳基、-O-C5-10杂环、-(CHR)nC(O)CF3、-(CHR)nC(OH)(CF3)2、-(CH2)n卤素、-OR10、-NR11R12、-NRaCOR11、-NRaCOOR11、-NRaSO2R11、-NRaCONR11R12、-COR11、四唑、-(CHR)n四唑、-S-C1-6烷基、或–CONR11R12,其中各所述烷基、烯基、炔基、芳基、环烷基和杂环独立地任选被1至2个R8基团取代;
或者,R4和R5与它们接合的原子一起形成含有一个或多个选自氮、氧和硫的杂原子的3-6元任选取代的杂环基;
R7和R10独立地选自氢、卤素、CN、NH2、NO2、C1-4卤代烷基、-OC1-4卤代烷基、C1-6烷基、C2-6烯基、C2-6炔基、-(CHR)nC6-10芳基、-(CHR)nC5-8杂环、-(CHR)nC3-8环烷基、-O-C6-10芳基、-O-C5-10杂环、-C(O)CF3、-(CH2)n卤素、-(CHR)n-(O)n-C(=O)R8、-(CHR)n-(S)n-C(=O)R8、-ORa、-NR11R12、-NRaCOR11、-NRaCOORa、-NRaSO2R、-NRaCONR11R12、-CORa、-(CHR)nCOORa、-S-C1-6烷基、和–CONR11R12,其中各所述烷基、烯基、炔基、芳基、环烷基和杂环独立地任选被1至2个R8基团取代;
R11和R12独立地选自氢、NRaC(=O)R、卤素、CN、NH2、NHRa、NO2、C1-4卤代烷基、-OC1-4卤代烷基、C1-6烷基、C2-8烯基、-S-C1-6烷基、-C(=O)-(O)n-Ra、-(CHR)n-(O)n-C(=O)R8、-(CHR)n-(S)n-C(=O)R8、-ORa、-(CHR)nC3-10环烷基、-(CHR)nC6-10芳基、-(CHR)nC5-10杂芳基、和-(CHR)nC5-10杂环,其中各所述烷基、烯基、环烷基、芳基、杂芳基和杂环独立地任选被1至2个R8基团取代,并且其中所述烷基的一个或多个碳原子可被一个或多个选自氮、氧和硫的杂原子取代;
或者,R11和R12与它们接合的原子一起形成含有一个或多个选自氮、氧和硫的杂原子的3-6元任选取代的杂环基;其中任选的取代基是R8;并且
R各自独立地表示氢、卤素、CN、NO2、NH2、或C1-6烷基;
Ra各自独立地表示氢或C1-6烷基;
R8各自独立地表示C1-6烷基、卤素、CN、NO2、NH2、NHRa、SO2R11、或NRaSO2R11;并且
n表示0-3的整数,即,0、1、2、或3;
有以下前提:
当R2是CH2时,R4不是H或CH3;
当R2是NCH2CH2OH时,(a)R4不是H或OCH3,或者(b)R5不是OCH3;并且
当R2是N(CH3)时,R4不是H、CH3、OCH3、或F。
在式(I)的一个实施方式中,R1选自氢、-(CH2)n卤素、-CN、-CH3、NH2、NHRa、和-C1-3烷基;
在式(I)的一个实施方式中,R4选自-C(O)OR11、-SO2NHC(=O)CH3、-C(CF3)(CF3)OH、-SO2NH2、-C(O)NR11R12、-CN、-CF3、-NO2、-C(O)CF3、-(CH2)n卤素、
在式(I)的一个实施方式中,R3、R5、R6和R9是氢。
在式(I)的一个实施方式中,R2选自
在式(I)的一个实施方式中,A1和A2是氧;R1表示NH2;R2表示NR7或CHR7;R3、R5、R6、和R9是氢;R7是C5-8杂环或C3-8环烷基;并且R4选自-C(O)OR11、-SO2NHC(=O)CH3、-C(CF3)(CF3)OH、-SO2NH2、-C(O)NR11R12、-CN、-CF3、-NO2、-C(O)CF3、-(CH2)n卤素、
在R2的一个实施方式中,其选自
在另一个方面,本发明提供了结构为式(II)的化合物:
或其盐、溶剂合物、酯、或前药;
其中:
X表示N或CH;
R4表示选自-(CHR)nCOOR11、-(CHR)nSO2R11、-(CHR)nC5-8杂环或-(CHR)nC(OH)(CF3)2的羧基生物电子等排体,其中各所述杂环独立地任选被1至2个R8基团取代;
R11独立地选自氢、C1-6烷基、NH2、NHRa、和NRaC(=O)R,其中各所述烷基独立地任选被1至2个R8基团取代,并且其中所述烷基的一个碳原子可被一个选自氮、氧、和硫的杂原子取代;
R8各自独立地表示C1-6烷基、卤素、CN、NO2、NH2、NHRa、SO2R11、或NRaSO2R11;
R各自独立地表示氢、卤素、CN、NO2、NH2或C1-6烷基;
Ra各自独立地表示氢或C1-6烷基;并且
n表示0。
在式(II)的一个实施方式中,X表示N。
在式(II)的一个实施方式中,R4表示-COOR11,其中R11是氢。在式(II)的一个实施方式中,R4表示-COOR11,其中R11是C1-6烷基。在式(II)的一个实施方式中,R4表示–COOR11,其中R11是C1-6烷基,其中所述C1-6烷基的一个碳原子被一个氮原子取代。
在式(II)的一个实施方式中,X表示N且R4表示-COOR11,其中R11是氢。
在式(II)的另一个实施方式中,R4表示-SO2R11,其中R11是NH2或NRaC(=O)R。在式(II)的一些实施方式中,R4表示-SO2R11,其中R11是NHC(=O)R并且其中R是C1-6烷基。
在式(II)的一个实施方式中,R4表示C5杂环,其中该杂环是四唑。
在某些具体实施方式中,式(I)和/或式(II)的化合物选自
表1
表1所列的化合物也可由它们的以下化学名称表示:
ID IUPAC名称
10 4-{[4-氨基-3-(4-环己基哌嗪-1-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯磺酰胺;
12 4-{[4-氨基-3-(4-环己基哌嗪-1-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯甲酸;
14 N-[(4-{[4-氨基-3-(4-环己基哌嗪-1-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯基)磺酰基]乙酰胺;
16 1-氨基-2-(4-环己基哌嗪-1-基)-4-{[4-(2H-四唑-5-基)苯基]氨基}蒽-9,10-二酮;
18 1-氨基-2-(4-环己基哌嗪-1-基)-4-{[4-(1H-四唑-5-基)苯基]氨基}蒽-9,10-二酮;
20 1-氨基-2-(4-环己基哌嗪-1-基)-4-{[4-(1,1,1,3,3,3-六氟-2-羟丙-2-基)苯基]氨基}蒽-9,10-二酮;
22 4-{[4-氨基-3-(4-环己基哌嗪-1-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯甲酸甲酯;
24 4-{[4-氨基-3-(4-环己基哌嗪-1-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯甲酸2-(二甲基氨基)乙酯;
26 4-{[4-氨基-3-(4-环己基哌嗪-1-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯甲酸乙酯;
30 4-{[4-氨基-3-(1,4'-二哌啶-1'-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯磺酰胺;
32 4-{[4-氨基-3-(1,4'-二哌啶-1'-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯甲酸;
34 N-[(4-{[4-氨基-3-(1,4'-二哌啶-1'-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯基)磺酰基]乙酰胺;
36 1-氨基-2-(1,4'-二哌啶-1'-基)-4-{[4-(2H-四唑-5-基)苯基]氨基}蒽-9,10-二酮;
38 4-{[4-氨基-3-(1,4'-二哌啶-1'-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯甲酸2-(二甲基氨基)乙酯;和
40 1-氨基-2-(1,4'-二哌啶-1'-基)-4-{[4-(1,1,1,3,3,3-六氟-2-羟丙-2-基)苯基]氨基}蒽-9,10-二酮。
在本发明的一个实施方式中,表2中所列的基于式(III)的化合物被排除。
表2
化合物编号 | X | R<sup>4</sup> | R<sup>5</sup> |
E1 | CH<sub>2</sub> | H | H |
E2 | CH<sub>2</sub> | CH<sub>3</sub> | H |
E3 | NCH<sub>3</sub> | H | H |
E4 | NCH<sub>3</sub> | CH<sub>3</sub> | H |
E5 | NCH<sub>3</sub> | F | H |
E6 | NCH<sub>3</sub> | OCH<sub>3</sub> | H |
E7 | NCH<sub>3</sub> | H | F |
E8 | NCH<sub>3</sub> | H | OCH<sub>3</sub> |
E9 | NCH<sub>2</sub>CH<sub>2</sub>OH | H | H |
E10 | NCH<sub>2</sub>CH<sub>2</sub>OH | OCH<sub>3</sub> | H |
E11 | NCH<sub>2</sub>CH<sub>2</sub>OH | H | OCH<sub>3</sub> |
5.3化合物的合成
用于制备本发明的化合物的多种方法示于以下方案和实施例。按照本领域已知或本文所示的过程来制备起始材料。本发明中使用了以下缩写:Me:甲基;Et:乙基;t-Bu:叔丁基;Ar:芳基;Ph:苯基;Bn:苄基;BuLi:丁基锂;Piv:新戊酰;Ac:乙酰基;THF:四氢呋喃;DMSO:二甲亚砜;EDC:N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺;Boc:叔丁氧基羰基;Et3N:三乙胺;DCM:二氯甲烷;DCE:二氯乙烷;DME:二甲氧基乙烷;DBA:二乙胺;DAST:二乙氨基三氟化硫;EtMgBr:乙基溴化镁;BSA:牛血清白蛋白;TFA:三氟乙酸;DMF:N,N-二甲基甲酰胺;SOCl2:亚硫酰氯;CDI:羰二咪唑;rt:室温;HPLC:高效液相色谱;TLC:薄层色谱。本文所述的化合物可以本领域技术人员已知的多种方式制备。
用于合成本发明的化合物的本文所述的过程可包括一个或多个步骤的保护和去保护(例如,缩醛的形成和去除)。另外,下述的合成过程可包括多种纯化,如柱色谱、快速色谱、薄层色谱(TLC)、重结晶、蒸馏、高压液相色谱(HPLC)等。同时,也可使用化学领域所熟知的多种用于鉴定和定量化学反应产物的技术,如质子和碳-13核磁共振(1H和13CNMR)、红外和紫外光谱(IR和UV)、X-射线晶体法、元素分析(EA)、HPLC和质谱(MS)。保护和去保护、纯化和鉴定以及定量的方法是化学领域所熟知的。
式(I)和/或式(II)的化合物的合成方案的示例:
中间体2的制备,2,30.0kg的4-氨基-10-羟基蒽-9(10H)-酮(起始材料1)在MeOH(70L)中悬浮。在60℃下,向该悬浮液中加入53.7kg的溴,约1小时。在加入溴之后,反应混合物在50-60℃下搅拌约18-24小时。然后冷却反应混合物。所得的悬浮液过滤,用MTBE洗涤。对红色固体进行干燥以得到红色固体的中间体2(约50.0kg,产率98%)。HPLC分析显示96%纯度。1H-NMR(CDCl3,300Hz)δ8.26(m,2H),8.09(s,1H),7.80(m,2H)。
中间体3a的制备。将2.99kg的NaNO2温和加入冷却H2SO4(27.8L)溶液中。在35℃下将该混合物搅拌1小时。然后向混合物中加入中间体2(15.0kg)并且在50-55℃下搅拌4小时。在冷却至室温后,将反应混合物倒入碎冰中。黄色固体析出。过滤收集固体,用冰水洗涤,之后用乙醇/MTBE的1:1混合物洗涤来得到湿润固体,其经干燥。获得24.7kg的粗潮湿产品。所述产物不经过进一步纯化就用于下一步骤。
中间体3的制备。100L夹套式反应器中加入含NaN3(2.73kg)的水溶液。在室温下加入中间体3a,并且混合物在室温下搅拌过夜。然后向混合物中缓慢加入NaOH(6N)水溶液。然后固体通过过滤收集并用水洗涤。滤饼用水浆料化、过滤并且用水洗涤,之后用丙酮/水(9:1)混合物洗涤,空气干燥以得到粗中间体3(23.2kg的湿固体)。HPLC分析显示95%纯度。1H-NMR(300MHz,DMSO-d6)δ8.51(s,1H),8.11-8.15(m,2H),7.91-7.94(m,2H)。
中间体4的制备。在约50-70℃下向甲苯中加入26.5kg的粗中间体3。然后将混合物在50-70℃下搅拌过夜。在反应温度冷却至室温后,收集固体产物。用甲醇清洗所述滤饼。所得固体在甲醇中重悬并且在室温下搅拌约1-3小时。过滤后,获得黄色固体的13.3kg的中间体4的湿产物。HPLC分析显示98.7%纯度。1H-NMR(300MHz,DMSO-d6):δ8.27(m,2H),8.13(m,1H),7.91(m,1H),7.78(m,1H)。
中间体5的制备。在DMAc中混合4-氨基苯甲酸和氢氧化锂,然后在约40-60℃下将3,5-二溴-6H-蒽[1,9-cd]异噁唑-6-酮加入混合物中。将反应混合物搅拌最多24小时。向反应混合物中加入MTBE。过滤固体并干燥,得到4-((3-溴-6-氧代-6H-蒽[1,9-cd]异噁唑-5-基)氨基)苯甲酸(中间体5)。
中间体6的制备。在DMSO中溶解中间体5,然后在约50-70℃的温度下向溶液中加入三乙胺和1-环己基哌嗪。加入MTBE和MeOH溶液。分离并用MTBE和MeOH洗涤湿饼,之后过滤得到固体中间体6。
化合物12的制备。在烧瓶中,中间体6、Pd/C和肼混合并加热约4小时。反应混合物冷却至室温并过滤,然后其在TFA/DMA和活性炭中重溶,然后过滤通过硅藻土。加入NaHCO3来中和混合物并且通过过滤收集固体。化合物12经纯化并干燥。其得到约99%(HPLC,面积%)的纯度。质谱得到[M+l]-525.5.TI-NMR(300MHz,DMSO-d6),ppm(8):12.36(1H,s),8.27(2H,d),7.95(2H,d),7.85(2H,t),7.42(2H,d),7.25(1H,s),2.96(4H,m),2.74(4H,m),2.27(2H,m),1.57-1.80(6H,m),1.06-1.23(5H,m)。
5.3生物活性
在基于放射性的胶束试验中的化合物抑制:在25μL的最终反应体积中,TrkA(h)(3nM)与激酶反应缓冲剂(20mM HEPES(pH 7.5),10mM MgCl2,1mM EGTA,0.02%Brij 35,0.02mg/ml BSA,0.1mM Na3VO4,2mM DTT,1%DMSO)、0.2mg/ml底物PolyEY(4:1)和2nM MnCl2以及[33P-ATP](具体活性约500cpm/pmol,浓度根据需要)孵育。加入MgATP混合物启动反应。室温孵育至少40分钟之后,加入5μL 3%的磷酸溶液终止反应。10L的反应液点样到P30Filtermat上,在75mM磷酸中洗涤三次持续5分钟,一旦在甲醇中之后,进行干燥和闪烁计数。TrkA:重组人胞质结构域(氨基酸441-796),组氨酸标记,在昆虫细胞中表达。体外通过自磷酸化激活。Mw=42.8kDa。激酶底物:poly(EY)对于TRKA;poly(EY)(4:1)和2mM MnCl2,平均Mw=16kDa标准条件(除非另有说明):30nM TRKA,0.2mg/ml poly(EY)+2mM MnCl2,和10μΜ([γ-33Ρ])ATP。其他激酶的重组人胞质结构域使用类似试验条件,也可测量其他激酶的活性。
可通过这些试验来确定可用于本发明的化合物的TrkA激酶拮抗剂活性。具体地,本发明上述实施例,包括表1的化合物具有在上述试验中拮抗TrkA激酶活性的活性,通常有低于约25μΜ的IC50。在前述试验中,本发明优选的化合物有拮抗TrkA激酶活性的活性,其具有低于约2.5μΜ的IC50。在前述试验中,本发明进一步优选的化合物有拮抗TrkA激酶活性的活性,其具有低于约0.25μΜ的IC50。在前述试验中,本发明更进一步优选的化合物有拮抗TrkA激酶活性的活性,其具有低于约0.1μΜ的IC50。例如,本发明的化合物A具有0.085μΜ的IC50;本发明的化合物12在10μΜ浓度下抑制约99.6%的TrkA激酶或具有约50至150nM的IC50并且对于拮抗例如以下结构相关的蛋白激酶和其他超过400种激酶具有超过约10μΜ的IC50值,包括TrkB、TrkC、ABL1、AKT1、ALK5/TGFB-R1、ARAF、AXL、BMX、BTK、CDKl/cyclinB、CDK2/cyclinA、CDK2/cyclinE、c-ΜET、c-Src、EPHA1、FES/FPS、FGFR1、FGR、FLT1、FLT3(CD)、FMS、FYN、IGF-1R、1R、ITK、JAK3、JNK3、LCK、LYN、MEK1、MEK2、MLK1/MAP3K9、MUSK、P38a/MAPK14、P38b/MAPK11、PDGFRa、PDGFRb、PKA、PKCalpha、PKCbetaI、PKCbetaII、PKCdelta、PKCepsilon、PKCeta、PKCgamma、PKCiota、PKCmu/PKDl、PKCtheta、PKCzeta、PKD2/PRKD2、PKGla、PKGlb、RAF 1、RET、TEC、TGFbR2、TIE2/TEK、VEGFR2/KDR、VEGFR3/FLT4(一式两份,泛激酶抑制剂,星孢素或K-252a的阳性对照化合物)。这种结果显示用作TrkA激酶活性的同种型选择性拮抗剂的化合物的固有活性。
基于整个活细胞的功能性试验中的化合物抑制:有几种方法来衡量活细胞中被天然配体或激动剂NGF激活的整个长度的TrkA的活性。例如,由DiscoveRx(弗里蒙特,加利福尼亚州)提供的PathHunter剖析服务。该PathHunter技术是酶片段互补,提供用于检测蛋白质与蛋白质相互作用的一种新的,通用的功能细胞为基础的检测格式适应。在这种细胞为基础的检测方法,在U2OS细胞的背景下,一个小肽抗原决定簇(PK表位)为表达对细胞内的C-端TrkA的(人类的全长蛋白)。这是与更大的序列一起表达,称为酶受体(EA),EA是连接到一个会在细胞内与TrkA互动的细胞质蛋白SHC1。NGF诱导的TrkA的激活导致同质或异质的TrkA在交叉磷酸化的二聚体。该SHC1-EA融合蛋白与磷酸化TrkA受体的结合强迫PK和EA片段互补。这种相互作用产生一个积极的β-半乳糖苷酶,它是用化学发光底物检测。
在这种基于细胞的功能分析中,本发明的化合物12在低纳摩尔浓度时抑制NGF刺激的TrkA激活(细胞IC50约为50nM至150nM),而实际上对BDNF刺激的TrkB或NT3刺激的TrkC激活没有影响(这两种情况下,IC50都大于10μM,试验重复三次,泛激酶抑制剂,十字孢碱或内部激动剂K-252a作为阳性对照物以及一个阴性对照化合物)。
对ATP的抑制模式。在室温下进行TrkA激酶试验。使用声学技术向酶/底物混合物中加入4种浓度的化合物(0,0.037,0.11,和0.33μΜ),并且孵育40分钟以确保所有的化合物平衡并结合至酶。然后加入各种浓度的ATP(10,100,200,350,和500μΜATP与0.2mg/mlpoly(EY))以启动反应。以每5-15分钟的时程监测活性。这种动态分析显示化合物D,例如,对于ATP非竞争性抑制TrkA:Lineweaver-Burk双倒数曲线显示在Vmax中的差异,而不是4种条件的km。
对底物的抑制模式。以与ATP研究类似的方式进行激酶试验。使用声学技术向酶/底物混合物中加入各种浓度的化合物(0,0.037,0.11,和0.33μΜ),并且孵育40分钟以确保所有的化合物平衡并结合至酶。然后加入10μΜATP与各种浓度的底物(0.02,0.05,0.1,0.2和0.5mg/mlpoly(EY))以启动反应。以每5-15分钟的时程监测活性。这种动态分析显示化合物D,例如,对于底物非竞争性抑制TrkA:Lineweaver-Burk双倒数曲线显示在Vmax中的差异,而不是4种条件的km。
细胞活力和增殖分析。为了评价肿瘤细胞的化学敏感性,基于生产商的说明书,通过发光细胞活力分析仪(美国威斯康星州的普洛麦格公司(Promega))测量细胞活力。简言之,在RPMI培养基配制的增加浓度的药物(测试物0-100μM)或载体的存在下,在96孔无菌板中以5×103至7×105细胞/毫升培养细胞。然后将板孵育24-96小时,加入100μl CellTiter-Glo试剂溶解细胞。室温下孵育10分钟之后,在发光计中记录发光,积分时间1s/孔。由载体处理细胞获得的发光信号对药物处理细胞的发光信号进行标准化。作为定量细胞护理的替代方法,可使用台盼蓝排除法。通过以下方法分析载体或药物处理的细胞:将台盼蓝溶液(0.4%,在磷酸盐缓冲盐水[PBS]中)加入到培养基中。3分钟后,将保留该染料的死细胞的数量与总的细胞数量进行比较以计算细胞活力。采用GraphPad Prism 5软件计算IC50和药物的效果-剂量曲线图。多板读数计:EnVision 2104(帕金埃尔默公司(PerkinElmer))。%对照活力=100*[(X(药物处理)-L(基线))/(H(载体对照)–L(基线))]。该分析显示,孵育24小时之后,在AsPC-1、MIA PaCa-2、BxPC-3、Capan-1和Panc-1的人胰腺癌细胞(来自ATCC)中,化合物12的IC50值约为2-5μM;在SK-HEP-1和HepG2的人肝癌细胞中约为约5μM;并且在NCI-N87的人胃癌细胞中约为7μM。紫杉醇、埃罗替尼、索拉非尼和吉西他滨用作对照,在胰腺癌细胞中,本发明的化合物与吉西他滨协同或叠加,或者在肝癌细胞中,本发明的化合物与索拉非尼协同或叠加。
CD-1小鼠中口服和腹膜内(i.p.)处理生物利用后的药代动力学和生物利用度。确定了CD-1小鼠(每剂量组n=4)中口服和腹膜内处理后的药代动力学和生物利用度。例如,对于化合物12,CD-1小鼠中,在50mg/kg的口服药物剂量后,口服生物利用度为约100%;在50mg/kg腹膜内药物剂量后,腹膜内身而过物利用度为约100%;化合物12的清除半衰期为静脉内给药后约1小时和腹膜内给药后约3.5小时以及口服给药后约4.5小时。
大鼠的慢性挤压伤(CCI)的神经性疼痛模型。CCI模型是最常用的单神经性疼痛模型之一,它是由本内特和谢首先详细描述的(Bennett GJ,Xie YK,疼痛杂志,1988;33(1):87-107)。它模仿像机械痛敏和热痛觉过敏等重要的临床慢性疼痛症状。根据本内特和谢的方法,慢性坐骨神经挤压伤是左侧坐骨神经松捆绑四道结扎线而产生的。此过程导致左后肢的触觉异常性疼痛。校准冯弗雷丝被用来确定最低机械(触觉)阈值可以唤起大鼠后爪的一个活跃爪子的反射退缩。在冯弗雷测试前,大鼠被允许在网笼里适应15-20分钟。使用冯弗雷丝的退缩爪的阈值(PWTs)在CCI手术前(预手术0天基线)进行了评估。在第14天服用药物前,每只大鼠服药前的基准线都被记录下来。只有不表现出运动功能障碍(如爪拖动或下降)以及PWT在4克以下的大鼠才会被列入研究。只使用没有用过药CCI-大鼠(每组4-6只)。口服载剂为含0.5%CMC-Na/0.1%吐温80的蒸馏水。阳性对照物加巴喷丁溶于运载体;其口服剂量为100毫克/公斤(口服灌胃)。测试化合物在载剂中悬浮并且以50mg/kg和100mg kg口服给予。每个CCI大鼠都是在PWT评估2个小时前单剂量口服给药:测试化合物,加巴喷丁或运载体对照。在这种大鼠神经性疼痛模型中,例如,与3mg/kg皮下吗啉(HCl)产生的止痛效果相比,化合物12显示在150mg/kg口服剂量下约48%的相对止痛效果。
结果表明,本发明化合物D的口服给药能够在神经性疼痛的CCI大鼠模型中以剂量依赖性方式显著减少机械性触诱发痛。另外,在相同的100mg/kg口服剂量下,化合物D比加巴喷丁在CCI神经性疼痛中抑制机械性触诱发痛方面更有效约98%,加巴喷丁是现有的神经性疼痛的金标药物,而甚至50mg/kg口服化合物D比100mg/kg口服加巴喷丁更有效约28%。值得注意的是,喂食加巴喷丁的CCI大鼠显示有嗜睡或动作不协调,这与已知的加巴喷丁的副作用是一致的。然而,喂食化合物D的CCI大鼠没有这样的或其他异常效果。
此外,对于用100mg/kg的化合物D的相同单一口服剂量处理的同一组CCI大鼠,在第14天和第20天时测量的抗触诱发痛效果上没有显著差异,表明没有耐受性问题。
脊神经结扎(SNL)的单神经病理性疼痛大鼠模型。手术步骤按照Kim和Chung所描述的(Kim SH,Chung JM.Pain.1992;50(3):355-63)。此过程将导致(大鼠)左后肢的触觉异常性疼痛。只有不表现出运动功能障碍(如爪拖动或下降)和PWT为4.0克以下的大鼠才会被列入研究。
试验化合物抗痛敏测试的剂量反应:在手术后14天,大鼠会被灌胃喂食测试化合化合物的四个剂量中之一,运载体或阳性对照组,并且PWT由校准冯弗雷丝在时间点0(在马上给药前,前剂量基线),0.5,1,2,4和6小时确定。
忍耐力的影响:14天的测试后的第6天,即手术后第20天,对同一组CCI-大鼠重复第14天同样的程序和一样具有相同的(有效)剂量。测试化合物的抗触诱发痛效果就是对第14天及第20天测试的结果进行比较,看看是否有任何化合物在动物忍耐的影响。
重复给予测试化合物的抗触诱发痛效果:将在手术后第7天开始给予测试化合物,每天一次持续7天。PWT由校准冯弗雷丝每天一次,服药后2小时确定。经过7天给药,测量将继续进行,每隔一天,连续7天(没有再服药)。PWT将取决于在上述特定时间点。
热痛觉过敏效果。热痛觉过敏可在SNL大鼠中通过在上述给定的时间点用单一剂量的测试化合物的足底测试来评价。
链脲佐菌素诱发糖尿病多神经性疼痛模型。糖尿病周围神经病变是由于糖尿病的长期并发症。大鼠腹腔将注射链脲佐菌素(链脲佐菌素,50mg/kg,注射前溶于pH值4.5的柠檬酸缓冲液)来诱导胰岛素依赖型糖尿病,并产生触觉异常性疼痛。一个星期后,从尾静脉抽取血样使用标准测试条和色度检测血糖水平。只有血糖水平>350mg/dL的动物将被视为有糖尿病并包括在测试内。在STZ注射后大约2至3周,将开始在后爪有神经性疼痛(触觉异常性疼痛)。4周后,通常会达成异常性疼痛的一个稳定水平。在这一点上,低于4.5克PWT的大鼠将参加测试化合物。在痛觉超敏状态将保持不变,直到STZ注射8周后。在研究期间内所有的动物将被观察和每天定期称重。这种神经性疼痛模型模拟糖尿病患者神经病变的症状(Lynch JJ,3rd,等,Eur J Pharmacol.1999;364(2-3):141-6;Caicutt NA,J NeurolSci.2004;220(l-2):137-9)。
测试化合物的剂量依赖的抗痛觉超敏效果:在STZ注射后28天,老鼠将被口服灌胃喂食测试化合物的四个剂量之一,或控制(载体和阳性对照),和PWT将使用校准冯弗雷(vonFrey)丝在时间点0(在马上给药之前,前剂量基线),0.5,1,2,4和6小时确定。
耐受影响:28天的测试后的第6天,即注射STZ第34天后,对同一组老鼠重复第28天同样的程序和一样具有相同的(有效)剂量。测试化合物的抗痛敏效应就是对第28天及第34天的结果进行比较,看看是否有任何化合物在动物忍耐的影响。
重复给予测试化合物的抗触诱发痛效果:将在STZ注射后第21天开始口服给予测试化合物,每天一次持续7天。PWT由校准冯弗雷丝每天一次,服药后1小时确定。经过7天给药,测量将继续进行,每隔一天,连续7天(没有再服药)。PWT将取决于在上述特定时间点。通过足底测试的热痛觉过敏评价在用单一剂量的STZ模型中进行并且会在上述给定时间点处确定PWL。
角叉菜胶疼痛模型。角叉菜胶模型是用于评价拮抗剂阻断炎性疼痛的能力的快速可靠模型。使用大鼠中角叉菜胶诱导的疼痛模型来测试测试物组合对疼痛生成的拮抗效果。成年雄性Sprague-Dawley大鼠每天一次持续2天(第-2天和第-1天)并且在第0天角叉菜胶注射前30分钟(时间=0)口服给予研究药物(载剂,本发明的化合物)。对于角叉菜胶注射,轻微麻醉动物并且将0.1ml的2%角叉菜胶注射到右后爪的跖面中。在即将注射角叉菜胶前口服给予阳性对照吲哚美辛(30mg/kg,口服)。在第-2天给予药物之前使用Plethysmometer来测量爪体积(右和左)并且用作基线测量值。在注射角叉菜胶后2小时再次测量爪体积。由盲观察者使用施加于后爪跖面的冯弗雷丝以增加的编号顺序测量机械性触诱发痛的程度。各丝增加了施加在爪上的力。施加丝直至实现动物爪回缩。该过程在给予药物前(第-2天)、第-1天和第0天时间=注射角叉菜胶后0、20、40、60、80和120分钟时进行。注射角叉菜胶后的爪回缩所需的力(以克表示)减去注射角叉菜胶前的爪回缩所需的力。结果表示成在注射角叉菜胶后的5个时间点上对于基线的平均变化。在这种大鼠疼痛模型中,例如,与吲哚美辛(30mg/kg,口服)产生的约100%止痛效果相比,化合物12显示在150mg/kg口服剂量下约85%的相对止痛效果。
式(I)和/或式(II)的化合物在PANC-1皮下人胰腺癌异种移植小鼠模型中抗肿瘤
功效的体内评价。
评价式(I)和/或式(II)的化合物(测试物)及其与吉西他滨的组合对BALB/c雌性裸小鼠(体重范围18-23克)中PANC-1皮下人胰腺癌异种移植的体内治疗功效。
动物饲养:将动物在恒温和恒定湿度下保持在层流室中,各笼中4或3只动物。温度:22±3℃.湿度:50±20%。光循环:12小时光和12小时黑暗。笼:使用包埋软木材料的300mm x 180mm x 150mm的聚碳酸酯笼。每周改变基底2次。饮食:动物自由进食认证的市售实验室饮食。由生产商周期性分析饮食中污染物的浓度以确保污染物低于它们的最高限并且因此不会影响肿瘤生长。
水:动物自由饮用无菌饮用水。笼标识:各笼的标识标签含有以下信息:动物数量、性别、品系、接收日期、处理、组编号和处理开始日期。简言之,PANC-1细胞系原始购自ATCC(CRL-1469)并且PANC-1原代细胞系来自PANC-1皮下异种移植肿瘤。在37℃下和5%CO2气氛中,PANC-1原代细胞在体外补充了10%热灭活胎牛血清、100U/ml青霉素和100μg/ml链霉素以及L-谷氨酰胺(2mM)的DMEM培养基中维持为单层培养物。收获对数期生长的细胞并且计数用于肿瘤接种。
肿瘤细胞接种和随机化:各动物在右胁皮下接种0.1mL PBS中的PANC-1原代肿瘤细胞(5x 106/动物)。肿瘤发育不受破坏直至肿瘤体积达到约85mm3。动物然后随机分成6组,每组由8只动物组成。按照预定方案向荷瘤动物给予测试物。该研究中所有涉及动物控制、护理和处理的过程都按照遵照实验动物评估和认证委员会(AAALAC)的指南的测试实验室的实验动物照料和使用委员会(IACUC)批准的指南进行。在常规监测的时间,检查动物的肿瘤生长对正常行为的任何影响,如运动性、食物和水消耗(仅通过观察)、体重(BW)获得/失去(每周2次测量BW)、眼/毛发缠结以及任何其他异常影响。基于各亚组内动物的数量记录死亡和观察的临床征兆。
肿瘤测量和终点:主要终点是评价肿瘤生长是否可被抑制。用卡尺每周2次测量肿瘤并且使用下式估计肿瘤体积(mm3):TV=a x b2/2,其中a和b分别是肿瘤的长直径和短直径。然后肿瘤尺寸用于T/C值和TGI(肿瘤生长抑制),其指示抗肿瘤效果。T/C值(百分比)指示抗肿瘤效果。T和C分别是处理和对照组在指定日的平均体积。使用下式计算表示为%的BW变化:BW变化(%)=(BW_DayX/BW_Day0)x 100,其中BW_DayX是指定日的BW,并且BW_Day0是第0天(肿瘤接种)的BW。
肿瘤样品收集:分别来自组1、2和3的2个肿瘤样品;来自组4的6个肿瘤样品;分别来自组5和6的5个肿瘤样品在液氮中速冻并储存于-80℃。收集总共22个肿瘤样品。
统计学分析:进行单因素ANOVA来比较组间肿瘤体积。使用SPSS17.0软件分析所有数据;p<0.05被认为是统计学显著。化合物12单独或与吉西他滨组合的体内抗肿瘤功效列于下面的2个表中。
结果显示化合物12单独或与现有标准护理药物吉西他滨联用时在减少肿瘤生长上有效,化合物12与吉西他滨的组合显示很大的协同效果并且比单独化合物12或吉西他滨有更大的肿瘤减小。
不同组的平均肿瘤体积
注:a平均±SEM
化合物12及其与吉西他滨的组合在治疗皮下PANC-1人胰腺癌异种抑制模型中的抗肿瘤活性
注:a平均±SEM;b与对照相比。
P值:G2对比G3<0.001;G2对比G4=0.008;G2对比G5<0.001;G2对比G6<0.004;
G3对比G4=0.094;G3对比G5=0.134;03对比06=0.062;
G4对比G5<0.001;G4对比G6<0.001;
G5对比G6=0.998
5.4治疗用途
按照本发明,向患有多种病症的患者,优选人给予本发明的化合物,或其盐、溶剂合物、酯和/或前药,或含有该化合物、或其盐、溶剂合物、酯和/或前药的药物组合物。这些包括癌症、焦虑、全身疼痛病症、急性疼痛、慢性疼痛、炎性疼痛和神经性疼痛。
虽然已经根据某些优选的实施方式描述了本发明,但是本领域技术人员将意识到,在不背离本发明精神的情况下可以作出各种修改、变化和替代。
5.5治疗性/预防性给药
本发明的化合物,或其盐、溶剂合物、酯和/或前药,或含有本发明的化合物、或其盐、溶剂合物、酯和/或前药的药物组合物可优选用于人类药物。如前述部分6.4所示,本发明的化合物可用于治疗或预防各种疾病。
当用于治疗或预防上述疾病或病症时,本发明的化合物可单独给予或施用,或者与其他活性药剂(例如,其他疼痛药剂)联用。
本发明提供了通过向有这种治疗需要的患者给予有效量的异种或多种本发明的化合物、或其盐、溶剂合物、酯和/或前药来进行治疗和预防的方法。所述患者可为动物,更优选哺乳动物,并最优选人。
可口服给予本发明的化合物、或其盐、溶剂合物、酯和/或前药。本发明的化合物、或其盐、溶剂合物、酯和/或前药也可通过任何其他方便的途径给予,例如,通过输注或推注,通过吸附经过上皮或粘膜皮肤衬里(例如,口腔粘膜、直肠和肠粘膜等)。给药可以是全身给药或局部给药。各种递送系统已知,(例如,包封于脂质体、微颗粒、微胶囊、胶囊等)可用于给予化合物和/或其药物组合物。给药的方法包括但不限于,真皮内、肌内、腹膜内、静脉内、皮下、鼻内、硬膜外、口服、舌下、鼻内、大脑内、阴道内、透皮、直肠,或通过局部吸入,尤其是耳、鼻、眼、或皮肤。优选的给药模式根据操作者判断并且将部分取决于医学病症的部位。在大多数情况中,给药将导致本发明的化合物、或其盐、溶剂合物、酯和/或前药释放到患者的血流中。
在具体实施方式中,可能需要向需要治疗的区域局部给予一种或多种本发明的化合物、或其盐、溶剂合物、酯和/或前药。这可通过以下方式实现:例如不限于,手术区间局部输注、局部施用(例如与术后伤口敷料联用)、注射、利用导管、利用栓剂、利用植入物,所述植入物是有孔、无孔或凝胶状物质,包括膜,如唾液酸膜(sialastic membrane)或纤维。在一些实施方式中,可通过在癌症或关节炎的部位(或之前的部位)直接注射来完成给药。
在某些实施方式中,可能需要将一种或多种本发明的化合物、或其盐、溶剂合物、酯和/或前药通过任意何时的途径,包括心室内、鞘内和硬膜外注射来引入患者的中枢神经系统。可通过例如接合至储器如Ommaya储器的心室内导管来促进心室内注射。
也可通过吸入直接向肺给予本发明的化合物、或其盐、溶剂合物、酯和/或前药。对于通过吸入给药,本发明的化合物、或其盐、溶剂合物、酯和/或前药可通过多种不同的装置方便地递送至肺。例如,采用含有合适的低沸点推进剂(例如,二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或任何其他合适气体)的罐的计量吸入器(“MDI”)可用于将本发明的化合物直接递送至肺。
或者,可使用干粉吸入器(“DPI”)装置来将本发明的化合物、或其盐、溶剂合物、酯和/或前药给予肺。DPI装置一般使用一定机制使得气体爆炸以在容器内产生干粉云,其然后被患者吸入。DPI装置也是本领域熟知的。常见变化形式是多剂量DPI(“MDDPI”)系统,其允许递送超过一个治疗剂量。例如,可将用于吸入器或吹入器内的胶囊和药筒(例如,由明胶制成)配制成含有本发明的化合物和对于这些系统合适的粉末基料(如乳糖或淀粉)的粉末混合物。
可用于向肺递送本发明的化合物、或其盐、溶剂合物、酯和/或前药的另一类型的装置是由例如加利福尼亚州海沃德的阿拉迪姆公司(AradigmCorporation)提供的液体喷雾装置。液体喷雾系统使用极小的喷嘴孔以使液体药物制剂雾化,其然后可直接吸入肺。
在一些实施方式中,使用喷雾器来向肺递送本发明的化合物、或其盐、溶剂合物、酯和/或前药。喷雾器从通过使用,例如超声能量来从液体药物制剂中产生气溶胶以形成可易于吸入的细颗粒(参见例如,Verschoyle等,British J.Cancer,1999,80,Suppl.2,96)。喷雾器购自多个商业来源,如史菲/系统性肺部输递有限公司(Sheffield/SystemicPulmonary Delivery Ltd)。Aventis和Bateile肺部治疗公司(Aventis and BateilePulmonary Therapeutics)。
在一些实施方式中,使用流体电动力型(“EHD”)气雾装置来向肺递送本发明的化合物、或其盐、溶剂合物、酯和/或前药。EHD气雾装置使用电能来雾化液体药物溶液或悬液(参见例如,Noakes等,美国专利号4,765,539)。制剂的电化学形式可能是用EHD气雾装置来向肺递送本发明的化合物、或其盐、溶剂合物、酯和/或前药时待优化的重要参数并且通常由本领域技术人员之一来常规进行这种优化。EHD气雾装置可比现有的肺部递送技术更高效地向肺递送药物。
在其他实施方式中,本发明的化合物、或其盐、溶剂合物、酯和/或前药可在囊泡,尤其是脂质体中递送(参见,Langcr,1990,Science,249:1527-1533;Treat等,《感染性疾病和癌症治疗中的脂质体》(Liposomes in the Therapy of Infectious Disease andCancer),Lopez-Berestein和Fidler(编),Liss,纽约,第353-365页(1989);一般参见,《感染性疾病和癌症治疗中的脂质体》,Lopez-Berestein和Fidler(编),Liss,纽约,第353-365页(1989))。
在其他实施方式中,本发明的化合物、或其盐、溶剂合物、酯和/或前药可通过缓释系统递送。在其他实施方式中,缓释系统是口服缓释系统。在其他实施方式中,可使用泵(参见Langer同上;Sefton,1987,CRC Crit.Ref.Biomed.Eng.14:201;Saudek等,1989,N.Engl.J.Med.321:574)。
在其他实施方式中,本发明的化合物、或其盐、溶剂合物、酯和/或前药中可使用多聚物质(示例性多聚物质参见Medical Applications of Controlled Release(《控释的药物应用》),Langer和Wise(编),佛罗里达州波卡拉顿的CRC出版社(CRC Pres.),(1974);Controlled Drug Bioavailability,Drug Product Design and Performance(《受控药物的生物利用度,药物产品设计和性能》),Smolen和Ball(编),纽约的威利出版公司(Wiley),(1984);Ranger和Peppas,J.Macromol.Sci.Rev.Macromol.Chem.23:61(1983);也参见Levy等,Science 228:190(1985);During等,Ann.Neurol.25:351(1989);Howard等,J.Neurosurg.71:105(1989))。在其他实施方式中,聚合物质用于缓释递送口服药物组合物。示例性的聚合物包括但不限于羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素和羟乙基纤维素(最优选,羟丙基甲基纤维素)。已经描述了其他纤维素醚(Alderman,Int.J.Pharm.Tech.&Prod.Mfr.,1984,5(3)1-9)。影响药物释放的因素是本领域技术人员所熟知的并且已经描述于本领域(Bamba等,Int.J.Pharm.,1979,2,307)。
在其他实施方式中,肠衣制备物也可用于口服缓释给药。包衣材料包括但不限于,具有pH-依赖溶解性的聚合物(即,pH-控释)、具有低或pH-依赖溶胀、融除或腐蚀速率的聚合物、(即,时间控释)、由酶降解的聚合物(即,酶控释)和形成在增加的压力下破坏的坚固层的聚合物(即,压力控释)。
在其他实施方式中,使用渗透递送系统用于口服缓释给药(Verma等,DrugDev.Ind.Pharm.,2000,26:695-708)。在其他实施方式中,使用OROSTM渗透装置用于口服缓释递送装置(Theeuwes等,美国专利号3,845,770;Theeuwes等,美国专利号3,916,899)。
在其他实施方式中,可将控释系统放置于本发明的化合物、或其盐、溶剂合物、酯和/或前药的治疗靶点附近,因此仅需要全身剂量的一部分(参见例如Goodson,《控释的医学应用》(Medical Applications of Controlled Release),同上,第2卷,第115-138页(1984))。也可使用Langer,1990,Science 249:1527-1533中所述的其他控释系统。
5.6本发明的药物组合物
在一个方面中,本发明提供可包含一种或多种本发明的化合物的药物组合物,本发明的化合物包括具有结构为式(I)和/或式(II)的化合物及其任何亚组以及部分5.2中所述的具体实施方式。
本发明的药物组合物包含治疗有效量的一种或多种本发明的化合物、或其盐、溶剂合物、酯和/或前药(优选纯化形式),连同适当的量的药学上可接受的运载体,例如提供适合给予患者的形式。给予患者时,本发明的化合物和药学上可接受的运载体优选的无菌的。水是静脉注射给药的优选运载体。盐水溶液和右旋糖水溶液和甘油溶液也可用作液体运载体,特别适用于注射液。合适的药用运载体包括:淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩(chalk)、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙烯、二醇、水、乙醇等。如果需要,本发明的药物组合物也可含有少量润湿剂或乳化剂或pH缓冲剂。此外,助剂,稳定剂,增稠剂,润滑剂和着色剂也可能使用。
药物组合物可通过常规的混合、溶解、造粒、制造糖衣丸、水飞、乳化、封装、包封或冻干工艺进行制造。药物组合物可按常规方式使用一种或多种生理学上可以接受的载体,稀释剂,辅料和助剂制成剂型,以更好将本发明的化合物制成为可用的药剂。适当的制剂依赖于所选的给药途径。
目前的药物组合物可以是以下形式:溶液,悬浮液,乳液,片剂,丸剂,颗粒,胶囊,含有液体的胶囊,粉末,缓释制剂,栓剂,乳剂,气雾剂,喷雾剂,悬浮液,或任何其他适合形式。在一些实施方式中,药学上可接受的运载体是胶囊(见例如,格里斯沃尔德等。美国专利号5,698,155)。其他合适的药物运载体的例子已被描述(见雷明顿,药剂的科学与实践,费城药剂及科学学院,第20版,2000)。
局部给药时,化合物制剂可以是本领域熟知的溶液,凝胶,膏,霜,悬浮液等。
全身给药剂型包括注射给药,如皮下注射,静脉注射,肌肉注射,鞘内注射或腹腔注射,以及透皮,透粘膜,口腔或肺部给药。全身制剂可以与另一种活性剂如另一种抗癌剂联合制备。
在一些实施方式中,按照常规方法将本发明的化合物、或其盐、溶剂合物、酯和/或前药配制成适合静脉内给予人类的药物组合物。静脉内给予的化合物通常是溶于无菌等渗水性缓冲液的溶液。就注射而言,本发明的化合物,或其盐,溶剂化物,酯,和/或其前药可配制在水溶液中,所述水溶液优选生理相容性缓冲液,如汉克斯(Hank’s)溶液、林格(Ringer’s)溶液或生理盐水缓冲液。该溶液可包含配制剂,如助悬剂、稳定剂和/或分散剂。必要时,药物组合物可能还包括助溶剂。用于静脉注射的药物组合物可以任选地包括诸如利多卡因的局部麻醉剂,以减轻在注射部位的疼痛。通常,各成分单独提供或混合在一起以单位剂型的形式提供,例如作为标明活性物质含量的密封容器(如安瓿或药囊)中的冻干粉末或无水浓缩物。通过输液给予本发明的化合物、或其盐、溶剂合物、酯和/或前药时,可用含有无菌药物级水或盐水的输液瓶分配该组合物。通过注射给予本发明的化合物、或其盐、溶剂合物、酯和/或前药时,可提供一安瓿的无菌注射用水或盐水,以便在给药前与药物成分混合。
就经粘膜给药而言,在适合于待渗透屏障的制剂中采用渗透剂。此类渗透剂是本领域公知的。
口服给药的药物组合物可是例如片剂,锭剂,水性或油性悬浮液,颗粒,粉末,乳剂,胶囊,糖浆,或酊剂的形式。口服药物组合物可包含一个或多个可选物,例如,甜味剂,如果糖,阿斯巴甜或糖精,调味剂,如薄荷,冬青油,或樱桃着色剂和保护剂,以提供药学上可口的制剂。此外,药片或药丸可涂外层以延迟药物成分在胃肠道的解体和吸收,从而提供了一个长时间持续的药效。选择性渗透膜包上渗透压推动药物释放机制也适用于该发明化合物口服。在这些后来的平台,胶囊周围环境的液体由推动剂吸收而膨胀,从而将药品成分从小口释放。这些传递平台可以提供一个基本是零级释放,而不是立即释放制剂的峰值特征。也可使用时间延迟材料如甘油单硬脂酸酯或甘油硬脂酸。口服组合物可含有标准载剂,例如甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。这些运载体最好是制药级标准。
用于口服液体制剂,例如悬浮液,酊剂和溶液,适合的运载体,赋形剂或稀释剂包括水,盐水,烷基二醇(例如,丙二醇),聚烷基二醇(如聚乙二醇)油,醇,pH4-6的微酸缓冲剂(例如,醋酸,柠檬酸,抗坏血酸,大约5.0至50.0mM)等。此外,也可加入调味剂,防腐剂,着色剂,胆盐,酰基肉碱等。
就含服给药而言,该药物组合物可采用常规方式配制的片剂或锭剂等形式。
适用于喷雾器和液体喷涂设置和弹流喷雾装置的液体药物制剂通常包括本发明的化合物和药学上可接受的载剂。在一些实施方式中,在药学上可接受的载剂是液体,如酒精,水,聚乙二醇或全氟化碳。或者,可添加另一种材料以改变该化合物溶液或悬浮气溶胶特性。这种材料优选液体,如酒精,二醇,聚二醇或脂肪酸。其他适合气溶胶装置制备液体药物溶液或悬浮液的方法已是本领域熟知(见例如,比萨尔斯基,美国专利号5112598;比萨尔斯基,美国专利号5,556,611)。
本发明的化合物、或其盐、溶剂合物、酯和/或前药还可配制成直肠或阴道药物组合物,例如栓剂或滞留灌肠剂,例如含有传统栓剂基料,如可可油或其他甘油酯。
除了如前所述剂型,本发明的化合物、或其盐、溶剂合物、酯和/或前药也可以配制成植入剂。这种长效制剂可通过植入(例如皮下或肌肉内植入)或肌肉内注射给药。因此,例如,本发明的化合物、或其盐、溶剂合物、酯和/或前药也可与合适的聚合物材料或疏水材料(例如,用可接受的油配制成乳剂)或离子交换树脂配制在一起,或者配制成微溶性衍生物,例如,微溶性盐。
5.7治疗剂量
提供了本发明的化合物、或其盐、前药或软性药物、前药或软性药物的盐、溶剂合物或水合物以及药学上可接受的载剂,一般以实现指定目的的有效量使用。为了治疗或预防特征为下调的凋亡的疾病或病症,化合物和/或其药物组合物以治疗有效量给予或施用。
有效治疗本文所述的具体病症或状况的本发明的化合物、或其盐、溶剂合物、酯和/或前药的量将取决于病症或状况的性质并且由本领域已知的标准临床技术确定。此外,可任选地进行体外或体内试验以助于鉴别最优的剂量范围。当然,本发明的化合物、或其盐、溶剂合物、酯和/或前药的给药剂量也取决于接受治疗的对象、对象的体重、病情严重性、给药方式及处方医生的判断等因素。
例如,药物组合物的剂量给药可以一次,多次或控制释放传递给药。在一些实施方式中,本发明的化合物、或其盐、溶剂合物、酯和/或前药可通过口服缓释给药递送。只要是疾病状态或病症的有效治疗所需,给药可以是重复间歇性,可以是单独或与其他药物联合应用,可以持续。
口服给予需要的患者的合适的剂量范围(口服单位剂型)取决于本发明化合物的功效,但通常约为0.001mg至约200mg本发明化合物/kg体重;更优选地,约为0.01mg至约50mg本发明化合物/kg体重;甚至更优选地,约为0.05mg至约20mg本发明化合物/kg体重;并且患者是动物;更优选是哺乳动物;并且最优选是人。剂量范围可以通过本领域普通技术人员已知的方法容易地确定。
静脉内(i.v.)给予需要的患者的合适的剂量范围约为0.001mg至约100mg/kg体重;更优选地,约为0.01mg至约20mg本发明化合物/kg体重;并且患者是动物;更优选是哺乳动物;且最优选是人。鼻内给予需要的患者的合适的剂量范围约为0.001mg/kg体重至约10mg/kg体重;更优选地,约为0.01mg至约1mg本发明化合物/kg体重;并且患者是动物;更优选是哺乳动物;且最优选是人。栓剂通常包含约0.01毫克至约50毫克本发明化合物/kg体重,包含约0.5重量%至约10重量%的活性成分。皮内、肌内、腹膜内、皮下、硬膜外、舌下或大脑内给予需要的患者的推荐剂量约为0.001mg至约100mg/kg体重;患者是动物;更优选是哺乳动物;最优选是人。有效剂量可从体外或动物模型测试系统所得剂量反应曲线外推。这些动物模型和体系是本领域公知的。
在人体中使用之前,本发明的化合物、或其盐、溶剂合物、酯和/或前药优选在体外和体内进行分析,确定所需的治疗或预防活性。例如,可使用体外试验来确定给予本发明的特定化合物或化合物组合是否优选用于诱导过表达bcl-2蛋白或蛋白激酶的细胞凋亡或信号转导。也可使用动物模型系统证明本发明的化合物、或其盐、溶剂合物、酯和/或前药的有效性和安全性。
优选地,治疗有效剂量的本发明的化合物、或其盐、溶剂合物、酯和/或前药将提供疗效而不会导致实质性的毒性。本发明的化合物、或其盐、溶剂合物、酯和/或前药的毒性可由本领域熟练技术员按标准的制药程序确定。毒性和疗效的剂量比例是治疗指数。本发明的化合物、或其盐、溶剂合物、酯和/或前药一般在治疗凋亡相关疾病和病症中显示出特别高的治疗指数。本发明的化合物、或其盐、溶剂合物、酯和/或前药的剂量优选的剂量最好是其包括有效剂量的循环浓度范围内且很少或根本没有毒性。
5.8组合治疗
在本发明的某些实施方式中,本发明的化合物、或其盐、溶剂合物、酯和/或前药可与至少一种其他活性或治疗剂联合治疗。本发明的化合物、或其盐、溶剂合物、酯和/或前药与至少一种其他活性或治疗剂可有叠加或更优选是协同作用。在一些实施方式中,本发明的化合物、或其盐、溶剂合物、酯和/或前药可与其他治疗剂同时,按顺序,或分别给药。示例性的活性或化疗剂包括但不限于,乙酰葡萄糖内酯、阿柔比星、六甲蜜胺、氨鲁米特;5-氨基乙酰丙酸、安吖啶、阿那曲唑、盐酸环胞苷、17-1a抗体、抗淋巴细胞免疫球蛋白、抗瘤酮a10、天门冬酰胺酶、培门冬酶、阿扎胞苷、硫唑嘌呤、巴马司他、苯并卟啉衍生物、比卡鲁胺、盐酸比生群、硫酸博来霉素、布喹那钠、溴匹立明、白消安、campath-ih、卡醋胺、卡贝替姆、卡铂、卡波醌、卡莫氟、卡莫司汀、苯丁酸氮芥、氯脲霉素、色霉素、顺铂、克拉屈滨、小棒杆菌、环磷酰胺、环孢菌素、阿糖孢苷、达卡巴嗪、放线菌素D、盐酸柔红霉素、地西他滨、地吖醌、双氯乙基硫醚、代代宁B、多西紫杉醇、去氧氟尿苷、盐酸阿霉素、屈洛昔芬、棘霉素、依达曲沙、甲基羟基玫瑰树碱、依莫司汀、恩洛铂、依诺他滨、盐酸表柔比星、埃罗替尼、磷酸钠雌二醇氮芥、依他硝唑、乙环氧啶、依托泊甙、盐酸法倔唑、法扎拉滨、芬维A胺、氟尿苷、磷酸氟达拉滨、氟尿嘧啶、氟他胺、福司曲星、福莫司汀、硝酸镓、吉西他滨、胍立莫司、高三尖杉酯碱、羟基脲、盐酸去甲氧基柔红霉素、异环磷酰胺、伊莫福新、对甲苯磺酸胺丙磺酯、伊诺莫单抗、白介素-2;依立替康、jm-216、来曲唑、加莫锂、洛铂、环己亚硝脲、氯尼达明、马磷酰胺、马法兰、美诺立尔、巯嘌呤、甲氨蝶呤、甲氨蝶呤钠、米铂、米替福新、甲氧甲基硝基咪唑乙醇、二溴甘露醇、二盐酸丙脒腙、二溴卫矛醇、丝裂霉素、米托坦、盐酸咪唑立宾、莫哌达醇、莫特莱切尔多肽(muitlaichilpeptide)、莫罗单抗-CD3、盐酸氮芥、霉酚酸、霉酚酸酯、奈达、尼鲁米特、盐酸尼莫司汀、奥沙利铂、紫杉醇、皮诺斯塔啶(penostatin)、硫酸培洛霉素、哌泊溴烷、吡柔比星、吡曲克辛脒、盐酸吡罗蒽醌、普卡霉素、卟吩姆钠、泼尼莫司汀、盐酸丙卡巴肼、雷替曲塞、雷莫司汀、丙亚胺、罗谷亚胺、罗喹美克、司铂、司莫司、西罗莫司、西佐喃、索布佐生、溴茴丙烯酸钠、索拉非尼、膦门冬酸、磷乙酰天冬氨酸钠、链脲霉素、磺氯苯脲、他克莫司、他莫昔芬、替加氟、盐酸替洛蒽醌、替莫唑胺、替尼泊苷、睾内酯、磷酸钠卟啉磺酸、硫鸟嘌呤、硫肌苷、噻替哌、拓扑替康、托瑞米芬、曲奥舒凡、三甲曲、曲洛磷胺、肿瘤坏死因子、乌苯美司、乌拉莫司汀、硫酸长春碱,硫酸长春新碱,硫酸长春地辛、酒石酸长春瑞滨、伏氯唑、净司他丁、阿佐莫单抗、和盐酸佐柔比星等,单独或以任意组合,蛋白激酶A(PKA)的抑制剂、cAMP信号转导的抑制剂、PKC(ε或α或β)蛋白激酶的抑制剂、Bcl-2(Bcl-2、或MCL-1、或Bcl-xL)的抑制剂、非甾体抗炎药物、前列腺素合成抑制剂、局部麻醉剂、抗惊厥剂、抗抑郁剂、阿片类受体激动剂、和精神抑制剂、苯并二氮杂巴比妥盐、神经甾体和吸入麻醉剂、麻醉剂和其他镇痛剂。
上述详细的描述是说明性质的而没有不必要的限制,相应的修改在本领域是显而易见的。这不是一个承认:此处所提供的任何信息是已有技术或目前要求的发明有关,或者任何出版物的专门或含蓄的引用是已有技术。
本文描述了本发明的实施方式,包括本发明人已知的实施本发明所需的最佳模式。首选体现的变化对阅读描述的本领域的专家来说是显而易见的。本发明人预期,普通技术人员将适当地利用这些变型,本发明人旨在使本发明在本文具体描述之外以其他方式进行实施。因此,根据申请原则,本发明包括所附权利要求书所涉及主题的所有改进和等同形式。而且,所有可能的变型中上述要素的任意组合包括在本发明范围内,除非另有说明或者清楚指出相反。
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Claims (4)
1.一种结构为式(II)的化合物或其药学上可接受的盐在制备用于治疗与NGF受体TrkA相关的癌症的药物中的用途:
其中:
X表示N或CH;
R11独立地选自氢、NRaC(=O)R、卤素、CN、NH2、NHRa、NO2、C1-4卤代烷基、-OC1-4卤代烷基、-S-C1-6烷基、-C(=O)-(O)n-Ra、-ORa或C1-6烷基,其中所述烷基的一个或多个碳原子可被一个或多个选自氮、氧和硫的杂原子取代;
R表示氢、卤素、CN、NO2或C1-6烷基;
Ra各自独立地表示氢或C1-6烷基;并且
n表示0,
其中,所述癌症选自胰腺癌、肝癌或胃癌。
2.如权利要求1所述的用途,所述化合物选自下组:
4-{[4-氨基-3-(4-环己基哌嗪-1-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯磺酰胺;
4-{[4-氨基-3-(4-环己基哌嗪-1-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯甲酸;
N-[(4-{[4-氨基-3-(4-环己基哌嗪-1-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯基)磺酰基]乙酰胺;
1-氨基-2-(4-环己基哌嗪-1-基)-4-{[4-(2H-四唑-5-基)苯基]氨基}蒽-9,10-二酮;
1-氨基-2-(4-环己基哌嗪-l-基)-4-{[4-(lH-四唑-5-基)苯基]氨基}蒽-9,10-二酮;
1-氨基-2-(4-环己基哌嗪-1-基)-4-{[4-(1,1,1,3,3,3-六氟-2-羟丙-2-基)苯基]氨基}蒽-9,10-二酮;
4-{[4-氨基-3-(4-环己基哌嗪-1-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯甲酸甲酯;
4-{[4-氨基-3-(4-环己基哌嗪-l-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯甲酸2-(二甲基氨基)乙酯;
4-{[4-氨基-3-(4-环己基哌嗪-l-基)-9,10-二氧代-9,10-二氢蒽-1-基]氨基}苯甲酸乙酯;
或其盐。
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