CN108864101A - 氘代sgx523及其用途 - Google Patents
氘代sgx523及其用途 Download PDFInfo
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- CN108864101A CN108864101A CN201710335418.1A CN201710335418A CN108864101A CN 108864101 A CN108864101 A CN 108864101A CN 201710335418 A CN201710335418 A CN 201710335418A CN 108864101 A CN108864101 A CN 108864101A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明涉及氘代SGX523及其用途,具体涉及下式(I)所示的氘代的6‑((6‑(1‑甲基‑1H‑吡唑‑4‑基)‑[1,2,4]‑三唑并[4,3‑b]哒嗪‑3‑基)硫)喹啉类化合物或其药学上可接受的盐,其制备方法和药物组合物,以及在制备用于预防或治疗由蛋白酪氨酸激酶信号介导的疾病的药物中的应用。
Description
技术领域
本发明涉及药物化学和药物治疗学领域,具体涉及氘代的6-((6-(1-甲基-1H-吡唑-4- 基)-[1,2,4]三唑并[4,3-b]哒嗪-3-基)硫)喹啉或其药学上可接受的盐,其制备方法,包含所述化合物或其药学上可接受的盐的药物组合物,以及在制备用于预防或治疗由蛋白酪氨酸激酶,尤其是c-Met激酶信号介导的疾病的药物中的用途。
背景技术
蛋白酪氨酸激酶(PTKs)是一类具有调节多种重要的生物学功能的一组酶,包括细胞生长、分化、器官形成、新生血管形成、组织修复和再生等等。蛋白酪氨酸激酶通过催化蛋白酪氨酸残基的磷酸化发挥它们的生物学效应,然后调节底物蛋白的生物活性。一类蛋白酪氨酸激酶的失调可能导致肿瘤生成和增长,并进一步对肿瘤的生存和发展起着重要作用(Blume J P,Hunter T.Oncogenic kinase signaling[J].Nature,2001,411(6835):355-365)。因此,与肿瘤密切相关的蛋白酪氨酸激酶代表一类最重要的癌症治疗和药物发展相关的蛋白靶点。
c-Met是肝细胞生长因子受体(HGFR),由MET原癌基因编码。c-Met在绝大部分的癌及部分肉瘤中具有高表达且和预后差紧密相关,如肺癌、乳腺癌、结肠癌、前列腺癌、胰癌、胃癌、肝癌、卵巢癌、肾癌、神经胶质瘤、黑色素瘤等。c-Met通过与其配体HGF/SF 相互作用或者通过其他途径激活胞内段的酪氨酸激酶,诱导细胞增殖、侵袭、迁移,抑制细胞凋亡,促进血管生成,在肿瘤的发生发展过程中发挥重要的作用。
SGX523,即6-((6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-b]哒嗪-3-基)硫)喹啉,是由SGX公司研发的选择性c-Met抑制剂。WO2008051808A2公开该化合物可用于治疗蛋白酪氨酸激酶(包括c-Met激酶)失调引起的肿瘤疾病。文献报道该化合物由醛氧化酶(AO)介导的代谢产物M1的产生导致了肾毒性而于2008年终止于临床I期研究(DrugMetab.Dispos.2010,38,1277-1285.)。因此,开发出能够被人类机体接受的、具有c-Met 抑制活性的化合物作为肿瘤的治疗药物显得尤为重要。
发明内容
本发明人经过长期而深入的研究,意外地发现,氘代的SGX523在具有良好的蛋白酪氨酸激酶抑制活性的同时,给药后能够显著减少毒性代谢产物M1的产生,从而降低了毒副作用。基于上述发现,发明人完成了本发明。
因此,本发明的一个目的是提供一种具有蛋白酪氨酸激酶抑制活性,特别是具有c-Met抑制活性的化合物。
本发明的另一个目的是提供上述化合物的制备方法。
本发明的再一个目的是提供上述化合物的用途。
本发明的又一个目的是提供包含上述化合物作为活性成分的药物组合物。
根据本发明的第一方面,提供了一种如下式(I)所示的化合物,或其药学上可接受的盐:
式中:
D代表氘原子;
R1、R2、R3、R4、R5、R6、R7、R8、R9各自独立地为氢原子或氘原子;
R10选自:CH3、CH2D、CHD2和CD3。
在一优选例中,氘在氘取代位置的氘同位素含量至少大于天然氘同位素含量(天然氘同位素含量为0.015%),较佳地,在氘取代位置的氘同位素含量为大于30%,更佳地为大于50%,更佳地为大于75%,更佳地为大于95%,更佳地为大于99%。
在另一优选例中,式(I)化合物中除H之外的其他元素(如N、C、S等)全部或基本上为丰度最高的天然存在的元素,例如14N、12C和32S。在另一优选例中,R1、R2、R3、 R4、R5、R6、R7、R8、R9均为氢原子。
在另一优选例中,R10为CH3。
根据本发明的第二方面,提供了制备式(I)所示的化合物的方法,如下反应式所示:
其中,使式(a)所示的化合物和式(b)所示的化合物进行偶联反应,得到式(I)所示的化合物;
式中:
D代表氘原子;
R1、R2、R3、R4、R5、R6、R7、R8、R9各自独立地为氢原子或氘原子;
R10选自:CH3、CH2D、CHD2和CD3。
在一优选例中,氘在氘取代位置的氘同位素含量至少大于天然氘同位素含量(天然氘同位素含量为0.015%),较佳地,在氘取代位置的氘同位素含量为大于30%,更佳地为大于50%,更佳地为大于75%,更佳地为大于95%,更佳地为大于99%。
在另一优选例中,式(I)化合物中除H之外的其他元素(如N、C、S等)全部或基本上为丰度最高的天然存在的元素,例如14N、12C和32S。在另一优选例中,R1、R2、R3、 R4、R5、R6、R7、R8、R9均为氢原子。
在另一优选例中,R10为CH3。
在另一优选例中,所述的式(I)化合物为以下式(Ⅱ)所示的化合物:
式(II)所示的氘代6-((6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑[4,3-b]哒嗪-3-基)硫)喹啉可以通过本领域常用的制备氘代化合物的方法制备。
根据本发明的第三方面,提供了一种制备式(II)所示的化合物(2-氘-6-((6-(1-甲基 -1H-吡唑-4-基)-[1,2,4]三唑[4,3-b]哒嗪-3-基)硫)喹啉)的方法,如下反应式所示:
其中,使式(III)所示的化合物和式(IV)所示的化合物进行偶联反应,得到式(II)所示的化合物。
在一个优选例中,所述偶联反应在有机溶剂中进行,所述有机溶剂选自:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸或其组合。
在另一优选例中,所述偶联反应在约50℃~约200℃下进行,优选在约100℃下进行。
在另一优选例中,所述偶联反应时间为约5小时~约72小时,优选约24小时。
在一个优选例中,所述的偶联反应在三(二亚苄基丙酮)二钯和9,9-二甲基-4,5-双二苯基膦氧杂蒽存在下进行。
在本发明的一个优选实施方式中,所述式(III)所示的化合物是通过以下方法制备的:
其中,使式(V)所示的化合物与还原试剂进行还原反应,得到式(III)所示的化合物;优选地,所述的还原试剂是铁粉;更佳地,所述的还原反应在冰醋酸存在下进行。
在一个优选例中,所述还原反应在有机溶剂中进行,所述有机溶剂优选选自:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸或其组合。
在另一优选例中,所述还原反应在约50℃~约200℃下进行,优选在约110℃下进行。
在另一优选例中,所述还原反应时间为约5小时~约24小时,优选约3小时。
在本发明的一个优选例中,所述式(V)所示的化合物是通过以下方法制备的:
其中,使式(VI)所示的化合物与重水进行氘代反应,得到式(V)所示的化合物。优选地,所述氘代反应在叔丁醇钠存在下进行。
在一个优选例中,所述氘代反应在有机溶剂中进行,所述有机溶剂优选选自:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸或其组合。
在另一优选例中,所述氘代反应在约50℃~约200℃下进行,优选约100℃下进行。
在另一优选例中,所述氘代反应时间为约5小时~约72小时,优选约12小时。
在本发明的一个优选例中,所述式(IV)所示的化合物通过以下方法制备:
其中,使式(VII)所示的化合物与二硫化碳进行关环反应,得到式(IV)所示的化合物。优选地,所述的关环反应在乙醇存在下进行。
在一个优选例中,所述关环反应在有机溶剂中进行,所述有机溶剂优选选自:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸或其组合。
在另一优选例中,所述关环反应在约50℃~约200℃下进行,优选约100℃下进行。
在另一优选例中,所述关环反应时间为约5小时~约72小时,优选约12小时。
在一个优选例中,制备式(II)所示的化合物的方法包括如下步骤:从1-氧-6-溴喹啉出发,经氘代、还原得到中间体(III),另一中间体(IV)由3-肼基-6-(1-甲基-1H-吡唑-4-基) 哒嗪经关环得到,中间体(III)和中间体(IV)经偶联反应得到目标产物。
具体地说,所述制备方法包括:
从1-氧-6-溴喹啉出发,经重水与叔丁醇钠反应,得到氘代的式(V)所示的化合物;
式(V)所示的化合物被铁粉在冰醋酸存在下还原成式(III)所示的化合物;
式(VII)所示的化合物在氢氧化钾、二硫化碳和乙醇存在下转化成式(IV)所示的化合物;
式(III)所示的化合物和式(IV)所示的化合物在三(二亚苄基丙酮)二钯和9,9-二甲基 -4,5-双二苯基膦氧杂蒽存在发生偶联反应得到式(Ⅱ)所示的化合物。
根据本发明的第四方面,提供了一种药物组合物,该药物组合物包含式(I)所示的化合物或其药学上可接受的盐作为活性成分。优选地,所述药物组合物包括:治疗有效量的如本发明第一方面所述的式(I)化合物或其药学上可接受的盐;和药学上可接受的载体。
在一个优选例中,所述药物组合物包括治疗有效量的式(II)所示的化合物,即2-氘-6-((6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑[4,3-b]哒嗪-3-基)硫)喹啉、或其药学上可接受的盐:
和
药学上可接受的载体。
在另一优选例中,所述药物组合物还包括治疗有效量的其他活性成分,且所述其他活性成分包括选自下组的一种或多种活性成分:细胞毒剂、信号转导抑制剂,和其他抗肿瘤物质。
在另一优选例中,所述药物组合物可配制成选自下组的制剂:片剂、胶囊剂、丸剂、散剂、颗粒剂或注射剂;优选为片剂、胶囊剂或静脉注射剂。
在另一优选例中,当所述药物组合物是片剂时,所述药物组合物可包括选自下组的药学上可接受的载体:胶体二氧化硅、硬脂酸镁、改性淀粉、微晶纤维素、乳糖,或其组合。
在另一优选例中,当所述药物组合物是胶囊剂时,所述的药物组合物可包括选自下组的药学上可接受的载体:淀粉、微晶纤维素,或其组合。
在另一优选例中,当所述药物组合物是静脉注射剂时,所述的药物组合物可包括选自下组的药学上可接受的载体:无菌注射用水。
在另一优选例中,所述药物组合物是长效制剂。
根据本发明的第五方面,提供了一种制备本发明的药物组合物的方法,所述方法包括以下步骤:将药学上可接受的载体与如本发明所述的式(I)所示的化合物,或其药学上可接受的盐进行混合,从而形成药物组合物。
本发明的第六方面,提供了本发明所述的式(I)所示的化合物或其药学上可接受的盐或者本发明的药物组合物用于制备用于预防或治疗酪氨酸激酶介导的疾病,尤其是c-Met 介导的疾病的药物的用途;用于制备治疗或预防与酪氨酸激酶活性或表达量相关的疾病,优选为与c-Met的活性或表达量相关的疾病的药物的用途;用于制备调节选自细胞生长(包括例如分化、细胞存活和/或增殖)、肿瘤细胞生长(包括例如分化、细胞存活和/或增殖)、肿瘤消退等的一个或多个过程的药物的用途;用于制备预防或治疗过度增殖性疾病的药物的用途。
本发明的第七方面,提供了预防或治疗酪氨酸激酶介导的疾病,尤其是c-Met介导的疾病的方法,治疗或预防与酪氨酸激酶活性或表达量相关的疾病,优选为与c-Met的活性或表达量相关的疾病的方法,调节用于制备调节选自细胞生长(包括例如分化、细胞存活和/或增殖)、肿瘤细胞生长(包括例如分化、细胞存活和/或增殖)、肿瘤消退(例如肿瘤大小的减小或肿瘤在体内分布范围的降低)等的一个或多个过程的方法,预防或治疗过度增殖性疾病的方法,所述方法包括向有该需要的对象施用本发明所述的式(I)所示的化合物或其药学上可接受的盐或者本发明的药物组合物。
在一个优选例中,所述疾病包括例如细胞增殖紊乱、癌症、肿瘤等的c-Met异常导致的相关疾病。例如,所述疾病选自:乳头状瘤、芽状神经胶质瘤、肉瘤(包括但不限于软骨肉瘤、组织肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤以及横纹肌肉瘤)、黑素瘤、血管瘤、瘢痕瘤、鳞状细胞癌、星细胞瘤、淋巴瘤(包括但不限于非霍奇金淋巴瘤、AIDS相关淋巴瘤、皮肤T细胞淋巴瘤、霍奇金病以及中枢神经系统淋巴瘤)、呼吸道癌(包括但不限于肺癌,例如小细胞及非小细胞肺癌,以及支气管腺瘤和胸膜肺母细胞瘤)、头颈癌(包括但不限于头癌、颈癌、喉癌、下咽癌、鼻咽癌和/或口咽癌以及嘴唇和口腔癌)、膀胱癌、乳癌(包括但不限于浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌)、消化道癌(包括但不限于肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、直肠癌、胃癌、小肠癌以及唾液腺癌)、甲状腺癌、副甲状腺癌及其远距离转移灶、胰腺癌、肝癌(包括但不限于肝细胞癌(具有或不具有纤维板层形式的肝细胞癌)、胆管细胞癌以及混合型肝细胞胆管细胞癌)、白血病(包括但不限于急性成淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓白血病、慢性骨髓性白血病以及绒毛细胞白血病)、脑癌(包括但不限于脑干和垂体神经胶质瘤、成神经管细胞瘤、小脑和大脑星细胞瘤、室鼓膜瘤以及神经外胚瘤和松果腺瘤)、生殖器官癌(包括但不限于前列腺癌、睾丸癌、卵巢癌、子宫内膜癌、宫颈癌、阴道癌和外阴癌以及子宫肉瘤)、尿道癌、眼癌(包括但不限于眼内黑素瘤和成视网膜细胞瘤)、皮肤癌(包括但不限于卡波西肉瘤、鳞状细胞瘤、恶性黑素瘤、梅克尔细胞皮肤癌以及非黑素瘤皮肤癌)、骨癌、肾癌(也称为肾细胞癌和肾腺癌)。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
活性成分
本发明的化合物或其药学上可接受的盐可以以溶剂合物(例如水合物)的形式存在,因此,本发明的化合物或其药学上可接受的盐的含义涵盖了这些溶剂合物(例如水合物)。
本发明的化合物或其药学上可接受的盐,包括其溶剂合物(例如水合物),可能存在多种晶型形式。因此,本发明的化合物或其药学上可接受的盐的含义也涵盖了这些晶型。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合成盐的酸包括但不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸、甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸、苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
式(Ⅱ)所示的化合物在药代动力学上明显优于SGX523
对比SGX523和式(II)所示的化合物在猴肝S9孵化体系中可能的代谢产物,结果显示,式(II)所示的化合物在给药同等剂量情况下在血浆中代谢物M1的含量比SGX523 低70%,相比SGX523更能够降低导致肾毒性物质的产生,具有明显更优异的药代动力学性能,因此更适合作为抑制c-Met激酶的化合物,进而更适用于制备治疗癌症以及相关疾病的药物,因此具有开发被人体接受的抗肿瘤药物的潜在价值。
使用方法
本发明提供了能调节涉及蛋白酪氨酸激酶,尤其是c-Met激酶介导的信号转导途径的化合物。c-Met是参与包括细胞生长、细胞存活和侵入在内的许多重要的细胞过程的调控的重要的信号分子。HGF/c-Met这条信号通路存在于大部分肿瘤细胞中。c-Met信号通路失调是人类癌症中最为普遍发生的。c-Met信号的错乱在许多实体瘤和血液瘤中均得到了证实。联系c-Met和癌症的最有力的证据是最初发现的几乎所有患有遗传性肾乳头瘤(PRCC)的病人机体中都存在着c-Met的过度表达。承载HGF和c-Met基因的7号染色体三体在PRCC病人中普遍存在。也有报道c-Met突变在许多癌症(如胃癌、脑瘤、肝癌、卵巢癌、非小细胞肺癌和甲状腺癌等)中有所发生。多个c-Met突变体潜在的致癌性已在临床前模型中得到了确证。这里所描述的化合物可以用于抑制其活性。
术语“调节”是指与所述化合物不存在时的正常活性相比改变了所述途径(或其组分) 的功能活性。这一作用包括任何数量或程度上的调节,这包括提高、刺激、激活、增强、增加、促进、降低、减少、减小、阻碍、抑制、拮抗等等。
本发明所述化合物也可以调节以下一个或多个过程,这些过程包括但不限于例如细胞生长(包括例如分化、细胞存活和/或增殖)、肿瘤细胞生长(包括例如分化、细胞存活和/或增殖)、肿瘤消退等等。
虽然不希望受到任何作用机理或机制的束缚,已经发现本发明所述化合物具有调节激酶活性的能力。然而,本发明所述的方法不局限于任何具体机制或所述化合物如何实现其治疗作用。术语“激酶活性”是指其中将一个γ磷酸根从三磷酸腺苷(ATP)转移到蛋白底物中的一个氨基酸残基(例如丝氨酸、苏氨酸或酪氨酸)上的催化活性。化合物可以调节激酶活性,例如通过直接与ATP竞争激酶的ATP结合位点抑制其活性、通过在酶的结构上产生构象变化影响其活性(例如通过破坏具有生物学活性的三维结构)等等。
本发明所述化合物可以用于治疗和/或预防涉及蛋白酪氨酸激酶,尤其是c-Met激酶介导的细胞信号转导途径异常所导致的任何疾病或病症。术语“治疗”按照其常规意义使用,例如出于抗击、减轻、降低、解除、改善疾病或功能紊乱的症状等等目的对患者进行处理或照顾。所述化合物也可以以用于预防和/或治疗由所述信号分子介导的疾病和/或病症进行描述。术语“介导”表示例如所述信号分子是在所述疾病和/或病症中异常或失常的途径的一部分。
可以治疗的疾病和病症包括任何上面和下面所提及的疾病以及包括例如细胞增殖紊乱、癌症、肿瘤等等的c-Met异常导致的相关疾病。所述疾病包括乳头状瘤、芽状神经胶质瘤、卡波济氏肉瘤、黑素瘤、肺癌、卵巢癌、前列腺癌、鳞状细胞癌、星细胞瘤、头癌、颈癌、膀胱癌、乳癌、结肠直肠癌、甲状腺癌、胰腺癌、胃癌、肝细胞癌、白血病、淋巴瘤、血管瘤、瘢痕瘤。
本发明所述方法包括调节肿瘤细胞增殖,这包括抑制细胞增殖。后者表示肿瘤细胞的生长和/或分化得到降低、减少、削弱、减缓等等。术语“增殖”包括涉及细胞生长和分裂的任何过程,并包括分化和凋亡。如上所述,c-Met激酶在涉及细胞增殖、分化和凋亡的细胞质信号级联的活化中发挥重要作用。
本发明所述方法中包括使用式(I)所述化合物或其药学上可接受的盐,及包括其的组合物以治疗哺乳动物过度增殖性疾病的方法,所述方法包括对有此需要的人在内的哺乳动物给予有效治疗所述疾病的量的本发明所述化合物和/或其药学上可接受的盐。过度增殖性疾病包括但不限于实体肿瘤,诸如乳癌、呼吸道癌、脑癌、生殖器官癌、消化道癌、尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、副甲状腺癌及其远距离转移灶。这些疾病也包括淋巴瘤、肉瘤和白血病。
可以对任何肿瘤进行治疗,这些肿瘤包括但不限于在c-Met及其所参与的信号途径的任何上游或下游成员中具有一个或多个突变的肿瘤。如先前所述,肿瘤可以用本发明所述化合物进行治疗而不考虑其所对应的机制。可以对任何器官的肿瘤进行治疗,这包括但不限于例如结肠癌、胰腺癌、前列腺癌、骨癌、肝癌、肾癌、肺癌、睾丸癌、乳癌、皮肤癌、胃癌、结肠直肠癌、肾细胞癌、肝细胞癌、黑素瘤等等。
乳癌的例子包括但不限于浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌。
呼吸道癌的例子包括但不限于小细胞及非小细胞肺癌、以及支气管腺瘤和胸膜肺母细胞瘤。
脑癌的例子包括但不限于脑干和垂体神经胶质瘤、成神经管细胞瘤、小脑和大脑星细胞瘤、室鼓膜瘤以及神经外胚瘤和松果腺瘤。
男性生殖器官肿瘤包括但不限于前列腺癌和睾丸癌。女性生殖器官肿瘤包括但不限于卵巢癌、子宫内膜癌、宫颈癌、阴道癌和外阴癌以及子宫肉瘤。
消化道肿瘤包括但不限于肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、直肠癌、胃癌、小肠癌以及唾液腺癌。
眼癌包括但不限于眼内黑素瘤和成视网膜细胞瘤。
肝癌的例子包括但不限于肝细胞癌(具有或不具有纤维板层形式的肝细胞癌)、胆管细胞癌以及混合型肝细胞胆管细胞癌。
皮肤癌包括但不限于卡波西肉瘤、鳞状细胞瘤、恶性黑素瘤、梅克尔细胞皮肤癌以及非黑素瘤皮肤癌。
头颈癌包括但不限于喉癌、下咽癌、鼻咽癌和/或口咽癌以及嘴唇和口腔癌。
淋巴瘤包括但不限于非霍奇金淋巴瘤、AIDS相关淋巴瘤、皮肤T细胞淋巴瘤、霍奇金病以及中枢神经系统淋巴瘤。
肉瘤包括但不限于软骨肉瘤、组织肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤以及横纹肌肉瘤。
白血病包括但不限于急性成淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓白血病、慢性骨髓性白血病以及绒毛细胞白血病。
除了抑制肿瘤细胞增殖,本发明所述化合物也能引起肿瘤消退,例如肿瘤大小的减小或肿瘤在体内分布范围的降低。
基于本发明所述化合物的药物组合物
本发明也涉及包含本发明所述化合物,或其药学上可接受的盐的药物组合物。可以给予有此需要的患者这些组合物以达到所期望的药理学效果。患者是需要对具体症状或疾病进行治疗的包括人在内的哺乳动物,这是本发明所要达到的目的。因此,本发明包括含有药学上可接受的载体和药物有效量的本发明所述化合物或其盐的药物组合物。药学上可接受的载体是以与所述活性成分的有效活性相匹配的浓度对于患者相对无毒无害从而使载体引起的任何副作用不损害活性成分的有益作用的任何载体。化合物的药物有效量是对所治疗的具体症状产生效果或发挥作用的量。本发明所述化合物可以通过本领域所熟知的药学上可接受的载体使用包括快速释放制剂、缓释和定时释放制剂在内的任何有效的常规剂量单位形式经口服、非肠道、局部、眼部、眼球、鼻部、舌下、直肠、阴道等等方式给药。
对于口服给药,所述化合物可以配制成诸如胶囊、药丸、片剂、糖锭、锭剂、粉末、熔体、溶液、乳状液或悬浮液等固体或液体制剂,并且可以按照本领域内已知的用于生产药物组合物的方法进行制备。固体单位剂量形式可以是普通的软壳或硬壳的明胶类胶囊,包含例如表面活性剂、滑润剂以及诸如蔗糖、乳糖、玉米淀粉和磷酸钙的惰性填充剂。
在另一种实施方式中,本发明所述化合物可以用诸如乳糖、蔗糖和玉米淀粉等常规药片基质与诸如阿拉伯树胶、明胶或玉米淀粉等粘合剂;诸如马铃薯淀粉、玉米淀粉、褐藻酸、以及瓜尔豆胶、阿拉伯树胶、黄芪胶等用于给药后帮助药片分裂与溶解的崩解剂;例如滑石、硬脂酸或硬脂酸镁、钙或锌等用于提高药片制粒流并防止药片原料与药片模具及压片机粘连的滑润剂;用于提高药片外观质量并使其更为患者所接受的染料、着色剂、以及诸如冬青油、薄荷油、或樱桃调味剂等的调味剂组合制备片剂。用于口服固体剂型的适当的赋形剂包括磷酸二钙和诸如水和醇(例如乙醇、苯甲醇和聚乙二醇)的包含或不含药学上可接受的表面活性剂、悬浮剂或乳化剂的稀释剂。各种其他材料可以以糖衣形式或是为了以其他方式对剂型的物理形式进行修饰而存在。例如,药片、药丸或胶囊可以用虫胶、糖或这两者包被。
可分散粉末和颗粒适于制备水性悬浮液。它们提供了与分散剂或湿润剂、悬浮剂以及一种或多种防腐剂混合的活性成分。适当的湿润剂或分散剂和悬浮剂通过上面已经提到的内容举例。也可以存在额外的赋形剂,例如上述的那些甜味剂、调味剂和着色剂。
本发明所述药物组合物也可以是水包油乳剂形式的。油相可以是诸如液体石蜡的植物油或是植物油混合物。适当的乳化剂可以是(1)诸如大豆磷脂和卵磷脂的天然磷脂,(2)诸如阿拉伯树胶和黄芪胶的天然树胶,(3)部分酯与环氧乙烷的缩合产物,例如聚氧乙烯单油酸山梨醇酐,(4)酯或部分酯衍生形式脂肪酸和己糖醇酐,例如单油酸山梨醇酐。所述乳剂也可以包含甜味剂和调味剂。
油性悬浮液可以通过将活性成分在例如橄榄油、花生油、椰子油或芝麻油等植物油或诸如液体石蜡等矿物油中悬浮配制。油性悬浮液可以包含诸如硬石蜡、蜂蜡或鲸蜡醇等增稠剂。所述悬浮液也可以包括一种或多种例如对羟基苯甲酸正丙酯或对羟基苯甲酸乙酯的防腐剂;一种或多种着色剂;一种或多种调味剂;以及一种或多种诸如糖精或蔗糖的甜味剂。
可以用诸如丙二醇、甘油、蔗糖或山梨醇等甜味剂配制糖浆或酏剂。这样的制剂也可以包含缓和剂和防腐剂(诸如对羟基苯甲酸丙酯和对羟基苯甲酸甲酯)以及调味剂和着色剂。
本发明所述的化合物也可以以生理上可接受的稀释剂中包含该化合物的注射剂量非肠道给药,即皮下注射、静脉内注射、眼内给药、滑膜内给药、肌内给药或腹膜给药,所述稀释剂可以包括诸如水,盐水,水性葡萄糖和相关糖溶液,诸如乙醇、异丙醇或十六醇的醇,诸如丙二醇或聚乙二醇的甘醇,诸如2,2-甲基-1,1-噁茂烷-4-甲醇的甘油缩酮,诸如聚乙二醇400的醚、油、脂肪酸、脂肪酸酯或脂肪酸甘油酯,或乙酰化的脂肪酸甘油酯的无菌液体或液体混合物的药物载体,其中包含或不含诸如脂肪酸盐的药学上可接受的表面活性剂或去垢剂、诸如卡波姆、果胶、甲基纤维素、羧甲基纤维素或羟丙基甲基纤维素的悬浮剂、或乳化剂以及其他药物佐剂。
可以在本发明的非肠道剂型中使用的油的例子是石油、合成来源的油、动物油或植物油,例如软石蜡、矿物油、花生油、大豆油、芝麻油、棉籽油、玉米油和橄榄油。适当的脂肪酸包括油酸、硬脂酸、异硬脂酸和肉豆蔻酸。适当的脂肪酸酯是例如肉豆蔻酸异丙酯和油酸乙酯。适当的脂肪酸盐包括脂肪酸碱金属、脂肪酸铵和脂肪酸三乙胺,并且适当的表面活性剂包括阳离子表面活性剂,例如卤化烷基吡啶和醋酸烷基胺、卤化二甲基二烷基铵;阴离子表面活性剂,例如烷基、芳基和烯烃磺酸盐、烷基、烯烃、乙醚和单酸甘油脂硫酸盐以及磺基琥珀酸盐;非离子型表面活性剂,例如氧化脂肪胺、链烷醇酰胺脂肪酸、和聚(氧乙烯-氧丙基)或氧乙烯或氧丙烯共聚物;以及两性表面活性剂,例如2-烷基咪唑啉季铵盐和烷基-β-氨基丙酸盐,及其混合物。
本发明所述非肠道组合物通常应在溶液中包含重量比从约0.5%到约25%的活性成分。也可以方便地使用防腐剂和缓冲液。为了最小化或消除注射位置上的刺激,这样的组合物可以包含具有介于约12到约17之间的亲水-亲脂平衡常数(HLB)的非离子表面活性剂。在这样的剂型中的表面活性剂的含量介于重量比约5%到约15%之间。所述表面活性剂可以是具有以上HLB的单一组分或可以是具有所需HLB的两种或更多组分的混合物。
在所述非肠道剂型中使用的表面活性剂的例子是聚乙烯山梨糖醇脂肪酸酯类表面活性剂,例如山梨糖醇单油酸酯和氧乙烯与疏水碱通过丙二醇与过氧丙烯缩合形成的高分子量加合物。
所述药物组合物可以是无菌注射用水性悬浮液形式的。这样的悬浮液可以按照已知方法进行配制,其中使用适当的分散剂或湿润剂和诸如羧甲基纤维素钠、羟丙基甲基纤维素、甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄芪胶和阿拉伯树胶的悬浮剂;分散剂或湿润剂可以是诸如卵磷脂的天然磷脂、例如聚氧乙烯硬脂酸酯的烯化氧与脂肪酸的缩合产物、例如十七-乙烯氧十六醇的氧乙烯与长链脂肪醇的缩合产物、诸如聚氧乙烯山梨醇单油酸酯的氧乙烯与由脂肪酸和己糖醇衍生的部分酯的缩合产物、或是例如聚氧乙烯山梨聚糖单油酸酯的乙烯氧与从脂肪酸和己糖醇酐衍生的部分酯的缩合产物。
所述无菌的注射用制剂也可以是位于无毒的非肠道给药允许的稀释剂或溶剂中的无菌的注射用溶液或悬浮液。可以使用的稀释剂或溶剂是例如水、林格溶液、等压葡萄糖溶液和等压氯化钠溶液。此外,无菌的不挥发油通常被用作溶剂或悬浮用媒介。为此目的,可以使用包括合成的甘油单酯或甘油二酯在内的任何无刺激性的不易挥发的油。此外,诸如油酸的脂肪酸可以用于注射剂的制备。
本发明所述组合物也可以以用于直肠给药的栓剂形式进行给药。这些组合物可以通过将药物与适当的无刺激赋形剂混合进行制备,其中所述赋形剂在通常温度下是固体但在直肠温度下是液体并从而能在直肠中熔解以释放药物。这样的材料例如是可可油和聚乙二醇。
本发明所述方法中使用的另一种剂型采用透皮递药装置(“药膏”)。这样的透皮药膏可以用于提供受控量的本发明所述化合物的连续或间断灌注。用于药物递送的透皮药膏的构建和使用是本领域内所熟知的(参见例如,通过参考结合在本说明书中的1991年6月11日公开的美国专利No.5,023,252)。可以构建这样的药膏用于连续、脉冲、或按要求的药物递送。
可能要求或需要将所述药物组合物通过机械递送装置向患者给药。用于药物递送的机械递送装置的构建和使用是本领域内所熟知的。例如直接向脑部给药的直接递药技术通常包括将给药导管置于患者脑室系统以绕过血脑屏障。1991年4月30日公开的美国专利No.5,011,472中描述了这样一种用于向身体的特定解剖学区域运输物质的植入递药系统。
用于非肠道给药的控释制剂包括本领域内已知的脂质体、聚合物微粒和聚合物胶体制剂。
在需要或希望的情况下本发明所述组合物也可以包含通常称为载体或稀释剂的常规的药学上可接受的混合成分。可以采用制备适当剂量形式的这样的组合物的常规工艺。这样的成分和工艺包括以下通过参考组合在本说明书中的参考文献中所描述的内容:Powell,M.F.等《非肠道剂型赋形剂概述》(Compendium of Excipients for ParenteralFormulations),PDA Journal of Pharmaceutical Science&Technology 1998,52(5),238-311; Strickley,R.G《美国市场交易的小分子药剂的非肠道剂型,1999年第一部分》(Parenteral Formulations of Small Molecule Therapeutics Marketed in theUnited States(1999)-Part-l), PDA Journal of Pharmaceutical Science&Technology1999,53(6),324-349;以及Nenia,S. 等《注射用产品中的赋形剂及其使用》(Excipientsand Their Use in Injectable Products), PDA Journal of Pharmaceutical Science&Technology 1997,51(4),166-171。
针对其设计的给药路线与组合物剂型相匹配的常用药物成分包括:
●酸化剂(例子包括但不限于醋酸、柠檬酸、富马酸、盐酸、硝酸);
●碱化剂(例子包括但不限于氨溶液、碳酸铵、二乙醇胺、乙醇胺、氢氧化钾、硼酸钠、碳酸钠、氢氧化钠、三乙醇胺);
●吸附剂(例子包括但不限于粉末状纤维素和活性碳);
●气溶胶喷射剂(例子包括但不限于二氧化碳、CCl2F2、 F2ClC-CClF2、以及CClF3);
●空气置换剂(例子包括但不限于氮气和氩气);
●抗氧化剂(例子包括但不限于抗坏血酸、抗坏血酸棕榈酸盐、次磷酸、硫代甘油、丁羟茴醚、丁羟甲苯、丙基没食子酸、抗坏血酸钠、重亚硫酸钠、甲醛次硫酸氢钠、偏亚硫酸氢钠);
●抗真菌防腐剂(例子包括但不限于苯甲酸、对羟基苯甲酸丁酯、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、对羟基苯甲酸乙酯、苯甲酸钠);
●抗菌防腐剂(例子包括但不限于苄烷氯铵、苄索氯铵、三氯叔丁醇、苯甲基醇、苯乙醇、氯化十六烷基吡啶、苯酚、硝酸苯汞和硫柳汞钠);
●缓冲剂(例子包括但不限于偏磷酸钾、磷酸氢二钾、醋酸钠、无水柠檬酸钠、二水柠檬酸钠);
●粘合材料(例子包括但不限于嵌段聚合物、天然及合成橡胶、聚丙烯酸酯、聚亚胺酯、硅树脂、聚硅氧烷和苯乙烯-丁二烯共聚物);
●承载剂(例子包括但不限于阿拉伯树胶糖浆、芳香糖浆、芳香酏剂、樱桃糖浆、橙味糖浆、糖浆、可可糖浆、玉米油、矿物油、花生油、芝麻油、抑菌氯化钠注射剂及抑菌注射用水);
●螯合剂(例子包括但不限于依地酸(即乙二胺四乙酸)和依地酸二钠);
●着色剂(例子包括但不限于FD&C Red No.3、FD&C Red No.20、FD&C YellowNo.6、FD&C Blue No.2、D&C Green No.5、D&C Orange No.5、D&C Red No.8、焦糖以及氧化铁红);
●澄清剂(例子包括但不限于阿拉伯树胶、聚乙二醇、十六烷基醇、单硬脂酸甘油酯、卵磷脂、单油酸聚山梨醇酯、聚氧乙烯50单硬脂酸酯);
●胶囊剂(例子包括但不限于明胶及纤维醋法酯);
●食用香精(例子包括但不限于茴芹油、肉桂油、可可、薄荷醇、桔油、胡椒薄荷油和香兰素);
●保湿剂(例子包括但不限于甘油、丙二醇和山梨醇);
●研磨剂(例子包括但不限于矿物油和甘油);
●油膏基质(例子包括但不限于羊毛脂、亲水油膏、聚乙二醇油膏、矿脂、亲水矿脂、白油膏、黄油膏以及玫瑰红水油膏);
●油(例子包括但不限于落花生油、矿物油、橄榄油、花生油、芝麻油和植物油);
●渗透增强剂(透皮递药)(例子包括但不限于单羟基或多羟基醇、单价或多价醇、饱和或不饱和脂肪醇、饱和或不饱和脂肪酯、饱和或不饱和二羧基酸、香精油、磷脂酰衍生物、脑磷脂、萜烯、酰胺、醚、酮和脲);
●溶剂(例子包括但不限于乙醇、玉米油、棉籽油、甘油、异丙醇、矿物油、油酸、花生油、纯水、注射用水、注射用无菌水和输液用无菌水);
●可塑剂(例子包括但不限于邻苯二酸二乙酯和甘油);
●硬化剂(例子包括但不限于十六烷基醇、十六烷基酯、蜡、微晶蜡、石蜡、硬酯醇、白蜡和黄蜡);
●栓剂基质(例子包括但不限于可可油和聚乙二醇(混合物));
●表面活性剂(例子包括但不限于苄烷氯铵、壬苯聚醇10、oxtoxynol 9、聚山梨醇酯80、十二烷基硫酸钠和山梨聚醇单棕榈酸酯);
●悬浮剂(例子包括但不限于琼脂、膨润土、卡波姆、羧乙基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、高岭土、甲基纤维素、黄芪胶和硅酸镁铝(veegum));
●甜味剂(例子包括但不限于阿斯巴甜糖、右旋糖、甘油、甘露醇、丙二醇、糖精钠、山梨醇和蔗糖);
●药片粘合剂(例子包括但不限于阿拉伯树胶、海藻酸、羧甲基纤维素钠、可压性蔗糖、乙基纤维素、明胶、液体葡萄糖、甲基纤维素和明胶化淀粉);
●药片防粘剂(例子包括但不限于硬脂酸镁和滑石粉);
●药片及胶囊稀释剂(例子包括但不限于磷酸氢钙、高岭土、乳糖、甘露醇、微晶纤维素、粉末化纤维素、沉淀的碳酸钙、碳酸钠、磷酸钠、山梨醇和淀粉);
●药片包被剂(例子包括但不限于液体葡萄糖、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、纤维醋法酯和虫胶);
●药片直接压缩赋形剂(例子包括但不限于磷酸氢钙);
●药片崩裂剂(例子包括但不限于海藻酸、羧甲基纤维素钙、微晶纤维素、波拉克林钾(polacrillin potassium)、藻酸钠、羟乙酸钠淀粉和淀粉);
●药片滑润剂(例子包括但不限于硬脂酸钙、硬脂酸镁、矿物油、硬脂酸和硬脂酸锌);
●药片滑动剂(例子包括但不限于胶体硅、玉米淀粉和滑石粉);
●药片抛光剂(例子包括但不限于棕榈蜡和白蜡);
●药片/胶囊不透明剂(例子包括但不限于二氧化钛);
●增稠剂(例子包括但不限于蜂蜡、十六烷醇和石蜡);
●粘性增强剂(例子包括但不限于海藻酸、膨润土、卡波姆、羧甲基纤维素钠、甲基纤维素、藻酸钠和黄芪胶);
●张性剂(例子包括但不限于右旋糖和氯化钠);
●增湿剂(例子包括但不限于十七烷乙烯氧十六醇、卵磷脂、山梨醇单油酸酯、聚氧乙烯山梨醇单油酸酯和聚氧乙烯硬脂酸酯)。
本发明所述药物组合物的剂量
在已知的对可以用于治疗任何上述疾病的化合物进行评价的常规实验室技术的基础上,通过常规毒性测试和通过用于确定哺乳动物中上述症状疗效的常规药理学检测方法,并通过将这些结果与用于治疗这些症状的已知药物的结果进行比较,可以方便地确定本发明所述化合物对治疗每种所需指征治疗的有效剂量。在对这些病症中的一种进行治疗中所述活性成分的给药量可以大范围地变化,这取决于诸如所使用的具体化合物和剂量单位、给药方式、疗程、所治疗患者的年龄和性别以及所治疗病症的特征和程度等因素。
所述活性成分总的给药量可以介于每天约0.01毫克/千克体重到约50毫克/千克体重之间,并且优选地介于每天约0.1毫克/千克体重到约10毫克/千克体重之间。单位剂量可以优选地含约1毫克到约300毫克活性成分,并可以每天一次或多次给药。口服给药的每日剂量应优选地介于0.1到5毫克/千克体重。通过注射给药(包括静脉注射、皮下注射、肌内注射和非肠道注射)以及使用灌注技术给药的每日剂量应优选地介于0.1到5毫克/千克体重。每日直肠给药方案应优选地介于0.1到15毫克/千克体重。每日局部给药方案应优选介于0.1到5毫克/千克体重每日给药1到4次。透皮浓度应优选需要维持0.1到3毫克/千克体重的日剂量。每日吸入给药方案应优选0.1到5毫克/千克体重。其他剂量和数量可以按常规选择。
具体的初始及持续剂量方案对于每位患者有所不同,这取决于主治医生所确定的病症的特征及严重程度、所使用具体化合物的活性、患者的年龄及身体状况、给药时间、给药路线、药物排泄速度、药物组合等等。治疗所需的模式以及本发明所述化合物或其药学上可接受的盐或组合物的剂量数可以由精通本领域的人员使用常规治疗检测加以确定。
与其他活性成分的组合用药
本发明所述化合物可以以单一药剂形式或与一种或多种其他药剂组合给药,其中所述的组合不引起不能接受的有害结果。这对于治疗诸如癌症的过度增殖性疾病可能是尤其实用的。在这种情况下,本发明所述化合物可以与已知的细胞毒剂、信号转导抑制剂、或与其他抗肿瘤物质及其混合物和组合物组合使用。
在一种实施方式中,本发明所述化合物可以与细胞毒抗肿瘤物质组合使用。所述物质的例子可以参见《墨克索引》第11版(Merck Index(1996))。这些物质包括但不限于天冬酰胺酶、左旋门冬酰胺酶、博莱霉素、卡铂、顺铂、氮芥、卡氮芥、苯丁酸氮芥、环磷酰胺、阿糖胞苷、达卡巴嗪、放射菌素D、柔红霉素、表阿霉素、阿霉素、依托泊苷、6-巯基嘌呤、甲氨喋呤、5-氟尿嘧啶、六甲密胺、羟基脲、异环磷酰胺、甲酰四氢叶酸、洛莫司汀、美司钠、丝裂霉素C、盐酸米托蒽醌、甲苄肼、雷洛昔芬、链脲菌素、它莫西芬、硫鸟嘌呤、托泊替康、伊利替康、泼尼松龙、波尼松、长春碱、长春新碱、长春地辛。
其他适于与本发明所述化合物组合使用的细胞毒药物包括但不限于Goodman和Oilman所著《药物的药理学基础》(The Pharmacological Basis of Therapeutics(NinthEdition, 1996,McGraw-Hill))中所述的公认的用于治疗肿瘤疾病的那些化合物。这些物质包括但不限于氨鲁米特、L-天冬酰胺酶、硫唑嘌呤、5-氮杂胞苷、克拉屈滨、白消安、己烯雌酚、 2',2'-双氟去氧胞苷、普卡霉素、多烯紫杉醇、赤羟壬基腺嘌呤、雌三醇、5-氟脱氧尿苷、 5-氟脱氧尿苷单磷酸盐、磷酸氟达拉滨、氟甲睾酮、氟他胺、己酸羟孕酮、紫杉醇、去甲氧柔红霉素、干扰素、醋酸甲羟孕酮、醋酸甲地孕酮、美法仑、米托坦、N-二氧磷乙酰-L- 天冬氨酸盐(PALA)、喷司他丁、司莫司汀、替尼泊甙、丙酸睾酮、噻替派、三甲基蜜胺、尿嘧啶以及长春瑞滨。
其他适于与本发明所述化合物组合使用的细胞毒抗肿瘤物质也包括新发现的细胞毒剂,诸如吉西他滨、卡培他滨、埃博霉素、奥沙利铂及其天然和合成的衍生物、替莫唑胺、托西莫单抗(Bexxar)、trabedectin、以及驱动蛋白纺锤体蛋白Eg5的抑制剂。
在另一种实施方式中,本发明所述化合物可以与其他信号转导抑制剂组合使用。特别感兴趣的是针对EGFR家族(诸如EGFR、HER-2和HER-4)及其各自的配体的信号转导抑制剂。这样的物质的例子包括但不限于诸如赫赛汀(曲妥珠单抗)、艾比特思(西妥昔单抗) 和波替珠单抗(pertuzumab)的抗体药物。这样的药物的例子也包括但不限于小分子激酶抑制剂,诸如ZD-1839/Iressa、CM033、OSI-774/Tarceva、CP-724,714、EKB-569及GW-2016。
有益效果
本发明的化合物与现有技术中已知的不携带氘的化合物相比,具有一系列的优点。本发明的主要优点包括:
(1)本发明化合物对酪氨酸激酶诸如c-Met具有优异的抑制活性。
(2)本发明的化合物相较于未氘化的化合物相比,在动物体内更不容易被代谢,这导致首过效应的降低,因此可以改变剂量并形成长效制剂,其也可以长效制剂的形式改善适用性。
(3)通过氘化还改变了药代动力学作用,使得本发明的化合物在生物体中的分布明显不同于未氘代的化合物。
(4)本发明的化合物在动物体内的药物浓度更高,从而提高了药效。
实施例
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
下述实施例所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1 2-氘-6-((6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-b]哒嗪-3-基)硫)喹啉的制备
步骤1:2-氘-6-溴喹啉-1-氧(V)的制备
将10克6-溴喹啉-1-氧、10.7克叔丁醇钠、氘水33毫升的混合物于100℃油浴加热12小时。将反应液冷却至室温,以二氯甲烷萃取,有机层浓缩至干,得浅黄色固体6.7 克,收率67%。
1H-NMR(300Hz,DMSO-d6)δ:7.55(d,J=8.4Hz,1H),7.89-7.97(m,2H),8.42-8.47(m, 2H).LRMS(ESI)m/z[M+H]+:225.3.
步骤2:2-氘-6-溴喹啉(III)的制备
将4克2-氘-6-溴喹啉-1-氧溶于70毫升冰醋酸中,分批加入8 克铁粉,加热回流3小时。将反应液浓缩至干,残余物加水溶解,以碳酸钠固体调pH=8,以二氯甲烷萃取,有机层浓缩至干,得浅棕色油状物2.5克,收率67%。
1H-NMR(300Hz,CDCl3)δ:8.10(d,J=8.1Hz,1H),7.97-8.00(m,2H),7.81(dd,J=2.4, 9.0Hz,1H),7.45(d,J=8.7Hz,1H).
步骤3:6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-b]哒嗪-3-硫醇(IV)的制备
将10克3-肼基-6-(1-甲基-1H-吡唑-4-基)哒嗪、3.1克氢氧化钾、7毫升二硫化碳、35 毫升水和130毫升乙醇的混合物于90℃油浴加热2小时。将反应液浓缩至干,以1M的氢氧化钠溶解,以1M盐酸调pH至2~3。过滤,滤饼水洗,干燥,得黄色固体9.6克,收率79%。
1H-NMR(300Hz,DMSO-d6)δ:8.53(s,1H),8.19(d,J=9.3Hz,1H),8.14(s,1H),7.75(d, J=9.3Hz,1H),3.94(s,3H).
步骤4:2-氘-6-((6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-b]哒嗪-3-基)硫)喹啉(II) 的制备
将2.5克6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-b]哒嗪-3-硫醇、2.3克2-氘-6-溴喹啉、1.2克三(二亚苄基丙酮)二钯、1.4克9,9-二甲基-4,5-双二苯基膦氧杂蒽、4毫升 N,N-二异丙基乙基胺和50毫升N,N-二甲基甲酰胺的混合物置换氩气后于105℃加热搅拌 24小时。将反应液浓缩至干,残余物以二氯甲烷/甲醇=40:1柱层析,得黄色固体500毫克,收率13%。
1H-NMR(400Hz,DMSO-d6)δ:8.04-8.13(m,4H),7.95(d,J=0.4Hz,1H),7.89(s,1H),7.84(dd,J=2.0,8.8Hz,1H),7.43(d,J=8.4Hz,1H),7.35(d,J=10.0Hz,1H),3.98(s,3H).
实施例2式(II)所示的化合物在猴肝S9中代谢研究
每个体外孵化体系总体积为200μL,介质为100mM磷酸缓冲液(PBS,pH7.4),包括终浓度为3μM的SGX523或式(II)所示的化合物和2mM的NADPH(还原型烟酰胺腺嘌呤二核苷酸磷酸),采用37℃水浴进行孵化。预孵化3min后,向缓冲液-底物-辅助因子混合物中分别加入猴肝S9蛋白起始反应,反应60min后加入同体积冰冷乙腈终止反应。对照组别实验条件同上,但NADPH以PBS代替;此外,空白对照组中,S9蛋白经过高温失活处理。所有孵化样本均为双样本。
取双样本各取200μL合并,加入400μL乙腈,涡流混合1min,离心5min(14000rpm),全部上清液取出,转移至10mL塑料管中,40℃氮气流下吹干,残留物以80μL乙腈-水 (10:90,v/v)溶解,取10μL进行UPLC-UV/Q-TOF MS分析。
采用UPLC-UV/Q-TOF MS法鉴定了SGX523和式(II)所示的化合物猴肝S9孵化体系中可能的代谢产物,结果显示同等剂量下式(II)所示的化合物血浆中代谢物M1的含量比SGX523低70%。
实施例3药物组合物
药片
将上述物质混合均匀,通过常规工艺制备1000片药片。可以使用适当的水性或非水性包衣以提高适口程度、改善外观和稳定性或延缓吸收。
胶囊
式(II)所示的化合物(实施例1制备) 30g
淀粉 140g
微晶纤维素 60g
按常规方法,将上述物质混合均匀,装入普通明胶胶囊,制备1000颗胶囊。
无菌IV溶液
式(II)所示的化合物(实施例1制备) 0.2g
无菌注射用水 50mL
将式(II)所示的化合物用无菌的注射用水配制成4毫克/毫升溶液并按需要调节pH。用5%无菌右旋糖稀释至1.5-2.0毫克/毫升静脉输液给药。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述教导之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种如下式(I)所示的化合物或其药学上可接受的盐:
式(I)中:
D代表氘原子;
R1、R2、R3、R4、R5、R6、R7、R8、R9各自独立地为氢原子或氘原子,优选均为氢原子;
R10选自CH3、CH2D、CHD2和CD3,优选为CH3。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中,式(I)所示的化合物为以下式(Ⅱ)所示的化合物:
3.权利要求1所述的式(I)所示的化合物的制备方法,如下反应式所示:
其中,使式(a)所示的化合物和式(b)所示的化合物进行偶联反应,得到式(I)所示的化合物;
式中:
D代表氘原子;
R1、R2、R3、R4、R5、R6、R7、R8、R9各自独立地为氢原子或氘原子,优选均为氢原子;
R10选自CH3、CH2D、CHD2和CD3,优选为CH3。
4.根据权利要求3所述的制备方法,其中,所述的式(I)所示的化合物为以下式(Ⅱ)所示的化合物:
该制备方法如下反应式所示:
其中,使式(III)所示的化合物和式(IV)所示的化合物进行偶联反应,得到式(II)所示的化合物。
5.根据权利要求3或4所述的制备方法,其中,所述偶联反应在有机溶剂中进行,所述有机溶剂选自:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸或其组合;和/或,所述偶联反应在50℃~200℃下进行;和/或,所述偶联反应时间为5小时~72小时;和/或,所述的偶联反应在三(二亚苄基丙酮)二钯和9,9-二甲基-4,5-双二苯基膦氧杂蒽存在下进行。
6.根据权利要求4所述的制备方法,其中,所述式(III)所示的化合物是通过以下方法制备的:
其中,使式(V)所示的化合物与还原试剂进行还原反应,得到式(III)所示的化合物;优选地,所述的还原试剂是铁粉;更优选地,所述的还原反应在冰醋酸存在下进行;优选地,所述还原反应在有机溶剂中进行,所述有机溶剂优选选自:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸或其组合;优选地,所述还原反应在50℃~200℃下进行;优选地,所述还原反应时间为5小时~24小时;
优选地,所述式(V)所示的化合物是通过以下方法制备的:
其中,使式(VI)所示的化合物与重水进行氘代反应,得到式(V)所示的化合物;优选地,所述氘代反应在叔丁醇钠存在下进行;优选地,所述氘代反应在有机溶剂中进行,所述有机溶剂优选选自:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸或其组合;优选地,所述氘代反应在50℃~200℃下进行;优选地,所述氘代反应时间为5小时~72小时;和/或
所述式(IV)所示的化合物通过以下方法制备:
其中,使式(VII)所示的化合物与二硫化碳进行关环反应,得到式(IV)所示的化合物;优选地,所述的关环反应在乙醇存在下进行;优选地,所述关环反应在有机溶剂中进行,所述有机溶剂优选选自:二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、正丁醇、丙酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、乙二醇二甲醚、二氧六环、四氢呋喃、冰醋酸或其组合;优选地,所述关环反应在50℃~200℃下进行;优选地,所述关环反应时间为5小时~72小时。
7.一种药物组合物,其包含权利要求1或2所述的化合物或其药学上可接受的盐作为活性成分,优选所述药物组合物进一步包含药学上可接受的载体,更优选所述药物组合物进一步包含其他活性成分,且所述其他活性成分包括选自下组的一种或多种活性成分:细胞毒剂、信号转导抑制剂和抗肿瘤物质。
8.根据权利要求7所述的药物组合物,其配制成选自下组的制剂:片剂、胶囊剂、丸剂、散剂、颗粒剂或注射剂;优选为片剂、胶囊剂或静脉注射剂。
9.权利要求1或2所述的化合物或其药学上可接受的盐或者权利要求7或8所述的药物组合物在制备用于预防或治疗酪氨酸激酶介导的疾病,尤其是c-Met介导的疾病的药物中的用途;用于制备治疗或预防与酪氨酸激酶活性或表达量相关的疾病,优选为与c-Met的活性或表达量相关的疾病的药物的用途;用于制备调节选自细胞生长(包括例如分化、细胞存活和/或增殖)、肿瘤细胞生长(包括例如分化、细胞存活和/或增殖)、肿瘤消退的一个或多个过程的药物的用途;用于制备预防或治疗过度增殖性疾病的药物的用途。
10.根据权利要求9所述的用途,其中,所述酪氨酸激酶介导的疾病包括细胞增殖紊乱、癌症和肿瘤;优选地,所述酪氨酸激酶介导的疾病选自:乳头状瘤、芽状神经胶质瘤、肉瘤(包括软骨肉瘤、组织肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤以及横纹肌肉瘤)、黑素瘤、血管瘤、瘢痕瘤、鳞状细胞癌、星细胞瘤、淋巴瘤(包括非霍奇金淋巴瘤、AIDS相关淋巴瘤、皮肤T细胞淋巴瘤、霍奇金病以及中枢神经系统淋巴瘤)、呼吸道癌(包括肺癌,例如小细胞及非小细胞肺癌,以及支气管腺瘤和胸膜肺母细胞瘤)、头颈癌(包括头癌、颈癌、喉癌、下咽癌、鼻咽癌和/或口咽癌以及嘴唇和口腔癌)、膀胱癌、乳癌(包括浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌)、消化道癌(包括肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、直肠癌、胃癌、小肠癌以及唾液腺癌)、甲状腺癌、副甲状腺癌及其远距离转移灶、胰腺癌、肝癌(包括肝细胞癌(具有或不具有纤维板层形式的肝细胞癌)、胆管细胞癌以及混合型肝细胞胆管细胞癌)、白血病(包括急性成淋巴细胞白血病、慢性淋巴细胞白血病、急性骨髓白血病、慢性骨髓性白血病以及绒毛细胞白血病)、脑癌(包括脑干和垂体神经胶质瘤、成神经管细胞瘤、小脑和大脑星细胞瘤、室鼓膜瘤以及神经外胚瘤和松果腺瘤)、生殖器官癌(包括前列腺癌、睾丸癌、卵巢癌、子宫内膜癌、宫颈癌、阴道癌和外阴癌以及子宫肉瘤)、尿道癌、眼癌(包括眼内黑素瘤和成视网膜细胞瘤)、皮肤癌(包括卡波西肉瘤、鳞状细胞瘤、恶性黑素瘤、梅克尔细胞皮肤癌以及非黑素瘤皮肤癌)、骨癌和肾癌。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008155378A1 (en) * | 2007-06-21 | 2008-12-24 | Janssen Pharmaceutica Nv | Polymorphic and hydrate forms, salts and process for preparing 6-{difluoro[6-(1-methyl-1h-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl}quinoline |
CN101553490A (zh) * | 2006-10-23 | 2009-10-07 | Sgx药品公司 | 用作蛋白激酶调节剂的二环三唑类化合物 |
CN103459396A (zh) * | 2011-02-10 | 2013-12-18 | 诺瓦提斯公司 | 作为c-Met酪氨酸激酶抑制剂的[1,2,4]三唑并[4,3-b]哒嗪化合物 |
CN106279176A (zh) * | 2015-06-11 | 2017-01-04 | 中国科学院上海药物研究所 | 氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪及其应用 |
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WO2008155378A1 (en) * | 2007-06-21 | 2008-12-24 | Janssen Pharmaceutica Nv | Polymorphic and hydrate forms, salts and process for preparing 6-{difluoro[6-(1-methyl-1h-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl}quinoline |
CN103459396A (zh) * | 2011-02-10 | 2013-12-18 | 诺瓦提斯公司 | 作为c-Met酪氨酸激酶抑制剂的[1,2,4]三唑并[4,3-b]哒嗪化合物 |
CN106279176A (zh) * | 2015-06-11 | 2017-01-04 | 中国科学院上海药物研究所 | 氘代的3-[(6-喹啉基)二氟甲基]-6-[(1-甲基)-4-吡唑基][1,2,4]三唑并[4,3-b]哒嗪及其应用 |
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