CN104817497B - 一种炔代喹啉衍生物及其制备方法和用途 - Google Patents
一种炔代喹啉衍生物及其制备方法和用途 Download PDFInfo
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- CN104817497B CN104817497B CN201510126189.3A CN201510126189A CN104817497B CN 104817497 B CN104817497 B CN 104817497B CN 201510126189 A CN201510126189 A CN 201510126189A CN 104817497 B CN104817497 B CN 104817497B
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- phenyl
- fluoro
- quinoline
- fluorophenyl
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07F9/02—Phosphorus compounds
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- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
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Abstract
本发明公开了一种炔代喹啉衍生物及其制备方法和用途,所述的炔代喹啉衍生物为通式I所示的炔代喹啉类化合物及其药学上可接受的盐、水合物、溶剂化物、前药,它们的制备方法。本发明还是涉及通式I的化合物具有抑制多种蛋白酪氨酸激酶(例如c‑Met和VEGFR)活性,因此它们可用作抗癌药物,治疗人的癌症。
Description
技术领域
本发明涉及医药技术领域,尤其涉及涉及炔代喹啉衍生物,它们的制备方法,含有该化合物作为活性成分的药物组合物,治疗与抑制生长因子受体(例如c-Met和VEGFR2)蛋白酪氨酸激酶活性相关的疾病的方法,从而它们可用作抗癌药物,及其作为药物在温血动物(例如人类)中抑制酪氨酸激酶活性的用途。
背景技术
受体酪氨酸激酶是贯穿细胞膜的蛋白酶,其构成有与生长因子结合的细胞外结构域、跨膜结构域和作为激酶来磷酸化蛋白质中特定酪氨酸残基并因此影响细胞增殖的细胞内部分。酪氨酸激酶可分类为生长因子受体(例如VEGFR1、VEGFR2、c-Met、EGFR、erbB2、erbB3、PDGFR、FGFR)或非受体(例如c-src和bcr-abl)激酶。这类激酶在常见的人类癌症,例如肝癌、非小细胞肺癌、乳腺癌、结/直肠癌、胃癌、白血病、卵巢癌、支气管癌、胰腺癌中可异常表达。
c-Met激酶是异质二聚体受体酪氨酸激酶(RTKs)亚科的原型成员,RTKs包括c-Met、Ron和Sea。c-Met的促进血管生成和促进增殖的活性使其成为一个有吸引力的靶点。c-Met的内源性配体是肝细胞生长因子(HGF),因其体外可以干扰集落的形成又名离散因子(SF)。HGF是一种衍生化细胞因子,通过自身磷酸化诱导受体活化使得在正常细胞和肿瘤细胞中的受体依赖信号增加(Sonnenberg等,J.Cell Biol.123:223-235,1993;Matsumato等,Crit.Rev.Oncog.3:27-54,1992;Stoker等,Nature327:239-242,1987)。已证实抗HGF抗体或者HGF拮抗剂也能抑制肿瘤转移。
正常的血管生成在许多生理如过程胚胎发育、伤口愈合和生殖功能等中具有重要的作用。不良的或者病理性的血管生成与多种疾病有关,包括糖尿病视网膜病变、癌症、动脉粥样化。肿瘤血管生成,新的血管的形成及其渗透性主要由肿瘤衍生的血管内皮细胞生长因子(VEGF)调节。VEGF至少通过两种不同的受体起作用:VEGF-R1(Flt-1)和VEGF-R2(KDR,Flk-1)。KDR受体高度特异性地存在于血管内皮细胞(Endocr.Rev.1992,13,18;FASEBJ.1999,13,9)。
本发明的基础是,发现了对多重受体酪氨酸激酶如c-Met,VEGFR有很强抑制作用的化合物。这些化合物能有效地抑制c-Met和VEGF以及其他信号传输,可以用来治疗与细胞增生、血管生成和/或其他信号转导通路有关的疾病,例如癌症、牛皮癣、风湿性关节炎、自身免疫性疾病、过度疤痕形成和粘连、淋巴水肿、功能失调性子宫出血和伴有视网膜血管增生的眼病等。
已经发现如下所述的式I化合物是一类新的具有优良药理学性质的化合物,该类化合物可抑制蛋白酪氨酸激酶的活性,例如c-Met、VEGFR、kit、Ron、Tie2等。如前所述,阻断HGF-c-Met的信号转导可作为抗肿瘤治疗的策略之一。选择性阻断该通路不仅能够抑制肿瘤生长,还能够抑制肿瘤的转移。同时阻断VEGF-VEGFR信号通道,可以抑制肿瘤微血管生成,达到抑制肿瘤增长的效果。现今Exelixis公司研发的Cabozantinib小分子抑制剂得到FDA批准治疗很罕见的晚期甲状腺癌症,同时在进行3期肝癌等多个临床试验。
由于c-Met和KDR多重激酶抑制剂类,尤其是小分子抑制剂类抗肿瘤药物多处于临床研究,尚未完全进入市场,给该类药物的研发提供了广阔的空间。因此,c-Met/KDR多激酶抑制剂是一个富有前景的抗肿瘤药物研究领域。
发明内容
本发明提供了一种炔代喹啉衍生物及其制备方法和用途。
本发明采用如下技术方案:
本发明涉及通式I化合物,药学上可接受的盐、水合物、溶剂化物或前药:
通式I
其中,X选自H或卤素;
R1选自氢、烷基、取代的烷基、环烷基、取代的环烷基、杂环基、取代的杂环基;
R2选自以下基团:
优选的,通式I所述化合物及其可药用的盐、水合物、溶剂化物或前药,其中,X是氟。
优选的,通式I化合物选自下述化合物中:
本文使用的术语“卤素”,除非另有说明,包括氟、氯、溴或碘,例如氟或氯。
本文使用的术语“烷基”指饱和的烃基团,包括1到12个碳原子的直链和支链基团。优选含有1到6个碳原子的烷基,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基等。更优选的是含有1到3个碳原子的低级烷基,例如甲基、乙基、丙基、异丙基。
本文使用的术语“取代的烷基”是指烷基被一个或多个取代基取代。除非其他方面表明,一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷基,烯基,炔基,杂环基,巯基,芳氧基等等。
本文使用的术语“芳基”,除非另有说明,包括从芳香烃移除一个氢原子得到的有机基团,例如苯基或萘基。优选苯基,并且未被取代或被一或两个或三个取代基取代,所述取代基选自卤素、卤素取代的低级烷基、低级烷基、低级烯基、低级炔基、氰基、低级烷基氰基、羟基、低级烧氧基、竣基、竣基烧基、氣基、氣基甲酸基、氣基甲酸氧基(carbamate)、疏基、磺基、低级烷基磺酰基、磺酰氨基;芳基包括一个芳香环与一个饱和或者部分饱和的脂肪环的稠环结构,例如四氢萘基。
本文使用的术语“环烷基”,除非另有说明,包括含有3-10个环碳原子的环状基团,包括但不仅限于环丙基、环丁基、环戊基、环己基等。环烷基可以是多环,含1-3个环,优选单环或双环。双环可以是连环或稠环或螺环。
本文使用的术语“取代的环烷基”,除非另有说明,是指环烷基被一个或多个取代基取代。除非其他方面表明,一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷基,烯基,炔基,杂环基,巯基,芳氧基等。
本文使用的术语“杂环基”,除非另有说明,包括非芳香的饱和或者部分饱和的单环或者稠环结构,每个环可含有至多4个独立地选自0、N和S的杂原子。每个杂环适当地含有4-8个环原子,优选5-6个环原子。稠合杂环可包含碳环并且仅需要包含一个饱和或者部分饱和的杂环。杂环基包括单环、双环和三环杂芳香环结构,并且含有至多4个,优选1或2个,各自选自0、N和S的杂原子。每个环可具有4-8个,优选5或6个环原子。双环或者三环结构可包含碳环。碳环包括环烷基、环烯基或芳香环。杂环基的实例包括但不仅限于:氮杂环丁烷、吡咯烷、批咯烷酮、哌啶、哌啶酮、哌嗪、吗啉、氧杂环丁烷、四氢呋喃、四氢吡喃、咪唑啉、吡唑烷、乙内酰脲、吡咯、吲哚、吡唑、吲唑、三唑、苯并三唑、咪唑、苯并咪唑、噻吩、苯并噻吩、噻唑、苯并噻唑、呋喃、苯并呋喃、噁唑、苯并噁唑、异噁唑、四氮唑、吡啶、嘧啶、三嗪、喹啉、异喹啉、喹唑啉、吲哚啉、吲哚酮、苯并四氢呋喃、四氢喹啉、四氢异喹啉、亚甲基二氧苯基。
本文使用的术语“取代的杂环基”,除非另有说明,是指杂环基被一个或多个取代基取代。除非其他方面表明,一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷基,烯基,炔基,杂环基,巯基,芳氧基等。
除非其他方面表明,本发明所描述的结构式包括所有的同分异构形式(如对映异构,非对映异构,和几何异构(或构象异构)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体,和(Z)、(E)的构象异构体。因此,本发明的化合物的单个立体化学异构体或其对映异构体,非对映异构体,或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明所使用的术语“互变异构体”或“互变异构形式”表示具有不同能量的结构同分异构体可以越过低能垒,从而互相转化。譬如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如酮-烯醇式互变和亚胺-烯胺同分异构化作用。化合价互变异构体包括通过一些成键电子重组而进行互变。
除非其他方面表明,本发明的化合物的所有互变异构形式都包含在本发明的范围之内。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的。
药学上可接受的无毒的酸形成的盐包括,但并不限于,与氨基基团反应形成的无机酸盐有盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐,和有机酸盐如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐,或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐,藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,苯甲酸盐,重硫酸盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊基丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,反丁烯二酸盐,葡庚糖酸盐,甘油磷酸盐,葡萄糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖醛酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,丙二酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,棕榈酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,硬脂酸盐,硫氰酸盐,对甲苯磺酸盐,十一酸盐,戊酸盐,等等。通过适当的碱得到的盐包括碱金属,碱土金属,铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1-8磺酸化物和芳香磺酸化物。
通式I化合物可以单独施用或与一种或多种其他治疗剂联合施用,所述其他治疗剂包括但不仅限于17a-炔雌醇、二乙基己烯雌酚、睾酮、强的松、氟甲睾酮、屈他雄酮丙酸酯、睾内酯、醋酸甲地孕酮、甲基强的松龙、甲基睾酮、泼尼松龙、去炎松、氯烯雌醚、羟孕酮、氨鲁米特、雌莫司汀、醋酸甲羟孕酮、亮丙瑞林、氟他胺、托瑞米芬、诺雷德、基质金属蛋白酶抑制剂、包括吉非替尼、埃罗替尼、西妥昔单抗的合适的EGFR抑制剂。Pan Her抑制剂,包括卡奈替尼、EKB-569、GW-572016。VEGF抑制剂,例如阿伐斯汀、ZD6474和SU6668、瓦他拉尼、BAY-43-9006、SU11248、CP-547632和CEP-7055。同时也包括Src抑制剂和Casodexi(比卡鲁胺,阿斯利康)、他莫昔芬、MEK-1激酶抑制剂、MAPK激酶抑制剂、PI3抑制剂和TOGF抑制剂例如伊马替尼。同时也包括IGFlR抑制剂,非受体和受体酪氨酸激酶抑制剂,和整联蛋白(integrin)信号抑制剂。同时也包括抗血管生成和抗血管药物,该类药物通过阻碍血液进入实体瘤,剥夺癌症细胞营养物质使其休眠。其他的细胞毒性药物包括美法仑、六甲基三聚氰胺、噻替哌、阿糖胞苷、依达曲沙、三甲曲沙、达卡巴嗪、L-天冬酰胺酶、喜树碱、拓扑替康、比卡鲁胺、氟他胺、亮丙瑞林、吡啶并苯并吲哚衍生物、干扰素和白介素。其他的抗癌药物包括微管稳定药物,例如紫杉醇、多西他赛(09/712352,2000年11月14日申请)、C-4甲基碳酸酯紫杉醇、埃博霉素A、埃博霉素B、埃博霉素C、埃博霉素D、脱氧埃博霉素A、脱氧埃博霉素和微管干扰药物。合适的抗癌药物也包括⑶K抑制剂,抗增生的细胞周期抑制剂epidophyllotoxin;抗肿瘤酶;拓扑异构酶抑制剂;甲节肼;米托蒽醌;钼配位复合物例如顺钼和卡钼;生物反应调节剂;生长抑制剂;抗激素治疗药;甲酰四氢叶酸;喃氟啶和造血生长因子。抑制雄性激素依赖性癌细胞增生的阉割,也可在此使用。可能采用的联合治疗形式是:固定的联合或者本发明化合物和一种或者多种其它治疗剂交叉给予或者彼此独立地给药,或者将固定联合给药和一种或多种其它治疗剂联合给药。
特别是对于肿瘤治疗而言,式I化合物可以与化疗、放疗、外科手术或其组合联合给药。作为如上文所述的其它治疗策略的辅助治疗,长期给药同样是可行的。其他可能的治疗指维持病人在肿瘤消退后的状态,甚至指例如有风险的病人的化学预防治疗。式I化合物可用于治疗多种癌症,包括但不仅限于:(a)癌症,包括膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌(包括小细胞肺癌)、食管癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌以及皮肤癌(包括鳞状细胞癌);(b)淋巴造血系统肿瘤,包括白血病、急性淋巴细胞性白血病、急性淋巴母细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯克特淋巴瘤;(c)髓系造血系统肿瘤,包括急性和慢性粒细胞白血病、骨髓增生异常综合征和早幼粒细胞白血病;(d)起源于间充质的肿瘤,包括纤维肉瘤和横纹肌肉瘤;(e)中枢和外周神经系统肿瘤,包括星形细胞瘤、神经母细胞瘤、神经胶质瘤和神经鞘瘤;(f)其他肿瘤,包括黑色素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病(xenoderoma pigmentosum),角化棘皮瘤(keratoacanthoma)、甲状腺滤泡癌和卡波西肉瘤。
本发明的化合物可以是晶体或非晶体形式,如果是晶体,可以是水合物或者溶剂化物。在本发明范围内,所述水合物含有化学计量的水或可变量的水。
通式I的化合物可以单元剂量制剂通过口服、局部、非肠道、吸入或喷雾或直肠给药,所述制剂含有常规无毒的药学上可接受的载体、辅料和赋形剂。特别优选以丸剂、胶囊、酏剂、糖浆、锭剂、片剂等形式口服给药。本文所使用的术语非肠道包括皮下注射、皮内注射、血管内(例如静脉)注射、肌内注射、脊内注射、鞘内注射等注射或输液方法。另外,本文提供了包含通式I化合物和药学上可接受的载体的药物制剂。一种或多种通式I化合物可与一种或多种无毒的药学上可接受的载体和/或稀释剂和/或辅料和可能需要的其他活性成分进行组合。包括通式I的化合物的药物组合物可以是采用适于口服给药的形式,例如片剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳剂、硬或软胶囊、糖浆、酏剂。
供口服的组合物可采用本领域已知的制备药物组合物的任何方法进行制备,所述组合物可含有一种或多种选自甜味剂、矫味剂、着色剂、防腐剂的试剂以提供药学上美观和可口的制剂。片剂含有活性成分和适合制备片剂的无毒性的药学上可接受的赋形剂。所述赋形剂可以是例如惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解齐IJ,例如玉米淀粉、海藻酸;粘合剂,例如淀粉、明胶、阿拉伯胶;润滑剂,例如硬脂酸镁、硬脂酸、滑石粉。片剂可以不包衣,也可以通过已知的方法包衣以延迟在胃肠道的崩解和吸收,达到在长时间内的持续性作用。例如,可采用例如单硬脂酸甘油酯或双硬脂酸甘油酯的延释材料达到上述作用。
供口服的组合物也可为硬明胶胶囊剂,所述硬明胶胶囊剂中,活性成分与惰性固体稀释剂混合,例如碳酸钙、磷酸钙或高岭土,或为软明胶胶囊剂,其中活性成分与水或油性介质混合,例如花生油、液体石蜡或橄榄油。
水混悬液包含活性物质和适合制备水混悬液的赋形剂。所述赋形剂指助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶、阿拉伯胶;分散或润湿剂可以是天然磷脂,例如卵磷脂,或环氧烷烃和脂肪酸的缩合物,例如聚氧乙烯硬脂酸酯,或环氧乙烷和长链脂肪醇的缩合物,例如十七乙烯氧十六醇,或环氧乙烷和脂肪酸与己糖醇部分酯化物的缩合物,例如聚氧乙烯山梨醇单油酸酯,或环氧乙烷和脂肪酸与己糖醇酐部分酯化物的缩合物,例如聚氧乙烯山梨醇酐单油酸酯。水混悬液可含有一或多种防腐剂,例如对羟基苯甲酸乙酯、对羟基苯甲酸正丙酯,一种或多种着色剂,一种或多种调味剂,一种或多种甜味剂,例如蔗糖或糖精。
油混悬剂可通过将活性成分悬浮在植物油,例如花生油、橄榄油、芝麻油、椰子油或矿物油(例如液体石蜡)中制备。油混悬剂可含有增稠剂,例如蜂蜡、固体石蜡、十六醇。可以加入上文所列举的甜味剂和矫味剂从而提供可口的口服制剂。所述组合物可通过加入抗氧化物(例如抗坏血酸)进行保存。
分散性粉剂和颗粒剂包含活性成分和分散剂或润湿剂、助悬剂和一种或多种防腐剂混合物,适用于通过加入水制备成水性混悬剂。合适的分散剂或润湿剂和助悬剂如上文所述。还可以存在其他赋形剂,例如甜味剂、调味剂和着色剂。
本发明的药物组合物可以是无菌注射的水性或油性混悬液。这种混悬液可采用上文所述的合适的分散剂或润湿剂和助悬剂根据已知方法制备。所述无菌注射制品可以是溶于无毒的肠道外可接受的稀释剂或溶剂的无菌注射溶液或混悬液,例如1,3-丁二醇溶液。可接受的赋形剂和溶剂可以是水、林格氏溶液和等渗氯化钠溶液。另外,无菌的非挥发油也是常用的溶剂或混悬介质。对于上述目的,任何无刺激的非挥发性油都可以使用,包括合成的甘油单酯或二酯。另外例如油酸的脂肪酸也可以在注射剂的制备中使用。
本文所述的通式I化合物的所有施用方法中,每天口服给药的剂量优选于0.01到200mg/Kg体重。每天注射给药(包括静脉内、肌内、皮下、肠胃外和输液)的剂量优选0.01到200mg/Kg体重。每天直肠给药的剂量优选0.01到200mg/Kg体重。每天阴道给药的剂量优选0.01到200mg/Kg体重。每天局部给药的剂量优选0.01到200mg,每天给药I~4次。经皮给药的药物浓度优选能够保持每天的给药量0.01到200mg/Kg体重。每天吸入给药的剂量优选为0.01到200mg/Kg体重。
然而,应当理解,每一位病人的特定给药剂量受到诸多因素的影响,包括具体选用的化合物的活性、年龄、体重、健康状况、性别、饮食、给药时间、给药途径、排泄速率、药物联用和正在治疗的特定疾病的严重程度。
一般合成过程
一般地,本发明的化合物可以通过本发明所描述的方法制备得到,除非有进一步的说明,其中取代基的定义如式(I)。下面的反应方案和实施方案用于进一步举例说明本发明的内容。
相关领域的专业人员将能认识到:本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物,且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如,根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成,如适当的保护干扰基团,通过利用其他已知的试剂除了本发明所描述的,或将反应条件做一些常规的修改。另外,本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
附图说明
图1是实验例9和10对BALB/c裸鼠GTL-16胃癌移植肿瘤的肿瘤体积的影响(每组4只裸鼠)。
图2是实验例9和10对BALB/c裸鼠GTL-16胃癌移植肿瘤的裸鼠体重的影响(每组4只裸鼠)。
具体实施方式
下面所描述的实施方案,除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Alfa ChemicalCompany,AK Scientific,CombiBlocks等。反应用溶剂如四氢呋喃、二氧六环、甲苯、乙醚、二甲基亚砜、N、N-二甲基乙酰胺、N,N-二甲基甲酰胺、二氯甲烷和氯等是由EM Science购得。
以下反应一般是在氮气正压下。
低分辨率质谱(MS)数据的条件是:Agilent 1100Series LCMS(ZorbaxSB_C18,
2.1父30_,4微米,1011^11,流速为0.6111171^11,5-95%(0.1%溶于H2O的蚁酸)中的(0.1%溶于CH3CN的蚁酸)),在210/254nm用UV检测,用低响应电喷模式(ESI)。
下面简写词的使用贯穿本发明:
HOAc 乙酸
MeCN,CH3CN 乙腈
HATU 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
BSA 牛血清白蛋白
B0C,Boc 叔丁氧基羰基
DIEA N-乙基二异丙基胺
DMF N,N-二甲基甲酰胺
DMAP 4-二甲氨基吡啶
DMSO 二甲基亚砜
EDC,EDCI 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
Dppa 叠氮磷酸二苯酯
EtOAc 乙酸乙酯
FBS 胎牛血清
g 克
h 小时
LiHMDS 六甲基二硅基基锂
LDA 二异丙基胺基锂
MCPBA 间氯过氧苯甲酸
MgSO4 硫酸镁
MeOH,CH3OH 甲醇
MeI 碘甲烧
CH2Cl2,DCM 二氯甲烷
NMP N-甲基吡咯烷酮
mL,ml 毫升
Pd/C 钯/碳
Pd(OAc)2 醋酸钯
Pd(PPh3)4 四(三苯基膦)钯
Pd(dppf)Cl2, 1,1,-二(二苯基膦基)二茂铁二氯化钯
POCl3 三氯氧磷
K2CO3 碳酸钾
KOH 氢氧化钾
RT rt 室温
NaHCO3 碳酸氢钠
NaBH4 硼氢化钠
NaBH3CN 氰基硼氢化钠
NaOtBu 叔丁醇钠
NaH 氢化钠
NaI 碘化钠
Na2SO4 硫酸钠
THF 四氢呋喃
Et3N,TEA 三乙胺
TFA 三氟乙酸
NBS N-溴丁二酰亚胺
TBAI 四丁基碘化铵
反应方案1
通式I类化合物可以通过反应方案1获得,其中PG为保护基团,如苄基。苯胺类化合物II和合适的酸偶合得到通式III所展示的化合物。去保护反应产生通式IV类化合物。。通式IV类化合物与三氟甲磺酸酐产生通式V类化合物。通过钯催化下的三氟甲磺酸酯和炔类化合物的耦合反应(Sonogoshira反应),通式I的化合物可以得到。
反应方案2
通式II展示的中间产物可以通过反应方案2获得。保护化合物II-1的羟基得的II-2类化合物。如用PG是苄基,反应条件可以是苄基溴或苄基氯如II-1在回流的K2CO3和乙腈。II-2的硝化反应可以用硝酸,所随后用锌或铁在微酸条件下还原得到通式II-3所显示的化合物。苯胺类化合物3与甲酸酯类化合物如甲酸乙酯在碱性条件下缩合得到取代的喹啉类化合物II-4,化合物II-4和三氯氧磷(POCl3)回流尝试通式II-5类化合物。化合物II-5类化合物与合适的芳基衍生物反应得到取代的二芳醚类化合物II-6。
制备本发明所述中间体的典型方法如以下实施例所示。
本发明使用了如下缩略语,其它的全部用标准化学式表示。
EtOH:乙醇,MeOH:甲醇,RT:室温,DIPEA:二异丙基乙基胺,DCM:二氯甲烷,DMF:N,N-二甲基甲酰胺,EtOAc:乙酸乙酯,HOBt:水合1-羟基苯并三唑,EDC:1_(3_二甲基氨基丙基)-3_乙基碳化二亚胺盐酸盐,MsCl:甲磺酰氯,eq:当量,g:克,mg:毫克,ml:毫升。
实施例A:7-苄氧基-4-羟基-5-甲氧基喹啉(A)
步骤A1:1-(4-苄氧基-5-甲氧基苯基)乙酮(A.1)
47.7g(287mmol)的1-(4-羟基-5-甲氧基苯基)乙酮,47.5g(344mmol,1.2当量)的K2CO3,0.5g的KI和53.3g(37.0mL,301mmol,1.05当量)苄基溴在400mL的乙腈中的混合物被加热到80度,12小时。反应液冷却到室温,用硅胶(50g)过滤,乙酸乙酯(100mL)洗两次。滤液抽干后得到白色晶状固体,直接用于下一步实验。LCMS m/z=257(M+1)
步骤A2:1-(4-苄氧基-5-甲氧基-2-硝基苯基)乙酮(A.2)
上一步得到的固体溶在AcOH(500mL)中并冷却到0度。向这个溶中滴加入硝酸(50mL,1.2mole)。所得溶液在室温下搅拌14小时,然后倒入碎冰(约500g)。析出的白色固体抽滤,水洗并干燥,直接用于下一步。LCMS m/z=302(M+1)
步骤A3:1-(2-胺基-4-苄氧基-5-甲氧基苯基)乙酮(A.3)
向上一步得到的固体中加入铁粉(58g,1.0mole),醋酸胺((1.2mmol,73g),甲苯((800mL)和水(800ML)在机械搅拌下,加热到88度,18小时。反应液用硅胶土过滤,EtOAc洗二次(每次100mL)。滤液有机层被分开,并用水和饱和食盐水洗,用Na2SO4干燥,抽滤,蒸干得到粗产品。出产品溶解在CH2Cl2(300mL),用硅胶(200g)过滤,40%的EtOAC/己烷洗。抽干后得到棕色固体54.5g(三步,70%产率)。LCMS m/z=272(M+1).
步骤A4:7-苄氧基-4-羟基-6-甲氧基喹啉(中间体A)
向化合物A-3(68.1g,250mmol)在DME(500mL)的溶液中加入甲醇钠(108g,2.0mol)。搅拌30分钟后,再加入甲酸甲酯(1.0mol)。反应在常温下搅拌15小时。反应用水(40mL)稀释,并用盐酸(1.0M)中和到中性。析出的固体抽滤,水洗,并完全干燥得到中间体A(51g,73%).1H NMR(300MHz,CDCl3):δ10.7(br s,IH),7.70(s,IH),7.49-7.46(t,IH),7.43-7.41(br d,2H),7.37-7.33(t,2H),7.30-7.28(d,IH),6.84(s,IH),6.21-6.19(d,IH),5.21(s,2H),3.96(s,3H).LC/MS m/z=282(M+H).
实施例B:1-(4-氟苯基胺基甲酰)-环丙基羧酸(中间体B)
将环丙基-1,1-二羧酸(10g,77mmol)THF(100mL)溶液在冰水浴中冷却,滴加入三乙胺(8.0g,79mmol)。滴加过程中冰水浴温度控制在10度以下。所得溶液搅拌30分钟,然后滴加入二氯亚砜(SOCl2,9.0g,76mmol),然后滴加入4-氟苯胺(9.0mL)THF(30mL),整个滴加过程中冰水浴温度控制在10度以下。搅拌继续4小时,反应升温到室温。反应用200mL的EtOAc稀释,然后用NaOH水溶液(1.0M,50mL),水(40mL)和饱和食盐水(40mL)洗。所得有机溶液用Na2SO4干燥,抽滤并蒸干到~30mL。向所得粘稠液体中加入庚烷(200mL),很多片状固体析出,抽滤并干燥得到中间体B(15.8g,93%)。
实验例C:N-【3-氟-4-(-7-三氟甲磺酰氧基-6-甲氧基-4-喹啉基氧基)苯基】-N-(4-氟苯基)环丙基-1,1-二甲酰胺
步骤C1:7-苄氧基-4-氯-6-甲氧基喹啉(C.1)
向在冰浴中的固态中间体A(135g,0.48mmoL)慢慢加入三氯氧磷(POCl3,300mL),耗时20分钟。反应然后加热回流4小时,反应冷却后,用旋转蒸发仪蒸出大多数POCl3(水浴稳定控制在60度以下),所得半固态剩余物慢慢倒入碎冰(~700g)中,用少量丙酮冲洗反应瓶。所得水溶液用Na2CO3中和到pH~9。抽滤,干燥得到深灰色固体(122g),直接用于下一步反应。LC/MS m/z=300(M+H).
步骤C2:7-苄氧基-4-(2-氟-4-硝基苯氧基)-6-甲氧基喹啉(C.2)
上步反应所得固体(20.8g,69mmol),2-氟-4-硝基苯酚(14.1g,90mmol)溶解在无水2,6-二甲基吡啶(200mL)中,加热回流5小时。反应冷却到约70度,加入水(200mL),K2CO3水溶液(2.0M,50mL)。所得化合物冷却到0度,大量固体析出,抽滤并干燥得到13.6g产品(47%)。LC/MS m/z=422(M+H).
步骤C3:7-苄氧基-4-(4-胺基-2-氟苯氧基)-6-甲氧基喹啉(C.3)
铁粉(17g,330mmol),醋酸胺(24.3g,400mmol),上一步所得固体C.2(23.1g,55mmol),甲苯(150ml)和水(100ML)的混合物加热到88度14小时。混合物用硅藻土(100g)过滤,EtOAc洗二次(每次100mL)。滤液分离,有机层水洗(50mL,2次),饱和食盐水洗(50mL),用Na2SO4干燥,抽滤得到粗产品。粗产品用EtOAc/己烷(1:2)重结晶得到19.2g浅绿-灰色产品。LCMS m/z=421(M+H).
步骤C4:N-【4-【(7-苄氧基-6-甲氧基-4-喹啉基)氧基】-3-氟--N-(4-氟苯基)环丙基-1,1-二甲酰(C.4)
中间体B(7.80g,35mmol)和DMF(0.11mL)的DCM(100mL)溶液用冰水浴冷却,慢慢加入草酰氯(35mmol),保持水浴温度在15度以下。所得溶液在成为下搅拌12小时,然后放入冰水浴。向反应慢慢加入上一步的固体C3(11.7g,30mmol)三乙胺(10mL)的THF(50mL)溶液,历时30分钟并保持水温在5度以下。反应继续搅拌一个小时,加入EtOAc(100mL)和水(50mL),并分离出有机层。有机层用Na2CO3(1.0M水溶液,20mL),水(20mL)和饱和食盐水(10mL)洗,Na2SO4干燥,用硅胶过滤,蒸干得到粗产品。用EtOAc重结晶得到灰白色的产物((15.3g),LCMS m/z=597(M+H).
步骤C5:-【4-【(7-羟基-6-甲氧基-4-喹啉基)氧基】-3-氟--N-(4-氟苯基)环丙基-1,1-二甲酰(C.5)
上一步所得的化合物C.4(8.0g,13.4mmol),5%的Pd-C(0.5g)和甲醇(80mL)的混合物在氢气气球下搅拌5小时。反应用硅藻土过滤,蒸干后,直接用于下一步反应。
步骤C6:N-【3-氟-4-(-7-三氟甲基磺酰氧基-6-甲氧基-4-喹啉基氧基)苯基】-N-(4-氟苯基)环丙基-1,1-二甲酰胺(中间体C)
上一步所得化合物C.5溶解在DCM/吡啶(20mL/10mL)中,冷却到0度,慢慢加入三氟甲磺酸酐(15mmol)。反应在常温下搅拌1小时,加入饱和氯化铵水溶液(10mL)。反应液用EtOAc(100mL)稀释,用水(50mL,两次),饱和NaHCO3水溶液(50mL)洗,MgSO4干燥,抽滤,蒸干。所得粗产品用硅胶柱分离(0-50%EtOAc/DCM)得到中间体(6.8g),LCMS m/z=640(M+H).
实验例D:N-(3-氟-4-(6-甲氧基-7-三氟甲基磺酰氧基-4-喹啉基氧)苯基)-1,5-二甲基-3-氧基-2-苯基-吡唑-4-甲酰胺(中间体D)
使用和合成中间体C完全相同的途径,由化合物C.3和antipyric acid(1,5-二甲基-3-氧基-2-苯基-2,3-二氢-1H-吡唑-4-羧酸)合成成中间体D。
实例1:N-(3-氟-4-(6-甲氧基-7-(3-甲基-4-吗啉-1-基)-4-喹啉基氧)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺
步骤1.1:4-(丙炔-2-基)吗啉
向吗啉((4.36g,50mmol),3-氯-3-甲基-1-丁炔(6.63g,65mmol),三乙胺(7.1g,70mmol)的THF(100mL)溶液中加入氯化亚铜(5mmol)。人员搅拌半小时后,加入乙醚(100mL),硅胶土过滤,醋酸乙酯洗。滤液用饱和食盐水(30mL)洗,用MgSO4干燥,抽滤并蒸干得到白色固体,直接用于下一步。
步骤1.2:N-(3-氟-4-(6-甲氧基-7-(3-甲基-4-吗啉-1-基)-4-喹啉基氧)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺
向中间体C(64mg,0.1mmol),上一步所得化合物(100mg),CuI(10mg),Pd(dppf)Cl2(7mg)和三亚按(0.5mL)在DMF(2mL)中的混合物中通氮气3分钟,然后加热到80度,8小时。反应蒸干,混合物用硅胶柱分离,用0-10%甲醇/DCM溶剂分离得到产物(48mg)。LCMS m/z=641(M+H)
表1.实例2-15:使用和合成实例1完全相同的合成方法,合成出实例2-15
实例16:N-(3-氟-4-(6-甲氧基-7-[3-(4-甲基哌嗪-1-基)-丙炔-1-基-4-喹啉基氧)苯基)-1,5-二甲基-3-氧基-2-苯基-吡唑-4-甲酰胺
向中间体D(33mg,0.05mmol),3-(4-甲基哌嗪-1-基)-丙炔(100mg),CuI(10mg),Pd(dppf)Cl2(7mg)和三亚按(0.5mL)在DMF(2mL)中的混合物中通氮气3分钟,然后加热到80度,8小时。反应蒸干,混合物用硅胶柱分离,用0-10%甲醇/DCM溶剂分离得到产物(19mg),LCMS m/z=617(M+H)。
表2 实例17-18.使用和合成实例16完全相同的合成方法,合成出实例17-18.
实例19.激酶活性测试
所有激酶的活性是在美国Reaction Biology Corp用放射性标记方法测试(地址:1Great Valley Parkway,Suite 2;Malvern,PA 19355;website:http:// www.reactionbiology.com/)。
测试方法:化合物测试使用10个剂量的IC50方法,起始浓度1.0microM(μM),3倍系列稀释。标准对照为星形孢菌素(Staurosporine),其测试方法为10剂量-IC50,起始浓度20(μM),3倍系列稀释.酶反应是在1μM ATP浓度下进行.
初始反应缓冲液:20mM:Hepes(羟乙基哌嗪乙硫磺酸),(pH 7.5),10mM MgCl2,1mMEGTA(乙二醇双(2-氨基乙基醚)四乙酸),0.02%Brij35(十二烷基聚乙二醇醚),0.02mg/ml BSA(牛血清白蛋白),0.1mM Na3VO4,2mM DTT(二硫苏糖醇),1%DMSO
操作步骤
1.底物溶液:在新鲜配制的初始反应缓冲液中加入相应的底物
2.将任何所需的辅因子(cofactor)加进底物溶液
3.将相应的激酶加进底物溶液并轻轻混匀,制备成激酶反应混合
4.将所测化合物的DMSO溶液(10mM)加入激酶反应混合
5.将33P-ATP(具体放射性:10μCi/μl)加入反应混合物,启动激酶反应
6.室温下,进行激酶反应120分钟
7.将反应点在P81离子交换纸上(Whatman#3698-915)
8.将离子交换纸在0.75%的磷酸中清洗掉未反应的磷酸根
9.检测放射活性,从而确定激酶活性
IC50值的计算:以化合物浓度的对数为横坐标,抑制率为纵坐标,在GraphPadPrism5中,拟合非线性曲线:log(inhibitor)vs.response—Variable slope,求出酶抑制率为50%时的待测化合物浓度即IC50。
实验结果:本发明部分化合物对c-Met和VEGFR2(KDR)激酶活性的半抑制浓度(IC50)见表3。
表3.化合物对激酶活性抑制
实例20.实例化合物9和10对Balb/c裸鼠中GTL-16异种移植胃癌的抗癌作用
从ATCC购得GTL-16细胞,并培养在RPMI1640+10%FBS+1%P/S抗生素中。Balb/c裸鼠为雄性,6-8周龄,重18±2g。以每0.1ml PBS5.0×106个细胞将细胞皮下植入裸鼠(右侧)中。当肿瘤大小达到200(150-200)mm3的体积时,将源自GTL-16细胞的荷瘤小鼠随机分配到4组中(4只小鼠/组)。所有小鼠口服每天一次给药。对一组给予载剂、一组给予cabozantinib(30mg/kg游离碱),剩余两组分别给予实例9和实例10(90mg/kg,每天一次口服灌胃)。施用时间持续3周。一周测量肿瘤体积2次,在整个研究中在临测量肿瘤体积之前测量体重。对实例9和实例10化合物的肿瘤生长抑制率为79%和92%,而cabozantinib的肿瘤生长抑制率为49%(见图1和图2)。所有3个化合物对裸鼠体重影响都很小。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (3)
1.一种炔代喹啉衍生物,其特征在于:所述的炔代喹啉衍生物选自以下化合物:
N-(3- 氟 -4-(6- 甲 氧 基 -7-(3-(4- 甲 基 -4- 氧 -1,4- 氮 磷 环 己 烷 -1-基 )丙炔 -1- 基 )-4- 喹啉基氧 ) 苯基 )-N-(4- 氟苯基 ) 环丙烷 -1,1- 二甲酰胺;
N-(3- 氟 -4-(6- 甲氧基 -7-(3- 二甲胺基 )-3- 甲基 - 丁炔 -1- 基 )-4- 喹啉基氧 )苯基 )-N-(4- 氟苯基 ) 环丙烷 -1,1- 二甲酰胺;
N-(3- 氟 -4-(7-(2- 环丙基乙炔基 )-6- 甲氧基 -4- 喹啉基氧 ) 苯基 )-N-(4-氟苯基 ) 环丙烷 -1,1- 二甲酰胺;
N-(3- 氟 -4-(7-(3- 羟基 -3- 甲基 - 丁炔 -1- 基 )-6- 甲氧基 -4- 喹啉基氧 )苯基 )-N-(4- 氟苯基 ) 环丙烷 -1,1- 二甲酰胺;
N-(3- 氟 -4-(6- 甲氧基 -7-(3-(4- 甲基哌嗪 -1- 基 ) 丙炔 -1- 基 )-4- 喹啉基氧)苯基 )-N-(4- 氟苯基 ) 环丙烷 -1,1- 二甲酰胺;
N-(3-氟-4-(6-甲氧基-7-(3-(1,1-二氧-1,4-硫代吗啉-4-基)丙炔-1-基)-4-喹啉基氧 ) 苯基 )-N-(4- 氟苯基 ) 环丙烷 -1,1- 二甲酰胺;
N-(3- 氟 -4-(6- 甲氧基 -7-(3-(2- 甲砜乙基胺基 ) 丙炔 -1- 基 )-4- 喹啉基氧) 苯基 )-N-(4- 氟苯基 ) 环丙烷 -1,1- 二甲酰胺;
N-(3- 氟 -4-(6- 甲 氧 基 -7-(2-((2S)- 吡 咯 -2- 基 ) 乙 炔基 -4- 喹 啉 基氧)苯基 )-N-(4- 氟苯基 ) 环丙烷 -1,1- 二甲酰胺;
N-(3- 氟 -4-(6- 甲氧基 -7-(2-((2S)-1- 甲基吡咯 -2- 基 ) 乙炔基 -4- 喹啉基氧 )苯基 )-N-(4- 氟苯基 ) 环丙烷 -1,1- 二甲酰胺;
N-(3- 氟 -4-(6- 甲氧基 -7-(2-( 氮杂环丁烷 -3- 基 ) 乙炔基 -4- 喹啉基氧 )苯基 )-N-(4- 氟苯基 ) 环丙烷 -1,1- 二甲酰胺;
N-(3- 氟 -4-(6- 甲氧基 -7-(2-(1- 甲基 - 氮杂环丁烷 -3- 基 ) 乙炔基 -4- 喹啉基氧 ) 苯基 )-N-(4- 氟苯基 ) 环丙烷 -1,1- 二甲酰胺。
2.一种药物组合物,其特征在于:其中含有治疗有效量的如权利要求 1所述的炔代喹啉衍生物或其盐作为活性成分以及药学上可接受的赋形剂。
3.权利要求 1所述的炔代喹啉衍生物在制备抗肿瘤药物中的用途。
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