CN102532107B - 4-取代苯胺基-7-取代烷氧高哌嗪基-喹唑啉衍生物及其制备方法和用途 - Google Patents
4-取代苯胺基-7-取代烷氧高哌嗪基-喹唑啉衍生物及其制备方法和用途 Download PDFInfo
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- CN102532107B CN102532107B CN201010596305.5A CN201010596305A CN102532107B CN 102532107 B CN102532107 B CN 102532107B CN 201010596305 A CN201010596305 A CN 201010596305A CN 102532107 B CN102532107 B CN 102532107B
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Abstract
本发明涉及4-取代苯胺基-7-取代烷氧高哌嗪基喹唑啉衍生物(通式I)及其制备方法和用途，其中R1，R2和n分别具有在说明书中限定的含义。本发明还涉及这些衍生物的制备方法，其与无机或有机的酸所形成的生理上可接受的盐，含有它们的药物组合物。所述化合物具有有价值的药理性质，对因酪氨酸激酶(PTK)所引起的信号转导有抑制效果，特别是突变型EGFR(L858R/T790M)具有较高的抑制活性，且毒性较低。本发明还关于其在治疗疾病，特别是肿瘤疾病上的用途及其制备方法。
Description
技术领域
本发明涉及药物合成领域，具体涉及4-取代苯胺基-7-取代烷氧高哌嗪基-喹唑啉衍生物的制备方法。
背景技术
肿瘤是一系列以异常细胞失控增生和扩散为特征的疾病，是严重威胁人类生命健康的重大疾病，据统计，每年全球肿瘤死亡总数约790多万人，我国每年死于肿瘤者160多万人，并逐渐增加，已成为城市人口的第一位死因。
蛋白酪氨酸激酶(PTK)是一类在正常细胞生长中起重要作用的酶，它能够催化磷酸基团从ATP转移到蛋白底物的残基上。许多表皮生长因子受体(EGFR)蛋白都具有蛋白酪氨酸激酶的作用，而且这些受体和生长因子的相互作用也是正常调节细胞生长所必须的。然而EGFR的过度表达，通过其自身酪氨酸激酶的作用，会引起细胞过度增值，最终导致肿瘤的生成。
基于失调的受体激酶在癌症病理中所起的重要作用，特异性的PTK抑制剂作为潜在抗癌治疗剂的开发是目前抗癌剂的研究热点。因此目前许多合成的化合物都具有抑制表皮生长因子受体酪氨酸激酶(EGFR-PTK)的活性，尤其以喹唑啉类化合物研究的最深入，其中 ZD1839于2003年被FDA批准上市用于治疗非小细胞肺癌(Ranson，M.Epideraml growth factor receptor tyrosine kinase inhibitors.British J.Cancer 2004，90，2250-2255.)。ZD6474既具有抑制EGFR的活性，同时具有抑制VEGFR的活性，于2009年申报上市(Alessandro，M.Vandetanib(ZD6474)，a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor(VEGFR)and Epidermal Growth Factor Receptor(EGFR)Tyrosine Kinase：Current Status and Future DirectionsThe Oncologist 2009，14，378-390.)。WO 99/06378、WO 2000/31048和WO2000/06555(中国专利CN99808949)也涉及某些取代的喹唑啉的衍生物具有不可逆的PTK抑制剂活性。
传统的喹唑啉衍生物在治疗细胞过度增生导致的疾病中，需要一个很大的计量才能达到有效的治疗，这往往会加剧其产生的痢疾和皮疹等副作用，为此需要进行进一步研究去寻找有效且低毒副作用的药物。
WO 97/30035公开了喹唑啉类衍生物ZD6474以及其作为PTK抑制剂的应用。实验证明，此类化合物对人脐静脉内皮细胞(HUVEC)具有较好的抑制作用。
在我国，高哌嗪主要用于制药工业，以其为原料的医药品有20多种。目前，国外流行开发高哌嗪衍生物的药用功效。用高哌嗪合成的某些衍生物可用作消炎剂，另外一些衍生物可以降低血糖，从而对治疗糖尿病，肥胖症等有较好的效果。高哌嗪的七元杂环是多边环，它们的中间体多数具有强烈的生物活性和药用价值。含氮杂环化合物高 哌嗪是药物合成的重要中间体。所含的双氮原子能够与许多有机化合物反应，尤其是在化学药物的结构修饰与改造中有着极其重要的作用。高哌嗪双氮原子与喹唑啉对接后可以有效的与肿瘤靶标结合，使肿瘤药物的活性显著提高。同时，与ZD6474类衍生物相比，包括哌啶以及哌嗪等侧链，高哌嗪结构能够较好的提高整个分子的理化参数，改善其药代动力学性质，因而对高哌嗪系列化合物的研究愈来愈受到重视。
因此，将高哌嗪与喹唑啉母核有机的结合起来，对T790M与L858R突变的EGFR与VEGFR2表现出极高的耐受活性，且毒副作用较低，得到了意想不到的作用效果，其体外活性是ZD6474十倍以上，对作为药物研究具有广阔的应用前景，由此可见对其进行合成及衍生物的研究具有实用价值。
发明内容
本发明的目的是提供一类新型4-取代苯胺基-7-取代烷氧高哌嗪基-喹唑啉衍生物，以及该类化合物在抗肿瘤药物中作为活性成分的用途。
本发明即喹唑啉衍生物如通式(I)所示：
通式(I)
其中：
R1表示：氢、甲氧基，优选自甲氧基；
R2表示：氢、甲基、乙基，优选自氢和甲基；
n表示：1、或2、或3、或4，优选自3。
以下是本发明化合物的制备方法，其中起始化合物(II)可以商购。
化合物(II)与氯化亚砜经氯化反应制备得到化合物III，化合物III与2-氟-4溴-苯胺经氮烷基化反应得到化合物IV；化合物IV在三氟代乙酸条件下脱苄基得到V，化合物V再与不同的卤代烷烃反应得到化合物VI，再与Boc-高哌嗪反应、脱Boc、N-烷基化得到通式(I)目标化合物。
其中R1，R2和n如上所定义。
本发明所述式(I)化合物的药学上可接受的盐，根据不同衍生物可以含有羧基或胺基，羧基可与碱性物质(如碱金属或碱土金属的氢氧化物、碳酸盐和碳酸氢盐)反应，它们包括，但不限于：氢氧化钠，氢氧化钾，氢氧化钙，碳酸钠等形成药学上可接受的盐，如相应的钠盐，钾盐或钙盐等等。也可采用无毒的有机碱如甲胺、三乙胺、葡甲胺等生成盐；胺基可与酸性物质(如盐酸、氢溴酸、硫酸等)反应，它们包括，但不限于：盐酸，氢溴酸，硫酸，磷酸等形成药学上可接受的盐，也可采用有机酸如乙酸、草酸、柠檬酸等生成盐。式(I)的化合物及其盐的形式具有抗肿瘤活性，
本发明所述式(I)化合物或其药学上可接受的盐，可以与一种或多种药学上可接受的载体、赋形剂或稀释剂共同制成药物组合物。该药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型。
所述固体及液体口服制剂包括：片剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖浆剂、颗粒剂、口服溶液剂。可采用乳糖或淀粉作为所述固体口服制剂的载体；使用明胶，甲基纤维素、羟丙甲纤维素、聚乙烯吡咯烷酮、淀粉浆等作为粘合剂；使用淀粉、羧甲基纤维素钠、羧甲淀粉钠、低取代羟丙甲纤维素、交联聚维酮、微晶纤维素作为崩解剂；使用滑石粉，微份硅胶，硬脂酸甘油酯，硬脂酸钙或镁等作为抗粘合剂和润滑剂。所述固体口服制剂的制备方法包括以下步骤：将活性成分与载体以及选择性地与一份崩解添加剂组成混合物，然后使该混合物与粘合剂的含水溶液，醇性或含水醇性溶液在合适的设备中 进行湿法或干法制粒，干燥颗粒，随后加入其它的崩解剂、润滑剂和抗粘剂制成适当的制剂。
所述注射剂包括：小针、冻干粉针和大输液等。所述注射剂的制备方法包括以下步骤：取注射用水，称取处方量的辅料搅拌使溶解，加入样品搅拌溶解，调pH值至适当范围，加入0.1％-0.5％的活性炭吸附一定时间后，脱碳、滤过，再分装或冻干。
本发明通过体外均相时间分辨荧光法(HTRF)试验表明：具有通式I结构的喹唑啉衍生物对EGFR(L858R/T790M)和VEGFR-2具有很强的抑制作用，同时对小鼠体内模型试验表明，此类化合物毒性较低。
具体实施方式
下面的实施例可以使本专业技术人员更全面的理解本发明，但不以任何方式限制本发明。
实施例17-(3-(1，4-二氮杂环庚烷-1-基)丙氧基)-N-(4-溴-2-氟苯基)-6-甲氧基喹唑啉-4-胺(VIII)的制备
第一步：将7-苄氧基-6-甲氧基喹唑啉-4-酮(5.0g，0.018mol)溶解在DMF(20mL)中，滴加二氯亚砜，加热回流3h。蒸除溶剂，乙酸乙酯重结晶，得到白色固体7-苄氧基-4-氯-6-甲氧基喹唑啉(4.8g，90.2％)，m.p.247℃；1H NMR(400MHz，DMSO)：δ3.84(s，3H，CH3O)，5.26(s，2H，CH2O)，7.23(s，1H，ArH)，7.41-7.55(m，7H，ArH)，7.99(s，1H，Ar).ESI-MS：m/z 301[M+H]+.
第二步：将7-苄氧基-4-氯-6-甲氧基喹唑啉(4.8g，0.016mol)和2- 氟-4-溴-苯胺(3.0g，0.016mol)溶解在异丙醇(100mL)中，加热回流2h。溶液冷却后，过滤，异丙醇和***洗，干燥得7-苄氧基-N-(2-溴-4-氟苯基)-6-甲氧基喹唑啉-4-胺(6.9g，95.8％)，m.p.231-233℃；1HNMR(400MHz，DMSO)：δ3.99(s，3H，CH3O)，5.26(s，2H，CH2O)，7.38-7.50(m，10H，ArH)，8.13(s，1H，Ar)，8.77(s，1H，Ar).ESI-MS：m/z455[M+H]+.
第三步：将7-苄氧基-N-(4-溴-2-氟苯基)-6-甲氧基喹唑啉-4-胺(6.9g，0.015mol)溶解在50mL的三氟代醋酸中，加热回流1h。冷却后，混合物倒入碎冰中，过滤，固体溶解在甲醇中，用氨水调节pH为11，浓缩后过滤，***洗，真空干燥，得到白色固体4-(4-溴-2-氟苯胺)-6-甲氧基喹唑啉-7-酚(4.9g，88.6％)，m.p.145-147℃；1H NMR(400MHz，DMSO)：δ3.94(s，3H，CH3O)，7.33-7.55(m，4H，ArH)，7.56-7.88(m，2H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar).ESI-MS：m/z 364[M+H]+.
第四步：将4-(4-溴-2-氟苯胺)-6-甲氧基喹唑啉-7-酚(4.9g，0.013mol)、3-溴1-氯丙烷(2.0g，0.013mol)、碳酸钾(3.7g，0.026mol)和100mL DMF加热到60℃反应10h。蒸干溶剂，粗品柱层析(乙酸乙酯∶石油醚＝4∶1)得到白色固体N-(4-溴-2-氟苯胺基)-7-(3-氯丙烷基)-6-甲氧基喹唑啉-4胺5.0g，收率71.0％，m.p.134-136℃；1HNMR(400MHz，DMSO)：δ1.22-1.65(m，2H，CH2)，1.98-1.2.01(m，2H，CH2)，2.38-2.55(m，2H，CH2)，3.94(s，3H，CH3O)，7.33-7.55(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar)，8.77(s，1H，Ar).ESI-MS：m/z 440[M+H]+。
第五步：将5.0g(11.36mmol)N-(4-溴-2-氟苯胺基)-7-(3-氯丙烷基)-6-甲氧基喹唑啉-4胺和2.8g(140mmol)N-BOC-高哌嗪，溶解在70mlDMA中，加碳酸钾4.7g(34.08mmol)，升温至70℃反应3h，TLC检测反应完毕，冷却至室温，将反应液倒入冰水中，有黄色固体析出，过滤，水洗滤饼，干燥，乙酸乙酯重结晶得黄色固体叔丁基-4-(3-((4-((4溴-2-氟苯基)氨基)-6-甲氧基喹唑啉-7-基)氧基)丙基)-1，4-二氮杂环庚烷-1-羧酸酯5.49g，产率80％，m.p.154-155℃；1H NMR(400MHz，DMSO)：δ1.05(s，9H，3×CH3)，1.22-1.65(m，2H，CH2)，1.98-2.01(m，2H，CH2)，2.38-2.55(m，2H，CH2)，2.71-3.42(m，10H，5×CH2)，3.94(s，3H，CH3O)，7.33-7.55(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar)，8.77(s，1H，Ar).ESI-MS：m/z 604[M+H]+。
第六步：将5.0g(8.28mmol)叔丁基-4-(3-((4-((4溴-2-氟苯基)氨基)-6-甲氧基喹唑啉-7-基)氧基)丙基)-1，4-二氮杂环庚烷-1-羧酸酯投入反应瓶中，加60ml二氯甲烷，部分溶解，搅拌下加入60ml三氟乙酸，反应液完全澄清，反应液颜色变为棕色，室温搅拌反应1h，TLC检测反应完全，减压蒸出三氟乙酸，用少量***洗2次，弃醚层，水层用2M氢氧化钠调pH到10，二氯甲烷萃取，合并有几层，无水硫酸镁干燥，过滤，减压蒸干二氯甲烷得到黄色固体，用乙酸乙酯重结晶得到黄色固体7-(3-(1，4-二氮杂环庚烷-1-基)丙氧基)-N-(4-溴-2-氟苯基)-6-甲氧基喹唑啉-4-胺(VIII)3.75g，产率90％，m.p.177-179℃； 1H NMR(400MHz，DMSO)：δ1.22-1.65(m，2H，CH2)，1.98-2.01(m，2H，CH2)，2.08-2.09(m，1H，NH)，2.38-2.55(m，2H，CH2)，2.71-3.42(m，10H， 5×CH2)，3.94(s，3H，CH3O)，7.33-7.55(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar)，8.77(s，1H，Ar).ESI-MS：m/z 504[M+H]+。
实施例2N-(4-溴-2-氟苯基)-6-甲氧基-7-(3-(4-甲基-1，4-二氮杂环庚烷-1-基)丙氧基)喹唑啉-4-胺(I-1)的制备
将1.0g(3.96mmol)7-(3-(1，4-二氮杂环庚烷-1-基)丙氧基)-N-(4-溴-2-氟苯基)-6-甲氧基喹唑啉-4-胺溶解在20ml甲酸中，室温搅拌下加入10ml37％甲醛，加毕反应液为棕色，升温到95℃反应4h，TLC检测反应完毕，减压蒸出未反应的甲酸及甲醛，加水溶解，水层用2M氢氧化钠调pH＝11，水层用乙酸乙酯萃取，合并有机层，无水硫酸镁干燥，过滤，母液直接拌样，快速制备柱分离纯化(乙酸乙酯/甲醇＝10∶1)，得到黄色固体N-(4-溴-2-氟苯基)-6-甲氧基-7-(3-(4-甲基-1，4-二氮杂环庚烷-1-基)丙氧基)喹唑啉-4-胺(I-1)1.64g，产率80％，，m.p.166-167℃；1H NMR(400MHz，DMSO)：δ1.22-1.65(m，2H，CH2)，1.98-2.01(m，2H，CH2)，2.23(S，3H，CH3N)，2.38-2.55(m，2H，CH2)，2.71-3.42(m，10H，5×CH2)，3.94(s，3H，CH3O)，7.33-7.55(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar)，8.77(s，1H，Ar).ESI-MS：m/z 518[M+H]+。
实施例3
片剂制备方法如下：
处方 用量/片
I-1 100mg
微晶纤维素 50mg
淀粉 40mg
聚维酮 8mg
羧甲基淀粉钠 10mg
硬脂酸镁 qs
工艺：将活性成分辅料分别过100目筛，称取处方量的主药和辅料(一半羧甲基淀粉钠)充分混合，加入聚乙烯吡咯烷酮水溶液适量制软材，过24目筛，制得湿颗粒于50-60℃烘箱中干燥约2-3小时，将剩余羧甲基淀粉钠和硬脂酸镁与颗粒混合均匀，整粒，测定中间体含量，用Φ8mm浅冲压片。
实施例4
注射液的制备
I-3 200mg
磷酸二氢钠 10mg
柠檬酸 30mg
注射用水 50ml
工艺：取注射用水50ml，称取处方量的柠檬酸、磷酸二氢钠搅拌使溶解，加入样品搅拌溶解，用0.1mol/L的盐酸或氢氧化钠调pH值为4.0-5.0，加入0.1％的活性炭吸附20分钟。先用0.45μm滤膜滤过，再用0.22μm精滤。按每安瓿5毫升灌装，105℃高温灭菌30分钟即得注射液。
化合物VIII和I-1的体外抗肿瘤酶活性试验及体内小鼠急毒试验
一、体外抗肿瘤酶活性试验
(一)材料及仪器：
1实验材料：Cisbio公司试剂盒HTRF KinEASE-TK kit(货号：62TKOPEB)；双蒸水
2检测仪器：SpectraMax M5：Mplecular Devices产品
(二)试验步骤：
1.溶液的配制及反应浓度
2.实验步骤：
1)计算各种试剂所需用量。
2)配制好ATP、TK Substrate-biotin的工作液。
3)按体积比例ATP∶TK Substrate-biotin∶Kinase buffer＝2∶2∶1取液混匀后，按5μL/孔取混合液至BP管中。
4)加入药物，2μL/孔。无药孔用2μL kinase buffer补齐。混匀。
5)配制好酶的工作液。
6)加入酶，3μL/孔。无酶孔用3μL kinase buffer补齐。混匀。
7)将反应液转移至384孔板中。
8)置37℃温育30min。
9)配制Streptavidin-XL665的工作液，计算用量，按体积比例Streptavidin-XL665∶TK Antibody-Cryptate＝1∶1混匀。温育结束后，按10μL/孔取混合液加至反应体系中，混匀以终止反应。
10)室温放置30min检测，于酶标仪314nm单波长激发，测定620nm和665nm发射光，试验结果见表1和表2。
抑制率(％)＝[1-(实验组665nm/620nm-空白组665nm/620nm)/(对照组665nm/620nm-空白组665nm/620nm)]×100％。Bliss法计算受试化合物IC50值。
3.结果
表1.对EGFR(L858R/T790M)和VEGFR-2的抑制率(％)
表2.对EGFR(L858R/T790M)和VEGFR-2的IC50(nM)
二、体内小鼠急毒试验
实验动物：昆明种小鼠(雌雄各半)
实验方法：
1.实验前一晚禁食12小时；
2.小鼠随机分组，雌雄各半，称量体重；
3.小鼠设置2-3个剂量组给药，药品称重，加入吐温-80研磨，1％CMC-Na溶解稀释；
4.每只小鼠0.5mL口服给药(ig)；
5.观察小鼠给药后反应；记录中毒症状、持续时间及恢复情况；如出现死亡，则记录动物死亡时间及死前症状等；
6.对死亡小鼠进行解剖检查，记录解剖结果；
7.连续观察7天，每天称量小鼠体重，记录体重变化情况；
8.求出半数致死量(LD50)或最大耐受量(MTD)。
Claims (9)
1.一种通式（Ⅰ）喹唑啉衍生物或其药学上可接受的盐：
通式（Ⅰ）
其中：
R1表示：氢，甲氧基；
R2表示：氢，甲基，乙基；
n表示：1，或2，或3，或4。
2.根据权利要求1所述的一种通式（Ⅰ）喹唑啉衍生物或其药学上可接受的盐，其特征在于R1优选自甲氧基。
3.根据权利要求1所述的一种通式（Ⅰ）喹唑啉衍生物或其药学上可接受的盐，其特征在于R2优选自氢和甲基。
4.根据权利要求1所述的一种通式（Ⅰ）喹唑啉衍生物或其药学上可接受的盐，其特征在于n优选自3。
5.根据权利要求1-4任一项所定义的通式（Ⅰ）化合物或其药学上可接受的盐，所述化合物或其药学上可接受的盐选自，
N-(4-溴-2-氟苯基)-6-甲氧基-7-(3-(4-甲基-1,4-二氮杂环庚烷-1-基)丙氧基)喹唑啉-4-胺；
7-(3-(1,4-二氮杂环庚烷-1-基)丙氧基)-N-(4-溴-2-氟苯基)-6-甲氧基喹唑啉-4-胺。
6.根据权利要求1-4任一项所述的一种通式（Ⅰ）喹唑啉衍生物或其药学上可接受的盐，其特征在于药学上可接受的盐为：式1化合物·HqX，X代表卤素，硫酸根，硝酸根，磷酸根，有机酸根，q为1，或2，或3。
7.根据权利要求1-4任一项所述的化合物作为制备抗肿瘤药物的用途。
8.一种药物组合物，含有药学有效量的权利要求1所定义的通式（Ⅰ）化合物或其药学上可接受的盐以及适当的载体或赋形剂。
9.权利要求8所述的一种药物组合物，所述的组合物包括各种固体口服制剂、液体口服制剂、注射剂。
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| WO1995019774A1 (en) * | 1994-01-25 | 1995-07-27 | Warner-Lambert Company | Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
| CN1116286C (zh) * | 1996-03-05 | 2003-07-30 | 曾尼卡有限公司 | 4－苯胺基喹唑啉衍生物 |
| WO2007068552A1 (de) * | 2005-12-12 | 2007-06-21 | Boehringer Ingelheim International Gmbh | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
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| WO1995019774A1 (en) * | 1994-01-25 | 1995-07-27 | Warner-Lambert Company | Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
| CN1116286C (zh) * | 1996-03-05 | 2003-07-30 | 曾尼卡有限公司 | 4－苯胺基喹唑啉衍生物 |
| WO2007068552A1 (de) * | 2005-12-12 | 2007-06-21 | Boehringer Ingelheim International Gmbh | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
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