CN102127087A - 喹唑啉衍生物 - Google Patents
喹唑啉衍生物 Download PDFInfo
- Publication number
- CN102127087A CN102127087A CN 201110024193 CN201110024193A CN102127087A CN 102127087 A CN102127087 A CN 102127087A CN 201110024193 CN201110024193 CN 201110024193 CN 201110024193 A CN201110024193 A CN 201110024193A CN 102127087 A CN102127087 A CN 102127087A
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- China
- Prior art keywords
- acid
- halo
- alkyl
- pharmaceutically acceptable
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 21
- -1 nitro, amino Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
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Abstract
本发明涉及通式为(Ⅰ)喹唑啉衍生物或其可药用盐，式中R、Q如正文所述；其制备方法以及含有效剂量的通式(Ⅰ)化合物或其可药用盐组合物。通式为(Ⅰ)的化合物或其药用盐可以用于治疗如癌症等细胞增生类疾病以及与激酶相关的其他病症。
Description
技术领域
本发明涉及通式为(I)的喹唑啉衍生物或其可药用盐，和其制备方法以及该化合物单独或和其他药物联合使用在治疗细胞增生类疾病中的应用。
背景技术
传统的抗肿瘤化疗药物具有选择性差，毒副作用强，易产生耐药性等缺点。随着分子生物学和肿瘤生物学的发展，人们对肿瘤的认识逐渐从细胞水平上升到亚细胞水平和分子水平。一些与肿瘤发生和生长密切相关的生物过程逐渐被人们所了解，如：细胞的信号传导，细胞周期的调节，细胞凋亡的诱导，肿瘤血管的生长等。其中细胞的信号传导备受研究者所关注。因为肿瘤从某种意义上说就是细胞信号传导发生错误和异常，从而导致细胞分化和生长的异常。蛋白酪氨酸激酶是细胞信号传导过程中最为重要的一类激酶。蛋白酪氨酸激酶通过催化ATP上的γ-磷酸转移到许多重要蛋白质的酪氨酸残基上，使其发生磷酸化从而传递细胞信号，对细胞生长、增殖、转化起到重要作用。蛋白酪氨酸激酶的异常表达往往会引起细胞生长、增殖、转化的异常从而引发肿瘤。
蛋白酪氨酸激酶包括两类：受体型蛋白酪氨酸激酶和非受体型蛋白酪氨酸激酶。目前已经被发现受体型蛋白酪氨酸激酶目前有近60个成员，非受体型蛋白酪氨酸激酶32个。这些蛋白酪氨酸激酶中已经有多个被发现与肿瘤的发生具有明确的关系，因而被研究者作为靶点进行抗肿瘤药物的开发。其中，针对作用最为明显的几种蛋白酪氨酸激酶(如表皮生长因子受体，血管内皮生长因子受体，bcr-abl融合蛋白等)已经有多个药物上市或进入临床。
1993年，针对非受体型蛋白酪氨酸激酶-bcr-abl融合蛋白，诺华公司的科学家开发第一个酪氨酸激酶抑制剂STI571。2001年，STI571被FDA批准上市，用于治疗慢性粒细胞白血病，商品名为格列卫，成为第一个先了解病因后合理设计的肿瘤治疗药物。格列卫的开发成功不仅是酪氨酸激酶抑制剂发展中的里程碑，更可以说是癌症治疗的一个里程碑。
1994年，捷利康公司的研究者在Science上发表文章报道了苯胺喹唑啉类表皮生长因子受体(EGFR)抑制剂PD153035(IC50＝29pM)，该化合物虽然最终未能上市，但却堪称蛋白酪氨酸激酶抑制剂最为成功的先导化合物之一。目前围绕苯胺喹唑啉母核的改造和修饰先后开发了多个药物上市或进入临床。如2002年，2004年Iressa和Tarceva先后上市并且取得了重大成功。2007年，第一个EGFR，HER2双重抑制剂拉帕替尼(lapatinib)被FDA批准上市，由于增加了HER2抑制活性，使该药在乳腺癌的治疗中表现出很好的效果。
除此之外，靶向VEGFR和PDGFR等多个酪氨酸激酶靶点的小分子酪氨酸激酶抑制剂索拉非尼(sorafenib，Nexavar)、舒尼替尼(sunitinib，Sutent)先后于2005年底和2006年初获得美国FDA批准用于治疗肾细胞癌，包括c-KIT等作用靶点的舒尼替尼同时被批准用于治疗恶性胃肠道间质瘤。
这些药物的成功上市和在临床的优异表现证明以酪氨酸激酶为靶点进行抗肿瘤药物的研发是21世纪最有可能获得突破性进展的抗肿瘤药物领域，具有十分广阔的前景。
发明内容：
本发明的目的在于提供一类喹唑啉衍生物或其可药用盐；本发明的另一目的在于提供一种制备喹唑啉类化合物或其可药用盐的方法：本发明的又一目的在于提供该类喹唑啉类化合物或其可药用盐单独或和其他药物联合使用在治疗细胞增生类疾病(如癌症)中的应用。
本发明的目的是由以下技术方案来达到的，本发明涉及通式为(I)的喹唑啉衍生物或其可药用盐。
式中：
m＝1或2；
Q为取代或未取代的杂芳环、取代或未取代的芳环，取代或未取代的饱和或部分饱和的杂环；
“杂芳环”指5到12个环原子的不饱和的碳环，其中一个或多个碳被杂原子例如氧、氮、硫等置换。杂芳环可以是单环，也可以是双环，即通过两个环稠合而成。具体的杂芳环可以是吡啶基，嘧啶基，吡嗪基，异恶唑基，异噻唑基、吡唑基、噻唑基、恶唑基和咪唑基等。杂芳环可以是取代的或未取代的。杂芳环的取代基选自卤素、硝基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C3-6环烷基、卤代C3-6环烷基；
“芳环”指5到12个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳环的非限制性实例有苯环、萘环和蒽环。芳环可以是取代的或未取代的。芳环的取代基选自卤素、硝基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C3-6环烷基、卤代C3-6环烷基；
“杂环”指单环或稠合环基团，在环中具有5到9个环原子，其中一个或两个环原子是选自N、O或S(O)m(其中m是0至2的整数)的杂原子，其余环原子是C。这些环可以具有一条或多条双键，但这些环不具有完全共轭的π电子系统。未取代的杂脂环基的非限制性实例有吡咯烷基、哌啶子基、哌嗪子基、吗啉代基、硫代吗啉代基、高哌嗪子基等。杂环可以是取代的或未取代的。杂环的取代基选自卤素、硝基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C3-6环烷基、卤代C3-6环烷基。
“卤素”表示氟、氯、溴或碘，优选为氟或氯。
R选自烷基，-(CH2)n-N(CH3)2，
-(CH2)n-OH
n＝2-6；
根据本发明中通式为(I)的喹唑啉衍生物或其可药用盐，Q优选为苯基，取代苯基，哌啶，四氢吡咯；苯基的取代基选自C1-6烷基、C1-6烷氧基；
根据本发明中通式为(I)的喹唑啉衍生物或其可药用盐，Q优选为
根据本发明中通式为(I)的喹唑啉衍生物或其可药用盐，其优选化合物包括：
本发明还提供本发明所述的化合物或其可药用盐在制备酪氨酸激酶抑制剂中的应用，特别是在制备治疗细胞增生疾病中的应用。所述的细胞增生疾病包括癌症。换言之，本发明提供喹唑啉类化合物或其可药用盐单独或和其他药物联合使用在治疗增生类疾病(如癌症)中的应用。能和本发明所提供的化合物或其可药用盐联合使用的抗肿瘤药包括但并非限定至少一种以下种类：有丝分裂抑制剂(如长春碱、长春地辛和长春瑞宾)；微管蛋白分解抑制剂(如泰素)；烷基化试剂(如顺铂、卡铂和环磷酰胺)；抗代谢物(如5-氟尿嘧啶、替加氟、甲氨蝶呤、阿糖胞苷和羟基脲)；可插入抗生素(如阿雷素、丝裂霉素和争光霉素)；酶(如天门冬氨酶)；拓朴异构酶抑制剂(如依托伯苷和喜树碱)；生物反应调节剂(如干扰素)。
本发明所得化合物进行了体外生化酶水平的JAK和EGFR抑制活性测试。
酶活测定1.立即将酶从-80℃移至冰上，待融化后在4℃短暂离心至管底，并迅速放回冰上；2.加10μl DTT(1.25M)到2.5ml的4×HTScan激酶缓冲液中(200mMHEPES，pH 7.5，20mM MgCl2，20mM MnCl2，12μM Na3VO4)。取0.6ml加入上述酶管，取12.5μl，并加入12.5μl不同浓度的化合物，同时设立阴性对照孔(100μM EDTA，作为酶100％抑制的本底)及阳性对照孔(灭菌水，作为酶0％抑制的最大信号)，在室温下孵育5分钟；3.加10μl mM ATP到1.25ml 6μM底物肽中，用灭菌水稀释至2.5ml，取25μl至上述体系中，37℃孵育30分钟；4.加50μl/孔终止液(50mM EDTA，pH 8)终止反应，每孔取25μl，并加入75μl ddH2O至Streptavidin包被的酶标板中，37℃孵育60分钟。洗板机350μl/孔PBS/T(1×PBS，0.05％Tween-20)洗三次；5.加100μl/孔0.5％BSA/PBS 1∶1000稀释的P-Tyr-100(Phospho-Tyrsine mAb)，37℃孵育60分钟。洗板机350μl/孔PBS/T洗三次；6.加100μl/孔0.5％BSA/PBS 1∶3000稀释的辣根过氧化物酶标记的羊抗鼠抗体，37℃孵育60分钟。洗板机350μl/孔PBS/T洗六次；7.加100μl/孔TMB，显色3-10分钟到恰当的颜色后，加50μl/孔的2M H2SO4终止反应，用Infinite M200测定A450nm。
列公式求得抑制率：
表1.本发明所述的部分化合物以及EGFR和JAK抑制活性
结论：从上表可以看出，所合成的化合物体外均具有较好的EGFR抑制活性和JAK抑制活性。
具体实施方式
为了更详细说明本发明。给出下述制备实例。但本发明的范围并非限定于此。
实施例一
化合物I的制备
4-氯-6-(4-戊烯氧基)-7-甲氧基喹唑啉
向4-氯-6-羟基-7-甲氧基喹唑啉(250mg，1.0eq)的DMSO(5mL)溶液中加入5-溴-1-戊烯(265mg，1.5eq)和Na2CO3(250mg 2.0eq)，50℃反应24小时。加入150mL水，用乙酸乙酯提取水层，乙酸乙酯层用少量水洗，无水硫酸钠干燥，浓缩后得到产物为橙色粉末(214mg)，MS：[M+H]+＝279.2。
4-[3-(烯丙氧基甲基)苯基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉
在氮气保护下，向4-氯-6-(4-戊烯氧基)-7-甲氧基喹唑啉(200mg 1.0eq)和3-(烯丙氧基甲基)苯硼酸(207mg，1.5eq)，d Cs2CO3(700mg)的二氧六环(4mL)溶液中加入Pd(dba)2(41mg，0.1eq)和2-(二环己基膦基)联苯(50mg，0.2eq)，反应液在100℃反应过夜，冷却至室温后，蒸干反应溶剂，加入20mL水，用乙酸乙酯提取水相，乙酸乙酯层用少量饱和氯化钠水溶液洗涤后加入无水硫酸钠干燥，滤除无水硫酸钠后蒸干溶剂得到粗品630mg。反应粗品硅胶柱层析(40％to 50％EA/PE)得产物为黄色油状物(158mg)，MS：[M+H]+＝391.1。
化合物I
室温条件，氮气保护下，向二代Grubbs催化剂(64mg)的二氯甲烷(700mL)溶液中加入4-[3-(烯丙氧基甲基)苯基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉的二氯甲烷(100mL)溶液，室温反应过夜，减压蒸干二氯甲烷，所得粗品柱层析得到淡橙色粉末(55mg)，MS：[M+H]+＝363.4
1H-NMR(DMSO-d6，500MHz)，δ7.41-9.13(m，7H)，5.63-5.67(m，2H)，4.59-4.61(d，2H，J＝10.6Hz)，4.11-4.18(m，3H)，4.01(s，1H)，2.10-2.17(m，2H)，1.86-1.89(m，2H)。
实施例二
化合物II的制备
4-[3-(烯丙氧基甲基)-4-甲氧基苯基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉制备方法同实施例一中4-[3-(烯丙氧基甲基)苯基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉的合成，不同之处在于将3-(烯丙氧基甲基)苯硼酸改为3-(烯丙氧基甲基)-4-甲氧基苯硼酸。
化合物II
制备方法同实施例一中化合物I的合成，不同之处在于将4-[3-(烯丙氧基甲基)苯基]-7-甲氧基-6-6-(4-戊烯氧基)喹唑啉改为4-[3-(烯丙氧基甲基)-4-甲氧基苯基]-7-甲氧基-6-6-(4-戊烯氧基)喹唑啉。MS：[M+H]+＝393.2，
1H-NMR(DMSO-d6，300MHz)，δ7.24-9.09(m，6H)，5.66-5.81(m，2H)，4.62-4.63(d，2H，J＝2.91)，3.40-4.17(m，10H，)，2.16-2.20(t，2H)，1.88-1.91(d，2H，J＝7.32)。
实施例三
4-氯-6-(4-戊烯氧基)-7-(3-乙酰氧基)丙基喹唑啉
制备方法同实施例1中4-氯-6-(4-戊烯氧基)-7-甲氧基喹唑啉的合成，不同之处在于将4-氯-6-羟基-7-甲氧基喹唑啉改为4-氯-6-羟基-7-(3-乙酰氧基)丙基喹唑啉。MS：[M+H]+＝365.1.
4-[3-(烯丙氧基甲基)苯基]-6-(4-戊烯氧基)-7-(3-乙酰氧基)丙基喹唑啉制备方法同实施例1中4-[3-(烯丙氧基甲基)苯基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉的合成，不同之处在于将4-氯-6-(4-戊烯氧基)-7-甲氧基喹唑啉改为4-氯-6-(4-戊烯氧基)-7-(3-乙酰氧基)丙基喹唑啉。
化合物III
制备方法同实施例1中化合物I的合成，不同之处在于将4-[3-(烯丙氧基甲基)苯基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉改为4-[3-(烯丙氧基甲基)苯基]-6-(4-戊烯氧基)-7-(3-乙酰氧基)丙基喹唑啉
实施例四
化合物IV
向化合物IV(250mg)的甲醇(6mL)溶液加入NH3H2O(2mL)。室温反应过夜，减压蒸除甲醇和氨水，柱层析得到产物为淡棕色固体。MS：[M+H]+＝407.1。
1H-NMR(DMSO-d6，500MHz)，δ7.24-9.10(m，7H)，5.44-5.48(m，2H)，4.59-4.61(t，1H)，4.27-4.61(m，6H)，3.58-3.61(t，2H)，3.16-3.17(d，2H)，2.38-2.39(d，2H)，2.11-2.13(t，2H)，1.94-1.99(m，2H)
实施例五
化合物V
向化合物IV(500mg)的二氯甲烷(10mL)溶液中加入三乙胺(372mg，3.0eq)和MsCl(211mg，1.5eq)，室温反应过夜，反应液先后用少量水，0.5N盐酸溶液，饱和碳酸氢钠溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥后蒸干溶剂得产物为淡棕色油状物(642mg)，MS：[M+H]+＝485.1。
实施例六
化合物VI
向化合物V(149mg)的DMF溶液(1.5mL)中加入四氢吡咯(0.552g，26eq)。50℃反应1.5小时。向反应液中加入二氯甲烷(20mL)，二氯甲烷层先后用水、饱和食盐水洗涤，二氯甲烷层干燥后蒸干溶剂，得到产物为黄色固体(52.2mg)，MS：[M+H]+＝460.2，1H-NMR(DMSO-d6，400MHz)，δ7.22-9.23(m，7H)，5.40-5.53(m，2H)，4.13-4.29(m，6H)，1.96(s，4H)，1.88-1.91(m，4H)，1.82(s，4H)，1.67(s，6H)。
实施例七
化合物VII
制备方法同实施例6中化合物6的合成，不同之处在于将四氢吡咯改为二甲胺，核磁数据：
1H-NMR(DMSO-d6，400MHz)，δ7.22-9.09(m，7H)，5.45-5.49(d，2H，J＝16)，4.10-4.30(m，6H)，2.35-2.39(m，2H)，2.10-2.14(m，10H)，1.91-1.94(m，2H)，1.81-1.82(d，2H)。
实施例八
化合物VIII
制备方法同实施例6中化合物6的合成，不同之处在于将四氢吡咯改为N-甲基哌啶，
核磁数据：
1H-NMR(DMSO-d6，400MHz)，δ7.27-9.08(m，7H)，5.43-5.49(m，2H)，4.09-4.29(m，6H)，2.36-2.52(m，10H)，2.10-2.14(m，6H)，1.92-1.95(m，3H)，1.80-1.81(d，2H)。
实施例九
化合物IX
制备方法同实施例6中化合物6的合成，不同之处在于将四氢吡咯改为吗啡啉，核磁数据：
1H-NMR(DMSO-d6，400MHz)，δ7.22-9.25(m，7H)，5.45-5.53(m，2H)，4.10-4.31(m，6H)，3.57-3.58(d，4H，J＝4)2.33-2.45(m，7H)，2.11-2.37(m，2H)，1.94-1.98(t，3H)，1.82(s，2H)。
实施例十
4-[4-(烯丙氧基亚甲基)哌啶-1-基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉
向4-氯-6-(4-戊烯氧基)-7-甲氧基喹唑啉(200mg)的二氯甲烷(6mL)溶液中加入三乙胺(108mg)和4-(烯丙氧基亚甲基)哌啶(167mg)。50℃反应3天。蒸干溶剂后柱层析得产物为淡棕色油状物(269mg).MS：[M+H]+＝398.1.
化合物X
制备方法同实施例1中化合物I的合成，不同之处在于将4-[3-(烯丙氧基甲基)苯基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉改为4-[4-(烯丙氧基亚甲基)哌啶-1-基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉。MS：[M+H]+＝370.3，
1H-NMR(DMSO-d6，500MHz)，δ7.08-8.49(m，3H)，5.58-5.82(m，2H)，4.18-4.22(t，2H)，3.89-3.97(m，7H)，2.90-2.96(t，2H)，2.17-2.18(d，4H)，1.68-1.88(m，7H)。
实施例十一
4-[3-(烯丙氧基亚甲基)哌啶-1-基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉制备方法同实施例10中4-[4-(烯丙氧基亚甲基)哌啶-1-基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉的合成，不同之处在于将4-(烯丙氧基亚甲基)哌啶改为3-(烯丙氧基亚甲基)哌啶，MS：[M+H]+＝370.3。
化合物XI
制备方法同实施例1中化合物I的合成，不同之处在于将4-[3-(烯丙氧基甲基)苯基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉改为4-[3-(烯丙氧基亚甲基)哌啶-1-基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉。MS：[M+H]+＝370.3，
1H-NMR(DMSO-d6，500MHz)，δ7.11-8.54(m，3H)，5.56-5.73(m，2H)，4.03-4.18(m，2H)，3.90-4.07(m，7H)，2.62-3.30(m，2H)，2.27-2.30(t，4H)，1.76-1.92(m，7H)。
实施例十二
4-[3-(烯丙氧基亚甲基)四氢吡咯-1-基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉制备方法同实施例10中4-[4-(烯丙氧基亚甲基)哌啶-1-基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉的合成，不同之处在于将4-(烯丙氧基亚甲基)哌啶改为3-(烯丙氧基亚甲基)四氢吡咯，MS：[M+H]+＝384.2。
化合物XII
制备方法同实施例1中化合物I的合成，不同之处在于将4-[3-(烯丙氧基甲基)苯基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉改为4-[3-(烯丙氧基亚甲基)四氢吡咯-1-基]-7-甲氧基-6-(4-戊烯氧基)喹唑啉。MS：[M+H]+＝356.3，
1H-NMR(DMSO-d6，500MHz)，δ7.09-8.52(m，3H)，5.53-5.69(m，2H)，4.01-4.16(m，2H)，3.88-4.03(m，7H)，2.59-3.27(m，2H)，2.25-2.32(d，4H)，1.76-1.90(m，5H).。
Claims (8)
1.一种通式为 (Ⅰ) 的喹唑啉类化合物或其可药用盐，
式中：
m=1或2；
Q为取代杂芳环或未取代的杂芳环、取代或未取代的芳环、取代或未取代的，饱和或部分饱和的杂环；
杂芳环的取代基选自卤素、硝基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C3-6环烷基、卤代C3-6环烷基；
芳环的取代基选自卤素、硝基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C3-6环烷基、卤代C3-6环烷基；
杂环的取代基选自卤素、硝基、氨基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C3-6环烷基、卤代C3-6环烷基；
R选自烷基，-(CH2)n-N(CH3)2，
，
，
，-(CH2)n-OH，
n = 2 – 6。
2.根据权利要求l所述的化合物或其可药用盐，其特征在于Q为苯基，取代苯基，哌啶，四氢吡咯；苯基的取代基选自C1-6烷基、C1-6烷氧基。
3.根据权利要求l或2所述的化合物或其可药用盐，其特征在于Q为下式所示。
4.根据权利要求1所述的化合物或其可药用盐，其特征在于所述化合物的盐为有机酸盐或无机酸盐，有机酸选自乙酸、三氯乙酸、二氯乙酸、丙酸、丁酸、马来酸和对甲苯磺酸；无机酸选自盐酸、硫酸、磷酸、甲磺酸。
5.根据权利要求l-3中任一项所述的化合物或其可药用盐，其特征在于所述化合物为下式所示。
6.一种含有药物有效剂量的如权利要求l-5中任何一项所述的化合物或其可药用盐和药学上可接受的载体的药物组合物。
7.如权利要求l-5所述的化合物或其可药用盐在制备治疗细胞增生疾病的药物中的应用。
8.如权利要求7所述的应用，其特征在于细胞增生疾病为癌症。
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Effective date of registration: 20230504 Address after: No. 699-18 Xuanwu Avenue, Xuanwu District, Nanjing City, Jiangsu Province Patentee after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 210046 6, F6, Jiangsu science and Technology Innovation Park, 9 Wei Di Road, Qixia, Nanjing, Jiangsu. Patentee before: NANJING NORATECH PHARMACEUTICALS Co.,Ltd. |
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