CN104341407A - 喹唑啉类化合物及其制备方法和用途 - Google Patents
喹唑啉类化合物及其制备方法和用途 Download PDFInfo
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- CN104341407A CN104341407A CN201310312161.XA CN201310312161A CN104341407A CN 104341407 A CN104341407 A CN 104341407A CN 201310312161 A CN201310312161 A CN 201310312161A CN 104341407 A CN104341407 A CN 104341407A
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- quinazoline compounds
- cancer
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- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract description 4
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- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 8
- 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract description 8
- 201000000050 myeloid neoplasm Diseases 0.000 claims abstract description 8
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 7
- 201000007270 liver cancer Diseases 0.000 claims abstract description 7
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 7
- 239000012453 solvate Substances 0.000 claims abstract description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 201000005202 lung cancer Diseases 0.000 claims abstract description 5
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 20
- 150000003246 quinazolines Chemical class 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
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Abstract
本发明提供了一种喹唑啉类化合物的制备方法和抗肿瘤用途，为具有通式I的化合物，其中R是苯环上含有不同取代基的基团。本发明具有通式I的喹唑啉类化合物及其药学上可接受的盐或溶剂合物对人肝癌细胞、人乳腺癌细胞、人肺癌细胞、人胃癌细胞、人前列腺癌细胞和人骨髓瘤细胞有抑制作用，可用于制备治疗人肝癌、人乳腺癌、人肺癌、人胃癌、人前列腺癌和人骨髓瘤的药物。
Description
技术领域
本发明涉及喹唑啉类化合物及其制备方法和抗肿瘤用途，属于医药制备技术领域。
背景技术
癌症是严重危害人类健康的疾病，全世界每年有上千万人死于癌症，传统的抗癌药物主要是细胞毒类药物，这些药物大多数是非选择性的，在杀伤癌细胞的同时，也会杀伤机体的正常细胞，具有选择性差、毒副作用强、易产生耐药性的缺点。抗癌药物的研发深受科学家们的关注，研发新型、高效和低毒的抗肿瘤药物已成当务之急。
喹唑啉类化合物广泛应用于生物医药领域，有良好的抗癌活性和高选择性(Arch.Pharm.Pharm.Med.Chem.2001，334：357)，该类化合物是一类较早的表皮生长因子受体酪氨酸激酶的抑制剂(EGFR-TKI)，一系列的报道证明了喹唑啉化合物通过与ATP的结合位点结合，高度选择性地抑制EGFR的磷酸化，从而抑制肿瘤细胞的生长。近年来上市含有喹唑啉结构单元的新药有吉非替尼(Gefitinib)、厄洛替尼和拉帕替尼(Lapatinib)等(Bioscience Biotechnology Biochemistry，2005，69：2349；W02009016072)，显示对肿瘤有良好的抑制性。
本发明通过在喹唑啉的6位上引入2-胺基苯并恶唑基团，合成了一类新型的抗肿瘤活性化合物，该类化合物能明显抑制肿瘤细胞的生长，有望成为高效和低毒的抗肿瘤药物。
发明内容
本发明目的是寻找一类新型、高效、低毒具有抗肿瘤活性的喹唑啉类化合物。
本发明的喹唑啉类化合物，为具有通式I的化合物：
通式I中，R是苯环上含有不同取代基的基团：
本发明通式I的喹唑啉类化合物及其药学上可接受的盐或溶剂合物可用于制备治疗包含但不限于人肝癌、人乳腺癌、人肺癌、人胃癌、人前列腺癌和人骨髓瘤药物的用途。
通式I的喹唑啉类化合物的制备路线如下：
以6-溴-4-氯喹唑啉为起始原料，同哌嗪环上含有不同芳香取代基的化合物2反应制得化合物3，反应溶剂包含但不限于异丙醇、乙醇、乙腈、正丁醇、二氧六环、四氢呋喃、DMF和甲苯等，用的碱包含但不限于碳酸钾、碳酸钠、氢化钠、碳酸铯、叔丁醇钾和叔丁醇钠、三乙胺、二异丙基乙胺等，反应温度在0-120℃。
化合物I合成用的偶联试剂包含但不限于2-胺基-苯并恶唑-5-硼酸、2-胺基-苯并恶唑-5-硼酸盐酸盐和2-胺基-苯并恶唑-5-硼酸酯，用的催化剂包含但不限于四三苯基磷钯、叔丁基磷钯、PdCl2(dppf)、Pd2(dba)3和醋酸钯等，用的碱包含但不限于碳酸钠、碳酸钾、碳酸氢钠等，反应溶剂包含但不限于二氧六环-水、DMF-水、乙醇-水、乙二醇二甲醚-水和甲苯-水等，反应温度在80-120℃。
具有通式I的喹唑啉类化合物可以成为药学上可接受的盐，成的盐包含但不限于盐酸盐、硫酸盐、草酸盐、乙酸盐、富马酸盐、酒石酸盐、马来酸盐、柠檬酸盐、甲磺酸盐、苯磺酸盐、乳酸盐、扁桃酸盐、琥珀酸盐、延胡索酸盐和苹果酸盐等。
具有通式I的喹唑啉类化合物可以成为药学上可接受的溶剂合物，所述溶剂合物为有机溶剂或水合物，优选醇合物或水合物。
具有通式I的喹唑啉类化合物可给药于人和动物，可以口服、直肠、肠胃外、局部给药。所述化合物可以单独给药，或者与其它药学上可接受的化合物联合给药。用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。固体剂型如片剂、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。
用于肠胃外注射的组合物包含生理上可接受的无菌水或无水溶液、分散剂、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。
用于局部给药的剂型包括软膏剂、散剂、喷射剂和吸入剂。
本发明具有如下的有益效果：
本发明制备的喹唑啉类化合物是一类新型和高效的化合物，对多种肿瘤细胞有明显的抑制作用，该类化合物选择性好，毒副作用小，有望开发成治疗肿瘤的新药。
具体实施方式
本具体实施例合成过程如下：
6-溴-4-氯喹唑啉(1)参照文献WO2008/89310合成；
1-(3-(2-(吡咯烷-1-基)乙基氨基)-4-甲基-5-(哌嗪-1-基)苯基)
丙酮(2a)参照文献BMCL2012，22，2693和CN102690270合成；
2-胺基-苯并恶唑-5-硼酸盐酸盐(4)参照文献W02010/051042合成。
实施例1：合成1-(3-(2-(吡咯烷-1-基)乙基氨基)-5-(4-(6-溴喹唑啉-4-基)哌嗪-1-基)-4-甲基苯基)丙酮(化合物3a)
6-溴-4-氯喹唑啉(100mg，0.41mmol)、化合物2a(158mg，0.46mmol)、无水碳酸钾(566mg，4.1mmol)和DMF(3mL)，室温搅拌过夜，加入水(10mL)，振摇，抽滤，水洗，干燥得淡黄色固体1-(3-(2-(吡咯烷-1-基)乙基氨基)-5-(4-(6-溴喹唑啉-4-基)哌嗪-1-基)-4-甲基苯基)丙酮(化合物3a)135mg，产率：59.7％。El-MS MS(m/z)：551.2(M+)
1H-NMR(CDCl3，400MHz)：δ8.76(s，1H)，8.09(d，1H)，7.81～7.77(m，2H)，7.16(d，1H)，7.04(d，1H)，4.45(m，1H)，3.37(m，2H)，3.29(m，4H)，3.12(q，2H)，2.81(t，2H)，2.56(m，4H)，2.21(s，3H)，1.80～1.77(m，8H)，1.21(t，3H).
实施例2：合成1-(3-(2-(吡咯烷-1-基)乙基氨基)-5-(4-(6-(2-氨基苯并恶唑-5-基)喹唑啉-4-基)哌嗪-1-基)-4-甲基苯基)丙酮(化合物I-a)
化合物3a(105mg，0.19mmol)、2-胺基-苯并恶唑-5-硼酸盐酸盐(53mg，0.25mmol)、四三苯基磷钯(18mg，0.016mmol)、碳酸钠(101mg，0.95mmol)和二氧六环-水(10mL-3mL)，氩气保护下回流3小时，冷却，抽滤，乙酸乙酯(100mL)萃取，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，浓缩至干，硅胶柱纯化(二氯甲烷∶甲醇＝15∶1洗脱)，浓缩得类白色固体1-(3-(2-(吡咯烷-1-基)乙基氨基)-5-(4-(6-(2-氨基苯并恶唑-5-基)喹唑啉-4-基)哌嗪-1-基)-4-甲基苯基)丙酮(化合物I-a)80mg，产率：69.6％。EI-MS MS(m/z)：605.3(M+)
1H-NMR(DMSO-d6，400MHz)：δ8.66(s，1H)，8.15～8.11(m，2H)，7.88(d，1H)，7.61(s，1H)，7.52(s，2H)，7.45(d，1H)，7.38(d，1H)，7.05(s，1H)，6.94(s，1H)，5.01～4.98(m，1H)，3.98(br，4H)，3.28～3.24(m，2H)，3.03～2.96(m，6H)，2.73～2.70(m，2H)，2.55～2.50(m，4H)，2.15(s，3H)，1.71(br，4H)，1.06(t，3H).
按照实施例1和实施例2的方法制备通式I的化合物I-a至I-s，结构式如表1所示。
表1
实施例3：抑制肿瘤活性评估试验
供试靶标：
人肝癌细胞株HepG2、人乳腺癌细胞株MCF-7、人肺癌细胞株A549、人胃癌细胞株SGC7901、人前列腺癌细胞PC-3、和人骨髓瘤细胞株RPMI8226。
细胞培养及药物处理：
将冻存细胞复苏后，加入适量RPMI-1640培养液(含10％胎牛血清、100U/mL青霉素、100U/mL链霉素)接种于培养瓶，放培养箱(37℃，5％CO2)中培养，每隔2～3天传代1次。将细胞接种于96孔培养板中，细胞密度为5000个/孔，加入不同浓度的化合物溶液(化合物用DMSO溶解，再用培养液稀释)，每种剂量设四个重复。
试验方法：
1.贴壁细胞采用MTT法(人肝癌细胞、人乳腺癌细胞、人肺癌细胞、人胃癌细胞、人前列腺癌细胞)：
药物处理48h后，每孔加入0.25mg/mL MTT(噻唑兰)试剂10uL，放入37℃，5％CO2培养箱中继续培养4h，吸除培养液，每孔加入100uLDMSO溶解颗粒，然后用酶标仪测570nm下的吸光度(0D)值，实验重复三次。测出抑制率，计算抑制50％细胞生长所需浓度IC50。
2.悬浮细胞采用CCK-8法(人骨髓瘤细胞)：
药物处理48h后，每孔加入CCK-8(含MTS0.19mg/ml)试剂20uL，放入37℃，5％CO2培养箱中继续培养2h，用酶标仪测450nm下的OD值，实验重复三次。测出抑制率，计算抑制50％细胞生长所需浓度IC50。
说明：IC50值越小，则化合物抑制肿瘤的效果就越好、越明显。
其中：
IC50＜1uM，以“++++”表示；
IC50＝1-10uM，以“+++”表示；
IC50＝10-50uM，以“++”表示；
IC50＞50uM，以“+”表示。
评估对照如表2：
表2(化合物与抑制肿瘤IC50活性表)
如表2所述，具有通式I的喹唑啉类化合物对人肝癌细胞、人乳腺癌细胞、人肺癌细胞、人胃癌细胞、人前列腺癌细胞和人骨髓瘤细胞有抑制作用，可用于制备治疗人肝癌、人乳腺癌、人肺癌、人胃癌、人前列腺癌和人骨髓瘤的药物。
Claims (6)
1.喹唑啉类化合物，其特征在于，为具有通式I的化合物：
其中，R是苯环上含有不同取代基的基团：
2.如权利要求1所述通式I的喹唑啉类化合物及其药学上可接受的盐或溶剂合物可用于制备治疗包含但不限于人肝癌、人乳腺癌、人肺癌、人胃癌、人前列腺癌和人骨髓瘤药物的用途。
3.具有通式I的喹唑啉类化合物的合成路线：
(a)以6-溴-4-氯喹唑啉为起始原料，同哌嗪环上含有不同苯环取代基的化合物2反应制得化合物3，反应溶剂包含但不限于异丙醇、乙醇、乙腈、正丁醇、二氧六环、四氢呋喃、DMF和甲苯等，用的碱包含但不限于碳酸钾、碳酸钠、氢化钠、碳酸铯、叔丁醇钾和叔丁醇钠、三乙胺、二异丙基乙胺等，反应温度在0-120℃。
(b)化合物I合成用的偶联试剂包含但不限于2-胺基-苯并恶唑-5-硼酸、2-胺基-苯并恶唑-5-硼酸盐酸盐和2-胺基-苯并恶唑-5-硼酸酯，用的催化剂包含但不限于四三苯基磷钯、叔丁基磷钯、PdCl2(dppf)、Pd2(dba)3和醋酸钯等，用的碱包含但不限于碳酸钠、碳酸钾、碳酸氢钠等，反应溶剂包含但不限于二氧六环-水、DMF-水、乙醇-水、乙二醇二甲醚-水和甲苯-水等，反应温度在80-120℃。
4.具有通式I的喹唑啉类化合物可以成为药学上可接受的无机盐或有机盐，包含但不限于盐酸盐、硫酸盐、草酸盐、甲酸盐、乙酸盐、富马酸盐、酒石酸盐、马来酸盐、柠檬酸盐、甲磺酸盐、苯磺酸盐、乳酸盐、扁桃酸盐、琥珀酸盐、延胡索酸盐和苹果酸盐等。
5.具有通式I的喹唑啉类化合物可以成为药学上可接受的溶剂合物，所述溶剂合物为有机溶剂或水合物，优选醇合物或水合物。
6.具有通式I的喹唑啉类化合物可给药于人和动物，可以口服、直肠、肠胃外、局部给药。所述化合物可以单独给药，或者与其它药学上可接受的化合物联合给药。用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。
用于肠胃外注射的组合物包含生理上可接受的无菌水或无水溶液、分散剂、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。
用于局部给药的剂型包括软膏剂、散剂、喷射剂和吸入剂。
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| JP2020518561A (ja) * | 2017-04-20 | 2020-06-25 | ギリアード サイエンシーズ， インコーポレイテッド | Ｐｄ−１／ｐｄ−ｌ１阻害剤 |
| US11555029B2 (en) | 2018-02-13 | 2023-01-17 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
| US12269812B2 (en) | 2018-07-13 | 2025-04-08 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
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| JP2020518561A (ja) * | 2017-04-20 | 2020-06-25 | ギリアード サイエンシーズ， インコーポレイテッド | Ｐｄ−１／ｐｄ−ｌ１阻害剤 |
| JP2022116244A (ja) * | 2017-04-20 | 2022-08-09 | ギリアード サイエンシーズ， インコーポレイテッド | Ｐｄ－１／ｐｄ－ｌ１阻害剤 |
| JP7161491B2 (ja) | 2017-04-20 | 2022-10-26 | ギリアード サイエンシーズ， インコーポレイテッド | Ｐｄ－１／ｐｄ－ｌ１阻害剤 |
| JP7512323B2 (ja) | 2017-04-20 | 2024-07-08 | ギリアード サイエンシーズ， インコーポレイテッド | Ｐｄ－１／ｐｄ－ｌ１阻害剤 |
| US11555029B2 (en) | 2018-02-13 | 2023-01-17 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
| US12338233B2 (en) | 2018-02-13 | 2025-06-24 | Gilead Sciences, Inc. | PD-1/Pd-L1 inhibitors |
| US12269812B2 (en) | 2018-07-13 | 2025-04-08 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
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