CN107245075A - 2,4,6‑三取代吡啶并[3,4‑d]嘧啶类化合物及其盐和应用 - Google Patents
2,4,6‑三取代吡啶并[3,4‑d]嘧啶类化合物及其盐和应用 Download PDFInfo
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- CN107245075A CN107245075A CN201710661158.7A CN201710661158A CN107245075A CN 107245075 A CN107245075 A CN 107245075A CN 201710661158 A CN201710661158 A CN 201710661158A CN 107245075 A CN107245075 A CN 107245075A
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- pyrimidines
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- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 24
- 150000003222 pyridines Chemical class 0.000 title claims abstract description 17
- 150000003839 salts Chemical class 0.000 title claims abstract description 12
- 150000001875 compounds Chemical group 0.000 claims abstract description 33
- 230000035772 mutation Effects 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims description 69
- -1 substituted-amino Chemical group 0.000 claims description 43
- 238000006467 substitution reaction Methods 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002246 antineoplastic agent Substances 0.000 claims description 10
- 229940041181 antineoplastic drug Drugs 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
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- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 2
- 229950005953 camsilate Drugs 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 229940050410 gluconate Drugs 0.000 claims description 2
- 229930195712 glutamate Natural products 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 claims 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims 1
- 229940001468 citrate Drugs 0.000 claims 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims 1
- RIKMMFOAQPJVMX-UHFFFAOYSA-N fomepizole Chemical compound CC=1C=NNC=1 RIKMMFOAQPJVMX-UHFFFAOYSA-N 0.000 claims 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims 1
- 125000002757 morpholinyl group Chemical group 0.000 claims 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
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- 239000003814 drug Substances 0.000 abstract description 17
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 60
- 239000000843 powder Substances 0.000 description 57
- 238000000034 method Methods 0.000 description 54
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- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 16
- 229940125851 compound 27 Drugs 0.000 description 16
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- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 6
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Abstract
本发明提供了2,4,6‑三取代吡啶并[3,4‑d]嘧啶类化合物及其盐和应用,属于抗癌药物技术领域。该类化合物结构新颖,易于合成,具有抑制表皮生长因子受体(EGFR)酪氨酸激酶的活性,对于单突变(L858R)和双突变(L858R/T790M)的EGFR均有明显的抑制活性,具有明显的体内、外抗肿瘤活性,可用于与EGFR突变相关的癌症的治疗,而且其合成原料易得、合成方法容易实现。
Description
技术领域
本发明属于抗癌药物技术领域,具体涉及2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物及其盐类化合物、制备方法和应用。
背景技术
癌症是严重威胁人类健康的恶性疾病之一。近30年来,我国癌症发生率正处于快速上升期,癌症发病率约为200/10万人,每年新发病例达320万例以上,死亡约270多万,在治患者700万人以上。
目前癌症的主要治疗手段仍然是手术治疗、放射治疗及药物治疗,但在很大程度上仍是以药物治疗为主。因此,研究开发新的抗癌药物具有重要意义。
传统的抗肿瘤药物活性强,但缺乏选择性,毒性大。近年来,随着肿瘤分子生物学研究的进展,对肿瘤发病机理有了更多的认识,找到了许多抗癌药物作用的新靶点,如表皮生长因子(EGFR)酪氨酸激酶、PI3Ks,BTK等。
在多数肿瘤细胞中,一些激酶呈现高表达或过度激活。针对这一特点,已经开发了吉非替尼、伊马替尼、埃罗替尼、埃克替尼、索拉非尼、舒尼替尼和拉帕替尼等激酶抑制剂,用作抗癌药物。但是,吉非替尼等药物应用于临床后发现其有效率并不高,有些患者使用后产生获得性耐药。因此,研发新的高效低毒的抗癌药物具有重要意义。
发明内容
本发明的目的在于提供2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物及其盐和应用。该类化合物结构新颖,具有显著的抑制EGFR酪氨酸激酶的活性,具有明显的体内、外抗肿瘤活性,可应用于抗癌药物制剂的制备,而且其合成原料易得、合成方法容易实现。
本发明是通过以下技术方案来实现:
一种2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物,该化合物的结构式为:
式中,R1为取代氨基;
R2为芳基、取代的芳基、芳杂环基、取代的芳杂环基、环烷基、饱和杂环基或取代的甲基,其中,取代的甲基中的取代基为芳基、取代的芳基、芳杂环基、取代的芳杂环基、环烷基或饱和杂环基;
R3为取代氨基;
X为NH或O。
优选地,所述R1为二甲基氨基、二乙基氨基、1-吡咯烷基、1-哌啶基、4-吗啉基、丙烯酰氨基取代的-1-吡咯烷基、丙烯酰氨基取代的-1-哌啶基、1-丙烯酰基取代的吡咯烷基氨基或者丙烯酰基取代的哌啶基氨基。
优选地,所述R2中,芳基为苯基;取代的芳基为氟和/或氯取代的苯基、三氟甲基取代的苯基或者甲氧基取代的苯基;杂芳基为吡唑基、咪唑基或吡啶基;取代的杂芳基为1-烷基取代的吡唑基或取代的吡啶;环烷基为环己基或环戊基;饱和杂环基为四氢吡喃基、吗啉基或四氢呋喃基。
优选地,所述R2为苯基、3-氟苯基、4-氟苯基、3-氯-4-氟苯基、3,4-二氟苯基、3-三氟甲基苯基、2-吡啶基、3-吡啶基、苄基、吡啶-2-基甲基、吡啶-3-基甲基、吡啶-4-基甲基、4-四氢吡喃基、四氢吡喃-4-基甲基、环己基甲基、4-甲氧基苄基、4-氟基苄基或N-甲基-吡唑-4基。
优选地,所述R3为4-甲基-1-哌嗪基、4-乙基-1-哌嗪基、N-甲基-N-(2-二甲氨基乙基)氨基、4-二甲氨基-1-哌啶基或丙烯酰氨基。
优选地,所述化合物为如下化合物中的一种:
2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物的合成方法,包括以下步骤:
步骤一:在叔胺存在下,2,4,6-三氯吡啶并[3,4-d]嘧啶与R1-H在溶剂中搅拌得到4-取代-2,6-二氯吡啶并[3,4-d]嘧啶,即中间体a;
步骤二:在酸催化下,中间体a与芳胺或取代的芳胺反应;或者,在碱存在下,中间体a与R2-OH、环烷基取代的胺、饱和杂环基取代的胺或取代的甲基取代的胺反应;或者,中间体a与杂芳基胺或取代的杂芳基胺通过Buchwald反应;反应完成后分离获得中间体b或c;
步骤三:在钯催化剂、有机膦配体和碱存在下,中间体b或c与2-氨基吡啶类化合物反应,可生成2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物P。
合成路线如下:
优选地,所述的叔胺为三乙胺、二异丙基乙胺、DBU或吡啶;所述的钯催化剂为醋酸钯或三(二亚苄基丙酮)二钯;所述的有机膦配体为2-二环己基磷-2,4,6-三异丙基联苯、4,5-双二苯基膦-9,9-二甲基氧杂蒽或1,1'-联萘-2,2'-双二苯膦;所述的碱为碳酸钾、碳酸铯或氢化钠。
所述的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物的可药用盐,所述可药用盐为包括盐酸盐、氢溴酸盐、硝酸盐、磷酸盐、硫酸盐、醋酸盐、富马酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、马来酸盐、乳酸盐、枸橼酸盐、樟脑磺酸盐、苯甲酸盐、葡糖酸盐、谷氨酸盐、羟乙磺酸盐、琥珀酸盐或甲磺酸盐。
2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物或其可药用盐在制备抗癌药物制剂中的应用。
优选地,所述抗癌药物制剂是能够抑制双突变或三突变的EGFR的药物制剂。更进一步地,三突变的EGFR是L858R/T790M/C797S的EGFR;双突变的EGFR是L858R/T790M的EGFR。
优选地,所述抗癌药物制剂为片剂、胶囊剂或注射剂,其中每片、每粒或每支制剂中含50~500mg的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物或其可药用盐。
优选地,所述抗癌药物制剂还包括辅料,辅料包括稳定剂、增溶剂、润滑剂和崩解剂中的一种或几种。进一步优选地,辅料包括淀粉、糊精、葡萄糖、乳糖、纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮、果胶、环糊精、土温-80、聚乙烯醇、硬脂酸镁和滑石粉中的一种或多种。
与现有技术相比,本发明具有以下有益的技术效果:
本发明将吡啶并[3,4-d]嘧啶作为药物骨架,提供的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物或其盐类化合物结构新颖、易于合成。
本发明提供的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物或其盐类化合物具有抑制表皮生长因子受体(EGFR)酪氨酸激酶的活性,对于单突变(L858R)、双突变(L858R/T790M)和三突变(L858R/T790M/C797S)的EGFR均有明显的抑制活性,可用于与EGFR突变相关的癌症的治疗。
本发明提供的化合物具有抑制人肺癌细胞A549、HCC827、H1975等肿瘤细胞增殖的活性,比如化合物44对A549、HCC827和H1975的IC50分别为0.95μmol·L-1、0.008μmol·L-1和0.49μmol·L-1。而在同样条件下,阳性药奥希替尼(AZD9291)对A549、HCC827和H1975的IC50值分别为11.5、0.025和0.35μmol·L-1。
本发明提供的化合物具有显著的体内抗肿瘤活性。
本发明提供的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物及其盐类化合物,能够应用于制备抗癌药物制剂,其中每片或粒或支该药物制剂中含有50~500mg。在利用本发明给出的活性化合物制备抗癌药物制剂时,可以将该药物制成片剂、胶囊剂或注射剂。这些药物制剂可按照各种制剂的常规制备工艺制成。对于片剂或胶囊剂,优选的含量为50~300mg。并且本发明涉及的口服制剂中可含有药用辅料,包括添加剂、稳定剂、增溶剂、润滑剂、崩解剂等,如淀粉、糊精、葡萄糖、乳糖、纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮、果胶、环糊精、土温-80、聚乙烯醇、硬脂酸镁、滑石粉等。
具体实施方式
下面结合具体的实施例对本发明做进一步的详细说明,所述是对本发明的解释而不是限定。
本申请文件中,展示了本发明所合成的化合物中的部分代表性化合物及其制备方法。具体代表化合物的编号、结构和表征列举在表1中,其制备方法在具体实施例中进行展示。
表1:代表化合物的编号、结构和表征
实施例1:2-苯氨基-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物1)
步骤一:2,6-二氯-4-吡咯烷基吡啶并[3,4-d]嘧啶(中间体a1)的合成
向250mL茄型瓶中加入2,4,6-三氯吡啶并[3,4-d]嘧啶(2.50g,10.66mmol),将其用四氢呋喃溶解后,加入DIPEA(2.8mL,15.99mmol),磁力搅拌下滴加四氢吡咯(1.0mL,11.73mmol),滴加过程中不断有黄色固体析出,滴毕,室温搅拌4h,旋转蒸发蒸除溶剂,残余物用水悬浮,有大量黄色固体析出,抽滤,滤饼水洗,干燥得中间体a1,淡黄色固体粉末,2.61g,收率91.0%。1H NMR(400Mz,CDCl3)δ8.98(s,1H,Ar-H),7.94(s,1H,Ar-H),3.98(s,4H,NCH2),2.13(s,4H,CH2)。
步骤二:2-苯氨基-4-吡咯烷基吡啶并[3,4-d]嘧啶(中间体b1)的合成
向100mL茄型瓶中加入2,6-二氯-4-吡咯烷基吡啶并[3,4-d]嘧啶(中间体a1)(1.00g,3.72mmol),对甲苯磺酸(0.77g,4.48mmol)和仲丁醇(30mL),磁力搅拌下加入苯胺(0.370mL,4.08mmol),氩气保护下回流4h,回流过程中不断有黄色固体析出,旋转蒸发蒸除溶剂,残余物用碳酸氢钠水溶液悬浮,有大量固体析出,超声均匀后抽滤,水洗滤饼,干燥得中间体b1,淡黄色固体粉末,1.20g,收率99.2%。1H NMR(400Mz,CDCl3)δ8.75(s,1H,Ar-H),7.80(s,1H,Ar-H),7.70(d,J=7.7Hz,2H,Ar-H),7.34(t,J=8.0Hz,2H,Ar-H),7.16(s,1H,NH),7.04(t,J=7.4Hz,1H,Ar-H),3.91(s,4H,NCH2),2.09(t,J=6.5Hz,4H,CH2)。
步骤三:2-苯氨基-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物1)的合成
向50mL茄型瓶中加入2-苯氨基-4-吡咯烷基吡啶并[3,4-d]嘧啶(中间体b1)(50mg,0.15mmol),2-氨基-5-(4-甲基-1-哌嗪基)吡啶(38mg,0.20mmol),Pd(OAc)2(4mg,0.015mmol),X-phos(14mg,0.030mmol),Cs2CO3(122mg,0.38mmol)和1,4-二氧六环(10mL),混合物于氩气保护下回流3h,旋转蒸发蒸除溶剂,残余物经硅胶柱色谱分离,得化合物1,黄色固体粉末,36mg,收率48.6%。
实施例2:2-(3-氟苯氨基)-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物2)
方法同化合物1的制备,黄色固体粉末。
实施例3:2-(3-氯-4-氟苯氨基)-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物3)
方法同化合物1的制备,黄色固体粉末。
实施例4:2-(N-甲基-4-吡唑胺基)-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物4)
方法同化合物1的制备,黄色固体粉末。
实施例5:2-苯氨基-4-吡咯烷基-6-(4-(N-甲基-N-二甲氨基乙基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物5)
方法同化合物1的制备,黄色固体粉末。
实施例6:2-苯氨基-4-吡咯烷基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物6)
方法同化合物1的制备,黄色固体粉末。
实施例7:2-苯氨基-4-二甲胺基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物7)
方法同化合物1的制备,黄色固体粉末,收率65.8%。
实施例8:2-(3-三氟甲基苯氨基)-4-吡咯烷基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物8)
方法同化合物1的制备,黄色固体粉末。
实施例9:2-(3-氯-4-氟苯氨基)-4-吡咯烷基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物9)
方法同化合物1的制备,黄色固体粉末,收率11.0%。
实施例10:2-苯氨基-4-哌啶基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物10)
方法同化合物1的制备,黄色固体粉末,收率52.1%。
实施例11:2-苯氨基-4-吗啉基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物11)
方法同化合物1的制备,黄色固体粉末。
实施例12:2-苯氨基-4-哌啶基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物12)
方法同化合物1的制备,黄色固体粉末。
实施例13:2-苯氨基-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物13)
方法同化合物1的制备,黄色固体粉末。
实施例14:2-(3-三氟甲基苯氨基)-4-吗啉基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物14)
方法同化合物1的制备,黄色固体粉末。
实施例15:2-(3-三氟甲基苯氨基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物15)
方法同化合物1的制备,黄色固体粉末。
实施例16:2-(3-氯-4-氟苯氨基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物16)
方法同化合物1的制备,黄色固体粉末。
实施例17:2-(3,4-二氟苯氨基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物17)
方法同化合物1的制备,黄色固体粉末。
实施例18:2-(4-氟苯氨基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物18)
方法同化合物1的制备,黄色固体粉末。
实施例19:2-(3-吡啶氨基)-4-吗啉基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物19)
2-(3-吡啶氨基)-4-吗啉基吡啶并[3,4-d]嘧啶(中间体b2)的合成
向50mL茄型瓶中加入4-吗啉基吡啶并[3,4-d]嘧啶(500mg,1.75mmol),3-氨基吡啶(150mg,1.58mmol),Pd(OAc)2(40mg,0.18mmol),Xant-phos(314mg,0.53mmol),Cs2CO3(1.42g,4.38mmol)和乙二醇二甲醚(30mL),混合物于氩气保护下回流2.5h,旋转蒸发蒸除溶剂,残余物经硅胶柱色谱分离,得化合物中间体b2,淡黄色固体粉末,202mg,收率37.4%。1H NMR(400MHz,CDCl3)δ8.92(s,1H,Ar-H),8.62(d,J=8.5Hz,1H,Ar-H),8.30(dd,J=4.9,1.0Hz,1H,Ar-H),8.05(bs,1H,NH),7.79–7.71(m,1H,Ar-H),7.56(s,1H),7.02–6.94(m,1H,Ar-H),3.91–3.87(m,4H,OCH2),3.84–3.80(m,4H,NCH2)。
参考化合物1的制备步骤中的步骤三,用中间体b2替换中间体b1,制得化合物19,黄色固体粉末,收率31.4%。
实施例20:2-(3-吡啶氨基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物20)
方法同化合物19的制备,黄色固体粉末。
实施例21:2-(2-吡啶氨基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物21)
方法同化合物19的制备,黄色固体粉末。
实施例22:2-苄氨基-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物22)
2-苄氨基-4-吗啉基吡啶并[3,4-d]嘧啶(中间体b3)的合成
向100mL茄型瓶中加入2,6-二氯-4-吗啉基吡啶并[3,4-d]嘧啶(100mg,0.35mmol),苄胺(41μL,0.39mmol),碳酸钾(121mg,0.88mmol),二甲基亚砜,催化量的碘化钾和四丁基碘化铵,混合物于120℃油浴中搅拌3h,将反应混合物倒入水中,用乙酸乙酯(30mL×2)萃取,合并乙酸乙酯相,依次用水(30mL×3)和饱和食盐水(30mL×2)洗涤,无水硫酸钠干燥,减压除去乙酸乙酯,残留物经硅胶柱色谱分离,得黄色油状物,乙醇重结晶得中间体b3,黄色固体粉末,70mg,收率56.0%。1H NMR(400MHz,CDCl3)δ8.75(s,1H,Ar-H),7.47(s,1H,Ar-H),7.38–7.27(m,5H,Ar-H),5.40(bs,1H,NH),4.69(d,J=5.6Hz,2H,NHCH 2),3.85–3.69(m,8H,OCH2+NCH2)。
参考化合物1的制备步骤中的步骤三,用中间体b3替换中间体b1,制得化合物22,黄色固体粉末,收率43.0%。
实施例23:2-(2-吡啶基甲氨基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物23)
方法同化合物22的制备,黄色固体粉末。
实施例24:2-(3-吡啶基甲氨基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物24)
方法同化合物22的制备,黄色固体粉末。
实施例25:2-苯氨基-4-吗啉基-6-(1-甲基-4-吡唑氨基)吡啶并[3,4-d]嘧啶(化合物25)
方法同化合物1的制备,黄色固体粉末。
实施例26:2-(3-吡啶氧基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物26)
2-(3-吡啶基氧基)-4-吗啉基吡啶并[3,4-d]嘧啶(中间体c1)的合成
向100mL圆底烧瓶中加入2,6-二氯-4-吗啉基吡啶并[3,4-d]嘧啶(200mg,0.70mmol),3-羟基吡啶(67mg,0.70mmol),碳酸钾(100mg,1.76mmol)和DMF(10mL)。混合物于60℃油浴中搅拌5h,旋转蒸发除去DMF,残余物经硅胶柱色谱分离得中间体c1,淡黄色固体粉末,125mg,收率51.9%。1H NMR(400MHz,CDCl3)δ8.86(s,1H,Ar-H),8.60(d,J=2.4Hz,1H,Ar-H),8.52(d,J=4.3Hz,1H,Ar-H),7.65(s,1H,Ar-H),7.62(ddd,J=8.3,2.6,1.4Hz,1H,Ar-H),7.40(dd,J=8.3,4.8Hz,1H,Ar-H),3.93–3.89(m,4H,OCH2),3.88–3.83(m,4H,NCH2)。
2-(3-吡啶氧基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物26)的合成。
参考化合物1的制备步骤中的步骤三,用中间体c1替换中间体b1,制得化合物26,黄色固体粉末,收率73.9%。
实施例27:2-(4-四氢吡喃氧基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物27)
2-(4-四氢吡喃氧基)-4-吗啉基-吡啶并[3,4-d]嘧啶(中间体c2)的合成
将4-羟基四氢吡喃(72mg,0.77mmol)和四氢呋喃(10mL)加入圆底烧瓶中,搅拌下分批加入氢化钠(56mg,60%,1.40mmol),混合物在氩气保护下于室温搅拌30min,加入4-吗啉基2,6-二氯吡啶并[3,4-d]嘧啶(200mg,0.70mmol),室温搅拌过夜,旋转蒸发除去四氢呋喃,残余物经硅胶柱色谱分离得中间体c2,黄色固体粉末,171mg,收率69.5%。1H NMR(400MHz,CDCl3)δ8.90(s,1H,Ar-H),7.60(s,1H,Ar-H),5.40–5.27(m,1H,OCH),4.14–4.02(m,2H,OCH2),3.97–3.85(m,8H,OCH2+NCH2),3.71–3.59(m,2H,OCH2),2.20–2.09(m,2H,CH2),1.99–1.89(m,2H,CH2)。
参考化合物1的制备步骤中的步骤三,用中间体c2替换中间体b1,制得化合物27,黄色固体粉末。
实施例28:2-(四氢吡喃-4-甲氧基)-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物28)
方法同化合物27的制备,黄色固体粉末。
实施例29:2-(四氢吡喃-4-氧基)-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物29)
方法同化合物27的制备,黄色固体粉末。
实施例30:2-环己基甲氧基-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物30)
方法同化合物27的制备,黄色固体粉末。
实施例31:2-苄氧基-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物31)
方法同化合物27的制备,黄色固体粉末。
实施例32:2-(3-吡啶甲氧基)-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物32)
方法同化合物27的制备,黄色固体粉末。
实施例33:2-(4-吡啶甲氧基)-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物33)
方法同化合物27的制备,黄色固体粉末。
实施例34:2-(4-甲氧基苄氧基)-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物34)
方法同化合物27的制备,黄色固体粉末。
实施例35:2-(4-氟苄氧基)-4-吡咯烷基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物35)
方法同化合物27的制备,黄色固体粉末。
实施例36:2-(4-氟苄氧基)-4-吡咯烷基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物36)
方法同化合物27的制备,黄色固体粉末。
实施例37:2-(4-氟苄氧基)-4-二甲氨基-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物37)
方法同化合物27的制备,黄色固体粉末。
实施例38:(S)-2-苯氨基-4-(3-丙烯酰氨基-1-吡咯烷基)-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物38)
方法同化合物1的制备,黄色固体粉末。
实施例39:(R)-2-苯氨基-4-(3-丙烯酰氨基-1-吡咯烷基)-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物39)
方法同化合物1的制备,黄色固体粉末。
实施例40:(S)-2-苯氨基-4-(3-丙烯酰氨基-1-哌啶基)-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物40)
方法同化合物1的制备,黄色固体粉末。
实施例41:(R)-2-苯氨基-4-(3-丙烯酰氨基-1-哌啶基)-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物41)
方法同化合物1的制备,黄色固体粉末。
实施例42:(S)-2-苯氨基-4-(1-丙烯酰基-3-吡咯烷基氨基)-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物42)
方法同化合物1的制备,黄色固体粉末。
实施例43:(R)-2-苯氨基-4-(1-丙烯酰基-3-吡咯烷基氨基)-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物43)
方法同化合物1的制备,黄色固体粉末。
实施例44:(S)-2-苯氨基-4-(1-丙烯酰基-3-哌啶基氨基)-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物44)
方法同化合物1的制备,黄色固体粉末。
实施例45:(R)-2-苯氨基-4-(1-丙烯酰基-3-哌啶基氨基)-6-(5-(4-甲基-1-哌嗪基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物45)
方法同化合物1的制备,黄色固体粉末。
实施例46:2-苯氨基-4-(1-吡咯烷基)-6-(6-丙烯酰氨基-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物46)
方法同化合物1的制备,黄色固体粉末。
实施例47:2-(3-氟苯氨基)-4-(1-吡咯烷基)-6-(6-丙烯酰氨基-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物47)
方法同化合物1的制备,黄色固体粉末。
实施例48:2-苄氧基-4-(1-吡咯烷基)-6-(6-丙烯酰氨基-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物48)
方法同化合物27的制备,黄色固体粉末。
实施例49:2-(4-氟苄氧基)-4-(1-吡咯烷基)-6-(6-丙烯酰氨基-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物49)
方法同化合物27的制备,黄色固体粉末。收率35.0%。
实施例50:2-(4-(四氢吡喃)甲氧基)-4-(1-吡咯烷基)-6-(6-丙烯酰氨基-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物50)
方法同化合物27的制备,黄色固体粉末。收率27.6%。
实施例51:2-(4-(四氢吡喃)氧基)-4-(1-吡咯烷基)-6-(6-丙烯酰氨基-2-吡啶基)氨基吡啶并[3,4-d]嘧啶(化合物51)
方法同化合物27的制备,黄色固体粉末。
实施例52:2-苯氨基-4-吗啉基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶盐酸盐(化合物52)
将化合物13溶解于四氢呋喃,加入1.2倍摩尔量的浓盐酸,密封,混合物于室温度搅拌过夜,抽滤,干燥得化合物52。EI-MS:526.5(M+H+)。
实施例53:2-(3-三氟甲基苯氨基)-4-吡咯烷基-6-(5-(4-二甲氨基-1-哌啶基)-2-吡啶基)氨基吡啶并[3,4-d]嘧啶甲磺酸盐(化合物53)
方法同化合物52的制备。
实施例54:抑制EGFR-酪氨酸激酶活性的测定
方法:将待测定化合物分别用DMSO溶解配制成10mmol/L的母液,逐级稀释,得到浓度为1μmol/L的溶液,并将5μL待测定的不同药物或DMSO分别加入酶反应体系中。酶反应体系的组成为:40mmol/L Tris,pH 7.4,10mmol/L MgCl2,0.1mg/mL BSA,1mmol/L DTT,10μmol/L ATP,EGFR(L858R)或EGFR(L858R/T790M)25mg/L,底物为0.2mg/mL Poly(Glu,Tyr),反应体系的终体积为50μL,而药物的终浓度为100nmol/L。反应体系置于30℃反应40min后,加入终止液终止反应,并用荧光素酶的方法检测体系内的ATP含量,在MD-SpectraMax M5多功能酶标仪上检测化学发光信号,化学发光信号的强度与反应体系的酶的活性成反比。将检测到的化学发光信号值代入公式:
抑制率=[1-((Lu酶-Lu本底)/Lu药物-Lu本底)]×100%
式中:Lu药物表示给药组,Lu本底表示空白组(不加酶不加药),Lu酶表示溶剂对照组。
实验测定的结果展示在表2中。
表2.部分化合物在浓度为100nmol/L时对酶活性的抑制率(%)
“-”表示未测定。
实施例55:体外抗癌活性的验证
为了验证本发明合成的及其盐类化合物的抗癌活性,以AZD9291为阳性对照药物,采用体外MTT法测定了化合物1-53对人肺癌细胞HCC827、H1975生长抑制作用。
验证方法:将肿瘤细胞HCC827培养在含10%小牛血清的RPMI1640培养基中,内含青霉素有100U·mL-1,链霉素100μg·mL-1,于37℃、5%CO2培养箱中传代培养。取0.25%胰酶消化贴壁的肿瘤细胞,用含10%小牛血清的RPMI1640培养液配制细胞悬液,浓度为6×103个细胞/毫升。于96孔培养板内每孔接种200μL(约含1000个肿瘤细胞),37℃培养24h。给药组加入不同浓度药物,每药设定10、3.33、1.0、0.33和0.10μmol·L-1 5个浓度梯度,每组设3个平行孔。对照组加入与药等体积的溶剂,置于37℃、5%CO2培养箱中培养72h后弃去培养液,每孔加入20μL5mg·mL-1的MTT溶液,孵育4h后,弃去上清液,每孔加入DMSO 150μL,轻度振荡后用酶标仪在570nm下测定光密度值(OD)。
结果计算:
以溶剂对照处理的肿瘤细胞为对照组,按照下式求药物对肿瘤细胞的抑制率:
并进一步采用线性回归法求出半数抑制浓度(IC50)。
测定结果显示,化合物1-53对HCC827的IC50为0.008-5.17μmol·L-1;对H1975的IC50为0.44-5.63μmol·L-1;对A549的IC50值为0.16-8.39μmol·L-1。阳性药奥希替尼(AZD9291)对HCC827、H1975和A549的IC50值分别为0.025、0.35和11.5μmol·L-1。
实施例56:体内抗癌活性的验证
为了验证本发明提供化合物的体内抗癌活性,我们采用小鼠S180移植瘤模型,灌胃给药,考察了化合物53的体内抗癌活性。
验证方法:昆明种小鼠,雄性,体重20-23g。取出小鼠腹腔接种S180后第8天的腹水,用生理盐水以1:1比例稀释,制成S180细胞混悬液。用注射器在每只小鼠右腋窝皮下接种0.1mL。接种次日,将小鼠随机分为3组,每组8只,分别为:
1)空白对照组(NMP/PEG400/H2O)
2)化合物53低剂量组(5.0mg·kg-1)
3)化合物53高剂量组(15.0mg·kg-1)
将化合物53用NMP/PEG400/H2O(体积比为1:5:4)溶解。接种后第二天开始按上述给药方案灌胃给药,一日一次,连续给药8天。给药当日记为d1,给药体积为10mL·kg-1体重。每日给药前记录小鼠体重。停药次日(d9)将小鼠处死,剥离出瘤块,剔除其他组织后称重。
结果:化合物53在剂量为5.0mg·kg-1和15.0mg·kg-1时,对小鼠体内S180移植瘤的生长抑制率分别为52.5%和80.3%。
结论:本发明提供的化合物53具有明显的体内抗癌活性。
实施例57:急性毒性试验
化合物53用NMP、PEG400和水溶解,以不同的剂量,给昆明种小鼠一次性灌胃给药,观察7天。结果表明:本发明中编号53的化合物给药剂量为300mg·kg-1时,小鼠活动正常。试验结果表明本发明提供的化合物毒性很小。
Claims (10)
1.一种2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物,其特征在于,该化合物的结构式为:
式中,R1为取代氨基;
R2为芳基、取代的芳基、芳杂环基、取代的芳杂环基、环烷基、饱和杂环基或取代的甲基,其中,取代的甲基中的取代基为芳基、取代的芳基、芳杂环基、取代的芳杂环基、环烷基或饱和杂环基;
R3为取代氨基;
X为NH或O。
2.如权利要求1所述的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物,其特征在于,所述的R1为二甲基氨基、二乙基氨基、1-吡咯烷基、1-哌啶基、4-吗啉基、丙烯酰氨基取代的-1-吡咯烷基、丙烯酰氨基取代的-1-哌啶基、1-丙烯酰基取代的吡咯烷基氨基或者丙烯酰基取代的哌啶基氨基。
3.如权利要求1所述的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物,其特征在于,所述R2中,芳基为苯基;取代的芳基为氟和/或氯取代的苯基、三氟甲基取代的苯基或者甲氧基取代的苯基;杂芳基为吡唑基、咪唑基或吡啶基;取代的杂芳基为1-烷基取代的吡唑基或取代的吡啶;环烷基为环己基或环戊基;饱和杂环基为四氢吡喃基、吗啉基或四氢呋喃基。
4.如权利要求3所述的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物,其特征在于,所述R2为苯基、3-氟苯基、4-氟苯基、3-氯-4-氟苯基、3,4-二氟苯基、3-三氟甲基苯基、2-吡啶基、3-吡啶基、苄基、吡啶-2-基甲基、吡啶-3-基甲基、吡啶-4-基甲基、4-四氢吡喃基、四氢吡喃-4-基甲基、环己基甲基、4-甲氧基苄基、4-氟基苄基或N-甲基-吡唑-4-基。
5.如权利要求1所述的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物,其特征在于,所述R3为4-甲基-1-哌嗪基、4-乙基-1-哌嗪基、N-甲基-N-(2-二甲氨基乙基)氨基、4-二甲氨基-1-哌啶基或丙烯酰氨基。
6.如权利要求1所述的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物,其特征在于,所述化合物为如下化合物中的一种:
7.权利要求1~6任一项所述的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物的可药用盐,其特征在于,所述可药用盐包括盐酸盐、氢溴酸盐、硝酸盐、磷酸盐、硫酸盐、醋酸盐、富马酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、马来酸盐、乳酸盐、枸橼酸盐、樟脑磺酸盐、苯甲酸盐、葡糖酸盐、谷氨酸盐、羟乙磺酸盐、琥珀酸盐或甲磺酸盐。
8.权利要求1~6任一项所述的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物或权利要求7所述的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物的可药用盐在制备抗癌药物制剂中的应用。
9.如权利要求8所述的应用,其特征在于,所述抗癌药物制剂是能够抑制双突变或三突变的EGFR的药物制剂。
10.如权利要求8所述的应用,其特征在于,所述抗癌药物制剂为片剂、胶囊剂或注射剂,其中每片、每粒或每支制剂中含50~500mg的2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物或其可药用盐。
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CN107744520A (zh) * | 2017-10-25 | 2018-03-02 | 南京多宝生物科技有限公司 | 嘧啶类化合物在制备促进小肠蠕动药物中的应用 |
CN107892691A (zh) * | 2017-12-19 | 2018-04-10 | 西安交通大学 | 2,8,9‑三取代‑9h‑嘌呤类化合物及其盐和应用 |
CN107892691B (zh) * | 2017-12-19 | 2020-04-28 | 西安交通大学 | 2,8,9-三取代-9h-嘌呤类化合物及其盐和应用 |
EP4161926A4 (en) * | 2020-06-03 | 2024-06-19 | Yumanity Therapeutics, Inc. | PYRIDOPYRIMIDINES AND METHODS OF USE THEREOF |
CN113717245A (zh) * | 2021-09-08 | 2021-11-30 | 西安交通大学 | 含有2,8,9-三取代-9h-嘌呤结构片段的egfr降解剂及其盐和应用 |
WO2023071998A1 (zh) * | 2021-10-26 | 2023-05-04 | 杭州德睿智药科技有限公司 | 新型嘧啶或三嗪取代吡啶并杂环化合物 |
CN114315826A (zh) * | 2021-11-30 | 2022-04-12 | 西安交通大学 | 一种吡啶并嘧啶类化合物及其应用 |
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