CN114989147B - 一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用 - Google Patents
一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用 Download PDFInfo
- Publication number
- CN114989147B CN114989147B CN202210699572.8A CN202210699572A CN114989147B CN 114989147 B CN114989147 B CN 114989147B CN 202210699572 A CN202210699572 A CN 202210699572A CN 114989147 B CN114989147 B CN 114989147B
- Authority
- CN
- China
- Prior art keywords
- compound
- benzopyrimidine
- pharmaceutically acceptable
- acceptable salt
- preparing
- 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.)
- Active
Links
- -1 Benzopyrimidine compound Chemical class 0.000 title claims abstract description 37
- 150000003839 salts Chemical class 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 102200006538 rs121913530 Human genes 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- FMBVAOHFMSQDGT-UHFFFAOYSA-N (5-chloro-2-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(Cl)C=C1B(O)O FMBVAOHFMSQDGT-UHFFFAOYSA-N 0.000 claims description 3
- IODMEDPPCXSFLD-UHFFFAOYSA-N 5-nitrofuran-2-carboxylic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)O1 IODMEDPPCXSFLD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000035755 proliferation Effects 0.000 abstract description 4
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 102100030708 GTPase KRas Human genes 0.000 description 12
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 12
- 239000000203 mixture Substances 0.000 description 7
- 238000002835 absorbance Methods 0.000 description 6
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 2
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007783 downstream signaling Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100029974 GTPase HRas Human genes 0.000 description 1
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 229940124785 KRAS inhibitor Drugs 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000713862 Moloney murine sarcoma virus Species 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical class N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 102000016914 ras Proteins Human genes 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000036964 tight binding Effects 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本申请公开了一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用。所述苯并嘧啶类化合物结构式如式(Ⅰ)所示，本发明的苯并嘧啶类化合物能够对KRASG12C突变的肿瘤细胞增殖产生抑制作用。
Description
技术领域
本发明属于有机合成技术领域，尤其涉及一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用。
背景技术
鼠类肉瘤病毒癌基因(RAS)蛋白是GTP酶家族中的一个重要成员，包括NRAS，HRAS和KRAS。这些酶在细胞外信号转导，增殖，凋亡和分化中起重要作用。KRAS与鸟嘌呤三核苷酸磷酸(GTP)结合为活性构象，与鸟嘌呤二核苷酸磷酸(GDP)结合为无活性构象。突变的KRAS蛋白和GTP紧密结合使KRAS蛋白处于异常的持续激活构象，导致下游信号通路持续性激活。KRAS抑制剂通过识别突变KRAS，阻断KRAS/GEF相互作用，抑制KRAS下游效应因子从而产生抗肿瘤活性。然而，由于体内高水平的GTP和KRAS与GTP强有力的结合作用力，导致靶向KRAS变得非常困难。此外，KRAS蛋白是一个狭长的平坦口袋，这导致了基于KRAS药物的设计变得困难。KRAS被称为“不可成药靶点”。
KRAS G12C抑制剂通过占据蛋白构象变化时的SWII口袋，并且与突变的半胱氨酸共价结合，使突变的KRAS G12C停留在无活性构象，抑制下游信号通路，包括RAS-MEK-ERK信号通路，从而产生抗肿瘤作用。
发明内容
本发明旨在至少解决现有技术中存在的上述技术问题之一。为此，本发明提供了一种苯并嘧啶类化合物。
本发明还提供了所述苯并嘧啶类化合物的制备方法。
本发明还提供了所述苯并嘧啶类化合物的应用。
本发明的第一方面提供了一种苯并嘧啶类化合物，所述苯并嘧啶类化合物的结构式如式(Ⅰ)所示：
本发明关于苯并嘧啶类化合物或其药学上可接受的盐的技术方案，至少具有以下有益效果：
1、本发明的苯并嘧啶类化合物能够对KRAS G12C突变的肿瘤增殖产生抑制作用。抗肿瘤活性效果好。
2、根据权利要求1所述苯并嘧啶类化合物的制备方法，其特征在于，包括如下步骤：
S1.将化合物1在氯化亚砜溶液中进行反应得到化合物2；
S2.在第一有机溶剂中加入化合物2和Boc-哌嗪，在碱性条件下进行反应得到化合物3；
S3.化合物3和5-氯-2-甲氧基苯硼酸在钯催化条件下进行铃木反应得到化合物4；
S4.化合物4在酸性条件下脱Boc得到化合物5；
S5.化合物5与5-硝基-2-糠酸进行缩合反应得到目标产物。
所述化合物1～5的结构式如下：
5、根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S2所述第一有机溶剂分别独立地选自N,N-二甲基甲酰、甲苯或1,4二氧六环。
6、根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S2中所述有机碱为三乙胺、N,N-二异丙基乙胺。
6、根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S3中的所述钯催化剂为四三苯基膦钯或[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。
7、根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S4中所述缩合剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑、卡特缩合剂。
8、一种药物组合物，其特征在于，包含权利要求1所述苯并嘧啶类化合物或其药学上可接受的赋形剂。
9、权利要求1所述的苯并嘧啶类化合物或其药学上可接受的盐在制备用于治疗或预防癌症的药物中的应用。
一般术语
本发明中所述“药学上可接受的”是指在施用于动物或人类时不产生不良反应、过敏反应或其他不利反应的分子实体和组合物，如本发明中的“药学上可接受的赋形剂”包括任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等，此类赋形剂用于药学活性物质的使用是本领域所熟知的。
含有本发明所述的药物组合物能以常规方式来制造，例如通过常规混合、溶解、造粒、糖衣丸制备、磨细、乳化、囊封、捕集或冻干方法。适当的配制品取决于所选的施用途径。
附图说明
图1是实施例1制备的苯并嘧啶类化合物的核磁共振氢谱图；
图2是实施例1制备的苯并嘧啶类化合物的核磁共振碳谱图；
图3是实施例1制备的苯并嘧啶类化合物的质谱图。
具体实施方式
如无特殊说明，本发明所用原料、试剂及溶剂，均为商业购买未经任何处理或者可通过文献方法制得的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
RPMI-1640培养基购自Gibco；胎牛血清购自Gibco；二甲基亚砜(DMSO)、四甲基偶氮唑蓝(MTT)均购自Sigma。细胞购买自长沙优泽生物科技有限公司，所购细胞均经STR鉴定。ARS-1620购买于MCE。为了更清楚地说明本发明，下面结合优选实施例对本发明做进一步说明。
实施例1
实施例1提供了一种苯并嘧啶类化合物，所述苯并嘧啶类化合物的结构式如式(Ⅰ)所示：
其制备方法包括如下步骤：
S1.向化合物1(275.9mg,1mmol)的亚硫酰氯(8mL)溶液中，加入一滴N，N-二甲基甲酰胺并将所得混合物回流搅拌8小时。反应结束将混合物冷却至室温并真空浓缩，得到化合物2。
S2.将化合物2(293.8mg,1mmol)在N,N-二甲基甲酰胺(1mL)中加入DIPEA(130mg,1mmol)和哌嗪-1-甲酸叔丁酯(186mg,1mmol)，并将所得混合物在50℃搅拌2小时。反应结束加入水析出化合物3。
S3.将Pd(PPh3)4(40mg,0.35mmol)和Na 2CO3(111mg，1mmol)加入含化合物3(444.3mg,1mmol)的N,N-二甲基甲酰胺和水的混合溶液中(1mL水+3mL N,N-二甲基甲酰胺)，再加入2-甲氧基-5氯-苯硼酸(186.4mg，1mmol)，并将所得混合物在100℃搅拌24小时。反应结束后用水和乙酸乙酯萃取，有机层真空浓缩，并通过硅胶快速柱色谱法纯化，得到化合物4。
S4.将化合物4(506.1mg，1mmol)在盐酸-1,4-二氧六环溶液中搅拌半小时后，真空浓缩得到化合物5.
S5.将化合物5(406.0mg，1mmol)和5-硝基-2-糠酸(157.0mg，1mmol)溶于二氯甲烷中，加入卡特缩合剂(442.2mg，1mmol)、N,N-二异丙基乙胺(130mg，1mmol)后搅拌过夜，将所得溶液旋干，通过柱层析得到目标产物。
所述化合物1～5的结构式如下：
将所得到产物用核磁共振和质谱确认结构：
(4-(6-chloro-7-(5-chloro-2-methoxyphenyl)-8-fluoroquinazolin-4-yl)piperazin-1-yl)(5-nitrofuran-2-yl)methanone(KS-19)1H NMR(400MHz,CDCl3)δ8.84(s,1H),7.84(s,1H),7.44(dd,J＝8.8,2.5Hz,1H),7.40(d,J＝3.8Hz,1H),7.30(d,J＝3.8Hz,1H),7.25(d,J＝2.5Hz,1H),7.00(d,J＝8.9Hz,1H),4.22–3.79(m,8H),3.71(s,3H).13C NMR(101MHz,DMSO)δ161.96,157.38,155.92,154.69,153.53,151.71,147.84,130.86,130.71,129.80,126.63,126.45,124.53,122.50,121.00,117.74,116.97,113.89,113.30,56.52.MS(ESI)m/z 546.0750(M+H)+.
性能测试
应用例1
本申请实施例1制备的苯并嘧啶类化合物对人NIC-H358、NIC-H23肺癌细胞进行抗肿瘤活性研究，采用MTT法检测化合物对肿瘤细胞增殖的抑制效果。
实验原理：MTT比色法是一种检测细胞存活和生长的方法，其原理为活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性蓝紫色结晶甲瓒，并沉积在细胞中，而死细胞缺少这一功能。二甲基亚砜(DMSO)可以溶解活细胞中的甲瓒，用酶联免疫检测仪检测570nM下的吸光度值(OD值)，可以根据吸光度值反应活细胞的数量，在一定范围内，OD值越小，则表明细胞活性越弱，药物的抑制增殖效果越好。
试剂配制
1、MTT
将50mL的离心管用锡箔纸包裹避光，精密称取MTT粉末(Methylthiazolyldiphenyl-tetrazolium bromide，又名Thiazolyl Blue)250mg，加入到离心管中，加入50ml的PBS，使MTT粉末完全溶解，用0.22μm孔径的滤膜过滤除菌并分装，在-20℃条件下避光保存。
2、实施例1化合物配置
取高压好的EP管用于称取化合物，向EP管中加入对应量的DMSO，使液体成20mM的母液，使用时用相应量的培养基稀释1配成浓度为0.625μM，1.25μM，2.5μM，5μM，10μM工作液。
实验步骤：
(1)取对数生长期的细胞，消化，调整细胞数浓度为2.5×104/mL，按100μL/孔接种到96孔板中。在37℃，5％CO2细胞培养箱中培养过夜，待细胞贴壁。
(2)吸出原有培养基，每组加入不同浓度的实施例1化合物，化合物浓度分别为为0.625μM，1.25μM，2.5μM，5μM，10μM。以0.1％的DMSO设为对照组，在细胞培养箱中继续培养48h。
(3)每孔加入10μL MTT液，在培养箱中孵育4h。
(4)弃去培养基，每孔加入100μL DMSO，振荡15min充分溶解甲瓒结晶。
(5)用酶联免疫检测仪测定570nm下的吸光度值。
(6)按以下公式计算细胞生长抑制率：
抑制率＝[(As-Ab)/(Ac-Ab)]×100％；
As：实验孔的吸光度(含细胞、MTT、实施例1化合物)；
Ac：对照孔的吸光度(含细胞、MTT，无实施例1化合物)；
Ab：空白孔的吸光度(不含细胞和实施例1化合物，含MTT)；
根据上述试验，得出来的数据如表1所示：
表1实施例(I)的数据
根据上述体外实验结果，实施例1化合物能有效抑制抑制NCI-H358和NCI-H23细胞生长，IC50分别为0.46μM±0.02,0.87μM±0.04并且优于阳性对照ARS-1620。我们可以得出本申请所述的实施例1化合物能够抑制KRAS G12C突变的NCI-H358和NCI-H23肿瘤细胞生长。
Claims (8)
1.一种苯并嘧啶类化合物或其药学上可接受的盐，其特征在于，所述苯并嘧啶类化合物的结构式如式（Ⅰ）所示：
式（Ⅰ）。
2.根据权利要求1所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，包括如下步骤：
S1. 将化合物1在氯化亚砜溶液中进行反应得到化合物2；
S2. 在第一有机溶剂中加入化合物2和Boc-哌嗪，在碱性条件下进行反应得到化合物3；
S3. 化合物3和5-氯-2-甲氧基苯硼酸在钯催化条件下进行铃木反应得到化合物4；
S4. 化合物4在酸性条件下脱Boc得到化合物5；
S5. 化合物5与5-硝基-2-糠酸进行缩合反应得到目标产物；
所述化合物1~5的结构式如下：
。
3.根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S1所述第一有机溶剂分别独立地选自N,N-二甲基甲酰胺、甲苯或1,4二氧六环。
4.根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S2中所述碱性条件为有机碱存在的条件；所述有机碱为三乙胺或N,N-二异丙基乙胺。
5.根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S3中的钯催化条件为钯催化剂存在的条件；所述钯催化剂为四三苯基膦钯或[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。
6.根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S5中缩合反应中的缩合剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑、或卡特缩合剂。
7.一种药物组合物，其特征在于，包含权利要求1所述苯并嘧啶类化合物或其药学上可接受的赋形剂。
8.权利要求1所述的苯并嘧啶类化合物或其药学上可接受的盐在制备用于抑制KRASG12C突变的肺癌细胞生长的药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210699572.8A CN114989147B (zh) | 2022-06-20 | 2022-06-20 | 一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210699572.8A CN114989147B (zh) | 2022-06-20 | 2022-06-20 | 一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114989147A CN114989147A (zh) | 2022-09-02 |
| CN114989147B true CN114989147B (zh) | 2024-05-17 |
Family
ID=83035337
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210699572.8A Active CN114989147B (zh) | 2022-06-20 | 2022-06-20 | 一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114989147B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1675212A (zh) * | 2002-08-21 | 2005-09-28 | 贝林格尔英格海姆法玛两合公司 | 8－[3－氨基－哌啶－1－基]－黄嘌呤,其制备方法及作为药物制剂的用途 |
| WO2010146173A1 (en) * | 2009-06-18 | 2010-12-23 | Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg | Quinazoline derivatives as histamine h4-recept0r inhibitors for use in the treatment of inflammatory disorders |
| CN114222743A (zh) * | 2019-08-16 | 2022-03-22 | 劲方医药科技(上海)有限公司 | 氧代六元环并嘧啶类化合物，其制法与医药上的用途 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10011600B2 (en) * | 2014-09-25 | 2018-07-03 | Araxes Pharma Llc | Methods and compositions for inhibition of Ras |
-
2022
- 2022-06-20 CN CN202210699572.8A patent/CN114989147B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1675212A (zh) * | 2002-08-21 | 2005-09-28 | 贝林格尔英格海姆法玛两合公司 | 8－[3－氨基－哌啶－1－基]－黄嘌呤,其制备方法及作为药物制剂的用途 |
| WO2010146173A1 (en) * | 2009-06-18 | 2010-12-23 | Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg | Quinazoline derivatives as histamine h4-recept0r inhibitors for use in the treatment of inflammatory disorders |
| CN114222743A (zh) * | 2019-08-16 | 2022-03-22 | 劲方医药科技(上海)有限公司 | 氧代六元环并嘧啶类化合物，其制法与医药上的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114989147A (zh) | 2022-09-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1912973B1 (en) | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide | |
| BG107508A (bg) | Нови хетероарилови производни и тяхното използване като лекарствени средства | |
| BG107507A (bg) | Акридинови производни и тяхното използване като лекарствени средства | |
| JP6704422B2 (ja) | キナゾリン誘導体の塩およびその製造方法 | |
| RU2769050C1 (ru) | Кристаллическая форма и солевая форма соединения пиридоимидазола и соответствующий способ получения | |
| AU2019303777B2 (en) | Salt of LSD1 inhibitor and a polymorph thereof | |
| EP3502103A1 (en) | Crystal form, salt type of substituted 2-hydro-pyrazole derivative and preparation method therefor | |
| EP2870154A1 (en) | Solid state form of vemurafenib choline salt | |
| CN112028836A (zh) | 一种含有六元氮杂环的二芳基嘧啶类衍生物及其制备方法与应用 | |
| CN116987066A (zh) | 一种嘧啶类化合物及其制备方法和应用 | |
| RU2415839C2 (ru) | Новое производное ариламидина, его соль и содержащий их противогрибковый агент | |
| EP4085914A1 (en) | Crystal form of pyridopyrimidine derivative and preparation method thereof | |
| CN114989147B (zh) | 一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用 | |
| EP3275864B1 (en) | Compound of 3-hydroxyl pyridine, preparation method thereof and pharmaceutical use thereof | |
| CN109988110B (zh) | 4-苯氧基喹啉并磺酰脲类化合物、合成该化合物的中间体及其制备方法和用途 | |
| CN113956233B (zh) | 一种酰胺类化合物或其药学上可接受的盐及其制备方法和应用 | |
| WO2019114741A1 (zh) | 作为Akt抑制剂的盐型及其晶型 | |
| CN113493443B (zh) | 一种厄洛替尼衍生物在制备治疗食管癌的药物中的应用 | |
| CN103664972B (zh) | 二氨基二氢三嗪衍生物、其盐、制备方法、组合物及应用 | |
| CN113527195A (zh) | 一类5-芳基烟酰胺类lsd1/hdac双靶点抑制剂、其制备方法及应用 | |
| RU2794977C2 (ru) | Соль ингибитора lsd1 и её полиморфная форма | |
| EP4361140A1 (en) | Pharmaceutically acceptable salt and crystal form of fused pyridine ring derivative and preparation method therefor | |
| AU2019260240A1 (en) | Crystal form of c-MET inhibitor and salt form thereof and preparation method therefor | |
| CN114989195A (zh) | 一种噻吩并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用 | |
| CN115260162B (zh) | 3-羟基-4-吡啶酮—环丙沙星耦合物及其制备方法和用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20230328 Address after: Room B502, Building 2, No. 6, Xinrui Road, Huangpu District, Guangzhou, Guangdong 510535 Applicant after: Guangdong Chenkang Biotechnology Co.,Ltd. Address before: 528300 No. 818, floor 8, building 17, Shunlian Machinery City, Xingye 4th Road, Guanglong Industrial Park, Chihua neighborhood committee, Chencun Town, Shunde District, Foshan City, Guangdong Province Applicant before: Foshan Chenkang Biotechnology Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |