CN115677600A - 2,3-二氢喹唑啉-4(1h)-酮衍生物及其制备方法与应用 - Google Patents
2,3-二氢喹唑啉-4(1h)-酮衍生物及其制备方法与应用 Download PDFInfo
- Publication number
- CN115677600A CN115677600A CN202211374747.4A CN202211374747A CN115677600A CN 115677600 A CN115677600 A CN 115677600A CN 202211374747 A CN202211374747 A CN 202211374747A CN 115677600 A CN115677600 A CN 115677600A
- Authority
- CN
- China
- Prior art keywords
- acid
- dihydroquinazolin
- derivative
- compound
- indol
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 4' -chlorobiphenyl-4-yl Chemical group 0.000 claims abstract description 27
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 14
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 14
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 14
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 13
- 208000032612 Glial tumor Diseases 0.000 claims abstract description 12
- 206010018338 Glioma Diseases 0.000 claims abstract description 12
- 201000001441 melanoma Diseases 0.000 claims abstract description 11
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 6
- 201000005202 lung cancer Diseases 0.000 claims abstract description 6
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 6
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims abstract description 5
- 125000006268 biphenyl-3-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C(*)=C([H])C([H])=C1[H] 0.000 claims abstract description 4
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 4
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims abstract description 4
- XWWYZFUBBJHKSP-UHFFFAOYSA-N 2,3-dihydro-1h-quinazolin-4-one Chemical class C1=CC=C2C(=O)NCNC2=C1 XWWYZFUBBJHKSP-UHFFFAOYSA-N 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 230000000259 anti-tumor effect Effects 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 9
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 208000014018 liver neoplasm Diseases 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 239000007943 implant Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 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
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 60
- 150000001875 compounds Chemical class 0.000 description 60
- 230000022131 cell cycle Effects 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 238000009826 distribution Methods 0.000 description 22
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 description 18
- 230000004668 G2/M phase Effects 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 11
- 230000010190 G1 phase Effects 0.000 description 10
- 230000018199 S phase Effects 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003783 cell cycle assay Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 229930012538 Paclitaxel Natural products 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 229960001592 paclitaxel Drugs 0.000 description 8
- 238000001308 synthesis method Methods 0.000 description 8
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229960002949 fluorouracil Drugs 0.000 description 4
- 210000005084 renal tissue Anatomy 0.000 description 4
- UTAJMDSTGGBQSJ-UHFFFAOYSA-N 2-(2-hydroxynaphthalen-1-yl)-2,3-dihydro-1h-quinazolin-4-one Chemical compound N1C(=O)C2=CC=CC=C2NC1C1=C2C=CC=CC2=CC=C1O UTAJMDSTGGBQSJ-UHFFFAOYSA-N 0.000 description 3
- HMXRXBIGGYUEAX-SFHVURJKSA-N Evodiamine Natural products CN1[C@H]2N(CCc3[nH]c4ccccc4c23)C(=O)c5ccccc15 HMXRXBIGGYUEAX-SFHVURJKSA-N 0.000 description 3
- TXDUTHBFYKGSAH-SFHVURJKSA-N Evodiamine Chemical compound C1=CC=C2N(C)[C@@H]3C(NC=4C5=CC=CC=4)=C5CCN3C(=O)C2=C1 TXDUTHBFYKGSAH-SFHVURJKSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 210000005228 liver tissue Anatomy 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000012342 propidium iodide staining Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical group C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 2
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 2
- PWJNHCZVIHAJFG-UHFFFAOYSA-N 2-(1h-indol-3-yl)-2,3-dihydro-1h-quinazolin-4-one Chemical compound C1=CC=C2C(C3NC(C4=CC=CC=C4N3)=O)=CNC2=C1 PWJNHCZVIHAJFG-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000000149 argon plasma sintering Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000012154 double-distilled water Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000006481 glucose medium Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012192 staining solution Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- KKVYYGGCHJGEFJ-UHFFFAOYSA-N 1-n-(4-chlorophenyl)-6-methyl-5-n-[3-(7h-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine Chemical compound N=1C=CC2=C(NC=3C(=CC=CN=3)C=3C=4N=CNC=4N=CN=3)C(C)=CC=C2C=1NC1=CC=C(Cl)C=C1 KKVYYGGCHJGEFJ-UHFFFAOYSA-N 0.000 description 1
- ADZUEEUKBYCSEY-UHFFFAOYSA-N 1h-indole-5-carbaldehyde Chemical compound O=CC1=CC=C2NC=CC2=C1 ADZUEEUKBYCSEY-UHFFFAOYSA-N 0.000 description 1
- VSPBWOAEHQDXRD-UHFFFAOYSA-N 1h-indole-6-carbaldehyde Chemical compound O=CC1=CC=C2C=CNC2=C1 VSPBWOAEHQDXRD-UHFFFAOYSA-N 0.000 description 1
- SCFSEKFQRNAJOY-UHFFFAOYSA-N 2-(3-phenylphenyl)-2,3-dihydro-1h-quinazolin-4-one Chemical compound N1C2=CC=CC=C2C(=O)NC1C(C=1)=CC=CC=1C1=CC=CC=C1 SCFSEKFQRNAJOY-UHFFFAOYSA-N 0.000 description 1
- XRUAOBKXCFNPCK-UHFFFAOYSA-N 2-(4-phenylphenyl)-2,3-dihydro-1h-quinazolin-4-one Chemical compound N1C2=CC=CC=C2C(=O)NC1C(C=C1)=CC=C1C1=CC=CC=C1 XRUAOBKXCFNPCK-UHFFFAOYSA-N 0.000 description 1
- NTCCNERMXRIPTR-UHFFFAOYSA-N 2-hydroxy-1-naphthaldehyde Chemical compound C1=CC=CC2=C(C=O)C(O)=CC=C21 NTCCNERMXRIPTR-UHFFFAOYSA-N 0.000 description 1
- GHSUORIVDBPKKQ-UHFFFAOYSA-N 3-methyl-1h-indole-2-carbaldehyde Chemical compound C1=CC=C2C(C)=C(C=O)NC2=C1 GHSUORIVDBPKKQ-UHFFFAOYSA-N 0.000 description 1
- KFKSIUOALVIACE-UHFFFAOYSA-N 3-phenylbenzaldehyde Chemical compound O=CC1=CC=CC(C=2C=CC=CC=2)=C1 KFKSIUOALVIACE-UHFFFAOYSA-N 0.000 description 1
- UXCMNUUPBMYDLJ-UHFFFAOYSA-N 4-(4-chlorophenyl)benzaldehyde Chemical group C1=CC(Cl)=CC=C1C1=CC=C(C=O)C=C1 UXCMNUUPBMYDLJ-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102100032306 Aurora kinase B Human genes 0.000 description 1
- 102000015367 CRBN Human genes 0.000 description 1
- 102100024607 DNA topoisomerase 1 Human genes 0.000 description 1
- 229940125408 FGFR4 inhibitor Drugs 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101000798306 Homo sapiens Aurora kinase B Proteins 0.000 description 1
- 101000830681 Homo sapiens DNA topoisomerase 1 Proteins 0.000 description 1
- 101001008953 Homo sapiens Kinesin-like protein KIF11 Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000941994 Homo sapiens Protein cereblon Proteins 0.000 description 1
- 101000809797 Homo sapiens Thymidylate synthase Proteins 0.000 description 1
- 239000003458 I kappa b kinase inhibitor Substances 0.000 description 1
- 229940121730 Janus kinase 2 inhibitor Drugs 0.000 description 1
- 102100027629 Kinesin-like protein KIF11 Human genes 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 101100381978 Mus musculus Braf gene Proteins 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 241001078983 Tetradium ruticarpum Species 0.000 description 1
- 102100038618 Thymidylate synthase Human genes 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004305 biphenyl Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明专利涉及医药技术领域,尤其是指一种C2位取代的2,3-二氢喹唑啉-4(1H)-酮衍生物及其制备和应用。
背景技术
喹唑啉是一类重要的含氮杂环化合物。它广泛存在于各种生物碱和具有生物药理活性的有机分子中,喹唑啉类上市药物有10个,NDA申请有2个,临床三期有2个,临床二期有25个,临床一期有17个。按照靶点来分:HER家族抑制剂23个,VEGFR抑制剂和TYMS抑制剂各5个,SRC抑制剂和PI3K抑制剂各3个,JAK2抑制剂、KIF11抑制剂和AURKB抑制剂各2个,PDGFR抑制剂、FGFR4抑制剂、PKC抑制剂、B-raf抑制剂、SMO抑制剂、Tubulin抑制剂、TOP1抑制剂、PARP抑制剂、CRBN底物特异性的小分子调节剂、IKK抑制剂以及HDAC抑制剂各1个,因而在抗肿瘤领域具有很好的开发前景。
因此,研发一种新的喹唑啉类化合物显得很有必要。
发明内容
吴茱萸碱是一类从传统中药吴茱萸中分离得到的咔啉喹唑啉酮类生物碱,具有一定抗肿瘤活性,但不强【药学与临床研究,2017,25(3):221-226】,发明人以吴茱萸碱为模型化合物,对吴茱萸碱C环开环并简化其结构,发现某些新型2,3-二氢喹唑啉-4(1H)-酮衍生物具有一定抗肿瘤活性。但喹唑啉酮类化合物其大多数结构优化都是基于4(3H)-喹唑啉酮的2,3位的,而且其2-位取代基的长度对其药效有比较重要的作用【天然产物研究与开发,2015,27:1972-1978,1937;甘宜远,欧阳贵平,一类含吡啶基喹唑啉酮类衍生物合成及生物活性研究[D],贵州大学硕士研究生学位论文,2019】,我们进而在2,3-二氢喹唑啉-4(1H)-酮C2位上引入不同的吲哚基、联苯基和萘环等基团考察其抗肿瘤活性,寻找抗肿瘤活性更好的新型2,3-二氢喹唑啉-4(1H)-酮衍生物。
本发明旨在至少在一定程度上解决现有技术中存在的技术问题之一,由此,在本发明的第一方面,本发明提供一种2,3-二氢喹唑啉-4(1H)-酮衍生物,所述2,3-二氢喹唑啉-4(1H)-酮衍生物的结构如式(I)所示:
其中,R选自联苯-4-基、4'-氯联苯-4-基、联苯-3-基、2-羟基萘-1-基、2-烯丙氧基萘-1-基、3-甲基-吲哚-2-基、吲哚-3-基、吲哚-5-基和吲哚-6-基中的一种。
R为联苯-4-基时所述2,3-二氢喹唑啉-4(1H)-酮衍生物为化合物1、R为4'-氯联苯-4-基时所述2,3-二氢喹唑啉-4(1H)-酮衍生物为化合物2、R为联苯-3-基时所述2,3-二氢喹唑啉-4(1H)-酮衍生物为化合物3、R为2-羟基萘-1-基时所述2,3-二氢喹唑啉-4(1H)-酮衍生物为化合物4、R为2-烯丙氧基萘-1-基时所述2,3-二氢喹唑啉-4(1H)-酮衍生物为化合物5、R为3-甲基-吲哚-2-基时所述2,3-二氢喹唑啉-4(1H)-酮衍生物为化合物6、R为吲哚-3-基时所述2,3-二氢喹唑啉-4(1H)-酮衍生物为化合物7、R为吲哚-5-基时所述2,3-二氢喹唑啉-4(1H)-酮衍生物为化合物8、R为吲哚-6-基时所述2,3-二氢喹唑啉-4(1H)-酮衍生物为化合物9。
化合物1~9的结构式如下所示:
在本发明的第二方面,本发明提供一种在本发明第一方面所述的2,3-二氢喹唑啉-4(1H)-酮衍生物和/或其药用盐在制备抗肿瘤药物中的应用。
在本发明的一个或多个实施例中,所述肿瘤选自肝癌、胶质瘤、肺癌、胰腺癌和黑色素瘤中的一种或多种。
在本发明的一个或多个实施例中,所述药用盐由所述2,3-二氢喹唑啉-4(1H)-酮衍生物与无机酸或有机酸反应得到;优选地,所述无机酸选自盐酸、氢溴酸、氢氟酸、硫酸、硝酸和磷酸中的至少一种;所述的有机酸选自甲酸、乙酸、丙酸、柠檬酸、甲磺酸、乙磺酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、草酸和酒石酸中的至少一种。
在本发明的第三方面,本发明提供一种在本发明第一方面所述的2,3-二氢喹唑啉-4(1H)-酮衍生物的制备方法,所述2,3-二氢喹唑啉-4(1H)-酮衍生物由邻氨基苯甲酰胺和对应的醛RCHO反应得到,反应式如下所示:
在本发明的一个或多个实施例中,反应过程中加入对甲基苯磺酸,控制所述反应温度为50~70℃。
在本发明的一个或多个实施例中,所述反应在溶剂中进行,所述溶剂为醇,优选地,所述溶剂为乙醇。
在本发明的第四方面,本发明提供一种药物制剂,所述药物制剂包含在本发明第一方面所述的2,3-二氢喹唑啉-4(1H)-酮衍生物和/或其药用盐。
在本发明的一个或多个实施例中,所述药物制剂的剂型为片剂、丸剂、胶囊剂、注射剂、混悬剂、乳剂或植入剂。
在本发明的一个或多个实施例中,本发明提供一种在本发明的第四方面所述的药物制剂在制备抗肿瘤药物中的应用;优选地,所述肿瘤选自肝癌、胶质瘤、肺癌、胰腺癌和黑色素瘤中的一种或多种。
本发明的有益效果在于:
1、本发明提供一种2,3-二氢喹唑啉-4(1H)-酮的C2位衍生物,其对肝癌(HepG2),胶质瘤(U251),肺癌(A549),胰腺癌(PANC-1)和黑色素瘤(A375)等多种细胞株有较强的抑制作用,毒性小,优于5-氟尿嘧啶(5-Fu),其作用机制是主要作用于G2/M期。
2、本发明的2,3-二氢喹唑啉-4(1H)-酮的C2位衍生物急性毒性小,药物安全性高,可作为广谱抗肿瘤药物在临床应用;
3、本发明的2,3-二氢喹唑啉-4(1H)-酮的C2位衍生物可以制备成各种剂型抗肿瘤药物在临床应用。
附图说明
图1为化合物8低浓度组、中浓度组、高浓度组、空白对照组小鼠肝组织(200×)病理切片对比结果图;
图2为化合物8低浓度组、中浓度组、高浓度组、空白对照组小鼠肾组织(200×)病理切片对比结果图。
具体实施方式
以下结合具体实施例和附图对本发明作进一步说明,但下列实施例仅用于说明本发明,而不应视为限制本发明的范围。以下实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行,使用的方法如无特别说明,均为本领域公知的常规方法,使用的耗材和试剂如无特别说明,均为市场购得。除非另有说明,本文中所用的专业与科学术语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法或材料也可应用于本发明中。
实施例1 2-(联苯-4-基)-2,3-二氢喹唑啉-4(1H)-酮(化合物1)的合成
在100毫升圆底烧瓶中,分别加入邻氨基苯甲酰胺1.0克(7.34mmol)和4-苯基苯甲醛1.6克(8.81mmol)置于茄形瓶中,加15ml无水乙醇,磁力搅拌溶解,再加对甲基苯磺酸0.1克,于60℃反应至邻氨基苯甲酰胺耗尽。冷却至室温,搅拌下缓慢加水至有沉淀析出,置冰箱中过夜,过滤,沉淀用蒸馏水洗涤三次,真空干燥即得1.95克白色粉末,即为化合物1,产率:88.56%;熔点:222.0-223.1℃;1H NMR(600MHz,DMSO-d6)δ8.32(d,J=2.32Hz,1H),7.64(m,5H),7.56(d,J=7.96Hz,2H),7.44(t,J=7.79Hz,2H),7.34(td,J=7.33,1.26Hz,1H),7.23(ddd,J=8.50,7.20,1.54Hz,1H),7.14(s,1H),6.75(d,J=8.12Hz,1H),6.66(t,J=7.48Hz,1H),5.78(s,1H);13C NMR(151MHz,DMSO-d6)δ164.03,148.23,141.28,140.76,140.15,133.78,129.39,128.00,127.87,127.81,127.13,127.07,117.58,115.40,114.86,66.62;HRMS(ESI+):m/z calcd for C20H16N2O[M+H]+301.13409,found 301.13401。
实施例2 2-(4'-氯联苯-4-基)-2,3-二氢喹唑啉-4(1H)-酮(化合物2)的合成
将4'-氯联苯-4-甲醛替代实施例1中的4-苯基苯甲醛,合成方法同实施例1;得到化合物2,结构数据如下:白色固体,产率:80.7%;熔点:274.7-275.3℃;1HNMR(600MHz,DMSO-d6)δ8.33(d,J=3.78Hz,1H),7.67(d,J=8.00Hz,4H),7.60(t,J=5.58Hz,1H),7.55(d,J=7.90Hz,2H),7.49(d,J=8.11Hz,2H),7.23(t,J=7.72Hz,1H),7.15(s,1H),6.75(t,J=5.48Hz,1H),6.66(t,J=7.47Hz,1H),5.78(s,1H);13C NMR(151MHz,DMSO-d6)δ163.98,148.17,141.72,139.34,138.92,133.79,132.91,129.33,128.88,127.91,127.76,127.03,117.61,115.40,114.86,66.46;HRMS(ESI+):m/z calcd for C20H15N2OCl[M+H]+335.09512,found 335.09506。
实施例3 2-(联苯-3-基)-2,3-二氢喹唑啉-4(1H)-酮(化合物3)的合成
将联苯-3-甲醛替代实施例1中的4-苯基苯甲醛,合成方法同实施例1;得到化合物3,结构数据如下:白色固体,产率:79.5%;熔点:141.4-143.1℃:1H NMR(600MHz,DMSO-d6)δ8.34(d,J=2.31Hz,1H),7.76(s,1H),7.61(td,J=8.09,6.25Hz,4H),7.45(m,4H),7.35(t,J=7.44Hz,1H),7.22(m,1H),7.16(s,1H),6.74(d,J=8.10Hz,1H),6.65(t,J=7.49Hz,1H),5.81(s,1H);13C NMR(151MHz,DMSO-d6)δ164.08,148.29,142.66,140.60,140.36,135.08,133.78,129.41,128.03,127.78,127.40,127.10,126.29,125.82,117.64,115.43,114.85,66.84;HRMS(ESI+):m/z calcd C20H16N2O for[M+Na]+323.1154844,found323.11593。
实施例4 2-(2-羟基萘-1-基)-2,3-二氢喹唑啉-4(1H)-酮(化合物4)的合成
将2-羟基萘-1-甲醛替代实施例1中的4-苯基苯甲醛,合成方法同实施例1;得到化合物4,结构数据如下:白色固体,产率86.9%;熔点:173.9-174.2℃;1H NMR(600MHz,DMSO-d6)δ10.09(s,1H),8.80(d,J=8.71Hz,1H),8.02(s,1H),7.80(dd,J=8.56,5.13Hz,2H),7.69(dd,J=7.96,1.56Hz,1H),7.39(t,J=7.76Hz,1H),7.26(dt,J=17.97,7.21Hz,2H),7.18(dd,J=8.99,2.81Hz,1H),6.86(s,1H),6.73(dd,J=13.63,5.97Hz,3H);13CNMR(151MHz,DMSO-d6)δ165.29,154.43,150.16,133.52,133.46,131.24,129.29,128.74,128.14,126.26,125.88,122.94,118.42,117.63,115.83,114.91,114.41,61.16;HRMS(ESI+):m/z calcd for C18H14N2O2[M+H]+29 1.11335,found 291.11286。
实施例5 2-(2-烯丙氧基萘-1-基)-2,3-二氢喹唑啉-4(1H)-酮(化合物5)的合成
将2-烯丙氧基-1-萘醛替代实施例1中的4-苯基苯甲醛,合成方法同实施例1;得到化合物5,结构数据如下:产率:84.8%;熔点:290℃(分解);1H NMR(600MHz,DMSO-d6)δ8.93(d,J=8.78Hz,1H),8.10(s,1H),7.98(d,J=9.03Hz,1H),7.88(dd,J=8.24,1.39Hz,1H),7.70(dd,J=7.73,1.67Hz,1H),7.44(m,2H),7.37(ddd,J=8.13,6.71,1.26Hz,1H),7.25(td,J=7.68,1.68Hz,1H),6.91(s,1H),6.85(d,J=2.29Hz,1H),6.72(m,2H),6.06(ddt,J=17.31,10.41,5.10Hz,1H),5.39(dq,J=17.22,1.76Hz,1H),5.23(dq,J=10.57,1.63Hz,1H),4.72(dt,J=5.12,1.69Hz,2H);13CNMR(151MHz,DMSO-d6)δ165.10,155.13,149.96,134.20,133.58,132.93,131.69,130.07,128.79,128.15,126.78,126.03,124.00,118.64,117.98,117.64,115.69,114.86,114.83,70.62,61.0.HRMS(ESI+):m/z calcd forC21H18N2O2[M+H]+331.14465,found 331.14458。
实施例6 2-(3-甲基-吲哚-2-基)-2,3-二氢喹唑啉-4(1H)-酮(化合物6)的合成
将3-甲基-吲哚-2-甲醛替代实施例1中的4-苯基苯甲醛,合成方法同实施例1;得到化合物6,结构数据如下:白色固体,产率:81.2%;熔点:197.8-198.8℃;1H NMR(600MHz,DMSO-d6)δ11.08(s,1H),8.10(s,1H),7.66(d,J=7.75Hz,1H),7.48(d,J=7.86Hz,1H),7.33(d,J=8.14Hz,1H),7.26(t,J=7.80Hz,1H),7.08(t,J=7.67Hz,1H),6.97(m,2H),6.76(d,J=8.16Hz,1H),6.72(t,J=7.62Hz,1H),6.11(s,1H),2.27(d,J=2.37Hz,3H);13CNMR(151MHz,DMSO-d6)δ164.37,148.93,136.03,133.66,132.31,128.43,127.88,122.19,118.90,118.74,117.87,115.55,114.96,111.86,108.86,60.83,8.80;HRMS(ESI+):m/zcalcd for C17H15N3O[M+H]+278.12934,found 278.12918。
实施例7 2-(吲哚-3-基)-2,3-二氢喹唑啉-4(1H)-酮(化合物7)的合成
将吲哚-3-甲醛替代实施例1中的4-苯基苯甲醛,合成方法同实施例1;得到化合物7,结构数据如下:白色固体,产率:85.8%;熔点:196.1-197.8;1H NMR(600MHz,DMSO-d6)δ11.07(s,1H),8.14(s,1H),7.69(s,1H),7.51(m,2H),7.38(d,J=7.5Hz,1H),7.23(m,4H),6.99(t,J=7.48Hz,1H),6.66(q,J=7.99Hz,1H),6.02(d,J=3.25Hz,1H);13C NMR(151MHz,DMSO-d6)δ164.37,148.93,136.03,133.66,132.31,128.43,127.88,122.19,118.90,118.74,117.87,115.55,114.96,111.86,108.86,60.83;HRMS(ESI+):m/z calcd forC16H13N3O[M+H]+264.11369,found 264.11350。
实施例8 2-(吲哚-5-基)-2,3-二氢喹唑啉-4(1H)-酮(化合物8)的合成
将吲哚-5-甲醛替代实施例1中的4-苯基苯甲醛,合成方法同实施例1;得到化合物8,结构数据如下:白色固体,产率:83.2%;熔点:194.7-196.0℃;1H NMR(600MHz,DMSO-d6)δ11.11(s,1H),8.12(d,J=2.21Hz,1H),7.61(dd,J=7.67,1.64Hz,2H),7.39(d,J=8.37Hz,1H),7.34(q,J=2.68Hz,1H),7.26(dd,J=8.46,1.74Hz,1H),7.21(t,J=7.62Hz,1H),6.98(s,1H),6.72(m,1H),6.65(td,J=7.51,2.05Hz,1H),6.42(t,J=2.40Hz,1H),5.79(d,J=3.37Hz,1H);13C NMR(151MHz,DMSO-d6)δ164.16,148.61,136.38,133.60,132.21,127.78,127.61,126.41 120.54,119.16,117.35,115.37,114.74,111.71,101.74,68.02;HRMS(ESI+):m/zcalcd for C16H13N3O[M+H]+264.11369,found 264.11333。
实施例9 2-(吲哚-6-基)-2,3-二氢喹唑啉-4(1H)-酮(化合物9)的合成
将吲哚-6-甲醛替代实施例1中的4-苯基苯甲醛,合成方法同实施例1;得到化合物9,结构数据如下:白色固体,产率:82.3%;熔点:204.9-206.2℃;1H NMR(600MHz,DMSO-d6)δ11.14(s,1H),8.20(s,1H),7.61(d,J=7.6Hz,1H),7.52(d,J=8.18Hz,1H),7.48(s,1H),7.34(d,J=2.84Hz,1H),7.21(m,1H),7.14(d,J=8.23Hz,1H),7.05(s,1H),6.72(d,J=8.06Hz,1H),6.64(t,J=7.47Hz,1H),6.39(d,J=3.13Hz,1H),5.81(s,1H);13C NMR(151MHz,DMSO-d6)δ164.07,148.43,135.93,134.76,133.64,128.19,127.77,126.50,120.25,118.40,117.32,115.35,114.75,110.35,101.36,67.74;HRMS(ESI+):m/z calcdfor C16H13N3O[M+H]+264.11369,found 264.11353。
实施例10 2,3-二氢喹唑啉-4(1H)-酮衍生物体外抗肿瘤作用
1.细胞培养与传代
人肝癌细胞系(HepG2)、人恶性黑色素瘤细胞系(A375)、人非小细胞肺癌细胞系(A549)、人胰腺癌细胞系(panc1)和人胶质瘤细胞系(U251)于含10%FBS的DMEM高糖培养基中培养,生长至80-90%丰度时传代,37℃,5%CO2环境下培养。
2.化合物配制
待测化合物溶解于DMSO中制成浓度为50mg/mL母液,而后以含5%FBS高糖DMEM培养基稀释成50μg/mL、15μg/mL、5μg/mL、1.5μg/mL、0.5μg/mL、0.15μg/mL、0.05μg/mL、0.015μg/mL系列浓度。5-氟尿嘧啶作为阳性对照药物。
3.化合物对肿瘤细胞抑制实验
当肿瘤细胞生长至80-90%丰度时接种于96孔板,每孔接种约2000个细胞。次日细胞贴壁后将培养基更换为含有浓度分别为50μg/mL、15μg/mL、5μg/mL、1.5μg/mL、0.5μg/mL、0.15μg/mL、0.05μg/mL、0.015μg/mL化合物的5%FBS高糖DMEM培养基,置于37℃,5%CO2环境下培养72小时。MTT粉末通过浓度为0.1mol/L PBS溶解配置为5mg/mL的MTT溶液,每孔加入10μL MTT溶液,于细胞培养箱中避光孵育4小时。MTT染色4小时后用移液器吸走上清,每孔加入100μL DMSO溶解板底紫色结晶,酶标仪检测570nm处各孔吸光度,通过下述公式计算各浓度化合物对肿瘤细胞生长的抑制率。抑制率=(OD对照组-OD给药组)/OD对照组*100%。通过graphpad prism9软件计算获得各化合物的IC50,实验结果见表1。
从表1看,9个化合物对人肝癌细胞系(HepG2)、人胶质瘤细胞系(U251)、人胰腺癌细胞系(panc1)、人非小细胞肺癌细胞系(A549)和人恶性黑色素瘤细胞系(A375)等均显示了较强的广谱抗肿瘤活性,其中化合物1、化合物2、化合物4和化合物8有更强的广谱抗肿瘤活性,优于5-氟尿嘧啶(5-Fu),显示了较好的应用前景。
表1 2,3-二氢喹唑啉-4(1H)-酮衍生物抗肿瘤活性
5-Fu:5-氟尿嘧啶
实施例11 2,3-二氢喹唑啉-4(1H)-酮衍生物细胞周期检测
选择活性较好的化合物8进行细胞周期检测
1.细胞培养与传代
人肝癌细胞系(HepG2)、人恶性黑色素瘤细胞系(A375)、人非小细胞肺癌细胞系(A549)、人胰腺癌细胞系(panc1)和人胶质瘤细胞系(U251)于含10%FBS的DMEM高糖培养基中培养,生长至80-90%丰度时传代,37℃,5%CO2环境下培养。
2.化合物处理
2.1化合物配制
待测化合物溶解于DMSO中制成浓度为50mg/mL母液,以含5% FBS的高糖DMEM培养基稀释至10μg/mL和2μg/mL。
2.2细胞化合物处理
细胞生长至80-90%丰度时接种于六孔板中,次日细胞贴壁后经过无血清高糖DMEM培养基过夜处理,使细胞同步化于细胞分裂G0期;
同步化后,将无血清培养基更换为化合物浓度分别为10μg/mL(适用于A375、A549、panc1细胞系)和2μg/mL(适用于HepG2细胞系)的培养基。37℃,5%CO2环境下孵育72小时。
3.细胞周期检测
3.1收集六孔板中培养基上清于离心管中,用胰酶消化细胞,至细胞可被移液管或枪头吹打下来时,加入前面收集的培养液,吹打下所有贴壁细胞,收集入离心管中。1000rpm离心5分钟,沉淀细胞;
3.2去除上清,保留细胞沉淀,加入冰上预冷的0.01mol/L PBS缓冲液1ml,重悬细胞,再次1000rpm离心5分钟沉淀细胞,小心去除上清,保留细胞沉淀;
3.3细胞固定:加入1ml冰浴预冷的70%乙醇,吹打混匀,4℃固定。细胞固定完全后,1000rpm离心5分钟,沉淀细胞。小心去除上清。向细胞沉淀中加入1ml冰浴预冷PBS,重悬细胞。再次离心沉淀细胞,去除上清,得到细胞沉淀;
3.4碘化丙啶染色:按照细胞周期检测试剂盒说明书配制碘化丙啶染色液。每管细胞中加入0.5ml碘化丙啶染色液,缓慢并充分重悬细胞沉淀,37℃避光孵30分钟;
3.5流式细胞仪在激发波长488nm波长处检测红色荧光,同时检测光散射情况。FlowJo软件分析细胞DNA含量和光散射。
4细胞周期检测结果
4.1化合物作用于人肝癌细胞系(HepG2)的细胞周期检测
化合物8作用于人肝癌细胞系(HepG2)的细胞周期检测结果如下:空白对照组细胞周期分布G0/G1、S、G2/M期所占百分比分别为42.60±2.0%、26.10±0.67%、23.07±1.03%;化合物8给药组的细胞周期分布G0/G1、S、G2/M期所占百分比分别为21.73±3.71%、11.55±2.14%、50.6±1.63%;此外,给予5-Fu阳性给药组的细胞周期分布G0/G1、S、G2/M期所占百分比分别为52.55±2.05%、21.95±2.75%和9.58±0.33%;紫杉醇阳性给药组的细胞周期分布G0/G1、S、G2/M期所占百分比分别为21.73±3.71%、11.55±2.14%和50.6±1.63%,提示化合物8作用于人肝癌细胞系(HepG2)细胞的G2/M期。
4.2化合物作用于人胶质瘤细胞系(U251)的细胞周期检测
化合物8作用于人胶质瘤细胞系(U251)的细胞周期检测结果如下:空白对照组细胞周期分布G0/G1、S、G2/M期所占百分比分别为45.05±3.11%、19.66±2.09%和18.30±1.23%;化合物8给药组的细胞周期分布G0/G1、S、G2/M期所占百分比为32.98±0.35%、27.27±4.56%和29.7±5.58%;此外,5-Fu给药组的U251细胞周期分布G0/G1、S、G2/M期所占百分比分别为66.47±3.54%、10.57±2.82%和5.85±4.66%;紫杉醇给药组的U251细胞周期分布G0/G1、S、G2/M期所占百分比分别为6.29±0.88%、14.0±2.00%和57.93±4.25%,上述结果提示化合物8作用于人胶质瘤细胞系(U251)的细胞在G0/G1、S、G2/M期分布较均衡。
4.3化合物作用于人胰腺癌细胞系(panc1)的细胞周期检测
化合物8作用于人胰腺癌细胞系(panc1)的细胞周期检测结果如下:空白对照组的panc1细胞周期分布G0/G1、S、G2/M期所占百分比分别为39.77±0.91%、21.17±0.69%和27.23±0.95%,化合物8给药组的panc1细胞周期分布G0/G1、S、G2/M期所占百分比分别为14.67±5.30%、17.38±3.95%和59.18±7.36%;5-Fu阳性给药组的panc1细胞周期分布G0/G1、S、G2/M期所占百分比分别为34.03±1.72%、20.63±1.59%和35.17±1.32%;紫杉醇阳性给药组的panc1细胞周期分布G0/G1、S、G2/M期所占百分比分别为8.94±1.99%、15.43±2.87%和65.3±5.24%,提示化合物8的panc1细胞周期分布同阳性药紫杉醇类似,作用于人胰腺癌细胞系(panc1)的细胞G2/M期。
4.4化合物作用于人非小细胞肺癌细胞系(A549)的细胞周期检测
化合物8作用于人非小细胞肺癌细胞系(A549)的细胞周期检测结果如下:空白对照组A549细胞周期分布G0/G1、S、G2/M期所占百分比为66.32±2.47%、15.54±1.74%和11.74±2.40%,化合物8给药组的A549细胞周期分布G0/G1、S、G2/M期所占百分比分别为17.80±1.49%、19.38±2.04%和55.77±2.38%;5-Fu阳性给药组的A549细胞周期分布G0/G1、S、G2/M期所占百分比分别为65.73±1.33%、11.97±0.61%和14.20±0.37%;而给予紫杉醇阳性给药组的A549细胞周期分布G0/G1、S、G2/M期所占百分比分别为16.40±0.60%、18.35±1.85%和56.88±3.06%,上述结果提示化合物8的A549细胞周期分布同阳性药紫杉醇类似,作用于人非小细胞肺癌细胞系(A549)的细胞G2/M期。
4.5化合物作用于人恶性黑色素瘤细胞系(A375)的细胞周期检测
化合物8作用于人恶性黑色素瘤细胞系(A375)的细胞周期检测结果如下:空白对照组的A375细胞周期分布G0/G1、S、G2/M期所占百分比为42.67±1.28%、26.27±4.61%和21±4.57%;化合物8给药组的A375细胞周期分布G0/G1、S、G2/M期所占百分比为26.42±3.47%和45.08±1.22%和20.86±2.52%;5-Fu阳性给药组的A375细胞周期分布G0/G1、S、G2/M期所占百分比为31.1±14.16%、11.25±2.54%和9.94±7.88%。紫杉醇阳性给药组的A375细胞周期分布G0/G1、S、G2/M期所占百分比分别为23.07±0.45%、35.73±1.43%和29.57±4.76%。上述结果提示化合物8的A375细胞周期分布同阳性药紫杉醇类似。
实施例12 2,3-二氢喹唑啉-4(1H)-酮衍生物急性毒性实验
以活性较好的化合物8为例考察2,3-二氢喹唑啉-4(1H)-酮的C2位衍生物急性毒性。
一、实验材料与方法:
1.实验动物:KM小鼠,雄性,体质量36±4g,SPF级
2.实验耗材:
(1)20%DMSO溶液:分析纯DMSO用双蒸水稀释至浓度为20%
(2)0.2%吐温80-5%葡萄糖水溶液(100ml):5g葡萄糖溶于100ml双蒸水中,充分溶解后,加入0.2ml吐温80溶液,充分混匀,即得。
(3)化合物组分化合物8供试品溶液:称取化合物4 800mg,溶于20%DMSO中,加入0.2%吐温80-5%葡萄糖水溶液,混匀,定容至50mL。即得供试液16mg/mL(其中DMSO浓度为1.6%,v/v),静置5h后仍有部分沉淀,适量加入0.5%CMC-Na助悬,额外加入少量DMSO,致终浓度为4.8%。
3.实验动物分组
(1)低浓度组:20mg/kg 3只
(2)中浓度组:100mg/kg 3只
(3)高浓度组:200mg/kg 3只
(4)空白对照组等体积的溶剂1只
4.实验过程:各组小鼠每天11:00灌胃相应剂量的化合物8,隔天记录小鼠的基本生长情况和体重,连续给药7天。结束后,5%水合氯醛麻醉,下腔静脉采血后,肝素抗凝采血管,3500rpm离心10min,吸取上清液转移至新的EP管中,-80℃保存备用。取小鼠肝小叶和肾组织,中性多聚甲醛固定液固定24h后,脱水、包埋后,行H&E染色。
二、实验结果
小鼠体重观察结果见表2,小鼠肝肾生化指标检测结果见表3,小鼠肝组织(200×)病理切片见图1,小鼠肾组织(200×)病理切片见图2。从上述结果看,三个剂量组小鼠连续7天给药后,体重毛发没有明显变化,肝肾功能指标正常,小鼠肝、肾组织病理切片也显示化合物8对肝肾无明显损害,上述结果表明2,3-二氢喹唑啉-4(1H)-酮的C2位衍生物是一种新型安全有效的抗肿瘤药物。
表2小鼠体重观察结果(单位:g)
表3小鼠肝肾生化指标检测结果
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型,均应包含在本发明的保护范围之内。
Claims (10)
2.一种权利要求1所述的2,3-二氢喹唑啉-4(1H)-酮衍生物和/或其药用盐在制备抗肿瘤药物中的应用。
3.根据权利要求2所述的应用,其特征在于,所述肿瘤选自肝癌、胶质瘤、肺癌、胰腺癌和黑色素瘤中的一种或多种。
4.根据权利要求2所述的应用,其特征在于,所述药用盐由所述2,3-二氢喹唑啉-4(1H)-酮衍生物与无机酸或有机酸反应得到;优选地,所述无机酸选自盐酸、氢溴酸、氢氟酸、硫酸、硝酸和磷酸中的至少一种;所述的有机酸选自甲酸、乙酸、丙酸、柠檬酸、甲磺酸、乙磺酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、草酸和酒石酸中的至少一种。
6.根据权利要求5所述的2,3-二氢喹唑啉-4(1H)-酮衍生物的制备方法,其特征在于,反应过程中加入对甲基苯磺酸,控制所述反应温度为50~70℃。
7.根据权利要求5所述的2,3-二氢喹唑啉-4(1H)-酮衍生物的制备方法,其特征在于,所述反应在溶剂中进行,所述溶剂为醇,优选地,所述溶剂为乙醇。
8.一种药物制剂,其特征在于,所述药物制剂包含权利要求1所述的2,3-二氢喹唑啉-4(1H)-酮衍生物和/或其药用盐。
9.根据权利要求8所述的药物制剂,其特征在于,所述药物制剂的剂型为片剂、丸剂、胶囊剂、注射剂、混悬剂、乳剂或植入剂。
10.一种权利要求8所述的药物制剂在制备抗肿瘤药物中的应用;优选地,所述肿瘤选自肝癌、胶质瘤、肺癌、胰腺癌和黑色素瘤中的一种或多种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211374747.4A CN115677600A (zh) | 2022-11-04 | 2022-11-04 | 2,3-二氢喹唑啉-4(1h)-酮衍生物及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211374747.4A CN115677600A (zh) | 2022-11-04 | 2022-11-04 | 2,3-二氢喹唑啉-4(1h)-酮衍生物及其制备方法与应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115677600A true CN115677600A (zh) | 2023-02-03 |
Family
ID=85048770
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211374747.4A Pending CN115677600A (zh) | 2022-11-04 | 2022-11-04 | 2,3-二氢喹唑啉-4(1h)-酮衍生物及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115677600A (zh) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070134161A1 (en) * | 2004-06-01 | 2007-06-14 | Brown Milton L | Methods of determining beta-iii tubulin expression |
-
2022
- 2022-11-04 CN CN202211374747.4A patent/CN115677600A/zh active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070134161A1 (en) * | 2004-06-01 | 2007-06-14 | Brown Milton L | Methods of determining beta-iii tubulin expression |
Non-Patent Citations (4)
Title |
---|
AASHIQ HUSSAIN ETAL: "A novel PI3K axis selective molecule exhibits potent tumor inhibition in colorectal carcinogenesis", 《MOLECULAR CARCINOGENESIS》, pages 6 * |
GAURAVI YASHWANTRAO: "Solvent-Free, Mechanochemically Scalable Synthesis of 2, 3-Dihydroquinazolin-4(1H)-one Using Brønsted Acid Catalyst", 《ACS SUSTAINABLE CHEM. ENG.》, pages 2 * |
REGISTRY数据库: "RN:2759372-57-9、1354063-84-5、1057097-59-2", 《STN ON THE WEB REGISTRY数据库》 * |
SHINDE, ACHUT R.ETAL: "One-pot B(C6F5)3 catalyzed cascade synthesis of 2-substituted-2, 3-dihydroquinazolin-4(1H)-ones", 《SYNTHETIC COMMUNICATIONS》, pages 3 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105829312B (zh) | 一种n-苄基色胺酮衍生物及其制备方法和应用 | |
JP3040486B2 (ja) | キナゾリン誘導体,その製法及び抗癌作用を得るためのそれを含有する医薬品 | |
JPH11507329A (ja) | キナゾリン誘導体 | |
JPH11504031A (ja) | キナゾリン誘導体 | |
CN107929276A (zh) | 一种紫杉醇和cdks激酶抑制剂联合用药物组合物 | |
WO2006116733A2 (en) | Protein kinase inhibitors | |
CN107245075B (zh) | 2,4,6-三取代吡啶并[3,4-d]嘧啶类化合物及其盐和应用 | |
JP2015515995A (ja) | キナーゼ阻害剤として有用な置換アミノキナゾリン | |
CN103172641B (zh) | 杂环胺基烷氧基取代的喹唑啉衍生物及其用途 | |
CN114920704B (zh) | 一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 | |
CA3091153A1 (en) | Therapeutic agent for hepatocellular carcinoma | |
CN115677600A (zh) | 2,3-二氢喹唑啉-4(1h)-酮衍生物及其制备方法与应用 | |
CN105384738A (zh) | 作为蛋白激酶抑制剂的杂环类化合物及其制备方法和用途 | |
CN107892691B (zh) | 2,8,9-三取代-9h-嘌呤类化合物及其盐和应用 | |
CN114409636B (zh) | 一种喹唑啉酮化合物或其药学上可接受的盐及其制备方法和应用 | |
CN100415745C (zh) | 作为可诱导的no合成酶抑制剂的咪唑并吡啶衍生物 | |
US20230322687A1 (en) | Salt of arylaminoquinazoline-containing compound, and preparation method therefor and use thereof | |
Yong et al. | Synthesis of Isoxazole moiety containing thieno [2, 3-d] pyrimidine Derivatives and preliminarily in vitro anticancer activity (Part II) | |
US20230183265A1 (en) | Crystal Form of Macrocyclic Tyrosine Kinase Inhibitor and Preparation Method therefor | |
CN111362924B (zh) | 氘代的嘧啶衍生物及其用途 | |
CN109879887B (zh) | 含吲哚结构的噻吩并[3,2-d]嘧啶类衍生物及其应用 | |
CN108752336B (zh) | 咪唑并喹啉类衍生物及其用途 | |
CN102942561A (zh) | 4-氨基喹唑啉杂环化合物及其用途 | |
US10544144B2 (en) | Fused pyrimidine piperidine cyclic derivative, preparation process and use thereof | |
CN116239603A (zh) | 一种2-氨基嘧啶杂环类化合物及其应用 |
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 |