CN110283130A - 一种1-(2,5-二甲氧基苯基)-3-取代脲类结肠癌抑制剂及其制备和应用 - Google Patents
一种1-(2,5-二甲氧基苯基)-3-取代脲类结肠癌抑制剂及其制备和应用 Download PDFInfo
- Publication number
- CN110283130A CN110283130A CN201910605375.3A CN201910605375A CN110283130A CN 110283130 A CN110283130 A CN 110283130A CN 201910605375 A CN201910605375 A CN 201910605375A CN 110283130 A CN110283130 A CN 110283130A
- Authority
- CN
- China
- Prior art keywords
- dimethoxyphenyl
- cell
- pyrimidine
- urea compound
- substitute urea
- 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.)
- Granted
Links
- -1 1- (2,5- Dimethoxyphenyl) -3- substituted urea Chemical class 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 230000003327 cancerostatic effect Effects 0.000 title description 3
- 239000003795 chemical substances by application Substances 0.000 title description 3
- 210000001072 colon Anatomy 0.000 title description 3
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 16
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 12
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 11
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000003939 benzylamines Chemical class 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 30
- 239000004202 carbamide Substances 0.000 claims description 26
- 239000013067 intermediate product Substances 0.000 claims description 12
- 239000012948 isocyanate Substances 0.000 claims description 9
- 150000002513 isocyanates Chemical class 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- GWZBHIYSTKRISW-UHFFFAOYSA-N phenylmethanamine pyrimidine Chemical compound N1=CN=CC=C1.C(C1=CC=CC=C1)N GWZBHIYSTKRISW-UHFFFAOYSA-N 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- NAZDVUBIEPVUKE-UHFFFAOYSA-N 2,5-dimethoxyaniline Chemical compound COC1=CC=C(OC)C(N)=C1 NAZDVUBIEPVUKE-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 150000003672 ureas Chemical class 0.000 abstract description 4
- 201000010989 colorectal carcinoma Diseases 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 210000004072 lung Anatomy 0.000 abstract 1
- 230000035755 proliferation Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 24
- 235000013877 carbamide Nutrition 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 17
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000005311 nuclear magnetism Effects 0.000 description 6
- 239000004576 sand Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 229960001686 afatinib Drugs 0.000 description 3
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 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 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000000643 oven drying Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000007790 scraping Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- 206010013457 Dissociation Diseases 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 208000018459 dissociative disease Diseases 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 229960003278 osimertinib Drugs 0.000 description 1
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 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 1
- 238000011160 research Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940121646 third-generation egfr tyrosine kinase inhibitor Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- 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
Abstract
本发明公开了一种能作用于结肠癌的1‑(2,5‑二甲氧基苯基)‑3‑取代脲类化合物及其制备方法与应用。本发明的1‑(2,6‑二氯苯基)‑3‑(6‑(取代苄胺基)嘧啶‑4‑基)脲类化合物对BEAS‑2B细胞(肺正常细胞)的增殖无毒性作用，而对所选的三种结肠癌细胞系，包括SW116细胞(人大肠癌细胞),SW480细胞(人结肠癌细胞)和SW620细胞(人结肠癌细胞)都有一定的抑制作用，表现出一定的抗肿瘤活性。
Description
技术领域
本发明涉及医药化学技术领域，尤其涉及一种1-(2,5-二甲氧基苯基)-3-(6-(取代苄胺基)嘧啶-4-基)脲类结肠癌小分子抑制剂及其制备方法与应用。
背景技术
结肠癌是发病率、死亡率较高的癌症，在结肠癌前期治疗手段中，由于选择性差，带来了很大的毒副作用，限制了其临床应用疗效。
近十几年来，靶向治疗成为研究热点之一，其中表皮生长因子受体(epidermalgrowth factor receptor，EGFR)备受关注。第一代EGFR抑制剂如吉非替尼(Gefitinib)和厄洛替尼(Erlotinib)治疗癌症患者一段时间后，大多数都出现了对EGFR-TKI的耐药。第二代抑制剂如阿法替尼(Afatinib)可以有效的缓解第一代抑制剂所引起的耐药，但是FGFR1激活已被证明是阿法替尼耐药的重要机制之一。第三代EGFR-TKI类药物如AZD9291、CO-1686等具有良好的靶向选择性，能够抑制T790M突变(EGFR 20外显子中的一个点突变)和降低毒副作用，然而，获得性耐药在该类患者治疗过程中同样无法避免，如三代抑制剂会出现C797S突变(EGFR 19外显子中的一个点突变)。
发明内容
本发明提供了一种1-(2,5-二甲氧基苯基)-3-取代脲类结肠癌抑制剂及其制备和应用
本发明的技术方案如下：
一种1-(2,5-二甲氧基苯基)-3-取代脲类化合物，结构如式(I)所示：
R为C1～C5烷基、C1～C5烷基、卤素、三氟甲基中的一个或者多个。
作为优选，所述的R为甲基、甲氧基、F、Cl、Br、三氟甲基中的一个或者多个。
作为优选，为化合物W1～W10中的任意一个：
R的取代基如下：
作为优选，所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物为化合物W10；
化合物W10的名称为1-(2,5-二甲氧基苯基)-3-(6-((4-(哌啶-1-基)苄胺基)氨基)嘧啶-4-基)脲，结构式如下：
本发明还提供了一种所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物的制备方法，包括以下步骤：
(1)4-氨基-6-氯嘧啶与取代苄胺进行反应，得到嘧啶苄胺中间产物；
(2)2,5-二甲氧基苯胺与三光气进行反应，得到异氰酸酯中间产物；
(3)嘧啶苄胺中间产物与异氰酸酯中间产物进行取代反应，得到所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物。
嘧啶苄胺中间产物的合成方法如下：
步骤一：取一干燥的三口反应瓶，放入磁石。加入4-氨基-6-氯嘧啶(1eq)，KI(0.5eq)，并用的无水乙醇(35mL)溶解。在磁力搅拌器上，搅拌加热10min后，加入三氟乙酸(200mL)。活化。大约1h后，加入无水乙醇(15mL)溶解的取代苄胺(0.8eq)反应。注意，要以滴加的方式加进去，以达到长时过量反应的效果，滴加时间控制在1h左右。
步骤二：用TLC法，检测反应进程和反应效果。一般是反应36h后，反应几乎完全。反应完全后，先旋干溶剂无水乙醇，然后加入一定量的乙酸乙酯溶解。先用适量的20％的碳酸氢钠溶液除酸，后再加入一定量的50％的氯化钠溶液萃取分层，收集有机层并旋干至剩一定量，加入无水硫酸钠适量，除水过夜。
步骤三：抽滤，制砂，称取原料总和15到20倍的柱层硅胶粉装柱，过柱收集产物点。一般先是用石油醚:乙酸乙酯＝2:1过出第一个点(苯胺类点)，石油醚:乙酸乙酯＝1:1过出第二个点(嘧啶类点)，乙酸乙酯或甲醇冲出产物点。收集旋干产物点，放烘箱干燥，打质谱及核磁，验证。
所述的异氰酸酯中间产物的合成方法如下：
步骤一：取一干燥的三口反应瓶，加入磁石。称取三光气(0.5eq)，并用二氯甲烷(20mL)溶解，超声使其充分。于0℃下，缓慢滴加二氯甲烷(10mL)溶解的2,5-二甲氧基苯胺(1eq)，每一分钟一滴，滴加时间控制在0.5h左右。滴毕，记得加2～3滴的三乙胺。加热回流反应3～6h,反应一般会完全。减压浓缩至干，剩余物用乙酸乙酯溶解，依次用10％的硫酸氢钾溶液除碱、20％的碳酸氢钠溶液除酸和50％的氯化钠溶液洗涤除无机相，收集有机相并旋干，经无水硫酸钠除水干燥过夜后，抽滤，制砂。
步骤二：制砂，装柱，过出2,5-二甲氧基苯胺后，分离提纯异氰酸酯。送去打质谱和核磁，验证。
所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物的合成方法如下：
步骤一：取一干燥的三口反应瓶，加入磁石。称取的嘧啶苄胺(1eq)，异氰酸酯(1.2eq)，并用甲苯(10mL)溶解，于70～80℃加热回流反应8～10h，基本反应完全，TLC检测。冷却至室温，滤饼用甲苯洗涤2～3次，刮下后用乙酸乙酯溶解，20％的碳酸氢钠溶液洗涤除酸，再加入50％的氯化钠溶液萃取分层。收集并旋干有机层。
步骤二：点板检测纯度，送去打质谱及核磁，验证。
本发明还提供了一种所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物的应用，所述的化合物用于制备抗肿瘤药物。
作为优选，所述的抗肿瘤药物用于预防和治疗结肠癌。
作为优选，所述的抗肿瘤药物用于抑制结肠癌细胞；
本发明的1-(2,5-二甲氧基苯基)-3-(6-(取代苄胺基)嘧啶-4-基)脲类衍生物表现出一定的抗肿瘤活性。根据抗肿瘤活性测试结果，化合物对三个非结肠癌细胞系，都表现出了一定的抑制活性。
附图说明
图1为实施例2中测得的本发明化合物作用下BEAS-2B细胞的存活率；
图2为实施例2中测得的本发明化合物对SW116细胞的抑制率；
图3为实施例2中测得的本发明化合物对SW480细胞的抑制率；
图4为实施例2中测得的本发明化合物对SW620细胞的抑制率；
具体实施方式
下面的实施例是对本发明的进一步详细描述。
实施例1化合物的合成
1.1化合物的具体合成路线如下所示：
1.2合成步骤
a.第一步中间产物的合成：
步骤一：取一干燥的三口反应瓶，放入磁石。加入4-氨基-6-氯嘧啶(1eq)，KI(0.5eq)，并用的无水乙醇(35mL)溶解。在磁力搅拌器上，搅拌加热10min后，加入三氟乙酸(200mL)。活化。大约1h后，加入无水乙醇(15mL)溶解的取代苄胺(0.8eq)反应。注意，要以滴加的方式加进去，以达到长时过量反应的效果，滴加时间控制在1h左右。
步骤二：用TLC法，检测反应进程和反应效果。一般是反应36h后，反应几乎完全。反应完全后，先旋干溶剂无水乙醇，然后加入一定量的乙酸乙酯溶解。先用适量的20％的碳酸氢钠溶液除酸，后再加入一定量的50％的氯化钠溶液萃取分层，收集有机层并旋干至剩一定量，加入无水硫酸钠适量，除水过夜。
步骤三：抽滤，制砂，称取原料总和15到20倍的柱层硅胶粉装柱，过柱收集产物点。一般先是用石油醚:乙酸乙酯＝2:1过出第一个点(苯胺类点)，石油醚:乙酸乙酯＝1:1过出第二个点(嘧啶类点)，乙酸乙酯或甲醇冲出产物点。收集旋干产物点，放烘箱干燥，打质谱及核磁，验证。
b.第二步中间产物的合成：
步骤一：取一干燥的三口反应瓶，加入磁石。称取三光气(0.5eq)，并用二氯甲烷(20mL)溶解，超声使其充分。于0℃下，缓慢滴加二氯甲烷(10mL)溶解的2,5-二甲氧基苯胺(1eq)，每一分钟一滴，滴加时间控制在0.5h左右。滴毕，记得加2～3滴的三乙胺。加热回流反应3～6h,反应一般会完全。减压浓缩至干，剩余物用乙酸乙酯溶解，依次用10％的硫酸氢钾溶液除碱、20％的碳酸氢钠溶液除酸和50％的氯化钠溶液洗涤除无机相，收集有机相并旋干，经无水硫酸钠除水干燥过夜后，抽滤，制砂。
步骤二：制砂，装柱，过出2,5-二甲氧基苯胺后，分离提纯异氰酸酯。送去打质谱和核磁，验证。
c.第三步目标产物的合成：
步骤一：取一干燥的三口反应瓶，加入磁石。称取的嘧啶苄胺1eq)，异氰酸酯(1.2eq)，并用甲苯(10mL)溶解，于70～80℃加热回流反应8～10h，基本反应完全，TLC检测。冷却至室温，滤饼用甲苯洗涤2～3次，刮下后用乙酸乙酯溶解，20％的碳酸氢钠溶液洗涤除酸，再加入50％的氯化钠溶液萃取分层。收集并旋干有机层。
步骤二：点板检测纯度，送去打质谱及核磁，验证。
1.3实验结果
合成的所有目标化合物W1～W10结构如下：
R的取代基如下：
合成的包括活性化合物在内的目标化合物的MS、1H NMR和13C NMR等理化数据如下：
1-(2,5-Dimethoxyphenyl)-3-(6-((3,5-dimethoxyphenyl)benzylamine)pyrimidin-4
-yl)urea(W1).
Yellow powder,yield:44.1％；Mp/℃:185.4～186.4；ESI-MS[M+Na]+:440.24；1HNMR(600MHz,CDCL3)δ(ppm):8.441(s,1H,-NH-),7.974(s,1H,2-pyrimidine-H),6.845(s,1H,Ar-H),6.546(m,1H,Ar-H),6.524(d,J＝1.8Hz,1H,Ar-H),6.521(d,J＝1.8Hz,1H,Ar-H),6.441(s,1H,Ar-H),6.429(s,1H,Ar-H),5.354(s,2H,-CH2-),4.546(s,1H,5-pyrimidine-H),3.883(s,3H,-OCH3),3.743(s,6H,-OCH3),3.752(s,3H,-OCH3).13CNMR(600MHz,DMSO-d6)δ(ppm):161.021,160.758,160.543,157.742,156.454,153.317,151.840,142.401,141.642,129.142,111.864,106.377,105.646,99.949,98.249,94.245,90.183,56.544,55.270,55.149,55.047.
1-(6-((3-Chloro-4-fluorophenyl)benzylamine)pyrimidin-4-yl)-3-(2,5-dimethoxyphen
yl)urea(W2).
Yellow powder,yield:42.0％；Mp/℃:215.8～216.5；ESI-MS[M+Na]+:432.11；1HNMR(600MHz,CDCL3)δ(ppm):8.323(s,1H,-NH-),8.173(s,1H,2-pyrimidine-H),7.826(s,1H,-NH-),7.228(m,3H,Ar-H),7.114(d,J＝9.0Hz,1H,Ar-H),6.839(d,J＝9.0Hz,1H,Ar-H),6.595(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),3.283(s,3H,-OCH3),3.791(s,3H,-OCH3).13CNMR(600MHz,DMSO-d6)δ(ppm):160.730,152.676,157.009,153.323,151.795,142.393,132.540,129.069,120.765,119.726,119.228,116.813,116.623,111.869,106.422,105.523,90.567,56.527,55.267.
1-(2,5-Dimethoxyphenyl)-3-(6-((3-fluoro-4-methylphenyl)benzylamine)pyrimidin
-4-yl)urea(W3).
White powder,yield:42.8％；Mp/℃:193.8～194.2；ESI-MS[M+Na]+:412.95；1HNMR(600MHz,CDCL3)δ(ppm):8.287(s,1H,-NH-),7.126(s,2H,2-pyrimidine-H+Ar-H),7.025(s,1H,Ar-H),6.924(d,J＝7.2Hz,1H,Ar-H),6.922(d,J＝7.2Hz,1H,Ar-H),6.592(d,J＝8.4Hz,1H,Ar-H),6.579(d,J＝8.4Hz,1H,Ar-H),5.829(s,1H,5-pyrimidine-H),5.324(s,2H,-CH2-),3.776(s,6H,-OCH3),2.226(s,3H,-C H3).13CNMR(600MHz,DMSO-d6)δ(ppm):160.942,160.625,157.225,155.429,152.262,151.620,141.208,140.425,131.322,115.731,115.125,96.922,94.721,93.999,90.720,84.127,55.021,13.512.
1-(2,5-dimethoxyphenyl)-3-(6-((3-fluoro-5-methylphenyl)benzylamine)pyrimidin
-4-yl)urea(W4).
White powder,yield:42.3％；Mp/℃:192.3～195.0；ESI-MS[M+Na]+:412.38；1HNMR(600MHz,CDCL3)δ(ppm):8.426(s,1H,2-pyrimidine-H),7.193(s,1H,Ar-H),7.021(s,1H,Ar-H),6.992(d,J＝7.8Hz,1H,Ar-H),6.929(d,J＝7.8Hz,1H,Ar-H),6.926(s,1H,Ar-H),6.792(s,1H,-NH-),6.253(s,1H,Ar-H),6.240(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),3.826(s,6H,-OCH3),2.226(s,3H,-CH3).13CN MR(600MHz,DMSO-d6)δ(ppm):163.168,161.220,160.620,157.423,151.628,141.629,140.082,115.529,108.900,103.485,96.952,94.820,94.010,91.025,55.022,55.023,21.126.
1-(2,5-Dimethoxyphenyl)-3-(6-((3,4-dimethylphenyl)benzylamine)pyrimidin
-4-yl)urea(W5).
White powder,yield:52.1％；Mp/℃:197.2～198.0；ESI-MS[M+Na]+:408.91；1HNMR(600MHz,CDCL3)δ(ppm):8.332(s,1H,-NH-),7.932(s,1H,2-pyrimidine-H),7.132(d,J＝7.8Hz,1H,Ar-H),7.139(d,J＝7.8Hz,1H,Ar-H),7.033(d,J＝7.8Hz,1H,Ar-H),7.030(d,J＝7.8Hz,1H,Ar-H),6.846(s,1H,Ar-H),6.532(m,1H,Ar-H),6.308(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),3.834(s,3H,-OCH3),3.733(s,3H,-OCH3),2.257(s,6H,-CH3).13CNMR(600MHz,DMSO-d6)δ(ppm):161.235,157.538,156.838,153.334,151.835,142.418,137.433,136.236,130.332,129.313,129.130,121.735,118.030,111.836,106.231,105.632,89.233,56.569,55.237,19.536,18.638.
1-(2,5-Dimethoxyphenyl)-3-(6-((4-methoxy-3-methylphenyl)benzylamine)pyrimidin
-4-yl)urea(W6).
Black powder,yield:48.3％；Mp/℃:183.8～184.4；ESI-MS[M+Na]+:424.92；1HNMR(600MHz,CDCL3)δ(ppm):8.339(s,1H,-NH-),8.132(s,1H,-N H-),7.927(s,1H,2-pyrimidine-H),7.133(s,1H,-NH-),7.032(d,J＝7.8Hz,1H,Ar-H),7.053(d,J＝7.8Hz,1H,Ar-H),7.033(s,1H,Ar-H),6.831(d,J＝8.4Hz,1H,Ar-H),6.847(d,J＝8.4Hz,1H,Ar-H),6.371(s,1H,Ar-H),5.637(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),3.831(s,3H,-OCH3),3.3855(s,3H,-OCH3),3.763(s,3H,-OCH3),2.235(s,3H,-CH3).13CNMR(600MHz,DMSO-d6)δ(ppm):156.935,154.870,153.333,151.833,142.436,130.129,129.214,126.423,125.783,122.350,111.838,110.837,106.230,105.637,81.113,56.534,55.432,16.038.
1-(2,5-Dimethoxyphenyl)-3-(6-((4-ethylphenyl)benzylamine)pyrimidin-4-yl)urea(W7).
Yellow powder,yield:53.3％；Mp/℃:197.7～198.5；ESI-MS[M+Na]+:408.98；1HNMR(600MHz,CDCL3)δ(ppm):8.331(s,1H,-NH-),7.936(s,1H,2-pyrimidine-H),7.837(d,J＝2.4Hz,1H,Ar-H),7.833(d,J＝2.4Hz,1H,Ar-H),6.840(d,J＝7.8Hz,1H,Ar-H),6.837(d,J＝7.8Hz,1H,Ar-H),6.830(d,J＝8.4Hz,1H,Ar-H),6.792(d,J＝8.4Hz,1H,Ar-H),6.579(s,1H,Ar-H),6.525(s,1H,5-pyrimidine-H),5.352(s,2H,-CH2-),3.722(s,6H,-OCH3),2.683(m,2H,-CH2CH3),1.270(t,J＝7.2Hz,3H,-CH3).13CNMR(600MHz,DMSO-d6)δ(ppm):161.191,157.526,156.922,153.228,151.820,142.464,137.508,129.627,127.926,120.402,111.845,111.622,106.229,106.022,105.628,56.524,56.327,55.280,27.526,15.626.
1-(6-((3-(Tert-butyl)phenyl)benzylamine)pyrimidin-4-yl)-3-(2,5-dimetho xyphenyl)
urea(W8).
Taupe powder,yield:48.2％；Mp/℃:213.2～214.2；ESI-MS[M+Na]+:436.95；1HNMR(600MHz,CDCL3)δ(ppm):8.272(s,1H,-NH-),8.122(s,1H,2-p yrimidine-H),7.392(s,1H,Ar-H),7.382(t,J＝6.6～7.8Hz,1H,Ar-H),7.221(s,1H,Ar-H),7.122(d,J＝6.0Hz,1H,Ar-H),7.122(d,J＝6.0Hz,1H,Ar-H),6.228(m,2H,Ar-H),5.801(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),3.802(s,3H,-OCH3),3.625(s,3H,-OCH3),1.323(s,9H,-CH3).13CNMR(600MHz,DMSO-d6)δ(ppm):151.892,150.420,137.622,128.724,121.622,119.582,119.385,81.929,72.213,60.226,34.422,31.020,31.028.
1-(6-(Benzo[d][1,3]dioxol-5-ylbenzylamine)pyrimidin-4-yl)-3-(2,5-dimet hoxyphenyl)
urea(W9).
Taupe powder,yield:38.2％；Mp/℃:248.8～250.0；ESI-MS[M+Na]+:424.24；1HNMR(600MHz,CDCL3)δ(ppm):8.156(s,1H,2-pyrimidine-H),7.027(s,1H,Ar-H),6.849(d,J＝9.0Hz,1H,Ar-H),6.832(d,J＝9.0Hz,1H,Ar-H),6.821(s,1H,Ar-H),6.725(s,1H,Ar-H),6.722(s,1H,-NH-),6.029(d,J＝9.6Hz,1H,Ar-H),6.213(d,J＝9.6Hz,1H,Ar-H),5.681(s,1H,5-pyrimidine-H),5.324(s,2H,-CH2-),4.972(s,2H,CH2),3.908(s,3H,-OCH3),3.722(s,3H,-OCH3).13CNMR(600MHz,DMS O-d6)δ(ppm):162.824,160.524,156.827,147.160,142.420,134.524,113.527,108.024,105.628,103.026,100.827,83.358,56.523,55.280.
1-(2,5-dimethoxyphenyl)-3-(6-((4-(piperidin-1-yl)phenyl)benzylamine)py rimidin-4-yl)urea(W10).
Black powder,yield:42.2％；Mp/℃:250.3～250.9；ESI-MS[M+Na]+:463.90；1HNMR(600MHz,CDCL3)δ(ppm):8.344(s,1H,-NH-),7.962(s,1H,2-p yrimidine-H),7.202(s,1H,Ar-H),7.192(d,J＝8.4Hz,1H,Ar-H),7.182(d,J＝8.4Hz,1H,Ar-H),7.012(d,J＝8.4Hz,1H,Ar-H),6.992(d,J＝8.4Hz,1H,Ar-H),6.836(d,J＝9.0Hz,1H,Ar-H),6.523(m,1H,Ar-H),6.225(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),3.882(s,3H,-OCH3),3.771(s,3H,-OCH3),3.182(m,4H,-CH2),1.740(m,4H,-CH2),1.612(m,2H,-CH2).13CNMR(600MHz,DMSO-d6)δ(ppm):161.372,157.532,156.929,152.321,151.857,142.423,129.205,121.944,116.885,111.832,106.225,105.683,88.792,56.572,55.276,50.708,25.125,23.526.
本发明所合成目标化合物的性状及其溶解性如下：
目标化合物产率普遍较高。化合物W3-5均为白色固体；W1-2，W7，均为黄色固体；W8-9为灰褐色固体；W6，W10为黑色固体。易溶于乙酸乙酯、乙腈、二氯甲烷、DMSO、DMF；微溶于石油醚、甲醇、乙醇；不溶于甲苯。
本发明合成的目标化合物，在MS谱图中均显示了[M+1]+峰，且信号较强，部分化合物存在着同位素峰。1H-NMR谱图结果显示，所有目标化合物的氢信号，以及其化学位移，在图谱上都能清晰的看出。以DMSO-d6为溶剂时，核磁氢谱数据显示完全，即化合物氢的理论个数，与核磁氢谱图上氢的个数相吻合；而以CDCL3-d6为溶剂时，大多数的目标化合物的核磁氢谱数据显示不完全，核磁氢谱图上通常没有脲基胺上的两个氢。13C-NMR谱图结果显示，目标化合物碳峰位移及数目基本上与理论数据相符。
实施例2化合物抗肿瘤细胞活性
2.1MTT法测试化合物抗肿瘤活性
本实验采用MTT法。所选的正常肺细胞为BEAS-2B细胞；所选的三个癌细胞则包括SW116细胞(人大肠癌细胞),SW480细胞(人结肠癌细胞)和SW620细胞(人结肠癌细胞)。选取对数生长的上述细胞，将这些细胞消化，收集，并用细胞计数板进行计数。接着，将记过数的细胞，稀释至合适的浓度(5*10^4个/mL～8*10^4个/mL)，按每孔100μL将稀释的细胞悬液用排枪加入到96孔板中进行培养，并记得在同一块孔板上设置只含培养基的空白对照孔；铺板过夜培养后，更换为新鲜培养基，每孔加入一系列浓度梯度稀释的受试目标化合物，等药物作用72小时后，检测细胞的存活率；将20μL的MTT检测液，加入到96孔板的每个孔中，后将96孔板放置在37℃培养箱中，孵育四小时。去上清，并加入150μL的DMSO，溶解MTT甲臢沉淀。最后以酶标仪检测紫外吸收波长在490nm处的每孔的吸光值，并进行换算，计算出相应的细胞存活率，抑制率或IC50值等。本实验需进行至少三次重复实验，减小实验误差。
2.2实验结果
如下面的图1所示，在10μM的浓度下，所有受试目标化合物，对应的BEAS-2B细胞存活率均在70％以上。图2显示的是受试化合物对SW116细胞的抑制效果；图3所示为受试化合物对SW480细胞的抑制效果；受试化合物对SW620细胞的抑制效果，如图4所示。
尽管已经示出和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由所附权利要求及其等同物限定。
Claims (8)
1.一种1-(2,5-二甲氧基苯基)-3-取代脲类化合物，其特征在于，结构如式(I)所示：
R为C1～C5烷基、C1～C5烷基、卤素、三氟甲基中的一个或者多个。
2.根据权利要求1所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物，其特征在于，所述的R为甲基、甲氧基、F、Cl、Br、三氟甲基中的一个或者多个。
3.根据权利要求1所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物，其特征在于，为化合物W1～W10的任意一个：
R的取代基如下：
4.根据权利要求1所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物，其特征在于，为化合物W10；
化合物W10的结构式如下：
5.一种如权利要求1～4任一项所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物的制备方法，其特征在于，包括以下步骤：
(1)4-氨基-6-氯嘧啶与取代苄胺进行反应，得到嘧啶苄胺中间产物；
(2)2,5-二甲氧基苯胺与三光气进行反应，得到异氰酸酯中间产物；
(3)嘧啶苄胺中间产物与异氰酸酯中间产物进行取代反应，得到所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物。
6.一种如权利要求1～4任一项所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物的应用，其特征在于，所述的化合物用于制备抗肿瘤药物。
7.根据权利要求6所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物的应用，其特征在于，所述的抗肿瘤药物用于预防和治疗结肠癌。
8.根据权利要求6所述的1-(2,5-二甲氧基苯基)-3-取代脲类化合物的应用，其特征在于，所述的抗肿瘤药物用于抑制结肠癌细胞。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910605375.3A CN110283130B (zh) | 2019-07-05 | 2019-07-05 | 一种1-(2,5-二甲氧基苯基)-3-取代脲类结肠癌抑制剂及其制备和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910605375.3A CN110283130B (zh) | 2019-07-05 | 2019-07-05 | 一种1-(2,5-二甲氧基苯基)-3-取代脲类结肠癌抑制剂及其制备和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110283130A true CN110283130A (zh) | 2019-09-27 |
| CN110283130B CN110283130B (zh) | 2023-12-19 |
Family
ID=68020753
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910605375.3A Active CN110283130B (zh) | 2019-07-05 | 2019-07-05 | 一种1-(2,5-二甲氧基苯基)-3-取代脲类结肠癌抑制剂及其制备和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110283130B (zh) |
Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2386218A1 (en) * | 1999-10-07 | 2001-04-12 | Amgen Inc. | Triazine kinase inhibitors |
| CN101035769A (zh) * | 2004-06-24 | 2007-09-12 | 诺瓦提斯公司 | 作为激酶抑制剂的嘧啶脲衍生物 |
| CN101336237A (zh) * | 2005-12-21 | 2008-12-31 | 诺瓦提斯公司 | 作为fgf抑制剂的嘧啶基芳基脲衍生物 |
| CN102250065A (zh) * | 2011-05-20 | 2011-11-23 | 浙江海正药业股份有限公司 | 取代的三嗪苯脲衍生物及其用途 |
| CN102666498A (zh) * | 2009-08-28 | 2012-09-12 | 健泰科生物技术公司 | Raf抑制剂化合物及其使用方法 |
| WO2016049774A1 (en) * | 2014-10-03 | 2016-04-07 | The Royal Institution For The Advancement Of Learning/Mcgill University | Urea and bis-urea based compounds and analogues thereof useful in the treatment of androgen receptor mediated diseases or disorders |
| US20160176825A1 (en) * | 2013-07-09 | 2016-06-23 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
| CN107530304A (zh) * | 2015-02-27 | 2018-01-02 | 科泰纳制药公司 | Olig2活性的抑制 |
| WO2018045969A1 (zh) * | 2016-09-07 | 2018-03-15 | 法玛科技顾问股份有限公司 | 活化腺苷单磷酸活化蛋白激酶之化合物 |
| CN108348519A (zh) * | 2015-07-20 | 2018-07-31 | 台北医学大学 | 经氯苯取代的氮杂芳基化合物 |
| CN109053592A (zh) * | 2018-08-07 | 2018-12-21 | 温州医科大学 | 1-(2,5-二甲氧基苯基)-3-(取代嘧啶-4-基)脲类化合物及其制备和应用 |
| CN109516959A (zh) * | 2018-12-03 | 2019-03-26 | 陕西师范大学 | 2-芳氨基-4-取代嘧啶类衍生物及其在制备抗肿瘤药物中的应用 |
| CN109843868A (zh) * | 2016-08-26 | 2019-06-04 | 科泰纳制药公司 | Olig2活性的抑制 |
| CN110128299A (zh) * | 2019-05-13 | 2019-08-16 | 浙江大学 | 一种二苯基脲类抗肿瘤小分子抑制剂及其制备方法 |
-
2019
- 2019-07-05 CN CN201910605375.3A patent/CN110283130B/zh active Active
Patent Citations (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2386218A1 (en) * | 1999-10-07 | 2001-04-12 | Amgen Inc. | Triazine kinase inhibitors |
| CN101035769A (zh) * | 2004-06-24 | 2007-09-12 | 诺瓦提斯公司 | 作为激酶抑制剂的嘧啶脲衍生物 |
| CN101336237A (zh) * | 2005-12-21 | 2008-12-31 | 诺瓦提斯公司 | 作为fgf抑制剂的嘧啶基芳基脲衍生物 |
| CN102666498A (zh) * | 2009-08-28 | 2012-09-12 | 健泰科生物技术公司 | Raf抑制剂化合物及其使用方法 |
| CN102250065A (zh) * | 2011-05-20 | 2011-11-23 | 浙江海正药业股份有限公司 | 取代的三嗪苯脲衍生物及其用途 |
| US20160176825A1 (en) * | 2013-07-09 | 2016-06-23 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
| WO2016049774A1 (en) * | 2014-10-03 | 2016-04-07 | The Royal Institution For The Advancement Of Learning/Mcgill University | Urea and bis-urea based compounds and analogues thereof useful in the treatment of androgen receptor mediated diseases or disorders |
| US20170273922A1 (en) * | 2014-10-03 | 2017-09-28 | The Royal Institution For The Advacement Of Learning/Mcgill University | Urea and bis-urea based compounds and analogues thereof useful in the treatment of androgen receptor mediated diseases or disorders |
| CN107530304A (zh) * | 2015-02-27 | 2018-01-02 | 科泰纳制药公司 | Olig2活性的抑制 |
| CN108348519A (zh) * | 2015-07-20 | 2018-07-31 | 台北医学大学 | 经氯苯取代的氮杂芳基化合物 |
| CN109843868A (zh) * | 2016-08-26 | 2019-06-04 | 科泰纳制药公司 | Olig2活性的抑制 |
| WO2018045969A1 (zh) * | 2016-09-07 | 2018-03-15 | 法玛科技顾问股份有限公司 | 活化腺苷单磷酸活化蛋白激酶之化合物 |
| CN109053592A (zh) * | 2018-08-07 | 2018-12-21 | 温州医科大学 | 1-(2,5-二甲氧基苯基)-3-(取代嘧啶-4-基)脲类化合物及其制备和应用 |
| CN109516959A (zh) * | 2018-12-03 | 2019-03-26 | 陕西师范大学 | 2-芳氨基-4-取代嘧啶类衍生物及其在制备抗肿瘤药物中的应用 |
| CN110128299A (zh) * | 2019-05-13 | 2019-08-16 | 浙江大学 | 一种二苯基脲类抗肿瘤小分子抑制剂及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110283130B (zh) | 2023-12-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104803925B (zh) | 一类以fgfr为靶点的2，4，5‑三取代嘧啶类化合物及其制备方法和用途 | |
| WO2011029043A1 (en) | Heteroaryl btk inhibitors | |
| CN104292170B (zh) | 具有抗肿瘤作用的喹唑啉-芳基脲衍生物及其应用 | |
| CN107383004B (zh) | 2-氨基咪唑并吡啶类衍生物及制备和应用 | |
| CN108239083A (zh) | 芳香烃受体调节剂 | |
| CN114276354B (zh) | 1-氨基苯并[4,5]咪唑并[1,2-a]吡嗪-3-甲酰胺类化合物及其制备和应用 | |
| CN108101926B (zh) | 含喹啉酮的嘧啶并五元杂环类化合物、制备方法及其应用 | |
| CN104072493B (zh) | 一类含2-巯基苯并噻唑和三唑杂环的萘酰亚胺化合物，其制备方法及其应用 | |
| CN110746418A (zh) | 哌柏西利的杂质及其制备方法 | |
| CN108329274B (zh) | 布鲁顿酪氨酸激酶抑制剂 | |
| CN109053592B (zh) | 1-(2,5-二甲氧基苯基)-3-(取代嘧啶-4-基)脲类化合物及其制备和应用 | |
| CN105924387A (zh) | 一种具有抗肿瘤活性的双芳基脲化合物及其制备方法和应用 | |
| CN110283130A (zh) | 一种1-(2,5-二甲氧基苯基)-3-取代脲类结肠癌抑制剂及其制备和应用 | |
| CN109053593A (zh) | 1-(2,6-氯苯基)-3-(取代嘧啶-4-基)脲类化合物及其制备和应用 | |
| CN109384788B (zh) | 嘌呤系列衍生物及其制备方法和用途 | |
| CN109053594B (zh) | 1-(3,5-二甲氧基苯基)-3-(取代嘧啶-4-基)脲类化合物及其制备和应用 | |
| CN113461661B (zh) | 6-(吡啶-3-基)喹唑啉-4(3h)-酮类衍生物及其制备和应用 | |
| CN113956234B (zh) | 一种n-苯基取代1h-吲唑-3-胺类化合物及其制备和抗肿瘤活性的应用 | |
| CN110396066A (zh) | 一种1-(3,5-二甲氧基苯基)-3-取代脲类结肠癌抑制剂及其制备和应用 | |
| CN112225729B (zh) | 嘧啶类衍生物、其制备方法和应用以及药物组合物 | |
| CN110563657B (zh) | 一种1-(2,6-二氯苯基)-3-取代脲类结肠癌抑制剂及其制备和应用 | |
| CN111004215B (zh) | 2,4-取代嘧啶类衍生物及其制备方法和在制备抗肿瘤药物中的应用 | |
| CN112110864B (zh) | 一种4-酰胺取代嘧啶类靶向ddr1抑制剂及其制备和抗肿瘤活性的应用 | |
| CN110511226B (zh) | 化合物或其盐或溶剂合物、其应用和药物组合物 | |
| CN112759564B (zh) | 二芳基脲类化合物及其制法和药物用途 |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |