CN110563657B - 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 - Google Patents
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 Download PDFInfo
- Publication number
- CN110563657B CN110563657B CN201910604580.8A CN201910604580A CN110563657B CN 110563657 B CN110563657 B CN 110563657B CN 201910604580 A CN201910604580 A CN 201910604580A CN 110563657 B CN110563657 B CN 110563657B
- Authority
- CN
- China
- Prior art keywords
- cells
- dichlorophenyl
- pyrimidine
- colon cancer
- substituted
- 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 1- (2, 6-Dichlorophenyl) -3-substituted urea Chemical class 0.000 title claims abstract description 28
- 206010009944 Colon cancer Diseases 0.000 title claims abstract description 19
- 208000029742 colonic neoplasm Diseases 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 35
- 239000013067 intermediate product Substances 0.000 claims description 11
- 239000012948 isocyanate Substances 0.000 claims description 9
- 150000002513 isocyanates Chemical class 0.000 claims description 9
- 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
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 5
- 150000003939 benzylamines Chemical class 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- DUKKRSPKJMHASP-UHFFFAOYSA-N 6-chloropyrimidin-4-amine Chemical compound NC1=CC(Cl)=NC=N1 DUKKRSPKJMHASP-UHFFFAOYSA-N 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
- 239000003814 drug Substances 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 2
- 150000003672 ureas Chemical class 0.000 claims description 2
- GCDXWVWSBBYXKW-UHFFFAOYSA-N (4-bromo-2-methoxyphenyl)methanamine Chemical group COC1=CC(Br)=CC=C1CN GCDXWVWSBBYXKW-UHFFFAOYSA-N 0.000 claims 1
- 235000013877 carbamide Nutrition 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000004202 carbamide Substances 0.000 abstract description 20
- 230000000694 effects Effects 0.000 abstract description 10
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 abstract description 2
- 210000005265 lung cell Anatomy 0.000 abstract description 2
- 206010067482 No adverse event Diseases 0.000 abstract 1
- 231100000252 nontoxic Toxicity 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 20
- 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
- 239000000843 powder Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 230000005311 nuclear magnetism Effects 0.000 description 6
- 239000004576 sand Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 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
- 238000001914 filtration Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 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
- 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
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 201000011510 cancer Diseases 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
- 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
- 230000004083 survival effect Effects 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007790 scraping Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing 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
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 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
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 229960003887 dichlorophen Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 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 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 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 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000031700 light absorption Effects 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
- 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
- 239000002244 precipitate Substances 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
- 229950009855 rociletinib Drugs 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 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
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
本发明公开了一种能作用于结肠癌的1‑(2,6‑氯苯基)‑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-(2,6-氯苯基)-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-(2,6-氯苯基)-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-(2,6-氯苯基)-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S1~S12中的任意一个:
R的取代基如下:
作为优选,所述的1-(2,6-氯苯基)-3-取代脲类化合物为化合物S1;
化合物S1的结构式如下:
作为优选,所述的1-(2,6-氯苯基)-3-取代脲类化合物为化合物S2;
化合物S2的结构式如下:
作为优选,所述的1-(2,6-氯苯基)-3-取代脲类化合物为化合物S8;
化合物S8的结构式如下:
本发明还提供了一种所述的1-(2,6-氯苯基)-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)2,6-二氯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-(2,6-氯苯基)-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2,6-二氯苯胺(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2,6-二氯苯胺后,分离提纯异氰酸酯。送去打质谱和核磁,验证。
所述的1-(2,6-氯苯基)-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-(2,6-氯苯基)-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-(2,6-氯苯基)-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
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2,6-二氯苯胺(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2,6-二氯苯胺后,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S1~S12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-(2,6-Dichlorophenyl)-3-(6-((3,5-dimethoxyphenyl)benzylamine)pyrimidin-4-yl)
urea(S1).
Yellow powder,yield:46.6%;Mp/℃:200.7~201.3;ESI-MS[M+Na]+:448.12;1HNMR(600MHz,CDCL3)δ(ppm):8.339(s,1H,2-pyrimidine-H),7.321(s,1H,Ar-H),7.348(s,3H,Ar-H),7.192(s,1H,-NH-),7.132(s,1H,Ar-H),6.532(s,1H,Ar-H),6.402(s,1H,5-pyrimidine-H),5.352s,2H,-CH2-),3.754(s,6H,-OCH3).13CNMR(600MHz,DMSO-d6)δ(ppm):161.624,161.144,158.171,157.705,152.309,142.200,134.182,133.100,129.483,129.388,129.114,128.785,125.895,98.892,94.786,90.830,79.567,55.644.
1-(2,6-Dichlorophenyl)-3-(6-((2,5-dimethoxyphenyl)benzylamine)pyrimidin-4-yl)
urea(S2).
Taupe powder,yield:34.3%;Mp/℃:195.4~196.1;ESI-MS[M+Na]+:448.25;1HNMR(600MHz,CDCL3)δ(ppm):8.538(s,1H,-NH-),8.429(s,1H,2-pyrimidine-H),7.791(s,1H,Ar-H),7.387(d,J=7.8Hz,1H,Ar-H),7.354(d,J=7.8Hz,1H,Ar-H),7.205(m,1H,Ar-H),7.190(s,1H,Ar-H),6.833(m,1H,Ar-H),6.566(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),3.822(s,3H,-OCH3),3.786(s,3H,-OCH3).13CNMR(600MHz,DMSO-d6)δ(ppm):162.343,157.637,153.576,152.030,146.234,134.196,129.120,129.086,112.547,111.051,109.326,91.321,56.745,55.437.
1-(6-((5-Bromo-2-methoxyphenyl)benzylamine)pyrimidin-4-yl)-3-(2,6-dichlorophenyl)urea(S3).
White powder,yield:39.8%;Mp/℃:195.9~196.8;ESI-MS[M+Na]+:495.06;1HNMR(600MHz,CDCL3)δ(ppm):8.476(s,1H,-NH-),8.312(s,1H,2-pyrimidine-H),7.399(d,J=7.8Hz,1H,Ar-H),7.346(d,J=7.8Hz,1H,Ar-H),7.189(m,4H,Ar-H),6.922(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),3.921(s,3H,-OCH3).13CNMR(600MHz,DMSO-d6)δ(ppm):161.944,158.197,157.522,152.280,150.662,134.199,133.138,130.374,129.448,129.130,128.812,126.892,125.720,113.843,111.964,91.317,56.520.
1-(6-((4-Bromo-2-methoxyphenyl)benzylamine)pyrimidin-4-yl)-3-(2,6-dichlorophenyl)urea(S4).
Taupe powder,yield:42.3%;Mp/℃:205.3~207.0;ESI-MS[M+Na]+:495.00;1HNMR(600MHz,CDCL3)δ(ppm):8.533(s,1H,-NH-),8.436(s,1H,2-pyrimidine-H),7.414(d,J=7.8Hz,1H,Ar-H),7.329(d,J=7.8Hz,1H,Ar-H),7.189(m,4H,Ar-H),6.824(s,1H,5-pyrimidine-H),5.355(s,2H,-CH2-),3.911(s,3H,-OCH3).13CNMR(600MHz,DMSO-d6)δ(ppm):162.307,162.187,158.133,157.737,157.584,157.412,152.985,152.302,134.234,129.436,129.137,129.056,127.939,126.036,123.588,115.347.
1-(6-((3-Chloro-4-fluorophenyl)benzylamine)pyrimidin-4-yl)-3-(2,6-dichlorophen
yl)urea(S5).
White powder,yield:42.1%;Mp/℃:203.3~204.4;ESI-MS[M+Na]+:440.97;1HNMR(600MHz,CDCL3)δ(ppm):8.226(s,1H,2-pyrimidine-H),7.414(d,J=6.6Hz,1H,Ar-H),7.402(d,J=6.6Hz,1H,Ar-H),7.195(d,J=8.4Hz,1H,Ar-H),7.183(d,J=8.4Hz,1H,Ar-H),7.136(m,1H,Ar-H),6.346(s,1H,Ar-H),5.710(s,1H,-NH-),5.354(s,2H,-CH2-),5.150(s,1H,5-pyrimidine-H).13CNMR(600MHz,DMSO-d6)δ(ppm):161.531,158.492,157.800,152.295,140.596,134.194,133.033,131.914,129.450,129.156,115.939,106.932,90.953.
1-(2,6-Dichlorophenyl)-3-(6-((5-fluoro-2-methoxyphenyl)benzylamine)pyrimidin-4-
yl)urea(S6).
Green powder,yield:40.5%;Mp/℃:192.1~193.0;ESI-MS[M+Na]+:436.08;1HNMR(600MHz,CDCL3)δ(ppm):9.132(s,1H,-NH-),8.553(s,1H,2-pyrimidine-H),8.453(s,2H,Ar-H),7.471(m,2H,Ar-H),6.864(d,J=4.2Hz,1H,Ar-H),6.847(d,J=4.2Hz,1H,Ar-H),6.402(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),3.932(s,3H,-OCH3).13CNMR(600MHz,DMSO-d6)δ(ppm):162.040,157.716,157.544,157.133,155.660,152.033,147.545,134.667,129.131,112.685,112.647,110.181,92.504,56.831.
1-(2,6-Dichlorophenyl)-3-(6-((3-fluoro-4-methylphenyl)benzylamine)pyrimidin-4-
yl)urea(S7).
Taupe powder,yield:39.5%;Mp/℃:227.2~228.0;ESI-MS[M+Na]+:420.08;1HNMR(600MHz,CDCL3)δ(ppm):8.356(s,1H,2-pyrimidine-H),7.366(d,J=7.8Hz,1H,Ar-H),7.383(d,J=7.8Hz,1H,Ar-H),7.195(t,J=6.0~7.2Hz,1H,Ar-H),7.112(d,J=11.4Hz,1H,Ar-H),7.023(d,J=11.4Hz,1H,Ar-H),6.944(s,1H,Ar-H),6.878(s,1H,-NH-),6.260(s,1H,5-pyrimidine-H),5.324(s,2H,-CH2-),2.371(s,3H,-CH3).13CNMR(600MHz,DMSO-d6)δ(ppm):161.533,158.051,157.840,152.596,134.193,133.074,131.915,129.480,129.154,115.929,106.921,90.982.
1-(2,6-Dichlorophenyl)-3-(6-((3-fluoro-5-methylphenyl)benzylamine)pyrimidin-4-
yl)urea(S8).
White powder,yield:42.9%;Mp/℃:230.8~232.0;ESI-MS[M+Na]+:420.08;1HNMR(600MHz,CDCL3)δ(ppm):8.409(s,1H,2-pyrimidine-H),7.381(d,J=7.8Hz,1H,Ar-H),7.348(d,J=7.8Hz,1H,Ar-H),7.178(d,J=7.8Hz,1H,Ar-H),7.165(d,J=7.8Hz,1H,Ar-H),7.025(s,1H,Ar-H),6.939(s,1H,-NH-),6.722(s,1H,Ar-H),6.708(s,1H,5-pyrimidine-H),5.344(s,2H,-CH2-),2.364(s,3H,-CH3).13CNMR(600MHz,DMSO-d6)δ(ppm):163.611,162.033,161.635,161.536,158.124,157.959,157.775,152.584,134.191,133.357,129.457,12.167,116.306,21.745.
1-(2,6-Dichlorophenyl)-3-(6-((3,4-dimethylphenyl)benzylamine)pyrimidin-4-yl)urea(S9).
White powder,yield:445.7%;Mp/℃:208.8~209.6;ESI-MS[M+Na]+:416.17;1HNMR(600MHz,CDCL3)δ(ppm):8.433(s,1H,2-pyrimidine-H),7.407(d,J=7.8Hz,1H,Ar-H),7.384(d,J=7.8Hz,1H,Ar-H),7.183(m,3H,Ar-H),7.041(s,1H,Ar-H),7.035(s,1H,-NH-),7.026(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),2.238(s,6H,-CH3).13CNMR(600MHz,DMSO-d6)δ(ppm):162.048,158.034,157.575,151.245,138.082,136.970,130.238,122.318,118.628,20.255,19.369.
1-(2,6-Dichlorophenyl)-3-(6-((4-methoxy-3-methylphenyl)benzylamine)pyrimidin-4
-yl)urea(S10).
Black powder,yield:48.4%;Mp/℃:203.2~203.9;ESI-MS[M+Na]+:432.98;1HNMR(600MHz,CDCL3)δ(ppm):8.347(s,1H,-NH-),8.105(s,1H,2-pyrimidine-H),7.376(d,J=8.4Hz,1H,Ar-H),7.342(d,J=8.4Hz,1H,Ar-H),7.145(t,J=7.8Hz,1H,Ar-H),7.148(d,J=7.8Hz,1H,Ar-H),7.145(d,J=7.8Hz,1H,Ar-H),6.874(s,1H,Ar-H),5.354(s,2H,-CH2-),5.619(s,1H,5-pyrimidine-H),3.847(s,3H,-OCH3),2.244(s,3H,-CH3).13CNMR(600MHz,DMSO-d6)δ(ppm):162.144,158.014,157.738,152.340,134.240,133.140,129.414,129.129,126.344,111.046,56.104,55.984,16.784.
1-(2,6-Dichlorophenyl)-3-(6-((2-methoxy-5-(trifluoromethyl)phenyl)benzylamine)pyrimidin-4-yl)urea(S11).
White powder,yield:34.4%;Mp/℃:239.4~240.4;ESI-MS[M+Na]+:486.08;1HNMR(600MHz,CDCL3)δ(ppm):8.443(s,1H,-NH-),8.481(s,1H,2-pyrimidine-H),7.394(m,4H,Ar-H),7.218(d,J=8.4Hz,1H,Ar-H),7.204(d,J=8.4Hz,1H,Ar-H),6.947(s,1H,5-pyrimidine-H),5.354(s,2H,-CH2-),3.974(s,3H,-OCH3).13CNMR(600MHz,DMSO-d6)δ(ppm):162.211,158.020,157.667,153.045,134.245,129.341,129.124,121.652,121.245,119.944,112.241,92.348,56.642.
1-(2,6-Dichlorophenyl)-3-(6-((3-methoxy-5-(trifluoromethyl)phenyl)benzylamine)pyrimidin-4-yl)urea(S12).
Black powder,yield:34.9%;Mp/℃:246.7~247.9;ESI-MS[M+Na]+:486.14;1HNMR(600MHz,CDCL3)δ(ppm):8.542(s,1H,-NH-),8.444(s,1H,2-pyrimidine-H),7.349(m,3H,Ar-H),7.344(s,1H,Ar-H),7.146(s,1H,Ar-H),6.989(s,1H,Ar-H),6.444(s,1H,5-pyrimidine-H),5.344(s,2H,-CH2-),3.944(s,3H,-OCH3).13CNMR(600MHz,DMSO-d6)δ(ppm):162.142,157.745,157.468,153.996,129.348,129.141,121.654,121.245,119.944,112.248,92.349,56.652.
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S3,S5,S8-9,S11均为白色固体;S1,为黄色固体;S2,S4,S7均为灰褐色固体;S10,S12为黑色固体;化合物S6为淡绿色固体。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
2.1 MTT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 (3)
1.一种1-(2,6-二氯苯基)-3-取代脲类化合物,其特征在于,为化合物S4,结构式如下:
。
2.一种如权利要求1所述的1-(2,6-二氯苯基)-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)2,6-二氯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-(2,6-二氯苯基)-3-取代脲类化合物;
所述的取代苄胺为4-溴-2-甲氧基苄胺。
3.一种如权利要求1所述的1-(2,6-二氯苯基)-3-取代脲类化合物在制备用于抑制结肠癌细胞SW620的药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910604580.8A CN110563657B (zh) | 2019-07-05 | 2019-07-05 | 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 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910604580.8A CN110563657B (zh) | 2019-07-05 | 2019-07-05 | 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 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110563657A CN110563657A (zh) | 2019-12-13 |
CN110563657B true CN110563657B (zh) | 2024-05-03 |
Family
ID=68772922
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910604580.8A Active CN110563657B (zh) | 2019-07-05 | 2019-07-05 | 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 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110563657B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111777562B (zh) * | 2020-06-22 | 2022-04-19 | 温州医科大学 | 一种6-苯氧基取代嘧啶类靶向ddr1抑制剂及其制备和抗肿瘤活性的应用 |
CN112110864B (zh) * | 2020-06-22 | 2022-07-22 | 温州医科大学 | 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 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN109053594A (zh) * | 2018-08-07 | 2018-12-21 | 温州医科大学 | 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 |
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 |
CN109053593A (zh) * | 2018-08-07 | 2018-12-21 | 温州医科大学 | 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 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9783504B2 (en) * | 2013-07-09 | 2017-10-10 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
-
2019
- 2019-07-05 CN CN201910604580.8A patent/CN110563657B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN109053594A (zh) * | 2018-08-07 | 2018-12-21 | 温州医科大学 | 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 |
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 |
CN109053593A (zh) * | 2018-08-07 | 2018-12-21 | 温州医科大学 | 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 |
Also Published As
Publication number | Publication date |
---|---|
CN110563657A (zh) | 2019-12-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
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 | |
CN106432247B (zh) | 含有腙键的嘧啶并三氮唑类化合物、制备方法及其应用 | |
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 | |
CN109053593B (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 | |
CN104292170A (zh) | 具有抗肿瘤作用的喹唑啉-芳基脲衍生物及其应用 | |
CN112961120A (zh) | 一种萘基脲类化合物、其制备方法及应用 | |
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 | |
CN103396386B (zh) | 双取代二萘并[2,1-b:1′,2′-d]呋喃类衍生物及其制备方法和应用 | |
CN110283130B (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 | |
CN110396066B (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 | |
CN102267983B (zh) | 一种含均四嗪环的均三嗪衍生化合物及其制备方法 | |
CN113461661B (zh) | 6-(吡啶-3-基)喹唑啉-4(3h)-酮类衍生物及其制备和应用 | |
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 | |
CN104098524B (zh) | 1-间甲氧基苯甲酰基-3-苯基-1,4-二氢-1,2,4,5-四嗪及制备和应用 | |
CN102659692B (zh) | 双联厄洛替尼及其制备方法 | |
CN113024536B (zh) | 含嘧啶-哌嗪环的5-氨基噻唑甲酰胺类化合物及其制备方法和用途 | |
CN111533700B (zh) | 一种5-取代的尿嘧啶衍生物及其制备方法和应用 | |
CN115304605B (zh) | 具有抗肿瘤活性的氧杂环丁烷衍生物及其制备方法和应用 | |
WO2023093812A1 (zh) | 三氮唑酮类化合物的晶型及其应用 | |
CN115109033B (zh) | 一种1,8-萘二甲酰亚胺衍生物的合成及生物活性研究 | |
CN115611867B (zh) | (1,1,1-三氯-2)氨基甲酸酯类衍生物及其制备方法和应用 | |
CN111518078A (zh) | 一种含氨基吡啶的嘧啶类化合物及其应用 | |
CN107459494B (zh) | 苯并吗啉酮衍生物及其制备方法和用途 | |
CN104030980A (zh) | N-(3-甲氧基-4-氯苯基)-4-[(7-氯-4-喹啉)氨基]苯甲酰胺及其制备和应用 |
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 | ||
GR01 | Patent grant |