CN112920181A - N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound - Google Patents
N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound Download PDFInfo
- Publication number
- CN112920181A CN112920181A CN202110123907.7A CN202110123907A CN112920181A CN 112920181 A CN112920181 A CN 112920181A CN 202110123907 A CN202110123907 A CN 202110123907A CN 112920181 A CN112920181 A CN 112920181A
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- CN
- China
- Prior art keywords
- methyl
- oxy
- dimethoxyquinolin
- benzamide
- thiadiazol
- 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.)
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- -1 N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound Chemical class 0.000 title claims description 114
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 108
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 10
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 8
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000000051 benzyloxy group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 4
- 125000004799 bromophenyl group Chemical class 0.000 claims abstract description 4
- 125000001207 fluorophenyl group Chemical class 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 125000000068 chlorophenyl group Chemical class 0.000 claims abstract 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 72
- 239000002253 acid Substances 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 13
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 8
- 235000010233 benzoic acid Nutrition 0.000 claims description 7
- QOGPNCUTXVZQSL-UHFFFAOYSA-N 6,7-dimethoxy-1h-quinolin-4-one Chemical compound C1=CC(O)=C2C=C(OC)C(OC)=CC2=N1 QOGPNCUTXVZQSL-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 6
- 239000005711 Benzoic acid Substances 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 4
- LGDHZCLREKIGKJ-UHFFFAOYSA-N 3,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C=C1OC LGDHZCLREKIGKJ-UHFFFAOYSA-N 0.000 claims description 3
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical class NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 150000001559 benzoic acids Chemical class 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- BGRDGMRNKXEXQD-UHFFFAOYSA-N Maleic hydrazide Chemical compound OC1=CC=C(O)N=N1 BGRDGMRNKXEXQD-UHFFFAOYSA-N 0.000 claims 1
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 claims 1
- 150000003936 benzamides Chemical class 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- SATDLKYRVXFXRE-UHFFFAOYSA-N methyl 4-(chloromethyl)benzoate Chemical compound COC(=O)C1=CC=C(CCl)C=C1 SATDLKYRVXFXRE-UHFFFAOYSA-N 0.000 claims 1
- CUWHXIJMTMMRTI-UHFFFAOYSA-N thiadiazol-4-amine Chemical class NC1=CSN=N1 CUWHXIJMTMMRTI-UHFFFAOYSA-N 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- 230000035755 proliferation Effects 0.000 abstract description 3
- 238000012827 research and development Methods 0.000 abstract description 3
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 abstract description 2
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- 239000000126 substance Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 150000001805 chlorine compounds Chemical class 0.000 description 16
- 238000000034 method Methods 0.000 description 11
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- 230000005918 in vitro anti-tumor Effects 0.000 description 3
- 229940095102 methyl benzoate Drugs 0.000 description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- XHQZJYCNDZAGLW-UHFFFAOYSA-N 3-methoxybenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1 XHQZJYCNDZAGLW-UHFFFAOYSA-N 0.000 description 2
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- UHZHEOAEJRHUBW-UHFFFAOYSA-N 5-phenyl-1,3,4-thiadiazol-2-amine Chemical compound S1C(N)=NN=C1C1=CC=CC=C1 UHZHEOAEJRHUBW-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- ILUJQPXNXACGAN-UHFFFAOYSA-N O-methylsalicylic acid Chemical compound COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 0.000 description 2
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
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- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 2
- QUKGLNCXGVWCJX-UHFFFAOYSA-N 1,3,4-thiadiazol-2-amine Chemical compound NC1=NN=CS1 QUKGLNCXGVWCJX-UHFFFAOYSA-N 0.000 description 1
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical group O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 1
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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Abstract
本发明属于医药技术领域，涉及一类具有抗肿瘤活性的特定化学结构的化合物，具体涉及N‑((6，7‑二甲氧基喹啉‑4‑基)氧基)甲基)‑N‑(5‑苯基‑1，3，4‑噻二唑‑2‑基)苯甲酰胺类化合物及其制备方法和应用。所述的化合物的结构通式如下：其中：R基团为2位、3位或4位取代的单取代或双取的苯基、氟苯基、氯苯基、溴苯基、苯甲基、苯甲氧基、苯硝基或三氟甲基。药理研究显示本发明提供的化合物对HER‑2阳性的乳腺癌细胞SK‑Br‑3细胞具有较为显著的抑制增殖的作用，这一作用效果明显优于HER‑2阴性的乳腺癌细胞MCF‑7细胞，可用于制备抗肿瘤药物，为今后的肿瘤药物的深入研究和开发，开辟了新的途径。本发明提供制备方法简单可行，收率较高，易于大规模生产。The invention belongs to the technical field of medicine, and relates to a class of compounds with specific chemical structures having antitumor activity, in particular to N-((6,7-dimethoxyquinolin-4-yl)oxy)methyl)-N -(5-phenyl-1,3,4-thiadiazol-2-yl)benzamide compounds and preparation method and application thereof. The general structural formula of the compound is as follows: 
Wherein: R group is 2-, 3- or 4-substituted mono-substituted or double-substituted phenyl, fluorophenyl, chlorophenyl, bromophenyl, benzyl, benzyloxy, phenylnitro or trifluoromethyl. Pharmacological studies show that the compound provided by the present invention has a relatively significant inhibitory effect on the proliferation of HER-2-positive breast cancer cells SK-Br-3 cells, and this effect is obviously better than that of HER-2-negative breast cancer cells MCF-7 Cells can be used to prepare anti-tumor drugs, which opens up a new way for the in-depth research and development of tumor drugs in the future. The invention provides a simple and feasible preparation method, high yield and easy large-scale production.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a compound with a specific chemical structure and antitumor activity, in particular to an N- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound and a preparation method and application thereof.
Background
Chemotherapeutic drugs are always indispensable and effective means for treating cancer. Therefore, the development of chemotherapeutic drugs is an important task for medical research. HER-2 is also called ErbB2, is one of EGFR members and has important signal transduction function. HER-2 positive cancer patients have high malignancy and are difficult to treat. And HER-2 has become a prognostic indicator for a variety of cancers. Thus, the development of chemotherapeutic drugs directed against HER-2 targets has become an important medical task.
In the research of antitumor drugs aiming at HER-2 inhibitors, the research discovers that quinoline derivatives are emphasized as potential anticancer agents through the pharmacophore analysis of quinoline compounds and thiadiazole pharmacophore structures. And thiadiazole has been widely used in pharmaceutical chemistry as an important biological characteristic structure. The invention designs a series of brand new compounds with the common biological action of the two compounds by the splicing principle. So as to obtain a brand new compound with better antitumor activity, and the prior art does not have reports of related structures.
Disclosure of Invention
In view of the problems in the prior art, the invention aims to provide an N- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazol-2-yl) benzamide antitumor compound, and a preparation method and application thereof, and the N- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazol-2-yl) benzamide compound provided by the invention shows good results in an in vitro antitumor activity test and can be used for preparing antitumor drugs. Pharmacological research shows that the target compound provided by the invention has a relatively obvious proliferation inhibition effect on HER-2 positive breast cancer cell SK-Br-3 cells, and the effect is obviously better than that of HER-2 negative breast cancer cell MCF-7 cells.
In order to achieve the purpose, the invention adopts the following technical scheme.
An N- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazol-2-yl) benzamide compound has the following structural general formula I:
wherein: the R group is 2-position, 3-position or 4-position substituted mono-substituted or bi-substituted phenyl, fluorophenyl, chlorphenyl, bromophenyl, benzyl, benzyloxy, phenylnitro or trifluoromethyl.
Further, the N- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound has a general formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof, and the structure of the compound is selected from any one of the following compounds:
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazol-2-yl) benzamide (A1)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (2-fluorophenyl) -1,3, 4-thiadiazol-2-yl) benzamide (A2)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (3-fluorophenyl) -1,3, 4-thiadiazol-2-yl) benzamide (A3)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (4-fluorophenyl) -1,3, 4-thiadiazol-2-yl) benzamide (A4)
N- (5- (2-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide (A5)
N- (5- (3-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide (A6)
N- (5- (4-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide (A7)
N- (5- (2-bromophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide (A8)
N- (5- (3-bromophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide (A9)
N- (5- (4-bromophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide (A10)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (o-tolyl) -1,3, 4-thiadiazol-2-yl) benzamide (A11)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (m-tolyl) -1,3, 4-thiadiazol-2-yl) benzamide (A12)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (p-tolyl) -1,3, 4-thiadiazol-2-yl) benzamide (A13)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (2-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) benzamide (A14)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (3-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) benzamide (A15)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (4-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) benzamide (A16)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (2-nitrophenyl) -1,3, 4-thiadiazol-2-yl) benzamide (A17)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (3-nitrophenyl) -1,3, 4-thiadiazol-2-yl) benzamide (A18)
4- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (4-nitrophenyl) -1,3, 4-thiadiazol-2-yl) benzamide (A19)
4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (trifluoromethyl) -1,3, 4-thiadiazol-2-yl) benzamide (a 20).
However, the compound is not limited to the above compounds, and the compound structural formula satisfies the general formula, which is defined in the present invention.
The preparation method of the N- ((6, 7-dimethoxyquinoline-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound specifically comprises the following steps.
Step 1, condensing the resulting product with trimethylorthoformate and reacting the resulting product with 3, 4-dimethoxyaniline to obtain an intermediate 5- ((((3, 4-dimethoxyphenyl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione.
And 2, dehydrating and ring-closing the intermediate 5- ((((3, 4-dimethoxyphenyl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone obtained in the step 1 at high temperature to obtain 6, 7-dimethoxy-4-hydroxyquinoline.
And 3, taking 6, 7-dimethoxy-4-hydroxyquinoline and 4-chloromethyl methyl benzoate as raw materials, taking sodium hydride as alkali, and carrying out alkylation reaction to obtain an intermediate 4- ((6, 7-dimethoxy quinoline-4-yl) oxy) methyl benzoate.
And 4, carrying out hydrolysis reaction on the intermediate 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzoic acid methyl ester obtained in the step 3 to obtain a corresponding product, namely 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzoic acid.
And 5, refluxing the product obtained in the step 4 and thionyl chloride to prepare acyl chloride for later use.
And 6, refluxing trifluoroacetic acid or various substituted benzoic acids and thiosemicarbazide in phosphorus oxychloride, and adding water to react to obtain the aminothiadiazole with various substituents.
And 7, carrying out condensation reaction on the products obtained in the steps 5 and 6 to obtain corresponding target products.
A pharmaceutical composition comprises the N- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazol-2-yl) benzamide compound, pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier.
The (N- ((6, 7-dimethoxyquinoline-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound or pharmaceutically acceptable salt, hydrate or solvate thereof or the pharmaceutical composition is applied to the preparation of antitumor drugs.
Further, the tumor is breast cancer.
Further, the dosage form of the drug is a pharmaceutically therapeutically acceptable dosage form.
Further, the dose of the drug is a pharmaceutically therapeutically acceptable dose.
The invention also includes prodrugs of the compounds of the invention. Prodrugs of the compounds of the present invention are derivatives of formula I which are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form. The pharmaceutical composition of the present invention can be formulated into several dosage forms including, but not limited to, injections, tablets, capsules, powders, and the like.
Compared with the prior art, the invention has the following beneficial effects.
The N- ((6, 7-dimethoxyquinoline-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound provided by the invention has a remarkable effect in an in vitro antitumor activity test. Opens up a new way for the deep research and development of tumor drugs in the future. In the synthesis process, the synthesis steps are simplified, the reaction conditions are optimized, and the possibility is provided for future industrial production.
Detailed Description
The following examples further illustrate the embodiments of the present invention in detail. The following examples are provided to illustrate the present invention, but these examples are only for illustrating the present invention and the present invention is not limited to these.
An N- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazol-2-yl) benzamide compound has the following structural general formula I:
wherein: the R group is 2-position, 3-position or 4-position substituted mono-substituted or bi-substituted phenyl, fluorophenyl, chlorphenyl, bromophenyl, benzyl, benzyloxy, phenylnitro or trifluoromethyl.
Example 14 preparation of- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazol-2-yl) benzamide.
a. The method comprises the steps of using 10g of Mediterranean acid (69.38 mmol) and 29.45g of trimethyl orthoformate (277.53 mmol) as raw materials, reacting at 85 ℃ for 0.5h by using a 250mL round-bottom flask and a proper amount of isopropanol as a solvent, slowly adding 3, 4-dimethoxyaniline (10.73g and 70.08mmol) while stirring after the reaction is finished, continuing to react for 3h, cooling to room temperature after the reaction is finished, filtering, washing with isopropanol, washing with petroleum ether, and drying to obtain 14.92g of light yellow solid 5- ((((3, 4-dimethoxyphenyl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone with the yield of 69%.
b. Adding 5- ((((3, 4-dimethoxyphenyl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone (10g, 32.54mmol) diphenyl ether as a solvent into a 250mL round-bottom flask, carrying out ring closing reaction at 190 ℃, standing and cooling to room temperature after the reaction is finished, filtering, washing with methyl tert-butyl ether and diethyl ether, and drying to obtain a brown solid 6, 7-dimethoxy-4-hydroxy-quinoline 4.6g, wherein the yield is 70%.
c. Taking 6, 7-dimethoxy-4-hydroxy-quinoline (4g, 19.49mmol) and placing the mixture in a 250mL round-bottom flask, taking DMF as a solvent, extracting hydrogen from NaH (0.8g, 20.47mmol) under an ice-bath condition for 0.5h, slowly adding 4-chloromethyl methyl benzoate (4.32g, 23.39mmol), reacting for 6h at normal temperature, adding a large amount of water after the reaction is finished, filtering, and washing with ethyl acetate. Drying gave 4.2g of methyl 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzoate as a yellow solid in yield: 60 percent.
d. Adding methyl 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzoate (3g, 8.45mmol), NaOH (1.36g, 33.96mmol) and water as a solvent into a 250mL round-bottom flask, reacting at 50 ℃ for 3h, adjusting the pH to about 2 after the reaction is finished, and performing suction filtration to obtain 2.79g of light yellow solid 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzoic acid, wherein the yield is as follows: 97 percent.
e. A250 mL round bottom flask was charged with 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzoic acid (2g, 5.89mmol), SOCl2(2.10g, 17.68mmol) chloroform as solvent. Reacting at 50 ℃ for 4h, and after the reaction is finished, removing the solvent by vacuum rotary evaporation to obtain 1.5g of yellow solid for later use. Yield: 71 percent.
f. Benzoic acid (2g, 16.38mmol) and thiosemicarbazide (1.49g, 16.38mmol) were placed in a 250mL round bottom flask, phosphorus oxychloride (20mL) was added, the reaction was carried out at 75 ℃ for 3h, after completion of the reaction, the reaction was cooled to room temperature, 110mL of water was slowly added, and the reaction was continued at 100 ℃ for 4 h. After the reaction is finished, cooling, adjusting the pH value to about 8, and performing suction filtration to obtain a light yellow solid 5-phenyl-2-amino-1, 3, 4-thiadiazole, wherein 1.5g of ethanol is recrystallized.
g. Taking the intermediate acyl chloride (1g, 3.07mmol) obtained in the step e and 5-phenyl-2-amino-1, 3, 4-thiadiazole (0.55g, 3.07mmol) in a 100mL round-bottom flask, taking THF as a solvent and Et3N (0.94g, 9.22mmol) as an acid-binding agent, and reacting for 8h at normal temperature. After the reaction is finished, the reaction solvent is removed by vacuum rotary evaporation, and the target product is obtained by column chromatography purification, wherein the light yellow solid 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide is 0.78g, the yield is as follows: 51 percent.
1H NMR(500MHz,DMSO-d6)δ13.17(s,1H),8.14(d,J＝7.6Hz,1H),8.11(d,J＝7.8Hz,2H),7.97(d,J＝4.8Hz,2H),7.54(d,J＝4.4Hz,4H),7.43(d,J＝7.8Hz,2H),6.93(s,1H),6.10(d,J＝7.5Hz,1H),5.65(s,2H),3.81(s,3H),3.74(s,3H)。
Example 24 preparation of- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (2-fluorophenyl) -1,3, 4-thiadiazol-2-yl) benzamide.
Starting from the acid chlorides prepared in examples 1a-1e, 2-fluorobenzoic acid was used as the starting material to prepare 5- (2-fluorophenyl) -1,3, 4-thiadiazol-2-amine according to the method of example 1f and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (2-fluorophenyl) -1,3, 4-thiadiazol-2-yl) benzamide according to example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.22(s,1H),8.27(t,J＝7.5Hz,1H),8.13(dd,J＝14.3,7.8Hz,3H),7.61(dd,J＝13.1,7.0Hz,1H),7.54(s,1H),7.51–7.45(m,1H),7.42(dd,J＝15.6,7.8Hz,3H),6.93(s,1H),6.10(d,J＝7.6Hz,1H),5.65(s,2H),3.81(s,3H),3.74(s,3H)。
Example 34 preparation of- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (3-fluorophenyl) -1,3, 4-thiadiazol-2-yl) benzamide.
Starting from the acid chlorides prepared in examples 1a-1e, 3-fluorobenzoic acid was used as the starting material to prepare 5- (3-fluorophenyl) -1,3, 4-thiadiazol-2-amine according to the method of example 1f and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (3-fluorophenyl) -1,3, 4-thiadiazol-2-yl) benzamide according to example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.22(s,1H),8.13(dd,J＝17.6,7.4Hz,3H),7.81(d,J＝7.6Hz,2H),7.59(dd,J＝14.0,6.8Hz,1H),7.54(s,1H),7.43(d,J＝7.5Hz,2H),7.38(t,J＝8.5Hz,1H),6.93(s,1H),6.10(d,J＝7.4Hz,1H),5.65(s,2H),3.81(s,3H),3.74(s,3H)。
Example preparation of 44- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (4-fluorophenyl) -1,3, 4-thiadiazol-2-yl) benzamide.
Starting from 4-fluorobenzoic acid, 5- (4-fluorophenyl) -1,3, 4-thiadiazol-2-amine was prepared as in example 1f using the acid chlorides prepared in examples 1a-1e, and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (4-fluorophenyl) -1,3, 4-thiadiazol-2-yl) benzamide was prepared as in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),8.12(dd,J＝16.4,7.3Hz,3H),8.03(s,2H),7.54(s,1H),7.43(d,J＝7.1Hz,2H),7.38(t,J＝7.8Hz,2H),6.93(s,1H),6.09(d,J＝7.6Hz,1H),5.64(s,2H),3.81(s,3H),3.73(s,3H)。
Example 5 preparation of N- (5- (2-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide.
Starting from the acid chlorides prepared as in examples 1a to 1e, 2-chlorobenzoic acid was used as starting material to prepare 5- (2-chlorophenyl) -1,3, 4-thiadiazol-2-amine as in example 1f and N- (5- (2-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide as in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.22(s,1H),8.15(d,J＝7.6Hz,2H),8.11(d,J＝7.8Hz,2H),7.69(d,J＝7.9Hz,1H),7.60–7.51(m,3H),7.43(d,J＝7.9Hz,2H),6.93(s,1H),6.10(d,J＝7.5Hz,1H),5.65(s,2H),3.81(s,3H),3.74(s,3H)。
Example 6 preparation of N- (5- (3-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide.
Starting from the acid chlorides prepared as in examples 1a to 1e, 3-chlorobenzoic acid was used as starting material to prepare 5- (3-chlorophenyl) -1,3, 4-thiadiazol-2-amine as in example 1f and N- (5- (3-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide as in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.24(s,1H),8.15(d,J＝7.6Hz,1H),8.11(d,J＝7.9Hz,2H),8.02(s,1H),7.92(d,J＝7.4Hz,1H),7.62–7.52(m,3H),7.43(d,J＝7.9Hz,2H),6.93(s,1H),6.10(d,J＝7.6Hz,1H),5.65(s,2H),3.81(s,3H),3.74(s,3H)。
Example 7 preparation of N- (5- (4-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide.
Starting from 4-chlorobenzoic acid, 5- (4-chlorophenyl) -1,3, 4-thiadiazol-2-amine according to the procedure for example 1f was prepared and N- (5- (4-chlorophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide was prepared according to the procedure for example 1g using the acid chlorides prepared in examples 1a-1 e.
1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),8.12(dd,J＝17.2,7.7Hz,3H),7.99(d,J＝7.9Hz,2H),7.60(d,J＝7.9Hz,2H),7.54(s,1H),7.43(d,J＝7.9Hz,2H),6.93(s,1H),6.10(d,J＝7.6Hz,1H),5.64(s,2H),3.81(s,3H),3.74(s,3H)。
Example 8 preparation of N- (5- (2-bromophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide.
Starting from 2-bromobenzoic acid, 5- (2-bromophenyl) -1,3, 4-thiadiazol-2-amine was prepared as described in example 1f, and N- (5- (2-bromophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide was prepared as described in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.21(s,1H),8.15(d,J＝7.6Hz,1H),8.11(d,J＝7.9Hz,2H),7.98(d,J＝7.8Hz,1H),7.85(d,J＝8.0Hz,1H),7.59–7.53(m,2H),7.48(t,J＝7.7Hz,1H),7.44(d,J＝7.9Hz,2H),6.94(s,1H),6.10(d,J＝7.6Hz,1H),5.65(s,2H),3.82(s,3H),3.74(s,3H)。
Example 9 preparation of N- (5- (3-bromophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide.
Starting from 3-bromobenzoic acid, 5- (3-bromophenyl) -1,3, 4-thiadiazol-2-amine was prepared as described in example 1f, and N- (5- (3-bromophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide was prepared as described in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.23(s,1H),8.12(dd,J＝16.6,7.0Hz,4H),7.96(d,J＝7.4Hz,1H),7.72(d,J＝7.5Hz,1H),7.54(s,1H),7.49(t,J＝7.8Hz,1H),7.43(d,J＝7.7Hz,2H),6.93(s,1H),6.10(d,J＝7.2Hz,1H),5.64(s,2H),3.81(s,3H),3.74(s,3H)。
Example 10 preparation of N- (5- (4-bromophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide.
Starting from 4-bromobenzoic acid, 5- (4-bromophenyl) -1,3, 4-thiadiazol-2-amine was prepared as described in example 1f, and N- (5- (4-bromophenyl) -1,3, 4-thiadiazol-2-yl) -4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) benzamide was prepared as described in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.19(s,1H),8.12(dd,J＝17.0,7.7Hz,3H),7.92(d,J＝8.2Hz,2H),7.74(d,J＝8.2Hz,2H),7.54(s,1H),7.43(d,J＝8.1Hz,2H),6.93(s,1H),6.10(d,J＝7.4Hz,1H),5.64(s,2H),3.81(s,3H),3.74(s,3H)。
Example 114- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (o-tolyl) -1,3, 4-thiadiazol-2-yl) benzamide was prepared.
Starting from the preparation of the acid chlorides of examples 1a to 1e and 2-methylbenzoic acid, 5- (o-methylphenyl) -1,3, 4-thiadiazol-2-amine was prepared as in example 1f and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (o-tolyl) -1,3, 4-thiadiazol-2-yl) benzamide was prepared as in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),8.15(d,J＝7.6Hz,1H),8.10(d,J＝7.9Hz,2H),7.70(d,J＝7.7Hz,1H),7.54(s,1H),7.46–7.40(m,4H),7.35(t,J＝6.9Hz,1H),6.94(s,1H),6.10(d,J＝7.5Hz,1H),5.65(s,2H),3.81(s,3H),3.74(s,3H),2.52(s,3H)。
Example 124- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (m-tolyl) -1,3, 4-thiadiazol-2-yl) benzamide was prepared.
Starting from the preparation of the acid chlorides of examples 1a to 1e and 3-methylbenzoic acid, 5- (m-methylphenyl) -1,3, 4-thiadiazol-2-amine was prepared as in example 1f and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (m-tolyl) -1,3, 4-thiadiazol-2-yl) benzamide was prepared as in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.14(s,1H),8.12(dd,J＝19.2,7.7Hz,3H),7.82–7.74(m,2H),7.54(s,1H),7.42(t,J＝7.4Hz,3H),7.34(d,J＝7.3Hz,1H),6.93(s,1H),6.09(d,J＝7.6Hz,1H),5.64(s,2H),3.81(s,3H),3.74(s,3H),2.40(s,3H)。
Example preparation of 134- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (p-tolyl) -1,3, 4-thiadiazol-2-yl) benzamide.
Starting from 4-methylbenzoic acid, 5- (p-methylphenyl) -1,3, 4-thiadiazol-2-amine was prepared as in example 1f using the acid chlorides prepared in examples 1a-1e, and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (p-tolyl) -1,3, 4-thiadiazol-2-yl) benzamide was prepared as in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.14(s,1H),8.19(d,J＝7.7Hz,1H),8.14(d,J＝7.8Hz,1H),8.10(d,J＝7.5Hz,2H),7.86(t,J＝8.2Hz,2H),7.54(s,1H),7.43(d,J＝7.6Hz,2H),7.35(d,J＝7.1Hz,2H),6.93(s,1H),6.10(d,J＝7.4Hz,1H),5.64(s,2H),3.81(s,3H),3.74(s,3H),2.37(s,3H)。
Example 144- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (2-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) benzamide is prepared.
Starting from the preparation of the acid chlorides of examples 1a to 1e, 2-methoxybenzoic acid was used as starting material to prepare 5- (2-methoxyphenyl) -1,3, 4-thiadiazol-2-amine according to the method of example 1f, and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (2-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) benzamide was prepared according to the method of example 1 g.
1H NMR(500MHz,DMSO-d6)δ12.96(s,1H),8.30(d,J＝7.7Hz,1H),8.15(d,J＝7.6Hz,1H),8.11(d,J＝7.8Hz,2H),7.56–7.50(m,2H),7.43(d,J＝7.9Hz,2H),7.28(d,J＝8.4Hz,1H),7.14(t,J＝7.5Hz,1H),6.94(s,1H),6.10(d,J＝7.6Hz,1H),5.65(s,2H),4.03(s,3H),3.82(s,3H),3.74(s,3H)。
Example 154 preparation of- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (3-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) benzamide.
The acid chlorides were prepared as described in examples 1a-1e, 5- (3-methoxyphenyl) -1,3, 4-thiadiazol-2-amine was prepared as described in example 1f starting from 3-methoxybenzoic acid and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (3-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) benzamide was prepared as described in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.21(s,1H),8.52(t,J＝5.5Hz,1H),8.13(dd,J＝20.7,7.7Hz,3H),7.61(t,J＝8.3Hz,1H),7.53(d,J＝7.7Hz,1H),7.43(dd,J＝14.3,6.4Hz,3H),7.10(d,J＝7.9Hz,1H),6.93(s,1H),6.10(d,J＝7.8Hz,1H),5.65(s,2H),3.85(s,3H),3.81(s,3H),3.74(s,3H)。
Example preparation of 164- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (4-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) benzamide.
Starting from the preparation of the acid chlorides of examples 1a to 1e and 4-methoxybenzoic acid, 5- (4-methoxyphenyl) -1,3, 4-thiadiazol-2-amine was prepared as described in example 1f, and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (4-methoxyphenyl) -1,3, 4-thiadiazol-2-yl) benzamide was prepared as described in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.06(s,1H),8.15(d,J＝7.6Hz,1H),8.10(d,J＝7.8Hz,2H),7.91(d,J＝7.9Hz,2H),7.54(s,1H),7.43(d,J＝7.8Hz,2H),7.09(d,J＝8.0Hz,2H),6.93(s,1H),6.10(d,J＝7.3Hz,1H),5.65(s,2H),3.84(s,3H),3.82(s,3H),3.74(s,3H)。
Example 174- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (2-nitrophenyl) -1,3, 4-thiadiazol-2-yl) benzamide is prepared.
Starting from the preparation of the acid chlorides of examples 1a to 1e, 2-nitrobenzoic acid was used as starting material to prepare 5- (2-nitrophenyl) -1,3, 4-thiadiazol-2-amine according to the procedure of example 1f and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (2-nitrophenyl) -1,3, 4-thiadiazol-2-yl) benzamide according to example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.28(s,1H),8.12(dt,J＝15.7,7.7Hz,4H),7.91(d,J＝7.8Hz,1H),7.86(t,J＝7.4Hz,1H),7.80(t,J＝7.6Hz,1H),7.55(s,1H),7.44(d,J＝7.9Hz,2H),6.93(s,1H),6.10(d,J＝7.5Hz,1H),5.65(s,2H),3.82(s,3H),3.74(s,3H)。
Example 184- ((6, 7-Dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (3-nitrophenyl) -1,3, 4-thiadiazol-2-yl) benzamide is prepared.
Starting from the preparation of the acid chlorides of examples 1a to 1e, 3-nitrobenzoic acid was used as starting material to prepare 5- (3-nitrophenyl) -1,3, 4-thiadiazol-2-amine according to the method of example 1f and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (3-nitrophenyl) -1,3, 4-thiadiazol-2-yl) benzamide according to example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.30(s,1H),8.70(s,1H),8.36(dd,J＝18.2,7.8Hz,2H),8.13(t,J＝8.8Hz,3H),7.82(t,J＝7.9Hz,1H),7.55(s,1H),7.44(d,J＝7.8Hz,2H),6.93(s,1H),6.10(d,J＝7.5Hz,1H),5.64(s,2H),3.81(s,3H),3.74(s,3H)。
Example 194 preparation of- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (4-nitrophenyl) -1,3, 4-thiadiazol-2-yl) benzamide.
Starting from the preparation of the acid chlorides of examples 1a to 1e and 4-nitrobenzoic acid, 5- (4-nitrophenyl) -1,3, 4-thiadiazol-2-amine was prepared as in example 1f and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (4-nitrophenyl) -1,3, 4-thiadiazol-2-yl) benzamide was prepared as in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.37(s,1H),8.36(d,J＝8.5Hz,2H),8.27(t,J＝8.7Hz,2H),8.13(dd,J＝15.7,7.8Hz,3H),7.54(s,1H),7.44(d,J＝8.3Hz,2H),6.93(s,1H),6.10(d,J＝7.6Hz,1H),5.65(s,2H),3.81(s,3H),3.74(s,3H)。
Example 204 preparation of- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (trifluoromethyl) -1,3, 4-thiadiazol-2-yl) benzamide.
Starting from trifluoroacetic acid, 5- (trifluoromethyl) -1,3, 4-thiadiazol-2-amine was prepared as in example 1f using the acid chlorides prepared in examples 1a-1e, and 4- ((6, 7-dimethoxyquinolin-4-yl) oxy) methyl) -N- (5- (trifluoromethyl) -1,3, 4-thiadiazol-2-yl) benzoyl was prepared as in example 1 g.
1H NMR(500MHz,DMSO-d6)δ13.73(s,1H),8.13(dd,J＝13.4,7.8Hz,3H),7.54(s,1H),7.44(d,J＝7.8Hz,2H),6.92(s,1H),6.11(d,J＝7.5Hz,1H),5.66(s,2H),3.81(s,3H),3.73(s,3H)。
Example 21 inhibition of tumor cell proliferation assay.
The compound of the invention is subjected to tumor cell proliferation inhibition experiments, and the test method adopts a conventional CCK-8 method.
Culturing of tumor cells: the cell strain selects Her-2 positive expression SK-Br-3 cells (human three positive breast cancer cells) and HER-2 negative expression MCF-7 cells (human three negative breast cancer cells), and is cultured by DMEM + 10% FBS + double antibody (penicillin 100 unit/mL, streptomycin 100 mu g/mL) culture solution. And MCF-10A cells (human mammary epithelial cells) were also used as healthy controls.
Sample preparation: after the compound was dissolved in DMSO, PBS (-) was added to prepare a solution or a uniform suspension of 1000. mu.g/mL, followed by gradient dilution with an incomplete medium. The final concentrations were: 20. mu.M, 10. mu.M, 5. mu.M, 2.5. mu.M, 1.25. mu.M. Lignitinib was used as a control.
Test methods for inhibition of cell proliferation: the concentration of the added solution in each hole of a 96-hole plate is 4 multiplied by 104Cell suspension 100. mu.L/mL, at 37 ℃ in 5% CO2In the incubator. After 24 hours, the sample solution and the control solution were added to each well at 10. mu.L/well, 3 wells at 37 ℃ and 5% CO2The reaction was carried out for 36 hours. Adding 10 mu L of CCK-8 solution with the concentration of 5mg/mL into each hole, placing the hole in an incubator and keeping away from light for 4 hours, measuring the OD value at 490nm by using an MK-2 full-automatic enzyme standard instrument, and calculating the inhibition rate.
The results are shown in Table 1.
TABLE 1 in vitro proliferation inhibitory Activity IC50 values of samples on human tumor cells.
The experimental data show that the N- ((6, 7-dimethoxyquinoline-4-yl) oxy) methyl) -N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound has better in-vitro anti-tumor activity and lower toxicity to mammary epithelial cells, thereby opening up a new way for further research and development of new anti-tumor drugs.
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