CN109776413A - A kind of isoquinilone derivatives and application with hypoglycemic activity - Google Patents
A kind of isoquinilone derivatives and application with hypoglycemic activity Download PDFInfo
- Publication number
- CN109776413A CN109776413A CN201910085622.1A CN201910085622A CN109776413A CN 109776413 A CN109776413 A CN 109776413A CN 201910085622 A CN201910085622 A CN 201910085622A CN 109776413 A CN109776413 A CN 109776413A
- Authority
- CN
- China
- Prior art keywords
- derivatives
- aryl
- derivative
- compound
- quinoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000002218 hypoglycaemic effect Effects 0.000 title claims abstract description 24
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 12
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims abstract description 11
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000002240 furans Chemical class 0.000 claims abstract description 10
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 150000003233 pyrroles Chemical class 0.000 claims abstract description 8
- 230000003178 anti-diabetic effect Effects 0.000 claims abstract description 6
- 239000003472 antidiabetic agent Substances 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- -1 methoxyl group Chemical group 0.000 claims description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 26
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 17
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 16
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 16
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 15
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 15
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 14
- LOCUXGFHUYBUHF-UHFFFAOYSA-N 4-phenylquinoline Chemical class C1=CC=CC=C1C1=CC=NC2=CC=CC=C12 LOCUXGFHUYBUHF-UHFFFAOYSA-N 0.000 claims description 12
- 229940126214 compound 3 Drugs 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 229950003545 octaverine Drugs 0.000 claims description 11
- 238000010898 silica gel chromatography Methods 0.000 claims description 11
- 102100024295 Maltase-glucoamylase Human genes 0.000 claims description 10
- 239000007832 Na2SO4 Substances 0.000 claims description 10
- 108010028144 alpha-Glucosidases Proteins 0.000 claims description 10
- 229910052786 argon Inorganic materials 0.000 claims description 10
- 239000007789 gas Substances 0.000 claims description 10
- 239000012044 organic layer Substances 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 10
- 238000007711 solidification Methods 0.000 claims description 10
- 230000008023 solidification Effects 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 7
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 6
- 229910019213 POCl3 Inorganic materials 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- CGWOEOXQHIMZEQ-UHFFFAOYSA-N 3-[1-[[4-(2-phenylquinolin-3-yl)phenyl]methyl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound OC1=NC2=CC=CC=C2N1C(CC1)CCN1CC(C=C1)=CC=C1C1=CC2=CC=CC=C2N=C1C1=CC=CC=C1 CGWOEOXQHIMZEQ-UHFFFAOYSA-N 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 150000003248 quinolines Chemical class 0.000 claims description 4
- 229910015845 BBr3 Inorganic materials 0.000 claims description 3
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 claims description 3
- 229940111121 antirheumatic drug quinolines Drugs 0.000 claims description 3
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Substances BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 230000017858 demethylation Effects 0.000 claims description 3
- 238000010520 demethylation reaction Methods 0.000 claims description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 241001597008 Nomeidae Species 0.000 claims 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- RBJOTRVJJWIIER-UHFFFAOYSA-N 3-phenylisoquinoline Chemical compound C1=CC=CC=C1C1=CC2=CC=CC=C2C=N1 RBJOTRVJJWIIER-UHFFFAOYSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 229910052792 caesium Inorganic materials 0.000 claims 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 150000004800 hydroisoquinoline derivatives Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 13
- 102000004190 Enzymes Human genes 0.000 abstract description 10
- 108090000790 Enzymes Proteins 0.000 abstract description 10
- 230000005764 inhibitory process Effects 0.000 abstract description 7
- 238000011160 research Methods 0.000 abstract description 7
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 238000010189 synthetic method Methods 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 10
- 239000002585 base Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 4
- 229960002632 acarbose Drugs 0.000 description 4
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- RPWPRIVEZXDLST-ZIQFBCGOSA-N (2s,3r,4s,5s,6r)-6-(hydroxymethyl)-2-(4-nitrophenyl)oxane-2,3,4,5-tetrol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@]1(O)C1=CC=C([N+]([O-])=O)C=C1 RPWPRIVEZXDLST-ZIQFBCGOSA-N 0.000 description 3
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- ASQOQJYHIYYTEJ-GBESFXJTSA-N (1r,7s,9as)-7-decyl-2,3,4,6,7,8,9,9a-octahydro-1h-quinolizin-1-ol Chemical compound O[C@@H]1CCCN2C[C@@H](CCCCCCCCCC)CC[C@H]21 ASQOQJYHIYYTEJ-GBESFXJTSA-N 0.000 description 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 2
- XNMYNYSCEJBRPZ-UHFFFAOYSA-N 2-[(3-butyl-1-isoquinolinyl)oxy]-N,N-dimethylethanamine Chemical compound C1=CC=C2C(OCCN(C)C)=NC(CCCC)=CC2=C1 XNMYNYSCEJBRPZ-UHFFFAOYSA-N 0.000 description 2
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 2
- QYFVPBVFXFGKHA-UHFFFAOYSA-N 3-(4-fluorophenyl)isoquinoline Chemical compound C1=CC(F)=CC=C1C1=CC2=CC=CC=C2C=N1 QYFVPBVFXFGKHA-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- KAXQBGPFESZQIL-UHFFFAOYSA-N 6,8-dimethylisoquinoline Chemical compound C1=NC=CC2=CC(C)=CC(C)=C21 KAXQBGPFESZQIL-UHFFFAOYSA-N 0.000 description 2
- 229940126650 Compound 3f Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229940125907 SJ995973 Drugs 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940125796 compound 3d Drugs 0.000 description 2
- NFABMCCMPXXBFY-UHFFFAOYSA-N dioxyline Chemical compound C1=C(OC)C(OCC)=CC=C1CC1=NC(C)=CC2=CC(OC)=C(OC)C=C12 NFABMCCMPXXBFY-UHFFFAOYSA-N 0.000 description 2
- 229950010935 dioxyline Drugs 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 150000002537 isoquinolines Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical group C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229960005038 quinisocaine Drugs 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- WELSVHHDAXZSJK-ZIQFBCGOSA-N (2S,3R,4S,5S,6R)-6-(hydroxymethyl)-2-phenyloxane-2,3,4,5-tetrol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@]1(O)C1=CC=CC=C1 WELSVHHDAXZSJK-ZIQFBCGOSA-N 0.000 description 1
- CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 description 1
- PDYBUYVOPAJLKP-UHFFFAOYSA-M 2,3,10,11-tetramethoxy-8-methylisoquinolino[2,1-b]isoquinolin-7-ium;chloride Chemical compound [Cl-].C1=C(OC)C(OC)=CC2=CC3=C(C=C(C(OC)=C4)OC)C4=CC=[N+]3C(C)=C21 PDYBUYVOPAJLKP-UHFFFAOYSA-M 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- YXSLJKQTIDHPOT-UHFFFAOYSA-N Atracurium Dibesylate Chemical compound C1=C(OC)C(OC)=CC=C1CC1[N+](CCC(=O)OCCCCCOC(=O)CC[N+]2(C)C(C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 YXSLJKQTIDHPOT-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 235000016551 Potentilla erecta Nutrition 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 241000372442 Wachendorfia thyrsiflora Species 0.000 description 1
- WQZGKKKJIJFFOK-UHFFFAOYSA-N alpha-D-glucopyranose Natural products OCC1OC(O)C(O)C(O)C1O WQZGKKKJIJFFOK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960001862 atracurium Drugs 0.000 description 1
- IZTUINVRJSCOIR-UHFFFAOYSA-N benzylisoquinoline Chemical compound N=1C=CC2=CC=CC=C2C=1CC1=CC=CC=C1 IZTUINVRJSCOIR-UHFFFAOYSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- MYCMTMIGRXJNSO-UHFFFAOYSA-N moxaverine Chemical compound N=1C(CC)=CC2=CC(OC)=C(OC)C=C2C=1CC1=CC=CC=C1 MYCMTMIGRXJNSO-UHFFFAOYSA-N 0.000 description 1
- 229960002902 moxaverine Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000000837 restrainer Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of isoquinilone derivatives with hypoglycemic activity, the isoquinolin is 3- aryl isoquinolines derivative and/or 4- aryl quinoline derivatives；Wherein, the following II of general structure of general structure I, 4- aryl quinoline derivatives of the 3- aryl isoquinolines derivative:R in general formula I1For 6,8- dimethoxy, 6,8- dihydroxy, 6- hydroxyl -8- methoxyl group, 6- methoxyl group -8- hydroxyl, R2For substituted or non-substituted furans, pyrroles, pyrimidine, phenyl；R in general formula II1For 6,7- dimethoxy；R2For substituted or non-substituted furans, pyrroles, pyrimidine, phenyl.The present invention synthesizes for the first time and the isoquinilone derivatives for being found to have hypoglycemic activity have good alpha-glucosaccharase enzyme inhibition activity, the derivative has good alpha-glucosaccharase enzyme inhibition activity, it can apply in terms of prepare antidiabetic medicine, open up the research direction of a kind of novel therapeutic diabetes medicament.
Description
Technical field
The invention belongs to noval chemical compound synthesis and medicinal application technical field, especially a kind of 3- aryl isoquinolines and 4- virtue
Base quinoline derivatives and its preparation method and application.
Background technique
Isoquinolin and its derivative are a kind of important heterocyclic compounds, are present in numerous natural products.It is 1848, first
The secondary papaverine extracted from bloodroot is with the natural of the isoquinoline-containing ring structure for inhibiting fungi, virus activity
Product Compound is still important antispasmodic up to now.
In recent years, isoquinolin skeleton is usually used in the active structure group in design medicine molecule, such as atracurium, Nuo meter Fen
Pungent, moxaverine, dimoxyline (dimoxyline), quinisocaine (dimethisoquin) etc..The fully synthetic and part of isoquinolin and its derivative is tied
Structure modification, the research of structure-activity relationship and pharmaceutical activity become more and more active, and the synthesis of especially isoquinolin ring has become the heat of research
Point field.
Tiwari et al. synthesizes a series of new 1- aryl tetrahydro isoquinoline derivatives, determines 1- by In vitro Bactericidal Experiments
Aryl-6,7- dimethoxy -1,2,3,4- tetrahydroisoquinoline have antibacterial activity；10 simple type isoquinolines of Iwasa et al. logarithm
Quinoline alkali, benzylisoquinoline alkali antibacterial activity structure-activity relationship analyzed, the bacteriostasis of most compounds is fainter；Makhey
Et al. synthesized series compound by lead compound of coralyne, and carry out antitumor research.
In conclusion no matter research natural drug or the novel isoquinoline derivatives synthesized are derivative with the present invention above
The structure of object is different, and study progress above is antibacterial experiment and anti-tumor experiment mostly, not to hypoglycemic activity
It is studied.
Summary of the invention
Present invention aims in place of the deficiencies in the prior art, provide a kind of 3- aryl isoquinolines to spread out with 4- aryl quinoline class
Biology and its preparation method and application, the present invention synthesizes for the first time and the isoquinilone derivatives for being found to have hypoglycemic activity have well
Alpha-glucosaccharase enzyme inhibition activity, the derivative have good alpha-glucosaccharase enzyme inhibition activity, can apply and prepare
In in terms of antidiabetic medicine, the research direction of a kind of novel therapeutic diabetes medicament has been opened up.
The technical solution adopted by the present invention to solve the technical problems is:
A kind of isoquinilone derivatives with hypoglycemic activity, the isoquinolin are 3- aryl isoquinolines derivative and/or 4-
Aryl quinoline derivatives；
Wherein, the general structure II of general structure I, 4- aryl quinoline derivatives of the 3- aryl isoquinolines derivative is such as
Under:
Wherein, R in general formula I1For 6,8- dimethoxy, 6,8- dihydroxy, 6- hydroxyl -8- methoxyl group, 6- methoxyl group -8- hydroxyl
Base, R2For substituted or non-substituted furans, pyrroles, pyrimidine, phenyl；R in general formula II1For 6,7- dimethoxy, R2For replace or it is non-
Substituted furans, pyrroles, pyrimidine, phenyl.
Moreover, the synthetic route and preparation step of the 3- aryl isoquinolines derivative are as follows:
Wherein, preparing above-mentioned isoquinilone derivatives 4, specific step is as follows:
(1) at 0 DEG C, by POCl3It is added drop-wise in DMF, is warmed to room temperature after solidification, benzyl cyanide, POCl is added3: DMF: take
Equivalent proportion for benzene acetonitrile is 1.5:1.5:1.0,65 DEG C of reaction 1h to reaction solidification yellowly, monitoring after reaction, with satisfying
And NaHCO3It is extracted with ethyl acetate, collects organic phase and drying, silica gel chromatographic column chromatograph to obtain light yellow compound 2；
(2) under argon gas protection, by step, (1) gained desciccate 2 is dissolved in toluene, is added and is replaced phenyl boric acid, PdCl2
(dppf), desciccate 2: cesium carbonate replaces phenyl boric acid: PdCl2(dppf): the equivalent proportion of cesium carbonate is 1.0:1.2:0.05:
3,6h is reacted at 125 DEG C, after fully reacting, is diluted, is washed with water with ethyl acetate, organic layer Na2SO4After drying, filtering
Solvent evaporated, silica gel chromatography obtain compound 3；
(3) compound 3 is dissolved in methylene chloride, at 0 DEG C, BBr is added dropwise3, compound 3:BBr3Equivalent proportion be 1:3, room
Temperature reaction 12h is quenched with ice water after reaction, is extracted with saturated sodium carbonate and ethyl acetate, is collected organic phase and drying,
Silica gel chromatographic column chromatographs to obtain compound 4 to get 3- aryl isoquinolines derivative.
Moreover, the synthetic route and preparation step of the 4- aryl quinoline derivatives are as follows:
Wherein, preparing above-mentioned quinoline 6, specific step is as follows:
Under argon gas protection, quinoline raw material is dissolved in toluene, is added and is replaced phenyl boric acid, PdCl2(dppf), cesium carbonate, quinoline
Raw material: replace phenyl boric acid: PdCl2(dppf): the equivalent proportion of cesium carbonate is 1.0:1.2:0.05:3,6h is reacted at 125 DEG C, instead
After answering completely, is diluted, be washed with water with ethyl acetate, organic layer Na2SO4Dry, filter rear solvent evaporated, silica gel column chromatography
Purifying obtains product 6 to get 4- aryl quinoline derivatives.
Moreover, the 3- aryl isoquinolines derivative is 3- octaverine, the 4- aryl quinoline derivatives
For 4- phenylchinoline derivative；
The general structure IV of general structure III, 4- phenylchinoline derivative of the 3- octaverine is as follows:
Wherein, R in general formula III1For 6,8- dimethoxy, 6,8- dihydroxy, 6- hydroxyl -8- methoxyl group, 6- methoxyl group -8-
Hydroxyl, R2For alkyl, trifluoromethyl, methoxyl group, halogen, hydroxyl, nitro or cyano；R in general formula IV1For 6,7- dimethoxy, R2
For alkyl, trifluoromethyl, methoxyl group, halogen, hydroxyl, nitro or cyano.
Moreover, the synthetic route and preparation step of the 3- octaverine are as follows:
Using benzyl cyanide as raw material, corresponding derivative is then formed by the substituent group of Suzuki coupling reaction, so
3 demethylation of compound is obtained into serial hydroxy derivatives 4 to get 3- octaverine afterwards:
Moreover, the synthetic route and preparation step of the 4- phenylchinoline derivative are as follows:
Using substd quinolines as raw material, compound 6 is obtained to get 4- phenylchinoline derivative by Suzuki coupling reaction；
Moreover, the 3- aryl isoquinolines derivative is 3- substituted-phenyl Hydroisoquinoline derivatives；
The general structure V of the 3- substituted-phenyl Hydroisoquinoline derivatives is as follows:
Wherein, R1For 6,8- dimethoxy, 6,8- dihydroxy, 6- hydroxyl -8- methoxyl group, 6- methoxyl group -8- hydroxyl；R2For
Alkyl, trifluoromethyl, methoxyl group, halogen, hydroxyl, nitro or cyano；R3For hydrogen.
Moreover, the synthetic route of the 3- substituted-phenyl Hydroisoquinoline derivatives and the preparation method is as follows: with compound 3
For raw material, catalytic hydrogen reduction obtains compound 7 to get 3- substituted-phenyl Hydroisoquinoline derivatives；
The isoquinilone derivatives with hypoglycemic activity as described above in terms of inhibit alpha-glucosidase activity in answer
With.
The isoquinilone derivatives with hypoglycemic activity as described above in terms of prepare antidiabetic medicine in application.
The advantages of present invention obtains and good effect are as follows:
1, the present invention synthesizes for the first time and the isoquinilone derivatives for being found to have hypoglycemic activity have good alpha-glucosaccharase
Enzyme inhibition activity, the derivative have good alpha-glucosaccharase enzyme inhibition activity, can apply and prepare antidiabetic medicine
In aspect, the research direction of a kind of novel therapeutic diabetes medicament has been opened up.
2, there is 3- aryl isoquinolines and 4- aryl quinoline analog derivative of the present invention good alpha-glucosidase to inhibit to live
Property, synthetic method is simple.
Detailed description of the invention
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of 4- (6,8- dimethylisoquinoline -3- base) benzonitrile (compound 3a) in the present invention；
Fig. 2 is the nucleus magnetic hydrogen spectrum figure of 3- (4- fluorophenyl) -6,8- dimethoxy-isoquinoline (compound 3b) in the present invention；
Fig. 3 is the nuclear-magnetism of 6,8- dimethoxy -3- (4- (trifluoromethyl) phenyl) isoquinolin (compound 3c) in the present invention
Hydrogen spectrogram；
Fig. 4 is the nucleus magnetic hydrogen spectrum figure of 6,8- dimethoxy -3- (4- nitrobenzophenone) isoquinolin (compound 3d) in the present invention；
Fig. 5 is the core of 6,8- dimethoxy -3- (3,4,5- trimethoxyphenyl) isoquinolin (compound 3e) in the present invention
Magnetic hydrogen spectrogram；
Fig. 6 is the nucleus magnetic hydrogen spectrum figure of 3- (furans -2- base) -6,8- dimethoxy-isoquinoline (compound 3f) in the present invention；
Fig. 7 is the nucleus magnetic hydrogen spectrum figure of 3- (4- fluorophenyl) isoquinolin -6,8- glycol (compound 4a) in the present invention；
Fig. 8 is the nucleus magnetic hydrogen spectrum figure of 3- (4- fluorophenyl) -8- methoxyisoquinoliae -6- alcohol (compound 4b) in the present invention；
Fig. 9 is the nucleus magnetic hydrogen spectrum figure of 3- (4- fluorophenyl) -6- methoxy quinoline -8- alcohol (compound 4c) in the present invention；
Figure 10 is the nucleus magnetic hydrogen spectrum figure of 4- (4- fluorophenyl) -6,7- dimethyl quinoline (compound 6a) in the present invention；
Figure 11 is the nucleus magnetic hydrogen spectrum figure of 4- (6,7- dimethoxy quinoline quinoline -4- base) benzonitrile (compound 6b) in the present invention；
Figure 12 is 6,8- dimethoxy -3- (3,4,5- trimethoxyphenyl) -1,2,3,4- tetrahydroisoquinoline in the present invention
The nucleus magnetic hydrogen spectrum figure of (compound 7).
Specific embodiment
The embodiment of the present invention is described in detail below, it should be noted that the present embodiment is narrative, is not limited
, this does not limit the scope of protection of the present invention.
Raw material used in the present invention is unless otherwise specified conventional commercial product；Used in the present invention
Method is unless otherwise specified the conventional method of this field.
A kind of isoquinilone derivatives with hypoglycemic activity, the isoquinolin are 3- aryl isoquinolines derivative and/or 4-
Aryl quinoline derivatives；
Wherein, the general structure II of general structure I, 4- aryl quinoline derivatives of the 3- aryl isoquinolines derivative is such as
Under:
Wherein, R in general formula I1For 6,8- dimethoxy, 6,8- dihydroxy, 6- hydroxyl -8- methoxyl group, 6- methoxyl group -8- hydroxyl
Base, R2For substituted or non-substituted furans, pyrroles, pyrimidine, phenyl；R in general formula II1For 6,7- dimethoxy, R2For replace or it is non-
Substituted furans, pyrroles, pyrimidine, phenyl.
More preferably, the synthetic route and preparation step of the 3- aryl isoquinolines derivative are as follows:
Wherein, preparing above-mentioned isoquinilone derivatives 4, specific step is as follows:
(1) at 0 DEG C, by POCl3It is added drop-wise in DMF, is warmed to room temperature after solidification, benzyl cyanide, POCl is added3: DMF: take
Equivalent proportion for benzene acetonitrile is 1.5:1.5:1.0,65 DEG C of reaction 1h to reaction solidification yellowly, monitoring after reaction, with satisfying
And NaHCO3It is extracted with ethyl acetate, collects organic phase and drying, silica gel chromatographic column chromatograph to obtain light yellow compound 2；
(2) under argon gas protection, by step, (1) gained desciccate 2 is dissolved in toluene, is added and is replaced phenyl boric acid, PdCl2
(dppf), desciccate 2: cesium carbonate replaces phenyl boric acid: PdCl2(dppf): the equivalent proportion of cesium carbonate is 1.0:1.2:0.05:
3,6h is reacted at 125 DEG C, after fully reacting, is diluted, is washed with water with ethyl acetate, organic layer Na2SO4After drying, filtering
Solvent evaporated, silica gel chromatography obtain compound 3；
(3) compound 3 is dissolved in methylene chloride, at 0 DEG C, BBr is added dropwise3, compound 3:BBr3Equivalent proportion be 1:3, room
Temperature reaction 12h is quenched with ice water after reaction, is extracted with saturated sodium carbonate and ethyl acetate, is collected organic phase and drying,
Silica gel chromatographic column chromatographs to obtain compound 4 to get 3- aryl isoquinolines derivative.
More preferably, the synthetic route and preparation step of the 4- aryl quinoline derivatives are as follows:
Wherein, preparing above-mentioned quinoline 6, specific step is as follows:
Under argon gas protection, quinoline raw material is dissolved in toluene, is added and is replaced phenyl boric acid, PdCl2(dppf), cesium carbonate, quinoline
Raw material: replace phenyl boric acid: PdCl2(dppf): the equivalent proportion of cesium carbonate is 1.0:1.2:0.05:3,6h is reacted at 125 DEG C, instead
After answering completely, is diluted, be washed with water with ethyl acetate, organic layer Na2SO4Dry, filter rear solvent evaporated, silica gel column chromatography
Purifying obtains product 6 to get 4- aryl quinoline derivatives.
More preferably, the 3- aryl isoquinolines derivative is 3- octaverine, and the 4- aryl quinoline is derivative
Object is 4- phenylchinoline derivative；
The general structure IV of general structure III, 4- phenylchinoline derivative of the 3- octaverine is as follows:
Wherein, R in general formula III1For 6,8- dimethoxy, 6,8- dihydroxy, 6- hydroxyl -8- methoxyl group, 6- methoxyl group -8-
Hydroxyl, R2For alkyl, trifluoromethyl, methoxyl group, halogen, hydroxyl, nitro or cyano；R in general formula IV1For 6,7- dimethoxy, R2
For alkyl, trifluoromethyl, methoxyl group, halogen, hydroxyl, nitro or cyano.
More preferably, the synthetic route and preparation step of the 3- octaverine are as follows:
Using benzyl cyanide as raw material, corresponding derivative is then formed by the substituent group of Suzuki coupling reaction, so
3 demethylation of compound is obtained into serial hydroxy derivatives 4 to get 3- octaverine afterwards:
More preferably, the synthetic route and preparation step of the 4- phenylchinoline derivative are as follows:
Using substd quinolines as raw material, compound 6 is obtained to get 4- phenylchinoline derivative by Suzuki coupling reaction；
More preferably, the 3- aryl isoquinolines derivative is 3- substituted-phenyl Hydroisoquinoline derivatives；
The general structure V of the 3- substituted-phenyl Hydroisoquinoline derivatives is as follows:
Wherein, R1For 6,8- dimethoxy, 6,8- dihydroxy, 6- hydroxyl -8- methoxyl group, 6- methoxyl group -8- hydroxyl；R2For
Alkyl, trifluoromethyl, methoxyl group, halogen, hydroxyl, nitro or cyano；R3For hydrogen.
More preferably, the synthetic route of the 3- substituted-phenyl Hydroisoquinoline derivatives and the preparation method is as follows: with chemical combination
Object 3 is raw material, and catalytic hydrogen reduction obtains compound 7 to get 3- substituted-phenyl Hydroisoquinoline derivatives；
The above-mentioned isoquinilone derivatives with hypoglycemic activity can be applied in terms of inhibit alpha-glucosidase activity.
The above-mentioned isoquinilone derivatives with hypoglycemic activity can be applied in terms of prepare antidiabetic medicine.
More specifically:
A kind of isoquinilone derivatives with hypoglycemic activity, preparing for the derivative are as follows:
One, 3- aryl isoquinolines derivative 4 is synthesized by the following way route and obtains:
Wherein, above-mentioned isoquinilone derivatives 4 are prepared specifically include the following steps:
At (1) 0 DEG C, by POCl3(1.5eq) is added drop-wise in DMF (1.5eq), is warmed to room temperature after solidification, and substituted benzene second is added
Nitrile (1.0eq), 65 DEG C of reaction 1h to reaction solidification yellowly are monitored after reaction, with saturation NaHCO3Extract with ethyl acetate
It takes, collects organic phase and drying, silica gel chromatographic column chromatograph to obtain light yellow compound 2；
(2) under argon gas protection, by step, (1) gained desciccate 2 (1.0eq.) is dissolved in toluene, is added and is replaced phenyl boric acid
(1.2eq.)、PdCl2(dppf) (0.05eq.), cesium carbonate (3eq), about 6h is reacted at 125 DEG C, after fully reacting, uses acetic acid
Ethyl ester dilution, is washed with water, organic layer Na2SO4Rear solvent evaporated is dried, filtered, silica gel chromatography obtains compound 3.
(3) product 3 (1eq) is dissolved in methylene chloride, at 0 DEG C, BBr is added dropwise3(3eq) reacts at room temperature 12h, reaction knot
Shu Hou is quenched with ice water, is extracted with saturated sodium carbonate and ethyl acetate, collects organic phase and drying, silica gel chromatographic column chromatograph
To compound 4.
Correlation preparation embodiment is as follows:
Embodiment 1
The synthesis of 4- (6,8- dimethylisoquinoline -3- base) benzonitrile (compound 3a).
At (1) 0 DEG C, by POCl3(1.5eq) is added drop-wise in DMF (1.5eq), is warmed to room temperature after solidification, and 3,5- diformazan is added
Oxygroup benzene acetonitrile (1.0eq), 65 DEG C of reaction 1h to reaction solidification yellowly are monitored after reaction, with saturation NaHCO3And second
Acetoacetic ester extraction, collects organic phase and drying, silica gel chromatographic column chromatograph to obtain light yellow product；
(2) under argon gas protection, by step, (1) gained desciccate (1.0eq.) is dissolved in toluene, and 4- cyanophenylboronic acid is added
(1.2eq.)、PdCl2(dppf) (0.05eq.), cesium carbonate (3eq), about 6h is reacted at 125 DEG C, after fully reacting, uses acetic acid
Ethyl ester dilution, is washed with water, organic layer Na2SO4Rear solvent evaporated is dried, filtered, silica gel chromatography obtains product 3.
Structural parameters:1H NMR(400MHz,CDCl3) δ 9.50 (s, 1H), 8.21 (d, J=8.4Hz, 2H), 7.92 (s,
1H), 7.77 (d, J=8.0Hz, 2H), 6.71 (s, 1H), 6.55 (d, J=1.2Hz, 1H), 4.01 (s, 3H), 3.95 (s, 3H),
As shown in Figure 1.
Embodiment 2
The synthesis of 3- (4- fluorophenyl) -6,8- dimethoxy-isoquinoline (compound 3b).
Synthetic method of the synthetic method of embodiment 2 with above-described embodiment 1.
Yield: 35%；Structural parameters:1H NMR(400MHz,CDCl3)δ9.46(s,1H),8.06(dd,J1=5.6Hz,
J2=8.8Hz, 2H), 7.81 (s, 1H), 7.16 (t, J=8.8Hz, 2H), 6.66 (d, J=2.0Hz, 1H), 6.48 (d, J=
2.0Hz, 1H), 3.99 (s, 3H), 3.93 (s, 3H), as shown in Figure 2.
Embodiment 3
The synthesis of 6,8- dimethoxy -3- (4- (trifluoromethyl) phenyl) isoquinolin (compound 3c).
Synthetic method of the synthetic method of embodiment 3 with above-described embodiment 1.
Yield: 35%；Structural parameters:1H NMR(400MHz,CDCl3) δ 9.50 (s, 1H), 8.20 (d, J=8.0Hz,
2H), 7.90 (s, 1H), 7.73 (d, J=8.4Hz, 2H), 6.69 (d, J=1.6Hz, 1H), 6.52 (d, J=1.6Hz, 1H),
4.00 (s, 3H), 3.94 (s, 3H), as shown in Figure 3.
Embodiment 4
The synthesis of 6,8- dimethoxy -3- (4- nitrobenzophenone) isoquinolin (compound 3d).
Synthetic method of the synthetic method of embodiment 4 with above-described embodiment 1.
Yield: 35%；Structural parameters:1HNMR(400MHz,CDCl3) δ 9.52 (s, 1H), 8.34 (d, J=8.8Hz, 2H),
8.28 (d, J=8.8Hz, 2H), 7.98 (s, 1H), 6.74 (d, J=2.0Hz, 1H), 6.57 (d, J=1.6Hz, 1H), 4.02
(s, 3H), 3.96 (s, 3H), as shown in Figure 4.
Embodiment 5
The synthesis of 6,8- dimethoxy -3- (3,4,5- trimethoxyphenyl) isoquinolin (compound 3e).
Synthetic method of the synthetic method of embodiment 5 with above-described embodiment 1.
Yield: 45%；Structural parameters:1H NMR(400MHz,CDCl3)δ9.47(s,1H),7.82(s,1H),7.263(s,
2H), 6.69 (s, 1H), 6.49 (s, 1H), 3.99-4.00 (m, 9H), 3.94 (s, 3H), 3.91 (s, 3H), as shown in Figure 5.
Embodiment 6
The synthesis of 3- (furans -2- base) -6,8- dimethoxy-isoquinoline (compound 3f).
Synthetic method of the synthetic method of embodiment 6 with above-described embodiment 1.
Yield: 25%；Structural parameters:1H NMR(400MHz,CDCl3)δ9.39(s,1H),7.85(s,1H),7.54(t,J
=0.8Hz, 1H), 7.10 (d, J=3.2Hz, 1H), 6.66 (d, J=1.6Hz, 1H), 6.55 (t, J=1.6Hz, 1H), 6.47
(d, J=2.4Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), as shown in Figure 6.
Embodiment 7
The synthesis of 3- (4- fluorophenyl) isoquinolin -6,8- glycol (compound 4a).
3- (4- fluorophenyl) -6,8- dimethoxy-isoquinoline (1eq) is dissolved in methylene chloride, at 0 DEG C, BBr is added dropwise3
(3eq), room temperature reaction 12h are quenched with ice water after reaction, are extracted with saturated sodium carbonate and ethyl acetate, collect organic phase
And it is dry, silica gel chromatographic column chromatographs to obtain product 4.
Yield: 5%；Structural parameters:1H NMR(400MHz,CD3OD-d4)δ9.17(s,1H),7.87(dd,J1=
5.6Hz,J2=8.8Hz, 2H), 7.76 (s, 1H), 7.15 (t, J=8.8Hz, 2H), 6.60 (d, J=1.6Hz, 1H), 6.46
(d, J=1.6Hz, 1H), as shown in Figure 7.
Embodiment 8
The synthesis of 3- (4- fluorophenyl) -8- methoxyisoquinoliae -6- alcohol (compound 4b).
Synthetic method of the synthetic method of embodiment 8 with above-described embodiment 7.
Yield: 15%；Structural parameters:1H NMR(400MHz,CD3OD-d4)δ9.24(s,1H),7.87(m,2H),7.87
(s, 1H), 7.13 (t, J=8.8Hz, 2H), 6.73 (d, J=2.0Hz, 1H), 6.44 (d, J=2.4Hz, 1H), 3.82 (s,
3H), as shown in Figure 8.
Embodiment 9
The synthesis of 3- (4- fluorophenyl) -6- methoxy quinoline -8- alcohol (compound 4c).
Synthetic method of the synthetic method of embodiment 9 with above-described embodiment 7.
Yield: 30%；Structural parameters:1H NMR(400MHz,CD3OD-d4)δ9.19(s,1H),7.90(dd,J1=
5.2Hz,J2=8.4Hz, 2H), 7.75 (s, 1H), 7.12 (t, J=8.8Hz, 2H), 6.64 (d, J=1.2Hz, 1H), 6.51
(d, J=1.6Hz, 1H), 3.93 (s, 3H), as shown in Figure 9.
Two, 4- aryl quinoline derivatives IV's the preparation method is as follows:
Wherein prepare above-mentioned quinoline 6 specifically include the following steps:
Under argon gas protection, quinoline raw material (1.0eq.) is dissolved in toluene, is added and is replaced phenyl boric acid (1.2eq.), PdCl2
(dppf) (0.05eq.), cesium carbonate (3eq), about 6h is reacted at 125 DEG C, after fully reacting, is diluted with ethyl acetate, uses water
Washing, organic layer Na2SO4Rear solvent evaporated is dried, filtered, silica gel chromatography obtains product 6.
Specific preparation embodiment is as follows:
Embodiment 10
The synthesis of 4- (4- fluorophenyl) -6,7- dimethyl quinoline (compound 6a).
Under argon gas protection, chloro- 6, the 7- dimethoxy-quinoline (1.0eq.) of 4- is dissolved in toluene, is added to fluorobenzoic boric acid
(1.2eq.)、PdCl2(dppf) (0.05eq.), cesium carbonate (3eq), about 6h is reacted at 125 DEG C, after fully reacting, uses acetic acid
Ethyl ester dilution, is washed with water, organic layer Na2SO4Rear solvent evaporated is dried, filtered, silica gel chromatography obtains compound
6a。
Yield: 56%；Structural parameters:1H NMR(400MHz,CDCl3) δ 8.74 (d, J=4.8Hz, 1H), 7.47-7.50
(m, 3H), 7.25 (t, J=8.0Hz, 2H), 7.16 (d, J=4.8Hz, 1H), 7.09 (s, 1H), 4.05 (s, 3H), 3.85 (s,
3H), as shown in Figure 10.
Embodiment 11
The synthesis of 4- (6,7- dimethoxy quinoline quinoline -4- base) benzonitrile (compound 6b).
Synthetic method of the synthetic method of embodiment 11 with above-described embodiment 10.
Yield: 62%；Structural parameters:1H NMR(400MHz,CDCl3) δ 8.78 (d, J=4.4Hz, 1H), 7.84 (d, J=
8.4Hz, 2H), 7.64 (d, J=8.4Hz, 2H), 7.51 (s, 1H), 7.16 (d, J=4.4Hz, 1H), 6.97 (s, 1H), 4.06
(s, 3H), 3.85 (s, 3H), as shown in figure 11.
Three, 3- substituted-phenyl Hydroisoquinoline derivatives V's the preparation method is as follows:
Isoquinilone derivatives V are synthesized by the following way route and obtain:
Compound III (1eq) is dissolved in dehydrated alcohol, PtO is added2(0.3eq) is passed through hydrogen catalytic hydrogenation, reaction
After, filtering reacting liquid is evaporated, the compound 7 of column chromatogram chromatography.
Embodiment 12
The synthesis of 6,8- dimethoxy -3- (3,4,5- trimethoxyphenyl) -1,2,3,4- tetrahydroisoquinoline (compound 7)
6,8- dimethoxy -3- (3,4,5- trimethoxyphenyl) isoquinolin (compound 3e) (1eq) is dissolved in anhydrous second
In alcohol, PtO is added2(0.3eq) is passed through hydrogen catalytic hydrogenation, and after reaction, filtering reacting liquid is evaporated, and column chromatogram chromatography obtains
Compound 7.
Yield: 26%；Structural parameters:1H NMR(400MHz,CDCl3) δ 6.68 (s, 1H), 6.31 (d, J=1.6Hz,
1H), 6.24 (s, 1H), 4.22 (d, J=15.6Hz, 1H), 3.78-3.87 (m, 15H), 2.87-2.98 (m, 2H), such as Figure 12 institute
Show.
The compounds of this invention inhibits alpha-glucosidase activity evaluation:
Using screening micropore plate model, using p-nitrophenyl-α-D- glucopyranose as substrate, test compound difference is dense
The inhibitory activity of alpha-glucosidase under degree.Experiment is divided into blank group, the control group of without inhibitor and sample to be tested group.Face
The alpha-glucosidase restrainer acarbose that bed uses is as positive control medicine.Inhibitor and acarbose are dissolved in DMSO,
DMSO solution mass content in enzyme test system is 5%；Buffer is phosphate buffer (pH=6.8,0.05M), to nitre
Base phenyl-α-D- glucopyranose is dissolved in phosphate buffer.
(1) buffer, 200 μ L of total volume blank group: is added.
(2) sample to be tested (10 μ L) of buffer (190 μ L) and various concentration, without inhibitor control group: is added.
(3) buffer (150 μ L), alpha-glucosidase (0.04U, 20 μ L) and substrate p-nitrophenyl-control group: is added
The aqueous solution of α-D- glucopyranose (0.5M, 30 μ L).
(4) sample to be tested group: being added buffer (140 μ L), alpha-glucosidase (0.04U, 20 μ L), sample to be tested
DMSO solution (10 μ L) and substrate p-nitrophenyl-α-D- glucopyranose (0.5M, 30 μ L).
In 96 orifice plates, according to different experiments group, it is separately added into buffer, the sample to be tested of various concentration, phlorose
The DMSO solution of glycosides enzyme and sample to be tested applies 5min in 37 DEG C of temperature, adds substrate p-nitrophenyl-α-D- glucopyranose,
The deposited 30min of temperature, absorbance is measured at microplate reader 405nm wavelength, calculates the inhibitor to alpha-glucosaccharase according to following equation
The inhibiting rate of enzyme.
OD value is the absorbance value under microplate reader test.
The alpha-glucosaccharase enzyme inhibition activity of 1 compound of table and positive control acarbose
aThe inhibiting rate when inhibiting rate of acarbose is 250 μM.
By 1 result of table it is known that such compound has certain inhibitory activity to alpha-glucosidase.
Although disclosing the embodiment of the present invention for the purpose of illustration, it will be appreciated by those skilled in the art that: not
Be detached from the present invention and spirit and scope of the appended claims in, various substitutions, changes and modifications be all it is possible, therefore, this
The range of invention is not limited to the embodiment and attached drawing disclosure of that.
Claims (10)
1. a kind of isoquinilone derivatives with hypoglycemic activity, it is characterised in that: the isoquinolin is derivative for 3- aryl isoquinolines
Object and/or 4- aryl quinoline derivatives；
Wherein, the general structure II of general structure I, 4- aryl quinoline derivatives of the 3- aryl isoquinolines derivative is as follows:
Wherein, R in general formula I1For 6,8- dimethoxy, 6,8- dihydroxy, 6- hydroxyl -8- methoxyl group, 6- methoxyl group -8- hydroxyl, R2
For substituted or non-substituted furans, pyrroles, pyrimidine, phenyl；R in general formula II1For 6,7- dimethoxy, R2It is substituted or non-substituted
Furans, pyrroles, pyrimidine, phenyl.
2. the isoquinilone derivatives according to claim 1 with hypoglycemic activity, it is characterised in that: the 3- aryl isoquinoline
The synthetic route and preparation step of quinoline derivant are as follows:
Wherein, preparing above-mentioned isoquinilone derivatives 4, specific step is as follows:
(1) at 0 DEG C, by POCl3It is added drop-wise in DMF, is warmed to room temperature after solidification, benzyl cyanide, POCl is added3: DMF: substituted benzene
The equivalent proportion of acetonitrile is 1.5:1.5:1.0, and 65 DEG C of reaction 1h are monitored to reaction solidification yellowly after reaction, with saturation
NaHCO3It is extracted with ethyl acetate, collects organic phase and drying, silica gel chromatographic column chromatograph to obtain light yellow compound 2；
(2) under argon gas protection, by step, (1) gained desciccate 2 is dissolved in toluene, is added and is replaced phenyl boric acid, PdCl2(dppf), carbon
Desciccate 2: sour caesium replaces phenyl boric acid: PdCl2(dppf): the equivalent proportion of cesium carbonate is 1.0:1.2:0.05:3, at 125 DEG C
Lower reaction 6h, after fully reacting, is diluted with ethyl acetate, is washed with water, organic layer Na2SO4Rear solvent evaporated is dried, filtered,
Silica gel chromatography obtains compound 3；
(3) compound 3 is dissolved in methylene chloride, at 0 DEG C, BBr is added dropwise3, compound 3:BBr3Equivalent proportion be 1:3, room temperature is anti-
It answers 12h, after reaction, be quenched with ice water, is extracted with saturated sodium carbonate and ethyl acetate, collect organic phase and drying, silica gel
Column chromatography obtains compound 4 to get 3- aryl isoquinolines derivative.
3. the isoquinilone derivatives according to claim 1 with hypoglycemic activity, it is characterised in that: the 4- aryl quinoline
The synthetic route and preparation step of derivative are as follows:
Wherein, preparing above-mentioned quinoline 6, specific step is as follows:
Under argon gas protection, quinoline raw material is dissolved in toluene, is added and is replaced phenyl boric acid, PdCl2(dppf), cesium carbonate, quinoline raw material:
Replace phenyl boric acid: PdCl2(dppf): the equivalent proportion of cesium carbonate is 1.0:1.2:0.05:3, reacts 6h at 125 DEG C, has reacted
Quan Hou is diluted with ethyl acetate, is washed with water, organic layer Na2SO4Dry, filter rear solvent evaporated, silica gel chromatography
Product 6 is obtained to get 4- aryl quinoline derivatives.
4. the isoquinilone derivatives according to claim 1 with hypoglycemic activity, it is characterised in that: the 3- aryl isoquinoline
Quinoline derivant is 3- octaverine, and the 4- aryl quinoline derivatives are 4- phenylchinoline derivative；
The general structure IV of general structure III, 4- phenylchinoline derivative of the 3- octaverine is as follows:
Wherein, R in general formula III1For 6,8- dimethoxy, 6,8- dihydroxy, 6- hydroxyl -8- methoxyl group, 6- methoxyl group -8- hydroxyl,
R2For alkyl, trifluoromethyl, methoxyl group, halogen, hydroxyl, nitro or cyano；R in general formula IV1For 6,7- dimethoxy, R2For alkane
Base, trifluoromethyl, methoxyl group, halogen, hydroxyl, nitro or cyano.
5. the isoquinilone derivatives according to claim 4 with hypoglycemic activity, it is characterised in that: the 3- phenyl isoquinolin
The synthetic route and preparation step of quinoline derivant are as follows:
Using benzyl cyanide as raw material, corresponding derivative is then formed by the substituent group of Suzuki coupling reaction, then will
3 demethylation of compound obtains serial hydroxy derivatives 4 to get 3- octaverine:
6. the isoquinilone derivatives according to claim 4 with hypoglycemic activity, it is characterised in that: the 4- phenylchinoline
The synthetic route and preparation step of derivative are as follows:
Using substd quinolines as raw material, compound 6 is obtained to get 4- phenylchinoline derivative by Suzuki coupling reaction；
7. the isoquinilone derivatives according to claim 1 with hypoglycemic activity, it is characterised in that: the 3- aryl isoquinoline
Quinoline derivant is 3- substituted-phenyl Hydroisoquinoline derivatives；
The general structure V of the 3- substituted-phenyl Hydroisoquinoline derivatives is as follows:
Wherein, R1For 6,8- dimethoxy, 6,8- dihydroxy, 6- hydroxyl -8- methoxyl group, 6- methoxyl group -8- hydroxyl；R2For alkyl,
Trifluoromethyl, methoxyl group, halogen, hydroxyl, nitro or cyano；R3For hydrogen.
8. the isoquinilone derivatives according to claim 7 with hypoglycemic activity, it is characterised in that: the 3- substituted-phenyl
The synthetic route of Hydroisoquinoline derivatives and the preparation method is as follows: be raw material with compound 3, catalytic hydrogen reduction obtains chemical combination
Object 7 is to get 3- substituted-phenyl Hydroisoquinoline derivatives；
9. the isoquinilone derivatives as claimed in any one of claims 1 to 8 with hypoglycemic activity are inhibiting alpha-glucosidase
Application in active aspect.
10. the isoquinilone derivatives as claimed in any one of claims 1 to 8 with hypoglycemic activity are preparing antidiabetic medicine
Application in aspect.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910085622.1A CN109776413A (en) | 2019-01-29 | 2019-01-29 | A kind of isoquinilone derivatives and application with hypoglycemic activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910085622.1A CN109776413A (en) | 2019-01-29 | 2019-01-29 | A kind of isoquinilone derivatives and application with hypoglycemic activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109776413A true CN109776413A (en) | 2019-05-21 |
Family
ID=66503489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910085622.1A Pending CN109776413A (en) | 2019-01-29 | 2019-01-29 | A kind of isoquinilone derivatives and application with hypoglycemic activity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109776413A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112047882A (en) * | 2020-10-15 | 2020-12-08 | 天津科技大学 | New application of isoquinoline and quinoline derivatives in preparation of blood fat reducing drugs |
| CN115286572A (en) * | 2022-07-15 | 2022-11-04 | 绍兴文理学院 | 4-acyl-isoquinoline derivative and preparation method and application thereof |
| CN115417817A (en) * | 2022-09-23 | 2022-12-02 | 徐州医科大学 | Preparation method of 4-amino-4-phenylisoquinoline-1,3-diketone derivative |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992020642A1 (en) * | 1991-05-10 | 1992-11-26 | Rhone-Poulenc Rorer International (Holdings) Inc. | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase |
| CN101641339A (en) * | 2007-02-01 | 2010-02-03 | 雷斯韦洛吉克斯公司 | Be used to prevent and treat the compound of cardiovascular disorder |
| WO2012136910A1 (en) * | 2011-04-08 | 2012-10-11 | Université De Marseille | Derivatives of 4-arylcoumarin and 4-arylquinoline, therapeutic uses thereof and method for synthesising same |
| CN104447550A (en) * | 2014-12-01 | 2015-03-25 | 张晓凤 | Compound used as allergy preventing agent |
| CN111315723A (en) * | 2017-08-31 | 2020-06-19 | 艾伯维公司 | Extramembranous nucleotide pyrophosphatase-phosphodiesterase 1(ENPP-1) inhibitor and application thereof |
-
2019
- 2019-01-29 CN CN201910085622.1A patent/CN109776413A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992020642A1 (en) * | 1991-05-10 | 1992-11-26 | Rhone-Poulenc Rorer International (Holdings) Inc. | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase |
| EP0584222A1 (en) * | 1991-05-10 | 1994-03-02 | Rhone Poulenc Rorer Int | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase. |
| CN101641339A (en) * | 2007-02-01 | 2010-02-03 | 雷斯韦洛吉克斯公司 | Be used to prevent and treat the compound of cardiovascular disorder |
| WO2012136910A1 (en) * | 2011-04-08 | 2012-10-11 | Université De Marseille | Derivatives of 4-arylcoumarin and 4-arylquinoline, therapeutic uses thereof and method for synthesising same |
| CN104447550A (en) * | 2014-12-01 | 2015-03-25 | 张晓凤 | Compound used as allergy preventing agent |
| CN111315723A (en) * | 2017-08-31 | 2020-06-19 | 艾伯维公司 | Extramembranous nucleotide pyrophosphatase-phosphodiesterase 1(ENPP-1) inhibitor and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| EDWARD A. FEHNEL，等: "Quinoline Analogs of Podophyllotoxin. I. Preliminary Experiments. Syntheses of Some 4-Phenylquinoline Derivatives", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| S. AHMAD, W. 6. WHALLEY，等: "The Chemistry of Fungi. Part LXVP A New Synthesis of lsoquinolines", 《JOURNAL OF THE CHEMICAL SOCIETY [SECTION] C: ORGANIC》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112047882A (en) * | 2020-10-15 | 2020-12-08 | 天津科技大学 | New application of isoquinoline and quinoline derivatives in preparation of blood fat reducing drugs |
| CN115286572A (en) * | 2022-07-15 | 2022-11-04 | 绍兴文理学院 | 4-acyl-isoquinoline derivative and preparation method and application thereof |
| CN115286572B (en) * | 2022-07-15 | 2023-10-13 | 绍兴文理学院 | 4-acyl-isoquinoline derivative and preparation method and application thereof |
| CN115417817A (en) * | 2022-09-23 | 2022-12-02 | 徐州医科大学 | Preparation method of 4-amino-4-phenylisoquinoline-1,3-diketone derivative |
| CN115417817B (en) * | 2022-09-23 | 2023-06-20 | 徐州医科大学 | Process for preparing 4-amino-4-phenylisoquinoline-1, 3-dione derivatives |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113164409B (en) | Compounds having estrogen receptor alpha degrading activity and uses thereof | |
| CA2617213C (en) | Pharmaceutical compositions for the prevention and treatment of complex diseases and their delivery by insertable medical devices | |
| CN109776413A (en) | A kind of isoquinilone derivatives and application with hypoglycemic activity | |
| Chang et al. | Synthesis and antiproliferative evaluations of certain 2-phenylvinylquinoline (2-styrylquinoline) and 2-furanylvinylquinoline derivatives | |
| Iwasaki et al. | Novel selective PDE IV inhibitors as antiasthmatic agents. Synthesis and biological activities of a series of 1-aryl-2, 3-bis (hydroxymethyl) naphthalene lignans | |
| US20090259048A1 (en) | Flavanoids and isoflavanoids for the prevention and treatment of cardiovascular diseases | |
| Zubkov et al. | A new approach to construction of isoindolo [1, 2-a] isoquinoline alkaloids Nuevamine, Jamtine, and Hirsutine via IMDAF reaction | |
| Rajguru et al. | Solvent-free, green and efficient synthesis of pyrano [4, 3-b] pyrans by grinding and their biological evaluation as antitumor and antioxidant agents | |
| CN103320118A (en) | Schiff base cooper ion fluorescence probe and preparation method thereof | |
| CN102924421B (en) | Preparation method and application of compound having tyrosinase inhibitory activity | |
| CN100586937C (en) | Ligustrazine stilbenoids derivatives, preparation method thereof, medicament composition and use | |
| Meyer et al. | Benzylisoquinoline alkaloids from the Papaveraceae: The heritage of Johannes Gadamer (1867–1928) | |
| Krishnakumar et al. | Quinoline-3-carboxylates as potential antibacterial agents | |
| Zhou et al. | Synthesis and antitumor activity of scopoletin derivatives | |
| CN103159755A (en) | Alpha-glycosidase inhibitor preparation method and purpose | |
| CN111303026A (en) | Propenone derivative of enrofloxacin and preparation method and application thereof | |
| Shirokova et al. | 1, 5-Hydride-Shift-Triggered Cyclization for the Synthesis of Unsymmetric Julolidines | |
| Goodwin et al. | Alkaloids of Lunasia amara Blanco. Structure of lunacrine | |
| CN102584773B (en) | Method for preparing mangiferin aglycone | |
| CA1159068A (en) | Carbostyril derivatives | |
| CN111646937B (en) | Propenone derivative of N-acetyl ciprofloxacin and preparation method and application thereof | |
| CN100348591C (en) | Substituted methylene pyrones derivatives and their preparing process and use | |
| CN108864089A (en) | A kind of new indole and pyridone drug molecule and its preparation method and application | |
| CN113072481B (en) | Indolo-cyclobutane skeleton compound, synthesis method and application | |
| CN111646975B (en) | N-methyl lomefloxacin allyl ketone derivative and preparation method and application thereof |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190521 |