CN106432039A - 3,4‑二芳基马来酰亚胺衍生物及其制备方法与应用 - Google Patents
3,4‑二芳基马来酰亚胺衍生物及其制备方法与应用 Download PDFInfo
- Publication number
- CN106432039A CN106432039A CN201610850934.3A CN201610850934A CN106432039A CN 106432039 A CN106432039 A CN 106432039A CN 201610850934 A CN201610850934 A CN 201610850934A CN 106432039 A CN106432039 A CN 106432039A
- Authority
- CN
- China
- Prior art keywords
- compound
- alkyl group
- fluorophenyl
- low alkyl
- hydroxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical group 0.000 claims abstract description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 68
- 238000006243 chemical reaction Methods 0.000 claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 48
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- -1 3- hydroxyl -3,3- diphenyl propyl Chemical group 0.000 claims description 34
- 239000011734 sodium Substances 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 239000002585 base Substances 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000001475 halogen functional group Chemical group 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 9
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 claims description 9
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 9
- 229940126657 Compound 17 Drugs 0.000 claims description 9
- 241000790917 Dioxys <bee> Species 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 8
- 125000001118 alkylidene group Chemical group 0.000 claims description 8
- 229940126142 compound 16 Drugs 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 7
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 6
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 6
- 229940125773 compound 10 Drugs 0.000 claims description 6
- 229940126543 compound 14 Drugs 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 6
- 230000000977 initiatory effect Effects 0.000 claims description 6
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 6
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 5
- 235000010290 biphenyl Nutrition 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 5
- 210000002381 plasma Anatomy 0.000 claims description 5
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 claims description 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 5
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125797 compound 12 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- QDPMLKBAQOZXEF-UHFFFAOYSA-N ethanesulfonic acid;sodium Chemical compound [Na].CCS(O)(=O)=O QDPMLKBAQOZXEF-UHFFFAOYSA-N 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 125000004344 phenylpropyl group Chemical group 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims 1
- 239000003292 glue Substances 0.000 claims 1
- 239000012312 sodium hydride Substances 0.000 claims 1
- 229910000104 sodium hydride Inorganic materials 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 201000001320 Atherosclerosis Diseases 0.000 abstract description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- 230000004044 response Effects 0.000 description 16
- 238000005292 vacuum distillation Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 150000002118 epoxides Chemical class 0.000 description 13
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 10
- 229910052794 bromium Inorganic materials 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 4
- 206010011224 Cough Diseases 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- CRZQGDNQQAALAY-UHFFFAOYSA-N Methyl benzeneacetate Chemical compound COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 3
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical class BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 3
- YOMBUJAFGMOIGS-UHFFFAOYSA-N 2-fluoro-1-phenylethanone Chemical compound FCC(=O)C1=CC=CC=C1 YOMBUJAFGMOIGS-UHFFFAOYSA-N 0.000 description 3
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 238000010009 beating Methods 0.000 description 3
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960000815 ezetimibe Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- 239000000693 micelle Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 3
- 229940032091 stigmasterol Drugs 0.000 description 3
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 3
- 235000016831 stigmasterol Nutrition 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- VNMNSTIGSQBDPI-UHFFFAOYSA-N 2,3-diphenyl-1h-pyrrole Chemical compound N1C=CC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 VNMNSTIGSQBDPI-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 239000007836 KH2PO4 Substances 0.000 description 2
- 125000003047 N-acetyl group Chemical group 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical class BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 241000283724 Bison bonasus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000001994 activation Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 1
- 229960005110 cerivastatin Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000005439 maleimidyl group Chemical class C1(C=CC(N1*)=O)=O 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- XGDZEDRBLVIUMX-UHFFFAOYSA-N methyl 2-(4-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(O)C=C1 XGDZEDRBLVIUMX-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940074096 monoolein Drugs 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 235000021395 porridge Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
- C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种由通式I表示的3,4‑二芳基马来酰亚胺衍生物及其药用盐形式。本发明还公开了前述的3,4‑二芳基马来酰亚胺衍生物的制备方法及其在制备预防或治疗动脉粥样硬化和制备降低血浆胆固醇水平的药物中的应用。与现有技术相比,本发明可以应用于治疗或预防动脉粥样硬化或降低血浆胆固醇水平,其降低血浆胆固醇活性更强,市场前景更广阔。
Description
技术领域
本发明属于化学合成技术领域,涉及在治疗和预防动脉粥样硬化、肝硬化、高血压中用作降低血浆总胆固醇药物的3,4-二芳基马来酰亚胺衍生物及其制备方法与应用
背景技术
心脑血管疾病是当今危害人类生命健康的第一大杀手,由血脂代谢紊乱所引起的高血脂症是引发动脉粥样硬化、肝硬化、高血压等心脑血管疾病的重要原因之一。目前临床上所使用的降胆固醇药物主要有他汀类药物、贝特类药物、烟酸衍生物及胆酸螯合剂,但这些药物的副作用也很明显,特别是他汀类药物中的西立伐他汀由于横纹肌溶解的副作用造成多例临床死亡的病例。(3R,4S)-1-(4-氟苯基)-3-[(3S)-3-(4-氟苯基)-3-羟丙基]-4-(4-羟苯基)-2-氮杂环丁酮(依泽替米贝,Ezetimibe,ZetiaTM)是Merck/Schering-Plough公司研制的新型胆固醇吸收抑制剂,于2002年11月在德国上市,同期在美国上市。该药选择性地抑制了胆固醇在肠道内的吸收,从而达到降低血清中胆固醇的目的,发挥降血脂作用。依泽替米贝是目前唯一上市的胆固醇吸收抑制剂,但其不能有效地逆转动脉粥样硬化、有潜在的安全性风险等问题。因此,寻求活性更强的胆固醇吸收抑制剂具有重要研究意义和应用前景。
发明内容
本发明所要解决的技术问题是提供一类新的胆固醇吸收抑制剂—3,4-二芳基马来酰亚胺衍生物,且其抑制活性更强。
本发明还要解决的技术问题是提供上述3,4-二芳基马来酰亚胺衍生物的制备方法。
本发明最后要解决的技术问题是提供上述3,4-二芳基马来酰亚胺衍生物的应用。
为解决上述技术问题,本发明采用的技术方案如下:
3,4-二芳基马来酰亚胺衍生物,它是由通式(I)表示的化合物及其可药用盐:
其中,n为0、2、3或4;
R1取代基独立选自包括:-OR2、-O(CO)R2、-O(CO)OR2、-O(CH2)1~5OR2、-O(CH2)1~2O-、-O(CO)NR2R3、-NR2R3、-NR2(CO)R3、-NR2(CO)OR3、-NR2(CO)NR3R4、-NR2SO2-低级烷基、-NR2SO2-芳基、-CONR2R3、-COR2、-SO3Na、-SO2NR2R3、S(O)0~2-芳基、-O(CH2)1~10COOR2、-O(CH2)1~10CONR2R3、氢、邻-卤代、间-卤代、对-卤代、邻-低级烷基、间-低级烷基、对-低级烷基、芳基、-NO2、-OCF3、-CF3、-低级亚烷基-COOR2或-CH=CH-COOR2;
R2、R3、R4独立选自:氢、低级烷基、芳基或芳基取代的低级烷基;
所述的低级烷基为C1~C6直链烷基或总碳数为C1~C6带支链的烷基,例如甲基、乙基、正丙级、异丙基、叔丁基、正戊基或正己基;优选C1~C3直链烷基或C1~C3带支链的烷烃。更优选是甲基、乙基或正丙级。
所述的低级亚烷基为C1~C6亚烷基,如亚甲基、1,2-亚乙基、1,3-亚丙基、1,4-亚丁基、1,5-亚戊基或1,6-亚己基等。
3,4-二芳基马来酰亚胺衍生物优选的方案是,
N为0、2、3或4,R1-为-H、-SO3Na或-N(C2H5)2;
上述3,4-二芳基马来酰亚胺衍生物,最优选以下任一化合物或其可药用盐或其药学上可接受的载体:
3-(4-氟苯基)-1-(3-羟基-3,3-二甲苯丙基)-4-(4-羟基苯基)-1H-吡咯烷-2,5-二酮(I-1);
3-(4-(2-(二乙胺基)乙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮(I-2);
3-(4-(2-(二乙胺基)丙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮(I-3);
3-(4-(2-(二乙胺基)丁氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮(I-4);
2-(4-(4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-2,5-二氧-2,5-二氢-1H-吡咯烷)苯氧基)乙磺酸钠(I-5);
2-(4-(4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-2,5-二氧-2,5-二氢-1H-吡咯烷)苯氧基)丙磺酸钠(I-6);
2-(4-(4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-2,5-二氧-2,5-二氢-1H-吡咯烷)苯氧基)丁磺酸钠(I-7)。
上述化合物I-1~I-7的R1-的基团与结构式选择见表1。
表1
上述3,4-二芳基马来酰亚胺衍生物的制备方法,它包括如下步骤:
(a)以化合物1(对氟苯乙酮)为起始原料,经过溴代反应得到化合物2(α-溴代对氟苯乙酮);化合物2与叠氮化钠反应得到化合物3;化合物3在常温常压下,钯碳催化氢化后再与盐酸成盐得到化合物4;
(b)以化合物5为起始原料,在LiOH作用下水解得到化合物6;
(c)步骤(a)制得的化合物4与步骤(b)制得的化合物6通过缩合反应得到化合物7,化合物7发生分子内缩合反应,得到化合物8(乙酰基保护的二苯基吡咯烷酮),化合物8在甲醇钠作用下脱去保护基得到化合物9(二苯基吡咯烷酮),化合物9低温下氧化得到化合物10;
(d)以化合物11为起始原料,与溴代乙酸乙酯反应得到二苯基中间体12;经过酯的还原得到中间体13,再与对甲苯磺酰氯反应得到中间体14;
(e)化合物14与步骤(c)制得的化合物10在K2CO3条件下反应得到PMB保护的中间体15;化合物15在硝酸铈铵催化下脱保护基后得到化合物16;
(f)以K2CO3为碱,化合物16与不同长度的碳链连接得到中间体17;化合物17分别与二乙胺连接,得到化合物I-2~I-4;化合物17分别与亚硫酸钠反应得到化合物I-5~I-7。
n为0、2、3或4;
R1代表1个取代基,它们独立选自包括:-OR2、-O(CO)R2、-O(CO)OR2、-O(CH2)1~5OR2、-O(CH2)1~2O-、-O(CO)NR2R3、-NR2R3、-NR2(CO)R3、-NR2(CO)OR3、-NR2(CO)NR3R4、-NR2SO2-低级烷基、-NR2SO2-芳基、-CONR2R3、-COR2、-SO3Na、-SO2NR2R3、S(O)0~2-芳基、-O(CH2)1~10COOR2、-O(CH2)1~10CONR2R3、氢、邻-卤代、间-卤代、对-卤代、邻-低级烷基、间-低级烷基、对-低级烷基、芳基、-NO2、-OCF3、-CF3、-低级亚烷基-COOR2或-CH=CH-COOR2;
R2、R3、R4独立选自:氢、低级烷基、芳基或芳基取代的低级烷基;
所述的低级烷基为C1~C6直链烷基或总碳数为C1~C6带支链的烷基,例如甲基、乙基、正丙级、异丙基、叔丁基、正戊基或正己基;优选C1~C3直链烷基或C1~C3带支链的烷烃。更优选是甲基、乙基或正丙级。
所述的低级亚烷基为C1~C6亚烷基,如亚甲基、1,2-亚乙基、1,3-亚丙基、1,4-亚丁基、1,5-亚戊基或1,6-亚己基等。
步骤(a)中,由化合物1制备化合物2的过程中,溴的摩尔量是对氟苯乙酮的1~1.1倍,反应时间是8~10h,反应温度为室温;
步骤(a)中,由化合物2制备化合物3的过程中,叠氮化钠的摩尔量是化合物2的1.2~1.5倍,反应时间是6h,反应温度为-5℃~5℃;
步骤(a)中,由化合物3制备化合物4的过程中,HCl的摩尔量是化合物3的2~4倍,钯碳的用量为催化量,反应温度为室温,反应时间为6~12h;
步骤(b)中,由化合物5制备化合物6的过程中,LiOH的摩尔量是化合物5的1.5~3倍,反应时间是4~8h,反应温度是室温;
步骤(c)中,由化合物4和化合物6缩合制备化合物7的过程中,化合物6的摩尔量是化合物4的1~1.5倍,反应时间是5~10h,反应温度为室温;
步骤(c)中,由化合物7制备化合物8的过程中,三乙胺的摩尔量是化合物7的5~10倍,反应时间是3~8h,反应温度是60℃~90℃;
步骤(c)中,由化合物8制备化合物9的过程中,甲醇钠的摩尔量是化合物8的1~1.5倍,反应时间是1~4h,反应温度是-10℃~10℃,反应结束后用与甲醇钠等摩尔量的CH3COOH终止反应;
步骤(c)中,由化合物9制备化合物10的过程中,有机碱的摩尔量是化合物9的1~3倍,选择的有机碱可以是NaH、CH3ONa、t-BuOK或DBU,优选NaH,反应选择的无水试剂可以是DMF、CH3OH、t-BuOH或CH3CN,优选DMF,反应时间是0.5~1.5h,反应温度为-5℃~5℃,该反应必须在氧气存在的条件下进行;
步骤(d)中,由化合物11制备化合物12的过程中,锌粉的摩尔量是化合物11的1~2倍,TMSCl的摩尔量是化合物11的0.1~0.2倍,溴代乙酸乙酯摩尔量是化合物11的1~1.5倍,反应时间是6~10h,反应温度30℃~50℃;
步骤(d)中,由化合物12制备化合物13的过程中,LiAlH4的摩尔量是化合物12的1~4倍,反应时间是2~6h,反应温度是-5℃~5℃;
步骤(d)中,由化合物13制备化合物14的过程中,对甲苯磺酰氯的摩尔量是化合物13的1~1.5倍,DMAP的摩尔量是催化量,三乙胺摩尔量是化合物13的1.5~3倍,反应温度是5℃~30℃,反应时间为6~12h;
步骤(e)中,由化合物14制备化合物15的过程中,步骤(c)中制得的化合物10的摩尔量是化合物14的1~1.5倍,K2CO3的摩尔量是化合物14的1.5~3倍,四丁基溴化铵的摩尔量是催化量,反应时间是8~11h,反应温度是50℃~80℃;
步骤(e)中,由化合物15制备化合物16的过程中,硝酸铈铵的摩尔量是化合物的2~5倍,反应时间是1~2h,反应温度是-5℃~10℃;
步骤(f)中,由化合物16制备化合物17的过程中,所述的不同长度的碳链为1,2-二溴乙烷、1,3二溴丙烷或者1,4二溴丁烷;其中,1,2-二溴乙烷、1,3二溴丙烷或者1,4二溴丁烷的摩尔量是化合物16的3~8倍,无机碱优选K2CO3,其摩尔量是化合物16的1~3倍,反应时间是8~12h,反应温度是80℃~100℃;
步骤(f)中,由化合物17制备3,4-二芳基马来酰亚胺衍生物I-2~I-4的过程中,化合物17二乙胺和K2CO3的摩尔比为1:1~3:1~3,反应时间6~12h,反应温度60℃~90℃。由化合物17制备3,4-二芳基马来酰亚胺衍生物I-5~I-7的过程中,化合物17和亚硫酸钠的摩尔比为1:2~6,反应时间为6~12h,反应温度为60~100℃。
上述3,4-二芳基马来酰亚胺衍生物或其可药用盐或其药学上可接受的载体在制备治疗或预防动脉粥样硬化或降低血浆胆固醇水平的药物中的应用。药学上可接受的载体是指一种或几种惰性,非毒性的固体或液体填充物、稀释剂、助剂等,它们不可逆与活性化合物或病人发生作用。
其药物剂型为片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂或注射液等药剂学上常用剂型。口服用药片和胶囊含有传统的赋形剂如填充物、稀释剂、润滑剂、分散剂以及粘合剂。可参照本领域中熟知的方法进行制备。
本发明活性化合物的剂量将因配方而异。一般的,证明有利的量为达到所需结果,每千克体重每24小时给药通式(I)化合物的总量为约0.01~100mg,优选总量为0.1~50mg。如果必要,以几次单剂量的形式给药。然而如果必要,也可以偏离上述用量,即这取决于待治疗的受试者的类型和体重、个体对药物的行为、疾病的性质和严重性、制剂和给药类型以及给药时间和间隔。
有益效果:本发明的3,4-二芳基马来酰亚胺衍生物可以应用于治疗或预防动脉粥样硬化或降低血浆胆固醇水平,其降低血浆胆固醇活性更强,市场前景更广阔。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
实施例1:2-溴-1-(4-氟苯基)乙酮的制备
将20g(144.7mmol)对氟苯乙酮溶于200mL乙腈中,缓慢滴加23.12g(144.7mmol)Br2的50mL乙腈溶液,室温下搅拌过夜。反应完全后,浓缩除去反应液,乙酸乙酯复溶,用饱和食盐水洗三次,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂,得到的白色油状物在低温下固化,用100mL正己烷加1mL乙酸乙酯打浆,过滤得白色固体28g,收率:89.2%,mp:40-41℃。
1H-NMR(300M,CDCl3):4.40(s,2H,-CH2-),7.17(m,2H,Ar-H),8.02(m,2H,Ar-H);MS:calcd.m/z[M]215.96,found m/z[M-H]-215.0.
实施例2:2-叠氮基-1-(4-氟苯基)乙酮的制备
将31.59g(146mmol)2-溴-1-(4-氟苯基)乙酮溶于150mL的甲醇中,0℃下缓慢加入50mL的11.38g(175mmol)NaN3水溶液,室温下搅拌反应过夜。反应完全后,0℃下缓慢滴加50mL水,有大量的白色固体析出,过滤,烘干,得到25.25g,收率:96.6%。
1H-NMR(300M,CDCl3):4.52(s,2H,-CH2-),7.17(m,2H,Ar-H),7.94(m,2H,Ar-H);MS:calcd.m/z[M]179.05,found m/z[M+H]+180.0.、
实施例3:2-氨基-1-(4-氟苯基)乙酮盐酸盐的制备
将25.25g(141mmol)2-叠氮基-1-(4-氟苯基)乙酮溶于100mL甲醇中,缓慢滴加42.85g(423mmol)浓盐酸(浓度36%),加入2g Pd/C,常温下催化氢化。反应完全后,过滤Pd/C,减压蒸馏除去溶剂,50mL乙醚打浆,过滤得白色固体22.72g,收率:85%,mp:213-215℃。
实施例4:(4-(4-甲氧基苄基)氧基)苯乙酸甲酯的制备
将2.6g(15.6mmol)对羟基苯乙酸甲酯、7g(50.6mmol)K2CO3和2g(12.8mmol)对甲氧基苄氯溶于40mL丙酮中,搅拌回流过夜。反应完全后,浓缩除去溶剂,用二氯甲烷复溶,饱和食盐水洗三次,水洗三次,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂,10mL乙醇打浆,过滤,得到白色固体3.9g,收率:87%,mp:53-56℃。
1H-NMR(500M,DMSO):3.59(s,2H,-CH2-),3.60(s,3H,CH3O),3.75(s,3H,CH3O),4.99(s,2H,PhCH2-),6.94(d,4H,J=6.95Hz,Ar-H),7.15(d,2H,J=8.45Hz,Ar-H),7.35(d,2H,J=8.5Hz,Ar-H);MS:calcd.m/z[M]286.12,found m/z[M+Na]+309.3.
实施例5:(4-(4-甲氧基苄基)氧基)苯乙酸的制备
将3.9g(4-(4-甲氧基苄基)氧基)苯乙酸甲酯溶于50mL的四氢呋喃中,搅拌条件下缓慢滴加1.14g(27.24mmol)LiOH的水溶液,室温下反应过夜。反应完全后,0℃下缓慢滴加1mol/L的盐酸,将pH调节至酸性,室温下继续搅拌30min。水相用二氯甲烷萃取三次,将有机相合并后水洗三次,无水硫酸钠干燥后过滤,减压蒸馏除去溶剂,得到白色固体3.4g,收率:91.6%,mp:140-145℃。
1H-NMR(300M,CDCl3):3.59(s,2H,-CH2-),3.81(s,3H,CH3O),4.97(s,2H,PhCH2-),6.92(m,4H,Ar-H),7.19(d,2H,J=8.46Hz,Ar-H),7.34(d,2H,J=8.43Hz,Ar-H);MS:calcd.m/z[M]272.10,found m/z[M+Na]+295.1.
实施例6:N-(2-(4-氟苯基)-2-氧-乙基)-2-(4-((4-甲氧基苄基)氧基)苯基)乙酰胺的制备
将10g(36.78mmol)(4-(4-甲氧基苄基)氧基)苯乙酸、9.48g(50.14mmol)EDCl、6.95g(50.14mmol)HOBt和13.27g(133.73mmol)N-甲基吗啉依次加入100mL的无水二氯甲烷中,0℃下搅拌1h后继续加入6.32g(33.43mmol)2-胺基-1-(4-氟苯基)乙酮盐酸盐,室温下搅拌过夜。反应完全后,0℃下搅拌,有大量固体析出,过滤,烘干,得到白色固体9.7g,收率:64.8%,mp:150-152℃。
1H-NMR(300M,CDCl3):3.45(s,2H,-CH2-),3.76(s,3H,CH3O-),4.58(d,2H,J=5.4Hz,-CH2N-),4.99(s,2H,PhCH2O-),6.92(m,4H,Ar-H),7.19(d,2H,J=8.37Hz,Ar-H),7.34(m,4H,Ar-H),8.06(m,2H,Ar-H),8.37(m,1H,-NH-);
MS:calcd.m/z[M]407.15,found m/z[M+Na]+430.4.
实施例7:N-乙酰基-4-(4-氟苯基)-3-(4-((4-甲氧基苄基)氧基)苯基)-1H-吡咯烷-2(5H)-酮的制备
将9.7g(23.82mmol)N-(2-(4-氟苯基)-2-氧-乙基)-2-(4-((4-甲氧基苄基)氧基)苯基)乙酰胺加入到30.36g(297.8mmol)乙酸酐中,氮气保护,0℃下缓慢滴加20.47g(202.50mmol)三乙胺,75℃下搅拌反应2h。反应完全后,减压蒸馏除去溶剂,二氯甲烷复溶后用饱和食盐水洗三次,无水硫酸钠干燥,过滤后减压蒸馏除去溶剂,用30mL乙醚打浆,得到淡黄色固体8.4g,收率:81.8%,mp:155-160℃。
1H-NMR(300M,CDCl3):2.63(s,3H,-CH3),3.83(s,3H,CH3O-),4.69(s,2H,-CH2N-),5.00(s,2H,PhCH2O-),6.99(m,6H,Ar-H),7.27(m,2H,Ar-H),7.38(m,4H,Ar-H);MS:calcd.m/z[M]431.50,found m/z[M-H]+430.9.
实施例8:4-(4-氟苯基)-3-(4-((4-甲氧基苄基)氧基)苯基)-1H-吡咯烷-2(5H)-酮的制备
将8.4g(19.48mmol)N-乙酰基-4-(4-氟苯基)-3-(4-((4-甲氧基苄基)氧基)苯基)-1H-吡咯烷-2(5H)-酮溶于40mL无水甲醇中,氮气保护,0℃下缓慢滴加3.94g的28%甲醇钠(20.45mmol)的甲醇溶液,0℃下搅拌反应1h。反应完全后,滴加1.23g(20.45mmol)乙酸淬灭反应,继续搅拌5min,减压蒸馏除去溶剂,二氯甲烷复溶,水洗三次,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂,20mL乙醚打浆,过滤烘干,得到淡黄色固体6.2g,收率:81.5%,mp:150-155℃。
1H-NMR(500M,CDCl3):3.53(s,3H,CH3O-),4.32(s,2H,-CH2N-),5.00(s,2H,PhCH2O-),6.98(m,6H,Ar-H),7.30(m,2H,Ar-H),7.36(m,2H,Ar-H);MS:calcd.m/z[M]389.14,found m/z[M+Na]+412.2.
实施例9:3-(4-氟苯基)-4-(4-((4-甲氧基苄基)氧基)苯基)-1H-吡咯烷-2,5-二酮的制备
将0.4g(1.02mmol)4-(4-氟苯基)-3-(4-((4-甲氧基苄基)氧基)苯基)-1H-吡咯烷-2(5H)-酮溶于4mL无水DMF中,0℃下加入0.16g(4.08mmol)的NaH(含量:60%),室温下搅拌反应30min。反应完全后,滴加3滴水淬灭反应,加入乙酸乙酯,饱和食盐水洗三次,无水硫酸钠干燥,减压蒸馏除去溶剂,柱层析(PE∶EA=5∶1)得到黄色固体0.32g,收率:77.2%,mp:140-145℃。
1H-NMR(500M,CDCl3):3.83(s,3H,CH3O-),5.03(s,2H,PhCH2O-),6.94(m,4H,Ar-H),7.07(t,2H,J=8.50Hz,Ar-H),7.35(d,2H,J=8.35Hz,Ar-H),7.40(s,1H,Ar-H),7.47(m,2H,Ar-H),7.51(m,2H,Ar-H);MS:calcd.m/z[M]403.12,found m/z[M-H]+402.2.
实施例10:3-羟基-3,3-二苯基丙酸乙酯的制备
将0.921mg(16.455mmol)的活化锌粉加入100mL的三颈瓶中,加入10mL无水乙醚,氮气保护,加入0.2g(1.317mmol)的溴代乙酸乙酯无水乙醚溶液,加入0.12g(1.1mmol)的TMSCl,反应放热,溶剂回流,加入1.8g(11.85mmol)的溴代乙酸乙酯无水乙醚溶液,搅拌回流直至锌粉不在减少,溶液变成绿色,加入2g(10.97mmol)二苯甲酮的无水乙醚溶液,回流反应过夜。反应完全后冷却到0℃,加入10%的硫酸将反应淬灭,用乙酸乙酯萃取三次后合并有机相,再用10%的硫酸、饱和食盐水、水分别洗三次,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂,柱层析(PE∶EA=50∶1→PE∶EA=3∶1),得到白色固体1.9g,收率:64%,mp:75-80℃。
1H-NMR(500M,CDCl3):1.145(t,3H,J=7.15Hz,CH3CH2-),3.259(s,2H,-CH2-),4.087(q,2H,J=7.10Hz,CH3CH2-),7.212(t,2H,J=7.30Hz,Ar-H),7.296(m,4H,Ar-H),7.434(m,4H,Ar-H);MS:calcd.m/z[M]270.13,found m/z[M+Na]+293.1.
实施例11:1,1-二苯基-1,3-丙二醇的制备
将0.841g(22.2mmol)LiAlH4加入到20mL的无水四氢呋喃中,0℃下缓慢滴加3g(11.1mmol)3-羟基-3,3-二苯基丙酸乙酯的无水四氢呋喃溶液,室温下搅拌反应2h。反应完全后,降温到0℃,滴加20%的NaOH水溶液淬灭反应,过滤后将四氢呋喃旋干,用乙酸乙酯萃取三次,无水硫酸钠干燥,过滤,柱层析(PE∶EA=20∶1→PE∶EA=5∶1),得到白色固体2.1g,收率:83%,mp:85-90℃。
1H-NMR(500M,CDCl3):2.564(t,2H,J=5.45Hz,-CH2-),2.679(s,1H,-OH),2.689(s,1H,-OH),3.760(t,2H,J=5.45Hz,-CH2-),7.236(m,2H,Ar-H),7.318(m,4H,Ar-H),7.426(d,4H,J=7.7Hz,Ar-H);MS:calcd.m/z[M]228.12,found m/z[M+Na]+251.1.
实施例12:3-羟基-3,3-二苯基对甲苯磺酸丙酯的制备
将2.4g(10.5mmol)的1,1-二苯基-1,3-丙二醇、2.4g(12.6mmol)的对甲苯磺酰氯和催化量的DMAP溶于50mL无水二氯甲烷中,0℃下缓慢滴加2.13g(21mmol)的三乙胺,室温下搅拌反应过夜。反应完全后,反应液用饱和食盐水洗三次,无水硫酸钠干燥,过滤,减压蒸馏除去溶剂,柱层析(PE∶EA=5∶1→PE∶EA=3∶1),得到白色固体2.5g,收率:62.5%。
1H-NMR(500M,CDCl3):2.438(s,3H,-PhCH3),2.710(t,2H,J=7.30Hz,-CH2-),4.092((t,2H,J=7.30Hz,-CH2-),7.27(m,12H,Ar-H),7.679(d,2H,J=8.20Hz,Ar-H)MS:calcd.m/z[M]382.12,found m/z[M+Na]+405.3.
实施例13:3-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-4-(4-(4-甲氧基苄基)氧基)苯基)-1H-吡咯烷-2,5-二酮的制备
将2.5g(6.54mmol)3-羟基-3,3-二苯基对甲苯磺酸丙酯和2.93g(7.84mmol)3-(4-氟苯基)-4-(4-(4-甲基氧基苄基)氧基)苯基)-1H-吡咯烷-2,5-二酮溶于50mL的乙腈中,加入1.81g(13.07mmol)K2CO3和221mg(0.65mmol)四丁基溴化铵,60℃反应过夜。反应完全后将溶剂旋干,乙酸乙酯复溶,饱和食盐水洗三次,干燥,过滤,减压蒸馏除去溶剂,柱层析(PE∶EA=10∶1→PE∶EA=5∶1)得到黄色固体2.8g,收率:73.5%。
1H-NMR(300M,CDCl3):3.83(s,3H,CH3O-),2.69(t,2H,J=6.6Hz,-CH2-),3.87(t,2H,J=6.6Hz,-CH2-),5.08(s,2H,PhCH2O-),6.91(d,2H,J=9Hz,Ar-H),7.04(m,2H,Ar-H),7.10(m,2H,Ar-H),7.25(m,8H,Ar-H),7.40(m,8H,Ar-H);
MS:calcd.m/z[M]583.22,found m/z[M+Na]+606.5.
实施例14:3-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-4-(4-羟基苯基)-1H-吡咯烷-2,5-二酮(I-1)
将1.2g(2.06mmol)3-(4-氟苯基)-1-(3-羟基-3,3-二苯基)-4-(4-苄基氧基苯基)-1H-吡咯烷-2,5-二酮溶于乙腈-水溶液,加入3.6g(6.18)CAN,在0℃下搅拌1h,加入食盐水稀释,再用乙酸乙酯萃取三次,干燥,过滤,减压蒸馏除去溶剂,柱层析(PE∶EA=3∶1→PE∶EA=2∶1)得到黄色油状物0.9g,收率:90%,mp:63-65℃。
1H-NMR(300M,CDCl3):2.74(t,2H,J=6.48Hz,-CH2-),3.88(t,2H,J=6.48Hz,-CH2-),6.78(m,2H,Ar-H),7.10(m,2H,Ar-H),7.13(m,2H,Ar-H),7.24(m,4H,Ar-H),7.30(m,2H,Ar-H),7.44(m,4H,Ar-H);
MS:calcd.m/z[M]493.17,found m/z[M-H]+492.1.
实施例15:3-(4-(2-溴乙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮
将150mg(0.304mmol)3-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-4-(4-羟基苯基)-1H-吡咯烷-2,5-二酮(Ⅰ-1)溶于5mL乙腈中,加入226mg(1.22mmol)的1.2-二溴乙烷和84mg(0.608mmol)K2CO3,回流搅拌过夜。反应完全后减压蒸馏除去旋干,乙酸乙酯复溶,水洗三次,干燥,过滤,减压蒸馏除去溶剂,柱层析(PE∶EA=10∶1→PE∶EA=5∶1)得到黄色油状物132mg,收率:72.1%。
1H-NMR(300M,CDCl3):2.74(t,2H,J=6.3Hz,-CH2-),3.45(s,1H,-OH),3.64(t,2H,J=6.3Hz,-CH2-),3.89(t,2H,J=6.3Hz,-CH2-),4.31(t,2H,J=6.3Hz,-CH2-),6.87(m,2H,Ar-H),7.09(m,2H,Ar-H),7.20(m,2H,Ar-H),7.26(m,2H,Ar-H),7.30(m,4H,Ar-H),7.45(m,4H,Ar-H);
MS:calcd.m/z[M]613.13,found m/z[M+Na]+636.4.
实施例16:3-(4-(3-溴丙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮的制备
参考实施例15。以3-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-4-(4-羟基苯基)-1H-吡咯烷-2,5-二酮和1,3-二溴丙烷为原料,摩尔比为1:4。收率:76.7%。
实施例17:3-(4-(3-溴丁氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮的制备
参考实施例15。以3-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-4-(4-羟基苯基)-1H-吡咯烷-2,5-二酮和1,4-二溴丁烷为原料,摩尔比为1:4。收率:62.0%。
实施例18:3-(4-(2-(二乙胺基)乙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮(Ⅰ-2)的制备
将75.7mg(0.126mmol)的3-(4-(4-溴乙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮溶于2mL乙腈,加入18.4mg(0.252mmol)二乙胺和34.8mg(0.252mmol)K2CO3,搅拌回流过夜。反应完全后减压蒸馏除去溶剂,二氯甲烷复溶,水洗三次,无水硫酸钠干燥,过滤,刮大板,得到黄色固体62mg,收率:54.8%,mp:99-103℃。
1H-NMR(500M,CDCl3):1.33(s,6H,-CH2CH3),2.73(s,4H,-CH2CH3),2.74(t,2H,J=6.5Hz,-CH2-),2.89(s,2H,-CH2-),3.46(s,2H,-CH2-),3.88(t,2H,J=6.5Hz,-CH2-),4.16(s,2H,-CH2-),6.84(d,J=9Hz,2H,Ar-H),7.02(t,J=9Hz,2H,Ar-H),7.12(t,J=7.5Hz,2H,Ar-H),7.22(t,J=7.5Hz,4H,Ar-H),7.26(d,J=8.5Hz,2H,Ar-H),7.31(m,2H,Ar-H),7.44(d,J=7.5Hz,2H,Ar-H);
MS:calcd.m/z[M]592.27,found m/z[M+H]+593.5.
实施例19:3-(4-(2-(二乙胺基)丙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮(Ⅰ-3)的制备
参考实施例18。以3-(4-(4-溴丙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮和二乙胺为原料,摩尔比为1:2,收率:51.1%。
1H-NMR(500M,CDCl3):1.37(t,J=7Hz,6H,-CH2CH3),2.32(s,2H,-CH2-),2.74(t,J=6Hz,2H,-CH2-),3.07(d,J=6Hz,2H,-CH2-),3.12(s,4H,-CH2CH3),3.88(t,J=6.5Hz,2H,-CH2-),4.10(t,J=5.5Hz,2H,-CH2-),6.82(d,J=8.5Hz,2H,Ar-H),7.02(t,J=8.5Hz,2H,Ar-H),7.12(t,J=7.5Hz,2H,Ar-H),7.22(t,J=7.5Hz,4H,Ar-H),7.29(m,4H,Ar-H),7.44(d,J=7.5Hz,2H,Ar-H);
MS:calcd.m/z[M]606.29,found m/z[M+H]+607..5.
实施例20:3-(4-(2-(二乙胺基)丁氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮(Ⅰ-4)的制备
参考实施例18。以3-(4-(4-溴丁氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮和二乙胺为原料,摩尔比为1:2,收率:54.8%。
1H-NMR(300M,CDCl3):1.31(t,6H,J=6.84Hz,-CH2CH3),1.88(s,4H,-CH2-),2.73(m,2H,-CH2-),3.25(m,2H,-CH2-),3.44(m,4H,-CH2CH2-),3.76(s,2H,-CH2-),4.07(s,2H,-CH2-),6.90(d,J=8.22Hz,2H,Ar-H),7.09(m,4H,Ar-H),7.22(m,4H,Ar-H),7.33(m,4H,Ar-H),7.43(d,J=7.47Hz,4H,Ar-H)
实施例21:2-(4-(4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-2,5-二氧-2,5-二氢-1H-吡咯烷)苯氧基)乙磺酸钠(Ⅰ-5)的制备
将131mg(0.218mmol)3-(4-(2-溴乙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮溶于6mL乙醇∶水=2∶1的混合溶液中,加入137mg(1.09mmol)Na2SO3,搅拌回流过夜。反应完全后减压蒸馏除去旋干,2mL甲醇打浆,过滤,减压蒸馏除去溶剂后用4mL石油醚∶乙酸乙酯=3∶1的混合溶液打浆,过滤得黄色固体83mg,收率:61%,mp﹥200℃。
1H-NMR(300M,CDCl3):2.76(t,2H,J=7.2Hz,-CH2-),3.28(t,2H,J=7.5Hz,-CH2-),3.79(t,2H,J=6.9Hz,-CH2-),4.41(t,2H,J=7.2Hz,-CH2-),6.96(d,2H,J=9Hz,Ar-H),7.14(m,2H,Ar-H),7.20(m,4H,Ar-H),7.25(m,2H,Ar-H),7.35(m,2H,Ar-H),7.47(m,4H,Ar-H);
MS:calcd.m/z[M]623.14,found m/z[M-Na]+600.3.
实施例22:2-(4-(4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-2,5-二氧-2,5-二氢-1H-吡咯烷)苯氧基)丙磺酸钠(Ⅰ-6)的制备
参考实施例21。以3-(4-(4-溴丙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮和磺酸钠为原料,摩尔比为1:5,收率:57%。
1H-NMR(300M,CDCl3):2.26(m,2H,J=6.9Hz,-CH2-),2.75(t,2H,J=6.9Hz,-CH2-),2.97(m,2H,-CH2-),3.78(t,2H,J=7.2Hz,-CH2-),4.16(t,2H,J=6.3Hz,-CH2-),6.92(d,2H,J=8.7Hz,Ar-H),7.12(m,4H,Ar-H),7.24(d,4H,J=7.8Hz,Ar-H),7.35(m,2H,Ar-H),7.40(m,2H,Ar-H),7.47(m,4H,Ar-H);
MS:calcd.m/z[M]637.15,found m/z[M-H]+613.8.
实施例23:2-(4-(4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-2,5-二氧-2,5-二氢-1H-吡咯烷)苯氧基)丁磺酸钠(Ⅰ-7)的制备
参考实施例21。以3-(4-(4-溴丁氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮和磺酸钠为原料,摩尔比为1:5,收率:48%。
1H-NMR(300M,CDCl3):1.83(m,2H,-CH2-),1.94(m,2H,-CH2-),2.71(m,2H,-CH2-),2.84(m,2H,-CH2-),3.76(t,2H,J=6.9Hz,-CH2-),4.03(t,2H,J=5.49Hz,-CH2-),6.83(m,2H,Ar-H),7.08(m,4H,Ar-H),7.14(m,8H,Ar-H),7.44(m,4H,Ar-H);
MS:calcd.m/z[M]651.17,found m/z[M+H]+674.
实施例24:药理学实验数据
1细胞、试剂及仪器
1.1细胞
Caco-2细胞,订购单位:中国科学院上海生命科学研究院细胞资源中心
1.2试剂
胆固醇购自Sigma公司,货号:C8667-5G
Penicillin-streptomycin solution购自HyClone公司,货号SV30010
DMEM购自WISENT公司,货号310-011-CL
0.25%Trypsin-EDTA购自Gibco公司,货号:25200-072
Sodium tauroclate hydrate购自Sigma公司,货号:86339-1G
甘油单油酸酯购自Sigma公司,货号:M7765-50mg
BCA蛋白浓度测定试剂盒购自碧云天(Beyotime)公司,货号:P0012
RIPA裂解液(强)购自碧云天(Beyotime)公司,货号:P0013B
NaCl购自Biosharp,批号:2012/09
Na2HPO4购自Sigma公司,货号:S5136-100G
KCl购自Amresco公司,货号:0395-500G
KH2PO4购自Amresco公司,货号:0781-500G
三氟乙酸购自国药集团,货号:20120608
1.3受试药物、阳性药物以及实验过程中用到的试剂的配置
培养基的配制:DMEM培养基中加入20%的FBS和1%的青霉素-链霉素溶液,混匀后4℃保存待用。
PBS缓冲液的配制:1L超纯水中加入8g NaCl、0.2g KCl、1.44g Na2HPO4和0.24gKH2PO4,超声溶清,高温灭菌。
豆甾醇胶束的配制:称取0.08065g牛磺胆酸钠、0.000535g油酸单甘油酯和0.2063g豆甾醇加入到200mL的DMEM培养基中,超声助溶2h,再经0.22μm的滤膜过滤,4℃冰箱保存待用。
细胞裂解液的配制:按照RIPA裂解液(强)∶蛋白酶抑制剂=100∶1的比例配制,冰浴保存,现配现用。
Jones试剂的配制:配制4mol/L的H2SO4以及4mol/L的CrO3水溶液,分别经0.22μm滤膜过滤,常温保存,使用前取等体积混匀使用。
阳性药(Ezetimibe)及受试化合物溶液的配制:将Ezetimibe或受试药用DMSO配成100mmol/L的母液待用。
1.4实验仪器
酶标仪购自Bio-Tek公司,型号:Synergy HT
高效液相购自日本岛津公司,型号:LC-20AT
2实验方法
培养Caco-2细胞于6孔板中,实验分为空白对照组、模型组、阳性药组和受试药组。每组6个平行组,当细胞培养到80%,将含有100μmol/L受试药的培养基加入到每孔中,每孔1.5mL,阳性药一样,另外空白组与模型组加入纯培养基,一起培养24h。24h后将培养液吸去,用PBS洗2遍,空白组每孔加1mL的DMEM培养24h,模型组、阳性药组和受试药组每孔加入1mL的豆甾醇胶束培养24h。吸取胆固醇胶束,用PBS洗2遍,最后破碎细胞,测蛋白含量及细胞内胆固醇的含量。
3实验结果
以上药理学数据显示,本发明通式(I)化合物具有较强的降低细胞内胆固醇作用。
Claims (7)
1.3,4-二芳基马来酰亚胺衍生物,它是由通式(I)表示的化合物及其可药用盐:
其中,
n为0、2、3或4;
R1取代基独立选自包括:-OR2、-O(CO)R2、-O(CO)OR2、-O(CH2)1~5OR2、-O(CH2)1~2O-、-O(CO)NR2R3、-NR2R3、-NR2(CO)R3、-NR2(CO)OR3、-NR2(CO)NR3R4、-NR2SO2-低级烷基、-NR2SO2-芳基、-CONR2R3、-COR2、-SO3Na、-SO2NR2R3、S(O)0~2-芳基、-O(CH2)1~10COOR2、-O(CH2)1~10CONR2R3、氢、邻-卤代、间-卤代、对-卤代、邻-低级烷基、间-低级烷基、对-低级烷基、芳基、-NO2、-OCF3、-CF3、-低级亚烷基-COOR2或-CH=CH-COOR2;
R2、R3和R4独立选自:氢、低级烷基、芳基或芳基取代的低级烷基;
所述的低级烷基为C1~C6直链烷基或总碳数为C1~C6带支链的烷基;
所述的低级亚烷基为C1~C6亚烷基。
2.根据权利要求1所述的3,4-二芳基马来酰亚胺衍生物,其特征在于,
n代表0、2、3或4,R1-代表-H、-SO3Na或-N(C2H5)2。
3.根据权利要求1所述的3,4-二芳基马来酰亚胺衍生物,其特征在于,其选自以下任一化合物或其可药用盐或其药学上可接受的载体:
3-(4-氟苯基)-1-(3-羟基-3,3-二甲苯丙基)-4-(4-羟基苯基)-1H-吡咯烷-2,5-二酮(Ⅰ-1);
3-(4-(2-(二乙胺基)乙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮(I-2);
3-(4-(2-(二乙胺基)丙氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮(I-3);
3-(4-(2-(二乙胺基)丁氧基)苯基)-4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-1H-吡咯烷-2,5-二酮(I-4);
2-(4-(4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-2,5-二氧-2,5-二氢-1H-吡咯烷)苯氧基)乙磺酸钠(I-5);
2-(4-(4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-2,5-二氧-2,5-二氢-1H-吡咯烷)苯氧基)丙磺酸钠(I-6);
2-(4-(4-(4-氟苯基)-1-(3-羟基-3,3-二苯基丙基)-2,5-二氧-2,5-二氢-1H-吡咯烷)苯氧基)丁磺酸钠(I-7)。
4.权利要求1所述3,4-二芳基马来酰亚胺衍生物的制备方法,其特征在于,它包括如下步骤:
(a)以化合物1为起始原料,室温下经过溴代反应得到化合物2;化合物2与叠氮化钠反应得到化合物3;以甲醇和浓盐酸为溶剂,通过常温常压下钯碳催化氢化化合物3得到化合物4;
(b)以化合物5为起始原料,室温下与LiOH经水解反应得到化合物6;
(c)步骤(a)制得的化合物4与步骤(b)制得的化合物6室温下缩合得到化合物7;化合物7在三乙胺的作用下发生分子内缩合反应,得到化合物8;化合物8在甲醇钠催化下脱去保护基得到化合物9;化合物9在氢化钠催化下氧化得到化合物10;
(d)以化合物11为起始原料,与溴代乙酸乙酯通过反应得到二苯基中间体12;化合物12经过LiAlH4还原得到中间体13;化合物13再与对甲苯磺酰氯经过催化反应得到中间体14;
(e)化合物14与步骤(c)制得的化合物10在K2CO3条件下反应得到PMB保护的中间体15;15在硝酸铈铵催化下脱保护基后得到化合物16(I-1);
(f)以K2CO3为碱,化合物16与不同长度的碳链连接得到中间体17;化合物17与二乙胺连接,得到化合物I-2~I-4;化合物17与亚硫酸钠反应,得到化合物I-5~I-7。
其中,
n代表0、2、3或4;
R1取代基选自包括:-OR2、-O(CO)R2、-O(CO)OR2、-O(CH2)1~5OR2、-O(CH2)1~2O-、-O(CO)NR2R3、-NR2R3、-NR2(CO)R3、-NR2(CO)OR3、-NR2(CO)NR3R4、-NR2SO2-低级烷基、-NR2SO2-芳基、-CONR2R3、-COR2、-SO3Na、-SO2NR2R3、S(O)0~2-芳基、-O(CH2)1~10COOR2、-O(CH2)1~10CONR2R3、氢、邻-卤代、间-卤代、对-卤代、邻-低级烷基、间-低级烷基、对-低级烷基、芳基、-NO2、-OCF3、-CF3、-低级亚烷基-COOR2或-CH=CH-COOR2;
R2、R3、R4独立选自:氢、低级烷基、芳基或芳基取代的低级烷基;
所述的低级烷基为C1~C6直链烷基或总碳数为C1~C6带支链的烷基;
所述的低级亚烷基为C1~C6亚烷基。
5.权利要求1所述的3,4-二芳基马来酰亚胺衍生物在制备治疗或预防动脉粥样硬化或降低血浆胆固醇水平的药物中的应用。
6.根据权利要求5所述的应用,其特征在于,所述的3,4-二芳基马来酰亚胺衍生物为通式(I)表示的化合物或其可药用盐或其药学上可接受的载体。
7.根据权利要求5所述的应用,其特征在于,药物剂型为片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂或注射液。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610850934.3A CN106432039B (zh) | 2016-09-27 | 2016-09-27 | 3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610850934.3A CN106432039B (zh) | 2016-09-27 | 2016-09-27 | 3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106432039A true CN106432039A (zh) | 2017-02-22 |
CN106432039B CN106432039B (zh) | 2019-02-22 |
Family
ID=58170528
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610850934.3A Active CN106432039B (zh) | 2016-09-27 | 2016-09-27 | 3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106432039B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1681789A (zh) * | 2002-09-17 | 2005-10-12 | 埃科特莱茵药品有限公司 | 1-吡啶-4-基-脲衍生物 |
CN103864658A (zh) * | 2014-03-06 | 2014-06-18 | 南京工业大学 | 氮杂环丁酮衍生物及其制备方法与应用 |
CN104447489A (zh) * | 2014-12-29 | 2015-03-25 | 南京工业大学 | 3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 |
-
2016
- 2016-09-27 CN CN201610850934.3A patent/CN106432039B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1681789A (zh) * | 2002-09-17 | 2005-10-12 | 埃科特莱茵药品有限公司 | 1-吡啶-4-基-脲衍生物 |
CN103864658A (zh) * | 2014-03-06 | 2014-06-18 | 南京工业大学 | 氮杂环丁酮衍生物及其制备方法与应用 |
CN104447489A (zh) * | 2014-12-29 | 2015-03-25 | 南京工业大学 | 3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 |
Non-Patent Citations (1)
Title |
---|
王玉斌,等: "单环β-内酰胺类衍生物的合成及其胆固醇吸收抑制活性", 《中国药科大学学报》 * |
Also Published As
Publication number | Publication date |
---|---|
CN106432039B (zh) | 2019-02-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111801324B (zh) | 甲状腺激素受体激动剂及其用途 | |
CN101228135B (zh) | 作为甲状腺激素受体激动剂的哒嗪酮衍生物 | |
CN101432265B (zh) | 11-β-羟类固醇脱氢酶1的抑制剂 | |
CN110167939A (zh) | 吡咯并[2,3-c]吡啶类衍生物、其制备方法及其在医药上的应用 | |
CN107033087B (zh) | 1h-吲唑-4-胺类化合物及其作为ido抑制剂的用途 | |
CN101426783A (zh) | 作为11-β-羟基甾族化合物脱氢酶1的抑制剂的环己基吡唑-内酰胺衍生物 | |
WO2006111560A2 (en) | 2,3 substituted pyrazine sulfonamides as inhibitors of crth2 | |
CN101910155A (zh) | 作为组胺-h3受体调节剂用于治疗与组胺-h3受体调节剂相关的障碍的联苯衍生物 | |
CN112839942A (zh) | 作为组蛋白去乙酰酶6抑制剂的1,3,4-噁二唑衍生物化合物以及包含其的药物组合物 | |
CN105026375A (zh) | Ship1调节剂和与其相关的方法 | |
CN111808078A (zh) | 一种抑制ido1活性的来那度胺衍生物及其制备方法和应用 | |
CN104447489B (zh) | 3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 | |
TW202033514A (zh) | 作為免疫調節劑的聯苯化合物及其用途 | |
CN106103417A (zh) | 1,2‑萘醌的衍生物及其制备方法 | |
Alam et al. | Discovery of (S)-flurbiprofen-based novel azine derivatives as prostaglandin endoperoxide synthase-II inhibitors: Synthesis, in-vivo analgesic, anti-inflammatory activities, and their molecular docking | |
Khouzani et al. | Development of coumarin tagged 1, 2, 3-triazole derivatives targeting α-glucosidase inhibition: Synthetic modification, biological evaluation, kinetic and in silico studies | |
CN103360342B (zh) | 3-氰基苯胺烷基芳基哌嗪衍生物及在制备药物中的应用 | |
CN103864658B (zh) | 氮杂环丁酮衍生物及其制备方法与应用 | |
CN104211666B (zh) | 2,3‑环氧丁二酰胺类化合物、其制备方法和用途 | |
CN106432039A (zh) | 3,4‑二芳基马来酰亚胺衍生物及其制备方法与应用 | |
CN101544591B (zh) | (e)-取代苯乙烯类化合物及其制备方法 | |
CN103664876B (zh) | 喹啉类衍生物及其用途 | |
CN107312005A (zh) | 具有ido/tdo抑制活性的稠合咪唑衍生物及其制备方法和应用 | |
CN107056673B (zh) | 一种3,4-二芳基马来酰亚胺衍生物及其制备方法与应用 | |
CN102250099B (zh) | 一类非肽类抗凝血酶抑制剂、其制法以及医药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |