CN1092068A - 烷氧基甲基取代的吡啶酮联苯 - Google Patents
烷氧基甲基取代的吡啶酮联苯 Download PDFInfo
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- CN1092068A CN1092068A CN93118887A CN93118887A CN1092068A CN 1092068 A CN1092068 A CN 1092068A CN 93118887 A CN93118887 A CN 93118887A CN 93118887 A CN93118887 A CN 93118887A CN 1092068 A CN1092068 A CN 1092068A
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- Prior art keywords
- represent
- pyridone
- compound
- biphenyl
- methyl
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- 125000004849 alkoxymethyl group Chemical group 0.000 title claims abstract description 18
- IVBSKJPSESGOEM-UHFFFAOYSA-N 1,1'-biphenyl;1h-pyridin-2-one Chemical group O=C1C=CC=CN1.C1=CC=CC=C1C1=CC=CC=C1 IVBSKJPSESGOEM-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- -1 pyridine ketone Chemical class 0.000 claims abstract description 13
- 206010020772 Hypertension Diseases 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000000217 alkyl group Chemical class 0.000 claims description 4
- 238000005336 cracking Methods 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 238000010931 ester hydrolysis Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Chemical group 0.000 claims description 2
- 230000000879 anti-atherosclerotic effect Effects 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims description 2
- 239000002220 antihypertensive agent Substances 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 6
- 230000003143 atherosclerotic effect Effects 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 37
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- 238000000034 method Methods 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 239000002904 solvent Substances 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 102000015427 Angiotensins Human genes 0.000 description 11
- 108010064733 Angiotensins Proteins 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 235000017550 sodium carbonate Nutrition 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 235000015320 potassium carbonate Nutrition 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 229910052500 inorganic mineral Inorganic materials 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 235000010755 mineral Nutrition 0.000 description 7
- 239000011707 mineral Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 5
- 238000009395 breeding Methods 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000012047 saturated solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 102000005862 Angiotensin II Human genes 0.000 description 4
- 101800000733 Angiotensin-2 Proteins 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 4
- 229910052728 basic metal Inorganic materials 0.000 description 4
- 150000003818 basic metals Chemical class 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 230000001488 breeding effect Effects 0.000 description 4
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- 230000005764 inhibitory process Effects 0.000 description 4
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- 239000011780 sodium chloride Substances 0.000 description 4
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- MARUHZGHZWCEQU-UHFFFAOYSA-N 5-phenyl-2h-tetrazole Chemical compound C1=CC=CC=C1C1=NNN=N1 MARUHZGHZWCEQU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 3
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
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- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 3
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- 229950006323 angiotensin ii Drugs 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
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- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 3
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- 150000007530 organic bases Chemical class 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- UHBXGHADNVDXMM-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[Li] Chemical compound C(C)(C)N(C(C)C)CC[Li] UHBXGHADNVDXMM-UHFFFAOYSA-N 0.000 description 2
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
用相应的吡啶酮与联苯基甲基卤化合物反应制
备烷氧基甲基取代的吡啶酮联苯。烷氧基甲基取代
的吡啶酮联苯可作为活性化合物用在具体来讲是治
疗高血压和动脉粥样硬化的药物中。
Description
本发明涉及烷氧基甲基取代的吡啶酮联苯,涉及其制备方法及其在药物方面、具体来讲是作为抗高血压和抗动脉粥样硬化剂的用途。
人们知道,肾素-蛋白水解酶在体内从血管紧张素原分裂出十肽血管紧张素Ⅰ,血管紧张素Ⅰ又在肺、肾或其它组织中被分解成增压的八肽血管紧张素Ⅱ。血管紧张素Ⅱ的各种作用如血管收缩作用、肾N+ a潴留、肾上腺醛固酮的释放和使交感神经系统的紧张性增加对血压升高具有协同作用。
此外,血管紧张素Ⅱ具有促进细胞如心肌细胞和平滑肌细胞的生长和繁殖的特性,这些细胞的生长和繁殖在各种疾病状态下(如高血压、动脉粥样硬化和心肌能不全)增加。
除抑制肾素活性外,干扰肾素-血管紧张素系统(RAS)的可能途径是抑制血管紧张素转化酶(ACE)的活性及阻断血管紧张素Ⅱ受体。
具抗高血压活性的吡啶酮取代的联苯在欧洲专利申请EP487745和500297中作了报道。
因此本发明涉及通式(Ⅰ)烷氧基甲基取代的吡啶酮联苯类及其盐,所述通式(Ⅰ)结构如下:
式中
R1代表羧基或代表C1-C8烷氧基羰基基团,
R2代表C1-C10烷基(直链或支链的),该烷基可以被苯基取代,
R3代表卤素、氢、C1-C6烷基、羟基、C1-C8烷氧基、三氟甲基或三氟甲氧基,
R4代表羧基或代表四唑基,以及
X代表氧或硫。
本发明烷氧基甲基取代的吡啶酮联苯也可以其盐的形式存在。在本文中一般可提及与有机碱或无机碱形成的盐。
本发明中优选生理上可接受的盐。
烷氧基甲基取代的吡啶酮联苯的生理上可接受的盐一般是本发明化合物的金属盐或铵盐。特别优选的盐是例如锂盐、钠盐、钾盐、镁盐或钙盐以及衍生自氨或以下有机胺的铵盐:例如乙胺、二乙胺或三乙胺、二乙醇胺或三乙醇胺、二环己胺、二甲氨基乙醇、精氨酸、赖氨酸或1,2-乙二胺。
本发明化合物可以存在立体异构体,或者为对映体,或者为非对映体。本发明既涉及对映体或非对映体,也涉及其个别的混合物。外消旋体同非对映体一样,可按已知的方法拆分成立体异构单一的成分[参见E.L.Eliel,Stereochemistry of Carbon Compounds,McGraw Hill,1962]。此外,可以形成atropic异构体。
优选的通式(Ⅰ)化合物是式中取代基如下定义的通式(Ⅰ)化合物及其盐:
R1代表羧基基团或代表C1-C6烷氧基羰基基团;
R2代表C1-C8烷基(直链或支链的),该烷基可以被苯基所取代,
R3代表氟、氯、溴、氢、C1-C6烷基、羟基、C1-C4烷氧基、三氟甲基或三氟甲氧基,
R4代表羧基或四唑基,以及
X代表氧。
特别优选的通式(Ⅰ)化合物是式中取代基如下定义的通式(Ⅰ)化合物及其盐:
R1代表羧基基团或代表C1-C4烷氧基羰基基团,
R2代表C1-C6烷基(直链或支链的),
R3代表氟、氯、氢、羟基、C1-C4烷基、甲氧基、三氟甲基或三氟甲氧基,
R4代表四唑基,以及
X代表氧。
最优选的通式(Ⅰ)化合物是式中取代基如下定义的通式(Ⅰ)化合物及其盐:
R1代表羧基、甲氧基羰基或乙氧基羰基,
R2代表乙基或甲基,
R3代表氟、氯、甲基、羟基、三氟甲基或三氟甲氧基,
R4代表四唑基,以及
X代表氧。
通式(Ⅰ)烷氧基甲基取代的吡啶酮联苯按下述方法制备:
[A]在惰性溶剂中且在碱存在下,若合适,加入催化剂,使通式(Ⅱ)吡啶酮与通式(Ⅲ)化合物反应,所述通式(Ⅱ)吡啶酮和通式(Ⅲ)化合物的结构如下:
式中
R1、R2和R3的定义同上,
E代表氯或溴,以及
R4′代表C1-C4烷氧基羰基,或者代表下式基团:
或者
[B]若R4代表四唑基,则在惰性溶剂中且在碱存在下并在金属催化下,使通式(Ⅳ)化合物与通式(Ⅴ)化合物反应,所述通式(Ⅳ)化合物和通式(Ⅴ)化合物的结构如下:
式中
R1、R2和R3的定义同上,
L代表典型的离去基团,例如溴、碘或者甲磺酰氧基、甲苯磺酰氧基、氟磺酰氧基或三氟甲磺酰氧基,最好为溴,以及
T代表氢,或代表三苯甲基基团;
然后,若制备游离的四唑(R4/T),则将三苯甲基基团用酸在有机溶剂和/或水中裂解掉;若制备羧酸(R4),则将相应的酯水解,并且如果合适,将该化合物用碱转化成它们的盐。
本发明方法可用以下反应式举例说明:
本方法适宜的溶剂是在该反应条件下不发生变化的常规有机溶剂,最好包括醚类,如乙醚、二噁烷、四氢呋喃或二甲氧基乙烷,或烃类,如苯、甲苯、二甲苯、己烷、环己烷或石油馏分,或卤代烃类,如二氯甲烷、氯仿、四氯化碳、二氯乙烯、三氯乙烯或氯苯,或乙酸乙酯,二甲亚砜,二甲基甲酰胺,六甲基磷酸三酰胺,乙腈,丙酮或硝基甲烷。也可以使用所述溶剂的混合物。优先选用四氢呋喃、丙酮、二甲基甲酰胺和二甲氧基乙烷。
无机碱或有机碱一般可用作本发明方法[A]中的碱。这些碱最好包括碱金属氢氧化物,如氢氧化钠或氢氧化钾,碱土金属氢氧化物,如氢氧化钡,碱金属碳酸盐,如碳酸钠或碳酸钾,碱土金属碳酸盐,如碳酸钙或碳酸铯,或者碱金属或碱土金属醇盐或氨化物,如甲醇钠或甲醇钾、乙醇钠或乙醇钾或叔丁醇钾、或二异丙基氨基化锂(LDA),或者有机胺类(三烷基(C1-C6)胺类),如三乙胺,或者杂环化合物,如1,4-二氮杂二环[2,2,2]辛烷(DABCO)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、吡啶、二氨基吡啶、甲基哌啶或吗啉。也可以使用碱金属如钠、或其氢化物如氢化钠作为碱。优先选用碳酸钾,氢化钠,叔丁醇钾或碳酸铯。
在方法[A]中,碱的用量一般为每摩尔式(Ⅲ)化合物0.05-10mol。
本发明方法[A]一般在-100℃-+100℃的温度范围内实施,0℃-80℃为佳。
本发明方法一般在常压下实施。但也可以在加压或减压条件下(如在0.5-5巴范围内)实施该方法。
本发明方法[B]适用的溶剂是在该反应条件下不发生变化的常规有机溶剂,最好包括醚类,如乙醚、二噁烷、四氢呋喃或二甲氧基乙烷,或烃类,如苯、甲苯、二甲苯、己烷、环己烷或石油馏分,或卤代烃类,如二氯甲烷、氯仿、四氯化碳、二氯乙烯、三氯乙烯或氯苯,或乙酸乙酯,三乙胺,吡啶,二甲亚砜,二甲基甲酰胺,六甲基磷酸三酰胺,乙腈,丙酮或硝基甲烷。也可以使用所述溶剂的混合物。
优选四氢呋喃、丙酮、二甲基甲酰胺和二甲氧基乙烷。也可以使用所述溶剂与水的混合物。
本发明方法[B]一般在-20-+150℃的温度范围内实施,以+40-+100℃为佳。
适宜的催化剂一般是镍、钯或铂的金属络合物,最好是钯(0)络合物,如四重三苯膦钯(tetrakistriphenylphosphinepalladium)。也可以使用相转移催化剂,如溴化四正丁基铵或冠醚。
催化剂的用量为每摩尔通式(Ⅳ)化合物0.005-0.2mol,最好是0.01-0.05mol。
适宜的碱一般为有机非亲核性叔碱,如三乙胺或二异丙基乙胺,或无机碱,如碱金属碳酸盐或碱金属氢氧化物,如碳酸钾或氢氧化钾、碳酸钠或氢氧化钠或者碳酸铊或氢氧化铊,或这些碱金属的醇盐。优选碳酸钠或碳酸钾。
碱的用量在每种情况下一般为每摩尔式(Ⅳ)化合物1-10mol,以1-5mol为佳。
如果合适,无机碱在水溶液中使用。
用乙酸或三氟乙酸和水或上述醇之一,或者在丙酮存在下用盐酸水液,或也用醇类,或在氯化氢的二噁烷溶液中将三苯甲基基团裂解掉。
该裂解一般在常压下于0-150℃、最好是20-100℃的温度范围内进行。
适宜的催化剂是碘化钾或碘化钠,以碘化钠为佳。
适宜于水解酯的碱是常规无机碱,最好包括碱金属氢氧化物或碱土金属氢氧化物,如氢氧化钠、氢氧化钾或氢氧化钡,或碱金属碳酸盐,如碳酸钠或碳酸钾、或碳酸氢钠,或碱金属醇盐,如甲醇钠、乙醇钠、甲醇钾、乙醇钾或叔丁醇钾。特别优先选用氢氧化钠或氢氧化钾。
适宜于水解的溶剂是水或常规水解用有机溶剂,最好包括醇类,如甲醇、乙醇、丙醇、异丙醇或丁醇,或醚类,如四氢呋喃或二噁烷,或二甲基甲酰胺或二甲亚砜。特别优先选用醇类,如甲醇、乙醇、丙醇或异丙醇。也可以使用所述溶剂的混合物。
如果合适,水解也可以用下述酸来完成:例如三氟乙酸、乙酸、盐酸、氢溴酸、甲磺酸、硫酸或高氯酸。优先选用三氟乙酸。
水解一般在0-+100℃、最好是在+20-+80℃的温度范围内进行。
水解一般在常压下进行。但也可以在减压或加压(如0.5-5巴)条件下进行水解。
在进行水解时,碱的用量一般为每摩尔酯1-3mol,以1-1.5mol为佳。特别优先选用摩尔量的反应剂。
叔丁酯的水解一般在上述的一种溶剂和/或水或其混合物、最好是二恶烷或四氢呋喃存在下用酸如盐酸或三氟乙酸来完成。
通式(Ⅱ)化合物是已知的,可按已知方法来制备。
通式(Ⅲ)化合物本身是已知的或可按已知方法制备。
式中T为H的式(Ⅴ)化合物是新化合物,可按下述方法来制备:首先使苯基四唑在惰性溶剂中并在碱存在及惰性气体气氛下反应,然后加入硼酸三甲酯,最后将产物用酸水解。
该方法适宜的溶剂是质子惰性的溶剂,如醚类,例如四氢呋喃、乙醚、甲苯,己烷或苯。优选四氢呋喃。
适宜的碱是伯丁基锂、仲丁基锂、叔丁基锂和苯基锂。优选正丁基锂。
碱的用量为每摩尔苯基四唑2-5mol,以2-3mol为佳。
适宜的酸一般为无机酸,如盐酸,C-C羧酸,如乙酸,或磷酸。优选盐酸。
酸的用量一般为1-10mol,以1-3mol为佳。
该方法一般在-70-+25℃、最好在-10-0℃的温度范围内实施。
本发明方法一般在常压下实施。但也可以在加压或减压条件下(例如在0.5-5巴范围内)实施该方法。
通式(Ⅳ)化合物大多数是新的,可按例如下述方法制备:在惰性溶剂中并在碱和/或催化剂存在下,使通式(Ⅵ)化合物与通式(Ⅶ)化合物反应;所述通式(Ⅵ)化合物和通式(Ⅶ)化合物的结构如下:
式中
R1、R2、R3、X和L的定义同上,以及
V代表卤素,最好是溴。
本方法适宜的溶剂是在该反应条件下不发生变化的常规有机溶剂,最好包括醚类,如乙醚、二噁烷、四氢呋喃或乙二醇二甲醚,或烃类,如苯、甲苯、二甲苯、己烷、环己烷或石油馏分,或卤代烃类,如二氯甲烷、氯仿、四氯化碳、二氯乙烯、三氯乙烯或氯苯,或乙酸乙酯,二甲亚砜,二甲基甲酰胺,或二甲氧基乙烷,六甲基磷酸三酰胺,乙腈,丙酮或硝基甲烷。也可以使用所述溶剂的混合物。优先选用四氢呋喃、丙酮、二甲基甲酰胺和二甲氧基乙烷,醇类,如甲醇、乙醇或丙醇,和/或水,甲苯和甲醇/水。
本发明方法可用的碱一般是无机碱或有机碱,最好包括碱金属氢氧化物,如氢氧化钠或氢氧化钾,碱土金属氢氧化物,如氢氧化钡,碱金属碳酸盐,如碳酸钠或碳酸钾,碱土金属碳酸盐,如碳酸钙或碳酸铯,或者碱金属或碱土金属醇盐或氨化物,如甲醇钠或甲醇钾、乙醇钠或乙醇钾或叔丁醇钾、碳酸铊或氢氧化铊或二异丙基氨基化锂(LDA),或者有机胺类(三烷基(C1-C6)胺类),如三乙胺,或者杂环化合物,如1,4-二氮杂二环[2,2,2]辛烷(DABCO)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、吡啶、二氨基吡啶、甲基哌啶或吗啉。也可以使用碱金属如钠、或其氢化物如氢化钠作为碱。优先选用碳酸钾,氢化钠,叔丁醇钾或碳酸钠。
碱的用量一般均为每摩尔式(Ⅶ)化合物0.05-10mol,以1-2mol为佳。
本发明方法一般在惰性气体气氛下于-100-+100℃、最好是0-80℃的温度范围内实施。
本发明方法一般在常压下实施。但也可以在加压或减压条件下(例如在0.5-5巴范围内)实施该方法。
本方法适宜的催化剂是碘化钾或碘化钠,以碘化钠为佳。也可以使用相转移催化剂,如溴化四正丁基铵或冠醚。
催化剂的用量为每摩尔通式(Ⅶ)化合物0.1-10mol,以1-2mol为佳。
以上制备方法仅为举例说明。本发明通式(Ⅰ)化合物的制备不限于这些方法,并且这些方法的任何改良同样都可以用于该制备。
本发明烷氧基甲基取代的吡啶酮联苯显示出出人意料的且有效的药理作用谱。
本发明化合物具有特异性地拮抗血管紧张素Ⅱ的作用,这是由于它们竞争性地抑制血管紧张素Ⅱ与受体的结合。它们抑制血管紧张素Ⅱ的血管收缩作用及刺激醛固酮分泌的作用。此外,它们抑制平滑肌细胞的繁殖。
因此,它们可用在治疗动脉压过高和动脉粥样硬化的药物中。此外,它们可用于治疗冠状心脏病、心肌能不全、大脑功能障碍、局部缺血性大脑疾病、外周循环障碍,肾和肾上腺机能不良、呼吸道的支气管痉挛和与血管相关的疾病、钠潴留及水肿。
抑制由激动剂所致收缩的研究
将兔(雌雄均有)在颈部一击打昏并放血,或者在某些情况下用戊巴比妥(静注,约60-80mg/Kg)麻醉并开胸处死。分出胸主动脉,去除粘连的结缔组织,分成1.5mm宽的环节,并使其负重约3.5g。然后将其逐一放入10ml器官浴中,所述器官浴温控在37℃并盛有充有卡波金气体的克-汉二氏营养液,该营养液含有下列成分:119mmol/1 NaCl;2.5mmol/1 CaCl2×2H2O;1.2mmol/l KH2PO4;10mmol/1葡萄糖;4.8mmol/1 KCl;1.4mmol/1 MgSO4×7H2O和25mmol/1 NaHCO3。
收缩用Statham UC2细胞通过桥放大器(得自Mülheim或DSM Aalen)等同记录并用A/D转化器(570系统,Keithley Munich)来洋地黄化并对收缩进行评价。激动剂/剂量效应曲线(DEC)按小时标绘。对于每一个DEC的测定来说,是将3或4个独立的浓度以4分钟的间隔加到该器官浴中。在DECs测定结束后进行循环冲洗(用上述营养液,每种情况冲洗16次,每次约5秒钟)。随后为28分钟休息,即潜伏期,在这期间,收缩通常再次达到开始的值。
将在正常情况下的第3个DEC的水平作为评价在后续操作中待研究的试验物质的参比参数。在每种情况下,将试验物质在后续的DECs测定中在潜伏期开始的时候以增加的剂量加到该器官浴中。在该过程中,每个动脉环总是被用同一种激动剂刺激一整天。
激动剂及其标准浓度(每单剂量的应用体积=100μl):
KCl 22.7;32.7;42.7;52.7 mmol/l
1-去甲肾上腺素 3×10-9;3×10-8;3×10-7;3×10-6g/ml
血清素 10-8;10-7;10-6;10-5g/ml
B-HT 920 10-7;10-6;10-5g/ml
美速胺 10-7;10-6;10-5g/ml
血管紧张素II 3×10-9;10-8;3×10-8;10-7g/ml
为计算IC50(待研究物质产生50%抑制作用时的浓度),将每种情况下第3个效应(等于次最大激动剂浓度)作为基准。
本发明化合物以剂量的函数的方式抑制血管紧张素Ⅱ引起的离体免动脉的收缩。对于由钾去极化或其它激动剂所致的收缩无抑制作用或仅在高浓度下有效弱的抑制作用。
对血管紧张素Ⅱ输注的大鼠进行血压测量
将体重为300-350g的雄性Wistar大鼠(Moellegaard,哥本哈根,丹麦)用硫喷妥钠(100mg/Kg,腹膜内给药)麻醉。气管造口术后,将用于血压测量的插管插入股动脉,用于输注血管紧张素Ⅱ的插管和物质给药用插管插入股静脉。在给神经节阻断剂安血定(5mg/Kg,静注)后,开始输注血管紧张素Ⅱ(0.3μg/kg/分钟)。当血压值达到稳定的平稳段后通过或者静注,或者口服在0.5% Tylose絮凝剂中的悬浮液或溶液给试验物质。
在清醒的患高血压的大鼠身上测定抗高血压的活性
用手术致一侧肾动脉狭窄的清醒的大鼠试验本发明化合物的口服抗高血压活性。为此,用内径为0.18mm的银夹将右肾动脉缩窄。对于这种类型的高血压,在该操作后的头六周内,血浆肾素的活性增加。服用试验物质后,在给定的时间间隔用“尾套箍”(“tail cuff”)不流血地测量这些动物的动脉血压。将待试物质按不同的剂量以在Tylose絮凝剂中的悬浮液形成用管饲法胃内(口服)给药。本发明化合物在临床相应的剂量下能降低高血压大鼠的动脉血压。
此外,本发明化合物以其浓度的函数的方式抑制放射性血管紧张素Ⅱ的特异性结合。
本发明化合物与在肾上腺皮质(牛的)膜部分的血管紧张素Ⅱ受体的相互作用
将完全去除囊髓质的刚分离出来的牛肾上腺皮质(AC)在蔗糖溶液(0.32M)中用Ultra-Turrax(Janke & Kunkel,Staufen i.B.)粉碎成粗的膜匀浆,然后经两个离心步骤部分纯化成膜部分。
关于受体结合的研究用放射性血管紧张素Ⅱ在牛AC的部分纯化的膜部分上进行,测定体积为0.25ml,它具体包含部分纯化的膜(50-80μg),3H-血管紧张素Ⅱ(3-5nM),试验缓冲溶液(50mM Tris,PH7.2),5mM MgCl2和待研究物质。于室温培养60分钟后,将样品的未结合的放射性用湿润的玻璃纤维滤器(Whatman GF/C)滤除,结合的放射性在用冰冷却的缓冲溶液(50mM Tris/HCl,pH7.4,5%聚乙二醇6000)洗除蛋白质后在闪烁合剂(scintillation cocktail)中用分光光度法测定。原始数据用计算机程序分析得Ki和IC50值(Ki:用所用的放射性校正的IC50值;IC50值:待研究物质对放射性配体的特异性结合产生50%抑制作用时的浓度)。
本发明化合物对平滑肌细胞繁殖的抑制作用的研究
将用培养基移植技术(the media explantate technique)[R.Ross,J.Cell.Biol.50,第172页,1971]从大鼠主动脉分离出来的平滑肌细胞用于测定化合物的抗繁殖作用。将这些细胞接种在适宜的培养皿(通常是96孔平皿)中并于37℃在199培养基中并在5%CO2存在下培养2-3天,所述培养基含有7.5%FCS和7.5%NCS,2mM L-谷氨酰胺和15mM HEPES,其pH为7.4。然后通过去除血清2-3天使细胞生长同步,然后用血管紧张素Ⅱ、血清或其它因素刺激细胞生长。同时加入试验化合物。16-20小时后加入1μ Ci3H-胸腺嘧啶核苷,再过4小时后测定该物质与可用TCA沉淀的细胞的DNA的结合。
在顺序稀释活性化合物时,由10%FCS所致的胸腺嘧啶核苷结合产生50%的最大抑制的活性化合物的浓度适于定义IC50值。
新的活性化合物可用惰性、无毒且药学上适宜的赋形剂或溶剂按已知的方法转化成常规制剂,如片剂,包衣片剂,丸剂,颗粒剂,气雾剂,糖浆剂,乳剂,悬浮液和溶液。在各制剂中活性化合物的治疗量应约为该混合物总重量的0.5-90%,即该含量足以达到所述的剂量范围。
制剂可通过例如将活性化合物搀入溶剂和/或赋形剂中来制备。若合适,可以使用乳化剂和/或分散剂。例如若用水作稀释剂,如果合适,则可以用有机溶剂作辅助溶剂。
按常规方式给药,以口服或肠道外给药为佳,经舌给药或静注给药为最好。
若经肠道外给药,可以使用以适宜的液体赋形物质制成的活性化合物溶液。
业已证明,一般按下述剂量给药较为有利:若静脉内给药,给药量约为0.001-1mg/Kg体重、最好是约0.01-0.5mg/Kg体重则产生有效的结果;若口服给药,则剂量为约0.01-20mg/Kg体重,以0.1-10mg/Kg体重为佳。
然而有时可能需要偏离上述的剂量,尤其是为以下因素的函数时:体重或给药途径的性质、或个体对该药物的反应、其制剂的性质以及给药时间或间隔。因此,在某些情况下使用小于上述的最低剂量可能足够,而在另一些情况下则必须超出上述剂量的最高限。若服用相对大的剂量时,最好是将其分成每日若干单剂服用。
原料化合物
实施例1
N-(1-羟基-2-甲基丙-2-基)-2-甲氧基苯甲酰胺
将15.2g(100mmol)2-甲氧基苯甲酸溶于300ml二氯甲烷中,并将该溶液与14.2g(105mmol)1-羟基苯甲酸三唑×1H2O和21.66g(105mmol)N,N-二环己基碳化二亚胺于0℃一起搅拌。将如此得到的混悬液于室温搅拌0.5小时,再次冷却至0℃,并加入9.89g(111mmol)1-羟基-2-甲基-2-丙胺和12.65g(125mmol)三乙胺的二氯甲烷(300ml)溶液。1小时后反应完全。将反应混合物用1M盐酸和碳酸钠饱和溶液洗涤,硫酸钠干燥并真空浓缩。将粗产物与石油醚一起搅拌,吸滤,随后用溶剂漂洗并在高真空条件下干燥。
实施例Ⅱ
4,5-二氢-5,5-二甲基-2-(2-甲氧基苯基)噁唑
将17.1ml(283.4mmol)亚硫酰氯于室温加至16.0g(71.7mmol)得自实施例Ⅰ的化合物中并搅拌3小时。然后将过量的试剂蒸除,残留物用500ml乙醚搅拌并吸滤。将固体溶于水中,将该溶液用乙醚层覆盖,并用2M氢氧化钠溶液释出相应的碱。水相用乙酸乙酯提取3次后,将合并的有机相用硫酸钠干燥并蒸发,在高真空条件下将残留物中残留溶剂去除。
实施例Ⅲ
4,5-二氢-5,5-二甲基-2(3′-氟-4′-甲基联苯-2-基)噁唑
一开始将14.7g(605.7mol)镁屑在氩气条件下加至50ml分析纯四氢呋喃中,并在搅拌下加入117.7g(623mmol)4-溴-2-氟甲苯的分析纯四氢呋喃(500ml)溶液。在35-40℃下,2小时内形成澄清的溶液。于室温滴加74.0g(360.5mmol)得自实施例Ⅱ的化合物的分析纯四氢呋喃(500ml)溶液,然后将该混合物于约25℃搅拌16小时,最初轻微冷却。蒸除溶剂,然后将粗产物用600ml乙酸乙酯和800ml氯化铵饱和溶液于10℃漂洗,用硫酸钠干燥并真空蒸发。为纯化,而将该产物溶于600ml乙醚中,吸滤出所有固体残留物,该粗产物经2M盐酸若干次提取而转入水相中。将该水相用乙醚层覆盖并用氢氧化钠溶液调至pH13。用乙醚提取三次后,将该产物相用硫酸钠干燥并蒸发,高真空除去残留溶剂。
实施例Ⅳ
2-(3-氟-4-甲基苯基)苄腈
先将97.0g(343mmol)得自实施例Ⅲ的化合物放入500ml吡啶中,然后于0℃搅拌下加入31.3ml(343mmol)磷酰氯。将混合物慢慢加热,最终使其沸腾回流1小时。冷至室温后,加入乙醚和适量1M盐酸,使水相的pH为1.5。有机相用1M硫酸洗涤3次以上,用硫酸钠干燥并用旋转蒸发器蒸发。在高真空条件下除去残留物中的残留溶剂。
实施例Ⅴ
5-(3′-氟-4′-甲基联苯-2-基)-1H-四唑
将2.26(10.7mmol)得自实施例Ⅳ的化合物与3.48g(53.6mmol)叠氮化钠和7.37g(53.6mmol)氯化三乙基铵在30ml分析纯二甲基甲酰胺中沸腾回流24小时。冷却后,将混合物分配于乙醚和1M硫酸中。有机相用水洗涤并用硫酸钠干燥,蒸除溶剂。将粗产物在甲苯中搅拌提取,吸滤后将产物真空干燥(1.89g,7.2mmol)。将母液用旋转蒸发器蒸发,将残留物按上述方法再次纯化(0.43g,1.7mmol)。
实施例Ⅵ
5-(3-氟-4-甲基联苯-2-基)-2-三苯甲基-1H-四唑
将50.55g(199.2mmol)得自实施例Ⅴ的化合物于室温与58.58g(210.0mmol)三苯基氯甲烷和33.2ml(239.0mmol)三乙胺在700ml二氯甲烷中搅拌17小时。将反应混合物分别用水和1M柠檬酸水溶液洗涤一次,用硫酸钠干燥并用旋转蒸发器蒸发,经高真空除去残留物中的残留溶剂。
实施例Ⅶ
5-(4′-溴甲基-3′-氟联苯-2-基)-2-三苯甲基-1H-四唑
将82.90g(173.2mmol)得自实施例Ⅵ的化合物与30.84g(173.2mmol)N-溴代琥珀酰亚胺和0.87g(5.3mmol)偶氮二异丁腈(作为自由基引发剂)一起在11四氯化碳中沸腾回流6小时。冷却后将沉淀析出的琥珀酰亚胺吸滤出并用四氯化碳洗涤。将滤液蒸发,残留物在高真空条件下干燥。
实施例Ⅷ
2,4-二氧代-5-甲氧基戊酸甲酯
将88.1g(1mol)甲氧基丙酮和118.1g(1mol)草酸二甲酯的甲醇(150ml)溶液用30分钟时间滴加至处于回流状态下的59.4g(1.1mol)甲醇钠的甲醇(200ml)溶液中,并将该混合物再加热回流2小时。将冷却的反应混合物倒入800ml冰水中,用浓硫酸调至pH1.5并用乙酸乙酯洗涤三次,每次500ml。合并的有机相用500ml1%碳酸氢钠溶液洗涤,用硫酸钠干燥并蒸馏。
(沸点125℃/20毫巴)。
实施例Ⅸ
3-氰基-4-甲氧基羰基-6-甲氧基甲基-2-氧代-1,2-二氢吡啶
将18.9g(0.224mol)氰基乙酰胺,31g(0.224mol)碳酸钾和34.6g(0.224mol)得自实施例Ⅷ的化合物在200ml丙酮中加热回流2小时。将反应混合物溶于500ml水中并用乙醚洗涤2次,每次250ml。将产物所在的水相用的浓盐酸调至pH1.5并将沉淀吸滤出。
熔点:200-203℃(分解)。
实施例Ⅹ
4-羧基-6-甲氧基甲基-2-氧代-1,2-二氢吡啶
将10.41g(46.8mmol)得自实施例Ⅸ的化合物在20ml水和16.7ml浓硫酸中加热回流4小时。将反应混合物倒入700ml冰水中并用5N氢氧化钠溶液调至pH2。溶液用氯化钠饱和,吸滤出粘沉淀物并将其冷冻干燥。
实施例Ⅺ
4-甲氧基羰基-6-甲氧基甲基-2-氧代-1,2-二氢吡啶
将4ml(55.4mmol)亚硫酰氯滴加至8.95g(48.9mmol)得自实施例Ⅹ的化合物的甲醇(100ml)混悬液中并将该反应混合物于50℃搅拌18小时。将其浓缩至干并将残留物用100g硅胶60层析,用二氯甲烷/甲醇混合物(20∶1-7∶1)洗脱。
溶点:165℃。
实施例Ⅻ
4-甲氧基羰基-6-甲氧基甲基-2-氧代-1-{[3-氟-2′(N-三苯甲基四唑-5-基)联苯-4-基]甲基}-1,2-二氢吡啶
将1.99g(10.1mmol)得自实施例Ⅺ的化合物和3.29g(10.1mmol)碳酸铯的二甲氧基乙烷(20ml)混悬液于室温搅拌10分钟,加入5.84g(10.1mmol)得自实施例Ⅶ的化合物二甲氧基乙烷(20ml)溶液,并将该混合物于室温搅拌20小时。然后加热回流2小时。加入100ml水后,将反应溶液用3×100ml乙酸乙酯提取。有机相经干燥、浓缩及硅胶层析(石油醚∶乙酸乙酯=5∶1→1∶1洗脱),得无色泡沫状物。
实施例ⅩⅢ
2-(四唑-5′-基)苯基硼酸
将17.6ml(44mmol)2.5M正丁基锂的正己烷溶液于-5℃并在充氩条件下加至2.9g(20mmol)5-苯基四唑的四氢呋喃(50ml)溶液中。将混合物于-5℃-0℃搅拌30分钟并在该温度下加入10ml(88mmol)硼酸三甲酯。然后移出冷却浴,于室温将10ml半浓盐酸加至该溶液中。1小时后,混合物用100ml乙酸乙酯提取,分出有机相。水相用乙酸乙酯提取2次,每次20ml。将合并的有机相用硫酸钠干燥并浓缩,残留物用硅胶层析纯化,用甲苯/冰乙酸/甲醇(38∶0.1∶2)洗脱。
产量:2.65g(收率为70%)
Rf=0.26(甲苯/甲醇/冰乙酸=32∶8∶1)
13C-NMR:δ=156.7;137.9;133.5;129.8;128.9;127.7;126.9ppm。
实施例ⅩⅣ
4-甲氧基羰基-6-甲氧基甲基-2-氧代-1-(2-氟-4-碘苯基甲基)-1,2-二氢吡啶
将2g(10.14mmol)得自实施例Ⅺ的化合物、4.12g(13.1mmol)2-氟-4-碘苄基溴和4.89g(15mmol)碳酸铯的四氢呋喃(20ml)溶液在20℃及充氩条件下搅拌16小时。然后真空除去溶剂,将残留物溶于二氯甲烷/水中。水相用二氯甲烷提取一次。将合并的有机相用硫酸钠干燥并浓缩。残留物用硅胶层析纯化,用石油醚/乙酸乙酯(5∶1和3∶1)洗脱。
产量:1.3g(收率:30%)
Rf:0.16(石油醚/乙酸乙酯=3∶1)。
实施例ⅩⅤ
4-甲氧基羰基-6-甲氧基甲基-2-氧代-1-(2-氯-4-碘苯基甲基)-1,2-二氢吡啶
按类似于实施例ⅩⅣ的操作方法制得标题化合物。
Rf:0.25(溶剂∶石油醚∶乙酸乙酯1∶2)。
实施例ⅩⅥ
3-氯-4-三氟甲基磺酰氧基苯甲酸甲酯
将5.5ml三氟甲磺酸酐(33mmol)于0℃缓慢滴加至5.49g 3-氯-4-羟基苯甲酸甲酯(29.4mmol)的吡啶(15ml)溶液中。将反应混合物于0℃搅拌5分钟以及于室温搅拌4小时后分配于水和乙醚中。有机相依次用水、浓度为10%的盐酸、水和氯化钠饱和溶液洗涤,用硫酸钠干燥并浓缩。残留物经硅胶层析(用二氯甲烷洗脱)得8.93g淡黄色稀的流动性的油[收率为95.2%,Rf0.63(己烷∶乙酸乙酯=3∶1)]。
实施例ⅩⅦ
5-(2′-氯-4′-甲氧基羰基联苯-2-基)-2-三苯甲基-1H-四唑
将氩气通入1.00g(3.14mmol)得自实施例ⅩⅥ的化合物的甲苯(50ml)溶液。加入168mg Pd(P(C6H5)3)4(0.146mmol)、6ml甲醇、1.63g(3.77mmol)2-(N-三苯甲基四唑-5-基)苯基硼酸和333mg(3.14mmol)碳酸钠的脱气水(4ml)溶液后,将该乳液于100℃搅拌过夜。加入相同量的催化剂,然后于100℃搅拌2.5小时后完成该反应。将反应混合物分配于水和乙酸乙酯中。有机相用稀碳酸钠溶液和氯化钠饱和溶液洗涤,用硫酸钠干燥并浓缩。残留物进行硅胶层析(己烷∶乙酸乙酯=10∶1-8∶1洗脱),得10.1g淡黄色固体[收率:57.9%,Rf0.46(己烷∶乙酸乙酯=3∶1)]。
实施例ⅩⅧ
5-(2′-氯-4′-羟基甲基联苯-2-基)-2-三苯甲基-1H-四唑
将1.27g甲醇(39.6mmol)和1.29g硼氢化锂(59.4mmol)加至22.0g得自实施例ⅩⅦ的化合物(39.6mmol)的四氢呋喃(180ml)溶液中,然后将该混合物于室温搅拌30分钟并回流1小时。再加入0.63g甲醇(0.20mmol)并回流搅拌1小时使反应完全。将反应混合物浓缩,将残留物溶于200ml二氯甲烷中。在强烈的氩气流并使用冰浴的条件下缓慢加入100ml 1N硫酸氢钾溶液。分出有机相后,水相用二氯甲烷提取。将合并的有机相用氯化钠饱和溶液洗涤,用硫酸钠干燥并浓缩,得20.5g白色结晶[收率为98.19%,熔点186-187℃(分解);Rf0.15(己烷∶乙酸乙酯=3∶1)]。
实施例ⅪⅩ
5-(4′-溴甲基-2′-氯联苯-2-基)-2-三苯甲基-1H-四唑
在充氩和冰浴条件下,先向11.2g三苯膦(42.5mmol)的二氯甲烷(100ml)溶液中滴加6.79g溴(42.5mmol),然后滴加20.4g得自实施例ⅩⅦ的化合物的二氯甲烷(300ml)溶液。将反应混合物于室温搅拌1小时后通过硅胶过滤,并用二氯甲烷洗脱。将滤液浓缩,残留物用己烷浸提,得15.8g白色结晶(收率为68.9%;熔点156-160℃,Rf 0.40(己烷/乙酸乙酯=3∶1)]。
实施例ⅩⅩ
4-甲氧基羰基-6-甲氧基甲基-2-氧代-1-{[2-氯-2′-(N-三苯甲基四唑-5-基)联苯-4-基]甲基}-1,2-二氢吡啶
按类似于实施例Ⅻ的操作方法,由0.46g得自实施例Ⅺ的化合物(2.33mmol)和1.38g得自实施例ⅪⅩ的化合物(2.33mmol)制得0.17g标题化合物[收率为10%;Rf0.31(己烷∶乙酸乙酯=1∶1)]。
制备实施例
实施例1
4-甲氧基羰基-6-甲氧基甲基-2-氧代-1-[(3-氟-2′-四唑-5-基联苯-4-基)甲基]-1,2-二氢吡啶
将3.19g(4.61mmol)得自实施例Ⅻ的化合物溶于30ml甲醇和1.53ml(18.4mmol)12N盐酸中。1小时后,将该混悬液冷却并吸滤出沉淀物。
实施例2
4-羧基-6-甲氧基甲基-2-氧代-1-[(3-氟-2′-四唑-5-基联苯-4-基)甲基]-1,2-二氢吡啶二钠盐
将1.04g(2.4mmol)得自实施例1的化合物于室温在5ml甲醇、5ml四氢呋喃和4.8ml 1N氢氧化钠溶液中搅拌2小时。蒸除溶剂并将残留水液冰冻干燥。
Rf:0.11(甲苯/乙酸乙酯/冰乙酸=10∶30∶1)
实施例3
4-羧基-6-甲氧基甲基-2-氧代-1-[3-氟-2′-四唑-5-基联苯-4-基)甲基]-1,2-二氢吡啶
将321mg四重三苯膦钯(0)、8.34ml(16.7mmol)2M碳酸钠溶液、634mg(3.34mmol)得自实施例ⅩⅢ的化合物和1.5ml乙醇依次加至1.2g(2.78mmol)得自实施例ⅩⅣ的化合物的DMF(20ml)溶液中,并将该混合物加热回流16小时。将反应混合物冷却后,用硅藻土吸滤,残留物用甲醇清洗,除去溶剂并将残留物用硅胶层析纯化(用甲苯/乙酸乙酯/冰乙酸(30∶10∶1和20∶20∶1)洗脱)。
产量:285mg(收率为24%)
Rf:0.11(甲苯/乙酸乙酯/冰乙酸=10∶30∶1)。
用与实施例1、2和3类似的方法,制得下表中所列的化合物:
Claims (10)
2、按照权利要求1的烷氧基甲基取代的吡啶酮联苯及其盐,其中:
R1代表羧基基团或代表C1-C6烷氧基羰基基团,
R2代表C1-C8烷基(直链或支链的),该烷基可以被苯基所取代,
R3代表氟、氯、溴、氢、C1-C6烷基、羟基、C1-C4烷氧基、三氟甲基或三氟甲氧基,
R4代表羧基或四唑基,以及
X代表氧。
3、按照权利要求1的烷氧基甲基取代的吡啶酮联苯及其盐,
其中
R1代表羧基基团或代表C1-C4烷氧基羰基基团,
R2代表C1-C6烷基(直链或支链的),
R3代表氟、氯、氢、羟基、C1-C4烷基、甲氧基、三氟甲基或三氟甲氧基,
R4代表四唑基,以及
X代表氧。
4、按照权利要求1的烷氧基甲基取代的吡啶酮联苯及其盐,
其中
R1代表羧基、甲氧基羰基或乙氧基羰基,
R2代表乙基或甲基,
R3代表氟、氯、甲基、羟基、三氟甲基或三氟甲氧基,
R4代表四唑基,以及
X代表氧。
5、按照权利要求1的烷氧基甲基取代的吡啶酮的联苯的治疗用途。
6、按照权利要求1的烷氧基甲基取代的吡啶酮联苯的制备方法,其特征在于:
[A]在惰性溶剂中且在碱存在下,若合适,加入催化剂,使通式(Ⅱ)吡啶酮与通式(Ⅲ)化合物反应,所述通式(Ⅱ)吡啶酮和通式(Ⅲ)化合物的结构如下:
式中
R1、R2和R3的定义同上,
E代表氯或溴,以及
R4′代表C1-C4烷氧基羰基,或者代表下式基团:
或者
[B]若R4代表四唑基,则在惰性溶剂中且在碱存在下并在金属催化下,使通式(Ⅳ)化合物与通式(Ⅴ)化合物反应,所述通式(Ⅳ)化合物和通式(Ⅴ)化合物的结构如下:
式中
R1、R2和R3的定义同上,
L代表典型的离去基团,例如溴、碘或者甲磺酰氧基、甲苯磺酰氧基、氟磺酰氧基或三氟甲磺酰氧基,最好为溴,以及
T代表氢,或代表三苯甲基基团;
然后,若制备游离的四唑(R4/T),则将三苯甲基基团用酸在有机溶剂和/或水中裂解掉;若制备羧酸(R4/R1),则将相应的酯水解,并且如果合适,将该化合物用碱转化成它们的盐。
7、含至少一种按照权利要求1的烷氧基甲基取代的吡啶酮联苯的药物。
8、按照权利要求7的药物,用于治疗高血压和动脉粥样硬化。
9、按照权利要求1的烷氧基甲基取代的吡啶酮联苯在制药中的用途。
10、按照权利要求9的用途,用于制备抗高血压剂和抗动脉粥样硬化剂。
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DE4319040A DE4319040A1 (de) | 1992-10-23 | 1993-06-08 | Alkoxymethylsubstituierte Pyridonbiphenyle |
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CA2469435A1 (en) | 2001-12-21 | 2003-07-24 | X-Ceptor Therapeutics, Inc. | Modulators of lxr |
US7482366B2 (en) | 2001-12-21 | 2009-01-27 | X-Ceptor Therapeutics, Inc. | Modulators of LXR |
ES2251292B1 (es) | 2004-04-20 | 2007-07-01 | Inke, S.A. | Procedimiento para la obtencion de un compuesto farmaceuticamente activo y de sus intermedios de sintesis. |
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HU9303003D0 (en) | 1994-01-28 |
MX9306420A (es) | 1994-04-29 |
AU4864693A (en) | 1994-05-05 |
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AU666222B2 (en) | 1996-02-01 |
IL107334A0 (en) | 1994-01-25 |
NO933592D0 (no) | 1993-10-07 |
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FI934647A (fi) | 1994-04-24 |
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