CN87104319A - 苯并吡喃衍生物 - Google Patents
苯并吡喃衍生物 Download PDFInfo
- Publication number
- CN87104319A CN87104319A CN87104319.XA CN87104319A CN87104319A CN 87104319 A CN87104319 A CN 87104319A CN 87104319 A CN87104319 A CN 87104319A CN 87104319 A CN87104319 A CN 87104319A
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- China
- Prior art keywords
- formula
- compound
- hydrogen atom
- phenyl
- represent
- Prior art date
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- Granted
Links
- 150000001562 benzopyrans Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 137
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 26
- 239000001301 oxygen Substances 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 15
- -1 tetrazyl Chemical group 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical class C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims 1
- 230000003424 uricosuric effect Effects 0.000 abstract description 10
- 230000003276 anti-hypertensive effect Effects 0.000 abstract description 8
- 230000001882 diuretic effect Effects 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000460 chlorine Substances 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 238000004821 distillation Methods 0.000 description 10
- 238000003756 stirring Methods 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 210000002700 urine Anatomy 0.000 description 8
- ILPUOPPYSQEBNJ-UHFFFAOYSA-N 2-methyl-2-phenoxypropanoic acid Chemical compound OC(=O)C(C)(C)OC1=CC=CC=C1 ILPUOPPYSQEBNJ-UHFFFAOYSA-N 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- 229930192474 thiophene Natural products 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 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 description 5
- 208000004880 Polyuria Diseases 0.000 description 5
- 230000035619 diuresis Effects 0.000 description 5
- 230000029142 excretion Effects 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 4
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 229940116269 uric acid Drugs 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 3
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 229940063656 aluminum chloride Drugs 0.000 description 3
- 229940055858 aluminum chloride anhydrous Drugs 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 229910052728 basic metal Inorganic materials 0.000 description 3
- 150000003818 basic metals Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 125000003386 piperidinyl group Chemical class 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000011218 segmentation Effects 0.000 description 3
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 2
- DPZNOMCNRMUKPS-UHFFFAOYSA-N 1,3-Dimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1 DPZNOMCNRMUKPS-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical class COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- FGCLOJOLJQDQOG-UHFFFAOYSA-N ethoxymethanediol Chemical class CCOC(O)O FGCLOJOLJQDQOG-UHFFFAOYSA-N 0.000 description 2
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- 235000020828 fasting Nutrition 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical class CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- 239000002994 raw material Substances 0.000 description 2
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- 239000011592 zinc chloride Substances 0.000 description 2
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- NJIAKNWTIVDSDA-FQEVSTJZSA-N 7-[4-(1-methylsulfonylpiperidin-4-yl)phenyl]-n-[[(2s)-morpholin-2-yl]methyl]pyrido[3,4-b]pyrazin-5-amine Chemical compound C1CN(S(=O)(=O)C)CCC1C1=CC=C(C=2N=C(NC[C@H]3OCCNC3)C3=NC=CN=C3C=2)C=C1 NJIAKNWTIVDSDA-FQEVSTJZSA-N 0.000 description 1
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- 125000001246 bromo group Chemical class Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
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- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 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 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- AGHANLSBXUWXTB-UHFFFAOYSA-N tienilic acid Chemical compound ClC1=C(Cl)C(OCC(=O)O)=CC=C1C(=O)C1=CC=CS1 AGHANLSBXUWXTB-UHFFFAOYSA-N 0.000 description 1
- 229960000356 tienilic acid Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 1
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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Abstract
由下式代表的苯并吡喃衍生物及其医药上可用的盐类,
这些化合物具有促尿酸尿活性,利尿活性及抗高血压活性,因而在医药上是有用的。
Description
本发明叙述具有促尿酸尿的活性,利尿活性及降血压活性的苯并吡喃衍生物及其盐,因而这些化合物在医药上是有用的。
具有利尿及促尿酸尿的活性的已知化合物包括噻苯氧酸(tienilic acid)(〔2,3-二氯-4-(2-噻吩甲酰)苯氧〕乙酸)公开在美国专利3,758,506中,茚满酮酸(indacrinone)(〔6,7-二氯-2,3-二氢-2-甲基-1-氧代-2-苯基-1H-茚基-5)氧〕乙酸)公开发表在Journal of Medicinal Chemistry,21卷,437-442页(1978)上,以及一些化合物公开在日本专利申请(OPI)500573/85,764948/83及102522/84中(术语“OPI”在此处意为“未审查公布的日本专利申请”)。然而,这些化合物在促尿酸尿,利尿,及降血压的活性方面是不令人满意的。
同样,在Arzneim.Forsch.,30卷,2126页(1980)中报导一种苯并吡喃衍生物具有利尿及排盐作用,但此化合物没有促尿酸尿的作用。
由于为解决上述问题所做的大量研究的结果,现在发现由下面式(Ⅰ)表示的新化合物及其盐类显示明显的促尿酸尿,利尿及降压活性。
式(Ⅰ)表示为
其中:
R1及R2各代表氢原子,低级烷基,取代的或未取代的环烷基,单或二低级烷氨基,取代或未取代的环氨基,取代或未取代的芳基,或取代或未取代的芳烷基;
Y1及Y2各代表氢原子,低级烷基,卤原子或三卤甲基;Z代表羧基,低级烷氧羰基,四唑基,羟基或-CONR3R4,其中R3及R4各代表氢原子或低级烷基;
n代表整数1至6;
在上述结构中,应排除下面两种组合方式,即一种组合其中Y1,Y2及R2各代表氢原子,R1代表苯基,n代表1,Z代表羧基或烷氧羰基,键 代表双键,和另一种组合其中Y1,Y2,及R1各代表氢原子,R2代表苯基,n代表1,Z代表羧基或烷氧羰基,及键 代表双键。
在式(Ⅰ)中,术语“低级烷基”用于R1,R2,Y1,Y2,R3,及R4时意指含有1至6个碳原子的烷基,包括甲基,乙基,丙基,异丙基,正丁基,异丁基,叔丁基等等。术语“环烷基”用于R1或R2时包括环丙基,环丁基,环戊基,环己基,环庚基等等,这些环基可有一个或多个取代基。环烷基上的取代基包括低级烷基等等。在二低级烷基氨基中的烷基用于R1或R2时可以是相同的或不同的。R1或R2的环氨基包括1-吡咯烷基,1-哌啶基,1-哌嗪基,4-吗啉基,4-硫代吗啉基,1-高哌嗪基等等,环氨基可以有一个或多个取代基。在环氨基上的取代基包括低级烷基等等。芳基包括苯基,萘基,联苯基等等,并且芳基可以有一个或多个取代基。在芳基上的取代基包括羟基,卤原子,低级烷基,低级烷氧基,等等。芳烷基包括苄基,苯乙基,萘甲基,萘乙基,联苯甲基,苯丙基等等,并且芳烷基可以有一个或多个取代基。在芳烷基上的取代基包括羟基,卤原子,低级烷基,低级烷氧基,等等。这些取代基可以连结在芳烷基的芳基上或其亚烷基上。当前面说的环烷基,环氨基,芳基或芳烷基有二个或多个取代基时,这种取代基可以是相同的或不同的。卤原子包括氟,氯,溴,及碘原子。
当式(Ⅰ)化合物中的Z代表羧基或四唑基时,它可形成碱金属或碱土金属的盐,如,钠盐,钾盐,钙盐,镁盐等;铵盐及胺盐,如N-甲基葡萄糖胺盐,乙醇胺盐等。同样,式(Ⅰ)化合物中R1或R2代表单或二低级烷氨基或环氨基时它可与无机酸(如盐酸,硫酸等)或有机酸形成酸加成盐。
下列式(Ⅰ′)代表了式(Ⅰ)化合物的一类较好化合物。
其中X代表卤原子,A代表氢原子,卤原子,低级烷基或低级烷氧基。
上面式(Ⅰ′)中,当X代表氯原子,A代表氢原子,2-氯原子,2-甲基或4-甲氧基时,为一类更好的化合物。
本发明的化合物能用下列a)至e)方法之一来制备,这取决于式(Ⅰ)化合物中取代基的定义。
在上式中,R1,R2,Y1,Y2,及n定义如上述,R5代表低级烷氧羰基或羟基;Q代表卤原子。
用式(Ⅱ)化合物与式(Ⅲ)化合物反应能制备式(Ⅰa)化合物,用量为每摩尔式(Ⅱ)化合物用式(Ⅲ)化合物1至1.5摩尔,反应在有机溶剂如二甲基甲酰胺和丙酮中进行,在碱金属或碱土金属碳酸盐或氢氧化物的存在下,如碳酸钾,氢氧化钠,氢氧化钾等,它们的用量为每摩尔式(Ⅱ)化合物用1至2摩尔上述碱。反应可在室温(如1至30°)至100℃左右进行,反应0.5至24小时。溶剂的一般用量为式(Ⅱ)化合物量的5至100倍(以重量计)。
在上式中,R1,R2,Y1,Y2,n,及Q的定义如上述。
按Journal of Medicinal Chemistry,21卷,437-442页(1978)所描述的已知方法由式(Ⅱ)化合物与式(Ⅵ)化合物反应来制备式(Ⅴ)化合物。然后,式(Ⅴ)化合物能与氢化叠氮的金属盐如叠氮钠,在氯化铵存在下,在有机溶剂如二甲基甲酰胺中,在50至100℃下反应0.5至24小时,来制备式(Ⅰb)化合物。氢化叠氮的金属盐及氯化铵用量的摩尔比率为每摩尔式(Ⅴ)化合物用1-1.5摩尔。溶剂用量一般为式(Ⅴ)化合物量的5至100倍(以重量计)。
在上式中,R1,R2,Y1,Y2及n的定义如前述,R6代表低级烷基。
式Ⅰc化合物能用式(Ⅰa′)化合物与一个无机碱,如碱金属或碱土金属的氢氧化物,在水或水与有机溶剂的混合溶剂中进行反应来制备,所用有机溶剂如乙醇,甲醇,二噁烷,二甲基甲酰胺等。反应在室温至50℃进行0.5至24小时。溶剂用量一般为式(Ⅰa′)化合物量的5至10倍(以重量计)。无机碱所用摩尔比为每摩尔式(Ⅰa′)化合物用1至10摩尔碱。
制备式(Ⅰc)化合物亦可用式(Ⅰa′)化合物与三溴化硼在有机溶剂如二氯乙烷等中,在0至100℃进行反应0.5至12小时。溶剂用量一般与上面所述的量相同。三溴化硼用量的摩尔比为每摩尔式(Ⅰa′)化合物用1至10摩尔。
在上式中,R1,R2,Y1,Y2,R3,R4,n和Q的定义如前述。
式(Ⅰd)化合物可从式(Ⅰc)化合物与卤化试剂如亚硫酰氯来制备,反应可以无溶剂存在或在溶剂如氯仿,二氯甲烷,1,2-二氯乙烷中进行,在室温至100℃反应30分钟到12小时。溶剂用量一般为式(Ⅰc)化合物量的5至100倍(以重量计)。卤化试剂用量为式(Ⅰc)化合物的等摩尔量或过量。
所得到的式(Ⅰd)化合物与胺NHR3R4在有机溶剂如苯等中,在室温至50℃反应1至12小时能制备式(Ⅰe)化合物。溶剂用量一般是式(Ⅰd)化合物量的5至100倍(以重量计)。胺NHR3R4用量的摩尔比为每摩尔式(Ⅰd)化合物用1至10摩尔。
在上式中,R1,R2,Y1,Y2,Z及n的定义如前述。
式(Ⅰg)化合物,可用式(Ⅰf)化合物催化还原来制备。反应在适当的有机溶剂如甲醇,乙醇等中,有催化剂如氧化铂(Ⅳ),钯碳等存在时,按照Jikken Kagaku Koza,21卷(第二集),175页中描述的已知方法进行。催化还原反应可以在室温至50℃进行直至氢吸收完全。溶剂用量一般为式(Ⅰe)化合物量的5至200倍(以重量计)。所用催化剂量为每份重量的式(Ⅰe)化合物用0.01至0.1份的催化剂。
在上面描述的反应中用作原料的式(Ⅱ)化合物,按照其取代基的定义,能用下面f)及g)的方法来制备。
在上式中,R1,Y1及Y2的定义如前述;R21代表低级烷基,取代的或未取代的环烷基,取代的或未取代的芳基,或取代的或未取代的芳烷基。
式(Ⅵ)化合物能与式(Ⅶ)化合物在有机溶剂如1,2-二氯乙烷中,有无水氯化铝存在时进行反应来制备式(Ⅷ)化合物。然后式(Ⅷ)化合物在吡啶及六氢吡啶存在下,按照在化学文摘,46卷500d中描述的方法,与式(Ⅸ)化合物反应来制备式(Ⅹ)化合物。式(Ⅹ)化合物中当R1是氢原子时即为式(Ⅹa)化合物,也能用式(Ⅷ)化合物与甲酸乙酯在氢化钠或钠的存在下,按照化学文摘,49卷,13981a或Journal of Society India Research,113卷,347-348页(1952)中描述的已知方法进行反应来制备。在此反应中,有时产生式(Ⅷ′)付产物。式(Ⅷ′)付产物在140到170℃加热能转变成式(Ⅹa)化合物。这样得到的式(Ⅹ)化合物能与无水氯化铝在非极性有机溶剂,如苯中,在大约50至100℃反应制备式(Ⅱa)化合物。
在上式中,R1,Y1,及Y2定义如上述;R22代表单或二低级烷氨基或取代的或未取代的环氨基。
式(Ⅵ)化合物,当有无水氯化铝存在时,可与乙酰氯反应,制备式(Ⅺ)化合物。然后此化合物可按合成(Synthesis)卷11,901-903页(1979)中所描述的已知方法,与式(Ⅻ)化合物反应,制备式(ⅩⅢ)化合物。所得式(ⅩⅢ)化合物可与溴反应得到式(ⅩⅣ)化合物,然后此化合物可与式(ⅩⅤ)化合物反应,制备式(ⅩⅥ)化合物。式(ⅩⅥ)化合物可与氢溴酸反应,制备式(Ⅱb)化合物。
在f)方法中用作原料的式(Ⅶ)化合物,可由式(ⅩⅦ)化合物与亚硫酰氯反应制得,如下所示
(ⅩⅦ)
其中R21定义如上述。
本发明的式(Ⅰ)化合物及其盐类有极佳的促尿酸尿活性,利尿活性以及抗高血压活性,因此可作为药物应用。
本发明的化合物的药理作用在下面实验中描述。在这些实验中,用了下列试验化合物
(a):〔(5-氯-4-氧代-3-苯基-4H-1-苯并吡喃基-7)氧〕乙酸
(b):〔(5-甲基-4-氧代-3-苯基-4H-1-苯并吡喃基-7)氧〕乙酸
(c):{〔5-氯-3-(2-氯苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸
(d):{〔5-氯-3-(2-甲基苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸
(e):〔(3-苄基-5-氯-4-氧代-4H-1-苯并吡喃基-7)氧〕乙酸
1)利尿活性及排钠活性:
将体重150至250克雄性大鼠禁食过夜,次晨,给予口服或(1)25毫升/千克的生理盐水(对照组)或(2)悬浮在0.5重量%的羧甲基纤维素中的试验化合物,将给药后5个小时的尿收集起来,测出尿量及钠浓度。从试验组减去对照组的数值来计算每一参数。所得结果示于下列表1中。
表 1
试验 排尿量的 尿中钠Na+
化合物 动物数 剂量 增加 的增加量
(毫克/千克) (△毫升/千克) (△uEq)
(a) 7 300 51.8**1220**
(b) 7 300 23.6**987**
(c) 7 300 41.0**1015**
(d) 7 300 49.6**1196**
(e) 7 300 37.9**967**
噻苯氧酸 7 300 10.2*353.4**
*P<0.05,与对照组相比。**P<0.01,与对照组相比。
从表1显然可见,本发明的化合物与噻苯氧酸相比呈现出较高的利尿作用和利钠作用。
2)促尿酸尿的活性:
将体重150至250克的雄性大鼠禁食过夜,次晨给予口服或(1)25毫升/千克的生理盐水(对照组),或(2)悬浮于0.5重量%的羧甲基纤维素中的试验化合物。在给试验化合物60分钟后,收集30分钟的尿液。然后,在麻醉下从颈动脉取血,用酶法测定在尿及血清中尿酸的浓度。另一方面,用雅费氏(Jaffe′s)方法测定尿及血清中肌酸的浓度,以获得尿酸的分段排泄量。试验组的分段排泄量除以对照组的分段排泄量计算出尿酸排泄的百分比。所得结果如下示于表2。
表 2
试验
化合物 动物数 剂量 尿酸排泄量的%
(毫克/千克)
(a) 7 100 136**
(b) 7 100 66**
(c) 7 100 36**
(d) 7 100 56**
(e) 7 100 39**
噻苯氧酸 7 200 38**
*P<0.05,与对照组相比;**P<0.01,与对照组相比
从表2显然可见,本发明的化合物与噻苯氧酸相比呈现出更优的促尿酸尿的活性。
3)抗高血压活性
按照Seyle等人在American Heart Journal,37卷,1009页(1949)中所述的方法,将体重120至150克的4周龄的雄性大鼠,皮下注射DOCA(醋酸去氧皮质酮),并喂以1%生理盐水使产生高血压。每日一次将试验化合物喂给高血压的大鼠,共4星期。从喂药开始,每星期用尾套法量动物的血压。所得结果示于下列表3。
表 3
试验 抗高血压活性(△mmHg)
化合物 动物数 剂量 1星期后 2星期后 3星期后
毫克/千克
(a) 7 100 13.7*37.0**49.0**
(b) 7 100 10.0**17.9**15.0
(c) 7 100 13.6*20.7**29.3**
(d) 7 100 12.1 14.3*15.7
(e) 7 100 6.2 28.7**39.4**
噻苯氧酸 7 300 23.6**35.0 44.3
*P<0.05,与对照组相比;**P<0.01,与对照组相比
从对照组的收缩压减去试验组的收缩压,即得表3中的抗高血压活性(△mmHg)。
从表3显然可见,本发明化合物比噻苯氧酸呈现出较高的抗高血压活性。
从以上结果明显可见,和已知的有代表性的化合物相比,本发明的化合物呈现出优越的促尿酸尿的,利尿的及抗高血压的活性。
本发明的化合物的毒性低,式(Ⅰ)典型化合物的急性毒性(LD50)示于下列表4中。
表 4
试验化合物 LD50
(口服毫克/千克,大鼠)
(a) 1021
(b) 936
(c) 1412
本发明化合物可以口服或不经肠胃给药。本发明化合物的口服剂量,成人(体重约50千克)一般为每天在10毫克至200毫克范围之间。
含有本发明化合物的药物制剂包括片剂,胶囊,粉剂,颗粒等等。这些制剂能用常规方法来制造,用合适的添加剂如乳糖,玉米淀粉,晶状纤维素,聚乙烯醇,羧甲基纤维素钙,硬脂酸镁,滑石粉等等。
用下面的参考实例及实例更详细地对本发明加以阐明,但须知本发明并不局限于此。
参考实例1
1)1-(2-氯-6-羟基-4-甲氧基)苯基-2-(2-甲基苯基)-1-乙酮的合成
将390克无水氯化铝及38克氯化锌悬浮在4升1,2-二氯乙烷中,并在0℃搅拌悬浮液30分钟。将含有483克5-氯-1,3二甲氧基苯的400毫升1,2-二氯乙烷溶液加入到上述悬浮液中。将含有470克2-甲基-苯乙酰氯的400毫升1,2-二氯乙烷溶液,在1.5小时期间内,滴加入上述混合液中,同时同冰及氯化钠冷却,将温度保持在-10℃。滴加完毕后,室温搅拌反应混合物1小时,然后在70℃再搅拌1小时。将反应混合物倒入含有盐酸的冰水中并用氯仿提取。氯仿层用水洗,用硫酸钠干燥,在减压下蒸馏以除去溶剂。残留物用苯重结晶,得到380克标题化合物其熔点为107至108℃
2)5-氯-7-甲氧基-3-(2-甲基苯基)-4-氧代-4H-1-苯并吡喃的合成。
将上面得到的化合物303克溶于1升1,4-二噁烷中,并将1.3升甲酸乙酯加入其中。在冰冷却及搅拌下将113克60%氢化钠分小批加入混合液中。混合液在40℃加温3小时。将反应混合物倒入含有盐酸的冰水中,并用氯仿提取。氯仿层用水洗,用硫酸钠干燥,并减压蒸馏以除去溶剂。将残留物在160℃减压加热1小时,然后用苯重结晶,得到250克标题化合物,其熔点为159至160℃。
3)5-氯-7-羟基-3-(2-甲基苯基)-4-氧代-4H-1-苯并吡喃的合成
将上面得到的化合物225克悬浮于2.5升苯中,将300克无水氯化铝加入其中,然后迴流1小时。冷却后,将1.5升石油醚加入反应混合物中,静置过夜。用倾析法移去有机层。将冰水加至残留物中,激烈搅拌混合物。过滤收集不溶的晶体,用热水洗,干燥,得到标题化合物,其熔点在290℃以上。
参考实例2-12
以参考实例1的同样方法制备下列化合物。
参考实例编号 R1R2Y1Y2熔点
(℃)
2 H Cl H >290
3 H F H
4 H CH3H 247-248
5 H CH3H 228-230
6 H Cl H
7 H Cl H 297-300
8 H Cl H >300
9 H Cl H
10 H Cl H 290-292
11 H Cl H 170-172
12 H Cl H 240-241
(分解)
参考实例13
1) 1-(2-氯-6-羟基-4-甲氧基)苯基-3-甲基-1-丁酮的合成
以参考实例1-1)的同样方法制备标题化合物
2) 5-氯-3-异丙基-7-甲氧基-4-氧代-4H-1-苯并吡喃的合成
将44克上面得到的化合物溶于230毫升甲酸乙酯中,将124克钠丝加到溶液中去,然后在室温搅拌3小时。当钠完全溶解后,将反应混合物加热至60℃并在该温度搅拌2小时。将反应混合物倒入含盐酸的冰水中,分离出有机层。水层用氯仿提取。有机层和氯仿层合并,相继用水及饱和氯化钠水溶液洗,用硫酸钠干燥。减压蒸馏除去溶剂,残留物在160℃减压加热1小时。残留物用苯重结晶,得到17.6克标题化合物,其熔点为177℃至179℃
3) 5-氯-3-异丙基-7-羟基-4-氧代-4H-1-苯并吡喃的合成
从上面2)得到的化合物,用参考实例1-3)的同样方法制备标题化合物。熔点:256-260℃(分解)
参考实例14
5-氯-3-环戊基-7-羟基-4-氧代-4H-1-苯并吡喃的制备方法和参考实例13的一样。熔点:282-284℃
参考实例15
1) 1-(2,3-二氯-6-羟基-4-甲氧基)-苯基-2-苯基-1-乙酮的合成
以参考实例1-1)的同样方法制备标题化合物。熔点:179-180℃
2) 5,6-二氯-7-甲氧基-4-氧代-3-苯基-4H-1-苯并吡喃的合成
将包括28.4克由1)得到的化合物,173毫升原甲酸乙酯,230毫升干燥吡啶,9毫升干燥六氢吡啶的混合物迴流4小时。将反应混合物倒入含有盐酸的冰水中,不溶解的物质用二氯甲烷提取。有机层用水洗并用硫酸钠干燥。减压蒸馏除去溶剂,残留物用硅胶柱色谱法处理。得到的粗结晶从苯中重结晶,得14.3克标题化合物,
熔点为216-218℃
3) 5,6-二氯-7-羟基-4-氧代-3-苯基-4H-1-苯并吡喃的合成
从上面2)得到的化合物,以参考实例1-3)的同样方法制备标题化合物。熔点:290℃以上
参考实例16至21
以参考实例15的同样方法制备了下列化合物。
参考实例编号 R1R2Y1Y2熔点
(℃)
16 H CH3H 252-253
17 H Cl H >290
18 H Cl H >290
19 H Cl CH3>300
20 H Cl H 288-289
21 H I H 268-270
参考实例22
1) 5-氯-7-甲氧基-2-甲基-3-(2-甲基苯基)-4-氧代-4H-1-苯并吡喃的合成
将17.6克按参考实例1-1)制备的1-(2-氯-6-羟基-4-甲氧基)苯基-2-(2-甲基苯基)-1-乙酮溶解在150毫升干燥吡啶中,并将6.5毫升干燥六氢吡啶及75克原甲酸乙酯加到溶液中,然后迴流7小时。冷却后,将反应混合物倒入稀盐酸中,并用乙酸乙酯提取。有机层以硫酸钠干燥,并减压蒸馏除去溶剂。残留物用硅胶柱色谱法处理。所得粗结晶用乙醇重结晶。得3.0克标题化合物,熔点为138-140℃。
2) 5-氯-7-羟基-2-甲基-3-(2-甲基苯基)-4-氧代-4H-1-苯并吡喃的合成
从上面1)得到的化合物,以参考实例1-3)的同样方法制备标题化合物。
参考实例23
以参考实例22的同样方法制备5-氯-7-羟基-2-甲基-3-苯基-4-氧代-4H-1-苯并吡喃。熔点:300℃以上。
参考实例24
1) 2-氯-6-羟基-4-甲氧基苯乙酮的合成
将46.4克磨细的无水氯化铝及4.74克氯化锌加入到460毫升1,2-二氯乙烷中,然后搅拌30分钟。在冰冷却下,加入含有60克5-氯-1,3-二甲氧基苯的150毫升1,2-二氯乙烷溶液。在30分钟内将27.3克乙酰氯滴加入反应混合物中,同时温度保持在-10至-15℃。加完后,在0℃继续搅拌2小时,然后在70℃再搅拌1.5小时。待反应混合液冷却后,倒入含盐酸的冰水中,用氯仿提取,氯仿层用硫酸钠干燥,并减压浓缩。残留物用石油醚重结晶,得到45.0克标题化合物,混有副产物4-氯-2-羟基-6-甲氧基-苯乙酮。
2) 1-(2-氯-6-羟基-4-甲氧基)苯基-3-二甲基氨基-2-丙烯-1-酮的合成
将44克上面得到的化合物溶于44毫升二甲基甲酰胺二甲基缩醛中,溶液在60℃搅拌30分钟。减压蒸馏除去过剩的二甲基甲酰胺二甲基缩醛,残留物以硅胶柱色谱纯化,得到26克标题化合物的粗结晶。
3) 3-溴-5-氯-7-甲氧基-4-氧代-4H-1-苯并吡喃的合成
将上面得到的26克化合物溶于260毫升氯仿中。该溶液冷却至-10至-15℃,搅拌并滴加入含有5.24毫升溴的5毫升氯仿溶液。再继续在0℃搅拌30分钟。加水,继续搅拌,用氯仿提取反应混合物。氯仿层以硫酸钠干燥,减压浓缩。残留物用苯重结晶,得8.4克标题化合物,熔点为176-177℃
4) 5-氯-7-甲氧基-4-氧代-3-六氢吡啶基-4H-1-苯并吡喃的合成
将上面得到的化合物2.8克溶于20毫升六甲基磷酰胺中,加入5.7毫升六氢吡啶,在室温搅拌2天。将反应混合物倒入冰水中,过滤收集沉出的结晶。用硅胶柱色谱处理粗结晶,得到2.8克标题化合物,熔点为122-125℃
5) 5-氯-7-羟基-4-氧代-3-(1-六氢吡啶基)-4H-1-苯并吡喃氢溴酸盐的合成。
将从上面得到的2.8克化合物悬浮在130毫升48%(重量比)氢溴酸中,在150℃搅拌悬浮液6小时。反应混合物冷却,过滤收集沉出的结晶,用水洗,干燥后得3.3克标题化合物。
实例1
{〔5-氯-3-(2-甲基苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸乙酯的合成
将114克5-氯-7-羟基-3-(2-甲基苯基)-4-氧代-4H-1-苯并吡喃悬浮于1升丙酮中,加入60.4克无水碳酸钾及73.0克溴乙酸乙酯,然后迴流1.5小时。冷却后,过滤除去不溶物,滤液减压浓缩。用乙醇重结晶残留物,得132克标题化合物,熔点为122至123℃
实例2至24
以实例1的同样方法制备下列化合物。
实例编号 R1R2Y1Y2熔点
(℃)
2 H Cl H 130-131
3 H Cl Cl
4 H CH3H 127-129
5 H Cl H
6 H Cl H
7 H Cl H
8 H F H 109-110
9 H Cl H
10 H Cl CH3
11 H Cl H
12 H CH3H 99-100
13 H CH3H
14 H Cl H 117-118
15 H Cl H 166-168
实例编号 R1R2Y1Y2熔点
(℃)
16 H Cl H 186-187
17 H Cl H 142-143
18 H Cl H 188-190
19 H Cl H 123-125
20 H Cl H 114-115
21 H I H 155-156
22 CH3Cl H 122-123
23 CH3Cl H 99-100
24 H Cl H 109-111
实例25
{〔4-氧代-3-苯基-5-三氟甲基-4H-1-苯并吡喃基-7〕氧}乙酸乙酯的合成
将9.5克铜粉及30毫升六甲基磷酰胺放入不锈钢制的反应管中,在干冰丙酮冷却下,经一封闭系统加入6毫升三氟甲基碘。将混合物加热到125℃并在该温度搅拌2.5小时。冷却后,加入3.5克{〔5-碘-4-氧代-3-苯基-4H-1-苯并吡喃基-7〕氧}乙酸乙酯。通氮气于液面上方,混合物在45℃搅拌12小时。将反应混合物倒入500毫升苯-乙酸乙酯混合液(1∶1体积比)中,然后加入500毫升冰水,接着搅拌30分钟。通过硅藻土过滤,除去生成的沉淀物,滤液用水洗,用硫酸钠干燥。减压蒸馏除去溶剂,用硅胶柱色谱法处理残留物。所得粗品以乙醇重结晶,得到2.65克标题化合物,熔点为139至140℃。
实例26
{〔5-氯-3-(4-甲氧基苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸乙酯的合成
加热将5.5克{〔5-氯-3-(4-羟基苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸乙酯溶入150毫升丙酮中,再加入4.8克无水碳酸钾。将3.4毫升碘甲烷加到溶液中,然后回流2小时。冷却后,减压蒸馏除去溶剂。将水加到残留物中,用乙酸乙酯提取不溶物。有机层用硫酸钠干燥,减压蒸馏除去溶剂。残留物用乙醇-氯仿重结晶,得5克标题化合物,熔点为121至122℃。
实例27及28
以实例26的同样方法制备下列化合物。
实例编号 R1R2Y1Y2熔点
(℃)
EXAMPLE29
实例29
{〔5-氯-3-(2-甲基苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸的合成
将132克{〔5-氯-3-(2-甲基苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸乙酯悬浮在1.2升乙醇中,在室温将0.53升1N氢氧化钠水溶液缓慢地滴入悬浮液中,在室温搅拌3小时。滤去不溶物,用水冷却并搅拌下将滤液用盐酸酸化。连续在室温搅拌过夜。过滤收集沉出的结晶,用水洗,干燥,得到105克标题化合物,熔点为191至192℃
核磁共振谱:δppm(DMSO-d6,TMS):
2.16(3H,s),4.94(2H,s),
7.1-7.3(4H,m),8.20(1H,s)
实例30至53
以实例29的同样方法制备下列化合物。
核磁共振谱
实例编号 R1R2Y1Y2熔点 δppm(DMSO-d6,TMS)
(℃)
7.2-7.6(5H,m),8.26(1H,s)
(分解) 8.33(1H,s)
6.88(1H,d),6.86(1H,d),
7.2-7.6(5H,m),8.20(1H,s)
7.4-7.7(4H,m),8.40(1H,s)
8.35(1H,s)
35 H -CH(CH3)2Cl H 172-174 1.14(6H,d),2.6-3.2(1H,m),
4.86(2H,s),7.02(2H,s),
7.93(1H,s)
7.25(2H,dd),7.58(2H,dd),
8.39(1H,s)
6.95(1H,m),7.20-7.60(5H,m),
8.25(1H,s)
4.89(2H,s),7.08(2H,s),
8.04(1H,s)
7.11(1H,s),7.20-7.60(5H,m),
8.31(1H,s)
7.3-7.7(4H,m),
8.32(1H,s),
4.70(2H,s),6.79(2H,s),
7.10-7.40(4H,m),
7.74(1H,s)
(CDCl3in place of DMSO-d6)
6.90(1H,s),6.96(1H,s),
7.30-7.65(4H,m),
8.22(1H,s)
核磁共振谱
实例编号 R1R2Y1Y2熔点 NMR δppm (DMSO-d6,TMS)
(℃)
43 H Cl H 171-173 4.90(2H,s),7.13(2H,s),
7.10-7.50(4H,m),
8.30(1H,s)
7.01(2H,s),7.20(5H,s),
8.06(1H,s)
45 H Cl H >300 4.86(2H,s),6.76(2H,d),
7.04(2H,s),7.20(5H,s),
8.14(1H,s)
6.92(2H,dd),7.06(2H,s),
7.40(2H,d),8.21(1H,s)
7.07(2H,s),6.80-7.50(4H,m),
8.10(1H,s)
4.87(2H,s),6.73(1H,d),
6.76(1H,s),7.02(1H,d),
7.07(2H,s),8.05(1H,s)
7.12(2H,s),7.2-7.6(4H,m),
8.05(1H,s)
6.95-7.06(2H),7.16(5H,s),
7.90(1H,s)
7.03(2H,s),
7.10-7.50(5H,m)
7.06(2H,s),
7.00-7.33(4H,m)
(盐酸盐) 3.1-3.4(4H,m),
4.71(2H,s),6.66(1H,d),
7.01(1H,d),7.80(1H,s)
实例54
{〔5-氯-3-(2-羟基苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸的合成
将1.7克{〔5-氯-3-(2-羟基苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸乙酯溶于100毫升干燥二氯甲烷中,溶液用干冰-丙酮冷却。将3毫升三溴化硼分小批多次加到冷却的溶液中,将所形成的混合物迴流3小时,冷却后,减压蒸馏去溶剂,将稀盐酸加到残留物中。过滤收集沉出的结晶,用水洗,空气干燥,用乙醇重结晶,得到1.0克标题化合物,熔点为188至189℃(分解)
核磁共振谱δppm(DMSO-d6,TMS)
4.87(2H,S),6.65-6.90(2H,m),7.07(2H,S)
6.95-7.30(2H,m),8.10(1H,S),9.22(1H,S)
实例55
{〔5-氯-2,3-二氢-4-氧代-3-苯基-4H-1-苯并吡喃基-7〕氧}乙酸的合成
将1克{〔5-氯-4-氧代-3-苯基-4H-1-苯并吡喃基-7〕氧}乙酸加热溶于200毫升甲醇中,将50毫克氧化铂(Ⅳ)加入溶液中。在吸收等摩尔氢后,过滤除去铂催化剂。蒸馏除去滤液中的甲醇,残留物用氯仿重结晶,得到0.4克标题化合物,熔点171至173℃
核磁共振谱δppm(DMSO-d6,TMS)
4.11(1H,dd),4.6-5.0(4H,m),6.58(1H,d)
6.75(1H,d),7.30(5H br.S)
实例56
{〔5-氯-3-(2-氯苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙腈的合成
将1。4克5-氯-3-(2-氯苯基)-7-羟基-4-氧代-4H-1-苯并吡喃溶于50毫升丙酮中并将0.7克无水碳酸钾,0.38克氯乙腈及0.15克碘化钾加入该溶液中,随后回流8小时。将水加入反应混合物中,过滤收集沉出的结晶。用乙醇重结晶,得到1.4克标题化合物,熔点为174至175℃。
2){〔5-氯-3-(2-氯苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧甲基}四唑的合成
将1.2克{〔5-氯-3-(2-氯苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙腈溶于60毫升二甲基甲酰胺中。将0.26克叠氮钠,0.21克氯化铵加到溶液中,并将混合物在100至110℃反应12小时。将反应混合物倒入含有盐酸的冰水中,过滤收集沉出的结晶,用水洗,干燥,得到标题化合物1.1克,熔点为192至195℃
核磁共振谱 δppm(DMSO-d6,TMS):
5.64(2H,S),7.16-7.56(6H,m),8.25(1H,S)
鉴于本发明被详细地,且用有关具体实例加以描述,技术熟练的人员显然可以在不背离其精神及范围的情况下对它作出各种改变和修改。
勘 误 表
Claims (8)
1、具有下述通式的苯并吡喃衍生物及其医药上可用的盐类,
其中:
R1及R2各代表氢原子,低级烷基,取代的或未取代的环烷基,单或二低级烷氨基,取代的或未取代的环氨基,取代的或未取代的芳基,或取代的或未取代的芳烷基;
Y1及Y2各代表氢原子,低级烷基,卤原子或三卤甲基;
Z代表羧基,低级烷氧羰基,四唑基,羟基或-CONR3R4,其中R3及R4各代表氢原子或低级烷基;
2、按照权利要求1的苯并吡喃衍生物及其医药上可用的盐类,其中R2代表苯基,它可以被一个卤原子,一个低级烷基或一个低级烷氧基取代,R1代表氢原子,Y1代表卤原子,Y2代表氢原子,n代表1,Z代表羧基。
3、按照权利要求1的〔(5-氯-4-氧代-3-苯基-4H-1-苯并吡喃基-7)氧〕乙酸及其医药上可用的盐类。
4、按照权利要求1的〔(5-甲基-4-氧代-3-苯基-4H-1-苯并吡喃基-7)氧〕乙酸及其医药上可用的盐类。
5、按照权利要求1的{〔5-氯-3-(2-氯苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸及其医药上可用的盐类。
6、按照权利要求1的{〔5-氯-3-(2-甲基苯基)-4-氧代-4H-1-苯并吡喃基-7〕氧}乙酸及其医药上可用的盐类。
7、按照权利要求1的〔(3-苄基-5-氯-4-氧代-4H-1-苯并吡喃基-7)氧〕乙酸及其医药上可用的盐类。
8、制备式(Ⅰ)苯并吡喃衍生物及其医药上可用的盐的方法,
其中:
R1及R2各代表氢原子,低级烷基,取代的或未取代的环烷基,单或二低级烷氨基,取代的或未取代的环氨基,取代的或未取代的芳基,或取代的或未取代的芳烷基;
Y1及Y2各代表氢原子,低级烷基,卤原子或三卤甲基;
Z代表羧基,低级烷氧羰基,四唑基,羟基或-CONR3R4,其中R3及R4各代表氢原子或低级烷基;
但须排除下述两种组合,一种组合是其中Y1,Y2和R2各代表氢原子,R1代表苯基,n代表1,Z代表羧基或烷氧羰基,键 代表双键,另一种组合是其中Y1,Y2,及R1各代表氢原子,R2代表苯基,n代表1,Z代表羧基或烷氧羰基,键 代表双键,
该方法包括:
1)式(Ⅱ)化合物与式(Ⅲ)化合物反应,
式(Ⅱ)中R1,R2,Y1及Y2定义如上述;
式(Ⅲ)中n定义如上述,R5代表低级烷氧羰基或羟基,Q代表卤原子;
2)式(Ⅴ)化合物与氢化叠氮的金属盐反应;
式(Ⅴ)中R1,R2,Y1,Y2和n定义如上述;
3)式(Ⅰa′)化合物与无机碱或三溴化硼反应
式(Ⅰa′)中R1,R2,Y1,Y2,及n定义如上述,R6代表低级烷基;
4)式(Ⅰd)化合物与胺NHR3R4反应,其中R3和R4定义如上述,
式(Ⅰd)中R1,R2,Y1,Y2,n及Q定义如上述;或
5)将式(Ⅰf)化合物在催化剂存在下进行还原,
式(Ⅰf)中R1,R2,Y1,Y2,Z及n定义如上述。
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JP129420/86 | 1986-06-04 |
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US (1) | US4841076A (zh) |
EP (1) | EP0248420B1 (zh) |
JP (1) | JPH0681750B2 (zh) |
KR (1) | KR930009793B1 (zh) |
CN (1) | CN1020100C (zh) |
AT (1) | ATE67491T1 (zh) |
AU (1) | AU611083B2 (zh) |
CA (1) | CA1319694C (zh) |
DE (1) | DE3773053D1 (zh) |
DK (1) | DK164862C (zh) |
ES (1) | ES2044867T3 (zh) |
GR (1) | GR3003372T3 (zh) |
IE (1) | IE60203B1 (zh) |
NZ (1) | NZ220540A (zh) |
PH (1) | PH24882A (zh) |
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CN101679341B (zh) * | 2007-06-07 | 2012-06-06 | 东亚制药株式会社 | 作为粘液分泌刺激剂的3',4',5-三甲氧基黄酮衍生物、其制备方法以及包含该化合物的药物组合物 |
CN103044377A (zh) * | 2013-01-08 | 2013-04-17 | 中国药科大学 | 具有抑制黄嘌呤氧化酶和降尿酸作用的化合物以及组合物 |
CN105431150A (zh) * | 2013-08-27 | 2016-03-23 | 中国中化股份有限公司 | 含取代苄氧基的醚类化合物作为制备抗肿瘤药物的应用 |
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WO1994014477A1 (en) * | 1992-12-21 | 1994-07-07 | Mallinckrodt Medical, Inc. | Polyhydric phenol compounds |
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- 1987-06-02 CA CA000538633A patent/CA1319694C/en not_active Expired - Fee Related
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- 1987-06-04 AU AU73815/87A patent/AU611083B2/en not_active Ceased
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101679341B (zh) * | 2007-06-07 | 2012-06-06 | 东亚制药株式会社 | 作为粘液分泌刺激剂的3',4',5-三甲氧基黄酮衍生物、其制备方法以及包含该化合物的药物组合物 |
CN103044377A (zh) * | 2013-01-08 | 2013-04-17 | 中国药科大学 | 具有抑制黄嘌呤氧化酶和降尿酸作用的化合物以及组合物 |
CN105431150A (zh) * | 2013-08-27 | 2016-03-23 | 中国中化股份有限公司 | 含取代苄氧基的醚类化合物作为制备抗肿瘤药物的应用 |
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CA1319694C (en) | 1993-06-29 |
AU611083B2 (en) | 1991-06-06 |
KR880000421A (ko) | 1988-03-25 |
EP0248420B1 (en) | 1991-09-18 |
YU101787A (en) | 1988-10-31 |
ES2044867T3 (es) | 1994-01-16 |
DE3773053D1 (de) | 1991-10-24 |
GR3003372T3 (en) | 1993-02-17 |
CN1020100C (zh) | 1993-03-17 |
KR930009793B1 (ko) | 1993-10-11 |
DK281687D0 (da) | 1987-06-02 |
DK281687A (da) | 1987-12-05 |
ATE67491T1 (de) | 1991-10-15 |
IE60203B1 (en) | 1994-06-15 |
PH24882A (en) | 1990-12-26 |
YU46209B (sh) | 1993-05-28 |
IE871462L (en) | 1987-12-04 |
AU7381587A (en) | 1987-12-10 |
DK164862C (da) | 1993-01-18 |
JPS63107971A (ja) | 1988-05-12 |
ZA873745B (en) | 1988-10-26 |
EP0248420A3 (en) | 1988-10-12 |
JPH0681750B2 (ja) | 1994-10-19 |
NZ220540A (en) | 1990-04-26 |
DK164862B (da) | 1992-08-31 |
US4841076A (en) | 1989-06-20 |
EP0248420A2 (en) | 1987-12-09 |
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