CN1025855C - 制备氧代酞嗪基乙酸及同系物方法 - Google Patents
制备氧代酞嗪基乙酸及同系物方法 Download PDFInfo
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- CN1025855C CN1025855C CN90102797A CN90102797A CN1025855C CN 1025855 C CN1025855 C CN 1025855C CN 90102797 A CN90102797 A CN 90102797A CN 90102797 A CN90102797 A CN 90102797A CN 1025855 C CN1025855 C CN 1025855C
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- formula
- oxo
- oxophthalazinyl
- compound
- acetate
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- 238000000034 method Methods 0.000 title claims description 13
- 235000011054 acetic acid Nutrition 0.000 title 1
- 150000001243 acetic acids Chemical class 0.000 title 1
- 239000000543 intermediate Substances 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 150000003512 tertiary amines Chemical class 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 37
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 12
- -1 nitrophenyl compound Chemical class 0.000 abstract description 10
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 abstract description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 abstract 2
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical group CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 abstract 2
- LMEZRNAEUMFZDX-UHFFFAOYSA-N acetic acid;ethanethioamide Chemical compound CC(O)=O.CC(N)=S LMEZRNAEUMFZDX-UHFFFAOYSA-N 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 description 4
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 102000016912 Aldehyde Reductase Human genes 0.000 description 3
- 108010053754 Aldehyde reductase Proteins 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003288 aldose reductase inhibitor Substances 0.000 description 3
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 2
- 206010007749 Cataract diabetic Diseases 0.000 description 2
- 208000002249 Diabetes Complications Diseases 0.000 description 2
- 206010012655 Diabetic complications Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- 208000027472 Galactosemias Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 201000007025 diabetic cataract Diseases 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 210000003497 sciatic nerve Anatomy 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- QHJAJOLAWRTRIH-UHFFFAOYSA-N tert-butyl 2-(5-oxo-6h-pyrido[2,3-d]pyridazin-8-yl)acetate Chemical compound C1=CN=C2C(CC(=O)OC(C)(C)C)=NNC(=O)C2=C1 QHJAJOLAWRTRIH-UHFFFAOYSA-N 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- BWTZGCWATMESND-UHFFFAOYSA-N 1-chloro-2,3,5-trifluoro-4-methyl-6-nitrobenzene Chemical compound CC1=C(F)C(F)=C(Cl)C([N+]([O-])=O)=C1F BWTZGCWATMESND-UHFFFAOYSA-N 0.000 description 1
- TZGFQIXRVUHDLE-UHFFFAOYSA-N 1-chloro-2-nitro-4-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1Cl TZGFQIXRVUHDLE-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- JEEDFPVACIKHEU-UHFFFAOYSA-N 2-(2h-indazol-3-yl)acetic acid Chemical compound C1=CC=CC2=C(CC(=O)O)NN=C21 JEEDFPVACIKHEU-UHFFFAOYSA-N 0.000 description 1
- VMVSSVCXGNALAH-UHFFFAOYSA-N 2-(chloromethyl)-5-(trifluoromethyl)-1,3-benzothiazole Chemical compound FC(F)(F)C1=CC=C2SC(CCl)=NC2=C1 VMVSSVCXGNALAH-UHFFFAOYSA-N 0.000 description 1
- BVBLIUFTALMDFD-UHFFFAOYSA-N 2-[3-[(7-chloro-1,3-benzothiazol-2-yl)methyl]-4-oxophthalazin-1-yl]acetic acid Chemical compound O=C1C2=CC=CC=C2C(CC(=O)O)=NN1CC1=NC2=CC=CC(Cl)=C2S1 BVBLIUFTALMDFD-UHFFFAOYSA-N 0.000 description 1
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 1
- XAEBTCPOZVEMHR-UHFFFAOYSA-N 2-methylpropan-2-ol;potassium Chemical compound [K].CC(C)(C)O XAEBTCPOZVEMHR-UHFFFAOYSA-N 0.000 description 1
- HYPUMFMZZIWURX-UHFFFAOYSA-N C(C)(=S)NN1N=C(C2=CC=CC=C2C1=O)CC(=O)OCC Chemical compound C(C)(=S)NN1N=C(C2=CC=CC=C2C1=O)CC(=O)OCC HYPUMFMZZIWURX-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- ZWZUFQPXYVYAFO-UHFFFAOYSA-N Tert-butyl (triphenylphosphoranylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC(C)(C)C)C1=CC=CC=C1 ZWZUFQPXYVYAFO-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- MCQOWYALZVKMAR-UHFFFAOYSA-N furo[3,4-b]pyridine-5,7-dione Chemical compound C1=CC=C2C(=O)OC(=O)C2=N1 MCQOWYALZVKMAR-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000005181 nitrobenzenes Chemical class 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- GETAINHXWXSIFS-UHFFFAOYSA-N tert-butyl 2-(8-oxo-7h-pyrido[2,3-d]pyridazin-5-yl)acetate Chemical compound C1=CC=C2C(CC(=O)OC(C)(C)C)=NNC(=O)C2=N1 GETAINHXWXSIFS-UHFFFAOYSA-N 0.000 description 1
- UMUDOLOGMVLQJD-UHFFFAOYSA-N tert-butyl 2-[5-oxo-6-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]pyrido[2,3-d]pyridazin-8-yl]acetate Chemical compound O=C1C2=CC=CN=C2C(CC(=O)OC(C)(C)C)=NN1CC1=NC2=CC(C(F)(F)F)=CC=C2S1 UMUDOLOGMVLQJD-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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Abstract
本文介绍了具有苯并噻唑侧链的氧代酞嗪基乙酸的制备方法，即使氧代酞嗪基硫代乙酰胺乙酸酯与硫化氢和具有反应基团的硝基苯基化合物反应，通过硫代乙酰胺基的环合，形成苯并噻唑侧链。所述氧代酞嗪基硫代乙酰胺按下法制备：在叔胺存在下，使相应的氰甲基氧代酞嗪基乙酸酯与硫化氢反应。可用同样方法制备类似物吲唑和氧代吡啶并哒嗪酮乙酸，具有噻唑吡啶基侧链的氧代酞嗪基、吲唑和氧代吡啶并哒嗪酮乙酸。
Description
本发明涉及制备氧代酞嗪基乙酸及同系物的方法和中间体，该类化合物是醛糖还原酶抑制剂，可用于预防或减轻与糖尿病相关的慢性并发症。
在欧洲专利申请公开号222576中公开了用本发明方法可制备醛糖还原酶抑制剂。在欧洲专利申请公开号0295051中，公开了本发明方法用腈类作为起始物料。
西德专利申请DE 3337859号涉及苯并噻唑衍生物的制备，即将2-取代的苯胺或硝基苯化合物与硫代酰胺衍生物环合。
本发明涉及制备式Ⅰ化合物的方法，式Ⅰ如下：
式中X和Y分别为CH或N;Z是N或CR6;A是共价键或C＝0;R1是C1-6烷基;R3和R4可相同或不同，它们是氢、氟、氯、溴、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4烷硅基、C1-4烷基亚硫酰基、C1-4烷基磺酰基或硝基，或者R3和R4连接在一起为C1-4烷烃二氧基;R5和R6可相同或不同，它们是氢，氟，氯，溴，三氟甲硫基，硝基，氰基，C1-4烷基，C1-4烷氧基，C1-4烷硫基，C1-4烷基亚硫酰基，C1-4烷基磺酰基，三氟甲基，三氟甲氧基或三氟乙酰基，其前提是X或Y是N，而R3和R4可相同或不同，它们是氢，CF3或C1-4烷基。所述制备方法包括：在硫化氢存在下，使式ⅡB化合物与式Ⅲ化合物反应，式ⅡB
如下
式中W是-CN或
X、Y、A、R1、R3和R4的定义同上，式Ⅲ如下
式中Z和R5的定义同上，B是F、Cl、Br、I、SCN或OSO2R7，其中R7是C1-4烷基、苯基、甲苯基、硝苯基或溴苯基;该反应的前提是W为CN时，则在叔胺存在下进行。
取代基R3和R4不是三氟甲基或C1-4烷基时，不能直接连接，或者不能直接位于X或Y（当它们不是氮时）的邻位。
在本发明优选实施例中，当W是
时，该反应可在叔胺存在下进行。
本发明还涉及式Ⅳ化合物。
式中W是
或-CN;R1是C1-6烷基;R3和R4可相同或不同，它们是氢、氟、氯、溴、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基亚硫酰基、C1-4烷基磺酰基或硝基，或者R3和R4连接在一起为C1-4烷二氧基;X和Y分别为CH或N，A是共价键或C＝0，其前提是X或Y是N时，R3和R4可相同或不同，它们是三氟甲基或C1-4烷基，而且当W为CN和A为C＝0时，X和Y均不是CH。
本发明还涉及式Ⅵ化合物：
式中X和Y分别为CH或N;Z是N或CR6;R1是C1-6烷基;R3和R4可相同或不同，它们是氢、三氟甲基或C1-4烷基;R5和R6可相同或不同，它们是氢、氟、氯、溴、三氟甲基、硝基、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基亚硫酰基、C1-4烷基磺酰基、三氟甲硫基、三氟甲氧基或三氟乙酰基;其前提是X和Y均不是CH。
本发明还包括抑制醛糖还原酶活性的组合物，它包括有效量的能抑制醛糖还原酶活性的式Ⅵ化合物和药学上可接受的载体的混合物。
本发明方法示于反应路线Ⅰ中。
使式ⅡB化合物与式Ⅲ化合物反应，制备式Ⅰ化合物。一般，该反应在极性溶剂中进行。适宜的溶剂包括四氢噻吩砜（四氢噻吩-1，1-二氧化物），吡啶，二甘醇二烃基醚（例如二甘醇二乙基醚），N-甲基吡咯烷酮及它们混合物，优选的溶剂是二甲基甲酰胺。反应温度一般为约110℃至180℃，最好是溶剂的回流温度。反应压力并不严格，一般为约0.5至2个大气压，最好为常压（例如约1个大气压）。在叔胺存在下，使式中W是CN的式ⅡB化合物与式Ⅲ化合物反应，适宜的叔胺是三（C2-6）烷基胺例如三乙胺。
可在碱水溶液中水解式Ⅰ化合物，以制备式Ⅴ化合物，当R1是叔丁基时，在浓硫酸或三氟乙酸中，式Ⅴ化合物的水解更容易进行。
式中W是氰基的式ⅡB化合物可按下法制备：在碱存在下，使式ⅡA化合物与式L-CH2CN化合物反应，式中L是氯、溴、-OSO2（C1-4烷基）或-OSO2芳基，其中芳基是苯基或由C1-4烷基、卤素或硝基任意取代的萘基。适宜的碱的例子包括碱金属氢化物，例如氢化钠;碱金属碳酸盐，例如碳酸钾;碱金属氢氧化物，例如氢氧化钠或氢氧化钾;以及碱金属醇盐，例如叔丁醇钾和甲醇钠。该反应可在反应条件下是惰性的溶剂中进行，适宜的溶剂是惰性溶剂，例如二甲基甲酰胺，二甲基乙酰胺，丙酮和二甘醇二甲醚。该反应温度一般为约0℃至100℃，最佳反应温度为约40至60℃。
式中W是-C（S）NH2的式ⅡB化合物可按下法制备：在诸如三（C2-6）烷基胺的叔胺的叔胺（如三乙胺）存在下，使式中W是CN的式ⅡB化合物与硫化氢在吡啶或二甲基甲酰胺的溶剂中进行反应，该反应最好在二甲基甲酰胺中进行。反应温度一般为室温至100℃，最好为约40至60℃。
式Ⅴ的新化合物及其药物上可接受的盐可用作醛糖还原酶抑制剂，以预防和减烃慢性糖尿病并发症，例如糖尿病内障，视网膜病，肾病
和神经病。该化合物可通过各种常规给药途径例如口服、非肠道和局部给于需要治疗的患者。这些化合物的口服或非肠道给药剂量为约0.5至25mg/kg体重/日，以1.0至10mg/kg为佳，然而，施用剂量的变化需取决于接受治疗患者的病情。该化合物可单独施用或与药物上可接受载体合并使用，可采用单次剂量，也可采用多次剂量。含有式Ⅰ新化合物或其药学上可接受盐及药学上可接受载体的药用组合物可以以各种剂型给药，例如片剂、粉剂、锭剂、糖浆和注射液。
式Ⅰ化合物及其药学上可接受盐也可通过局部给药治疗糖尿病内障。眼用制剂可含浓度为约0.01-0.5%（重量），最好为0.05-0.5%（重量）的式Ⅰ化合物或其药学上可接受的盐，呈药学上可接受的溶液、混悬液或油膏剂型。浓度的变化需取决于所用的具体化合物和受治疗患者的病情。
通过许多标准的生物学或药理学试验，可以测定本发明式Ⅵ化合物作为控制慢性糖尿病并发症药物的活性。合适的试验包括（1）测量它们抑制剂分离的醛糖还原酶酶活性的能力;（2）测量它们降低或抑制急性链脲菌素化（即患糖尿病）大鼠的坐骨神经和晶状体中山梨糖醇累积的能力;（3）测量在链脲菌素诱发慢性糖尿病的鼠的坐骨神经和晶状体中已升高的山梨糖醇含量的逆转能力;（4）测量它们防止或抑制患急性半乳糖血证大鼠晶状体中半乳糖醇形成的能力;（5）测量它们延迟串半乳糖血症大鼠的内障形成和降低晶状体浊斑严重性的能力;（6）测量它们防止用葡萄糖培养分离的大鼠晶状体中山梨梨糖醇累积和内障形成的能力;（7）测量它们降低用葡萄糖培养分离的大鼠晶状体中已升高的山梨糖醇含量的能力。
下述实施例说明本发明的方法，所有m.p.均未经校正。
实施例1
3-硫代乙酰氨基-4-氧代-酞嗪-1-基乙酸乙酯
将54.2g 3-氰基甲基-4-氧代-酞嗪-1-基乙酸乙酯溶于含有1ml三乙胺的200ml二甲基甲酰胺中，将硫化氢通入该溶液中，反应温度保持于60℃。15分钟后，停止通入硫化氢，继续加热2小时，将该溶液冷却至室温，然后缓慢倒于冰水（2000ml）中，滤出粒状沉淀物，用水洗涤（2×200ml），然后空气干燥，得到标题化合物（得量为57.8g，m.p.＝149-151℃）。
实施例2
3-（5-三氟甲基苯并噻唑-2-基甲基）-4-氧代-3-H-酞嗪-1-基乙酸乙酯
方法A
将3-氰基甲基-4-氧代-酞嗪-1-基乙酸乙酯（10.84g）和催化量的三乙胺（0.2g）溶于二甲基甲酰胺（40ml）中，反应温度保持于50-55℃，将硫化氢通入该溶液中，通15分钟，停止通入后，该反应继续3小时，在此阶段，该溶液再用硫化氢饱和，将4-氯-3-硝基三氟甲苯（9.47g）加到该反应混合物中，该反应混合物立即变为浅橙色，然后加热至140℃2.5小时，冷却至室温后滴入冰水和乙醇（800ml，4∶1）的混合物中，用几滴6N盐酸将乙醇水溶液的pH值调至约2.0，过滤出生成的粒状固体，残留物用500ml乙醇-二氯甲烷混合物（3∶1）结晶，过滤收集固体，然后空气干燥，得到标题化合物（12.2g）。该母液中还含标题化合物（分析估计约含1.0g）。
方法B
将3-硫代乙酰氨基-4-氧代-酞嗪-1-基乙酸乙酯（6.1g）溶于二甲基甲酰胺（30ml）中，用硫代氢饱和该溶液，加入4-氯-3-硝基三氟甲苯（4.5g），所得溶液缓慢加热回流，达到回流温度时，将硫代氢低速通入该溶液中，继续回流4小时，然后冷却该反应混合物，倒入冰水（500ml）中，倾析分离出胶状物，用乙醇（75ml）研
磨，过滤出浅黄色粒状固体，收集沉淀物，于乙醇（200ml）中结晶，得标题化合物（4.1g）。
采用同样方法，分别利用2，3-二氯硝基苯和2，5-二氯-3-氟-硝基苯取代4-氯-3-硝基三氟甲苯，制备了3-（7-氯苯并噻唑-2-基甲基）-4-氧代-3-H-酞嗪-1-基乙酸乙酯（m.p.＝119℃）和3-（5-氯-7-氟苯并噻唑-2-基甲基）-4-氧代-3-H-酞嗪-1-基乙酸乙酯（m.p.202-204℃）。
实施例3
Ⅰ.1H-吲唑-3-基乙酸甲酯
按J.Am.Chem.Soc.，79，5245（1957）介绍的方法制备1H-吲唑-3-乙酸（1.0g）并将其溶于含有5滴浓硫酸的30ml甲醇中，回流8小时，将该反应混合物浓缩成小体积，用乙酸乙酯（20ml）稀释，有机层先用水（2×10ml）洗涤，再用碳酸氢钠液（10ml，10%）洗涤，收集乙酸乙酯层，干燥，得到标题化合物（0.8g，m.p.＝146℃）。
Ⅱ.（1-氰基甲基）-1-H-吲唑-3-基-乙酸甲酯
将氢化钠（0.58g，50%（重量）油分散体）加到1-H-吲唑-3-基乙酸甲酯（1.9g）的二甲基甲酰胺（4ml）溶液中，于室温搅拌15分钟，然后加入溶有氯代乙腈（1.9g）的二甲基甲酰胺（2ml），将该反应混合物搅拌6小时，然后倒入冰水（20ml）中，加入足量稀盐酸将pH值调至约3，收集所得沉淀物，空气干燥（得产物1.87g），m.p.＝128-134℃。
实施例4
3-（7-氯苯并噻唑-2基甲基）-4-氧代-3-H-酞嗪-1-基乙酸
将3-（7-氯苯并噻唑-2-基甲基）-4-氧代-3-H-酞嗪-1-基乙酸乙酯（800mg）溶于30ml乙醇和四氢呋喃的混合物（2∶1）
中，加入5ml 1%氢氧化钾水溶液，于室温搅拌2小时，该混合物减压浓缩，所得残留物用水（10ml）稀释，用足够量的10%盐酸将溶液pH值调至2左右，得到沉淀物，过滤收集之，空气干燥，然后于二氯甲烷（10ml）中结晶，得标题化合物（273mg），m.p.＝168℃。
同样地，将3-（5-氯-7-氟-苯并噻唑-2-基甲基）-4-氧代-3-H-酞嗪-基乙酸乙酯水解，得3-（5-氯-7-氟-苯并噻唑-2-基-甲基）-4-氧代-3-H-酞嗪-1-基乙酸（m.p.＝207-207.5℃）。
实施例5
Ⅰ.3-氧代-吡啶并[3.2-C]呋喃-1-亚基乙酸叔丁酯和3-氧代-吡啶并[2.3-C]呋喃-1-亚基乙酸叔丁酯
将市售的2，3-吡啶二羧酸酐（29.8g），（叔丁氧羰基亚甲基）三苯基正膦（75.2g）和二氯甲烷（1000ml）的混合物于室温搅拌60小时，蒸干，残留物用硅胶（2.0kg）层析，用二氯甲烷的乙酸乙酯溶液（49∶1）小心洗脱，并用薄板层析检测洗脱液，分离得两种产物，标记为A的极性较小的产物确定为E或Z3-氧代-吡啶并[2，3-C]呋喃-1-亚基乙酸叔丁酯[｀H NMR（CDCl3，250MHz）;1.5（S，9H），6.1（S，1H），7.8（dd，J＝6Hz，1H），8.40（dd，J1＝6Hz，J2＝1Hz，1H），9.1（dd，J1＝6Hz，J2＝1Hz，1H）]和E3-氧代-吡啶并[3，2-C]呋喃-1-亚基乙酸叔丁酯[｀H NMR（CDCl3，250MHz）;1.5（S，9H），6.2（S，1H），7.9（dd，J＝6Hz，1H），9.0（dd，J＝6Hz，1H），9.2（d，J＝12Hz，1H）的混合物（1∶1）。
标记为B的极性较大的产物确定为E3-氧代-吡啶并[3，2-C]呋喃-1-亚基乙酸叔丁酯和E或Z3-氧代-吡啶并[2，3-C]呋喃-1-亚基乙酸叔丁酯的混合物（1∶1）。极性较小的产物A不能
分离成纯的化合物。极性较大的产物B用硅胶（500g）再层析，用二氯甲烷的乙酸乙酯溶液（9∶1）洗脱，蒸发先馏出的馏份，得到纯的E3-氧代-吡啶并[3，2-C]呋喃-1-亚基乙酸叔丁酯（1.8g，m.p.＝113-114℃）。蒸发后馏出的馏份得纯的E或Z3-氧代-吡啶并[2，3-C]-呋喃-1-亚基乙酸叔丁酯（11.5g，m.p.＝118℃）。
Ⅱ.8-氧代-7H-吡啶并[2，3-d]哒嗪-5-基乙酸叔丁酯
将水合肼（1.3ml）谨慎地加到E3-氧代-吡啶并[3，2-C]呋喃-1-亚基乙酸叔丁酯（1.85g）的乙醇（10ml）溶液中，然后缓慢地回流1小时，浓缩涂去乙醇，残留物用水（20ml）稀释，加入足量的10%盐酸将其pH值调至约2.0，收集沉淀出的固体，空气干燥（1.36g，m.p.＝186-188℃）。
实施例6
Ⅰ.5-氧代-6H-吡啶并[2，3-d]哒嗪-8-基乙酸叔丁酯
将水合肼（10ml）滴入E或Z3-氧代-吡啶并[2，3-C]呋喃-1-亚基乙酸叔丁酯（m.p.＝118℃;10.0g）的乙醇（25ml）溶液中，将所得溶液回流10分钟，蒸发涂去乙醇，残留物用水（20ml）稀释，加入足量的10%盐酸将其pH值调至约6，过滤沉淀出的固体，将收集的固体空气干燥（8.9g，m.p.＝178-179℃）。
Ⅱ.6-（5-三氟甲基苯并噻唑-2-基-甲基）-5-氧代-6H-吡啶并[2，3-d]哒嗪-8-基乙酸叔丁酯
将5-三氟甲基-2-氯甲基苯并噻唑（0.55g）加到5-氧代-6H-吡啶并[2，3-d]哒嗪-8-基乙酸叔丁酯（0.5g）的二甲基甲酰胺（5ml）（含有0.25g叔丁醇钾）的溶液中，于室温搅拌过夜，然后倒入冰水（20ml）中，加入足量的10%盐酸将其pH值调至约5.0，收集沉淀出来的固体粗产物，经硅胶层析，用二氯甲烷/乙酸乙酯（1∶1）混合物洗脱，得到产物（0.66g，m.p.＝121-122℃）。
Claims (1)
1、制备式Ⅰ化合物的方法，式Ⅰ为
式中R1是C1-6烷基；R5和R6可相同或不同，它们是氢，氟，氯或三氟甲基，所述方法的特征在于，在硫化氢和一种叔胺存在下，使式ⅡB化合物与式Ⅲ化合物反应，式ⅡB为
式中R1的定义同上，式Ⅲ为
式中R5和R6的定义同上。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US350,997 | 1989-05-11 | ||
| US07/350,997 US4954629A (en) | 1989-05-11 | 1989-05-11 | Process and intermediates for the preparation of oxophthalazinyl acetic acids and analogs thereof |
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| CN1025855C true CN1025855C (zh) | 1994-09-07 |
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| US (1) | US4954629A (zh) |
| EP (1) | EP0397350B1 (zh) |
| JP (1) | JPH035479A (zh) |
| KR (1) | KR920006419B1 (zh) |
| CN (1) | CN1025855C (zh) |
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| AU (2) | AU618898B2 (zh) |
| BG (1) | BG50609A3 (zh) |
| CA (1) | CA2016504C (zh) |
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| DD (1) | DD294257A5 (zh) |
| DE (1) | DE69007846T2 (zh) |
| DK (1) | DK0397350T3 (zh) |
| EG (1) | EG19082A (zh) |
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| HU (1) | HU212304B (zh) |
| IE (1) | IE62591B1 (zh) |
| IL (3) | IL114271A (zh) |
| MX (2) | MX167455B (zh) |
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| NZ (1) | NZ233597A (zh) |
| PH (1) | PH26567A (zh) |
| PL (1) | PL164427B1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4996204A (en) * | 1989-05-11 | 1991-02-26 | Pfizer Inc. | Pyrido[2,3-d]pyridazinones as aldose reductase inhibitors |
| IL124236A (en) * | 1997-05-05 | 2003-01-12 | Pfizer | Pharmaceutical composition for treating or reversing diabetic cardiomyopathy comprising aldose reductase inhibitor |
| EP0982306A3 (en) * | 1998-08-21 | 2000-07-05 | Pfizer Products Inc. | Polymorph of zopolrestat monohydrate |
| US8916563B2 (en) | 2010-07-16 | 2014-12-23 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and uses thereof |
| PL3597650T3 (pl) * | 2010-07-16 | 2023-02-06 | The Trustees Of Columbia University In The City Of New York | Inhibitory reduktazy aldozy i ich zastosowania |
| CN102558184B (zh) * | 2011-12-30 | 2014-07-16 | 西南大学 | 酞嗪类衍生物的合成方法 |
| CN102702108A (zh) * | 2012-06-27 | 2012-10-03 | 上海大学 | 1,2-二氢酞嗪类化合物及其合成方法 |
| CN102863393A (zh) * | 2012-09-26 | 2013-01-09 | 上海大学 | 1,2-二氢酞嗪类化合物及其合成方法 |
| DK3757107T3 (da) | 2016-06-21 | 2023-11-27 | Univ Columbia | 4-oxo-3,4-dihydrothieno[3,4-d]pyridazinforbindelser som aldosereduktasehæmmere og metoder til anvendelse deraf |
| PT3658142T (pt) | 2017-07-28 | 2024-06-27 | Applied Therapeutics Inc | Composições e métodos para tratar galactosemia |
| CN113840825A (zh) | 2019-04-01 | 2021-12-24 | 应用治疗公司 | 醛糖还原酶抑制剂 |
| CA3136100A1 (en) | 2019-05-07 | 2020-11-12 | Stephan L. ZUCHNER | Treatment and detection of inherited neuropathies and associated disorders |
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| IE47592B1 (en) * | 1977-12-29 | 1984-05-02 | Ici Ltd | Enzyme inhibitory phthalazin-4-ylacetic acid derivatives, pharmaceutical compositions thereof,and process for their manufacture |
| DE3337859A1 (de) * | 1983-01-21 | 1984-07-26 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von benzthiazolen |
| CA1299178C (en) * | 1985-11-07 | 1992-04-21 | Banavara Lakshmana Mylari | Heterocyclic oxophtalazinyl acetic acids |
| EP0222576B1 (en) * | 1985-11-07 | 1992-03-18 | Pfizer Inc. | Heterocyclic oxophthalazinyl acetic acids |
| JPH0676391B2 (ja) * | 1987-06-09 | 1994-09-28 | フアイザー・インコーポレイテツド | ベンゾチアゾール等の複素環側鎖を有するオキソフタラジニル酢酸類の製造方法 |
| EP0322153A3 (en) * | 1987-12-21 | 1990-08-16 | Pfizer Inc. | Heterocyclic oxophtalazinyl acetic acids |
| WO1989006651A1 (en) * | 1988-01-19 | 1989-07-27 | Pfizer Inc. | 1h-indazole-3-acetic acids as aldose reductase inhibitors |
| US4996204A (en) * | 1989-05-11 | 1991-02-26 | Pfizer Inc. | Pyrido[2,3-d]pyridazinones as aldose reductase inhibitors |
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