FI94133B - Förfarande för framställning av griseolinsyraderivat som används som läkemedel - Google Patents
Förfarande för framställning av griseolinsyraderivat som används som läkemedel Download PDFInfo
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- FI94133B FI94133B FI861655A FI861655A FI94133B FI 94133 B FI94133 B FI 94133B FI 861655 A FI861655 A FI 861655A FI 861655 A FI861655 A FI 861655A FI 94133 B FI94133 B FI 94133B
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- 239000002253 acid Substances 0.000 title claims abstract description 114
- 238000000034 method Methods 0.000 title claims description 68
- 238000002360 preparation method Methods 0.000 title claims description 28
- 230000008569 process Effects 0.000 title claims description 17
- 239000003814 drug Substances 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 319
- 238000006243 chemical reaction Methods 0.000 claims description 358
- 239000002904 solvent Substances 0.000 claims description 145
- -1 benzhydryl group Chemical group 0.000 claims description 99
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 69
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 52
- 230000002829 reductive effect Effects 0.000 claims description 49
- 125000006239 protecting group Chemical group 0.000 claims description 48
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 43
- 239000007858 starting material Substances 0.000 claims description 29
- 239000007864 aqueous solution Substances 0.000 claims description 27
- 125000002252 acyl group Chemical group 0.000 claims description 26
- 239000002585 base Substances 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 150000002148 esters Chemical class 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000003277 amino group Chemical group 0.000 claims description 19
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
- 150000001408 amides Chemical class 0.000 claims description 15
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 15
- 150000007523 nucleic acids Chemical class 0.000 claims description 15
- 108020004707 nucleic acids Proteins 0.000 claims description 15
- 102000039446 nucleic acids Human genes 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 13
- 125000001931 aliphatic group Chemical group 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 150000001350 alkyl halides Chemical class 0.000 claims description 10
- 150000007530 organic bases Chemical class 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 9
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 8
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 5
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 150000007514 bases Chemical class 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 150000002978 peroxides Chemical class 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 3
- 150000008049 diazo compounds Chemical class 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910014033 C-OH Inorganic materials 0.000 claims 1
- 229910014570 C—OH Inorganic materials 0.000 claims 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 1
- 229910017604 nitric acid Inorganic materials 0.000 claims 1
- AYNNSCRYTDRFCP-UHFFFAOYSA-N triazene Chemical compound NN=N AYNNSCRYTDRFCP-UHFFFAOYSA-N 0.000 claims 1
- IAPZXUKYTCQQFE-QZKDJMESSA-N (2r,3r,3as,5s)-2-(6-aminopurin-9-yl)-5-[carboxy(hydroxy)methyl]-3-hydroxy-3,3a-dihydro-2h-furo[3,2-b]furan-5-carboxylic acid Chemical class NC1=NC=NC2=C1N=CN2[C@H]1[C@H](O)[C@@H]2O[C@](C(O)=O)(C(O)C(O)=O)C=C2O1 IAPZXUKYTCQQFE-QZKDJMESSA-N 0.000 abstract description 9
- 235000000346 sugar Nutrition 0.000 abstract description 9
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 abstract description 6
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 abstract description 6
- 239000003112 inhibitor Substances 0.000 abstract description 6
- IAPZXUKYTCQQFE-UHFFFAOYSA-N Griseolic acid Natural products NC1=NC=NC2=C1N=CN2C1C(O)C2OC(C(O)=O)(C(O)C(O)=O)C=C2O1 IAPZXUKYTCQQFE-UHFFFAOYSA-N 0.000 abstract description 4
- 150000003212 purines Chemical class 0.000 abstract description 4
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 165
- 239000000243 solution Substances 0.000 description 126
- 239000000203 mixture Substances 0.000 description 124
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 107
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 103
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 60
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
- 239000003153 chemical reaction reagent Substances 0.000 description 42
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 37
- 238000004821 distillation Methods 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- 230000002411 adverse Effects 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 26
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
- 235000017557 sodium bicarbonate Nutrition 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 238000001914 filtration Methods 0.000 description 19
- 239000000843 powder Substances 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 17
- 238000001704 evaporation Methods 0.000 description 17
- 125000005843 halogen group Chemical group 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- 230000008020 evaporation Effects 0.000 description 16
- 239000000463 material Substances 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 150000001298 alcohols Chemical class 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 12
- 150000001204 N-oxides Chemical class 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 10
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 230000002378 acidificating effect Effects 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 150000002170 ethers Chemical class 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 125000004665 trialkylsilyl group Chemical group 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 8
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 8
- 239000003638 chemical reducing agent Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 230000002441 reversible effect Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 description 8
- 239000007868 Raney catalyst Substances 0.000 description 7
- 229910000564 Raney nickel Inorganic materials 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 238000005858 glycosidation reaction Methods 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000002198 insoluble material Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 150000008282 halocarbons Chemical class 0.000 description 5
- 239000012433 hydrogen halide Substances 0.000 description 5
- 229910000039 hydrogen halide Inorganic materials 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
- 235000010288 sodium nitrite Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 229960000278 theophylline Drugs 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 239000012670 alkaline solution Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 231100000989 no adverse effect Toxicity 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 125000005270 trialkylamine group Chemical group 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000002841 Lewis acid Substances 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 125000004849 alkoxymethyl group Chemical group 0.000 description 3
- 150000003973 alkyl amines Chemical class 0.000 description 3
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 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
- 238000010511 deprotection reaction Methods 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
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- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000007933 aliphatic carboxylic acids 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
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 1
- 125000005262 alkoxyamine group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000003974 aralkylamines Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- YXASHNSJWVCWQQ-UHFFFAOYSA-N bromomethyl propanoate Chemical compound CCC(=O)OCBr YXASHNSJWVCWQQ-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 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
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
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- 230000004663 cell proliferation Effects 0.000 description 1
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- 229910052801 chlorine Inorganic materials 0.000 description 1
- SMJYMSAPPGLBAR-UHFFFAOYSA-N chloromethyl acetate Chemical compound CC(=O)OCCl SMJYMSAPPGLBAR-UHFFFAOYSA-N 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000001245 hexylamino group Chemical group [H]N([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- IHYNKGRWCDKNEG-UHFFFAOYSA-N n-(4-bromophenyl)-2,6-dihydroxybenzamide Chemical compound OC1=CC=CC(O)=C1C(=O)NC1=CC=C(Br)C=C1 IHYNKGRWCDKNEG-UHFFFAOYSA-N 0.000 description 1
- MXSMRDDXWJSGMC-UHFFFAOYSA-N n-(6-oxo-3,7-dihydropurin-2-yl)acetamide Chemical compound N1C(NC(=O)C)=NC(=O)C2=C1N=CN2 MXSMRDDXWJSGMC-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 150000004967 organic peroxy acids Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- AFDMODCXODAXLC-UHFFFAOYSA-N phenylmethanimine Chemical compound N=CC1=CC=CC=C1 AFDMODCXODAXLC-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000005389 trialkylsiloxy group Chemical group 0.000 description 1
- 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 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Claims (3)
1 L> R39= 15 R6 RS r22°0C 20 r^ooc-Q·0 OH R iiyiB dar R5, R6, R22, R23, R29, R1 är definierade som ovan och R39 är en sub-25 stltuerad metylengrupp, sedan, vid behov, avlägsnas alkoxi- eller aralkyloxigruppen -OR1 med en ätgärd som beskrivits tidigare för att fä en förening med formeln (LVIII) li 35 94133 nh2 Λ"> L_>°^
10 R200Cx/_y7 B2300C—<W p29 R livnil 15 dä.r R5, R6, R22, R23, R29, R30 är definierade som ovan, vid behov kan 6-aminogruppen ändras till en hydroxigrupp genom att lata föreningen reagera med en nitrit med en atgärd som beskrivits ovan för att fa en förening med formeln (LIX) 20 OH r^jC > r33 = N/^H'^'I R6 R5 R^OOC /“W R%C-/N QH \29 κ I LIX) 35 94133 där R5, R6, R29, R22, R23 och R39 defineras som ovan, och därefter vid behov, avlägsnas den substltuerade metylengruppen som skyddar 2-aminogruppen i purinbasen tillsammans med de bägge karboxiskyd-5 dande grupperna R22 och R23 pä ett sätt som beskrivits tidigare för att far en förening med formeln (LVI) OH
10 I rV> HjirN^u 15 r6 „5 -fLVI) hooc^O WK-C0 OH
20 R29 som är en förening med formel (I), där R5, R6 är definerar som ovan, R29 25 är R2, R3 och R4 är karboxigrupper, R1 är en OH-grupp, R7 är en OH-grupp och R8 är en NH2-grupp, eller efter vid behov bildas ett salt, ester eller en amid av föreningen (LVI). 30
1. Förfarande för framställning av griseolinsyraderivat med formeln (I) som är användbara som läkemedel, i vilken formel (I) 5 «7 . tl) R6 SlS I i^<k 15 sVT_/ ι^0/Λι V R 20 R1 och R2 avser grupper med formeln -OR9, där R9 avser en väteatom eller en benzoylgrupp; R3 och Ra är oberoende av varandra karbamoylgrupper och karboxigrupper och 25 lägre alkoxikarbonylgrupper, varvid nämnda karboxylgrupper valbart är substituerade med en benzhydrylgrupp; bäde R5 och R6 avser väteatomer eller de bildar tillsammans en extra kol-kol-bindning mellan de kolatomer tili vilken de är fästa; 30 R7 avser en OH-grupp eller en grupp med formeln -NR10 R11, där R10, R11 oberoende av varandra avser väteatomer, lägre alkoxi-grupper som är substituerade med en fenylgrupp, hydroxigrupper, lägre alkylgrupper och benzhydrylgrupper; R8 är en grupp med formeln NR1ZR13, SH, OH, 35 94133 där R12 och R13 avser dimetylaminometylengruppen, väteatomer eller ena gruppen är en väteatom och den andra är en (^-020 alifatisk acylgrupp; 5 eller för framställning av farmaceutiskt acceptabla salter eller estrar av dessa föreningar, kännetecknat därav, att griseolinsyra (A) hh2 & 15 o HOOC HOOC-C'0 0H 20 °H (AI far reagera sä att hydroxi- och karboxigrupperna av denna skyddas; och dä 25 sä önskas ändras aminogruppen i 6-positionen av griseolinsyran tili en hydroxigrupp genom att läta griseolinsyra eller en skyddad griseolinsyra reagera raed ett sait av salpetersyrlighet, varefter i förfarande alternativ a) 30 först, vid behov, reduceras den extra kol-kol-bindningen som bildas av grupperna R5 och R6, sedan ändras nukleinsyrabasen i 1'-positionen tili en alkanoyloxigrupp 35 genom att läta den ovan erhällna föreningen reagera med i) svavelsyra il » 94133 eller trifluormetansulfonsyra, ii) med en lägre karboxylsyra och iii) dess anhydrid för att fä en förening med formeln (XVIII) 5 0 . , V« R° R5 . * l0 R^oci-^y R2300C—(^O^OR24 g2a (XYIII1 15 där R5 och R6 är väteatomer R2a avser en väteatom eller en skyddad hydroxigrupp; 20 R22 och R23 är likadana eller olika grupper och bägge tvä avser en karbo-xiskyddande grupp; R2* avser en hydroxiskyddande grupp; 25 R28 avser en lägre alkylgrupp; varefter man med sockerderivatet av formeln (XVIII) utför en glykoside-ringsreaktion genom att läta denna reagera med ett derivat av purin som 30 fungerar som en trimetylsilylerad nukleinsyrabas för att fä en förening med formeln (XXVI) 35 94133 Υ1 5 y^'O'V* „ UkN (XXVI1 10 r“0QC„/\ 7 R23OOC—OR21, R2a 15 där R5, R6, R2a, R22, R23 och R24 är definierade som ovan och Y1 och Y2 är definierade som R7 respektiv R8, vilken förening är en förening med formeln I, där grupperna med formlerna R2200C och R2300C avser grupper som definierats som grupperna R3 och R* utom karbamoylgrupper och karboxigrup-20 per, varefter man vid behov later föreningen med formeln (XXVI) reagera sa att de skyddande grupperna försvinner för att fä en förening med formeln (XXVII) • 25 Ä> 30 r c uxvti) R6 R5 n hooc
35 HOOC-ζο 0H II 94133 där Y1, Y2, R5, R6 är definerade som ovan och R29 avser samma som R2 ovan, vilken förening (XXVII) är en förening med formeln I, där R3 och R4 är karboxigrupper; 5. förfarandealternativ b) lösgörs den skyddande gruppen frän den skyddade formen av föreningen (A) för att fä en förening (XXIX)
10 K «2 Cx> N "
15 R6 R5 r22°0Cn/—¢/ R2300C-\ 0 OH 20 \r29 (XXIX) där R5, R6, R22, R23 och R29 är definerade som ovan, 25 varefter föreningen med formeln (XXIX) fär reagera med en peroxid tili en N1-oxid med formeln (XXX) N H? '1> H R6 R5 . 35 r22ooc λ-W R2300C—(^° OH p29 (XXX) där R5, R6, R22, R23 och R29 är definerade som ovan, 94133 den erhällna föreningen (XXX) fär reagera med en lägre alkylhalogenid eller aralkylhalogenid tili en N1-alkoxi- eller N1-aralkyloxiförening med 5 formeln (XXXI) «% JL. CI> R6 R5 0 15 r22ooc } R2300C-\ 0 OH p 29 (XXXI) 20 där R5, R6, R22, R23 och R29 är definierade som ovan och R30 är en alkyl-grupp eller en aralkylgrupp, 1 il 35 25 den erhällna föreningen med formeln (XXXI) fär reagera med en alkalisk vattenlösning med resultatet att ringen av föreningen med formeln (XXXI) öppnas och resulterar i avlägsnande av en formylgrupp och ocksä de skyddande grupperna R22 och R23, vilka är, med en reaktion som beskrivs ovan, substituerade med nya skyddande grupper R31 och R32 för att fä en 30 förening med formeln (XXXII), 94133 Λ Τ2 r6 r5 o R%cJ V / «32ooc>° \29 K (XXXII) där R5, R6, R29 och R30 är definierade som ovan och R31 och R32 avser 15 väteatomer eller karboxiskyddande grupper, förening med formeln (XXXII) som erhalls reduceras katalytiskt för att avlägsna alkyl- eller aralkylgruppen R30 för att fä en förening med formeln (XXXIV) 20 HH2 Η0-Η<ί^γ^Ν\ t. 25 H2N ^ r5 r5 r32°0C-< 0 OH " (XXXIV) 35 där R5, R6, R29, R31 och R32 är definierade som ovan, 94135 U8 förening med formeln (XXXIV) far reagera med koldisulfid som resulterar i ring bildning för att fä en förening med formeln (XXXV) nh2 nc'> R6 R5 , R31ooc R32OOC-\ 0 OH No29
15 IXXXV) som är en förening med formeln (I), där grupperna med formlerna R31OOC och R32OOC avser grupper som definieras för grupperna R3 och R4, R5 och R6 är definierade som ovan, R7 avser en NH2-grupp och R8 avser en SH-grupp och R1 avser en OH-grupp och R29 avser en grupp R2, 20 i förfarandealternativ c) later man föreningen med formeln (XXX) som framställdes i föregäende alternativ b) reagera med en cyanohalid till en polycyklisk förening med 1 25 formeln (XXXVIII) X0 . - s(V> R6 R5 0 ” R2300C—( 0 OH R29 (XXXVIII1 där R5, R6, R22, R23 och R29 är definierade som ovan, 94133 den erhällna föreningen med formeln (XXXVIII) för reagera med en basisk förening tili en l^-cyano-N^oxid med formeln (XXXIX) 5 n NHCX 1° R6 R5 . "22°oc>/~tv R2300C—OH > (XXXIX) 20 föreningen med formeln (XXXIX) far reagera med en lägre alkylhalogenid eller aralkylhalogenid tili en l^-alkoxi- eller N1-aralkyloxiförening (XL) R6 R5 Q R 2200C^“W
35 R2300C-( o oh A29 (XL) där R5, R6, R22, R23, R29 och R30 är definierade som ovan, 15° 94133 varefter föreningen med formeln (XL) behandlas med ett alkali i lösnings-medel vid ett pH-värde pä 12-13, varvid pyrimidinringen öppnas (och 5 varvid, beroende pä reaktionsförhällandena ocksä de karboxiskyddande grupperna kan avlägsnas), och en ring bildas igen, vilket resulterar i en förening med formel (XLI), där karboxigrupperna är oskyddade (med andra ord bäde R31 och R32 avser väteatomer) 10 NHOR30 rV> R6 R5 g
20 R31OOC\ i R3200C-C° oh R (XLI) 25 och där R5, R6, R29 eller R30 är definierade som ovan, 30 eller tili en förening med formeln (XLIII), varvid de karboxiskyddande grupperna kvarblir 35 li 94133 NHOR30 R6 R5 „
22 Hr 7 R2200C^/ \_/ ÄC-\7° OH nw (XUII) 15 och R5, R6, Rzz, R23, R29, R30 är definierade som ovan, 20 varefter vid behov alkyl- eller aralkylgruppen R30 avlägsnas frän före-ningen med formeln (XLI) och substitueras med en väteatom genom kataly-tisk reduktion för att fär en förening med formeln (XLII)
25 NHOH Ä> H^N N " 30 fi ς R5 R5 0 R3ToOC r32ooc -H° oh 35 \23 K (XLII) 94133 där R5, R6, R29, R31 och R32 är definierade som ovan, som är en förening med formeln (I), där R7 är NR10,Rn, där R10 är väte och R11 är en OH-grupp, R8 är en NH2-grupp och R31OOC och R32OOC är R3 respektive R4, R29 är R2 och R1 är en OH-grupp, 5 i förfarandealternativ d) substitueras alkoxi- eller aralkyloxigruppen -OR30 i föreningen med formeln (XLI) med en väteatom genom att behandla föreningen med en aktiv 10 metall i närvaro av att ett lösningsmedel (och de karboxiskyddande grupperna avlägsnas och/eller de ändras tili amider och/eller de ändras till salter och/eller tili en annan karboxiskyddande förening) för att fä en förening med formeln (XLIV) 15 nh2 N iT"\
20. II / H2N'^K^'N R6 R5 0 • 25 r31o°c J~w R32ooc-<^oxoh R" , (XLIV) 30 som i andra avseenden är samma förening med formeln (I) som föreningene (XLII) utom att R7 är en NH2-grupp, 35 vid behov ändras föreningen med formeln (XLIV) tili en monohydroxiföre-ning med formeln (XLVIII) eller en dehydroxiförening med formeln (XLIX) li 94133 genom att läta denna reagera med en diazoförening eller en triazenföre-ning HH2 aX> HO H " 06 φ R^OOC R%C—OH is R (XLVffl) som i andra avseenden är samma förening med formeln (I) som (XLIV), men R8 är en OH-grupp, 20 OH aXv> : « ho^h^h R6 R5 R32OOC-<10 OH R29 ixux) 35 som i andra avseenden är samma förening med formeln (I) som (XLVIII), men R7 är en OH-grupp, 94133 i förfarandealternativ e) later man föreningen med formeln (XLIII) ovan reagera med en acetal eller aldehyd av dimetylformamid och en organisk bas för att skydda aminogrup-5 pen i 2-positionen med en substituerad metylengrupp för att fä en före-ning med formeln (LVII)
10 HNOR1
2. Förfarande enligt patentkrav 1, kännetecknat därav, att startmaterialen och reaktionförhällandena väljes för att framställa: 6-desamino-6-hydroxi-2-amino-2-dehydro-4',5'-dihydrogriseolsyra eller ett farmaceutiskt acceptabelt salt eller en ester därav. II 35 94133
3. Förfarande enligt patentkrav 1, kännetecknat därav, att startmaterialen och reaktionförhällandena väljes för att framställa: 2-amino-6-desamino-6-hydroxigriseolsyra eller ett farmaceutiskt accepta-belt sait eller en ester därav. 5
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI921238A FI90427C (sv) | 1985-04-19 | 1992-03-20 | Som mellanprodukter användbara N'-alkoxi- eller N'-aralkyloxi-N6-cyano-griseolinsyraderivat |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8213285 | 1985-04-19 | ||
| JP8213285 | 1985-04-19 | ||
| JP9198985 | 1985-04-27 | ||
| JP9198785 | 1985-04-27 | ||
| JP9198985 | 1985-04-27 | ||
| JP9198785 | 1985-04-27 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI861655A0 FI861655A0 (sv) | 1986-04-18 |
| FI861655A FI861655A (sv) | 1986-10-20 |
| FI94133B true FI94133B (sv) | 1995-04-13 |
| FI94133C FI94133C (sv) | 1995-07-25 |
Family
ID=27303820
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI861655A FI94133C (sv) | 1985-04-19 | 1986-04-18 | Förfarande för framställning av griseolinsyraderivat som används som läkemedel |
Country Status (11)
| Country | Link |
|---|---|
| US (5) | US5498819A (sv) |
| EP (1) | EP0214708B1 (sv) |
| KR (1) | KR930007385B1 (sv) |
| AT (2) | ATE129501T1 (sv) |
| CA (1) | CA1267409A (sv) |
| DE (3) | DE3650297T2 (sv) |
| DK (1) | DK167878B1 (sv) |
| ES (4) | ES8802054A1 (sv) |
| FI (1) | FI94133C (sv) |
| HK (2) | HK1005739A1 (sv) |
| NO (1) | NO169901C (sv) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1331380C (en) * | 1987-12-02 | 1994-08-09 | Mitsuo Yamazaki | Griseolic acid monoesters, their preparation and use |
| US5091431A (en) * | 1988-02-08 | 1992-02-25 | Schering Corporation | Phosphodiesterase inhibitors |
| US4971972A (en) * | 1989-03-23 | 1990-11-20 | Schering Corporation | Phosphodiesterase inhibitors having an optionally substituted purine derivative portion and a benzo- or cyclopenta-furan portion |
| JPH04112889A (ja) * | 1990-09-04 | 1992-04-14 | Kyowa Hakko Kogyo Co Ltd | Ｋｓ―５０５誘導体 |
| US5866702A (en) * | 1996-08-02 | 1999-02-02 | Cv Therapeutics, Incorporation | Purine inhibitors of cyclin dependent kinase 2 |
| CA2238283C (en) * | 1997-05-30 | 2002-08-20 | Cell Pathways, Inc. | Method for identifying compounds for inhibition of neoplastic lesions, pharmaceutical compositions from such compounds and uses of such compounds and compositions for treating neoplastic lesions |
| US6558787B1 (en) * | 1999-12-27 | 2003-05-06 | Kodak Polychrome Graphics Llc | Relation to manufacture of masks and electronic parts |
| EP1312363A1 (en) * | 2001-09-28 | 2003-05-21 | Pfizer Products Inc. | Methods of treatment and kits comprising a growth hormone secretagogue |
| US7342884B2 (en) * | 2002-03-13 | 2008-03-11 | Harmonic, Inc. | Method and apparatus for one directional communications in bidirectional communications channel |
| US20040043014A1 (en) * | 2002-08-30 | 2004-03-04 | Hiroyoshi Moriyama | Platelet aggregation inhibitor and supplement food effective for inhibiting platelet aggregation |
| US20050130971A1 (en) * | 2003-08-22 | 2005-06-16 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and phosphodiesterase inhibitor for the treatment of ischemic mediated central nervous system disorders or injury |
| GB0601951D0 (en) | 2006-01-31 | 2006-03-15 | Novartis Ag | Organic compounds |
| US20110190192A1 (en) * | 2009-12-15 | 2011-08-04 | Cebix Inc. | Methods for treating erectile dysfunction in patients with insulin-dependent diabetes |
| KR102204379B1 (ko) | 2013-08-12 | 2021-01-19 | 사우디 베이식 인더스트리즈 코포레이션 | 올레핀 중합용 촉매 시스템 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4035370A (en) * | 1971-11-03 | 1977-07-12 | Richter Gedeon Vegyeszeti Gyar Rt. | Alkaloid esters |
| US4167565A (en) * | 1976-11-08 | 1979-09-11 | Abbott Laboratories | Adenosine-5'-carboxamides and method of use |
| JPS5668695A (en) * | 1979-11-10 | 1981-06-09 | Sankyo Co Ltd | Enzyme inhibitor griseolic acid and its preparation |
| US4803271A (en) * | 1982-02-01 | 1989-02-07 | Syntex (U.S.A.) Inc. | Process for preparing guanine derivatives |
| JPS6094992A (ja) * | 1983-10-28 | 1985-05-28 | Sankyo Co Ltd | グリゼオ−ル酸誘導体 |
| US4783532A (en) * | 1983-10-28 | 1988-11-08 | Sankyo Company Limited | Process for preparing griseolic acid derivatives |
| JPS60246396A (ja) * | 1984-05-22 | 1985-12-06 | Sankyo Co Ltd | 酵素阻害物質ジヒドロデスオキシグリゼオ−ル酸及びその塩類 |
| US4788190A (en) * | 1986-12-24 | 1988-11-29 | Schering Corporation | 2,4,4-tri- and 2,2,4,4-tetra substituted-1,3-dioxolane antifungal, antiallergy compounds |
| US5091431A (en) * | 1988-02-08 | 1992-02-25 | Schering Corporation | Phosphodiesterase inhibitors |
| US4966912A (en) * | 1989-09-29 | 1990-10-30 | Uniroyal Chemical Company, Inc. | Fungicidal 3-imino-1,4-oxathiins |
| EP0492430A1 (en) * | 1990-12-27 | 1992-07-01 | Nippon Kayaku Kabushiki Kaisha | Oxetanocin derivative having imidazole base group |
| JPH0639472B2 (ja) * | 1991-12-21 | 1994-05-25 | メルシャン株式会社 | アゾール誘導体 |
-
1986
- 1986-04-18 NO NO861533A patent/NO169901C/no not_active IP Right Cessation
- 1986-04-18 DK DK179586A patent/DK167878B1/da not_active IP Right Cessation
- 1986-04-18 FI FI861655A patent/FI94133C/sv not_active IP Right Cessation
- 1986-04-19 ES ES554178A patent/ES8802054A1/es not_active Expired
- 1986-04-19 KR KR1019860003049A patent/KR930007385B1/ko not_active IP Right Cessation
- 1986-04-21 CA CA000507140A patent/CA1267409A/en not_active Expired - Fee Related
- 1986-04-21 DE DE3650297T patent/DE3650297T2/de not_active Expired - Fee Related
- 1986-04-21 EP EP86303000A patent/EP0214708B1/en not_active Expired
- 1986-04-21 DE DE8686303000T patent/DE3667470D1/de not_active Expired - Fee Related
- 1986-04-21 AT AT88121487T patent/ATE129501T1/de not_active IP Right Cessation
- 1986-04-21 DE DE3650429T patent/DE3650429T2/de not_active Expired - Fee Related
- 1986-04-21 AT AT88121486T patent/ATE121097T1/de not_active IP Right Cessation
-
1987
- 1987-05-21 ES ES557559A patent/ES8801665A1/es not_active Expired
- 1987-05-21 ES ES557558A patent/ES8801664A1/es not_active Expired
- 1987-05-21 ES ES557560A patent/ES8801666A1/es not_active Expired
-
1993
- 1993-09-30 US US08/130,154 patent/US5498819A/en not_active Expired - Fee Related
-
1994
- 1994-10-06 US US08/319,413 patent/US5760042A/en not_active Expired - Fee Related
-
1995
- 1995-05-09 US US08/437,632 patent/US5532369A/en not_active Expired - Fee Related
- 1995-05-09 US US08/437,634 patent/US5556975A/en not_active Expired - Fee Related
- 1995-05-09 US US08/437,644 patent/US5616600A/en not_active Expired - Fee Related
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1998
- 1998-06-03 HK HK98104840A patent/HK1005739A1/xx not_active IP Right Cessation
- 1998-06-03 HK HK98104838A patent/HK1005738A1/xx not_active IP Right Cessation
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Owner name: SANKYO COMPANY LIMITED |