JP6456143B2 - カテコール−ｏ−メチル転移酵素阻害剤を調製するための中間体として有用な化学的化合物 - Google Patents
カテコール−ｏ−メチル転移酵素阻害剤を調製するための中間体として有用な化学的化合物 Download PDFInfo
- Publication number
- JP6456143B2 JP6456143B2 JP2014547135A JP2014547135A JP6456143B2 JP 6456143 B2 JP6456143 B2 JP 6456143B2 JP 2014547135 A JP2014547135 A JP 2014547135A JP 2014547135 A JP2014547135 A JP 2014547135A JP 6456143 B2 JP6456143 B2 JP 6456143B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- reaction
- mixture
- product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims description 123
- 239000000543 intermediate Substances 0.000 title description 17
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 title description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 175
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 121
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 90
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 88
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 84
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 64
- 239000000203 mixture Substances 0.000 claims description 63
- 238000000034 method Methods 0.000 claims description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 46
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 45
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 44
- 235000019253 formic acid Nutrition 0.000 claims description 44
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 40
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 23
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 21
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 16
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- PPQJCISYYXZCAE-UHFFFAOYSA-N 1,10-phenanthroline;hydrate Chemical compound O.C1=CN=C2C3=NC=CC=C3C=CC2=C1 PPQJCISYYXZCAE-UHFFFAOYSA-N 0.000 claims description 11
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 claims description 10
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 claims description 10
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 238000010520 demethylation reaction Methods 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 6
- 238000006396 nitration reaction Methods 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 5
- 238000010168 coupling process Methods 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 230000017858 demethylation Effects 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 238000002955 isolation Methods 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- BVWTXUYLKBHMOX-UHFFFAOYSA-N methyl vanillate Chemical compound COC(=O)C1=CC=C(O)C(OC)=C1 BVWTXUYLKBHMOX-UHFFFAOYSA-N 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 239000000047 product Substances 0.000 description 87
- 239000000725 suspension Substances 0.000 description 65
- 238000002360 preparation method Methods 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 32
- 229960000583 acetic acid Drugs 0.000 description 29
- 239000007787 solid Substances 0.000 description 26
- 238000002425 crystallisation Methods 0.000 description 23
- 230000008025 crystallization Effects 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 238000001953 recrystallisation Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 19
- 239000012043 crude product Substances 0.000 description 18
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 17
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 17
- 230000003197 catalytic effect Effects 0.000 description 15
- 238000004821 distillation Methods 0.000 description 14
- 239000000463 material Substances 0.000 description 13
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- AEDVAGWYAKIOIM-UHFFFAOYSA-N 4-hydroxy-3-methoxy-5-nitrobenzoic acid Chemical compound COC1=CC(C(O)=O)=CC([N+]([O-])=O)=C1O AEDVAGWYAKIOIM-UHFFFAOYSA-N 0.000 description 11
- 239000008367 deionised water Substances 0.000 description 11
- 229910021641 deionized water Inorganic materials 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 9
- 229910017604 nitric acid Inorganic materials 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 238000000227 grinding Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- MIQPIUSUKVNLNT-UHFFFAOYSA-N tolcapone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 description 7
- 229960004603 tolcapone Drugs 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- MDAYSECURTYDPB-UHFFFAOYSA-N 4-hydroxy-3-methoxy-5-nitrobenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC([N+]([O-])=O)=C1O MDAYSECURTYDPB-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 102000006378 Catechol O-methyltransferase Human genes 0.000 description 5
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 5
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 5
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 5
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 229960004502 levodopa Drugs 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
- 238000010935 polish filtration Methods 0.000 description 5
- WRFGQLDAKOYZHS-UHFFFAOYSA-N 2,5-dichloro-n'-hydroxy-4,6-dimethylpyridine-3-carboximidamide Chemical compound CC1=NC(Cl)=C(C(N)=NO)C(C)=C1Cl WRFGQLDAKOYZHS-UHFFFAOYSA-N 0.000 description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003610 charcoal Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 125000002887 hydroxy group Chemical class [H]O* 0.000 description 4
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 3
- 102000003823 Aromatic-L-amino-acid decarboxylases Human genes 0.000 description 3
- 108090000121 Aromatic-L-amino-acid decarboxylases Proteins 0.000 description 3
- 229940123736 Decarboxylase inhibitor Drugs 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- -1 alkaline earth metal salts Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003954 decarboxylase inhibitor Substances 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- ASOADIZOVZTJSR-UHFFFAOYSA-N opicapone Chemical compound CC1=C(Cl)C(C)=[N+]([O-])C(Cl)=C1C1=NOC(C=2C=C(C(O)=C(O)C=2)[N+]([O-])=O)=N1 ASOADIZOVZTJSR-UHFFFAOYSA-N 0.000 description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 150000000180 1,2-diols Chemical class 0.000 description 2
- UCGWYTUBYASPFG-UHFFFAOYSA-N 2,5-dichloro-4,6-dimethylpyridine-3-carbonitrile Chemical compound CC1=NC(Cl)=C(C#N)C(C)=C1Cl UCGWYTUBYASPFG-UHFFFAOYSA-N 0.000 description 2
- AGMWEOLWLPKJFM-UHFFFAOYSA-N 4-[3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl]-2-methoxy-6-nitrophenol Chemical group [O-][N+](=O)C1=C(O)C(OC)=CC(C=2ON=C(N=2)C=2C(=NC(C)=C(Cl)C=2C)Cl)=C1 AGMWEOLWLPKJFM-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 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 2
- 239000002841 Lewis acid Substances 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000007819 coupling partner Substances 0.000 description 2
- 230000001335 demethylating effect Effects 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- ZQIHGTCQYHQBMY-UHFFFAOYSA-N methyl 4-hydroxy-3-methoxy-5-nitrobenzoate Chemical compound COC(=O)C1=CC(OC)=C(O)C([N+]([O-])=O)=C1 ZQIHGTCQYHQBMY-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000005070 ripening Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000010977 unit operation Methods 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 description 1
- CFBYEGUGFPZCNF-UHFFFAOYSA-N 2-nitroanisole Chemical compound COC1=CC=CC=C1[N+]([O-])=O CFBYEGUGFPZCNF-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- KMCLQJQHGNKJAF-UHFFFAOYSA-N CC1=CC(C)=C(C(N)=N)C=N1 Chemical compound CC1=CC(C)=C(C(N)=N)C=N1 KMCLQJQHGNKJAF-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- PVRDAVSDHWPSOF-UHFFFAOYSA-N Vanillic acid methyl ester Natural products COC(=O)C(=O)C1=CC=C(O)C(OC)=C1 PVRDAVSDHWPSOF-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 125000004408 aryl N-oxide group Chemical group 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 229940078916 carbamide peroxide Drugs 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical class C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000005661 deetherification reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 1
- 229960003337 entacapone Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- SYJRVVFAAIUVDH-UHFFFAOYSA-N ipa isopropanol Chemical compound CC(C)O.CC(C)O SYJRVVFAAIUVDH-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N nmp n-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 208000027232 peripheral nervous system disease Diseases 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 150000003007 phosphonic acid derivatives Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Neurosurgery (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161570141P | 2011-12-13 | 2011-12-13 | |
| GB1121413.7 | 2011-12-13 | ||
| GBGB1121413.7A GB201121413D0 (en) | 2011-12-13 | 2011-12-13 | Chemical compounds and processes |
| US61/570,141 | 2011-12-13 | ||
| US201261593625P | 2012-02-01 | 2012-02-01 | |
| US61/593,625 | 2012-02-01 | ||
| GBGB1201758.8A GB201201758D0 (en) | 2012-02-01 | 2012-02-01 | Chemical compounds and processes |
| GB1201758.8 | 2012-02-01 | ||
| US201261718589P | 2012-10-25 | 2012-10-25 | |
| US61/718,589 | 2012-10-25 | ||
| PCT/PT2012/000048 WO2013089573A1 (en) | 2011-12-13 | 2012-12-12 | Chemical compound useful as intermediate for preparing a catechol-o-methyltransferase inhibitor |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017207738A Division JP6721558B2 (ja) | 2011-12-13 | 2017-10-27 | カテコール−ｏ−メチル転移酵素阻害剤を調製するための中間体として有用な化学的化合物 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2015500335A JP2015500335A (ja) | 2015-01-05 |
| JP2015500335A5 JP2015500335A5 (enExample) | 2016-02-12 |
| JP6456143B2 true JP6456143B2 (ja) | 2019-01-23 |
Family
ID=48612903
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2014547135A Active JP6456143B2 (ja) | 2011-12-13 | 2012-12-12 | カテコール−ｏ−メチル転移酵素阻害剤を調製するための中間体として有用な化学的化合物 |
| JP2017207738A Active JP6721558B2 (ja) | 2011-12-13 | 2017-10-27 | カテコール−ｏ−メチル転移酵素阻害剤を調製するための中間体として有用な化学的化合物 |
| JP2019214566A Withdrawn JP2020059729A (ja) | 2011-12-13 | 2019-11-27 | カテコール−ｏ−メチル転移酵素阻害剤を調製するための中間体として有用な化学的化合物 |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017207738A Active JP6721558B2 (ja) | 2011-12-13 | 2017-10-27 | カテコール−ｏ−メチル転移酵素阻害剤を調製するための中間体として有用な化学的化合物 |
| JP2019214566A Withdrawn JP2020059729A (ja) | 2011-12-13 | 2019-11-27 | カテコール−ｏ−メチル転移酵素阻害剤を調製するための中間体として有用な化学的化合物 |
Country Status (15)
| Country | Link |
|---|---|
| US (2) | US9126988B2 (enExample) |
| EP (2) | EP2791134B1 (enExample) |
| JP (3) | JP6456143B2 (enExample) |
| BR (1) | BR112014014341A2 (enExample) |
| CA (2) | CA2858025C (enExample) |
| CY (1) | CY1122580T1 (enExample) |
| DK (1) | DK2791134T3 (enExample) |
| ES (2) | ES2758659T3 (enExample) |
| HR (1) | HRP20192133T8 (enExample) |
| HU (1) | HUE047856T2 (enExample) |
| PL (1) | PL2791134T3 (enExample) |
| PT (2) | PT3604299T (enExample) |
| RS (1) | RS59666B1 (enExample) |
| SI (1) | SI2791134T1 (enExample) |
| WO (1) | WO2013089573A1 (enExample) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102816157B (zh) | 2005-07-26 | 2016-05-18 | 比艾尔-坡特拉有限公司 | 作为comt抑制剂的硝基儿茶酚衍生物 |
| EP1845097A1 (en) | 2006-04-10 | 2007-10-17 | Portela & Ca., S.A. | Oxadiazole derivatives as COMT inhibitors |
| LT2481410T (lt) | 2007-01-31 | 2016-11-10 | Bial - Portela & Ca., S.A. | Nitrokatecholio dariniai kaip komt inhibitoriai vartojami konkrečiu dozavimo režimu |
| BRPI0908731A2 (pt) | 2008-03-17 | 2017-05-16 | Bial - Portela & C A S A | formas cristalinas de 5-[3-(2,5-dicloro-4,6-dimetil-1-óxi-piridina-3-il)[1,2,4]oxadiazol-5-il]-3-nitrobenzeno-1,2-diol |
| US9132094B2 (en) | 2009-04-01 | 2015-09-15 | Bial—Portela & Ca, S.A. | Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making thereof |
| US20140045900A1 (en) | 2011-02-11 | 2014-02-13 | Bial-Portela & Ca, S.A. | Administration regime for nitrocatechols |
| CA2858025C (en) * | 2011-12-13 | 2020-09-22 | Bial-Portela & Ca., S.A. | 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene as an intermediate to prepare a catechol-o-methyltransferase inhibitor |
| RU2017120184A (ru) | 2014-11-28 | 2018-12-28 | БИАЛ - ПОРТЕЛА ЭНД Ка, С.А. | Лекарства для замедления течения болезни паркинсона |
| GB2563858A (en) * | 2017-06-27 | 2019-01-02 | Azad Pharmaceutical Ingredients Ag | New route of synthesis for opicapone |
| WO2019123066A1 (en) * | 2017-12-18 | 2019-06-27 | Unichem Laboratories Ltd | Process for the preparation of opicapone and intermediates thereof |
| EP3860602A1 (en) | 2018-10-05 | 2021-08-11 | Neurocrine Biosciences, Inc. | Methods for the administration of comt inhibitors |
| EP3860603A1 (en) | 2018-10-05 | 2021-08-11 | Neurocrine Biosciences, Inc. | Methods for the administration of comt inhibitors |
| CN109529881A (zh) * | 2018-11-12 | 2019-03-29 | 刘晓菊 | 一种治疗帕金森药物用中间体5-硝基香草酸的制备方法 |
| CN115335036A (zh) * | 2020-03-13 | 2022-11-11 | 巴尔-波特拉及康邦亚股份有限公司 | 微粉化的奥匹卡朋 |
| TW202200138A (zh) * | 2020-05-26 | 2022-01-01 | 日商小野藥品工業股份有限公司 | 包含奧匹卡朋（ｏｐｉｃａｐｏｎｅ）之錠劑 |
| GB202011709D0 (en) | 2020-07-28 | 2020-09-09 | Bial Portela & Ca Sa | Solid dispersion of opicapone |
| GB202016425D0 (en) | 2020-10-16 | 2020-12-02 | Bial Portela & Ca Sa | Treatment regimens for parkinson's disease |
| WO2022131944A1 (en) | 2020-12-17 | 2022-06-23 | Bial-Portela & Ca., S.A. | Treatment regimens for early idiopathic parkinson's disease |
| CN112375014A (zh) * | 2020-12-17 | 2021-02-19 | 重庆柳江医药科技有限公司 | 一种奥匹卡朋工艺杂质及制备方法和用途 |
| US20240300930A1 (en) * | 2021-02-26 | 2024-09-12 | Msn Laboratories Private Limited, R&D Center | Novel process for the preparation of 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide |
| CN113292489B (zh) * | 2021-06-16 | 2022-08-30 | 泓博智源(开原)药业有限公司 | 二氯代二烷基烟腈的制备方法 |
| GB202204798D0 (en) | 2022-04-01 | 2022-05-18 | Bial Portela & Ca Sa | Prodrugs of opicapone |
| GB202212082D0 (en) | 2022-08-18 | 2022-10-05 | Bial Portela & Ca Sa | Treatment regimens for parkinson's disease |
| GB202219669D0 (en) | 2022-12-23 | 2023-02-08 | Bial Portela & Ca Sa | Processes and intermediates for synthesising opicapone |
| WO2024242579A1 (en) | 2023-05-25 | 2024-11-28 | Bial-Portela & Ca., S.A. | Treatment regimens for early idiopathic parkinson's disease |
| WO2024260874A1 (en) * | 2023-06-19 | 2024-12-26 | Medichem, S.A. | Process for preparing opicapone |
| WO2025012643A1 (en) | 2023-07-11 | 2025-01-16 | Tay Therapeutics Limited | Compounds comprising a naphthyridine or pyridopyrimidine core as ptc read-through agents |
| CN119775271A (zh) * | 2024-12-31 | 2025-04-08 | 南京海纳医药科技股份有限公司 | 一种奥吡卡朋粗品的精制方法 |
| CN120081837A (zh) * | 2025-02-14 | 2025-06-03 | 江苏天士力帝益药业有限公司 | 一种低单杂高纯度的奥匹卡朋中间体05的制备方法 |
Family Cites Families (72)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1532178A (en) | 1921-07-25 | 1925-04-07 | Louis A Godbold | Lubricator |
| FR1260080A (fr) | 1960-03-22 | 1961-05-05 | Materiel De Forage Soc De Fab | Trépan à molettes étanche |
| IL31990A (en) | 1968-04-26 | 1974-05-16 | Chinoin Gyogyszer Es Vegyeszet | Pyridyl 1,2,4-oxadiazole derivatives,process for the preparation thereof and pharmaceutical compositions containing same |
| US4022901A (en) | 1975-03-05 | 1977-05-10 | E. R. Squibb & Sons, Inc. | 3-Pyridinyl-5-isothiocyanophenyl oxadiazoles |
| US4264573A (en) | 1979-05-21 | 1981-04-28 | Rowell Laboratories, Inc. | Pharmaceutical formulation for slow release via controlled surface erosion |
| US4386668A (en) | 1980-09-19 | 1983-06-07 | Hughes Tool Company | Sealed lubricated and air cooled rock bit bearing |
| DK175069B1 (da) | 1986-03-11 | 2004-05-24 | Hoffmann La Roche | Pyrocatecholderivater |
| US5236952A (en) | 1986-03-11 | 1993-08-17 | Hoffmann-La Roche Inc. | Catechol derivatives |
| YU213587A (en) | 1986-11-28 | 1989-06-30 | Orion Yhtymae Oy | Process for obtaining new pharmacologic active cateholic derivatives |
| DE3840954A1 (de) | 1988-12-05 | 1990-06-07 | Shell Int Research | Herstellung von 2-chlornicotinsaeureestern |
| EP0462639A1 (en) | 1990-06-05 | 1991-12-27 | Shell Internationale Researchmaatschappij B.V. | Preparation of 2-chloropyridine derivatives |
| DK0487774T3 (da) | 1990-11-29 | 1994-11-21 | Wei Ming Pharmaceutical Mfg Co | Hjælpestof til direkte tablettering |
| US5622976A (en) | 1991-12-31 | 1997-04-22 | Fujisawa Pharmaceutical Co., Ltd. | Oxadiazole derivatives having acetylcholinesterase-inhibitory and muscarinic agonist activity |
| FR2730322B1 (fr) | 1995-02-02 | 1997-04-30 | Imago | Monture de lunettes metallique |
| DE19628617A1 (de) | 1996-07-16 | 1998-01-22 | Basf Ag | Direkttablettierhilfsmittel |
| US6206110B1 (en) | 1996-09-09 | 2001-03-27 | Smith International, Inc. | Protected lubricant reservoir with pressure control for sealed bearing earth boring drill bit |
| CA2337755C (en) | 1998-09-18 | 2008-07-29 | Vertex Pharmaceuticals Incorporated | Inhibitors of p38 |
| GB2344819A (en) | 1998-12-18 | 2000-06-21 | Portela & Ca Sa | 2-Phenyl-1-(3,4-dihydroxy-5-nitrophenyl)-1-ethanones |
| FI109453B (fi) | 1999-06-30 | 2002-08-15 | Orion Yhtymae Oyj | Farmaseuttinen koostumus |
| HUP0202757A3 (en) | 1999-08-19 | 2006-03-28 | Nps Pharmaceuticals Inc Salt L | Heteropolycyclic compounds, pharmaceutical compositions containing them and their use as metabotropic glutamate receptor antagonists |
| US6660753B2 (en) | 1999-08-19 | 2003-12-09 | Nps Pharmaceuticals, Inc. | Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists |
| FI20000635A0 (fi) | 2000-03-17 | 2000-03-17 | Orion Yhtymae Oyj | COMT-inhibiittoreiden käyttö analgeettina |
| SE0001438D0 (sv) | 2000-04-18 | 2000-04-18 | Axon Chemicals Bv | New chemical compounds and their use in therapy |
| DE10029201A1 (de) | 2000-06-19 | 2001-12-20 | Basf Ag | Verfahren zur Herstellung fester oraler Darreichungsformen mit retardierender Wirkstoffreisetzung |
| GB2363792A (en) | 2000-06-21 | 2002-01-09 | Portela & Ca Sa | Nitrocatechols |
| CN1166626C (zh) | 2000-08-30 | 2004-09-15 | 李凌松 | 三或四取代苯基化合物、其制备方法及应用 |
| ES2334888T3 (es) | 2000-11-28 | 2010-03-17 | Zymogenetics, L.L.C. | Receptor de citocina zcytor19. |
| US20040097555A1 (en) | 2000-12-26 | 2004-05-20 | Shinegori Ohkawa | Concomitant drugs |
| EP1354603A1 (en) | 2000-12-26 | 2003-10-22 | Takeda Chemical Industries, Ltd. | Concomitant drugs |
| UA74419C2 (uk) | 2001-02-21 | 2005-12-15 | Ен Пі Ес Фармасьютікалс, Інк. | Заміщені піридини та їх застосування як антагоністів рецептору метаботропного глутамату |
| JP2004534779A (ja) | 2001-05-30 | 2004-11-18 | エルジー ライフサイエンス リミテッド | 疾病治療用プロテインキナーゼ阻害剤 |
| CA2449544A1 (en) | 2001-06-08 | 2002-12-19 | Cytovia, Inc. | Substituted 3-aryl-5-aryl-[1,2,4]-oxadiazoles and analogs |
| HUP0402092A3 (en) | 2001-07-26 | 2010-06-28 | Merck Patent Gmbh | Use of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane and its physiologically acceptable salts for preparation of pharmaceutical compositions |
| JP4379853B2 (ja) | 2001-10-05 | 2009-12-09 | 惠民製藥股▲分▼有限公司 | 直接錠剤化用調合物および補助剤の調合方法 |
| US7144876B2 (en) | 2002-12-18 | 2006-12-05 | Cytovia, Inc. | 3,5-Disubstituted-[1,2,4]-oxadiazoles and analogs as activators of caspases and inducers of apoptosis and the use thereof |
| WO2005006945A2 (en) | 2003-07-03 | 2005-01-27 | The Salk Institute For Biological Studies | Methods for treating neural disorders and compounds useful therefor |
| TW200514776A (en) | 2003-08-06 | 2005-05-01 | Vertex Pharma | Aminotriazole compounds useful as inhibitors of protein kinases |
| DE10338174A1 (de) | 2003-08-20 | 2005-03-24 | Lts Lohmann Therapie-Systeme Ag | Transdermale Arzneimittelzubereitungen mit Wirkstoffkombinationen zur Behandlung der Parkinson-Krankheit |
| US7300406B2 (en) | 2003-09-30 | 2007-11-27 | Carter Vandette B | Medical examination apparatus |
| GB0325956D0 (en) | 2003-11-06 | 2003-12-10 | Addex Pharmaceuticals Sa | Novel compounds |
| ATE464303T1 (de) | 2004-04-28 | 2010-04-15 | Vertex Pharma | Als inhibitoren von rock und anderen proteinkinasen geeignete zusammensetzungen |
| GB0510143D0 (en) | 2005-05-18 | 2005-06-22 | Addex Pharmaceuticals Sa | Novel compounds A1 |
| US20060173074A1 (en) | 2004-11-10 | 2006-08-03 | Juha Ellmen | Treatment of restless legs syndrome |
| WO2006061697A1 (en) | 2004-12-06 | 2006-06-15 | Themis Laboratories Private Limited | Sulfonylurea compositions and a process for its preparation |
| US20080051441A1 (en) | 2004-12-28 | 2008-02-28 | Astrazeneca Ab | Aryl Sulphonamide Modulators |
| CN101090895A (zh) | 2004-12-28 | 2007-12-19 | 阿斯利康(瑞典)有限公司 | 芳基磺酰胺调节剂 |
| US8017631B2 (en) | 2005-04-26 | 2011-09-13 | Neurosearch A/S | Oxadiazole derivatives and their medical use |
| US20060257473A1 (en) | 2005-05-11 | 2006-11-16 | Porranee Puranajoti | Extended release tablet |
| GB0510139D0 (en) | 2005-05-18 | 2005-06-22 | Addex Pharmaceuticals Sa | Novel compounds B1 |
| ATE530519T1 (de) | 2005-06-03 | 2011-11-15 | Abbott Lab | Cyclobutylaminderivate |
| JP2007024970A (ja) | 2005-07-12 | 2007-02-01 | Miyakawa:Kk | 液晶表示装置の開口効率を上昇させるための樹脂レンズ製造法及びその製造装置 |
| US20090000437A1 (en) | 2005-07-14 | 2009-01-01 | Provo Craft And Novelty, Inc. | Methods for Cutting |
| CN102816157B (zh) | 2005-07-26 | 2016-05-18 | 比艾尔-坡特拉有限公司 | 作为comt抑制剂的硝基儿茶酚衍生物 |
| FR2889525A1 (fr) | 2005-08-04 | 2007-02-09 | Palumed Sa | Nouveaux derives de polyquinoleines et leur utilisation therapeutique. |
| US20070048384A1 (en) | 2005-08-26 | 2007-03-01 | Joerg Rosenberg | Pharmaceutical compositions |
| EP1954137A4 (en) | 2005-11-18 | 2008-12-17 | Janssen Pharmaceutica Nv | 2-KETO-OXAZOLE AS MODULATORS OF FATTY ACID AMIDHYDROLASE |
| WO2007063946A1 (ja) | 2005-11-30 | 2007-06-07 | Fujifilm Ri Pharma Co., Ltd. | アミロイドの凝集及び／又は沈着に起因する疾患の診断薬及び治療薬 |
| GB0606774D0 (en) | 2006-04-03 | 2006-05-10 | Novartis Ag | Organic compounds |
| EP1845097A1 (en) | 2006-04-10 | 2007-10-17 | Portela & Ca., S.A. | Oxadiazole derivatives as COMT inhibitors |
| PE20080906A1 (es) | 2006-08-17 | 2008-07-05 | Kemia Inc | Derivados heteroarilo como inhibidores de citocina |
| US8486979B2 (en) | 2006-12-12 | 2013-07-16 | Abbvie Inc. | 1,2,4 oxadiazole compounds and methods of use thereof |
| US20080167286A1 (en) | 2006-12-12 | 2008-07-10 | Abbott Laboratories | Pharmaceutical compositions and their methods of use |
| LT2481410T (lt) * | 2007-01-31 | 2016-11-10 | Bial - Portela & Ca., S.A. | Nitrokatecholio dariniai kaip komt inhibitoriai vartojami konkrečiu dozavimo režimu |
| WO2009029632A1 (en) | 2007-08-27 | 2009-03-05 | Helicon Therapeutics, Inc. | Therapeutic isoxazole compounds |
| BRPI0908340A2 (pt) | 2008-02-28 | 2018-12-26 | Bial Portela & Ca Sa | composição farmacêutica para fármacos pouco solúveis |
| BRPI0908731A2 (pt) | 2008-03-17 | 2017-05-16 | Bial - Portela & C A S A | formas cristalinas de 5-[3-(2,5-dicloro-4,6-dimetil-1-óxi-piridina-3-il)[1,2,4]oxadiazol-5-il]-3-nitrobenzeno-1,2-diol |
| JP6165412B2 (ja) | 2008-07-29 | 2017-07-19 | ノヴィファーマ，エス．アー． | ニトロカテコールの投与計画 |
| WO2010114405A2 (en) | 2009-04-01 | 2010-10-07 | Bial - Portela & Ca., S.A. | Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making the same |
| US9132094B2 (en) | 2009-04-01 | 2015-09-15 | Bial—Portela & Ca, S.A. | Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making thereof |
| EP2542220B1 (en) | 2010-03-04 | 2016-11-02 | Orion Corporation | Use of levodopa, carbidopa and entacapone for treating parkinson's disease |
| US20140045900A1 (en) | 2011-02-11 | 2014-02-13 | Bial-Portela & Ca, S.A. | Administration regime for nitrocatechols |
| CA2858025C (en) | 2011-12-13 | 2020-09-22 | Bial-Portela & Ca., S.A. | 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene as an intermediate to prepare a catechol-o-methyltransferase inhibitor |
-
2012
- 2012-12-12 CA CA2858025A patent/CA2858025C/en active Active
- 2012-12-12 ES ES12806720T patent/ES2758659T3/es active Active
- 2012-12-12 EP EP12806720.4A patent/EP2791134B1/en active Active
- 2012-12-12 WO PCT/PT2012/000048 patent/WO2013089573A1/en not_active Ceased
- 2012-12-12 DK DK12806720T patent/DK2791134T3/da active
- 2012-12-12 EP EP19194756.3A patent/EP3604299B1/en active Active
- 2012-12-12 CA CA3088684A patent/CA3088684C/en active Active
- 2012-12-12 ES ES19194756T patent/ES2960805T3/es active Active
- 2012-12-12 PL PL12806720T patent/PL2791134T3/pl unknown
- 2012-12-12 RS RS20191562A patent/RS59666B1/sr unknown
- 2012-12-12 US US14/365,265 patent/US9126988B2/en active Active
- 2012-12-12 HR HRP20192133TT patent/HRP20192133T8/hr unknown
- 2012-12-12 BR BR112014014341A patent/BR112014014341A2/pt not_active Application Discontinuation
- 2012-12-12 PT PT191947563T patent/PT3604299T/pt unknown
- 2012-12-12 HU HUE12806720A patent/HUE047856T2/hu unknown
- 2012-12-12 PT PT128067204T patent/PT2791134T/pt unknown
- 2012-12-12 JP JP2014547135A patent/JP6456143B2/ja active Active
- 2012-12-12 SI SI201231703T patent/SI2791134T1/sl unknown
-
2015
- 2015-07-31 US US14/814,603 patent/US9630955B2/en active Active
-
2017
- 2017-10-27 JP JP2017207738A patent/JP6721558B2/ja active Active
-
2019
- 2019-11-27 CY CY20191101241T patent/CY1122580T1/el unknown
- 2019-11-27 JP JP2019214566A patent/JP2020059729A/ja not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| PT3604299T (pt) | 2023-10-31 |
| SI2791134T1 (sl) | 2020-01-31 |
| US9126988B2 (en) | 2015-09-08 |
| JP2018052949A (ja) | 2018-04-05 |
| JP6721558B2 (ja) | 2020-07-15 |
| CA3088684A1 (en) | 2013-06-20 |
| CA2858025C (en) | 2020-09-22 |
| EP2791134A1 (en) | 2014-10-22 |
| EP2791134B1 (en) | 2019-09-25 |
| ES2960805T3 (es) | 2024-03-06 |
| EP3604299A1 (en) | 2020-02-05 |
| JP2020059729A (ja) | 2020-04-16 |
| DK2791134T3 (da) | 2019-12-09 |
| HRP20192133T8 (hr) | 2021-02-19 |
| PL2791134T3 (pl) | 2020-03-31 |
| WO2013089573A1 (en) | 2013-06-20 |
| BR112014014341A2 (pt) | 2017-08-22 |
| JP2015500335A (ja) | 2015-01-05 |
| PT2791134T (pt) | 2019-12-18 |
| US9630955B2 (en) | 2017-04-25 |
| US20140350057A1 (en) | 2014-11-27 |
| CA2858025A1 (en) | 2013-06-20 |
| CA3088684C (en) | 2021-10-26 |
| HRP20192133T1 (hr) | 2020-02-21 |
| RS59666B1 (sr) | 2020-01-31 |
| US20160009700A1 (en) | 2016-01-14 |
| HUE047856T2 (hu) | 2020-05-28 |
| ES2758659T3 (es) | 2020-05-06 |
| CY1122580T1 (el) | 2021-01-27 |
| EP3604299B1 (en) | 2023-07-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6456143B2 (ja) | カテコール−ｏ−メチル転移酵素阻害剤を調製するための中間体として有用な化学的化合物 | |
| TWI684593B (zh) | 製備（４ｓ）-４-（４-氰基-２-甲氧基苯基）-５-乙氧基-２,８-二甲基-１,４-二氫-１,６-萘啶-３-羧醯胺之方法及其純化用於作為醫藥活性成分 | |
| CN103492361B (zh) | 取代的1-苄基环烷基羧酸及其用途 | |
| CN100430384C (zh) | 制备4-(4-氨基苯基)-3-吗啉酮的方法 | |
| WO2011012321A1 (en) | Processes for crystallization of rivaroxaban | |
| WO2004072030A2 (en) | Process for preparing pyrrolotriazine kinase inhibitors | |
| AU779931B2 (en) | Novel processes for making- and a new crystalline form of- leflunomide | |
| JP2019523273A (ja) | ベリノスタットの多形形態、およびその調製のためのプロセス | |
| CN100999522B (zh) | 巴马汀的制备方法 | |
| CN112390750B (zh) | 作为选择性磷酸二酯酶2抑制剂的喹啉酮类化合物及其制备方法 | |
| JP2007500685A (ja) | 新規の６−フェニルフェナントリジン | |
| WO2019037161A1 (zh) | 一种合成氯法齐明关键中间体n-(4-氯苯基)-1，2-苯二胺的方法 | |
| HK1040078B (zh) | 3-(2，4-二氯苄基)-2-甲基-n-(戊璜酰基)-3h-苯并咪唑-5-羧酰胺的晶形 | |
| JP2009513582A (ja) | ４−オキソ−１−（３置換フェニル）−１，４−ジヒドロ−１，８−ナフチリジン−３−カルボキサミドホスホジエステラーゼ４阻害剤及びその製造方法 | |
| CN101921194A (zh) | 一种制备4-氯二苯甲胺的方法 | |
| EP3650444B1 (en) | Salt and polymorph of benzopyrimidinone compound and pharmaceutical composition and use thereof | |
| JP6147432B2 (ja) | サルポグレラート塩酸塩のｉｉ型結晶の製造方法 | |
| CN109280028B (zh) | 喹啉类化合物及其在dpp-4酶抑制剂的应用 | |
| EP1713769B1 (en) | Amorphous tamsulosin hydrochloride | |
| CN117903138A (zh) | 一种拉罗替尼的制备方法和其应用 | |
| CN116924886A (zh) | 8-氧代-2,2,14,14-四甲基十五烷二酸的合成方法 | |
| CN120757448A (zh) | 孟布酮钠晶型a、晶型b、晶型c及其制备方法与应用 | |
| Kiss et al. | All about Drugs Live by Dr Anthony Melvin Crasto | |
| PL194428B1 (pl) | Sposób wytwarzania 5-[4-[2-(N-metylo-N-(pirydylo-2)-amino)-etoksy]-benzylo]-tiazolidyno-2,4-dionu | |
| CN106432095A (zh) | 匹莫苯丹关键中间体6‑(3,4‑二氨基苯基)‑5‑甲基‑4,5‑二氢哒嗪‑3(2h)‑酮的制备 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20140819 |
|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20140819 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20151211 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20151211 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20160616 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160712 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20161006 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20161206 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170112 |
|
| RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20170615 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20170627 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180718 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180907 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20181218 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6456143 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |