WO1993008173A1 - Chinoxalin-derivate, mit affinität an die quisqualat-rezeptoren - Google Patents
Chinoxalin-derivate, mit affinität an die quisqualat-rezeptoren Download PDFInfo
- Publication number
- WO1993008173A1 WO1993008173A1 PCT/DE1992/000895 DE9200895W WO9308173A1 WO 1993008173 A1 WO1993008173 A1 WO 1993008173A1 DE 9200895 W DE9200895 W DE 9200895W WO 9308173 A1 WO9308173 A1 WO 9308173A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dioxo
- acid
- nitro
- alkyl
- substituted
- Prior art date
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- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title abstract 4
- 102000003678 AMPA Receptors Human genes 0.000 title description 9
- 108090000078 AMPA Receptors Proteins 0.000 title description 9
- -1 CF¿3? Chemical group 0.000 claims abstract description 56
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 35
- 239000001257 hydrogen Substances 0.000 claims abstract description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 19
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- QOMQWUVIIVYNHO-UHFFFAOYSA-N (6-amino-2,3-dioxo-4h-quinoxalin-1-yl)methylphosphonic acid Chemical compound OP(=O)(O)CN1C(=O)C(=O)NC2=CC(N)=CC=C21 QOMQWUVIIVYNHO-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 6
- 150000002460 imidazoles Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical compound CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 4
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
- TUVFMMNANXKTRP-UHFFFAOYSA-N Ethenamine, N-methylene- Chemical compound C=CN=C TUVFMMNANXKTRP-UHFFFAOYSA-N 0.000 claims description 3
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 3
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 150000002912 oxalic acid derivatives Chemical class 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 claims description 2
- 229960000911 benserazide Drugs 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229940052760 dopamine agonists Drugs 0.000 claims description 2
- 239000003136 dopamine receptor stimulating agent Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- FIZJZOZMVQFGPM-UHFFFAOYSA-N [2,3-dioxo-6-(trifluoromethyl)-4h-quinoxalin-1-yl]methylphosphonic acid Chemical compound C1=C(C(F)(F)F)C=C2NC(=O)C(=O)N(CP(O)(=O)O)C2=C1 FIZJZOZMVQFGPM-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 60
- 230000008018 melting Effects 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- 239000000203 mixture Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000000354 decomposition reaction Methods 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-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
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- BWJLAJURYPUBJI-UHFFFAOYSA-N (6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)methylphosphonic acid Chemical compound C1=C([N+]([O-])=O)C=C2NC(=O)C(=O)N(CP(O)(=O)O)C2=C1 BWJLAJURYPUBJI-UHFFFAOYSA-N 0.000 description 4
- UYCUMNRCCJNSBR-UHFFFAOYSA-N 2-ethoxy-2-oxoacetic acid;hydrochloride Chemical compound Cl.CCOC(=O)C(O)=O UYCUMNRCCJNSBR-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
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- 239000003054 catalyst Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
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- SAUYTDLSSGZDMZ-UHFFFAOYSA-N (6-iodo-2,3-dioxo-4h-quinoxalin-1-yl)methylphosphonic acid Chemical compound C1=C(I)C=C2NC(=O)C(=O)N(CP(O)(=O)O)C2=C1 SAUYTDLSSGZDMZ-UHFFFAOYSA-N 0.000 description 3
- TZAFLAJENIMHJK-UHFFFAOYSA-N 1-[2-amino-4-(trifluoromethyl)anilino]ethylphosphonic acid Chemical compound OP(=O)(O)C(C)NC1=CC=C(C(F)(F)F)C=C1N TZAFLAJENIMHJK-UHFFFAOYSA-N 0.000 description 3
- XPRXSVUVVFZBIB-UHFFFAOYSA-N 1-[2-nitro-4-(trifluoromethyl)anilino]ethylphosphonic acid Chemical compound OP(=O)(O)C(C)NC1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O XPRXSVUVVFZBIB-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 150000005840 aryl radicals Chemical class 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000003257 excitatory amino acid Substances 0.000 description 3
- 230000002461 excitatory amino acid Effects 0.000 description 3
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 229910052979 sodium sulfide Inorganic materials 0.000 description 3
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- QVQRFNNFBQRNPM-UHFFFAOYSA-N (6-bromo-2,3-dioxo-4h-quinoxalin-1-yl)methylphosphonic acid Chemical compound C1=C(Br)C=C2NC(=O)C(=O)N(CP(O)(=O)O)C2=C1 QVQRFNNFBQRNPM-UHFFFAOYSA-N 0.000 description 2
- IZFPMHONRRSWFK-UHFFFAOYSA-N 1-(6-bromo-2,3-dioxo-4h-quinoxalin-1-yl)ethylphosphonic acid Chemical compound C1=C(Br)C=C2NC(=O)C(=O)N(C(C)P(O)(O)=O)C2=C1 IZFPMHONRRSWFK-UHFFFAOYSA-N 0.000 description 2
- LLPWERCBDBEKLS-UHFFFAOYSA-N 1-[2,3-dioxo-6-(trifluoromethyl)-4h-quinoxalin-1-yl]ethylphosphonic acid Chemical compound C1=C(C(F)(F)F)C=C2NC(=O)C(=O)N(C(C)P(O)(O)=O)C2=C1 LLPWERCBDBEKLS-UHFFFAOYSA-N 0.000 description 2
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- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
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- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- QDDPGPGILSLCNV-UHFFFAOYSA-N [2-amino-4-(trifluoromethyl)anilino]methylphosphonic acid Chemical compound NC1=CC(C(F)(F)F)=CC=C1NCP(O)(O)=O QDDPGPGILSLCNV-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 229960003116 amyl nitrite Drugs 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
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- 150000001450 anions Chemical class 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229950005228 bromoform Drugs 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
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- 239000000872 buffer Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
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- 210000003169 central nervous system Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
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- 230000008025 crystallization Effects 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 125000004986 diarylamino group Chemical group 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 229940042400 direct acting antivirals phosphonic acid derivative Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- HWYLITPIHMKCKW-UHFFFAOYSA-N ethoxy-[(6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)methyl]phosphinic acid Chemical compound C1=C([N+]([O-])=O)C=C2NC(=O)C(=O)N(CP(O)(=O)OCC)C2=C1 HWYLITPIHMKCKW-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 150000007928 imidazolide derivatives Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 208000028867 ischemia Diseases 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
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([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
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229960003587 lisuride Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- PPYZIQMKGHBTDA-UHFFFAOYSA-N methyl 4-[(6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN1C(=O)C(=O)NC2=CC([N+]([O-])=O)=CC=C21 PPYZIQMKGHBTDA-UHFFFAOYSA-N 0.000 description 1
- HCXDRJKEHCKYEK-UHFFFAOYSA-N methyl 4-[(7-nitro-2,3-dioxo-4h-quinoxalin-1-yl)methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN1C(=O)C(=O)NC2=CC=C([N+]([O-])=O)C=C21 HCXDRJKEHCKYEK-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- XRPITCBWOUOJTH-UHFFFAOYSA-N n,n-diethylpyridin-2-amine Chemical compound CCN(CC)C1=CC=CC=N1 XRPITCBWOUOJTH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003007 phosphonic acid derivatives Chemical class 0.000 description 1
- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- SEPKUNXLGWMPHL-UHFFFAOYSA-N quinoxaline-2,3-dione Chemical compound C1=CC=CC2=NC(=O)C(=O)N=C21 SEPKUNXLGWMPHL-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229960004558 terguride Drugs 0.000 description 1
- GSRBHDHXDPTIDH-UHFFFAOYSA-N tert-butyl 2-[2,3-dioxo-6-(trifluoromethyl)-4h-quinoxalin-1-yl]acetate Chemical compound C1=C(C(F)(F)F)C=C2NC(=O)C(=O)N(CC(=O)OC(C)(C)C)C2=C1 GSRBHDHXDPTIDH-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
- C07F9/650994—Six-membered rings having the nitrogen atoms in the positions 1 and 4 condensed with carbocyclic rings or carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
Definitions
- the invention relates to quinoxalinedione carboxylic acid and phosphonic acid derivatives, their preparation and use in medicaments.
- quinxaline derivatives have affinity for the quisqualate receptors and, because of their affinity, are suitable as medicaments for the treatment of diseases of the central nervous system.
- the compounds according to the invention have the formula I.
- substituted with R 2 is substituted C 1-12 alkyl, with R 2
- R 2 is substituted with C 3-7 cycloalkyl, - (CH 2) n -C 6-12 -aryl, which in the aryl radical or
- Alkyl radical is substituted by R 2 or - (CH 2 ) n -hetaryl which is substituted by R 2 in the hetaryl or alkyl radical,
- R 5 , R 6 , R 7 and R 8 are the same or different and are hydrogen, halogen, nitro, NR 9 R 10 , NHCOR 11 , SO R 12 , C 3-7 cycloalkyloxy, COR 13 , cyano, CF 3 , C 1-6 alkyl, C 1-4 alkoxy or optionally with cyano, C 1-4 alkyl or
- R 5 and R 6 or R 7 and R 8 represent a fused-on benzene ring
- R 2 -CO-R 3 or -PO-XY and R 2 is one or two times the same or different and n is 0, 1, 2, 3, 4 or 5 and
- R 3 is hydroxy, C 1-6 alkoxy or NR 9 R 10 ,
- X and Y are the same or different and are hydroxy, C 1-6 alkoxy, C 1-4 alkyl or NR 9 R 10 and
- R 9 and R 10 are the same or different and are hydrogen, C 1-4 alkyl or together with the nitrogen atom a saturated 5- or
- R 11 is C 1-6 alkyl or phenyl
- R 12 is hydrogen, C 1-4 alkyl, NH-, N ⁇ C 1-4 alkyl), and
- R 13 is hydroxy, C 1-6 alkoxy, C 1-6 alkyl or NR 9 R 10
- R 1 cannot be carbamoylmethyl, 1-carboxy-1-phenylmethyl or straight-chain C 1-6 alkyl, that is substituted in the 1-position with -COOH or -COO-C 1-6 -alkyl, and if R is straight-chain C 1-6 -alkyl, which is in the 1-position with -COOH or
- R 6 and / or R 7 or R 6 and R 8 cannot be fluorine, chlorine or bromine and R 4 -R 8 in each case
- R 6 and R 7 are not methyl or simultaneously
- R 6 or R 7 are not NO 2 and R 4 -R 8 are each hydrogen.
- the compounds of general formula I also include the possible tautomeric forms and include the E or Z isomers or, if a chiral center is present, the racemates or enantiomers.
- the substituents are preferably in the 6- and / or 7-position.
- the substituent R 2 is one or two times the same or different in any position on the alkyl, alkenyl, alkynyl, cycloalkyl, hetaryl or aryl radical.
- Alkyl is in each case to be understood as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, h ⁇ xyl, heptyl, octyl, nonyl, decyl, C 1-6 alkyl radicals being preferred.
- alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl, h ⁇ xyl, heptyl, octyl, nonyl, decyl, C 1-6 alkyl radicals being preferred.
- Alkenyl contains in particular C 2-6 alkenyl radicals, which can be straight-chain or branched, such as 2-propenyl, 2-butenyl,
- alkynyl radicals are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl with 2-4 carbon atoms.
- C 3-7 cycloalkyl is in each case cyclopropyl, cyclobutyl, cyclopentyl,
- Cyclohexyl and cycloheptyl mean especially C 3-5 cycloalkyl.
- 5- or 6-membered heteroaromatics with 1-3 nitrogen atoms are suitable as the hetaryl radical, for example pyrazole, imidazole, pyrazine, pyridine, pyrimidine, pyridazine, triazine.
- Halogen means fluorine, chlorine, bromine and iodine.
- R 9 and R 10 form a saturated heterocycle together with the nitrogen atom, this means, for example, piperidine, pyrrolidine, morpholine, thiomorpholine or piperazine.
- R 1 is C 1-12 -alkyl and R 2 COR 3 , R 5 -R 8 are in particular substituents such as NO 2 , NR 9 R 10 , NHCOR 11 , SO 2 R 12 , C 3-7 -cycloalkyloxy, COR 13 , Cyano, CF 3 , C 1-4 alkoxy, optionally substituted imidazole or a fused-on benzene ring.
- Physiologically compatible salts include salts of organic and inorganic bases such as, for example, the readily soluble alkali and alkaline earth metal salts and also N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, To understand tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.
- organic and inorganic bases such as, for example, the readily soluble alkali and alkaline earth metal salts and also N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, To understand tris-hydroxy-methyl-amino-methane, aminopropan
- the compounds of the formula I and their physiologically tolerable salts can be used as medicaments because of their affinity for the quisqualate receptors.
- the compounds according to the invention are suitable for the treatment of diseases which are caused by hyperactivity of excitatory amino acids such as glutamate or aspartate. Since the new compounds act as antagonists of excitatory amino acids and show a high specific affinity for the AMPA receptors by using the radioactively labeled specific agonist (RS) ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) from displace the AMPA receptors, they are particularly suitable for
- AMPA receptor Treatment of diseases which can be influenced via the receptors of excitatory amino acids, in particular the AMPA receptor, such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's disease, epilepsy, hypoglycemia, psychoses, muscle stiffness,
- the invention also includes the combination of the compounds according to the invention with dopamine agonists such as lisuride, terguride, bromocriptine, amantadine derivatives, memantine and its derivatives and the compounds described in EP-A-351 352 and the combination with L-DOPA or L-DOPA and Benserazide.
- dopamine agonists such as lisuride, terguride, bromocriptine, amantadine derivatives, memantine and its derivatives and the compounds described in EP-A-351 352 and the combination with L-DOPA or L-DOPA and Benserazide.
- the dose of the conventional drug to be administered is reduced and its effect is synergistically increased.
- the compounds are potent, centrally acting AMPA antagonists. They are therefore suitable for the treatment of illnesses that are associated with a disturbance in the glutamate metabolism. They are particularly suitable for the treatment of cerebral ischemia of various origins, Parkinson's disease and also of the other diseases mentioned in the previous paragraph.
- the compounds according to the invention are brought into the form of a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as water, gelatin, gum arabic, milk sugar, starch, Contains magnesium stearate, talc, vegetable oils, polyalkylene glycols etc.
- the pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions. Suspensions or emulsions are present. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
- Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
- Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
- Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as juice, to which a sweetener may be added.
- the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
- the daily dose is 0.5-1000 mg, preferably 50-200 mg, it being possible for the dose to be administered as a single dose to be administered once or divided into 2 or more daily doses.
- R 1 , R 5 , R 6 , R 7 and R 8 have the above meaning, with reactive
- R 4 , R 5 , R 6 , R 7 and R 8 have the above meaning, reacted with R 1 -X to give compounds of the formula I and, if desired, saponifying the ester group or esterifying or amidating the acid group or the
- U and V are leaving groups and R 11 is hydrogen, cyano or COOC 1-6 alkyl and R 12 is hydrogen or C 1-6 alkyl, converted to an imidazole derivative or separating the isomers or forming the salts.
- the cyclization of the compounds of formula II with a reactive oxalic acid derivative takes place in one or two stages.
- the two-stage process is to be regarded as preferred, in which the diamine with an oxalic acid derivative such as the oxal ester half chloride in polar solvents such as dimethylformamide or cyclic or acyclic ethers or halogenated hydrocarbons, for example tetrayhdrofuran, diethyl ether or methylene chloride in the presence of a base such as organic amines, for example triethylamine, pyridine, Hünig -Base or Diethylaminopyridin is implemented.
- polar solvents such as dimethylformamide or cyclic or acyclic ethers or halogenated hydrocarbons, for example tetrayhdrofuran, diethyl ether or methylene chloride
- a base such as organic amines, for example triethylamine
- the subsequent cyclization can be carried out in a basic or acidic manner, but preferably in an acidic environment, and alcohol can be added to the solvent.
- the substituents R 1 and R 4 are introduced by the customary alkylation methods, by adding the quinoxalinedione with R 1 - or R 4 ' -X, where X is tosylate, mesylate or in particular triflate or halogen, in the presence of bases at room temperature or higher Temperature in aprotic solvents.
- the anion can also be generated before R 1 - or R 4 ' X are added.
- bases are, for example
- Alkali compounds such as potassium carbonate, sodium hydroxide, alkali alcoholates and particularly suitable metal hydrides such as sodium hydride.
- the alkali compounds can possibly also be reacted under phase transfer conditions. You get mixtures of compounds with the
- Suitable solvents for the reaction are aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone but also cyclic ethers such as dioxane or tetrahydrofuran. If in process variant b) the reaction is carried out with 2 mol R -X under otherwise analogous reaction conditions, the substituents R 1 and R 4 are introduced simultaneously.
- the subsequent saponification of an ester group can be carried out in a basic or, preferably, acidic manner by hydrolysing at elevated temperature to the boiling point of the reaction mixture in the presence of acids such as high concentrated aqueous hydrochloric acid in solvents such as trifluoroacetic acid or alcohols.
- acids such as high concentrated aqueous hydrochloric acid in solvents such as trifluoroacetic acid or alcohols.
- Phosphonic acid esters are preferably hydrolyzed by heating in highly concentrated aqueous acids such as concentrated hydrochloric acid or by treatment with trimethylsilyl bromide and subsequent treatment with water.
- esterification of the carboxylic acid or phosphonic acid takes place in a manner known per se with the corresponding alcohol in acid or in the presence of an activated acid derivative.
- suitable acid derivatives are acid chloride, imidazolide or anhydride.
- Phosphonic acids can be reacted with orthoesters of the corresponding alcohol.
- the reaction with the adduct of dicyclohexylcarbodiimide and the corresponding alcohol also leads to the ester.
- Methyl esters can be prepared by reaction with diazomethane.
- amidation takes place on the free acids or on their reactive derivatives such as acid chlorides, mixed anhydrides, imidazolides or azides by reaction with the corresponding amines at room temperature.
- the nitro group is reduced to the amino group catalytically in polar solvents at room temperature or elevated temperature below Hydrogen pressure.
- Metals such as Raney nickel or noble metal catalysts such as palladium or platinum are optionally present as catalysts
- Suitable for carriers instead of hydrogen, ammonium formate can also be used in a known manner.
- Reducing agents such as tin (II) chloride or titanium (III) chloride can be used as well as complex metal hydrides, possibly in the presence of heavy metal salts. It may be advantageous to introduce the ester group before the reduction.
- alkylation can be carried out using alkyl halides, for example, using customary methods. Reductive amination with an aldehyde and reducing agents such as sodium cyanoborohydride is also possible.
- the acylation takes place according to the known methods. For example, it is reacted in an aqueous medium in the presence of a base with the corresponding acid anhydrides or acid halides.
- the cyano group can be introduced using the Sandmeyer reaction; for example, the diazonium salts formed as intermediates from the amino compounds with nitrites can be reacted with cyanides in the presence of Cu-I cyanide or with K 2 Ni (CN) 4 .
- the introduction of the halogens chlorine, bromine or iodine via the amino group cannot be aqueous or aqueous; for example, according to Sandmeyer, aqueous, by reacting the diazonium salts formed intermediately with nitrites with Cu (I) chloride or Cu (I) bromide in the presence of the corresponding acid, hydrochloric acid or hydrobromic acid, or with potassium iodide.
- the hydrochloride is reacted in non-aqueous manner in a known manner with i-amyl nitrite and, for example, methylene iodide or bromoform in aprotic solvents such as dimethylformamide.
- Fluorine can be introduced, for example, through the Balz-Schiemann reaction of diazonium tetrafluoroborate.
- the reaction of the amino group with 2-azabutadienes of the formula IV to the imidazole derivatives takes place in the presence of acids at temperatures from 0 to 150 ° C.
- the escape groups U and V can be the same or different; C 1-3 dialkylamines, such as dimethyl,
- the reaction is carried out, for example, in such a way that the amine derivative and the azadiene are initially in an organic acid, such as, for example, formic acid, acetic acid, propionic acid or trifluoroacetic acid
- organic acid such as, for example, formic acid, acetic acid, propionic acid or trifluoroacetic acid
- Reaction mixture (up to about 120 ° C) is heated.
- the acid can be used both as a reactant and as
- solvents such as alcohols, ethers, ketones, esters such as ethyl acetate, hydrocarbons such as toluene or halogenated hydrocarbons such as carbon tetrachloride can also be added.
- the amount of acid can be varied within wide limits, but is used in excess. A 3-10-fold excess of acid, based on the amine and the azadiene, is preferably selected.
- the isomer mixtures can be converted into diastereomers such as e.g. by conventional methods such as crystallization, chromatography or conversion. Salt formation can be separated into the enantiomers or E / Z isomers.
- the salts are prepared in a customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of an alkali metal or alkaline earth metal compound, which is optionally in solution, and separating off the precipitate or working up the solution in a conventional manner.
- the compounds of formula II can be prepared by preparing 2,4-dinitroarylamines according to the Sanger method, in that o-halo-nitroaromatics, preferably o-fluoro-nitroaromatics such as dinitrofluorobenzene in aqueous solution with amino acid derivatives in the presence of a base like sodium carbonate or Sodium bicarbonate at temperatures between 0 ° C to reflux and then reduced.
- o-halo-nitroaromatics preferably o-fluoro-nitroaromatics such as dinitrofluorobenzene in aqueous solution with amino acid derivatives in the presence of a base like sodium carbonate or Sodium bicarbonate at temperatures between 0 ° C to reflux and then reduced.
- This reaction can also be applied to other substituted 2-nitrohalogen compounds.
- Diarylamino compounds can also be obtained by Ulimann's reaction of dinitrochlorobenzene with an aromatic amine.
- High-boiling solvents such as dimethylform
- Enantiomer separation can be carried out on the final stage or in the intermediate stages by optically active auxiliary bases such as e.g. Brucine or 1-phenethylamine take place or also by chromatography over optically active carrier materials.
- optically active auxiliary bases such as e.g. Brucine or 1-phenethylamine take place or also by chromatography over optically active carrier materials.
- the enantiomers can also be synthesized
- Aminoethylphoshonic acid added dropwise in 10 ml of water and 600 mg of sodium carbonate. The mixture is stirred at temperature for 1.5 hours. After the ethanol has been distilled off, the mixture is extracted against acetic acid. The aqueous phase is mixed with 200 mg of imidazole and heated to 110 ° C. for 2 hours. Then another 200 mg of imidazole are added and the mixture is heated to 110 ° C. for 2 hours. It is acidified with 4N hydrochloric acid, suctioned off from the undissolved and the filtrate washed with ethyl acetate. The aqueous phase is concentrated and boiled with ethanol.
- the hydrochloride is placed well dried in 10 ml of dimethylformamide and 4 ml of methylene iodide and 0.6 ml of i-amyl nitrite are added in succession. After 2 hours at 80 ° C bath temperature, everything has dissolved. It is concentrated in vacuo at the Kugelrohr and the residue is silanized
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CZ19931387A CZ286351B6 (cs) | 1991-10-26 | 1992-10-25 | Deriváty chinoxalinu, způsob jejich výroby, jejich použití v léčivech a farmaceutický prostředek tyto látky obsahující |
SK727-93A SK281518B6 (sk) | 1991-10-26 | 1992-10-25 | Deriváty chinoxalínu, spôsob ich výroby a ich použitie v liečivách |
AU28894/92A AU664212B2 (en) | 1991-10-26 | 1992-10-25 | Quinoxaline derivates with affinity for quisqualate-receptors |
KR1019930701948A KR100262371B1 (ko) | 1991-10-26 | 1992-10-25 | 퀴스퀄레이트 수용체에 대한 친화성이 있는 퀴녹살린 유도체 |
PL92299929A PL171125B1 (pl) | 1991-10-26 | 1992-10-25 | Sposób wytwarzania nowych pochodnych chinoksaliny PL PL PL PL |
JP50735393A JP3258008B2 (ja) | 1991-10-26 | 1992-10-25 | キノキサリン誘導体、その製造および医薬中での使用 |
FI932959A FI932959A0 (fi) | 1991-10-26 | 1993-06-24 | Kinoxalin derivat, deras framstaellning och anvaendning i laekemedel |
NO932116A NO304693B1 (no) | 1991-10-26 | 1993-06-25 | Kinoksalinderivater med affinitet for quisqualatreseptorer |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP4135871.6 | 1991-10-26 | ||
DE4135871A DE4135871A1 (de) | 1991-10-26 | 1991-10-26 | Chinoxalinderivate, deren herstellung und verwendung in arzneimitteln |
DEP4224200.2 | 1992-07-17 | ||
DE4224200 | 1992-07-17 |
Publications (1)
Publication Number | Publication Date |
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WO1993008173A1 true WO1993008173A1 (de) | 1993-04-29 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/DE1992/000895 WO1993008173A1 (de) | 1991-10-26 | 1992-10-25 | Chinoxalin-derivate, mit affinität an die quisqualat-rezeptoren |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP0565683A1 (fi) |
JP (1) | JP3258008B2 (fi) |
KR (1) | KR100262371B1 (fi) |
CN (1) | CN1038840C (fi) |
AU (1) | AU664212B2 (fi) |
CA (1) | CA2099270A1 (fi) |
CZ (1) | CZ286351B6 (fi) |
FI (1) | FI932959A0 (fi) |
HU (1) | HUT64756A (fi) |
IL (1) | IL103538A (fi) |
NO (1) | NO304693B1 (fi) |
NZ (1) | NZ244896A (fi) |
PL (1) | PL171125B1 (fi) |
PT (1) | PT101004B (fi) |
RU (1) | RU2117663C1 (fi) |
SK (1) | SK281518B6 (fi) |
WO (1) | WO1993008173A1 (fi) |
Cited By (16)
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WO1994025470A1 (de) * | 1993-04-28 | 1994-11-10 | Schering Aktiengesellschaft | Benzo[f]chinoxalindionderivative, deren herstellung und verwendung in arzneimitteln |
WO1994025469A1 (de) * | 1993-04-28 | 1994-11-10 | Schering Aktiengesellschaft | Neue chinoxalindionderivative, deren herstellung und verwendung in arzneimitteln |
EP0647137A1 (en) * | 1992-06-22 | 1995-04-12 | The Regents Of The University Of California | Glycine receptor antagonists and the use thereof |
US5504085A (en) * | 1991-09-20 | 1996-04-02 | Novo Nordisk A/S | Triazolo quinoxalines and their preparation and use |
WO1996012725A1 (de) * | 1994-10-25 | 1996-05-02 | Schering Aktiengesellschaft | Neue chinoxalindionderivate, deren herstellung und verwendung in arzneimitteln |
WO1996012724A1 (de) * | 1994-10-25 | 1996-05-02 | Schering Aktiengesellschaft | Neue chinoxalindionderivate, deren herstellung und verwendung in arzneimitteln |
WO1997019066A1 (de) * | 1995-11-24 | 1997-05-29 | Schering Aktiengesellschaft | Neue chinoxalindionderivate, deren herstellung und verwendung in arzneimitteln |
EP0784054A1 (en) * | 1994-09-27 | 1997-07-16 | Yamanouchi Pharmaceutical Co. Ltd. | 1,2,3,4-tetrahydroquinoxalinedione derivative |
WO1999000384A1 (de) * | 1997-06-27 | 1999-01-07 | Schering Aktiengesellschaft | Chinoxalindionderivate als ampa-rezeptor-antagonisten |
EP0900568A2 (en) * | 1997-09-05 | 1999-03-10 | Pfizer Products Inc. | AMPA antagonists for the treatment of dyskinesias associated with dopamine agonist therapy |
EP0900567A2 (en) * | 1997-09-05 | 1999-03-10 | Pfizer Products Inc. | Quinazoline-4-one AMPA antagonists for the treatment of dyskinesias associated with dopamine agonist therapy |
EP0919554A1 (en) * | 1996-06-06 | 1999-06-02 | Yamanouchi Pharmaceutical Co. Ltd. | Imidazole-substituted quinoxalinedione derivatives |
US6015800A (en) * | 1997-09-03 | 2000-01-18 | Warner-Lambert Company | Substituted quinoxaline-2-ones as glutamate receptor antagonists |
US6110911A (en) * | 1995-06-07 | 2000-08-29 | Warner-Lambert Company | Cyclic amine derivatives of substituted quinoxaline 2,3-diones as glutamate receptor antagonists |
EP0783495B1 (en) * | 1994-09-24 | 2002-02-27 | Pfizer Limited | Quinoxaline derivatives useful in therapy |
EP1625134A2 (en) * | 2003-05-17 | 2006-02-15 | QUEEN MARY & WESTFIELD COLLEGE | Substituted phosphonate fluorescent sensors and use thereof |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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DE4428152A1 (de) * | 1994-06-22 | 1996-01-04 | Basf Ag | Neue Amido-chinoxalindione, ihrer Herstellung und Verwendung |
DE19521058A1 (de) * | 1995-06-09 | 1996-12-12 | Basf Ag | Verfahren zur Herstellung von Aromaten enthaltenden Polyetherpolyolen |
DE19624808A1 (de) | 1996-06-21 | 1998-01-02 | Basf Ag | Pyrrolylchinoxalindione, ihre Herstellung und Verwendung |
FR2769309B1 (fr) | 1997-10-08 | 2001-06-15 | Oreal | Composition de teinture d'oxydation des fibres keratiniques comprenant un derive d'aminoacide en tant que base d'oxydation et nouveaux derives d'aminoacides |
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EP0118982A1 (en) * | 1983-02-01 | 1984-09-19 | Sumitomo Chemical Company, Limited | Organic phosphorous quinoxalinone and their production and use |
EP0315959A2 (en) * | 1987-11-10 | 1989-05-17 | Novo Nordisk A/S | Quinoxaline compounds and their preparation and use |
WO1991013878A1 (en) * | 1990-03-16 | 1991-09-19 | Novo Nordisk A/S | Quinoxaline compounds and their preparation and use |
-
1992
- 1992-10-23 PT PT101004A patent/PT101004B/pt not_active IP Right Cessation
- 1992-10-25 EP EP92922676A patent/EP0565683A1/de not_active Withdrawn
- 1992-10-25 IL IL10353892A patent/IL103538A/en not_active IP Right Cessation
- 1992-10-25 AU AU28894/92A patent/AU664212B2/en not_active Ceased
- 1992-10-25 CA CA002099270A patent/CA2099270A1/en not_active Abandoned
- 1992-10-25 SK SK727-93A patent/SK281518B6/sk unknown
- 1992-10-25 CZ CZ19931387A patent/CZ286351B6/cs not_active IP Right Cessation
- 1992-10-25 KR KR1019930701948A patent/KR100262371B1/ko not_active IP Right Cessation
- 1992-10-25 HU HU9301877A patent/HUT64756A/hu unknown
- 1992-10-25 WO PCT/DE1992/000895 patent/WO1993008173A1/de not_active Application Discontinuation
- 1992-10-25 JP JP50735393A patent/JP3258008B2/ja not_active Expired - Fee Related
- 1992-10-25 PL PL92299929A patent/PL171125B1/pl unknown
- 1992-10-25 RU RU93044489A patent/RU2117663C1/ru active
- 1992-10-26 CN CN92113338A patent/CN1038840C/zh not_active Expired - Fee Related
- 1992-10-27 NZ NZ244896A patent/NZ244896A/en unknown
-
1993
- 1993-06-24 FI FI932959A patent/FI932959A0/fi unknown
- 1993-06-25 NO NO932116A patent/NO304693B1/no not_active IP Right Cessation
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EP0118982A1 (en) * | 1983-02-01 | 1984-09-19 | Sumitomo Chemical Company, Limited | Organic phosphorous quinoxalinone and their production and use |
EP0315959A2 (en) * | 1987-11-10 | 1989-05-17 | Novo Nordisk A/S | Quinoxaline compounds and their preparation and use |
WO1991013878A1 (en) * | 1990-03-16 | 1991-09-19 | Novo Nordisk A/S | Quinoxaline compounds and their preparation and use |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5504085A (en) * | 1991-09-20 | 1996-04-02 | Novo Nordisk A/S | Triazolo quinoxalines and their preparation and use |
EP0647137A4 (en) * | 1992-06-22 | 1998-09-16 | Univ California Weber Eckard | GLYCINE RECEPTOR ANTAGONISTS AND THEIR USE. |
EP0647137A1 (en) * | 1992-06-22 | 1995-04-12 | The Regents Of The University Of California | Glycine receptor antagonists and the use thereof |
AU683258B2 (en) * | 1993-04-28 | 1997-11-06 | Schering Aktiengesellschaft | Benzo(F)quinoxalindione derivatives, their preparation and their use in drugs |
US5955461A (en) * | 1993-04-28 | 1999-09-21 | Schering Aktiengesellschaft | Quinoxalinedione derivatives, their production and use in pharmaceutical agents |
US5710138A (en) * | 1993-04-28 | 1998-01-20 | Schering Aktiengesellschaft | Benzo f!quinoxalinedione derivatives, their production and use in pharmaceutical agents |
US5750525A (en) * | 1993-04-28 | 1998-05-12 | Schering Aktiengesellschaft | Quinoxalinedione derivatives, their production and use in pharmaceutical agents |
WO1994025469A1 (de) * | 1993-04-28 | 1994-11-10 | Schering Aktiengesellschaft | Neue chinoxalindionderivative, deren herstellung und verwendung in arzneimitteln |
WO1994025470A1 (de) * | 1993-04-28 | 1994-11-10 | Schering Aktiengesellschaft | Benzo[f]chinoxalindionderivative, deren herstellung und verwendung in arzneimitteln |
EP0783495B1 (en) * | 1994-09-24 | 2002-02-27 | Pfizer Limited | Quinoxaline derivatives useful in therapy |
EP0784054A1 (en) * | 1994-09-27 | 1997-07-16 | Yamanouchi Pharmaceutical Co. Ltd. | 1,2,3,4-tetrahydroquinoxalinedione derivative |
EP0784054A4 (en) * | 1994-09-27 | 1998-01-07 | Yamanouchi Pharma Co Ltd | 1,2,3,4-TETRAHYDROQUINOXALINDIONE DERIVATIVE |
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WO1997019066A1 (de) * | 1995-11-24 | 1997-05-29 | Schering Aktiengesellschaft | Neue chinoxalindionderivate, deren herstellung und verwendung in arzneimitteln |
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EP1625134A2 (en) * | 2003-05-17 | 2006-02-15 | QUEEN MARY & WESTFIELD COLLEGE | Substituted phosphonate fluorescent sensors and use thereof |
Also Published As
Publication number | Publication date |
---|---|
SK72793A3 (en) | 1993-10-06 |
NZ244896A (en) | 1995-07-26 |
AU2889492A (en) | 1993-05-21 |
CZ138793A3 (en) | 1994-01-19 |
JP3258008B2 (ja) | 2002-02-18 |
KR100262371B1 (ko) | 2000-08-01 |
FI932959A (fi) | 1993-06-24 |
RU2117663C1 (ru) | 1998-08-20 |
IL103538A (en) | 2001-07-24 |
NO932344D0 (no) | 1993-06-25 |
CN1038840C (zh) | 1998-06-24 |
EP0565683A1 (de) | 1993-10-20 |
JPH06503583A (ja) | 1994-04-21 |
CA2099270A1 (en) | 1993-04-27 |
PT101004B (pt) | 1999-10-29 |
AU664212B2 (en) | 1995-11-09 |
CZ286351B6 (cs) | 2000-03-15 |
SK281518B6 (sk) | 2001-04-09 |
HUT64756A (en) | 1994-02-28 |
IL103538A0 (en) | 1993-03-15 |
FI932959A0 (fi) | 1993-06-24 |
NO932344L (no) | 1993-06-25 |
HU9301877D0 (en) | 1993-09-28 |
CN1072929A (zh) | 1993-06-09 |
KR930703271A (ko) | 1993-11-29 |
PL171125B1 (pl) | 1997-03-28 |
PT101004A (pt) | 1994-01-31 |
PL299929A1 (en) | 1994-04-05 |
NO304693B1 (no) | 1999-02-01 |
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