CA2106882C - Azaquinoxalines, processes for their preparation and their use - Google Patents
Azaquinoxalines, processes for their preparation and their use Download PDFInfo
- Publication number
- CA2106882C CA2106882C CA002106882A CA2106882A CA2106882C CA 2106882 C CA2106882 C CA 2106882C CA 002106882 A CA002106882 A CA 002106882A CA 2106882 A CA2106882 A CA 2106882A CA 2106882 C CA2106882 C CA 2106882C
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- CA
- Canada
- Prior art keywords
- formula
- dihydro
- compound
- alkyl
- hydroxyl
- 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.)
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- 238000000034 method Methods 0.000 title claims description 20
- 238000002360 preparation method Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- 229910052720 vanadium Inorganic materials 0.000 claims abstract description 19
- 229910052721 tungsten Inorganic materials 0.000 claims abstract description 17
- 229910052727 yttrium Inorganic materials 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 239000000460 chlorine Substances 0.000 claims description 80
- 229910052801 chlorine Inorganic materials 0.000 claims description 79
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 78
- 239000011737 fluorine Substances 0.000 claims description 76
- 229910052731 fluorine Inorganic materials 0.000 claims description 76
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 61
- 125000003545 alkoxy group Chemical group 0.000 claims description 60
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 239000001257 hydrogen Substances 0.000 claims description 42
- 229910052794 bromium Inorganic materials 0.000 claims description 38
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 37
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 125000004423 acyloxy group Chemical group 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- 229910052717 sulfur Chemical group 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004442 acylamino group Chemical group 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000011593 sulfur Chemical group 0.000 claims description 8
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 238000005987 sulfurization reaction Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 claims description 4
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229950005228 bromoform Drugs 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 238000005932 reductive alkylation reaction Methods 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- -1 3-substituted 4,5-dihydro-5-isopropyl-4-oxoimidazo[1,5-a]quinoxalines Chemical class 0.000 description 160
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 125000001153 fluoro group Chemical group F* 0.000 description 60
- 238000002844 melting Methods 0.000 description 53
- 230000008018 melting Effects 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 125000004043 oxo group Chemical group O=* 0.000 description 43
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 37
- 125000003282 alkyl amino group Chemical group 0.000 description 36
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 31
- 125000004663 dialkyl amino group Chemical group 0.000 description 31
- 125000004414 alkyl thio group Chemical group 0.000 description 30
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 26
- 125000000217 alkyl group Chemical group 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 125000000464 thioxo group Chemical group S=* 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 10
- 125000003710 aryl alkyl group Chemical group 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 8
- 238000006555 catalytic reaction Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 229940086542 triethylamine Drugs 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000007868 Raney catalyst Substances 0.000 description 6
- 229910000564 Raney nickel Inorganic materials 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 150000001340 alkali metals Chemical class 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- OZEJKXBTUYFTHF-UHFFFAOYSA-N 3-phenyl-3,4-dihydro-1h-pyrido[2,3-b]pyrazin-2-one Chemical compound O=C1NC2=CC=CN=C2NC1C1=CC=CC=C1 OZEJKXBTUYFTHF-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 102100034343 Integrase Human genes 0.000 description 5
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 230000003455 independent Effects 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
- AMMGCGVWJMRTQI-UHFFFAOYSA-N prop-1-en-2-yl carbonochloridate Chemical compound CC(=C)OC(Cl)=O AMMGCGVWJMRTQI-UHFFFAOYSA-N 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000003396 thiol group Chemical class [H]S* 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 125000005018 aryl alkenyl group Chemical group 0.000 description 4
- 125000005110 aryl thio group Chemical group 0.000 description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- SURLGNKAQXKNSP-DBLYXWCISA-N chlorin Chemical compound C\1=C/2\N/C(=C\C3=N/C(=C\C=4NC(/C=C\5/C=CC/1=N/5)=CC=4)/C=C3)/CC\2 SURLGNKAQXKNSP-DBLYXWCISA-N 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- SHCWQWRTKPNTEM-UHFFFAOYSA-N 2,6-dichloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1Cl SHCWQWRTKPNTEM-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 3
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 3
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 3
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 3
- 125000005015 aryl alkynyl group Chemical group 0.000 description 3
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 3
- 229910001863 barium hydroxide Inorganic materials 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 150000002829 nitrogen Chemical class 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 150000003195 pteridines Chemical class 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000002821 scintillation proximity assay Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- GLKCOBIIZKYKFN-UHFFFAOYSA-N 2-aminopteridine-4,7-diol Chemical compound N1=CC(O)=NC2=NC(N)=NC(O)=C21 GLKCOBIIZKYKFN-UHFFFAOYSA-N 0.000 description 2
- ZLTOSZCCCUKJRR-UHFFFAOYSA-N 2-methyl-1-(3-methylbut-2-enyl)-2,4-dihydropyrido[3,4-b]pyrazin-3-one;hydrobromide Chemical compound Br.C1=NC=C2NC(=O)C(C)N(CC=C(C)C)C2=C1 ZLTOSZCCCUKJRR-UHFFFAOYSA-N 0.000 description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 241000006460 Cyana Species 0.000 description 2
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical group [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 241001061127 Thione Species 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 125000005090 alkenylcarbonyl group Chemical group 0.000 description 2
- 125000005137 alkenylsulfonyl group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 125000004691 alkyl thio carbonyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000005225 alkynyloxycarbonyl group Chemical group 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- KTMOZZKFOZPLBJ-QMMMGPOBSA-N methyl (2s)-2-(pyridin-2-ylmethylamino)propanoate Chemical compound COC(=O)[C@H](C)NCC1=CC=CC=N1 KTMOZZKFOZPLBJ-QMMMGPOBSA-N 0.000 description 1
- IOMFKPFJYISUMW-JTQLQIEISA-N methyl (2s)-2-[(6-chloro-3-nitropyridin-2-yl)-(pyridin-2-ylmethyl)amino]propanoate Chemical compound N=1C(Cl)=CC=C([N+]([O-])=O)C=1N([C@@H](C)C(=O)OC)CC1=CC=CC=N1 IOMFKPFJYISUMW-JTQLQIEISA-N 0.000 description 1
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- NVWZNEDLYYLQJC-UHFFFAOYSA-N methyl 2-amino-2-methylpropanoate;hydrochloride Chemical compound Cl.COC(=O)C(C)(C)N NVWZNEDLYYLQJC-UHFFFAOYSA-N 0.000 description 1
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- MKRXCQFWPZANDJ-UHFFFAOYSA-N propan-2-yl 5-methoxy-3-(methylsulfanylmethyl)-2-sulfanylidene-1,3-dihydropyrazino[2,3-d]pyridazine-4-carboxylate Chemical compound N1C(=S)C(CSC)N(C(=O)OC(C)C)C2=C1C=NN=C2OC MKRXCQFWPZANDJ-UHFFFAOYSA-N 0.000 description 1
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- KDXPODRGWFEAQO-UHFFFAOYSA-N propan-2-yl 6-methoxy-3-(methylsulfanylmethyl)-2-sulfanylidene-1,3-dihydropyrido[2,3-b]pyrazine-4-carboxylate Chemical compound N1C(=S)C(CSC)N(C(=O)OC(C)C)C2=NC(OC)=CC=C21 KDXPODRGWFEAQO-UHFFFAOYSA-N 0.000 description 1
- WENSJJMFDVDAJF-UHFFFAOYSA-N propan-2-yl 6-methyl-7-oxo-6,8-dihydropteridine-5-carboxylate Chemical compound C1=NC=C2N(C(=O)OC(C)C)C(C)C(=O)NC2=N1 WENSJJMFDVDAJF-UHFFFAOYSA-N 0.000 description 1
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- YCSWRJRYPVDVEZ-UHFFFAOYSA-N propan-2-yl n-[3-methyl-4-(2-methylpropanoyl)-2-oxo-1,3-dihydropyrido[2,3-b]pyrazin-6-yl]-n-propylcarbamate Chemical compound N1C(=O)C(C)N(C(=O)C(C)C)C2=NC(N(C(=O)OC(C)C)CCC)=CC=C21 YCSWRJRYPVDVEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- OUFHXMSGJIYFPW-UHFFFAOYSA-N pyrazino[2,3-c]pyridazine Chemical class N1=NC=CC2=NC=CN=C21 OUFHXMSGJIYFPW-UHFFFAOYSA-N 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- YEYHFKBVNARCNE-UHFFFAOYSA-N pyrido[2,3-b]pyrazine Chemical class N1=CC=NC2=CC=CN=C21 YEYHFKBVNARCNE-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 101150094969 rfp1 gene Proteins 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- IOVGROKTTNBUGK-SJCJKPOMSA-N ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- FGEJJBGRIFKJTB-UHFFFAOYSA-N silylsulfanylsilane Chemical class [SiH3]S[SiH3] FGEJJBGRIFKJTB-UHFFFAOYSA-N 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 230000002311 subsequent effect Effects 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- BDIWFCKBPZPBQT-UHFFFAOYSA-N tributyl(tributylstannylsulfanyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)S[Sn](CCCC)(CCCC)CCCC BDIWFCKBPZPBQT-UHFFFAOYSA-N 0.000 description 1
- NBTHYJWPOYZDHL-UHFFFAOYSA-N tricyclohexyl(tricyclohexylstannylsulfanyl)stannane Chemical compound C1CCCCC1[Sn](C1CCCCC1)(C1CCCCC1)S[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1 NBTHYJWPOYZDHL-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- NTCQOKPUDSWFJF-UHFFFAOYSA-N triphenyl(triphenylstannylsulfanyl)stannane Chemical compound C=1C=CC=CC=1[Sn](C=1C=CC=CC=1)(C=1C=CC=CC=1)S[Sn](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NTCQOKPUDSWFJF-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Radar Systems Or Details Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4232392 | 1992-09-26 | ||
| DEP4232392.4 | 1992-09-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2106882A1 CA2106882A1 (en) | 1994-03-27 |
| CA2106882C true CA2106882C (en) | 2007-04-17 |
Family
ID=6468974
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002106882A Expired - Fee Related CA2106882C (en) | 1992-09-26 | 1993-09-24 | Azaquinoxalines, processes for their preparation and their use |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US5424311A (OSRAM) |
| EP (1) | EP0590428B1 (OSRAM) |
| JP (1) | JPH06211855A (OSRAM) |
| KR (1) | KR940007035A (OSRAM) |
| AT (1) | ATE187724T1 (OSRAM) |
| AU (1) | AU664643B2 (OSRAM) |
| CA (1) | CA2106882C (OSRAM) |
| CZ (1) | CZ9302005A3 (OSRAM) |
| DE (1) | DE59309902D1 (OSRAM) |
| DK (1) | DK0590428T3 (OSRAM) |
| ES (1) | ES2141744T3 (OSRAM) |
| GR (1) | GR3032520T3 (OSRAM) |
| HU (1) | HUT65302A (OSRAM) |
| IL (1) | IL107081A (OSRAM) |
| MX (1) | MX9305894A (OSRAM) |
| NZ (1) | NZ248762A (OSRAM) |
| PH (1) | PH30348A (OSRAM) |
| PT (1) | PT590428E (OSRAM) |
| TW (1) | TW274550B (OSRAM) |
| ZA (1) | ZA937081B (OSRAM) |
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| EP0743855A1 (en) * | 1994-01-03 | 1996-11-27 | Acea Pharmaceuticals, Inc. | 8-aza, 6-aza and 6,8-diaza-1,4-dihydroquinoxaline-2,3-diones and the use thereof as antagonists for the glycine/nmda receptor |
| US5801183A (en) * | 1995-01-27 | 1998-09-01 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | Aza and aza (N-oxy) analogs of glycine/NMDA receptor antagonists |
| US5646130A (en) * | 1995-06-30 | 1997-07-08 | Ocean University Of Oingdao | Low molecular weight sulfated polysaccharides and uses thereof |
| ZA973884B (en) * | 1996-05-23 | 1998-11-06 | Du Pont Merck Pharma | Tetrahydropteridines and pyridylpiperazines for treatment of neurological disorders |
| DE69916414T2 (de) | 1998-07-16 | 2005-05-19 | Aaron Tabor | Sojazubereitungen und deren verwendung zur gesundheitsförderung |
| US6930101B1 (en) | 1999-05-17 | 2005-08-16 | The Regents Of The University Of California | Thiazolopyrimidines useful as TNFα inhibitors |
| AU2003220401A1 (en) | 2002-03-18 | 2003-10-08 | Bristol-Myers Squibb Company | Uracil derivatives as inhibitors of tnf-alpha converting enzyme (tace) and matrix metalloproteinases |
| US6861422B2 (en) * | 2003-02-26 | 2005-03-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Dihydropteridinones, processes for preparing them and their use as pharmaceutical compositions |
| PT1636228E (pt) * | 2003-05-23 | 2009-02-02 | Aeterna Zentaris Gmbh | Novas piridopirazinas e sua utilização como moduladores de cinases |
| DE10323345A1 (de) * | 2003-05-23 | 2004-12-16 | Zentaris Gmbh | Neue Pyridopyrazine und deren Verwendung als Kinase-Inhibitoren |
| MY147767A (en) * | 2004-06-16 | 2013-01-31 | Janssen Pharmaceutica Nv | Novel sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
| DE102004029784A1 (de) | 2004-06-21 | 2006-01-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 2-Benzylaminodihydropteridinone, Verfahren zur deren Herstellung und deren Verwendung als Arzneimittel |
| DE102004033670A1 (de) * | 2004-07-09 | 2006-02-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Pyridodihydropyrazinone, Verfahren zu Ihrer Herstellung und Ihre Verwendung als Arzneimittel |
| US20060074088A1 (en) * | 2004-08-14 | 2006-04-06 | Boehringer Ingelheim International Gmbh | Dihydropteridinones for the treatment of cancer diseases |
| US7728134B2 (en) * | 2004-08-14 | 2010-06-01 | Boehringer Ingelheim International Gmbh | Hydrates and polymorphs of 4[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, process for their manufacture and their use as medicament |
| US20060058311A1 (en) | 2004-08-14 | 2006-03-16 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation |
| US20060035903A1 (en) * | 2004-08-14 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Storage stable perfusion solution for dihydropteridinones |
| US7759485B2 (en) * | 2004-08-14 | 2010-07-20 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dihydropteridinones |
| EP1632493A1 (de) * | 2004-08-25 | 2006-03-08 | Boehringer Ingelheim Pharma GmbH & Co.KG | Dihydropteridinonderivative, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
| EP1630163A1 (de) * | 2004-08-25 | 2006-03-01 | Boehringer Ingelheim Pharma GmbH & Co.KG | Dihydropteridinonderivative, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
| DE102004058337A1 (de) * | 2004-12-02 | 2006-06-14 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung von annelierten Piperazin-2-on Derivaten |
| US7439358B2 (en) * | 2006-02-08 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Specific salt, anhydrous and crystalline form of a dihydropteridione derivative |
| ES2366239T3 (es) * | 2006-04-21 | 2011-10-18 | Pfizer Products Inc. | Piridin[3,4-b]pirazinonas. |
| US7601716B2 (en) * | 2006-05-01 | 2009-10-13 | Cephalon, Inc. | Pyridopyrazines and derivatives thereof as ALK and c-Met inhibitors |
| GB0614471D0 (en) * | 2006-07-20 | 2006-08-30 | Syngenta Ltd | Herbicidal Compounds |
| EP2457913B1 (en) * | 2006-10-19 | 2017-04-19 | Signal Pharmaceuticals, LLC | Heteroaryl compounds, compositions thereof, and methods of treatment therewith |
| ZA200902384B (en) * | 2006-10-19 | 2010-07-28 | Signal Pharm Llc | Heteroaryl compounds, compositions thereof, and use thereof as protein kinase inhibitors |
| WO2008063455A1 (en) * | 2006-11-13 | 2008-05-29 | Hines Richard A | Over-the wire exclusion device and system for delivery |
| EP2185559A1 (en) * | 2007-08-03 | 2010-05-19 | Boehringer Ingelheim International GmbH | Crystalline form of a dihydropteridione derivative |
| US8110578B2 (en) | 2008-10-27 | 2012-02-07 | Signal Pharmaceuticals, Llc | Pyrazino[2,3-b]pyrazine mTOR kinase inhibitors for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway |
| BRPI0923305B1 (pt) * | 2008-12-09 | 2019-01-22 | Gilead Sciences Inc | moduladores de receptores toll-like, seu uso e composição farmacêutica que os compreende |
| MY152386A (en) * | 2009-01-23 | 2014-09-15 | Takeda Pharmaceutical | Substituted 6a,7,8,9-tetrahydropyrido[3,2-e] pyrrolo[1,2-a]pyrazin-6(5h)-ones |
| US8541417B2 (en) | 2009-07-30 | 2013-09-24 | Takeda Pharmaceutical Company Limited | Poly (ADP-ribose) polymerase (PARP) inhibitors |
| NZ598384A (en) * | 2009-09-14 | 2014-04-30 | Gilead Sciences Inc | Modulators of toll-like receptors |
| CA2778615C (en) * | 2009-10-26 | 2019-04-23 | Signal Pharmaceuticals, Llc | Methods of synthesis and purification of heteroaryl compounds |
| WO2011097333A1 (en) | 2010-02-03 | 2011-08-11 | Signal Pharmaceuticals, Llc | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
| US8546566B2 (en) | 2010-10-12 | 2013-10-01 | Boehringer Ingelheim International Gmbh | Process for manufacturing dihydropteridinones and intermediates thereof |
| US9358233B2 (en) | 2010-11-29 | 2016-06-07 | Boehringer Ingelheim International Gmbh | Method for treating acute myeloid leukemia |
| US9370535B2 (en) | 2011-05-17 | 2016-06-21 | Boehringer Ingelheim International Gmbh | Method for treatment of advanced solid tumors |
| CA2852921C (en) | 2011-10-19 | 2023-10-10 | Signal Pharmaceuticals, Llc | Treatment of cancer with tor kinase inhibitors |
| US9351974B2 (en) | 2011-11-10 | 2016-05-31 | OSI Pharmaceuticals, LLC | Substituted pteridinones for the treatment of cancer |
| SG11201402766UA (en) | 2011-12-02 | 2014-06-27 | Signal Pharm Llc | PHARMACEUTICAL COMPOSITIONS OF 7-(6-(2-HYDROXYPROPAN-2-YL)PYRIDIN-3-YL)-1-((TRANS)-4-METHOXYCYCLOHEXYL)-3,4-DIHYDROPYRAZINO [2,3-<i>B</i>]PYRAZIN-2(1<i>H</i>)-ONE, A SOLID FORM THEREOF AND METHODS OF THEIR USE |
| WO2013126636A1 (en) | 2012-02-24 | 2013-08-29 | Signal Pharmaceuticals, Llc | Methods for treating non- small cell lung cancer using tor kinase inhibitor combination therapy |
| AU2013203714B2 (en) | 2012-10-18 | 2015-12-03 | Signal Pharmaceuticals, Llc | Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity |
| JP2016505041A (ja) | 2013-01-16 | 2016-02-18 | シグナル ファーマシューティカルズ，エルエルシー | 置換型ピロロピリミジン化合物、その組成物、およびこれらを用いた治療方法 |
| SG10201801965RA (en) | 2013-04-17 | 2018-04-27 | Signal Pharm Llc | Treatment of cancer with dihydropyrazino-pyrazines |
| MX2015014455A (es) | 2013-04-17 | 2016-07-21 | Signal Pharm Llc | Terapia de combinacion que comprende un inhibidor de tor cinasa y n-(3-(5-fluoro-2-(4-(2-metoxietoxi)fenilamino)pirimidin-4-ilamino )fenil)acrilamida para tratar cancer. |
| WO2014172432A1 (en) | 2013-04-17 | 2014-10-23 | Signal Pharmaceuticals, Llc | Combination therapy comprising a tor kinase inhibitor and a cytidine analog for treating cancer |
| US9359364B2 (en) | 2013-04-17 | 2016-06-07 | Signal Pharmaceuticals, Llc | Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b] pyrazin-2(1H)-one |
| CA2908957C (en) | 2013-04-17 | 2021-05-18 | Signal Pharmaceuticals, Llc | Combination therapy comprising a dihydropyrazino-pyrazine compound and an androgen receptor antagonist for treating prostate cancer |
| AU2014254053B2 (en) | 2013-04-17 | 2019-06-06 | Signal Pharmaceuticals, Llc | Treatment of cancer with Dihydropyrazino-Pyrazines |
| US9474757B2 (en) | 2013-04-17 | 2016-10-25 | Signal Pharmaceuticals, Llc | Methods for treating cancer using TOR kinase inhibitor combination therapy |
| CN105407892B (zh) | 2013-05-29 | 2019-05-07 | 西格诺药品有限公司 | 一种化合物的药物组合物、其固体形式及它们的使用方法 |
| US20150031699A1 (en) | 2013-07-26 | 2015-01-29 | Boehringer Ingelheim International Gmbh | Treatment of myelodysplastic syndrome |
| ES2823756T3 (es) | 2014-04-16 | 2021-05-10 | Signal Pharm Llc | Métodos para tratar el cáncer usando terapia de combinación de inhibidores de quinasa TOR |
| NZ714742A (en) | 2014-04-16 | 2017-04-28 | Signal Pharm Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use |
| US9512129B2 (en) | 2014-04-16 | 2016-12-06 | Signal Pharmaceuticals, Llc | Solid forms comprising 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer |
| US9718824B2 (en) | 2014-04-16 | 2017-08-01 | Signal Pharmaceuticals, Llc | Solid forms comprising 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and a coformer, compositions and methods of use thereof |
| PT3166607T (pt) | 2014-07-11 | 2022-12-07 | Gilead Sciences Inc | Moduladores de receptores de tipo toll para o tratamento do vih |
| EP3169686A4 (en) | 2014-07-14 | 2018-01-24 | Signal Pharmaceuticals, LLC | Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof |
| NZ629796A (en) | 2014-07-14 | 2015-12-24 | Signal Pharm Llc | Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use |
| PT3194401T (pt) | 2014-09-16 | 2020-12-23 | Gilead Sciences Inc | Formas sólidas de modulador de recetor tipo toll |
| EP3194402B1 (en) | 2014-09-16 | 2018-11-21 | Gilead Sciences, Inc. | Methods of preparing toll-like receptor modulators |
| US9867831B2 (en) | 2014-10-01 | 2018-01-16 | Boehringer Ingelheim International Gmbh | Combination treatment of acute myeloid leukemia and myelodysplastic syndrome |
| BR112019027402A2 (pt) | 2017-06-22 | 2020-07-07 | Celgene Corporation | tratamento de carcinoma hepatocelular caracterizado por infecção pelo vírus da hepatite b |
| KR102272284B1 (ko) * | 2020-01-13 | 2021-07-02 | 금오공과대학교 산학협력단 | 정밀 압력제어가 가능한 다단 스프링 압력제어밸브 |
| TW202523311A (zh) * | 2023-10-16 | 2025-06-16 | 美商克洛諾斯生技有限公司 | 離胺酸乙醯基轉移酶抑制劑 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4077955A (en) * | 1977-02-17 | 1978-03-07 | E. R. Squibb & Sons, Inc. | Amino derivatives of 1,2,3,4-tetrahydro-2-oxopyrido[2,2-b]-pyrazine carboxylic acids and esters |
| GR72941B (OSRAM) * | 1978-10-20 | 1984-01-16 | Lilly Co Eli | |
| IE58312B1 (en) * | 1984-05-18 | 1993-09-08 | Union Pharma Scient Appl | Heterocyclic derivatives, processes for their preparation and drugs in which they are present, which are useful especially as aldose reductase inhibitors |
| JPH0276860A (ja) * | 1987-10-05 | 1990-03-16 | Toyo Jozo Co Ltd | ６−置換アルコキシ−２−オキソ−１，２−ジヒドロキノキサリン誘導体 |
| DK160876C (da) * | 1987-12-08 | 1991-10-14 | Novo Nordisk As | Imidazoquinoxalinforbindelser, fremgangsmaade til deres fremstilling, anvendelse af forbindelserne og farmaceutiske praeparater, hvori forbindelserne indgaar |
| EP0509398B1 (de) * | 1991-04-15 | 2001-09-19 | Aventis Pharma Deutschland GmbH | Chinoxaline, Verfahren zu ihrer Herstellung und ihre Verwendung |
-
1993
- 1993-09-09 TW TW082107380A patent/TW274550B/zh active
- 1993-09-16 DE DE59309902T patent/DE59309902D1/de not_active Expired - Fee Related
- 1993-09-16 ES ES93114934T patent/ES2141744T3/es not_active Expired - Lifetime
- 1993-09-16 DK DK93114934T patent/DK0590428T3/da active
- 1993-09-16 AT AT93114934T patent/ATE187724T1/de not_active IP Right Cessation
- 1993-09-16 PT PT93114934T patent/PT590428E/pt unknown
- 1993-09-16 EP EP93114934A patent/EP0590428B1/de not_active Expired - Lifetime
- 1993-09-23 US US08/125,163 patent/US5424311A/en not_active Expired - Lifetime
- 1993-09-23 IL IL10708193A patent/IL107081A/en not_active IP Right Cessation
- 1993-09-23 AU AU47553/93A patent/AU664643B2/en not_active Ceased
- 1993-09-24 ZA ZA937081A patent/ZA937081B/xx unknown
- 1993-09-24 MX MX9305894A patent/MX9305894A/es not_active IP Right Cessation
- 1993-09-24 CZ CZ932005A patent/CZ9302005A3/cs unknown
- 1993-09-24 HU HU9302696A patent/HUT65302A/hu unknown
- 1993-09-24 CA CA002106882A patent/CA2106882C/en not_active Expired - Fee Related
- 1993-09-24 JP JP5237679A patent/JPH06211855A/ja active Pending
- 1993-09-24 PH PH46948A patent/PH30348A/en unknown
- 1993-09-24 NZ NZ248762A patent/NZ248762A/en unknown
- 1993-09-25 KR KR1019930019733A patent/KR940007035A/ko not_active Withdrawn
-
2000
- 2000-01-31 GR GR20000400216T patent/GR3032520T3/el not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| US5424311A (en) | 1995-06-13 |
| ZA937081B (en) | 1994-04-18 |
| JPH06211855A (ja) | 1994-08-02 |
| ES2141744T3 (es) | 2000-04-01 |
| CA2106882A1 (en) | 1994-03-27 |
| TW274550B (OSRAM) | 1996-04-21 |
| NZ248762A (en) | 1996-01-26 |
| GR3032520T3 (en) | 2000-05-31 |
| IL107081A0 (en) | 1993-12-28 |
| EP0590428A1 (de) | 1994-04-06 |
| MX9305894A (es) | 1994-03-31 |
| DK0590428T3 (da) | 2000-05-22 |
| EP0590428B1 (de) | 1999-12-15 |
| PH30348A (en) | 1997-04-02 |
| PT590428E (pt) | 2000-04-28 |
| IL107081A (en) | 1999-07-14 |
| HU9302696D0 (en) | 1993-12-28 |
| HUT65302A (en) | 1994-05-02 |
| ATE187724T1 (de) | 2000-01-15 |
| KR940007035A (ko) | 1994-04-26 |
| AU664643B2 (en) | 1995-11-23 |
| AU4755393A (en) | 1994-03-31 |
| CZ9302005A3 (en) | 1994-04-13 |
| DE59309902D1 (de) | 2000-01-20 |
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| EEER | Examination request | ||
| MKLA | Lapsed |