NO333165B1 - Forbindelse og sammensetning, og anvendelse av samme - Google Patents
Forbindelse og sammensetning, og anvendelse av samme Download PDFInfo
- Publication number
- NO333165B1 NO333165B1 NO20052529A NO20052529A NO333165B1 NO 333165 B1 NO333165 B1 NO 333165B1 NO 20052529 A NO20052529 A NO 20052529A NO 20052529 A NO20052529 A NO 20052529A NO 333165 B1 NO333165 B1 NO 333165B1
- Authority
- NO
- Norway
- Prior art keywords
- compound
- dimethyl
- group
- alkyl
- pyridyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 176
- 239000000203 mixture Substances 0.000 title claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 82
- -1 methylpiperazinyl Chemical group 0.000 claims description 46
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
- 230000003444 anaesthetic effect Effects 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 239000001301 oxygen Substances 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical group C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 229910052717 sulfur Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 230000001624 sedative effect Effects 0.000 claims description 6
- 239000011593 sulfur Chemical group 0.000 claims description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 5
- 239000005864 Sulphur Substances 0.000 claims description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 239000000932 sedative agent Substances 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 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 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 2
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 238000010253 intravenous injection Methods 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 206010002091 Anaesthesia Diseases 0.000 abstract description 11
- 230000037005 anaesthesia Effects 0.000 abstract description 11
- 241000124008 Mammalia Species 0.000 abstract description 6
- 206010039897 Sedation Diseases 0.000 abstract description 3
- 230000036280 sedation Effects 0.000 abstract description 3
- 230000001939 inductive effect Effects 0.000 abstract description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 114
- 239000000243 solution Substances 0.000 description 72
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 54
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 47
- 238000005160 1H NMR spectroscopy Methods 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 20
- 239000013078 crystal Substances 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 238000010438 heat treatment Methods 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000012300 argon atmosphere Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- GSCXPNAZEUKIRW-UHFFFAOYSA-N 2-(5,6-dimethyl-3-oxo-2-pyridin-3-yl-1h-isoindol-1-yl)acetic acid Chemical compound O=C1C=2C=C(C)C(C)=CC=2C(CC(O)=O)N1C1=CC=CN=C1 GSCXPNAZEUKIRW-UHFFFAOYSA-N 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- HGHNFTPDMNDNAT-UHFFFAOYSA-N propyl 2-(5,6-dimethyl-3-oxo-2-pyridin-3-yl-1h-isoindol-1-yl)acetate Chemical compound O=C1C2=CC(C)=C(C)C=C2C(CC(=O)OCCC)N1C1=CC=CN=C1 HGHNFTPDMNDNAT-UHFFFAOYSA-N 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- CMQYISATYUYSAC-UHFFFAOYSA-N 5,6-dimethyl-2-benzofuran-1,3-dione Chemical compound C1=C(C)C(C)=CC2=C1C(=O)OC2=O CMQYISATYUYSAC-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000003193 general anesthetic agent Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- AOAQTWFVCRFMNZ-UHFFFAOYSA-N 5,6-diethyl-2-benzofuran-1,3-dione Chemical compound C1=C(CC)C(CC)=CC2=C1C(=O)OC2=O AOAQTWFVCRFMNZ-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000002198 insoluble material Substances 0.000 description 5
- 239000002869 intravenous anesthetic agent Substances 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- SDJHPPZKZZWAKF-UHFFFAOYSA-N 2,3-dimethylbuta-1,3-diene Chemical compound CC(=C)C(C)=C SDJHPPZKZZWAKF-UHFFFAOYSA-N 0.000 description 4
- SKBDLRWFSRLIPP-UHFFFAOYSA-N 4,5-Dimethoxy-1,2-benzenedicarboxylic acid Chemical compound COC1=CC(C(O)=O)=C(C(O)=O)C=C1OC SKBDLRWFSRLIPP-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- KPFOHKBCRCNQET-UHFFFAOYSA-N ethyl 2-(5,6-dimethyl-3-oxo-2-pyridin-3-yl-1h-isoindol-1-yl)acetate Chemical compound O=C1C2=CC(C)=C(C)C=C2C(CC(=O)OCC)N1C1=CC=CN=C1 KPFOHKBCRCNQET-UHFFFAOYSA-N 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 229940102223 injectable solution Drugs 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 4
- 231100000636 lethal dose Toxicity 0.000 description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 4
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 230000011514 reflex Effects 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- SCNRSSJYBCTXRS-UHFFFAOYSA-N 2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-1h-isoindole-1-carboxylic acid Chemical compound O=C1C=2C=C(C)C(C)=CC=2C(C(O)=O)N1C1=CC=CC(F)=C1 SCNRSSJYBCTXRS-UHFFFAOYSA-N 0.000 description 3
- NJFLCFRMAMBFPR-UHFFFAOYSA-N 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-1h-isoindol-1-yl]ethyl methanesulfonate Chemical compound O=C1C=2C=C(C)C(C)=CC=2C(CCOS(C)(=O)=O)N1C1=CC=C(F)C=C1 NJFLCFRMAMBFPR-UHFFFAOYSA-N 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- GZDVRHDRMZHOMX-UHFFFAOYSA-N 3-(2-hydroxyethyl)-5,6-dimethyl-2-pyridin-3-yl-3h-isoindol-1-one Chemical compound O=C1C=2C=C(C)C(C)=CC=2C(CCO)N1C1=CC=CN=C1 GZDVRHDRMZHOMX-UHFFFAOYSA-N 0.000 description 3
- IHUYUMPALWUDCU-UHFFFAOYSA-N 4,6-dimethyl-2-benzofuran-1,3-dione Chemical compound CC1=CC(C)=CC2=C1C(=O)OC2=O IHUYUMPALWUDCU-UHFFFAOYSA-N 0.000 description 3
- PLFXUMVRDDKJDH-UHFFFAOYSA-N 5,6-dimethyl-2-pyridin-3-ylisoindole-1,3-dione Chemical compound O=C1C=2C=C(C)C(C)=CC=2C(=O)N1C1=CC=CN=C1 PLFXUMVRDDKJDH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- KCHNCQINIRYRBS-UHFFFAOYSA-N ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-1h-isoindol-1-yl]acetate Chemical compound O=C1C2=CC(C)=C(C)C=C2C(CC(=O)OCC)N1C1=CC=C(F)C=C1 KCHNCQINIRYRBS-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000003301 hydrolyzing effect Effects 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 229960004134 propofol Drugs 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229960000340 thiopental sodium Drugs 0.000 description 3
- AWLILQARPMWUHA-UHFFFAOYSA-M thiopental sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC([S-])=NC1=O AWLILQARPMWUHA-UHFFFAOYSA-M 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- UKSYDMMYGPSGSO-CXUHLZMHSA-N (2e)-2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxoisoindol-1-ylidene]acetic acid Chemical compound OC(=O)/C=C/1C=2C=C(C)C(C)=CC=2C(=O)N\1C1=CC=C(F)C=C1 UKSYDMMYGPSGSO-CXUHLZMHSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
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- 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
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
- C07D209/64—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with an oxygen atom in position 1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/70—[b]- or [c]-condensed containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Anesthesiology (AREA)
- Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Steroid Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002342399 | 2002-11-26 | ||
| PCT/JP2003/014986 WO2004048332A1 (fr) | 2002-11-26 | 2003-11-25 | Derive de l'isoindoline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO20052529L NO20052529L (no) | 2005-06-23 |
| NO333165B1 true NO333165B1 (no) | 2013-03-25 |
Family
ID=32375878
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20052529A NO333165B1 (no) | 2002-11-26 | 2005-05-26 | Forbindelse og sammensetning, og anvendelse av samme |
Country Status (24)
| Country | Link |
|---|---|
| US (2) | US7521451B2 (fr) |
| EP (1) | EP1566378B1 (fr) |
| KR (1) | KR101149978B1 (fr) |
| CN (1) | CN100548980C (fr) |
| AR (1) | AR042139A1 (fr) |
| AU (1) | AU2003284669B2 (fr) |
| BR (1) | BR0316645A (fr) |
| CA (1) | CA2505029C (fr) |
| DK (1) | DK1566378T3 (fr) |
| EC (1) | ECSP055886A (fr) |
| ES (1) | ES2393645T3 (fr) |
| HK (1) | HK1079201A1 (fr) |
| IL (1) | IL168477A (fr) |
| MX (1) | MXPA05005580A (fr) |
| NO (1) | NO333165B1 (fr) |
| NZ (1) | NZ539834A (fr) |
| PE (1) | PE20040698A1 (fr) |
| PL (1) | PL376890A1 (fr) |
| PT (1) | PT1566378E (fr) |
| RU (1) | RU2343145C2 (fr) |
| TW (1) | TWI320408B (fr) |
| UY (1) | UY28094A1 (fr) |
| WO (1) | WO2004048332A1 (fr) |
| ZA (1) | ZA200503697B (fr) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005113501A1 (fr) * | 2004-05-24 | 2005-12-01 | Maruishi Pharmaceutical Co., Ltd. | Composition d’agent de contrôle de douleurs neurogènes |
| EP1960385A1 (fr) * | 2005-11-01 | 2008-08-27 | Janssen Pharmaceutica N.V. | Dihydroisoindolones substitutées modulateurs utilisées en tant que allostériques de la glucokinase |
| US8110681B2 (en) | 2006-03-17 | 2012-02-07 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Compounds for the treatment of spinal muscular atrophy and other uses |
| WO2008008020A1 (fr) * | 2006-07-12 | 2008-01-17 | Astrazeneca Ab | DÉrivÉs de 3-OXOISOINDOLINE-1-CARBOXAMIDE en tant qu'analgÉsiques |
| TWI417100B (zh) * | 2007-06-07 | 2013-12-01 | Astrazeneca Ab | 二唑衍生物及其作為代謝型麩胺酸受體增效劑-８４２之用途 |
| CA2700841A1 (fr) * | 2007-09-27 | 2009-04-02 | The United States Of America, As Represented By The Secretary, Departmen T Of Health And Human Services | Composes d'isoindoline pour le traitement d'une amyotrophie spinale et autres utilisations |
| GB0811643D0 (en) | 2008-06-25 | 2008-07-30 | Cancer Rec Tech Ltd | New therapeutic agents |
| US9682967B2 (en) | 2013-01-28 | 2017-06-20 | H. Lundbeck A/S | N-substituted-5-substituted phthalamic acids as sortilin inhibitors |
| CN105254554B (zh) * | 2014-07-14 | 2018-01-30 | 南开大学 | 一种制备异吲哚啉酮类化合物的方法 |
| CN104803905B (zh) * | 2015-04-17 | 2017-10-10 | 复旦大学 | 一种合成异吲哚啉‑1‑酮衍生物的方法 |
| ITRM20150196A1 (it) * | 2015-05-05 | 2016-11-05 | Univ Degli Studi Di Salerno | Isoindolinoni, procedimenti per la produzione di loro derivati chirali e impiego di questi ultimi |
| GB201517217D0 (en) | 2015-09-29 | 2015-11-11 | Astex Therapeutics Ltd And Cancer Res Technology Ltd | Pharmaceutical compounds |
| GB201517216D0 (en) | 2015-09-29 | 2015-11-11 | Cancer Res Technology Ltd And Astex Therapeutics Ltd | Pharmaceutical compounds |
| GB201704965D0 (en) | 2017-03-28 | 2017-05-10 | Astex Therapeutics Ltd | Pharmaceutical compounds |
| GB201704966D0 (en) | 2017-03-28 | 2017-05-10 | Astex Therapeutics Ltd | Pharmaceutical compounds |
| CN110698445B (zh) * | 2018-07-09 | 2023-05-12 | 四川大学 | 一类3-胺烷基苯酞类化合物、其制备方法和用途 |
| CN114641337A (zh) * | 2019-08-27 | 2022-06-17 | 密歇根大学董事会 | Cereblon e3连接酶抑制剂 |
| CN110498759A (zh) * | 2019-09-12 | 2019-11-26 | 天津瑞岭化工有限公司 | 异吲哚啉酮类化合物的合成方法 |
| TW202140448A (zh) * | 2020-01-16 | 2021-11-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | 並環醯亞胺類衍生物、其製備方法及其在醫藥上的應用 |
| WO2021143816A1 (fr) * | 2020-01-16 | 2021-07-22 | 江苏恒瑞医药股份有限公司 | Dérivé imide fusionné, son procédé de préparation et son utilisation médicale |
| CN114539124B (zh) * | 2022-02-28 | 2023-07-21 | 大连大学 | 一种对映选择性合成n,3-二取代-1-异吲哚啉酮化合物的方法 |
| CN114394926B (zh) * | 2022-02-28 | 2023-06-27 | 大连大学 | N,3-二取代-1-异吲哚啉酮类化合物的高产率合成方法 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2101081B1 (fr) | 1970-08-19 | 1974-01-11 | Rhone Poulenc Sa | |
| US3679686A (en) | 1970-09-09 | 1972-07-25 | Janssen Pharmaceutica Nv | N-(bicycloamino-alkanoyl)-anilines |
| FR2117740B1 (fr) * | 1970-12-14 | 1974-04-12 | Rhone Poulenc Sa | |
| JPS4712322U (fr) | 1971-03-09 | 1972-10-13 | ||
| GB1472793A (en) * | 1974-03-28 | 1977-05-04 | Ici Ltd | Pharmaceutical compositions |
| OA05287A (fr) | 1975-04-07 | 1981-02-28 | Rhone Poulenc Ind | Nouveaux composés hétérocycliques et leur préparation. |
| JPS58189163A (ja) | 1982-04-02 | 1983-11-04 | Takeda Chem Ind Ltd | 縮合ピロリノン誘導体 |
| ATE39483T1 (de) * | 1982-04-02 | 1989-01-15 | Takeda Chemical Industries Ltd | Kondensierte pyrrolinon-derivate, und ihre herstellung. |
| US5932613A (en) | 1996-07-03 | 1999-08-03 | Millennium Pharmaceuticals, Inc. | Anticancer agents |
| KR19980074060A (ko) * | 1997-03-21 | 1998-11-05 | 김윤배 | 신규한 치환된 3,4-디알콕시페닐 유도체 |
| WO1999000121A1 (fr) * | 1997-06-26 | 1999-01-07 | Eli Lilly And Company | Agents antithrombotiques |
| ATE335482T1 (de) | 1999-06-10 | 2006-09-15 | Bridge Pharma Inc | Dermale anästhetika |
| WO2005113501A1 (fr) * | 2004-05-24 | 2005-12-01 | Maruishi Pharmaceutical Co., Ltd. | Composition d’agent de contrôle de douleurs neurogènes |
-
2003
- 2003-11-25 ZA ZA200503697A patent/ZA200503697B/en unknown
- 2003-11-25 RU RU2005120003/04A patent/RU2343145C2/ru not_active IP Right Cessation
- 2003-11-25 CN CNB2003801091898A patent/CN100548980C/zh not_active Expired - Fee Related
- 2003-11-25 AU AU2003284669A patent/AU2003284669B2/en not_active Ceased
- 2003-11-25 PE PE2003001193A patent/PE20040698A1/es not_active Application Discontinuation
- 2003-11-25 PL PL376890A patent/PL376890A1/pl not_active Application Discontinuation
- 2003-11-25 BR BR0316645-7A patent/BR0316645A/pt not_active IP Right Cessation
- 2003-11-25 US US10/534,414 patent/US7521451B2/en not_active Expired - Fee Related
- 2003-11-25 EP EP03774195A patent/EP1566378B1/fr not_active Expired - Lifetime
- 2003-11-25 MX MXPA05005580A patent/MXPA05005580A/es active IP Right Grant
- 2003-11-25 CA CA2505029A patent/CA2505029C/fr not_active Expired - Fee Related
- 2003-11-25 PT PT03774195T patent/PT1566378E/pt unknown
- 2003-11-25 DK DK03774195.6T patent/DK1566378T3/da active
- 2003-11-25 AR ARP030104343A patent/AR042139A1/es not_active Application Discontinuation
- 2003-11-25 TW TW092133012A patent/TWI320408B/zh not_active IP Right Cessation
- 2003-11-25 ES ES03774195T patent/ES2393645T3/es not_active Expired - Lifetime
- 2003-11-25 KR KR1020057009070A patent/KR101149978B1/ko not_active IP Right Cessation
- 2003-11-25 UY UY28094A patent/UY28094A1/es not_active Application Discontinuation
- 2003-11-25 WO PCT/JP2003/014986 patent/WO2004048332A1/fr not_active Application Discontinuation
- 2003-11-25 NZ NZ539834A patent/NZ539834A/en not_active IP Right Cessation
-
2005
- 2005-05-09 IL IL168477A patent/IL168477A/en not_active IP Right Cessation
- 2005-05-26 NO NO20052529A patent/NO333165B1/no not_active IP Right Cessation
- 2005-06-22 EC EC2005005886A patent/ECSP055886A/es unknown
- 2005-12-06 HK HK05111157.1A patent/HK1079201A1/xx not_active IP Right Cessation
-
2008
- 2008-12-30 US US12/318,453 patent/US20090170835A1/en not_active Abandoned
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| CHAD | Change of the owner's name or address (par. 44 patent law, par. patentforskriften) |
Owner name: MARUISHI PHARMACEUTICAL CO LTD, JP |
|
| MM1K | Lapsed by not paying the annual fees |