DE69722003T2 - Substituierte bisindolylmaleimide zur inhibierung der zellproliferation - Google Patents
Substituierte bisindolylmaleimide zur inhibierung der zellproliferation Download PDFInfo
- Publication number
- DE69722003T2 DE69722003T2 DE69722003T DE69722003T DE69722003T2 DE 69722003 T2 DE69722003 T2 DE 69722003T2 DE 69722003 T DE69722003 T DE 69722003T DE 69722003 T DE69722003 T DE 69722003T DE 69722003 T2 DE69722003 T2 DE 69722003T2
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- alkyl
- compound
- indol
- formula
- 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.)
- Expired - Fee Related
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- 230000004663 cell proliferation Effects 0.000 title claims description 3
- 230000002401 inhibitory effect Effects 0.000 title claims 2
- 150000003924 bisindolylmaleimides Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
- -1 acetic acid-1-methyl-3- [4- (1-methyl-1H-indol-3-yl) -2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl ] -1H-indol-6-yl-methylester Chemical compound 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 12
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 150000007513 acids Chemical class 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 150000007514 bases Chemical class 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- FIHANSAKBFCDEI-UHFFFAOYSA-N 3-[6-(hydroxymethyl)-1-methylindol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=C(CO)C=C3N(C)C=2)C(=O)NC1=O FIHANSAKBFCDEI-UHFFFAOYSA-N 0.000 claims description 2
- AQLOOCUUKNWXPG-UHFFFAOYSA-N 3-[6-(methoxymethyl)-1-methylindol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C1=CC=C2C(C3=C(C(NC3=O)=O)C=3C4=CC=C(C=C4N(C)C=3)COC)=CN(C)C2=C1 AQLOOCUUKNWXPG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- 239000000460 chlorine Substances 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 150000003233 pyrroles Chemical class 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 238000005987 sulfurization reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- DVINAGLCMNECAC-UHFFFAOYSA-N 1-methyl-3-[4-(1-methylindol-3-yl)-2,5-dioxopyrrol-3-yl]indole-6-carbonitrile Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=C(C=C3N(C)C=2)C#N)C(=O)NC1=O DVINAGLCMNECAC-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
- 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YDMPSBJXPPXTCM-UHFFFAOYSA-N (1-methylindol-6-yl)methanol Chemical compound C1=C(CO)C=C2N(C)C=CC2=C1 YDMPSBJXPPXTCM-UHFFFAOYSA-N 0.000 description 2
- GMZLJGSFSROWDH-UHFFFAOYSA-N (1-propan-2-ylindol-6-yl)methanol Chemical compound C1=C(CO)C=C2N(C(C)C)C=CC2=C1 GMZLJGSFSROWDH-UHFFFAOYSA-N 0.000 description 2
- SFQHEVSHOZMLHO-UHFFFAOYSA-N 1-methyl-3-[4-(1-methylindol-3-yl)-2,5-dioxopyrrol-3-yl]indole-5-carbonitrile Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC(=CC=C3N(C)C=2)C#N)C(=O)NC1=O SFQHEVSHOZMLHO-UHFFFAOYSA-N 0.000 description 2
- JDFHTCHKNZWWME-UHFFFAOYSA-N 1-methyl-3-[4-(1-methylindol-3-yl)-2,5-dioxopyrrol-3-yl]indole-6-carboxamide Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=C(C=C3N(C)C=2)C(N)=O)C(=O)NC1=O JDFHTCHKNZWWME-UHFFFAOYSA-N 0.000 description 2
- FOGAAHLMYPQCJG-UHFFFAOYSA-N 1-methylindole-6-carbonitrile Chemical compound C1=C(C#N)C=C2N(C)C=CC2=C1 FOGAAHLMYPQCJG-UHFFFAOYSA-N 0.000 description 2
- RDUNGWNDEZRPNR-UHFFFAOYSA-N 3-[6-(methoxymethyl)-1-propan-2-ylindol-3-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C1=CC=C2C(C3=C(C(NC3=O)=O)C=3C4=CC=C(C=C4N(C(C)C)C=3)COC)=CN(C)C2=C1 RDUNGWNDEZRPNR-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- FYANEFRVLHNRCQ-UHFFFAOYSA-N 6-(methoxymethyl)-1-methylindole Chemical compound COCC1=CC=C2C=CN(C)C2=C1 FYANEFRVLHNRCQ-UHFFFAOYSA-N 0.000 description 2
- QIGUKECNAHDTBJ-UHFFFAOYSA-N 6-(methoxymethyl)-1-propan-2-ylindole Chemical compound COCC1=CC=C2C=CN(C(C)C)C2=C1 QIGUKECNAHDTBJ-UHFFFAOYSA-N 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- QFHTWTKDRUFTJW-UHFFFAOYSA-N methyl 1-propan-2-ylindole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=CN(C(C)C)C2=C1 QFHTWTKDRUFTJW-UHFFFAOYSA-N 0.000 description 2
- FWZSWIXOPWURKN-UHFFFAOYSA-N methyl 3-amino-4-(2,2-dimethoxyethyl)benzoate Chemical compound COC(OC)CC1=CC=C(C(=O)OC)C=C1N FWZSWIXOPWURKN-UHFFFAOYSA-N 0.000 description 2
- IGBYHOJRPXOEHX-UHFFFAOYSA-N methyl 4-(2,2-dimethoxyethyl)-3-(propan-2-ylamino)benzoate Chemical compound COC(OC)CC1=CC=C(C(=O)OC)C=C1NC(C)C IGBYHOJRPXOEHX-UHFFFAOYSA-N 0.000 description 2
- IUYADMKILLYZCD-UHFFFAOYSA-N methyl 4-(2,2-dimethoxyethyl)-3-nitrobenzoate Chemical compound COC(OC)CC1=CC=C(C(=O)OC)C=C1[N+]([O-])=O IUYADMKILLYZCD-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000004001 thioalkyl group Chemical group 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- NSEKMGOCNRXLEG-UHFFFAOYSA-N (1-methylindol-6-yl)methyl acetate Chemical compound CC(=O)OCC1=CC=C2C=CN(C)C2=C1 NSEKMGOCNRXLEG-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- MDWMQNXUCMJGRZ-UHFFFAOYSA-N 1-methyl-3-[4-(1-methylindol-3-yl)-2,5-dioxopyrrol-3-yl]indole-6-carbaldehyde Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=C(C=O)C=C3N(C)C=2)C(=O)NC1=O MDWMQNXUCMJGRZ-UHFFFAOYSA-N 0.000 description 1
- BQVYRVFEBOGTBZ-UHFFFAOYSA-N 1-methyl-3-[4-(1-methylindol-3-yl)-2,5-dioxopyrrol-3-yl]indole-6-carboxylic acid Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=C(C=C3N(C)C=2)C(O)=O)C(=O)NC1=O BQVYRVFEBOGTBZ-UHFFFAOYSA-N 0.000 description 1
- DYZZFEHAJOLDEX-UHFFFAOYSA-N 1-methylindole-5-carbonitrile Chemical compound N#CC1=CC=C2N(C)C=CC2=C1 DYZZFEHAJOLDEX-UHFFFAOYSA-N 0.000 description 1
- QGAKKGIWURKKHV-UHFFFAOYSA-N 1-methylindole-6-carbaldehyde Chemical compound C1=C(C=O)C=C2N(C)C=CC2=C1 QGAKKGIWURKKHV-UHFFFAOYSA-N 0.000 description 1
- DJQOGNYSBOIJKE-UHFFFAOYSA-N 1-methylindole-6-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2N(C)C=CC2=C1 DJQOGNYSBOIJKE-UHFFFAOYSA-N 0.000 description 1
- WRMZOPANDOHWJU-UHFFFAOYSA-N 1h-indol-6-ylmethanol Chemical compound OCC1=CC=C2C=CNC2=C1 WRMZOPANDOHWJU-UHFFFAOYSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- WEFXNTLSKCMIME-UHFFFAOYSA-N 2-(6-cyano-1-methylindol-3-yl)-2-oxoacetyl chloride Chemical compound C1=C(C#N)C=C2N(C)C=C(C(=O)C(Cl)=O)C2=C1 WEFXNTLSKCMIME-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- PQCIKDQZCZDCAD-UHFFFAOYSA-N 2-methylsulfanyl-1,3,2,4-dithiadiphosphetane Chemical compound CSP1SPS1 PQCIKDQZCZDCAD-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- BBEWSMNRCUXQRF-UHFFFAOYSA-N 4-methyl-3-nitrobenzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1[N+]([O-])=O BBEWSMNRCUXQRF-UHFFFAOYSA-N 0.000 description 1
- LSBHSDZNFDNMSD-UHFFFAOYSA-N 6-(methoxymethyl)-1h-indole Chemical compound COCC1=CC=C2C=CNC2=C1 LSBHSDZNFDNMSD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UYVZKMXNEGJIOQ-UHFFFAOYSA-N CN1C=C(C2=CC=CC=C12)C=1C(NC(C1C1=CN(C2=CC=CC=C12)C)=O)=O.C(C)(=O)O Chemical compound CN1C=C(C2=CC=CC=C12)C=1C(NC(C1C1=CN(C2=CC=CC=C12)C)=O)=O.C(C)(=O)O UYVZKMXNEGJIOQ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- 229910052783 alkali metal Inorganic materials 0.000 description 1
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- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
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- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- MHOPHBTXZRCXJY-UHFFFAOYSA-N ethyl 1-methyl-3-[4-(1-methylindol-3-yl)-2,5-dioxopyrrol-3-yl]indole-6-carboxylate Chemical compound C1=CC=C2C(C3=C(C(NC3=O)=O)C=3C4=CC=C(C=C4N(C)C=3)C(=O)OCC)=CN(C)C2=C1 MHOPHBTXZRCXJY-UHFFFAOYSA-N 0.000 description 1
- DONAUJDYIXJJJF-UHFFFAOYSA-N ethyl 1-methylindole-6-carboxylate Chemical compound CCOC(=O)C1=CC=C2C=CN(C)C2=C1 DONAUJDYIXJJJF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 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 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
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- 150000007522 mineralic acids Chemical class 0.000 description 1
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- 230000000771 oncological effect Effects 0.000 description 1
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- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- KHBZWURVKMBOJF-UHFFFAOYSA-N propan-2-yl 2-(1-methylindol-3-yl)ethanimidate;hydrochloride Chemical compound Cl.C1=CC=C2C(CC(=N)OC(C)C)=CN(C)C2=C1 KHBZWURVKMBOJF-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
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000012418 sodium perborate tetrahydrate Substances 0.000 description 1
- IBDSNZLUHYKHQP-UHFFFAOYSA-N sodium;3-oxidodioxaborirane;tetrahydrate Chemical compound O.O.O.O.[Na+].[O-]B1OO1 IBDSNZLUHYKHQP-UHFFFAOYSA-N 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- 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
- C07D403/14—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 three or more hetero rings
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2207996P | 1996-07-29 | 1996-07-29 | |
| US22079P | 1996-07-29 | ||
| PCT/EP1997/003889 WO1998004552A1 (en) | 1996-07-29 | 1997-07-19 | Substituted bisindolylmaleimides for the inhibition of cell proliferation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69722003D1 DE69722003D1 (de) | 2003-06-18 |
| DE69722003T2 true DE69722003T2 (de) | 2004-04-01 |
Family
ID=21807711
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69722003T Expired - Fee Related DE69722003T2 (de) | 1996-07-29 | 1997-07-19 | Substituierte bisindolylmaleimide zur inhibierung der zellproliferation |
Country Status (23)
| Country | Link |
|---|---|
| US (2) | US5856517A (cg-RX-API-DMAC7.html) |
| EP (1) | EP0915872B1 (cg-RX-API-DMAC7.html) |
| JP (1) | JP2000516589A (cg-RX-API-DMAC7.html) |
| KR (1) | KR20000029637A (cg-RX-API-DMAC7.html) |
| CN (2) | CN1151149C (cg-RX-API-DMAC7.html) |
| AR (1) | AR008267A1 (cg-RX-API-DMAC7.html) |
| AT (1) | ATE240318T1 (cg-RX-API-DMAC7.html) |
| AU (1) | AU739742B2 (cg-RX-API-DMAC7.html) |
| BR (1) | BR9711605A (cg-RX-API-DMAC7.html) |
| CA (1) | CA2262092A1 (cg-RX-API-DMAC7.html) |
| CO (1) | CO4900055A1 (cg-RX-API-DMAC7.html) |
| CY (1) | CY2483B1 (cg-RX-API-DMAC7.html) |
| DE (1) | DE69722003T2 (cg-RX-API-DMAC7.html) |
| DK (1) | DK0915872T3 (cg-RX-API-DMAC7.html) |
| ES (1) | ES2198001T3 (cg-RX-API-DMAC7.html) |
| HR (1) | HRP970414A2 (cg-RX-API-DMAC7.html) |
| MA (1) | MA24287A1 (cg-RX-API-DMAC7.html) |
| PE (1) | PE91698A1 (cg-RX-API-DMAC7.html) |
| PT (1) | PT915872E (cg-RX-API-DMAC7.html) |
| SA (1) | SA97180473A (cg-RX-API-DMAC7.html) |
| TR (1) | TR199900157T2 (cg-RX-API-DMAC7.html) |
| WO (1) | WO1998004552A1 (cg-RX-API-DMAC7.html) |
| ZA (1) | ZA976492B (cg-RX-API-DMAC7.html) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR200002580T2 (tr) * | 1998-03-17 | 2000-11-21 | F.Hoffmann-La Roche Ag | Hücre çoğalmasının engellenmesinde kullanılan ikameli bisindolimaleimitler |
| WO2001044247A2 (en) * | 1999-12-16 | 2001-06-21 | Eli Lilly And Company | Agents and methods for the treatment of proliferative diseases |
| ATE267194T1 (de) * | 1999-12-16 | 2004-06-15 | Lilly Co Eli | Medikamente geeignet zur behandlung von proliferativen erkrankungen |
| US6743785B2 (en) * | 1999-12-16 | 2004-06-01 | Eli Lilly And Company | Agents and methods for the treatment of proliferative diseases |
| US6313143B1 (en) * | 1999-12-16 | 2001-11-06 | Hoffmann-La Roche Inc. | Substituted pyrroles |
| US6281356B1 (en) * | 1999-12-22 | 2001-08-28 | Hoffmann-La Roche Inc. | Substituted pyrroles |
| TWI335221B (en) | 2001-09-27 | 2011-01-01 | Alcon Inc | Inhibtors of glycogen synthase kinase-3 (gsk-3) for treating glaucoma |
| US20030139373A1 (en) * | 2001-11-20 | 2003-07-24 | Breimer Lars Holger | Method for cancer therapy |
| MY142390A (en) * | 2002-05-22 | 2010-11-30 | Glaxosmithkline Llc | 3' - [(2z)-[1-(3,4-dimethylphenyl)-1,5- dihydro-3- methyl-5-0xo-4h-pyrazol-4- ylidene]hydrazino]-2' -hydroxy -[1,1' -biphenyl]-3-carboxylic acid bis-(monoethanolamine) |
| US7012100B1 (en) | 2002-06-04 | 2006-03-14 | Avolix Pharmaceuticals, Inc. | Cell migration inhibiting compositions and methods and compositions for treating cancer |
| SI1846406T1 (sl) | 2005-02-09 | 2011-02-28 | Arqule Inc | Maleimidni derivati, farmacevtski sestavki in postopki za zdravljenje raka |
| MX2009006533A (es) * | 2006-12-19 | 2009-06-26 | Novartis Ag | Derivados de indolil-maleimida como inhibidores de cinasa. |
| US8232285B2 (en) | 2007-06-22 | 2012-07-31 | Arqule, Inc. | Quinazolinone compounds and methods of use thereof |
| CA2690799C (en) | 2007-06-22 | 2015-06-16 | Arqule, Inc. | Pyrrolidinone, pyrrolidine-2,5-dione, pyrrolidine and thiosuccinimide derivatives, compositions and methods for treatment of cancer |
| US8513292B2 (en) | 2007-06-22 | 2013-08-20 | Arqule, Inc. | Compositions and methods for the treatment of cancer |
| JP2009035537A (ja) * | 2007-07-10 | 2009-02-19 | Nippon Synthetic Chem Ind Co Ltd:The | Ｎ−置換アニリン誘導体及び１−置換インドール誘導体の製造方法 |
| FR2927075A1 (fr) * | 2008-02-04 | 2009-08-07 | Centre Nat Rech Scient | Molecules comprenant un squelette bis-(heteroaryl)maleimide, et leur utilisation dans l'inhibition d'enzymes |
| GB201111427D0 (en) * | 2011-07-05 | 2011-08-17 | Amakem Nv | Novel bisindolylmaleimides, pan-pkc inhibitors |
| AU2015217152A1 (en) | 2014-02-11 | 2016-08-11 | Mitokinin, Inc. | Compositions and methods using the same for treatment of neurodegenerative and mitochondrial disease |
| JP2017524739A (ja) | 2014-07-17 | 2017-08-31 | アンセルムＩｎｓｅｒｍ | 神経筋接合部関連疾患の処置方法 |
| WO2016207366A1 (en) | 2015-06-26 | 2016-12-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of viral infections |
| AU2018290225A1 (en) * | 2017-06-21 | 2020-01-23 | Mitokinin, Inc. | Compositions and methods using the same for treatment of neurodegenerative and mitochondrial disease |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL89167A (en) * | 1988-02-10 | 1994-02-27 | Hoffmann La Roche | Substituted pyrroles, their manufacture and pharmaceutical compositions containing them |
| US5380746A (en) * | 1989-05-05 | 1995-01-10 | Goedecke Aktiengesellschaft | Bis-(1H-indol-3-YL)-maleinimide derivatives, processes for the preparation thereof and pharmaceutical compositions containing them |
| CA2015996C (en) * | 1989-05-05 | 2001-08-28 | Hartmut Osswald | Bis-(1h-indol-3-yl)-maleinimide derivatives and their use as pharmaceuticals |
| DE4005969A1 (de) * | 1990-02-26 | 1991-08-29 | Boehringer Mannheim Gmbh | Neue trisubstituierte pyrrole, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten |
| JPH0539289A (ja) * | 1991-02-15 | 1993-02-19 | Masahiro Irie | 無水マレイン酸誘導体およびその製造方法 |
| WO1993018765A1 (en) * | 1992-03-20 | 1993-09-30 | The Wellcome Foundation Limited | Indole derivatives with antiviral activity |
| DE4217964A1 (de) * | 1992-05-30 | 1993-12-02 | Goedecke Ag | Indolocarbazol-Imide und deren Verwendung |
-
1997
- 1997-07-15 PE PE1997000630A patent/PE91698A1/es not_active Application Discontinuation
- 1997-07-19 DE DE69722003T patent/DE69722003T2/de not_active Expired - Fee Related
- 1997-07-19 AT AT97934498T patent/ATE240318T1/de not_active IP Right Cessation
- 1997-07-19 AU AU37690/97A patent/AU739742B2/en not_active Ceased
- 1997-07-19 CA CA002262092A patent/CA2262092A1/en not_active Abandoned
- 1997-07-19 CN CNB971967768A patent/CN1151149C/zh not_active Expired - Fee Related
- 1997-07-19 TR TR1999/00157T patent/TR199900157T2/xx unknown
- 1997-07-19 KR KR1019997000706A patent/KR20000029637A/ko not_active Abandoned
- 1997-07-19 WO PCT/EP1997/003889 patent/WO1998004552A1/en not_active Ceased
- 1997-07-19 EP EP97934498A patent/EP0915872B1/en not_active Expired - Lifetime
- 1997-07-19 BR BR9711605A patent/BR9711605A/pt not_active Application Discontinuation
- 1997-07-19 ES ES97934498T patent/ES2198001T3/es not_active Expired - Lifetime
- 1997-07-19 CN CNA031275400A patent/CN1495182A/zh active Pending
- 1997-07-19 JP JP10508453A patent/JP2000516589A/ja not_active Ceased
- 1997-07-19 DK DK97934498T patent/DK0915872T3/da active
- 1997-07-19 PT PT97934498T patent/PT915872E/pt unknown
- 1997-07-22 AR ARP970103309A patent/AR008267A1/es not_active Application Discontinuation
- 1997-07-22 ZA ZA9706492A patent/ZA976492B/xx unknown
- 1997-07-24 US US08/899,852 patent/US5856517A/en not_active Expired - Fee Related
- 1997-07-25 CO CO97042581A patent/CO4900055A1/es unknown
- 1997-07-25 HR HR60/022,079A patent/HRP970414A2/hr not_active Application Discontinuation
- 1997-07-29 MA MA24744A patent/MA24287A1/fr unknown
- 1997-10-06 SA SA97180473A patent/SA97180473A/ar unknown
-
1998
- 1998-10-05 US US09/166,766 patent/US6030994A/en not_active Expired - Fee Related
-
2004
- 2004-11-15 CY CY0400081A patent/CY2483B1/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US6030994A (en) | 2000-02-29 |
| US5856517A (en) | 1999-01-05 |
| KR20000029637A (ko) | 2000-05-25 |
| HRP970414A2 (en) | 1998-06-30 |
| PE91698A1 (es) | 1998-12-24 |
| EP0915872B1 (en) | 2003-05-14 |
| BR9711605A (pt) | 1999-08-24 |
| CY2483B1 (en) | 2005-06-03 |
| CO4900055A1 (es) | 2000-03-27 |
| ZA976492B (en) | 1998-01-29 |
| PT915872E (pt) | 2003-09-30 |
| SA97180473A (ar) | 2005-12-03 |
| DE69722003D1 (de) | 2003-06-18 |
| JP2000516589A (ja) | 2000-12-12 |
| WO1998004552A1 (en) | 1998-02-05 |
| CN1151149C (zh) | 2004-05-26 |
| ES2198001T3 (es) | 2004-01-16 |
| EP0915872A1 (en) | 1999-05-19 |
| AU3769097A (en) | 1998-02-20 |
| AR008267A1 (es) | 1999-12-29 |
| MA24287A1 (fr) | 1998-04-01 |
| TR199900157T2 (xx) | 1999-04-21 |
| CA2262092A1 (en) | 1998-02-05 |
| AU739742B2 (en) | 2001-10-18 |
| CN1495182A (zh) | 2004-05-12 |
| CN1226247A (zh) | 1999-08-18 |
| ATE240318T1 (de) | 2003-05-15 |
| DK0915872T3 (da) | 2003-09-08 |
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| 8364 | No opposition during term of opposition | ||
| 8339 | Ceased/non-payment of the annual fee |