FI106378B - Förfarande för framställning av terapeutiskt användbara 3-substituerade 2-oxoindolderivat - Google Patents
Förfarande för framställning av terapeutiskt användbara 3-substituerade 2-oxoindolderivat Download PDFInfo
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- FI106378B FI106378B FI901915A FI901915A FI106378B FI 106378 B FI106378 B FI 106378B FI 901915 A FI901915 A FI 901915A FI 901915 A FI901915 A FI 901915A FI 106378 B FI106378 B FI 106378B
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- alkyl
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- 238000000034 method Methods 0.000 title claims description 76
- -1 3-substituted 2-oxoindole Chemical class 0.000 title claims description 31
- 230000008569 process Effects 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 110
- 238000006243 chemical reaction Methods 0.000 claims description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 49
- 229910052801 chlorine Inorganic materials 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 21
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 239000012442 inert solvent Substances 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 101100134927 Gallus gallus COR8 gene Proteins 0.000 claims 1
- 239000007787 solid Substances 0.000 description 109
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 96
- 239000000243 solution Substances 0.000 description 79
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 63
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 60
- 239000002585 base Substances 0.000 description 59
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 49
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 49
- 238000004458 analytical method Methods 0.000 description 45
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 41
- 239000000203 mixture Substances 0.000 description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 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 26
- 239000000460 chlorine Substances 0.000 description 25
- 238000001953 recrystallisation Methods 0.000 description 25
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 125000000623 heterocyclic group Chemical group 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 20
- 235000019341 magnesium sulphate Nutrition 0.000 description 20
- WGRHBRAKCHCGER-UHFFFAOYSA-N 5-chloro-2-oxo-3h-indole-1-carboxamide Chemical compound ClC1=CC=C2N(C(=O)N)C(=O)CC2=C1 WGRHBRAKCHCGER-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 230000001133 acceleration Effects 0.000 description 17
- 229960000583 acetic acid Drugs 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 230000002378 acidificating effect Effects 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000000538 analytical sample Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 229960004592 isopropanol Drugs 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- 230000003187 abdominal effect Effects 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 230000036407 pain Effects 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- YIBNHAJFJUQSRA-YNNPMVKQSA-N prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000001665 trituration Methods 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 235000011089 carbon dioxide Nutrition 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- ZMRUPTIKESYGQW-UHFFFAOYSA-N propranolol hydrochloride Chemical compound [H+].[Cl-].C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 ZMRUPTIKESYGQW-UHFFFAOYSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
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- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 239000011260 aqueous acid Substances 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
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- 239000001569 carbon dioxide Substances 0.000 description 4
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
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- 229920006395 saturated elastomer Polymers 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
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- 238000006467 substitution reaction Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 3
- UYINJAQCJCYCGO-UHFFFAOYSA-N 2-oxo-3h-indole-1-carboxamide Chemical class C1=CC=C2N(C(=O)N)C(=O)CC2=C1 UYINJAQCJCYCGO-UHFFFAOYSA-N 0.000 description 3
- NEODFWFSTQAKDS-UHFFFAOYSA-N 4-methylsulfanylthiophene-2-carboxylic acid Chemical compound CSC1=CSC(C(O)=O)=C1 NEODFWFSTQAKDS-UHFFFAOYSA-N 0.000 description 3
- HYHZGBOWRWIEGW-UHFFFAOYSA-N 5-methoxycarbonylthiophene-2-carboxylic acid Chemical compound COC(=O)C1=CC=C(C(O)=O)S1 HYHZGBOWRWIEGW-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
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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
- 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- 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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D405/02—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 two hetero rings
- C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
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- 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
- C07D417/04—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 directly linked by a ring-member-to-ring-member bond
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- C07D417/14—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 three or more hetero rings
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Claims (8)
1. Förfarande för framställning av terapeutiskt användbara 3-substituerade 2-oxoindolderivat med formeln I 5 (CR2)n-Q 10 j k2 samt farmaceutiskt godtagbara salter därav, i vilken forme 1
15 X är H, F, Cl, Br, (C^Cg) alkyl eller CF3; Y är H, F, Cl, Br, (Cj^-Cg) alkyl eller CF3; R1 är H; R2 är CONR7R8; Q är 20 ^^A eller Q2-A1; A är H, F, Cl, Br, I, CF3, OR9, S(0)pRl°, COOR11, ·, 2 5 CONR9R11, COR10, CHjOR11, OCOR10, NR^11, S02NR9R11, 12 ellsr ' 30 : B är H, F, Cl, Br, I eller CF3; under förutsättning att bade A och B inte är H, eller A och B är tillsammans bundna till samma ringkol i Q1 och bildar oxogruppen, eller när A inte är H, da betecknar 35 B samma som ovan definierats eller är (C1-C4) alkyl; 106378 A1 är F, Cl, Br, I, CF3, OR9, S(0)pR10, COOR11, CONR9R11, COR10, CHjOR11, OCOR10, NR9RX1 eller S02NR9R11 ; Q1 är O O O 10 n—w r^N>N O O Q2 är 15 /N^N /N N --. - < i . O , M \^w \w/ eller N\ y ' Nw 20 bäde n och p är 0, 1 eller 2; bäde W och Z är O eller S; var och en av R7, R8, R9 och R11 är H eller (Ci-Ce) alkyl; R10 är (Cj^-Cg) alkyl; och ·. 25 R12 är H, F, Cl, Br, CF3 eller (Cj-Cg) alkyl; kännetecknat därav att man upplöser en förening med formeln III Q- (CH2) nCOCl (III) 30 I väri Q och n betecknar samraa som ovan, i ett reaktions- inert lösningsmedel och blandar längsamt in i en lösning som innehäller ungefär en ekvimolär mängd av en förening med formeln IV 35 X 76 106378 7“5<N-, UAA väri X, Y och R2 betecknar samma sora ovan, och ett molärt överskott av ett basiskt medel i ett reaktionsinert lös-ningsmedel vid en temperatur cirka 0 °C; läter reaktions-10 blandningen att uppvärma tili en temperatur cirka 25 °C; och gör reaktionsblandningen surt, varvid erhälls en före-ning raed formeln I; och eventuellt överför den erhällna föreningen med for-meln I pä i och för sig kännt sätt tili ett farmaceutiskt 15 godtagbart sait.
2. Förfarande enligt patentkrav 1, k ä n n e -t e c k n a t därav, att Q1 2 är I-V N-W /N\. O · o och Q3 4 5 6 är / ' f eller J' \ 25 \w/. Förfarande enligt patentkrav 1 eller 2, k ä n - 2 netecknat därav, att bade X och Y är H, F, Cl,
3 (Ci-C3) alkyl eller CF3.
4 30 4. Förfarande enligt nägot av patentkraven 1-3, 5 ‘ kännetecknat därav, att A är H, F, Cl, Br, CF3, 6 OR7, COR8 eller CH^R9 och B är H, F, Cl, Br eller CF3 el 7 ler A och B är tillsammans bundna tili samma ringkol i Q1 8 och bildar oxogruppen, eller när A inte är H, dä betecknar 35 B samma som ovan definierats eller är (Cx-C3) alkyl; och A1 9 är F. 106378 77
5. Förfarande enligt nägot av patentkraven 1 - 4, kännetecknat därav, att n är 0 eller 1. 1
6. Förfarande enligt patentkrav 5, känne tecknat därav, att n är 0, X är 5-F, Y är 6-Cl och 5 Q är 10
7. Förfarande enligt patentkrav 5, känne tecknat därav, att n är 0, X är 5-Cl, Y är H och Q är
8. Förfarande enligt nägot av patentkraven 1-7, kännetecknat därav, att det reaktionsinerta 20 lösningsmedlet är Ν,Ν-dimetylformamid, N,N-dimetylactamid, N-metylpyrrolidon eller dimetylsulfoxid och det basiska medlet är trimetylamin, trietylamin, tributylamin, N-me-tylmorfolin, N-metylpiperidin, pyridin eller 4-(N,N-dime-tylamino)pyridin. 25 t. «*
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FI954169A FI106459B (sv) | 1989-04-18 | 1995-09-06 | Förfarande för framställning av 3-substituerade 2-oxoindolderivat |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US34011389A | 1989-04-18 | 1989-04-18 | |
US34011389 | 1989-04-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
FI901915A0 FI901915A0 (fi) | 1990-04-17 |
FI106378B true FI106378B (sv) | 2001-01-31 |
Family
ID=23331948
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Application Number | Title | Priority Date | Filing Date |
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FI901915A FI106378B (sv) | 1989-04-18 | 1990-04-17 | Förfarande för framställning av terapeutiskt användbara 3-substituerade 2-oxoindolderivat |
Country Status (33)
Country | Link |
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US (4) | US5047554A (sv) |
EP (1) | EP0393936B1 (sv) |
JP (2) | JP2506478B2 (sv) |
KR (1) | KR920006394B1 (sv) |
CN (1) | CN1022832C (sv) |
AP (1) | AP142A (sv) |
AT (1) | ATE118767T1 (sv) |
AU (1) | AU633767B2 (sv) |
BG (1) | BG60646B1 (sv) |
CA (1) | CA2014467C (sv) |
CZ (1) | CZ284340B6 (sv) |
DD (1) | DD293822A5 (sv) |
DE (1) | DE69017066T2 (sv) |
DK (1) | DK0393936T3 (sv) |
EG (1) | EG19122A (sv) |
ES (1) | ES2068334T3 (sv) |
FI (1) | FI106378B (sv) |
GR (1) | GR3015811T3 (sv) |
HU (2) | HUT58314A (sv) |
IE (1) | IE65091B1 (sv) |
IL (3) | IL94047A (sv) |
IS (1) | IS1636B (sv) |
MA (1) | MA21808A1 (sv) |
MX (1) | MX20359A (sv) |
NO (1) | NO176759C (sv) |
NZ (1) | NZ233320A (sv) |
OA (1) | OA09205A (sv) |
PL (2) | PL163941B1 (sv) |
PT (1) | PT93785B (sv) |
RO (1) | RO106402B1 (sv) |
RU (2) | RU2039042C1 (sv) |
YU (1) | YU47588B (sv) |
ZA (1) | ZA902871B (sv) |
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-
1990
- 1990-01-31 US US07/473,266 patent/US5047554A/en not_active Expired - Lifetime
- 1990-04-08 IL IL9404790A patent/IL94047A/en not_active IP Right Cessation
- 1990-04-08 IL IL110173A patent/IL110173A/xx not_active IP Right Cessation
- 1990-04-09 IS IS3570A patent/IS1636B/is unknown
- 1990-04-09 AP APAP/P/1990/000175A patent/AP142A/en active
- 1990-04-12 EP EP90303992A patent/EP0393936B1/en not_active Expired - Lifetime
- 1990-04-12 ES ES90303992T patent/ES2068334T3/es not_active Expired - Lifetime
- 1990-04-12 OA OA59776A patent/OA09205A/xx unknown
- 1990-04-12 CZ CS901848A patent/CZ284340B6/cs not_active IP Right Cessation
- 1990-04-12 CA CA002014467A patent/CA2014467C/en not_active Expired - Fee Related
- 1990-04-12 AT AT90303992T patent/ATE118767T1/de not_active IP Right Cessation
- 1990-04-12 DK DK90303992.3T patent/DK0393936T3/da active
- 1990-04-12 DE DE69017066T patent/DE69017066T2/de not_active Expired - Fee Related
- 1990-04-12 NZ NZ233320A patent/NZ233320A/xx unknown
- 1990-04-16 BG BG91773A patent/BG60646B1/bg unknown
- 1990-04-17 PL PL90284817A patent/PL163941B1/pl unknown
- 1990-04-17 FI FI901915A patent/FI106378B/sv not_active IP Right Cessation
- 1990-04-17 NO NO901684A patent/NO176759C/no not_active IP Right Cessation
- 1990-04-17 HU HU902462A patent/HUT58314A/hu unknown
- 1990-04-17 RO RO144837A patent/RO106402B1/ro unknown
- 1990-04-17 PL PL90287812A patent/PL163951B1/pl unknown
- 1990-04-17 PT PT93785A patent/PT93785B/pt not_active IP Right Cessation
- 1990-04-17 MA MA22068A patent/MA21808A1/fr unknown
- 1990-04-17 CN CN90102176A patent/CN1022832C/zh not_active Expired - Fee Related
- 1990-04-17 KR KR1019900005296A patent/KR920006394B1/ko not_active IP Right Cessation
- 1990-04-17 ZA ZA902871A patent/ZA902871B/xx unknown
- 1990-04-17 YU YU75590A patent/YU47588B/sh unknown
- 1990-04-18 JP JP2102775A patent/JP2506478B2/ja not_active Expired - Fee Related
- 1990-04-18 DD DD90339845A patent/DD293822A5/de not_active IP Right Cessation
- 1990-04-18 MX MX2035990A patent/MX20359A/es unknown
- 1990-04-18 IE IE136090A patent/IE65091B1/en not_active IP Right Cessation
- 1990-04-18 EG EG23590A patent/EG19122A/xx active
-
1991
- 1991-06-05 US US07/712,169 patent/US5290802A/en not_active Expired - Fee Related
- 1991-10-01 RU SU5001607/04A patent/RU2039042C1/ru not_active IP Right Cessation
-
1992
- 1992-01-28 AU AU10510/92A patent/AU633767B2/en not_active Ceased
- 1992-01-31 RU SU925010870A patent/RU2073671C1/ru active
-
1993
- 1993-11-04 US US08/148,764 patent/US5919809A/en not_active Expired - Fee Related
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1994
- 1994-06-30 IL IL11017394A patent/IL110173A0/xx unknown
- 1994-08-08 JP JP6186078A patent/JP2581525B2/ja not_active Expired - Fee Related
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1995
- 1995-04-17 GR GR950400941T patent/GR3015811T3/el unknown
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- 1995-06-23 HU HU95P/P00430P patent/HU211150A9/hu unknown
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