Substituted di-hydroxyl-indol derivatives as protein tyrosine kinase and as protein serine/threenine kinase inhibitors

A technology of hydroxyl and biological hydrolysis, which is applied in the direction of medical preparations containing active ingredients, anti-toxic agents, anti-inflammatory agents, etc.

Inactive Publication Date: 2001-01-03
GLAXO GRP LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Alternatively, there is also the possibility that certain kinases may still be useful in the treatment of disorders when the kinases are not dysregulated, but are still necessary to maintain the disorder

Method used

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  • Substituted di-hydroxyl-indol derivatives as protein tyrosine kinase and as protein serine/threenine kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 17

[0324] Example 17: 4-[N'-(4-isopropoxy-2-oxo-1,2-dihydro-indole-3-ylidene)-hydrazino]-benzenesulfonamide

[0325] A solution of 3.78 g (25.0 mmol) of 3-isopropoxyaniline and di-tert-butyl dicarboxylate in 25 ml of THF was heated to reflux for 2 hours. The solution was cooled to ambient temperature and the solvent was removed in vacuo. The residue was dissolved in 100 mL of EtOAc and the solution was washed with 3 50 mL portions of 0.5M citric acid and 50 mL of brine. Dilute the solution with MgSO 4 Drying and removal of solvent in vacuo afforded N-(tert-butoxy-carbonyl)-3-isopropoxyaniline (5.75 g, 92%) as a white solid: mp 79-81°C; 1 H NMR (DMSO-d 6 ): δ1.21 (d, J=6.0Hz, 6H), 1.43 (s, 9H), 4.46 (septet, J=6Hz, 1H), 6.47 (dd, J=2. 1, 8.1Hz, 1H), 6.94(d, J=8.1Hz, 1H), 7.0-7.1(m, 2H), 9.23(s, 1H); APCl-MS m / z 274(M+Na) + . At -78°C, add 15ml (25mmol) 1.7M tert-butyllithium hexane to a solution of 2.5g (10mmol) N-(tert-butoxycarbonyl)-3-isopropoxyaniline in 15ml anhydrous...

Embodiment 27

[0330] Example 27: Methyl 2-oxo-3-(4-sulfamoyl-phenylamino-methylene)-2,3-dihydro-1H-indole-5-carboxylate (Z-isomer body)

[0331] Under stirring, a solution of 2.66 g (20.0 mmol) of ethyl (methylthio)acetate dissolved in 200 ml of dichloromethane was cooled to -70°C and 2.7 g (20.0 mmol) of sulfonyl chloride was added. The reaction was stirred at -70°C for 30 minutes and 3.0 g (20 mol) of methyl 4-aminobenzoate and 4.3 g (20 mmol) of Proton Sponge were added dropwise within 1 hour  250 mL of dichloromethane solution, the resulting pink slurry was treated with a 2.3 g (23 mmol) portion of TEA and the solution was allowed to warm to room temperature. The solution was washed with three 250ml portions of water, MgSO 4 Drying and concentration gave an oil. This was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to afford 2.0 g (42% yield) of 3-methylthio-2-oxo-2,3-dihydro- Methyl 1H-indole-5-carboxylate:

[0332] 1 H NMR (DMSO-d 6 ): δ1.97(s, 3H), 3.35(s, 3H...

Embodiment 99

[0339] Example 99: C-{4-[N'-(5-Hydroxy-4,6-dimethyl-2-oxo-1,2-dioxin(3-ylidene)hydrazino]phenyl} -N-Methylmethanesulfonamide

[0340] 4,6-Dimethyl-5-hydroxy-1H-2,3-dione was prepared from 3,5-dimethyl-4-hydroxyaniline according to method A: 1 H NMR (DMSO-d 6 ): δ2.17(s, 3H), 2.30(s, 3H), 6.45(s, 1H), 8.29(s, 1H), 10.65(s, 1H); ES1-MS m / z 190(M-H) - . 100mg (0.52mmol) of 4,6-dimethyl-5-hydroxy-1H-indole-2,3-dione and 144mg (0.57mmol) of C-(4-hydrazinophenyl)-N- A mixture of methylmethanesulfonamide hydrochloride in 5 ml EtOH was heated to 80°C for 1 hour. After cooling, add 10ml H 2O and the solid was collected by vacuum filtration and dried in a vacuum oven at 60 °C to afford the title compound (79 mg, 79%) as a yellow solid; mp 252-255 °C; 1 H NMR (DMSO-d 6 ): δ2.16(s, 3H), 2.44(s, 3H) 2.52(d, J=4.9Hz, 3H), 4.25(s, 2H), 6.47(s, 1H ), 6.84(q, J=4.9Hz, 1H), 7.28-7.34(m, 4H), 7.92(s, 1H), 10.69(s 1H), 12.87 (s, 1H); APCl-MS m / z 411 (M+Na) + . Elemental analysis, calc...

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Abstract

Compounds of formula (I): wherein X is N, CH, CCF3, or C(C1-12 aliphatic); R4 is sulfonic acid, C1-12 aliphatic-sulfonyl, sulfonyl-C1-12 aliphatic, C1-12 aliphatic-sulfonyl-C1-6 aliphatic, C1-6 aliphatic-amino, R7-sulfonyl, R7 sulfonyl-C1-12 aliphatic, R7-aminosulfonyl, R7aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7-sulfonylamino-C1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Arylamino, (R8)1-3-Arylsulfonyl, (R8)1-3-Aryl-aminosulfonyl, (R8)1-3-Aryl-sulfonylamino, Het-amino, Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino, or aminoiminoaminosulfonyl, R5 is hydrogen; and further wherein R4 and R5 are optionally joined to form a fused ring, pharmaceutical formulations comprising them and their use in therapy, especially in the treatment of diseases mediated by CDK2 activity, such as alopecia induced by cancer chemotherapy or radiotherapy.

Description

[0001] The present invention provides novel compounds, novel compositions, methods of their use and methods of their preparation. Such compounds are pharmacologically useful as agents for certain conditions, usually by altering mitogen-activated signaling pathways, especially by inhibiting or antagonizing protein kinases whose pathology involves abnormal cell proliferation, such conditions include tumor growth, Restenosis, atherosclerosis and thrombosis. In particular, the present invention relates to a series of substituted oxindoles which are protein tyrosine kinase and protein serine / threonine kinase inhibitory and are useful for protecting patients undergoing chemotherapy from chemotherapy-induced alopecia. Background of the invention [0002] In higher eukaryotes, cell growth, differentiation, metabolism, and function are tightly controlled. The ability of a cell to respond promptly and appropriately to the external and internal information it conti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/403A61K31/404A61K31/407A61K31/4155A61K31/4162A61K31/4178A61K31/4196A61K31/422A61K31/424A61K31/429A61K31/433A61K31/437A61K31/4427A61K31/443A61K31/4439A61K31/506A61K31/5377A61P3/10A61P7/00A61P9/00A61P9/10A61P13/12A61P17/06A61P17/14A61P25/00A61P27/02A61P29/00A61P35/00A61P39/00A61P43/00C07D209/34C07D209/40C07D401/06C07D401/12C07D403/04C07D403/12C07D405/12C07D413/04C07D417/12C07D471/04C07D487/04C07D491/04C07D491/056C07D498/04C07D513/04C07D521/00
CPCC07D231/12C07D471/04C07D403/04C07D403/12C07D209/40C07D401/06C07D513/04C07D405/12C07D401/12C07D413/04C07D209/34C07D491/04C07D249/08C07D487/04C07D233/56A61P13/12A61P17/06A61P17/14A61P25/00A61P27/02A61P29/00A61P3/10A61P35/00A61P39/00A61P43/00A61P7/00A61P9/00A61P9/10
Inventor S·T·戴维斯S·H·迪克森S·V·弗尔耶P·A·哈尔里斯R·N·亨特尔三世L·F·库伊珀K·E·拉基M·J·鲁兹奥J·M·维尔D·H·瓦尔克
Owner GLAXO GRP LTD
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