Combination chemotherapy

A composition and inhibitor technology, applied in the directions of drug combinations, active ingredients of heterocyclic compounds, active ingredients of amides, etc., can solve the problems of interphase and mitotic function inhibition, microtubules not functioning normally, etc.

Inactive Publication Date: 2002-01-30
WARNER-LAMBERT CO
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Thus stabilized microtubules cannot function normally, which in tur

Method used

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  • Combination chemotherapy
  • Combination chemotherapy
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0071] Example 14-fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid

[0072] Add 10 ml (0.020 mol) of 2.0 M lithium diisopropylamide in THF / Solution in heptane / vinylbenzene (Aldrich). The resulting green suspension was stirred vigorously for 15 minutes, then a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to rise slowly to room temperature, where it was stirred for 2 days. The reaction mixture was concentrated. A 10% aqueous hydrochloric acid solution was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO 4 ), then boil on a jet bath to reduce volume and cool to room temperature. Off-white fibers were collected by vacuum filtration, rinsed with hexane and dried in a vacuum oven (76 °C; about 10 mmHg) to give 1.10 g (47%) of the desired material; mp 224-229.5 °C; 1 H NMR (400MHz; DMSO): δ9.72(s, 1H), 7.97(dd, 1H, J=7.0, ...

Embodiment 2-30

[0074] According to the general procedure of Example 1, the following benzoic acid and salts of formula (I) were prepared. Melting point of Example No. compound ℃ 2 3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 206-210 3 3,4-difluoro-2-(4 -Iodo-2-methyl-phenylamino)-benzoic acid 240.5-244.5 4 5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 259.5 -262 5 5-chloro-2-(2-(chloro-4-iodo-phenylamino)-benzoic acid 255-260 6 5-chloro-2-(4-iodo-2-methyl-phenylamino) - Benzoic acid 234-238 7 5-chloro-2-(4-iodo-2-methyl-phenylamino)-sodium benzoate 310-320 decomposition 8 5-bromo-2-(4-iodo-2-methyl -phenylamino)-5-nitro-benzoic acid 239.5-240 9 2-(2-chloro-4-iodo-phenylamino)-5-nitro-benzoic acid 289-29310 4-fluoro-2-( 3-fluoro-4-iodo-2-methyl-phenylamino)-benzoic acid 233-23511 2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzoic acid 264-26712 2-(2-fluoro-4-iodo-phenylamino)-5-nitro-benzoic acid 256-25813 2-(4-bromo-2-methyl-phenylamino)-4-fluoro-benzoic a...

Embodiment 315

[0075] Example 315-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide

[0076] To a stirred solution containing 0.1020 g (0.2632 mmol) of 5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 0.1 ml (1.7 mmol) ethanolamine and 0.05 ml (0.29 0.15 g (0.29 mmol) of solid PyBOP powder was added directly to a solution of 1:1 (v / y) tetrahydrofuran-dichloromethane solution in 5 mL of diisopropylethylamine. The reaction mixture was stirred overnight at room temperature. Solvent was removed in vacuo. The crude residue was partitioned between diethyl ether (50 mL) and 10% aqueous hydrochloric acid (50 mL). The organic phase was washed with 10% aqueous NaOH (50 mL), dried (MgSO 4 ) and concentrated under vacuum to give a yellow-brown oil, which was crystallized from hexane-ether to give 0.0831 g (73%) of a green-yellow powder; mp 120-121°C; 1 H NMR (400MHz; CDCl 3 ): δ9.11(s, 1H), 7.56 (d, 1H, J=1.4Hz), 7.46-7.41(m, 2H), 7.20(dd, 1H, J=8.9, 2.4Hz), 7.00(t, 2H, J=9...

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Abstract

Mitotic inhibitors such as paclitaxel have improved antitumor activity when used in combination with a selective MEK inhibitor, especially a phenyl amine compound of Formula (I) and (II).

Description

field of invention [0001] The present invention relates to a method of treating cancer in a patient in need thereof, said method comprising the steps of administering to the patient an inhibitor of mitosis and administering to the patient a MEK inhibitor. The invention also relates to compositions or packaging units comprising a mitotic inhibitor and a MEK inhibitor. Background of the invention [0002] Cancer chemotherapy may require the use of combinations of agents, often as a way to reduce the toxic effects of the individual agents when used alone, and in some instances because the combination is more potent than either agent alone. [0003] Mitotic inhibitors are antineoplastic agents that adversely affect the microtubular network in cells that is essential for mitotic and interphase cell function. Mitosis inhibitors usually bind to free tubulin in cells, promoting the assembly of tubulin into stable microtubules while inhibiting their disassembly. The stabilized micr...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K31/135A61K31/136A61K31/165A61K31/166A61K31/18A61K31/196A61K31/245A61K31/335A61K31/337A61K31/341A61K31/35A61K31/351A61K31/352A61K31/381A61K31/40A61K31/41A61K31/4409A61K31/4453A61K31/475A61K31/495A61K31/5375A61K35/00A61PA61P35/00A61P43/00C07D
CPCA61K31/475A61K31/335A61K31/35A61P35/00A61P43/00A61K2300/00A61K31/352
Inventor R·C·高恩J·塞博特-利奥波特
Owner WARNER-LAMBERT CO
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