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Methods of using mek inhibitors

A medicinal salt and patient technology, applied to medical preparations containing active ingredients, pharmaceutical formulas, anti-tumor drugs, etc., can solve the problem of reducing the transformation ability of mutant Ras

Inactive Publication Date: 2009-12-16
EXELIXIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, expression of dominant-negative MEK or ERK reduces the transformation capacity of mutant Ras as seen in cell culture and in vivo primary and metastatic growth of human tumor xenografts

Method used

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  • Methods of using mek inhibitors
  • Methods of using mek inhibitors
  • Methods of using mek inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0175] In one embodiment, cancer is at least partially regulated by inhibiting MEK.

[0176] In another embodiment, the cancer is selected from the group consisting of melanoma, colon cancer, rectal cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, papillary thyroid cancer, anaplastic thyroid cancer, endometrial cancer, and ovarian cancer.

[0177] In another embodiment, the one or more treatments are one or more chemotherapeutic agents.

[0178] In another embodiment, the one or more chemotherapeutic agents are selected from the group consisting of taxanes, platinum agents, topoisomerase inhibitors, alkylating agents, antimetabolites, antimicrotubule agents, and bcr-abl inhibitors . In another embodiment, the one or more chemotherapeutic agents are anti-microtubule agents selected from vincristine, vinblastine, vinorelbine, and vindesine.

[0179] In another embodiment, the one or more chemotherapeutic agents are selected from ra...

Embodiment 1

[1043] 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

[1044]

[1045] A method similar to that described in US 7,019,033 was used to prepare 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (2.1 g, 5.3 mmol), which was added to DMF ( 10 mL), followed by the addition of PyBOP (2.6 g, 5.3 mmol), and the mixture was stirred at room temperature over 15 minutes. Azetidin-3-ol hydrochloride (870 mg, 8.0 mmol) and DIPEA (1.85 mL, 11.2 mmol) were then added and the mixture was allowed to continue stirring at room temperature for 1 hour. The mixture was then partitioned between ethyl acetate and 0.5M aqueous sodium hydroxide. The organic layer was then washed with water (3x), followed by brine, and dried over anhydrous sodium sulfate. Filtration and concentration followed by flash chromatography on silica gel using ethyl acetate:ethane (5:1) afforded 1-({3,4-difluoro-2-[(2- Fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (2.09 g,...

Embodiment 2

[1053] N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2,N2-two Ethyl Glutamine

[1054]

[1055] 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (200 mg, 0.51 mmol) (prepared using a method similar to that described in US 7,019,033), PyBOP (256 mg, 0.51 mmol ), commercially available tert-butyl azetidin-3-ylcarbamate (131 mg, 0.77 mmol) and N,N-diisopropylethylamine (180 μL, 1.02 mmol) in dimethylformamide (3 mL) The solution in was stirred at room temperature for 15 hours. The reaction mixture was partitioned between 5% aqueous lithium chloride and ethyl acetate. The organic portion was washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a brown residue which was purified by column chromatography on silica gel with 30% ethyl acetate / hexane Elution with alkane afforded [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}c...

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Abstract

The present invention provides methods of treating cancer by administering a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with other cancer treatments.

Description

technical field [0001] The present invention relates to methods of treating cancer with compounds that inhibit the enzymatic activity of protein kinases and the resulting effects on cells such as proliferation, differentiation, apoptosis, migration, chemical invasion, and metabolism, in combination with anticancer agents regulation. Background technique [0002] Improvements in the specificity of agents used to treat various disease states, such as cancer, metabolic diseases, and inflammatory diseases, are of great interest because side effects associated with the administration of these agents can be reduced Realized therapeutic benefit. Traditionally, major improvements in cancer treatment have been associated with the identification of therapeutic agents that act through novel mechanisms. [0003] Protein kinases are enzymes that catalyze the phosphorylation of proteins at the hydroxyl groups of their tyrosine, serine, and threonine residues. The kinase complement of t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/397A61P35/00
CPCA61K31/4427A61K31/397A61K31/513A61P35/00A61P35/02A61P43/00
Inventor 彼得·拉姆
Owner EXELIXIS INC
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