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Substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carbonitriles and substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carboxamides as tubulin polymerization inhibitors

A technology of polymerization inhibitor and tubulin, which can be used in drug combinations, medical preparations containing active ingredients, organic chemistry, etc., and can solve problems such as no activity being given.

Inactive Publication Date: 2012-03-28
TELIK INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

No specific activity is given although the compound is said to have activity against each of the listed target enzymes that is 3σ higher than the mean activity of a population of predominately inactive compounds against the same target enzyme

Method used

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  • Substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carbonitriles and substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carboxamides as tubulin polymerization inhibitors
  • Substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carbonitriles and substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carboxamides as tubulin polymerization inhibitors
  • Substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carbonitriles and substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carboxamides as tubulin polymerization inhibitors

Examples

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Embodiment

[0081] The following examples illustrate the preparation of compounds of the invention and their activity in predictive in vitro and in vivo anticancer assays. These results are believed to be predictive for efficacy in human anticancer chemotherapy, as other anticancer agents tested in these assays have shown anticancer activity in humans. They are given to enable those skilled in the art to understand and realize the present invention more clearly, but these embodiments should not be considered as limiting the scope of the present invention, but merely to illustrate and describe the present invention.

[0082] Preparation and Synthesis Examples

[0083] The compounds of the present invention can be prepared by conventional methods of organic chemistry. See, eg, Larock, "Comprehensive Organic Transformations", Wiley-VCH, New York, New York, U.S.A. In some cases, protecting groups can be introduced and subsequently removed. Suitable protecting groups are described in Greene...

preparation Embodiment 1

[0084] Preparation Example 1. Preparation of 4-[2-(dimethylamino)ethoxy]phenylisothiocyanate, which is an intermediate of compound 36A

[0085]Diisopropylethylamine (344mg, 2.66mmol, 2.4eq. (eq.)) was added to 4-[2-(dimethylamino)ethoxy]aniline (200mg, 1.11mmol, 1eq.) with stirring In a solution (0° C.) of tetrahydrofuran (2 mL), thiophosgene (153 mg, 1.33 mmol, 1.2 eq.) was then added dropwise with stirring. The reaction mixture was allowed to warm to room temperature with stirring and stirred at room temperature for 40 minutes during which time a precipitate formed. THF was removed in vacuo and the residue was dissolved in ethyl acetate, washed with brine (3 x 10 mL), then the ethyl acetate layer was dried over magnesium sulfate and the ethyl acetate was evaporated to give 4-[2-( Methylamino)ethoxy]phenylisothiocyanate (0.20 g) as a tan oil was used without further purification.

preparation Embodiment 2

[0086] Preparation Example 2: Preparation of 2-bromo-4'-[2-(dimethylamino)ethoxy]acetophenone, which is an intermediate of compound 39A

[0087] 2-(Dimethylamino)ethyl chloride hydrochloride (3.49g, 23.2mmol, 1.1eq.) was added to 4'-hydroxyacetophenone (3.00g, 22.0mmol, 1eq.) in acetone (100mL) To the solution in , potassium carbonate (9.12 g, 66.0 mmol, 3 eq.) was then added. The reaction mixture was heated at reflux overnight, cooled, and filtered; the filtrate was concentrated, and water (50 mL) was added, forming a cloudy solution. Hydrochloric acid (0.1 N, 20 mL) was added and the resulting clear solution was extracted three times with ethyl acetate. The aqueous phase was made basic with aqueous sodium hydroxide to form a turbid mixture which was extracted with ethyl acetate (5 x 50 mL), then the ethyl acetate layer was dried over magnesium sulfate and the ethyl acetate was evaporated to give 4'-[2 - (Dimethylamino)ethoxy]acetophenone (2.90 g) as pale yellow oil, identi...

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Abstract

Substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carbonitriles and substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carboxamides and their salts are tubulin polymerization inhibitors, useful in the treatment of cancer.

Description

[0001] References to related applications [0002] This application claims the title "Substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carbonitriles and substituted 4- -Amino-5-benzoyl-2-(phenylamino)thiophene-3-carboxamide” under 35USC 119(e) of U.S. Provisional Patent Application No. 61 / 169,785, the full disclosure of which application The contents are incorporated into this application by reference. technical field [0003] This application relates to substituted 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carbonitriles and 4-amino-5-benzoyl-2-(phenylamino)thiophene-3-carboxylates Amides, their salts, pharmaceutical compositions comprising them, and their use as inhibitors of tubulin polymerization and in the treatment of cancer. Background technique [0004] Microtubules are cytoskeletal protein polymers that are composed of α-tubulin and β-tubulin polymers. They are essential components of all cells and are critical for maintaining cell shape. Microtubules ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/10C07D409/12A61K31/381A61P35/00C07D333/10
CPCA61K31/381C07D409/12C07D333/38A61P35/00A61P35/02A61P43/00C07D333/10C07D409/10
Inventor 保罗·P·比罗扎科马思·V·达摩达兰斯特拉·路易马文利王卓徐华
Owner TELIK INC
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