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Certain chemical entities, compositions, and methods

A chemical and compound technology, applied in the field of chemicals, can solve the problems of mitotic spindle malformation, cell cycle arrest, obstacles, etc.

Inactive Publication Date: 2007-08-22
CYTOKINETICS INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Experimental perturbation of mitotic kinesin function results in malformation or dysfunction of the mitotic spindle, often resulting in cell cycle arrest and cell death

Method used

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  • Certain chemical entities, compositions, and methods
  • Certain chemical entities, compositions, and methods
  • Certain chemical entities, compositions, and methods

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0629]

[0630] To a solution of 4-isopropoxybenzoic acid (25 g, 140 mmol) in DMF (150 mL) was added NCS (24 g, 182 mmol). The reaction mixture was stirred overnight. h 2 O (500 mL) was added to the reaction mixture. The precipitate was collected and washed with water and dried under vacuum to yield 2 (26.4 g, 88%) as a white solid which was used in the next step without further purification. LRMS (M+H + ) m / z 213.0.

[0631] To a solution of 2 (20 g, 93 mmol) in DCM was added pentafluorotrifluoroacetate (20 mL, 112 mmol) and triethylamine (17 mL, 112 mmol) at 0°C. The solution was concentrated and the mixture was purified by flash column chromatography (100% DCM) to yield 3 (35 g, total) as a white solid. LRMS (M+H + ) m / z 586.3.

[0632] To a solution of 3 in DMF (2.0 molar), amino acid (1.2 equiv) and N,N-diisopropylethylamine (3 equiv) were added. The reaction was monitored by LC / MS. Upon completion, methylamine (2 M in THF, 1.5 equiv) and HBTU (1.5 equiv) were...

Embodiment 2

[0634]

[0635]To a solution of H-Phe-(4-Br)-OH (2, 2.5 g, 10 mmol) in DMF (20 mL) was added 3 (4.7 g, 12 mmol) and diisopropyl Ethylamine (5.4 mL, 30 mmol). The reaction mixture was monitored by LC / MS. Upon completion, methylamine (2M in THF, 7.7 mL, 15 mmol) and HBTU (5.8 mL, 15 mmol) were added to the reaction solution. The reaction mixture was stirred for 2 days. The mixture was filtered, and the filtrate was analyzed by RP-HPLC using acetonitrile and H 2 The O mixture was purified to yield 4 (2.3 g, 50%). LRMS (M+H + ) m / z 455.0.

[0636] To a suspension of 4 (71 mg, 0.16 mmol) in dioxane (1 mL), piperazine (16 mg, 0.19 mg, palladium(II) acetate (4 mg, 0.016 mmol), dicyclohexyl Phosphino-2'-(N,N'-dimethylamino)-biphenyl (6 mg, 0.016 mmol) and cesium carbonate (104 mg, 0.32 mmol).The resulting mixture was stirred at 110°C for 36 hours The reaction mixture was diluted with EtOAc. The organic layer was diluted with saturated NaHCO 3 (20 ml) and brine washing, in N...

Embodiment 3

[0638]

[0639] For H-Tyr-NH in DMF (5 ml) 2 HCl (2,830 mg, 3.8 mmol) solution, 3 (1.8 g, 4.5 mmol) and diisopropylethylamine (3.4 mL, 19 mmol) were added at room temperature. The reaction was stirred for 20 hours and filtered after adding water. The white precipitate was recrystallized from DCM and methanol to yield 4 (1.120 g, 78%) as white crystals. LRMS (M+H + ) m / z 377.1.

[0640] To a solution of 4 (50 mg, 0.13 mmol) in DMF (1 mL) was added (s)-(+)-3-bromo-2-methyl-1-propanol (0.083 mL, 0.8 mmol) and potassium carbonate (110 mg, 0.8 mmol). The resulting mixture was stirred at 0°C for 15 hours. The mixture was filtered, and the filtrate was analyzed by RP-HPLC using acetonitrile and H 2 The O mixture was purified to yield 1b (30 mg, 51%). LRMS (M+H + ) m / z 499.1.

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Abstract

Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of one or more mitotic kinesins are disclosed.

Description

[0001] This application claims the benefit of US Patent Application Serial No. 60 / 569,510, filed May 6, 2004, which is incorporated herein by reference. technical field [0002] The present invention relates to chemicals that are inhibitors of one or more mitotic kinesins and are useful in the treatment of cell proliferative disorders such as cancer, hyperplasia, restenosis, cardiac hypertrophy, immune disorders, fungal disorders and inflammation. Background technique [0003] Among the therapeutic agents used to treat cancer, taxanes and vinca alkaloids act on microtubules. Microtubules are the major structural elements of the mitotic spindle. The mitotic spindle is responsible for the distribution of copies of the genome to each of the two daughter cells resulting from cell division. It is hypothesized that the mitotic spindle is broken down by these drugs, resulting in inhibition of cancer cell division and induction of cancer cell death. However, microtubules form othe...

Claims

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Application Information

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IPC IPC(8): C07C233/65A61K31/165
Inventor 钱向平安德鲁・I.・麦克唐纳周汉杰卢克・W.・阿什克拉夫特姚冰姜红霞黄国珍王建潮小戴维・J.・摩根斯布拉德利・P.・摩根古斯塔夫・贝格内斯达什扬特・德哈纳克史蒂文・D.・奈特尼古拉斯・D.・亚当斯辛西娅・A.・帕理什凯文・达菲杜克・菲奇罗莎娜・泰代斯科
Owner CYTOKINETICS INC
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