Imidazolothiazole compounds for the treatment of disease

a technology of imidazolothiazole and compounds, which is applied in the field ofimidazolothiazole compounds for the treatment of diseases, can solve the problems of impaired rtks deactivation and virus life cycle disruption, and achieve the effect of effectively treating, managing or ameliorating the disease or ameliorating or eliminating one or more symptoms

Inactive Publication Date: 2015-05-07
AMBIT BIOSCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0070]In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds, which are formulated for oral, systemic, including parenteral or intravenous delivery, or for local or top

Problems solved by technology

Preventing cells from entering DNA synthesis after viral infection by inhibition of essential S-phase initiating activities, may disrupt the virus life cycle by preventing virus replication.
Finally, while overactivation of RTK signaling pa

Method used

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  • Imidazolothiazole compounds for the treatment of disease
  • Imidazolothiazole compounds for the treatment of disease
  • Imidazolothiazole compounds for the treatment of disease

Examples

Experimental program
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example 1

Preparation of N-(5-tert-Butyl-isoxazol-3-yl)-N′-imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea [Compound A1]

[0469]A. To prepare the intermediate 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole, 2-aminobenzothiazole (751 mg, 5 mmol) and 2-bromo-4′-nitroacetophenone (1.22 g, 5 mmol) were dissolved in ethanol and heated to reflux overnight. The solution was then cooled at room temperature for 24 hours. The precipitate was collected by filtration, washed with methanol and dried under vacuum.

[0470]B. To prepare the 2-(4-amino-phenyl)imidazo[2,1-b][1,3]benzothiazole, the intermediate from step A (428 mg, 1.5 mmol) was prepared as a suspension in isopropyl alcohol, and to it was added iron powder (419 mg, 7.5 mmol). The suspension was heated to reflux overnight with vigorous stirring. Completion of the reaction was confirmed by LCMS. 1N HCl was added to the mixture and allowed to cool to room temperature. The precipitate was collected by filtration and washed with several volumes of m...

example 2

Preparation of 1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-morpholin-4-yl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]urea; [Compound A6]

[0477]A. Preparation of the intermediate 6-morpholin-4-yl-benzothiazol-2-amine: To a solution of 4-N-morpholinoaniline (1.78 g, 10 mmol) in acetic acid (20 mL) was added NH4SCN (2.28 g, 30 mmol) in small amounts several times. After stirring the mixture for 30 minutes, a solution of bromine in acetic acid (1.6 g in 5 mL) was added to the mixture and stirred overnight at room temperature. The mixture was then heated at 90° C. for 30 minutes, and then was cooled and neutralized with saturated NaHCO3, and then extracted three times with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated to dryness. To the residue was added 30 mL of 10% HCl and neutralized with saturated NaHCO3, to give a brown solid (1.541 g, 66%).

[0478]B. Preparation of the intermediate 7-morpholin-4-yl-2-(4-nitro-phenyl)-imidazo[2,1-b][1,3]benzothiazole: A mixture ...

example 3

Preparation of N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea [Compound B1]

[0482]A. The intermediate 2-amino-1,3-benzothiazol-6-ol was prepared according to a slightly modified literature procedure by Lau and Gompf: J. Org. Chem. 1970, 35, 4103-4108. To a stirred solution of thiourea (7.6 g, 0.10 mol) in a mixture of 200 mL ethanol and 9 mL concentrated hydrochloric acid was added a solution of 1,4-benzoquinone (21.6 g, 0.20 mol) in 400 mL of hot ethanol. The reaction was stirred for 24 hours at room temperature and then concentrated to dryness. The residue was triturated with hot acetonitrile and the resulting solid was filtered and dried.

[0483]The free base was obtained by dissolving the hydrochloride salt in water, neutralizing with sodium acetate, and collecting the solid by filtration. The product (2-amino-1,3-benzothiazol-6-ol) was obtained as a dark solid that was pure by LCMS (M+H=167) and NMR. Yield: 13.0 g ...

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Abstract

Compounds, compositions and methods are provided for modulating the activity of receptor kinases and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by receptor kinases.

Description

[0001]This application claims priority to U.S. provisional application Ser. No. 60 / 743,543, filed Mar. 17, 2006, entitled “Imidazolothiazole Derivatives For The Treatment Of Disease”. The disclosure of the above referenced application is incorporated by reference herein in its entirety.FIELD[0002]New small molecule compounds, compositions and methods for treating disease are provided. The compounds provided are modulators of activity of enzymes, such as kinases, and are useful in the treatment, prevention, or amelioration of a disease or disorder related to enzyme activity or one or more symptoms thereof.BACKGROUND[0003]Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. Protein kinases, and in particular the receptor protein tyrosine kinase (RTK) family of protein kinases, act primarily as growth factor receptors and play a central role in signal transduction pathways regulating a number of ce...

Claims

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Application Information

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IPC IPC(8): A61K31/5377A61K31/496A61K31/454A61K31/429
CPCA61K31/5377A61K31/454A61K31/496A61K31/429C07D513/04A61P1/04A61P11/00A61P11/06A61P13/12A61P17/02A61P19/02A61P19/10A61P25/00A61P27/16A61P29/00A61P31/00A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/14A61P9/10A61P3/10
Inventor BHAGWAT, SHRIPADCHAO, QIGROTZFELD, ROBERT M.PATEL, HITESH K.SPRANKLE, KELLY G.
Owner AMBIT BIOSCIENCES
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