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Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith

A kind of aryl and compound technology, applied in halogenated aryl substituted aminopurine, its composition and its treatment field, can solve problems such as incomplete response in treatment

Inactive Publication Date: 2008-03-12
SIGNAL PHARMA LLC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in recent clinical trials, patients developed resistance to Gleevec®, or showed an incomplete response to treatment

Method used

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  • Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith
  • Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith
  • Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 51

[0357] Example 5.1: Synthesis of 4-({8-[(2,6-difluorophenyl)amino]-9-cyclopentylpurin-2-yl)amino)trans-cyclohexyl-1-ol

[0358]

[0359] 1.(2-Chloro-5-nitropyrimidin-4-yl)cyclopentylamine

[0360] 2,4-Dichloro-5-nitropyrimidine (10.31mmol, 2g) and cyclopentylamine (10.31mmol, 1.02mL) were dissolved in THF (60mL) and cooled to -78°C. N,N-diisopropylethylamine (10.31 mmol, 1.8 mL) was added dropwise. The reaction mixture was stirred at -78°C for about 45 minutes. The cooling bath was removed, and the reaction mixture was stirred at room temperature for about 16 hours. After removing the solvent, the residue was dissolved in EtOAc again and washed with water and brine. MgSO for organic layer 4 Dry and evaporate the solvent. Column chromatography (SiO 2 , 9:1 n-hexane / ethyl acetate) for purification to obtain the desired product (2.11 g, yield 84%). ES-MS: 242 (M+1). When replacing the above cyclopentylamine with amine hydrochloride, use 2-3 equivalents of N,N-diisopropylethylamine ...

Embodiment 52

[0367] Example 5.2: Synthesis of trans-(4-aminocyclohexyl){8-[2,4-difluorophenyl]amino]-9-cyclopentylpurin-2-yl}amine

[0368]

[0369] 1. Trans-(4-aminocyclohexyl){8-[2,4-difluorophenyl]amino]-9-cyclopentylpurin-2-yl}amine

[0370] N-[4-({8-[(2,4-difluorophenyl)amino]-9-cyclopentylpurin-2-yl}amino)trans-cyclohexyl](tert-butoxy)methyl The amide (0.71 mmol, 375 mg) was dissolved in ethanol (6 mL) and cooled to 0°C. Acetyl chloride (3 mL) was added dropwise, the reaction was carried out at room temperature, and the mixture was stirred overnight. The precipitate was filtered off, washed with ether, and dried under high vacuum to obtain 372 g (98% yield) of trihydrochloride. ES-MS: 428 (M+1).

[0371] Alternatively, N-[4-({8-[(2,4-difluorophenyl)amino]-9-cyclopentylpurin-2-yl}amino)trans-cyclohexyl](tert-butyl The oxy) formamide was dissolved in 9 mL of dichloromethane, followed by 2.25 mL of TFA. The reaction mixture was stirred for about 2 hours. The solvent was removed in vacuo a...

Embodiment 53

[0372] Example 5.3: Synthesis of 8-(2-fluorophenylamine)-2-(4-methoxyphenylamine)-9-(trans-4-(methylamino)cyclohexyl)-9H-purine

[0373]

[0374] The Boc-protected amine (481 mg, 0.88 mmol) was dissolved in THF (6 mL), and lithium aluminum hydride (1.0 M in THF, 2.64 mL, 2.64 mmol) was added. The reaction mixture was heated to 65°C overnight. The reaction mixture was cooled to 0°C, and water was added dropwise to stop the reaction until no more hydrogen gas appeared. The precipitate was filtered off and washed thoroughly with ethyl acetate. The solvent was removed in vacuo, and the residue was purified by semi-preparative HPLC (20% acetonitrile / water (0.1% TFA)→80% acetonitrile / water (0.1% TFA), 30 min) to obtain 191 mg of product.

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Abstract

Provided herein are Aminopurine Compounds having the following structure: (I) wherein R<1 >, R<2> and and R<3> are as defined herein, compositions comprising an effective amount of an Aminopurine Compound and methods for treating or preventing cancer, a cardiovascular disease, a renal disease, an autoimmune condition, an inflammatory condition, macular degeneration, ischemia-reperfusion injury, pain and related syndromes, disease-related wasting, an asbestos-related condition, pulmonary hypertension or a condition treatable or preventable by inhibition of the JNK pathway comprising administering an effective amount of an Aminopurine Compound to a patient in need thereof.

Description

[0001] This application claims the rights and interests of the U.S. Provisional Application 60 / 643,796 filed on January 13, 2005 and the U.S. Provisional Application 60 / 709,980 filed on August 19, 2005. The entire content of each provisional application is incorporated into this application for reference. 1. Technical Field [0002] The present invention relates to certain amino-substituted purine compounds, a composition containing an effective amount of the compound, and the treatment or prevention of cancer, cardiovascular disease, nephropathy, autoimmune disease, inflammatory disease, macular degeneration, ischemia reperfusion Injury, pain and related syndromes, disease-related weight loss, asbestos-related diseases, pulmonary hypertension, central nervous system (CNS) injury / damage, or methods for treatable or preventable diseases by inhibiting kinase pathways, the method It includes administering an effective amount of the aminopurine compound to the desired patient. 2. Back...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/00C07D473/32A61K31/52A61P3/00A61P9/00
Inventor 罗纳德·艾尔伯斯莱蒂西亚·阿亚拉史蒂文·S·克莱林玛丽亚·M·德尔加多·米堤若斯罗伯特·希尔格拉夫赛伊·海德格凯文·休斯亚当·考伊斯薇罗尼卡·普朗特维-克拉尼斯基梅格·麦卡里克利萨·纳多尔尼摩尔西·帕兰克基兰·萨哈斯亚布赫约翰·塞派泽佐藤喜孝玛丽亚·斯洛斯伊莉斯·萨德贝克乔纳森·赖特安德鲁·G·科尔伊恩·亨德森
Owner SIGNAL PHARMA LLC
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