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Haloaryl Substituted Aminopurines, Compositions Thereof, And Methods Of Treatment Therewith

A technology of aryl and compound, applied in haloaryl substituted aminopurine, its composition and its therapeutic field, capable of solving problems such as incomplete response to treatment

Inactive Publication Date: 2013-05-08
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 were have developed resistance, or have shown 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-alcohol

[0358]

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

[0360] 2,4-Dichloro-5-nitropyrimidine (10.31 mmol, 2 g) and cyclopentylamine (10.31 mmol, 1.02 mL) were dissolved in THF (60 mL), 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 removal of solvent, the residue was redissolved in EtOAc, washed with water and brine. MgSO for organic layer 4 After drying, the solvent was evaporated. The residue was subjected to column chromatography (SiO 2 , 9:1 n-hexane / ethyl acetate) to obtain the desired product (2.11g, yield 84%). ES-MS: 242 (M+l). When replacing the aforementioned cyclopentylamine with amine hydrochloride, 2-3 eq...

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, and the reaction was carried out at room temperature and stirred overnight. The precipitate was filtered off, washed with ether, and dried under high vacuum to afford 372 g (98% yield) of the trihydrochloride. ES-MS: 428 (M+l).

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

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 the reaction was quenched by adding water dropwise until hydrogen gas no longer appeared. The precipitate was filtered off and washed well 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 give 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 is a divisional application of the invention application dated January 13, 2006, application number 200680008179.9, and titled "halogenated aryl substituted aminopurine, its composition and its treatment method". [0002] This application claims the benefit of US Provisional Application 60 / 643,796, filed January 13, 2005, and US Provisional Application 60 / 709,980, filed August 19, 2005, each of which is incorporated by reference in its entirety. 1. Technical field [0003] The present invention relates to certain amino-substituted purine compounds, compositions containing effective amounts of such compounds, and the treatment or prevention of cancer, cardiovascular disease, kidney disease, autoimmune disease, inflammatory disease, macular degeneration, ischemia-reperfusion A method of injury, pain and related syndromes, disease-related wasting, asbestos-related disease, pulmonary hypertension, central nervous system (CNS) injury / damage, or disease treata...

Claims

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Application Information

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IPC IPC(8): C07D473/32A61K31/52A61K31/5377A61K31/551A61P1/00A61P1/04A61P1/08A61P1/12A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P11/08A61P13/12A61P17/00A61P19/02A61P21/00A61P21/04A61P25/00A61P25/02A61P25/04A61P25/06A61P25/08A61P25/20A61P25/28A61P27/02A61P29/00A61P3/00A61P3/04A61P3/10A61P31/00A61P31/06A61P31/18A61P35/00A61P37/00A61P37/02A61P43/00A61P5/14A61P9/00A61P9/10
CPCC07D473/00C07D473/32A61K31/52A61P1/00A61P1/04A61P1/08A61P1/12A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P11/08A61P13/12A61P17/00A61P19/02A61P21/00A61P21/04A61P25/00A61P25/02A61P25/04A61P25/06A61P25/08A61P25/20A61P25/28A61P27/02A61P29/00A61P3/00A61P3/04A61P31/00A61P31/06A61P31/18A61P35/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/14A61P5/16A61P9/00A61P9/10A61P9/12A61P3/10
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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