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Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith

A kind of compound, the technology of the substituent, applied in the substituted aminopurine compound, its composition and its treatment field, can solve the problem such as low response rate median survival time

Active Publication Date: 2017-08-01
SIGNAL PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(Villanueva J et al., Cancer Cell, 2010, 18(6): 683-695; Spagnolo F et al., Archives of Dermatology Research, 2012, 304: 177-184) Ipilmumab can induce long-term responses in subgroups of patients, But its efficacy is limited by its low response rate of 10% to 15% and its improved median survival time by only two months

Method used

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  • Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith
  • Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith
  • Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0301] Example 1. (1s,4s)-4-(8-((4-chloro-2,6-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino )-9H-purin-9-yl)cyclohexane-1-carboxamide

[0302]

[0303] tert-butyl cis-(4-carbamoyl-cyclohexyl)-carbamate. cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1 equiv) and TEA (1.1 equiv) were dissolved in 0.3M THF, and the mixture was cooled to 0°C. Ethyl chloroformate (1.1 equiv) was added dropwise. After stirring at 0°C for 30 min, NH3 in THF was added. The mixture was stirred at -78°C for 2 hours. The mixture was diluted with water, and the solvent was evaporated until only water remained. The resulting precipitate was collected by filtration and dried under vacuum to give cis-(4-carbamoyl-cyclohexyl)-carbamate tert-butyl ester (45%) as a white solid. 1 H NMR (400MHz, DMSO-d 6)δppm 7.10(brs,1H),6.69(brs,2H),3.41(brs,1H),2.10(m,1H),1.72(m,2H),1.53(m,2H),1.42(m,4H) ,1.36(s,9H).

[0304] cis-4-amino-cyclohexanecarboxylic acid amide hydrochloride. To a ...

Embodiment 2

[0311] Example 2. (1s,4s)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)- 9H-purin-9-yl)cyclohexane-1-carboxamide

[0312]

[0313] (1s,4s)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purine- 9-yl) cyclohexane-1-carboxamide. (1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide was stirred at room temperature (1 equiv) and 1,3,5-trichloro-2-isothiocyanatobenzene (1 equiv) for 2 hours. EDC (2 equiv) in THF (0.17M) was added and the reaction was heated to 60°C and stirred for 1 hour. The reaction was cooled, and the organic solvent was concentrated well. The resulting residue was diluted with water, stirred for 30 minutes, and filtered. Standard workup and purification methods afforded (1s,4s)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)-8-((2,4,6-trichlorophenyl )amino)-9H-purin-9-yl)cyclohexanecarboxamide (79% yield). 1 H NMR (400MHz, DMSO-d 6 )δppm: 8.11 (br.s., 1H) 7.69 ...

Embodiment 3

[0314] Example 3. (1s,4s)-4-(8-((2-chloro-4,5-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino )-9H-purin-9-yl)cyclohexanecarboxamide

[0315]

[0316] 1-Chloro-4,5-difluoro-2-isothiocyanatobenzene. To a mixture of 2-chloro-4,5-difluoroaniline (1 equiv) and sodium hydroxide (3 equiv) in DCM (0.24M) and water (0.24M) was added thiophosgene dropwise at 0 °C (3 equivalents). The reaction mixture was stirred overnight at 25°C. TLC showed the reaction was complete. The organic phase was separated and washed with MgSO 4 Drying followed by concentration afforded 1-chloro-4,5-difluoro-2-isothiocyanatobenzene (53%) as a white solid.

[0317](1s,4s)-4-(8-((2-chloro-4,5-difluorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H- Purin-9-yl) cyclohexanecarboxamide. To (1s,4s)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexanecarboxamide (1 equivalent) 1-Chloro-4,5-difluoro-2-isothiocyanatobenzene (1.1 equiv) was added in one portion to a s...

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Abstract

Provided herein are Aminopurine Compounds having the following structures wherein R1, R2, and R3 are as defined herein, composition comprising an effective amount of an Aminopurine Compound, and methods for treating or preventing a cancer, for example, melanoma. Provided herein are compounds having the following formula (I) and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof, wherein R1, R2 and R3 are as defined herein.

Description

[0001] This application claims the benefit of US Provisional Application No. 62 / 060,339, filed October 6, 2014, which is hereby incorporated by reference in its entirety. [0002] field of invention [0003] Provided herein are certain aminopurine compounds, compositions comprising effective amounts of such compounds, and methods for treating or preventing cancer comprising administering an effective amount of such aminopurine compounds to a subject in need thereof. Background technique [0004] Melanoma is a cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes). Malignant melanoma develops from the neoplastic transformation of melanocytes, which are mainly found in the basal layer of the epidermis and in the eye. (Spagnolo F et al., Archives of Dermatology Research, 2012, 304:177-184; Hurst E A et al., Archives of Dermatology Research, 2003, 139:1067-1073). Malignant melanoma is the most aggressive form of skin cancer, and in 2014, there w...

Claims

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Application Information

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IPC IPC(8): C07D473/40
CPCC07D473/32C07D239/50C07D405/12C07D409/12C07D401/12A61K31/52A61K31/5377A61P35/00
Inventor 马修·亚历山大索哥利·巴曼亚约翰·弗雷德里克·博伊兰约书亚·汉森黄德华罗伯特·哈伯德布兰登·杰菲吉姆·莱斯滕迈赫兰·穆贾达姆拉杰·K·拉赫加希瑟·雷蒙金佰利·施华兹玛丽安·斯洛斯艾杜亚度·托里斯塔姆·明·特朗徐水蟾赵晶晶
Owner SIGNAL PHARMA LLC
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