Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use

A form, solid technology, applied in 2-(tert-butylamino)-4-((1R, can solve problems such as complex determination and selection of pharmaceutical compounds

Inactive Publication Date: 2016-11-23
SIGNAL PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Given that changes in solid form can affect various physical and chemical properties, which can provide advantages or disadvantages in terms of processing, formulation, stability, bioavailability, storage, handling (e.g., transportation), among pharmaceutically important characteristics, pharmaceutical compounds The determination and selection of the solid form of the

Method used

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  • Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
  • Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
  • Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0858] Example 1: 2-(tert-butylamino)-4-{[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide

[0859]

[0860] 2-Chloro-4-{[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide: Add (1R,2R, 5R)-5-amino-2-methylcyclohexanol hydrochloride (16.0kg), 2,4-dichloropyrimidine-5-carboxamide (19.0kg), K 2 CO 3 (14.9kg) and THF (160L). The batch was cooled to 0 °C and water (160 L) was added. Stirring of the batch was continued at 0°C for 1 hour and the temperature was raised to 25°C and held for 16 hours. Water (288 L) was added to the batch while maintaining the batch at 25°C, the batch was cooled to 15°C and stirring was continued for 4 hours. The batch was filtered, rinsed twice with water (2 x 80 L), and dried in a vacuum oven at 40 °C under a nitrogen purge for 24 hours to give 2-chloro-4-{[(1R,3R,4R)-3 -Hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide as a white powder (23.3 kg, yield 86%). 1 H NMR (DMSO-d 6 )δ0.93(d, J=5.7...

Embodiment 2

[0863]Example 2: 4-(tert-butylamino)-2-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxamide

[0864]

[0865] 4-(tert-butylamino)-2-chloropyrimidine-5-carboxamide: Stir 2,4-dichloro-pyrimidine-5-carboxamide (10.0g), DIPEA (11mL) in NMP (30mL ) in the mixture. Tert-butylamine (6.6 mL) was charged to the mixture, and the mixture was stirred at 25°C for 16 hr. Water (100 mL) was added to the mixture at 25°C. The mixture was stirred for 1 hour. The suspension was filtered, washed with water (50 mL) and dried in a vacuum oven at 40 °C under nitrogen purge for 24 hours to give 4-(tert-butylamino)-2-chloropyrimidine-5-carboxamide as a white solid (8.7 g, 84%). 1 H NMR (DMSO-d 6 ) δ 9.41 (s, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.67 (s, 1H), 1.42 (s, 9H).

[0866] 4-(tert-butylamino)-2-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxamide: 4-(tert-butylamino)-2-chloropyrimidine-5-carboxamide (0.5g), trans-4-aminocyclohexanol hydrochloride (0.40g), Na 2 CO 3 (0.28 g)...

Embodiment 3

[0868] Example 3: 4-(bicyclo[1.1.1]pent-1-ylamino)-2-(((1R,3S)-3-hydroxycyclohexyl)amino)pyrimidine-5-carboxamide

[0869]

[0870] 4-(bicyclo[1.1.1]pent-1-ylamino)-2-chloropyrimidine-5-carboxamide: Stir 2,4-dichloro-pyrimidine-5-carboxamide (2 g) at 25°C, A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (1.18 g), sodium bicarbonate (1.75 g) and NMP (10 mL) for 24 hours. Water (10 mL) was charged and the reaction temperature was maintained below 30°C, and the mixture was stirred at 25°C for 2 hours. The suspension was filtered and washed with NMP:water (1:1 10 mL), then water (2×10 mL), and dried in a vacuum oven at 40° C. under a nitrogen purge to give 4-(bicyclo[1.1.1]penta- 1-ylamino)-2-chloropyrimidine-5-carboxamide as a white solid (1.97 g, 83% yield). 1 H NMR (DMSO-d 6 )δ2.14(s, 6H), 2.51-2.53(m, 1H), 7.76(br.s., 1H), 8.23(br.s., 1H), 8.60(s, 1H), 9.57(s, 1H).

[0871] 4-(bicyclo[1.1.1]pent-1-ylamino)-2-(((1R,3S)-3-hydroxycyclohexyl)amino)pyrimidine-5-carb...

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Abstract

Provided herein are formulations, processes, solid forms and methods of use relating to 2-(tert-butylamino)-4-((1R,3R,4R)-3- hydroxy-4-methy1cydohexylamino)-pyrimidine-5-carboxamide (Compound I). In another aspect, provided herein are methods for preparing certain compounds, including compound I as described herein, as well as intermediates useful in such methods. In certain aspects, the solid forms of compound I are useful for inhibiting a kinase in a cell expressing said kinase, for example JNK1 or JNK2. In another aspect, the solid forms of compound I are useful for treating or preventing one or more disorders selected from interstitial pulmonary fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody mediated rejection, or lupus.

Description

[0001] References to related applications [0002] This application claims the benefit of U.S. Provisional Application No. 61 / 933,636, filed January 30, 2014, and U.S. Provisional Application No. 62 / 025,161, filed July 16, 2014, each in its entirety Incorporated herein by reference. technical field [0003] Provided herein are methods for the preparation of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide and 2-(tert Solid forms of butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof, for use in the treatment of diseases, disorders or disorders of use, and solid forms for use in such methods. Background technique [0004] Given that changes in solid form can affect various physical and chemical properties, which can provide advantages or disadvantages in terms of processing, formulation, stability, bioavailability, storage, handling (e.g., transportation), among pharmaceutic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/505
CPCA61K31/505C07D239/48C07D239/42A61P1/16A61P11/00A61P13/12A61P17/00A61P37/06A61P43/00A61P3/10A61P37/02A61P37/00C07D239/28C07B2200/13
Inventor 安东尼奥·克里斯蒂安·费雷蒂汉华·曼亚莱·穆斯尔希丁诺格卢珍·徐凯文·辛-英·咏玛丽·乔治·彼彻姆斯莫希特·阿塔尔·柯塔尔邹难非纳森·安德鲁·波尔森李英罗伯特·希尔格拉夫马克·A·纳吉邹道忠黄亷丰
Owner SIGNAL PHARMA LLC
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