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Imidazo[1,2-a]pyrazin-8-ylamines useful as modulators of kinase activity

An alkyl and hydroxyl technology, applied in the field of imidazo[1,2-a]pyrazin-8-ylamines that can be used as kinase activity regulators, can solve the problems of lack of significant improvement in the course of the disease

Inactive Publication Date: 2008-02-13
CGI PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, in a standard murine preclinical model of systemic lupus erythematosus (SLE), Btk deficiency has been shown to lead to a marked improvement in disease course

Method used

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  • Imidazo[1,2-a]pyrazin-8-ylamines useful as modulators of kinase activity
  • Imidazo[1,2-a]pyrazin-8-ylamines useful as modulators of kinase activity
  • Imidazo[1,2-a]pyrazin-8-ylamines useful as modulators of kinase activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0460] 4-tert-butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazine-6- Synthesis of )-phenyl)-benzamide

[0461] Step 1: 2-(2-Methyl-3-nitrophenyl)-5,5-dimethyl[1,3,2]dioxaborinane

[0462]

[0463] 2-Bromo-6-nitrotoluene (3.2g; 14.8mmol), bis(neopentyl glycol) diboron (4g; 17.7mmol), and dichloromethane (362mg; 0.44mmol) were mixed 1:1 A mixture of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, potassium acetate (7.3 g; 73.8 mmol) and dioxane (75 mL) was heated under reflux for 3 h.

[0464] The mixture was then cooled to room temperature, treated with water (100 mL), and extracted with ethyl acetate (3 x 80 mL). The extract was washed with water (2 x 50 mL) and brine (1 x 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash silica gel chromatography (gradient elution with hexane / ethyl acetate 95 / 5-6 / 1) to give 2-(2-methyl-3-nitrophenyl)-5,5-dimethyl [1,3,2]Dioxaborinane as...

Embodiment 2

[0486] 6-tert-butyl-N-{2-methyl-3-[8-(4-morpholin-4-ylmethyl-phenylamino)-imidazo[1,2-a]pyrazine-6- Synthesis of ]-phenyl}-nicotinamide

[0487]

[0488] Step 1: 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid

[0489] Dissolve ethyl 4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoate (10.0 g; 27.7 mmol) in 200 mL of ethanol (200 strength) and add 100 mL of 1N NaOH. The reaction was refluxed for 2 hours, then cooled to room temperature. The resulting solid was collected by filtration, then slurried with 0.1N HCl (75 mL) and washed with CH 2 Cl 2 (2 x 75 mL) for extraction. Merged CH 2 Cl 2 The layer was washed with brine, then dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid as a white solid (8 g).

[0490]

[0491] Step 2: [4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-methanone

[0492] 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid (4.0 g; 12...

Embodiment 3

[0509] Synthesis of 3-(5,5-Dimethyl-[1,3,2]dioxaborin-2-yl)-2-fluoro-aniline

[0510]

[0511] Step 1: 2-(2-Fluoro-3-nitro-phenyl)-5,5-dimethyl-[1,3,2]dioxaborinane

[0512] 1-Bromo-2-fluoro-3-nitrobenzene (800mg; 3.63mmol), bis(neopentyl glycol) diboron (900mg; 3.98mmol), and dichloromethane (100mg; 0.12mmol) 1:1 A mixed mixture of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, potassium acetate (1.0 g; 10.2 mmol) and dioxane (20 mL) was heated under reflux for 16 h.

[0513] The mixture was cooled to room temperature, treated with water (100 mL), and extracted with ethyl acetate (3 x 25 mL).

[0514] The extract was washed with water (2 x 25 mL) and brine (1 x 25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluted with ether / hexane 1 / 2) to give 2-(2-fluoro-3-nitro-phenyl)-5,5-dimethyl-[1,3,2 ] Pale yellow solid of dioxaborinane (350 mg).

[0515]

[0516] Step 2: 3-(5,5...

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Abstract

Chemical entities chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, crystal forms, chelates, non-covalent complexes, prodrugs, and mixtures thereof, are described herein. Pharmaceutical compositions comprising at least one chemical entity of Formula 1, together with at least one pharmaceutically acceptable vehicle chosen from carriers adjuvants, and excipients, are described. Methods of treating patients suffering from certain diseases responsive to inhibition of Btk activity and / or B-cell proliferation are described. Methods for determining the presence of Btk in a sample are described.

Description

[0001] related application [0002] This application claims U.S. Application Nos. 10 / 985,023, filed November 10, 2004, 60 / 630,860, filed November 24, 2004, 60 / 630,645, filed November 24, 2004, and Priority to Application No. 60 / 630,861 filed November 24, 2004, each of which is hereby incorporated by reference in its entirety. technical field [0003] The present invention provides certain imidazo[1,2-a]pyrazinylamines and related compounds, compositions containing such compounds, and methods of use thereof. Background technique [0004] The largest class of human enzymes, protein kinases, contains more than 500 proteins. Bruton's Tyrosine Kinase (Btk) is a member of the Tec family of tyrosine kinases and is a regulator of early B-cell development as well as mature B-cell activation, signaling and survival. [0005] B-cell signaling through the B-cell receptor (BCR) produces numerous biological outputs, which in turn depend on the developmental stage of the B-cell. The am...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P37/00A61K31/4985A61P29/00A61P35/00
Inventor K·S·柯里J·E·克罗普夫J·W·达罗R·W·德西蒙
Owner CGI PHARM INC
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