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Salts of epidermal growth factor receptor kinase inhibitor

A technology of hydrochloric acid and hydrobromide, which can be used in polymorphic form to treat various diseases and can solve problems such as dose-limiting toxicity

Active Publication Date: 2015-01-14
CELGENE CAR LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Current drugs in development, including second-generation covalent inhibitors such as BIBW2992, HKI-272, and PF-0299804, are effective against T790M resistance mutations but exhibit dose-limiting toxicity due to concurrent inhibition of WT EGFR

Method used

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  • Salts of epidermal growth factor receptor kinase inhibitor
  • Salts of epidermal growth factor receptor kinase inhibitor
  • Salts of epidermal growth factor receptor kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0257] Preparation of compound 1

[0258] The synthesis of compound 1 is described in detail in Example 3 of the '061 application.

[0259]

[0260] step 1:

[0261] Pre-equipped with electromagnetic stirrer, thermal bag and CaCl 2 N-Boc-1,3-diaminobenzene (0.96 g) and n-butanol (9.00 mL) were charged into a 25 mL 3-neck round bottom flask with a protective tube. The reaction mixture was cooled to 0°C. At 0°C, 2,4-dichloro-5-trifluoromethylpyrimidine (1.0 g) was added dropwise to the above reaction mixture. At 0°C, diisopropylethylamine (DIPEA) (0.96 mL) was added dropwise to the above reaction mixture and the reaction mixture was stirred at 0°C to 5°C for 1 hour. Finally, the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for another 4 hours at room temperature. Using hexane: ethyl acetate (7:3), the completion of the reaction was monitored by TLC. The precipitated solid was filtered off and washed with 1-butanol (2 mL). The solid ...

example 1

[0288] Primary salt screening

[0289] Based on the general preparation of compound 2, the results of the primary salt screening are shown in Table 1. Table 1 indicates the relative ions, solvents and resulting solid forms.

[0290] Table 1. Results of primary salt screening

[0291]

[0292] S1 = salt, polymorph form 1

[0293] S2 = salt, polymorphic form 2

[0294] S3 = salt, polymorphic form 3

[0295] S4 = salt, polymorphic form 4

[0296] SP = salt, partially crystalline

[0297] FA = free acid

[0298] FC = free compound 1

[0299] XR=Different XRPD patterns, but only a few peaks in the diffraction pattern (may indicate degradation)

[0300] AM = amorphous

[0301] GM = solid that quickly turns into a jelly after separation

example 2

[0303] Primary salt screening

[0304] For the potential salt obtained during the primary salt screening in Example 1, the sample was set at 40°C / 75% RH (open vial) and 80°C (open vial) for a 1-week stability study. After the stability study, TGA is performed on samples containing sufficient substances. Still in aqueous medium (pH <2) Test the solubility of the sample. The results of the stability and solubility studies are indicated in Table 2.

[0305] Table 2. Stability and solubility results of potential salts obtained in primary salt screening

[0306]

[0307]

[0308]

[0309] Based on these results, bis-benzenesulfonate was selected and acetone was used as a solvent to increase it proportionally. In addition, the hydrobromide salt is selected, and acetonitrile: water (90:10) is used as a solvent to increase it proportionally. The mono-maleate and bis-hydrochloride salts were also selected for scale-up experiments to assess whether these salts were solvated / hydrated.

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Abstract

The present invention provides a salt form and compositions thereof, which are useful as an inhibitor of EGFR kinases and which exhibits desirable characteristics for the same.

Description

[0001] Cross reference of related cases [0002] This application claims priority of U.S. Provisional Application No. 61 / 611,400 filed on March 15, 2012, the entire content of which is hereby incorporated by reference. Technical field [0003] The present invention provides salt forms of compounds suitable as mutation-selective inhibitors of epidermal growth factor receptor (EGFR) kinase, including polymorphic forms of certain salts. The present invention also provides pharmaceutically acceptable compositions comprising the salt forms of the present invention and methods of using the compositions to treat various disorders. Background technique [0004] Protein tyrosine kinases are a class of enzymes that catalyze the transfer of phosphate groups from ATP or GTP to tyrosine residues located on protein substrates. Receptor tyrosine kinases transmit signals from the outside of the cell to the inside by activating the second message-transmitting effector through phosphorylation events...

Claims

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Application Information

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IPC IPC(8): A01N43/54
CPCC07D239/48A61P35/00A61P43/00A61K31/506C07D403/12C07B2200/13C07C55/02C07C55/07C07C62/02C07C309/04C07C309/05C07C309/27C07C309/29C07C309/30C07C309/35
Inventor 赖美史蒂文·理查德·维特沃斯基里奇兰德·韦恩·特斯特李洸镐
Owner CELGENE CAR LLC
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