Solid forms of an epidermal growth factor receptor kinase inhibitor

A form of solid technology, used in plant growth regulators, biocides, animal repellants, etc., to solve problems such as dose-limiting toxicity

Active Publication Date: 2015-01-21
BRISTOL MYERS SQUIBB CO
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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-029980

Method used

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  • Solid forms of an epidermal growth factor receptor kinase inhibitor
  • Solid forms of an epidermal growth factor receptor kinase inhibitor
  • Solid forms of an epidermal growth factor receptor kinase inhibitor

Examples

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Comparison scheme
Effect test

example 1

[0227] Preparation Form A

[0228] Approximately 120 mg of Compound 1 was weighed into a vial and slurried in approximately 2 ml of acetonitrile. This slurry was temperature cycled between about 0°C and ambient (about 22°C) in a 2 hour cycle with stirring for a period of 2-3 days. Keep samples at about 2-5°C overnight. The solid material was separated and allowed to dry under vacuum for 7 days.

[0229] XRPD analysis ( figure 1 ) shows that the material is crystalline. PLM analysis (not shown) indicated very fine birefringent needles. TGA / DTA ( figure 2 ) shows a 0.4% weight loss from start to about 150°C, probably due to unbound solvent. No significant weight loss was seen prior to degradation. DSC analysis ( image 3 ) shows a single endotherm at onset about 203.2°C (peak 207.5°C) due to melting. IR analysis ( Figure 4 ) is consistent with the input free base substance. in deuterated DMSO 1 H NMR (not shown) showed a spectrum consistent with the input free bas...

example 2

[0232] Preparation Form B

[0233] About 120 mg of compound 1 was weighed into a vial and slurried in about 2 ml of tetrahydrofuran. This slurry was temperature cycled between about 0°C and ambient (about 22°C) in a 2 hour cycle with stirring for a period of 2-3 days. Keep samples at about 2-5°C overnight. The solid material was separated and allowed to dry under vacuum at ambient for 7 days and at 40° C. for 2 days.

[0234] XRPD analysis ( Figure 6 ) shows that the resulting material is crystalline. PLM analysis (not shown) indicated birefringent rod crystals. TGA / DTA ( Figure 7 ) shows no significant weight loss before degradation after 7 days of ambient drying under vacuum and a further 2 days at 40°C. DSC analysis ( Figure 8 ) shows an endotherm at onset 153.6°C (peak 157.6°), followed directly by an exotherm at peak 161.3°C, indicating a polymorphic transition. There was another small endotherm at peak 186.0°C, followed by a final endotherm at onset 203.9°C (p...

example 3

[0238] Preparation Form C

[0239] Approximately 120 mg of Compound 1 was weighed into a vial and slurried in approximately 100 μl DMF. The slurry was temperature cycled between about 0°C and ambient (about 22°C) in a 2 hour cycle with agitation. After about 2 hours, another 300 μl of DMF was added. The temperature cycle was continued for a period of 2-3 days. Keep samples at about 2-5°C overnight. The solid material was separated and allowed to dry under vacuum at ambient for 7 days and at 40° C. for 2 days.

[0240] XRPD analysis ( Figure 12 ) shows that the material is crystalline. PLM analysis (not shown) indicated birefringent rod crystals. TGA / DTA ( Figure 13 ) showed a weight loss of about 8.2% after 7 days of ambient drying under vacuum and a further 2 days at 40°C (the monosolvate required 11.6 wt% DMF). DSC analysis ( Figure 14 ) showed a broad endotherm between 85-125 °C, consistent with weight loss in TGA. A final endotherm was seen with onset at about...

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Abstract

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

Description

[0001] Cross References to Related Cases [0002] This application claims priority to US Provisional Application No. 61 / 611,376, filed March 15, 2012, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention provides solid forms of compounds useful as mutation-selective inhibitors of epidermal growth factor receptor (EGFR) kinase. The invention also provides pharmaceutically acceptable compositions comprising the solid forms of the invention and methods of using said compositions to treat various conditions. Background technique [0004] Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP or GTP to a tyrosine residue located on a protein substrate. Receptor tyrosine kinases transmit signals from the outside of the cell to the inside by activating second message-transmitting effectors through phosphorylation events. A variety of cellular processes are promoted through thes...

Claims

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Application Information

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IPC IPC(8): A01N43/54
CPCC07D239/48A61K31/506A61P35/00A61P43/00C07D403/12
Inventor 赖美
Owner BRISTOL MYERS SQUIBB CO
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