Succinate Salt Form of a CDK4/6 Inhibitor for Oral Bioavailability
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Solution Overview
Problem
Existing compounds like N-Cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine face issues with solubility, stability, and oral bioavailability, hindering their development as effective CDK inhibitors for treating proliferative disorders.
Innovation Solution
Conversion of the compound into pharmaceutically acceptable salts, particularly succinate, with specific preparation methods to enhance solubility and stability, and improve bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the compound is used in its original form, then it shows CDK inhibitory activity, but it has poor solubility and oral bioavailability
Solution Approach 1:
The patent applies parameter changes by converting the compound into different salt forms (succinate, maleate, fumarate, citrate, hydrochloride, sulfate, phosphate, nitrate, hydrobromide, methanesulfonate, benzenesulfonate, benzoate, p-toluenesulfonate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, hippurate, glutarate, adipate, ascorbate, malonate, gentisate, nicotinate, L-malate, L-tartrate, or DL-lactate). This chemical modification changes the physical and chemical parameters of the compound, particularly improving water solubility and oral bioavailability while maintaining CDK inhibitory activity.
2Ease of operation
If the compound is converted to salt forms to improve solubility, then solubility and bioavailability improve, but the compound structure becomes more complex
Solution Approach 1:
The patent uses salt formation as an intermediary approach. By introducing pharmaceutically acceptable counterions (such as succinate, maleate, fumarate, citrate, hydrochloride, sulfate, phosphate, nitrate, hydrobromide, methanesulfonate, benzenesulfonate, benzoate, p-toluenesulfonate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, hippurate, glutarate, adipate, ascorbate, malonate, gentisate, nicotinate, L-malate, L-tartrate, or DL-lactate), the compound's solubility and bioavailability are enhanced without fundamentally altering the core pharmacophore structure responsible for CDK inhibition.
Data Source
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AI summary
Disclosed are salts of N-Cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine and polymorphs thereof, which are inhibitors of protein kinases, in particular cyclin-dependent kinase 4/6 (CDK4/6), and can be used to treat proliferative disorders, such as cancer, and other diseases related to protein kinase/CDK activity.