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Salts of plk inhibitors
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A fumarate and compound technology, which can be used in antiviral agents, medical preparations containing active ingredients, cardiovascular system diseases, etc., and can solve problems such as poor solubility
Active Publication Date: 2015-10-21
NERVIANO MEDICAL SERVICES SRL
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In addition, it is well known that hydrated forms are generally less soluble than the corresponding anhydrous forms, which also has the potential to adversely affect the dissolution rate properties of the active compound itself and its absorption profile through the gastrointestinal tract
In the same way, a transition from crystalline to amorphous form can be observed in the presence of humidity, with potential disadvantages in terms of physical stability
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Embodiment 1
[0123] Example 1: Small-scale preparation of compound 937 salt
[0124] Dissolve one portion of compound 937 free base (approximately 40÷50 mg) in 4÷5 mL of a 2:1 mixture of methanol and dichloromethane at RT to give a nominal concentration of approximately 10 mg / mL.
[0125] Several salt formation experiments were then performed by adding a 1:1 stoichiometric amount of counterion to a solution of 4÷5 mL of the compound 937 free base at RT.
[0126] The cooling crystallization experiment was carried out at -30°C, and the standing time was about 24-36 hours.
[0127] The resulting precipitate was collected via vacuum filtration and dried in vacuo at 40°C.
[0129] In some cases, a further recrystallization step (e.g., trituration of the compound in diethyl ether) was required to separate the crystalline or at least powd...
Embodiment 2
[0132] Example 2: Gram scale preparation of compound 937 L-tartrate, succinate, fumarate, citrate, maleate and L-malate.
[0133] Dissolve the free base (500 mg, 0.939 mmol) in a 2:1 mixture of dichloromethane:methanol (24 mL) at reflux at room temperature, then add 1 equivalent of the acidic counterion dissolved in methanol, or in fumar In the case of acids, 1 equivalent of acidic counterion dissolved in 96% ethanol was added. The solution was reduced to 10 mL in vacuo, then cooled to -20 °C. The precipitated material was then filtered, washed with diethyl ether and finally dried under vacuum at 40° C. for at least 24 hours.
Embodiment 3
[0134] Example 3: Scaled-up preparation of compound 937 fumarate salt Form I
[0135] A certain amount of compound 937 free base was heated under reflux and stirring in absolute ethanol for 30 minutes to completely dissolve the starting material (concentration about 25g / L).
[0136] Then about 1 equivalent of fumaric acid was dissolved in ethanol (concentration about 29 g / L) and added to the free base solution.
[0137] After refluxing for 30 minutes to complete the salinization, the heating was interrupted.
[0138] The mixture was cooled to about 5°C, stirred at this temperature for about 1 hour, filtered, washed with absolute ethanol, and dried under vacuum at 35-40°C.
[0139] The resulting material was the ethanol solvate of compound 937 fumarate.
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Abstract
The present invention relates to novel crystalline, water-soluble salts of a plk inhibitor. Such crystal salts are for example L-tartrate, succinate, phosphate, mesylate, maleate, L-malate, hydrochloride, fumarate (half mole of counterion), fumarate, citrate (half mole of counterion), benzenesulfonate and L-aspartate (half mole of counterion). New crystal forms of the base as well as solvates and hydrates of such new salt forms, a process for their preparation, their utility in therapy and to the pharmaceutical compositions containing them are also claimed and described in the present application.
Description
[0001] This application is a divisional application of a Chinese patent application with the application number 201080033461.9 (PCT / EP2010 / 060659), the filing date is July 22, 2010, and the invention title is "Salts of PLK Inhibitors". technical field [0002] The present invention relates to new crystals, water-soluble salts of PLK inhibitors, processes for their preparation, hydrates, solvates and polymorphs of the new salt forms, their use in therapy and pharmaceutical compositions containing them . Background technique [0003] Cancer is the leading cause of death in humans; surgery, radiation and chemotherapy are useful methods of combating cancer. [0004] PLK1 is a serine-threoninekinase essential for the development of proper mitosis. [0005] PLK1 expression is seen in all proliferative normal tissues, while its overexpression has been observed in a range of tumors, including breast, prostate, ovarian, lung, gastric and colon cancers. When RNAi led to depletion o...
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