HK1136282A - Novel imatinib camsylate and method for preparing thereof - Google Patents

Description

Novel imatinib camsylate and method for preparing same

Technical Field

[1] The present invention relates to a novel imatinib (d-camphorsulfonate) and a method for preparing the same.

Background

[2] Imatinib is the generic name for 4- [ (4-methyl-1-piperazinyl) methyl ] -N- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyl ] amino ] phenyl ] benzamide and is the first anticancer drug that has less effect on normal cells but is effective on leukemia cells having an abnormal chromosome called philadelphia chromosome (due to reciprocal translocation between chromosome 9 and chromosome 22), thereby inhibiting tumor cell proliferation and promoting tumor cell death.

[3] Us patent 5,521,184 discloses imatinib and a method for preparing the same. For pharmaceutical use, imatinib is suitably administered in a pharmaceutically acceptable acid salt thereof. For example, imatinib is currently sold in many countries as the monomethanesulfonate salt (imatinib mesylate) under the trade name GLIVEC (or GLEEVEC).

[4] Later, a number of pharmaceutically acceptable imatinib salt forms were disclosed by WO2005/075454 a2 to Novartis, examples of which are tartrate (D, L), hydrochloride, citrate, malate, D-malate, fumarate, succinate, benzoate, benzenesulfonate, pyrantel (pamoate salt), formate, malonate, 1, 5-naphthalenedisulfonate, salicylate, cyclamate, lactate, (S) -lactate, mandelate, (R) - (-) mandelate, glutarate, adipate, squarate (squarate salt), vanillitate, oxaloacetate, ascorbate, (L) -ascorbate, and sulfate, as well as methods for their preparation and their aqueous solubility. However, no salts are mentioned which are excellent in various properties, in particular pharmacokinetic properties.

[5] Meanwhile, among various acid addition salts of imatinib, there are no reports on D- (+) -camphorsulfonate, L- (-) -camphorsulfonate, D, L- (±) -camphorsulfonate of imatinib.

[6] Accordingly, the present inventors prepared imatinib camsylate by using 10-camphorsulfonic acid having relatively low toxicity. They found that imatinib camsylate prepared therefrom has a faster absorption rate and a higher absorption concentration in terms of pharmacokinetics and also has good water solubility, compared with commercially available imatinib mesylate, thus completing the present invention.

Disclosure of Invention

Technical problem

[7] The invention aims to provide novel imatinib camsylate and a preparation method thereof.

Advantageous effects

[8] Imatinib camsylate according to the present invention has a faster absorption rate and a higher absorption concentration in terms of pharmacokinetics and further has good water solubility, as compared with commercially available imatinib mesylate.

Brief Description of Drawings

[9] Fig. 1 is a graph showing the pharmacokinetic properties of D- (+) -camphorsulfonate, L- (-) -camphorsulfonate and D, L- (±) -camphorsulfonate of imatinib according to the present invention.

Preferred embodiments of the invention

[10] The present invention provides imatinib camsylate represented by the following formula 1:

[11] [ formula 1]

[13] Wherein HX is D- (+) -camphorsulfonic acid, L- (-) -camphorsulfonic acid or D, L- (+ -) -camphorsulfonic acid.

[14] Further, the present invention provides a method for preparing imatinib camsylate of formula 1, comprising the steps of:

[15]1) dissolving imatinib of the following formula 2 in an organic solvent;

[16]2) adding an acid selected from the following formulas 3 or 4 or a mixture thereof (1: 1), or adding the acid or the mixture dissolved in an organic solvent to the reaction solution of step 1) to prepare a mixture;

[17]3) stirring the mixture and filtering the precipitated solid to form an acid addition salt; and [18]4) if necessary, dissolving the acid addition salt in an organic solvent to recrystallize and purify the acid addition salt.

[19] Formula 2

[21] Formula 3

[23] Formula 4

[25] Preferably, in the preparation method, the step 3) of forming an acid addition salt and the step 4) of purifying an acid addition salt may further include a step of washing and drying the resulting solid after filtration.

[26] In order to effectively promote the crystallization in step 1), imatinib is preferably used in a concentration of 2 to 60% by weight, more preferably 5 to 20% by weight, based on the total weight of the reaction solution.

[27] In step 2), D- (+) -10-camphorsulfonic acid of formula 3, L- (-) -10-camphorsulfonic acid of formula 4, or racemic D, L- (+ -) -10-camphorsulfonic acid, which is a mixture (1: 1) of formula 3 and formula 4, is preferably used as the acid. Camphorsulfonic acid is a safe acid widely used in pharmaceuticals and is a stable colorless solid without hygroscopicity and corrosiveness. In addition, camphorsulfonic acid is not harmful to the human body, and thus can be safely and conveniently used for mass production. Camphorsulfonic acid is preferably used in an amount of 0.5 to 3 molar equivalents, more preferably 1.0 to 1.3 molar equivalents, based on 1 molar equivalent of imatinib.

[28]Examples of the organic solvent used in the steps 1), 2) and 4) may include C₁-C₄Lower alcohols such as methanol, ethanol, isopropanol, etc.; hydrocarbons such as pentane, hexane, cyclohexane, and the like; ethers such as tetrahydrofuran, 1, 4-dioxane, and the like; polar solvents such as acetone, dimethylformamide, dimethylsulfoxide, and the like; and mixtures thereof.

[29] In steps 3) and 4), the formation and purification of the acid addition salts is preferably carried out at a temperature in the range of-10 to 120 ℃, more preferably 25 to 90 ℃.

[30] Imatinib camsylate according to the present invention has a faster absorption rate and a higher absorption concentration in terms of pharmacokinetics and further has good water solubility, as compared with commercially available imatinib mesylate.

[31] In the following, preferred embodiments are provided for a better understanding. However, these examples are for illustrative purposes only, and the present invention will not be limited to these examples.

Modes for carrying out the invention

[32] Example 1: preparation of imatinib D, L- (+/-) -camphorsulfonate

[32] To 20mL of methanol was added 5g of 4- [ (4-methyl-1-piperazinyl) methyl ] -N- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyl ] amino ] phenyl ] benzamide. To the mixture was slowly added 2.4g of D, L- (±) -camphorsulfonic acid and 0.1g of activated carbon while stirring, and further stirred at room temperature for 1 hour. The solution was filtered, washed with 5mL of methanol, and then distilled under reduced pressure. Then, 50mL of isopropyl alcohol was added thereto, and stirred at room temperature for 1 hour. The solid mixture was filtered and washed with 10mL of isopropanol, then dried under reduced pressure to give 6.7g of a solid (91.1%).

[34] Melting point (m.p.): 144 ℃ to 148 DEG C

[35] Example 1-1: alternative preparation of imatinib D, L- (+/-) -camphorsulfonate

[36] To 20mL of tetrahydrofuran was added 5g of 4- [ (4-methyl-1-piperazinyl) methyl ] -N- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyl ] amino ] phenyl ] benzamide. To the mixture was added 2.4g of D, L- (±) -camphorsulfonic acid while stirring, and further stirred at room temperature for 1 hour. To the reaction solution was added 10mL of tetrahydrofuran, and refluxed for 1 hour with stirring. The solution was then cooled and filtered. The product was washed with 10mL tetrahydrofuran and dried under reduced pressure to give 6.9g of a solid (93.8%).

[37] Melting point (m.p.): 144 ℃ to 148 DEG C

[38] Example 2: preparation of imatinib D- (+) -camphorsulfonate

[39] To 20mL of methanol was added 5g of 4- [ (4-methyl-1-piperazinyl) methyl ] -N- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyl ] amino ] phenyl ] benzamide. To the mixture, 2.4g of D- (+) -camphorsulfonic acid and 0.1g of activated carbon were slowly added while stirring, and further stirred at room temperature for 1 hour. The solution was filtered, washed with 5mL of methanol, and then distilled under reduced pressure. Then, 50mL of isopropyl alcohol was added thereto, and stirred at room temperature for 1 hour. The solid mixture was filtered and washed with 10mL of isopropanol, then dried under reduced pressure to give 4.8g of a solid (65.2%).

[40] Melting point (m.p.): 130 ℃ C. and 132 ℃ C

[41] Example 3: preparation of imatinib L- (-) -camphorsulfonate

[42] To 20mL of methanol was added 5g of 4- [ (4-methyl-1-piperazinyl) methyl ] -N- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyl ] amino ] phenyl ] benzamide. To the mixture, 2.4g of L- (-) -camphorsulfonic acid and 0.1g of activated carbon were slowly added while stirring, and further stirred at room temperature for 1 hour. The solution was filtered, washed with 5mL of methanol, and then distilled under reduced pressure. Then, 50mL of isopropyl alcohol was added thereto, and stirred at room temperature for 1 hour. The solid mixture was filtered and washed with 10mL of isopropanol, then dried under reduced pressure to give 5.8g of a solid (78.5%).

[43] Melting point (m.p.): 135 ℃ C. & lt 136 ℃ C. & gt

[44]

[45] Experimental example 1: pharmacokinetic properties of imatinib camsylate

[46] In order to determine the pharmacokinetic properties of imatinib camsylate according to the present invention, the following experiments were performed.

[47] Male SD rats (body weight 180-220g) were orally administered 50mg/kg of each of the imatinib camsylate prepared in examples 1 to 3. After 0.5, 1, 1.5, 2, 2.5, 3, 5 and 8 hours, blood samples were taken from rats to isolate plasma. HPLC was performed to determine the concentration of imatinib in plasma. As a control group, commercially available imatinib mesylate was used. Animals used in the experiment were fasted for 16 hours prior to dosing. The concentration of imatinib according to time post-administration is shown in table 1 and fig. 1.

[48]

[49] TABLE 1

[50]

[51] As shown in table 1 and fig. 1, imatinib camsylate according to the present invention was found to have a faster absorption rate and a higher absorption concentration in terms of pharmacokinetics than commercially available imatinib mesylate.

[52]

[53] Experimental example 2: solubility test

[54] The water solubility of each of the imatinib camsylate prepared in examples 1-3 was determined at 25 ℃. As a control group, commercially available imatinib mesylate was used.

[55] The results are shown in Table 2.

[56]

[57] TABLE 2

Examples	Salt (salt)	Solubility (mg/ml)
			1	D, L- (+/-) -camphorsulfonic acid	≥3000
2	D- (+) -camphorsulfonic acid	≥3000
			3	L- (-) -camphorsulfonic acid	≥3000
Control group	Methanesulfonic acid	≥1200

[58]

[59] As shown in table 2, imatinib camsylate according to the present invention was found to have higher solubility than commercially available imatinib mesylate.

Claims (7)

1. Imatinib camsylate represented by the following formula 1:

formula 1:

wherein HX is D- (+) -camphorsulfonic acid, L- (-) -camphorsulfonic acid or D, L- (+ -) -camphorsulfonic acid.

2. Imatinib camsylate according to claim 1, wherein imatinib camsylate is a D- (+) -camphorsulfonate, an L- (-) -camphorsulfonate or a D, L- (±) -camphorsulfonate of imatinib.

3. A process for preparing imatinib camsylate of formula 1 below comprising the steps of:

1) dissolving imatinib of the following formula 2 in an organic solvent;

2) adding an acid selected from the group consisting of formula 3 or formula 4 below or a mixture thereof (1: 1), or adding the acid or the mixture dissolved in an organic solvent to the reaction solution of step 1) to prepare a mixture;

3) stirring the mixture and filtering the precipitated solid to form an acid addition salt; and

4) if necessary, dissolving the acid addition salt in an organic solvent to recrystallize and purify the acid addition salt,

formula 1:

wherein HX is D- (+) -camphorsulfonic acid, L- (-) -camphorsulfonic acid or D, L- (+ -) -camphorsulfonic acid,

formula 2:

formula 3:

formula 4:

4. the process for preparing imatinib camsylate according to claim 3, wherein in step 1), imatinib is used at a concentration of 2 to 60% by weight, based on the total weight of the reaction solution.

5. The process for preparing imatinib camsylate according to claim 3, wherein in step 2), the acid is used in an amount of 0.5 to 3 molar equivalents based on 1 molar equivalent of imatinib.

6. The process for preparing imatinib camsylate according to claim 3, wherein in steps 1), 2) and 4), said organic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, pentane, hexane, cyclohexane, tetrahydrofuran, 1, 4-dioxane, acetone, dimethylformamide, dimethyl sulfoxide, and mixtures thereof.

7. The process for preparing imatinib camsylate according to claim 3, wherein in steps 3) and 4), the formation and purification of the acid addition salt is carried out at a temperature ranging from-10 ℃ to 120 ℃.