MXPA06008818A - Salt forms of 4-(4-methylpiperazin -1-ylmethyl)-n -[4-methyl-3- (4-pyridin-3-yl) pyrimidin-2- ylamino)phenyl]-benzamide - Google Patents

Abstract

The present invention relates to acid addition salts of 4-[4-methyl-1 -piperazinylmethyl]-N -[4-methyl-3- [[4-¢3-pyridinyl-2 -pyrimidinyl]amino]phenyl]- benzamide, which are selected from the group consisting of a tartrate salt, such as a (D)(-) tartrate salt or a (L)(+) tartrate salt, a hydrochloride salt, a citrate sat, a malate salt, a fumarate salt, a succinate salt, a benzoate salt, a benzenesulfonate salt, a pamoate salt, a formate salt, a malonate salt, a 1,5-naphthalenedisulfonate salt, a salicylate salt, a cyclohexanesulfamate salt, a lactate salt, a mandelate salt, aq glutarate salt, an adipate salt, a squarate salt, a vanillate salt, an oxaloacetate salt, an ascorbate salt and a sulfate salt.

Description

FORMS OF SALT OF 4- (4-METHYLPIPERAZIN-1-methylmethyl) -N- [4-METHYL-3- (4-PYRIDIN-3-IL) PYRIMIDIN-2-ILAMINO) PHENYL] -BENZAMIDE DESCRIPTION OF THE INVENTION The present invention relates to salt forms of the pharmaceutically active compound of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- ( 3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide. The pharmaceutically active compound of 4 - [(4-methyl-1-p¡perazinyl) methyl] -? - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] pheny] -benzamide is commonly known for its INN called Imatinib. He Imatinib and its preparation are described in U.S. Patent No. 5,521,184. The basic pharmaceutically active compounds are commonly formulated in pharmaceutical preparations as an acid addition salt form, particularly as a crystalline acid addition salt. For example, matinib is marketed in many countries as its monomethanesulfonate salt (imatinib mesylate) under the trade name GLIVEC or GLEEVEC. Two crystal forms of imatinib mesylate are described in WO 99/03854. The crystal form designated as the beta form is described with physical properties that make it advantageous for the manufacture of solid oral pharmaceutical dosage forms, such as tablet and capsule dosage forms. Although it is known that the preparation of salt forms can improve the physical or pharmaceutical properties of a basic pharmaceutically active compound, it is not possible to predict which salt forms may possess the advantages for a particular purpose before the present preparation and characterization of the form of salt. The present invention relates to imatinib salt forms, with the exception of imatinib mesylate, which are useful for the manufacture of solid or liquid pharmaceutical dosage forms, particularly solid oral dosage forms, such as tablets and capsules, and forms of liquid oral dosages, such as orally administered solutions and suspensions, as well as suppositories and other pharmaceutical dosage forms. Each of these salt forms possesses one or more properties that provide advantages when used as a pharmaceutically active ingredient, such as physical properties that make it easier to manufacture one or more dosage forms, improved stability, improved bioavailability and other properties that are they are known to one skilled in the art. The imatinib salt forms are prepared by methods known in the art for making acid addition salts of amines, for example, by treating imatinib with a convenient anion exchange reagent or acid. Normally, the matinib or a solution of imatinib is combined with a solution of an organic or mineral acid in, for example, a lower alcohol, such as methanol or ethanol, with or without heating. The salt is isolated by crystallization or evaporation of the solvent and, if desired, purified by recrystallization from an appropriate recrystallization solvent by methods known to one skilled in the art.

In order to administer a salt of 4 - [(4-methyl-1-piperazinyl) methyl] - - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] - benzamide by means of an oral solution, in general these salts having an increased water solubility compared to the free base are preferred. Salts having a lower water solubility compared to the free base make them, in general, more suitable for the manufacture of sustained release formulations compared to the free base. Important embodiments of this invention include salts of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, selected from the group consisting of a tartrate salt, such as a salt of (D) (-) tartrate or salt of (L) (+) tartrate, hydrochloride salt, citrate salt, malate salt , particularly a D-malate salt, fumarate salt, succinate salt, benzoate salt, benzenesulfonate salt, pamoate salt, formate salt, malonate salt, 1,5-naphthalenedisulfonate salt, silicate salt, cyclohexanesulfamiate salt, lactate salt, particularly a salt of ( S) -lactate, mandelate salt, particularly a salt of (ft) (-) mandelate, glutarate salt, adipate salt, squarate salt, vanilate salt, oxaloacetate salt, ascorbate salt, particularly a salt of ( ) ascorbate and sulfate salt. Other important embodiments of this invention include imatinib ascorbate, imatinib formate, imatinib malonate, imatinib oxaloacetate, imatinib esquatrate, and imatinib vanilate. In a preferred embodiment of the present invention, the acid addition salt is selected from the group consisting of a tartrate salt, such as a salt of (D) (-) tartrate or a salt of () (+) tartrate, hydrochloride salt, citrate salt, malate salt, particularly a D-malate salt, fumarate salt, succinate salt, benzoate salt, benzenesulfonate salt, pamoate salt, hemiformate salt, malonate salt, salt of salicylate, cyclohexanesulfamiate salt, mandelate salt, particularly a salt of (R) (-) mandelate, salt of hemiglutarate, adipate salt, vanilate salt and sulphate. In another preferred embodiment of the present invention, the acid addition salt is selected from the group consisting of matinib D-tartrate, imatinib D-malate, imatinib hemiformate, imatinib malonate, imatinib silicate, hematlutamate imatinib, imatinib cyclohexansulfamiate, imatinib mandelate, particularly (f?) (-) imatinib mandelate, imatinib adipate, imatinib vanilate and imatinib sulfate. The present invention further relates to a pharmaceutical composition comprising one of the aforementioned salts of imatinib and a pharmaceutically acceptable carrier. In one embodiment, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an acid addition salt of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, selected from the group consisting of a tartrate salt, such as a salt of (D) (-) tartrate or salt of () (+) tartrate, hydrochloride salt, citrate salt, malate salt, particularly a D-malate salt, fumarate salt, succinate salt, benzoate salt, benzenesulfonate salt, pamoate salt, formate salt, salt of malonate, salt 1, 5-naphthalenedisulfonate, silicate salt, cyclohexanesulfamiate salt, lactate salt, particularly a salt of (S) -lactate, mandelate salt, particularly a salt of (R) (-) mandelate, salt of aqueous glutarate, adipate salt, squarate salt, valinate salt, oxaloacetate salt, ascorbate salt, particularly a salt of (L) -ascorbate and sulfate salt. In an important embodiment, the acid addition salt is selected from the group consisting of imatinib ascorbate, imatinib formate, imatinib malonate, imatinib oxaloacetate, imatinib esquatrate and imatinib vanilate. The invention also relates to a process for the treatment of warm-blooded animals suffering from a tumor disease, wherein an amount of an acid addition salt of 4 - [(4-methyl-1-piperazinyl) methyl] - ? / - [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide disclosed herein which is effective against the aforementioned disease, especially an antiproliferatively effective amount and especially to inhibit a tumor, it is administered to warm-blooded animals in need of such treatment, especially the treatment of gliomas, ovarian tumors, prostate tumors, gastrointestinal stromal tumors, colon tumors, and lung tumors, such as especially carcinoma. of small cell lung, and breast tumors or other gynecological tumors and, in particular, leukemia. Depending on the species, age, individual condition, mode of administration, and the clinical picture in question, the effective doses, for example daily doses of approximately 10-2000 mg, preferably 25-1000 mg, especially 50-800 mg, are administered to warm-blooded animals of approximately 70 kg body weight. In a further aspect, the present invention relates to the use of an acid addition salt of 4 - [(4-methyl-1-piperazinyl) methyl] - / V- [4-methyl-3-] [[4- (3-pyridinyl) -2-pyridinyl] amino] phenol] -benzamide according to any of claims 1 to 4 for the manufacture of a pharmaceutical composition for the treatment of a tumor disease, especially the treatment of gliomas, ovarian tumors, prostate tumors, gastrointestinal stromal tumors, colon tumors, and lung tumors, such as especially small cell lung carcinoma, and breast tumors or other gynecological tumors and, in particular leukemia. The following examples illustrate the invention without limiting the scope thereof.

Example 1 4 - [(4-methyl-1-piperazinyl) methyl] - / V- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, tartrate 4 - [(4-Methyl-1-piperazinyl) methyl] - / V- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (4.94 g, mmol) was added to a solution of (2R, 3R) -2,3-dihydroxybutanedioic acid (L - (+) - tartaric acid; Fluka, Buchs, Switzerland; (1.50 g, 10 mmol) in hot ethanol ( 40 ml) The solution was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from methanol to produce, after filtering and drying, 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, tartrate as a pale yellow crystalline solid, having the following analytical properties: Analysis found: C, 60.1 8; H, 5.96; N, 14. 86%; H2O, 2.25%. Calculated for C 33 H 37 N 7 O 7 - 0.82 H2O: C, 60.1 9; H, 5.91; N, 14.89%. H2O, 2.24%.

Example 2 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidin] amino] ] phenyl] -benzamide, hydrochloride Aqueous hydrochloric acid (0.99 g of 37%) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3- [ [4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (4.94 g, 10 mmol) in ethanol (20 ml). The solution was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from ethanol-ethyl acetate. The product was filtered and recrystallized from isopropanol to yield, after filtering and drying, 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3 -pyridinyl) -2-pyrimidinyl] amino] phenol] -benzamide, hydrochloride as a light yellow crystalline solid, which has the following analytical properties: Analysis found: C, 65.27; H, 6.07; N, 18.19; Cl, 6.55% 0.56%.

Calculated for C29H32N7OCI - 0.17 H2O: C, 65.33; H, 6.1 1; N, 18.39; Cl, 6.65%; H2O, 0.57%.

Example 3 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] pheny] -benzamide, citrate 4 - [(4-Methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (4.94 g , 10 mmol) was added to a solution of anhydrous 2-hydroxy-1, 2,3-propanedicarboxylic acid, (citric acid, Merck, Darmstadt, BRD, 1.92 g, 10 mmol) in methanol (30 ml) room temperature. Upon cooling, 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, citrate was crystallized and filtered and dried to yield a pale yellow crystalline solid, which has the following analytical properties: Analysis found: C, 59.24; H, 5.71; N, 13.60%, H2O, 2.14%. Calculated for C35H3gN708 - 0.83 H2O: C, 60.00; H, 5.85; N, 13.99%; H2O, 2.13%.

Example 4 4 - [(4-Methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino ] phenyl] -benzamide, malate 4 - [(4-Methyl-1-piperazinyl) methyl] -V- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (4.94 g, 10 mmol) was added to a solution of (2S) - (-) - hydroxybutanedioic acid (L - (-) - malic acid; Fluka, Buchs, Switzerland: 1.34 g, 10 mmol) in water (40 ml). The mixture was heated and the resulting hot solution was filtered and evaporated to dryness under reduced pressure to give a residue which was recrystallized from ethanol, filtered and dried to give 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, malate as a light yellow crystalline solid, having the following analytical properties: found: C, 62.88; H, 6.04; N, 15.60%; H2O, 0.45%. Calculated for C 33 H 37 N 7 O 6 - 0.1 6 H 2 O: C, 62.86; H, 5.97; N, 15.55%; H2O, 0.46%.

Example 5 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino-phenyl-benzamide, fumarate (Trans) -butenedioic acid (fumaric acid; Fluka, Buchs, Switzerland; 1.16 g, 10 mmol) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) - 2-pyrimidinyl] amino] phenyl] -benzamide (4.94 g, 10 mmol) in ethanol (25 ml). The mixture was heated to 90 ° C, treated with water (18 g) and filtered. Upon cooling, the product was crystallized and filtered and dried to yield 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) - 2-pyrimidinyl] amino] phenyl] -benzamide, fumarate a pale yellow crystalline solid, which has the following analytical properties: Analysis found: C, 63.91; H, 5.99; N, 15.74%; H2O, 1.27%. Calculated for C33H35N7O5 - 0.44 H2O: C, 64.18; H, 5.86; N, 15.88%; H2O, 1 .28%.

Example 6 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide , succinate 4 - [(4-Methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (4.94 g, 10 mmol) was added to a solution of butanedioic acid (succinic acid; Fluka, Buchs, Switzerland; 1.1 g, 10 mmol) was added to a solution of ethanol (25 ml). The mixture was heated to 90 ° C, treated with water (0.2 g) and filtered. Upon cooling, the product was crystallized and filtered and dried to yield 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyr Dinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, succinate as a light yellow crystalline solid, having the following analytical properties: Analysis found: C, 64.19; H, 6.1 1; N, 15.82%; H20, 0.87%. Calculated for C33H37N7O5 - 0.30 H2O: C, 64.23; H, 6.14; N, 15.89%; H2O, 0.88%.

EXAMPLE 7 4 - [(4-Methyl-1-piperazinyl) methyl] - / V- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] ] phenyl] -benzamide, benzoate 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (4.94 g, 10 mmol) was added to a solution of benzoic acid (Fluka, Buchs, Switzerland, 1.22 g, 10 mmol) in xylene (50 ml). The mixture was heated and the resulting hot solution was filtered. Upon cooling, the product was crystallized and filtered and dried to yield 4 - [(4-methyl-1-piperazinyl) methyl] - / V- [4-methylene-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, benzoate as pale brown crystalline solid, having the following analytical properties: Analysis found: C, 70.13; H, 6.12; N, 16.24%. Calculated for C36H3 N7O3: C, 70.22; H, 6.06; N, 15.92%.

Example 9 4 - [(4-methyl-1-piperazinyl) methyl] - / \ / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide , benzenesulfonate 4 - [(4-Methyl-1-piperazinyl) methyl] - / V- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (4.94 g, 10 mmol) was added to a solution of benzenesulfonic acid (Fluka, Buchs, Switzerland: 1.61 g, 10 mmol) in hot toluene (40 ml). The solution was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from ethanol-ethyl acetate. The product was filtered and dried to yield 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] aminojphenylj-benzamide , benzenesulfonate as a pale yellow crystalline solid, which has the following analytical properties: Analysis found: C, 64.19; H, 5.68; N, 14.93; S, 4.87%; H2O, 0.34%. Calculated for C35H37N7O4S-0.12 H2O: C, 64.28; H, 5.74; N, 14.99; S, 4.90%; H2O, 0.33%.

Example 10 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, pamoate A mixture of 4 - [(4-methyl-1-piperazinyl) methyl] - / V- [4-methyl-3- [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide ( 4.94 g, 10 mmol) and 4,4'-methylenebis [3-hydroxy-2-naphthoic acid (Fluka, Buchs, Switzerland, 3.88 g, 10 mmol) was heated in ethanol (50 ml). Then water (25 ml) was added. Upon cooling, the product crystallized and was filtered and dried to yield 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2 pyrimidinyl] amino] phenyl] -benzamide, pamoate as a light yellow solid, having the following analytical properties: Analysis found: C, 69.12; H, 5.62; N, 10.88%; H2O, 2.50%. Calculated for C52H47N7O7-1.26 H2O: C, 69.04; H, 5.52; N, 10.84%; H2O, 2.51%.

Example 1 1 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, salicylate A solution of 2-hydroxybenzoic acid (salicylic acid; Fluka, Buchs, Switzerland; 558 mg, 4 mmol) in ethanol (50 ml) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] - ? / - [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (1.975 g, 4 mmol) in hot ethanol (150 ml at 90 ° C) . The hot solution is reduced in volume to 80 ml by rotary evaporation at 90 ° C and 400 mbar and then cooled slowly to 20 ° C to produce, after filtering and drying, 4 - [(4-methyl-1-piperazinyl) methyl] ] - - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, silicate as a crystalline solid, having the following analytical properties: Analysis found: C, 68.18; H, 5.93; N, 15.52; O, 10. 42%. H2O, 0.31%. Calculated for C36H37N704 - 0.1 1 H2O: C, 68.23; H, 5.92; N, 15.47; O, 10.38%. H2O, 0.31%.

EXAMPLE 12 4 - [(4-Methy1-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl ] amino] phenyl] -benzamide, vanilate A solution of 4-hydroxy-3-methoxybenzoic acid (vanillic acid; Fluka, Buchs, Switzerland; 694 mg, 4 mmol) in ethanol (50 ml) was added to a solution of [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (1.975 g, 4 mmol) in hot ethanol (150 ml at 90 ° C). The solution was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from ethanol-acetone. The product was filtered and dried to yield 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [(4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl ] - benzamide, vanilate as a crystalline solid, which has the following analytical properties: Analysis found: C, 66.61; H, 6.18; N, 14.74; O, 12.86%, H2O, 0.84%, calculated for C37H39N7O5 - 0.31 H2O: C , 66. 59; H, 5.98; N, 14.69; O, 12.73%. H2O, 0.84%.

EXAMPLE 13 4 - [(4-Methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, cyclohexanesulfamiate A Solution of α / - cyclohexylsulfamic acid (Fluka, Buchs, Switzerland: 732 mg, 4 mmol) in ethanol (100 ml) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-meth1l-3 - [[4- (3-pyridinyl) -2-pyrimidinyl-3-amino] phenyl] -benzamide (1.975 g, 4 mmol) in hot ethanol (150 ml at 90 ° C). The solution was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from ethanol-isopropanol. The product was filtered and dried to yield 4 - [(4-methyl-1-piperazinyl) methyl] -? - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, sulfamiate as a crystalline solid, having the following analytical properties: Analysis found: C, 61.13; H, 6.75; N, 15.87; O, 1 1 .80; S, 4.57%.

H2O, 1.69%. Calculated for C35H44N8O4S - 0.40 / -PrOH - 0.70 H2O: C, 61.28; H, 6.90; N, 15.79; O, 1 1 .50; S, 4.52%. H2O, 1.78%.

Example 14 4 - [(4-Methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [(4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, hemiglutarate One solution of 1,5-pentanedioic acid (glutaric acid; Fluka, Buchs, Switzerland; 539 mg, 4 mmol) in ethanol (60 ml) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3- pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (1.975 g, 4 mmol) in hot ethanol (150 ml at 90 ° C). The hot solution is reduced in volume to 80 ml by rotary evaporation at 90 ° C and 400 mbar and then cooled slowly to 20 ° C to produce, after filtering and drying, 4 - [(4-methyl-1-piperazinyl) methyl] ] -A / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenylj-benzamide, hemiglutarate as a crystalline solid, having the following analytical properties: Analysis found: C, 64.62; H, . 81; N, 16.81; O, 1 1 .96%. H2O, 4.14%. Calculated for C 32 H 36 N 7 O 3 -1 .5 H 2 O: C, 64.74; H, 6.62; N, 16.51; OR, 12. 13% H2O, 4.55%.

Example 15 4 - [(4-Methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, malonate A solution of 1,3-propanedioic acid (malonic acid; Fluka, Buchs, Switzerland; 420.5 mg, 4 mmol) in ethanol (60 ml) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (1.975 g, 4 mmol) in hot ethanol (150 ml to 90) ° C). The hot solution was cooled slowly to 20 ° C to produce, after filtering and drying, 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3 -pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, malonate as a crystalline solid, having the following analytical properties: Analysis found: C, 64.0; H, 6.1; N, 16.3; O, 13.6%. H2O, < 0.3%. Calculated for C 32 H 35 N 7 O 5: C, 64.31; H, 5.90; N, 16.40; O, 13.38%.

Example 16 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, sulfate A solution of sulfuric acid (Fluka, Buchs, Switzerland, 4.0 ml of 1 M) in ethanol (50 ml) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [ 4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (1.975 g), 4 mmol) in hot ethanol (350 ml at 90 ° C). The hot solution was cooled slowly to 20 ° C to produce, after filtering and drying, 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3- pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, sulfate as a crystalline solid, which has the following analytical properties: Analysis found: C, 55.17; H, 5.82; N, 15.57; O, 18.29; S, 5.26%. HO, 5.89%. Calculated for C29H33N7O5S 2.06 H2O: C, 55.34; H, 5.95; N, 15.59; O, 17.96; S, 5.10%. H2O, 5.90%. Example 17 4 - [(4-Methyl-1-piperazinyl) methyl] -A / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, adipate A solution of 1,6-hexanedioic acid (adipic acid; Fluka, Buchs, Switzerland; 1081 mg, 4 mmol) in ethanol (80 ml) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (1.975 g, 4 mmol) in hot ethanol (150 ml at 90 ° C) ). The hot solution is reduced in volume to 80 ml by rotary evaporation at 90 ° C and 400 mbar and then cooled slowly to 20 ° C to produce, after filtering and drying, 4 - [(4-methyl-1-piperazinyl) methyl] ] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenylj-benzamide, adipate as a crystalline solid, having the following analytical properties: Analysis found: C, 64.97; H, 6.33; N, 15.44; O, 12.77%. H2O, 1 .43%. Calculated for C35H41 N7O5 - 0.5 H2O: C, 64.76; H, 6.53; N, 1 5.1 0; O, 13. 61%. H2O, 1.44%.

EXAMPLE 18 4 - [(4-Methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, (R) - (-) - mandelate A solution of (R) - (-) - alpha-hydroxybenzenacetic acid ((D) - (-) - mandelic acid, Fluka, Buchs, Switzerland, 553 mg, 3.13 mmol) in ethanol (60 ml) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] ] amino] phenyl] -benzamide (1.975 g, 4 mmol) in hot ethanol (150 ml at 90 ° C). The hot solution is reduced in volume to 80 ml by rotary evaporation at 90 ° C and 400 mbar and then cooled slowly to 20 ° C to produce, after filtering and drying, 4 - [(4-methyl-1-piperazinyl) methyl ] -? - [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, mandelate as a crystalline solid, having the following analytical properties: Analysis found: C, 68.60; H, 6.27; N, 15.19; O, 9.91%. H2O, 0.22%. Calculated for C37H39N7O4 - 0.08 H2O: C, 68. 67; H, 6.1 0; N, 1 5.15; O, 10.09%. H2O, 0.22%.

Example 19 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, malay A solution of (2R) - (-) - hydroxybutanedioic acid ((D) -malic acid; Fluka, Buchs, Switzerland; 553 mg, 2.83 mmol) in ethanol (60 ml) was added to a solution of 4- [ (4-meth1l-1-piperazinyl) methyl] -V- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide (1.975 g, 4 mmol) in hot ethanol (150 ml at 90 ° C). The hot solution is reduced in volume to 80 ml by rotary evaporation at 90 ° C and 400 mbar and then cooled slowly to 20 ° C to produce, after filtering and drying, 4 - [(4-methyl-1-piperazinyl) methyl ] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide. malate as a crystalline solid, which has the following analytical properties: Analysis found C, 62.14; H, 6.33; N, 15.48; Or, 16.18%. H2O, 1 .99%. Calculated for C33H3 N7O6 - 0.71 H2O: C, 61.88; H, 6.05; N, 15.31; O, 16.76%. H2O, 2.00%. EXAMPLE 20 4 - [(4-Methyl-1-piperazinyl) methyl] - / V- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzam da, (D) - (-) - tartrate A solution of (2S, 3S) -2,3-dihydroxy-butanedioic acid (tartaric acid; Fluka, Buchs, Switzerland; 606.5 mg, 1.97 mmol) in ethanol (90 ml) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] ] amino] phenyl] -benzamide (1.975 g, 4 mmol) in hot ethanol (150 ml at 90 ° C). The hot solution was cooled slowly to 20 ° C to produce, after filtering and drying, 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3 -pyridinyl) -2-pyrimidinyl] amino] phenylj-benzamide, tartrate as a crystalline solid, having the following analytical properties: Analysis found: C, 60.54; H, 6.08; N, 14.37; O, 18. 89%. H2O, 1 .32%. Calculated for C33H37N7O7 -0.50 EtOH-0.50 H2O: C, 60.43; H, 6.12; N, 14.51; O, 18.94%. H2O, 1 .33%.

EXAMPLE 21 4 - [(4-Methyl-1-piperazinyl) methyl] -W- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, hemiformate A solution of formic acid (Fluka, Buchs, Switzerland: 368 mg, 8 mmol) in ethanol (20 ml) was added to a solution of 4 - [(4-methyl-1-piperazinyl) methyl] - / V- [4-methyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinol] amino] phenyl] -benzamide (1.975 g, 4 mmol) in hot ethanol (150 ml at 90 ° C). The solution was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from acetone. The product was filtered and dried to yield 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide, hemiformate as a crystalline solid, which has the following analytical properties: Analysis found: C, 68.50; H, 6.24; N, 18.93; O, 6.43%. H2O, 1.69%. Calculated for C59H64N14O4-1.80 H2O: C, 68.46; H, 6.25; N, 18.95; O, 6.34%. H2O, 0.17%.

Example 22 - Capsules Capsules containing 100 mg of salt of 4 - [(4-methyl-1-piperazinyl) methyl] -A / - [4-methyl-3 - [[4- (3-pyridinyl) -2- pyrimidinyl] amino] phenyl] -benzamide ("Salt") are generally prepared in the following composition: Composition Salt 100 mg Avicel 200 mg PVPPXL 15 mg Aerosil 2 mg Magnesium stearate 1.5 mq 318.5 mg Capsules are prepared by mixing the components and filling the mixture in hard gelatin capsules, size 1.

Example 23 - Solubility in Aqua The solubility in water at room temperature of the salt of 4 - [(4-methyl-1-piperazinyl) methyl] -? - [4-Methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide is as listed in Table 1 below. For comparison, the solubility of the free base in water at room temperature is 0.44 mg / ml. Table 1

Claims (7)

1 . An acid addition salt of 4 - [(4-methyl-1-piperazinyl) methyl] - / V- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide is selected from the group consisting of a tartrate salt, such as (D) (-) tartrate salt or (L) (+) tartrate salt, hydrochloride salt, citrate salt, malate salt, particularly a D-malate salt, fumarate salt, succinate salt, benzoate salt, benzenesulfonate salt, pamoate salt, formate salt, malonate salt, 1, 5-naphthalenedisulfonate salt, silicate salt, salt of cyclohexanesulfamiate, lactate salt, particularly a salt of (S) -lactate, mandelate salt, particularly a salt of (ft) (-) mandelate, glutarate salt, adipate salt, squarate salt, vanillate salt, salt of oxaloacetate, ascorbate salt, particularly a salt of (ascorbate) and sulfate salt.

2. An acid addition salt selected from the group consisting of imatinib ascorbate, imatinib formate, imatinib malonate, imatinib oxaloacetate, imatinib escuarate and imatinib vanilate.

3. An acid addition salt of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] -benzamide selected from the group consisting of a tartrate salt, such as a salt of (D) (-) tartrate or salt of (L) (+) tartrate, hydrochloride salt, citrate salt, malate salt, particularly a D-malate salt, fumarate salt, succinate salt, benzoate salt, benzenesulfonate salt, pamoate salt, hemiformate salt, malonate salt, silicate salt, cyclohexanesulfamiate salt, mandelate salt, particularly a salt of (/) (-) mandelate, hemiglutarate salt, adipate salt, vanilate salt and sulphate salt.

4. An acid addition salt selected from the group consisting of imatinib D-tartrate, imatinib D-malate, imatinib hemiformate, imatinib malonate, imatinib silicate, imatinib hemiglutamate, imatinib cyclohexansulfamiate, imatinib mandelate, particularly (?) (-) matinib mandelate, imatinib adipate, imatinib lantilate and imatinib sulfate.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an addition salt of 4 - [(4-methyl-1-piperazinyl) methyl] J- / V- [4-methyl-3 - [[4- (3-pyridinyl)] ) -2-pyrimidinyl] amino] phenyl] -benzamide of selected from the group consisting of a tartrate salt, such as a salt of (D) (-) tartrate or salt of () (+) tartrate, salt of hydrochloride, citrate salt, malate salt, particularly a D-malate salt, fumarate salt, succinate salt, benzoate salt, benzenesulfonate salt, pamoate salt, formate salt, malonate salt, salt of 1, 5-naphthalenedisulfonate, silicate salt, cyclohexanesulfamiate salt, lactate salt, particularly a salt of (S) -lactate, mandelate salt, particularly a salt of (R) (-) mandelate, aqueous glutarate salt, adipate salt , salt of squarate, vanilate salt, oxaloacetate salt, ascorbate salt, particularly a salt of (L) ascorbate and sulfate salt.

6. A pharmaceutical composition of claim 3, wherein the acid addition salt is selected from the group consisting of matinib ascorbate, imatinib formate, imatinib malonate, imatinib oxaloacetate, imatinib esquatrate, and imatinib vanilate.

7. Use of an acid addition salt of 4 - [(4-methyl-1-piperazinyl) methyl] -? / - [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrim] dinyl] amino] phenyl] -benzamide according to any of claims 1 to 4 for the manufacture of a pharmaceutical composition for the treatment of a tumor disease, especially the treatment of leukemia.