Abstract:
The present invention relates to acid addition salts of the pharmaceutically active compound (3,5-Bistrifluoromethyl)-N-[4-methyl-3-(4-pyridin-3yl-pyrimidin-2ylamino)-phenyl]-benzamide(I): 
     
       
                 
         
             
             
         
       
       
         
           
             Development Code—AN019 
           
         
       
     
     The invention also relates to processes for the preparation these acid addition salts and to their use as anti tumor agent in humans.

Description:
This application is a Continuation-In-Part of U.S. application Ser. No. 13/053,908, filed 22 Mar. 2011, which is a Continuation-in-Part of U.S. application Ser. No. 12/042,240, filed 4 Mar. 2008, which is a Continuation-in-Part of U.S. application Ser. No. 11/714,565 filed 5 Mar. 2007, which is a Continuation-in-Part of PCT/IN2005/000243 filed 19 Jul. 2005, which claims benefit of Serial No. 908/CHE/2004 filed 9 Sep. 2004 in India and which applications are incorporated herein by reference. A claim of priority to all, to the extent appropriate is made. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to acid addition salts of the pharmaceutically active compound (3,5-Bistrifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide(I): 
     
       
                 
         
             
             
         
      
     
     Development Code—AN019 
     The invention also relates to processes for the preparation these acid addition salts and to their use as anti tumor agent in humans. 
     BACKGROUND OF THE INVENTION 
     The preparation of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide of formula-I, and the use thereof, especially as an anti-tumor agent, are described in Examples 3 and 4 of WO2006/027795 (PCT/IN05/00243 filed Jul. 19, 2005, published 16 Mar. 2006) and in equivalent applications in numerous other countries including the USA (pub. No.: US 2007/0232633). The crystal forms of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide of formula I are described in US2009227611. In these publications, acid addition salts are not discussed. 
     Basic pharmaceutical active compounds are commonly formulated into pharmaceutical preparations as an acid addition salt form, particularly as a crystalline acid addition salt. Although it is known that the preparation of salt forms may improve the physical or pharmaceutical properties of a basic pharmaceutical active compound, it is not possible to predict which salt forms may possess advantages for a particular purpose prior to the actual preparation and characterization of the salt form. 
     SUMMARY OF THE INVENTION 
     The present invention includes a compound of formula (II): 
                                
This compound can be identified by the chemical name (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide, 4-toluene sulfonate.
 
     The present invention also includes a method of preparing a compound of formula (II): 
                                
This method can include treating a compound of formula (I):
 
                                
with 4-toluene sulfonic acid in methanol at room temperature.
 
     The present invention also includes a method of treating chronic myelogenous leukemia in a subject in need thereof. This method can include administering to the subject an effective amount of a compound of formula II: 
     
       
                 
         
             
             
         
      
     
     The present invention also includes a method of treating glioma, ovarian tumor, pancreatic tumor, tumor of the lung, tumor of the breast, or leukemia in a subject in need thereof. This method can include administering to the subject an effective amount of a compound of formula II, which is shown above. 
     The present invention also includes a salt of the compound (3,5-bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; wherein the salt comprises an acid addition salt selected from the group consisting of hydrochloride, hydrobromide, sulphate, methane sulfonate, acetate, propionate, sulphate, phosphate, butyrate, oxalate, nicotinate, camphor sulfonate, para-toluene methane sulfonate, benzene sulfonate, trifluoro methane acetate, trifluoro sulfonate, stearate, and oleate. This salt can be employed in a method of treating a proliferative disorder in a subject in need thereof. This method can include administering to the subject an effective amount of the salt. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  illustrates the results of differential scanning calorimetry obtained for the tosylate salt of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide. 
         FIG. 2  illustrates a powder X-ray diffraction (PXRD) pattern obtained for the tosylate salt of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention relates to salt forms of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide that are useful, for example, for the manufacture of solid or liquid pharmaceutical dosage forms. Suitable solid oral dosage forms include tablets and capsules. Suitable liquid oral dosage forms include orally administered solutions and suspensions. Other suitable dosage forms include suppositories and the like. Each of the present salt forms possesses one or more properties that provides advantages when used as a pharmaceutical active ingredient, such as physical properties that make it easier to manufacture one or more dosage forms, improved stability, improved bioavailability and other such properties. 
     In an embodiment, the salt form of the present invention includes (3,5-bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide acid addition salts selected from the group consisting of hydrochloride, hydrobromide, sulphate, methane sulfonate, acetate, propionate, sulphate, phosphate, butyrate, oxalate, nicotinate, camphor sulfonate, para-toluene methane sulfonate, benzene sulfonate, trifluoro methane acetate, trifluoro sulfonate, stearate, and oleate. In an embodiment, the salt form of the present invention includes (3,5-bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide acid addition salts such as tosylate, mesylate, or hydrochloride. 
     The inventors also surprisingly found that the acid addition salt form of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide and “p-toluene sulfonic acid” provides the advantages considerably high solubility, low hygroscopicity, and good flow properties, which make it suitable for use in dosage forms. (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide tosylate salt has the following general formula (II): 
     
       
                 
         
             
             
         
      
     
     The salt forms of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide can be prepared by known methods for making acid addition salts of amines, e.g., by treatment with an acid or a suitable anion exchange reagent. For example, (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide or a solution of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3yl-pyrimidin-2-ylamino)-phenyl]-benzamide can be combined with a solution of an organic or mineral acid in, e.g., an alcohol (such as methanol, isopropanol, or butanol) with or without heating. The salt can be isolated by crystallization or by evaporation of the solvent and, if desired, purified by re-crystallization from an appropriate re-crystallization solvent by known methods. 
     For the purpose of administering a salt of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide by means of an oral solution, those salts that have an increased water solubility compared to the free base can be advantageous. Salts having a lower water solubility compared to the free base can be more suitable for the manufacture of sustained release formulations. 
     The invention also relates to a method of treating warm-blooded animals suffering from a tumor disease including administering a predetermined dose of the tosylate addition salt of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide effective against the disease concerned. The p-toluene sulfonate salt (II) of the present invention exhibits anti-proliferative and tumor inhibiting activity and can be administered to warm-blooded animals in need of such treatment. The p-toluene sulfonate salt (II) of the present invention can be administered for treating gliomas, ovarian tumors, pancreatic tumors, tumors of the lung (e.g., small cell lung carcinoma), tumors of the breast, and leukemia. In an embodiment, the p-toluene sulfonate salt (II) of the present invention can be administered for treating leukemia. 
     In an embodiment, the present invention includes a compound of formula (II): 
                                
This compound of formula II has the chemical name (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide, 4-toluene sulfonate. In an embodiment, this compound can remain essentially non hygroscopic at the relative humidity of 75% and at 45° C. In an embodiment, this compound has powder x-ray diffraction (PXRD) characteristics as depicted in  FIG. 2 . Table A below provides a peak list corresponding to the diffractogram shown in  FIG. 2 .
 
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 Pos.[°2Th.] 
                 Height[cts] 
                 FWHM[°2Th.] 
                 d-spacing[Å] 
                 Rel.Int.[%] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 5.8241 
                 5154.71 
                 0.1560 
                 15.16250 
                 61.56 
               
               
                 8.2882 
                 3705.53 
                 0.0936 
                 10.65932 
                 44.25 
               
               
                 11.6764 
                 220.10 
                 0.1872 
                 7.57276 
                 2.63 
               
               
                 13.0558 
                 407.53 
                 0.2496 
                 6.77563 
                 4.87 
               
               
                 13.5452 
                 432.43 
                 0.1560 
                 6.53190 
                 5.16 
               
               
                 13.9956 
                 188.90 
                 0.1872 
                 6.32269 
                 2.26 
               
               
                 14.7444 
                 373.73 
                 0.1716 
                 6.00321 
                 4.46 
               
               
                 16.4041 
                 8373.23 
                 0.1248 
                 5.39939 
                 100.00 
               
               
                 16.6228 
                 1805.88 
                 0.1092 
                 5.32882 
                 21.57 
               
               
                 17.2141 
                 959.93 
                 0.1404 
                 5.14710 
                 11.46 
               
               
                 17.6181 
                 2479.55 
                 0.1092 
                 5.02998 
                 29.61 
               
               
                 18.1581 
                 2187.94 
                 0.1716 
                 4.88158 
                 26.13 
               
               
                 18.4828 
                 906.11 
                 0.1092 
                 4.79656 
                 10.82 
               
               
                 20.3078 
                 1497.52 
                 0.1560 
                 4.36944 
                 17.88 
               
               
                 20.7242 
                 1704.60 
                 0.1248 
                 4.28256 
                 20.36 
               
               
                 21.0171 
                 5927.63 
                 0.0936 
                 4.22355 
                 70.79 
               
               
                 22.7017 
                 1808.96 
                 0.1560 
                 3.91380 
                 21.60 
               
               
                 23.5617 
                 434.74 
                 0.1560 
                 3.77285 
                 5.19 
               
               
                 24.2855 
                 1384.77 
                 0.1560 
                 3.66202 
                 16.54 
               
               
                 24.7146 
                 3241.18 
                 0.1092 
                 3.59940 
                 38.71 
               
               
                 26.0839 
                 2937.61 
                 0.2496 
                 3.41347 
                 35.08 
               
               
                 26.5020 
                 1305.60 
                 0.1716 
                 3.36056 
                 15.59 
               
               
                 27.1497 
                 573.99 
                 0.3120 
                 3.28184 
                 6.86 
               
               
                 27.7036 
                 476.27 
                 0.3120 
                 3.21747 
                 5.69 
               
               
                 29.2557 
                 979.34 
                 0.1248 
                 3.05020 
                 11.70 
               
               
                 31.4251 
                 232.38 
                 0.3744 
                 2.84441 
                 2.78 
               
               
                 32.2667 
                 250.22 
                 0.2808 
                 2.77212 
                 2.99 
               
               
                 34.6355 
                 152.49 
                 0.3744 
                 2.58775 
                 1.82 
               
               
                 36.0878 
                 397.55 
                 0.1248 
                 2.48687 
                 4.75 
               
               
                 37.6449 
                 562.83 
                 0.1248 
                 2.38751 
                 6.72 
               
               
                 38.2346 
                 404.70 
                 0.1872 
                 2.35203 
                 4.83 
               
               
                 39.7475 
                 451.90 
                 0.1248 
                 2.26593 
                 5.40 
               
               
                 42.9248 
                 367.27 
                 0.3120 
                 2.10527 
                 4.39 
               
               
                   
               
             
          
         
       
     
     In an embodiment, this compound has anti-proliferative properties against the cell lines K562 and T315I. In an embodiment, this compound is effective for treating a subject suffering from chronic myelogenous leukemia. 
     The present invention also includes a method of preparing a compound of formula (II): 
                                
This method can include treating a compound of formula (I):
 
                                
with 4-toluene sulfonic acid in methanol at room temperature.
 
     The present invention also includes a method of treating chronic myelogenous leukemia in a subject in need thereof. This method includes administering to the subject an effective amount of a compound of formula II: 
     
       
                 
         
             
             
         
      
     
     In an embodiment the compound of Formula (II) can be employed in a method of treating glioma, ovarian tumor, pancreatic tumor, tumor of the lung, tumor of the breast, or leukemia in a subject in need thereof. This embodiment includes administering to the subject an effective amount of a compound of formula II. 
     In an embodiment, the present invention includes a method of treating a proliferative disorder in a subject in need thereof. This embodiment includes administering to the subject an effective amount of a salt of the compound (3,5-bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; wherein the salt comprises an acid addition salt selected from the group consisting of hydrochloride, hydrobromide, sulphate, methane sulfonate, acetate, propionate, sulphate, phosphate, butyrate, oxalate, nicotinate, camphor sulfonate, para-toluene methane sulfonate, benzene sulfonate, trifluoro methane acetate, trifluoro sulfonate, stearate, and oleate. In an embodiment, the acid addition salt includes or is tosylate, mesylate, or hydrochloride. In an embodiment, the acid addition salt includes or is tosylate. In an embodiment, the proliferative disorder includes or is chronic myelogenous leukemia. In an embodiment, the proliferative disorder includes or is a tumor. 
     The present invention may be better understood with reference to the following examples. These examples are intended to be representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention. 
     EXAMPLES 
     Example-1 
     (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide hydrochloride 
     Aqueous hydrochloric acid (1.06 g of 37%) was added to a refluxing solution of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (5 g, 0.0096 moles) in n-butanol (150 ml). The clear solution was brought to room temperature and maintained under stirring for 2 hours. The separated product was filtered-off and dried to yield (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide hydrochloride as a pale-yellow crystalline solid having the following analytical properties: 
     Moisture content by Karl-Fischer method: 0.6% (wt/wt) 
     HCl content: 6.4% 
     Melting range: 235-245° C. 
     Example-2 
     (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide methane sulfonate 
     Methane sulfonic acid (1.85 g, 0.0193 moles) was added to a suspension of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (10 g, 0.0193 moles) in methanol (110 ml) at room temperature. To the clear solution isopropyl alcohol (30 ml) was added and stirred at room temperature for 3 hours. The precipitated (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide mesylate was filtered and dried to afford a pale-yellow crystalline solid having the following analytical properties: 
     Moisture content by Karl-Fischer method: 0.6% (wt/wt) 
     Melting range: 224-227° C. 
     Example-3 
     (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide 4-toluene sulfonate monohydrate 
     p-Toluene sulfonic acid (7.35 g, 0.0386 moles) was added to a suspension of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (20 g, 0.0386 moles) in methanol (400 ml) at room temperature. The solution was refluxed for 30 minutes and brought to room temperature. The crystallized (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide 4-toluene sulfonate was filtered and dried to afford a yellow crystalline solid having the following analytical properties: 
     Moisture content by Karl-Fischer method: 2.7% (wt/wt) 
     Melting range: 255-258° C. 
     Example-4 
     Stability Under High Humidity Conditions 
     For illustration of the non-hygroscopic nature of the (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide hydrochloride, mesylate, and tosylate salts, these salts were kept in stability chambers and their water contents were determined by Karl-Fischer method. The results are tabulated below. 
                                 TABLE 1                       Final moisture   Final moisture               content -   content -           Initial   After 48 hours at   After 48 hours at           moisture   25° C. at humidity   40° C. at humidity       Sample   content (%)   of 60%   of 75%                   (3,5-Bis trifluoromethyl)-N-[4-   0.6%   0.7%   0.7%       methyl-3-(4-pyridin-3yl-       pyrimidin-2ylamino)-phenyl]-       benzamide hydrochloride       (3,5-Bis trifluoromethyl)-N-[4-   0.6%   0.7%   0.7%       methyl-3-(4-pyridin-3yl-       pyrimidin-2ylamino)-phenyl]-       benzamide mesylate       (3,5-Bis trifluoromethyl)-N-[4-   2.7%   2.7%   2.8%       methyl-3-(4-pyridin-3yl-       pyrimidin-2ylamino)-phenyl]-       benzamide tosylate                    
The above table shows that the hydrochloride, mesylate, and tosylate salts of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide are non-hygroscopic and have substantial stability even under humidity conditions.
 
     Example-5 
     Solubility 
     Solubility of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide salts was determined by the shake flask method and the results obtained are shown below. General conditions: Room temperature (25° C.), stirring speed: 200 RPM, Analytical method: UV 
     
       
         
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                 Solubility 
               
               
                 Sample 
                 Medium 
                 (mg/ml) 
               
               
                   
               
             
             
               
                 (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4- 
                 Water 
                 Almost no 
               
               
                 pyridin-3yl-pyrimidin-2ylamino)-phenyl]- 
                   
                 solubility 
               
               
                 benzamide hydrochloride 
                 0.1N HCl 
                 0.0134 
               
               
                 (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4- 
                 Water 
                 0.0014 
               
               
                 pyridin-3yl-pyrimidin-2ylamino)-phenyl]- 
                 0.1N HCl 
                 0.03120 
               
               
                 benzamide mesylate 
               
               
                 (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4- 
                 Water 
                 0.0078 
               
               
                 pyridin-3yl-pyrimidin-2ylamino)-phenyl]- 
                 0.1N HCl 
                 0.04020 
               
               
                 benzamide tosylate 
               
               
                 (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4- 
                 Water 
                 Almost no 
               
               
                 pyridin-3yl-pyrimidin-2ylamino)-phenyl]- 
                   
                 solubility 
               
               
                 benzamide (base) 
                 0.1N HCl 
                 0.0013 
               
               
                   
               
             
          
         
       
     
     Table-2 shows that (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3yl-pyrimidin-2-ylamino)-phenyl]-benzamide tosylate showed improved solubility properties among other salts investigated. 
     Example-6 
     Maximum Tolerated Dose—Non-Toxic Nature 
     The following results (Table-3) compare the maximum tolerated dose (MTD) for 14 days of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide tosylate to that of the basic form, (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide(base). 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                   
                   
                 MTD 
               
               
                 Sample 
                 Species 
                 (mg/kg, po) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 (3,5-Bis trifluoromethyl)-N-[4-methyl-3- 
                 Mice 
                 500.0 
               
               
                 (4-pyridin-3yl-pyrimidin-2ylamino)- 
               
               
                 phenyl]-benzamide (base) 
               
               
                 (3,5-Bis trifluoromethyl)-N-[4-methyl-3- 
                 Mice 
                 1000.0 
               
               
                 (4-pyridin-3yl-pyrimidin-2ylamino)- 
               
               
                 phenyl]-benzamide tosylate 
               
               
                   
               
             
          
         
       
     
     The results in Table-3 show that (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide tosylate was observed to be substantially less toxic than the corresponding base, rendering the tosylate salt an unexpectedly advantageous form for the administration of this drug. 
     Example-7 
     Flow Properties 
     The following results (Table-4) illustrate the measured angle of repose of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide tosylate compared to the corresponding base. 
     
       
         
               
               
               
             
           
               
                   
                 TABLE 4 
               
               
                   
                   
               
               
                   
                   
                 Angle of Repose 
               
               
                   
                 Sample 
                 (degrees °) 
               
               
                   
                   
               
             
             
               
                   
                 (3,5-Bis trifluoromethyl)-N-[4- 
                 41.57 
               
               
                   
                 methyl-3-(4-pyridin-3yl-pyrimidin- 
               
               
                   
                 2ylamino)-phenyl]-benzamide (base) 
               
               
                   
                 (3,5-Bis trifluoromethyl)-N-[4- 
                 30.74 
               
               
                   
                 methyl-3-(4-pyridin-3yl-pyrimidin- 
               
               
                   
                 2ylamino)-phenyl]-benzamide tosylate 
               
               
                   
                   
               
             
          
         
       
     
     The results reported in Table-4 show that (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide tosylate exhibited a lower angle of repose and better flow properties when compared with corresponding base. 
     Example-8 
     Activity in Cell Culture 
     The following results (Table-5) are from a study carried out to determine the activity of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide tosylate (AN-019T) against the corresponding base (AN-019) on K562 and T315I cell lines at 0.312×10 5  and 0.625×10 5  cells/ml respectively using dilutions of 10 μM to 0.156 μM of the test compound for 72 Hrs. Imatinib was used as standard. 
     
       
         
               
               
               
               
             
           
               
                   
                 TABLE 5 
               
               
                   
                   
               
               
                   
                 Cell Line 
                 Test Compound 
                 IC 50  (μM) 
               
               
                   
                   
               
             
             
               
                   
                 K562 
                 Imatinib 
                 0.4074 
               
               
                   
                 Chronic myelogenous 
                 AN-019 
                 0.2056 
               
               
                   
                 leukemia (CML) 
                 AN-019T 
                 0.2647 
               
               
                   
                 T315I 
                 Imatinib 
                 0.4477 
               
               
                   
                 Chronic myelogenous 
                 AN-019 
                 0.0993 
               
               
                   
                 leukemia (CML) 
                 AN-019T 
                 0.1087 
               
               
                   
                 Mutant 
               
               
                   
                   
               
             
          
         
       
     
     CONCLUSION 
     By comparing the measured IC 50  values of AN-19 and AN-19T, it was concluded that AN-19 and AN-19T are comparable in inhibiting the cell proliferation of K562 and T315I. These compounds are more potent than Imatinib. 
     Example-9 
     A Formulation of the Tosylate Salt of AN-019 
     Table-6 (below) lists the contents of an embodiment of a formulation of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide tosylate (AN-019T). 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 6 
               
               
                   
                   
               
               
                   
                 Components 
                 % (w/w) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 AN-019 tosylate 
                 57.75 
               
               
                   
                 Sodium Lauryl Sulfate 
                 2.64 
               
               
                   
                 Crospovidone 
                 22.18 
               
               
                   
                 Starch 1500 
                 12.15 
               
               
                   
                 Colloidal silicon dioxide 
                 4.22 
               
               
                   
                 Magnesium Stearate 
                 0.53 
               
               
                   
                 Talc 
                 0.53 
               
               
                   
                   
               
             
          
         
       
     
     Example-10 
     Bioavailability of Tosylate Salt of AN-019 
     Table-7 (below) presents the results of a study that compared the bioavailability of the tosylate salt of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide tosylate (AN-019T) to the corresponding base (AN-019) of this compound. 
                                                                           AUC   T max     C max         Dosage form   Animal   (ng hour/mL)   (hour)   (ng/mL)                                AN-019 API   Mice   611.46   6   93.7       NRC-AN-019   Mice   2853.11   6   617.253       Tosylate tablets                    
The above table shows that AN-019 Tosylate is more bioavailable than AN-019
 
     It should be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. 
     All publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this invention pertains. 
     The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.