Anhydrous crystalline free base form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzisoxazole

Abstract

A crystalline form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole is provided which is useful in the treatment of infections caused by Picornaviridae such as human rhinovirus (HRV), and in particular the crystal form is an anhydrous crystalline free base form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole. In addition, a method of manufacturing the free base crystalline form is also provided, including a step of micronizing the compound particles, optionally using a wetting agent, as well as pharmaceutical compositions incorporating the free base crystalline form such as tablets or suspensions, and methods of therapeutic treatments using this form and pharmaceutical compositions thereof.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising an anhydrous crystalline free base form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole and a pharmaceutically acceptable carrier. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the crystalline free base form has a needle-like crystal habit. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the crystalline form has XRPD peaks (d-space, Å) selected from the group consisting of approximately the following values: 19.5, 8.0, 6.5, 4.4, 4.3, 4.0, 3.8, 3.6, and 3.5. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the crystalline form XRPD peaks (2θ) selected from the group consisting of the following approximate values: 4.5, 11.0, 13.6, 20.3, 20.6, 22.1, 23.1, 24.5, and 25.7. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the crystalline form has XRPD peaks (d-space, Å) selected from the group consisting of approximately the following values: 19.2, 8.5, 8.0, 6.5, 5.5, 5.3, 5.0, 4.35, 4.27, 4.12, 4.03, 3.99, 3.96, 3.80 and 3.60. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the crystalline form XRPD peaks (2θ) selected from the group consisting of the following approximate values: 4.6, 11.1, 13.7, 16.1, 20.4, 20.8, 22.3, and 24.8. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the crystalline form has XRPD peaks (2θ) selected from the group consisting of the following approximate values: 4.6, 10.4, 11.1, 13.7, 16.1, 16.7, 17.8, 20.4, 20.8, 21.6, 22.1, 22.3, 22.4, 23.4, and 24.8. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the crystalline form has the XRPD pattern shown in  FIG. 1A, 1B, 2A, 2B or 3 . 
     
     
         9 . The pharmaceutical composition of  claim 1  wherein the compound has the formula (I) below: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the compound of is present in an amount of between 20 to 80 percent by weight of the total pharmaceutical composition. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the composition is in the form selected from the group consisting of a tablet, a caplet, a capsule, a suspension, other forms suitable for oral administration, and a suppository. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the composition is in the form of a suspension. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the suspension includes buffers, preservatives and/or a viscosity-enhancer. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the composition is in the form of a tablet. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the composition is in the form of a resuspendable sachet or powder. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the composition comprises 200-400 mg of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole. 
     
     
         17 . A pharmaceutical composition comprising an anhydrous crystalline free base form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole having a needle-like crystal habit, and a suitable pharmaceutical carrier. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole is present in an amount of between 20-80 percent by weight of the total pharmaceutical composition. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the composition is in the form selected from the group consisting of a tablet, a caplet, a capsule, a suspension, other forms suitable for oral administration, and a suppository. 
     
     
         20 . The pharmaceutical composition of  claim 17 , wherein the composition is in the form of a tablet. 
     
     
         21 . The pharmaceutical composition of  claim 20  wherein the composition comprises the following ingredients: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   BTA-798 Free Base (Micronized) 
                      2-3% 
                 
                     
                   Microcrystalline Cellulose and 
                      1-2% 
                 
                     
                   Carboxymethylcellulose Sodium 
                     
                 
                     
                   Xanthan Gum 
                    0.01-1% 
                 
                     
                   Polysorbate 80 
                    0.01-1% 
                 
                     
                   Propylene Glycol 
                    0.1-2% 
                 
                     
                   Butylparaben 
                   0.001-0.05% 
                 
                     
                   Glycerin 
                      1-10% 
                 
                     
                   Flavor 
                    0.01-.50% 
                 
                     
                   Sucrose 
                     30-50% 
                 
                     
                   0.1M Citric Acid 
                     40-60% 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         22 . The pharmaceutical composition of  claim 17 , wherein the composition comprises 200 to 400 mg 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole. 
     
     
         23 . The pharmaceutical composition of  claim 17 , wherein the composition comprises 300 mg 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole. 
     
     
         24 . A method for manufacturing a crystalline free base form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole comprising the steps of:
 a) combining a compound having the formula:   
       
         
           
           
               
               
           
         
         with a compound having the formula: 
       
       
         
           
           
               
               
           
         
         in a suitable reaction medium to produce the anhydrous free base form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole having a needle-like crystal habit. 
       
     
     
         25 . The method of  claim 24  wherein the reaction medium is an N-methylpyrolidine solvent. 
     
     
         26 . The method of  claim 24 , further comprising recrystallizating the 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole in a recrystallization solution. 
     
     
         27 . The method of  claim 26 , wherein the recrystallization solution is selected from the group consisting of ethanol or another alcohol, acetone, acetonitrile, dichloromethane, 1,4-dioxane, methyl ethyl ketone, 1-propanol, 2-propanol, tetrahydrofuran, and toluene. 
     
     
         28 . The method of  claim 24 , further comprising a step of micronizing the 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole. 
     
     
         29 . The method of  claim 28 , wherein the micronized 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole has an average particle size of less than 5 microns. 
     
     
         30 . The method of  claim 29 , wherein the micronization is carried out in combination with the addition of a wetting agent. 
     
     
         31 . A method of treating a viral infection comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 1  to a patient in need of said treatment. 
     
     
         32 . The method of  claim 31 , wherein the compound of the pharmaceutical composition has a needle-like crystal habit. 
     
     
         33 . The method of  claim 31 , wherein the viral infection is a picornavirus. 
     
     
         34 . The method of  claim 33 , wherein the picornavirus is human rhinovirus (HRV). 
     
     
         35 . The method of  claim 31 , wherein the compound is administered in an amount selected from the group consisting of 100 to 1500 mg per day, 300 mg to 1200 mg per day, and from 600 to 1000 mg per day. 
     
     
         36 . A method of treating a viral infection comprising administering a therapeutically effective amount of a compound comprising an anhydrous crystalline free base form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzoxazole to a patient in need of said treatment. 
     
     
         37 . The method of  claim 36 , wherein the compound has a needle-like crystal habit. 
     
     
         38 . The method of  claim 36 , wherein the compound is administered in an amount of 0.1 to 1000 mg per day. 
     
     
         39 . The method of  claim 36 , wherein the compound is administered in an amount selected from the group consisting of 100 to 1500 mg per day, 300 mg to 1200 mg per day, and from 600 to 1000 mg per day. 
     
     
         40 . The method of  claim 36 , wherein the compound is administered along with a suitable pharmaceutical carrier. 
     
     
         41 . A method of treating, alleviating, preventing or reducing the symptoms or exacerbations of asthma or chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 1  to a patient in need of said treatment. 
     
     
         42 . A method of treating, alleviating, preventing or reducing the symptoms or exacerbations of asthma or chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 17  to a patient in need of said treatment. 
     
     
         43 . The method of  claim 42 , wherein the symptom is reduced lung function. 
     
     
         44 . A method of treating hand foot and mouth disease comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 1  to a patient in need of said treatment. 
     
     
         45 . A method of treating hand foot and mouth disease comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 17  to a patient in need of said treatment.