Crystalline form of beta2 adrenergic receptor agonist

Abstract

The invention provides a novel β 2 adrenergic receptor agonist in crystalline salt form. The invention also provides pharmaceutical compositions comprising the novel β 2 adrenergic receptor agonist in crystalline salt form, formulations containing the pharmaceutical compositions, methods of using the crystalline salt to treat diseases associated with β 2 adrenergic receptor activity, and processes useful for preparing such crystalline compounds.

1 - 28 . (canceled)  
     
     
         29 . Crystalline N-{2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]-ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine monohydrochloride, wherein the crystalline monohydrochloride salt is characterized by an x-ray powder diffraction pattern having two or more diffraction peaks at 2θ values selected from 6.00±0.2, 7.99±0.2, 9.98±0.2, 15.98±0.2, 24.05±0.2, 24.53±0.2, 25.35±0.2, 26.08±0.2 26.77±0.2, 28.13±0.2, 34.31±0.2, and 38.49±0.2.  
     
     
         30 . The crystalline monohydrochloride salt of  claim 29  wherein the crystalline monohydrochloride salt is characterized by an x-ray powder diffraction pattern having two or more diffraction peaks at 2θ values selected from 15.98±0.2, 24.05±0, 26.08±0.2, and 28.13±0.2.  
     
     
         31 . The crystalline monohydrochloride salt of  claim 29  wherein the crystalline monohydrochloride salt is characterized by an x-ray powder diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in  FIG. 1 .  
     
     
         32 . The crystalline monohydrochloride salt of  claim 29 , wherein the crystalline monohydrochloride salt has an infrared absorption spectrum with significant absorption bands at about 699, 788, 810, 827, 875, 970, 1026, 1056, 1080, 1101, 1213, 1296, 1374, 1441, 1546, 1596, 1660, 3371, and 3553 cm −1 .  
     
     
         33 . The crystalline monohydrochloride salt of  claim 29 , wherein the crystalline monohydrochloride salt is characterized by a differential scanning calorimetry trace which shows an onset of endothermic heat flow at about 200° C.  
     
     
         34 . The crystalline monohydrochloride salt of  claim 29  wherein the crystalline monohydrochloride salt is characterized by a differential scanning calorimetry trace which is substantially in accordance with that shown in  FIG. 2 .  
     
     
         35 . A pharmaceutical composition comprising a therapeutically effective amount of the crystalline monohydrochloride salt of  claim 29  and a pharmaceutically acceptable carrier.  
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the composition further comprises a therapeutically effective amount of one or more other therapeutic agents selected from corticosteroids, antichlolinergic agents, and PDE4 inhibitors.  
     
     
         37 . The pharmaceutical composition of  claim 35 , wherein the composition is formulated for administration by inhalation.  
     
     
         38 . A combination comprising the crystalline monohydrochloride salt of  claim 29  and 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester.  
     
     
         39 . A process for preparing the crystalline monohydrochloride salt of  claim 29 , the process comprising the steps of: 
 (a) dissolving N-{2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine in a polar solvent to form a first solution; and (b) adding between about 0.9 and about 1 molar equivalent of hydrochloric acid to form a second solution from which the crystalline monohydrochloride salt of  claim 29  is formed.    
     
     
         40 . The process of  claim 39  wherein the second solution comprises isopropanol and water in a ratio of isopropanol:water of from about 4:1 to about 10:1.  
     
     
         41 . The process of  claim 39  further comprising in step (a): heating the first solution to a temperature of between about 40° C. and about 60° C. and then cooling the first solution to about room temperature.  
     
     
         42 . A process for preparing the crystalline monohydrochloride salt of  claim 29 , the process comprising the steps of: 
 (a) dissolving N-{2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine in a polar solvent to form a first solution; and    (b) adding a molar excess of an aqueous solution of an inorganic chloride at a pH of between about 5 and about 6 to form a second solution from which the crystalline monohydrochloride salt of  claim 29  is formed.    
     
     
         43 . A method of treating a mammal having a disease or condition associated with β 2  adrenergic receptor activity, the method comprising administering to the mammal, a therapeutically effective amount of the crystalline monohydrochloride salt of  claim 29 .  
     
     
         44 . The method of  claim 43  wherein the disease or condition is asthma or chronic obstructive pulmonary disease.  
     
     
         45 . A method of treating asthma or chronic obstructive pulmonary disease in a mammal, the method comprising administering to the mammal, a therapeutically effective amount of the crystalline monohydrochloride salt of  claim 29  and a pharmaceutically acceptable carrier.  
     
     
         46 . The method of  claim 45  wherein the method further comprises administering to the mammal a therapeutically effective amount of one or more other therapeutic agents selected from corticosteroids, antichlolinergic agents, and PDE4 inhibitors.  
     
     
         47 . The method of  claim 45  wherein the method further comprises administering to the mammal a therapeutically effective amount of 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester.