Crystalline forms of a biphenyl compound

Abstract

The invention provides crystalline forms of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester, and pharmaceutically acceptable solvates thereof. The crystalline form can be a freebase, or a salt such as a diphosphate, monosulfate or dioxalate salt. The invention also provides pharmaceutical compositions comprising these crystalline compounds or prepared using these compounds; processes and intermediates for preparing the crystalline compounds; and methods of using these compounds to treat a pulmonary disorder.

1 . A crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.  
   
   
       2 . The compound of  claim 1 , wherein the crystalline form is a diphosphate salt.  
   
   
       3 . The compound of  claim 2 , characterized by a powder x-ray diffraction pattern having two or more diffraction peaks at 2θ values selected from 6.4±0.2, 7.6±0.2, 8.6±0.2, 13.7±0.2, 15.0±0.2, 19.4±0.2, 21.6±0.2, 22.1±0.2, 22.9±0.2, and 23.7±0.2.  
   
   
       4 . The compound of  claim 3 , wherein the powder x-ray diffraction pattern comprises diffraction peaks at 2θ values of 15.0±0.2, 19.4±0.2, 21.6±0.2, and 23.7±0.2.  
   
   
       5 . The compound of  claim 2 , characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in  FIG. 1 .  
   
   
       6 . The compound of  claim 2 , characterized by a differential scanning calorimetry trace which shows a maximum endothermic heat flow at about 154.5° C.  
   
   
       7 . The compound of  claim 2 , characterized by a differential scanning calorimetry trace substantially in accordance with that shown in  FIG. 2 .  
   
   
       8 . The compound of  claim 1 , wherein the crystalline form is a monosulfate salt.  
   
   
       9 . The compound of  claim 8 , characterized by a powder x-ray diffraction pattern having two or more diffraction peaks at 2θ values selected from 7.7±0.2, 8.4±0.2, 8.8±0.2, 12.6±0.2, 13.7±0.2, 14.1±0.2, 15.3±0.2, 16.0±0.2, 19.7±0.2, 20.6±0.2, 23.0±0.2, and 24.4±0.2.  
   
   
       10 . The compound of  claim 9 , wherein the powder x-ray diffraction pattern comprises diffraction peaks at 2θ values of 12.6±0.2, 19.7±0.2, 23.0±0.2, and 24.4±0.2.  
   
   
       11 . The compound of  claim 8 , characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in  FIG. 8 .  
   
   
       12 . The compound of  claim 8 , characterized by a differential scanning calorimetry trace which shows a maximum endothermic heat flow at about 76.5° C.  
   
   
       13 . The compound of  claim 8 , characterized by a differential scanning calorimetry trace substantially in accordance with that shown in  FIG. 10 .  
   
   
       14 . The compound of  claim 1 , wherein the crystalline form is a dioxalate salt.  
   
   
       15 . The compound of  claim 14 , characterized by a powder x-ray diffraction pattern having two or more diffraction peaks at 2θ values selected from 7.7±0.2, 8.7±0.2, 13.5±0.2, 14.0±0.2, 14.8±0.2, 15.4±0.2, 15.8±0.2, 19.4±0.2, 22.9±0.2, 23.3±0.2, and 24.6±0.2.  
   
   
       16 . The compound of  claim 15 , wherein the powder x-ray diffraction pattern comprises diffraction peaks at 2θ values of 8.7±0.2, 14.0±0.2, 19.4±0.2, and 22.9±0.2.  
   
   
       17 . The compound of  claim 14 , characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in  FIG. 13 .  
   
   
       18 . The compound of  claim 14 , characterized by a differential scanning calorimetry trace which shows a maximum endothermic heat flow at about 73.7° C.  
   
   
       19 . The compound of  claim 14 , characterized by a differential scanning calorimetry trace substantially in accordance with that shown in  FIG. 15 .  
   
   
       20 . The compound of  claim 1 , wherein the crystalline form is a freebase.  
   
   
       21 . The compound of  claim 20 , characterized by a powder x-ray diffraction pattern having two or more diffraction peaks at 2θ values selected from 4.7±0.2, 9.6±0.2, 12.7±0.2, 13.7±0.2, 16.7±0.2, 17.4±0.2, 18.5±0.2, 19.4±0.2, 20.8±0.2, 21.4±0.2, 24.2±0.2, and 25.6±0.2.  
   
   
       22 . The compound of  claim 21 , wherein the powder x-ray diffraction pattern comprises diffraction peaks at 2θ values of 4.7±0.2, 18.5±0.2, 20.8±0.2, and 25.6±0.2.  
   
   
       23 . The compound of  claim 20 , characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in  FIG. 18 .  
   
   
       24 . The compound of  claim 20 , characterized by a differential scanning calorimetry trace which shows a maximum endothermic heat flow at about 102.7° C.  
   
   
       25 . The compound of  claim 20 , characterized by a differential scanning calorimetry trace substantially in accordance with that shown in  FIG. 19 .  
   
   
       26 . The compound of  claim 20 , characterized by a powder x-ray diffraction pattern having two or more diffraction peaks at 2θ values selected from 4.6±0.2, 9.3±0.2, 12.9±0.2, 13.6±0.2, 14.0±0.2, 14.6±0.2, 16.5±0.2, 18.6±0.2, 19.1±0.2, 20.9±0.2, 22.1±0.2, 22.7±0.2, and 25.7±0.2.  
   
   
       27 . The compound of  claim 26 , wherein the powder x-ray diffraction pattern comprises diffraction peaks at 2θ values of 4.6±0.2, 18.6±0.2, 22.1±0.2, and 22.7±0.2.  
   
   
       28 . The compound of  claim 20 , characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in  FIG. 23 .  
   
   
       29 . The compound of  claim 20 , characterized by a differential scanning calorimetry trace which shows a maximum endothermic heat flow at about 98.6° C.  
   
   
       30 . The compound of  claim 20 , characterized by a differential scanning calorimetry trace substantially in accordance with that shown in  FIG. 25 .  
   
   
       31 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoyl piperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.  
   
   
       32 . The composition of  claim 31 , which further comprises a therapeutically effective amount of an agent selected from β 2  adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof; wherein the crystalline form and the agent are formulated together or separately.  
   
   
       33 . The composition of  claim 32 , which comprises a therapeutically effective amount of a β 2  adrenergic receptor agonist and a steroidal anti-inflammatory agent.  
   
   
       34 . The composition of  claim 32 , wherein the β 2  adrenergic receptor agonist is a monohydrochloride salt of N-{2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine.  
   
   
       35 . The composition of  claim 32 , wherein the steroidal anti-inflammatory agent is 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester.  
   
   
       36 . The composition of  claim 32 , wherein the compound and the agent are formulated together.  
   
   
       37 . The composition of  claim 32 , wherein the compound and the agent are formulated separately.  
   
   
       38 . The composition of  claim 31 , wherein the composition is formulated for administration by inhalation.  
   
   
       39 . The composition of  claim 31 , wherein the carrier is an aqueous isotonic saline solution having a pH in the range of from about 4 to about 6.  
   
   
       40 . The composition of  claim 39 , which comprises a citrate buffer.  
   
   
       41 . A drug delivery device comprising a dry powder inhaler containing a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.  
   
   
       42 . A crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof, in micronized form.  
   
   
       43 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof, in micronized form.  
   
   
       44 . The composition of  claim 43 , wherein the carrier is lactose.  
   
   
       45 . A process for preparing a crystalline diphosphate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino} ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof, comprising contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl) piperidin-4-yl ester with phosphoric acid.  
   
   
       46 . A process for preparing a crystalline monosulfate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino} ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof, comprising contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl) piperidin-4-yl ester with sulfuric acid.  
   
   
       47 . A process for preparing a crystalline dioxalate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof, comprising: 
 forming a seed crystal of a crystalline dioxalate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with oxalic acid:    forming a dioxalate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with oxalic acid, and dissolving the salt in an inert diluent to form a solution; and    adding the seed crystal to the solution.    
   
   
       48 . A process for preparing a crystalline freebase biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof, comprising: 
 forming a seed crystal of a crystalline freebase by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with an inert diluent;    forming a crystalline freebase by contacting biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester with an inert diluent, and dissolving the resulting crystalline ester to form a solution; and    adding the seed crystal to the solution.    
   
   
       49 . A process for purifying biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester, comprising forming a crystalline salt or a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester.  
   
   
       50 . The product prepared by the process of any one of  claims 45  to  49 .  
   
   
       51 . A method for antagonizing a muscarinic receptor in a mammal, comprising administering to the mammal a therapeutically effective amount of a crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}[ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.  
   
   
       52 . A method for treating a pulmonary disorder, the method comprising administering to a patient a therapeutically effective amount of a crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.  
   
   
       53 . A method of producing bronchodilation comprising administering to a patient by inhalation, a bronchodilation-producing amount of a crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.  
   
   
       54 . A method of treating chronic obstructive pulmonary disease or asthma, comprising administering to a patient a therapeutically effective amount of a crystalline form of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable solvate thereof.