Polymorphic forms of (r)-4-(1-((3-(difluoromethyl)-1-methyl-1h-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-n-(isoxazol-3-yl)piperidine-1-carboxamide

Abstract

The present invention provides novel polymorphs of (R)-4-(1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide (I-491) that are useful for the treatment of cardiac disorders including systolic dysfunction, dilated cardiomyopathy (DCM), heart failure with reserved ejection fraction (HFrEF), and conditions associated with left and/or right ventricular systolic dysfunction or systolic reserve. The synthesis and characterization of the polymorphs is described, as well as methods for treating systolic dysfunction, DCM, HFrEF, and other forms of heart disease.

1 . A composition comprising a polymorph of formula (I-491): 
       
         
           
           
               
               
           
         
       
       wherein the polymorph is Form A. 
     
     
         2 . The composition of  claim 1 , wherein the polymorph has a chiral purity of at least 99.9%. 
     
     
         3 . The composition of  claim 1 , wherein the polymorph is characterized by at least one of:
 a. a X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having two or more peaks expressed in degrees 2-theta±0.2° and selected from 6.62, 10.98, 13.26, 14.48, 15.02, 15.48, 15.78, 16.08, 16.32, 17.72, 19.26, 19.86, 19.94, 20.44, 21.68, 21.90, 22.04, 22.60, 23.78, 26.16, 26.36, 26.58, 27.24, and 28.04 degrees; or   b. a DSC thermogram showing an endotherm at about 181-200° C.   
     
     
         4 . The composition of  claim 1 , wherein the polymorph is characterized by a X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta±0.2° at each of 10.98, 15.78, 16.08, 20.44, 23.78, and 26.58 degrees. 
     
     
         5 .- 8 . (canceled) 
     
     
         9 . The composition of  claim 1 , wherein the polymorph is characterized by a X-ray powder diffraction pattern essentially the same as shown in  FIG. 1A . 
     
     
         10 . The composition of  claim 1 , wherein the polymorph is characterized by a X-ray powder diffraction pattern essentially the same as shown in  FIG. 1B . 
     
     
         11 . The composition of  claim 4 , wherein the polymorph is characterized by a X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks expressed in degrees 2-theta±0.05° at each of 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80 degrees. 
     
     
         12 .- 14 . (canceled) 
     
     
         15 . The composition of  claim 1 , wherein the polymorph is characterized by a melt onset of about 181° C. 
     
     
         16 .- 17 . (canceled) 
     
     
         18 . The composition of  claim 1 , wherein the polymorph has a triclinic crystal system and a space group of P1. 
     
     
         19 . The composition of  claim 18 , wherein the polymorph has unit cell dimensions of about a=6.403 Å, b=11.343 Å, c=13.507 Å, α=81.91°, β=85.73°, and γ=85.18°. 
     
     
         20 . The composition of  claim 1 , wherein the composition is substantially free of other forms of I-491. 
     
     
         21 .- 23 . (canceled) 
     
     
         24 . A composition comprising Form A of I-491, wherein the molar ratio of the amount of Form A of I-491 to the sum of the amounts of other forms is equal to or greater than 80:20. 
     
     
         25 .- 28 . (canceled) 
     
     
         29 . A composition comprising Form A of I-491 and Form D of I-491, wherein the molar ratio of the amount of Form A of I-491 to Form D of I-491 is equal to or greater than 80:20. 
     
     
         30 .- 32 . (canceled) 
     
     
         33 . A pharmaceutical composition comprising an effective amount of the composition of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         34 . A polymorph of formula (I-491): 
       
         
           
           
               
               
           
         
       
       wherein the polymorph is Form B of I-491. 
     
     
         35 . The polymorph of  claim 34 , wherein the polymorph has a chiral purity of at least 99.9%. 
     
     
         36 . The polymorph of  claim 34 , characterized by at least one of:
 a. a X-ray powder diffraction pattern obtained by irradiation with Cu-Kα pattern having two or more peaks expressed in degrees 2-theta±0.2° and selected from 7.32, 7.88, 10.20, 10.88, 13.40, 14.68, 15.24, 15.42, 16.28, 17.70, 18.48, 19.02, 20.18, 20.70, 21.56, 21.98, 22.94, 23.16, 23.86, 24.24, 24.78, 25.38, 26.40, 26.88, and 28.74 degrees; or   b. a DSC thermogram showing an endotherm at about 170-185° C.   
     
     
         37 . The polymorph of  claim 34 , characterized by a X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta±0.2° at each of 15.42, 16.28, 19.02, 20.70, and 26.88 degrees. 
     
     
         38 .- 42 . (canceled) 
     
     
         43 . The polymorph of  claim 34 , characterized by a X-ray powder diffraction pattern essentially the same as shown in  FIG. 6A . 
     
     
         44 . The polymorph of  claim 34 , characterized by a X-ray powder diffraction pattern essentially the same as shown in  FIG. 6B . 
     
     
         45 . The polymorph of  claim 37 , characterized by a X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks expressed in degrees 2-theta±0.05° at each of 0 to 6.80 and 8.15 to 9.00 degrees. 
     
     
         46 .- 47 . (canceled) 
     
     
         48 . The polymorph of  claim 34 , characterized by a melt onset of about 170° C. 
     
     
         49 .- 52 . (canceled) 
     
     
         53 . The polymorph of  claim 34 , wherein the polymorph has a triclinic crystal system and a space group of P1. 
     
     
         54 . The polymorph of  claim 53 , wherein the polymorph has unit cell dimensions of a=11.926 Å, b=13.239 Å, c=13.511 Å, α=65.40°, β=80.08°, and γ=89.18°. 
     
     
         55 . A composition comprising the polymorph of  claim 34  wherein the composition is substantially free of other forms of I-491. 
     
     
         56 .- 58 . (canceled) 
     
     
         59 . A composition comprising Form B of I-491, wherein the molar ratio of the amount of Form B of I-491 to the sum of the amounts of other forms is equal to or greater than 80:20. 
     
     
         60 .- 63 . (canceled) 
     
     
         64 . A pharmaceutical composition comprising an effective amount of the polymorph of  claim 34 , and a pharmaceutically acceptable carrier. 
     
     
         65 . A pharmaceutical composition comprising:
 a. Form A of I-491; and   b. one or more diluents.   
     
     
         66 .- 72 . (canceled) 
     
     
         73 . A pharmaceutical composition comprising Form A of I-491, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, and magnesium stearate. 
     
     
         74 . A method of treating a disease selected from the group consisting of systolic dysfunction, diastolic dysfunction, HFrEF, HFpEF, chronic heart failure, and acute heart failure, comprising administering to a subject in need thereof an effective amount of a polymorph of  claim 34 . 
     
     
         75 . (canceled) 
     
     
         76 . A method of treating systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a polymorph of  claim 34 . 
     
     
         77 .- 78 . (canceled) 
     
     
         79 . A method of treating HFrEF, comprising administering to a subject in need thereof an effective amount of a polymorph of  claim 34 . 
     
     
         80 .- 81 . (canceled) 
     
     
         82 . A method of treating dilated cardiomyopathy (DCM), comprising administering to a subject in need thereof an effective amount of a polymorph of any one of  claim 34 . 
     
     
         83 .- 84 . (canceled) 
     
     
         85 . A method of treating a disease characterized by left ventricular systolic dysfunction or symptoms or reduced exercise capacity due to systolic dysfunction; in conjunction with therapies aimed at treating heart failure, comprising administering to a subject in need thereof an effective amount of a polymorph of  claim 34 . 
     
     
         86 .- 92 . (canceled) 
     
     
         93 . A polymorph of I-491, wherein the polymorph is Form A of I-491, prepared by a process comprising the steps of recrystallizing I-491 in a mixture of methanol and water via slow evaporation. 
     
     
         94 . A polymorph of I-491, wherein the polymorph is Form B of I-491, prepared by a process comprising the steps of recrystallizing I-491 in a mixture of acetonitrile and water. 
     
     
         95 .- 96 . (canceled) 
     
     
         97 . A polymorph of I-491, wherein the polymorph is Form B of I-491, prepared by a process comprising the steps of recrystallizing I-491 from a slurry of I-491 in solvent selected from the group consisting of water, ethanol, methanol, ethyl acetate, methyl isobutyl ketone, ethanol and water mixture, methanol and water mixture, and water. 
     
     
         98 .- 112 . (canceled) 
     
     
         113 . A pharmaceutical composition comprising:
 a. Form B of I-491; and   b. one or more diluents.   
     
     
         114 .- 120 . (canceled) 
     
     
         121 . A pharmaceutical composition comprising Form B of I-491, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, and magnesium stearate.