Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

Abstract

Disclosed are crystalline free base ansolvate forms of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (or Compound 1), such as the free base Form I, Form II and Material N. Also disclosed are crystalline free base solvates of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (or Compound 1).

1 .- 20 . (canceled) 
     
     
         21 . A method of increasing oxygen affinity of hemoglobin S in a patient in need thereof comprising administering to the patient in need thereof a crystalline ansolvate of Compound 1: 
       
         
           
           
               
               
           
         
         wherein the crystalline ansolvate is characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
       
     
     
         22 . The method of  claim 21 , wherein the crystalline ansolvate is characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         23 . The method of  claim 21 , wherein the crystalline ansolvate is characterized by at least three powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         24 . The method of  claim 21 , wherein the crystalline ansolvate is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         25 . The method of  claim 21 , wherein the crystalline ansolvate is characterized by an X-ray powder diffraction pattern (Cu Kα radiation) substantially similar to that of  FIG. 5 . 
     
     
         26 . The method of  claim 21 , wherein the crystalline ansolvate of Compound 1 is substantially free of a solvated polymorph of Compound 1. 
     
     
         27 . The method of  claim 21 , wherein the crystalline ansolvate of Compound 1 is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ), and less than about 25 mole %, 10 mole %, or 5 mole % of one or more of crystalline Form I, Material N, or amorphous forms of Compound 1. 
     
     
         28 . A method of increasing oxygen affinity of hemoglobin S in a patient in need thereof comprising administering to the patient in need thereof a pharmaceutical composition comprising a crystalline ansolvate of Compound 1: 
       
         
           
           
               
               
           
         
         and at least one pharmaceutically acceptable excipient, wherein the crystalline ansolvate is characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
       
     
     
         29 . The method of  claim 28 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         30 . The method of  claim 28 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         31 . The method of  claim 28 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         32 . The method of  claim 28 , wherein the crystalline ansolvate of the pharmaceutical composition of Compound 1 is substantially free of a solvated polymorph of Compound 1. 
     
     
         33 . The method of  claim 28 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ), and less than about 25 mole %, 10 mole %, or 5 mole % of one or more of crystalline Form I, Material N, or amorphous forms of Compound 1. 
     
     
         34 . A method of treating sickle cell disease in a patient having sickle cell disease comprising administering to the patient in need thereof a crystalline ansolvate of Compound 1: 
       
         
           
           
               
               
           
         
         wherein the crystalline ansolvate is characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
       
     
     
         35 . The method of  claim 34 , wherein the crystalline ansolvate is characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         36 . The method of  claim 34 , wherein the crystalline ansolvate is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         37 . The method of  claim 34 , wherein the crystalline ansolvate is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         38 . The method of  claim 34 , wherein the crystalline ansolvate is characterized by an X-ray powder diffraction pattern (Cu Kα radiation) substantially similar to that of  FIG. 5 . 
     
     
         39 . The method of  claim 34 , wherein the crystalline ansolvate of Compound 1 is substantially free of a solvated polymorph of Compound 1. 
     
     
         40 . The method of  claim 34 , wherein the crystalline ansolvate of Compound 1 is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ), and less than about 25 mole %, 10 mole %, or 5 mole % of one or more of crystalline Form I, Material N, or amorphous forms of Compound 1. 
     
     
         41 . A method of treating sickle cell disease in a patient having sickle cell disease comprising administering to the patient in need thereof a pharmaceutical composition comprising a crystalline ansolvate of Compound 1: 
       
         
           
           
               
               
           
         
       
       and at least one pharmaceutically acceptable excipient, wherein the crystalline ansolvate of the pharmaceutical composition is characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         42 . The method of  claim 41 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         43 . The method of  claim 41 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         44 . The method of  claim 41 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         45 . The method of  claim 41 , wherein the crystalline ansolvate of the pharmaceutical composition is substantially free of a solvated polymorph of Compound 1. 
     
     
         46 . The method of  claim 41 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ), and less than about 25 mole %, 10 mole %, or 5 mole % of one or more of crystalline Form I, Material N, or amorphous forms of Compound 1. 
     
     
         47 . A method of treating pulmonary disorder in a patient having a pulmonary disorder comprising administering to the patient in need thereof a crystalline ansolvate of Compound 1: 
       
         
           
           
               
               
           
         
         wherein the crystalline ansolvate is characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
       
     
     
         48 . The method of  claim 47 , wherein the crystalline ansolvate is characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         49 . The method of  claim 47 , wherein the crystalline ansolvate is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         50 . The method of  claim 47 , wherein the crystalline ansolvate is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         51 . The method of  claim 47 , wherein the crystalline ansolvate is substantially free of a solvated polymorph of Compound 1. 
     
     
         52 . The method of  claim 47 , wherein the crystalline ansolvate is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ), and less than about 25 mole %, 10 mole %, or 5 mole % of one or more of crystalline Form I, Material N, or amorphous forms of Compound 1. 
     
     
         53 . A method of treating pulmonary disorder in a patient having a pulmonary disorder comprising administering to the patient in need thereof a pharmaceutical composition comprising a crystalline ansolvate of Compound 1: 
       
         
           
           
               
               
           
         
         wherein the crystalline ansolvate is characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
       
     
     
         54 . The method of  claim 53 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         55 . The method of  claim 53 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         56 . The method of  claim 53 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ). 
     
     
         57 . The method of  claim 53 , wherein the crystalline ansolvate of the pharmaceutical composition is substantially free of a solvated polymorph of Compound 1. 
     
     
         58 . The method of  claim 53 , wherein the crystalline ansolvate of the pharmaceutical composition is characterized by X-ray powder diffraction peaks (Cu Kα radiation) of 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ), and less than about 25 mole %, 10 mole %, or 5 mole % of one or more of crystalline Form I, Material N, or amorphous forms of Compound 1.