Crystalline forms of [3-(4- {2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1h-imidazol-4-yl} -phenoxy)-propyl]-diethyl-amine

Abstract

The present invention relates to crystalline forms of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine (“COMPOUND I”) useful in the treatment of RAGE mediated diseases.

1 . A solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the solid state form is selected from the group consisting of:
 a) a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2°; and   b) a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2°.   
     
     
         2 . The solid state form of  claim 1 , characterized by an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2°. 
     
     
         3 . The solid state form of  claim 2 , characterized by an XRPD pattern as shown in  FIG. 1 . 
     
     
         4 . The solid state form of  claim 2 , characterized by an endothermic peak at about 59° C., as determined by DSC. 
     
     
         5 . The solid state form of  claim 2 , characterized by a DSC profile as shown in  FIG. 2 . 
     
     
         6 . The solid state form of  claim 2 , characterized by an about 2.3 wt% loss between room temperature and about 150° C., as determined by TGA. 
     
     
         7 . The solid state form of  claim 2 , characterized by TGA profile as shown in  FIG. 2 . 
     
     
         8 . The solid state form of  claim 2 , characterized by at least two of the following features (I-i)-(I-iii):
 (I-i) an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2°;   (I-ii) a DSC profile as shown in  FIG. 2 ; or   (I-iii) a TGA profile as shown in  FIG. 2 .   
     
     
         9 . The solid state form of  claim 2 , which is Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)- propyl]-diethylamine. 
     
     
         10 . The solid state form of any one of  claims 2 - 9 , wherein the solid state form is at least 80% pure. 
     
     
         11 . The solid state form of any one of  claims 2 - 10 , wherein the solid state form is substantially pure. 
     
     
         12 . A mixture comprising the solid state form of any one of  claims 2 - 9  and a second solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 18.8° and 20.1° ±0.2. 
     
     
         13 . The solid state form of  claim 1 , characterized by an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2°. 
     
     
         14 . The solid state form of  claim 13 , characterized by an XRPD pattern having peaks at 2θ angles of 5.4, 19.7°, 21.8, 22.0°, and 30.2° ±0.2°. 
     
     
         15 . The solid state form of  claim 13 , characterized by an XRPD pattern as shown in FIG. cm  3 . 
     
     
         16 . The solid state form of  claim 13 , characterized by an endothermic peak at about 51.9° C., as determined by DSC. 
     
     
         17 . The solid state form of  claim 13 , characterized by a DSC profile as shown in  FIG. 4 . 
     
     
         18 . The solid state form of  claim 13 , characterized by an about 4.2 wt% loss between room temperature and about 150° C., as determined by TGA. 
     
     
         19 . The solid state form of  claim 13 , characterized by a TGA profile as shown in  FIG. 4 . 
     
     
         20 . The solid state form of  claim 13 , characterized by at least two of the following features (I-i)-(I-iii):
 (I-i) an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2°;   (I-ii) a DSC profile as shown in  FIG. 4 ; or   (I-iii) a TGA profile as shown in  FIG. 4 .   
     
     
         21 . The solid state form of  claim 13 , which is Form IV. 
     
     
         22 . The solid state form of any one of  claims 13 - 21 , wherein the solid state form is at least 80% pure. 
     
     
         23 . The solid state form of any one of  claims 13 - 22 , wherein the solid state form is substantially pure. 
     
     
         24 . A mixture comprising the solid state form of any one of  claims 13 - 21  and a second solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 18.8° and 20.1° ±0.2 
     
     
         25 . A mixture comprising forms Form III and Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)- propyl]-diethylamine. 
     
     
         26 . A method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent at room temperature to make a solution;   b) allowing the solution from step a) to evaporate at room temperature; and   c) collecting the solid produced from step b).   
     
     
         27 . The method of  claim 26 , wherein the suitable solvent is 2-methyltetrahydrofuran or tetrahydrofuran. 
     
     
         28 . Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of  claim 26  or  27 . 
     
     
         29 . A method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyI]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent at room temperature to make a solution;   b) stirring the solution from step a);   c) adding a suitable amount of a suitable anti-solvent; and   d) collecting the solid product produced from step c).   
     
     
         30 . The method of  claim 29 , wherein the suitable solvent in step a) is selected from the group consisting of ethanol, n-propyl alcohol, isopropyl alcohol, 2-methyltetrahydrofuran, isopropyl acetate, and methyl ethyl ketone. 
     
     
         31 . The method of  claim 29  or  30 , wherein the suitable anti-solvent is selected from the group consisting of water, hexane, and n-heptane. 
     
     
         32 . Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of  claims 29 - 31 . 
     
     
         33 . A method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) slurrying a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at a suitable temperature; and   b) collecting the solid produced from step a).   
     
     
         34 . The method of  claim 33 , wherein the suitable solvent system is selected from the group consisting of isopropyl alcohol, ethanol, ethyl acetate, cyclopentyl methyl ether, acetone, ethanol/water, n-propyl alcohol/heptane, ethanol/hexane, methyl ethyl ketone/hexane, 4-methyl-2-pentanone/hexane, isopropyl alcohol/hexane, ethyl acetate/hexane, toluene/hexane, 2-methyltetrahydrofuran/hexane, dioxane/hexane, cyclohexane, anisole, anisole/hexane, and methyl tert-butyl ether/hexane. 
     
     
         35 . The method of  claim 33  or  34 , wherein the suitable temperature is room temperature or 35° C. 
     
     
         36 . Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of  claims 33 - 35 . 
     
     
         37 . A method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a solution;   b) adding a suitable amount of a polymer mixture to the solution from step a) to make a suspension;   c) allowing the suspension of step b) to evaporate at room temperature; and   d) collecting the solid produced from step c).   
     
     
         38 . The method of  claim 37 , wherein the suitable solvent system is selected from the group consisting of isopropyl alcohol, cyclohexane, ethyl acetate/hexane, acetone/hexane, isopropyl acetate/hexane, methyl ethyl ketone/hexane, and n-propyl alcohol/water. 
     
     
         39 . The method of  claim 37  or  38 , wherein the polymer mixture is selected from the group consisting of polyvinylpyrrolidone/polyvinyl alcohol/polyvinyl chloride/hypromellose/methyl cellulose or poly(methyl methacrylate)/sodium alginate/hydroxyethyl cellulose. 
     
     
         40 . Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of  claims 37 - 39 . 
     
     
         41 . A method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a solution in a vessel;   b) adding a suitable amount of a volatile solvent to the vessel of step a);   c) sealing the vessel after step b);   d) maintaining the vessel at room temperature for a sufficient amount of time for the volatile solvent to interact with the solution; and   e) collecting the solid produced from step c).   
     
     
         42 . The method of  claim 41 , wherein the suitable solvent system is methyl ethyl ketone and the suitable volatile solvent is hexane. 
     
     
         43 . Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of  claim 41  or  42 . 
     
     
         44 . A method for preparing solid state form Form Ill of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) suspending a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a suspension;   b) heating the suspension from step a) to a suitable temperature and equilibrating for a suitable amount of time;   c) optionally filtering the suspension from step b);   d) slowly cooling to a suitable temperature over a suitable amount of time; and   e) collecting the solid produced from step d).   
     
     
         45 . The method of  claim 44 , wherein the suitable solvent system is selected from the group consisting of isopropyl alcohol, acetonitrile, cyclohexane, n-butanol, ethanol/n-heptane, methyl ethyl ketone/n-heptane, isopropyl alcohol/n-heptane, methyl tert-butyl ether/n-heptane, trichloromethane/hexane, isopropyl alcohol/hexane, methyl tert-butyl ether/hexane, ethyl acetate/hexane, toluene/hexane, and cyclopentyl methyl ether/hexane. 
     
     
         46 . The method of  claim 44  or  45 , wherein in step b), the suitable temperature is about 40° C. and the suitable amount of time is about 1 hour. 
     
     
         47 . The method of any of  claims 44 - 46 , wherein in step d), the suitable temperature is about 5° C. and the suitable time is about 5.5 hours. 
     
     
         48 . The method of  claim 47 , wherein if no solid is obtained after cooling to about 5° C., a further cooling to −20° C. step is performed. 
     
     
         49 . The method of  claim 47 , wherein if no solid is obtained after cooling to about 5° C., an evaporation at room temperature step is performed. 
     
     
         50 . Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of  claims 44 - 49 . 
     
     
         51 . A method for preparing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) adding a suitable amount of a volatile solvent to a suitable amount of solid [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a vessel;   b) sealing the vessel after step b);   c) maintaining the vessel at room temperature for a sufficient amount of time for the volatile solvent to interact with the solid [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]- diethylamine; and   d) collecting the solid form from the vessel.   
     
     
         52 . The method of  claim 51 , wherein the volatile solvent is isopropyl alcohol. 
     
     
         53 . The method of  claim 50  or  51 , wherein the suitable time is 5 to 10 days. 
     
     
         54 . Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of  claims 51 - 53 . 
     
     
         55 . A method for preparing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent at room temperature to make a solution;   b) stirring the solution from step a);   c) adding a suitable amount of a suitable anti-solvent; and   d) collecting the solid product produced from step c).   
     
     
         56 . The method of  claim 55 , wherein the suitable solvent in step a) is toluene. 
     
     
         57 . The method of  claim 55  or  56 , wherein the suitable anti-solvent hexane. 
     
     
         58 . Solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of  claims 55 - 57 . 
     
     
         59 . A method for preparing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) slurrying a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at a suitable temperature; and   b) collecting the solid produced from step a).   
     
     
         60 . The method of  claim 59 , wherein the suitable solvent system is selected from the group consisting of toluene, ethyl acetate, anisole, ethyl acetate/hexane, toluene/hexane, and ethanol/hexane. 
     
     
         61 . The method of  claim 59  or  60 , wherein the suitable temperature is room temperature or 35° C. 
     
     
         62 . Solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of  claims 59 - 61 . 
     
     
         63 . A method for preparing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyI]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a solution;   b) adding a suitable amount of a polymer mixture to the solution from step a) to make a suspension;   c) allowing the suspension of step b) to evaporate at room temperature; and   d) collecting the solid produced from step c).   
     
     
         64 . The method of  claim 63 , wherein the suitable solvent system is isopropyl acetate/hexane. 
     
     
         65 . The method of  claim 63  or  64 , wherein the polymer mixture is poly(methyl methacrylate)/sodium alginate/hydroxyethyl cellulose. 
     
     
         66 . Solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of  claims 63 - 65 . 
     
     
         67 . A method for preparing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:
 a) suspending a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a suspension;   b) heating the suspension from step a) to a suitable temperature and equilibrating for a suitable amount of time;   c) optionally filtering the suspension from step b);   d) slowly cooling to a suitable temperature over a suitable amount of time; and   e) collecting the solid produced from step d).   
     
     
         68 . The method of  claim 67 , wherein the suitable solvent system is dioxane/water. 
     
     
         69 . The method of  claim 67  or  68 , wherein in step b), the suitable temperature is about 40° C. and the suitable amount of time is about 1 hour. 
     
     
         70 . The method of any of  claims 67 - 69 , wherein in step d), the suitable temperature is about 5° C. and the suitable time is about 5.5 hours. 
     
     
         71 . The method of  claim 70 , wherein if no solid is obtained after cooling to about 5° C., a further cooling to −20° C. step is performed. 
     
     
         72 . The method of  claim 70 , wherein if no solid is obtained after cooling to about 5° C., an evaporation at room temperature step is performed. 
     
     
         73 . Solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of  claims 67 - 72 . 
     
     
         74 . A pharmaceutical composition comprising one or more of the solid state forms of  claims 1 - 73  and one or more pharmaceutically acceptable carriers or diluents. 
     
     
         75 . A method for treating Alzheimer's disease comprising administering the pharmaceutical composition of  claim 74  to a patient in need thereof. 
     
     
         76 . A method for treating Alzheimer's disease comprising administering one or more of the solid state forms of  claims 1 - 73 .