POLYMORPHS OF 5-(4-(2-(5-ETHYLPYRIDIN-2-YL)-2-OXOETHOXY)BENZYL)- 1,3-THIAZOLIDINE-2,4-DIONE (MITOGLITAZONE)

CROSSREFERENCETORELATEDAPPLICATION

[0001] This PCT application claims priority to U.S. Application No.61/231 ,426, filed on August 5, 2009. The entire contents of the aforementioned application is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to novel polymorphs of 5-(4-(2-(5-cthylpyridin-2-yl)- 2-oxoethoxy)benzyl)-1,3 -thiazolidiiie-2,4-dione of Formula (I) and processes for the preparation thereof and pharmaceutical compositions comprising novel crystalline polymorphs.

BACKGROUND

[0003] Thiazolidinedione analogs either prevent or ameliorate an insulin resistance state, which occurs genetically or is induced by dietary means. 5-(4-(2-(5-Ethylpyridin-2-yl)-2- oxoethoxy)benzyl)-l,3-thiazolidine-2,4-dione of Formula (I) (Mitoglitazonc) is an antidiabetic thiazolidinedione being evaluated for the treatment of non-insulin-dependent diabetes mellitus. Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease characterized by a reduction in the response of the peripheral target tissue to insulin and the inability of pancreatic insulin reserves to overcome the reduced response. Improvement of insulin sensitivity of the target tissue not only reduces the consequences of the disease but actually aids in the prevention of NIDDM.

[0004] The synthesis of Mitoglitazone has been reported (J. Med. Chem. , 1966, 39, 5053- 5063; Org. Pro. Res. & Dev. (OPRD), 2002, 6, 721-728 and U.S. PaL No. 5,441,971).

[0005] Polymorphism is the ability of a compound to exhibit more than one orientation or conformation of molecules within a crystal lattice. Many organic compounds, including active pharmaceutical ingredients (API's), exhibit polymorphism. Drug substances may exist in various polymorphic forms, which may differ from each other in terms of stability, solubility, compressibility, fiowability and spectroscopic properties, thus affecting dissolution, bioavailability, and handling characteristics of the substance. Rate of dissolution of an API in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administrated API can reach the patient's bloodstream. Flowability affects the ease with which the material is handled while processing a pharmaceutical product Knowledge of the existence of different crystal phases and their overall physical and chemical behavior is required for selection of a polymorphic form for use in the preparation of a final dosage form of a pharmaceutical composition. It is preferable to have a single, pure and stable polymorphic form in the final drug product To this end, investigation of crystal polymorphism is an essential step in pharmaceutical research due to the influence of solid-state properties on dosage form.

[0006] Polymorphism is not reported for Mitoglitazone, so there is a need to study the polymorphism of Mitoglitazone. Thus, the present invention provides novel polymorphs of Mitoglitazone having good flow properties, especially good bulk flow properties, and therefore amenable to large scale pharmaceutical processing and formulation.

SUMMARY OF Tffg fffygffiioN

[0007] According to one aspect, the present invention provides crystalline Form I substantially free of other forms of Mitoglitazone. In some embodiments, the crystalline polymorph. Form I, of Mitoglitazone has an XRPD pattern of: 9.54, U .61 , 1522, 16.07, and 1738° ± 0.2° on a 2Θ scale. In other embodiments, the crystalline polymorph of Form I is further characterized by an XRPD pattern of: 8.03, 9.34, 11.61, 14.88, 15.22, 16.07, 17.38, 20.86, 21.08, 2323, 23.92° ± 0.2° on a 2Θ scale. In some embodiments, the crystalline polymorph of Form I is further characterized by an FTIR absorption spectrum of 3172, 3080, 2964, 1757, 1718, 1703, 1608, 1587, 1514, 1326, 1249, 1224, 1205, 1166, 1153, 995 cm ¹ . And in some embodiments, the crystalline polymorph of Form I is further characterized by a DSC thermogram having an endotherm at a temperature of from about 146 °C to about 150 °C.

[0008] Another aspect of the present invention provides a process for the

preparation of a polymorph. Form I, of Mitoglitazone substantially free of other forms of Mitoglitazone comprising the steps of:

£L mixing Mitoglitazone with a first solvent at a first temperature to

generate a first solution;

b. optionally, filtering the first solution of step a to generate a filtrate;

c. optionally, adding a second solvent to the filtrate of step b or the first solution of step a to generate a second solution; and . d. cooling and stirring the filtrate of step b, the first solution of step a, or the second solution of step c at a second temperature to generate solids, wherein the first temperature is higher than the second temperature.

[0009] In several embodiments, the process further comprises filtering the first solution of step a to generate a filtrate. In several embodiments, the process further comprises adding a second solvent to the filtrate of step b to generate a second solution. And, in some processes the first temperature is within ± 10°C of the reflux temperature of the first solvent For example, the first temperature is from about 50 °C to about 100°C. In other examples, the first temperature is from about 60°C to about 80 °C. In some processes, the second temperature is from about 20°C to about 3S°C. And, some processes further comprise filtering and drying the solids of stepd. For example, the solids of step d are dried at a temperature of from about 5O°C to about 70 °C.

[0010] In several processes, the first solvent comprises an alcohol, a ketone, an ester, a nitrite, an ether, a chlorinated hydrocarbon, or any combination thereof. In one example, the first solvent comprises an alcohol. Exemplary alcohols include ethanol, 1- propanol, 2-propanol, or any combination thereof. In another example, the first solvent comprises a ketone. Exemplary ketones include acetone, 2-butanone, diethyl ketone, or any combination thereof. In another example, the first solvent comprises an ester. Exemplary esters include ethyl acetate, methyl acetate, butyl acetate, or any combination thereof. In another example, the first solvent comprises a chlorinated hydrocarbon. Exemplary chlorinated hydrocarbons include methylene dkhloride, ethylene dkhloride, carbon tetrachloride, chloroform, or any combination thereof. In another example, the first solvent comprises a nitrite. Exemplary nitrites include acetonitrile. In another example, the first solvent comprises an ether.

Exemplary ethers include tetrahydrofuran, 1,4-dioxane, or any combination thereof. In some processes, the first solvent is anhydrous.

[0011] In some embodiments, the first solution of step a, the filtrate of step b, or the second solution of step c is dried over anhydrous sodium sulfate.

[0012] In some embodiments, the second solvent comprises an aliphatic ether, an aliphatic hydrocarbon, an aromatic hydrocarbon, or any combination thereof. For example, the second solvent comprises an aliphatic hydrocarbon or an aromatic hydrocarbon. In some examples, the second solvent comprises an aliphatic hydrocarbon, and the aliphatic hydrocarbon comprises pentane, hexane, heptane, or any combination thereof. In other examples, the second solvent comprises an aromatic hydrocarbon, and the aromatic hydrocarbon comprises toluene, xylene, or any combination thereof.

[0013] Another aspect of the present invention provides a process for the preparation of Form I of Mitoglitazone substantially free of other forms of

Mitoglitazone comprising drying any polymorphic Form of Mitoglitazone at a temperature of from about 60 °C to about 100 °C (e.g., from about 80 °C to about 90 ⁰ Q for a period of from about 6 to about 26 hours (e.g., from about 8 to about 24 hours, from about 10 to about 16 hours, or about 12 hours).

[0014] Another aspect of the present invention provides a process for the preparation of Form I of Mitoglitazone substantially free of other forms of

Mitoglitazone comprising the steps of:

a. mixing Mitoglitazone with a water miscible aliphatic cyclic ether at a temperature of from about 25 °C to about 3O°C to generate a first solution;

b. optionally, filtering the solution of step a to generate filtrate;

c. adding water to the first solution of step a or the filtrate of step b and stirring the resultant mixture for a period of from about 4 to about 5 hrs at a temperature of from about 25°C to about 30 °C to generate solids; and

d. collecting the resultant solids of step c.

[0015] In some embodiments, the water miscible aliphatic cyclic ether comprises tetrahydrofuran, 1,4-dioxane, or any combination thereof.

[0016] Another aspect of the present invention provides a crystalline polymorph, Form II, of Mitoglitazone having an XRPD pattern of: 9.11, 13.44, 20.17, and 25.41° ± 0.2° on a 2Θ scale. In some embodiments, the crystalline polymorph is further characterized by an XRPD pattern of: 9.11, 12.04, 13.44, 19.43, 20.17, 21.05, 22.67, 23.79, 25.41, 26.09, 28.04, 30.79, 9.11, 12.04, 13.44, 19.43, 20.17, 21.05, 22.67, 23.79, 25.41, and 26.09° ± 0.2° on a 2Θ scale. In other embodiments, the crystalline polymorph is further characterized by an FTIR absorption spectrum of 3394, 3159, 3070, 2966, 2783, 1751, 1720, 1703, 1510, 1245, 997, 831, 707, 655, and 569 cm ^! . And, in some embodiments, the crystalline polymorph is further characterized by a DSC thermogram having a first endotherm at a temperature from about 85 °C to about 100 °C and a second endotherm at a temperature of from about 135 °C to about 150°C. [0017] Another aspect of the present invention provides a process for the preparation of Form π of Mitoglitazone substantially free of other forms of

Mitoglitazone comprising the steps of:

a. mixing Mitoglitazone with a first solvent at a first temperature to generate a first solution;

b. optionally, filtering the solution of step a to generate a filtrate;

c. optionally, adding a second solvent, which is miscible with the first solvent, to the filtrate solution of step b to generate a second solution; and

d. cooling and stirring the first solution of step a, the filtrate of step b, or the second solution of step c to a second temperature to generate solids, wherein the first temperature is higher than the second temperature.

[0018] In some embodiments, the first solvent comprises water. In other embodiments, the first solvent comprises 25 % or less of water by volume. For example, the first solvent comprises from about IS % to about S % water by volume.

In some embodiments the first solvent additionally comprises an alcohol, a ketone, an ester, a nitrile, an ether, a chlorinated hydrocarbon, or any combination thereof, as described above.

[0019] In some embodiments, the second temperature is from about 25 °C to about

30°C.

[0020] In other embodiments, the first temperature is from about 50 °C to about

90 °C. For example, the first temperature is the reflux temperature of the first solvent

[0021] In several embodiments the process further comprises filtering the solution of step a to generate a filtrate. Other embodiments further comprise adding a second solvent, which is miscible with the first solvent, to the filtrate of step b to generate a second solution.

[0022] In several embodiments, the second solvent comprises water. In other embodiments, the second solvent comprises an aliphatic hydrocarbon solvent comprising pentane, hexane, heptane, or any combination thereof.

[0023] Some embodiments further comprise drying the solids of step d at a temperature of from about 25 °C to about 60 °C.

[0024] Another aspect of the present invention provides a process for the preparation of Form π of Mitoglitazone substantially free of other forms of

Mitoglitazone comprising the steps of: a. mixing Mitoglitazone Form I with a first solvent comprising water at a first temperature to generate a mixture;

b. stirring the mixture for a period of from about 4 hours to about 16 hours; and

c. drying the mixture at a temperature of from about 70 ⁹ C to about 12O°C for a period of from about 2 to about 30 hours.

[0025] Another aspect of the present invention provides a crystalline polymorph, Form III, of Mitoglitazone having an XRFD pattern of: 9.11, 13.44, 20.17, and 25.41° ± 0.2° on a 2Θ scale. In some embodiments, the crystalline polymorph is further characterized by an XRPD pattern of: 9.11, 12.04, 13.44, 20.17, 22.67, 23.79, 25.41, 28.04, and 30.79° ± 0.2° on a 2Θ scale. In other embodiments, the crystalline polymorph is further characterized by an FTIR absorption spectrum of 3143, 3031, 2976, 2933, 1743, 1705, 1608, and 991 cm ¹ . And, in some embodiments, the crystalline polymorph is further characterized by a DSC thermogram having a first endotherm at a temperature of from about 126 °C to about 130 °C and a second endotherra at a temperature of from about 135 °C to about 145 °C.

[0026] Another aspect of the present invention provides a process for the preparation of Form III of Mitoglitazone comprising the steps of:

a. mixing Mitoglitazone with a first solvent comprising an alcohol at a first temperature to generate a first solution;

b. optionally, filtering the first solution of step a to generate a filtrate; and c. cooling and stirring the first solution of step a or the filtrate of step b to a second temperature to generate solids,

wherein the first temperature is higher than the second temperature.

[0027] In several embodiments, the second temperature is from about S °C to about 10°C.

[0028] In some embodiments, the first solvent comprises methanol, ethanol, 1 - propanol, 2-ρropanol, or any combination thereof.

[0029] In some embodiments, the first temperature is from about 60 °C to about 70°C.

[0030] Other embodiments further comprise drying the solids at a temperature of from about 50 °C to about 70 °C.

[0031] In some embodiments, the Mitoglitazone of step a comprises Mitoglitazone Form I, Form II, or any combination thereof. [0032] Another aspect of the present invention provides a crystalline polymorph, Form IV, of Mitoglitazone having an XRFD pattern of: 14.03, 17.85, 20.55, and 24.88° ± 0.2° on a 2Θ scale. In some embodiments, the crystalline polymorph is further characterized by an XRPD pattern of: 9.14, 14.03, 17.85, 20.55, 20.85, 24 Sl, 24.88, 26.63, 2739, 32.75, and 33.13° ± 0.2° on a 2Θ scale. In other embodiments, the crystalline polymorph is further characterized by an FUR absorption spectrum of 3504, 3051, 2941, 2910, 1751, 1695, 1512, 1240, 993, 877, 839, 792 and 669 cm ¹ . And, in some embodiments, the crystalline polymorph is further characterized by a DSC thermogram having a first endotherm at a temperature of from about 80 °C to about 95 °C and a second endotherm at a temperature of from about 146 °C to about 150°C.

[0033] Another aspect of the present invention provides a process for the preparation of Form IV of Mitoglitazone substantially free of other crystalline forms of Mitoglitazone comprising the steps of:

a. dissolving Mitoglitazone in a first solvent comprising alcohol at a first temperature to generate a first solution;

b. optionally, filtering the first solution of step a to generate a filtrate; and c. cooling and stirring the first solution of step a or the filtrate of step b at a second temperature to generate solids,

wherein the first temperature is higher than the second temperature.

[0034] In several embodiments, the second temperature is from about -60 °C to aboutO°C.

[0035] Other embodiments further comprise drying the solids of step c at a temperature of from about 20 °C to about 30 °C.

[0036] In several embodiments, the first solvent comprises methanol, emanol, 1 - propanol, 2-propanol, or any combination thereof.

[0037] In several embodiments, the Mitoglitazone of step a comprises Mitoglitazone Fbrm L

[0038] Another aspect of the present invention provides a crystalline polymorph. Form V, of Mitoglitazone having an XRPD pattern of: 14.03, 17.85, 20.55, and 24.88° ±0.2° on a 2Θ scale. In some embodiments, the crystalline polymorph is further characterized by an XRPD pattern of: 9.14, 14.03, 17.85, 20.55, 24.52, 24.88, 26.63, 27.39, 32.75, an 33.13° ± 0.2° on a 2Θ scale. In other embodiments, the crystalline polymorph is further characterized by an FTIR absorption spectrum of 3568, 3500, 3388, 3151, 2968, 2788, 1753, 1699, 1608, 1512, 1415, 1325, 1245,995, 864, 794, and 707 cm ^-1 . And, in some embodiments, the crystalline polymorph is further characterized by a DSC thermogram having a first endotherm at a temperature from about 80 °C to about 85 °C, a second endotherm at a temperature from about 95 °C to about 105 °C, and a third endotherm at a temperature of about 146 °C to about 15O°C.

[0039] Another aspect of the present invention provides a process for the preparation of Form V of Mitoglitazone comprising exposing Form IV of

Mitoglitazone to humidity at a first temperature.

[0040] In some embodiments, the Form IV of Mitoglitazone is exposed to 60-85% relative humidity for a period from about 12 hours to about 72 hours.

[0041] In some embodiments, the first temperature is from about 30 °C to about 50 °C.

[0042] In other embodiments, the Form IV of Mitoglitazone is exposed to 75% relative humidity for a period of 24 hrs at a temperature of about 40 °C.

[0043] Another amorphous form of Mitoglitazone having an XRPD pattern exhibiting a broad peak from about 10° to about 36° on a 2Θ scale. In some embodiments, the amorphous form is further characterized by an FTIR absorption spectrum of 2970, 2781, 1753, 1697, 1608, 1510,1325, 301,1180,977, 827 and 705 cm ^*1 . And, in some examples, the amorphous form is further characterized by a DSC thermogram having an exotherm at a temperature of from about 90 °C to about 110 °C and an endotherm at a temperature from about 146 °C to about 150 °C.

[0044] Another aspect of the present invention provides a process for the preparation of amorphous Mitoglitazone comprising the steps of:

a. heating Mitoglitazone to a first temperature to generate a melt; and b. cooling the melt to a second temperature to generate an amorphous solid,

wherein the first temperature is higher than the second temperature.

[0045] In some embodiments, the first temperature is from about 140 °C to about 170°C.

[0046] In other embodiments, the second temperature of from about 10 °C to about 3O °C.

[0047] Another aspect of the present invention provides a process for the preparation of amorphous Mitoglitazone comprising the steps of: a. mixing Mitoglitazone in a first solvent at a first temperature to generate a mixture; and

b. spray drying the mixture generated in step a to obtain an amorphous solid.

[0048] In some embodiments, the first temperature is from about 20 °C to about 40 °C.

[0049] In some embodiments, the concentration of Mitogiiazone in the mixture is from about 5% to about 25 % by wL

[0050] In other embodiments, the first solvent comprises an alcohol, a ketone, or any combination thereof. For example, the first solvent comprises an alcohol, and the alcohol comprises methanol. In another example, the first solvent comprises a ketone, and the ketone comprises acetone.

[0051] In some embodiments, the spray drying is performed using an inlet

temperature of from about 40 °C to about 140 °C and outlet temperature of from about 35 °C to about 85 °C.

[0052] Another aspect of the present invention provides Mitoglitazone obtained by any of the processes described above, wherein the Mitoglitazone has particle size d>o less than 200 microns. In some embodiments, the Mitoglitazone has a particle size dm of less than 50 microns.

[0053] Another aspect of the present invention provides Mitoglitazone or any polymorphic form thereof having:

0.15 wt% or less of N-methylsulphide (A); 0.15 wt% or less of keto benzylidene (B); 0.15 wt% or less of keto benzaldehyde (C);

Mitoglitazone alcohol (D); less man 0.3% of dimer impurities wherein M+l is 739.30; or any combination thereof.

[0054] In some embodiments, the Mitoglitazone has crystalline Form I. In other embodiments, the Mitoglitazone has crystalline Form II. In alternative embodiments, the Mitoglitazone has crystalline Form DI. Or, in some embodiments, the

Mitoglitazone has crystalline Form IV. And, in some other embodiments, the

Mitoglitazone is amorphous. [0055] Another aspect of the present invention provides a pharmaceutical composition comprising one or more of crystalline Forms I, π, in, IV, V of

Mitoglitazone or amorphous Mitoglitazone and a pharmaceutically acceptable carrier.

[0056] Yet another aspect the present invention provides methods for preparing

Mitoglitazone forms, Form I, Form II, Form III, Form IV, Form V and/or an amorphous form with a chemical purity of greater than 95%.

[0057] Another aspect of the present invention provides chemically and polymorphkally stable forms of Mitoglitazone and methods for the preparation thereof.

[0058] Another aspect of the present invention provides processes for improving the solubility of Mitoglitazone.

[0059] Another aspect of the present invention provides processes for improving the solubility of crystalline forms, Form I, Form II, Form m. Form IV, Form V and the amorphous form with a mean particle size distribution below 250 μm to improve solubility.

[0060] In another aspect the present invention provides pharmaceutical compositions containing one or more novel crystalline forms or an amorphous form of Mitoglitazone.

[0061] Another aspect of the present invention provides a process for generating a form of

Mitoglitazone having a selectable particle size.

BRIEF DESCRIPTION OF THE DRAWINGS

[0062] FIG. 1 is an X-ray powder diffraction pattern of Mitoglitazone Form I;

[0063] FIG. 2 is DSC of Mitoglitazone Form I;

[0064] FIG. 3 is FT-IR of Mitoglitazone Form I;

[0065] FIG.4 is an X-ray Powder diffraction pattern of Mitoglitazone Form II;

[0066] FIG.5 is DSC of Mitoglitazone Form D;

[0067] FIG.6 is FTIR of Mitoglitazone Form II;

[0068] FIG.7 is an X-ray powder diffraction pattern of Mitoglitazone Form Dl;

[0069] FIG.8 is DSC of Mitoglitazone Form HI;

[0070] FIG.9 is FTIR of Mitoglitazone Form HI;

[0071] FIG. 10 is an X-ray powder diffraction pattern of Mitoglitazone Form IV;

[0072] FIG. 11 is DSC of Mitoglitazone Form IV;

[0073] FIG. 12 is FTIR of Mitoglitazone Form IV;

[0074] FIG. 13 is an X-ray powder diffraction pattern of Mitoglitazone Form V;

[0075] FIG. 14 is DSC of Mitoglitazone Form V;

[0076] FIG. 15 is FTIR of Mitoglitazone Form V;

[0077] FIG. 16 is an X-ray powder diffraction pattern of amorphous Mitoglitazone; [0078] FIG. 17 is DSC of amorphous Mitoglitazone;

[0079] FIG. 18 is FTIR of amorphous Mitoglitazone;

[0080] FIG. 19 is an X-ray powder diffraction pattern of Mitoglitazone by JMC route;

[0081] FIG.20 is an X-ray powder diffraction pattern of Mitoglitazone by OFRD route; and

[0082] FIG. 21 is an X-ray powder diffraction pattern of Mitoglitazone from 95% aqueous ethanol.

[0083] The figures above are provided by way of example and are not intended to limit the scope of the present invention.

DgT^. flp PpSCRIFTlON OF THE INVENTION

[0084] The present invention relates to novel polymorphs of 5-(4-(2-(5-cmylpyridin-2-yl)- 2-oxocthoxy)benzyl)-l,3-thiazolidine-2,4-dione of Formula (I) (Mitoglitazone) and processes for the preparation thereof and pharmaceutical compositions comprising novel crystalline polymorphs of Mitoglitazone.

O

(D

[0085] i. ABBREVIAΉONS AND DEFINΓΠONS

[0086] As used herein, "XRPD" means X-ray Powder Diffraction.

[0087] As used herein, "FITR" means Fourier Transform Infrared Spectroscopy.

[0088] As used herein, "DSC" means Differential Scanning Calorimetry.

[0089] As used herein, "substantially free of other forms" means a polymorphic form of

Mitoglitazone having less than 5%, less than 1%, or less than 0.5% by weight of other polymorphic forms of Mitoglitazone.

[0090] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics,

75th Ed. Additionally, general principles of organic chemistry are described in "Organic

Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's

Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons,

New York: 2001, the entire contents of which are hereby incorporated by reference.

[0091] As described herein, "protecting group" refers to a moiety or functionality that is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. Standard protecting groups are provided in Greene and Wuts : "Greene's Protective Groups in Organic Synthesis" 4th Ed, Wuts, P.G.M and Greene, T. W., Wiley-Interscicncc, New York:2006.

[0092] As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.

(0093] As used herein, Ae term "Mitoglitazone" refers to 5-(4-(2-(5-Ethylρyridin-2-yl)-2- oxocthoxy)benzyl)-13-thiazolidine-2,4-dk)ne, having the structure of Formula I.

[0094] As used herein, the term "hydroxyl" or "hydroxy" refers to an -OH moiety.

[0095] As used herein the term "aliphatic" or "aliphatic hydrocarbon" are used

interchangeably and encompass the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.

[0096] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyi. An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cydoalkenyl], hcterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyi [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,

aralkylcarbonylamino, (heterocycloalkyDcarbonylamino,

(heterocycloalkylalkyOcarbonylamino, heteroarylcarbonylamino,

heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl,

heterocyc-oalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphatkamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphatk-SOj-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, hcterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyU aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SOramiiκ>)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.

[0097] As used herein, an "alkenyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at least one double bond. like an alkyl group, an alkenyl group can be straight or branched Examples of an alkenyl group include, but are not limited to allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can be optionally substituted with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or

heterocydoalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,

(aliphatic )carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,

heteroaryicarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,

cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphatkamino, cycloaliphaticamino,

heterocycloaliphaticamino, or aliphaticsulfonylamino], sulfonyl [e.g.,

alkyl-SO2-, cycloaliphatic-SOr, or aryl-SOH, sulfmyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl,

(sulfonylamino)alkenyl (such as (alkyl-SOramino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.

[0098] As used herein, an "alkynyl" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has at least one triple bond. An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl. An alkynyl group can be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsuifinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SOa-, aliphaticamino-SOr, orcycloaliphatic- SO ₂ -], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,

cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino,

(heterocycloalkyl)carbonylamino, (cycloalkytalkyl)carbonylamino,

heteroaralkylcarbonylamino, heteroaryicarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [e.g., (cycloaliphatic )carbonyl or (heterocycloaliphatkOcarbonyl], amino [e.g., aliphaticamino], sulfoxy, oxo, caiboxy, carbamoyl, (cycloaliphatic)oxy, (hcterocycloaliphatic)oxy, or (hetcroaryl)alkoxy.

[0099] As used herein, an "amido" encompasses both "aminocarbonyl" and

"carbonylamino". These terms when used alone or in connection with another group refer to an amido group such as -N(R ^X >C(O)-R ^Y or -C(O)-N(R ^X )2, when used terminally, and -C(O)- N(R ^X >- or -N(R ^X )-C(O)- when used internally, wherein R ^x and R ^γ can be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaraliphatic..

Examples of amido groups include alkylamido (such as alkylcarbonylamino or

alkylaminocarbonyl), (heterocycloa]iphatic)ainkk>, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

[0100] As used herein, an "amino" group refers to -NR ^X R ^Y wherein each of R ^x and R ^γ is independently hydrogen, aliphatic cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatk)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,

((heterocycloaliρhatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or

(heteroaraliphatic)carbonyl, each of which being defined herein and being optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NR ^X -, where R ^x has the same meaning as defined above.

[0101] As used herein, an "aryl" and "aromatic hydrocarbon" are used interchangeably to refer to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or

tetrahydroanthracenyU anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. The bicyclic and tricyclic groups include benzofused 2-3 membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more C-n carbocyclic moieties. An aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;

heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;

(cycloaliphatk)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (hcteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)caibonyl;

(heterocycloaliphatic)carbonyl; ((heterocycloaliphatk;)aliphark)carbonyl; or

(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SOr or amino-SOr]; sulfinyl [e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-]; sulfanyl (e.g., altphatic-S-]; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, an aryl can be unsubstituted.

[0102] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl,

((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amtdo)aryl [e.g.,

(aminocarbonyl)aryl, (((alkylamino)alkyl)amtnocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((hetcτoaryl)amino)carbonyl)aryl]; aminoaryl [e.g.,

((alkylsulfonyDamino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl; (alkoxy)aryl;

(sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;

(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryt; (hydroxy)aryl, ((carboxy)alkyl)aryl;

«(dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; «(alkylsulfonyl)amino)alkyl)aryl;

((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl-, (cyanoalkyi)aryl;

(hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m- alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heterocycloaliphatic)- o-(alkyl))aryl.

[0103] As used herein, an "araliphatic" such as an "aralkyl" group refers to an aliphatic group (e.g., a C _1-4 alkyl group) that is substituted with an aryl group. "Aliphatic," "alky I," and "aryl" are defined herein. An example of an araliphark such as an aralkyl group is benzyl.

[0104] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a C _1-4 alkyl group) that is substituted with an aryl group. Both "alkyl" and "aryl" have been defined above. An example of an aralkyl group is benzyl. An aralkyl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or eyeloalkenyl], (cycloalkyl)alkyl, heterocyctoalkyl, (hetcτocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,

heteroaralkyloxy, aroyl heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,

(cycloalkylalkyt)carbonylamino, arylcarbonylamino, aralkykarbonylamino,

(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0105] As used herein, a "tricyclic ring system" includes 8-12 (e.g., 9, 10, or 11) membercd structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicycloaliphabcs (e.g., bicycloalkyl or bicycloalkenyl), bicyclohcteroaliphatics, bicyclic aryls, and bkyclic heteroaryls.

[0106] As used herein, a "cycloaliphatic" group encompasses a "cydoalkyl" group and a "cycloalkenyl" group, each of which being optionally substituted as set forth below.

[0107] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., S-IO) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohcxyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.l)octyl,

bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bkyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0108] A "cycloalkenyl" group, as used herein, refers to a non-aromatk carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo(2.2.2}octenyl, or bicyclo(3.3.1]nonenyl.

[0109] A cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatk)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g.,

(aliphatk)carbonylamino, (cycloaliphatic)carbonylamino,

((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloakphatte)carbonylaπiino, ((hctcrocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonyiaπiino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic )carbonyl,

((cycloaliphatic) aliphatic)carbonyl, (araliphat)c)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatk)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-SO ₂ - and 8TyI-SO ₂ -], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0110] As used herein, the term ''heterocycloaliphatic'' encompasses heterocycloalkyl groups and heterocycloalkenyl groups, each of which being optionally substituted as set forth below.

[0111] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[6]thk>pheneyl, 2-oxa-bicyclo{2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[33.1.0 ^3>7 ]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, which would be categorized as heteroaryls.

[0112] A "heterocycloalkenyr group, as used herein, refers to a mono- or bicylic (e.g., S- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S).

Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature.

[0113] A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatk, (cycloaliphatic)aliρhatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,

heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)

aliphatic)carbonylamino, (aryl)carbonylamino, (arak ^' phatfc)carbonylamino,

(heterocycloaliphatic )carbonylamino, ((heterocycloaliphatic) aliphatic )carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic )carbonyl,

((cycloaliphatic) aliphatk)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0114] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to IS ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, bcnzo[fr]furyl, benzo[l>]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, IH- indazolyl, furyl, pyrrolyl thknyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, bcnzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[b]ruryl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

[0115] Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 13,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

[0116] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzoφjfuryl, benzo(fr]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[fr]furyl, bexo[2>]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H*quinolizyI, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, orpteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

[0117] A heteroaryl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, allcenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;

heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;

(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; hcteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [ e.g., aliphaticcarbonyl; (cycloaliρhatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;

(araliphatkOcarbonyl; (heterocydoaliphatic)carbonyl;

((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatksulfonyl or aminosulfonyl]; sulflnyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g.. aliphaticsulfanyl); nitro; cyano; halo; hydroxy; mcrcapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, a heteroaryl can be unsubstituted.

[0118] Non-limiting examples of substituted heteroaryls include (hak>)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)hcteroaryl and

((dialkyl)amino)heteroaryl3; (amido)heteroaryl [e.g., aminocarbonylheteroaryl,

((allcylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl^ieteroaryl,

(((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)hcteτoaryl, and ((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl;

(sulfamoyl)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,

(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl;

(hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl;

(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl;

(((alkylsulfonyl)amiiκ))alkyl)hcteroaryl; ((alkylsulfonyl)alkyl)heteioaryl;

(cyanoalkyl)heteroaryl; (acyl)heferoaryl [e.g., (alkykarbonyl)heteroaryl]; (alkyl)heteroaryl; or (haloalkyl)heteroaryi [e.g., trihaloalkylheteroaryl].

[0119] A "heteroaraliphaϋc (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a C _1-4 alkyl group) that is substituted with a heteroaryl group.

"Aliphatic," "alkyl," and "heteroaryl" have been defined above.

[0120] A "heteroaralkyr group, as used herein, refers to an alkyl group (e.g., a C _1-4 alkyl group) that is substituted with a heteroaryl group. Bom "alkyl" and "heteroaryl" have been defined above. A heteroaralkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloaQcyloxy, hcterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,

alkylcarbonyloxy, aminocarbonyt alkylcarbonylamino, cycloalkylcarbonylamino,

(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,

(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,

heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0121] As used herein, "cyclic moiety" and "cyclic group" refer to mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined. [0122] As used herein, a "bridged bicyclic ring system" refers to a tricyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyc!o[3.2.1]octyl, bicyclo{2.2.2]octyl, bicyclo[33.1]nonyl, bicyclo{3.3.2]decyl, 2-oxabicyclo{2.2.2}octyl, l-azab-cyc!o{2.12]octyl, 3- azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyc!o[33.1.0 ^3>7 ]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl _t heterocycloalkyl, (heterocycloalkyOalkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,

heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,

(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,

(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,

heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0123] As used herein, an "acyl" group refers to a formyl group or R ^X -C(O>- (such as alkyl-C(OK also referred to as "alkylcarbonyl") where R ^x and "alkyl" have been defined previously. Acetyl and pivaloyl are examples of acyl groups.

[0124] As used herein, an "aroyl" or "heteroaroyl" refers to an aryl-C(O)- or a

heteroaryl-C(O)-. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.

[0125] As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been defined previously.

[0126] As used herein, a "carbamoyl" group refers to a group having the structure

-O-CO-NR ^X R ^Y or -NR ^X -CO-O-R ^Z , wherein R ^x and R ^γ have been defined above and R ^z can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

[0127] As used herein, a "carboxy" group refers to -CXX)H, -COOR*, -OC(O)H,

-OC(O)R ^X , when used as a terminal group; or -OC(O)- or -C(O)O- when used as an internal group.

[0128] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group -CF ₃ .

[0129] As used herein, a "mercapto" group refers to -SH. [0130] As used herein, a "sulfo" group refers to -SOjH or -SO ₃ R* when used terminally or -S(O) ₃ - when used internally.

[0131] As used herein, a "sulfamide" group refers to the structure -NR ^X -S(O) ₂ -NR ^Y R ^Z when used terminally and -NR ^X -S(O) ₂ -NR ^Y - when used internally, wherein R ^x , R ^γ , and R ^z have been defined above.

[0132] As used herein, a "sulfamoyl" group refers to the structure -O-S(O)rNR ^Y R ^z wherein R ^γ and R ^z have been defined above.

[0133] As used herein, a "sulfonamide" group refers to the structure -S(O)rNR ^x R ^Y or -NR ^x -S(O)rR ^z when used terminally; or -S(0)rNR ^x - or -NR ^X -S(O) ₂ - when used internally, wherein R ^x , R ^γ , and R ^z are defined above.

[0134] As used herein a "sulfanyl" group refers to -S-R ^x when used terminally and -S- when used internally, wherein R ^x has been defined above. Examples of sulfanyls include aliphatic-S-, cycloaliphattc-S-, aryl-S-, or the like.

[0135] As used herein a "sulfinyl" group refers to -S(O>R ^X when used terminally and - S(O)- when used internally, wherein R ^x has been defined above. Exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl-S(O)-, beterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like.

[0136] As used herein, a "sulfonyl" group refers to-S(O)rR ^x when used terminally and S(Oh- when used internally, wherein R ^x has been defined above. Exemplary sulfonyl groups include aliphatic -S(O) ₂ -, aryl-S(O)r, (cycloaliphatic(aliphatic))-S(O)2-,

cycloaliphatic-S(O)2-. heterocycloaliphatic-S(O)r, heteroaryl-S(O)r.

(cycloaliphatic(amido(aiiphatic)))-S(0)2-or the like.

[0137] As used herein, a "sulfoxy" group refers to -O-SO-R ^X or -SO-O-R ^X , when used terminally and -OS(O)- or -S(O)-O- when used internally, where R ^x has been defined above.

[0138] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

[0139] As used herein, an "alkoxycarbonyl," which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O-C(O)-.

[0140] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.

[0141] As used herein, a "carbonyl" refer to -C(O)-.

[0142] As used herein, an "oxo" refers to =O.

[0143] As used herein, the terra "phospho" refers to phosphinates and phosphonates.

Examples of phosphinates and phosphonates include -P(OXR^, wherein R ^p is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaltphatic)oxy, (hetcrocycloaliphatic)oxy aryl hcteroaryl, cycloaliphatic or amino.

[0144] As used herein, an "aminoalkyl" refers to the structure (R ^x )}N-alkyl-.

[0145] As used herein, a "cyanoalkyl" refers to the structure (NC>-alkyl-.

[0146] As used herein, a "urea" group refers to the structure -NR ^X -CO-NR ^Y R ^Z and a

"thiourea" group refers to the structure -NR ^X -CS-NR ^Y R ^Z when used terminally and

-NR ^X -CO-NR ^Y - or -NR ^X -CS-NR ^Y - when used internally, wherein R ^x , R ^γ , and R ^z have been defined above.

[0147] As used herein, a "guamdine" group refers to the structure -N=C(N(R ^X R ^Y ))N(R ^X R ^Y ) or -NR ^X -C(=*NR ^X )NR ^X R ^Y wherein R ^x and R ^γ have been defined above.

[0148] As used herein, the term "amidino" group refers to the structure -C=(NR ^X )N(R ^X R ^Y ) wherein R ^x and R ^γ have been defined above.

[0149] In general, the term "vicinal" refers to the placement of substituents on a group mat includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.

[0150] In general, the term "gcminal" refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.

[0151] The terms "terminally" and "internally" refer to the location of a group within a substituent A group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure. Carboxyaikyl, i.e., R^OC-allcyl is an example of a carboxy group used terminally. A group is internal when the group is present in the middle of a substituent of the chemical structure. Alkylcarboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0152] As used herein, an "aliphatic chain" refers to a branched or straight aliphatic group

(e.g., aHcyl groups, alkenyl groups, or alkynyl groups). A straight aliphatic chain has the structure -[CH ₂ J,-. where v is 1-12. A branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain has the structure -[CQQ]v where Q is independently a hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above. [0153] The phrase "optionally substituted" is used interchangeably with the phrase

"substituted or unsubstituted." As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables Ri, R ₂ , R'2, Ra, R4, and other variables contained in Formula described herein encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables Ri, R ₂ , R'2, R3, Rt, and other variables contained therein can be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatjc, heteroaryl, haloalkyl, and alkyl. For instance, an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkxoy groups can form a ring together with the atom(s) to which they are bound.

[0154] In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be cither the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclk ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

[0155] The phrase "stable or chemically feasible," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0156] As used herein, an "effective amount" is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.

[0157] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single

stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds dut differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³ C- or ^M C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.

[0158] Chemical structures and nomenclature are derived from ChemDraw, version 11.0.1 , Cambridge, MA.

[0159] As used herein, the terms "first", "second", and/or "diird" do not refer to order or denote relative positions in space or time, but these terms are used to distinguish between two different elements or components. For example, a first solvent does not necessarily proceed a second solvent in time or space; however, the first solvent is not the second solvent and vice versa. Although it is possible for a first solvent to proceed a second solvent in space or time, it is equally possible that a second solvent proceeds a first solvent in space or time.

[0160] Π. DESCRIPTIONS OF NOVEL CRYSTALLINE FORMS OF

MΠΌGLΓΓAZONE AND METHODS OF PREPARAΉON [0161] The present invention provides novel crystalline forms of Mitoglitazone. For example, in one embodiment, the novel crystalline form of Mitoglitazone is Form I, Form II, Form IQ, Form IV, Form V, or amorphous Mitoglitazone. In another example, the novel crystalline form of Mitoglitazone is Form ED, Form IV, Form V, or amorphous

Mitoglitazone. The present invention further provides processes for preparation of Form I, Form π, Form IH, Form IV, Form V, and amorphous Mitoglitazone each of which is substantially free of other polymorphic forms.

[0162] A. Form I of Mitoglitazone

[0163] According to one embodiment of the present invention there is provided crystalline Form I of Mitoglitazone, substantially free of other forms of Mitoglitazone, which is characterized by X-ray powder diffraction (XRH)), Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared (FTIR) spectroscopy.

[0164] In several embodiments, Form I is characterized by an XRPD pattern comprising peaks having a relative intensity of 10% or greater and a 2-Thcta value of greater man 8.

[0165] In several embodiments, Form I is characterized by an XRFD pattern comprising the peaks provided in Table Ia:

[0166] In another embodiment, Form I is characterized by an XRPD pattern comprising the peaks provided in Table Ib:

[0167] In another embodiment, Form I is characterized by an XRPD pattern comprising the peaks provided in Table Ic:

[0168] In another embodiment, Form I is characterized by an XRFD pattern comprising the peaks provided in Table Id:

[0169] Another exemplary XRFD pattern of Form I, provided in FIG. 1, has the following peaks as shown in Table Ie.

[0170] DSC of pure crystalline Form I of Mitoglitazone exhibits a single endotherm in Ae range of from about 140 °C to about 150 °C (e.g., from about 145 °C to about 147 ⁰ Q as depicted in FIG. 2. An FTIR Spectrum of pure crystalline Form I of Mitoglitazone shows absorbance peaks at about 33172, 3080, 2964, 1757, 1718, 1703, 1608, 1587, 1514, 1326, 1249, 1224, 1205, 1166, 1153, 995 cm ^'1 , as depicted in FIG. 3. Water content in these exemplary samples was measured to be in the range of 0.2- 1.5 % as determined by the Karl-Fischer method.

[0171] Another embodiment of the present invention provides a process for the preparation of crystalline Form I of Mitoglitazone substantially free of other forms of Mitoglitazone comprising the steps of:

a. mixing Mitoglitazone with a first solvent at a first temperature to generate a first mixture (e.g., a solution);

b. optionally, filtering the first mixture (e.g., a first solution) of step a; c. optionally, adding a second solvent to the mixture (e.g., a first solution) of step a or the filtrate of step b to generate a second mixture (e.g., a second solution); and

d. cooling and stirring the first mixture (e.g., solution) of step a, the filtrate of step b, or the second mixture (e.g., solution) of step c to a second temperature to generate solids, wherein the first temperature is higher than the second temperature.

[0172] Some procedures may optionally include additional steps such as isolating the solids, drying the solids, or otherwise processing the solids to produce the desired form of Mitoglitazone. For example, the solids may be filtered from the first mixture of step a, the filtrate of step b, or the second mixture of step c.

[0173] The first solvent is selected based on the solubility of Mitoglitazone at temperatures of from about 25 °C to about 100 °C. In some embodiments, dissolution is obtained at a reflux temperature of the solvent [0174] Suitable first solvents include, for example, aliphatic alcohols, aliphatic ketones, aliphatic nitriles, chlorinated hydrocarbons, C5.7 cyclic aliphatic ethers, and/or aliphatic esters. In several embodiments, alcohols are selected from C _1-4 alcohols such as, for example, ethanol, isopropyl alcohol, or a combination thereof. In other embodiments, ketones are selected from Ci^ ketones such as, for example, acetone, 2-butanone, diethyl ketone, or any combination thereof. In some

embodiments, nitriles are selected from C _1-4 nitriles such as, for example, acetonitrile and propionhrile. In some embodiments, chlorinated hydrocarbons are selected from Ci- ₃ alkyl chlorides such as, for example, methylene dichloride, ethylene dichloride, carbon tetrachloride and chloroform. In some embodiments, cyclic aliphatic ethers are selected from, for example, tetrahydrofuran and 1 ,4-dioxane. In some

embodiments, aliphatic esters are selected from Q ₄ esters such as, for example, methyl acetate, ethyl acetate and butyl acetate. Mixtures of these solvents are also contemplated (e.g., mixtures of aliphatic alcohols, aliphatic ketones, aliphatic nitriles, chlorinated hydrocarbons, cyclic aliphatic ethers, aliphatic esters, or any combination thereof).

[0175] The mixing can be performed at a first temperature of from about 25 °C to about 100 °C. In some instances, the first temperature is the reflux temperature of the solvent or solvent system selected. The dissolution temperature in the first solvent is dependent on the solubility of Mitoglitazone in the solvent In some embodiments, dissolution may be at ambient temperature (e.g., from about 25 °C to about 30 °C) while in other embodiments dissolution is at the reflux temperature of the solvent (e.g., from about 80 °C to about 100 °C).

[0176] In one embodiment, Mitoglitazone is dissolved in a first solvent at a temperature of from about 25 °C to about 100 °C or at the reflux temperature of the solvent selected. The solution may be optionally filtered to remove insoluble impurities, then cooled to a temperature of from about 25 °C to about 30 °C followed by stirring at the same temperature for about 4 to 5 hrs to generate solids. The solid may be optionally collected and optionally dried at a temperature of about 60 °C (e.g., from about 55 °C to about 65 ⁰ Q to obtain Mitoglitazone Form L

[0177] In another embodiment, Mitoglitazone is dissolved in a first solvent at a temperature of from about 25 °C to about 100 °C, the solution is optionally filtered to remove insoluble impurities, a second solvent is added, the mixture then cooled as appropriate and stirred at a temperature of from about 25 °C to about 30 °C for a period of from about 4 to about S hrs.

[0178] Selection of the optional second solvent is based on low solubility of Mitoglitazone in the second solvent and miscibility of the second solvent with the first solvent In certain embodiments, the second solvent may be selected from aliphatic or aromatic hydrocarbons. In some embodiments, the second solvent is selected from aliphatic ethers. In other embodiments, the second solvent is water. Aliphatic hydrocarbons include, for example, pentane, hexane, heptane, or any combination thereof. Aromatic hydrocarbons include, for example, toluene, xylene, or any combination thereof. Aliphatic ethers include, for example, diethyl ether, raethyl-f- butyl ether, dϋsopropyl ether, or any combination thereof. Mixtures of the second solvents are contemplated (e.g., aliphatic ethers, water, aliphatic hydrocarbons, aromatic hydrocarbons, aliphatic ethers, or any combination thereof).

[0179] In a further embodiment, there is provided another process for the preparation of Mitoglitazone Form I that comprises conversion of any Form of Mitoglitazone by drying at elevated temperature. In some embodiments, any Form of Mitoglitazone is dried at a temperature of from about 70 °C to about 100 °C, or from about 80 °C to about 90 °C, for a period of from about 6 to about 26 hrs (e.g., from about 10 hours to about 16 hours, or about 12 hrs).

[0180] B. Form II of Mitoglitazone

[0181] According to another embodiment, the present invention provides crystalline Form π of Mitoglitazone substantially free of other forms of Mitoglitazone as characterized by XRFD, DSC and FTlR. The monohydrate nature of crystalline Form Q was confirmed by a water content in the range of about AS- 6.5%, as determined by the Karl Fischer method.

[0182] One exemplary XRFD pattern of Form π of Mitoglitazone shows peaks having a relative intensity of greater than 15% for 2-Theta values of greater than 9.

[0183] One exemplary X-Ray diffraction pattern has the following peaks shown in Table 2a.

[0184] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 2b.

[0185] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 2c.

[0186] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 2d.

[0187] Another exemplary X-Ray diffraction pattern, provided in FIG.4, has the following peaks shown in Table 2e.

[0188] I)SC of pure ciystalline Form π of Mitoglitazone shows two cndotherms: one endothcrm located at a temperature from about 80 °C to about 100 °C and a second endotherm located at a temperature of from about 145 °C to about 148 °C as depicted in FIG. 5. An FTIR spectrum of crystalline pure Form JI of Mitoglitazone shows absorptions at 3394, 3159, 3070, 2966, 2783, 1751, 1720, 1703, 1510, 1245, 997, 831, 707, 655, and 569. An FTIR spectrum of crystalline pure Form π of Mitoglitazone shows absorptions at 3394, 3159, 3070, 2966, 2783, 1751, 1720, 1703,1608, 1510, 1298, 1245, 1153, 997, 831, 738, 707, and 655 cm ¹ as depicted in HG.6.

[0189] According to another embodiment, the present invention provides a process for preparation of crystalline Form O of Mitoglitazone, substantially free of other crystalline forms of Mitoglitazone, comprising:

a. mixing Mitoglitazone with a first solvent at a first temperature to generate a first solution;

b. optionally, filtering the first solution of step a to generate a filtrate; c. optionally, adding a second solvent, which is miscible with the first solvent, to the first solution of step a or the filtrate of step b to generate a second solution; and

d. coolmg ami stiiTύig the first 8olutk>n of step a, the filtrate of step b, or the second solution of step c to a second temperature to generate solids, wherein the first temperature is higher than the second temperature. [0190] In some embodiments, the first solvent comprises water. For example, the first solvent has a water content of less than 25 % water by volume. In other examples, the first solvent comprises from about IS % to about 5 % (e.g., about 10 %) water by volume.

[0191] In some embodiments, the second temperature is from about 25 °C to about 30 °C. And, in some embodiments, the first temperature is from about 50°C to about 10O°C (e.g., from about 50 °C to about 90 °C, or from about 60 °C to about 80 ⁰ Q. In other embodiments, the first temperature is the reflux temperature of the first solvent [0192] The first solvent is selected from aliphatic alcohols, ketones, nitrites, chlorinated hydrocarbons and cyclic ethers or mixtures thereof, as described for the Form I polymorph. However, in some instances, the first solvent contains water in the range of from about 1-15 % by volume. The dissolution is carried out preferably at a temperature of from about 25°C to about 100 °C or, in some embodiments, at the reflux temperature of the solvent selected for dissolution.

[0193] In one embodiment, Mitoglitazone is combined with solvent and the mixture refluxed for a period of from about 15 to about 20 minutes to obtain dissolution, optionally filtering the mixture, men cooling to a temperature of from about 25 °C to about 30 °C. The mixture is stirred for about 4 to 5 hrs, and the resulting solids may undergo additional processing as mentioned above. For instance, the solids may be filtered, collected, and/or dried at about 60 °C to obtain Mitoglitazone Form II.

[0194] In another embodiment, Mitoglitazone Form O, substantially free of other forms of Mitoglitazone, is prepared by dissolving Mitoglitazone in a first solvent at a temperature of from about 25 °C to about 100 °C (e.g., from about 50°C to about 90°C, or from about 60°C to about 80 ⁰ Q, optionally filtering the mixture, adding a second solvent, and stirring the mixture at a temperature of from about 25 °C to about 30 °C for a period of from about 4 hours to about 5 hrs. The solids are collected and dried at about 60 °C to obtain Mitoglitazone Form IL

[0195] In another embodiment Mitoglitazone is combined with solvent at reflux temperature. The solution is refluxed for about 15 to 20 minutes to obtain a clear solution. The hot solution is filtered to remove insolubles and cooled to a temperature of about 25 °C to about 30 °C. The second solvent is added and the mixture is stirred at this temperature for from about 4 hrs to about 5 hrs. The separated solids are filtered then dried at about 60 °C to obtain Mitoglitazone Form IL [0196] In a further embodiment, a process for preparing Mitoglitazone Form II comprises suspending Mitoglitazone Form I in water at a temperature of about 65 °C

(e.g., from about 60 °C to about 70 °C) for a period of about 3 hrs, stirring the suspension for a period of from about 6 hrs to about 12 hrs at a temperature of from about 25 °C to about 30 °C, collecting and drying the solids at a temperature of about 60 °C for a period of from about 3 to about 24 hrs (e.g., from about 10 hrs to about 16 hrs, or about 12 hrs).

[0197] C. Form III of Mitoglitazone

[0198] According to another embodiment of the present invention there is provided

Form III of Mitoglitazone characterized by XRFD, DSC, and FTIR. The anhydrous nature of Form m was confirmed by water content in the range of 02- 1.5%, as determined by the Karl Fischer method.

[0199] One exemplary X-Ray diffraction pattern includes peaks having a relative intensity of greater than 20% at 2-Theta values of greater than 9.

[0200] One exemplary X-Ray diffraction pattern has the following peaks shown in

Table 3a.

[0201] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 3b.

[0202] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 3c.

[0203] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 3d.

[0204] Another exemplary X-Ray diffraction pattern, provided in FIG. 7, has the following peaks shown in Table 3c.

[0205] DSC of crystalline Foπn ID of Mitoglitazonc shows two endothcrms, provided in FIG. 8, wherein one endotherm occurs at a temperature of from about 126 °C to about 129 °C and a second endotherm occurs at a temperature of from about 142 °C to about 145 °C. An FTIR Spectrum, shown in FIG.9, of crystalline Form HI of Mitoglitazonc shows absorptions at 3143, 3031, 2976, 2933, 1743, 1705, 1608, 1587, 1569, 1510, 1440, 1415, 1330, 1296, 1249, 1178, 1153, 1109, 991, 935, 877, 825, 752, and 713 cm ¹ .

[0206] According to another embodiment of the present invention, a process for the preparation of Form in of Mitoglitazone comprising the steps of:

a. mixing Mitoglitazone with a first solvent comprising an alcohol at a first temperature to generate a first solution;

b. optionally, filtering the first solution of step a to generate a filtrate; and c. cooling and stirring the first solution of step a or the filtrate of step b to a second temperature to generate solids, wherein the first temperature is higher than the second temperature. [0207] In several embodiments, the first solvent comprises an alcohol, and the alcohol comprises methanol, ethanol, 1-propanol, 2-propanol (IPA), or any

combination.

[0208] In other embodiments, the first temperature is from about 55 °C to about 65 °C. In other embodiments, Ae first temperature is from about 60 °C to about 70°C.

[0209] In some embodiments, the second temperature is from about 5 °C to about 10 °C.

[0210] In some embodiment, the process further comprises drying the solids at a temperature of from about 50 °C to about 70 °C.

[0211] In some processes, the Mitoglitazone of step a comprises Mitoglitazone

Form I, Form π, or any combination thereof.

[0212] In another embodiment, a process for preparation of Mitoglitazone Form in comprises the steps of:

a. mixing Mitoglitazone (e.g., Form I or Form H) in methanol at reflux temperature to generate a mixture;

b. optionally, filtering the mixture of step a to generate a filtrate;

c. cooluTg α^ muture ofstep aor the filtrate of step b to a temperature of from about 5 °C to about 10 °C and stirring for about 1 to about 5 hrs at this temperature;

d. optionally, collecting the solids; and

e. optionally, drying the solids at a temperature of about 60 °C.

[0213] D. Form IV of Mitoglitazone

[0214] According to another embodiment of the present invention there is provided

Form IV of Mitoglitazone characterized by XRFD, DSC and FTIR. The monohydratc nature of crystalline Form IV was confirmed by water content, which is in the range of 4.5-6.5%, as determined using the Karl Fischer method.

[0215] One exemplary X-Ray diffraction pattern shows peaks having relative intensities of greater than 20% for values of 2-Theta greater than 13.5.

[0216] One exemplary X-Ray diffraction pattern has the following peaks shown in

Table 4a.

[0217] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 4b.

[0218] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 4c.

[0219] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 4d.

[0220] Another exemplary X-Ray diffraction pattern, provided in FIG. 10, has the following eaks shown in Table 4e.

[0221] DSC, provided in FIG. 11, of crystalline Form IV of Mitogiitazone shows two endotherms at temperatures of from about 80 °C to about 95 °C and from about 146 °C to about 150 °C. FITR Spectrum, provided in FIG. 12, of crystalline Form IV of Mitogiitazone shows absorptions at 3504, 3051, 2941, 2910, 1751, 1695, 1512, 1240, 993, 877, 839, 792, 669 cm' ¹ . The monohydrete nature of Form IV is confirmed by a water content of 45-65%, as determined by the Karl Fischer method.

[0222] Another embodiment of the present invention provides a process lor the

preparation of Form IV of Mitoglitazone substantially free of other crystalline forms of Mitoglitazone comprising the steps of:

a. dissolving Mitoglitazone in a first solvent comprising alcohol at a first temperature to generate a first solution;

b. optionally, filtering the first solution of step a to generate a filtrate; and c. cooling and stirring the first solution of step a or the filtrate of step b at a second temperature to generate solids,

wherein the first temperature is higher than the second temperature.

[0223] In several embodiments, the second temperature is from about -60 °C to

about O°C.

[0224] Other embodiments further comprise drying the solids at a temperature of from about 20 °C to about 30 °C.

[0225] In another embodiment, the first solvent comprises methanol, ethanol, 1 - propanol, 2-propanol, or any combination thereof.

[0226] In still another embodiments, the Mitoglitazone of step a comprises

Mitoglitazone Form I.

[0227] According to another embodiment of the present invention there is provided a process for preparation of Mitoglitazone Form IV comprising the steps of:

a. dissolving Mitoglitazone in a first solvent comprising alcohol at reflux temperature to generate a solution;

b. optionally, filtering the mixture of step a to generate a filtrate;

c. cooling the solution of step a or the filtrate of step b to a temperature of about -60 °C and stirring for about 1 to 2 hrs at this temperature;

d. optionally, collecting the solids; and

e. optionally, drying the solids at a temperature of from about 25 to about 30 °C.

[0228] The solvent is selected from a group consisting of alcohols. The alcohols are selected from methanol, ethanol, 1 -propanol, 2-propanol (IPA) or mixtures thereof.

The dissolution is sometimes performed at a temperature of from about 55 to about

65 °C.

[0229] E. Form V of Mitoglitazone [0230] According to another embodiment of the present invention there is provided

Form V of MitogHtazone characterized by XRFD, DSC and FTIIL The Sesquihydrate nature of crystalline Form V is confirmed by its water content of 6.0-7.5%, as determined by the Karl Fischer method.

[0231] One exemplary X-Ray diffraction pattern shows peaks having relative intensities of greater man 9% for 2-Theta values greater than 9.

[0232] One exemplary X-Ray diffraction pattern has the following peaks shown in

Table 5a.

[0233] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 5b.

[0234] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 5c.

[0235] Another exemplary X-Ray diffraction pattern has the following peaks shown in Table Sd.

[0236] Another exemplary X-Ray diffraction pattern, provided in FIG. 13, has the following peaks shown in Table 5e.

[0237] DSC ^stallinc Foπn V of Mitoglitazone shows three endotherms at temperatures from about 80 °C to about 85 °C, from about 95 °C to about 105 °C, and from about 146°C to about 150 °C, as provided in FlG. 14. The FTIR spectrum, provided in FIG. 15, of crystalline Form V of Mitoglitazone shows absorptions at 3568, 3500, 3388, 3151, 2968, 2788, 1753, 1699, !608, 1512, 1415, 1325, 1245, 995, 864, 794, 707 cm ¹ .

[0238] Another embodiment of the present invention provides a process for preparing Mitoglitazone Form V, which comprises exposing Mitoglitazone Form IV to an environment comprising 60-85% humidity at a temperature of from about 30 °C to about 50 °C for a period of from about 12 to about 72 hours (e.g., about 24 hours).

[0239] F. Amorphous Form of Mitoglitazone

[0240] According to another embodiment of the present invention there is provided a novel amorphous Form of Mitoglitazone characterized by XRFD, FTIR

spectroscopy and DSC.

[0241] The XRFD of amorphous Mitoglitazone exhibits a broad peak from about 10° to about 36° on a 2Θ scale as shown in FIG. 16. DSC of the amorphous Form Mitoglitazone shows an exotherm at from about 90 °C to about 110 °C and an endotherm at from about 146 °C to about 15O°C, as provided in FIG. 17. An FTIR spectrum, provided in FIG. 18, of amorphous Mitoglitazone shows absorptions at 2970, 2781, 1753, 1697, 1608, 1510, 1325, 1301, 1180, 977, 827, 705 cm ¹ .

[0242] Another embodiment of the present invention provides a process for preparing an amorphous form of Mitoglitazone which comprises the steps of;

a. heating Mitoglitazone to obtain a melt; and

b. cooling the melt to obtain amporphous Mitoglitazone.

[0243] In an embodiment, Mitoglitazone is heated to a temperature of from about 140 °C to about 170 °C (e.g. from about 155 °C to about 165 °C, or about 160°C) to obtain a melt Cooling the melt to a temperature of from about 10 °C to about 30 °C, or from about 15 °C to about 20 °C provides amorphous Mitoglitazone. [0244] Another embodiment of the present invention provides a process for preparing amorphous Mitoglitazone which comprises the steps of:

a. dissolving Mitoglitazone in a suitable solvent;

b. optionally, filtering the solution of step a; and

c. spray drying the obtained solution to provide amorphous Mitoglitazone.

[0245] The suitable solvent comprises alcohols such as, for example, methanol and ethanol; or ketones, such as, for example, acetone, or mixtures thereof. The concentration of Mitoglitazone used in spray drying is from about S % to about 25 % (e.g., about 20 %) by weight

[0246] In some embodiments, dissolution is performed at temperature of from about

20 °C to about 40 °C (e.g., about 30 ⁰ Q. In other embodiments, the spray drying is performed with an inlet temperature of from about 40 °C to about 140 °C and an outlet temperature of from about 35 °C to about 85 °C. In one embodiment,

Mitoglitazone is combined with solvent at a temperature of about 50 °C, the solution is filtered, and spray dried with an inlet temperature of about 12O°C and an outlet temperature of about 65 °C.

[0247] G. Exemplary Embodiments

[0248] Mitoglitazone obtained according to the present invention may be

micronized using conventional πϋcronization techniques to have a particle size d» less than 200 micron (e.g., less than 100 microns, less than 50 microns, less than 30 microns, less man 20 microns, or less than 10 microns).

[0249] Mitoglitazone used for the preparation of polymorphs of Mitoglitazone is selected from crude or pure or any polymorphic form of Mitoglitazone having less than 0.15% of N-methylsulphide (A), less than 0.15% of keto benzylidene (B), keto benzaldehyde (C) less than 0.15%, Mito alcohol (D) (Structure 4) less man 0.15% and dimer impurities less than 0.15%.

[0250] The dimer impurities are detected at an RRT (relative retention time) of about 1.473 and 1.485 (by HPLC) having M+l = 739.30.

[0251] Another embodiment of the present invention provides pharmaceutical compositions comprising crystalline forms of Mitoglitazone or its amorphous form along with a pharmaceutically acceptable carrier (e.g., one or more pharmaceutically acceptable excipients). The pharmaceutical compositions may be prepared by conventional techniques known in the art [0252] The novel polymorphs of Mitoglitazone are characterized by X-ray powder diffraction. X-ray powder diffraction pattern has been obtained on XperfPRO,

Panalytical, diffractometer equipped with accelerator detector using Copper Ka (it =

1.5406 A) radiation with scanning range between 4-50 °C at a scanning speed of

2 °C /rain.

[0253] Differential Scanning Caloriroetry was performed on Diamond DSC of

Perkin Elmer instrument Samples of 2 mg to 3 mg weighed in aluminum crucibles with holes were scanned at a heating rate of 10 °C per minute under nitrogen atmosphere at rate of 35 ml/min.

[0254] The FTIR spectra were obtained on a Shimadzu FTIR 8300 m the range of

400-4000 cm ^"1 with a resolution of 4 cm ¹ .

[0255] m. EXAMPLES

[0256] The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0257] Example 1: MϊtogUtazone by JΛfed.Chem. Method

[0258] Preparation 1: Mitoglitazone by JMecLChem. Method

[0259] 450 ml methylene chloride was added to a solution of 2Og 5-(4-<2-(5- ethylpyridin-2-yl)-2-hydroxvcthoxy)bcnzyl)-l,3-thia2θlidine -2,4-dione in warm 50 ml

DMSO. The resultant solution was cooled in ice water and 14. Ig P ₂ Os was added in three portions over 30 minutes followed by addition of 19-5 ml of triemylamine. The mixture was allowed to stir for 2 hr at 25-30 °C and then concentrated under vacuum.

The residue obtained was dissolved in THF. The pH of the solution was adjusted to 1 with 6N aqueous HO. The solution was allowed to stir at 25-30 °C for 1 hr. The solution was neutralized to pH 7 with sodium bicarbonate. The mixture was extracted with ethyl acetate to get sticky oil as crude Mitoglitazone. The crude Mitoglitazone thus obtained was purified by Column chromatography on a column of Silica gel using methylene dichloride and acetone (90: 10). The fraction after concentrating under vacuum afforded 25 g solid whose XRPD, as shown in FIO. 19.

[0260] Example 2: MltogUtazone by Org. Pro. Reg. & Dev. Procedure

[0261] Preparation 2: Mitoglitazone by Org. Pro. Res. & Dev. Procedure

[0262] 152g of P ₂ Os was added to a dry TL round bottomed flask followed by addition of 640 ml methylene chloride. The slurry obtained was cooled to 0 °C. A solution of 80 g 5-(4-(2-(5-emylpyridin-2-yl)-2-hydroxyethoxyM)enzyl)-l,3- diiazolkϋne-2,4-dione in 152 ml DMSO was added dropwise maintaining an internal temperature 0 °C then stirred for IS min. DIFEA, 112 mL, was then added dropwise maintaining 0 °C. After 45 minutes the reaction mixture was poured into t.2Lof water. The mixture was extracted with ethyl acetate (80OmL x 3). The combined organic layers were washed with water and the solvent was removed under vacuum to provide 80 g of residue which was crystallized from 2L ethanol to obtain 26 g of Mitoglitazone with K _f : 4.9%, whose XRPD is provided in FIO.20.

[0263] Example 3: Mitoglitazone from Aqueous Ethanol

[0264] Mitoglitazone from Aqueous Ethanol

[0265] 10 g of residue obtained by following Preparation 2 route was dissolved in 50 mL of 95% aqueous ethanol at reflux to obtain a clear solution. The solution was cooled to 30-35 °C and the resultant precipitate filtered. The wet solid obtained was characterized as shown in FIG. 21.

[Φ266] Example 4A: Mitoglitazone Form I

05 g Mitoglitazone was dissolved in 10 ml IPA at reflux temperature. The solution was refiuxed to get clear solution for 15*20 minutes. The hot solution was filtered and cooled to 25-30 °C. The solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 80 °C to get Mitoglitazone Form I.

[0267] Example 4B: Mitoglitazone Form I

[0268] 0.5 g Mitoglitazone was dissolved in 10 ml n-propanol at reflux temperature. The solution is refiuxed to get clear solution 15-20 minutes. The hot solution was filtered and cooled to 25-30 °C followed by stirring at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 80°C to get Mitoglitazone Form I.

[0269] Example 4C: Mitoglitazone Form I

[0270] 1 g Mitoglitazone is dissolved in 15 ml acetone at reflux temperature. The solution is refiuxed to get clear solution 15-20 minutes. The hot solution is filtered and cooled to 25-30 °C. The solution is stirred at the same temperature for 4-5 hrs. The separated solid is filtered and dried at 80 °C to get Mitoglitazone Form I.

[0271] Example 4D: Mitoglitazone Form I

[0272] 1 g Mitoglitazone was dissolved in 12 ml acetonitrile at reflux temperature. The solution was refiuxed to get clear solution 15-20 minutes. The hot solution was filtered and cooled to 25-30 °C. The solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 80 °C to get Mitoglitazone Form I.

[0273] Example 4E: Mitoglitazone Form I [0274] 0.5 g Mitoglitazone was dissolved in 10 ml ethyl acetate at reflux temperature. The solution is refluxed to get clear solution 15-20 minutes. The hot solution was filtered and cooled to 25-30 °C. The solution was stirred at the same temperature for 4-5hrs. The speared solid was filtered and dried at 80 °C to get Mitoglitazone Form L

[0275] Example 4F: Mitoglitazone Form I

[0276] 1 g Mitoglitazone was dissolved in 10 ml methylene dichloride (MDC) at reflux temperature and the solution was refluxed 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. The solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 80 °C to get Mitoglitazone Form L

[0277] Example 4G: Mitoglitazone Form I

[0278] 1 g Mitoglitazone was dissolved in 20 ml ethanol at reflux temperature. The solution was refluxed 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C.40 ml n-hexane was added to the obtained clear solution and the solution was stirred at 25-30 °C temperature for 4-5 hrs. The separated solid was filtered and dried at 80°C to get Mitoglitazone Form L

[0279] Example 4H: Mitoglitazone Form I

[0280] 1 g Mitoglitazone was dissolved in 8 ml acetone at reflux temperature. The solution was refluxed 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. 50 ml n-hexane was added to the obtained clear solution and the solution was stirred at 25-30 °C for 4-5 hrs. The separated solid was filtered and dried at 80 °C to get Mitoglitazone Form L

[0281] Example 41: Mitoglitazone Form I

[0282] 1 g Mitoglitazone was dissolved in 10 ml isopropyl alcohol (IPA) at 25-30 °C. The solution was filtered and 30 ml n-hexane was added to this clear solution and the solution was stirred at 25-30 °C for 4-5 hrs. The separated solid was filtered and dried at 80°C to get Mitoglitazone Form I.

[0283] Example 4J: Mitoglitazone Form I

[0284] 1 g Mitoglitazone was dissolved in 10 ml acetone at reflux temperature. The solution was refluxed 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C.40 ml toluene was added to the obtained clear solution and the solution was stirred at 25-30 °C for 4-5 hrs. The separated solid was filtered and dried at 8O°C to get Mitoglitazone Form I. [0285] Example 4K: Mitoglitazone Form I

[0286] I g Mitoglitazone Form II was dried at a temperature 90 °C fOT 12 hrs to obtain Mitoglitazone Form I.

[0287] Example 5A: MltogUtazooe Form π

[0288] 1 g Mitoglitazone was dissolved in IS ml 10% aqueous ethanol at reflux temperature. The solution is refluxed for 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. The solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitoglitazone Form II.

[0289] Example 5B: Mitoglitazone Form II

[0290] 1 g Mitoglitazone was dissolved in 25 ml 10% aqueous isopropyl alcohol (IPA) at reflux temperature. The solution was refluxed for 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. The solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitoglitazone Form BL

[0291] Example 5C: Mitoglitazone Form II

[0292] 1 g Mitoglitazone was dissolved in 10 ml 10% aqueous acetone at reflux temperature. The solution was refluxed for 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. The solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitoglitazone Form BL

[0293] Example 5D: Mitoglitazone Form U

[0294] 1 g Mitoglitazone was dissolved in 25 ml 10% aqueous acetonitrile at reflux temperature. The solution was refluxed for 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. The solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitoglitazone Form BL

[0295] Example 5E: Mitoglitazone Form H

[0296] 1 g Mitoglitazone was dissolved in 15 ml 10% aqueous tetrahydrofuran (THF) at reflux temperature. The solution was refluxed for 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. The solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitoglitazone Form π.

[0297] Example 5F: Mitoglitazone Form III [0298] 1 g Mitoglitazone wais dissolved in 10 ml 10% aqueous 1,4-dioxane at

reflux temperature. The solution was rcfluxed for 15-20 minutes to get clear solution.

The hot solution was filtered and cooled to 25-30 °C. The solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitoglitazone Form IL

[0299] Example 5G: MHogtttazoαe Form II

[0300] 1 g Mitoglitazone was dissolved in 20 ml ethanol at reflux temperature. The solution was rcfluxed for 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. 40 ml water was added to this clear solution and the solution was stirred at 25-30 °C temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitoglitazone Form π.

[0301] Example 5H: MftogUtaxoαe Form U

[0302] 1 g Mitoglitazone was dissolved in 20 ml 2-propanol at reflux temperature. The solution was refluxed for 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. 40 ml water was added to mis clear solution and the solution was stirred at 25-30 °C temperature for 4-5 hrs. The separated solid was filtered and dried at 60 ° to get Mitoglitazone Form IL

[0303] Example 51: MttofjUtasone Form π

[0304] 1 g Mitoglitazone was dissolved in 20 ml emyl acetate at reflux temperature.

The solution was refluxed for 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. 40 ml n-hexane was added to the obtained clear solution and the mixture was stirred at 25-30 °C for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitoglitazone Form II.

[0305] Example 5J: Mltogtttaxoαe Form D

[0306] 1 g Mitoglitazone was dissolved in 20 ml MDC at reflux temperature. The solution was refluxed for 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. 40 ml n-hexane was added to the obtained clear solution and the solution was stirred at 25-30 °C temperature for 4-5 hrs. The

separated solid was filtered and dried at 60 °C to get Mitoglitazone Form II.

[0307] Example 5K: Mttoglttazoαe Form O

[0308] 1 g Mitoglitazone was dissolved in 10 ml MDC at reflux temperature. The solution was refluxed for 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 25-30 °C. 100 ml diisopropyl ether was added to the obtained clear solution and the solution was stirred at 25-30 °C for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitogiitazone Form IL

[0309] Example 5K: MttogUtanme Form II

[0310] 1 g Mitogiitazone was dissolved in 10 ml THF at 25-30 °C. The solution was filtered and to this clear solution 40 ml n-Hexane was added and the solution was stirred at 25-30 °C temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitogiitazone Form DL

[0311] Example 5L: MftogUtazooe Form II

[0312] 1 g Mitogiitazone was dissolved in 15 ml 1,4-dioxane at 25-30 °C. The solution was filtered and 40 ml n-hexane was added to the obtained clear solution.

The solution was stirred at 25-30 °C temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitogiitazone Form π.

[0313] Example 5M: MhogUtazone Form II

[0314] 1 g Mitogiitazone was dissolved in 10 ml THF at 25-30 °C. The solution was filtered and 40 ml water was added to the obtained clear solution and the solution was stirred at 25-30 °C temperature for 4-5 hrs. The separated solid was filtered and dried at 60°C to get Mitogiitazone Form II.

[0315] Example 5N: Mitogiitazone Form π

[0316] 1 g Mitogiitazone was dissolved in 15 ml 1,4-dioxane at 25-30 °C. The solution was filtered and 40 ml water is added to the obtained clear solution. The solution was stirred at 25-30 °C for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitogiitazone Form OL

[0317] Example 5O: Mltogjitaxooe Form II

[0318] I g Mitogiitazone Form I was suspended in 20 ml water at 65 °C for 3 hrs.

The solution was cooled 25-30 °C and stirred for 12 hrs and filtered. The isolated solid was dried at 60 °C to get Mitogiitazone Form BL

[0319] Example 6A: Mitøflltazone Form IU

[0320] 1 g Mitogiitazone Form II was dissolved in 15 ml methanol at reflux temperature. The solution was refluxed 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 5-10 °C. The obtained clear solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get Mitogiitazone Form QL

[0321] Example€B: MftogUtazone Form OI [0322] Ig Mitoglitazone Form I was dissolved in IS ml methanol at reflux

temperature. The solution was refluxed 15-20 minutes to get clear solution. The hot solution was filtered and cooled to 5-10 °C. The solution was stirred at the same temperature for 4-5 hrs. The separated solid was filtered and dried at 60 °C to get

Mitoglitazone Form HI.

[0323] Example 7A: Mitoglitazone Form IV

[0324] 1 g Mitoglitazone Form I was dissolved in 50 ml methanol at reflux temperature. The solution was refluxed 15-20 minutes to get clear solution. The hot solution was filtered and cooled to -60 °C. The solution was stirred at the same temperature for 1-2 hrs. The separated solid was filtered and dried at 25-30°C to get Mitoglitazone Form IV.

[0325] Example 7B: Mitoglitazone Form IV

[0326] 1 g Mitoglitazone Form I was dissolved in 70 ml methanol at reflux

temperature. The solution was refluxed 15-20 minutes to get clear solution. The hot solution was filtered and cooled to -60 °C. The solution was stirred at the same temperature for 1-2 hrs. The separated solid was filtered and dried at 25-30 °C to get Mitoglitazone Form IV.

[0327] Example 8: Mitoglitazone Form V

[0328] 5 g Mitoglitazone Form IV was exposed to 75% humidity for 24 hrs at 40 °C to obtain Mitoglitazone Form V.

[0329] Example 9A: Amorphous

[0330] 100 ml round bottomed glass flask containing 2 gm of Mitoglitazone was closed with stopper and placed in an oil bath at 160 °C for 5 minutes. The active substance was turned into molten mass (light yellow melt) within 5 minutes. The obtained melt was allowed to cool to ambient temperature to get a solid The solid mass thus obtained was gently grinded to obtain desired particles of Mitoglitazone.

The XRFD pattern showed amorphous nature.

[0331] Example 9B: Amorphous Mitoglitazooe

[0332] 25g of Mitoglitazone was dissolved in 250ml methanol at 50 °C. The

solution was filtered to remove any undissolved solid particles. The obtained clear solution was subjected to spray drying at the inlet temperature 120 °C and outlet temperature 65 °C. The XRFD pattern showed amorphous nature.

[0333] Example 9C: Amorphous Mitoglitazone

[0334] 25 g of Mitoglitazone was dissolved in 375 ml acetone at 50 °C. The

solution was filtered to remove any undissolved solid particles. The obtained clear solution was subjected to spray drying at the inlet temperature 120°C and outlet temperature 65°C. The XRPD pattern showed amorphous nature.

OTHER EMBODIMENTS

[0335] Given our teachings herein, one of skill in the art will without undue experimentation be able to make variations and modifications of the foregoing. Thus, while we discuss numerous specific examples here, we intend the scope of our patent to be defined not by any specific examples) provided here, but by the appended claims.