WO2011017244A1 - Polymorphes de 5-(4-(2-(5-éthylpyridin-2-yl)-2-oxoéthoxy)benzyl)-l,3-thiazolidine-2,4-dione (mitoglitazone) - Google Patents

Polymorphes de 5-(4-(2-(5-éthylpyridin-2-yl)-2-oxoéthoxy)benzyl)-l,3-thiazolidine-2,4-dione (mitoglitazone) Download PDF

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WO2011017244A1
WO2011017244A1 PCT/US2010/044066 US2010044066W WO2011017244A1 WO 2011017244 A1 WO2011017244 A1 WO 2011017244A1 US 2010044066 W US2010044066 W US 2010044066W WO 2011017244 A1 WO2011017244 A1 WO 2011017244A1
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mitoglitazone
temperature
solution
solvent
solvent comprises
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PCT/US2010/044066
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English (en)
Inventor
Dhananjay Govind Sathe
Narayana Rao Mantripragada
Kamlesh Digambar Sawant
Tushar Anil Naik
Rajesh Ganpat Bhopalkar
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Metabolic Solutions Development Company
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Publication of WO2011017244A1 publication Critical patent/WO2011017244A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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.
  • NIDDM 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.
  • Polymorphism is the ability of a compound to exhibit more than one orientation or conformation of molecules within a crystal lattice.
  • 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.
  • the present invention provides crystalline Form I substantially free of other forms of Mitoglitazone.
  • Form I, of Mitoglitazone has an XRPD pattern of: 9.54, U .61 , 1522, 16.07, and 1738° ⁇ 0.2° on a 2 ⁇ scale.
  • 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 2 ⁇ scale.
  • 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 .
  • 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.
  • Another aspect of the present invention provides a process for the
  • Form I of Mitoglitazone substantially free of other forms of Mitoglitazone comprising the steps of:
  • step b optionally, filtering the first solution of step a to generate a filtrate
  • step 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.
  • the process further comprises filtering the first solution of step a to generate a filtrate.
  • the process further comprises adding a second solvent to the filtrate of step b to generate a second solution.
  • the first temperature is within ⁇ 10°C of the reflux temperature of the first solvent
  • the first temperature is from about 50 °C to about 100°C.
  • the first temperature is from about 60°C to about 80 °C.
  • the second temperature is from about 20°C to about 3S°C.
  • some processes further comprise filtering and drying the solids of stepd.
  • the solids of step d are dried at a temperature of from about 5O°C to about 70 °C.
  • the first solvent comprises an alcohol, a ketone, an ester, a nitrite, an ether, a chlorinated hydrocarbon, or any combination thereof.
  • the first solvent comprises an alcohol.
  • Exemplary alcohols include ethanol, 1- propanol, 2-propanol, or any combination thereof.
  • the first solvent comprises a ketone.
  • Exemplary ketones include acetone, 2-butanone, diethyl ketone, or any combination thereof.
  • the first solvent comprises an ester.
  • Exemplary esters include ethyl acetate, methyl acetate, butyl acetate, or any combination thereof.
  • the first solvent comprises a chlorinated hydrocarbon.
  • Exemplary chlorinated hydrocarbons include methylene dkhloride, ethylene dkhloride, carbon tetrachloride, chloroform, or any combination thereof.
  • the first solvent comprises a nitrite.
  • Exemplary nitrites include acetonitrile.
  • the first solvent comprises an ether.
  • Exemplary ethers include tetrahydrofuran, 1,4-dioxane, or any combination thereof.
  • the first solvent is anhydrous.
  • the first solution of step a, the filtrate of step b, or the second solution of step c is dried over anhydrous sodium sulfate.
  • the second solvent comprises an aliphatic ether, an aliphatic hydrocarbon, an aromatic hydrocarbon, or any combination thereof.
  • the second solvent comprises an aliphatic hydrocarbon or an aromatic hydrocarbon.
  • the second solvent comprises an aliphatic hydrocarbon, and the aliphatic hydrocarbon comprises pentane, hexane, heptane, or any combination thereof.
  • the second solvent comprises an aromatic hydrocarbon, and the aromatic hydrocarbon comprises toluene, xylene, or any combination thereof.
  • 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).
  • 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:
  • step b optionally, filtering the solution of step a to generate filtrate;
  • step 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;
  • step c collecting the resultant solids of step c.
  • the water miscible aliphatic cyclic ether comprises tetrahydrofuran, 1,4-dioxane, or any combination thereof.
  • 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 2 ⁇ scale.
  • 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 2 ⁇ scale.
  • 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 ! .
  • 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.
  • Mitoglitazone comprising the steps of:
  • step b optionally, filtering the solution of step a to generate a filtrate
  • step 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
  • step 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.
  • 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.
  • 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.
  • the second temperature is from about 25 °C to about
  • the first temperature is from about 50 °C to about
  • the first temperature is the reflux temperature of the first solvent
  • 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.
  • the second solvent comprises water.
  • the second solvent comprises an aliphatic hydrocarbon solvent comprising pentane, hexane, heptane, or any combination thereof.
  • Some embodiments further comprise drying the solids of step d at a temperature of from about 25 °C to about 60 °C.
  • Another aspect of the present invention provides a process for the preparation of Form ⁇ 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;
  • 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 2 ⁇ scale.
  • 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 2 ⁇ scale.
  • the crystalline polymorph is further characterized by an FTIR absorption spectrum of 3143, 3031, 2976, 2933, 1743, 1705, 1608, and 991 cm 1 .
  • 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.
  • Another aspect of the present invention provides a process for the preparation of Form III of Mitoglitazone comprising the steps of:
  • step 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,
  • the second temperature is from about S °C to about 10°C.
  • the first solvent comprises methanol, ethanol, 1 - propanol, 2- ⁇ ropanol, or any combination thereof.
  • the first temperature is from about 60 °C to about 70°C.
  • Other embodiments further comprise drying the solids at a temperature of from about 50 °C to about 70 °C.
  • the Mitoglitazone of step a comprises Mitoglitazone Form I, Form II, or any combination thereof.
  • 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 2 ⁇ scale.
  • 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 2 ⁇ scale.
  • 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 .
  • 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.
  • 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:
  • step 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,
  • the second temperature is from about -60 °C to aboutO°C.
  • Other embodiments further comprise drying the solids of step c at a temperature of from about 20 °C to about 30 °C.
  • the first solvent comprises methanol, emanol, 1 - propanol, 2-propanol, or any combination thereof.
  • the Mitoglitazone of step a comprises Mitoglitazone Fbrm L
  • 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 2 ⁇ scale.
  • 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 2 ⁇ scale.
  • 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 .
  • 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.
  • Another aspect of the present invention provides a process for the preparation of Form V of Mitoglitazone comprising exposing Form IV of
  • the Form IV of Mitoglitazone is exposed to 60-85% relative humidity for a period from about 12 hours to about 72 hours.
  • the first temperature is from about 30 °C to about 50 °C.
  • the Form IV of Mitoglitazone is exposed to 75% relative humidity for a period of 24 hrs at a temperature of about 40 °C.
  • 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 .
  • 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.
  • Another aspect of the present invention provides a process for the preparation of amorphous Mitoglitazone comprising the steps of:
  • the first temperature is from about 140 °C to about 170°C.
  • the second temperature of from about 10 °C to about 3O °C.
  • 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
  • step b spray drying the mixture generated in step a to obtain an amorphous solid.
  • the first temperature is from about 20 °C to about 40 °C.
  • the concentration of Mitogiiazone in the mixture is from about 5% to about 25 % by wL
  • the first solvent comprises an alcohol, a ketone, or any combination thereof.
  • the first solvent comprises an alcohol, and the alcohol comprises methanol.
  • the first solvent comprises a ketone, and the ketone comprises acetone.
  • the spray drying is performed using an inlet
  • 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.
  • Another aspect of the present invention provides Mitoglitazone or any polymorphic form thereof having:
  • Mitoglitazone alcohol (D) less man 0.3% of dimer impurities wherein M+l is 739.30; or any combination thereof.
  • 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.
  • Another aspect of the present invention provides a pharmaceutical composition comprising one or more of crystalline Forms I, ⁇ , in, IV, V of
  • Mitoglitazone or amorphous Mitoglitazone and a pharmaceutically acceptable carrier.
  • 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%.
  • Another aspect of the present invention provides chemically and polymorphkally stable forms of Mitoglitazone and methods for the preparation thereof.
  • Another aspect of the present invention provides processes for improving the solubility of Mitoglitazone.
  • 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 ⁇ m to improve solubility.
  • the present invention provides pharmaceutical compositions containing one or more novel crystalline forms or an amorphous form of Mitoglitazone.
  • Another aspect of the present invention provides a process for generating a form of
  • Mitoglitazone having a selectable particle size.
  • FIG. 1 is an X-ray powder diffraction pattern of Mitoglitazone Form I
  • FIG. 2 is DSC of Mitoglitazone Form I
  • FIG. 3 is FT-IR of Mitoglitazone Form I
  • FIG.4 is an X-ray Powder diffraction pattern of Mitoglitazone Form II
  • FIG.5 is DSC of Mitoglitazone Form D
  • FIG.6 is FTIR of Mitoglitazone Form II
  • FIG.7 is an X-ray powder diffraction pattern of Mitoglitazone Form Dl
  • FIG.8 is DSC of Mitoglitazone Form HI
  • FIG.9 is FTIR of Mitoglitazone Form HI
  • FIG. 10 is an X-ray powder diffraction pattern of Mitoglitazone Form IV
  • FIG. 11 is DSC of Mitoglitazone Form IV
  • FIG. 12 is FTIR of Mitoglitazone Form IV
  • FIG. 13 is an X-ray powder diffraction pattern of Mitoglitazone Form V
  • FIG. 14 is DSC of Mitoglitazone Form V
  • FIG. 15 is FTIR of Mitoglitazone Form V
  • FIG. 16 is an X-ray powder diffraction pattern of amorphous Mitoglitazone;
  • FIG. 17 is DSC of amorphous Mitoglitazone;
  • FIG. 18 is FTIR of amorphous Mitoglitazone
  • FIG. 19 is an X-ray powder diffraction pattern of Mitoglitazone by JMC route
  • FIG.20 is an X-ray powder diffraction pattern of Mitoglitazone by OFRD route.
  • FIG. 21 is an X-ray powder diffraction pattern of Mitoglitazone from 95% aqueous ethanol.
  • 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.
  • XRPD means X-ray Powder Diffraction.
  • FITR means Fourier Transform Infrared Spectroscopy.
  • DSC Differential Scanning Calorimetry
  • 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.
  • 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.
  • 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.
  • Mitoglitazone refers to 5-(4-(2-(5-Ethyl ⁇ yridin-2-yl)-2- oxocthoxy)benzyl)-13-thiazolidine-2,4-dk)ne, having the structure of Formula I.
  • hydroxyl or "hydroxy” refers to an -OH moiety.
  • alkyl alkenyl, alkynyl, each of which being optionally substituted as set forth below.
  • 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,
  • substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cydoalkenyl], hcterocycloalipha
  • heterocycloalkylalkyOcarbonylamino heteroarylcarbonylamino
  • amino e.g., aliphaticamino, cycloaliphatkamino, or heterocycloaliphaticamino
  • substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyU aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SOramii ⁇ >)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.
  • carboxyalkyl such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl
  • cyanoalkyl hydroxyalkyl, alkoxyalkyl, acylalkyU aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO
  • 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.,
  • heteroaryicarbonylamino heteroaralkylcarbonylamino alkylaminocarbonyl
  • cycloalkylaminocarbonyl amino [e.g., aliphatkamino, cycloaliphaticamino,
  • heterocycloaliphaticamino or aliphaticsulfonylamino
  • sulfonyl e.g.,
  • substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl,
  • (sulfonylamino)alkenyl such as (alkyl-SOramino)alkenyl
  • aminoalkenyl aminoalkenyl
  • amidoalkenyl aminoalkenyl
  • cycloaliphatic aminoalkenyl
  • haloalkenyl aminoalkenyl
  • 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,
  • acyl e.g., (cycloaliphatic )carbonyl or (heterocycloaliphatkOcarbonyl] amino [e.g., aliphaticamino], sulfoxy,
  • an “amido” encompasses both “aminocarbonyl” and
  • carbonylamino 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 ⁇ can be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaraliphatic.
  • amido groups examples include alkylamido (such as alkylcarbonylamino or
  • alkylaminocarbonyl (heterocycloa]iphatic)ainkk>, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.
  • an "amino" group refers to -NR X R Y wherein each of R x and R ⁇ 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,
  • amino groups include alkylamino, dialkylamino, or arylamino.
  • 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.
  • 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.
  • 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 (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;
  • 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.
  • an aryl can be unsubstituted.
  • 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,
  • aminocarbonyl)aryl (((alkylamino)alkyl)amtnocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((hetc ⁇ oaryl)amino)carbonyl)aryl]; aminoaryl [e.g.,
  • (sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;
  • 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.
  • 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, (hetc ⁇ ocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
  • substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g.
  • heteroaralkyloxy aroyl heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
  • heterocycloalkyl carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • 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.
  • a "cycloaliphatic” group encompasses a “cydoalkyl” group and a “cycloalkenyl” group, each of which being optionally substituted as set forth below.
  • a "cycloalkyl” group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., S-IO) carbon atoms.
  • 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.
  • a "cycloalkenyl” group 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.
  • 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., phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic
  • heterocycloalkyl 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).
  • heterocycloalkyl group examples 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-di
  • 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.
  • 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)ali ⁇ hatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,
  • substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatk, (cycloaliphatic)ali ⁇ hatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryl
  • heteroaryloxy e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)
  • heterocycloaliphatic )carbonylamino ((heterocycloaliphatic) aliphatic )carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino] nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic )carbonyl,
  • sulfonyl e.g., alkylsulfonyl or arylsulfonyl
  • a “heteroaryl” group 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.
  • 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).
  • heterocycloaliphatic moieties e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, bcnzo[fr]furyl, benzo[l>]thiophenyl, quinolinyl, or isoquinolinyl.
  • heteroaryl examples include 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
  • 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.
  • bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo ⁇ jfuryl, 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.
  • 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 (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; (cycloali ⁇ hatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;
  • heterocycloaliphatic aliphatic
  • carbonyl or (heteroaraliphatic)carbonyl]
  • sulfonyl e.g., aliphatksulfonyl or aminosulfonyl
  • sulflnyl e.g., aliphaticsulfinyl
  • sulfanyl e.g.. aliphaticsulfanyl
  • a heteroaryl can be unsubstituted.
  • 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
  • heterocycloaliphatic heteroaryl
  • cycloaliphatic heteroaryl
  • nitrogenalkyl heteroaryl
  • (cyanoalkyl)heteroaryl (acyl)heferoaryl [e.g., (alkykarbonyl)heteroaryl]; (alkyl)heteroaryl; or (haloalkyl)heteroaryi [e.g., trihaloalkylheteroaryl].
  • heteroaralkyl group refers to an aliphatic group (e.g., a C 1-4 alkyl group) that is substituted with a heteroaryl group.
  • heteroarylkyr group refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with a heteroaryl group.
  • alkyl e.g., a C 1-4 alkyl group
  • heteroaryl e.g., a C 1-4 alkyl group
  • 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,
  • substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo
  • heteroarylcarbonylamino heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • 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.
  • a "bridged bicyclic ring system” refers to a tricyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged.
  • 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,
  • substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl t heterocycloalkyl, (heterocycloalkyOalkyl, aryl, heteroaryl, alkoxy, cycl
  • heteroaralkyloxy aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
  • heteroarylcarbonylamino heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • 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.
  • 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.
  • alkoxy refers to an alkyl-O- group where “alkyl” has been defined previously.
  • a “carbamoyl” group refers to a group having the structure
  • R x and R ⁇ have been defined above and R z can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
  • a "carboxy” group refers to -CXX)H, -COOR*, -OC(O)H,
  • haloaliphatic refers to an aliphatic group substituted with 1-3 halogen.
  • haloalkyl includes the group -CF 3 .
  • a "mercapto” group refers to -SH.
  • a "sulfo" group refers to -SOjH or -SO 3 R* when used terminally or -S(O) 3 - when used internally.
  • 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 ⁇ , and R z have been defined above.
  • a "sulfamoyl” group refers to the structure -O-S(O)rNR Y R z wherein R ⁇ and R z have been defined above.
  • 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 ⁇ , and R z are defined above.
  • sulfanyl group refers to -S-R x when used terminally and -S- when used internally, wherein R x has been defined above.
  • sulfanyls include aliphatic-S-, cycloaliphattc-S-, aryl-S-, or the like.
  • 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.
  • 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.
  • 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.
  • halogen or halo group refers to fluorine, chlorine, bromine or iodine.
  • 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)-.
  • alkoxyalkyl refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.
  • the terra "phospho" refers to phosphinates and phosphonates.
  • phosphinates and phosphonates include -P(OXR ⁇ , wherein R p is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaltphatic)oxy, (hetcrocycloaliphatic)oxy aryl hcteroaryl, cycloaliphatic or amino.
  • aminoalkyl refers to the structure (R x ) ⁇ N-alkyl-.
  • cyanoalkyl refers to the structure (NC>-alkyl-.
  • urea refers to the structure -NR X -CO-NR Y R Z and a
  • thiourea refers to the structure -NR X -CS-NR Y R Z when used terminally and
  • 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.
  • 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.
  • terminal refers 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)-
  • alkylcarboxyaryl e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-
  • an "aliphatic chain” refers to a branched or straight aliphatic group
  • 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.
  • substituted or unsubstituted 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.
  • 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.
  • 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.
  • the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl.
  • the two alkxoy groups can form a ring together with the atom(s) to which they are bound.
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent
  • substituents are described above in the definitions and below in the description of compounds and examples thereof.
  • 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
  • substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • stable or chemically feasible 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.
  • 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.
  • 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.
  • 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 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 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,
  • stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
  • all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds dut differ only in the presence of one or more isotopically enriched atoms.
  • 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.
  • 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.
  • 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.
  • a second solvent proceeds a first solvent in space or time.
  • the present invention provides novel crystalline forms of Mitoglitazone.
  • the novel crystalline form of Mitoglitazone is Form I, Form II, Form IQ, Form IV, Form V, or amorphous Mitoglitazone.
  • the novel crystalline form of Mitoglitazone is Form ED, Form IV, Form V, or amorphous
  • the present invention further provides processes for preparation of Form I, Form ⁇ , Form IH, Form IV, Form V, and amorphous Mitoglitazone each of which is substantially free of other polymorphic forms.
  • 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.
  • XRH X-ray powder diffraction
  • DSC Differential Scanning Calorimetry
  • FTIR Fourier Transform Infrared
  • 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.
  • Form I is characterized by an XRFD pattern comprising the peaks provided in Table Ia:
  • Form I is characterized by an XRPD pattern comprising the peaks provided in Table Ib:
  • Form I is characterized by an XRPD pattern comprising the peaks provided in Table Ic:
  • Form I is characterized by an XRFD pattern comprising the peaks provided in Table Id:
  • Another exemplary XRFD pattern of Form I, provided in FIG. 1, has the following peaks as shown in Table Ie.
  • 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.
  • 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 first mixture e.g., a solution
  • step 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
  • step 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.
  • first mixture e.g., solution
  • second mixture e.g., solution
  • 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.
  • the solids may be filtered from the first mixture of step a, the filtrate of step b, or the second mixture of step c.
  • 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
  • Suitable first solvents include, for example, aliphatic alcohols, aliphatic ketones, aliphatic nitriles, chlorinated hydrocarbons, C5.7 cyclic aliphatic ethers, and/or aliphatic esters.
  • alcohols are selected from C 1-4 alcohols such as, for example, ethanol, isopropyl alcohol, or a combination thereof.
  • ketones are selected from Ci ⁇ ketones such as, for example, acetone, 2-butanone, diethyl ketone, or any combination thereof.
  • nitriles are selected from C 1-4 nitriles such as, for example, acetonitrile and propionhrile.
  • chlorinated hydrocarbons are selected from Ci- 3 alkyl chlorides such as, for example, methylene dichloride, ethylene dichloride, carbon tetrachloride and chloroform.
  • cyclic aliphatic ethers are selected from, for example, tetrahydrofuran and 1 ,4-dioxane.
  • 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).
  • the mixing can be performed at a first temperature of from about 25 °C to about 100 °C.
  • 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
  • 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).
  • 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
  • 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.
  • the second solvent may be selected from aliphatic or aromatic hydrocarbons.
  • the second solvent is selected from aliphatic ethers.
  • 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, d ⁇ sopropyl 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).
  • 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).
  • the present invention provides crystalline Form ⁇ 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.
  • One exemplary XRFD pattern of Form ⁇ of Mitoglitazone shows peaks having a relative intensity of greater than 15% for 2-Theta values of greater than 9.
  • One exemplary X-Ray diffraction pattern has the following peaks shown in Table 2a.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 2b.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 2c.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 2d.
  • Another exemplary X-Ray diffraction pattern provided in FIG.4, has the following peaks shown in Table 2e.
  • I)SC of pure ciystalline Form ⁇ 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 ⁇ 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.
  • the present invention provides a process for preparation of crystalline Form O of Mitoglitazone, substantially free of other crystalline forms of Mitoglitazone, comprising:
  • step 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
  • the first solvent comprises water.
  • the first solvent has a water content of less than 25 % water by volume.
  • the first solvent comprises from about IS % to about 5 % (e.g., about 10 %) water by volume.
  • the second temperature is from about 25 °C to about 30 °C.
  • 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.
  • the first temperature is the reflux temperature of the first solvent
  • 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.
  • 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.
  • 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
  • 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
  • a process for preparing Mitoglitazone Form II comprises suspending Mitoglitazone Form I in water at a temperature of about 65 °C
  • 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.
  • One exemplary X-Ray diffraction pattern includes peaks having a relative intensity of greater than 20% at 2-Theta values of greater than 9.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 3b.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 3d.
  • Another exemplary X-Ray diffraction pattern, provided in FIG. 7, has the following peaks shown in Table 3c.
  • DSC of crystalline Fo ⁇ n 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 .
  • the first solvent comprises an alcohol
  • the alcohol comprises methanol, ethanol, 1-propanol, 2-propanol (IPA), or any
  • 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.
  • the second temperature is from about 5 °C to about 10 °C.
  • the process further comprises drying the solids at a temperature of from about 50 °C to about 70 °C.
  • the Mitoglitazone of step a comprises Mitoglitazone
  • a process for preparation of Mitoglitazone Form comprises the steps of:
  • step b optionally, filtering the mixture of step a to generate a filtrate
  • step b cooluTg ⁇ 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;
  • drying the solids at a temperature of about 60 °C.
  • 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.
  • One exemplary X-Ray diffraction pattern shows peaks having relative intensities of greater than 20% for values of 2-Theta greater than 13.5.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 4b.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 4c.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 4d.
  • FIG. 10 Another exemplary X-Ray diffraction pattern, provided in FIG. 10, has the following eaks shown in Table 4e.
  • 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.
  • Another embodiment of the present invention provides a process lor the
  • step 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,
  • the second temperature is from about -60 °C to
  • Other embodiments further comprise drying the solids at a temperature of from about 20 °C to about 30 °C.
  • the first solvent comprises methanol, ethanol, 1 - propanol, 2-propanol, or any combination thereof.
  • the Mitoglitazone of step a comprises
  • step b optionally, filtering the mixture of step a to generate a filtrate
  • step 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;
  • drying the solids at a temperature of from about 25 to about 30 °C.
  • 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
  • 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.
  • One exemplary X-Ray diffraction pattern shows peaks having relative intensities of greater man 9% for 2-Theta values greater than 9.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 5b.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table 5c.
  • Another exemplary X-Ray diffraction pattern has the following peaks shown in Table Sd.
  • Another exemplary X-Ray diffraction pattern, provided in FIG. 13, has the following peaks shown in Table 5e.
  • DSC ⁇ stallinc Fo ⁇ n 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 .
  • 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).
  • the XRFD of amorphous Mitoglitazone exhibits a broad peak from about 10° to about 36° on a 2 ⁇ 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 .
  • Another embodiment of the present invention provides a process for preparing an amorphous form of Mitoglitazone which comprises the steps of;
  • 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.
  • Another embodiment of the present invention provides a process for preparing amorphous Mitoglitazone which comprises the steps of:
  • step b optionally, filtering the solution of step a;
  • the suitable solvent comprises alcohols such as, for example, methanol and ethanol; or ketones, such as, for example, acetone, or mixtures thereof.
  • concentration of Mitoglitazone used in spray drying is from about S % to about 25 % (e.g., about 20 %) by weight
  • dissolution is performed at temperature of from about
  • 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.
  • Mitoglitazone obtained according to the present invention may be any organic compound having the same function as Mitoglitazone obtained according to the present invention.
  • 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%.
  • A N-methylsulphide
  • B keto benzylidene
  • C keto benzaldehyde
  • D Mito alcohol
  • 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).
  • 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,
  • Example 1 M ⁇ togUtazone by J ⁇ fed.Chem.
  • 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.
  • Example 2 MltogUtazone by Org. Pro. Reg. & Dev. Procedure
  • Example 3 Mitoglitazone from Aqueous Ethanol
  • Mitoglitazone 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.
  • Mitoglitazone 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.
  • Example 4E Mitoglitazone Form I
  • 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
  • Example 5A MltogUtazooe Form ⁇
  • Example 5F Mitoglitazone Form III [0298] 1 g Mitoglitazone wais dissolved in 10 ml 10% aqueous 1,4-dioxane at
  • Example 5N Mitogiitazone Form ⁇
  • Example 6A Mit ⁇ flltazone Form IU
  • Example €B MftogUtazone Form OI
  • Ig Mitoglitazone Form I was dissolved in IS ml methanol at reflux
  • Example 7A Mitoglitazone Form IV
  • the XRFD pattern showed amorphous nature.
  • Example 9B Amorphous Mitoglitazooe
  • Example 9C Amorphous Mitoglitazone

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Abstract

La présente invention concerne de nouveaux polymorphes de 5-(4-(2-(5-éthylpyridin-2-yl)-2-oxoéthoxy)benzyl)-l,3-thiazolidine-2,4-dione de formule (I) et des procédés pour les préparer et des compositions pharmaceutiques comprenant les nouveaux polymorphes cristallins. Formule (I)
PCT/US2010/044066 2009-08-05 2010-08-02 Polymorphes de 5-(4-(2-(5-éthylpyridin-2-yl)-2-oxoéthoxy)benzyl)-l,3-thiazolidine-2,4-dione (mitoglitazone) WO2011017244A1 (fr)

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US8912335B2 (en) 2009-12-15 2014-12-16 Metabolic Solutions Development Company, Llc PPAR-sparing thiazolidinedione salts for the treatment of metabolic diseases
US8969581B2 (en) 2013-03-14 2015-03-03 Deuterx, Llc 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US9925175B2 (en) 2007-09-26 2018-03-27 Deuterx, Llc Deuterium-enriched pioglitazone
US10188639B2 (en) 2014-01-15 2019-01-29 Deuterx, Llc Methods of treating neurological, metabolic, and other disorders using enantiopure deuterium-enriched pioglitazone
US11319313B2 (en) 2020-06-30 2022-05-03 Poxel Sa Crystalline forms of deuterium-enriched pioglitazone
US11767317B1 (en) 2020-06-30 2023-09-26 Poxel Sa Methods of synthesizing enantiopure deuterium-enriched pioglitazone
WO2024017851A1 (fr) 2022-07-18 2024-01-25 The University Court Of The University Of Glasgow Inhibiteurs du métabolisme du pyruvate mitochondrial pour le traitement de la leucémie myéloïde chronique

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Cited By (17)

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US10576071B2 (en) 2007-09-26 2020-03-03 Poxel Sa Deuterium-enriched pioglitazone
US11918567B2 (en) 2007-09-26 2024-03-05 Poxel Sa Deuterium-enriched pioglitazone
US10940143B2 (en) 2007-09-26 2021-03-09 Poxel Sa Deuterium-enriched pioglitazone
US9925175B2 (en) 2007-09-26 2018-03-27 Deuterx, Llc Deuterium-enriched pioglitazone
US9126959B2 (en) 2009-12-15 2015-09-08 Metabolic Solutions Development Company, Llc PPAR-sparing thiazolidinedione salts for the treatment of metabolic diseases
US8912335B2 (en) 2009-12-15 2014-12-16 Metabolic Solutions Development Company, Llc PPAR-sparing thiazolidinedione salts for the treatment of metabolic diseases
US9833445B2 (en) 2013-03-14 2017-12-05 Deuterx, Llc 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US10265305B2 (en) 2013-03-14 2019-04-23 Poxel Sa 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US9416117B2 (en) 2013-03-14 2016-08-16 Deuterx, Llc 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US11123336B2 (en) 2013-03-14 2021-09-21 Poxel Sa 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US11918569B2 (en) 2013-03-14 2024-03-05 Poxel Sa 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US8969581B2 (en) 2013-03-14 2015-03-03 Deuterx, Llc 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US10188639B2 (en) 2014-01-15 2019-01-29 Deuterx, Llc Methods of treating neurological, metabolic, and other disorders using enantiopure deuterium-enriched pioglitazone
US11141411B2 (en) 2014-01-15 2021-10-12 Poxel Sa Methods of treating neurological, metabolic, and other disorders using enantiopure deuterium-enriched pioglitazone
US11319313B2 (en) 2020-06-30 2022-05-03 Poxel Sa Crystalline forms of deuterium-enriched pioglitazone
US11767317B1 (en) 2020-06-30 2023-09-26 Poxel Sa Methods of synthesizing enantiopure deuterium-enriched pioglitazone
WO2024017851A1 (fr) 2022-07-18 2024-01-25 The University Court Of The University Of Glasgow Inhibiteurs du métabolisme du pyruvate mitochondrial pour le traitement de la leucémie myéloïde chronique

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