WO2022082100A1 - Co-cristaux de l-4-chlorokynurénine, compositions et utilisations thérapeutiques associées - Google Patents

Co-cristaux de l-4-chlorokynurénine, compositions et utilisations thérapeutiques associées Download PDF

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WO2022082100A1
WO2022082100A1 PCT/US2021/055409 US2021055409W WO2022082100A1 WO 2022082100 A1 WO2022082100 A1 WO 2022082100A1 US 2021055409 W US2021055409 W US 2021055409W WO 2022082100 A1 WO2022082100 A1 WO 2022082100A1
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cocrystal
chlorokynurenine
acid
acid cocrystal
peaks
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Joanne Holland
Alex Eberlin
Christopher Frampton
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Vistagen Therapeutics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/08—Malonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C57/42—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the rings
    • C07C57/44—Cinnamic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/06—Glycolic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/08—Lactic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C07C63/08—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the invention relates to cocrystals of L-4-chlorokynurenine, pharmaceutical compositions containing those cocrystals and methods of use of such cocrystals and compositions in treating neurological or psychiatric disorders mediated at least in part by the NMDA receptor.
  • NMDAR N-methyl-D-aspartate receptor
  • NMDA N-methyl-D-aspartate receptor
  • NMDAR N-methyl-D-aspartate receptor
  • NMDA N-methyl-D-aspartate receptor
  • NR1 and NR2 GluN2 subunits
  • Hyperactivation of NMDAR has been associated with memory loss and is implicated in the pathogenesis of various neurodegenerative conditions, including Alzheimer's disease. Lancelot E, Beal MF. Prog. Brain Res.(1998)116:331-347. Hypoactivation on the other hand may be associated with a number of psychiatric symptoms and signs, including psychosis, mania, depression, and may be implicated in a number of psychiatric disorders, (Gunduz-Bruce H., Brain research reviews.
  • Antagonism of NMDARs can also be achieved through blockade of a modulatory site on the NMDAR, known as the glycine B (GlyB) coagonist site.
  • GlyB glycine B
  • GlyB antagonists When compared with classic NMDAR antagonists, GlyB antagonists have a better safety profile and generally do not cause the adverse side effects that are associated with "classic" NMDAR antagonists, Carter AJ., Drugs Future 1992;17:595-613; Leeson PD, Iversen LL, J Med Chem 1994;37(24):4053-4067; Rundfeldt C., Wlaz P., Loscher W., Brain Res 1994;653(l-2): 125-130, including ketamine, Zanos, P., Piantadosi, S., Wu, H., Pribut, H., Dell, M., Can, A., Snodgrass, H., Zarate, C., Schwarcz, R., Gould, T., J Pharmacol Exp Ther 2015; 355:76-85.
  • Kynurenic acid is a metabolically related brain constituent with anticonvulsant and neuroprotective properties (Stone, T.W.; Pharmacol. Rev. 1993, 45, 309-379).
  • the biological activities of various derivatives of kynurenic acid and their kynurenine precursors have been studied (Camacho, E. et al. J. Med. Chern. 2002, 45, 263-274; Varasi, M. et al. Ear. J. Med. Chern. 1996,31, 11-21; Salituro, F.G. etal. J. Med. Chern. 1994,37, 334-336). Kynurenine compounds are converted to kynurenic acids in vivo.
  • US Patent 5,547,991 describes methods of making 4,6-disubstituted tryptophan derivatives and their use as N-methyl-D-aspartate (NMDA) antagonists.
  • NMDA N-methyl-D-aspartate
  • 7-chlorokynurenic acid (7-CI-KYNA) has been shown to prevent excitotoxic and ischemic neuronal damage, but like most GlyB antagonists does not cross the blood-brain barrier. Thus, its clinical use is limited.
  • L-4-chlorokynurenine (L-4-CI-KYN, also known as AV-101) is a synthetic prodrug of 7- chlorokynurenic acid.
  • L-4-chlorokynurenine (structure shown below) readily crosses the blood-brain barrier gaining access to the central nervous system (CNS) after administration.
  • L-4-chlorokynurenine (L-4-CI-KYN or AV-101)
  • L-4-chlorokynurenine presumably a zwitterion at physiological pH, is efficiently converted to L-7- chlorokynurenic acid within activated astrocytes, and, after dosing with L-4-chlorokynurenine, brain levels of L-7-chlorokynurenic acid are increased at sites of neuronal injury or excitotoxic insult as a result of astrocyte activation.
  • L-4-chlorokynurenine has shown anti-seizure activity in rats. The compound also was found to increase the firing rate and burst firing activity of dopaminergic neurons in the brains of rats.
  • U.S. Patent No. 9,993,453 describes methods of treating depression comprising the step of orally administering to a human subject in need thereof a therapeutically effective amount of L-4-chlorokynurenine.
  • L-4-chlorokynurenine Given the beneficial pharmacological properties and efficicay of L-4-chlorokynurenine, there is a need to develop pharmaceutical formulations of L-4-chlorokynurenine that may be administered to patients.
  • Crystalline forms of therapeutic drugs have been used to alter the physicochemical properties of the particular drug.
  • Each crystalline form of a drug can have different solid-state (physical and chemical) properties which may be relevant for drug delivery. Crystalline forms often have better chemical and physical properties than corresponding non-crystalline forms such as the amorphous form.
  • the differences in physical properties exhibited by a novel solid form of a drug affect pharmaceutical parameters such as melting point, storage stability, compressibility and density (relevant for formulation and product manufacturing), and dissolution rates and solubility (relevant factors in achieving suitable bioavailability).
  • Suitable crystalline forms possess the desired properties of a particular drug.
  • Such suitable crystalline forms may be obtained by forming a cocrystal between the drug and a coformer.
  • Cocrystals often possess more favorable pharmaceutical and pharmacological properties or may be easier to process than known forms of the drug itself.
  • a cocrystal is one way to avoid polymorph formation of the drug.
  • a cocrystal may have different dissolution and solubility properties than the drug.
  • cocrystals may be used as a convenient vehicle for drug delivery, and new drug formulations comprising cocrystals of a given drug may have superior properties.
  • a cocrystal of a drug is a distinct chemical composition between the drug and coformer, and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the drug and coformer individually.
  • salts which possess a neutral net charge, but which are comprised of charge-balanced components
  • cocrystals are comprised of neutral species.
  • charge balance unlike a salt, one cannot determine the stoichiometry of a cocrystal based on charge balance. Indeed, one can often obtain cocrystals having stoichiometric ratios of drug to coformer of greater than or less than 1:1.
  • the stoichiometric ratio of an API to coformer is a generally unpredictable feature of a cocrystal.
  • cocrystal may be thought of as a multi-component crystal composed of neutral molecules. These multi-component assemblies are continuing to excite and find usefulness, particularly within the pharmaceutical arena, for their ability to alter and/or provide new physicochemical properties. More specifically, cocrystals have been reported to alter melting point, aqueous solubility and/or dissolution rates, increase stability with respect to relative humidity, and improve bioavailability of active pharmaceutical ingredients. [0010] In a cocrystal, the drug and the coformers each possess unique lattice positions within the unit cell of the crystal lattice.
  • Crystallographic and spectroscopic properties of cocrystals can be analyzed as with other crystalline forms such as with X-ray powder diffraction (XRPD) among other techniques. Cocrystals often also exhibit distinct thermal behavior compared with other forms of the corresponding drug. Thermal behavior may be analyzed by such techniques as capillary melting point, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) to name a few. These techniques can be used to identify and characterize the cocrystals.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • the invention relates to cocrystals of L-4-chlorokynurenine, pharmaceutical compositions containing those cocrystals and methods of use of such cocrystals and compositions in treating neurological or psychiatric disorders mediated at least in part by the NMDA receptor.
  • the cocrystals of L-4-chlorokynurenine according to the invention are selected from a 1:1 L-4-chlorokynurenine (AV-101)
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a L-4-chlorokynurenine cocrystal according to the invention and a pharmaceutically acceptable excipient.
  • the invention relates to a method of treating a neurological or psychiatric disorder associated with the glycine B site of the N-methyl-D-aspartate receptor in neuronal cells, including a step of administering to a human subject in need thereof a therapeutically effective amount of a L-4- chlorokynurenine cocrystal according to the invention or a pharmaceutical composition according to the invention Description of the Figures
  • FIG. 1 is the experimental XRPD pattern of the 1:1 AV-1014-Aminobenzoic Acid cocrystal.
  • FIG. 2 is a stack plot showing the XRPD patterns of AV-101, 4-aminobenzoic acid and the 1:1
  • FIG. 3 is an ORTEP diagram of the 1:1 AV-1014-aminobenzoic acid cocrystal at 100 K.
  • FIG. 4 is a calculated XRPD pattern based on the single crystal data and structure for the 1:1 AV-1014-aminobenzoic acid cocrystal at 100 K.
  • FIG. 5 is the differential scanning calorimetry (DSC) trace for the 1:1 AV-1014-Aminobenzoic Acid cocrystal.
  • FIG. 6 is the thermal gravimetric analysis (TGA) trace for the 1:1 AV-1014-Aminobenzoic Acid cocrystal.
  • FIG. 7 is the experimental Infrared Spectrum for the 1:1 AV-1014-Aminobenzoic Acid cocrystal.
  • FIG. 8 is the experimental XRPD pattern of the 1:1 AV-101 Salicylic Acid cocrystal.
  • FIG. 9 is a stack plot showing the XRPD patterns of AV-101, salicylic acid and the 1:1 AV-101 Salicylic Acid Cocrystal.
  • FIG. 10 is the differential scanning calorimetry (DSC) trace of the 1:1 AV-101 Salicylic Acid cocrystal.
  • FIG. 11 is the thermal gravimetric analysis (TGA) trace of the 1:1 AV-101 Salicylic Acid cocrystal.
  • FIG. 12 is the experimental Infrared Spectrum of the 1:1 AV-101 Salicylic Acid cocrystal.
  • FIG. 13 is the experimental XRPD pattern of the 1:1 AV-101 Malonic Acid cocrystal.
  • FIG. 14 is the stack plot showing the XRPD patterns of AV-101, Malonic acid and the 1:1 AV-101
  • FIG. 15 is the differential scanning calorimetry (DSC) trace of the 1:1 AV-101 Malonic Acid cocrystal.
  • FIG. 16 is the thermal gravimetric analysis (TGA) trace of the 1:1 AV-101 Malonic Acid cocrystal.
  • FIG. 17 is the experimental Infrared Spectrum of the 1:1 AV-101 Malonic Acid cocrystal.
  • FIG. 18 is the experimental XRPD pattern of the 1:1 AV-101 Cinnamic Acid cocrystal.
  • FIG. 19 is a stack plot showing the XRPD patterns of AV-101, Cinnamic Acid and the 1:1 AV-101
  • FIG. 20 is the differential scanning calorimetry (DSC) trace of the 1:1 AV-101 Cinnamic Acid cocrystal.
  • FIG. 21 is the thermal gravimetric analysis (TGA) trace of the 1:1 AV-101 Cinnamic Acid cocrystal.
  • FIG. 22 is the experimental Infrared Spectrum of the 1:1 AV-101 Cinnamic Acid cocrystal.
  • FIG. 23 is the experimental XRPD pattern of the 3:2 AV-101 Gentisic Acid cocrystal.
  • FIG. 24 is the stack plot showing the XRPD patterns of AV-101, Gentisic acid and the 3:2 AV-101
  • FIG. 25 is the differential scanning calorimetry (DSC) trace of the 3:2 AV-101 Gentisic Acid cocrystal.
  • FIG. 26 is the thermal gravimetric analysis (TGA) trace of the 3:2 AV-101 Gentisic Acid cocrystal.
  • FIG. 27 is the experimental Infrared Spectrum of the 3:2 AV-101 Gentisic Acid cocrystal.
  • FIG. 28 is the Gravimetric Vapor Sorption (GVS) Analysis of the 3:2 AV-101 Gentisic Acid cocrystal.
  • FIG. 29 is the experimental XRPD pattern of the 2:1 AV-101 Oxalic Acid Monohydrate cocrystal.
  • FIG. 30 is a stack plot showing the XRPD patterns of AV-101, Oxalic acid and the2:l AV-101 Oxalic Acid Monohydrate Cocrystal.
  • FIG. 31 is an ORTEP diagram of the 2:1 AV-101 Oxalic Acid Monohydrate Cocrystal.
  • FIG. 32 is the differential scanning calorimetry (DSC) trace of the 2:1 AV-101 Oxalic Acid
  • FIG. 33 is the thermal gravimetric analysis (TGA) trace for the 2:1 AV-101 Oxalic Acid
  • FIG. 34 is the experimental Infrared Spectrum of the 2:1 AV-101 Oxalic Acid Monohydrate cocrystal.
  • FIG. 35 is the Gravimetric Vapor Sorption (GVS) Analysis of the 2:1 AV-101 Oxalic Acid Monohydrate Cocrystal.
  • FIG. 36 is the experimental XRPD pattern of the 1:1 AV-101 Benzoic Acid cocrystal.
  • FIG. 37 is the experimental XRPD pattern of 1:1 AV-101 2,4-dihydroxybenzoic Acid cocrystal.
  • FIG. 38 is the experimental XRPD pattern of the 1:1 AV-101 3,4-dihydroxybenzoic Acid cocrystal.
  • FIG. 39 is the experimental XRPD pattern of the 1:1 AV-101 2-Furoic Acid cocrystal.
  • FIG. 40 is the experimental XRPD pattern of the 1:1 AV-101 Glycolic Acid cocrystal.
  • FIG. 41 is the experimental XRPD pattern of the 1:1 AV-101 3-Hydroxy-2-naphthoic acid cocrystal.
  • FIG. 42 is the differential scanning calorimetry (DSC) trace of the 1:1 AV-1013-Hydroxy-2- naphthoic acid cocrystal.
  • FIG. 43 is the experimental XRPD pattern of the 1:1 AV-1014-Hydroxybenzoic Acid cocrystal.
  • FIG. 44 is the experimental XRPD pattern of the 1:1 AV-101 Lactic Acid cocrystal.
  • FIG. 45 is the differential scanning calorimetry (DSC) trace of the 1:1 AV-101 Lactic Acid cocrystal.
  • FIG. 46 is the experimental XRPD pattern of the 1:1 AV-101 L-Malic Acid cocrystal.
  • the invention relates to cocrystals of L-4-chlorokynurenine (as referred to as AV-101), pharmaceutical compositions containing those cocrystals and methods of use of such cocrystals and compositions in treating neurological or psychiatric disorders mediated at least in part by the NMDA receptor.
  • the cocrystals of L-4-chlorokynurenine according to the invention are selected from a 1:1 L-4- chlorokynurenine (AV-101) - 4-Aminobenzoic Acid cocrystal, a 1:1 L-4-chlorokynurenine (AV-101) - Salicylic Acid cocrystal, a 1:1 L-4-chlorokynurenine (AV-101) - Malonic Acid cocrystal, a 1:1 L-4- chlorokynurenine (AV-101) - Cinnamic Acid cocrystal, a 3:2 L-4-chlorokynurenine (AV-101) - Gentisic Acid cocrystal, a 2:1 L-4-chlorokynurenine (AV-101) - Oxalic Acid Monohydrate cocrystal, a 1:1 L-4- chlorokynurenine (AV-101) - Benzoic Acid cocrystal, a 1:1 L-4-chlorokynurenine (AV-101) -
  • the invnenion paticualrly relates to a cocrystal of L-4-chlorokynurenine selected from the group of a 1:1 L-4-chlorokynurenine 4-Aminobenzoic Acid cocrystal, a 1:1 L-4-chlorokynurenine Salicylic Acid cocrystal, a 1:1 L-4-chlorokynurenine Malonic Acid cocrystal, a 1:1 L-4-chlorokynurenine Cinnamic Acid cocrystal, a 3:2 L-4-chlorokynurenine Gentisic Acid cocrystal, and a 2:1 L-4- chlorokynurenine Oxalic Acid Monohydrate cocrystal.
  • the preparation and characterization of these L- 4-chlorokynurenine cocrystals are described in the Examples below.
  • the invention generally relates to compositions and methods for treatment of neurological or psychiatric disorders.
  • the invention relates to a method of treating a neurological or psychiatric disorder associated with the glycine B site of the N-methyl-D-aspartate receptor in neuronal cells, comprising a step of administering to a human subject in need thereof a therapeutically effective amount of a L-4- chlorokynurenine cocrystal according to the invention.
  • the invention also to the use of a therapeutically effective amount of a L-4-chlorokynurenine cocrystal according to the invention to treat a neurological or psychiatric disorder associated with the glycine B site of the N-methyl-D-aspartate receptor in neuronal cells in a human subject in need thereof.
  • Administering each L-4-chlorokynurenine cocrystal according to the invention represents separate embodiments of such a method or use in treatment.
  • the neuronal cells are present in the central nervous system.
  • disorders associated with neuronal cells present in the central nervous system include neurosphychiatric disorders, depression, and encephalitis.
  • the neuronal cells are present in the peripheral nervous system.
  • disorders associated with neuronal cells present in the peripheral nervous system include neuropathies associated with viral infections and anti-cancer drugs, complex peripheral syndrome, chronic neuropathic pain, and peripheral nerve damage.
  • a "therapeutically effective amount" to treat a disorder refers to the amount of a L-4- chlorokynurenine cocrystal according to the invention administered which is sufficient to inhibit, halt, or cause an improvement in a disorder or condition being treated in a particular subject or subject population.
  • the therapeutically effective amount is sufficient to produce a clinical improvement in neurological or psychiatric function, for example, as would be manifested for a subject or patient as a decrease in neuropathic pain (for example, including but not limited to hyperlalgesia; neuropathic paid associated with diabetes, with chemotherapy or with amputation; central neuropathic apin, peripheral neuropathic pain, etc.), an increase in feelings of well-being or reduction in depressive mood or feelings of depression, a reduction in suicide ideation, a reduction in Parkinsonian symptoms, or a reduction in Parkinson's-associated dyskineasias.
  • neuropathic pain for example, including but not limited to hyperlalgesia; neuropathic paid associated with diabetes, with chemotherapy or with amputation; central neuropathic apin, peripheral neuropathic pain, etc.
  • an increase in feelings of well-being or reduction in depressive mood or feelings of depression a reduction in suicide ideation, a reduction in Parkinsonian symptoms, or a reduction in Parkinson's
  • a therapeutically effective amount of a L-4-chlorokynurenine cocrystal administered may range from about 50 mg/day to about 2,880 mg/day.
  • the amount of a L-4-chlorokynurenine cocrystal administered may range from about 100 mg/day to about 2,500 mg /day, from about 150 mg/day to 1,500 mg/day, or from about 300 mg/day to about 750 mg/day. Within these those dose ranges, 300-500 mg/day, 800-1,100 mg/day and 1,200- 1,500 mg/day may also be used.
  • any particular disease, disorder, or condition for any particular patient may depend upon a variety of factors including, for example, the particular disease, disorder, or condition being treated; the disease state being treated and its severity; the specific pharmaceutical composition employed; the age, body weight, general health, sex, and diet of the patient; the mode of administration; the time of administration; the route of administration; the rate of excretion; the duration of the treatment; any drugs used in combination or coincidental with the specific compound employed; and other such factors well known in the medical arts. These factors are discussed in Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein by reference.
  • the disorders include those which can be ameliorated by down-regulating NMDAR signaling.
  • Antagonism of NMDARs can be achieved through blockade of a modulatory site on the NMDAR, known as the glycine B (GlyB) coagonist site. Parsons et al., Journal of Pharmacology and Experimental Therapeutics 1997, 283 (3) 1264-1275.
  • the disorders include depression, major depressive disorder, pain, including neuropathic pain and pain caused by cancer, symptions associated with Parkinson's disease, L-Dopa mediated dyskinesias, anti-NMDA encephalitis, epilepsy, tinnitus, post-traumatic stress disorder (PTSD) and suicide ideation.
  • Other contemplated disorders include social anxiety, stroke, autism, obsessive compulsive disorder (OCD), cerebral inflammation associated with infections, e.g. malaria and various encephalitis's, AIDS Dementia Complex, and cognition.
  • the neurological or psychiatric disorder associated with the GlyB site of the NMDAR is selected from the group consisting of depression, neuropathic pain, L-Dopa mediated dyskinesias, tinnitus, obsessive compulsive disorder (OCD), and anti-NMDA receptor encephalitis.
  • “Treatment”, “treat”, or “treating” refers to the acute or prophylactic diminishment or alleviation of at least one symptom or characteristic associated with or caused by a disorder being treated. In certain embodiments, treatment can include diminishment of several symptoms of a disorder or complete eradication.
  • a daily dosing regimen may be from about 5 to about 30 days, including shorter and longer dosing regimens as determined by a subject's physician.
  • dosing regimens of about 7 to about 24 days, and about 12 to about 16 days are expressly contemplated.
  • a daily dosing regimen can include administration of one or more unit doses per day.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a L-4-chlorokynurenine cocrystal according to the invention and a pharmaceutically acceptable excipient.
  • these pharmaceutical compositions are therapeutically useful to treat or prevent disorders such as those discussed above.
  • a pharmaceutical composition of the invention may be a solid dosage form, or a liquid formulation made with a L-4-chlorokynurenine cocrystal according to the invention.
  • Individual pharmaceutical compositions comprising a therapeutically effective amount of each L-4-chlorokynurenine cocrystal according to the invention and a pharamaceutically acceptable carrier represent separate embodiments of the invention.
  • a pharmaceutical composition of the invention may be in any pharmaceutical form which contains a L-4-chlorokynurenine cocrystal according to the invention.
  • the pharmaceutical composition may be, for example, a tablet, a capsule, an oral solution, an injectable composition, a rectal suppository composition, a topical composition, an inhalable composition, or a transdermal composition.
  • Liquid pharmaceutical compositions may be prepared using a L-4-chlorokynurenine cocrystal according to the invention and represent a particular embodiment of the invention.
  • a L-4-chlorokynurenine cocrystal may be dissolved in a solvent, e.g. water, at the time and point of care.
  • the pharmaceutical composition may also be a suspension formulation, e.g. a non-polar and/or non-aqueous suspension, containing L-4-chlorokynurenine cocrystal according to the invention.
  • the pharmaceutical compositions generally contain, for example, about 0.1% to about 99.9% by weight of a L-4-chlorokynurenine cocrystal according to the invention, for example, about 0.5% to about 99% by weight of a L-4-chlorokynurenine cocrystal according to the invention and, for example, 99.5% to 0.5% by weight of at least one suitable pharmaceutical excipient or solvent.
  • the composition may be between about 5% and about 75% by weight of a L-4- chlorokynurenine cocrystal according to the invention with the rest being at least one suitable pharmaceutical excipient, solvent, or at least one other adjuvant, as discussed below.
  • a pharmaceutical composition of the invention may be formulated as a unit dose of a L-4-chlorokynurenine cocrystal according to the invention.
  • a "unit dose" is a single dose that is administered to a patient for treatment.
  • the pharmaceutically acceptable carrier may be chosen from any one or a combination of carriers known in the art.
  • the choice of pharmaceutically acceptable carrier depends upon the pharmaceutical form and the desired method of administration to be used.
  • a carrier should be chosen that maintains the crystalline form. In other words, the carrier should not substantially alter a L-4-chlorokynurenine cocrystal according to the invention.
  • compositions of the invention may be prepared by methods known in the pharmaceutical formulation art, for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990), which is incorporated herein by reference.
  • a L-4-chlorokynurenine cocrystal according to the invention may be admixed with at least one pharmaceutically acceptable excipient such as, for example, sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as, for example, cellulose derivatives, starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, such as, for example, glycerol, (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, such as, for example, paraffin, (f) absorption accelerators, such as, for example, paraffin
  • the dosage forms may also comprise buffering agents.
  • Pharmaceutically acceptable adjuvants known in the pharmaceutical formulation art may also be used in the pharmaceutical compositions of the invention. These include, but are not limited to, preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms may be ensured by inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • Solid dosage forms as described above may be prepared with coatings and shells, such as enteric coatings and others, as is known in the pharmaceutical art. They may contain pacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner.
  • Non-limiting examples of embedded compositions that may be used are polymeric substances and waxes.
  • the active compounds may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Suspensions in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • Liquid dosage forms may be aqueous, may contain a pharmaceutically acceptable solvent as well as traditional liquid dosage form excipients known in the art which include, but are not limited to, buffering agents, flavorants, sweetening agents, preservatives, and stabilizing agents.
  • compositions for rectal administrations are, for example, suppositories that may be prepared by mixing a L-4-chlorokynurenine cocrystal according to the invention with, for example, suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which may be solid at ordinary temperatures but may be liquid at body temperature and, therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which may be solid at ordinary temperatures but may be liquid at body temperature and, therefore, melt while in a suitable body cavity and release the active component therein.
  • Bruker D2 X-Ray Powder Diffraction Characterisation X-ray powder diffraction patterns for the samples were acquired on a Bruker 2nd Gen D2-Phaser diffractometer using CuKa radiation (30V, 10mA), 0-20 goniometer, V4 receiving slits, a Ge monochromator and a Lynxeye detector. The instrument is performance checked using a certified Corundum standard (NIST 1976). The data were collected at ambient temperature over an angular range of 2° to 35° 20 (using a step size of 0.05° 20 and a step time of 2.0 seconds) or an angular range of 2° to 42° 20 (using a step size of 0.025° 20 and a step time of 5.0 seconds). Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately, 20 mg of the sample was gently packed into sample holder and all samples were analysed using Diffrac Plus EVA v4.2.0.14.
  • DSC Thermal Analysis - Differential Scanning Calorimetry: DSC data were collected on a PerkinElmer Pyris 4000 DSC equipped with a 45-position sample holder. The instrument was verified for energy and temperature calibration using certified indium. A predefined amount of the sample, 0.5- 3.0mg, was placed in a pin holed aluminium pan and heated at 20 9 C.min 1 from 30 to 350 9 C. A purge of dry nitrogen at 60ml. min 1 was maintained over the sample. The instrument control, data acquisition and analysis were performed with Pyris Software v9.0.1.0203.
  • TGA Thermo-Gravimetric Analysis
  • FT-IR FT-IR spectra were obtained using a Perkin Elmer Spectrum 2 spectrometer and collected between 450cm-l and 4000cm-l using 4scans and a resolution of 4cm-l. A Universal ATR diamond accessory was used and the data were analysed using software version NIOS2 main 00.02.0064.
  • Example 1 1:1 AV-101 4-Aminobenzoic Acid Cocrystal
  • AV-101 (515 mg, 2.12 mmol) and 4-aminobenzoic acid (291 mg, 2.12 mmol) were milled together with a few drops of TBME for 3 x 15 minutes at 30 Hz in a Retsch MIVI400 ball mill. The product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • FIG. 1 The experimental XRPD pattern of the 1:1 AV-101 4-Aminobenzoic Acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 1.
  • Table 1 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 1. The entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal as well as by an XRPD pattern substantially similar to FIG. 1.
  • the cocrystal may be characterized by one, by at least two, by at least three, by at least four, by at least five or by six peaks selected from the group consisting of 4.6, 9.3, 11.8, 13.3, 14.0 and 17.0 °20 ⁇ 0.2 °20.
  • FIG. 2 is a stack plot showing the XRPD patterns of AV-101, 4-aminobenzoic acid and the 1:1 AV-101 4-Aminobenzoic Acid Cocrystal.
  • FIG. 3 An ORTEP diagram of the 1:1 AV-101 4-aminobenzoic acid cocrystal at 100 K showing the numbering system employed is shown in FIG. 3. Anisotropic atomic displacement ellipsoids for the non-hydrogen atoms are shown at the 50% probability level and hydrogen atoms are displayed as spheres of arbitrary radius.
  • the calculated XRPD pattern based on the single crystal data and structure for the 1:1 AV-1014-aminobenzoic acid cocrystal at 100 K is shown in FIG. 3. It is also noted that there are some small temperature shifts in some of the peaks owing to the fact that the experimental XRPD pattern was collected at room temperature and the calculated XRPD pattern is derived from data collected at 100 K. There are also small intensity differences owing to preferred orientation effects, present in the experimental pattern.
  • the cocrystal may be characterized by its crystal system, space group and/or unit cell parameters and by an XRPD pattern substantially similar to FIG. 3.
  • TGA thermal gravimetric analysis
  • FIG. 7 The experimental Infrared Spectrum of the 1:1 AV-101 4-Aminobenzoic Acid Cocrystal is shown in FIG. 7.
  • the significant peaks identified in the experimental infrared spectrum of FIG. 7 are 3470, 3355, 3211, 1660, 1625, 1614, 1600, 1558, 1530, 1512, 1427, 1405, 1383, 1339, 1311, 1269, 1237, 1212, 1169, 1127, 1095, 1074, 1054, 1008, 951, 901, 871, 849, 823, 780, 742, 700, 636, 612, 581, 565, 522 and 493cm 1 ⁇ 1 cm 1 .
  • the entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an infrared pattern substantially similar to FIG. 7.
  • the 1:1 AV- 101 4-aminobenzoic acid cocrystal may be characterized by at least three peaks selected from the peaks at 1555, 1512, 1427, 1269 and 1212 cm 1 ⁇ 1 cm 1 .
  • AV101 (104mg, 0.43mmol) and 4-Aminobenzoic acid (55mg, 0.40mmol, 0.94eq) were matured between RT and 40'C overnight in 2ml of a TBIV1 E solvent saturated with 4-Aminobenzoic acid. After this time the sample was filtered, washed with 0.5ml of TBME and further dried in-vacuo at 40°C for Bit.
  • Example 2 1:1 AV-101 Salicylic Acid Cocrystal
  • AV-101(525 mg, 2.16 mmol) and salicylic acid (299 mg, 2.16 mmol) were milled together with a few drops of nitromethane for 3 x 15 minutes at 30 Hz in a Retsch MIVI400 ball mill. The product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the cocrystal may be characterized by one, by at least two, by at least three, by at least four, or by five peaks selected from the group consisting of 4.7, 9.5, 14.4, 15.1, and 19.3 °20 ⁇ 0.2 °20.
  • FIG. 9 is a stack plot showing the XRPD patterns of AV- 101, salicylic acid and the 1:1 AV-101 Salicylic Acid Cocrystal.
  • TGA thermal gravimetric analysis
  • the experimental Infrared Spectrum of the 1:1 AV-101 salicylic Acid Cocrystal is shown in FIG. 12.
  • the significant peaks identified in the experimental infrared spectrum of FIG. 12 are 3450, 3342, 1660, 1611, 1583, 1515, 1484, 1430, 1363, 1299, 1245, 1214, 1155, 1092, 1031, 992, 859, 909, 841, 785, 748, 697, 660, 636, 598, 575, 526 and 498cm 1 ⁇ 1 cm - 1 .
  • the entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an infrared pattern substantially similar to FIG. 12.
  • the 1:1 AV-101 salicylic acid cocrystal may be characterized by at least four peaks selected from the peaks at 1660, 1611, 1583, 1484, 1299 and 1245 cm 1 ⁇ 1 cm - 1 .
  • AV-101 (127mg, 0.52mmol) and Salicylic acid (70mg, O.Slmmol, 0.97eq) were matured between R.T and 40°C overnight in 2ml of Nitromethane solvent saturated with Salicylic acid. After this time the sample was filtered, washed with 0.5ml of Nitromethane and further dried in-vacuo at 40"C for Bit.
  • Example 3 1:1 AV-101 Malonic Acid Cocrystal
  • AV-101 (508 mg, 2.09 mmol) and malonic acid (218 mg, 2.09 mmol) were milled together with a few drops of nitromethane for 3 x 15 minutes at 30 Hz in a Retsch MM400 ball mill. The product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the cocrystal may be characterized by one, by at least two, by at least three, by at least four, or by five peaks selected from the group consisting of 5.4, 9.4 , 10.8, 12.6 or 15.5 °20 ⁇ 0.2 °20.
  • FIG. 14 is a stack plot showing the XRPD patterns of AV-101, Malonic acid and the 1:1 AV-101 Malonic Acid Cocrystal. Table 3
  • the differential scanning calorimetry (DSC) trace shows a double endotherm with the major endotherm having a peak maximum at 175.6°C.
  • TGA thermal gravimetric analysis
  • the experimental Infrared Spectrum of the 1:1 AV-101 malonic Acid Cocrystal is shown in FIG. 17.
  • the significant peaks identified in the experimental infrared spectrum of FIG. 17 are 3497, 3363, 2981, 1732, 1679, 1637, 1614, 1596, 1575, 1534, 1475, 1427, 1380, 1289, 1211, 1170, 1156, 1100, 1058, 1003, 961, 934, 909, 854, 825, 787, 763, 654, 577 and 497 cm 1 ⁇ 1 cm - 1 .
  • the entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an infrared pattern substantially similar to FIG. 17.
  • the 1:1 AV-101 malonic acid cocrystal may be characterized by at least four peaks selected from the peaks at 1679, 1637, 1575, 1475, 1380 and 1211 cm 1 ⁇ 1 cm - 1 .
  • AV101 USmg, 0.47mmol
  • Malonic acid 45mg, 0.43mmol, 0.32eq
  • AV101 USmg, 0.47mmol
  • Malonic acid 45mg, 0.43mmol, 0.32eq
  • Example 4 1:1 AV-101 Cinnamic Acid Cocrystal
  • AV-101 Cinnamic Acid Cocrystal used for characterisation was prepared as follows: [00127] AV-101 (515 mg, 2.12 mmol) and cinnamic acid (315 mg, 2.12 mmol) were milled together with a few drops of nitromethane for 3 x 15 minutes at 30 Hz in a Retsch MM400 ball mill. The product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the cocrystal may be characterized by one, by at least two, by at least three, by at least four, by at least five, by at least six or by seven peaks selected from the group consisting of 4.1, 8.3, 10.5, 12.8, 15.9, 17.8 and 19.5 °20 ⁇ 0.2 °20.
  • FIG. 19 is a stack plot showing the XRPD patterns of AV-101, Cinnamic Acid and the 1:1 AV-101 Cinnamic Acid Cocrystal.
  • the differential scanning calorimetry (DSC) trace FIG. 20, shows a single endotherm with peak maximum at 204 °C
  • TGA thermal gravimetric analysis
  • FIG. 22 The experimental Infrared Spectrum of the 1:1 AV-101 cinnamic Acid Cocrystal is shown in FIG. 22.
  • the significant peaks identified in the experimental infrared spectrum of FIG. 22 are 3478, 3366, 3203, 2981, 2888, 1671, 1616, 1556, 1533, 1429, 1384, 1347, 1267, 1239, 1200, 1159, 1138, 1096, 1064, 1028, 982, 954, 906, 876, 642, 783, 772, 743, 714, 683, 629, 583, 525 and 481 cm 1 ⁇ 1 cm *.
  • the entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an infrared pattern substantially similar to FIG. 22.
  • the 1:1 AV-101 malonic acid cocrystal may be characterized by at least four peaks selected from the peaks at 1616, 1556, 1533, 1429, 1384 and 1200 cm 1 ⁇ 1 cm - 1 .
  • AV101 (121mg, 0.50mmol) and Cinnamic acid (72mg, 0.49mmol, 0.97eq) were matured between RT and 40°C overnight in 1ml of Nitromethane solvent saturated with Cinnamic acid. After this time the sample was filtered, washed with 0.5ml of Nitromethane and further dried in-vacuo at 40°C for lhr.
  • Example 5 3:2 AV-101 Gentisic Acid (2,5-Dihydroxybenzoic Acid) Cocrystal
  • FIG. 23 The experimental XRPD pattern of the 3:2 AV-101 Gentisic Acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 23.
  • Table 5 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 23. The entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal as well as by an XRPD pattern substantially similar to FIG. 23.
  • the cocrystal may be characterized by one, by at least two, by at least three, by at least four, by at least five, by at least six or by seven peaks selected from the group consisting of 5.2, 6.7, 8.1, 9.4, 10.9, 12.7 and 13.5 °20 ⁇ 0.2 °20.
  • FIG. 24 is a stack plot showing the XRPD patterns of AV-101, Gentisic Acid and the 3:2 AV-101 Gentisic Acid Cocrystal.
  • TGA thermal gravimetric analysis
  • FIG. 27 The experimental Infrared Spectrum of the 3:2 AV-101 gentisic Acid cocrystal is shown in FIG. 27.
  • the significant peaks identified in the experimental infrared spectrum of FIG. 27 are 3659, 3487, 3430, 3341, 2981, 2889, 1673, 1640, 1583, 1554, 1466, 1424, 1397, 1336, 1275, 1233, 1206, 1186, 1102, 1091, 1073, 1051, 999, 957, 910, 892, 848, 822, 777, 748, 674, 623, 556, 513 and 496 cm 1 ⁇ 1 cm *.
  • the entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an infrared pattern substantially similar to FIG. 27.
  • the 1:1 AV-101 malonic acid cocrystal may be characterized by at least four peaks selected from the peaks at 1583, 1554, 1486, 1424, 1397 and 1186 cm 1 ⁇ 1 cm - 1 .
  • Example 6 2:1 AV-101 Oxalic Acid Monohydrate Cocrystal
  • AV-101 (507 mg, 2.09 mmol) and cinnamic acid (95 mg, 1.05 mmol) were milled together with a few drops of water for 3 x 15 minutes at 30 Hz in a Retsch MM400 ball mill. The product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • FIG. 29 The experimental XRPD pattern of the 2:1 AV-101 Oxalic Acid Monohydrate Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 29.
  • Table 6 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 29. The entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal as well as by an XRPD pattern substantially similar to FIG. 29.
  • the cocrystal may be characterized by one, by at least two, by at least three, by at least four or by five peaks selected from the group consisting of 4.6, 7.3, 9.4, 13.5 and 14.1 °20 ⁇ 0.2 °20.
  • FIG. 30 is the stack plot showing the XRPD patterns of AV-101, Oxalic acid and the2:l AV-101 Oxalic Acid Monohydrate Cocrystal.
  • Oxalic cocrystal grown from methanol was obtained and shows a 1:0.5 ratio between AV101 and Oxalic acid and water and methanol present in the crystal.
  • the crystal structure also shows a mixed cocrystal/salt with one molecule of AV101 protonated and one molecule in the zwitterionic form (neutral).
  • the cocrystal formed from grinding in pure water has a similar XRPD to the methanol/water structure shown below, however the data suggests that the structure has just one water molecule present.
  • An ORTEP diagram of the 2:1 AV-101 Oxalic Acid Monohydrate Cocrystal is shown in FIG. 31.
  • Thermal analysis and particularly Gravimetric Vapor Sorption (GVS) Analysis analysis indicate that lmol of water is present within the structure (ca. 3.5% w/w water content).
  • the differential scanning calorimetry (DSC) trace shows a broad endotherm in the temperature range 70-100 °C and also two endotherms with peak maximums at 170.2 and 185.6 °C.
  • the broad endotherm in the temperature range 70-100 °C may be the loss of water which could impact the integrity of the cocrystal in the continued scan at higher temperatures.
  • TGA thermal gravimetric analysis
  • the experimental Infrared Spectrum of the 2:1 AV-101 oxalic acid monohydrate cocrystal is shown in FIG. 34.
  • the significant peaks identified in the experimental infrared spectrum of FIG. 34 are 3451, 3333, 1702, 1654, 1610, 1588, 1535, 1488, 1426, 1375, 1198m, 1096, 1062, 965, 899, 848, 782, 701, 577 and 492 cm 1 ⁇ 1 cm - 1 .
  • the entire list of peaks, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an infrared pattern substantially similar to FIG. 34.
  • the 1:1 AV-101 malonic acid cocrystal may be characterized by at least four peaks selected from the peaks at 1610, 1588, 1535, 1488, 1426 and 1198 cm 1 ⁇ 1 cm - 1 .
  • Example 7 1:1 AV-101 Benzoic Acid Cocrystal
  • AV-101 50 mg, 0.21 mmol
  • benzoic acid 27 mg, 0.22 mmol
  • the product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the experimental XRPD pattern of the 1:1 AV-101 Benzoic Acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 36.
  • Table 7 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 36. The entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal as well as by an XRPD pattern substantially similar to FIG. 36.
  • the cocrystal may be characterized by one, by at least two, or by three peaks selected from the group consisting of 9.5, 14.3 and 17.6 °20 ⁇ 0.2 °20. Table 7
  • Example 8 1:1 AV-1012,4-Dihydroxybenzoic Acid Cocrystal
  • AV-101 47 mg, 0.19 mmol
  • 2,4-dihydroxybenzoic acid 30 mg, 0.19 mmol
  • the product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the experimental XRPD pattern of the 1:1 AV-101 2,4-dihydroxybenzoic Acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 37.
  • Table 8 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 37. The entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an XRPD pattern substantially similar to FIG. 37.
  • the cocrystal may be characterized by peaks at 5.2 and/or 11.8 °20 ⁇ 0.2 °20.
  • Example 9 1:1 AV-1013,4-Dihydroxybenzoic Acid Cocrystal
  • AV-101 46 mg, 0.19 mmol
  • 3,4-dihydroxybenzoic acid 29 mg, 0.19 mmol
  • the product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the experimental XRPD pattern of the 1:1 AV-101 3,4-dihydroxybenzoic Acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 38.
  • Table 9 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 38.
  • the entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an XRPD pattern substantially similar to FIG. 38.
  • the cocrystal may be characterized by a peak at 5.3 and/or 15.1 °20 ⁇ 0.2 °20.
  • Example 10 1:1 AV-101 2-Furoic Acid Cocrystal
  • AV-101 51 mg, 021 mmol
  • 2-furoic acid 28 mg, 0.25 mmol
  • the product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the experimental XRPD pattern of the 1:1 AV-101 2-Furoic Acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 39.
  • Table 10 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 39.
  • the entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an XRPD pattern substantially similar to FIG. 39.
  • the cocrystal may be characterized by one, by at least two or by three peaks selected from the group consisting of 4.9, 10.0 and 15.1 °20 ⁇ 0.2 °20.
  • Example 11 Crystalline 1:1 AV-101 Glycolic Acid Cocrystal
  • AV-101 33 mg, 0.14 mmol
  • glycolic acid 11 mg, 0.14 mmol
  • the product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the experimental XRPD pattern of the 1:1 AV-101 Glycolic Acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 40.
  • Tabe 11 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 40.
  • the entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an XRPD pattern substantially similar to FIG. 40.
  • the cocrystal may be characterized by at least two, at least three, at least four, or five peaks selected from the group consisting of 5.3, 9.7, 15.1, 17.7 and 18.6 °20 ⁇ 0.2 °20.
  • Example 12 1:1 AV-101 3-Hydroxy-2-naphthoic acid Cocrystal
  • AV-101 35 mg, 0.14 mmol
  • 3-Hydroxy-2-naphthoic acid 26 mg, 0.14 mmol
  • the product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the experimental XRPD pattern of the 1:1 AV-101 3-Hydroxy-2-naphthoic acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 41.
  • Table 12 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 41.
  • the entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an XRPD pattern substantially similar to FIG. 41.
  • the cocrystal may be characterized by at least two, at least three or four peaks selected from the group consisting of 4.2, 8.5, 16.3 and 17.2 °20 ⁇ 0.2 °20.
  • the differential scanning calorimetry (DSC) trace shows a single endotherm with a peak maximum of 218 °C.
  • Example 13 1:1 AV-101 4-Hydroxybenzoic Acid Cocrystal
  • AV-101 4-Hydroxybenzoic Acid Cocrystal used for characterisation was prepared as follows: [00209] AV-101 (35 mg, 0.14 mmol) and 4-hydroxybenzoic acid (20 mg, 0.14 mmol) were milled together with a few drops of acetone for 3 x 15 minutes at 30 Hz in a Retsch MIVI400 ball mill. The product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the experimental XRPD pattern of the 1:1 AV-1014-Hydroxybenzoic Acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 43.
  • Table 13 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 43.
  • the entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an XRPD pattern substantially similar to FIG. 43.
  • the cocrystal may be characterized by one, by at least two, by at least three or by four peaks selected from the group consisting of 4.4, 13.3, 14.5 and 19.9 °20 ⁇ 0.2 °20.
  • Example 14 1:1 AV-101 Lactic Acid Cocrystal
  • the experimental XRPD pattern of the 1:1 AV-101 Lactic Acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 44.
  • Table 14 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 44.
  • the entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an XRPD pattern substantially similar to FIG. 44.
  • the cocrystal may be characterized by a peak at 5.3 and/or 10.7 °20 ⁇ 0.2 °20.
  • DSC differential scanning calorimetry
  • Example 15 1:1 AV-101 L-Malic Acid Cocrystal
  • AV-101 32 mg, 0.13 mmol
  • L-malic acid (19 mg, 0.14 mmol) were milled together with a few drops of acetone for 3 x 15 minutes at 30 Hz in a Retsch MIVI400 ball mill. The product was dried under ambient conditions overnight and then in vacuo at 40°C for lhr.
  • the experimental XRPD pattern of the 1:1 AV-101 L-Malic Acid Cocrystal as acquired on the Bruker 2nd Gen D2-Phaser diffractometer is shown in FIG. 46.
  • Table 14 lists the angles, °20 ⁇ O.2°20, and d value of the peaks identified in the experimental XRPD pattern of FIG. 36.
  • the entire list of peaks or corresponding d values, or a subset thereof, may be sufficient to characterize the cocrystal, as well as by an XRPD pattern substantially similar to FIG. 36.
  • the cocrystal may be characterized by one, by at least two or by three peaks selected from the group consisting of 5.1, 12.0 and 16.6 °20 ⁇ 0.2 °20.

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Abstract

L'invention concerne des co-cristaux de L-4-chlorokynurénine, des compositions pharmaceutiques contenant ces co-cristaux et des méthodes d'utilisation de tels co-cristaux et de telles compositions dans le traitement de troubles neurologiques ou psychiatriques induits au moins en partie par le récepteur NMDA.
PCT/US2021/055409 2020-10-16 2021-10-18 Co-cristaux de l-4-chlorokynurénine, compositions et utilisations thérapeutiques associées WO2022082100A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160031800A1 (en) * 2013-03-14 2016-02-04 Vistagen Therapeutics, Inc. Synthesis of chiral kynurenine compounds and intermediates
US20160158178A1 (en) * 2013-01-22 2016-06-09 Vistagen Therapeutics, Inc. Dosage forms and therapeutic uses l-4-chlorokynurenine
US20180327351A1 (en) * 2015-09-08 2018-11-15 Cephalon, Inc. Prodrugs of chlorokynurenines
WO2019157426A1 (fr) * 2018-02-09 2019-08-15 Vistagen Therapeutics, Inc. Synthèse de 4-chlorokynurénines et intermédiaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160158178A1 (en) * 2013-01-22 2016-06-09 Vistagen Therapeutics, Inc. Dosage forms and therapeutic uses l-4-chlorokynurenine
US20160031800A1 (en) * 2013-03-14 2016-02-04 Vistagen Therapeutics, Inc. Synthesis of chiral kynurenine compounds and intermediates
US20180327351A1 (en) * 2015-09-08 2018-11-15 Cephalon, Inc. Prodrugs of chlorokynurenines
WO2019157426A1 (fr) * 2018-02-09 2019-08-15 Vistagen Therapeutics, Inc. Synthèse de 4-chlorokynurénines et intermédiaires

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