WO2020033344A1 - Polymorphic compounds and uses thereof - Google Patents

Polymorphic compounds and uses thereof Download PDF

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Publication number
WO2020033344A1
WO2020033344A1 PCT/US2019/045206 US2019045206W WO2020033344A1 WO 2020033344 A1 WO2020033344 A1 WO 2020033344A1 US 2019045206 W US2019045206 W US 2019045206W WO 2020033344 A1 WO2020033344 A1 WO 2020033344A1
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Prior art keywords
compound
present
xrpd
peaks
provides
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Ceased
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PCT/US2019/045206
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English (en)
French (fr)
Inventor
Stephen Gitu MACHATHA
Jonathan James LOUGHREY
Hannah Ruth MCLACHLAN
Gregor SNEDDON
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Aldeyra Therapeutics Inc
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Aldeyra Therapeutics Inc
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Priority to AU2019319740A priority Critical patent/AU2019319740A1/en
Priority to CN201980061502.6A priority patent/CN112714762A/zh
Priority to US17/265,757 priority patent/US12006298B2/en
Priority to JP2021506407A priority patent/JP2021533154A/ja
Priority to EP19847975.0A priority patent/EP3833660A4/en
Publication of WO2020033344A1 publication Critical patent/WO2020033344A1/en
Anticipated expiration legal-status Critical
Priority to US17/365,604 priority patent/US11312692B1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/05—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing at least two sulfo groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/07—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton
    • C07C309/08—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton containing hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • 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
    • 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
    • C07C59/10—Polyhydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application relates to various forms and compositions, and methods, useful for treating various conditions in which aldehyde toxicity is implicated in the pathogenesis by the administration of small molecule therapeutics acting as a scavenger for toxic aldehydes.
  • A2E phosphatidylethanolamine
  • AMD Age Related Macular Degeneration
  • Novel small molecule therapeutics can be used to scavenge“escaped” retinaldehyde in the retina, thus reducing A2E formation and lessening the risk of AMD (Jordan et al. (2006)).
  • Aldehydes are implicated in diverse pathological conditions such as dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Larsson Syndrome, ischemic-reperfusion injury, inflammation, diabetes, neurodegeneration ( e.g ., Parkinson’s disease), scleroderma, amyotrophic lateral sclerosis, autoimmune disorders (e.g., lupus), cardiovascular disorders (e.
  • MDA, HNE and other toxic aldehydes are generated by a myriad of metabolic mechanisms involving: fatty alcohols, sphingolipids, glycolipids, phytol, fatty acids, arachadonic acid metabolism (Rizzo (2007)), polyamine metabolism (Wood et al. (2006)), lipid peroxidation, oxidative metabolism (Buddi et al. (2002), Zhou et al. (2005)), and glucose metabolism (Pozzi et al. (2009)).
  • Aldehydes can cross link with primary amino groups and other chemical moieties on proteins, phospholipids, carbohydrates, and DNA, leading in many cases to toxic consequences, such as mutagenesis and carcinogenesis (Marnett (2002)).
  • MDA is associated with diseased corneas, keratoconus, bullous and other keratopathy, and Fuch’s endothelial dystrophy corneas (Buddi et al. (2002)).
  • skin disorders e.g., Sjogren-Larsson Syndrome
  • octadecanal and hexadecanal e.g., Sjogren-Larsson Syndrome
  • increased lipid peroxidation and resultant aldehyde generation are associated with the toxic effects of blister agents (Sciuto et al. (2004) and Pal et al. (2009)).
  • Compounds provided by this invention are also useful for the study of certain aldehydes in biology and pathological phenomena.
  • FIG. 1 depicts the XRPD pattern of Compound A, Form A.
  • FIG. 2 depicts a TG/DTA trace of Compound A, Form A.
  • FIG. 3 depicts the XRPD pattern of Compound A, Form B.
  • FIG. 4 depicts a TG/DTA trace of Compound A, Form B.
  • FIG. 5 depicts the XRPD pattern of Compound A, Form C.
  • FIG. 6 depicts a TG/DTA trace of Compound A, Form C.
  • FIG. 7 depicts the XRPD pattern of Compound 1, Form A.
  • FIG. 8 depicts a TG/DTA trace of Compound 1, Form A.
  • FIG. 9 depicts the XRPD pattern of Compound 2, Form A.
  • FIG. 10 depicts a TG/DTA trace of Compound 2, Form A.
  • FIG. 11 depicts the XRPD pattern of Compound 2, Form B.
  • FIG. 12 depicts a TG/DTA trace of Compound 2, Form B.
  • FIG. 13 depicts the XRPD pattern of Compound 3, Form A.
  • FIG. 14 depicts a TG/DTA trace of Compound 3, Form A.
  • FIG. 15 depicts the XRPD pattern of Compound 3, Form B.
  • FIG. 16 depicts a TG/DTA trace of Compound 3, Form B.
  • FIG. 17 depicts the XRPD pattern of Compound 4, Form A.
  • FIG. 18 depicts the XRPD pattern of Compound 5, Form A.
  • FIG. 19 depicts a TG/DTA trace of Compound 5, Form A.
  • FIG. 20 depicts the XRPD pattern of Compound 5, Form B.
  • FIG. 21 depicts a TG/DTA trace of Compound 5, Form B.
  • FIG. 22 depicts the XRPD pattern of Compound 5, Form C.
  • FIG. 23 depicts a TG/DTA trace of Compound 5, Form C.
  • FIG. 24 depicts the XRPD pattern of Compound 6, Form A.
  • FIG. 25 depicts a TG/DTA trace of Compound 6, Form A.
  • FIG. 26 depicts the XRPD pattern of Compound 7, Form A.
  • FIG. 27 depicts a TG/DTA trace of Compound 7, Form A.
  • FIG. 28 depicts the XRPD pattern of Compound 7, Form B.
  • FIG. 29 depicts a TG/DTA trace of Compound 7, Form B.
  • FIG. 30 depicts the XRPD pattern of Compound 8, Form A.
  • FIG. 31 depicts a TG/DTA trace of Compound 8, Form A.
  • FIG. 32 depicts the XRPD pattern of Compound 8, Form B.
  • FIG. 33 depicts a TG/DTA trace of Compound 8, Form B.
  • FIG. 34 depicts the XRPD pattern of Compound 9, Form A.
  • FIG. 35 depicts a TG/DTA trace of Compound 9, Form A.
  • FIG. 36 depicts the XRPD pattern of Compound 10, Form A.
  • FIG. 37 depicts the XRPD pattern of Compound 11, Form A.
  • FIG. 38 depicts the XRPD pattern of Compound 12, Form A.
  • FIG. 39 depicts a TG/DTA trace of Compound 12, Form A.
  • FIG. 40 depicts a unit cell of compound A.
  • FIG. 41 depicts simulated and experimental XRPD patterns of compound A.
  • compound A can exist in a variety of physical forms.
  • compound A can be in solution, suspension, or in solid form.
  • compound A is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides a form of compound A substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include different forms of compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound A.
  • at least about 95% by weight of a form of compound A is present.
  • at least about 99% by weight of a form of compound A is present.
  • a form of compound A is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of compound A contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • a form of compound A contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for a form of compound A is also meant to include all tautomeric forms of compound A. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound A can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • polymorph refers to the different crystal structures into which a compound, or a salt or solvate thereof, can crystallize.
  • compound A is a crystalline solid. In other embodiments, compound A is a crystalline solid substantially free of amorphous compound A. As used herein, the term "substantially free of amorphous compound A" means that the compound contains no significant amount of amorphous compound A. In certain embodiments, at least about 95% by weight of crystalline compound A is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound A is present.
  • compound A can exist in at least three distinct polymorphic forms.
  • the present invention provides a polymorphic form of compound A referred to herein as Form A.
  • the present invention provides a polymorphic form of compound A referred to herein as Form B.
  • the present invention provides a polymorphic form of compound A referred to herein as Form C.
  • compound A is amorphous. In some embodiments, compound A is amorphous, and is substantially free of crystalline compound A.
  • Form A of compound A has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 1 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound A is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 8.2, about 16.2 and about 22.2 degrees 2-theta. In some embodiments, Form A of compound A is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 8.2, about 16.2 and about 22.2 degrees 2-theta. In some embodiments, Form A of compound A is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 8.2, about 16.2 and about 22.2 degrees 2-theta. As used herein, the term "about”, when used in reference to a degree 2-theta value refers to the stated value ⁇ 0.2 degree 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 1.
  • Form B of compound A has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 2 below.
  • the position 2Q is within ⁇ 0.2.
  • Form B of compound A is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 10.2, about 11.5 and about 23.3 degrees 2-theta. In some embodiments, Form B of compound A is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 10.2, about 11.5 and about 23.3. In some embodiments, Form B of compound A is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 10.2, about 11.5 and about 23.3.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 3.
  • Form C of compound A has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 3 below.
  • the position 2Q is within ⁇ 0.2.
  • Form C of compound A is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 15.8, about 23.0 and about 23.1 degrees 2-theta. In some embodiments, Form C of compound A is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 15.8, about 23.0 and about 23.1. In some embodiments, Form C of compound A is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 15.8, about 23.0 and about 23.1.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 5.
  • the present invention provides compound A:
  • the present invention provides compound A, wherein said compound is substantially free of amorphous compound A.
  • the present invention provides compound A, wherein said compound is substantially free of impurities.
  • the present invention provides compound A, wherein said compound has one or more peaks in its XRPD selected from those at about 8.2, about 16.2 and about 22.2 degrees 2-theta. In some such embodiments, the present invention provides compound 1, wherein said compound has at least two peaks in its XRPD selected from those at about about 8.2, about 16.2 and about 22.2 degrees 2-theta. In some such embodiments, the present invention provides Compound A, wherein said compound is of Form A.
  • the present invention provides compound A, wherein said compound has an XRPD substantially similar to that depicted in Figure 1.
  • the present invention provides compound A, wherein said compound has one or more peaks in its XRPD selected from those at about 10.2, about 11.5 and about 23.3 degrees 2-theta. In some such embodiments, the present invention provides compound A, wherein said compound has at least two peaks in its XRPD selected from those at about 10.2, about 11.5 and about 23.3 degrees 2-theta. In some such embodiments, the present invention provides compound A, wherein said compound is of Form B.
  • the present invention provides compound A, wherein said compound has an XRPD substantially similar to that depicted in Figure 3.
  • the present invention provides compound A, wherein said compound has one or more peaks in its XRPD selected from those at about 15.8, about 23.0 and about 23.1 degrees 2-theta. In some such embodiments, the present invention provides compound A, wherein said compound has at least two peaks in its XRPD selected from those at about 15.8, about 23.0 and about 23.1 degrees 2-theta. In some such embodiments, the present invention provides compound A, wherein said compound is of Form C.
  • the present invention provides compound A, wherein said compound has an XRPD substantially similar to that depicted in Figure 5. [0082] In some embodiments, the present invention provides a composition comprising compound A and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound A or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound A or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Larsson
  • an acid and compound A are ionically bonded to form one of compounds 1 through 12, described below.
  • compounds 1 through 12 can exist in a variety of physical forms.
  • compounds 1 through 12 can be in solution, suspension, or in solid form.
  • compounds 1 through 12 are in solid form.
  • said compounds may be amorphous, crystalline, or a mixture thereof. Exemplary such solid forms of compounds 1 through 12 are described in more detail below.
  • Compound 1 Mesylate Salts of Compound A
  • the present invention provides a mesylate salt of compound A, represented by compound 1 :
  • compound 1 can exist in a variety of physical forms.
  • compound 1 can be in solution, suspension, or in solid form.
  • compound 1 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 1 substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess methanesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 1.
  • extraneous matter may include excess methanesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 1.
  • at least about 95% by weight of compound 1 is present.
  • at least about 99% by weight of compound 1 is present.
  • compound 1 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 1 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 1 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 1 is also meant to include all tautomeric forms of compound 1. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 1 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 1 is a crystalline solid. In other embodiments, compound 1 is a crystalline solid substantially free of amorphous compound 1. As used herein, the term "substantially free of amorphous compound 1" means that the compound contains no significant amount of amorphous compound 1. In certain embodiments, at least about 95% by weight of crystalline compound 1 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 1 is present.
  • compound 1 can exist in at least three distinct polymorphic forms.
  • the present invention provides a polymorphic form of Compound 1 referred to herein as Form A.
  • the present invention provides a polymorphic form of compound 1 referred to herein as Form B.
  • the present invention provides a polymorphic form of compound 1 referred to herein as Form C.
  • compound 1 is amorphous. In some embodiments, compound 1 is amorphous, and is substantially free of crystalline compound 1.
  • Form A of compound 1 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 4 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 1 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 14.9, about 17.7 and about 19.2 degrees 2-theta. In some embodiments, Form A of compound 1 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 14.9, about 17.7 and about 19.2 degrees 2-theta. In some embodiments, Form A of compound 1 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 14.9, about 17.7 and about 19.2 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 7.
  • Form B of compound 1 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 5 below.
  • the position 2Q is within ⁇ 0.2.
  • Form B of compound 1 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 10.5, about 14.9 and about 19.6 degrees 2-theta. In some embodiments, Form B of compound 1 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 10.5, about 14.9 and about 19.6 degrees 2-theta. In some embodiments, Form B of compound 1 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 10.5, about 14.9 and about 19.6 degrees 2-theta.
  • Form C of compound 1 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 6 below.
  • the position 2Q is within ⁇ 0.2.
  • Form C of compound 1 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 12.4, about 17.9 and about 19.4 degrees 2-theta. In some embodiments, Form C of compound 1 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 12.4, about 17.9 and about 19.4 degrees 2-theta. In some embodiments, Form C of compound 1 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 12.4, about 17.9 and about 19.4 degrees 2-theta.
  • the present invention provides compound 1:
  • the present invention provides compound 1, wherein said compound is crystalline.
  • the present invention provides compound 1, wherein said compound is a crystalline solid substantially free of amorphous compound 1.
  • the present invention provides compound 1, wherein said compound is substantially free of impurities.
  • the present invention provides compound 1, wherein said compound has one or more peaks in its XRPD selected from those at 14.9, about 17.7 and about 19.2 degrees 2-theta. In some such embodiments, the present invention provides compound 1, wherein said compound has at least two peaks in its XRPD selected from those at about 14.9, about 17.7 and about 19.2 degrees 2-theta. In some such embodiments, the present invention provides compound 1, wherein said compound is of Form A.
  • the present invention provides compound 1, wherein said compound has an XRPD substantially similar to that depicted in Figure 7.
  • the present invention provides compound 1, wherein said compound has one or more peaks in its XRPD selected from those at aboutl0.5, about 14.9 and about 19.6 degrees 2-theta. In some such embodiments, the present invention provides compound 1, wherein said compound has at least two peaks in its XRPD selected from those at about 10.5, about 14.9 and about 19.6 degrees 2-theta. In some such embodiments, the present invention provides compound 1, wherein said compound is of Form B. [00112] In some embodiments, the present invention provides compound 1, wherein said compound has one or more peaks in its XRPD selected from those at about 12.4, about 17.9 and about 19.4 degrees 2-theta.
  • the present invention provides compound 1, wherein said compound has at least two peaks in its XRPD selected from those at about 12.4, about 17.9 and about 19.4 degrees 2-theta. In some such embodiments, the present invention provides compound 1, wherein said compound is of Form C.
  • the present invention provides a composition comprising compound 1 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 1 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 1 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Larsson
  • the present invention provides a besylate salt of compound A, represented by compound 2:
  • compound 2 can exist in a variety of physical forms.
  • compound 2 can be in solution, suspension, or in solid form.
  • compound 2 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 2 substantially free of impurities.
  • the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess benzenesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 2.
  • extraneous matter may include excess benzenesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 2.
  • at least about 95% by weight of compound 2 is present.
  • at least about 99% by weight of compound 2 is present.
  • compound 2 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 2 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 2 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 2 is also meant to include all tautomeric forms of compound 2. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 2 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 2 is a crystalline solid. In other embodiments, compound 2 is a crystalline solid substantially free of amorphous compound 2. As used herein, the term "substantially free of amorphous compound 2" means that the compound contains no significant amount of amorphous compound 2. In certain embodiments, at least about 95% by weight of crystalline compound 2 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 2 is present.
  • compound 2 can exist in at least three distinct polymorphic forms.
  • the present invention provides a polymorphic form of Compound 2 referred to herein as Form A.
  • the present invention provides a polymorphic form of compound 2 referred to herein as Form B.
  • the present invention provides a polymorphic form of compound 2 referred to herein as Form C.
  • compound 2 is amorphous. In some embodiments, compound 2 is amorphous, and is substantially free of crystalline compound 2.
  • Form A of compound 2 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 7 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 15.8, about 17.8 and about 19.0 degrees 2-theta. In some embodiments, Form A of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 15.8, about 17.8 and about 19.0 degrees 2-theta. In some embodiments, Form A of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 15.8, about 17.8 and about 19.0 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 9.
  • Form B of compound 2 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 8 below.
  • the position 2Q is within ⁇ 0.2.
  • Form B of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 17.3, about 19.4 and about 25.9 degrees 2-theta. In some embodiments, Form B of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 17.3, about 19.4 and about 25.9 degrees 2-theta. In some embodiments, Form B of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 17.3, about 19.4 and about 25.9 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 11.
  • Methods for preparing Form B of compound 2 are described infra.
  • Form C of compound 2 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 9 below.
  • the position 2Q is within ⁇ 0.2.
  • Form C of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 15.1, about 16.7 and about 21.9 degrees 2-theta. In some embodiments, Form C of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 15.1, about 16.7 and about 21.9 degrees 2-theta. In some embodiments, Form C of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 15.1, about 16.7 and about 21.9 degrees 2-theta.
  • the present invention provides compound 2:
  • the present invention provides compound 2, wherein said compound is crystalline.
  • the present invention provides compound 2, wherein said compound is a crystalline solid substantially free of amorphous compound 2.
  • the present invention provides compound 2, wherein said compound is substantially free of impurities.
  • the present invention provides compound 2, wherein said compound has one or more peaks in its XRPD selected from those at about 15.8, about 17.8 and about 19.0 degrees 2-theta. In some such embodiments, the present invention provides compound 2, wherein said compound has at least two peaks in its XRPD selected from those at about 15.8, about 17.8 and about 19.0 degrees 2-theta. In some such embodiments, the present invention provides compound 2, wherein said compound is of Form A.
  • the present invention provides compound 2, wherein said compound has an XRPD substantially similar to that depicted in Figure 9.
  • the present invention provides compound 2, wherein said compound has one or more peaks in its XRPD selected from those at about 17.3, about 19.4 and about 25.9 degrees 2-theta. In some such embodiments, the present invention provides compound 2, wherein said compound has at least two peaks in its XRPD selected from those at about 17.3, about 19.4 and about 25.9 degrees 2-theta. In some such embodiments, the present invention provides compound 2, wherein said compound is of Form B.
  • the present invention provides compound 2, wherein said compound has an XRPD substantially similar to that depicted in Figure 11.
  • the present invention provides compound 2, wherein said compound has one or more peaks in its XRPD selected from those at about 15.1, about 16.7 and about 21.9 degrees 2-theta. In some such embodiments, the present invention provides compound 2, wherein said compound has at least two peaks in its XRPD selected from those at about 15.1, about 16.7 and about 21.9 degrees 2-theta. In some such embodiments, the present invention provides compound 2, wherein said compound is of Form C.
  • the present invention provides a composition comprising compound 2 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 2 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 2 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Larsson
  • the present invention provides a sulfate salt of compound A, represented by compound 3:
  • compound 3 can exist in a variety of physical forms.
  • compound 3 can be in solution, suspension, or in solid form.
  • compound 3 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 3 substantially free of impurities.
  • substantially free of impurities means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess sulfuric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 3.
  • extraneous matter may include excess sulfuric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 3.
  • at least about 95% by weight of compound 3 is present.
  • at least about 99% by weight of compound 3 is present.
  • compound 3 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 3 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 3 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 3 is also meant to include all tautomeric forms of compound 3. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 3 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 3 is a crystalline solid. In other embodiments, compound 3 is a crystalline solid substantially free of amorphous compound 3. As used herein, the term "substantially free of amorphous compound 3" means that the compound contains no significant amount of amorphous compound 3. In certain embodiments, at least about 95% by weight of crystalline compound 3 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 3 is present.
  • compound 3 is amorphous. In some embodiments, compound 3 is amorphous, and is substantially free of crystalline compound 3.
  • Form A of compound 3 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 10 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 3 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 11.8, about 13.2 and about 16.8 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 11.8, about 13.2 and about 16.8 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 11.8, about 13.2 and about 16.8 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 13.
  • Form B of compound 3 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 11 below.
  • the position 2Q is within ⁇ 0.2.
  • Form B of compound 3 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 12.8 and about 24.7 degrees 2-theta. In some embodiments, Form B of compound 3 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 12.8 and about 24.7 degrees 2-theta. In some embodiments, Form B of compound 3 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 12.8 and about 24.7 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 15.
  • Form C of compound 3 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 12 below.
  • the position 2Q is within ⁇ 0.2.
  • Form C of compound 3 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 14.7, about 20.0 and about 25.6 degrees 2-theta. In some embodiments, Form C of compound 3 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 14.7, about 20.0 and about 25.6 degrees 2-theta. In some embodiments, Form C of compound 3 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 14.7, about 20.0 and about 25.6 degrees 2-theta.
  • the present invention provides compound 3:
  • the present invention provides compound 3, wherein said compound is crystalline.
  • the present invention provides compound 3, wherein said compound is a crystalline solid substantially free of amorphous compound 3.
  • the present invention provides compound 3, wherein said compound is substantially free of impurities.
  • the present invention provides compound 3, wherein said compound has one or more peaks in its XRPD selected from those at about 11.8, about 13.2 and about 16.8 degrees 2-theta. In some such embodiments, the present invention provides compound 3, wherein said compound has at least two peaks in its XRPD selected from those at about 11.8, about 13.2 and about 16.8 degrees 2-theta. In some such embodiments, the present invention provides compound 3, wherein said compound is of Form A.
  • the present invention provides compound 3, wherein said compound has an XRPD substantially similar to that depicted in Figure 13.
  • the present invention provides compound 3, wherein said compound has one or more peaks in its XRPD selected from those at about 6.0, about 12.8 and about 24.7 degrees 2-theta. In some such embodiments, the present invention provides compound 3, wherein said compound has at least two peaks in its XRPD selected from those at about 6.0, about 12.8 and about 24.7 degrees 2-theta. In some such embodiments, the present invention provides compound 3, wherein said compound is of Form B. [00174] In some embodiments, the present invention provides compound 3, wherein said compound has an XRPD substantially similar to that depicted in Figure 15.
  • the present invention provides compound 3, wherein said compound has one or more peaks in its XRPD selected from those at about 14.7, about 20.0 and about 25.6 degrees 2-theta. In some such embodiments, the present invention provides compound 3, wherein said compound has at least two peaks in its XRPD selected from those at about 17.2, about 23.8 and about 25.5 degrees 2-theta. In some such embodiments, the present invention provides compound 3, wherein said compound is of Form C.
  • the present invention provides a composition comprising compound 3 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 3 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 3 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Larsson
  • the present invention provides a tosylate salt of compound A, represented by compound 4:
  • tosylate is meant -toluene sulfonate, i.e., the ionic form of /Moluenesulfonic acid. It will be appreciated by one of ordinary skill in the art that the /Moluenesulfonic acid and compound A are ionically bonded to form compound 4. It is contemplated that compound 4 can exist in a variety of physical forms. For example, compound 4 can be in solution, suspension, or in solid form. In certain embodiments, compound 4 is in solid form. When compound 4 is in solid form, said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 4 substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess /Moluenesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 4.
  • extraneous matter may include excess /Moluenesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 4.
  • at least about 95% by weight of compound 4 is present.
  • at least about 99% by weight of compound 4 is present.
  • compound 4 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 4 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 4 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 4 is also meant to include all tautomeric forms of compound 4. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 4 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 4 is a crystalline solid. In other embodiments, compound 4 is a crystalline solid substantially free of amorphous compound 4. As used herein, the term "substantially free of amorphous compound 4" means that the compound contains no significant amount of amorphous compound 4. In certain embodiments, at least about 95% by weight of crystalline compound 4 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 4 is present.
  • compound 4 is amorphous. In some embodiments, compound 4 is amorphous, and is substantially free of crystalline compound 4.
  • Form A of compound 4 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 13 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 4 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 11.2, about 11.4 and about 12.9 degrees 2-theta. In some embodiments, Form A of compound 4 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 11.2, about 11.4 and about 12.9 degrees 2-theta. In some embodiments, Form A of compound 4 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 11.2, about 11.4 and about 12.9 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 17.
  • the present invention provides compound 4:
  • the present invention provides compound 4, wherein said compound is crystalline.
  • the present invention provides compound 4, wherein said compound is a crystalline solid substantially free of amorphous compound 4.
  • the present invention provides compound 4, wherein said compound is substantially free of impurities.
  • the present invention provides compound 4, wherein said compound has one or more peaks in its XRPD selected from those at about 11.2, about 11.4 and about 12.9 degrees 2-theta. In some such embodiments, the present invention provides compound 4, wherein said compound has at least two peaks in its XRPD selected from those at about 11.2, about 11.4 and about 12.9 degrees 2-theta. In some such embodiments, the present invention provides compound 4, wherein said compound is of Form A.
  • the present invention provides compound 4, wherein said compound has an XRPD substantially similar to that depicted in Figure 17.
  • the present invention provides a composition comprising compound 4 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 4 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 4 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Larsson
  • the present invention provides a hydrochloride salt of compound A, represented by compound 5:
  • compound 5 can exist in a variety of physical forms.
  • compound 5 can be in solution, suspension, or in solid form.
  • compound 5 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 5 substantially free of impurities.
  • substantially free of impurities means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess hydrochloric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 5.
  • extraneous matter may include excess hydrochloric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 5.
  • at least about 95% by weight of compound 5 is present.
  • at least about 99% by weight of compound 5 is present.
  • compound 5 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 5 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 5 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 5 is also meant to include all tautomeric forms of compound 5. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 5 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 5 is a crystalline solid. In other embodiments, compound 5 is a crystalline solid substantially free of amorphous compound 5. As used herein, the term "substantially free of amorphous compound 5" means that the compound contains no significant amount of amorphous compound 5. In certain embodiments, at least about 95% by weight of crystalline compound 5 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 5 is present.
  • compound 5 is amorphous. In some embodiments, compound 5 is amorphous, and is substantially free of crystalline compound 5.
  • Form A of compound 5 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 14 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 5 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 13.6, about 16.7 and about 25.4 degrees 2-theta. In some embodiments, Form A of compound 5 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 13.6, about 16.7 and about 25.4 degrees 2-theta. In some embodiments, Form A of compound 5 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 13.6, about 16.7 and about 25.4 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 18.
  • Form B of compound 5 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 15 below.
  • the position 2Q is within ⁇ 0.2.
  • Form B of compound 5 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 18.8, about 23.1 and about 25.1 degrees 2-theta. In some embodiments, Form B of compound 5 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 18.8, about 23.1 and about 25.1 degrees 2-theta. In some embodiments, Form B of compound 5 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 18.8, about 23.1 and about 25.1 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 20.
  • Methods for preparing Form B of compound 5 are described infra.
  • Form C of compound 5 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 16 below.
  • the position 2Q is within ⁇ 0.2.
  • Form C of compound 5 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 13.4, about 14.1 and about 25.8 degrees 2-theta. In some embodiments, Form C of compound 5 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 13.4, about 14.1 and about 25.8 degrees 2-theta. In some embodiments, Form C of compound 5 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 13.4, about 14.1 and about 25.8 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 22.
  • the present invention provides compound 5:
  • the present invention provides compound 5, wherein said compound is crystalline.
  • the present invention provides compound 5, wherein said compound is a crystalline solid substantially free of amorphous compound 5.
  • the present invention provides compound 5, wherein said compound is substantially free of impurities.
  • the present invention provides compound 5, wherein said compound has one or more peaks in its XRPD selected from those at about 13.6, about 16.7 and about 25.4 degrees 2-theta. In some such embodiments, the present invention provides compound 5, wherein said compound has at least two peaks in its XRPD selected from those at about 13.6, about 16.7 and about 25.4 degrees 2-theta. In some such embodiments, the present invention provides compound 5, wherein said compound is of Form A.
  • the present invention provides compound 5, wherein said compound has an XRPD substantially similar to that depicted in Figure 18.
  • the present invention provides compound 5, wherein said compound has one or more peaks in its XRPD selected from those at about 18.8, about 23.1 and about 25.1 degrees 2-theta. In some such embodiments, the present invention provides compound 5, wherein said compound has at least two peaks in its XRPD selected from those at about 18.8, about 23.1 and about 25.1 degrees 2-theta. In some such embodiments, the present invention provides compound 5, wherein said compound is of Form A.
  • the present invention provides compound 5, wherein said compound has an XRPD substantially similar to that depicted in Figure 20.
  • the present invention provides compound 5, wherein said compound has one or more peaks in its XRPD selected from those at about 13.4, about 14.1 and about 25.8 degrees 2-theta. In some such embodiments, the present invention provides compound 5, wherein said compound has at least two peaks in its XRPD selected from those at about 18.8, about 23.1 and about 25.1 degrees 2-theta. In some such embodiments, the present invention provides compound 5, wherein said compound is of Form A.
  • the present invention provides compound 5, wherein said compound has an XRPD substantially similar to that depicted in Figure 22.
  • the present invention provides a composition comprising compound 5 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 5 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 5 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Larsson
  • the present invention provides an oxalate salt of compound A, represented by compound 6:
  • compound 6 can exist in a variety of physical forms.
  • compound 6 can be in solution, suspension, or in solid form.
  • compound 6 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 6 substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess oxalic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 6.
  • extraneous matter may include excess oxalic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 6.
  • at least about 95% by weight of compound 6 is present.
  • at least about 99% by weight of compound 6 is present.
  • compound 6 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 6 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 6 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 6 is also meant to include all tautomeric forms of compound 6. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 6 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 6 is a crystalline solid. In other embodiments, compound 6 is a crystalline solid substantially free of amorphous compound 6. As used herein, the term "substantially free of amorphous compound 6" means that the compound contains no significant amount of amorphous compound 6. In certain embodiments, at least about 95% by weight of crystalline compound 6 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 6 is present.
  • compound 6 is amorphous. In some embodiments, compound 6 is amorphous, and is substantially free of crystalline compound 6.
  • Form A of compound 6 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 17 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 6 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 10.6, about 12.4 and about 26.2 degrees 2-theta. In some embodiments, Form A of compound 6 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 10.6, about 12.4 and about 26.2 degrees 2-theta. In some embodiments, Form A of compound 6 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 10.6, about 12.4 and about 26.2 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 24.
  • the present invention provides compound 6:
  • the present invention provides compound 6, wherein said compound is crystalline.
  • the present invention provides compound 6, wherein said compound is a crystalline solid substantially free of amorphous compound 6.
  • the present invention provides compound 6, wherein said compound is substantially free of impurities.
  • the present invention provides compound 6, wherein said compound has one or more peaks in its XRPD selected from those at about 10.6, about 12.4 and about 26.2 degrees 2-theta. In some such embodiments, the present invention provides compound 6, wherein said compound has at least two peaks in its XRPD selected from those at about 10.6, about 12.4 and about 26.2 degrees 2-theta. In some such embodiments, the present invention provides compound 6, wherein said compound is of Form A.
  • the present invention provides compound 6, wherein said compound has an XRPD substantially similar to that depicted in Figure 24.
  • the present invention provides a composition comprising compound 6 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 6 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 6 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Lars
  • the present invention provides a phosphate salt of compound A, represented by compound 7 :
  • compound 7 can exist in a variety of physical forms.
  • compound 7 can be in solution, suspension, or in solid form.
  • compound 7 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 7 substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess phosphoric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 7.
  • extraneous matter may include excess phosphoric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 7.
  • at least about 95% by weight of compound 7 is present.
  • at least about 99% by weight of compound 7 is present.
  • compound 7 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 7 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 7 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 7 is also meant to include all tautomeric forms of compound 7. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 7 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 7 is a crystalline solid. In other embodiments, compound 7 is a crystalline solid substantially free of amorphous compound 7. As used herein, the term "substantially free of amorphous compound 7" means that the compound contains no significant amount of amorphous compound 7. In certain embodiments, at least about 95% by weight of crystalline compound 7 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 7 is present.
  • compound 7 is amorphous. In some embodiments, compound 7 is amorphous, and is substantially free of crystalline compound 7.
  • Form A of compound 7 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 18 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 7 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.9, about 13.2 and about 22.7 degrees 2-theta. In some embodiments, Form A of compound 7 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.9, about 13.2 and about 22.7 degrees 2-theta. In some embodiments, Form A of compound 7 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 5.9, about 13.2 and about 22.7 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 26.
  • Form B of compound 7 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 19 below.
  • the position 2Q is within ⁇ 0.2.
  • Form B of compound 7 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 13.4 and about 23.0 degrees 2-theta. In some embodiments, Form B of compound 7 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 13.4 and about 23.0 degrees 2-theta. In some embodiments, Form B of compound 7 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 13.4 and about 23.0 degrees 2-theta. [00268] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 28.
  • Form C of compound 7 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 20 below.
  • Form C of compound 7 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 11.4, about 13.9 and about 25.2 degrees 2-theta. In some embodiments, Form C of compound 7 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 11.4, about 13.9 and about 25.2 degrees 2-theta. In some embodiments, Form C of compound 7 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 11.4, about 13.9 and about 25.2 degrees 2-theta.
  • the present invention provides compound 7:
  • the present invention provides compound 7, wherein said compound is crystalline.
  • the present invention provides compound 7, wherein said compound is a crystalline solid substantially free of amorphous compound 7.
  • the present invention provides compound 7, wherein said compound is substantially free of impurities.
  • the present invention provides compound 7, wherein said compound has one or more peaks in its XRPD selected from those at about 5.9, about 13.2 and about 22.7 degrees 2-theta. In some such embodiments, the present invention provides compound 7, wherein said compound has at least two peaks in its XRPD selected from those at about 5.9, about 13.2 and about 22.7degrees 2-theta. In some such embodiments, the present invention provides compound 7, wherein said compound is of Form A.
  • the present invention provides compound 7, wherein said compound has an XRPD substantially similar to that depicted in Figure 26. [00279] In some embodiments, the present invention provides compound 7, wherein said compound has one or more peaks in its XRPD selected from those at about 6.0, about 13.4 and about 23.0 degrees 2-theta. In some such embodiments, the present invention provides compound 7, wherein said compound has at least two peaks in its XRPD selected from those at about 6.0, about 13.4 and about 23.0 degrees 2-theta. In some such embodiments, the present invention provides compound 7, wherein said compound is of Form B.
  • the present invention provides compound 7, wherein said compound has an XRPD substantially similar to that depicted in Figure 28.
  • the present invention provides compound 7, wherein said compound has one or more peaks in its XRPD selected from those at about 11.4, about 13.9 and about 25.2 degrees 2-theta. In some such embodiments, the present invention provides compound 7, wherein said compound has at least two peaks in its XRPD selected from those at about 11.4, about 13.9 and about 25.2 degrees 2-theta. In some such embodiments, the present invention provides compound 7, wherein said compound is of Form C.
  • the present invention provides a composition comprising compound 7 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 7 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 7 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Lars
  • the present invention provides a tartrate salt of compound A, represented by compound 8:
  • compound 8 can exist in a variety of physical forms.
  • compound 8 can be in solution, suspension, or in solid form.
  • compound 8 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 8 substantially free of impurities.
  • the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess tartaric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 8.
  • at least about 95% by weight of compound 8 is present. In still other embodiments of the invention, at least about 99% by weight of compound 8 is present.
  • compound 8 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 8 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 8 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 8 is also meant to include all tautomeric forms of compound 8. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 8 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 8 is a crystalline solid. In other embodiments, compound 8 is a crystalline solid substantially free of amorphous compound 8. As used herein, the term "substantially free of amorphous compound 8" means that the compound contains no significant amount of amorphous compound 8. In certain embodiments, at least about 95% by weight of crystalline compound 8 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 8 is present.
  • compound 8 is amorphous. In some embodiments, compound 8 is amorphous, and is substantially free of crystalline compound 8.
  • Form A of compound 8 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 21 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 8 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.5, about 10.6 and about 17.0 degrees 2-theta. In some embodiments, Form A of compound 8 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.5, about 10.6 and about 17.0 degrees 2-theta. In some embodiments, Form A of compound 8 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 5.5, about 10.6 and about 17.0 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 30.
  • Form B of compound 8 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 22 below.
  • the position 2Q is within ⁇ 0.2.
  • Form B of compound 8 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.5, about 19.9 and about 26.3 degrees 2-theta. In some embodiments, Form B of compound 8 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.5, about 19.9 and about 26.3 degrees 2-theta. In some embodiments, Form B of compound 8 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 5.5, about 19.9 and about 26.3 degrees 2-theta. [00299] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 32.
  • the present invention provides compound 8:
  • the present invention provides compound 8, wherein said compound is crystalline.
  • the present invention provides compound 8, wherein said compound is a crystalline solid substantially free of amorphous compound 8.
  • the present invention provides compound 8, wherein said compound is substantially free of impurities.
  • the present invention provides compound 8, wherein said compound has one or more peaks in its XRPD selected from those at about 5.5, about 10.6 and about 17.0 degrees 2-theta. In some such embodiments, the present invention provides compound 8, wherein said compound has at least two peaks in its XRPD selected from those at about 5.5, about 10.6 and about 17.0 degrees 2-theta. In some such embodiments, the present invention provides compound 8, wherein said compound is of Form A.
  • the present invention provides compound 8, wherein said compound has an XRPD substantially similar to that depicted in Figure 30.
  • the present invention provides compound 8, wherein said compound has one or more peaks in its XRPD selected from those at about 5.5, about 19.9 and about 26.3 degrees 2-theta. In some such embodiments, the present invention provides compound 8, wherein said compound has at least two peaks in its XRPD selected from those at about 5.5, about 19.9 and about 26.3 degrees 2-theta. In some such embodiments, the present invention provides compound 8, wherein said compound is of Form B. [00308] In some embodiments, the present invention provides compound 8, wherein said compound has an XRPD substantially similar to that depicted in Figure 32.
  • the present invention provides a composition comprising compound 8 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 8 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 8 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Lars
  • the present invention provides an isethionate salt of compound A, represented by compound 9:
  • compound 9 can exist in a variety of physical forms.
  • compound 9 can be in solution, suspension, or in solid form.
  • compound 9 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 9 substantially free of impurities.
  • the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess oxalic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 9.
  • extraneous matter may include excess oxalic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 9.
  • at least about 95% by weight of compound 9 is present.
  • at least about 99% by weight of compound 9 is present.
  • compound 9 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 9 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 9 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 9 is also meant to include all tautomeric forms of compound 9. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 9 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 9 is a crystalline solid.
  • compound 9 is a crystalline solid substantially free of amorphous compound 9.
  • the term "substantially free of amorphous compound 9" means that the compound contains no significant amount of amorphous compound 9. In certain embodiments, at least about 95% by weight of crystalline compound 9 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 9 is present.
  • compound 9 is amorphous. In some embodiments, compound 9 is amorphous, and is substantially free of crystalline compound 9.
  • Form A of compound 9 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 23 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 9 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 22.3, about 32.4 and about 32.5 degrees 2-theta. In some embodiments, Form A of compound 9 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 22.3, about 32.4 and about 32.5 degrees 2-theta. In some embodiments, Form A of compound 9 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 22.3, about 32.4 and about 32.5 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 34.
  • the present invention provides compound 9:
  • the present invention provides compound 9, wherein said compound is crystalline.
  • the present invention provides compound 9, wherein said compound is a crystalline solid substantially free of amorphous compound 9.
  • the present invention provides compound 9, wherein said compound is substantially free of impurities.
  • the present invention provides compound 9, wherein said compound has one or more peaks in its XRPD selected from those at about 22.3, about 32.4 and about 32.5 degrees 2-theta. In some such embodiments, the present invention provides compound 9, wherein said compound has at least two peaks in its XRPD selected from those at about 22.3, about 32.4 and about 32.5 degrees 2-theta. In some such embodiments, the present invention provides compound 9, wherein said compound is of Form A.
  • the present invention provides compound 9, wherein said compound has an XRPD substantially similar to that depicted in Figure 34.
  • the present invention provides a composition comprising compound 9 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 9 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 9 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Lars
  • the present invention provides an aspartane salt of compound A, represented by compound 10:
  • compound 10 can exist in a variety of physical forms.
  • compound 10 can be in solution, suspension, or in solid form.
  • compound 10 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 10 substantially free of impurities.
  • the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess oxalic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 10.
  • at least about 95% by weight of compound 10 is present.
  • at least about 99% by weight of compound 10 is present.
  • compound 10 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 10 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 10 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 10 is also meant to include all tautomeric forms of compound 10. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 10 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 10 is a crystalline solid. In other embodiments, compound 10 is a crystalline solid substantially free of amorphous compound 10. As used herein, the term "substantially free of amorphous compound 10" means that the compound contains no significant amount of amorphous compound 10. In certain embodiments, at least about 95% by weight of crystalline compound 10 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 10 is present.
  • compound 10 is amorphous. In some embodiments, compound 10 is amorphous, and is substantially free of crystalline compound 10.
  • Form A of compound 10 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 24 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 10 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 14.8, about 28.1 and about 28.7 degrees 2-theta. In some embodiments, Form A of compound 10 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 14.8, about 28.1 and about 28.7 degrees 2-theta. In some embodiments, Form A of compound 10 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 14.8, about 28.1 and about 28.7 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 36.
  • the present invention provides compound 10:
  • the present invention provides compound 10, wherein said compound is crystalline. [00347] In some embodiments, the present invention provides compound 10, wherein said compound is a crystalline solid substantially free of amorphous compound 10.
  • the present invention provides compound 10, wherein said compound is substantially free of impurities.
  • the present invention provides compound 10, wherein said compound has one or more peaks in its XRPD selected from those at about 14.8, about 28.1 and about 28.7 degrees 2-theta. In some such embodiments, the present invention provides compound 10, wherein said compound has at least two peaks in its XRPD selected from those at about 14.8, about 28.1 and about 28.7 degrees 2-theta. In some such embodiments, the present invention provides compound 10, wherein said compound is of Form A.
  • the present invention provides compound 10, wherein said compound has an XRPD substantially similar to that depicted in Figure 36.
  • the present invention provides a composition comprising compound 10 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 10 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 10 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Lars
  • the present invention provides a malonate salt of compound A, represented by compound 11:
  • compound 11 can exist in a variety of physical forms.
  • compound 11 can be in solution, suspension, or in solid form.
  • compound 11 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 11 substantially free of impurities.
  • substantially free of impurities means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess oxalic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 11.
  • extraneous matter may include excess oxalic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 11.
  • at least about 95% by weight of compound 11 is present.
  • at least about 99% by weight of compound 11 is present.
  • compound 11 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 11 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 11 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 11 is also meant to include all tautomeric forms of compound 11. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 11 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 11 is a crystalline solid. In other embodiments, compound 11 is a crystalline solid substantially free of amorphous compound 11. As used herein, the term "substantially free of amorphous compound 11" means that the compound contains no significant amount of amorphous compound 11. In certain embodiments, at least about 95% by weight of crystalline compound 11 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 11 is present.
  • compound 11 is amorphous. In some embodiments, compound 11 is amorphous, and is substantially free of crystalline compound 11.
  • Form A of compound 11 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 25 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 11 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 10.9, about 11.1 and about 12.9 degrees 2-theta. In some embodiments, Form A of compound 11 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 10.9, about 11.1 and about 12.9 degrees 2-theta. In some embodiments, Form A of compound 11 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 10.9, about 11.1 and about 12.9 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 37.
  • the present invention provides compound 11:
  • the present invention provides compound 11, wherein said compound is crystalline.
  • the present invention provides compound 11, wherein said compound is a crystalline solid substantially free of amorphous compound 11.
  • the present invention provides compound 11, wherein said compound is substantially free of impurities.
  • the present invention provides compound 11, wherein said compound has one or more peaks in its XRPD selected from those at about 10.9, about 11.1 and about 12.9 degrees 2-theta. In some such embodiments, the present invention provides compound 11, wherein said compound has at least two peaks in its XRPD selected from those at about 10.9, about 11.1 and about 12.9 degrees 2-theta. In some such embodiments, the present invention provides compound 11, wherein said compound is of Form A.
  • the present invention provides compound 11, wherein said compound has an XRPD substantially similar to that depicted in Figure 37.
  • the present invention provides a composition comprising compound 11 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 11 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 11 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Lars
  • the present invention provides an edisylate salt of compound A, represented by compound 12:
  • compound 12 can exist in a variety of physical forms.
  • compound 12 can be in solution, suspension, or in solid form.
  • compound 12 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present invention provides compound 12 substantially free of impurities.
  • the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess oxalic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 12.
  • extraneous matter may include excess oxalic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 12.
  • at least about 95% by weight of compound 12 is present.
  • at least about 99% by weight of compound 12 is present.
  • compound 12 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 12 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 12 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 12 is also meant to include all tautomeric forms of compound 12. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • compound 12 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • compound 12 is a crystalline solid. In other embodiments, compound 12 is a crystalline solid substantially free of amorphous compound 12. As used herein, the term "substantially free of amorphous compound 12" means that the compound contains no significant amount of amorphous compound 12. In certain embodiments, at least about 95% by weight of crystalline compound 12 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 12 is present.
  • compound 12 is amorphous. In some embodiments, compound 12 is amorphous, and is substantially free of crystalline compound 12.
  • Form A of compound 12 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 26 below.
  • the position 2Q is within ⁇ 0.2.
  • Form A of compound 12 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 11.2, about 13.0 and about 24.5 degrees 2-theta. In some embodiments, Form A of compound 12 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 11.2, about 13.0 and about 24.5 degrees 2-theta. In some embodiments, Form A of compound 12 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 11.2, about 13.0 and about 24.5 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 38.
  • the present invention provides compound 12:
  • the present invention provides compound 12, wherein said compound is crystalline.
  • the present invention provides compound 12, wherein said compound is a crystalline solid substantially free of amorphous compound 12.
  • the present invention provides compound 12, wherein said compound is substantially free of impurities.
  • the present invention provides compound 12, wherein said compound has one or more peaks in its XRPD selected from those at about 11.2, about 13.0 and about 24.5 degrees 2-theta. In some such embodiments, the present invention provides compound 12, wherein said compound has at least two peaks in its XRPD selected from those at about 11.2, about 13.0 and about 24.5 degrees 2-theta. In some such embodiments, the present invention provides compound 12, wherein said compound is of Form A.
  • the present invention provides compound 12, wherein said compound has an XRPD substantially similar to that depicted in Figure 38.
  • the present invention provides a composition comprising compound 12 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient compound 12 or composition thereof.
  • the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 12 or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Lars
  • the present invention provides a compound selected from: compound A, Form A; compound A, Form B; compound A, Form C; compound 1, Form A; compound 1, Form B; compound 1, Form C; compound 2, Form A; compound 2, Form B; compound 2, Form C; compound 3, Form A; compound 3, Form B; compound 3, Form C; compound 4, Form A; compound 5, Form A; compound 5, Form B; compound 5, Form C; compound 6, Form A; compound 7, Form A; compound 7, Form B; compound 7, Form C; compound 8, Form A; compound 8, Form B; compound 9, Form A; compound 10, Form A; compound 11, Form A; and compound 12, Form A.
  • the present invention provides a composition comprising one of the above compound forms and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of inhibiting or preventing the accumulation of A2E in a patient comprising administering to said patient one of the above compound forms or composition thereof. In some embodiments, the present invention provides a method of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient one of the above compound forms or composition thereof.
  • the various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis may include dry eye, cataracts, keratoconus, Fuch’s endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid degradation or lacrimal gland dysfunction, inflammatory ocular conditions such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Larsson Syndrome, ischemic-reperfusion injury, inflammation, diabetes, neurodegeneration (e.g, Parkinson’s disease), scleroderma, amyotrophic lateral sclerosis, autoimmune disorders (e.g,
  • Compound A is prepared according to the methods described in detail in the '500 publication, the entirety of which is hereby incorporated herein by reference.
  • Salt compounds of general formula X which formula encompasses, inter alia , salt compounds 1 through 9, and/or particular forms thereof, are prepared from compound A, according to the general Scheme below.
  • each of compounds 1 through 12, and forms thereof are prepared from compound A by combining compound A with an appropriate acid to form a salt of that acid.
  • another aspect of the present invention provides a method for preparing compounds 1 through 12, and forms thereof.
  • the present invention provides a method for preparing a salt compound of the general formula X:
  • a suitable acid is methanesulfonic acid.
  • the present invention provides a method of making a mesylate salt of compound A.
  • the mesylate salt of compound A is compound 1.
  • the mesylate salt of compound A is Form A of compound 1.
  • the mesylate salt of compound A is Form B of compound 1.
  • the mesylate salt of compound A is Form C of compound 1.
  • a suitable acid is benzenesulfonic acid.
  • the present invention provides a method of making a besylate salt of compound A.
  • the besylate salt of compound A is compound 2.
  • the besylate salt of compound A is Form A of compound 2.
  • the besylate salt of compound A is Form B of compound 2.
  • the besylate salt of compound A is Form C of compound 2.
  • a suitable acid is sulfuric acid.
  • the present invention provides a method of making a sulfate salt of compound A.
  • the sulfate salt of compound A is compound 3.
  • the sulfate salt of compound A is Form A of compound 3.
  • the sulfate salt of compound A is Form B of compound 3.
  • the sulfate salt of compound A is Form C of compound 3.
  • a suitable acid is / oluenesulfonic acid.
  • the present invention provides a method of making a tosylate salt of compound A.
  • the tosylate salt of compound A is compound 4.
  • the tosylate salt of compound A is Form A of compound 4.
  • a suitable acid is hydrochloric acid.
  • the present invention provides a method of making a hydrochloride salt of compound A.
  • the hydrochloric salt of compound A is compound 5.
  • the hydrochloride salt of compound A is Form A of compound 5.
  • the hydrochloride salt of compound A is Form B of compound 5.
  • the hydrochloride salt of compound A is Form C of compound 5.
  • a suitable acid is oxalic acid.
  • the present invention provides a method of making an oxalate salt of compound A.
  • the oxalate salt of compound A is compound 6.
  • the oxalate salt of compound A is Form A of compound 6.
  • a suitable acid is phosphoric acid.
  • the present invention provides a method of making a phosphate salt of compound A.
  • the phosphate salt of compound A is compound 7.
  • the phosphate salt of compound A is Form A of compound 7.
  • the phosphate salt of compound A is Form B of compound 7.
  • the phosphate salt of compound A is Form C of compound 7.
  • a suitable acid is tartaric acid.
  • the present invention provides a method of making a tartrate salt of compound A.
  • the tartrate salt of compound A is compound 8.
  • the tartrate salt of compound A is Form A of compound 8.
  • the tartrate salt of compound A is Form B of compound 8.
  • a suitable acid is isethionic acid.
  • the present invention provides a method of making an isethionate salt of compound A.
  • the isethionate salt of compound A is compound 9.
  • the isethionate salt of compound A is Form A of compound 9.
  • a suitable acid is aspartic acid.
  • the present invention provides a method of making an aspartate salt of compound A.
  • the aspartate salt of compound A is compound 10.
  • the aspartate salt of compound A is Form A of compound 10.
  • a suitable acid is malonic acid. In some embodiments, the present invention provides a method of making a malonate salt of compound A. In certain embodiments, the malonate salt of compound A is compound 11. In certain embodiments, the malonate salt of compound A is Form A of compound 11. [00411] In some embodiments, a suitable acid is edisylic acid. In some embodiments, the present invention provides a method of making an edisylate salt of compound A. In certain embodiments, the edisylate salt of compound A is compound 12. In certain embodiments, the edisylate salt of compound A is Form A of compound 12.
  • a suitable solvent may be any solvent system (e.g., one solvent or a mixture of solvents) in which compound A and/or an acid are soluble, or are at least partially soluble.
  • suitable solvents useful in the present invention include, but are not limited to protic solvents, aprotic solvents, polar aprotic solvent, or mixtures thereof.
  • suitable solvents include an ether, an ester, an alcohol, a ketone, or a mixture thereof.
  • the solvent is one or more organic alcohols.
  • the solvent is chlorinated.
  • the solvent is an aromatic solvent.
  • a suitable solvent is methanol, ethanol, isopropanol, or acetone wherein said solvent is anhydrous or in combination with water or heptane.
  • suitable solvents include tetrahydrofuran, dimethylformamide, dimethylsulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile.
  • a suitable solvent is ethanol.
  • a suitable solvent is anhydrous ethanol.
  • the suitable solvent is MTBE.
  • a suitable solvent is ethyl acetate.
  • a suitable solvent is a mixture of methanol and methylene chloride.
  • a suitable solvent is a mixture of acetonitrile and water.
  • a suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran.
  • a suitable solvent is diethylether.
  • a suitable solvent is water.
  • a suitable solvent is methyl ethyl ketone.
  • a suitable solvent is toluene.
  • the present invention provides a method for preparing a salt compound of the general formula X, comprising one or more steps of removing a solvent and adding a solvent.
  • an added solvent is the same as the solvent removed.
  • an added solvent is different from the solvent removed. Means of solvent removal are known in the synthetic and chemical arts and include, but are not limited to, any of those described herein and in the Exemplification.
  • a method for preparing a salt compound of the general formula X comprises one or more steps of heating or cooling a preparation.
  • a method for preparing a salt compound of the general formula X comprises one or more steps of agitating or stirring a preparation.
  • a method for preparing a salt compound of the general formula X comprises a step of adding a suitable acid to a solution or slurry of compound A.
  • a method for preparing a salt compound of the general formula X comprises a step of heating.
  • a salt compound of formula X precipitates from the mixture. In another embodiment, a salt compound of formula X crystallizes from the mixture. In other embodiments, a salt compound of formula X crystallizes from solution following seeding of the solution (i.e., adding crystals of a salt compound of formula X to the solution).
  • a salt compound of formula X can precipitate out of the reaction mixture, or be generated by removal of part or all of the solvent through methods such as evaporation, distillation, filtration (ex. nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by adding an anti-solvent such as heptane, by cooling or by different combinations of these methods.
  • a salt compound of formula X is optionally isolated. It will be appreciated that a salt compound of formula X may be isolated by any suitable physical means known to one of ordinary skill in the art. In certain embodiments, precipitated solid salt compound of formula X is separated from the supernatant by filtration. In other embodiments, precipitated solid salt compound of formula X is separated from the supernatant by decanting the supernatant.
  • a salt compound of formula X is separated from the supernatant by filtration.
  • an isolated salt compound of formula X is dried in air. In other embodiments, isolated salt compound of formula X is dried under reduced pressure, optionally at elevated temperature.
  • Certain compounds described herein are found to be useful in scavenging toxic aldehydes, such as MDA and HNE.
  • the compounds described herein undergo a Schiff base condensation with MDA, HNE, or other toxic aldehydes, and form a complex with the aldehydes in an energetically favorable reaction, thus reducing or eliminating aldehydes available for reaction with a protein, lipid, carbohydrate, or DNA.
  • compounds described herein can react with aldehydes to form a compound having a closed-ring structure that contains the aldehydes, thus trapping the aldehydes and preventing the aldehydes from being released back into the cellular milieu.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment is administered after one or more symptoms have developed.
  • treatment is administered in the absence of symptoms.
  • treatment is administered to a susceptible individual prior to the onset of symptoms (e.g ., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent, delay or lessen the severity of their recurrence.
  • the invention relates to compounds described herein for the treatment, prevention, and/or reduction of a risk of diseases, disorders, or conditions in which aldehyde toxicity is implicated in the pathogenesis.
  • Examples of the diseases, disorders, or conditions in which aldehyde toxicity is implicated include an ocular disease, disorder, or condition, including, but not limited to, a corneal disease (e.g., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and Fuch’s endothelial dystrophy), other ocular disorders or conditions (e.g, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with PRK healing and other corneal healing, and conditions associated with tear lipid degradation or lacrimal gland dysfunction), and other ocular conditions associated with high aldehyde levels as a result of inflammation (e.g, uveitis, scleritis, ocular Stevens Johnson Syndrome, ocular rosacea (with or without meibomian gland dysfunction)).
  • a corneal disease e.g., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and F
  • the ocular disease, disorder, or condition is not macular degeneration, such as age-related macular degeneration (“AMD”), or Stargardt’s disease.
  • AMD age-related macular degeneration
  • the ocular disease, disorder, or condition is dry eye syndrome, ocular rosacea, or uveitis.
  • Examples of the diseases, disorders, conditions, or indications in which aldehyde toxicity is implicated also include non-ocular disorders, including psoriasis, topical (discoid) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, Sjogren-Larsson Syndrome and other ichthyosis, solar elastosis/wrinkles, skin tone firmness, puffmess, eczema, smoke or irritant induced skin changes, dermal incision, a skin condition associated burn and/or wound, lupus, scleroderma, asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, inflammatory bowel disease, sepsis, atherosclerosis, ischemic- reperfusion injury, Parkinson’s disease, Alzheimer’s disease, succinic semialdehyde dehydrogenase deficiency, multiple ocular disorders
  • the non-ocular disorder is a skin disease, disorder, or condition selected from contact dermatitis, atopic dermatitis, allergic dermatitis, and. radiation dermatitis.
  • the non-ocular disorder is a skin disease, disorder, or condition selected from Sjogren-Larsson Syndrome and a cosmetic indication associated burn and/or wound.
  • the diseases, disorders, or conditions in which aldehyde toxicity is implicated are an age-related disorder.
  • age-related diseases, disorders, or conditions include wrinkles, dryness, and pigmentation of the skin.
  • Examples of the diseases, disorders, or conditions in which aldehyde toxicity is implicated further include conditions associated with the toxic effects of blister agents or burns from alkali agents.
  • the compounds described herein reduce or eliminate toxic aldehydes and thus treat, prevent, and/or reduce a risk of these diseases or disorders.
  • the invention relates to the treatment, prevention, and/or reduction of a risk of an ocular disease, disorder, or condition in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to a subject in need thereof a compound described herein.
  • the ocular disease, disorder, or condition includes, but is not limited to, a corneal disease (e.g ., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and Fuch’s endothelial dystrophy in the cornea), other ocular disorders or conditions (e.g., allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with PRK healing and other corneal healing, and conditions associated with tear lipid degradation or lacrimal gland dysfunction), and other ocular conditions where inflammation leads to high aldehyde levels (e.g ., uveitis, scleritis, ocular Stevens Johnson Syndrome, ocular rosacea (with or without meibomian gland dysfunction)).
  • a corneal disease e.g ., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and Fuch’s endothelial dystrophy in the cornea
  • the ocular disease, disorder, or condition does not include macular degeneration, such as AMD, or Stargardt’s disease.
  • the amount or concentration of MDA or HNE is increased in the ocular tissues or cells.
  • the amount or concentration of aldehydes e.g., MDA or HNE
  • the amount or concentration of aldehydes is increased for at least 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 5 fold, 10 fold as compared to that in normal ocular tissues or cells.
  • Compounds described herein, such as Compound 1 decrease aldehyde (e.g, MDA and HNE) concentration in a time-dependent manner.
  • aldehydes e.g, MDA or HNE
  • MDA or HNE aldehydes
  • the ocular disease, disorder, or condition is dry eye syndrome.
  • the ocular disease, disorder, or condition is a condition associated with PRK healing and other corneal healing.
  • the invention is directed to advancing PRK healing or other corneal healing, comprising administering to a subject in need thereof a compound described herein.
  • the ocular disease, disorder, or condition is an ocular condition associated with high aldehyde levels as a result of inflammation (e.g, uveitis, scleritis, ocular Stevens Johnson Syndrome, and ocular rosacea (with or without meibomian gland dysfunction).
  • the ocular disease, disorder, or condition is keratoconus, cataracts, bullous and other keratopathy, Fuchs’ endothelial dystrophy, ocular cicatricial pemphigoid, or allergic conjunctivitis.
  • the compound described herein may be administered topically or systemically, as described herein below.
  • the invention relates to the treatment, prevention, and/or reduction of a risk of a skin disorder or condition or a cosmetic indication, in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to a subject in need thereof a compound described herein.
  • the skin disorder or condition includes, but is not limited to, psoriasis, scleroderma, topical (discoid) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, and Sjogren-Larsson Syndrome and other ichthyosis, and the cosmetic indication is solar elastosis/wrinkles, skin tone firmness, puffmess, eczema, smoke or irritant induced skin changes, dermal incision, or a skin condition associated burn and/or wound.
  • the invention related to age-related diseases, disorders, or conditions of the skin, as described herein.
  • SLS Sjogren-Larsson Syndrome
  • aldehyde dehydrogenase which metabolizes aldehydes is dysfunctional in SLS patients.
  • compounds that reduce or eliminate aldehydes can be used to treat, prevent, and/or reduction of a risk of skin disorders or conditions in which aldehyde toxicity is implicated in the pathogenesis, such as those described herein.
  • aldehyde-mediated inflammation including fibrosis and elastosis (Chairpotto et al.
  • the skin disease, disorder, or condition is psoriasis, scleroderma, topical (discoid) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, or Sjogren-Larsson Syndrome and other ichthyosis.
  • the skin disease, disorder, or condition is contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, or Sjogren-Larsson Syndrome and other ichthyosis.
  • the cosmetic indication is solar elastosis/wrinkles, skin tone firmness, puffmess, eczema, smoke or irritant induced skin changes, dermal incision, or a skin condition associated burn and/or wound.
  • the invention relates to the treatment, prevention, and/or reduction of a risk of a condition associated with the toxic effects of blister agents or burns from alkali agents in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to a subject in need thereof a compound described herein.
  • Blister agents include, but are not limited to, sulfur mustard, nitrogen mustard, and phosgene oxime.
  • Toxic or injurious effects of blister agents include pain, irritation, and/or tearing in the skin, eye, and/or mucous, and conjunctivitis and/or corneal damage to the eye.
  • Sulfur mustard is the compound bis(2-chlorethyl) sulfide.
  • Nitrogen mustard includes the compounds bis(2-chlorethyl)ethylamine, bis(2-chlorethyl)methylamine, and tris(2-chlorethyl)amine.
  • Sulfur mustard or its analogs can cause an increase in oxidative stress and in particular in HNE levels, and by depleting the antioxidant defense system and thereby increasing lipid peroxidation, may induce an oxidative stress response and thus increase aldehyde levels (Jafari el al. (2010); Pal el al. (2009)).
  • Antioxidants when applied topically, attenuate skin injury induced from exposure to sulfur mustard or its analogs, and increased activities of antioxidant enzymes may be a compensatory response to reactive oxygen species generated by the sulfur mustard (Jafari et al. (2010); Tewari-Singh et al. (2012)). Further, intervention to reduce free radical species was an effective treatment post exposure for phosgene induced lung injury (Sciuto et al. (2004)).
  • compounds that reduce or eliminate aldehydes such as compounds described herein, can be used to treat, prevent, and/or reduce a risk of a condition associated with the toxic effects of blister agents, such as sulfur mustard, nitrogen mustard, and phosgene oxime.
  • Alkali agents include, but are not limited to, lime, lye, ammonia, and drain cleaners.
  • Compounds that reduce or eliminate aldehydes, such as compounds described herein, can be used to treat, prevent, and/or reduce a risk of a condition associated with burns from an alkali agent.
  • the invention relates to the treatment, prevention, and/or reduction of a risk of an autoimmune, immune-mediated, inflammatory, cardiovascular, or neurological disease, disorder, or condition, or metabolic syndrome, or diabetes, in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to a subject in need thereof a compound described herein.
  • the autoimmune or immune-mediated disease, disorder, or condition includes, but is not limited to, lupus, scleroderma, asthma, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis.
  • the inflammatory disease, disorder, or condition includes, but is not limited to, rheumatoid arthritis, inflammatory bowel disease (e.g ., Crohn’s disease and ulcerative colitis), sepsis, and fibrosis (e.g., renal, hepatic, pulmonary, and cardiac fibrosis).
  • the cardiovascular disease, disorder, or condition includes, but is not limited to, atherosclerosis and ischemic-reperfusion injury.
  • the neurological disease, disorder, or condition includes, but is not limited to, Parkinson’s disease, Alzheimer’s disease, succinic semialdehyde dehydrogenase, deficiency, multiple sclerosis, amyotrophic lateral sclerosis, and the neurological aspects of Sjogren-Larsson Syndrome (cognitive delay and spasticity).
  • a disease, disorder, or condition listed herein may involve more than one pathological mechanism.
  • a disease, disorder, or condition listed herein may involve dysregulation in the immunological response and inflammatory response.
  • the above categorization of a disease, disorder, or condition is not absolute, and the disease, disorder, or condition may be considered an immunological, an inflammatory, a cardiovascular, a neurological, and/or metabolic disease, disorder, or condition.
  • aldehydes levels are elevated in multiple sclerosis, amyotrophic lateral sclerosis, autoimmune diseases such as lupus, rheumatoid arthritis, lupus, psoriasis, scleroderma, and fibrotic diseases, and increased levels of HNE and MDA are implicated in the progression of atherosclerosis and diabetes (J. Cell. Mol.
  • MDA is further implicated in the increased formation of foam cells leading to atherosclerosis (Leibundgut et al ., Current Opinion in Pharmacology 13 : 168 (2013)).
  • aldehyde-related toxicity plays an important role in the pathogenesis of many inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD) (Bartoli et al. , Mediators of Inflammation 2011, Article 891752).
  • COPD chronic obstructive pulmonary disease
  • compounds that reduce or eliminate aldehydes can be used to treat, prevent, and/or reduce a risk of an autoimmune, immune-mediated, inflammatory, cardiovascular, or neurological disease, disorder, or condition, or metabolic syndrome, or diabetes.
  • compounds described herein prevent aldehyde-mediated cell death in neurons.
  • compounds described herein downregulate a broad spectrum of pro-inflammatory cytokines and/or upregulate anti-inflammatory cytokines, which indicates that compounds described herein are useful in treating inflammatory diseases, such as multiple sclerosis and amyotrophic lateral sclerosis.
  • a disclosed composition may be administered to a subject in order to treat or prevent macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin. Other diseases, disorders, or conditions characterized by the accumulation A2E may be similarly treated.
  • a compound is administered to a subject that reduces the formation of A2E.
  • the compound may compete with PE for reaction with trans-RAL , thereby reducing the amount of A2E formed.
  • a compound is administered to a subject that prevents the accumulation of A2E.
  • the compound competes so successfully with PE for reaction with /ra//.s-RAL, no A2E is formed.
  • compositions are administered topically or systemically at one or more times per month, week or day. Dosages may be selected to avoid side effects, if any, on visual performance in dark adaptation. Treatment is continued for a period of at least one, three, six, or twelve or more months. Patients may be tested at one, three, six, or twelve months or longer intervals to assess safety and efficacy. Efficacy is measured by examination of visual performance and retinal health as described above.
  • a subject is diagnosed as having symptoms of macular degeneration, and then a disclosed compound is administered.
  • a subject may be identified as being at risk for developing macular degeneration (risk factors include a history of smoking, age, female gender, and family history), and then a disclosed compound is administered.
  • risk factors include a history of smoking, age, female gender, and family history
  • a disclosed compound is administered.
  • a subject may have dry AMD in both eye, and then a disclosed compound is administered.
  • a subject may have wet AMD in one eye but dry AMD in the other eye, and then a disclosed compound is administered.
  • a subject may be diagnosed as having Stargardt disease and then a disclosed compound is administered.
  • a subject is diagnosed as having symptoms of other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin, and then the compound is administered.
  • a subject may be identified as being at risk for developing other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin, and then the disclosed compound is administered.
  • a compound is administered prophylactically.
  • a subject has been diagnosed as having the disease before retinal damage is apparent.
  • a subject is found to carry a gene mutation for ABCA4 and is diagnosed as being at risk for Stargardt disease before any ophthalmologic signs are manifest, or a subject is found to have early macular changes indicative of macular degeneration before the subject is aware of any effect on vision.
  • a human subject may know that he or she is in need of the macular generation treatment or prevention.
  • a subject may be monitored for the extent of macular degeneration.
  • a subject may be monitored in a variety of ways, such as by eye examination, dilated eye examination, fundoscopic examination, visual acuity test, and/or biopsy. Monitoring can be performed at a variety of times. For example, a subject may be monitored after a compound is administered. The monitoring can occur, for example, one day, one week, two weeks, one month, two months, six months, one year, two years, five years, or any other time period after the first administration of a compound. A subject can be repeatedly monitored. In some embodiments, the dose of a compound may be altered in response to monitoring.
  • the disclosed methods may be combined with other methods for treating or preventing macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin, such as photodynamic therapy.
  • a patient may be treated with more than one therapy for one or more diseases or disorders.
  • a patient may have one eye afflicted with dry form AMD, which is treated with a compound of the invention, and the other eye afflicted with wet form AMD which is treated with, e.g ., photodynamic therapy.
  • a compound for treating or preventing macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin may be administered chronically.
  • the compound may be administered daily, more than once daily, twice a week, three times a week, weekly, biweekly, monthly, bimonthly, semi-annually, annually, and/or biannually.
  • Sphingosine 1 -phosphate a bioactive signalling molecule with diverse cellular functions, is irreversibly degraded by the endoplasmic reticulum enzyme sphingosine 1 -phosphate lyase, generating trans-2-hexadecenal and phosphoethanolamine. It has been demonstrated that trans-2-hexadecenal causes cytoskeletal reorganization, detachment, and apoptosis in multiple cell types via a JNK-dependent pathway. See Biochem Biophys Res Commun. 2012 Jul 20;424(l): 18- 21.
  • Succinic semialdehyde dehydrogenase deficiency also known as 4- hydroxybutyric aciduria or gamma-hydroxybutyric aciduria, is the most prevalent autosomal- recessively inherited disorder of GABA metabolism (Vogel et al 2013), manifests a phenotype of developmental delay and hypotonia in early childhood, and severe expressive language impairment and obsessive-compulsive disorder in adolescence and adulthood. Epilepsy occurs in half of patients, usually as generalized tonic-clonic seizures although sometimes absence and myoclonic seizures occur (Pearl et al 2014).
  • the compounds of the disclosure are used to treat inflammatory disorders.
  • the compounds are administered in a therapeutically effective amount to a subject to treat a systemic inflammatory disorder.
  • the systemic inflammatory disorder is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), inflammatory bowel disease (IBD) Crohn’s disease, ulcerative colitis (ETC), psoriasis, IBS (irritable bowel syndrome or spastic colon), including spastic colon, ankylosing spondylitis, osteoporosis, rheumatoid arthritis (RA), psoriatic arthritis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (including idiopathic pulmonary fibrosis), atherosclerosis, psoriatic arthritis, pulmonary arterial hypertension, pyridoxine-dependent epilepsy, atopic dermatitis, rosacea, multiple sclerosis
  • NAFLD non-alcoholic fatty liver disease
  • the compounds of the disclosure are used to treat a systemic disease, disorder, or condition.
  • the systemic disease, disorder, or condition is light chain deposition disease, IgA nephropathy, end stage renal disease, gout, pseudogout, diabetic nephrophathy, diabetic neuropathy, traumatic brain injury, noise-induced hearing loss, Alzheimer’s Disease, Parkinson’s Disease, Huntington Disease, amyotrophic lateral sclerosis, primary biliary cirrhosis, primary sclerosing cholangitis, uterine leiomyoma, sarcoidosis, or chronic kidney disease.
  • the compounds of the disclosure are administered in an effective amount to treat non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • the compounds of the disclosure are administered in an effective amount to treat non-alcoholic steatohepatitis (NASH).
  • the compounds of the disclosure are administered in an effective amount to treat inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the compounds of the disclosure are administered in an effective amount to treat Crohn’s disease.
  • the compounds of the disclosure are administered in an effective amount to treat ulcerative colitis (UC).
  • UC ulcerative colitis
  • the compounds of the disclosure are administered in an effective amount to treat psoriasis.
  • the compounds of the disclosure are administered in an effective amount to treat IBS (irritable bowel syndrome) or spastic colon.
  • the compounds of the disclosure are administered in an effective amount to treat ankylosing spondylitis.
  • the compounds of the disclosure are administered in an effective amount to treat osteoporosis.
  • the compounds of the disclosure are administered in an effective amount to treat rheumatoid arthritis (RA).
  • RA rheumatoid arthritis
  • the compounds of the disclosure are administered in an effective amount to treat psoriatic arthritis.
  • the compounds of the disclosure are administered in an effective amount to treat chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the compounds of the disclosure are administered in an effective amount to treat interstitial lung disease (including idiopathic pulmonary fibrosis).
  • the compounds of the disclosure are administered in an effective amount to treat atherosclerosis.
  • the compounds of the disclosure are administered in an effective amount to treat psoriatic arthritis.
  • the compounds of the disclosure are administered in an effective amount to treat pulmonary arterial hypertension.
  • the compounds of the disclosure are administered in an effective amount to treat pyridoxine-dependent epilepsy.
  • the compounds of the disclosure are administered in an effective amount to treat atopic dermatitis.
  • the compounds of the disclosure are administered in an effective amount to treat rosacea.
  • the compounds of the disclosure are administered in an effective amount to treat multiple sclerosis (MS).
  • the compounds of the disclosure are administered in an effective amount to treat systemic lupus erythematosus (SLE).
  • SLE systemic lupus erythematosus
  • the compounds of the disclosure are administered in an effective amount to treat lupus nephritis.
  • the compounds of the disclosure are administered in an effective amount to treat sepsis.
  • the compounds of the disclosure are administered in an effective amount to treat eosinophilic esophagitis.
  • the compounds of the disclosure are administered in an effective amount to treat chronic kidney disease (CKD).
  • CKD chronic kidney disease
  • the compounds of the disclosure are administered in an effective amount to treat fibrotic renal disease.
  • the compounds of the disclosure are administered in an effective amount to treat chronic eosinophilic pneumonia.
  • the compounds of the disclosure are administered in an effective amount to treat extrinsic allergic alveolitis.
  • the compounds of the disclosure are administered in an effective amount to treat pre-clampsia.
  • the compounds of the disclosure are administered in an effective amount to treat endometriosis.
  • the compounds of the disclosure are administered in an effective amount to treat polycystic ovary syndrome (PCOS).
  • PCOS polycystic ovary syndrome
  • the compounds of the disclosure are administered in an effective amount to treat reduced female fertility.
  • the compounds of the disclosure are administered in an effective amount to treat reduced sperm viability and motility.
  • the compounds of the disclosure are administered in an effective amount to treat cyclophosphamide-induced hemorrhagic cystitis.
  • the inflammatory disorder is an ocular inflammatory disorder.
  • the ocular inflammatory disorder is diabetic macular edema (DME), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), age-related macular degeneration (AMD), dry eye disease (DED), allergic conjunctivitis (AC), dry eye disease with allergic conjunctivitis, noninfectious anterior uveitis, posterior uveitis, pan-uveitis, post-surgical ocular pain and inflammation.
  • DME diabetic macular edema
  • ACD age-related macular degeneration
  • DED dry eye disease
  • AC allergic conjunctivitis
  • dry eye disease with allergic conjunctivitis noninfectious anterior uveitis, posterior uveitis, pan-uveitis, post-surgical ocular pain and inflammation.
  • the compound of the disclosure is administered in an effective amount for the prevention of corneal fibrosis after radial keratotomy, prevention of corneal fibrosis after trauma or exposure to vesicants, or prevention of corneal fibrosis after infection.
  • the compounds of the disclosure are administered in an effective amount to treat diabetic macular edema (DME).
  • DME diabetic macular edema
  • the diabetic macular edema for treatment is non-clinically significant macular edema (Non-CSME).
  • the diabetic macular edema for treatment is clinically significant macular edema (CSME).
  • the compounds of the disclosure are administered in an effective amount to treat uveitis, including pan-uveitis, anterior uveitis, posterior uveitis, and non-infectious uveitis, which are ocular disorders that can be secondary to a primary underlying disorder.
  • uveitis including pan-uveitis, anterior uveitis, posterior uveitis, and non-infectious uveitis, which are ocular disorders that can be secondary to a primary underlying disorder.
  • Some of the disorders with which uveitis is sometimes associated are Behcet’s syndrome, ankylosing spondylitis, Lyme disease, sarcoidosis, and psoriasis.
  • Uveitis is an inflammation of the iris, ciliary body, and choroid. It is associated with blurred vision; seeing dark, floating spots (“floaters”); eye pain; redness of the eye; and sensitivity to light (photophobia).
  • the compounds of the disclosure are administered in an effective amount to treat atopic keratoconjunctivitis (AKC) or vernal keratoconjunctivitis (VKC).
  • ACD age-related macular degeneration
  • the compounds of the disclosure are administered in an effective amount to treat dry eye disease (DED).
  • DED dry eye disease
  • the compounds of the disclosure are administered in an effective amount to treat allergic conjunctivitis (AC).
  • the compounds of the disclosure are administered in an effective amount to treat dry eye disease with allergic conjunctivitis.
  • the compounds of the disclosure are administered in an effective amount to treat post-surgical ocular pain and inflammation.
  • the compounds of the disclosure are administered in an effective amount for prevention of corneal fibrosis after radial keratotomy.
  • the compounds of the disclosure are administered in an effective amount for prevention of corneal fibrosis after trauma.
  • the compounds of the disclosure are administered in an effective amount for prevention of corneal fibrosis after infection.
  • the compounds of the disclosure are administered in an effective amount to treat non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of light chain deposition disease.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of IgA nephropathy.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of end stage renal disease.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of gout.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of pseudogout.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of diabetic nephrophathy.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of diabetic neuropathy.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of traumatic brain injury.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of noise-induced hearing loss.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of Alzheimer’s Disease,
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of Parkinson’s disease.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of Huntington Disease.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of amyotrophic lateral sclerosis.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of primary biliary cirrhosis.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of primary sclerosing cholangitis.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of uterine leiomyoma.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of sarcoidosis.
  • the compounds of the disclosure are administered in an effective amount for treatment and/or prevention of chronic kidney disease.
  • the compounds and compositions, according to the method of the present invention are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided above.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention are administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention can also be administered topically, such as directly to the eye, e.g. , as an eye-drop or ophthalmic ointment.
  • Eye drops typically comprise an effective amount of at least one compound of the invention and a carrier capable of being safely applied to an eye.
  • the eye drops are in the form of an isotonic solution, and the pH of the solution is adjusted so that there is no irritation of the eye.
  • the epithelial barrier interferes with penetration of molecules into the eye.
  • most currently used ophthalmic drugs are supplemented with some form of penetration enhancer.
  • penetration enhancers work by loosening the tight junctions of the most superior epithelial cells (Burstein, 1985, Trans Ophthalmol Soc U K l04(Pt 4): 402-9; Ashton et ah, 1991, J Pharmacol Exp Ther 259(2): 719-24; Green et ah, 1971, Am J Ophthalmol 72(5): 897-905).
  • the most commonly used penetration enhancer is benzalkonium chloride (Tang et ah, 1994, J Pharm Sci 83(1): 85-90; Burstein et al, 1980, Invest Ophthalmol Vis Sci 19(3): 308-13), which also works as preservative against microbial contamination. It is typically added to a final concentration of 0.01-0.05%.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Polarised Light Microscopy was used to determine the presence of crystallinity (birefringence) with an Olympus BX50 polarising microscope, equipped with a Motic camera and image capture software (Motic Images Plus 2.0). All images were recorded using the 20x objective, unless otherwise stated.
  • TGA Thermogravimetric Analysis: approximately, 5 mg of material was weighed into an open aluminium pan and loaded into a simultaneous thermogravimetric/differential thermal analyser (TG/DTA) and held at room temperature. The sample was then heated at a rate of l0°C/min from 20°C to 300°C during which time the change in sample weight was recorded along with any differential thermal events (DTA). Nitrogen was used as the purge gas, at a flow rate of 300 cnT/min.
  • DSC Differential Scanning Calorimetry
  • Dynamic Vapour Sorption approximately, 10 mg of sample was placed into a mesh vapour sorption balance pan and loaded into a DVS-1 dynamic vapour sorption balance, a DVS Intrinsic dynamic vapour sorption balance or a DVS Advantage dynamic vapour sorption balance by Surface Measurement Systems. The sample was subjected to a ramping profile from 40 - 90% relative humidity (RH) at 10% increments, maintaining the sample at each step until a stable weight had been achieved (dm/dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes) at 25°C. After completion of the sorption cycle, the sample was dried using the same procedure to 0% RH and then a second sorption cycle back to 40% RH. Two cycles were performed. The weight change during the sorption/desorption cycles were plotted, allowing for the hygroscopic nature of the sample to be determined. XRPD analysis was then carried out on any solid retained.
  • RH relative humidity
  • High Performance Liquid Chromatography-Ultraviolet Detection (HPLC-UV) parameters were as follows: Column: AC Excel 3 C18-AR 75 x 4.6 mm 3 pm; Column Temperature: 30 °C; Autosampler Temperature: Ambient; UV wavelength: 275 nm; Injection Volume: 6 pL; Flow Rate: 1.0 mL/min; Mobile Phase A: 0.1 % TFA in water; Mobile Phase B: 0.1 % TFA in acetonitrile; and a gradient program as shown below.
  • Liquid chromatography -mass spectrometry (LC-MS) parameters were as follows: Column: ACE Excel 3 Super C18, 75mmx 4.6mm, 3pm; Mobile Phase A: 0.1% Formic Acid in Deionised water; Mobile Phase B: 0.1% Formic Acid in Acetonitrile; Diluent: Acetonitrile; Flow Rate: 1.0 mL/min; Runtime: 20 minutes; Column Temperature: 30°C; Injection Volume: 10 pL; Needle Wash: Acetonitrile, Vial position # 100; PDA Range: 190-400 nm; a gradient program as shown below:
  • a secondary jacketed vessel equipped with mechanical agitation, baffle and nitrogen bleed was charged with ethyl acetate (16L) and deionized water (22L).
  • the reaction mixture was vacuum transferred into this vessel and held at high agitation for not less than 30 minutes.
  • the aqueous layer was discharged and the organic layer washed with saturated sodium chloride (2 x 8L) then dried over sodium sulfate before evaporation in vacuo to Compound A3 as a deep brown oil (2.lkg, 100.8%), suitable for use in following step without purification.
  • reaction mixture was filtered through a celite pad, washing sequentially with deionized water (8L) and ethyl acetate (8L).
  • the organic layer was extracted sequentially with deionized water (2 x 5L), saturated sodium chloride (4L), dried over sodium sulfate and evaporated in vacuo.
  • Compound A7 was obtained as a brown solid, suitable for use without further purification (0.8kg, 104.1%).
  • a primary polymorph screen using an initial set of 24 solvents was performed as follows: A) To 24 x 20 mL vials, approximately 50 mg of the received ADX-103 was added; B) The solids were then slurried in 2 mL of the solvents and left placed in an incubator/shaker to temperature cycle between ambient and 40 °C in 4 hour cycles; C) After 72 hours temperature cycling, the mother liquors were removed from the vials and split evenly between 4 x 2 mL vials.
  • Evaporation The 24 vials containing mother liquor were un-capped and left to evaporate at ambient temperature for a minimum of 72 hours. Once fully evaporated, any solids present were analysed in the first instance by XRPD. The vials were left evaporating for a total of 3 weeks with any observations noted throughout this time.
  • Crash Cooling to 2 °C After temperature cycling the mother liquor samples for crash cooling were capped and crash cooled to 2 °C and left to stand. The samples were held at this temperature for a minimum of 72 hours. When sufficient solid was noted the samples were separated and the solids analysed by XRPD in the first instance. Samples which did not return solid were stored at 2 °C for up to 2 weeks.
  • Crash Cooling to -18 °C After temperature cycling the mother liquor samples for crash cooling were capped and crash cooled to -18 °C and left to stand. The samples were held at this temperature for a minimum of 72 hours. When sufficient solid was noted the samples were separated and the solids analysed by XRPD in the first instance. Samples which did not return solid were stored at -18 °C for up to 2 weeks.
  • Compound A Forms B Scale-Up: Approximately 200 mg of Compound A material was added to a 20 mL vial and dissolved in 4 mL acetone. The vial was then temperature cycled between ambient temperature and 40 °C in 4 hour cycles for approximately 72 hours. After 72 hours the vial was removed from the incubator/shaker and left uncapped to evaporate at ambient temperature. After 24 hours the sample had fully evaporated and the resulting solid material was analysed by XRPD. Once formation of Compound A, Form B was confirmed by XRPD, the material was further characterized by PLM, TG/DTA, DSC, NMR, DVS with post-DVS XRPD analysis, LC-MS and HPLC purity.
  • Compound A Forms C Scale-Up: Approximately 200 mg of Compound A material was added to a 20 mL vial and dissolved in 12 mL acetonitrile. The vial was then temperature cycled between ambient temperature and 40 °C in 4 hour cycles for approximately 72 hours. After 72 hours the vial was removed from the incubator/shaker and placed in the freezer at -18 °C. After 72 hours solid was noted in the vial and sample was separated. The solid was then dried for ca. 30 minutes at ambient before being analysed by XRPD. Once formation of Compound A, Form C was confirmed by XRPD, the material was further characterized by PLM, TG/DTA, DSC, NMR, DVS with post-DVS XRPD analysis, LC-MS and HPLC purity.
  • Compound A was characterised as crystalline Form A, with a rod-like morphology and a purity of 94.4 %. Prior to melt at onset 156 °C, a weight loss of 1.1 % is noted in the TGA. NMR analysis of the material was consistent with the received structure for Compound A. The received material also had a mass of 268 m/z by LC-MS analysis. DVS analysis of Form A showed the material to be slightly hygroscopic, with an uptake of 0.6 % at 90 % RH. Post-DVS the material was found to be consistent with the input material by XRPD.
  • the primary polymorph screen was carried out using a total of 28 solvent systems and 7 experimental techniques. The majority of solids recovered were identified as Form A by XRPD, with 2 other patterns also being identified. Form B was identified from evaporation after temperature cycling in acetone and from temperature cycling in acetone:water (75 :25 v/v%). Form C was identified from crash cooling to -18 °C after temperature cycling in acetonitrile.
  • Form C material was produced through crash cooling to -18 °C in acetonitrile, the material produced through this scale-up was identified as being similar to the previous Form C material. Despite offering a higher melt, the material was found to readily convert to ADX-103 Form A when ground to return a mixture of Forms A and C. PLM analysis showed birefringent particles with no clear morphology, while analysis by DVS indicated that the material was slightly hygroscopic with the uptake similar to that of Form A material. Post-DVS the material was found to be Form A by XRPD. After 1 week under stability conditions all three samples were noted to have converted to Form A by XRPD. The purity of Form C stability samples showed limited change over the stability period, with a slight drop at 40 °C/75 % RH by 0.1 % and no change at the other conditions from the input Form C purity.
  • Figure 1 depicts an XRPD pattern of Form A of compound A.
  • Figure 2 depicts a TG/DTA trace of Form A of compound A.
  • Form B of compound A was prepared as described above. [00586] Table 2, supra , is reproduced below and sets forth the X-ray diffraction peaks observed for Form B of compound A.
  • Figure 3 depicts an XRPD pattern of Form B of compound A.
  • Figure 4 depicts a TG/DTA trace of Form B of compound A.
  • Form C of compound A was prepared as described above. [00590] Table 3, supra , is reproduced below and sets forth the X-ray diffraction peaks observed for Form C of compound A.
  • Figure 5 depicts an XRPD pattern of Form C of compound A.
  • Figure 6 depicts a TG/DTA trace of Form C of compound A.
  • Example 2 Preparation of Forms A, B and C of Compound 1
  • Form A of compound 1 was prepared as described above. Form A of compound 1 was scaled-up as follows.
  • Figure 7 depicts an XRPD pattern of Form A of compound 1.
  • Figure 8 depicts a TG/DTA trace of Form A of compound 1.
  • Figure 9 depicts an XRPD pattern of Form A of compound 2.
  • Figure 10 depicts a TG/DTA trace of Form A of compound 2.
  • Form B of compound 2 was prepared as described above.
  • Figure 11 depicts an XRPD pattern of Form B of compound 2.
  • Figure 12 depicts a TG/DTA trace of Form B of compound 2.
  • Figure 13 depicts an XRPD pattern of Form A of compound 3.
  • Figure 14 depicts a TG/DTA trace of Form A of compound 3.
  • Form B of compound 3 was prepared as described above.
  • Figure 15 depicts an XRPD pattern of Form B of compound 3.
  • Figure 16 depicts a TG/DTA trace of Form B of compound 3.
  • Figure 17 depicts an XRPD pattern of Form A of compound 4.
  • Figure 18 depicts an XRPD pattern of Form A of compound 5.
  • Figure 19 depicts a TG/DTA trace of Form A of compound 5.
  • Form B of compound 5 was prepared as described above.
  • Figure 20 depicts an XRPD pattern of Form B of compound 5.
  • Figure 21 depicts a TG/DTA trace of Form B of compound 5.
  • Form C of compound 5 was prepared as described above. Form C of compound 5 was scaled-up as follows.
  • Figure 22 depicts an XRPD pattern of Form C of compound 5.
  • Figure 23 depicts a TG/DTA trace of Form C of compound 5.
  • Example 7 Preparation of Form A of Compound 6
  • Form A of compound 6 was prepared as described above. Form A of compound 6 was scaled-up as follows.
  • Figure 24 depicts an XRPD pattern of Form A of compound 6.
  • Figure 25 depicts a TG/DTA trace of Form A of compound 6.
  • Figure 26 depicts an XRPD pattern of Form A of compound 7.
  • Figure 27 depicts a TG/DTA trace of Form A of compound 7.
  • Form B of compound 7 was prepared as described above. Form B of compound 7 was scaled-up as follows.
  • Table 19 is reproduced below and sets forth the X-ray diffraction peaks observed for Form B of compound 7.
  • Figure 28 depicts an XRPD pattern of Form B of compound 7.
  • Figure 29 depicts a TG/DTA trace of Form B of compound 7.
  • Form A of compound 8 was prepared as described above. Form A of compound 8 was scaled-up as follows.
  • the sample was then filtered using a Buchner flask and funnel and the solids dried at ambient temperature under vacuum for ca. 16 hours.
  • the solid material was analyzed by XRPD, PLM, TG/DTA, DSC, DVS/GVS, FT-IR, NMR and HPLC. Solid material was observed to have precipitated from the mother liquor of the temperature cycled material, this solid was analyzed by XRPD.
  • Figure 30 depicts an XRPD pattern of Form A of compound 8.
  • Figure 31 depicts a TG/DTA trace of Form A of compound 8.
  • Form B of compound 8 was prepared as described above.
  • Figure 32 depicts an XRPD pattern of Form B of compound 8.
  • Figure 33 depicts a TG/DTA trace of Form B of compound 8.
  • Figure 34 depicts an XRPD pattern of Form A of compound 9.
  • Figure 35 depicts a TG/DTA trace of Form A of compound 9.
  • Table 24, supra is reproduced below and sets forth the X-ray diffraction peaks observed for Form A of compound 10.
  • Figure 36 depicts an XRPD pattern of Form A of compound 10.
  • Figure 37 depicts an XRPD pattern of Form A of compound 11.
  • Figure 38 depicts an XRPD pattern of Form A of compound 12.
  • Figure 39 depicts a TG/DTA trace of Form A of compound 12.
  • Form A of Compound 1 is far more soluble than Form C of Compound 5, Form A of Compound 6, Form B of Compound 7 and Form B of Compound 8.
  • the unit cell was observed to be asymmetric and to contain two complete Compound A formula units, with hydrogen bonding association between the two molecules.
  • Figure 40 depicts a unit cell of compound A.
  • Figure 41 depicts simulated and experimental XRPD patterns of compound A.

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US11312692B1 (en) 2022-04-26
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