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WO2025029769A1 - Formes solides de bloqueurs de canaux de shaker potassiques kv1.3 et leur procédé d'utilisation - Google Patents

Formes solides de bloqueurs de canaux de shaker potassiques kv1.3 et leur procédé d'utilisation Download PDF

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Publication number
WO2025029769A1
WO2025029769A1 PCT/US2024/040114 US2024040114W WO2025029769A1 WO 2025029769 A1 WO2025029769 A1 WO 2025029769A1 US 2024040114 W US2024040114 W US 2024040114W WO 2025029769 A1 WO2025029769 A1 WO 2025029769A1
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crystalline form
solid form
compound
theta
diffraction angle
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David Andrew Coates
David Michael Remick
Saurin Hiren RAWAL
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Eli Lilly and Co
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Eli Lilly and Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates generally to the field of pharmaceutical science. More particularly, the invention relates to solid forms of a compound useful as pharmaceuticals as potassium channel blockers.
  • Kvl.3 potassium (K + ) channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues and regulate a large number of physiological processes such as neurotransmitter release, heart rate, insulin secretion, and neuronal excitability. Kvl.3 channels can regulate membrane potential and thereby indirectly influence calcium signaling in human effector memory T cells.
  • Effector memory T cells are mediators of several conditions, including multiple sclerosis, Type I diabetes mellitus, psoriasis, spondylitis, parodontitis, and rheumatoid arthritis. Upon activation, effector-memory T cells increase expression of the Kvl.3 channel.
  • Kvl.3 channels Amongst human B cells, naive and early memory B cells express small numbers of Kvl.3 channels when they are quiescent. In contrast, class-switched memory B cells express high numbers of Kvl.3 channels. Furthermore, the Kvl.3 channel promotes the calcium homeostasis required for T-cell receptor-mediated cell activation, gene transcription, and proliferation (Panyi, G., et al., 2004, Trends Immunol. , 565-569). Blockade of Kvl.3 channels in effector memory T cells suppresses activities like calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation.
  • cytokine production interferon-gamma, interleukin 2
  • a number of peptide toxins with multiple disulfide bonds from spiders, scorpions, and anemones are known to block Kvl.3 channels.
  • a few selective, potent peptide inhibitors of the Kvl.3 channel have been developed.
  • a synthetic derivative of stichodactyla toxin (shk) with an unnatural amino acid (shk-186) is the most advanced peptide toxin.
  • Shk has demonstrated efficacy in preclinical models and is currently in a phase I clinical trial for treatment of psoriasis.
  • Shk can suppress proliferation of TEM cells resulting in improved condition in animal models of multiple sclerosis.
  • Shk also binds to the closely-related Kvi channel subtype found in CNS and heart.
  • Kvl .3 channel-selective inhibitors there is a need for Kvl .3 channel-selective inhibitors to avoid potential cardio- and neuro-toxicity. Additionally, small peptides like shk-186 are rapidly cleared from the body after administration, resulting in short circulating half-lives, frequent administration events.
  • Kvl.3 channel inhibitors for the treatment of chronic inflammatory diseases
  • WO2021071821, WO2021071806, W02021071812, W02021071802, WO2021071832, W02021071803, WO2022212296, WO2022251561, and WO2022076285 describe new Kvl.3 channel blockers and their therapeutic uses. Nevertheless, there remains a need for development of novel solid forms of such Kvl.3 channel blockers with sufficient stability, purity, and proper impurity profile, preferably in crystalline form, as pharmaceutical agents, ideally in an oral formulation.
  • the compound of Formula I is also referred to as (R)-l-(4-((R)-amino(5-chl oro-2 - hydroxy-4-methylphenyl)methyl)piperidin-l-yl)-2,3-dihydroxypropan-l-one.
  • the solid forms described herein can block Kvl.3 potassium (K + ) channels and be used in the treatment of a variety of conditions. Methods for synthesizing the compound of Formula I, as well as the solid forms thereof are described herein. Pharmaceutical compositions including the solid forms, and methods of using these solid forms and pharmaceutical compositions described herein are useful for treating conditions in vitro and in vivo. Such solid forms, pharmaceutical compositions, and methods of treatment have a number of clinical applications, including as pharmaceutically active agents and methods for treating cancer, an immunological disorder, a Central Nerve System (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, a kidney disease or a combination thereof.
  • the solid forms described herein are salt forms of the compound of Formula I. In some embodiments, provided herein are pharmaceutically acceptable salts of the compound of Formula I.
  • a solid form of a compound of formula: or a pharmaceutically acceptable salt thereof wherein the solid form degrades less than about 1% by weight after being maintained at a temperature of 40°C and a relative humidity of 75% for a period of 14 days.
  • the solid form is a carboxylic acid salt of the compound.
  • the solid form is crystalline.
  • the solid form is a carboxylic monoacid salt of the compound. In some embodiments, the solid form is a benzoic acid salt of the compound. In some embodiments, the solid form is characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2-theta of 6.0°, and one or more peaks at diffraction angle 2-theta of 6.4°, 12.0°, or 19.8°, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.5°, 9.9°, 12.6°, 15.5°, 16.9°, 17.4°, 18.5°, 19.2°, 21.7°, or 24.3°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • the solid form is a cinnamic acid salt of the compound.
  • the solid form is characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2-theta of 5.9°, and one or more peaks at diffraction angle 2-theta of 4.8°, 16.5°, or 18.1°, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.1°, 8.3°, 10.3°, 11.1°, 12.4°, or 20.7°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • the solid form is a carboxylic diacid salt of the compound. In some embodiments, the solid form is a glutaric acid salt of the compound. In some embodiments, a molar concentration associated with an ionic form of the compound and a molar concentration associated with carboxylic acid group of the carboxylic acid is at a ratio of about 1 :1. In some embodiments, the solid form is a hemi -glutarate salt of the compound. In some embodiments, the solid form is a solvate. In some embodiments, the solvate is a hydrate.
  • a molar concentration associated with the compound and a molar concentration associated with a solvent molecule of the solvate is at a ratio of about 2: 1.
  • the solid form is of a hemi -glutarate hemihydrate.
  • the solid form is characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2-theta of 16.5°, and one or more peaks at diffraction angle 2-theta of 14.4°, 17.3°, or 18.2°, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.7°, 7.8°, 9.4°, 10.8°, 11.6°, 13.2°, 15.5°, 18.9°, 19.7°, 20.5°, 21.1°, 21.9°, 22.8°, or 23.3°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • a pharmaceutical composition comprising a solid form of any one of previous embodiments, and a pharmaceutically acceptable carrier or diluent.
  • the composition degrades less than about 2% by weight after being maintained at a temperature of 40°C and a relative humidity of 75% for a period of 10 days.
  • the composition comprises Total Related Substances associated with the solid form in an amount less than about 2 % by weight.
  • a method of treating a condition in a patient comprising administering to the patient a therapeutically effective amount of a solid form of any one of embodiments described herein, or a pharmaceutical composition described herein, wherein the condition is selected from the group consisting of cancer, an immunological disorder, a Central Nerve System (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.
  • CNS Central Nerve System
  • solid form refers to a form of a compound, or a pharmaceutically acceptable salt of the compound, each in the solid state.
  • solid form encompasses the the compound or its pharmaceutically acceptable salt each in an unsolvated solid form (including any unhydrated solid form) and in any solvated solid form (including hydrated solid form, e.g. being structurally associated with water).
  • solid form encompasses the compound as a free base form and as a pharmaceutically acceptable salt, each in an amorphous solid form or in any crystalline solid form.
  • salt(s) denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • a compound of the present invention contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein.
  • the compounds of the present invention may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include, but are not limited to, acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemi sulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxy ethanesulfonates (e.g., 2-hydroxy ethanesulfonates), lactates, maleates, methanesulfonates,
  • salts refers to salts that are useful for pharmaceutical development and may include relatively non-toxic and physiologically acceptable inorganic and organic acid addition salts of the compound.
  • Such salts include but are not limited to those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • the reaction may be in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • crystalline form refers to a solid form of the compound or its pharmacetucally acceptable salt, whether solvated or not, in a crystalline state.
  • hemi- when used as a prefix in the nomenclature of a salt of a compound refers to the stoichiometry where an ionic form of the compound and the counterion exist in a molar ratio of about 2: 1.
  • the term when used as a prefix in the nomenclature of a solvate of a compound refers to the stoichiometry where the compound and the associated solvent molecule exist in a molar ratio of about 2: 1.
  • the solid forms are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to greater than 95%, equal to or greater than 99% of the solid forms (“substantially pure” solid forms), which is then used or formulated as described herein. Such “substantially pure” solid forms of the present invention are also contemplated herein as part of the present invention.
  • the present invention also includes solid forms of isotopically labeled compound of Formula I, which are identical to the compound for Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, such as 2 H, 3 H, 13 C, n C, 14 C, 15 N, 18 O, 17 O, and 36 C1, respectively.
  • Solid forms of such isotopically labeled compound of Formula I or pharmaceutically acceptable salt or solvate thereof, which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically labeled compounds of the present invention for example, those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, z.e., 3 H, and carbon-14, z.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • stable preferably refers to solid forms which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein.
  • cancer and, equivalently, “tumor” refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject.
  • the cancer can be a malignant or non-malignant cancer.
  • Cancers or tumors include, but are not limited to, biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasms; leukemias; lymphomas; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; as well as other carcinomas and sarcomas. Cancers can be primary or metastatic.
  • Noncancer diseases may include: neurofibromatosis; Leopard syndrome; Noonan syndrome; Legius syndrome; Costello syndrome; Cardio-facio-cutaneous syndrome; Hereditary gingival fibromatosis type 1; Autoimmune lymphoproliferative syndrome; and capillary malformation-arterovenous malformation.
  • an effective amount refers to any amount that is necessary or sufficient for achieving or promoting a desired outcome.
  • an effective amount is a therapeutically effective amount.
  • a therapeutically effective amount is any amount that is necessary or sufficient for promoting or achieving a desired biological response in a subject.
  • the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation.
  • the term “subject” refers to a vertebrate animal.
  • the subject is a mammal or a mammalian species.
  • the subject is a human.
  • the subject is a non-human vertebrate animal, including, without limitation, non-human primates, laboratory animals, livestock, racehorses, domesticated animals, and non-domesticated animals.
  • the term “patient” refers to a human subject in need of a treatment provided.
  • the term “related substance” with respect to a solid form refers to a byproduct from the synthesis of the solid form or a compound of the solid form that is not isolated therefrom and carried with the solid form into the use or test.
  • the term “mechanistic degradant” with respect to a solid form refers to a molecule produced during the use of the solid form from degradation, such as degradation at the storage condition of the solid form, or degradations at an accelerated stress condition (e.g. those described below).
  • Total Related Substances refers collectively to all related substantces to the solid form and all mechanistic degradants from the solid form.
  • WO2021071806 describes several hundred novel compounds potentially useful as selective Kvl.3 potassium channel blockers that do not block the hERG channel thus having desirable cardiovascular safety profiles.
  • a particular compound, (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one, having a structure of Formula I: or a pharmaceutically acceptable salt thereof is particularly desirable as compared to other disclosed compounds therein, in part due to its favorable balance among factors including efficacy, toxicity, and immunosuppression effect. Additionally, this compound possesses increased ion channel selectivity, reduced cardiotoxicity risk, improved pharmacokinetics, increased solubility among other favorable characteristics. Accordingly, the compound of Formula I was selected for further study.
  • a pharmaceutically acceptable salt of a compound of Formula I is provided herein.
  • the salt is a carboxylic acid salt.
  • solid forms described herein possess surprisingly improved stability, as manifested in under accelerated stress conditions (as further described below).
  • Embodiment IE A solid form of a compound of Formula I, which is a salt of formic acid.
  • Embodiment 2A A solid form of a compound of formula: or a pharmaceutically acceptable salt thereof, wherein the solid form degrades less than about 2% by weight after being maintained at a temperature of 40°C and a relative humidity of 75% for a period of 14 days; wherein optionally:
  • Embodiment 2B A solid form of a compound of formula: or a pharmaceutically acceptable salt thereof, wherein the solid form degrades less than about 0.5% by weight after being maintained at a temperature of 40°C and a relative humidity of 75% for a period of 14 days; wherein optionally:
  • the solid form degrades less than about 0.5% by weight, after being maintained at a temperature of 50°C and a relative humidity of 75% for a period of 14 days;
  • TRS associated with the solid form after being maintained at a temperature of 50°C and a relative humidity of 75% for a period of 14 days accounts for no more than 0.5% of the total weight.
  • Embodiment 2C A solid form of a compound of formula: or a pharmaceutically acceptable salt thereof, wherein the solid form degrades less than about 0.2% by weight after being maintained at a temperature of 40°C and a relative humidity of 75% for a period of 14 days; wherein optionally:
  • the solid form degrades less than about 0.1% by weight, after being maintained at a temperature of 50°C and a relative humidity of 75% for a period of 14 days;
  • Embodiment 2E A solid form of a compound of formula: or a pharmaceutically acceptable salt thereof, wherein Total Related Substances (TRS) associated with the solid form after being maintained at a temperature of 40°C and a relative humidity of 75% for a period of 14 days account for no more than 0.1% of the total weight.
  • TRS Total Related Substances
  • Embodiment 2F A solid form of a compound of formula: or a pharmaceutically acceptable salt thereof, wherein the solid form degrades less than about 0.1% by weight, after being maintained at a temperature of 50°C and a relative humidity of 75% for a period of 14 days.
  • Embodiment 2G A solid form of a compound of formula: or a pharmaceutically acceptable salt thereof, wherein the TRS associated with the solid form after being maintained at a temperature of 50°C and a relative humidity of 75% for a period of 14 days accounts for no more than 0.1% of the total weight.
  • Embodiment 3 The solid form of embodiment 1 or 2, wherein the solid form is a pharmaceutically acceptable carboxylic acid salt of the compound.
  • Embodiment 4 The solid form of any of embodiments 1-3, which is crystalline. In some embodiments, the crystallinity is above 90%. In some embodiments, the crystallinity is above 95%. In some embodiments, the crystallinity is above 97%. In some embodiments, presence of moisture induces crystallization of amorphous materials into crystalline forms described herein.
  • Embodiment 5 The solid form of any of embodiments 1-4, wherein the solid form is a pharmaceutically acceptable carboxylic monoacid salt of the compound.
  • Embodiment 6 The solid form of any of embodiments 1-5, wherein the solid form is a benzoic acid salt of the compound.
  • Embodiment 6A A solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one benzoate, which is crystalline.
  • Embodiment 7 The solid form of any of embodiments 1-5, wherein the solid form is a cinnamic acid salt of the compound.
  • cinnamic acid salt of the compound presents improved stability, higher purity, and/or more favorable impurity profile across a broader range of the dose range as compared to other solid forms.
  • Embodiment 7A A solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one cinnamate, which is crystalline.
  • Embodiment 8 The solid form of any of embodiments 1-4, wherein the solid form is a pharmaceutically acceptable carboxylic diacid salt of the compound.
  • Embodiment 9. The solid form of any of embodiments 1-4, and 8, wherein the solid form is a glutaric acid salt of the compound.
  • glutaric acid salt of the compound presents further improved stability, higher purity, and/or more favorable impurity profile than across a broader dose range as compared to some other solid forms of the compound.
  • Embodiment 10 The solid form of any of embodiments 1-9, wherein a molar concentration associated with an ionic form of the compound within the solid form and a molar concentration associated with carboxylic acid group of the carboxylic acid within the solid form is at a ratio of about 1 : 1.
  • Embodiment 11 The solid form of any of embodiments 1-10, wherein the solid form is a solvate.
  • Embodiment 11 A The solid form of embodiment 9 or 10, wherein the solid form is a solvate.
  • Embodiment 12 The solid form of embodiment 11, wherein the solvate is a hydrate.
  • Embodiment 13 The solid form of embodiment 11 or 12, wherein a molar concentration associated with the compound within the solid form and a molar concentration associated with a solvent molecule of the solvate within the solid form is at a ratio of about 2: 1.
  • Embodiment 14 The solid form of embodiment 6, which is crystalline, characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2-theta of 6.0°, and one or more peaks at diffraction angle 2- theta of 6.4°, 12.0°, or 19.8°, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.5°, 9.9°, 12.6°, 15.5°, 16.9°, 17.4°, 18.5°, 19.2°, 21.7°, or 24.3°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • Embodiment 14A The solid form of embodiment 6, which is crystalline, characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2-theta of 6.0°, and one or more peaks at diffraction angle 2- theta of 6.4°, 19.8°, or 24.3°, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.5°, 9.9°, 12.0°, 12.6°, 15.5°, 16.9°, 17.4°, 18.5°, 19.2°, or 21.7°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • Embodiment 14B The solid form of embodiment 6, which is crystalline, characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2-theta of 6.0°, and one or more peaks at diffraction angle 2- theta of 6.4°, 12.0°, 19.8°, or 24.3°, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.5°, 9.9°, 12.6°, 15.5°, 16.9°, 17.4°, 18.5°, 19.2°, or 21.7°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • Embodiment 15 The solid form of embodiment 7, which is crystalline, characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2-theta of 5.9°, and one or more peaks at diffraction angle 2- theta of 4.8°, 16.5°, or 18.1°, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.1°, 8.3°, 10.3°, 11.1°, 12.4°, or 20.7°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • Embodiment 15 A The solid form of embodiment 7, which is crystalline, characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2-theta of 5.9°, and one or more peaks at diffraction angle 2- theta of 4.8°, 16.5°, 18.1°, or 20.7°, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.1°, 8.3°, 10.3°, 11.1°, or 12.4°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • Embodiment 15B Embodiment 15B.
  • Embodiment 18 A The solid form of embodiment 17, which is crystalline, characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2-theta of 16.5°, and one or more peaks at diffraction angle 2- theta of 14.4°, 17.3°, 18.2°, or 23.3°, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.7°, 7.8°, 9.4°, 10.8°, 11.6°, 13.2°, 15.5°, 18.9°, 19.7°, 20.5°, 21.1°, 21.9°, or 22.8°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • Embodiment 18B The solid form of embodiment 17, which is crystalline, characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2-theta of 16.5°, and one or more peaks at diffraction angle 2- theta of 14.4°, 17.3°, 18.2°, 20.5°, or 23.3°, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.7°, 7.8°, 9.4°, 10.8°, 11.6°, 13.2°, 15.5°, 18.9°, 19.7°, 21.1°, 21.9°, or 22.8°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • Embodiment 20G A pharmaceutical composition, comprising a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one cinnamate, which is crystalline, characterized by an X-ray powder diffraction pattern using CuKa radiation comprising a peak at diffraction angle 2- theta of 5.9°, and one or more peaks at diffraction angle 2-theta of 4.8°, 8.3°, 16.5°, 18.1°, or 20.7°, and a pharmaceutically acceptable carrier or diluent, wherein the X-ray powder diffraction pattern optionally further comprises one or more peaks at diffraction angle 2-theta of 7.1°, 10.3°, 11.1°, or 12.4°, and wherein the diffraction angle 2-theta each has a tolerance of ⁇ 0.2 degrees.
  • Embodiment 2 IE A pharmaceutical composition comprising a solid form of comprising a solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one cinnamate, wherein the composition degrades less than about 1% by weight after being maintained at a temperature of 40°C and a relative humidity of 75% for a period of 10 days; wherein optionally:
  • Embodiment 21G A pharmaceutical composition comprising a solid form of comprising a solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one benzoate, wherein the composition degrades less than about 1% by weight after being maintained at a temperature of 40°C and a relative humidity of 75% for a period of 10 days; wherein optionally:
  • the solid form degrades less than about 1% by weight, after being maintained at a temperature of 50°C and a relative humidity of 75% for a period of 10 days;
  • Embodiment 22A A pharmaceutical composition comprising a solid form of any one of embodiments 1-19, and Total Related Substances associated with the solid form in an amount less than about 2 % by weight.
  • Embodiment 22B A pharmaceutical composition comprising a solid form of any one of embodiments 1-19, and Total Related Substances associated with the solid form in an amount less than about 1 % by weight.
  • Embodiment 22C A pharmaceutical composition comprising a solid form of any one of embodiments 1-19, and Total Related Substances associated with the solid form in an amount less than about 0.5 % by weight.
  • Embodiment 22D A pharmaceutical composition comprising a solid form of any one of embodiments 1-19, and Total Related Substances associated with the solid form in an amount less than about 0.1 % by weight.
  • Embodiment 22H A pharmaceutical composition comprising a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan- 1 -one cinnamate, and Total Related Substances associated with the solid form in an amount less than about 2 % by weight.
  • Embodiment 22 A pharmaceutical composition comprising a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one cinnamate, and Total Related Substances associated with the solid form in an amount less than about 1 % by weight.
  • Embodiment 22J A pharmaceutical composition comprising a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one cinnamate, and Total Related Substances associated with the solid form in an amount less than about 0.5 % by weight.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.
  • Methods of preparing these formulations or compositions include the step of bringing into association a solid form of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a solid form of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a suspension in an aqueous or nonaqueous liquid, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and the like, each containing a predetermined amount of a solid form of the present invention as an active ingredient.
  • a solid form of the present invention may also be administered as a bolus, electuary, or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl
  • compositions may also comprise buffering agents.
  • 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 sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be, made by molding in a suitable machine a mixture of the powdered solid form moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the solid forms of the invention include pharmaceutically acceptable suspensions.
  • 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, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl 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, solubilizing agents and emulsifiers, such as ethyl alcohol, isobutyl alcohol
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the solid form, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, a — r— agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, a — r— agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration of a solid form of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, and patches.
  • the solid form may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to the solid form of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a solid form of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Transdermal patches have the added advantage of providing controlled delivery of the compound of Formula I to the body.
  • dosage forms can be made by dissolving, or dispersing the pharmaceutical agents in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the pharmaceutical agents of the invention across the skin. The rate of such flux can be controlled, by either providing a rate controlling membrane or dispersing the solid form in a polymer matrix or gel.
  • compositions of this invention suitable for parenteral administration comprise one or more solid forms of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • the solid forms of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the solid forms and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the solid forms and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the solid form of the present invention may be administered concurrently with another therapeutic agent).
  • Non-limiting examples of another therapeutic agent including biological and small molecule anticancer agent, immunomodulator, immunosuppressant, anti-inflammatory agent, anti-arthritis agent, corticosteroid, antidiarrheal agent, anti coagulation agent, and antithrombotic agent.
  • the solid forms, and pharmaceutical compositions of the invention may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means.
  • the solid forms, and pharmaceutical compositions may be used to treat arthritic conditions in mammals (e.g., humans, livestock, and domestic animals), race horses, birds, lizards, and any other organism, which can tolerate the compound.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the present invention provides a method for treating a condition in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one solid form described herein, wherein the condition is selected from the group consisting of cancer, an immunological disorder, a central nerve system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.
  • CNS central nerve system
  • the cancer is selected from the group consisting of biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, intraepithelial neoplasms, leukemias, lymphomas, liver cancer, lung cancer, melanoma, neuroblastomas, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal (kidney) cancer, sarcomas, skin cancer, testicular cancer, and thyroid cancer.
  • biliary tract cancer brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, intraepithelial neoplasms, leukemias, lymphomas, liver cancer, lung cancer, melanoma, neuroblastomas, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal
  • the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitits, or an inflammatory neuropathy.
  • the gastroenterological disorder is an inflammatory bowel disease such as Crohn’s disease or ulcerative colitis.
  • the immunological disorder is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or Type I diabetes mellitus).
  • the Central Nerve System (CNS) disorder is Alzheimer’s disease.
  • the metabolic disorder is obesity or Type II diabetes mellitus.
  • the cardiovascular disorder is an ischemic stroke.
  • the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.
  • the mammalian species is human.
  • the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Type I diabetes mellitus, Alzheimer’s disease, inflammatory skin condition, inflammatory neuropathy, psoriasis, spondylitis, parodontitis, inflammatory bowel disease, obesity, Type II diabetes mellitus, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and a combination thereof.
  • a method of blocking Kvl.3 potassium channel in a mammalian species in need thereof including administering to the mammalian species a therapeutically effective amount of at least one solid form described herein.
  • the solid forms described herein are selective in blocking the Kv 1.3 potassium channels with minimal or no off-target inhibition activities against other potassium channels, or against calcium or sodium channels. In some embodiments, the solid forms described herein do not block the hERG channels and therefore have desirable cardiovascular safety profiles.
  • Embodiment 23 A method of treating a condition in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of any one of embodiments 1-19, or a pharmaceutical composition of any of embodiments 20-22, wherein the condition is selected from the group consisting of cancer, an immunological disorder, a Central Nerve System (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.
  • CNS Central Nerve System
  • Embodiment 23 A A method of treating a condition in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan- 1 -one hemi -glutarate hemi-hydrate, wherein the condition is selected from the group consisting of cancer, an immunological disorder, a Central Nerve System (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.
  • CNS Central Nerve System
  • Embodiment 23B A method of treating a condition in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one cinnamate, wherein the condition is selected from the group consisting of cancer, an immunological disorder, a Central Nerve System (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.
  • CNS Central Nerve System
  • Embodiment 23C A method of treating a condition in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one benzoate, wherein the condition is selected from the group consisting of cancer, an immunological disorder, a Central Nerve System (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a metabolic disorder, a cardiovascular disorder, and a kidney disease.
  • CNS Central Nerve System
  • Embodiment 24 The method of embodiment 23, wherein the condition is selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 24A The method of embodiment 23, wherein the condition is psoriasis.
  • Embodiment 24B The method of embodiment 23, wherein the condition is plaque psoriasis.
  • Embodiment 24C The method of embodiment 23, wherein the condition is mild-to- moderate plaque psoriasis.
  • Embodiment 24D The method of embodiment 23, wherein the condition is moderate- to- severe plaque psoriasis.
  • Embodiment 24E The method of embodiment 23, wherein the condition is rheumatoid arthritis.
  • Embodiment 24F The method of embodiment 23, wherein the condition is systemic lupus erythematosus.
  • Embodiment 24G The method of embodiment 23, wherein the condition is lupus nephritis.
  • Embodiment 24R The method of embodiment 23, wherein the condition is chronic obstructive pulmonary disease.
  • Embodiment 24T The method of embodiment 23, wherein the condition is mycosis fungoides.
  • Embodiment 24V The method of embodiment 23, wherein the condition is transplant rejection or an autoimmune disease.
  • Embodiment 24W The method of embodiment 23, wherein the condition is Type I diabetes mellitus.
  • Embodiment 24X The method of embodiment 23, wherein condition is Alzheimer’s disease.
  • Embodiment 24 Y The method of embodiment 23, wherein the condition is an inflammatory skin condition, arthritis, psoriasis, spondylitis, parodontitits, or an inflammatory neuropathy.
  • Embodiment 24Z The method of embodiment 23, wherein the condition is obesity or Type II diabetes mellitus.
  • Embodiment 24 AA The method of embodiment 23, wherein the condition is an ischemic stroke.
  • Embodiment 24 AB The method of embodiment 23, wherein the condition is chronic kidney disease, nephritis, or chronic renal failure.
  • Embodiment 24AF A method of treating psoriasis in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one benzoate.
  • Embodiment 24AG A method of treating rheumatoid arthritis in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one hemi -glutarate hemi-hydrate.
  • Embodiment 24AI A method of treating rheumatoid arthritis in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one benzoate.
  • Embodiment 25 A method of blocking Kvl .3 potassium channel in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of any of embodiments 1-19, or a pharmaceutical composition of any of embodiments 20- 22.
  • Embodiment 25A A method of blocking Kvl.3 potassium channel in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one hemi -glutarate hemi-hydrate.
  • Embodiment 25B A method of blocking Kvl.3 potassium channel in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one cinnamate.
  • Embodiment 25C A method of blocking Kvl.3 potassium channel in a patient, comprising administering to the patient a therapeutically effective amount of a solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one cinnamate.
  • a method of blocking Kvl .3 potassium channel in a patient comprising administering to the patient a therapeutically effective amount of a solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one benzoate.
  • Embodiment 26 A method of treating a condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula: or pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 26A The method of embodiment 26, wherein the condition is psoriasis.
  • Embodiment 26B The method of embodiment 26, wherein the condition is rheumatoid arthritis.
  • Embodiment 26C The method of embodiment 26, wherein the condition is systemic lupus erythematosus.
  • Embodiment 26D The method of embodiment 26, wherein the condition is lupus nephritis.
  • Embodiment 26E The method of embodiment 26, wherein the condition is atopic dermatitis.
  • Embodiment 26F The method of embodiment 26, wherein the condition is alopecia areata.
  • Embodiment 27 The method of embodiment 26, wherein the administering is conducted with a pharmaceutically acceptable salt of the compound.
  • Embodiment 28 The method of embodiment 26, wherein the administering is conducted with a solid form according to any one of embodiments 1-19.
  • Embodiment 29 The method of any of embodiments 23-28, wherein the administering comprises administering orally.
  • Embodiment 30 A solid form according to any of embodiments 1-19 for use in therapy.
  • Embodiment 30A A solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one hemi -glutarate hemihydrate for use in therapy.
  • Embodiment 30B A solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one cinnamate for use in therapy.
  • Embodiment 30C A solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one benzoate for use in therapy.
  • Embodiment 31 A solid form according to any of embodiments 1-19 for use in treating a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 31 A A solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one hemi -glutarate hemihydrate for use in treating a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 3 IB A solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one cinnamate for use in treating a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 31C A solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one cinnamate for use in treating a condition selected from the group consisting of psoriasis, rheum
  • Embodiment 32 Use of a solid form according to any of embodiments 1-19 in the manucture of a medicament for treatment of a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 32A Use of a solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one hemi -glutarate hemihydrate in the manucture of a medicament for treatment of a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 32B Use of a solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one cinnamate in the manucture of a medicament for treatment of a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 32C Use of a solid form of (2R)-l-[4-[(R)-amino(5-chloro-2-hydroxy-4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one benzoate in the manucture of a medicament for treatment of a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • compositions for use in therapy of the present invention are described below without limitation thereto.
  • Embodiment 33 A pharmaceutical composition comprising a solid form according to any of embodiments 1-19 for use in treating a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 33A A pharmaceutical composition comprising a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one hemi -glutarate hemi-hydrate for use in treating a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 33B A pharmaceutical composition comprising a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one cinnamate for use in treating a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • Embodiment 33C A pharmaceutical composition comprising a solid form of (2R)-1- [4-[(R)-amino(5-chloro-2-hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3- dihydroxypropan-l-one benzoate for use in treating a condition selected from the group consisting of psoriasis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, atopic dermatitis, and alopecia areata.
  • compositions useful according to the methods of the present invention thus can be formulated in any manner suitable for pharmaceutical use.
  • an effective amount of the solid form can be administered to a subject by any mode allowing the compound to be taken up by the appropriate target cells.
  • administering the pharmaceutical composition of the present invention can be accomplished by any means known to the skilled artisan. Specific routes of administration include, but are not limited to, oral, transdermal e.g., via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, intravaginal, etc.). An injection can be in a bolus or a continuous infusion.
  • the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above.
  • the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of present methods for drug delivery, see Langer R (1990) Science 249: 1527-33, which is incorporated herein by reference.
  • concentration of compound (e.g. derived from the solid forms described herein) included in compositions used in the methods of the invention can range from about 1 nM to about 100 pM. Effective doses are believed to range from about 10 picomol e/kg to about 100 micromol e/kg.
  • the pharmaceutical compositions are preferably prepared and administered in dose units.
  • Liquid dose units are vials or ampoules for injection or other parenteral administration.
  • Solid dose units are tablets, capsules, powders, and suppositories.
  • purpose of the administration z.e., prophylactic or therapeutic
  • nature and severity of the disorder age and body weight of the patient
  • different doses may be necessary.
  • the administration of a given dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units. Repeated and multiple administration of doses at specific intervals of days, weeks, or months apart are also contemplated by the invention.
  • Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v).
  • Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004- 0.02% w/v).
  • compositions suitable for parenteral administration conveniently include sterile aqueous preparations, which can be isotonic with the blood of the recipient.
  • acceptable vehicles and solvents are water, Ringer’s solution, phosphate buffered saline, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed mineral or non-mineral oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, etc. administrations can be found in Remington ’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.
  • the solid forms useful in the invention can be delivered in mixtures of more than two such solid forms.
  • a mixture can further include one or more adjuvants in addition to the combination of solid forms.
  • a variety of administration routes is available. The particular mode selected will depend, of course, upon the particular form selected, the age and general health status of the subject, the particular condition being treated, and the dosage required for therapeutic efficacy.
  • the methods of this invention generally speaking, can be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of response without causing clinically unacceptable adverse effects. Preferred modes of administration are discussed above.
  • compositions can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the solid forms into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the solid form into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the solid form, increasing convenience to the subject and the physician.
  • Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copoly oxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075,109.
  • Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di-and tri-glycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like.
  • lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di-and tri-glycerides
  • hydrogel release systems silastic systems
  • peptide-based systems such as mono-di-and tri-glycerides
  • wax coatings such as those described in U.S. Pat. Nos. 4,452,775, 4,675,189, and 5,736,152
  • diffusional systems in which an active component permeates at a controlled rate from a polymer such as described in U.S. Pat. Nos.
  • pump-based hardware delivery systems can be used, some of which are adapted for implantation.
  • the carboxylic acid salt of a compound can be prepared by contacting a free base form of the compound with the carboxylic acid.
  • a free base form may be prepared from a strong acid salt of the compound (e.g. a HC1 salt of the compound) by lowering the pH with a base (such as sodium hydroxide).
  • a base such as sodium hydroxide
  • the carboxylic acid salt of the compound of Formula I prepared this way suffer significant degradation thus low purity. It is surprisingly discovered that by implementing methods described below, the degradation is largely mitigated, and an improvement in yield of at least 10% is achieved.
  • Embodiment 34 A method, comprising contacting a strong acid salt of a compound of Formula I with a metal salt of a carboxylic acid, under a condition sufficient to provide an ion exchange reaction therebetween to form a carboxylic acid salt of the compound of Formula I.
  • the “strong acid salt” refers to a salt of an acid that completely ionizes in an aqueous solution.
  • the strong acid salt is a salt of hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, or the like.
  • the strong acid salt is a hydrochloric acid salt.
  • Embodiment 34A The method of embodiment 34, wherein the carboxylic acid is an organic acid having a pKa value of about 2 to 5. In some embodiments, the carboxylic acid is an organic acid having a pKa value of about 3 to 4. In some embodiments, the carboxylic acid is selected from benzoic acid, cinnamic acid, and glutaric acid. In some embodiments, the carboxylic acid is glutaric acid.
  • the solid forms as described herein are tested for their activities against Kvl.3 potassium channel. In some embodiments, the solid forms as described herein are tested for their Kvl .3 potassium channel electrophysiology. In some embodiments, the solid forms as described herein are tested for their hERG el ectrophy si ol ogy .
  • the XRPD patterns of crystalline solids are obtained on a Bruker D8 Endeavor X-ray powder diffractometer, equipped with a CuKa (1.5418 A) source and a Linxeye detector, operating at 40 kV and 40 mA.
  • the sample is scanned between 4 and 42 29°, with a step size of 0.009 29° and a scan rate of 0.5 seconds/step, and using 0.3° primary slit opening, and 3.9° PSD opening.
  • the dry powder is packed on a quartz or silicon sample holder and a smooth surface is obtained using a glass slide.
  • the crystal form diffraction patterns are collected at ambient temperature and relative humidity.
  • Crystal peak positions are determined in MDI-Jade after whole pattern shifting based on an internal NIST 675 standard with peaks at 8.853 and 26.774 29°. It is well known in the crystallographic art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly.
  • peak positions can shift due to a variation in the temperature at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard.
  • a peak position variability of ⁇ 9.2 29° is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks.
  • Example 1A ((S)-N-((R)-(2-(allyloxy)-5-chloro-4-methylphenyl)(piperidin- 4- yl)methyl)-2-methylpropane-2-sulfinamide)
  • Step a To a stirred solution of 2-bromo-5-methylphenol (42.00 g, 224.56 mmol) in l,l,l,3,3,3-hexafluoropropan-2-ol (500 mL) was added NCS (31.00 g, 235.78 mmol) in portions at room temperature under air atmosphere. The reaction solution was allowed to warm to 50 °C and stirred for 16 h under air atmosphere. After cooling to room temperature, the resulting solution was concentrated under reduced pressure.
  • Step b To a stirred mixture of 2-bromo-4-chloro-5-methylphenol (31.00 g, 0.14 mol) and K2CO3 (39.00 g, 0.28 mol) in DMF (300 mL) was added allyl bromide (29.00 g, 0.24 mol) dropwise at room temperature under air atmosphere. The reaction mixture was stirred for 16 h at 40 °C under air atmosphere. After cooling to room temperature, the resulting mixture was diluted with water (300 mL) and extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (6 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step c To a stirred solution of l-bromo-5-chloro-4-methyl-2-(prop-2-en-l- yloxy)benzene (29.00 g, 0.12 mol) in THF (900 mL) was added n-BuLi (48 mL, 0.12 mol, 2.5 M in hexane) dropwise at -90 °C under nitrogen atmosphere.
  • Step d To a stirred solution of tert-butyl 4-[(R)-[5-chloro-4-methyl-2-(prop-2- en-1- yloxy)phenyl]([[(S)-2-methylpropane-2-sulfmyl]amino])methyl]piperidine-l- carboxylate (48.00 g, 95.77 mmol) in DCM (380 mL) was added TFA (96 mL) dropwise at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The mixture was basified to pH 8 with saturated aq. NaHCCL. The resulting mixture was extracted with EA (3 x 1 L).
  • Step a To a stirred mixture of (4A)-2,2-dimethyl-l,3-dioxolane-4-carboxylic acid (38 mg, 0.26 mmol) and HATU (0.10 g, 0.26 mmol) in DMF (1 mL) were added a solution of (5)-A-[(A)-[5-chloro-4-methyl-2-(prop-2-en-l-yloxy)phenyl](piperidin-4- yl)methyl]-2-methylpropane-2-sulfinamide (70 mg, 0.18 mmol) in DMF (1 mL) and EtsN (35 mg, 0.35 mmol) at room temperature.
  • Step b To a stirred mixture of (5 -A-((A)-(2-(allyloxy)-5-chloro-4- methylphenyl)(l-((A)-2,2-dimethyl-l,3-dioxolane-4-carbonyl)piperidin-4-yl)methyl)-2- methylpropane-2-sulfmamide (0.12 g, 0.23 mmol) and Pd(PPhs)4 (52 mg, 0.05 mmol) in THF (2 mL) was added NaBH4 (17 mg, 0.46 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere.
  • Step c To a stirred solution of (5)-A-[(A)-(5-chloro-2-hydroxy-4- methylphenyl)([l-[(47?)-2,2-dimethyl-l,3-dioxolane-4-carbonyl]piperidin-4-yl])methyl]- 2-methylpropane-2-sulfinamide (0.12 g, crude) in THF (2 mL) was added aq. HC1 (47V, 1 mL) at room temperature. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure to provide crude HC1 salt.
  • the received product was characterized with XRPD using CuKa radiation as having diffraction peaks (2 -theta values) as described in Table 1, and in particular comprising a peak at diffraction angle 2-theta of 6.0°, and one or more peaks at diffraction angle 2-theta of 6.4°, 7.5°, 9.9°, 12.0°, 12.6°, 15.5°, 16.9°, 17.4°, 18.5°, 19.2°, 19.8°, 21.7°, or 24.3°, with a tolerance for the diffraction angles of ⁇ 0.2 degrees.
  • thermogravimetric analysis TGA
  • DSC differential scanning calorimetry
  • the received product was characterized with XRPD using CuKa radiation as having diffraction peaks (2 -theta values) as described in Table 2, and in particular comprising a peak at diffraction angle 2-theta of 5.9°, and one or more peaks at diffraction angle 2-theta of 4.8°, 7.1°, 8.3°, 10.3°, 11.1°, 12.4°, 16.5°, 18.1°, or 20.7°, with a tolerance for the diffraction angles of ⁇ 0.2 degrees.
  • the received product was further characterized with thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC).
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • a stock aqueous solution of L-glutaric acid having a concentration of 17 g per 170 mL of water was prepared shortly before the experiment.
  • About 70 g of hydrochloric acid salt of Compound of Formula I was dissolved in 400 mL of water at 25°C.
  • About 37 mL of 5N NaOH was added to the solution to form an in-situ free base.
  • the stock solution containing about 0.7 mol of L-glutaric acid was added to the reactor vessel.
  • About 200 mL of acetone was added to the vessel to provide a uniform suspension. The suspension was heated to 40°C for less than an hour and cooled back to 20°C.
  • the solid suspension was isolated via vacuum filtration and dried at 50°C under vacuum over a 24-hour period.
  • the cake material was sieved through a 500 micron screen to provide uniform powder of ((2R)-l-[4-[(R)-amino(5-chloro-2- hydroxy-4-methylphenyl)methyl]piperidin-l-yl]-2,3-dihydroxypropan-l-one) hemiglutarate hemi-hydrate. Yield was >70%.
  • the product may be prepared as following: Hydrochloric acid salt of the Compound of Formula I (1 eq.) was dissolved in water in a reactor at a temperature between about 20°C and about 30°C. An aqueous solution of disodium glutarate (0.6 eq.) was slowly introduced into the reactor at a temperature between about 20°C to about 30°C in portions. After each portion was introduced, the mixture was held for several hours. At completion, the mixture was cooled down slowly to form the crude product. The crystalline final product was rinsed and dried to provide the hemi -glutarate hemi- hydrate salt of the compound of Formula I. The yield was about 91%.
  • the received product is characterized with XRPD pattern using CuKa radiation as having diffraction peaks (2 -theta values) as described in Table 3, and in particular comprising a peak at diffraction angle 2-theta of 16.5°, and one or more peaks at diffraction angle 2-theta of 7.7°, 7.8°, 9.4°, 10.8°, 11.6°, 13.2°, 14.4°, 15.5°, 17.3°, 18.2°, 18.9°, 19.7°, 20.5°, 21.1°, 21.9°, 22.8°, or 23.3°, with a tolerance for the diffraction angles of ⁇ 0.2 degrees.
  • the received product was further characterized with thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC).
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • the DSC demonstrates an endotherm peaking at 158.8°C with an onset at 153.4 °C.
  • the TGA demonstrates minimal degradation until approaching about 100°C.
  • DSC Dynamic Vapor Sorption
  • the stability testing shows a surprising level of physical stability for the claimed forms, especially for (2R)-l-[4-[(R)-amino(5-chl oro-2 -hydroxy -4- methylphenyl)methyl]piperidin-l-yl]-2,3 -dihydroxypropan- 1 -one hemi -glutarate hemihydrate.
  • Solid forms described herein can be tested in assays described in W02021071806 to demonstrate their activities as active Kvl.3 potassium channel blockers, while not blocking the hERG channel. Their improved stability provides higher purity and more favorable profile.

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Abstract

L'invention concerne des formes solides de composé de (2R)-1-[4-[(R)-amino(5-chloro-2-hydroxy-4-méthylphényl)méthyl]pipéridin-1-yl]-2,3-dihydroxypropan-1-one. La forme solide peut être un sel pharmaceutiquement acceptable du composé. Le sel peut être un sel d'acide carboxylique, tel qu'un sel d'acide benzoïque, un sel d'acide cinnamique ou un sel d'acide glutarique. L'invention concerne également des compositions pharmaceutiques les comprenant et leur procédé d'utilisation dans le traitement d'une affection telle que le psoriasis, la polyarthrite rhumatoïde, le lupus érythémateux disséminé, la néphrite lupique, la dermatite atopique et l'alopécie areata.
PCT/US2024/040114 2023-07-31 2024-07-30 Formes solides de bloqueurs de canaux de shaker potassiques kv1.3 et leur procédé d'utilisation Pending WO2025029769A1 (fr)

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