Compositions and methods for treating huntington's disease and htt proteinopathies

Abstract

The present disclosure provides compounds, compositions and / or methods for treating, preventing, inhibiting, ameliorating, or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject. The methods may include administering to the subject an effective amount of a peptidomimetic compound, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1, 2, 4-oxadiazol-5-yl) pentyl) amino)-3-(4-hydroxy-2, 3, 4-triazole-3-yl)-3-(4-hydroxyl-2, 3, 4-triazole-3-yl)-3-(4-hydroxyl-2, 3, 4-triazole-3-yl)-3-(4-hydroxyl-2, 3, 4-triazole-3-yl)-3-(4- The present invention relates to a pharmaceutical composition, in particular, a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 343,230, filed on May 18, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The technology of the present invention generally relates to compounds, compositions / medicines and / or methods for treating, preventing, inhibiting, ameliorating Huntington's disease and / or HTT proteinopathy and / or delaying the onset thereof. In addition, the technology of the present invention relates to administering an effective amount of a peptide mimetic compound such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof to a subject suffering from Huntington's disease and / or HTT proteinopathy or at risk of Huntington's disease and / or HTT proteinopathy. Background Art

[0004] The following description is provided to aid the reader's understanding. No admission is made that the information provided or the references cited are prior art to the compositions and methods disclosed herein.

[0005] Neurodegenerative diseases and disorders affect the patient's activities, such as balance, movement, conversation, breathing and / or heart function. Neurodegenerative diseases and disorders are generally incurable and debilitating conditions that lead to progressive degeneration and / or death of nerve cells. In many cases, neurodegenerative diseases often directly or indirectly cause the death of the subject. Typically, there are available drugs to address the symptoms, but there is usually no treatment to curb the progression or severity of the disease or disorder itself. This specification relates to Huntington's disease and / or HTT protein disease.

[0006] Huntington's disease is a progressive neurodegenerative disorder that causes movement disorders, cognitive decline and behavioral changes. Huntington's disease is characterized as a protein disease, which is related to the aggregation of huntingtin protein (HTT) in the brain. Although the pathology of the disease involves the accumulation of huntingtin protein in the brain, Huntington's disease is a hereditary autosomal dominant disease caused by a mutation in the gene HTT that causes CAG repeat expansion. The age of onset and aggressiveness of the disease seem to be closely related to the length of CAG repeat expansion (Lee et al., Neurology (2012) 78: 690-695). Repeat expansion seems to increase during the life of the subject (Kacher et al. eLife (2021) 10: e64674). The disease usually develops symptoms between the ages of 30 and 50, but can occur at any time, even in early childhood (at 2 years old or more) and in old age (e.g. > 70 years old). The average life expectancy after Huntington's disease is diagnosed is about 10 to 30 years, with an average of about 15-17 years. There is no effective treatment available for Huntington's disease. Currently available drugs are directed to treating or ameliorating symptoms. Therefore, there is a need in the art to develop treatment options for subjects with Huntington's disease and / or HTT proteinopathy. Summary of the invention

[0007] In one aspect, the present disclosure provides a method for treating, preventing, inhibiting, ameliorating or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide mimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula I or Formula Ia, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

[0008] In some embodiments, the subject has been diagnosed with Huntington's disease. In some embodiments, the subject has been diagnosed with HTT proteinopathy.

[0009] In some embodiments, the peptide mimetic is administered to the subject daily for 2 weeks or more, for 12 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, once diagnosed, the peptide mimetic is administered daily for the rest of the subject's life.

[0010] In some embodiments, treating, preventing, inhibiting or ameliorating comprises treating, preventing, inhibiting or ameliorating one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

[0011] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0012] In some embodiments, the peptide mimetic is administered orally. In some embodiments, the peptide mimetic is administered subcutaneously. In some embodiments, the peptide mimetic is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ocularly, intrathecally, intracerebroventricularly, by iontophoresis, transmucosally, intravitreally, or intramuscularly.

[0013] In some embodiments, the method further comprises administering to the subject an additional treatment, either individually, sequentially or simultaneously. In some embodiments, the additional treatment comprises administering a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (sodium valproate) and (lamotrigine). In some embodiments, the therapeutic agent is elamipretide (also known as SS-31 or bendavia). In some embodiments, the combination of a peptide mimetic and an additional therapeutic agent has a synergistic effect in preventing or treating Huntington's disease and / or HTT proteinopathy.

[0014] In some embodiments, the pharmaceutically acceptable salt of the peptide mimetic comprises tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in each case, monoacid salt, diacid salt or triacid salt). In some embodiments, the pharmaceutically acceptable salt comprises monoacetate, diacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, tritrifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotoluenesulfonate, bistoluenesulfonate or tritoluenesulfonate. In some embodiments, the peptide mimetic is formulated as tri-HCl salt, bis-HCl salt or mono-HCl salt.

[0015] In one aspect, the present disclosure provides the use of a composition for the preparation of a medicament for treating, preventing, inhibiting, ameliorating or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof, wherein the composition comprises a therapeutically effective amount of a peptide mimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula I or Formula Ia, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

[0016] In some embodiments, the subject has been diagnosed with Huntington's disease. In some embodiments, the subject has been diagnosed with HTT proteinopathy.

[0017] In some embodiments, the drug is administered to the subject daily for 2 weeks or more, for 12 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the drug is administered daily for the rest of the subject's life.

[0018] In some embodiments, the use of the drug for treating, preventing, inhibiting or ameliorating includes treating, preventing, inhibiting or ameliorating one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

[0019] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0020] In some embodiments, the drug is formulated for oral administration. In some embodiments, the drug is formulated for subcutaneous administration. In some embodiments, the drug is formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ocular, intrathecal, intracerebroventricular, by iontophoresis, transmucosal, intravitreal, or intramuscular administration.

[0021] In some embodiments, the drug is used alone, sequentially or simultaneously with another treatment. In some embodiments, the other treatment comprises the use of a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (Sodium valproate) (lamotrigine). In some embodiments, the therapeutic agent is iguratimod (also known as SS-31 or Bendavia). In some embodiments, the combination of the drug and the additional treatment has a synergistic effect in preventing or treating Huntington's disease and / or HTT proteinopathy.

[0022] In some embodiments, pharmaceutically acceptable salts include tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in each case, mono-, di- or tri-acid salts). In some embodiments, pharmaceutically acceptable salts include monoacetate, diacetate, triacetate, mono-trifluoroacetate, bis-trifluoroacetate, tri-trifluoroacetate, mono-hydrochloride, di-hydrochloride, tri-hydrochloride, mono-toluenesulfonate, bis-toluenesulfonate or tri-toluenesulfonate. In some embodiments, peptide mimetics are formulated as tri-HCl salts, bis-HCl salts or mono-HCl salts.

[0023] In yet another aspect, the present disclosure provides peptide mimetics, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof, for use in treating, preventing, inhibiting, ameliorating Huntington's disease and / or HTT proteinopathy in a subject in need thereof and / or delaying its onset. The peptide mimetic can be used alone or formulated as a medicament. In some embodiments, the peptide mimetic is a peptide mimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula I or Formula Ia, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

[0024] In some embodiments, the subject has been diagnosed with Huntington's disease. In some embodiments, the subject has been diagnosed with HTT proteinopathy.

[0025] In some embodiments, the peptide mimetic (alone or formulated as a medicament) is administered to the subject daily for 2 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the peptide mimetic is administered daily for the rest of the subject's life.

[0026] In some embodiments, treating, preventing, inhibiting or ameliorating comprises treating, preventing, inhibiting or ameliorating one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

[0027] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0028] In some embodiments, the peptide mimetics are formulated for oral administration. In some embodiments, the peptide mimetics are formulated for subcutaneous administration. In some embodiments, the peptide mimetics are formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ocular, intrathecal, intracerebroventricular, by iontophoresis, transmucosal, intravitreal, or intramuscular administration.

[0029] In some embodiments, the peptide mimetic is used alone, sequentially or simultaneously with another treatment. In some embodiments, the other treatment comprises the use of a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (Sodium valproate) (lamotrigine). In some embodiments, the therapeutic agent is iguratimod (also known as SS-31 or Bendavia). In some embodiments, the combination of the drug and the additional treatment has a synergistic effect in preventing or treating Huntington's disease and / or HTT proteinopathy.

[0030] In some embodiments, pharmaceutically acceptable salts include tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in each case, mono-, di- or tri-acid salts). In some embodiments, pharmaceutically acceptable salts include monoacetate, diacetate, triacetate, mono-trifluoroacetate, bis-trifluoroacetate, tri-trifluoroacetate, mono-hydrochloride, di-hydrochloride, tri-hydrochloride, mono-toluenesulfonate, bis-toluenesulfonate or tri-toluenesulfonate. In some embodiments, peptide mimetics are formulated as tri-HCl salts, bis-HCl salts or mono-HCl salts.

[0031] In yet another aspect, the present disclosure provides formulations or medicaments comprising a peptide mimetic (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof) for treating, preventing, inhibiting, ameliorating and / or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula I or Formula Ia, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

[0032] In some embodiments, the subject has been diagnosed with Huntington's disease. In some embodiments, the subject has been diagnosed with HTT proteinopathy.

[0033] In some embodiments, the formulation or drug is administered to the subject daily for 2 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the formulation or drug is administered daily for the rest of the subject's life.

[0034] In some embodiments, treating, preventing, inhibiting or ameliorating comprises treating, preventing, inhibiting or ameliorating one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

[0035] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0036] In some embodiments, the formulation or drug is administered orally. In some embodiments, the formulation or drug is administered subcutaneously. In some embodiments, the formulation or drug is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ocularly, intrathecally, intracerebroventricularly, by iontophoresis, transmucosally, intravitreally, or intramuscularly.

[0037] In some embodiments, the use of the formulation or medicament further comprises administering to the subject an additional treatment, either alone, sequentially or simultaneously. In some embodiments, the additional treatment comprises administering a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (Sodium valproate) (lamotrigine). In some embodiments, the therapeutic agent is iguratimod (also known as SS-31 or bendavia). In some embodiments, the combination of the formulation or drug and the additional treatment has a synergistic effect in preventing or treating Huntington's disease and / or HTT proteinopathy.

[0038] In some embodiments, pharmaceutically acceptable salts include tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in each case, mono-, di- or tri-acid salts). In some embodiments, pharmaceutically acceptable salts include monoacetate, diacetate, triacetate, mono-trifluoroacetate, bis-trifluoroacetate, tri-trifluoroacetate, mono-hydrochloride, di-hydrochloride, tri-hydrochloride, mono-toluenesulfonate, bis-toluenesulfonate or tri-toluenesulfonate. In some embodiments, peptide mimetics are formulated as tri-HCl salts, bis-HCl salts or mono-HCl salts. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is a graphic summary of the study design for the mouse study described in Example 1. This study evaluated the effects of administration of Compound (Ia) to R6 / 2 transgenic mice.

[0040] Figure 2 is a graph of body weight (g) of mice studied as described in Example 1 (body weight (g) of R6 / 2 mice treated with Compound (Ia)). Data are presented as mean ± SEM. *P<0.05, R6 / 2 vehicle vs. WT vehicle.

[0041] Figure 3 is a bar graph summarizing the data of the motor performance in the rotarod assay of mice studied as described in Example 1 (latency of R6 / 2 mice treated with Compound (Ia)). Data are presented as mean ± SEM. ****P<0.001, R6 / 2 vehicle vs. WT vehicle; *P<0.05, R6 / 2 5 mg / kg Compound (Ia) vs. R6 / 2 vehicle.

[0042] Figure 4 is a bar graph summarizing data on the total distance traveled by mice studied as described in Example 1 (total distance traveled in an open field by R6 / 2 mice treated with Compound (Ia)). Data are presented as mean ± SEM. ****P < 0.001, R6 / 2 vehicle vs. WT vehicle; *P < 0.05, R6 / 2 5 mg / kg Compound (Ia) vs. R6 / 2 vehicle.

[0043] Figure 5is a bar graph summarizing data on total feeding frequency in the open field for mice studied as described in Example 1 (Total feeding frequency in the open field for R6 / 2 mice treated with Compound (Ia)). Data are presented as mean ± SEM. ****P<0.0001, R6 / 2 vehicle vs. WT vehicle.

[0044] Figure 6 Summarize the studies in mice described in Example 1 18 Bar graph of the data of F-FDG uptake. Data are presented as mean ± SEM. For each tissue, data from the following groups are presented from left to right: WT vehicle, R6 / 2 vehicle and R6 / 2 5mg / kg compound (Ia). *P<0.05, R6 / 2 vehicle and WT vehicle. **P<0.01, R6 / 2 5mg / kg compound (Ia) and R6 / 2 vehicle. Tissues (from left to right along the x-axis) are: amygdala L, amygdala R, basal forebrain septum, brainstem, central gray matter, cerebellum, cortex, hippocampus L, hippocampus R, hypothalamus, hypothalamus L, hypothalamus R, midbrain L, midbrain R, olfactory bulb, striatum L, striatum R, superior colliculus, thalamus and whole brain.

[0045] Figure 7 is a bar graph summarizing flow cytometry data from MitoSOX analysis of reactive oxygen species (ROS) formation in peripheral blood mononuclear cells (PBMCs) of mice studied as described in Example 1. Data are presented as mean ± SEM. **P < 0.01, R6 / 2 vehicle vs. heat stressed cells, unpaired Welch t-test.

[0046] Figure 8 is a bar graph summarizing data on ATP generation in PBMCs of mice studied as described in Example 1. Data are presented as mean ± SEM. Statistical significance: **P < 0.01, R6 / 2 vehicle vs. heat stressed cells, unpaired Welch t-test. DETAILED DESCRIPTION

[0047] It should be understood that certain aspects, modes, embodiments, variations and features of the technology of the present invention are described below in different levels of detail in order to provide a substantial understanding of the technology of the present invention. Definitions of certain terms as used in this specification are provided below. Unless otherwise defined, all technical terms and scientific terms used herein generally have the same meaning as those commonly understood by those of ordinary skill in the art to which the technology of the present invention belongs.

[0048] In practicing the techniques of the present invention, many conventional techniques in molecular biology, protein biochemistry, cell biology, immunology, microbiology and recombinant DNA are used. Such techniques are well known and are explained in, for example, Current Protocols in Molecular Biology, Volumes I-III, Ausubel ed. (1997); Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989); DNA Cloning: A Practical Approach, Volumes I and II, Glover ed. (1985); Oligonucleotide Synthesis, Gait ed. (1984); Nucleic Acid Hybridization, Hames and Higgins ed. (1985); Transcription and Translation, Hames and Higgins ed. (1984); Animal Cell Culture, Freshney ed. (1986); Immobilized Cells and Enzymes (IRL Press, 1986); Perbal, A Practical Guide to Molecular Cloning; the series, Meth. Enzymol., (Academic Press, Inc., 1984); Gene Transfer Vectors for Mammalian Cells, Miller and Calos, eds. (Cold Spring Harbor Laboratory, NY, 1987); and Meth. Enzymol., Vol. 154 and Vol. 155, edited by Wu and Grossman and Wu, respectively.

[0049] I. Chemical Definition

[0050] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the following: Periodic Table of the Elements, GAS version, Handbook of Chemistry and Physics, 7Sh edition, inside pages. In addition, the general principles of organic chemistry as well as specific functional moieties and reactivity are described in the following literature: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0051] Abbreviations used herein have their conventional meanings in the chemical field and the biological field. The chemical structure and chemical formula set forth herein are intended to meet the standard rules of chemical valence known in the chemical field. When listing the range of values, each value and subrange within the range are intended to be covered. For example, "C1-C6 alkyl" is intended to cover C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C5, C3-C4, C4-C6, C4-C5 and C5-C6 alkyl.

[0052] Some compounds of the present application may exist in non-solvated form and solvated form (including hydrated form). Solvated form may exist, for example, because it is difficult or impossible to remove all solvents from the compound after synthesis. Generally, solvated form is equivalent to non-solvated form, and is included in the scope of the present application. Some compounds of the present application may exist in multiple crystals or amorphous forms. Some compounds of the present application may exist in various tautomeric forms. Some compounds of the present application may exist in various salt forms. Generally, all physical forms are equivalent for the purposes contemplated by the present application, and are intended to be within the scope of the present disclosure.

[0053] As used herein, the term "amino acid" includes both naturally occurring amino acids and non-natural amino acids. Unless otherwise specified, the term "amino acid" includes separated amino acid molecules (i.e., molecules including hydrogen connected to an amino group and hydroxyl connected to a carbonyl carbon) and amino acid residues (i.e., molecules in which either or both of the hydroxyl connected to an amino group or a carbonyl carbon is removed). The amino group may be an α-amino group, a β-amino group, etc. For example, the term "amino acid alanine" may refer to any of the separated alanine H-Ala-OH or alanine residues H-Ala-, -Ala-OH or -Ala-. Unless otherwise specified, all amino acids found in the compounds described herein may be in D configuration or L configuration. Amino acids in D configuration may be written so that "D" is before the amino acid abbreviation. For example, "D-Arg" represents arginine in D configuration. The term "amino acid" includes salts thereof, including pharmaceutically acceptable salts. Any amino acid may be protected or unprotected. The protecting group can be attached to an amino group (e.g., an α-amino group), a backbone carboxyl group, or any functional group of a side chain. For example, phenylalanine protected by a benzyloxycarbonyl group (Z) on the α-amino group would be represented as Z-Phe-OH.

[0054] Except for the N-terminal amino acid, all amino acid abbreviations in the present disclosure (e.g., Phe) represent the structure of -NH-C(R)(R')-CO-, where R and R' are each independently hydrogen or a side chain of an amino acid (e.g., for Phe, R = benzyl and R' = H). Thus, phenylalanine is H-Phe-OH. The designation "OH" for these amino acids or peptides (e.g., Lys-Val-Leu-OH) indicates that the C-terminus is a free acid. For example, Phe-D-Arg-Phe-Lys-NH 2 The name "NH 2 ” indicates that the C-terminus of the protected peptide fragment is amidated. In addition, certain R and R', alone or in combination as ring structures, may include functional groups that require protection during liquid or solid phase synthesis.

[0055] In the case of amino acids having isomeric forms, it is the L form of the amino acid, unless otherwise specifically indicated as the D form, e.g., D-Arg. It is noteworthy that many amino acid residues are commercially available in both the D-form and the L-form. For example, D-Arg is a commercially available D-amino acid.

[0056] The capital letter "D" used with the abbreviations of amino acid residues refers to the D-form of the amino acid residue.

[0057] The term "DMT" refers to 2,6-di(methyl)tyrosine (eg, 2,6-dimethyl-L-tyrosine; CAS 123715-02-6).

[0058] As used herein, the term "hydrate" refers to a compound that is associated with water. The number of water molecules contained in a hydrate of a compound may (or may not) be in a certain ratio to the number of compound molecules in the hydrate.

[0059] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a therapeutically active compound that can be prepared with relatively nontoxic acids or bases depending on the specific substituents found on the compounds described herein. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amine salts, or magnesium salts or similar salts. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, and zinc salts, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine (NEt3), trimethylamine, tripropylamine, tromethamine, and the like, such as where the salt comprises a protonated form of the organic base (e.g., [HNEt3]+). Salts derived from pharmaceutically acceptable inorganic acids include salts of the following acids: boric acid, carbonic acid, hydrohalic acid (hydrobromic acid, hydrochloric acid, hydrofluoric acid or hydroiodic acid), nitric acid, phosphoric acid, sulfamic acid and sulfuric acid. Salts derived from pharmaceutically acceptable organic acids include salts of the following acids: aliphatic hydroxy acids (e.g., citric acid, gluconic acid, glycolic acid, lactic acid, lactobionic acid, malic acid and tartaric acid), aliphatic monocarboxylic acids (e.g., acetic acid, butyric acid, formic acid, propionic acid and trifluoroacetic acid), amino acids (e.g., aspartic acid and glutamic acid), aromatic carboxylic acids (e.g., benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentisic acid, hippuric acid and triphenylacetic acid), aromatic hydroxy acids (e.g., o-hydroxybenzoic acid, p-hydroxybenzoic acid,

[0013] Examples of the present invention include benzoic acid, 1-hydroxynaphthalene-2-carboxylic acid and 3-hydroxynaphthalene-2-carboxylic acid), ascorbic acid, dicarboxylic acids (e.g., fumaric acid, maleic acid, oxalic acid and succinic acid), glucuronic acid, mandelic acid, mucic acid, nicotinic acid, orotic acid, dihydroxy acids, pantothenic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, isethionic acid, methanesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid and p-toluenesulfonic acid (PTSA)), hydroxynaphthoic acid, and the like.In some embodiments, the pharmaceutically acceptable counterion is selected from the group consisting of acetate, benzoate, benzenesulfonate, bromide, camphorsulfonate, chloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, methanesulfonate, methylsulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate. In some embodiments, the salt is tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, maleate, trifluoroacetate, hydrochloride, or toluenesulfonate. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present application may contain both basic and acidic functional groups that allow the compound to be converted into a base addition salt or an acid addition salt or to exist in the form of a zwitterion. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for the technology of the present invention.

[0060] As used herein, the term "peptide mimetic" refers to a compound of formula (II):

[0061]

[0062] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof, as more fully described and / or claimed in WIPO published application WO2019 / 118878 (see below for the definitions of variables AA1, AA2, R1, R2a, R2b, R3 and X). In some embodiments, the peptide mimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide (Compound I, shown below as I) or a pharmaceutically acceptable salt thereof (e.g., Compound (Ia), shown below as the triHCl salt of Formula (Ia)), stereoisomer, tautomer, hydrate and / or solvate thereof.

[0063] As used herein, the term "small molecule" refers to any organic compound with a molecular weight less than 900 Daltons that affects a biological process. It should be understood that for the purpose of this definition, molecular mass is calculated without reference to any associated (i.e., non-covalently bonded) molecules such as salts, water or other solvent molecules. As used herein, "small molecule peptide mimics" are peptide mimics with a free base molecular weight less than 900 Daltons. Examples of such small molecule peptide mimics are (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazole-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide (CAS No. 2356106-71-1; free base molecular weight is 607.76) or its pharmaceutically acceptable salts, stereoisomers, tautomers, hydrates and / or solvates.

[0064] As used herein, the term "solvate" refers to a compound form that may associate with a solvent via a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone, hexane, DMSO, THF, ether, and the like.

[0065] As used herein, the term "tautomer" refers to a compound that is an interchangeable form of a particular compound structure and that varies in the displacement of hydrogen atoms and electrons. Thus, the two structures can reach equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they can be rapidly interconverted by treatment with an acid or base. Tautomeric forms can be relevant to the acquisition of optimal chemical reactivity and biological activity of the compound of interest.

[0066] As used herein, the terms "(R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide", "(D-Arg-DMT-NH((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide" and "(D-Arg-DMT-NH((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide" are used herein. The following small molecule peptide mimetics are used interchangeably herein and refer to compounds of formula (I):

[0067]

[0068] (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide.

[0069] The terms "(R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide", (2R)-2-amino-N-[(1S)-1-{[(1S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide]

[00136] The term "(D-Arg-DMT-NH((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl]carbamoyl}-2-(4-hydroxy-2,6-dimethylphenyl)ethyl]-5-aminoamidopentanamide, or "(D-Arg-DMT-NH((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentan-1-yl)" is intended to include pharmaceutically acceptable salt forms thereof, such as the tris (tri- or tris)-HCl salt of formula (Ia):

[0070]

[0071] II. Other Definitions

[0072] It should be understood that certain aspects, modes, embodiments, variations and features of the technology of the present invention are described below in different levels of detail in order to provide a substantial understanding of the present application. Definitions of certain terms as used in this specification are provided below. Unless otherwise defined, all technical terms and scientific terms used herein generally have the same meaning as those commonly understood by those of ordinary skill in the art to which the technology belongs.

[0073] As used in this specification and the accompanying examples, the singular forms "a", "the" and "the" include plural referents unless the content clearly dictates otherwise. For example, reference to "a cell" includes a combination of two or more cells, etc.

[0074] As used herein, "administering" or "administration" of an agent (i.e., a therapeutic agent) or compound / drug product (including a composition) to a subject includes any route of introducing or delivering the compound / drug product to a subject to perform its intended function. Administration may be performed by any suitable route, such as oral administration. Administration may be performed subcutaneously. Administration may be performed intravenously. Administration may be performed intraocularly. Administration may be performed systemically. Alternatively, administration may be performed topically, intranasally, intraperitoneally, intradermally, intraocularly, intrathecally, intraventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly. Administration includes self-administration, administration by another person, or administration using a device (e.g., an infusion pump).

[0075] As used herein, "ameliorate" or "ameliorating" a disease, disorder or condition means making the disease, disorder or condition (or its signs, symptoms or conditions) better or more tolerable in a statistical sample or specific subject, relative to a control sample or subject, in the sample or subject to which the therapeutic agent is administered.

[0076] As used herein, the terms "carrier" and "pharmaceutically acceptable carrier" refer to a diluent, adjuvant, excipient or vehicle with which a compound / drug product / composition (including a drug) is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, oils, and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, silicon dioxide particles (nanoparticles or microparticles), urea, and the like. In addition, adjuvants, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by EW Martin, which is incorporated herein by reference in its entirety.

[0077] As used herein, the phrase "delaying the onset of..." means delaying, preventing the occurrence of a disease, disorder or condition in a sample or subject to which a therapeutic agent is administered, or causing one or more signs, symptoms or symptoms of a disease, disorder or condition to occur more slowly than normal in a statistical sample, relative to a control sample or subject.

[0078] As used herein, the term "effective amount" refers to the amount of a compound / composition / drug product sufficient to achieve the desired therapeutic and / or preventive effects, for example, to treat, prevent, inhibit, improve a disease, disorder or condition or delay its onset, or the amount of a physiological sign, symptom or condition of a disease or condition. In the context of therapeutic or preventive applications, in some embodiments, the amount of the compound / composition / drug product applied to the subject will depend on the type and severity of the disease and on individual characteristics, such as overall health, age, sex, body weight and tolerance to the drug. In some embodiments, it also depends on the degree, severity and type of the disease. Those skilled in the art will be able to determine appropriate dosages based on these and other factors. The compound / composition / drug product can also be administered in combination with one or more other therapeutic compounds / agents (so-called "co-administration", wherein, for example, other therapeutic agents can be administered simultaneously, sequentially or by administering alone).

[0079] As used herein, "inhibit" or "inhibiting" refers to a reduction in an objectively measurable amount or degree of signs, symptoms or conditions (e.g., risk factors) associated with a disease, disorder or condition associated with Huntington's disease and / or HTT protein disease compared to a control. In one embodiment, inhibition or inhibition refers to a reduction of at least a statistically significant amount compared to a control (or control subject). In one embodiment, inhibition or inhibition refers to a reduction of at least 5% compared to a control (or control subject). In each separate embodiment, inhibition or inhibition refers to a reduction of at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 33%, 40%, 50%, 60%, 67%, 70%, 75%, 80%, 90%, 95% or 99% compared to a control (or control subject).

[0080] As used herein, "prevention" or "preventing" of a disease, disorder or condition refers to a result that shows a reduction in the occurrence of a disease, disorder or condition in a sample or subject to which a therapeutic agent is administered relative to a control sample or subject in a statistical sample, or a delay in the onset of one or more symptoms of a disease, disorder or condition relative to a control sample or subject. Such prevention is sometimes referred to as prophylactic treatment.

[0081] As used herein, the term "separate" therapeutic use refers to the simultaneous or substantially simultaneous administration of at least two active ingredients (eg, therapeutic agents) by different routes.

[0082] As used herein, the term "sequential" therapeutic use refers to the administration of at least two active ingredients at different times, with the same or different routes of administration. More specifically, sequential use refers to the complete administration of one active ingredient before the administration of another or other active ingredients begins. Thus, one active ingredient may be administered a few minutes, hours, or days before the administration of one or more other active ingredients. Simultaneous treatment does not exist under this definition.

[0083] As used herein, the term "simultaneous" therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or substantially at the same time.

[0084] As used herein, "subject" refers to a living animal. In various embodiments, the subject is a mammal. In various embodiments, the subject is a non-human mammal, including but not limited to mice, rats, hamsters, guinea pigs, rabbits, sheep, goats, cats, dogs, pigs, miniature pigs, horses, cattle, or non-human primates. In certain embodiments, the subject is a human.

[0085] It is also to be understood that the various ways of treating or preventing a medical condition as described herein are intended to mean "substantial," which includes complete treatment or prevention but also includes less than total treatment or prevention, and where some biologically or medically relevant result is achieved.

[0086] As used herein, the term "synergistic therapeutic effect" refers to a greater than additive therapeutic effect produced by a combination of at least two agents and exceeding the effect produced by the other separate administration of the agents. For example, a lower dose of one or more agents can be used to treat Huntington's disease and / or HTT proteinopathy.

[0087] As used herein, the term "treating" or "treatment" refers to therapeutic treatment, wherein the purpose is to reduce, alleviate or slow down (mitigate) a pre-existing disease or disorder or its associated signs, symptoms or conditions. As an example, but not limited to, a subject is successfully "treated" for a disease, disorder or condition if, after receiving an effective amount of a compound / composition / drug product, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof, the subject shows an observable and / or measurable reduction or absence of one or more signs, symptoms or conditions associated with the disease, disorder or condition. It should also be understood that the various modes of treating medical conditions as described are intended to represent "substantial," which encompasses complete improvement of the condition, sign or symptom of the disease or disorder, as well as "partial," wherein some biologically or medically relevant results are achieved.

[0088] III. Huntington's disease

[0089] Huntington's disease is a progressive neurodegenerative disorder that causes movement disorders, cognitive decline and behavioral changes. Huntington's disease is characterized as a protein disease, which is related to the aggregation of huntingtin protein (HTT) in the brain. Although the pathology of the disease involves the accumulation of huntingtin protein in the brain, Huntington's disease is a hereditary autosomal dominant disease caused by a mutation in the gene HTT that causes CAG repeat expansion. The age of onset and aggressiveness of the disease seem to be closely related to the length of CAG repeat expansion (Lee et al., Neurology (2012) 78: 690-695). During the life of the subject, repeat expansion seems to increase (Kacher et al. eLife (2021) 10: e64674). The disease usually develops symptoms between the ages of 30 and 50, but can occur at any time, even in early childhood (2 years old or more) or in old age (e.g. > 70 years old). The average life expectancy after Huntington's disease is diagnosed is about 10 to 30 years, with an average of about 15 to 17 years. There is no effective treatment available for Huntington's disease.

[0090] There are a variety of signs and symptoms of Huntington's disease. Symptoms of Huntington's disease related to movement disorders include weight loss, falls, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, and eventually loss of the ability to walk. Symptoms of Huntington's disease related to behavioral changes include personality changes, loss of initiative, mood changes, apathy, irritability, aggression, anger, depression, and frustration. Symptoms of Huntington's disease related to cognitive decline include difficulty concentrating, short-term memory impairment, decreased organizational skills, disorientation, and loss of cognitive abilities.

[0091] The only FDA-approved treatment for Huntington's disease is (Tetrabenazine) (deutetrabenazine), but these are only approved for reducing movement disorders associated with the disease. Some other drugs being evaluated for treating various signs and symptoms of Huntington's disease include (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (Sodium valproate) (Lamotrigine). There are no approved therapeutic agents for treating the underlying cause of Huntington's disease itself.

[0092] IV. Peptide Mimetics

[0093] In some embodiments, the present disclosure provides a peptide mimetic compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof:

[0094]

[0095] in

[0096] AA 1 Selected from

[0097] AA 2 Selected from

[0098] R 1 Selected from

[0099] R 2a Selected from

[0100] R 2b is H or Me;

[0101] R 3 and R 4 are independently selected from H and (C 1 -C 6 )alkyl;

[0102] R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl; or R 5 and R 6 Together with the N atom to which they are attached, they form a 4-6 membered heterocyclic group;

[0103] R 7 Selected from H, (C 1 -C 6 ) alkyl, cycloalkyl and aryl;

[0104] R 8 and R 9 are independently selected from H and (C 1 -C 6 ) alkyl, cycloalkyl and aryl; or R 8 and R 9 Together with the N atom to which they are attached, they form a 4-6 membered heterocyclic group;

[0105] n is 1, 2, or 3;

[0106] X is selected from as well as

[0107] * indicates X and R 1 connection point.

[0108] In some embodiments, AA 1 yes In some embodiments, AA 1 yes In some embodiments, AA 1 yes In some embodiments, AA 1 yes In some embodiments, AA 1 yes In some embodiments, AA 1 yes

[0109] In some embodiments, AA 2 yes In some embodiments, AA 2 yes In some embodiments, AA 2 yes In some embodiments, AA 2 yes

[0110] In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes

[0111] In some embodiments, R 2a yes In some embodiments, R2a yes In some embodiments, R 2a yes In some embodiments, R 2a yes In some embodiments, R 2a yes In some embodiments, R 2a yes In some embodiments, R 2a yes In some embodiments, R 2a yes

[0112] In some embodiments, R 2b is H. In some embodiments, R 2b It's methyl.

[0113] In some embodiments, R 3 is H. In some embodiments, R 3 Yes (C 1 -C 6 In some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. 3 In some embodiments, R 3 It is ethyl.

[0114] In some embodiments, R 4 is H. In some embodiments, R 4 Yes (C 1 -C 6 In some embodiments, R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. 4 In some embodiments, R 4 It is ethyl.

[0115] In some embodiments, R 3 and R 4 In some embodiments, R 3 and R 4 different.

[0116] In some embodiments, R 5 is H. In some embodiments, R 5 It's methyl.

[0117] In some embodiments, R 6 is H. In some embodiments, R6 It's methyl.

[0118] In some embodiments, R 5 and R 6 In some embodiments, R 5 and R 6 In some embodiments, R 5 and R 6 Both are H.

[0119] In some embodiments, R 5 and R 6 Together with the N atom to which they are attached, they form a 4-6 membered heterocyclic group. In some embodiments, the heterocyclic group is a 4-6 membered ring. In some embodiments, the heterocyclic group is an azetidinyl, pyrrolidinyl or piperidinyl.

[0120] In some embodiments, R 7 is H. In some embodiments, R 7 Yes (C 1 -C 6 In some embodiments, R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. 7 In some embodiments, R 7 In some embodiments, R 7 is cyclopropyl, cyclobutyl, cyclopropyl or cyclohexyl. In some embodiments, R 7 In some embodiments, R 7 It is phenyl.

[0121] In some embodiments, R 8 is H. In some embodiments, R 8 Yes (C 1 -C 6 In some embodiments, R 8 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. 8 In some embodiments, R 8 In some embodiments, R 8 is cyclopropyl, cyclobutyl, cyclopropyl or cyclohexyl. In some embodiments, R 8 In some embodiments, R 8 It is phenyl.

[0122] In some embodiments, R 9 is H. In some embodiments, R 9 Yes (C 1 -C 6In some embodiments, R 9 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. 9 In some embodiments, R 9 In some embodiments, R 9 is cyclopropyl, cyclobutyl, cyclopropyl or cyclohexyl. In some embodiments, R 9 In some embodiments, R 9 It is phenyl.

[0123] In some embodiments, R 8 and R 9 In some embodiments, R 8 and R 9 In some embodiments, R 8 and R 9 Both are H. In some embodiments, R 8 and R 9 Together with the N atom to which they are attached, they form a 4-6 membered heterocyclic group. In some embodiments, the heterocyclic group is a 4-6 membered ring. In some embodiments, the heterocyclic group is an azetidinyl, pyrrolidinyl or piperidinyl.

[0124] In some embodiments, X is In some embodiments, X is In some embodiments, X is In some embodiments, X is In some embodiments, X is In some embodiments, X is

[0125] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0126] In some embodiments, peptide mimics are small molecule peptide mimics. In some embodiments, peptide mimics are peptide mimics of formula I or formula Ia. Peptide mimics disclosed herein can exist in non-solvated form and solvated form (including hydrated form). Solvated form can exist, for example, because it is difficult or impossible to remove all solvents from the peptide mimics after synthesis. Generally, solvated form is equivalent to non-solvated form, and is included in the scope of the present application. Some peptide mimics of the present application can exist in multiple crystalline forms or amorphous forms. Some peptide mimics of the present application can exist in various tautomeric forms. Some peptide mimics of the present application can exist in various salt forms. Generally, all physical forms are equivalent for the intended use of the present application, and are intended to fall within the scope of the present application. The chiral center of the peptide mimics disclosed herein can be in R-configuration or S-configuration, as discussed in more detail below.

[0127] V. Chirality / Stereochemical Considerations

[0128] The peptide mimetics described herein may include one or more asymmetric centers, and therefore may exist in various isomeric forms, for example, enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from a mixture by methods known to those skilled in the art (including the formation and crystallization of chiral high pressure liquid chromatography (HPLC) and chiral salts); or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Peptide mimetics additionally encompass compounds described herein in the form of individual isomers that are substantially free of other isomers, as well as alternatively in the form of mixtures of various isomers.

[0129] As used herein, a pure enantiomer peptide mimetic is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound, and is therefore in enantiomeric excess relative to the "R" form. With respect to amino acids (which are more commonly described in terms of "D" and "L" enantiomers), it is understood that for "D"-amino acids, the configuration is "R", and for "L"-amino acids, the configuration is "S". In some embodiments, 'substantially free' refers to: (i) an aliquot of the "R" form of a compound containing less than 2% of the "S" form; or (ii) an aliquot of the "S" form of a compound containing less than 2% of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or greater than 99.9% by weight of the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0130] In the compositions provided herein, enantiomerically pure compounds can be present with other active ingredients or inactive ingredients. For example, a pharmaceutical composition or drug comprising an enantiomerically pure "R" form compound can comprise, for example, about 90% of an excipient and about 10% of an enantiomerically pure "R" form compound. In certain embodiments, the enantiomerically pure "R" type compound in such a composition can, for example, include at least about 95% by weight of the "R" type compound and up to about 5% by weight of the "S" type compound by the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure "S" form compound can comprise, for example, about 90% of an excipient and about 10% of the enantiomerically pure "S" form compound. In certain embodiments, the enantiomerically pure "S" type compound in such a composition can, for example, include at least about 95% by weight of the "S" type compound and up to about 5% by weight of the "R" type compound by the total weight of the compound. In certain embodiments, the active ingredient may be formulated with minimal or no excipients or carriers.

[0131] VI. Synthesis of Peptide Mimetics

[0132] The peptide mimetic compounds described herein can be prepared in whole or in part using well-known peptide synthesis methods such as conventional liquid phase (also referred to as solution phase) peptide synthesis or solid phase peptide synthesis, or by peptide synthesis with the aid of an automated peptide synthesizer (Kelley et al., Genetics Engineering Principles and Methods, Setlow, JK ed., Plenum Press NY. (1990) Vol. 12, p. 1 to p. 19; Stewart et al., Solid-Phase Peptide Synthesis (1989) WH; Houghten, Proc. Natl. Acad. Sci. USA (1985) 82: p. 5132). The peptide mimetic thus produced can be collected or purified by conventional methods, for example chromatography, such as gel filtration chromatography, ion exchange column chromatography, affinity chromatography, reverse phase column chromatography and HPLC, ammonium sulfate fractionation, ultrafiltration and immunoadsorption.

[0133] In solid phase peptide synthesis, peptides are typically synthesized from the carbonyl group side (C-terminal) of the amino acid chain to the amino group side (N-terminal). In certain embodiments, the amino acid protected by the amino acid is covalently bound to the solid phase support material through an ester or amide bond, and optionally through a linking group. The amino group can be deprotected, and a coupling agent is used to react the carbonyl group of the amino acid protected by the second amino group (i.e., "coupling" with it) to produce a dipeptide bound to a solid phase support. After coupling, the resin is optionally treated with a blocking agent to block (inactivate it to subsequent coupling steps) any unreacted amine groups. These steps (i.e., deprotection, coupling, and optionally blocking) can be repeated to form a desired peptide chain. Once the desired peptide chain is completed, the peptide can be cut from the solid phase support. Peptide mimetics (or its peptide portion) can also be prepared in solution.

[0134] In certain embodiments, the protecting groups used on the amino groups of the amino acid residues (of the peptides and / or peptidomimetics) include the 9-fluorenylmethoxycarbonyl group (Fmoc) and the tert-butyloxycarbonyl group (Boc). The Fmoc group is removed from the amino terminus with a base, while the Boc group is removed with an acid. In alternative embodiments, the amino protecting group may be a substituted or unsubstituted group of the formyl, acryloyl (Acr), benzoyl (Bz), acetyl (Ac), trifluoroacetyl, aralkyloxycarbonyl type, such as benzyloxycarbonyl (Z), p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, 2-(p-biphenyl)isopropoxycarbonyl, 2-(3,5-dimethoxyphenyl)isopropoxycarbonyl, p-phenylazobenzyloxycarbonyl, triphenylphosphonoethoxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc), alkoxycarbonyl type Substituted or unsubstituted groups such as tert-butoxycarbonyl (BOC), tert-pentyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, 2-methylsulfonylethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, cycloalkyloxycarbonyl-type groups such as cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, adamantyloxycarbonyl or isobornyloxycarbonyl, and groups containing heteroatoms such as benzenesulfonyl, p-toluenesulfonyl, mesitylenesulfonyl, methoxytrimethylbenzenesulfonyl, 2-nitrobenzenesulfonyl, 2-nitrosulfinyl, 4-nitrobenzenesulfonyl or 4-nitrobenzenesulfinyl.

[0135] Many amino acids carry reactive functional groups in the side chain. In certain embodiments, such functional groups are protected to prevent these functional groups from reacting with the introduced amino acids. The protecting groups used with these functional groups must be stable to the conditions for peptide and / or peptide mimetic synthesis, but can be removed before, after or simultaneously with the cutting of the peptide from the solid support (if the support is bound), or in the case of liquid phase synthesis, removed at the time of final deprotection. Also refer to: Isidro-Llobet, A., Alvarez, M., Albericio, F., "Amino Acid-Protecting Groups"; Chem. Rev., 109: 2455-2504 (2009), which is a comprehensive review of the commonly used protecting groups in peptide synthesis (the protecting groups can also be used in peptide mimetic synthesis, wherein the peptide mimetic contains functional groups found in the peptide).

[0136] In certain embodiments, the solid support material used in the solid phase peptide synthesis method is a gel-type support, such as polystyrene, polyacrylamide or polyethylene glycol. Alternatively, the surface of a material such as controlled pore glass, cellulose fiber or polystyrene can be functionalized to provide a solid support for peptide synthesis.

[0137] The coupling reagents that can be used in the solid phase (or liquid phase) peptide synthesis described herein are typically carbodiimide reagents. Examples of carbodiimide reagents include, but are not limited to, N, N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and its HCl salt (EDC.HCl), N-cyclohexyl-N'-isopropylcarbodiimide (CIC), N, N'-diisopropylcarbodiimide (DIC), N-tert-butyl-N'-methylcarbodiimide (BMC), N-tert-butyl-N'-ethylcarbodiimide (BEC), bis[[4-(2,2-dimethyl-1,3-dioxolyl)]methyl]carbodiimide (BDDC) and N, N-dicyclopentylcarbodiimide. DCC is a preferred coupling reagent. Other coupling agents include HATU and HBTU, which are often used in combination with an organic base such as DIEA and a hindered pyridine base such as lutidine or collidine.

[0138] In some embodiments, the amino acid can be activated for coupling to a peptide or peptide mimetic by forming an N-carboxyanhydride as described in Fuller et al., Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Peptide Synthesis, Biopolymers (Peptide Science), Vol. 40, 183-205 (1996) and WO2018 / 034901.

[0139] Methods for preparing representative small molecule peptide mimetics such as compound 1 and compound (Ia) can be found in WO2019 / 118878, which is incorporated herein by reference. More specifically, the synthesis of compound (Ia) is specifically described in WO2019 / 118878 regarding the synthesis of compound 7a as described therein. Many other similar peptide mimetics have been prepared as described herein - thus demonstrating the feasibility and versatility of such methods to produce many different small molecule peptide mimetics.

[0140] VII. Pharmaceutical Compositions, Routes of Administration and Dosage

[0141] The small molecule peptide mimetics disclosed herein can be used alone or in combination with other therapeutically active ingredients to address the needs of subjects suffering from Huntington's disease and / or HTT protein disease. In order to be administered to subjects in need, small molecule peptide mimetics generally need to be formulated for a suitable route of administration. The formulated product can be considered to be a composition or drug comprising a small molecule peptide mimetic and optionally one or more additional active therapeutic agents.

[0142] In certain embodiments, the pharmaceutical composition of the present application may further include at least one additional therapeutic agent (e.g., an additional therapeutic agent used for combination therapy) in addition to the small molecule peptide mimetic. The at least one additional therapeutic agent may be an agent that can be used to treat Huntington's disease or HTT protein disease. Therefore, in some embodiments, the pharmaceutical composition of the present application can be prepared, for example, by combining one or more compounds of the present application (e.g., small molecule peptide mimetic) with a pharmaceutically acceptable carrier and optionally one or more additional therapeutic agents.

[0143] The pharmaceutical composition of the present application may contain an effective amount of a therapeutic compound / agent (or compound / agent) as described herein, and may be optionally distributed (e.g., dissolved, suspended or otherwise) in a pharmaceutically acceptable carrier. The components of the pharmaceutical composition may also be able to be mixed with the compounds of the present application, and mixed with each other in a manner that does not significantly impair the desired drug efficiency.

[0144] As described above, "effective amount" refers to any amount of an active compound (or compounds; alone or in combination) sufficient to achieve the desired biological effect. In conjunction with the teachings provided herein, by selecting among various active compounds and weighing factors such as efficacy, relative bioavailability, patient weight, severity of adverse side effects, and mode of administration, an effective preventive (i.e., prophylactic) or therapeutic treatment regimen can be planned that does not cause significant undesirable toxicity and is effective for treating a specific condition or disease of a specific subject. The effective amount of any particular indication may vary according to factors such as the disease, disorder or condition being treated, the specific compound or compounds administered, the size of the subject or the severity of the disease, disorder or condition, etc. The effective amount can be determined during preclinical trials and / or clinical trials by methods familiar to physicians and clinicians. A person of ordinary skill in the art can empirically determine the effective amount of a specific compound and / or other therapeutic agent without unnecessary experimentation. A maximum dose can be used, i.e., the highest safe dose according to some medical judgment. Multiple doses per day can be envisioned to achieve appropriate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring the peak or sustained plasma levels of the drug in the patient. "Dose" and "dosage" are used interchangeably herein. A dose can be administered by oneself, by another person, or by a device (eg, a pump).

[0145] For any compound described herein, the therapeutically effective amount can be determined, for example, initially from an animal model. The therapeutically effective dose can also be determined based on human data of compounds tested in humans and compounds known to exhibit similar pharmacological activity, such as other related active agents. Higher doses may be required for parenteral administration. The dose applied can be adjusted based on relative bioavailability and the efficacy of the compound administered. It is entirely within the capabilities of ordinary technicians to adjust the dose to achieve maximum efficacy based on the methods described above and other methods as known in the art.

[0146] Compounds for therapy or prevention (alone or formulated in a pharmaceutical composition / drug) can be tested in a suitable animal model system. Suitable animal model systems include, but are not limited to, rats, mice, chickens, cattle, monkeys, rabbits, pigs, miniature pigs, etc., before testing in human subjects. In in vivo testing, any animal model system known in the art can be used before administration to human subjects. In some embodiments, administration can be tested directly in humans.

[0147] The dosage, toxicity and therapeutic efficacy of any therapeutic compound / agent, composition (e.g., formulation or drug), other therapeutic agent or mixture thereof can be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example, to determine the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic effects and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compounds that exhibit high therapeutic indexes are advantageous. Although compounds that exhibit toxic side effects can be used, in such cases, delivery systems that target such compounds to the site of the affected tissue can be carefully designed to minimize potential damage to uninfected cells and thereby reduce side effects.

[0148] In some embodiments, the effective amount of the therapeutic compound / agent disclosed herein sufficient to achieve a therapeutic effect or preventive effect can be in the range of about 0.000001 mg / kg body weight / day to about 10,000 mg / kg body weight / day. Suitably, the dosage range is about 0.0001 mg / kg body weight / day to about 100 mg / kg body weight / day. For example, the dosage can be 1 mg / kg body weight or 100 mg / kg body weight every day, every two days or every three days, or every week, every two weeks or every three weeks in the range of 1-100 mg / kg body weight. In some embodiments, the single dose range of the therapeutic compound / agent disclosed herein is 0.001-10,000 micrograms / kg body weight. In some embodiments, the therapeutic compound / agent disclosed herein is dissolved or suspended in a carrier in the range of 0.2 micrograms / delivered milliliters to 2000 micrograms / delivered milliliters. In some embodiments, the dosage regimen meets the pharmacokinetic target concentration in the target tissue to achieve the desired therapeutic outcome.

[0149] An exemplary treatment regimen may require administration once a day, twice a day, three times a day, once a week, or once a month. In therapeutic applications, relatively high doses are sometimes required at relatively short intervals until the progression of the disease is reduced or terminated or until the subject shows partial or complete improvement in the symptoms of the disease. Thereafter, a preventive regimen may be administered to the patient.

[0150] In some embodiments, a therapeutically effective amount of a therapeutic compound / agent disclosed herein can be defined as 10% of the compound present at the target tissue. -12 Mole to 10 -4 mole (e.g., about 10 -7 This concentration can be delivered according to a systemic dose of 0.001 mg / kg to 100 mg / kg or an equivalent dose based on body surface area. The dosage schedule will be optimized to maintain therapeutic concentrations at the target tissue, such as by daily or weekly single administrations, but also encompasses continuous administration (e.g., oral, systemic, topical, subcutaneous, intranasal, parenteral infusion, or transdermal application).

[0151] In some embodiments, the intravenous or subcutaneous administration of the compound (alone or formulated) can typically be 0.01 μg / kg / day to 80 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the compound (alone or formulated) can typically be 0.01 μg / kg / day to 100 μg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the compound (alone or formulated) can typically be 0.1 μg / kg / day to 10 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the compound (alone or formulated) can typically be 10 μg / kg / day to 2 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the compound (alone or formulated) can typically be 500 μg / kg / day to 5 mg / kg / day. In some embodiments, the intravenous or subcutaneous administration of the compound (alone or formulated) can typically be 1 mg / kg / day to 100 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of the compound (alone or formulated) may generally range from 1 mg / kg / day to 50 mg / kg / day.

[0152] Typically, for human subjects, the daily oral dose of the compound (alone or formulated) will be about 0.01 micrograms / kg / day to 250 milligrams / kg / day. In certain embodiments, for human subjects, the daily oral dose of the compound (alone or formulated) will be about 1 milligram / kg / day to 100 milligrams / kg / day or about 10 milligrams / kg / day to 75 milligrams / kg / day, or it is expected that in one or more daily administrations, the compound (alone or formulated) ranges from 0.1 milligrams / kg to 50 milligrams / kg of oral dose will produce therapeutic results. Depending on the mode of administration, the dosage can be appropriately adjusted to reach the desired drug level locally or systemically. For example, it is expected that the dose administered intravenously every day will be reduced by an order of magnitude to several orders of magnitude. In the case of insufficient response of the subject at such a dosage, even higher dosages (or effective higher dosages by different, more local delivery routes) can be adopted within the range allowed by patient tolerance. It is envisioned that multiple doses per day are used to reach the appropriate systemic level of the compound.

[0153] For use in therapy, an effective amount of the compound (alone or formulated) can be administered to a subject by any mode of delivering the compound to the desired surface. Administration of the pharmaceutical composition can be accomplished by any means known to those skilled in the art. Routes of administration include, but are not limited to, oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ocular, intrathecal, intracerebroventricular, by iontophoresis, transmucosal, intravitreal, or intramuscular administration. Administration includes self-administration, administration by others, or administration by a device (e.g., pump).

[0154] The therapeutic compounds / agents disclosed herein can be delivered to a subject in formulations or medicaments (i.e., pharmaceutical compositions). Formulations and medicaments can be prepared, for example, by dissolving or suspending the therapeutic compounds / agents disclosed herein in water, a pharmaceutically acceptable carrier, a salt (e.g., NaCl or sodium phosphate), a buffer, a preservative, a compatible carrier, an adjuvant, and optionally other therapeutically acceptable ingredients.

[0155] The pharmaceutical composition (e.g., formulation or medicine) may include a carrier (e.g., a pharmaceutically acceptable carrier), which may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Appropriate fluidity may be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant. Prevention of the effects of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. Glutathione and other antioxidants may be included to prevent oxidation. In many cases, it will be advantageous to include an isotonic agent, such as a sugar (e.g., trehalose), a polyol (such as mannitol, sorbitol), or sodium chloride in the composition. The extended absorption of the injectable composition may be achieved by including an agent such as aluminum monostearate or gelatin in the composition that delays absorption.

[0156] Solutions or suspensions (e.g., formulations or medicaments) for parenteral, intradermal, subcutaneous or intraocular applications may include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be sealed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. For the convenience of the patient or treating physician, the dosing formulation may be provided alone or in a kit containing all the necessary equipment (e.g., drug vials, diluent vials, syringes and needles) for a course of treatment (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or longer).

[0157] When it is desired to deliver a therapeutic compound / agent or pharmaceutical composition systemically, the therapeutic compound / agent or pharmaceutical composition can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion (e.g., by IV injection or via a pump for metered administration within a limited time). The formulation for injection can be present in a unit dosage form, for example, in an ampoule or in a multi-dose container, with the addition of a preservative. These compositions can be in the form of a suspension, solution or emulsion such as in an oily vehicle or an aqueous vehicle, and can contain a formulation agent such as a suspending agent, a stabilizer and / or a dispersant. In addition, the suspension of the active compound can be prepared into a suitable oily injection suspension. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0158] Systemic formulations include those designed for administration by injection (eg, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as formulations designed for transdermal, transmucosal oral, or pulmonary administration.

[0159] For intravenous and other parenteral administration routes, the compounds can be formulated as lyophilized preparations, lyophilized preparations of active compounds embedded or encapsulated by liposomes, lipid complexes or salt complexes in aqueous suspensions. Lyophilized formulations are usually reconstituted in a suitable aqueous solution, for example, in sterile water or saline shortly before administration.

[0160] Pharmaceutical compositions (e.g., formulations or medicaments) suitable for injection may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). Compositions for administration by injection will generally be sterile and should have fluidity to the extent that they are easy to inject. They should be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0161] As required, sterile injectable solutions (e.g., formulations or medicaments) can be prepared by incorporating the active compound in the desired amount in an appropriate solvent having one or a combination of the ingredients listed above, followed by sterile filtration if necessary. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the desired other ingredients from the ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, typical preparation methods include vacuum drying and freeze drying, which can produce a powder of the active ingredient plus any additional desired ingredients from its previously sterile filtered solution.

[0162] For oral administration, the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the present application to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, or corn starch; a lubricant such as magnesium stearate or a stearate salt; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as mint, methyl salicylate or orange flavor.

[0163] Pharmaceutical preparations for oral use can be obtained as solid excipients, optionally grinding the resulting mixture after adding suitable adjuvants (if necessary), and processing the granular mixture to obtain tablets or dragee cores. Suitable excipients are particularly fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate, can be added. Optionally, oral formulations can also be formulated in saline or buffer, such as EDTA, for neutralizing internal acidic conditions, or can be administered without any carrier.

[0164] It is also specifically contemplated that the above oral dosage forms can be chemically modified so that oral delivery of the derivative is effective. Generally, the chemical modification contemplated is to attach at least one part to the therapeutic agent, ingredient and / or excipient, wherein the part allows: (a) inhibition of acid hydrolysis; and (b) uptake from the stomach or intestine into the bloodstream. It is also desirable to increase the overall stability of the therapeutic agent, ingredient and / or excipient and to increase the circulation time in the body. Examples of such parts include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts", see: Enzymes as Drugs, Hocenberg and Roberts, ed., Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J Appl Biochem 4: 185-9 (1982). Other polymers that may be used are poly-1,3-dioxolane and poly-1,3,6-trioxocane.As mentioned above, for pharmaceutical uses, polyethylene glycol (PEG) moieties of various molecular weights are suitable.

[0165] For formulations of therapeutic agents, ingredients and / or excipients, the location of release can be the stomach, small intestine (duodenum, jejunum or ileum) or large intestine. One skilled in the art has available formulations that will not dissolve in the stomach but will release the material elsewhere in the duodenum or intestine. Preferably, the release will avoid deleterious effects on the gastric environment by protecting the compound (or derivative) of the present application or by releasing the biologically active material outside the gastric environment (such as into the intestine).

[0166] A coating or mixture of coatings may also be used on tablets that are not intended to protect from the stomach. This may include a sugar coating or a coating that makes the tablet easier to swallow. Capsules may consist of a hard shell such as gelatin for delivery of dry therapeutic agents (e.g., powders); for liquid forms, a soft gelatin shell may be used. The shell material for cachets may be thick starch or other edible paper. For pills, lozenges, molded tablets, or tablet triturates, a moist massing technique may be used.

[0167] The therapeutic compound / agent or pharmaceutical composition can be included in the formulation as fine multiparticulates in the form of granules or pellets of about 1-2 mm particle size. The formulation of the material for capsule administration can also be a powder, a slightly compressed plug or even a tablet. The therapeutic compound / agent or pharmaceutical composition can be prepared by compression.

[0168] Both coloring agents and flavoring agents may be included. For example, the compounds or pharmaceutical compositions (or derivatives) of the present application may be formulated and then further included in edible products (such as refrigerated beverages containing coloring agents and flavoring agents).

[0169] One can dilute or increase the volume of the therapeutic compound / agent or pharmaceutical composition with inert materials. These diluents can include carbohydrates, especially mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextran, and starch. Certain inorganic salts can also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents are and

[0170] Disintegrants may be included in the formulation of the therapeutic compound / agent or composition in a solid dosage form. Materials used as disintegrants include, but are not limited to, starch, including the commercial starch-based disintegrant Explotab. Sodium starch glycolate, Sodium carboxymethylcellulose, super branched starch, sodium alginate, gelatin, orange peel, acidic carboxymethylcellulose, natural sponge and bentonite can all be used. Another form of disintegrating agent is an insoluble cation exchange resin. Powdered gums can be used as disintegrating agents and binders and these can include powdered gums such as agar, karaya gum or tragacanth. Alginic acid and its sodium salt can also be used as a disintegrating agent.

[0171] Binder can be used for therapeutic agent to be kept together to form hard tablet, and comprises the material from natural product such as gum arabic, tragacanth, starch and gelatin.Other binders include methylcellulose (MC), ethylcellulose (EC) and carboxymethylcellulose (CMC).Polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) can be used for therapeutic agent granulation in alcoholic solution.

[0172] Anti-friction agents may be included in the formulation of the therapeutic agent to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic agent and the mold wall, and these may include, but are not limited to: stearic acid (including its magnesium and calcium salts), polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Water-soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols (PEG) of various molecular weights, Carbowax TM 4000 and 6000.

[0173] Glidants may be added which may improve the flow characteristics of the drug during formulation and aid in rearrangement during compression. Glidants may include starch, talc, fumed silica, and hydrated aluminosilicates.

[0174] In order to help therapeutic compounds / medicaments or compositions (for example, medicine) to be dissolved in aqueous environments, surfactants can be added as wetting agents.Surfactants can include anionic detergents, such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.Cationic detergents can be used and the cationic detergents can include benzalkonium chloride and benzethonium chloride.Potential nonionic detergents that can be included in the formulation as surfactants include lauromacrogol 400, polyethylene glycol 40 stearate, polyoxyethylene hydrogenated castor oil 10,50 and 60, glyceryl monostearate, polysorbate 40,60,65 and 80, sucrose fatty acid esters, methylcellulose and carboxymethylcellulose.These surfactants can be present in the formulation of the compound of the application or derivatives alone or as mixtures of different ratios.

[0175] Pharmaceutical preparations that can be used orally include press-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Such press-fit capsules can contain active ingredients, which are mixed with fillers such as lactose, adhesives such as starch and / or lubricants such as talcum or magnesium stearate and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added. Microspheres formulated for oral administration can also be used. Such microspheres have been clearly defined in the art. All formulations for oral administration should be suitable for the dosage of such administration.

[0176] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0177] For topical administration, the compounds can be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art. Solutions, gels, ointments, creams, or suspensions can be applied topically. The compounds can also be formulated into rectal or vaginal compositions (such as suppositories or retention enemas), for example, containing conventional suppository bases (such as cocoa butter or other glycerides).

[0178] For administration by inhalation, the compounds or compositions (e.g., drugs) used in accordance with the present application can be conveniently delivered from a pressurized package or nebulizer in the form of an aerosol spray presentation using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In some embodiments, formulations, drugs or other therapeutic compounds / agents can be delivered from a pressurized container or dispenser containing a suitable propellant (e.g., a gas (such as carbon dioxide)) or from a nebulizer in the form of an aerosol spray. Such methods include those described in U.S. Patent No. 6,468,798. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for delivering a metered amount. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for delivering a metered amount. For example, capsules and cartridges (e.g., gelatin) for use in an inhaler or insufflator can be formulated into a powder mixture containing a therapeutic compound / agent and a suitable powder base (such as lactose or starch). Alternatively, the active compound may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

[0179] Nasal delivery of the therapeutic compound / agent or pharmaceutical composition of the present application is also contemplated. Nasal delivery allows the therapeutic compound / agent or pharmaceutical composition to be delivered directly to the bloodstream after being applied to the nose, without the need for the product to be deposited in the lungs. Formulations for nasal delivery include formulations containing dextran or cyclodextran.

[0180] For nasal administration, a useful device is a small hard bottle to which a metered dose sprayer is attached. In some embodiments, the metered dose is delivered by inhaling the pharmaceutical composition of the present application solution into a chamber of defined volume, the chamber having an orifice sized to atomize the aerosol formulation by forming a spray when the liquid in the chamber is compressed. The chamber is compressed to administer the therapeutic compound / agent or pharmaceutical composition. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[0181] Alternatively, a plastic squeeze bottle is used with an orifice or opening sized to atomize the aerosol formulation by forming a spray when squeezed. The opening is typically located at the top of the bottle, and the top is typically tapered to partially fit into the nasal passage for effective administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation to administer a measured dose of the therapeutic compound / agent or pharmaceutical composition.

[0182] Pulmonary delivery of the compounds disclosed herein is also contemplated herein. The compounds or pharmaceutical compositions are delivered to the lungs of a mammal upon inhalation and cross the lung epithelial lining to the bloodstream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(Suppl 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-γ and tumor necrosis factor α) and Platz et al., U.S. Pat. No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). Methods and compositions for pulmonary delivery of drugs to exert systemic effects are described in U.S. Pat. No. 5,451,569 (incorporated by reference), issued September 19, 1995 to Wong et al.

[0183] Contemplated for use in practicing this technology are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including, but not limited to, nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0184] Some specific examples of commercially available devices suitable for practicing this technique are the Ultravent TM Atomizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; Nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; Metered dose inhalers, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and Powder inhaler manufactured by Fisons Corp., Bedford, Mass.

[0185] All such devices require the use of formulations suitable for dispensing the compound / therapeutic agent. Typically, each formulation is specific to the type of device employed and may involve the use of appropriate propellant materials in addition to the usual diluents, adjuvants and / or carriers that may be used in therapy. In addition, the use of liposomes, microcapsules, microspheres, nanoparticles, nanospheres, inclusion complexes or other types of carriers is contemplated. Depending on the type of chemical modification or the type of device employed, the chemically modified compounds of the present application may also be prepared with different formulations.

[0186] Formulations suitable for use with a nebulizer (jet or ultrasonic) may, for example, contain the compound / therapeutic agent (or derivative) of the present application dissolved in water at a concentration of about 0.01 mg to 50 mg of biologically active compound per mL of solution. The formulation may also contain a buffer and a monosaccharide (e.g., for inhibitor stabilization and osmotic pressure regulation). The nebulizer formulation may also contain a surfactant to reduce or prevent surface-induced aggregation of the compound of the present application caused by atomization of the solution when forming an aerosol.

[0187] The formulation used with the metered dose inhaler device generally comprises a finely divided powder containing the compound (or derivative) of the present application, which is suspended in a propellant with the help of a surfactant. The propellant can be any conventional material used for this purpose, such as chlorofluorocarbons, fluorochlorocarbon compounds, hydrofluorocarbons or hydrocarbons, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane or a combination thereof. Suitable surfactants include sorbitan trioleate and soybean lecithin. Oleic acid can also be used as a surfactant.

[0188] The formulation for dispensing from the powder inhaler device can include a finely divided dry powder containing the compound (or derivative) of the present application, and can also include an extender, such as lactose, sorbitol, sucrose or mannitol, in an amount that helps the powder to disperse from the device, for example 50% to 90% by weight of the formulation. The compound / therapeutic agent (or derivative) of the present application can be advantageously prepared as a particle or nanoparticle form having an average particle size of less than 10 microns (μm), most preferably 0.5 to 5 μm, for most effective delivery to the deep lung.

[0189] For ophthalmic indications or intraocular indications, any suitable mode of delivering the therapeutic compound / agent or pharmaceutical composition to the eye or an area near the eye can be used. Generally, for ophthalmic formulations, see Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, NY (1993) and Havener, WH, Ocular Pharmacology, CV Mosby Co., St. Louis (1983). Non-limiting examples of pharmaceutical compositions suitable for intraocular or near-eye administration include, but are not limited to, ocular inserts, microtablets, and topical formulations, such as eye drops, ointments, and in situ gels. In one embodiment, contact lenses are coated with a pharmaceutical composition comprising a therapeutic compound / agent disclosed herein. In some embodiments, a single dose may include 0.1 ng to 5000 μg, 1 ng to 500 μg, or 10 ng to 100 μg of a therapeutic compound / agent or pharmaceutical composition applied to the eye.

[0190] Eye drops can include sterile liquid formulations that can be applied directly to the eye. In some embodiments, eye drops include at least one therapeutic compound / agent disclosed herein, and may further include one or more preservatives. In some embodiments, the optimal pH of eye drops is equal to the pH of tears, and is about 7.4. For eye drops, the therapeutic compound / agent may be present in the drop solution at about 0.1% to about 5% (w / v or v / v, depending on the physical properties of the active ingredient (i.e., solid or liquid)). In some embodiments, the therapeutic compound / agent may be present in the drop solution at about 1% to about 3% (w / v or v / v, as the case may be).

[0191] In situ gel is a viscous liquid that, when affected by external factors such as appropriate pH, temperature, and the presence of electrolytes, shows the ability to undergo a sol-to-gel transition. This property results in a slowed rate of drug discharge from the surface of the eyeball and increased bioavailability of the active ingredient. Commonly used polymers in in situ gel formulations include, but are not limited to, gellan gum, poloxamer, silicone-containing formulations, silicon dioxide-based formulations, and cellulose acetate phthalate. In some embodiments, therapeutic compounds / agents are formulated into in situ gels (as pharmaceutical compositions / drugs).

[0192] For topical ophthalmic administration, the therapeutic compound / agent or pharmaceutical composition can be formulated into solutions, gels, ointments, creams, suspensions, etc., as are well known in the art. Ointments are semisolid dosage forms for external use, such as for topical use on the eye or skin. In some embodiments, the ointment comprises a solid or semisolid hydrocarbon matrix having a melting or softening point close to the core temperature of the human body. In some embodiments, the ointment applied to the eye breaks down into small droplets that stay in the conjunctival sac for a longer time, thereby increasing bioavailability.

[0193] The ocular insert is a solid or semisolid dosage form without the disadvantages of conventional ophthalmic drug dosage forms. It is not susceptible to defense mechanisms (such as outflow through the nasolacrimal duct), can stay in the conjunctival sac for a longer time, and is more stable than conventional dosage forms. It also provides advantages such as precise administration of one or more therapeutic compounds / agents, slow release of one or more therapeutic compounds / agents at a constant rate, and limiting systemic absorption of one or more therapeutic compounds / agents. In some embodiments, the ocular insert includes one or more therapeutic compounds / agents as disclosed herein and one or more polymeric materials. The polymeric material may include, but is not limited to, methylcellulose and its derivatives (e.g., hydroxypropyl methylcellulose (HPMC)), ethyl cellulose, polyvinyl pyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethyl chitosan, gelatin, and various mixtures of the above polymers. The ocular insert may include silicon dioxide. The ocular insert may include liposomes, nanoparticles, or microparticles of a degradable or biodegradable polymer (as described in more detail below).

[0194] Microtablets are biodegradable solid pharmaceutical dosage forms that transform into a gel after application to the conjunctival sac, thereby prolonging the contact period between the active ingredient (i.e., the therapeutic compound / agent disclosed herein) and the surface of the eyeball, which in turn improves the bioavailability of the therapeutic compound / agent. The advantages of microtablets include easy application to the conjunctival sac, unaffected by defense mechanisms (such as tearing or outflow through the nasolacrimal duct), longer contact with the cornea due to the presence of mucoadhesive polymers, and gradual release of the active ingredient from the formulation at the application site due to swelling of the outer carrier layer. Microtablets may include one or more therapeutic compounds / formulations disclosed herein and one or more polymers. Non-limiting examples of polymers suitable for use in microtablet formulations include cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose, ethyl cellulose, acrylates (e.g., polyacrylic acid and its cross-linked forms), Or carbomer, chitosan and starch (e.g., drum-dried waxy corn starch). In some embodiments, the mini-tablet further comprises one or more excipients. Non-limiting examples of excipients include mannitol and magnesium stearate.

[0195] Ophthalmic or intraocular formulations and medicaments may contain nontoxic auxiliary substances, such as antibacterial components which are harmless when used, for example, thimerosal, benzalkonium chloride, methyl and propylparabens, benzyldimethyldodecyl ammonium bromide, benzyl alcohol or phenylethyl alcohol; buffering ingredients, such as sodium chloride, sodium borate, sodium acetate, sodium citrate or gluconate buffers; and other conventional ingredients, such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitate, ethylenediaminetetraacetic acid, and the like.

[0196] In certain embodiments, the viscosity of the ocular formulations comprising one or more therapeutic compounds / medicaments is increased to improve contact with cornea and bioavailability in eyes. Viscosity can be increased by adding a high molecular weight hydrophilic polymer, which can not diffuse through biofilm and forms a three-dimensional network in water. The limiting examples of this type of polymer include polyvinyl alcohol, poloxamer, hyaluronic acid, carbomer and polysaccharides, cellulose derivatives, gellan gum and xanthan gum.

[0197] In addition to the formulations described above, therapeutic compounds / agents disclosed herein can also be formulated as depot preparations. Such long-acting formulations can be formulated with suitable polymeric materials or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or are formulated as sparingly soluble derivatives, e.g., are formulated as sparingly soluble salts.

[0198] In some embodiments, the therapeutic agent is administered as a depot formulation, wherein the active therapeutic agent is encapsulated by silica-based microparticles or is disposed within silica-based microparticles. In some embodiments, the ocular formulation can be injected into the eye, for example as a sol-gel (e.g., a silica sol-gel). In some embodiments, the ocular formulation is a depot formulation, such as a controlled release formulation (see below). Such controlled release formulations can include particles, such as microparticles or nanoparticles.

[0199] The pharmaceutical composition may also include a suitable solid or gel-phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, silicon dioxide / silicone and polymers (such as polyethylene glycol).

[0200] Suitable liquid or solid drug formulation forms can be, for example, aqueous solutions or saline solutions for inhalation; microencapsulated, embedded, coated on microscopic gold particles, contained in liposomes, atomized aerosols, for implantation in the skin or drying to sharp objects to scrape into the pellets in the skin. Pharmaceutical compositions also include formulations of particles, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or sustained-release active compounds, in which excipients and additives and / or adjuvants (such as disintegrants, adhesives, coatings, swelling agents, lubricants, flavorings, sweeteners or solubilizers) are generally used as described above. The pharmaceutical composition can be applicable to a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249: 1527-33 (1990).

[0201] Therapeutic agents, specifically including but not limited to therapeutic compounds / agents disclosed herein, can be provided in particles. As used herein, particles mean nanoparticles or microparticles (or larger particles in some cases), which can be composed of therapeutic compounds / agents described herein or other therapeutic agents in whole or in part. The particles can contain therapeutic compounds / agents in a core surrounded by a coating, which includes but is not limited to an enteric coating. Therapeutic compounds / agents can also be dispersed throughout the particles. Therapeutic compounds / agents can also be adsorbed into the particles. The particles can have any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to therapeutic compounds / agents, particles can include any of those materials conventionally used in the field of pharmacy and medicine, including but not limited to erodible, insoluble, biodegradable or non-biodegradable materials or combinations thereof. The particles can be microcapsules containing therapeutic compounds / agents in a solution or semi-solid state. The particles can actually have any shape.

[0202] Non-biodegradable polymeric materials and biodegradable polymeric materials can both be used to manufacture particles for delivering therapeutic compounds / medicaments. Such polymers can be natural polymers or synthetic polymers. Polymers are selected based on the time period of the desired release. The bioadhesive polymers of particular concern include the bioerodible hydrogels described by the people (1993) Macromolecules 26:581-7 of Sawhney HS, and the teaching of the document is incorporated herein. These include polyhyaluronic acid, casein, gelatin, gelatin, polyanhydrides, polyacrylic acid, alginate, chitosan, polyethylene glycol (PEG), polyvinyl alcohol (PVA), poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), polylactic acid (PLA), poly(lactic-co-glycolic) acid (PLGA), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and poly(ε-caprolactone) or mixtures of two or more of the foregoing.

[0203] The therapeutic compound / agent or other therapeutic agent or mixture thereof can be formulated in a carrier system. The carrier can be a colloidal system. The carrier or colloidal system can be a liposome, a phospholipid bilayer medium. In one embodiment, the therapeutic compound / agent or other therapeutic agent or mixture thereof can be encapsulated in a liposome while maintaining the integrity of the therapeutic compound / agent or other therapeutic agent or mixture thereof. Those skilled in the art will appreciate that there are a variety of methods for preparing liposomes. (See Lichtenberg et al., Methods Biochem. Anal., 33: 337-462 (1988); Anselem et al., Liposome Technology, CRC Press (1993)). Liposomal formulations can delay clearance and increase cellular uptake (see Reddy, Ann. Pharmacother., 34 (7-8): 915-923 (2000)). For example, the active agent can also be loaded into particles prepared from pharmaceutically acceptable ingredients, including but not limited to soluble, insoluble, permeable, impermeable, biodegradable or gastroretentive polymers or liposomes. Such particles include but are not limited to nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles and viral vector systems.

[0204] The carrier can also be a polymer, such as a biodegradable, biocompatible polymer matrix. In one embodiment, the therapeutic compound or other therapeutic agent or a mixture thereof can be embedded in the polymer matrix while maintaining the integrity of the composition. The polymer can be a microparticle or nanoparticle encapsulating one or more therapeutic agents. The polymer can be natural, such as a polypeptide, protein or polysaccharide, or synthetic, such as poly-alpha-hydroxy acid. Examples include carriers made of, for example, collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharides, fibrin, gelatin and combinations thereof. In one embodiment, the polymer is polylactic acid (PLA), polylactic acid / glycolic acid (PLGA) or a mixture thereof. The polymer matrix can be prepared and separated in a variety of forms and sizes, including microspheres and nanospheres. Polymer formulations can lead to an extended duration of therapeutic effects. (See Reddy, Ann.Pharmacother., 34 (7-8): 915-923 (2000)). Polymer formulations for human growth hormone (hGH) have been used in clinical trials. (See Kozarich and Rich, Chemical Biology, 2:548-552 (1998)).

[0205] Examples of polymer microsphere slow release formulations are described in PCT Publication WO 99 / 15154 (Tracy et al.), U.S. Pat. Nos. 5,674,534 and 5,716,644 (both Zale et al.), PCT Publication WO 96 / 40073 (Zale et al.), and PCT Publication WO 00 / 38651 (Shah et al.). U.S. Pat. Nos. 5,674,534 and 5,716,644 and PCT Publication WO 96 / 40073 describe a polymer matrix containing erythropoietin particles that are stabilized with salt to prevent aggregation.

[0206] In some embodiments, the nanoparticles or microparticles may be silica-based or silane-based (see, for example, WO 2002 / 080977, entitled: "Biodegradable carrier and method for preparation thereof").

[0207] In some embodiments, the therapeutic compound / agent or other therapeutic agent or mixture thereof is prepared together with a carrier (such as a controlled release formulation, including implants and microencapsulated delivery systems) that protects the therapeutic compound / agent or other therapeutic agent or mixture thereof from rapid elimination from the body. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such formulations can be prepared using known techniques. These materials can also be commercially available, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (comprising liposomes targeted with monoclonal antibodies directed to cell-specific antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0208] The therapeutic compound / agent can be included in a controlled release system. The term "controlled release" is intended to refer to any formulation containing a drug, wherein the mode and curve of the drug release from the formulation is controlled. This refers to immediate release formulations and non-immediate release formulations, wherein non-immediate release formulations include but are not limited to sustained release formulations and delayed release formulations. The term "slow release" (also referred to as "extended release") is used with its conventional meaning to refer to a drug formulation that provides a gradual release of the drug over an extended period of time, and preferably but not necessarily causes a substantially constant blood level of the drug over an extended period of time. The term "delayed release" is used with its conventional meaning to refer to a drug formulation that has a time delay between the administration of the formulation and the release of the drug therefrom so that it can be used for a subject. "Delayed release" may or may not involve gradually releasing the drug over an extended period of time, and therefore may or may not be "sustained release".

[0209] The use of long-term sustained release implants or reservoir formulations may be particularly suitable for the treatment of chronic conditions.Terms "implant" and "reservoir formulations" are intended to include a single composition (such as a mesh) or a composition (for example, a fibrous mesh consisting of several independent mesh materials) or a plurality of independent compositions including multiple components, wherein the multiple compositions maintain localization, and provide the long-term sustained release occurring from the aggregate of the multiple compositions.As used herein, "long-term" release means that implants or reservoir formulations are constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continue at least 2 days.In certain embodiments, implants or reservoir formulations are constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continue at least 7 days.In certain embodiments, implants or reservoir formulations are constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continue at least 14 days.In certain embodiments, implants or reservoir formulations are constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continue at least 30 days. In certain embodiments, implant or reservoir composite is constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continues at least 60 days.In certain embodiments, implant or reservoir composite is constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continues at least 90 days.In certain embodiments, implant or reservoir composite is constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continues at least 180 days.In certain embodiments, implant or reservoir composite is constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continues at least one year.In certain embodiments, implant or reservoir composite is constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continues 15-30 days.In certain embodiments, implant or reservoir composite is constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continues 30-60 days.In certain embodiments, implant or reservoir composite is constructed and arranged to deliver the active ingredient of treatment level or prevention level, and continues 60-90 days. In certain embodiments, implant or reservoir composite is constructed and arranged to deliver the active ingredient of treatment level or prevention level, continues 90-120 days.In certain embodiments, implant or reservoir composite is constructed and arranged to deliver the active ingredient of treatment level or prevention level, continues 120-180 days.In certain embodiments, implant or reservoir composite is constructed and arranged to deliver the active ingredient of treatment level or prevention level, continues up to one year.In certain embodiments, long-term sustained release implant or reservoir composite is well known to those of ordinary skill in the art, and comprises some in the release system described above.In certain embodiments, such implant or reservoir composite can be applied by surgical operation.In certain embodiments, such implant or reservoir composite can be applied locally or by injection.

[0210] VIII. Formulations and Drugs:

[0211] The small molecule peptide mimetics disclosed herein (e.g., compounds of Formula I and Formula Ia) can be used alone or in combination with other therapeutically active ingredients to address the needs of subjects suffering from Huntington's disease and / or HTT protein disease. In order to be applied to subjects in need, small molecule peptide mimetics generally need to be formulated for a suitable route of administration. The formulated product can be considered to be a composition or drug comprising a small molecule peptide mimetic and optionally one or more additional active therapeutic agents. For example, if a small molecule peptide mimetic (alone or in combination with another active ingredient) is to be administered to a subject by injection, it will generally be formulated into an injectable liquid or liquid suspension. For example, this can be achieved by dissolving or suspending the small molecule peptide mimetic in a suitable diluent, adjuvant, excipient, vehicle, or pharmaceutically acceptable carrier as previously described herein (see the section with the following titles above: Pharmaceutical Compositions, Routes of Administration, and Dosing), optionally with one or more optionally one or more additional active therapeutic agents. In some embodiments, the diluent, adjuvant, excipient, vehicle or pharmaceutically acceptable carrier may be water, saline or a buffered aqueous solution.

[0212] Similarly, if the small molecule peptide mimetic (alone or in combination with another active therapeutic agent) is administered to a subject orally, the selected active ingredient can be formulated into a pill, tablet, capsule or other vehicle for such administration, as discussed above in the section entitled "Pharmaceutical Compositions, Routes of Administration, and Dosing" or as otherwise known to those skilled in the art.

[0213] Similarly, a small molecule peptidomimetic (alone or in combination with another active therapeutic agent) can be formulated for ocular, buccal, topical, nasal administration, or any other mode of administration previously discussed herein or known to those of ordinary skill in the art.

[0214] In short, any formulation described in the section entitled "Pharmaceutical Compositions, Routes of Administration, and Dosing" above (which, when formulated for administration to a subject suffering from a certain ailment or medical condition requiring medical care, may also be referred to as a drug or composition) can be used to produce a composition (i.e., formulation or drug) suitable for administration to a subject in need thereof. Thus, in some embodiments, the present application relates to compositions, formulations, and drugs suitable for administration to a subject suffering from or believed to suffer from Huntington's disease and / or HTT proteinopathy.

[0215] Therefore, in some embodiments, the present disclosure provides a formulation or medicament comprising a peptide mimetic (such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof) for treating, preventing, inhibiting, ameliorating and / or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula I or Formula Ia, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

[0216] In some embodiments, the subject has been diagnosed with Huntington's disease. In some embodiments, the subject has been diagnosed with HTT proteinopathy.

[0217] In some embodiments, the formulation or drug is administered to the subject daily for 2 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the formulation or drug is administered daily for the rest of the subject's life.

[0218] In some embodiments, treating, preventing, inhibiting or ameliorating comprises treating, preventing, inhibiting or ameliorating one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

[0219] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0220] In some embodiments, the formulation or drug is administered orally. In some embodiments, the formulation or drug is administered subcutaneously. In some embodiments, the formulation or drug is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ocularly, intrathecally, intracerebroventricularly, by iontophoresis, transmucosally, intravitreally, or intramuscularly.

[0221] In some embodiments, the formulation or drug embodies a combination therapy. Therefore, in some embodiments, the use of the formulation or drug further includes administering additional treatment to the subject individually, sequentially or simultaneously. In some embodiments, the additional treatment includes administering a therapeutic agent. The additional therapeutic agent can be a therapeutic agent for treating the disease itself or otherwise for solving symptoms or symptoms associated with the disease (in this case Huntington's disease and / or HTT protein disease). In some embodiments, the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (Sodium valproate) (lamotrigine). In some embodiments, the therapeutic agent is iguratimod (also known as SS-31 or bendavia). In some embodiments, the combination of the formulation or drug and the additional treatment has a synergistic effect in preventing or treating Huntington's disease and / or HTT proteinopathy.

[0222] In some embodiments, pharmaceutically acceptable salts include tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in each case, mono-, di- or tri-acid salts). In some embodiments, pharmaceutically acceptable salts include monoacetate, diacetate, triacetate, mono-trifluoroacetate, bis-trifluoroacetate, tri-trifluoroacetate, mono-hydrochloride, di-hydrochloride, tri-hydrochloride, mono-toluenesulfonate, bis-toluenesulfonate or tri-toluenesulfonate. In some embodiments, peptide mimetics are formulated as tri-HCl salts, bis-HCl salts or mono-HCl salts.

[0223] IX. Treatment methods and related uses

[0224] In one aspect, the present disclosure provides a method for treating, preventing, inhibiting, ameliorating or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide mimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula I or Formula Ia, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

[0225] In some embodiments, the subject has been diagnosed with Huntington's disease. In some embodiments, the subject has been diagnosed with HTT proteinopathy.

[0226] In some embodiments, the peptide mimetic is administered to the subject daily for 2 weeks or more, for 12 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, once diagnosed, the peptide mimetic is administered daily for the rest of the subject's life.

[0227] In some embodiments, treating, preventing, inhibiting or ameliorating comprises treating, preventing, inhibiting or ameliorating one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

[0228] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0229] In some embodiments, the peptide mimetic is administered orally. In some embodiments, the peptide mimetic is administered subcutaneously. In some embodiments, the peptide mimetic is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ocularly, intrathecally, intracerebroventricularly, by iontophoresis, transmucosally, intravitreally, or intramuscularly.

[0230] In some embodiments, the method involves a combination therapy. In practicing a combination therapy, the method further comprises administering an additional treatment to the subject, either individually, sequentially, or simultaneously. In some embodiments, the additional treatment comprises administering a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (Sodium valproate) (lamotrigine). In some embodiments, the therapeutic agent is iguratimod (also known as SS-31 or bendavia). In some embodiments, the combination of a peptide mimetic and an additional therapeutic agent has a synergistic effect in preventing or treating Huntington's disease and / or HTT proteinopathy.

[0231] In some embodiments, the pharmaceutically acceptable salt of the peptide mimetic comprises tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in each case, monoacid salt, diacid salt or triacid salt). In some embodiments, the pharmaceutically acceptable salt comprises monoacetate, diacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, tritrifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotoluenesulfonate, bistoluenesulfonate or tritoluenesulfonate. In some embodiments, the peptide mimetic is formulated as tri-HCl salt, bis-HCl salt or mono-HCl salt.

[0232] In one aspect, the present disclosure provides the use of a composition for the preparation of a medicament for treating, preventing, inhibiting, ameliorating or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof, wherein the composition comprises a therapeutically effective amount of a peptide mimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula I or Formula Ia, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropane-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

[0233] In some embodiments, the subject has been diagnosed with Huntington's disease. In some embodiments, the subject has been diagnosed with HTT proteinopathy.

[0234] In some embodiments, the drug is administered to the subject daily for 2 weeks or more, for 12 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the drug is administered daily for the rest of the subject's life.

[0235] In some embodiments, the use of the drug for treating, preventing, inhibiting or ameliorating includes treating, preventing, inhibiting or ameliorating one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

[0236] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0237] In some embodiments, the drug is formulated for oral administration. In some embodiments, the drug is formulated for subcutaneous administration. In some embodiments, the drug is formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ocular, intrathecal, intracerebroventricular, by iontophoresis, transmucosal, intravitreal, or intramuscular administration.

[0238] In some embodiments, the drug is used alone, sequentially or simultaneously with another treatment. In some embodiments, the other treatment comprises the use of a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) (diazepam), (escitalopram), (Fluoxetine), (sertraline), Cetirizine (quetiapine), (carbamazepine), (Sodium valproate) (lamotrigine). In some embodiments, the therapeutic agent is iguratimod (also known as SS-31 or Bendavia). In some embodiments, the combination of the drug and the additional treatment has a synergistic effect in preventing or treating Huntington's disease and / or HTT proteinopathy.

[0239] In some embodiments, pharmaceutically acceptable salts include tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in each case, mono-, di- or tri-acid salts). In some embodiments, pharmaceutically acceptable salts include monoacetate, diacetate, triacetate, mono-trifluoroacetate, bis-trifluoroacetate, tri-trifluoroacetate, mono-hydrochloride, di-hydrochloride, tri-hydrochloride, mono-toluenesulfonate, bis-toluenesulfonate or tri-toluenesulfonate. In some embodiments, peptide mimetics are formulated as tri-HCl salts, bis-HCl salts or mono-HCl salts.

[0240] In yet another aspect, the present disclosure provides peptide mimetics, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof, for use in treating, preventing, inhibiting, ameliorating and / or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is a peptide mimetic of Formula I or Formula Ia, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof. In some embodiments, the peptide mimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

[0241] In some embodiments, the subject has been diagnosed with Huntington's disease. In some embodiments, the subject has been diagnosed with HTT proteinopathy.

[0242] In some embodiments, the peptide mimetic is administered to the subject daily for 2 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more. In some embodiments, the peptide mimetic is administered daily for the rest of the subject's life.

[0243] In some embodiments, treating, preventing, inhibiting or ameliorating comprises treating, preventing, inhibiting or ameliorating one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

[0244] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0245] In some embodiments, the peptide mimetics are formulated for oral administration. In some embodiments, the peptide mimetics are formulated for subcutaneous administration. In some embodiments, the peptide mimetics are formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ocular, intrathecal, intracerebroventricular, by iontophoresis, transmucosal, intravitreal, or intramuscular administration.

[0246] In some embodiments, the peptide mimetic is used alone, sequentially or simultaneously with another treatment. In some embodiments, the other treatment comprises the use of a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (Sodium valproate) (lamotrigine). In some embodiments, the therapeutic agent is iguratimod (also known as SS-31 or Bendavia). In some embodiments, the combination of the drug and the additional treatment has a synergistic effect in preventing or treating Huntington's disease and / or HTT proteinopathy.

[0247] In some embodiments, pharmaceutically acceptable salts include tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate or maleate (in each case, mono-, di- or tri-acid salts). In some embodiments, pharmaceutically acceptable salts include monoacetate, diacetate, triacetate, mono-trifluoroacetate, bis-trifluoroacetate, tri-trifluoroacetate, mono-hydrochloride, di-hydrochloride, tri-hydrochloride, mono-toluenesulfonate, bis-toluenesulfonate or tri-toluenesulfonate. In some embodiments, peptide mimetics are formulated as tri-HCl salts, bis-HCl salts or mono-HCl salts.

[0248] Examples

[0249] The present technology is further demonstrated by the following examples, which should not be construed as limiting in any way.

[0250] Example 1-(R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentane 1-(4-hydroxy-2,6-dimethylphenyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (tri-HCl salt (compound Effects of drug (Ia) on motor deficits and brain and peripheral biomarkers of disease progression in R6 / 2 mice with Huntington's disease

[0251] Objective—The objective of this study was to investigate the effects of (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide as its tri-HCl salt (i.e., Compound (Ia)) on motor deficits and biomarkers of brain and peripheral disease progression in transgenic R6 / 2 mice with Huntington's disease.

[0252] Study Overview-A total of 46 male R6 / 2 mice and 15 male wild-type littermate control mice (WT) were used in the study. The mice were genotyped and divided into different treatment groups based on their pre-treatment body weight. Treatment with compound (Ia) (0.5 mg / kg or 5 mg / kg; 10 ml / kg, intraperitoneal (ip), QD) or vehicle (10 ml / kg, ip, QD) was started at 4 weeks of age. Body weight was measured before the start of treatment and continued to be measured twice a week until the end of the study. For all mice, fine kinematic analysis and rotation test were performed at 10 weeks of age, and open field activity and clenching behavior were measured at 12 weeks of age. At 8 and 12 weeks of age, the body weight was measured by 18F-FDG PET measured glucose uptake, and MR spectroscopy was used to measure striatal metabolites in 9-10 mice per group. At 13 weeks of age, 9-10 mice per group underwent tissue sampling, and brain and blood samples were collected. Blood samples were used to prepare peripheral blood mononuclear cells (PBMCs), which were subjected to flow cytometry / luminescence analysis for the following measurements: mitochondrial reactive oxygen species (ROS) (MitoSox) and ATP levels (Cell TiterGlow).

[0253] A total of 15 R6 / 2 mice died before the scheduled endpoint. For those mice that died before 12-week imaging, new replacement mice were enrolled and dosing began at the same age as the mice originally enrolled in the study.

[0254] Experimental procedures and assays

[0255] Animals-All animal experiments were performed in accordance with the provisions of a license authorized by the Finnish National Committee on Animal Experimentation (license number: ESAVI / 5071 / 04.10.07 / 2017) and in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (Bethesda, MD, USA). Animals were housed in a standard temperature (21 ± 1.5 °C) and light-controlled environment (lights on from 7 am to 8 pm) with ad libitum access to food and water.

[0256] Species: Mouse

[0257] Strain: R6 / 2 (Cat. No.: 006494)

[0258] Source: Jackson Laboratories (Bar Harbor, ME, USA)

[0259] Number of animals allocated for the study: 45 R6 / 2 and 15 WT male mice

[0260] Target age / weight at start of life stage: 4 weeks

[0261] Each animal is permanently labeled with a unique permanent identification number. Animals are identified using ear tags. After receipt of the animals at the testing facility, they are acclimated for a minimum of seven (7) days before the start of the life stage.

[0262] Animal housing - Different genotypes were not mixed in the same cage, and animals were housed in groups.

[0263] Cages - Individually ventilated cage systems (IVC) and polycarbonate Type II long cages (Allentown Inc.).

[0264] Bedding materials - Corn-o' Cobs (Andersons Ltd) and poplar wood chips (Tapvei Ltd).

[0265] Animal enrichment - Environmental enrichment for animals in accordance with the Government Decree on the protection of animals used for scientific or educational purposes (564 / 2013). Shelters were provided for all animals: plastic igloos, chewing material (poplar sticks) and nesting material.

[0266] Food - Standard food: Teklad Global 2016, Global 2016 pellets ad libitum.

[0267] Water - tap water. As desired.

[0268] Room temperature -21.5±1.5℃.

[0269] Veterinary care was provided throughout the study, and animals were examined by responsible trained personnel and supervised by a veterinarian based on clinical signs or other changes.

[0270] Animal Groupings - The animals are grouped as follows:

[0271] ● Group 1: 15 WT mice aged 4 to 13 weeks treated with vehicle (10 mL / kg, ip, QD)

[0272] ● Group 2: 16 R6 / 2 mice aged 4 to 13 weeks treated with vehicle (10 mL / kg, ip, QD)

[0273] ● Group 3: 15 R6 / 2 mice aged 4 to 13 weeks treated with compound (I(a)) (0.5 mg / kg, ip, QD)

[0274] ● Group 4: 15 R6 / 2 mice aged 4 to 13 weeks treated with compound (I(a)) (5 ​​mg / kg, ip, QD)

[0275] Experimental Design - see Figure 1 ; The in vivo procedures, observations, and measurements listed below were performed on all animals by an investigator blinded to the treatment. R6 / 2 mice mimic human Huntington's disease (HD) by expressing a portion of the human HD gene under the human gene promoter elements (1 kb of 5UTR sequence and exon 1 and approximately 120 CAG repeats). The expression of this amino-terminal fragment of the huntingtin protein and its polyglutamine expansion is sufficient to produce the phenotype of human HD.

[0276] Test Articles - Dosing formulations were prepared weekly by dissolving Compound (Ia) in sterile saline to the appropriate concentration for administration to animals and once prepared could be stored for 7 days at 2-8° C. Unused formulations were discarded at the end of 7 days and new dosing formulations were prepared as needed for the study.

[0277] Drug Delivery - Test article administration was performed by researchers blinded to treatment. The dose volume for each animal was based on body weight. Administration was given ip, 10 mL / kg. Daily dosing began at approximately 11 am to 1 pm.

[0278] Plasma bile acid level measurement-Portosystemic shunts have been identified in mice with a significant percentage of C57BL / 6J backgrounds, resulting in significant changes in brain morphometry, brain metabolites, physiological readings (e.g., body weight, liver enzymes) and cognitive deficits. Before the start of the study, plasma bile acid analysis was performed to exclude animals with abnormally high bile acid concentrations (>20 μmol / L), which is a surrogate marker for portosystemic hepatic shunts. Blood samples (100 μl) for bile acid analysis were collected from the saphenous vein into precooled (ice bath) Li-Hep tubes. The tubes were kept on ice and separated by centrifugation at 2000 g (+4 ° C). Approximately 50 μL of plasma from each mouse was aliquoted into precooled polypropylene tubes and stored at -80 ° C until analysis. Plasma samples were analyzed using Thermofisher Konelab Xti 20 according to the manufacturer's instructions. Mice with abnormally high bile acid levels (more than 20 μmol / L) in plasma were not included in the study.

[0279] Body Weight - Body weights were measured at 4 weeks of age (before treatment) and twice weekly until the end of the study. No final body weights were collected from moribund animals that were found dead or euthanized.

[0280] Rotarod test - At 10 weeks of age, all mice were subjected to the rotarod test. One day of training included a 5-minute training trial at 4 RPM on a rotarod apparatus (Med Associates Inc, St Albans, VT, USA). After 1 hour, mice were subjected to 3 consecutive 6-minute acceleration tests, in which the speed was changed from 0 to 40 RPM in 360 seconds, and the interval between trials was at least 30 minutes. The latency to fall from the rod was recorded.

[0281] Open field test - At 12 weeks of age, all mice were subjected to open field testing. Mice were brought to the laboratory for an adaptation period of at least 1 hour before testing. Activity chambers (Med Associates Inc, St Albans, VT; 27x27x20.3cm) were equipped with IR beams. Mice were placed in the center of the chamber and their behavior was recorded in a 5-minute box for 30 minutes. The following five related measurements were quantitatively analyzed: total movement, movement in the center of the open field, feeding rate in the center, total feeding frequency and speed. Mice were tested under low stress conditions, where the light intensity was reduced to approximately 10-30 lux red light.

[0282] 18 F-FDG-PET analysis - At 8 and 12 weeks of age, 9 mice per group were fasted overnight (water was allowed ad libitum) to normalize blood glucose levels. During this time, the mice were placed on a warm pad. 18 Prior to F-FDG, animals were rehydrated with warm saline (10 mL / kg, sc). For PET scanning, approximately 15 MBq of 18 F-FDG. 18 20 minutes after F-FDG-injection, animals were anesthetized with isoflurane, and PET scanning was started 30 minutes after injection. A single 15-minute PET scan of the head region was performed using BioPET small animal PET / CT (Sedecal, Madrid, Spain), followed by CT imaging of the same region. During imaging, the animal's body temperature and respiration were monitored (SA Instruments Inc., NY, USA) and maintained between +37°C and 70-100 bpm, respectively.

[0283] Images were reconstructed using the 3D OSEM algorithm with CT-based attenuation correction. Image analysis was performed using PMOD software (v 3.7, PMOD Technologies LLC, Zürich, Switzerland). 18 F-FDG uptake was expressed as standardized uptake value (SUV).

[0284] Euthanasia and Sample Collection - At 13 weeks of age, 9 mice per group were euthanized by deep anesthesia with sodium pentobarbital (180 mg / kg). The remaining mice were euthanized, and no samples were collected except for tail and ear samples. Terminal blood samples (as much as possible) were collected into syringes by cardiac puncture. Whole blood was placed in Li-Hep tubes at room temperature and used immediately for the preparation of PBMCs. The whole brain was collected and freshly frozen in liquid nitrogen and stored at -80°C. Blood was also collected from additional animals as staining controls for flow cytometry determinations (n=3 additional animals per day). Tail and ear samples were collected for possible re-genotyping after the study.

[0285] PBMC Extraction - Before starting PBMC isolation, store whole blood (approximately 400-500 μL) at room temperature (RT). PBMCs were isolated using 15 mL Sepmate tubes (SepMate-15 IVD catalog 85415, Stemcell technologies) according to the manufacturer's instructions. Sepmate is a tube that facilitates the isolation of PBMCs by density gradient centrifugation using density gradient media (Lymphoprep, catalog 07801, Stemcell technologies). Dilute the blood sample 1:1 into sterile Dulbecco's phosphate buffered saline containing 2% fetal bovine serum (DPBS + 2% FBS). Place 4.5 mL of density gradient media (Lymphoprep, catalog 07801, Stemcell technologies) in a 15 mL Sepmate tube and gently add the diluted blood sample by layering on the density gradient media, ensuring that the layers are not mixed before centrifugation. Centrifuge the sample at 1200g for 15 minutes at room temperature (the centrifuge brake should be on). PBMC is poured into a new tube from the Sepmate tube. PBMC is washed with 1mL sterile DPBS+2% FBS (catalog number 07905, Stemcell technologies), gently mixed and centrifuged at 300g for 10 minutes at +4°C (brake for forming a precipitate). The supernatant is removed, and 1mL DPBS+2% FBS is added, the cells are resuspended and centrifuged again. The supernatant is carefully removed. The remaining cell pellet is gently resuspended in 250 μL DPBS+2% FBS to obtain a clear suspension, and the tube is placed on ice. For cell counting, 10 μL samples are taken and 89 μL DPBS is added. Just before measurement, 1 μL of propidium iodide is added, and cell number and viability are determined by MACSquant analyzer 10 flow cytometers. An appropriate number of cells are divided equally into mitochondrial membrane potential (JC-1 dye), mitochondrial ROS (MitoSox) and ATP (Cell Titer Glow) analysis.

[0286] Biomarker assays - JC-1, Mitosox, and Assay kit to process PBMCs.

[0287] Immediately after staining, cells were analyzed using a MACSQuant Analyzer 10 (Miltenyi Biotec) and Cytation 3 (Celltiterglow). FlowJo software was used to further analyze JC-1 and Mitosox cell population data. Repeats were performed when sufficient samples were available.

[0288] Table 1 - Biomarkers and other reagents

[0289]

[0290] Mitochondrial ROS: MitoSOX Assay - MitoSOX TM MitoSOX Red is a novel fluorescent dye that specifically targets mitochondria in living cells. TM Oxidation of the red reagent by superoxide produces red fluorescence and can be used to reliably determine relative differences in mitochondrial ROS formation in cells. The assay control, heat-stressed cells (+63°C, 5 minutes) mixed 1:1 with healthy cells, was used as a positive control for reactive oxygen species formation.

[0291] MitoSOX TM Red reagent (Catalog M36008 ThermoFisher Scientific) was used according to the manufacturer's instructions.

[0292] Short name of the program :

[0293] 1. Preparation of 5 μM MitoSOX TM Reagent working solution. Dilute 5 mM MitoSOX in HBSS / Ca / Mg or appropriate buffer. TM Reagent stock solution (prepared above) to prepare 5 μM MitoSOX TM Reagent working solution. Note: MitoSOX TM The concentration of the reagent working solution should not exceed 5 μM. Concentrations above 5 μM can produce cytotoxic effects, including altered mitochondrial morphology and redistribution of fluorescence to the nucleus and cytoplasm.

[0294] 2. Plate 50,000 cells / well in DPBS in a multi-well plate suitable for flow cytometry.

[0295] 3. Spin cells at 250G for 5 minutes and remove supernatant.

[0296] 4. Add 200 μL of 5 μM MitoSOX TM Reagent working solutions were applied to cells.

[0297] 5. Incubate the cells at 37°C for 10 minutes in the dark.

[0298] 6. Gently wash the cells 3 times with 100 μL of warm DPBS. Spin the cells at 250G for 5 minutes during each wash step.

[0299] 7. Immediate data collection: room temperature measurements in the dark. ROS signals in the PE channel were detected using a MACSQuant Analyzer 10 (Miltenyi Biotech).

[0300] Determination details :Main gating is performed to include all cell materials while omitting most debris. This is further gated by frontal scattering and side scattering to include only singlet cells, omitting any multicellular aggregates. For Mitosox positive staining, singlet populations are gated for Mitosox red positive cells (red on the x-axis) and SSC (side scattered light) (on the y-axis). Gating is set for cells with heat stress according to the Mitosox red positive gate.

[0301] ATP Levels: CellTiter-Glo Determination - The 2.0 assay provides a homogenous method to determine the number of viable cells in culture by quantifying the amount of ATP present, which indicates the presence of metabolically active cells.

[0302] Use Cell Viability Assay Catalog G9241 Promega according to the manufacturer's instructions.

[0303] Short name of the program :

[0304] 1. Before performing the assay, prepare and equilibrate

[0305] 2. Place 50,000 cells / well of a white wall luminescence appropriate plate in DPBS.

[0306] 3. Prepare control wells containing medium without cells to determine background luminescence.

[0307] 4. Add a volume of 5% PBS equal to the volume of cell culture medium present in each well. Reagents (e.g., for a 96-well plate, 100 μL of The reagent was added to 100 μL of culture medium containing cells).

[0308] 5. Mix the contents on an orbital shaker for 2 minutes to induce cell lysis (see Appendix for more information on mixing).

[0309] 6. Allow the plate to incubate at room temperature for 10 minutes to stabilize the luminescent signal.

[0310] 7. Luminescence was recorded using Cytation 3 (BioTek).

[0311] Determination details : The plate was placed in a Cytation 3 plate reader and the amount of ATP present was determined by reading the chemiluminescence level in each well. An assay control, heat-shocked cells mixed 1:1 with healthy cells (+63°C, 5 minutes), was used to reduce the number of metabolically active cells (reducing the level of ATP in the heat-shocked control cells).

[0312] Statistical analysis and graphical presentation of data

[0313] Data quality checks and validation are performed prior to further statistical analysis. During this process, potential outliers are identified and evaluated. Outliers are not removed from the data without clear reasons for removal (e.g., measurement errors identified in laboratory records).

[0314] The planned comparisons in this study are:

[0315] ● Vehicle-treated R6 / 2 group and WT group

[0316] ●Compound (Ia)-treated R6 / 2 group vs. vehicle-treated R6 / 2 group

[0317] The assumption of normality for each data set was based primarily on experience (eg, the data within the population were known to be approximately Gaussian) and observations during the validation phase.

[0318] The PBMC biomarker analyses performed in JC1, Mitosox, and Cell Titer Glow and compared in this study were:

[0319] ● Vehicle-treated R6 / 2 group and WT group

[0320] ●Compound (Ia)-treated R6 / 2 group vs. vehicle-treated R6 / 2 group

[0321] ● Determination of control and vehicle-treated R6 / 2 groups

[0322] Simple comparisons between two groups were performed using the unpaired Welch's t test or, when the assumptions of normality or lognormality were not met, by the Mann–Whitney U test.

[0323] Comparisons involving three or more groups were performed using one-way ANOVA followed by Dunnett's multiple comparison test (treatment vs. control). If significantly different SDs were detected by the Brown-Forsythe test, the hypothesis of equal SDs was rejected and Welch's ANOVA followed by Dunnett's T3 multiple comparison test was used. The nonparametric counterpart was the Kruskal-Wallis test followed by Dunn's multiple comparison test.

[0324] All values ​​are presented as mean ± standard error of the mean. If there are two or more comparisons per family, multiple adjusted P values ​​are presented. All statistical analyses were performed with a significance level of α = 0.05 using GraphPad Prism (version 8.3, GraphPad Software, Inc., San Diego, CA) or the R statistical software environment (R: A language and environment for statistical computing; R Core Team / R Foundation for Statistical Computing; Vienna, Austria; 2019; available online at R-project.org).

[0325] result

[0326] Body weight - Effects of long-term administration of compound (Ia) (0.5 mg / kg or 5 mg / kg, ip) on body weight of wild-type and R6 / 2 mice Figure 2 There were no significant differences in body weight between the different groups of R6 / 2 mice (p>0.05, mixed effects model (REML)) ( Figure 2 ).

[0327] A total of 15 R6 / 2 mice died before the scheduled endpoint. For those mice that died before 12 weeks of imaging, new replacement mice were enrolled and dosing began at the same age as the mice originally enrolled in the study.

[0328] Rotarod-Effects of chronic administration of compound (Ia) (0.5 mg / kg or 5 mg / kg, ip) on the latency to fall from the rotarod in 10-week-old wild-type and R6 / 2 mice Figure 3 R6 / 2 mice treated with 5 mg / kg compound (Ia) had increased latency in the rotarod compared to vehicle-treated R6 / 2 mice (*p<0.05, one-way ANOVA) ( Figure 3 ).

[0329] Open field; total distance traveled - Effects of chronic administration of compound (Ia) (0.5 mg / kg or 5 mg / kg, ip) on the total distance traveled in an open field by 12-week-old wild-type and R6 / 2 mice. Figure 4Compared with vehicle-treated R6 / 2 mice, R6 / 2 mice treated with 5 mg / kg compound (Ia) traveled a longer total distance (*p<0.05, one-way ANOVA) ( Figure 4 )

[0330] Open field; total feeding frequency - Effects of chronic administration of compound (Ia) (0.5 mg / kg or 5 mg / kg, ip) on the total feeding frequency of 12-week-old wild-type and R6 / 2 mice in an open field Figure 5 There were no significant differences in total feeding frequency between the different groups of R6 / 2 mice (p>0.05, one-way ANOVA) ( Figure 5 ).

[0331] 18 F-FDG-PET Assay - Compared to WT vehicle, at both 8 and 12 weeks of age, F-FDG-PET was observed in the R6 / 2 vehicle group in all brain regions except the central gray matter and cerebellum. 18 Decreased F-FDG uptake ( Figure 6 ). However, genotype differences were only statistically significant in the cortex at 12 weeks of age (p < 0.05, mixed effects model (REML)) ( Figure 6 Treatment with compound (Ia) increased the expression of β-catenin in various brain regions of R6 / 2 mice. 18 F-FDG uptake. However, statistically significantly higher radioactivity was observed in the olfactory bulb only in R6 / 2 mice treated with 5 mg / kg Compound (Ia) at 12 weeks of age compared to vehicle-treated R6 / 2 mice (p<0.05, mixed effects model (REML)) ( Figure 6 ).

[0332] MitoSOX Assay - Mitosox flow cytometry results showed no significant difference in ROS formation between WT+Vehicle or R6 / 2+Vehicle or between R6 / 2+Vehicle and R6 / 2+Compound (Ia) (0.5mg / kg / 5mg / kg) treated groups, indicating that mitochondrial ROS formation was at similar levels between the groups ( Figure 7 Heat shock induced significant ROS production in mitochondria, as measured by a significant increase in the red fluorescent cell population in the heat shock group when compared to R6 / 2+vehicle treated mice ( Figure 7 ).

[0333] Cell Titer Glow Results (ATP Assay) - Cell Titer Glow showed no significant differences in ATP levels between WT+Vehicle and R6 / 2+Vehicle or between R6 / 2+Vehicle and R6 / 2+Compound (Ia) (0.5 mg / kg / 5 mg / kg) treated groups, indicating that ATP levels were the same between the groups ( Figure 8 The control, heat stressed cells were assayed and showed a significant decrease in ATP levels when compared to R6 / 2+ vehicle treated mice ( Figure 8 ).

[0334] in conclusion

[0335] R6 / 2 mice (Huntington's disease model) were treated once daily with compound (Ia) (0.5 mg / kg or 5 mg / kg; ip, QD) starting at 4 weeks of age. The mice were subjected to various behavioral tests to evaluate the characteristic motor deficits and progressive phenotype of R6 / 2 mice. In addition, the compound (Ia) was used to evaluate the characteristic motor deficits and progressive phenotype of R6 / 2 mice. 18 F-FDG PET imaging was used to evaluate the potential effects of compound (Ia) on factors affecting brain metabolism. The body weight of R6 / 2 mice was not significantly affected by treatment with compound (Ia), although the body weight of mice treated with a 5 mg / kg dose remained at a non-significantly higher level compared to vehicle-treated R6 / 2 mice. Similarly, R6 / 2 mice treated with a higher 5 mg / kg dose showed significant improvements in the rotarod and increased horizontal activity in the open field at 12 weeks of age. 18 F-FDG PET imaging showed increased 18 F-FDG uptake was also observed in various other brain regions. 18 There was a trend toward increased F-FDG uptake; however, the overall Anova did not reach statistical significance.

[0336] Mitosox flow cytometry results showed no significant differences in ROS formation between vehicle-treated R6 / 2 mice and wild-type mice or between different treatment groups of R6 / 2 mice, indicating that mitochondrial ROS formation was at similar levels between groups. Compared with wild-type mice, heat shock induced significant ROS production in mitochondria in vehicle-treated R6 / 2 mice, as measured by the significant increase in red fluorescent cell populations in the heat shock group. Cell Titer Glow showed no significant differences in ATP levels between different genotypes or different R6 / 2 groups, indicating that ATP levels were the same between groups. ATP level determination control, i.e., heat-stressed cells, showed that ATP levels were significantly reduced in R6 / 2 mice compared with wild-type mice.

[0337] In summary, the data highlight trends and metabolic biomarker improvements associated with administration of compound (Ia) to R6 / 2 mice (a mouse model of Huntington's disease). Therefore, these results indicate that compositions comprising compound (Ia) can be used in methods for treating, preventing, inhibiting, ameliorating Huntington's disease and / or HTT proteinopathy or delaying its onset.

[0338] Equivalent

[0339] The technology of the present invention is not limited to the specific embodiments described in this application, which are intended to be separate illustrations of a single aspect of the technology of the present invention. Without departing from the spirit and scope of the technology of the present invention, many modifications and changes can be made to the technology of the present invention, which will be obvious to those skilled in the art. According to the above description, in addition to those methods and devices listed herein, functionally equivalent methods and devices within the scope of the technology of the present invention will be obvious to those skilled in the art. Such modifications and changes are intended to fall within the scope of the appended claims. This technology is only limited by the terms of the appended claims and the full range of equivalents enjoyed by such claims. It should be understood that the technology of the present invention is not limited to a particular method, reagent, compound composition or biological system, and of course, the particular method, reagent, compound composition or biological system can change. It should also be understood that the terms used herein are only for the purpose of describing a particular embodiment and are not intended to be limited.

[0340] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0341] As will be understood by those skilled in the art, for any and all purposes, particularly in providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily considered to fully describe and enable the same range to be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be easily divided into a lower third, a middle third, and an upper third, etc. As will be understood by those skilled in the art, all languages, such as "up to", "at least", "greater than", "less than", etc., include the numbers listed, and refer to the ranges that can be subsequently decomposed into sub-ranges as described above. Finally, as will be understood by those skilled in the art, the range includes each individual member. Therefore, for example, a group with 1-3 cells refers to a group with 1, 2, or 3 cells. Similarly, a group with 1-5 cells refers to a group with 1, 2, 3, 4, or 5 cells, etc.

[0342] All patents, patent applications, provisional applications, and publications mentioned or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

[0343] Other embodiments are set forth in the dependent claims.

Claims

1. A method for treating, preventing, inhibiting, ameliorating or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide mimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

2. The method of claim 1, wherein the subject has been diagnosed with Huntington's disease.

3. The method of claim 1 or 2, wherein the peptide mimetic is administered to the subject daily for 2 weeks or more, for 12 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more.

4. The method of any one of the preceding claims, wherein the peptide mimetic is administered daily for the remainder of the subject's life.

5. A method according to any of the preceding claims, wherein the treatment, prevention, inhibition or improvement comprises treating, preventing, inhibiting or ameliorating one or more signs or symptoms of Huntington's disease or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggression, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

6. The method according to any one of the preceding claims, wherein the subject is a mammal.

7. The method of claim 6, wherein the mammalian subject is a human.

8. The method according to any one of claims 1 to 7, wherein the peptide mimetic is administered orally.

9. The method according to any one of claims 1 to 7, wherein the peptide mimetic is administered subcutaneously.

10. The method of any one of claims 1 to 7, wherein the peptide mimetic is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ocularly, intrathecally, intracerebroventricularly, by iontophoresis, transmucosally, intravitreally, or intramuscularly.

11. The method of any one of the preceding claims, further comprising administering to the subject an additional treatment, either separately, sequentially or simultaneously.

12. The method of claim 11, wherein the additional treatment comprises administration of a therapeutic agent.

13. The method of claim 12, wherein the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) and (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (sodium valproate) and (lamotrigine).

14. The method of claim 13, wherein the combination of treatment with the peptide mimetic and the additional therapeutic agent has a synergistic effect in treating Huntington's disease and / or HTT proteinopathy.

15. The method of any one of the preceding claims, wherein the pharmaceutically acceptable salt comprises tartrate, fumarate, monoacetate, diacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride, monotosylate, bistosylate, or tritosylate.

16. The method of any one of claims 1 to 14, wherein the peptide mimetic is formulated as a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

17. Use of a composition for the preparation of a medicament for treating, preventing, inhibiting, ameliorating or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof, wherein the composition comprises a therapeutically effective amount of a peptide mimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

18. The use according to claim 17, wherein the subject has been diagnosed with Huntington's disease.

19. The method of claim 17 or 18, wherein the drug is administered daily for 2 weeks or more, for 12 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more.

20. The use according to any one of claims 17 to 19, wherein the medicament is administered daily for the rest of the subject's life.

21. The use according to any one of claims 17 to 20, wherein the use of the drug for treating, preventing, inhibiting or improving includes treating, preventing, inhibiting or improving one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggressiveness, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, reduced organizational ability, disorientation, loss of cognitive ability and weight loss.

22. The use according to any one of claims 17 to 21, wherein the subject is a mammal.

23. The use according to claim 22, wherein the mammalian subject is a human.

24. The use according to any one of claims 17 to 23, wherein the medicament is formulated for oral administration.

25. The use according to any one of claims 17 to 23, wherein the medicament is formulated for subcutaneous administration.

26. The use according to any one of claims 17 to 23, wherein the medicament is formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ocular, intrathecal, intracerebroventricular, by iontophoresis, transmucosal, intravitreal or intramuscular administration.

27. The use according to any one of claims 17 to 26, wherein the medicament is used alone, sequentially or simultaneously with another treatment.

28. Use according to claim 27, wherein the additional treatment comprises the use of a therapeutic agent.

29. The use according to claim 28, wherein the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) and (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (sodium valproate) and (lamotrigine).

30. The use according to any one of claims 27 to 29, wherein the combination of the drug and the additional treatment has a synergistic effect in treating Huntington's disease and / or HTT proteinopathy.

31. The use according to any one of claims 17 to 30, wherein the pharmaceutically acceptable salt comprises tartrate, fumarate, monoacetate, diacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride, monotosylate, bistosylate or tritosylate.

32. The use according to any one of claims 17 to 30, wherein the peptide mimetic is formulated as a tri-HCl salt, a bis-HCl salt or a mono-HCl salt.

33. A peptide mimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof, for use in treating, preventing, inhibiting, ameliorating and / or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof.

34. The peptide mimetic for use according to claim 33, wherein the subject has been diagnosed with Huntington's disease.

35. The peptide mimetic for use according to claim 33 or 34, wherein the peptide mimetic is administered to the subject daily for 2 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more.

36. The peptide mimetic for use according to claim 33 or 34, wherein the peptide mimetic is administered daily for the rest of the subject's life.

37. A peptide mimetic for use according to any one of claims 33 to 36, wherein the treatment, prevention, inhibition or improvement comprises treating, preventing, inhibiting or improving one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, dysphagia, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggressiveness, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

38. The peptide mimetic for use according to any one of claims 33 to 37, wherein the subject is a mammal.

39. The peptide mimetic for use according to claim 38, wherein the mammalian subject is a human.

40. The peptide mimetic for use according to any one of claims 33 to 39, wherein the peptide mimetic is formulated for oral administration.

41. The peptide mimetic for use according to any one of claims 33 to 39, wherein the peptide mimetic is formulated for subcutaneous administration.

42. according to any one of claims 33 to 39, the peptide mimetic for use, wherein the peptide mimetic is formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ocular, intrathecal, intracerebroventricular, by iontophoresis, transmucosal, intravitreal or intramuscular administration.

43. The peptide mimetic for use according to any one of claims 33 to 42, wherein the peptide mimetic is used alone, sequentially or simultaneously with an additional treatment.

44. The peptide mimetic for use according to claim 43, wherein the additional treatment comprises the use of a therapeutic agent.

45. The peptide mimetic for use according to claim 44, wherein the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) and (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (sodium valproate) and (lamotrigine).

46. ​​The peptide mimetic for use according to any one of claims 33 to 45, wherein the combination of the peptide mimetic and the additional treatment has a synergistic effect for treating Huntington's disease and / or HTT proteinopathy.

47. A peptide mimetic for use according to any one of claims 33 to 46, wherein the pharmaceutically acceptable salt comprises tartrate, fumarate, monoacetate, diacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride, monotosylate, bistosylate or tritosylate.

48. The peptide mimetic for use according to any one of claims 33 to 46, wherein the peptide mimetic is formulated as a tri-HCl salt, a bis-HCl salt or a mono-HCl salt.

49. A formulation or medicament comprising a peptide mimetic such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof, for use in treating, preventing, inhibiting, ameliorating and / or delaying the onset of Huntington's disease and / or HTT proteinopathy in a subject in need thereof.

50. The formulation or medicament for use according to claim 49, wherein the subject has been diagnosed with Huntington's disease.

51. The formulation or medicament for use according to claim 49 or 50, wherein the formulation or medicament is administered to the subject daily for 2 weeks or more, for 24 weeks or more, for 36 weeks or more, for 48 weeks or more, or for 52 weeks or more.

52. The formulation or medicament for use according to claim 49 or 50, wherein the formulation or medicament is administered daily for the rest of the subject's life.

53. A formulation or medicament for use according to any one of claims 49 to 52, wherein the treatment, prevention, inhibition or improvement comprises treating, preventing, inhibiting or ameliorating one or more signs or symptoms of Huntington's disease and / or HTT proteinopathy, including stumbling, clumsiness, loss of coordination, loss of motor control, difficulty swallowing, difficulty speaking, loss of walking ability, personality changes, mood changes, apathy, irritability, aggressiveness, anger, depression, frustration, suicidal thoughts, difficulty concentrating, short-term memory loss, loss of initiative, decreased organizational ability, disorientation, loss of cognitive ability and weight loss.

54. The formulation or medicament for use according to any one of claims 49 to 53, wherein the subject is a mammal.

55. The formulation or medicament for use according to claim 54, wherein the mammalian subject is a human.

56. The formulation or medicament for use according to any one of claims 49 to 55, wherein the formulation or medicament is formulated for oral administration.

57. The formulation or medicament for use according to any one of claims 49 to 55, wherein the formulation or medicament is formulated for subcutaneous administration.

58. The formulation or medicament for use according to any one of claims 49 to 55, wherein the formulation or medicament is formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ocular, intrathecal, intracerebroventricular, by iontophoresis, transmucosal, intravitreal or intramuscular administration.

59. The formulation or medicament for use according to any one of claims 49 to 58, wherein the formulation or medicament is used alone, sequentially or simultaneously with an additional treatment.

60. The formulation or medicament for use according to claim 59, wherein the additional treatment comprises the use of a therapeutic agent.

61. The formulation or medicament for use according to claim 60, wherein the therapeutic agent is selected from the group consisting of: (Tetrabenazine), (deutetrabenazine), (Risperidone), (haloperidol), (Chlorpromazine), Benzodiazepine Drugs such as (clonazepam) and (diazepam), (escitalopram), (Fluoxetine), (sertraline), (quetiapine), (carbamazepine), (sodium valproate) and (lamotrigine).

62. The formulation or medicament for use according to any one of claims 59 to 61, wherein the combination of the peptide mimetic and the additional treatment has a synergistic effect for treating Huntington's disease and / or HTT proteinopathy.

63. The formulation or medicament for use according to any one of claims 49 to 62, wherein the pharmaceutically acceptable salt comprises tartrate, fumarate, monoacetate, diacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, trifluoroacetate, monohydrochloride, dihydrochloride, trihydrochloride, monotosylate, bistosylate or tritosylate.

64. The formulation or medicament for use according to any one of claims 49 to 62, wherein the peptide mimetic is formulated as a tri-HCl salt, a bis-HCl salt, or a mono-HCl salt.

Images