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WO2016040780A1 - Composés tricycliques à liaison animométhyle et méthyloxy utilisés en tant qu'inhibiteurs de l'agrégation de protéines - Google Patents

Composés tricycliques à liaison animométhyle et méthyloxy utilisés en tant qu'inhibiteurs de l'agrégation de protéines Download PDF

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WO2016040780A1
WO2016040780A1 PCT/US2015/049648 US2015049648W WO2016040780A1 WO 2016040780 A1 WO2016040780 A1 WO 2016040780A1 US 2015049648 W US2015049648 W US 2015049648W WO 2016040780 A1 WO2016040780 A1 WO 2016040780A1
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compound
disease
formula
pharmaceutically acceptable
independently
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Wolfgang Wrasidlo
Emily M. Stocking
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Neuropore Therapies Inc
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Neuropore Therapies Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to certain aminomethyl- and methyloxy-linked tricyclic derivatives, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer' s disease, Lewy body disease, Parkinson's disease dementia, fronto-temporal dementia, Huntington' s Disease, amyotrophic lateral sclerosis, and multiple system atrophy.
  • neurodegenerative diseases such as Parkinson's disease, Alzheimer' s disease, Lewy body disease, Parkinson's disease dementia, fronto-temporal dementia, Huntington' s Disease, amyotrophic lateral sclerosis, and multiple system atrophy.
  • Neurodegenerative disorders of the aging population such as Alzheimer' s disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD), affect over 20 million people in the United States and European Union alone and rank among the top causes of death for the elderly.
  • a common feature among these neurological disorders is the chronic accumulation of proteins into neurotoxic aggregates.
  • Each disease is characterized by the specific neuronal populations that are affected, the particular protein aggregates that are involved, and the clinical features that result from the neuronal degeneration.
  • ⁇ protein is a 38-42 amino acid (aa) transmembrane peptide derived from the cleavage of the amyloid precursor protein (APP).
  • APP amyloid precursor protein
  • aa 38-42 amino acid
  • APP amyloid precursor protein
  • a number of other proteins may accumulate in the brains of patients with AD, such as Tau, TDP43, and a-synuclein.
  • the cognitive impairment in patients with AD is closely associated with synaptic loss in the neocortex and limbic systems and increasing levels of ⁇ may contribute to this synaptic loss.
  • fibrillar aggregates are the main component of amyloid plaques, which are likewise useful diagnostic indicators for the neuropathological diagnosis of AD.
  • the fibrillar aggregates in the plaques are not directly toxic and may even represent an endogenous mechanism to isolate oligomers.
  • Inhibitors of ⁇ aggregates have been described, including relatively specific and non-specific ⁇ inhibitors (Broersen, K. et al. Alzheimers Res. Ther. 2010, 2, 12). These compounds include ⁇ "breakers," small peptides, phenolic compounds, and flavonoids such as curcumin. Such compounds tend to prevent amyloid formation and fibrillation and to display anti-oxidant properties. Most of the compounds of this type have less specific modes of action and target higher molecular weight aggregates and fibrils rather than the initial stages of the oligomerization process. Because evidence indicates the ⁇ oligomers rather than the fibrils are the toxic species, compounds that target these early aggregation processes in a specific manner would be useful as potential new therapies for AD and related conditions.
  • Various other neurodegenerative diseases involve the accumulation of neurotoxic protein-based aggregates.
  • IPD idiopathic Parkinson's disease
  • LPD dementia with Lewy bodies
  • PPD Parkinson's disease dementia
  • MSA multiple system atrophy
  • the neurotoxic aggregates are composed of a-synuclein (SYN), which is a synaptic protein that is intracellular under normal conditions.
  • SYN a-synuclein
  • FTD and amyotrophic lateral sclerosis (ALS) neurotoxic aggregates originate from other intracellular proteins such as tau, TDP-43, or SOD1.
  • AD amyotrophic lateral sclerosis
  • Additional diseases that are associated with the accumulation of aggregated ⁇ include peripheral amyloidosis, Lewy body dementia, inclusion body myositis, and cerebral amyloid angiopathy.
  • misfolded and/or aggregated proteins anchor to the various cell membrane structures. Binding of the misfolded or aggregated molecules to the plasma membrane or the membranes of organelles ⁇ e.g., mitochondria or lysosomes) may interfere with protein transcription, autophagy, mitochondrial function, and pore formation.
  • neurotoxic SYN aggregates and interacts with lipids in cell membranes, by a specific portion of the c-terminal region of the synuclein protein. Compounds that bind to this region can inhibit protein-protein or protein- lipid interactions and can therefore be used to block neurotoxic SYN oligomerization and membrane interaction.
  • aggregated protein is released from the anchored subunit and propagates to adjacent cells. This cell-to-cell propagation of toxic protein aggregates may then underlie the anatomic progression of neurodegeneration and worsening of symptoms. Small molecule drugs that interact with the target proteins may limit release and/or propagation, and therefore reduce the neurotoxic effects of aggregated proteins.
  • the invention relates to a chemical entity of the following Formula (I):
  • Y is -NCR 1 )- or -0-;
  • Y 2 is -N(R 2 )- or -0-;
  • R 1 and R 2 are each independently H or C 1-4 alkyl
  • R 3 , R 5 , R 6 , and R 8 are each independently C 1 _ 4 alkyl, halogen, hydroxy, C 1 _ 4 alkoxy, cyano,
  • R 4 and R 7 are each independently H or C 1-4 alkyl
  • X 1 1 and X 2" are each independently N or CH; and A moiety is a 5-membered monocyclic cycloalkyl or heteroaryl ring, or a 5-, 6-, or 7-membered monocyclic heterocycloalkyl ring, wherein the cycloalkyl and heterocycloalkyl rings are optionally substituted with oxo;
  • the compound of Formula (I) is a compound selected from those species described or exemplified in the detailed description below, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • Pharmaceutical compositions according to the invention may further comprise a pharmaceutically acceptable excipient.
  • the invention is also a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the invention is directed to a method of treating a disease or medical condition associated with protein or peptide aggregation, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention is also directed at use of a compound of Formula (I) in the preparation of a medicament for the treatment of such diseases and medical conditions, and the use of such compounds and salts for treatment of such diseases and medical conditions.
  • the invention is directed to a method of treating a neurodegenerative disease or condition associated with protein or peptide aggregation comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention relates to a method of interfering with the accumulation of protein or peptide aggregates in a cell, or preventing, slowing, reversing, or inhibiting protein or peptide aggregation in a cell, comprising contacting the cell with an effective amount of at least one compound of Formula (I) or a salt thereof, and/or with at least one pharmaceutical composition of the invention, wherein the contacting is in vitro, ex vivo, or in vivo.
  • FIG. 1 shows the effect of Example 1 on the formation of amyloid fibrils at various test concentrations, as described in Biological Example 1.
  • FIG. 2 shows the analysis of 6el0 immunolabeling of Abeta-protein in neuropil of frontal cortex in non-tg and APP tg mice treated with either vehicle or Example 1 as described in Biological Example 3. Data are expressed as the corrected optical densities and shown as the group mean + SEM. ( p ⁇ 0.0001 vs. non-tg/vehicle control group; p ⁇ 0.01 vs. APP tg/vehicle group).
  • FIG. 3 shows the hippocampal calbindin immunolabeling in the molecular layer of the dentate gyrus as described in Biological Example 3.
  • Data are expressed as the corrected optical densities and shown as the group mean + SEM.
  • Y 1 is -NCR 1 )- and Y 2 is -N(R 2 )-.
  • one of Y and Y is -O- and the other is not -0-.
  • R 1 and R2 are each H. In other embodiments, R 1 and R2 are each
  • R 1 and R2 are each methyl. In other embodiments, one of R 1 and R is H and the other is methyl or is C 1 _ 4 alkyl.
  • R 3 , R 5 , R 6 , and R 8 are each independently C 1-4 alkyl. In other embodiments, R 3 , R 5 , R 6 , and R 8 are each independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In other embodiments, R 3 , R 5 , R 6 , and R 8 are each methyl.
  • R 4 and R 7 are each independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R 4 and R 7 are the same. In some embodiments, R 4 and R 7 are each H. In other embodiments, R 4 and R 7 are each C 1-4 alkyl. In some embodiments, one of R 4 and R 7 is H and the other is C 1-4 alkyl or is methyl.
  • X 1 and X2 are each N. In other embodiments, X 1 and X2 are each
  • A is a cyclopentyl or cyclopentadienyl ring. In other embodiments, A is a 5-membered heteroaryl ring. In other embodiments, A is a 5-membered heterocycloalkyl ring, optionally substituted with oxo. In other embodiments, A is a 6- or 7- membered heterocycloalkyl ring, each optionally substituted with oxo.
  • A is tetrahydrofuran, tetrahydrothiophene, pyrrolidine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-triazole, pyrrolidine-3- one, pyrrolidine-2-one, tetrahydropyran, 1,4-dioxane, morpholine, oxathiane, azepane, oxepane, oxazolidin-4-one, or 1,3,4-oxazolidine.
  • A is tetrahydrofuran, furan, tetrahydrothiophene, or pyrrolidinone. In still other embodiments, A is tetrahydrofuran. In still other embodiments, A is a 5-membered ring with one heteroatom ring member, wherein the ring is optionally substituted with oxo. In still other embodiments, A is tetrahydrofuran, furan, or thiophene.
  • the invention relates to a chemical entity of the following Formula (II):
  • R 1 i 8 0 and X 1 1" 2" are defined as for Formula (I) or for the representative embodiments described herein;
  • W is O, S, NH, or C(O);
  • heteroaryl ring or a 5-, 6-, or 7-membered monocyclic heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with oxo;
  • the invention relates to a chemical entity of the following Formula (III):
  • R 1 i 8 0 and X 1 1" 2" are defined as for Formula (I) or for the representative embodiments described herein;
  • W is O, S, NH, or C(O);
  • Y and Z are each independently CH, CH 2 , N, NH, O, S, or C(O), as allowed by valency;
  • the invention relates to a chemical entity of the following Formula (IV):
  • R 1 i 8 0 and X 1 1" 2" are defined as for Formula (I) or for the representative embodiments described herein;
  • W is O, S, NH, or C(O);
  • Y and Z are each independently CH, N, O, or S;
  • the invention relates to a chemical entity of the following Formula (V):
  • R 1 i 8 0 and X 1 1" 2" are defined as for Formula (I) or for the representative embodiments described herein;
  • W is O, S, NH, or C(O);
  • Y and Z are each independently CH 2 , NH, O, S, or C(O);
  • the invention is directed to a compound selected from the group consisting of:
  • alkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain.
  • alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • alkoxy refers to an alkyl group as defined above, bonded to an oxygen atom.
  • the alkoxy group is connected to the parent structure via the oxygen atom.
  • amino refers to an -NH 2 group, or a mono- or dialkylamino group.
  • cycloalkyl refers to a saturated or partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle.
  • Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:
  • heteroaryl refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • heteroaryl groups include the following entities, in the form of properly bonded moieties:
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • halo' represents chloro, fluoro, bromo, or iodo.
  • oxo represents a carbonyl oxygen.
  • a cyclopentyl substituted with oxo is cyclopentanone.
  • heterocycloalkyl refers to a saturated or partially saturated, monocyclic or bicyclic (fused, bridged, or spiro) ring system that includes carbon atoms and at least one heteroatom (N, O, S) ring member.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency- allowed position on the system.
  • Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof.
  • any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, U C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P,
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
  • PET and SPECT studies may be performed as described, for example, by Brooks, D.J., "Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development," NeuroRx 2005, 2(2), 226-236, and references cited therein. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • deuterium i.e., H
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • C 1-3 refers independently to embodiments that have one carbon member (CO, embodiments that have two carbon members (C 2 ), and embodiments that have three carbon members (C 3 ).
  • any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • reference to disubstituent -A-B-, where A ⁇ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
  • the invention also includes pharmaceutically acceptable salts of the compounds represented by Formula (I), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
  • a "pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulf
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or
  • an inorganic acid such as hydrochloric acid, hydrobromic acid
  • the invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I), and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the present invention also relates to pharmaceutically active metabolites of compounds of Formula (I), and uses of such metabolites in the methods of the invention.
  • a "pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res.
  • compositions comprising the compounds described herein may further comprise one or more pharmaceutically- acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents.
  • pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.
  • compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions.
  • compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • the compounds of the invention may be formulated to yield a dosage of, e.g., from about 0.01 to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 to about 10 mg/kg daily.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethyl
  • the inventive compositions may be formulated for rectal administration as a suppository.
  • parenteral use including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 ⁇ g/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
  • the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration.
  • the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery.
  • treat and treatment encompass both “preventative” and “curative” treatment.
  • Preventative treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom.
  • “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • subject refers to a mammal in need of such treatment, such as a human.
  • Exemplary neurodegenerative diseases that are characterized by protein aggregation include Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease dementia, multiple system atrophy, amyotrophic lateral sclerosis, and Huntington's disease.
  • exemplary neurodegenerative diseases are those that are characterized by aggregation of amyloid beta.
  • amyloid aggregation diseases that are characterized by amyloid aggregation include peripheral amyloidosis, inclusion body myositis, cerebral amyloid angiopathy, amyloid neuropathy, sensorimotor polyneuropathy, carpal tunnel syndrome, autonomic neuropathy, familial amyloid polyneuropathy, primary light chain amyloidosis, and dialysis-related amyloidosis.
  • the compounds and pharmaceutical compositions of the invention specifically target a-synuclein, ⁇ -amyloid, and/or tau protein aggregates.
  • these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit aggregation of a-synuclein, ⁇ -amyloid, and/or tau proteins, and are used in methods of the invention to treat degenerative neurological diseases related to or caused by aggregation, e.g., such as aggregation of a-synuclein, ⁇ -amyloid, and/or tau proteins.
  • the methods of the invention target neurodegenerative diseases associated with aggregation of ⁇ -synuclein, ⁇ - amyloid, and/or tau protein.
  • methods of treatment target Parkinson's disease, Alzheimer's disease, Lewy body disease, or multiple system atrophy.
  • the compounds, compositions, and method of the present invention are also used to mitigate deleterious effects that are secondary to protein aggregation, such as neuronal cell death.
  • the compounds, compositions, and methods of the invention are used to target ⁇ aggregation. While the invention is not limited by any particular mechanism of action, ⁇ aggregation is thought to be caused by a mis-folding of the protein early in the disease process, which permits formation of abnormal protein multimers. As the number of monomer unites increases, the aggregated proteins can take on a pore-like shape, which can embed in the membrane of the neuron, disrupting ion flow and cell homeostasis.
  • an "effective amount” means an amount sufficient to reduce, slow the progression of, or reverse protein or peptide aggregation. Measuring the amount of aggregation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays.
  • the cell is preferably a nerve cell.
  • an "effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment.
  • Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject's health status, condition, and weight, and the judgment of the treating physician.
  • An exemplary dose is in the range of about 1 ⁇ g to 2 mg of active agent per kilogram of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/day.
  • the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
  • inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of neurodegenerative disorders.
  • additional active ingredients are those that are known or discovered to be effective in treating neurodegenerative disorders, including those active against another target associated with the disease, such as but not limited to, a) compounds that address protein misfolding (such as drugs which reduce the production of these proteins, which increase their clearance or which alter their aggregation and/or propagation); b) compounds that treat symptoms of such disorders (e.g., dopamine replacement therapies); and c) drugs that act as neuroprotectants by complementary mechanisms (e.g., those targeting autophagy, those that are anti-oxidants, and those acting by other mechanisms such as adenosine A2A antagonists).
  • complementary mechanisms e.g., those targeting autophagy, those that are anti-oxidants, and those acting by other mechanisms such as adenosine A2A antagonists.
  • compositions and formulations of the invention can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for a degenerative neurological disease related to or caused by protein aggregation, e.g., synuclein, beta-amyloid and/or tau protein aggregation, e.g., Parkinson's disease, Alzheimer's Disease (AD), Lewy body disease (LBD) and multiple system atrophy (MSA), or related symptoms or conditions.
  • the pharmaceutical compositions of the invention may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
  • additional active agents may be antibiotics (e.g., antibacterial or bacteriostatic peptides or proteins), e.g., those effective against gram positive or negative bacteria, fluids, cytokines, immunoregulatory agents, anti-inflammatory agents, complement activating agents, such as peptides or proteins comprising collagen-like domains or fibrinogen-like domains (e.g., a ficolin), carbohydrate -binding domains, and the like and combinations thereof.
  • antibiotics e.g., antibacterial or bacteriostatic peptides or proteins
  • cytokines e.g., those effective against gram positive or negative bacteria
  • cytokines e.g., those effective against gram positive or negative bacteria
  • cytokines e.g., those effective against gram positive or negative bacteria
  • immunoregulatory agents e.g., those effective against gram positive or negative bacteria
  • anti-inflammatory agents e.g., those effective against gram positive or negative bacteria
  • complement activating agents
  • Additional active agents include those useful in such compositions and methods include dopamine therapy drugs, catechol- O-methyl transferase (COMT) inhibitors, monamine oxidase inhibitors, cognition enhancers (such as acetylcholinesterase inhibitors or memantine), adenosine 2A receptor antagonists, beta-secretase inhibitors, or gamma-secretase inhibitors.
  • dopamine therapy drugs catechol- O-methyl transferase (COMT) inhibitors, monamine oxidase inhibitors, cognition enhancers (such as acetylcholinesterase inhibitors or memantine), adenosine 2A receptor antagonists, beta-secretase inhibitors, or gamma-secretase inhibitors.
  • CCT catechol- O-methyl transferase
  • monamine oxidase inhibitors such as acetylcholinesterase inhibitors or memantine
  • adenosine 2A receptor antagonists such as
  • At least one compound of the present invention may be combined in a pharmaceutical composition or a method of treatment with one or more drugs selected from the group consisting of: tacrine (Cognex ® ), donepezil (Aricept ® ), rivastigmine (Exelon ® ), galantamine (Reminyl ® ), physostigmine, neostigmine, Icopezil (CP- 118954, 5,7- dihydro-3-(2-(l-(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrrolo-[3,2-f]-l,2-benzisoxazol-6-one maleate), ER- 127528 (2-fluoro-2-((l-((3-fluorophenyl)methyl)-4-piperidinyl)methyl)-2,3- dihydro-5,6-dimethoxy-lH-inden-l-one hydrochloride), zanapezil (TAK
  • Such a combination may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound.
  • the additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition.
  • the additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention.
  • Compounds of Formula (I) may be prepared according to Scheme A.
  • Dicarbaldehydes Al are commercially available or prepared according to known methods.
  • Reductive amination of compounds Al with at least two equivalents of a suitably substituted amino-pyridine or amino-pyrazine provides compounds of Formula (I) where Y 1 and Y 2 are each NH.
  • bis-aminomethyl substituted compounds A2 may be used to displace a leaving group such as chloride from a suitably substituted chloro-pyridine or chloro-pyrazine to provide compounds of Formula (I) where Y 1 and Y 2 are each NH.
  • Alkylation of one or both amino groups yields additional variants where R 1 and/or R 2 are C 1 _ 4 alkyl.
  • Compounds of Formula (I) may also be prepared according to Scheme B. Dicarbaldehydes Al are reduced to the corresponding diols Bl.
  • the alcohol groups are activated and displaced with suitably substituted aminopyridines or aminopyrazines to generate compounds of Formula (I) in which Y 1 and Y2 are -N(R 1 )- and -N(R 2 ), respectively.
  • the activated groups (such as a mesylate or tosylate) may be displaced with sodium azide, and the resulting azide reduced to form the corresponding primary amine.
  • the diol groups are used to displace a leaving group such as chloride from suitably substituted chloro-pyridines or chloro-pyrazines to yield compounds of Formula (I) in which Y 1 and Y 2 are each O.
  • a leaving group such as chloride
  • chloro-pyridines or chloro-pyrazines to yield compounds of Formula (I) in which Y 1 and Y 2 are each O.
  • one diol group is used in each type of reaction, to produce compounds in which one of Y 1 and Y 2 is -N(R), and the other is O.
  • Step 1 2-Di(oxiran-2-yl)ethane.
  • m-chloroperbenzoic acid 1235 g, 85% by wt, 6.09 mol
  • the mixture was stirred at rt for 18 h and water (2000 mL) was added.
  • the organic layer was separated, washed with aqueous 1 N KOH (4000 mL x 3), dried over Na 2 S0 4 , filtered and evaporated to give the title compound (240 g, 86%) as a colorless oil.
  • 1H NMR 400 MHz, CDC1 3
  • Step 3 Tetrahydrofuran-2,5-diyl)dimethanamine dihydrobromide.
  • a suspension of 2,2'-(2,5-dihydroxyhexane-l,6-diyl)diisoindoline-l,3-dione (350 g, 0.86 mol) in aqueous 48% HBr (2300 mL) was heated at 120 °C for 24 h, then the mixture was cooled to 4 °C, and the precipitate removed by filtration. The aqueous filtrate was washed with ether (500 mL x 3) and concentrated in vacuum to give the title compound (246 g, 98.4%) as a brown solid.
  • Step 5 Salt Formation.
  • Example 6 N,N'-(Furan-2,5-diylbis(methylene))bis(3,6-dimethylpyrazin-2-amine).
  • Example 7 N,N'-(Thiophene- -diylbis(methylene))bis(3,6-dimethylpyrazin-2-amine).
  • Triethylamine (0.89 mL) and methanesulfonyl chloride (0.40 mL) were added and the mixture was stirred for 1 h at 0 °C and then 1 h at rt.
  • the mixture was treated with satd. aq. NaHC0 3 and extracted with EtOAc (3 x).
  • the combined organic layers were dried over Na 2 S0 4 , filtered and evaporated to provide 657 mg of crude thiophene-2,5-diylbis(methylene) dimethanesulfonate.
  • Example 30 N-((5-(((3,6-Dimethylpyrazin-2-yl)oxy)methyl)furan-2-yl)methyl)-3,6- dimethylp yrazin-2-amine .
  • Step 1 (5-(((3,6-Dimethylpyrazin-2-yl)amino)methyl)furan-2-yl)methanol.
  • the title compound was obtained as a side-product from the preparation of Example 6.
  • Step 2 To a solution of 29.2 mg of (5-(((3,6-dimethylpyrazin-2-yl)amino)methyl)furan- 2-yl)methanol in 1.25 mL of DMF was added 181 mg of Cs 2 C0 3 and 17.5 ⁇ ⁇ of 3-chloro-2,5- dimethylpyrazine. The mixture was heated at 120 °C in a sealed tube with stirring for 20 h and then cooled and stirred at rt for an additional 12 h. The reaction mixture was diluted with brine and extracted with EtOAc (3 x). The combined organic layers were dried over Na 2 S0 4 , filtered and evaporated. The crude product was purified by preparative TLC to provide 9.4 mg of the title compound.
  • Example 31 N-((5-(((3,6-Dimethylpyrazin-2-yl)oxy)methyl)thiophen-2-yl)methyl)-3,6- dimethylpyrazin-2-amine .
  • the seeded fibrillation assay measures the time-dependent formation of amyloid fibrils from monomeric amyloid beta and protofibril seeds using thioflavin T (ThT).
  • ThT thioflavin T
  • the principle of this assay is that ThT has little fluorescence on its own or in the presence of protofibril or monomers but becomes highly fluorescent when bound to amyloid beta fibrils.
  • Amyloid beta protofibrils seeds were prepared from amyloid beta fibrils by sonication.
  • the initial amyloid beta fibrils were generated by incubating monomeric amyloid beta at 37 °C for 4 days in Tris buffered saline - TBS (20 mM Tris buffer, 0.9% sodium Chloride, pH 7.4).
  • a stock solution of 2 mg/mL amyloid beta fibrils (150 ⁇ ) was sonicated on ice using a probe type sonicator (amplitude 40, 20 cycles of 5 seconds on and 5 seconds off). Following sonication dynamic light scattering was used to confirm that the protofibrile seeds had an approximate diameter of 100 nM.
  • ThT fluorescence was determined (emission -450 nM and excitation - 485 nM). Standard curves were generated by measuring ThT fluorescence with different
  • Example 1 the time-dependent formation of amyloid fibrils was measured in the presence of increasing concentrations of Example 1. At concentrations as low as 50 nM, the test compound produced a marked reduction in the formation of amyloid fibrils from monomeric amyloid beta and amyloid beta protofibrils. Example 1 decreased the formation of aggregates of amyloid beta in a concentration-dependent manner ( Figure 1). This finding indicates that Example 1 can directly interact with amyloid beta monomers or oligomers to prevent further aggregation.
  • Ex. 1 in male C57BL/6 mice were studied following administration of a single intravenous, intraperitoneal, or oral dose.
  • a group of 81 male C57BL/6 mice (8-12 weeks old, weighing between 20 to 35 g) were divided into three groups with each group comprising 27 mice.
  • Animals in Group 1 (i.v.) and Group 2 (i.p.) were dosed with an Ex. 1 solution formulation at a dose of 10 mg/kg.
  • Animals in Group 3 (p.o.) were dosed with an Ex. 1 suspension formulation at a dose of 10 mg/kg.
  • Blood samples were collected at pre-dose, 0.08, 0.25, 0.5, 1, 2, 4, 8 and 24 h post dose (i.v.
  • mice were humanely euthanized by C0 2 asphyxiation and brain was collected at pre-dose, 0.08, 0.25, 0.5, 1, 2, 4, 8 and 24 h (Group land Group 2) and at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h (Group 3) post dose.
  • the brain samples were washed in ice-cold phosphate buffer saline (pH 7.4), gently dried on filter paper, weighed and placed in polypropylene tubes. Further brain samples were homogenized using phosphate buffer saline pH 7.4 and the total homogenate volume was thrice the brain weight. The samples were then stored below -70 °C until bioanalysis.
  • Example 1 The chemical, ADMET, and pharmacokinetic data for Example 1 as compared to the pharmacokinetic properties for Comparative Example 1 (CEl), N,N'-((lr,4r)-cyclohexane- l,4- diylbis(methylene))bis(3,6-dimethylpyrazin-2-amine):
  • Example 1 (1 month, 5 mg/kg; p.o.) administration would produce decreases in ⁇ -protein and improvements in markers of CNS integrity in a transgenic mouse model of AD.
  • Example 1 was prepared as a 1 mg/mL solution in a vehicle consisting of 0.9% sterile saline solution (pH adjusted to 3.5) and was administered in a volume of 0.1 mL per 20 grams of body weight by oral gavage (PO) injection. Subjects received a daily administration (MWF) of either vehicle or 5 mg/kg dose of test compound. Animals were weighed prior to treatment and evaluated daily for signs of toxicity with any treatment. On Day 30, all subjects received a final injection and then were euthanized and brain and blood samples were collected.
  • MPF daily administration
  • the buffer solution (pH 8.8) was comprised of 1.0 mM HEPES, 5.0 mM benzamidine, 2.0 mM 2-mercaptoethanol, 3.0 mM EDTA, 0.5 mM magnesium sulfate, and 0.05% sodium azide. The sample was then
  • Immunolabeling studies of ⁇ -protein were conducted using methods described by Pham et ah, FEBS J. 2010, 277(14), 3051-3067. Immunolabeling studies of neurodegeneration- relevant markers utilized commercially available antibodies including synaptophysin (1: 100, MAB5258, (Millipore, Temecula, CA), GFAP (1:500, MAB3402, (Millipore, Temecula, CA), and calbindin (1:500, C-8666, Sigma- Aldrich, St. Louis, MO)). All sections were processed simultaneously under the same conditions. Sections were imaged with a Zeiss 63X (N.A.
  • Example 1 reduced concentrations of amyloid beta protein in the cerebral cortex and improved hippocampal levels of calbindin.

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Abstract

La présente invention concerne certains composés tricycliques à liaison aminométhyle et méthyloxy, des compositions pharmaceutiques les contenant et leurs méthodes d'utilisation, notamment des méthodes pour prévenir, inverser, ralentir ou inhiber l'agrégation de protéines et des méthodes pour traiter des maladies qui sont associées à l'agrégation de protéines, notamment les maladies neurodégénératives telles que la maladie de Parkinson, la maladie d'Alzheimer, la maladie du corps de Lewy, la démence Parkinsonienne, la démence fronto-temporale, la maladie de Huntington, la sclérose latérale amyotrophique et l'atrophie multisystématisée.
PCT/US2015/049648 2014-09-11 2015-09-11 Composés tricycliques à liaison animométhyle et méthyloxy utilisés en tant qu'inhibiteurs de l'agrégation de protéines Ceased WO2016040780A1 (fr)

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WO2013134371A1 (fr) * 2012-03-06 2013-09-12 Neuropore Therapies, Inc. Procédés et composés pouvant être utilisés pour traiter les maladies neurodégénératives
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WO2013134371A1 (fr) * 2012-03-06 2013-09-12 Neuropore Therapies, Inc. Procédés et composés pouvant être utilisés pour traiter les maladies neurodégénératives
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JP2020503314A (ja) * 2016-12-23 2020-01-30 アクイナ ファーマシューティカルズ， インコーポレイテッド 化合物、組成物、および使用方法
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