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WO2019074898A1 - Désagrégation d'alpha-synucléine avec de petites molécules - Google Patents

Désagrégation d'alpha-synucléine avec de petites molécules Download PDF

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Publication number
WO2019074898A1
WO2019074898A1 PCT/US2018/054961 US2018054961W WO2019074898A1 WO 2019074898 A1 WO2019074898 A1 WO 2019074898A1 US 2018054961 W US2018054961 W US 2018054961W WO 2019074898 A1 WO2019074898 A1 WO 2019074898A1
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Prior art keywords
alkyl
synuclein
emoxypine
compound
substituted
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Inventor
Claude Nicolau
Jean-Marie Lehn
Youssef ATOINI
Renald THINARD
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Alsatech Inc
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Alsatech Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention relates, in part, to treatments of synucleinopathies.
  • Parkinsonism or Parkinsonian syndromes are a group of progressive, neurodegenerative disorders that can significantly impair one's quality of life. Notable features of these diseases are tremor at rest, rigidity, bradykinesia and postural instability. Parkinson's disease afflicts 4% of the population over 80 years old.
  • the pathophysiology of Parkinson's disease is characterized, in part, by a synucleinopathy characterized by the abnormal accumulation of alpha-synuclein protein into inclusions called Lewy bodies in the brain.
  • the distribution of the Lewy bodies throughout the brain varies from one individual to another but is often directly associated with the expression and degree of the clinical symptoms.
  • Parkinson's disease is mainly based on observation of clinical symptoms. Postmortem confirmation is required for a definitive diagnosis.
  • the most widely used treatment, especially at earlier stages, is the dopamine precursor, levodopa (L-DOPA).
  • L-DOPA levodopa
  • most of the drug is metabolized before to reach the blood brain barrier (BBB), causing a variety of side effects, including gastrointestinal effects (such as anorexia, nausea or vomiting), dyskinesia and psychiatric symptoms.
  • Parkinson's disease remains an incurable disease and no effective disease-modifying treatment has been discovered yet. Therefore, there remains a need for more effective therapies for diseases such as Parkinson's disease.
  • the present invention provides, in one aspect, a method for treating or preventing a synucleinopathy, comprising administering an effective amount of a compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3-hydroxy-6-methyl picolinate (MHP ester) or a related compound) to a subject in need thereof, wherein the method comprises disaggregation of a-synuclein.
  • the synucleinopathy is a condition characterized by Lewy bodies, e.g., Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy.
  • the compound of formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl
  • each R 14 is independently H or (C1-C6)alkyl
  • n 1 , 2, 3, 4, or 5;
  • R 11 is H, -OR 14 , or
  • R 13 is null; each R 14 is independently H or (C1-C6)alkyl; m is 1 or 2; Xi is C; X 2 is N; X 3 is C; and X 4 is C.
  • m is 1 or 2;
  • Xi is C;
  • X 2 is N;
  • X 3 is C; and
  • X 4 is C.
  • R 13 is H; each R 14 is independently H or (C1-C6)alkyl;
  • m is 1 or 2;
  • Xi is C;
  • X 2 is C;
  • X3 is C; and
  • X4 is C.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound of formula (la) is:
  • R 1 is H or substituted or unsubstituted (C1-C6)alkyl or substituted or unsubstituted (C1-C8)heteroalkyl
  • R 2 is H or OR 5 or substituted or unsubstituted (C1-C6)alkyl, wherein R 5 is H or substituted or unsubstituted (C1-C6)alkyl
  • A is CH or N or CR 3 or CR 4
  • B is CH or N or CR 3 or CR 4 ;
  • C is CH or N or CR 3 or CR 4 ;
  • D is CH or N or CR 3 or CR 4 ;
  • R 3 is substituted or unsubstituted (C1-C6)alkyl or substituted or unsubstituted (C1-C8)heteroalkyl or -S0 2 (OR 6 ) or -OP(0)(OR 6 )(OR 7 ) wherein R 6 is H or substituted or unsubstituted (C1-C6)alkyl and R 7 is H or substituted or unsubstituted (C1-C6)alkyl; R 4 is substituted or unsubstituted (C1-C6)alkyl; with the proviso that no more than one member selected from the group consisting of A, B, C, and D is CR 3 ; with the proviso that no more than one member selected from the group consisting of A, B, C, and D is CR 4 ; with the proviso that no more than two members selected from the group
  • R 1 is H.
  • R 2 is H or OH.
  • Formula (I) is with the proviso that A, B, C, and D are not N; or with the proviso that one member selected from the group consisting of A, B, C, and D is N.
  • A is CH; B is CR 3 ; C is CH; and D is CH; or A is CR 3 ; B is CH; C is N; and D is CR 4 .
  • R 3 is -S0 2 (OR 6 ) or alkyl substituted with -OP(0)(OR 6 )(OR 7 ).
  • R 3 is -SO2OH.
  • R 3 is alkyl substituted with -OP(0)(OH)(OH).
  • R 3 is -CH 2 OP(0)(OR 6 )(OR 7 ).
  • R 3 is -CH 2 OP(0)(OH)(OH).
  • R 4 is methyl or ethyl or propyl or isopropyl.
  • R 4 is methyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound of formula (lb) is N-(2-aminoethyl)
  • R 19 is H or (C1-C6)alkyl
  • each R 14 is independently H or (C1-C6)alkyl
  • n 1 , 2, 3, 4, or 5;
  • R 18 is H or -OR 14 ;
  • R 19 is H or (C1-C6)alkyl; each R 14 is independently H or (C1-C6)alkyl; and m is 1 or 2.
  • R 18 is H or -OR 14 ;
  • R 19 is H or (C1-C6)alkyl; each R 14 is independently H or (C1-C6)alkyl; and m is 1.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the method treats or prevents Parkinson's disease, selected from Idiopathic Parkinson's disease, Vascular parkinsonism, drug-induced parkinsonism, dementia with Lewy bodies, Inherited Parkinson's, Juvenile Parkinson's disease.
  • Parkinson's disease selected from Idiopathic Parkinson's disease, Vascular parkinsonism, drug-induced parkinsonism, dementia with Lewy bodies, Inherited Parkinson's, Juvenile Parkinson's disease.
  • the method provides about a 20%, or about a 30%, or about a 40%, or about a 50%, or about a 60%, or about a 70%, or about a 80%, or about a 90%, or about a 95%, or about a 100% reduction in a- synuclein aggregation relative to an untreated subject.
  • the method provides does not substantially dissolve aggregates of beta-amyloid.
  • FIG. 1 A-K shows spectrofluorometry results.
  • FIG 1 A shows a first assay results for emission intensity 1 min.
  • FIG. 1 B shows a first assay results for emission intensity 30min.
  • FIG. 1C shows a first assay results for emission intensity 1 h.
  • FIG 1 D shows a first assay results for emission intensity 24h.
  • FIG. 1 E shows a first assay shows results for emission intensity 72 hr.
  • FIG. 1 F is a second assay showing results for emission intensity 1 min.
  • FIG. 1G shows a second assay results for emission intensity 30min.
  • FIG. 1 H shows a second assay results for emission intensity 1 h.
  • FIG 11 shows a second assay results for emission intensity 24hr.
  • FIG. 1 J is a second assay showing results for emission intensity 48h.
  • FIG. 1 K is a second assay showing results for emission intensity 72h.
  • FIG. 2A-C shows a tabulation of the spectrofluorometry data of FIG. 1.
  • FIG. 2A is a bar graph showing a first pyridoxal phosphate (PLP) disaggregation assay.
  • FIG. 2B is a bar graph showing a second pyridoxal phosphate disaggregation assay and
  • FIG. 2C is a bar graph showing the percentage of a-synuclein aggregates.
  • FIG. 3A-H shows scanning electron microscopy results.
  • FIGs. 3A, 3C, 3E, and 3G show a-synuclein aggregates and
  • FIGs. 3B, 3D, 3F, and 3H show a-synuclein aggregates with PLP.
  • FIG. 4 is an image of a schematic representation showing the process for the "preventive measure” (top) and for the curative measure (bottom).
  • FIG. 6 is a bar graph showing the percentage of ⁇ -synuclein amyloid fibrils left after addition of emoxypine with r 200, from 1 minute to 6 days (144 hours).
  • the light-shaded bar represents a sample without emoxypine, i.e. with 100% of aggregates left.
  • SEM scanning electron microscope
  • the far left bar is "Control ThT” sample
  • the next bar is the "Control Tht + Emo” sample
  • the next bar is the "Aggregates + ThT” sample (without emoxypine)
  • the far right bar is the "Aggregates + ThT+Emo” sample (with emoxypine).
  • FIG. 9 is a bar graph showing the percentage of ⁇ -synuclein amyloid fibrils left after addition of emoxypine (r 100).
  • the light-shaded bar (far left) represents a sample without emoxypine, i.e. with 100% of aggregates left.
  • FIG. 11 is a bar graph showing the emission intensity of ThT, in the presence of ⁇ -synuclein amyloids fibrils, with and without emoxypine (r 50), from 1 minute to 6 days (144 hours).
  • the far left bar is "Control ThT” sample
  • the next bar is the "Control ThT + Emo” sample
  • the next bar is the "Aggregates + ThT” sample (without emoxypine)
  • the far right bar is the "Aggregates + ThT+Emo” sample (with emoxypine).
  • FIG. 12 is a bar graph showing the percentage of ⁇ -synuclein amyloid fibrils left after addition of emoxypine (r 50).
  • the light-shaded bar (far left) represents a sample without emoxypine, i.e. with 100% of aggregates left.
  • FIG. 14 is a bar graph showing the emission intensity of ThT, in the presence of a-synuclein amyloids fibrils, with and without emoxypine (r 20), from 1 minute to 6 days (144 hours).
  • the far left bar is "Control ThT” sample
  • the next bar is the “Control ThT + Emo” sample
  • the next bar is the “Aggregates + ThT” sample (without emoxypine)
  • the far right bar is the "Aggregates + ThT+Emo” sample (with emoxypine).
  • FIG. 15 is a bar graph showing the percentage of a-synuclein amyloid fibrils left after addition of emoxypine (r 20).
  • the light-shaded bar (far left) represents a sample without emoxypine, i.e. with 100% of aggregates left.
  • FIG. 16 is a bar graph showing the emission intensity of ThT, in the presence of ⁇ -synuclein amyloids fibrils, with and without emoxypine using the preventive method and at different concentrations of emoxypine.
  • the light-shaded bar (far left) represents a sample without emoxypine.
  • FIG. 17 is a bar graph showing the percentage of ⁇ -synuclein amyloid fibrils formed for the curative method using different emoxypine concentration.
  • the light-shaded bar (far left) represents a sample without emoxypine, i.e. with 100% of aggregates left.
  • FIG. 18A-F are images showing a schematic representation of peptide bond and multivalent derivatives of MHP- ester: FIG. 18A and FIG. 18B show single peptide bond linkage; FIG. 18C and FIG. 18D show divalent peptide bond derivatives; FIG. 18E and FIG. 18F show multivalent peptide bond derivatives.
  • FIG. 18A, FIG. 18C, and FIG. 18E are schematic representations of the systems.
  • the far left bar is "Control ThT” sample
  • the next bar is the "Control ThT + MHP ester” sample
  • the next bar is the “Aggregates + MHP ester” sample
  • the far right bar is the "Aggregates + ThT+ MHP ester” sample.
  • FIG. 20 is a bar graph showing the percentage of ⁇ -synuclein amyloid fibrils left after addition of MHP-ester with r200, from 1 minute to 6 days (144 hours).
  • the dark-shaded bar (far left) represents a sample without MHP-ester, i.e. with 100% of aggregates left.
  • FIG. 21A-E are SEM images of samples containing ⁇ -synuclein amyloid fibrils and MHP-ester.
  • FIG. 24A-C are SEM images of: FIG. 24A, TDP-43 aggregates; FIG. 24B, TDP-43 aggregates with lgG37; FIG. 24C TDP-43 with Irr IgG. Images involving TDP-43 and Fab37 could not be recorded for sample instability reasons.
  • FIG. 25 are SEM images of a-synuclein aggregates (left image), and a-synuclein aggregates with Fab37 (right image).
  • the present invention is based, in part, on the surprising discovery of a novel activity of pyridoxal phosphate, emoxypine, or methyl 3-hydroxy-6-methyl picolinate (MHP ester), specifically, in dissolving aggregates of alpha- synuclein but not aggregates of beta-amyloid.
  • the present invention provides a method for treating or preventing a synucleinopathy, comprising administering an effective amount of compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3-hydroxy-6-methyl picolinate (MHP ester) to a subject in need thereof, wherein the method comprises disaggregation of ⁇ -synuclein.
  • the synucleinopathy is a condition characterized by Lewy bodies, e.g., Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy.
  • the method provides about a 20%, or about a 30%, or about a 40%, or about a 50%, or about a 60%, or about a 70%, or about a 80%, or about a 90%, or about a 95%, or about a 100% reduction in a- synuclein aggregation relative to an untreated subject.
  • the method provides does not substantially dissolve aggregates of beta-amyloid.
  • Neurodegenerative disorders such as Parkinson, Huntington and Alzheimer diseases, fronto-temporal lobar degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are associated with the accumulation of misfolded proteins both inside and outside of neuronal and glial cells in the central nervous system.
  • FTLD fronto-temporal lobar degeneration
  • ALS Amyotrophic Lateral Sclerosis
  • the present methods treat or prevent a synucleinopathy, e.g., Parkinson's disease by promoting the dissolution of aggregates of alpha-synuclein or preventing the accumulation of aggregates of alpha-synuclein, e.g., in the brain.
  • a synucleinopathy e.g., Parkinson's disease
  • Lewy bodies are the hallmark of Parkinson's disease which is mainly composed of alpha-synuclein.
  • Alpha-synuclein plays a role in the development of rare familial and more common sporadic cases of Parkinson's disease. In familial Parkinson's disease, the expression levels of alpha-synuclein gene is increased or an abnormal form of the protein is found which are toxic to brain cells and result in neuron dysfunction.
  • Alpha-synuclein is the primary structural component of Lewy bodies, suggesting that protein aggregation plays a role in sporadic Parkinson's disease.
  • Alpha-synuclein is abundant in the human brain at the neurons tips in specialized structures called presynaptic terminals.
  • alpha- synuclein is a presynaptic neuronal protein that is thought that its abnormal soluble oligomeric conformations, i.e. protofibrils, are the toxic species that mediate disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets, including synaptic function.
  • secreted alpha-synuclein may exert deleterious effects on neighboring cells, including seeding of aggregation, thus possibly contributing to disease propagation.
  • the present methods prevent or reduce the seeding of aggregation in a subject.
  • the human alpha-synuclein protein is made of 140 amino acids and is encoded by the SNCA gene.
  • the amino acid sequence of human alpha-synuclein is shown by SEQ ID NO.: 1 :
  • the present methods prevent or reduce the formation of Lewy bodies, e.g., in the brain.
  • Parkinsonism conditions that are treated or prevented by the present methods include Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, cortical-basal ganglionic degeneration, diffuse Lewy body disease, Parkinson-dementia, X-linked dystonia-parkinsonism, and secondary Parkinsonism (resulting from environmental etiology, e.g., toxins, drugs, post encephalitic, brain tumors, head trauma, normal pressure hydrocephalus).
  • environmental etiology e.g., toxins, drugs, post encephalitic, brain tumors, head trauma, normal pressure hydrocephalus.
  • the present methods prevent or reduce degeneration of dopaminergic neurons within the substantia nigra. In various embodiments, the present methods prevent or reduce tremor, hypokinesia (e.g., bradykinesia, akinesia, rigidity), postural instability, abnormal gait and swallowing disturbances.
  • Non-motor symptoms include autonomic and neuropsychiatric disturbances such as anosmia, or sleep abnormalities.
  • treatment includes the therapy, prevention, prophylaxis, retardation or reduction of symptoms provoked by or of the causes of Parkinsonism, e.g., Parkinson's disease.
  • treatment also designates a retardation or delayed onset of tremor, a reduction of pain, a decrease or reduction of bradykinesia, akinesia, rigidity, postural instability, abnormal gait, anosmia, and/or sleep abnormalities, and/or an increase of survival.
  • treatment includes in particular the control of disease progression and associated motor and non-motor symptoms.
  • treatment in various embodiments, particularly includes a protection against the toxicity caused by alpha- synuclein, or a reduction or retardation of this toxicity.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (C1 -10)alkyl or C1 -10 alkyl).
  • a numerical range such as “1 to 10” refers to each integer in the given range - e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term "alkyl” where no numerical range is specifically designated.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl.
  • the alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1 -methy lethy I (iso-propyl), n-butyl, n-pentyl, 1 , 1 -dimethylethyl (t-butyl) and 3- methylhexyl.
  • an alkyl group is optionally substituted by one or more of substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, - ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, C(0)ORa, -OC(0)N(Ra)2, -C(0)N(Ra)2, -N(Ra)C(0)ORa, - N(Ra)C(0)Ra, N(Ra)C(0)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(0)tRa (where t is 1 or 2), -S
  • alkoxy refers to the group -O-alkyI or -alkylene-O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and -CH2CH2- 0-CH3. "Lower alkoxy” refers to alkoxy groups containing one to six carbons.
  • aryl refers to an aromatic radical with six to ten ring atoms (e.g., C 6 -C 10 aromatic or C 6 -C 10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl).
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • a numerical range such as “6 to 10” refers to each integer in the given range; e.g., "6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, efc., up to and including 10 ring atoms.
  • an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , - OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -OR a , - OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a
  • Heteroalkyl includes optionally substituted alkyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a numerical range may be given - e.g., C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long.
  • a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, C(0)Ra, C(0)ORa, -OC(0)N(Ra)2, - C(0)N(Ra)2, -N(Ra)C(0)ORa, -N(Ra)C(0)Ra, N(Ra)C(0)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(0)tRa (where t is 1 or 2), -S(0)tORa (where t is 1 or 2)
  • Halo is intended to mean fluoro, chloro, bromo or iodo.
  • Heteroaryl or “heteroaromatic” or “HetAr” refers to a 5- to 18-membered aromatic radical (e.g., C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system.
  • a numerical range such as “5 to 18” refers to each integer in the given range - e.g., "5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, efc., up to and including 18 ring atoms.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical - e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • a N-containing "heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • the polycyclic heteroaryl group may be fused or non-fused.
  • the heteroatom(s) in the heteroaryl radical are optionally oxidized.
  • heteroaryl may be attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1 ,4]dioxepinyl, benzo[b][1 ,4]oxazinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuran
  • a heteroaryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SRa, - OC(0)-Ra, -N(Ra)2, C(0)Ra, C(0)ORa, -OC(0)N(Ra)2, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -N(Ra)C(0)Ra, N(Ra)C(0)Ra, N(Ra)C(0)ORa (where t is 1 or
  • substituted means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyi, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and
  • substituents themselves may be substituted, for example, a cycloalkyi substituent may itself have a halide substituent at one or more of its ring carbons.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • efficacy of treating Parkinson's disease using methods and compositions of the present invention may be assessed by various methods. For example, efficacy may be assessed by monitoring and assessing the motor symptoms of the disease, including tremor, bradykinesia, rigidity of limb and muscle tone, postural instability. Additionally, efficacy may be assessed by monitoring for improvements in neuropsychiatric symptoms which include, for example, speech, cognition, mood, behavior, and thought.
  • the present methods show an improvement in disease symptoms as measured by the Unified Parkinson's Disease Rating Scale as described in Movement Disorders Vol. 23, No. 15, 2008, pp. 2129— 2170, which is incorporated herein by reference in its entirety.
  • the present methods show an improvement in disease symptoms as measured by the MDS- UPDRS Movement Disorders. 22 (1): 41-47, which is incorporated herein by reference in its entirety.
  • the present methods pertain to the use of pyridoxal phosphate or a related compound as shown by Formula I:
  • Xi, X 2 , X3 ⁇ 4 X4, R 8 , R 9 , R 10 , R 11 and R 12 are as defined above.
  • the present methods pertain to the use of pyridoxal phosphate or a related compound shown by Formula la:
  • the present methods pertain to the use of pyridoxal phosphate (PLP, pyridoxal 5'- phosphate, P5P) (CsHioNOsP) or a related compound for the present treatments or preventions.
  • PRP pyridoxal phosphate
  • CsHioNOsP pyridoxal 5'- phosphate
  • a related compound for the present treatments or preventions.
  • Pyridoxal phosphate is a coenzyme in a variety of enzymatic reactions. It is the active form of vitamin ⁇ 3 ⁇ 4.
  • related compounds of the present invention include several forms (vitamers) of vitamin B6.
  • vitamin B6 pyridoxine
  • PL pyridoxal
  • PLA pyridoxal 5'-phosphate
  • PM pyridoxamine
  • PM pyridoxamine 5'- phosphate
  • PA 4-pyridoxic acid
  • pyritinol pyridoxine (PN)
  • PL pyridoxal 5'-phosphate
  • PM pyridoxamine
  • PMP 4-pyridoxic acid
  • PA 4-pyridoxic acid
  • pyritinol pyritinol
  • related compounds of the present invention include pyridoxal.
  • related compounds of the present invention include sulfosalicylic acid.
  • the present methods pertain to the use of pyridoxal phosphate or a related compound as shown by Formula lb:
  • R 15 , R 16 , R 17 , R 18 , R 19 are as defined above
  • the present methods pertain to the use of emoxypine or a related compound for the present treatments or preventions.
  • the present methods pertain to the use of methyl 3-hydroxy-6-methyl picolinate (MHP ester) or a related compound for the present treatments or preventions.
  • MHP ester methyl 3-hydroxy-6-methyl picolinate
  • acids and salts of the compounds described herein are provided.
  • a compound described herein (a compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3- hydroxy-6-methyl picolinate (MHP ester) or a related compound)) is an anion.
  • the counterpart species may be a counterion and the combination of a compound described herein with a counterion is an acid or salt.
  • Counter ions of a compound described herein may include, but are not limited to, cationic hydrogen species including protons; monovalent inorganic cations including lithium, sodium, and potassium; divalent inorganic cations including magnesium, calcium, manganese, zinc, copper and iron; polyvalent inorganic cations including iron; quaternary nitrogen species including ammonium, cycloheptyl ammonium, cyclooctyl ammonium, N, N-dimethylcyclohexyl ammonium, and other organic ammonium cations; sulfonium species including triethylsulfonium and other organic sulfonium compounds; organic cations including pyridinium, piperidinium, piperazinium, quinuclidinium, pyrrolium, tripiperazinium, and other organic cations; polymeric cations including oligomers, polymers, peptides, proteins, positively charged ionomers, and other macromolecular species that possess
  • the invention is not limited to pairings that are purely ionic; indeed, it is known in the art that paired ions may evidence some degree of covalent or coordinate bond characteristic between the two components of the pair.
  • the compounds of the invention may comprise a single type of counterion or may contain mixed counterions, and may optionally contain a mixture of anions of which a compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3-hydroxy-6-methyl picolinate (MHP ester) or a related compound) is one.
  • the compositions may optionally include crown ethers, cryptands, and other species capable of chelating or otherwise complexing the counterions.
  • the compounds of the invention may likewise optionally include acidic macrocycles or other species that are capable of complexing the compounds of the invention through hydrogen bonds or other molecular attractions.
  • the compounds described herein include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the compound such that covalent attachment does not prevent the activity of the compound.
  • derivatives include compounds that have been modified by, inter alia, glycosylation, lipidation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, efc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, or formylation. Additionally, the derivatives can contain one or more non-classical amino acids.
  • the compounds described herein may be modified to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and a targeting agent.
  • effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties
  • functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and a targeting agent.
  • the present invention provides for the compounds described herein and pharmaceutically acceptable esters, prodrugs, salts, solvates, enantiomers, stereoisomers, active metabolites, co-crystals, and other physiologically functional derivatives thereof.
  • the compound described herein is in the form of a pharmaceutically acceptable salt, namely those salts which are suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the free base function with a suitable acid or a free acid functionality with an appropriate alkaline moiety.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • the compounds described herein, or their pharmaceutically acceptable salts which are used in accordance with the present invention may exhibit stereoisomerism by virtue of the presence of one or more asymmetric or chiral centers in the compounds.
  • the present invention contemplates the various stereoisomers and mixtures thereof. Desired enantiomers can be obtained by chiral synthesis from commercially available chiral starting materials by methods well known in the art, or may be obtained from mixtures of the enantiomers by resolution using known techniques.
  • Solvate as used herein refers to a pharmaceutically acceptable solvate form of an agent that retains the biological effectiveness of such agent.
  • solvates include a compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3-hydroxy-6-methyl picolinate (MHP ester) or a related compound) of the invention in combination with, for example, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
  • Prodrug refers to an agent that is converted under physiological conditions or by solvolysis or metabolically (e.g., in vivo) to a specified agent that is pharmaceutically active.
  • Active metabolite refers to a pharmacologically active product produced through metabolism in the body of a specified agent.
  • Co-crystal refers to a physical association of two or more molecules which owe their stability through non-covalent interaction.
  • One or more components of this molecular complex provide a stable framework in the crystalline lattice.
  • the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates.
  • the present invention provides a compounds described herein, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition can be in any suitable form appropriate for the desired use and route of administration.
  • Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent described herein is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions.
  • suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.
  • compositions of the present invention may contain adjuvants such as preservatives, wetting agents, emulsifying agents, pH buffering agents, and dispersing agents. Further, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be included. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • the pharmaceutical compositions may also include isotonic agents such as sugars, sodium chloride, and the like.
  • compositions can also include a solubilizing agent.
  • agents can be delivered with a suitable vehicle or delivery device as known in the art.
  • Compositions for administration can optionally include a local anesthetic such as, for example, lidocaine to lessen pain at the site of the injection.
  • compositions of the present invention can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the pharmaceutical composition is in the form of a capsule.
  • the pharmaceutical composition is in the form of a tablet.
  • the administration of any of the described compounds is any one of oral, intravenous, and parenteral.
  • routes of administration include, for example: oral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, for example, to the ears, nose, eyes, or skin.
  • the administering is effected orally or by parenteral injection.
  • the mode of administration can be left to the discretion of the practitioner, and depends in-part upon the site of the medical condition.
  • administration results in the release of any agent described herein into the bloodstream.
  • Any compound and/or pharmaceutical composition described herein can be administered orally.
  • Such compounds and/or pharmaceutical compositions can also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, efc.) and can be administered together with an additional therapeutic agent.
  • Administration can be systemic or local. In some embodiments, administration is not at the site of infection to avoid, for example, hydrolysis of the compound at the site of infection.
  • Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, efc., and can be used. In specific embodiments, it may be desirable to administer locally to the area in need of treatment.
  • a compound of F Formula I, la, or lb e.g. pyridoxal phosphate, emoxypine, methyl 3- hydroxy-6-methyl picolinate (MHP ester) or a related compound
  • WO 2006/102748 e.g. pyridoxal phosphate, emoxypine, methyl 3- hydroxy-6-methyl picolinate (MHP ester) or a related compound
  • a compound described herein and/or pharmaceutical composition described herein is formulated in accordance with routine procedures as a composition adapted for oral administration to humans.
  • Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate, efc., and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, silicic acid, microcrystalline cellulose, and Bakers Special Sugar, efc., b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose (HPC), and hydroxymethyl cellulose efc., c) humectants such as glycerol, efc., d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, cross-linked polymers
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Non-limiting examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above- mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • Dosage forms suitable for parenteral administration include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g., lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Any compound described herein and/or pharmaceutical composition described herein can be administered by controlled-release or sustained-release means or by delivery devices that are known to those of ordinary skill in the art.
  • Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5, 120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety.
  • Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropyl cellulose, hydropropylmethyl cellulose, polyvinylpyrrolidone, Eudragit, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled- or sustained-release formulations can be readily selected for use with the active ingredients of the agents described herein.
  • the invention thus provides single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.
  • Formulations comprising the compounds described herein and/or pharmaceutical compositions of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art).
  • a carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional
  • the actual dose of the compounds described herein and/or pharmaceutical compositions of the present invention to be administered according to the present invention may vary according to the particular compound, the particular dosage form, and the mode of administration. Many factors that may modify the action of the inositpresent agents (e.g., body weight, gender, diet, time of administration, route of administration, rate of excretion, condition of the subject, drug combinations, genetic disposition and reaction sensitivities) can be taken into account by those skilled in the art. Administration can be carried out continuously or in one or more discrete doses within the maximum tolerated dose. Optimal administration rates for a given set of conditions can be ascertained by those skilled in the art using conventional dosage administration tests.
  • compositions of the present invention can be administered in unit dosage forms (e.g., tablets or capsules) containing, for example, from about 0.01 mg to about 1 ,000 mg, from about 0.01 mg to about 950 mg, from about 0.01 mg to about 900 mg, from about 0.01 mg to about 850 mg, from about 0.01 mg to about 800 mg, from about 0.01 mg to about 750 mg, from about 0.01 mg to about 700 mg, from about 0.01 mg to about 650 mg, from about 0.01 mg to about 600 mg, from about 0.01 mg to about 550 mg, from about 0.01 mg to about 500 mg, from about 0.01 mg to about 450 mg, from about 0.01 mg to about 400 mg, from about 0.01 mg to about 350 mg, from about 0.01 mg to about 300 mg, from about 0.01 mg to about 250 mg, from about 0.01 mg to about 200 mg, from about 0.01 mg to about 150 mg, from about 0.01 mg to about 100 mg, from about 0.1 mg to about 90 mg, from about
  • a unit dosage form can be about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 0.1 mg
  • the compounds described herein and/or pharmaceutical compositions of the present invention are administered at an amount of from about 0.01 mg to about 1 ,000 mg daily, from about 0.01 mg to about 950 mg daily, from about 0.01 mg to about 900 mg daily, from about 0.01 mg to about 850 mg daily, from about 0.01 mg to about 800 mg daily, from about 0.01 mg to about 750 mg daily, from about 0.01 mg to about 700 mg daily, from about 0.01 mg to about 650 mg daily, from about 0.01 mg to about 600 mg daily, from about 0.01 mg to about 550 mg daily, from about 0.01 mg to about 500 mg daily, from about 0.01 mg to about 450 mg daily, from about 0.01 mg to about 400 mg daily, from about 0.01 mg to about 350 mg daily, from about 0.01 mg to about 300 mg daily, from about 0.01 mg to about 250 mg daily, from about 0.01 mg to about 200 mg daily, from about 0.01 mg to about 150 mg daily, from about 0.1 mg to about 100 mg daily, from about 0.1 mg to about 95 mg daily, from about 0.
  • the compounds described herein and/or pharmaceutical compositions of the present invention are administered at a daily dose of about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about
  • a suitable dosage of the compounds described herein and/or pharmaceutical compositions of the present invention is in a range of about 0.01 mg/kg to about 10 mg/kg of body weight of the subject, for example, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, 1.9 mg/kg, about 2 mg/kg, about 3 mg
  • a suitable dosage of a compound of Formula I, la, or lb is in a range of about 0.01 mg/kg to about 10 mg/kg of body weight, in a range of about 0.01 mg/kg to about 9 mg/kg of body weight, in a range of about 0.01 mg/kg to about 8 mg/kg of body weight, in a range of about 0.01 mg/kg to about 7 mg/kg of body weight, in a range of 0.01 mg/kg to about 6 mg/kg of body weight, in a range of about 0.05 mg/kg to about 5 mg/kg of body weight, in a range of about 0.05 mg/kg to about 4 mg/kg of body weight, in a range of about 0.05 mg/kg to about 3 mg/kg of body weight, in a range of about 0.05 mg/kg to about 2 mg/kg of body weight,
  • MHP ester methyl 3-hydroxy-6-methyl picolinate
  • the compounds and/or pharmaceutical compositions described herein may be administered, for example, more than once daily, about once per day, about every other day, about every third day, about once a week, about once every two weeks, about once every month, about once every two months, about once every three months, about once every six months, or about once every year.
  • Administration of the present compounds may be combined with one or more additional therapeutic agents (e.g., 1 , or 2, or 3, or 4, or 5 additional therapeutic agents). Such combinations may lead to synergism and/or additive and/or potent effects at a lower dose of the present compounds and/or the one or more additional therapeutic agents. Coadministration of the present compounds and the additional therapeutic agent may be simultaneous or sequential. Further the pharmaceutical compositions including the present compounds may comprise the additional therapeutic agent (e.g., via co-formulation). Further, in some embodiments, the present compounds may be administered to a patient that is undergoing treatment with one or more additional therapeutic agent. Further, in some embodiments, the present compounds may supplant a patient's current treatment with one or more additional therapeutic agent.
  • additional therapeutic agents e.g., 1 , or 2, or 3, or 4, or 5 additional therapeutic agents.
  • the additional therapeutic agent and the present compounds are administered to a subject simultaneously.
  • the term "simultaneously" as used herein, means that the additional therapeutic agent and the present compounds are administered with a time separation of no more than about 60 minutes, such as no more than about 30 minutes, no more than about 20 minutes, no more than about 10 minutes, no more than about 5 minutes, or no more than about 1 minute.
  • Administration of the additional therapeutic agent and present compounds can be by simultaneous administration of a single formulation (e.g., a formulation comprising the additional therapeutic agent and the present compounds) or of separate formulations (e.g., a first formulation including the additional therapeutic agent and a second formulation including the present compounds).
  • Co-administration does not require the additional therapeutic agent to be administered simultaneously, if the timing of their administration is such that the pharmacological activities of the additional therapeutic agent and the present compounds overlap in time, thereby exerting a combined therapeutic effect.
  • the additional therapeutic agent and the present compounds can be administered sequentially.
  • the term "sequentially" as used herein means that the additional therapeutic agent and the present compounds are administered with a time separation of more than about 60 minutes.
  • the time between the sequential administration of the additional therapeutic agent and the present compounds can be more than about 60 minutes, more than about 2 hours, more than about 5 hours, more than about 10 hours, more than about 1 day, more than about 2 days, more than about 3 days, or more than about 1 week apart.
  • the optimal administration times may depend on the rates of metabolism, excretion, and/or the pharmacodynamic activity of the additional therapeutic agent and the present compounds being administered. Either the additional therapeutic agent or the present compound may be administered first.
  • Co-administration also does not require the additional therapeutic agents to be administered to the subject by the same route of administration. Rather, each therapeutic agent can be administered by any appropriate route, for example, parenterally or non-parenterally.
  • the additional therapeutic agent is a Parkinson's disease treatment agent.
  • the Parkinson's disease treatment agent is optionally selected from one or more of levodopa (for example, in combination with tolcapone, entacapone, carbidopa, or benserazide), dopamine agonists as described herein (for example, apomorphine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride), MAO-B inhibitors as described herein (for example, deprenyls such as selegiline and rasagiline), Piribedil, pramipexole (e.g., MIRAPEX, MIRAPEXIN, SIFROL), bromocriptine (e.g., PARLODEL, CYCLOSET, BROTIN), Ropinirole (e.g., REQUIP, REPREVE,
  • levodopa for example
  • PNU- 95,666 aplindore (e.g., DAB-452), amantadine, anticholinergics (for example, artane, Cogentin), quetiapine, cholinesterase inhibitors, modafinil, tyrosine hydroxylase, N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1 a- carboxamide (PHCCC), and non-steroidal anti-inflammatory drugs.
  • aplindore e.g., DAB-452
  • amantadine for example, artane, Cogentin
  • quetiapine for example, artane, Cogentin
  • quetiapine for example, artane, Cogentin
  • quetiapine for example, artane, Cogentin
  • quetiapine for example, artane, Cogentin
  • cholinesterase inhibitors for example, artane, Cogentin
  • modafinil t
  • the terms "patient” and “subject” are used interchangeably.
  • the subject and/or animal is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • methods of the invention are useful in treatment a human subject.
  • the human is a pediatric human.
  • the human is an adult human.
  • the human is a geriatric human.
  • the human may be referred to as a patient or a subject.
  • the human is a female.
  • the human is a male.
  • kits that can simplify the administration of the compounds and/or pharmaceutical compositions described herein.
  • the kit is an assemblage of materials or components, including at least one of the formulations described herein. The exact nature of the components configured in the kit depends on its intended purpose. In one embodiment, the kit is configured for the purpose of treating human subjects.
  • Instructions for use may be included in the kit.
  • Instructions for use typically include a tangible expression describing the technique to be employed in using the components of the kit to affect a desired outcome, such as to treat, for example, Parkinson's disease.
  • the kit also contains other useful components, such as, diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipetting or measuring tools, bandaging materials or other useful paraphernalia as may be readily recognized by those of skill in the art.
  • the materials and components assembled in the kit can be provided to the practitioner store in any convenience and suitable ways that preserve their operability and utility.
  • the components can be provided at room, refrigerated or frozen temperatures.
  • the components are typically contained in suitable packaging materials.
  • the packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant-free environment.
  • the packaging material may have an external label which indicates the contents and/or purpose of the kit and/or its components.
  • Example 1 Experiments Related to the ⁇ -synuclein Disaggregation with Pyridoxal Phosphate
  • PLP Pyridoxal phosphate
  • SPB Sodium phosphate buffer
  • SPB is prepared with a mix of two powder: disodium phosphate (Na 2 HP0 4 ) and monosodium phosphate (NaH 2 P0 4 ) diluted in distilled water and adjusted at a pH of 6 with addition of sodium hydroxide (NaOH 5M).
  • PLP solution at 5mg/mL is store at room temperature.
  • a-synuclein (60-95) human trifluoroacetate salt (Bachem, art n°4105037, lot n°3016948, purity 86.6%, molecular weight 3388.82 g/mol) were rehydrated with 5mL of Phosphate-Buffered Saline (PBS). Then, 5 mg of a- synuclein (60-95) at 3mg/mL in PBS pH 7.3 was used to produce aggregates incubating the solution for one week at 37°C.
  • PBS Phosphate-Buffered Saline
  • Tubes were analyzed at room temperature with spectrofluorometer Fluorolog (Horiba) with 2mm plastic cuvettes, run at 1s and slit at 5. Excitation is done with wavelength of 450nm and measures are registered between 470nm and 600nm.
  • spectrofluorometer Fluorolog Horiba
  • the first assay is shown in FIG. 1, panels A-E.
  • the second assay is shown in FIG. 1, panels F-K.
  • FIG. 1 The results of FIG. 1 are summarized in FIG. 2, panels A-C.
  • FIG. 3 shows scanning electron microscopy results.
  • FIGs. 3A, 3C, 3E, and 3G shows ⁇ -synuclein aggregates and FIGs. 3B, 3D, 3F, and 3H show ⁇ -synuclein aggregates with PLP.
  • Example 2 Methods Related to the Use of Emoxypine to Solubilize ⁇ -Synuclein Amyloids Fibrils
  • ⁇ -synuclein amyloids fibrils are responsible for neurodegenerative disease such as Parkinson's disease. These fibrils are formed by the aggregation of ⁇ -synuclein.
  • the aim of the experiments of this example is, therefore, the breaking, i.e. the solubilization of ⁇ -synuclein aggregates.
  • disclosed herein is a method of incorporating chemical species in a-synuclein amyloids fibrils. Chemical species can intercalate between the of a-synuclein proteins and hence break the aggregates (this can be called the "curative measure", as the proteins are already aggregated).
  • Another method of the present disclosure is the incorporation of the chemical species before aggregation, in order to prevent the amassment (this can be called the "preventive measure", as the proteins are not aggregated yet).
  • a schematic representation of both measures is displayed in FIG. 4.
  • emoxypine in the solubilization of ⁇ -synuclein amyloids fibrils.
  • NAC non-Abeta component
  • SEQ ID N0.2 The sequence, referred to herein as SEQ ID N0.2, is the following: EQVTNVGGAWTGVTAVAQKTVEGAGSIAAATGFV.
  • the structure of emoxypine is shown below:
  • thioflavin T As a fluorescent label, having the advantage of emitting at 482 nm only when linked to amyloid fibrils, but not to the single peptide.
  • the curative and preventive methods were studied, at different molar ratio emoxypine/ a-synuclein (200, 100, 50, 20).
  • fluorescence measurements were performed by comparing the emission of ThT in the presence of aggregates, without and with emoxypine at different times after emoxypine addition, from one minute to several days.
  • FIG.7A, FIG. 7B, FIG. 7C, and FIG. 7D In order to confirm these interesting results, scanning electron microscopy studies were performed on the same samples, and images are displayed in FIG.7A, FIG. 7B, FIG. 7C, and FIG. 7D.
  • FIG. 11 displays the emission intensities recorded versus the time. Interestingly, a certain percentage of disaggregation was observed, which was in this case less important than what was previously mentioned, meaning r 200 and r 100. Indeed, after 1 minute, 40% of the initial aggregates were destroyed, and this value slightly increased to reach, after 6 days, about 60% of solubilization.
  • a-synuclein 6 i-95 and emoxypine commercially available, were used as bought without any further purification. All the tubes, tips and buffers were sterilized prior to use.
  • the aggregation was performed as following:
  • the disaggregation i.e. solubilization
  • the disaggregation was performed as following:
  • Emission spectra were recorded on a Horiba Jobin-Yvon IBH FL-322 Fluorolog 3 spectrometer equipped with a 450 W xenon arc lamp, double-grating excitation, and emission monochromators (2.1 nm mm-1of dispersion; 1200 grooves mm-1) and a TBX-04 single photon-counting detector. Emission spectra were corrected for source intensity (lamp and grating) and emission spectral response (detector and grating) by standard corrections.
  • the cuvettes used for the fluorescence measurements are transparent polystyrene semi-micro cuvettes, with a maximum volume of 1.6 ml and 2 optical sides, suitable for use beginning at 330 nm. All the sample were excited at 450 nm and the emission spectra were recorded between 470 nm and 600 nm.
  • SEM images were recorded with a FEI Quanta FEG 250 instrument (FEI corporate, Hillsboro, Oregon, USA) with an acceleration voltage of 20 kV.
  • the sample is prepared by deposition of 5 ⁇ _ of the sample solution (200 ⁇ _) onto a glass cover slip, subsequently sputter coated with gold (Emitech K575X peltier cooled) for 60 s at 60 mA prior to fixation on an aluminum support.
  • Example 3 Methods Related to the Use of Methyl 3-hydroxy-6-methylpicolinate (MHP-Ester) to Solubilize a- Synuclein Amyloids Fibrils
  • FIG. 21C, FIG. 21 D, and FIG. 21 E display some of the images recorded from samples involving ⁇ -synuclein amyloid fibrils and MHP-ester.
  • Small particles of around 500 nm were observed, assembling together to form geometric patterns of around 4 ⁇ Those particles might refer to ⁇ -synuclein monomers.
  • Only a very few fibers were seen (FIG. 21 E. surrounded by circles). It was surprising not to observe more fibers, since according to the fluorescence experiments, 40% of fibers were left. Unfortunately, due to the instability of some samples destroyed by the electron beam, no picture could be recorded for samples without MHP-ester. This problem was quite recurrent; that is why other samples were needed to be prepared until obtain decent images were obtained.
  • analogues of MHP-ester can be examined, where the MHP group is linked to molecular scaffolds of different structures (e.g. linear, branched, cyclic)

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Abstract

L'invention concerne des utilisations de pyridoxal phosphate, d'émoxypine, ou de méthyl 3-hydroxy-6-méthyl picolinate (ester MHP) ou d'un composé apparenté dans le traitement ou la prévention, entre autres, de la maladie de Parkinson.
PCT/US2018/054961 2017-10-09 2018-10-09 Désagrégation d'alpha-synucléine avec de petites molécules Ceased WO2019074898A1 (fr)

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JP2022519779A (ja) * 2019-02-07 2022-03-24 アルサテック，インコーポレイテッド エモキシピンの多価誘導体
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