Classifications

• • 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
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • 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
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• the present invention relates to a low-dose regimen and low-dose formulation of the O-GlcNAcase (OGA) inhibitor N-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl- 1,2,4- oxadiazol-3-yl)methoxy]-l-piperidyl]methyl]thiazol-2-yl]acetamide, or pharmaceutically acceptable salt thereof, to treat neurodengerative diseases, including, neurodegenerative tauopathies such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), corticobasilar syndrome (CBS), and progressive supranuclear palsy (PSP).
• AD Alzheimer’s disease
• FDD frontotemporal dementia
• CBS corticobasilar syndrome
• PSP progressive supranuclear palsy
• U.S. Patent No. 10,081,625 discloses certain compounds, including 5-methy- l,2,4-oxadiazol-3-yl compounds, including N-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5- methyl-l,2,4-oxadiazol-3-yl)methoxy]-l-piperidyl]methyl]thiazol-2-yl]acetamide which are OGA inhibitors useful for treating neurodegenerative diseases and disorders, such as AD and PSP.
• AD neurodegenerative diseases
• PSP neurodegenerative tauopathies
• prescribed dosages of a drug are of a low dose providing a small unit dosage form, in order to faciliate swallowing when the drug is administered to the patient.
• reducing the number of dosage administrations per day will help minimize the risk that a patient will miss a dose and will also reduce the burden on the caregiver responsible for ensuring proper and timely administration of the drug.
• lower doses and less frequent dose administration will ameliorate or eliminate potential side effects, particularly those that might arise with chronic adminstration (See W. Cook, et. ak, 2020 Society of Toxicology Annual Meeting (virtual), Abstract No. 2911, May 12, 2020; https://www.toxicology.org/events/am/AM2020/docs/2020-ePoster-index.pdf).
• the invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, for use in treating a neurodegenerative disease wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day.
• the invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day for use in treating Alzheimer’s disease.
• the invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day for use in treating progressive supranuclear palsy.
• the invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day for use in preventing the progression of mild cognitive impairment to Alzheimer’s disease.
• the invention provides the use of a compound of Formula I: or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neurodegenerative disease wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day.
• the invention provides the use of a compound of Formula I: or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating Alzheimer’s disease wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day.
• the invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating progressive supranuclear palsy wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day.
• the invention provides the use of a compound of Formula I: or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing the progression of mild cognitive impairment to Alzheimer’s disease, wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day.
• the invention provides a method of treating a neurodegenerative disease, comprising administering to a patient in need of such treatment a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of of the compound of 0.1 mg/day to 5 mg/day.
• the invention provides a method of treating Alzheimer’s disease, comprising administering to a patient in need of such treatment a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day.
• the invention provides a method of treating progressive supranuclear palsy, comprising administering to a patient in need of such treatment a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day.
• the invention provides a method of preventing the progression of mild cognitive impairment to Alzheimer’s disease, comprising administering to a patient in need of such treatment a compound of the of Formula I: or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically acceptable salt thereof is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day.
• the invention provides a pharmaceutical composition, comprising a compound of Formula I: or a pharmaceutically acceptable salt thereof, for use in treating a neurodegenerative disease wherein the pharmaceutical composition is administered orally with a total dose of the compound of 0.1 mg/day to 5 mg/day.
• the invention provides a pharmaceutical composition, comprising a compound of Formula I: or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients wherein the pharmaceutical composition contains a total dose of the compound of 0.1 mg to 5 mg.
• the invention provides a pharmaceutical composition, comprising a compound of Formula I: or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients wherein the pharmaceutical composition contains a total dose of the compound of 0.1 mg to 5 mg in unit dose form wherein the unit dose is administered once per day.
• the invention provides a pharmaceutical composition, comprising a compound of Formula I: or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients wherein the pharmaceutical composition contains a total dose of the compound of 0.05 mg to 2.5 mg in unit dose form wherein the unit dose is administered twice per day.
• the total dose of the compound of Formula I is 0.25 mg/day to 5 mg/day.
• the total dose of the compound of Formula I is 0.1 mg/day to 3 mg/day.
• the total dose of the compound of Formula I is 0.25 mg/day to 3 mg/day.
• the total dose of the compound of Formula I is 0.1 mg/day to 2 mg/day.
• the total dose of the compound of Formula I is 0.25 mg/day to 2 mg/day.
• the total dose of the compound of Formula I is 0.1 mg/day to 1 mg/day.
• the total dose of the compound of Formula I is 0.25 mg/day to 1 mg/day.
• the total dose of the compound of Formula I is 5 mg/day.
• the total dose of the compound of Formula I is 3 mg/day.
• the total dose of the compound of Formula I is 2.5 mg/day.
• the total dose of the compound of Formula I is 2 mg/day.
• the total dose of the compound of Formula I is 1.5 mg/day.
• the total dose of the compound of Formula I is 1 mg/day.
• the total dose of the compound of Formula I is 0.75 mg/day. In a particular embodiment, the total dose of the compound of Formula I is 0.5 mg/day.
• the total dose of the compound of Formula I is 0.25 mg/day.
• the total dose of the compound of Formula I is 0.1 mg/day.
• the compound of Formula I or pharmaceutically acceptable salt thereof is administered in unit dosage form.
• the unit dosage form is selected from a capsule, tablet, gelcap, liquid solution, and liquid suspension.
• the unit dosage form is a capsule.
• the unit dosage form is a tablet.
• the total daily dose of the compound of Formula I is administered in one unit dose.
• the total daily dose of the compound of Formula I is administered in two unit doses.
• the total daily dose of the compound of Formula I is administered in two unit doses each containing equal amounts of the compound of Formula I.
• the total daily dose of the compound of Formula I is in two unit doses wherein the administration of each unit dose is separated by at least 8 hours.
• the total daily dose of the compound of Formula I is in two unit doses each containing equal amounts of the compound of Formula I wherein the administration of each unit dose is separated by at least 8 hours.
• Mild cognitive impairment has been defined as a potential prodromal phase of dementia associated with Alzheimer’s disease based on clinical presentation and on progression of patients exhibiting mild cognitive impairment to Alzheimer’s dementia over time.
• the term “preventing the progression of mild cognitive impairment to Alzheimer’s disease” includes restraining, slowing, stopping, or reversing the progression of mild cognitive impairment to Alzheimer’s disease in a patient.
• the terms “treating” or “to treat” includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom, disease, or disorder.
• the term "patient” refers to a human.
• the compounds of the present invention are preferably formulated as pharmaceutical compositions for oral administration.
• Such pharmaceutical compositions and processes for preparing same are well known in the art (See, e.g., Remington: The Science and Practice of Pharmacy, L.V. Allen, Editor, 22 nd Edition, Pharmaceutical Press, 2012).
• the compound of Formula I may be prepared by a variety of procedures known to one of ordinary skill in the art, for example following the procedures disclosed in United States Patent No. 10,081,625.
• the compound of Formula I is also known as N-[4-fluoro-5-[[(2S,4S)-2-methyl-4- [(5-methyl-l,2,4-oxadiazol-3-yl)methoxy]-l-piperidyl]methyl]thiazol-2-yl]acetamide.
• a Phase 1, single-center, subject- and investigator-blind, single-ascending dose, placebo-controlled, crossover, randomized study is performed to evaluate safety, tolerability, and pharmacokinetics (PK) of the compound of Formula I in healthy subjects.
• the study is conducted in 2 alternating cohorts (cohorts 1 and 2) in up to 3 study periods across 6 dose levels. Subjects are randomized to 1 of 3 treatment sequences in each cohort, with each sequence including 2 doses of compound of Formula I and 1 placebo dose over the 3 study periods in a complete crossover manner.
• the clinical study design is summarized in Table 1.
• oral capsules are administered with approximately 240 mL of room-temperature water in the morning of each dosing day in a sitting position.
• Doses of 0.15 mg to 2 mg are administered as an oral solution of compound of Formula I via an oral dosing syringe with water similar to oral capsule dosing.
• Tables 2a and 2b summarize the treatment regimens.
• the capsules containing the compound of Formula I are prepared extemporaneously. Oral doses of 0.15 mg to 2 mg of the compound of Formula I are prepared extemporaneously as drug in solution. For any specific cohort/dosing period, the total number of capsules administered is the same for all subjects, regardless of whether assigned to placebo or the compound of Formula I. However, the number of capsules may vary between dosing periods and cohorts. This is similarly the case for extemporaneously prepared oral dosing solutions to maintain the blind.
• the compound of Formula I is supplied in the form of free base with no inactive ingredients for extemporaneous preparation. A matching volume of oral solution vehicle without compound of Formula I is used as placebo for the doses of 0.15 mg to 2 mg.
• Venous blood samples of approximately 3 mL each are collected to determine the plasma concentrations of compound of Formula I. Concentrations of compound of Formula I are assayed using a validated liquid chromatography with tandem mass spectrometry method. PK parameter estimates for compound of Formula I are calculated using standard noncompartmental methods of analysis. Plasma concentrations of compound of Formula I are summarized by administered dose of compound of Formula I and the approximate time of PK blood sample collection. Following the procedure essentially as described above, PK data for a single ascending dose of the compound of Formula I in healthy subjects are set forth in Table 3 and Table 4. Table 3. Mean plasma concentrations for a single ascending dose study following oral administration of the compound of Formula I in healthy subjects.
• AeO-24 amount of compound of Formula I excreted in urine up to 24 hours postdose n
• CLr renal clearance 12
• N 5 13
• N 3
• [ 18 F]LSN3316612 is a positron-emitting radiopharmaceutical for in vivo imaging of OGA in the brain and is used to evaluate target engagement of compounds which inhibit OGA.
• the preparation and use of 18 F- LSN3316612 as a PET radioligand is known in the art, for example as described by S. Lu, et. al, Science Translational Medicine, 12, eaau2939 (2020) 13 May2020.
• This single dose PET study using the [ 18 F]LSN3316612 tracer assesses the brain OGA enzyme occupancy (EO) across a suitable range of doses that have been demonstrated to be safe and well tolerated.
• EO brain OGA enzyme occupancy
• Healthy subjects are assigned to 1 of 4 cohorts with 4 subjects in each cohort completing the study. All subjects undergo one baseline PET scan and two post-dose PET scans. A baseline PET scan is performed from up to approximately 14 days before dosing of the compound of Formula I. Overall, each subject receives a single dose of the compound of Formula I and 3 administrations of the [ 18 F]LSN3316612 PET tracer. Dosing of the compound of Formula I occurs after completion of the baseline PET scan. Scans are conducted at approximately 2 and 24 hours post-dose for the 0.25 mg and 5 mg doses of the compound of Formula I, and at approximately 2 and 24 hours or 30 and 54 hours post-dose for the 1 mg dose of the compound of Formula I. Dynamic PET data of the brain are acquired over 120 min immediately following tracer injection. EO is summarized by the compound of Formula I dose and approximate scanning time.
• the compound of Formula I is administered orally in capsule formulation for doses >3 mg.
• doses lower than 3 mg the compound of Formula I is weighed into a suitable container and dissolved in an appropriate volume of degassed Sprite ® or diluent.
• [ 18 F]LSN3316612 is produced in the clinical site radiochemistry facility from the nonradioactive precursor on the day of each PET scan.
• [ 18 F]LSN3316612 injection is a clear solution for intravenous injection formulated in normal saline containing ethanol, sterile water for injection, and sodium ascorbate.
• [ 18 F]LSN3316612 is delivered in normal saline (0.9% NaCl) formulated with the intent to contain approximately 3.3%
• [ 18 F]LSN3316612 is administered intravenously over a 3-minute infusion period using an infusion pump followed by a 10-mL saline flush.
• an intravenous catheter for radiotracer infusion
• Each subject receives a single injection of [ 18 F]LSN3316612 at each imaging visit.
• the radiopharmaceutical is injected intravenously at a dose of approximately 5 mCi (not more than 6 mCi), with a maximum mass dose of 10 pg and maximum volume of 10 mL.
• the radiochemistry laboratory synthesizes the radioligand from the precursor according to PET unit production protocol known in the art, such as that described by Lee, J., Liow, 3., Paul, S. etal PET quantification of brain O- GlcNAease with [ ls F]LSN3316612 in healthy human volunteers.
• Arterial blood samples are collected from all subjects during each PET scan to measure radioactivity to provide input for the PET tracer kinetic analysis.
• Venous blood samples are collected following dosing of compound of Formula I to measure plasma concentrations of compound of Formula I using a validated liquid chromatography with tandem mass spectrometry assay.
• the primary imaging outcome for the [ 18 F]LSN3316612 PET is the total distribution volume (V x ) which is determined in regions where OGA is present, including cortical regions, regions of basal ganglia, thalamus, and cerebellum. Analysis uses the decay-corrected time activity data in the different brain regions. Imaging data is analyzed with 2-tissue compartment model with arterial input function to determine V x. OGA EO after a single dose of the compound of Formula I is obtained using graphical analysis according to the occupancy plot:
• VT(Baseline) - VT(Dosing) Occupancy * (VT(Baseline) - V D), where VT(Baseline) and VT (Dosing) are the total distribution volumes in several regions obtained at baseline and after compound of Formula I administration, respectively.
• the occupancy is determined as the slope of the linear regression of the plot, and the nondisplaceable volume of distribution VND as the x-intercept.
• Table 5a Brain OGA Occupancy for the 0.25 mg dose of Compound of Formula I.
• Table 5b Brain OGA Occupancy for the 1 mg dose of Compound of Formula I.
• Table 5c Brain OGA Occupancy for the 5 mg dose of Compound of Formula I.
• Tables 5a-5c discloses a plasma concentration-dependent change in brain OGA EO with EO for the 5 mg dose of the compound of Formula I exceeding 90% EO at 24 hours post dose.
• the 1 mg dose of the compound of Formula I was found to be 80.6% EO at 24 hours post dose and 30.3% EO at 54 hours post dose.
• the 0.25 mg dose of the compound of Formula I was found to be 46% EO at 24 hours post dose.
• the low doses and dosage regimens for treating a neurodegenerative disease including AD, PSP, FTD, CBS, and other neurodegenerative tauopathies, with a compound of Formula I are set forth below:
• a total dose of the compound of Formula I of 0.25 mg/day to 5 mg/day.
• a total dose of the compound of Formula I of 0.1 mg/day to 3 mg/day.
• a total dose of the compound of Formula I of 0.25 mg/day to 3 mg/day.
• a total dose of the compound of Formula I of 0.1 mg/day to 2 mg/day.
• a total dose of the compound of Formula I of 0.25 mg/day to 2 mg/day.
• a total dose of the compound of Formula I of 0.1 mg/day to 1 mg/day.
• a total dose of the compound of Formula I of 0.25 mg/day to 1 mg/day.
• a total dose is the compound of Formula I of 0.25 mg/day.
• the total daily dose of compound of Formula I administered is in one unit dose.
• the total daily dose of the compound of Formula I administered is in two unit doses. It is preferred that the total daily dose of the compound of Formula I is administered in two unit doses wherein each dose contains equal amounts of the compound of Formula I. It is preferred that when the total daily dose of the compound of Formula I is administered in two unit doses, the administration of each unit dose is separated by at least 8 hours.
• total doses of the compound of Formula I in a pharmaceutical composition are set forth below:
• a total dose of the compound of Formula I is 0.25 mg to 5 mg.
• a total dose of the compound of Formula I is 0.1 mg to 3 mg.
• a total dose of the compound of Formula I is 0.25 mg to 3 mg.
• a total dose of the compound of Formula I is 0.1 mg to 2 mg.
• a total dose of the compound of Formula I is 0.25 mg to 2 mg.
• a total dose of the compound of Formula I is 0.1 mg to 1 mg.
• a total dose of the compound of Formula I is 0.25 mg to 1 mg.
• a total dose of the compound of Formula I is 3 mg.
• a total dose of the compound of Formula I is 2 mg.
• a total dose of the compound of Formula I is 1.5 mg.
• a total dose of the compound of Formula I is 1 mg.
• a total dose of the compound of Formula I is 0.75 mg.
• a total dose of the compound of Formula I is 0.25 mg.
• the total dose of the pharmaceutical composition comprising the compound of Formula I, or pharmaceutically acceptable salt thereof is contained in one unit dose.
• the total dose of the pharmaceutical composition comprising the compound of Formula I, or pharmaceutically acceptable salt thereof is contained in one unit dose wherein the single unit dose is administered once per day.
• the total dose of the pharmaceutical composition comprising the compound of Formula I, or pharmaceutically acceptable salt thereof is contained in two unit doses.
• the total dose of the pharmaceutical composition comprising the compound of Formula I, or pharmaceutically acceptable salt thereof is contained in two unit doses with each unit dose containing equal amounts of the compound of Formula I. It is further preferred that the total dose of the pharmaceutical composition comprising the compound of Formula I, or pharmaceutically acceptable salt thereof is contained in two unit doses wherein each dose is administered in one day. It is further prefereed that the total dose of the pharmaceutical composition comprising the compound of Formula I, or pharmaceutically acceptable salt thereof is contained in two unit doses with each unit dose containing equal amounts of the compound of Formula I wherein each dose is administered within one day, preferably separated by at least 8 hours.

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