The present invention relates to a low-dose regimen and low-dose formulation of
the 0-GlcNAcase (OGA) inhibitor N-[ 4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-
5 oxadiazol-3-yl)methoxy ]-1-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).
U.S. Patent No. 10,081,625 discloses certain compounds, including 5-methy-
1 0 1 ,2,4-oxadiazol-3 -yl compounds, including N-[ 4-fluoro-5-[[ (2S,4S)-2-methyl-4-[( 5-
methyl-1 ,2,4-oxadiazol-3-yl)methoxy ]-1-piperidyl ]methyl ]thiazol-2-yl ]acetamide which
are OGA inhibitors useful for treating neurodegenerative diseases and disorders, such as
AD andPSP.
Patients suffering from neurodegenerative diseases, including AD, PSP, and other
15 neurodegenerative tauopathies, may develop difficulty swallowing as the disease
progresses. Thus, it is desired that 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. Furthermore, in view of the progressive cognitive impairment
often associated with neurodegenerative diseases such as AD, reducing the number of
20 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. In addition, 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. al., 2020 Society of Toxicology
25 Annual Meeting (virtual), Abstract No. 2911, May 12, 2020;
https://www.toxicology.org/events/am/AM2020/docs/2020-ePoster-index.pdf).
Thus, low doses of OGA inhibitors are desired to provide treatment for
neurodegenerative diseases, such as AD and PSP and other neurodegenerative
tauopathies. In addition, administration of OGA inhibitors of no more than twice per day,
30 and preferably once per day, are further desired for treatment of neurodegenerative
diseases, including neurodegenerative tauopathies such as AD, FTD, CBS, and PSP.
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Accordingly, in one embodiment, the invention provides a compound of Formula
1:
Formula I
or a pharmaceutically acceptable salt thereof, for use in treating a neurodegenerative
5 disease wherein the compound, or pharmaceutically acceptable salt thereof is
administered orally with a total dose of the compound of0.1 mg/day to 5 mg/day.
In an embodiment, the invention provides a compound of Formula 1:
Formula I
or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically
10 acceptable salt thereof is administered orally with a total dose ofthe compound of0.1
mg/day to 5 mg/day for use in treating Alzheimer's disease.
In an embodiment, the invention provides a compound of Formula 1:
~N ,
r-N ~ 0..-- Q,.. N)-
~ S ° Formula I
F NAN~
H
or a pharmaceutically acceptable salt thereof, wherein the compound, or pharmaceutically
15 acceptable salt thereof is administered orally with a total dose ofthe compound of0.1
mg/day to 5 mg/day for use in treating progressive supranuclear palsy.
In an embodiment, the invention provides a compound of Formula 1:
Formula I
5
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-3-
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.
In an embodiment, the invention provides the use of a compound of Formula 1:
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
10 mg/day to 5 mg/day.
In an embodiment, the invention provides the use of a compound of Formula 1:
~N ,
r-N ~ 0..-- Q,.. N)-
~ S ° Formula I
F NAN~
H
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for
treating Alzheimer's disease wherein the compound, or pharmaceutically acceptable salt
15 thereof is administered orally with a total dose ofthe compound of0.1 mg/day to 5
mg/day.
In an embodiment, the invention provides a compound of Formula 1:
Formula I
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for
20 treating progressive supranuclear palsy wherein the compound, or pharmaceutically
wo 2022/020663 PCT/US2021/042877
-4-
acceptable salt thereof is administered orally with a total dose of the compound of 0.1
mg/ day to 5 mg/ day.
In an embodiment, the invention provides the use of a compound of Formula 1:
Formula I
5 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 com pound of 0. 1 mg/ day to 5 mg/ day.
In an embodiment, the invention provides a method of treating a
10 neurodegenerative disease, comprising administering to a patient in need of such
treatment a compound of Formula 1:
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
15 mg/day to 5 mg/day.

We Claim:
1. A pharmaceutical composition, comprising a compound of the formula:
,
or a pharmaceutically acceptable salt thereof 5 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.
2. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 0.25 mg to 5 mg.
10 3. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 0.1 mg to 3 mg.
4. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 0.25 mg to 3 mg.
5. The pharmaceutical composition according to claim 1 wherein the total dose of
15 the compound is 0.1 mg to 2 mg.
6. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 0.25 mg to 2 mg.
7. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 0.1 mg to 1 mg.
20 8. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 0.25 mg to 1 mg.
9. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 3 mg.
10. The pharmaceutical composition according to claim 1 wherein the total dose of
25 the compound is 2.5 mg.
11. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 2 mg.
-23-
12. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 1.5 mg.
13. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 1 mg.
14. The pharmaceutical composition 5 according to claim 1 wherein the total dose of
the compound is 0.75 mg.
15. The pharmaceutical composition according to claim 1 wherein the total dose of
the compound is 0.5 mg.
16. The pharmaceutical composition according to claim 1 wherein the total dose of
10 the compound is 0.25 mg.
17. The pharmaceutical composition according to any one of claims 1 to 16 wherein
the total dose of the compound is contained in one unit dose.
18. The pharmaceutical composition according to any one of claims 1 to 16 wherein
the total dose of the compound is contained in two unit doses.
15 19. The pharmaceutical composition according to any one of claims 1 to 16 wherein
the total dose of the compound is contained in two unit doses with each unit
dose containing equal amounts of the compound.