The present invention is in the field of treatment of diabetes and/or
hyperglycemia. In particular, the present invention relates to compounds that lower blood
5 glucose, pharmaceutical compositions containing such compounds and therapeutic uses of
such compounds.
Insulin replacement therapy for diabetic patients would ideally parallel, as closely
as possible, the pattern of endogenous insulin secretion in healthy individuals. The
physiological demand for insulin may be separated into two phases: (a) a nutrient
10 absorptive phase requiring a pulse of insulin to dispose of the meal-related blood glucose
surge, also known as "prandial" insulin, and (b) a post-absorptive phase requiring a
sustained delivery of insulin to regulate hepatic glucose output for maintaining optimal
fasting blood glucose, also known as a "basal" insulin.
Effective insulin therapy for people with diabetes generally may involve the
15 combined use of two types of exogenous insulin formulations: a rapid-acting, mealtime
prandial insulin, and a longer-acting basal insulin which is administered once or twice
daily to control blood glucose levels between meals. One or more characteristics of
endogenous insulin that may be desirable to emulate include a binding affinity for the
human insulin receptors, preferential binding to the human insulin receptors over the
20 human IGF -1 receptor, phosphorylation of the human insulin receptors, and glucose
lowering in the blood.
A desirable exogenous basal insulin should also provide an extended time
action-that is, it would control blood glucose levels for preferably 24 hours or more, and
most preferably for 168 hours or longer, without significant risk of hypoglycemia. Some
25 basal insulins have a duration of action of 24 hours or more. A compound with an
extended time-action profile, without significant variations in effectiveness during that
time, may lower the risk of nocturnal hypoglycemia and allow greater variability in daily
dosing times without increasing a patient's risk of hypoglycemia. Weekly administration
is, therefore, highly desirable. Characteristics of an exogenous basal insulin that may be
30 desirable include attenuated receptor binding, which can result in a reduced clearance rate
from the bloodstream, and/or chemical stability at multiple concentrations, which could
wo 2021/231676 -2- PCT/US2021/032144
contribute to extended shelf-life stability and/or stability in a concentrated formulation,
which would allow for the use in multi-dose devices.

WE CLAIM:
1. A compound of Formula I:
wherein X is selected from the group c 5 onsisting of -Lys-Gly-, -Lys-(2-[2-(2-
aminoethoxy)ethoxy]acetic acid)-, and -Lys-Gly-; or a pharmaceutically acceptable salt
thereof.
2. A compound of claim 1 wherein X is -Lys-Gly-, or a pharmaceutically
acceptable salt thereof.
10 3. A compound of claim 1 wherein X is -Lys-(2-[2-(2-aminoethoxy)ethoxy]acetic
acid)-, or a pharmaceutically acceptable salt thereof.
4. A compound of claim 1 wherein X is -Lys-Gly-, or a pharmaceutically
acceptable salt thereof.
5. A compound of claim 1 that is
15
, or a pharmaceutically acceptable salt thereof.
CLAIMS UNDER RULE 1 (PROVISIO) OF RULE 20
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6. A compound of claim 1 that is
,or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1 that is
5
, or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound of any one of claims 1
to 7, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically
acceptable excipients.
10 9. A compound selected from the group consisting of:
,
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,
and
.
, or a pharmaceutically acceptable salt thereof.