Note: Descriptions are shown in the official language in which they were submitted.
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TREATING UNTREATED OR TREATMENT-RESISTANT DIABETES
WITH GLUCOKINASE ACTIVATOR AND SODIUM-GLUCOSE
COTRANSPORTER-2 INHIBITOR
FIELD
[0001] Provided herein is a method of treating, preventing, or ameliorating
one or more
symptoms of an untreated or treatment-resistant diabetes with a glucokinase
activator (GKA)
in combination with a sodium-glucose cotransporter-2 (SGLT2) inhibitor.
BACKGROUND
[0002] Diabetes mellitus is a major health issue in the world. Nearly half
a billion people
are living with diabetes worldwide in 2019. IDF Diabetes Atlas; 9th ed.;
International
Diabetes Federation; 2019. Type 2 diabetes, i.e., non-insulin dependent
diabetes mellitus
(NIDDM), accounts for more than 90% of diabetes worldwide. Id. Type 2 diabetes
is a
hyperglycemic, chronic, metabolic dysfunction resulting from an imbalance of
blood glucose
homeostasis in the human body caused by insulin secretion disorder and insulin
resistance.
The blood glucose balance of the human body is mainly coordinated by two
hormones that
control blood glucose, including insulin and glucagon. Glucagon-like peptide-1
(GLP-1) is
involved in the regulation of insulin secretion. GLP-1 is also a therapeutic
drug for diabetes
that plays an important role in the blood glucose balance in human body.
Insulin and GLP-1
analogues have become important drugs for the treatment of diabetes.
[0003] Glucokinase (GK) plays a central role in stabilizing the blood
glucose balance in
human body. GK as a glucose sensor in glucose homeostasis, regulates the
secretion of
glucagon, insulin, and GLP-1 stimulated by glucose. GK is mainly distributed
in the liver,
where it rapidly converts glucose into hepatic glycogen for storage in
response to elevated
blood glucose and meanwhile lowers the glucose level in the blood. Defect of
glucokinase
causes impaired glucose tolerance (IGT) and type 2 diabetes. However, there is
currently no
GKAs approved for clinical use.
[0004] Because of the progressive failure of beta cells, type-2 diabetes is
an evolving
disease that requires progressive treatment intensification over time in order
to control
glucose adequately. Scheen, Expert Opin. Pharmacother. 2017, 18, 503-515.
Treatment
resistance is common and a major challenge in managing type-2 diabetes. Id.;
Stone et al.,
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Diabetes Care 2013, 36, 2628-2638. A large number of type-2 diabetes patients
have poor
glycemic control despite oral therapy combining metformin, a sulfonylurea, and
another
glucose-lowering agent. Scheen, Expert Op/n. Pharmacother. 2017, 18, 503-515.
Therefore,
there is a clinical need to be met in the field of a diabetes, particularly in
treating a treatment-
resistant diabetes.
SUMMARY OF THE DISCLOSURE
[0005] Provided herein is a method of treating an untreated or treatment-
resistant
diabetes, comprising administering to a subject in need thereof (i) a
therapeutically effective
amount of a GKA and (ii) a therapeutically effective amount of an SGLT2
inhibitor.
[0006] Also provided herein is a method of treating an untreated or
treatment-resistant
diabetes, comprising administering to a subject in need thereof (i) a
therapeutically effective
amount of a GKA and (ii) a therapeutically effective amount of an SGLT2
inhibitor; wherein
the GKA is (S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-1H-pyrrol-1-y1)-N-(1-
((R)-2,3-
dihydroxypropy1)-1H-pyrazol-3-y1)-4-methylpentanamide, or a tautomer, a
mixture of two or
more tautomers, or an isotopic variant thereof; or a pharmaceutically
acceptable salt, solvate,
hydrate, or prodrug thereof; and the SGLT2 inhibitor is empagliflozin, or a
tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof.
DETAILED DESCRIPTION
[0007] To facilitate understanding of the disclosure set forth herein, a
number of terms
are defined below.
[0008] Generally, the nomenclature used herein and the laboratory
procedures in organic
chemistry, medicinal chemistry, biochemistry, biology, and pharmacology
described herein
are those well known and commonly employed in the art. Unless defined
otherwise, all
technical and scientific terms used herein generally have the same meaning as
commonly
understood by one of ordinary skill in the art to which this disclosure
belongs.
[0009] The term "subject" refers to an animal, including, but not limited
to, a primate
(e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
The terms
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"subject" and "patient" are used interchangeably herein in reference, for
example, to a
mammalian subject, such as a human subject. In one embodiment, the subject is
a human.
[0010] The terms "treat," "treating," and "treatment" are meant to include
alleviating or
abrogating a disorder, disease, or condition, or one or more of the symptoms
associated with
the disorder, disease, or condition; or alleviating or eradicating the
cause(s) of the disorder,
disease, or condition itself
[0011] The terms "prevent," "preventing," and "prevention" are meant to
include a
method of delaying and/or precluding the onset of a disorder, disease, or
condition, and/or its
attendant symptoms; barring a subject from acquiring a disorder, disease, or
condition; or
reducing a subject's risk of acquiring a disorder, disease, or condition.
[0012] The terms "alleviate" and "alleviating" refer to easing or reducing
one or more
symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also
refer to
reducing adverse effects associated with an active ingredient. Sometimes, the
beneficial
effects that a subject derives from a prophylactic or therapeutic agent do not
result in a cure
of the disorder, disease, or condition.
[0013] The term "therapeutically effective amount" or "effective amount" is
meant to
include the amount of a compound that, when administered, is sufficient to
prevent
development of, or alleviate to some extent, one or more of the symptoms of
the disorder,
disease, or condition being treated. The term "therapeutically effective
amount" or "effective
amount" also refers to the amount of a compound that is sufficient to elicit a
biological or
medical response of a biological molecule (e.g., a protein, enzyme, RNA, or
DNA), cell,
tissue, system, animal, or human, which is being sought by a researcher,
veterinarian, medical
doctor, or clinician.
[0014] The term "pharmaceutically acceptable carrier," "pharmaceutically
acceptable
excipient," "physiologically acceptable carrier," or "physiologically
acceptable excipient"
refers to a pharmaceutically acceptable material, composition, or vehicle,
such as a liquid or
solid filler, diluent, solvent, or encapsulating material. In one embodiment,
each component
is "pharmaceutically acceptable" in the sense of being compatible with the
other ingredients
of a pharmaceutical formulation, and suitable for use in contact with the
tissue or organ of a
subject (e.g., a human or an animal) without excessive toxicity, irritation,
allergic response,
immunogenicity, or other problems or complications, commensurate with a
reasonable
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benefit/risk ratio. See, e.g., Remington: The Science and Practice of
Pharmacy, 22nd ed.;
Allen Ed.: Philadelphia, PA, 2012; Handbook of Pharmaceutical Excipients, 8th
ed.; Sheskey
et al., Eds.; The Pharmaceutical Press: 2017; Handbook of
PharmaceuticalAdditives, 3rd ed.;
Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical
Preformulation and
Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.
[0015] The term "about" or "approximately" means an acceptable error for a
particular
value as determined by one of ordinary skill in the art, which depends in part
on how the
value is measured or determined. In certain embodiments, the term "about" or
"approximately" means within 1, 2, 3, or 4 standard deviations. In certain
embodiments, the
term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%,
6%, 5%,
4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
[0016] In certain embodiments, "optically active" and "enantiomerically
active" refer to a
collection of molecules, which has an enantiomeric excess of no less than
about 80%, no less
than about 90%, no less than about 91%, no less than about 92%, no less than
about 93%, no
less than about 94%, no less than about 95%, no less than about 96%, no less
than about 97%,
no less than about 98%, no less than about 99%, no less than about 99.5%, or
no less than
about 99.8%. In certain embodiments, an optically active compound comprises
about 95% or
more of one enantiomer and about 5% or less of the other enantiomer based on
the total
weight of the enantiomeric mixture in question. In certain embodiments, an
optically active
compound comprises about 98% or more of one enantiomer and about 2% or less of
the other
enantiomer based on the total weight of the enantiomeric mixture in question.
In certain
embodiments, an optically active compound comprises about 99% or more of one
enantiomer
and about 1% or less of the other enantiomer based on the total weight of the
enantiomeric
mixture in question.
[0017] In describing an optically active compound, the prefixes R and S are
used to
denote the absolute configuration of the compound about its chiral center(s).
The (+) and (-)
are used to denote the optical rotation of the compound, that is, the
direction in which a plane
of polarized light is rotated by the optically active compound. The (-) prefix
indicates that
the compound is levorotatory, that is, the compound rotates the plane of
polarized light to the
left or counterclockwise. The (+) prefix indicates that the compound is
dextrorotatory, that
is, the compound rotates the plane of polarized light to the right or
clockwise. However, the
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sign of optical rotation, (+) and (-), is not related to the absolute
configuration of the
compound, R and S.
[0018] The term "isotopically enriched" refers to a compound that contains
an unnatural
proportion of an isotope at one or more of the atoms that constitute such a
compound. In
certain embodiments, an isotopically enriched compound contains unnatural
proportions of
one or more isotopes, including, but not limited to, hydrogen (1H), deuterium
(2H), tritium
(3H), carbon-11 ("C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14uz-,),
nitrogen-13 (13N),
nitrogen-14 (14-\IN),
nitrogen-15 (15N), oxygen-14 (140), oxygen-15 (150), oxygen-16 (160),
oxygen-17 (170), oxygen-18 (180),
fluorine-17 (17F), fluorine-18 ('T), phosphorus-31 (31P),
phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (328), sulfur-33 (338),
sulfur-34 (348),
sulfur-35 (358), sulfur-36 (368), chlorine-35 (35C1), chlorine-36 (36C1),
chlorine-37 (37C1),
bromine-79 (79Br), bromine-81 (81Br), iodine-123 (1231) iodine-125 (1251)
iodine-127 (1271),
iodine-129 (1291) and iodine-131 (1314 In certain embodiments, an isotopically
enriched
compound is in a stable form, that is, non-radioactive. In certain
embodiments, an
isotopically enriched compound contains unnatural proportions of one or more
isotopes,
including, but not limited to, hydrogen (1H), deuterium (2H), carbon-12 (12C),
carbon-13
(13C), nitrogen-14 (14-\IN),
nitrogen-15 (15N), oxygen-16 (160), oxygen-17 (170), oxygen-18
(18.,,u),
fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (328), sulfur-33 (338),
sulfur-34 (348),
sulfur-36 (368), chlorine-35 (35C1), chlorine-37 (37C1), bromine-79 (79Br),
bromine-81 (81Br),
and iodine-127 (1271). In certain embodiments, an isotopically enriched
compound is in an
unstable form, that is, radioactive. In certain embodiments, an isotopically
enriched
compound contains unnatural proportions of one or more isotopes, including,
but not limited
to, tritium (3H), carbon-11 ("C), carbon-14 ('4C), nitrogen-13 (13N), oxygen-
14 (140),
oxygen-15 (150), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P),
sulfur-35 (358),
chlorine-36 (36C1), iodine-123 (1231) iodine-125 (1251) iodine-129 (1291) and
iodine-131 (131I).
It will be understood that, in a compound as provided herein, any hydrogen can
be 2H, as
example, or any carbon can be 13C, as example, or any nitrogen can be 15N, as
example, or
any oxygen can be 180, as example, where feasible according to the judgment of
one of
ordinary skill in the art.
[0019] The term "isotopic enrichment" refers to the percentage of
incorporation of a less
prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a
given position in a
molecule in the place of a more prevalent isotope (e.g., 1H for protium or
hydrogen-1) of the
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element. As used herein, when an atom at a particular position in a molecule
is designated as
a particular less prevalent isotope, it is understood that the abundance of
that isotope at that
position is substantially greater than its natural abundance.
[0020] The term "isotopic enrichment factor" refers the ratio between the
isotopic
abundance in an isotopically enriched compound and the natural abundance of a
specific
isotope.
[0021] The term "deuterium enrichment" refers to the percentage of
incorporation of
deuterium at a given position in a molecule in the place of hydrogen. For
example, deuterium
enrichment of 1% at a given position means that 1% of molecules in a given
sample contain
deuterium at the specified position. Because the naturally occurring
distribution of deuterium
is about 0.0156% on average, deuterium enrichment at any position in a
compound
synthesized using non-enriched starting materials is about 0.0156% on average.
As used
herein, when a particular position in an isotopically enriched compound is
designated as
having deuterium, it is understood that the abundance of deuterium at that
position in the
compound is substantially greater than its natural abundance (0.0156%).
[0022] The terms "substantially pure" and "substantially homogeneous" mean
sufficiently homogeneous to appear free of readily detectable impurities as
determined by
standard analytical methods used by one of ordinary skill in the art,
including, but not limited
to, thin layer chromatography (TLC), gel electrophoresis, high performance
liquid
chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance
(NMR),
and mass spectrometry (MS); or sufficiently pure such that further
purification would not
detectably alter the physical, chemical, biological, and/or pharmacological
properties, such as
enzymatic and biological activities, of the substance. In certain embodiments,
"substantially
pure" or "substantially homogeneous" refers to a collection of molecules,
wherein at least
about 95%, at least about 96%, at least about 97%, at least about 98%, at
least about 99%, or
at least about 99.5% by weight of the molecules are a single compound,
including a single
enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by
standard
analytical methods. As used herein, when an atom at a particular position in
an isotopically
enriched molecule is designated as a particular less prevalent isotope, a
molecule that
contains other than the designated isotope at the specified position is an
impurity with respect
to the isotopically enriched compound. Thus, for a deuterated compound that
has an atom at
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a particular position designated as deuterium, a compound that contains a
protium at the same
position is an impurity.
[0023] The term "solvate" refers to a complex or aggregate formed by one or
more
molecules of a solute, e.g., a compound provided herein, and one or more
molecules of a
solvent, which are present in stoichiometric or non-stoichiometric amount.
Suitable solvents
include, but are not limited to, water, methanol, ethanol, n-propanol,
isopropanol, and acetic
acid. In certain embodiments, the solvent is pharmaceutically acceptable. In
one
embodiment, the complex or aggregate is in a crystalline form. In another
embodiment, the
complex or aggregate is in a noncrystalline form. Where the solvent is water,
the solvate is a
hydrate. Examples of hydrates include, but are not limited to, a hemihydrate,
monohydrate,
dihydrate, trihydrate, tetrahydrate, and pentahydrate.
[0024] The phrase "a tautomer, a mixture of two or more tautomers, or an
isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof' has the
same meaning as the phrase "(i) a tautomer, a mixture of two or more
tautomers, or an
isotopic variant of the compound referenced therein; or (ii) a
pharmaceutically acceptable
salt, solvate, hydrate, or prodrug of the compound referenced therein, or
(iii) a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug of a tautomer,
a mixture of two
or more tautomers, or an isotopic variant of the compound referenced therein."
[0025] In one embodiment, provided herein is a method of treating an
untreated or
treatment-resistant diabetes, comprising administering to a subject in need
thereof: (i) a
therapeutically effective amount of a GKA and (ii) a therapeutically effective
amount of an
SGLT2 inhibitor.
[0026] In one embodiment, the GKA is (S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-
dihydro-
1H-pyrrol-1-y1)-N-(1-((R)-2,3-dihydroxypropy1)-1H-pyrazol-3-y1)-4-
methylpentanamide, or a
tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. This
GKA is also
known as dorzagliatin having the structure shown below.
ci
NT:1\L'N
0
0 Hd OH
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[0027] In another embodiment, the GKA is one disclosed in U.S. Pat. No.
7,741,327 B2
or 9,388,168 B2, the disclosure of each of which is incorporated herein by
reference in its
entirety.
[0028] In certain embodiments, the GKA is deuterium-enriched. In certain
embodiments,
the GKA is carbon-13 enriched. In certain embodiments, the GKA is carbon-14
enriched. In
certain embodiments, the GKA contains one or more less prevalent isotopes for
other
elements, including, but not limited to, 15N for nitrogen; 170 or 180 for
oxygen, and 33, 34,
or 36S for sulfur.
[0029] In certain embodiments, the GKA has an isotopic enrichment factor of
no less
than about 5, no less than about 10, no less than about 20, no less than about
30, no less than
about 40, no less than about 50, no less than about 60, no less than about 70,
no less than
about 80, no less than about 90, no less than about 100, no less than about
200, no less than
about 500, no less than about 1,000, no less than about 2,000, no less than
about 5,000, or no
less than about 10,000. In any events, however, an isotopic enrichment factor
for a specified
isotope is no greater than the maximum isotopic enrichment factor for the
specified isotope,
which is the isotopic enrichment factor when the GKA at a given position is
100% enriched
with the specified isotope. Thus, the maximum isotopic enrichment factor is
different for
different isotopes. The maximum isotopic enrichment factor is 6,410 for
deuterium and 90
for carbon-13.
[0030] In certain embodiments, the GKA has a deuterium enrichment factor of
no less
than about 64 (about 1% deuterium enrichment), no less than about 130 (about
2% deuterium
enrichment), no less than about 320 (about 5% deuterium enrichment), no less
than about 640
(about 10% deuterium enrichment), no less than about 1,300 (about 20%
deuterium
enrichment), no less than about 3,200 (about 50% deuterium enrichment), no
less than about
4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80%
deuterium
enrichment), no less than about 5,450 (about 85% deuterium enrichment), no
less than about
5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95%
deuterium
enrichment), no less than about 6,220 (about 97% deuterium enrichment), no
less than about
6,280 (about 98% deuterium enrichment), no less than about 6,350 (about 99%
deuterium
enrichment), or no less than about 6,380 (about 99.5% deuterium enrichment).
The
deuterium enrichment can be determined using conventional analytical methods
known to
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one of ordinary skill in the art, including mass spectrometry and nuclear
magnetic resonance
spectroscopy.
[0031] In certain embodiments, the GKA has a carbon-13 enrichment factor of
no less
than about 1.8 (about 2% carbon-13 enrichment), no less than about 4.5 (about
5% carbon-13
enrichment), no less than about 9 (about 10% carbon-13 enrichment), no less
than about 18
(about 20% carbon-13 enrichment), no less than about 45 (about 50% carbon-13
enrichment),
no less than about 68 (about 75% carbon-13 enrichment), no less than about 72
(about 80%
carbon-13 enrichment), no less than about 77 (about 85% carbon-13 enrichment),
no less than
about 81 (about 90% carbon-13 enrichment), no less than about 86 (about 95%
carbon-13
enrichment), no less than about 87 (about 97% carbon-13 enrichment), no less
than about 88
(about 98% carbon-13 enrichment), no less than about 89 (about 99% carbon-13
enrichment),
or no less than about 90 (about 99.5% carbon-13 enrichment). The carbon-13
enrichment can
be determined using conventional analytical methods known to one of ordinary
skill in the
art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
[0032] In certain embodiments, at least one of the atoms of the GKA as
specified as
isotopically enriched has isotopic enrichment of no less than about 1%, no
less than about
2%, no less than about 5%, no less than about 10%, no less than about 20%, no
less than
about 50%, no less than about 70%, no less than about 80%, no less than about
90%, or no
less than about 98%. In certain embodiments, the atoms of the GKA as specified
as
isotopically enriched have isotopic enrichment of no less than about 1%, no
less than about
2%, no less than about 5%, no less than about 10%, no less than about 20%, no
less than
about 50%, no less than about 70%, no less than about 80%, no less than about
90%, or no
less than about 98%. In any events, the isotopic enrichment of the
isotopically enriched atom
of the GKA is no less than the natural abundance of the isotope specified.
[0033] In certain embodiments, at least one of the atoms of the GKA as
specified as
deuterium-enriched, has deuterium enrichment of no less than about 1%, no less
than about
2%, no less than about 5%, no less than about 10%, no less than about 20%, no
less than
about 50%, no less than about 70%, no less than about 80%, no less than about
90%, or no
less than about 98%. In certain embodiments, the atoms of the GKA as specified
as
deuterium-enriched, have deuterium enrichment of no less than about 1%, no
less than about
2%, no less than about 5%, no less than about 10%, no less than about 20%, no
less than
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about 50%, no less than about 70%, no less than about 80%, no less than about
90%, or no
less than about 98%.
[0034] In certain embodiments, at least one of the atoms of the GKA as
specified as 13C-
enriched, has carbon-13 enrichment of no less than about 2%, no less than
about 5%, no less
than about 10%, no less than about 20%, no less than about 50%, no less than
about 70%, no
less than about 80%, no less than about 90%, or no less than about 98%. In
certain
embodiments, the atoms of the GKA as specified as 13C-enriched, have carbon-13
enrichment
of no less than about 1%, no less than about 2%, no less than about 5%, no
less than about
10%, no less than about 20%, no less than about 50%, no less than about 70%,
no less than
about 80%, no less than about 90%, or no less than about 98%.
[0035] In certain embodiments, the GKA is isolated or purified. In certain
embodiments,
the GKA has a purity of at least about 50%, at least about 70%, at least about
80%, at least
about 90%, at least about 95%, at least about 98%, at least about 99%, or at
least about 99.5%
by weight.
[0036] The GKA is intended to encompass all possible stereoisomers, unless
a particular
stereochemistry is specified. Where the GKA contains an alkenyl group, the GKA
may exist
as one or mixture of geometric cis/trans (or Z/E) isomers. Where structural
isomers are
interconvertible, the GKA may exist as a single tautomer or a mixture of
tautomers. This can
take the form of proton tautomerism in the GKA that contains, for example, an
imino, keto,
or oxime group; or so-called valence tautomerism in the GKA that contain an
aromatic
moiety. It follows that a single GKA may exhibit more than one type of
isomerism.
[0037] The GKA can be enantiomerically pure, such as a single enantiomer or
a single
diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers,
e.g., a racemic
mixture of two enantiomers; or a mixture of two or more diastereomers. As
such, one of
ordinary skill in the art will recognize that administration of a GKA in its
(R) form is
equivalent, for GKAs that undergo epimerization in vivo, to administration of
the GKA in its
(5) form. Conventional techniques for the preparation/isolation of individual
enantiomers
include synthesis from a suitable optically pure precursor, asymmetric
synthesis from achiral
starting materials, or resolution of an enantiomeric mixture, for example,
chiral
chromatography, recrystallization, resolution, diastereomeric salt formation,
or derivatization
into diastereomeric adducts followed by separation.
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[0038] When the GKA contains an acidic or basic moiety, it can also be
provided as a
pharmaceutically acceptable salt. See, Berge et at., I Pharm. Sci. 1977, 66, 1-
19; Handbook
of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and
Wermuth Eds.;
Wiley-VCH and VHCA, Zurich, 2011.
[0039] Suitable acids for use in the preparation of pharmaceutically
acceptable salts of
the GKA include, but are not limited to, acetic acid, 2,2-dichloroacetic acid,
acylated amino
acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,
benzenesulfonic acid, benzoic
acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic
acid, (+)-
(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid,
cinnamic acid, citric
acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, ethane-
1,2-disulfonic
acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric
acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-
glucuronic acid, L-
glutamic acid, a-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic
acid,
hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, ( )-DL-lactic acid,
lactobionic acid,
lauric acid, maleic acid, (-)-L-malic acid, malonic acid, ( )-DL-mandelic
acid,
methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic
acid, 1-
hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic
acid, oxalic acid,
palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic
acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid,
succinic acid, sulfuric
acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic
acid, undecylenic
acid, and valeric acid.
[0040] Suitable bases for use in the preparation of pharmaceutically
acceptable salts of
the GKA, including, but not limited to, inorganic bases, such as magnesium
hydroxide,
calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide;
and organic
bases, such as primary, secondary, tertiary, and quaternary, aliphatic and
aromatic amines,
including L-arginine, benethamine, benzathine, choline, deanol,
diethanolamine,
diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-
ethanol,
ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine,
hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-
morpholine,
methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-
hydroxyethyl)-
pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine,
trimethylamine,
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triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-
propanediol, and
tromethamine.
[0041] The GKA may also be provided as a prodrug, which is a functional
derivative of
the GKA and is readily convertible into the parent GKA in vivo. Prodrugs are
often useful
because, in some situations, they may be easier to administer than the parent
GKA. They
may, for instance, be bioavailable by oral administration whereas the parent
GKA is not. The
prodrug may also have enhanced solubility in pharmaceutical compositions over
the parent
GKA. A prodrug may be converted into the parent drug by various mechanisms,
including
enzymatic processes and metabolic hydrolysis.
[0042] In certain embodiments, the GKA is formulated as a pharmaceutical
composition
comprising the GKA and a pharmaceutically acceptable excipient.
[0043] The GKA pharmaceutical composition can be formulated in various
dosage forms,
including, but not limited to, dosage forms for oral, parenteral, and topical
administration.
The GKA pharmaceutical composition can also be formulated as modified release
dosage
forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-,
controlled-,
accelerated-, fast-, targeted-, programmed-release, and gastric retention
dosage forms. These
dosage forms can be prepared according to conventional methods and techniques
known to
those skilled in the art. See, e.g., Remington: The Science and Practice of
Pharmacy, supra;
Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.;
Drugs and the
Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.
[0044] In one embodiment, a GKA pharmaceutical composition is formulated in
a dosage
form for oral administration. In another embodiment, a GKA pharmaceutical
composition is
formulated in a dosage form for parenteral administration. In yet another
embodiment, a
GKA pharmaceutical composition is formulated in a dosage form for intravenous
administration. In yet another embodiment, a GKA pharmaceutical composition is
formulated in a dosage form for intramuscular administration. In yet another
embodiment, a
GKA pharmaceutical composition is formulated in a dosage form for subcutaneous
administration. In still another embodiment, a GKA pharmaceutical composition
is
formulated in a dosage form for topical administration.
[0045] A GKA pharmaceutical composition provided herein can be provided in
a unit-
dosage form or multiple-dosage form. A unit-dosage form, as used herein,
refers to
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physically discrete a unit suitable for administration to a subject, and
packaged individually
as is known in the art. Each unit-dose contains a predetermined quantity of an
active
ingredient(s) (e.g., the GKA described herein) sufficient to produce the
desired therapeutic
effect, in association with the required pharmaceutical excipient(s). Examples
of a unit-
dosage form include, but are not limited to, an ampoule, syringe, and
individually packaged
tablet and capsule. A unit-dosage form may be administered in fractions or
multiples thereof
A multiple-dosage form is a plurality of identical unit-dosage forms packaged
in a single
container to be administered in a segregated unit-dosage form. Examples of a
multiple-
dosage form include, are not limited to, a vial, bottle of tablets or
capsules, or bottle of pints
or gallons.
[0046] The GKA pharmaceutical composition can be administered at once or
multiple
times at intervals of time. It is understood that the precise dosage and
duration of treatment
may vary with the age, weight, and condition of the subject being treated, and
may be
determined empirically using known testing protocols or by extrapolation from
in vivo or in
vitro test or diagnostic data. It is further understood that for any
particular individual,
specific dosage regimens should be adjusted over time according to the
subject's need and the
professional judgment of the person administering or supervising the
administration of the
GKA pharmaceutical composition.
[0047] In certain embodiments, the GKA pharmaceutical composition contains
a GKA
described herein (e.g., dorzagliatin) in an amount ranging from about 1 to
about 1,000, from
about 5 to about 500, from about 10 to about 250, from about 10 to about 150,
or from about
20 to about 100 mg per unit (e.g., a tablet). In certain embodiments, the GKA
pharmaceutical
composition contains a GKA described herein (e.g., dorzagliatin) in an amount
ranging from
about 1 to about 1,000 mg per unit (e.g., a tablet). In certain embodiments,
the GKA
pharmaceutical composition contains a GKA described herein (e.g.,
dorzagliatin) in an
amount ranging from about 5 to about 500 mg per unit (e.g., a tablet). In
certain
embodiments, the GKA pharmaceutical composition contains a GKA described
herein (e.g.,
dorzagliatin) in an amount ranging from about 10 to about 250 mg per unit
(e.g., a tablet). In
certain embodiments, the GKA pharmaceutical composition contains a GKA
described herein
(e.g., dorzagliatin) in an amount ranging from about 10 to about 150 mg per
unit (e.g., a
tablet). In certain embodiments, the GKA pharmaceutical composition contains a
GKA
described herein (e.g., dorzagliatin) in an amount ranging from about 25 to
about 100 mg per
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unit (e.g., a tablet). In certain embodiments, the GKA pharmaceutical
composition contains a
GKA described herein (e.g., dorzagliatin) in an amount of about 10, about 20,
about 25, about
30, about 40, about 50, about 55, about 60, about 65, about 70, about 75,
about 80, about 85,
about 90, about 95, about 100, about 110, about 120, about 130, about 140, or
about 150 mg
per unit (e.g., a tablet). In certain embodiments, the GKA pharmaceutical
composition
contains a GKA described herein (e.g., dorzagliatin) in an amount of about 25,
about 50,
about 75, or about 100 mg per unit (e.g., a tablet).
[0048] In one embodiment, the GKA pharmaceutical composition (hereinafter,
"dorzagliatin formulation") described herein comprises (S)-2-(4-(2-
chlorophenoxy)-2-oxo-
2,5-dihydro-1H-pyrrol-1-y1)-N-(1-((R)-2,3-dihydroxypropy1)-1H-pyrazol-3-y1)-4-
methylpentanamide, or a tautomer, a mixture of two or more tautomers, or an
isotopic variant
thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug
thereof; and a
pharmaceutically acceptable excipient.
[0049] In another embodiment, the dorzagliatin formulation is one disclosed
in U.S. Pat.
Appl. Pub. No. 2019/0328713 Al; the disclosure of which is incorporated herein
by reference
in its entirety.
[0050] In certain embodiments, the dorzagliatin formulation is formulated
for oral
administration. In certain embodiments, the dorzagliatin formulation is
formulated as
capsule. In certain embodiments, the dorzagliatin formulation is formulated as
a tablet. In
certain embodiments, the tablet is film-coated.
[0051] In certain embodiments, the dorzagliatin formulation contains (S)-2-
(4-(2-
chlorophenoxy)-2-oxo-2,5-dihydro-1H-pyrrol-1-y1)-N-(1-((R)-2,3-
dihydroxypropy1)-1H-
pyrazol-3-y1)-4-methylpentanamide in an amount ranging from about 1 to about
1,000, from
about 5 to about 500, from about 10 to about 250, from about 10 to about 150,
or from about
20 to about 100 mg per unit (e.g., a tablet). In certain embodiments, the
dorzagliatin
formulation contains (S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-1H-pyrrol-1-
y1)-N-(1-
((R)-2,3-dihydroxypropy1)-1H-pyrazol-3-y1)-4-methylpentanamide in an amount
ranging
from about 1 to about 1,000 mg per unit (e.g., a tablet). In certain
embodiments, the
dorzagliatin formulation contains (S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-
1H-pyrrol-
1-y1)-N-(1-((R)-2,3-dihydroxypropy1)-1H-pyrazol-3-y1)-4-methylpentanamide in
an amount
ranging from about 5 to about 500 mg per unit (e.g., a tablet). In certain
embodiments, the
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dorzagliatin formulation contains (S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-
1H-pyrrol-
1-y1)-N-(1-((R)-2,3-dihydroxypropy1)-1H-pyrazol-3-y1)-4-methylpentanamide in
an amount
ranging from about 10 to about 250 mg per unit (e.g., a tablet). In certain
embodiments, the
dorzagliatin formulation contains (S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-
1H-pyrrol-
1-y1)-N-(1-((R)-2,3-dihydroxypropy1)-1H-pyrazol-3-y1)-4-methylpentanamide in
an amount
ranging from about 10 to about 150 mg per unit (e.g., a tablet). In certain
embodiments, the
dorzagliatin formulation contains (S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-
1H-pyrrol-
1-y1)-N-(1-((R)-2,3-dihydroxypropy1)-1H-pyrazol-3-y1)-4-methylpentanamide in
an amount
ranging from about 20 to about 100 mg per unit (e.g., a tablet). In certain
embodiments, the
dorzagliatin formulation contains (S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-
1H-pyrrol-
1-y1)-N-(1-((R)-2,3-dihydroxypropy1)-1H-pyrazol-3-y1)-4-methylpentanamide in
an amount
of about 10, about 25, about 30, about 40, about 50, about 55, about 60, about
65, about 70,
about 75, about 80, about 85, about 90, about 95, about 100, about 110, about
120, about 130,
about 140, or about 150 mg per unit (e.g., a tablet). In certain embodiments,
the dorzagliatin
formulation contains (S)-2-(4-(2-chlorophenoxy)-2-oxo-2,5-dihydro-1H-pyrrol-1-
y1)-N-(1-
((R)-2,3-dihydroxypropy1)-1H-pyrazol-3-y1)-4-methylpentanamide in an amount of
about 25,
about 50, about 75, or about 100 mg per unit (e.g., a tablet).
[0052] In certain embodiments, the therapeutically effective amount of the
GKA (e.g.,
dorzagliatin) is ranging from about 0.1 to about 50, from about 0.2 to about
20, from about
0.5 to about 10, or from about 1 to about 5 mg/kg per day. In certain
embodiments, the
therapeutically effective amount of the GKA (e.g., dorzagliatin) is ranging
from about 0.1 to
about 50 mg/kg per day. In certain embodiments, the therapeutically effective
amount of the
GKA (e.g., dorzagliatin) is ranging from about 0.2 to about 20 mg/kg per day.
In certain
embodiments, the therapeutically effective amount of the GKA (e.g.,
dorzagliatin) is ranging
from about 0.5 to about 10 mg/kg per day. In certain embodiments, the
therapeutically
effective amount of the GKA (e.g., dorzagliatin) is ranging from about 1 to
about 5 mg/kg per
day. In certain embodiments, the therapeutically effective amount of the GKA
(e.g.,
dorzagliatin) is about 0.5, about 0.7, about 1, about 1.2, about 1.5, about
1.7, about 2, about
2.2, about 2.5, about 2.7, about 3, about 3.5, about 4, about 4.5, or about 5
mg/kg per day.
[0053] In certain embodiments, the therapeutically effective amount of the
GKA (e.g.,
dorzagliatin) is ranging from about 5 to about 1,000, from about 10 to about
500, or from
about 20 to about 200 mg per day. In certain embodiments, the therapeutically
effective
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amount of the GKA (e.g., dorzagliatin) is ranging from about 5 to about 1,000
mg per day. In
certain embodiments, the therapeutically effective amount of the GKA (e.g.,
dorzagliatin) is
ranging from about 10 to about 500 mg per day. In certain embodiments, the
therapeutically
effective amount of the GKA (e.g., dorzagliatin) is ranging from about 20 to
about 200 mg
per day. In certain embodiments, the therapeutically effective amount of the
GKA (e.g.,
dorzagliatin) is about 20, about 40, about 60, about 80, about 100, about 110,
about 120,
about 130, about 140, about 150, about 160, about 170, about 180, about 190,
or about 200
mg per day. In certain embodiments, the therapeutically effective amount of
the GKA (e.g.,
dorzagliatin) is about 25, about 50, or about 75 mg per day.
[0054] In certain embodiments, the GKA (e.g., dorzagliatin) is administered
once daily
(QD), or divided into multiple daily doses such as twice daily (BID), and
three times daily
(TID). In certain embodiments, the GKA (e.g., dorzagliatin) is administered
once daily
(QD). In certain embodiments, the GKA (e.g., dorzagliatin) is administered
twice daily
(BID). In certain embodiments, the GKA (e.g., dorzagliatin) is administered
three times daily
(TID).
[0055] In certain embodiments, the GKA is administered under fasted
conditions. In
certain embodiments, the GKA is administered without a food. In certain
embodiments, the
GKA is administered at least about 10, about 20, about 30, about 40, or about
60 min before a
meal. In certain embodiments, the GKA is administered at least 1, 2, or 3
hours after a meal.
[0056] It will be understood, however, that the specific dose level and
frequency of
dosage for any particular subject can be varied and will depend upon a variety
of factors
including the activity of the specific GKA (e.g., dorzagliatin), the metabolic
stability and
length of action of the compound, the age, body weight, general health, sex,
diet, mode and
time of administration, rate of excretion, drug combination, the severity of
the particular
condition, and the host undergoing therapy.
[0057] In one embodiment, the SGLT2 inhibitor is bexagliflozin,
canagliflozin,
dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin,
phlorizin,
remogliflozin, serglifozin, sotagliflozin, or tofogliflozin; or a tautomer, a
mixture of two or
more tautomers, or an isotopic variant thereof; or a pharmaceutically
acceptable salt, solvate,
hydrate, or prodrug thereof In another embodiment, the SGLT2 inhibitor is
canagliflozin,
dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, or tofogliflozin;
or a tautomer, a
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mixture of two or more tautomers, or an isotopic variant thereof or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof. In yet another
embodiment, the SGLT2
inhibitor is canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin; or
a tautomer, a
mixture of two or more tautomers, or an isotopic variant thereof; or a
pharmaceutically
acceptable salt, solvate, hydrate, or prodrug thereof. In still another
embodiment, the SGLT2
inhibitor is empagliflozin, or a tautomer, a mixture of two or more tautomers,
or an isotopic
variant thereof or a pharmaceutically acceptable salt, solvate, hydrate, or
prodrug thereof
[0058] In one embodiment, the SGLT2 inhibitor is (2S,3R,4R,5S,6R)-2-(4-
chloro-3-{[4-
(2-cyclopropoxyethoxy)phenyl]methyl}pheny1)-6-(hydroxymethyl)oxane-3,4,5-triol
(also
known as bexagliflozin):
cl 001\
0
HO
HO'ss OH
OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is bexagliflozin.
[0059] In another embodiment, the SGLT2 inhibitor is (2S,3R,4R,5S,6R)-2-(3-
{[5-(4-
fluorophenyl)thiophen-2-yl]methyl } -4-methylpheny1)-6-(hydroxymethyl)oxane-
3,4,5-triol
(also known as canagliflozin):
HOO
HO"(" OH
OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is canagliflozin.
[0060] In yet another embodiment, the SGLT2 inhibitor is (2S,3R,4R,5S,6R)-2-
{4-chloro-
3-[(4-ethoxyphenyl)methyl]pheny1}-6-(hydroxymethyl)oxane-3,4,5-triol
(2S,3R,4R,5S,6R)-
2-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-6-(hydroxymethyl)oxane-3,4,5-
triol (also
known as dapagliflozin):
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CI
HO 0
HOssµ 'OH
OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is dapagliflozin.
[0061] In yet another embodiment, the SGLT2 inhibitor is (2S,3R,4R,5S,6R)-2-
[4-chloro-
3-({4-[(3S)-oxolan-3-yloxy]phenylImethyl)pheny1]-6-(hydroxymethyl)oxane-3,4,5-
triol (also
known as empagliflozin):
0
0
HO
==
'OH
OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is empagliflozin.
[0062] In yet another embodiment, the SGLT2 inhibitor is (1S,2S,3S,4R,5S)-5-
{4-chloro-
3- [(4-ethoxyphenyl)methyl]phenyl -1-(hydroxymethyl)-6, 8-dioxabicyclo[3 .2.1]
octane-2,3 ,4-
triol (also known as ertugliflozin):
Cl
0
0
HO
'OH
OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is ertugliflozin.
[0063] In yet another embodiment, the SGLT2 inhibitor is (2S,3R,4R,5S,6R)-2-
{3-[(1-
benzothiophen-2-yl)methy1]-4-fluoropheny1}-6-(hydroxymethyl)oxane-3,4,5-triol
(also
known as ipragliflozin):
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0
HO
HO''s 'OH
OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is ipragliflozin.
[0064] In yet another embodiment, the SGLT2 inhibitor is (2S,3R,4R,5S,6R)-2-
{5-[(4-
ethoxyphenyl)methy1]-2-methoxy-4-methylphenyl} -6-(hydroxymethyl)thiane-3,4,5-
triol (also
known as luseogliflozin):
0
HO
HO' 'OH
OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is luseogliflozin.
[0065] In yet another embodiment, the SGLT2 inhibitor is 1-[2,4-dihydroxy-6-
[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypheny1]-3-(4-
hydroxyphenyl)propan-1-one (also known as phlorizin):
OH
0
O
HO H
s
HO's Y'''OH
OH OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is phlorizin.
[0066] In yet another embodiment, the SGLT2 inhibitor is ethyl
[(2R,3S,4S,5R,6S)-3,4,5-
trihydroxy-6-{ [5-methyl-1-(propan-2-y1)-4-{ [4-(propan-2-yloxy)phenyl]methyl
} -1H-pyrazol-
3-yl]oxy}oxan-2-yl]methyl carbonate (also known as remogliflozin etabonate):
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0
0
0
0 N -N
HO" "OH yõ
'OH
OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is remogliflozin.
[0067] In yet another embodiment, the SGLT2 inhibitor is ethyl
(((2R,3S,4S,5R,6S)-3,4,5-
trihydroxy-6-(2-(4-methoxybenzyl)phenoxy)tetrahydro-2H-pyran-2-yl)methyl)
carbonate
(also known as serglifozin etabonate):
o
0
0)-((y.=%,,,D.A0
HO"("OH
ss,
OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is serglifozin etabonate.
[0068] In yet another embodiment, the SGLT2 inhibitor is (2S,3R,4R,5S,6R)-2-
{4-chloro-
3-[(4-ethoxyphenyl)methyl]pheny1}-6-(methylsulfanyl)oxane-3,4,5-triol (also
known as
sotagliflozin):
Cl
s 0
HO' 'OH
OH
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is sotagliflozin.
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[0069] In still another embodiment, the SGLT2 inhibitor is
(1S,3'R,4'S,5'S,6'R)-6-[(4-
ethylphenyl)methy1]-6'-(hydroxymethyl)-3H-spiro[2-benzofuran-1,2'-oxane]-
3',4',5'-triol
(also known as tofogliflozin):
OH
HO 0
HO
OH
0
or a tautomer, a mixture of two or more tautomers, or an isotopic variant
thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In
certain
embodiments, the SGLT2 inhibitor is tofogliflozin.
[0070] In certain embodiments, the SGLT2 inhibitor is deuterium-enriched.
In certain
embodiments, the SGLT2 inhibitor is carbon-13 enriched. In certain
embodiments, the
SGLT2 inhibitor is carbon-14 enriched. In certain embodiments, the SGLT2
inhibitor
contains one or more less prevalent isotopes for other elements, including,
but not limited to,
15N for nitrogen; 170 or 180 for oxygen, and "S, 34S, or 36S for sulfur.
[0071] In certain embodiments, the SGLT2 inhibitor has an isotopic
enrichment factor of
no less than about 5, no less than about 10, no less than about 20, no less
than about 30, no
less than about 40, no less than about 50, no less than about 60, no less than
about 70, no less
than about 80, no less than about 90, no less than about 100, no less than
about 200, no less
than about 500, no less than about 1,000, no less than about 2,000, no less
than about 5,000,
or no less than about 10,000. In any events, however, an isotopic enrichment
factor for a
specified isotope is no greater than the maximum isotopic enrichment factor
for the specified
isotope, which is the isotopic enrichment factor when the SGLT2 inhibitor at a
given position
is 100% enriched with the specified isotope. Thus, the maximum isotopic
enrichment factor
is different for different isotopes. The maximum isotopic enrichment factor is
6410 for
deuterium and 90 for carbon-13.
[0072] In certain embodiments, the SGLT2 inhibitor has a deuterium
enrichment factor of
no less than about 64 (about 1% deuterium enrichment), no less than about 130
(about 2%
deuterium enrichment), no less than about 320 (about 5% deuterium enrichment),
no less than
about 640 (about 10% deuterium enrichment), no less than about 1,300 (about
20%
deuterium enrichment), no less than about 3,200 (about 50% deuterium
enrichment), no less
than about 4,800 (about 75% deuterium enrichment), no less than about 5,130
(about 80%
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deuterium enrichment), no less than about 5,450 (about 85% deuterium
enrichment), no less
than about 5,770 (about 90% deuterium enrichment), no less than about 6,090
(about 95%
deuterium enrichment), no less than about 6,220 (about 97% deuterium
enrichment), no less
than about 6,280 (about 98% deuterium enrichment), no less than about 6,350
(about 99%
deuterium enrichment), or no less than about 6,380 (about 99.5% deuterium
enrichment).
The deuterium enrichment can be determined using conventional analytical
methods known
to one of ordinary skill in the art, including mass spectrometry and nuclear
magnetic
resonance spectroscopy.
[0073] In certain embodiments, the SGLT2 inhibitor has a carbon-13
enrichment factor of
no less than about 1.8 (about 2% carbon-13 enrichment), no less than about 4.5
(about 5%
carbon-13 enrichment), no less than about 9 (about 10% carbon-13 enrichment),
no less than
about 18 (about 20% carbon-13 enrichment), no less than about 45 (about 50%
carbon-13
enrichment), no less than about 68 (about 75% carbon-13 enrichment), no less
than about 72
(about 80% carbon-13 enrichment), no less than about 77 (about 85% carbon-13
enrichment),
no less than about 81 (about 90% carbon-13 enrichment), no less than about 86
(about 95%
carbon-13 enrichment), no less than about 87 (about 97% carbon-13 enrichment),
no less than
about 88 (about 98% carbon-13 enrichment), no less than about 89 (about 99%
carbon-13
enrichment), or no less than about 90 (about 99.5% carbon-13 enrichment). The
carbon-13
enrichment can be determined using conventional analytical methods known to
one of
ordinary skill in the art, including mass spectrometry and nuclear magnetic
resonance
spectroscopy.
[0074] In certain embodiments, at least one of the atoms of the SGLT2
inhibitor as
specified as isotopically enriched has isotopic enrichment of no less than
about 1%, no less
than about 2%, no less than about 5%, no less than about 10%, no less than
about 20%, no
less than about 50%, no less than about 70%, no less than about 80%, no less
than about 90%,
or no less than about 98%. In certain embodiments, the atoms of the SGLT2
inhibitor as
specified as isotopically enriched have isotopic enrichment of no less than
about 1%, no less
than about 2%, no less than about 5%, no less than about 10%, no less than
about 20%, no
less than about 50%, no less than about 70%, no less than about 80%, no less
than about 90%,
or no less than about 98%. In any events, the isotopic enrichment of the
isotopically enriched
atom of the SGLT2 inhibitor is no less than the natural abundance of the
isotope specified.
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[0075] In certain embodiments, at least one of the atoms of the SGLT2
inhibitor as
specified as deuterium-enriched has deuterium enrichment of no less than about
1%, no less
than about 2%, no less than about 5%, no less than about 10%, no less than
about 20%, no
less than about 50%, no less than about 70%, no less than about 80%, no less
than about 90%,
or no less than about 98%. In certain embodiments, the atoms of the SGLT2
inhibitor as
specified as deuterium-enriched have deuterium enrichment of no less than
about 1%, no less
than about 2%, no less than about 5%, no less than about 10%, no less than
about 20%, no
less than about 50%, no less than about 70%, no less than about 80%, no less
than about 90%,
or no less than about 98%.
[0076] In certain embodiments, at least one of the atoms of the SGLT2
inhibitor as
specified as '3C-enriched has carbon-13 enrichment of no less than about 2%,
no less than
about 5%, no less than about 10%, no less than about 20%, no less than about
50%, no less
than about 70%, no less than about 80%, no less than about 90%, or no less
than about 98%.
In certain embodiments, the atoms of the SGLT2 inhibitor as specified as '3C-
enriched have
carbon-13 enrichment of no less than about 1%, no less than about 2%, no less
than about
5%, no less than about 10%, no less than about 20%, no less than about 50%, no
less than
about 70%, no less than about 80%, no less than about 90%, or no less than
about 98%.
[0077] In certain embodiments, the SGLT2 inhibitor is isolated or purified.
In certain
embodiments, the SGLT2 inhibitor has a purity of at least about 50%, at least
about 70%, at
least about 80%, at least about 90%, at least about 95%, at least about 98%,
at least about
99%, or at least about 99.5% by weight.
[0078] The SGLT2 inhibitors described herein are intended to encompass all
possible
stereoisomers, unless a particular stereochemistry is specified. Where the
SGLT2 inhibitor
contains an alkenyl group, the SGLT2 inhibitor may exist as one or mixture of
geometric
cis/trans (or Z/E) isomers. Where structural isomers are interconvertible, the
SGLT2
inhibitor may exist as a single tautomer or a mixture of tautomers. This can
take the form of
proton tautomerism in the SGLT2 inhibitor that contains, for example, an
imino, keto, or
oxime group; or so-called valence tautomerism in the SGLT2 inhibitor that
contain an
aromatic moiety. It follows that a single SGLT2 inhibitor may exhibit more
than one type of
isomerism.
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[0079] The SGLT2 inhibitor can be enantiomerically pure, such as a single
enantiomer or
a single diastereomer, or be stereoisomeric mixtures, such as a mixture of
enantiomers, e.g., a
racemic mixture of two enantiomers; or a mixture of two or more diastereomers.
As such,
one of ordinary skill in the art will recognize that administration of a SGLT2
inhibitor in its
(R) form is equivalent, for SGLT2 inhibitors that undergo epimerization in
vivo, to
administration of the SGLT2 inhibitor in its (5) form. Conventional techniques
for the
preparation/isolation of individual enantiomers include synthesis from a
suitable optically
pure precursor, asymmetric synthesis from achiral starting materials, or
resolution of an
enantiomeric mixture, for example, chiral chromatography, recrystallization,
resolution,
diastereomeric salt formation, or derivatization into diastereomeric adducts
followed by
separation.
[0080] When the SGLT2 inhibitor contains an acidic or basic moiety, it can
also be
provided as a pharmaceutically acceptable salt. See, Berge et al., I Pharm.
Sci. 1977, 66, 1-
19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.;
Stahl and
Wermuth Eds.; Wiley-VCH and VHCA, Zurich, 2011.
[0081] Suitable acids for use in the preparation of pharmaceutically
acceptable salts of
the SGLT2 inhibitor include, but are not limited to, acetic acid, 2,2-
dichloroacetic acid,
acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic
acid, benzenesulfonic
acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid,
camphorsulfonic
acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic
acid, cinnamic
acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric
acid, ethane-1,2-
disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic
acid, fumaric
acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-
glucuronic acid,
L-glutamic acid, a-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic
acid,
hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, ( )-DL-lactic acid,
lactobionic acid,
lauric acid, maleic acid, (-)-L-malic acid, malonic acid, ( )-DL-mandelic
acid,
methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic
acid, 1-
hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic
acid, oxalic acid,
palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic
acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid,
succinic acid, sulfuric
acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic
acid, undecylenic
acid, and valeric acid.
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[0082] Suitable bases for use in the preparation of pharmaceutically
acceptable salts of
the SGLT2 inhibitor, including, but not limited to, inorganic bases, such as
magnesium
hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium
hydroxide;
and organic bases, such as primary, secondary, tertiary, and quaternary,
aliphatic and
aromatic amines, including L-arginine, benethamine, benzathine, choline,
deanol,
diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine,
2-
(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,
isopropylamine, N-
methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-
hydroxyethyl)-
morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-
(2-
hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline,
triethanolamine,
trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-
1,3-
propanediol, and tromethamine.
[0083] The SGLT2 inhibitor may also be provided as a prodrug, which is a
functional
derivative of a SGLT2 inhibitor, for example, remogliflozin etabonate or
serglifozin
etabonate and is readily convertible into the parent SGLT2 inhibitor in vivo.
Prodrugs are
often useful because, in some situations, they may be easier to administer
than the parent
SGLT2 inhibitor. They may, for instance, be bioavailable by oral
administration whereas the
parent SGLT2 inhibitor is not. The prodrug may also have enhanced solubility
in
pharmaceutical compositions over the parent SGLT2 inhibitor. A prodrug may be
converted
into the parent drug by various mechanisms, including enzymatic processes and
metabolic
hydrolysis.
[0084] In certain embodiments, canagliflozin or a pharmaceutically
acceptable salt is
formulated as described in the package insert for INVOKANA . In certain
embodiments,
dapagliflozin or a pharmaceutically acceptable salt is formulated as described
in the package
insert for FARXIGA . In certain embodiments, empagliflozin or a
pharmaceutically
acceptable salt is formulated as described in the package insert for JARDIANCE
. In certain
embodiments, ertugliflozin or a pharmaceutically acceptable salt is formulated
as described in
the package insert for STEGLATRO .
[0085] In certain embodiments, the therapeutically effective amount of the
SGLT2
inhibitor (e.g., empagliflozin) is ranging from about 1 to about 1,000, from
about 1 to about
500, from about 1 to about 250, from about 1 to about 100, from about 2 to
about 50, or from
about 5 to about 50 mg per day mg per day. In certain embodiments, the
therapeutically
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effective amount of the SGLT2 inhibitor (e.g., empagliflozin) is ranging from
about 1 to
about 1,000 mg per day. In certain embodiments, the therapeutically effective
amount of the
SGLT2 inhibitor (e.g., empagliflozin) is ranging from about 1 to about 500 mg
per day. In
certain embodiments, the therapeutically effective amount of the SGLT2
inhibitor (e.g.,
empagliflozin) is ranging from about 1 to about 250 mg per day. In certain
embodiments, the
therapeutically effective amount of the SGLT2 inhibitor (e.g., empagliflozin)
is ranging from
about 1 to about 100 mg per day. In certain embodiments, the therapeutically
effective
amount of the SGLT2 inhibitor (e.g., empagliflozin) is ranging from about 2 to
about 50 mg
per day. In certain embodiments, the therapeutically effective amount of the
SGLT2 inhibitor
(e.g., empagliflozin) is ranging from about 5 to about 50 mg per day. In
certain
embodiments, the therapeutically effective amount of the SGLT2 inhibitor
(e.g.,
empagliflozin) is about 5, about 10, about 15, about 20, about 25, about 30,
about 35, about
40, about 45, or about 50 mg per day.
[0086] In certain embodiments, the SGLT2 inhibitor (e.g., empagliflozin) is
administered
under fasted conditions. In certain embodiments, the SGLT2 inhibitor (e.g.,
empagliflozin) is
administered without a food. In certain embodiments, the SGLT2 inhibitor
(e.g.,
empagliflozin) is administered at least about 10, about 20, about 30, about
40, or about 60
min before a meal. In certain embodiments, the SGLT2 inhibitor (e.g.,
empagliflozin) is
administered at least 1, 2, or 3 hours after a meal.
[0087] The GKA can be administered prior to (e.g., 5 min, 15 min, 50 min,
65 min, 1 h, 2
h, 6 h, 6 h, 12 h, 26 h, 68 h, 72 h, or 96 h before), concomitantly with, or
subsequent to (e.g.,
min, 15 min, 50 min, 65 min, 1 h, 2 h, 6 h, 12 h, 26 h, 68 h, 72 h, or 96 h
after) the
administration of the SGLT2 inhibitor to the subject. In one embodiment, the
GKA is
administered concurrently with the SGLT2 inhibitor. In another embodiment, the
GKA is
administered separately with the SGLT2 inhibitor. In yet another embodiment,
the GKA is
administered sequentially with the SGLT2 inhibitor. In yet another embodiment,
the GKA is
administered before the SGLT2 inhibitor. In yet another embodiment, the GKA is
administered after the SGLT2 inhibitor.
[0088] In one embodiment, the diabetes is an untreated or treatment-
resistant type 1
diabetes. In another embodiment, the diabetes is an untreated or treatment-
resistant type 2
diabetes.
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[0089] In certain embodiments, the diabetes is a diabetes with persistent
hyperglycemia.
In certain embodiments, the diabetes is a diabetes with a glycated hemoglobin
level (HbAlc)
of no less than about 7%. In certain embodiments, the diabetes is a diabetes
with an HbAl c
of no less than about 8%. In certain embodiments, the diabetes is a diabetes
with an HbAl c
of no less than about 9%. In certain embodiments, the is a diabetes with an
HbAl c of no less
than about 10%.
[0090] In certain embodiments, the diabetes is a diabetes with an HbAl c of
no less than
about 64 mmol/mol. In certain embodiments, the diabetes is a diabetes with an
HbAl c of no
less than about 75 mmol/mol. In certain embodiments, the diabetes is a
diabetes with an
HbAl c of no less than about 86 mmol/mol.
[0091] In certain embodiments, the treatment-resistant diabetes is a
diabetes with
persistent hyperglycemia despite pharmacological treatment with at least three
oral glucose-
lowering medications. In certain embodiments, the treatment-resistant diabetes
is a diabetes
with an HbAl c of no less than about 7% despite pharmacological treatment with
at least three
oral glucose-lowering medications. In certain embodiments, the treatment-
resistant diabetes
is a diabetes with an HbAl c of no less than about 8% despite pharmacological
treatment with
at least three oral glucose-lowering medications. In certain embodiments, the
treatment-
resistant diabetes is a diabetes with an HbAl c of no less than about 9%
despite
pharmacological treatment with at least three oral glucose-lowering
medications. In certain
embodiments, the treatment-resistant diabetes is a diabetes with an HbAl c of
no less than
about 10% despite pharmacological treatment with at least three oral glucose-
lowering
medications.
[0092] In certain embodiments, the treatment-resistant diabetes is a
diabetes with an
HbAl c of no less than about 64 mmol/mol despite pharmacological treatment
with at least
three oral glucose-lowering medications. In certain embodiments, the treatment-
resistant
diabetes is a diabetes with an HbAl c of no less than about 75 mmol/mol
despite
pharmacological treatment with at least three oral glucose-lowering
medications. In certain
embodiments, the treatment-resistant diabetes is a diabetes with an HbAl c of
no less than
about 86 mmol/mol despite pharmacological treatment with at least three oral
glucose-
lowering medications.
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[0093] In certain embodiments, the treatment-resistant diabetes is a
diabetes with
persistent poorly-controlled diabetes despite standard care with three oral
glucose-lowering
medications.
[0094] In one embodiment, the treatment-resistant diabetes is resistant to
metformin, a
meglitinide, a dipeptidyl peptidase 4 (DPP-4) inhibitor, an SGLT2 inhibitor,
an insulin, a
sulfonylurea, a thiazolidinedione, a glucagon-like peptide-1 (GLP-1) agonist,
or a
combination thereof.
[0095] In one embodiment, the treatment-resistant diabetes is resistant to
a DPP-4
inhibitor. In another embodiment, the treatment-resistant diabetes is
resistant to an SGLT-2
inhibitor. In yet another embodiment, the treatment-resistant diabetes is
resistant to
metformin. In yet another embodiment, the treatment-resistant diabetes is
resistant to a DPP-
4 inhibitor and an SGLT-2 inhibitor. In yet another embodiment, the treatment-
resistant
diabetes is resistant to a DPP-4 inhibitor and metformin. In yet another
embodiment, the
treatment-resistant diabetes is resistant to an SGLT-2 inhibitor and
metformin. In still
another embodiment, the treatment-resistant diabetes is resistant to a DPP-4
inhibitor, an
SGLT-2 inhibitor, and metformin.
[0096] In certain embodiments, the treatment-resistant diabetes is
resistant to a DPP-4
inhibitor. In certain embodiments, the treatment-resistant diabetes is
resistant to alogliptin,
anaglipitin, dutogliptin, evogliptin, gemigliptin, gosogliptin, linagliptin,
omarigliptin,
saxagliptin, sitagliptin, teneligliptin, trelaglitin, or vildagliptin. In
certain embodiments, the
treatment-resistant diabetes is resistant to alogliptin, anaglipitin,
evogliptin, gemigliptin,
gosogliptin, linagliptin, omarigliptin, saxagliptin, sitagliptin,
teneligliptin, trelaglitin, or
vildagliptin. In certain embodiments, the treatment-resistant diabetes is
resistant to alogliptin,
linagliptin, saxagliptin, or sitagliptin.
[0097] In certain embodiments, the treatment-resistant diabetes is
resistant to an SGLT2
inhibitor. In certain embodiments, the treatment-resistant diabetes is
resistant to
bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin,
ipragliflozin,
luseogliflozin, phlorizin, remogliflozin, serglifozin, sotagliflozin, or
tofogliflozin. In certain
embodiments, the treatment-resistant diabetes is resistant to canagliflozin,
dapagliflozin,
empagliflozin, ertugliflozin, ipragliflozin, or tofogliflozin. In certain
embodiments, the
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treatment-resistant diabetes is resistant to canagliflozin, dapagliflozin,
empagliflozin, or
ertugliflozin.
[0098] In certain embodiments, the treatment-resistant diabetes is
resistant to a GLP-1
receptor agonist. In certain embodiments, the treatment-resistant diabetes is
resistant to
albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, or
semaglutide.
[0099] In certain embodiments, the treatment-resistant diabetes is
resistant to an insulin.
In certain embodiments, the treatment-resistant diabetes is resistant to a
fast-acting insulin, a
short-acting insulin, an intermediate-acting insulin, a long-acting insulin,
or an ultra-long
acting insulin.
[00100] In certain embodiments, the treatment-resistant diabetes is
resistant to a
meglitinide. In certain embodiments, the treatment-resistant diabetes is
resistant to
nateglinide or repaglinide.
[00101] In certain embodiments, the treatment-resistant diabetes is
resistant to a
sulfonylurea. In certain embodiments, the treatment-resistant diabetes is
resistant to
cloropropamide, gliclazide, glimepiride, or tolazamide.
[00102] In certain embodiments, the treatment-resistant diabetes is
resistant to a
thiazolidinedione. In certain embodiments, the treatment-resistant diabetes is
resistant to
balaglitazone, ciglitazone, darglitazone, englitazone, lobeglitazone,
netoglitazone,
pioglitazone, rivoglitanzone, rosiglitazone, or troglitazone. In certain
embodiments, the
treatment-resistant diabetes is resistant to lobeglitazone, rosiglitazone, or
pioglitazone.
[00103] In certain embodiments, the subject with a treatment-resistant
diabetes fails a
monotherapy. In certain embodiments, the subject with a treatment-resistant
diabetes fails a
dual-agent therapy.
[00104] In certain embodiments, the subject is a mammal. In certain
embodiments, the
subject is a human.
[00105] A method provided herein encompasses treating a subject regardless of
subject's
age, although some diseases are more common in certain age groups.
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[00106] In one embodiment, provided herein is a method of treating a treatment-
resistant
diabetes, comprising administering to a subject in need thereof a
therapeutically effective
amount of dorzagliatin and a therapeutically effective amount of
empagliflozin. In certain
embodiments, the therapeutically effective amount of dorzagliatin is about 150
mg per day
and the therapeutically effective amount of empagliflozin is from about 10 to
about 50 mg
per day. In certain embodiments, the therapeutically effective amount of
dorzagliatin is about
150 mg per day and the therapeutically effective amount of empagliflozin is
about 25 mg per
day. In certain embodiments, dorzagliatin is administered in an amount of 75
mg twice daily
and empagliflozin is administered in an amount of about 25 mg daily. In
certain
embodiments, the therapeutically effective amount of dorzagliatin is about 25,
about 50, or
about 75 mg per day and the therapeutically effective amount of empagliflozin
is about 25
mg per day.
[00107] The disclosure will be further understood by the following non-
limiting examples.
EXAMPLES
[00108] As used herein, the symbols and conventions used in these processes,
schemes and
examples, regardless of whether a particular abbreviation is specifically
defined, are
consistent with those used in the contemporary scientific literature, for
example, the Journal
of the American Chemical Society, the Journal of Medicinal Chemistry, or the
Journal of
Biological Chemistry. Specifically, but without limitation, the following
abbreviations may
be used in the examples and throughout the specification: g (grams); mg
(milligrams); dL
(deciliters); mL (microliters); mM (millimolar); mol (moles); mmol
(millimoles); h (hour or
hours); and min (minutes).
Example 1
Phase 1, open-label, sequential, multiple-dose, drug-drug interaction (DDI)
study of
dorzagliatin and empagliflozin in subjects with type-2 diabetes mellitus
(T2DM)
[00109] This phase I study accessed the pharmacokinetic interaction between
dorzagliatin
and empagliflozin in T2DM subjects. This study also evaluated the safety and
tolerability of
dorzagliatin with simultaneous administration of empagliflozin in T2DM
subjects.
Moreover, this study accessed the pharmacodynamic responses of serum glucose,
insulin, C-
peptide, plasma glucagon, urinary glucose excretion following dorzagliatin,
empagliflozin, or
simultaneous administration of dorzagliatin and empagliflozin in T2DM
subjects.
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[00110] Sixteen eligible subjects were enrolled and 15 of them completed
the study. Study
drugs were administered according to the dosing scheme provided in Table 1.
TABLE 1: Treatment Scheme
Day Empagliflozin Dorzagliatin PK Sample Collection
1-5 25 mg (QD) for 5 days Day 5: Empagliflozin alone
75 mg (BID) for 4 days Day 10: Empagliflozin +
6-10 25 mg (QD) for 5 days
Morning dose only on Day 10 dorzagliatin
75 mg (BID) for 4 days
11-15 Day 15: Dorzagliatin alone
Morning dose only on Day 15
[00111] All subjects received: (i) empagliflozin (25 mg, QD) on Days 1-5; and
empagliflozin was taken 60 min prior to meals (except on Day 5, when it was
administered
30 min before glucose intake); (ii) empagliflozin (25 mg, QD) and dorzagliatin
(75 mg, BID)
on Days 6-10 (only the morning dose on Day 10); and empagliflozin and
dorzagliatin were
taken 60 min prior to meals (except on Day 10, when they were administered 30
min before
glucose intake); or (iii) dorzagliatin 75 mg BID on Days 11-15 (only the
morning dose on
Day 15); and dorzagliatin was taken 60 min prior to meals (except on Day 15,
when it was
administered 30 min before glucose intake).
[00112] Eligible subjects had a minimum 12-day run-in period prior to
admission to a
clinical research center (CRC), during which time they self-administered
empagliflozin (25
mg, QD) each morning. Empagliflozin, a glucometer, and a diary were dispensed
to each
subject by the CRC. Subjects were advised to monitor their blood glucose
levels and report
changes in health status to the CRC. Subjects completed the diary to record
empagliflozin
doses taken each day and the results of the blood glucose monitoring. On Day -
14, the CRC
trained the subjects in how to use the glucometer and fill out the diary. The
subjects then
tested their blood glucose levels and self-administered the Day -14 dose of
empagliflozin on-
site and were asked to record both in the diary immediately. A telephone call
was placed to
each subject at approximately Day -8 during the run-in period to assess
general health and
collect adverse event (AE) information. The subjects returned the glucometers
to the CRC on
Day -2.
[00113] Following completion of the run-in period, eligible subjects were
admitted to the
CRC on Day -2, had a total of 18 overnight stays, and were discharged after
End-of-Study
procedures were completed on Day 17 or at early termination.
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[00114] On Days 5, 10 and 15, a 75-gram glucose solution (oral glucose
tolerance test,
OGTT) was administered 30 min post-drug administration. No breakfast was
provided.
[00115] Blood samples for the determination of dorzagliatin and empagliflozin
concentrations and corresponding pharmacokinetic (PK) analysis were collected
at the
following time points on Days 5, 10 and 15: pre-dose (within 30 min prior to
drug dosing)
and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 h post-dose.
[00116] Pharmacodynamic (PD) responses, i.e., serum levels of glucose, insulin
and C-
peptide and plasma levels of glucagon, were evaluated on Days 5, 10 and 15:
pre-dose
(within 60 min prior to glucose intake) and at 0.5, 1, 1.5, 2, 2.5, 3 and 4 h
post-glucose intake.
Urine was collected for urinary glucose excretion on Days 5, 10 and 15: pre-
dose (for bladder
emptying only, no pre-dose glucose measurement), and over a series of
intervals (0-2 h, 2-4
h, 4-6 h, 6-8 h, 8-12 h and 12-24 h post-dose).
[00117] Safety assessments included monitoring of AEs, blood glucose via
glucometer
readings, vital signs (blood pressure, pulse rate, respiratory rate, and oral
temperature),
clinical laboratory findings, 12-lead ECGs, and PE findings including body
weight at various
time points during the study.
[00118] Vital signs were performed at screening, on Day -1, on Days 1-15
within 60
minutes prior to each study drug dose, and on Day 17. A staff used the
glucometer on the
subjects, three times a day, within 60 min before each meal or glucose intake
and after study
drug dosing when applicable (no measurement on Day 17). Clinical laboratory
evaluations
were performed at screening, on Day -1, Days 5, 10 and 15 and at the End-of-
Study on Day
17. A resting 12-lead ECG was completed at screening, Day -1, and 2 h post-
dose on Day 5,
Day 10 and Day 15, and at the End-of-Study on Day 17. PEs were conducted at
screening,
Day -1, and at the End-of-Study on Day 17.
[00119] Eligible subjects for the study were subjects diagnosed with T2DM at
least 3
months prior to screening and were currently taking a stable dose of the
following therapy
with no changes in the dosage for at least 4 weeks prior to screening: (i) >
1000 mg per day
of metformin; (ii) a DPP-4 inhibitor; (iii) an SGLT2 inhibitor; (iv) metformin
plus a DPP-4
inhibitor; or (v) metformin plus an SGLT2 inhibitor. Subjects must agree to
change their
current therapy to empagliflozin (25 mg, QD) for at least 14 days prior to
dosing on Day 1.
Additional inclusion criteria for the eligible subjects included (i) male
and/or female subjects
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between the ages of 30 and 65 years; (ii) with a body mass index (BMI) of 19
to 38 kg/m2 at
screening; (iii) fasting C-peptide test result > 0.3 nmol/L (>0.90 ng/mL);
(iv) HbAl c > 7%
and < 10.5%
[00120] The study excluded those with (i) fasting blood glucose at screening
or Day -1 <
110 or > 270 mg/dL; (ii) type 1 diabetes mellitus, or latent autoimmune
diabetes in adults;
diabetic neuropathy, retinopathy or nephropathy; (iii) reported incidence of
severe
hypoglycemia within 3 months prior to screening and/or within 3 months prior
to dosing on
Day 1; (iv) known contraindications to empagliflozin; (v) clinically
significant
gastrointestinal disorders; (vi) history or symptoms of clinically significant
cardiovascular
diseases; (vii) reported history of liver diseases; (viii) reported history of
clinically significant
renal diseases; (ix) estimated glomerular filtration rate (eGFR) < 60
mL/min/1.73 m2; (x)
acute or chronic metabolic acidosis, including diabetic ketoacidosis; (xi)
known or suspected
malignancy; (xii) any reported hypersensitivity or intolerance to
empagliflozin; (xiii)
antidiabetic treatment with insulin, sulfonylureas, thiazolidinediones or GLP-
1 agonist within
3 months prior to screening; (xiv) systolic blood pressure < 90 or > 160 mmHg
or diastolic
blood pressure < 60 or > 100 mmHg at screening; (xv) uncontrolled
hypertriglyceridemia >
500 mg/dL; (xvi) female is breast-feeding or planning to become pregnant; or
(xvii) reported
history of donation or acute loss of blood during the 90 days prior to
screening.
[00121] Dorzagliatin was provided as a film-coated tablet in 75 mg strength
for oral
administration 60 min prior to a meal. Empagliflozin was provided as JARDIANCE
(25
mg) film-coated tablets for oral administration 60 min prior to a meal. The
total duration of
participation in the study for each subject was about 45 days (up to 14-day
screening period,
12-day run-in period, and 19-day in-clinic period).
[00122] The plasma concentration-time data for dorzagliatin and empagliflozin
were
analyzed using non-compartmental methods to calculate PK parameters.
Empagliflozin did
not have a significant effect on dorzagliatin PK parameters based on the
analysis of plasma
dorzagliatin Cmax and AUCo-24h. Least squares geometric means for Cmax were
889 and 856
for dorzagliatin in combination with empagliflozin and dorzagliatin alone,
respectively, with
a percent ratio of geometric means (GMR) of 104% (90% CI: 90, 119). Least
squares
geometric means for AUCo-24h were 6,490 and 6,510 for dorzagliatin in
combination with
empagliflozin and dorzagliatin alone, respectively, with a percent GMR of
99.7% (90% CI:
95, 104). A lack of a significant drug-drug interaction for the effect of
empagliflozin on
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dorzagliatin PK parameters was supported by the percent GMR 90% CI for
dorzagliatin Cmax
and AUCo-24h being fully contained within the 80.00 to 125.00% boundaries.
[00123] Dorzagliatin did not have a significant effect on empagliflozin PK
parameters
based on the analysis of plasma empagliflozin Cmax and AUC0-24h. Least squares
geometric
means for Cmax were 387 and 393 for empagliflozin in combination with
dorzagliatin and
empagliflozin alone, respectively, with a percent GMR of 98.4% (90% CI: 84,
115). Least
squares geometric means for AUC0-24h were 3,030 and 3,108 for empagliflozin in
combination with dorzagliatin and empagliflozin alone, respectively, with a
percent GMR of
97.5% (90% CI: 94, 101). A lack of a significant drug-drug interaction for the
effect of
dorzagliatin on empagliflozin PK parameters is supported by the percent GMR
90% CI for
empagliflozin Cmax and AUCo-24h being fully contained within the 80.00 to
125.00%
boundaries.
[00124] Following the oral glucose tolerance test (OGTT), combination
treatment of
empagliflozin and dorzagliatin achieved significantly better glucose lowering
effect than
administration of either empagliflozin or dorzagliatin treatment alone, based
on the resulted
glucose PD parameters (baseline corrected AUEC0-4h, CEmax, and CEav) as
summarized in
Table 2.
TABLE 2: Glucose Responses
Parameter Statistic Empagliflozin Empagliflozin +
Dorzagliatin Dorzagliatin
CE max 16 15 15
(mg/dL) Mean (SD) 199 (51)** 145 (40) 163 (38)*
AUECo-4h n 16 15 15
(1-rmg/dL1 Mean (SD) 452 (165)** 279 (105) 364 (121)4
CEav fl 16 15 15
(mg/dL) Mean (SD) 113 (41)** 70(26) 91 (30)*
*P <0.01; **P <0.0001; #13< 0.05
[00125] As summarized in Table 3, mean baseline corrected insulin levels
following
combination treatment of empagliflozin and dorzagliatin were higher than
either
empagliflozin or dorzagliatin monotherapy.
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TABLE 3: Insulin Responses
Parameter Statistic Empagliflozin Empagliflozin +
Dorzagliatin Dorzagliatin
CE max 16 15 15
(mg/dL) Mean (SD) 46 (24) # 67 (38) 56 (27)
AUECo-4h 11 16 15 15
(1-ring/dL1 Mean (SD) 91 (39) # 127 (68) 110 (52)
CEav fl 16 15 15
(mg/dL) Mean (SD) 23 (9.7) # 32 (17) 28 (13)
#13 <0.05
[00126] As summarized in Table 4 and similar to insulin, baseline corrected
AUEC0-4h,
CEmax, and CEav of C-peptide following combination administration of
empagliflozin and
dorzagliatin were higher than those for administration of either empagliflozin
or dorzagliatin
monotherapy.
TABLE 4: C-peptide Responses
Parameter Statistic Empagliflozin Empagliflozin +
Dorzagliatin Dorzagliatin
CE max 16 14 15
(mg/dL) Mean (SD) 4.7(2.0)* 7.0 (4.0) 5.5(2.5)#
AUEC0_4h n 16 14 15
(1-ring/dL1 Mean (SD) 11 (4.7)* 16 (9.0) 13
(6.0)
CE, n 16 14 15
(mg/dL) Mean (SD) 2.7(1.2)* 4.0 (2.3) 3.2(1.5)#
*P <0.01; #13 <0.05
* * * * *
[00127] The examples set forth above are provided to give those of ordinary
skill in the art
with a complete disclosure and description of how to make and use the claimed
embodiments, and are not intended to limit the scope of what is disclosed
herein.
Modifications that are obvious to persons of skill in the art are intended to
be within the
scope of the following claims. All publications, patents, and patent
applications cited in this
specification are incorporated herein by reference as if each such
publication, patent or patent
application were specifically and individually indicated to be incorporated
herein by
reference.
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