U.S. patent application number 16/844522 was filed with the patent office on 2020-07-30 for treatment of metabolic disorders in equine animals.
The applicant listed for this patent is Boehringer Ingelheim Vetmedica GmbH. Invention is credited to Laura JOHNSTON, Nicole MOHREN, Dania Birte REICHE, Bruce SOMERVILLE, Rebecca K. VOTH.
Application Number | 20200237794 16/844522 |
Document ID | 20200237794 / US20200237794 |
Family ID | 1000004753987 |
Filed Date | 2020-07-30 |
Patent Application | download [pdf] |
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United States Patent
Application |
20200237794 |
Kind Code |
A1 |
REICHE; Dania Birte ; et
al. |
July 30, 2020 |
TREATMENT OF METABOLIC DISORDERS IN EQUINE ANIMALS
Abstract
One or more SGLT2 inhibitors or pharmaceutically acceptable
forms thereof are provided for use in the treatment and/or
prevention of a metabolic disorder of an equine animal. For
example, the treatment and/or prevention can be for laminitis,
vascular dysfunction, hypertension, hepatic lipidosis,
atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia
Dysfunction and/or Equine Metabolic Syndrome in an equine
animal.
Inventors: |
REICHE; Dania Birte; (Bingen
am Rhein, DE) ; MOHREN; Nicole; (Jugenheim, DE)
; JOHNSTON; Laura; (Thornleigh, AU) ; SOMERVILLE;
Bruce; (Parkville, MO) ; VOTH; Rebecca K.;
(Smiithville, MO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim Vetmedica GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
1000004753987 |
Appl. No.: |
16/844522 |
Filed: |
April 9, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14672705 |
Mar 30, 2015 |
|
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16844522 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 5/50 20180101; A61K
31/351 20130101; A61K 9/02 20130101; A61K 9/4866 20130101; A61K
31/7056 20130101; C07D 309/10 20130101; A61K 31/7048 20130101; A61K
9/08 20130101; A61K 47/02 20130101; A61K 31/382 20130101; A61K
31/7034 20130101; A61P 3/10 20180101; A61K 9/2059 20130101; A61K
31/7042 20130101 |
International
Class: |
A61K 31/7034 20060101
A61K031/7034; A61K 31/351 20060101 A61K031/351; A61P 3/10 20060101
A61P003/10; C07D 309/10 20060101 C07D309/10; A61P 5/50 20060101
A61P005/50; A61K 31/382 20060101 A61K031/382; A61K 9/08 20060101
A61K009/08; A61K 9/02 20060101 A61K009/02; A61K 9/48 20060101
A61K009/48; A61K 9/20 20060101 A61K009/20; A61K 47/02 20060101
A61K047/02; A61K 31/7056 20060101 A61K031/7056; A61K 31/7048
20060101 A61K031/7048; A61K 31/7042 20060101 A61K031/7042 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 1, 2014 |
EP |
14162983.2 |
Jul 11, 2014 |
EP |
14176714.5 |
Oct 1, 2014 |
EP |
14187223.4 |
Claims
1. A method of treating or preventing a metabolic disorder in an
equine comprising administering an SGLT2 inhibitor or
pharmaceutically acceptable form thereof, wherein the metabolic
disorder is one or more disorders selected from laminitis, vascular
dysfunction, hypertension, hepatic lipidosis, atherosclerosis,
hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or
Equine Metabolic Syndrome.
2. The method according to claim 1, wherein said SGLT2 inhibitor or
pharmaceutically acceptable form thereof is selected from the group
consisting of the following compounds or pharmaceutically
acceptable forms thereof: a glucopyranosyl-substituted benzene
derivative of the formula (1) ##STR00024## wherein R1 denotes
cyano, Cl or methyl; R2 denotes H, methyl, methoxy or hydroxyl; and
R3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine,
iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,
iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl,
cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl,
1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy,
difluoromethyl, trifluoromethyl, pentafluoroethyl,
2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl,
2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,
1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,
2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,
2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy,
2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl,
methlysulfonyl, ethylsulfinyl, ethyl sulfonyl, trimethylsilyl,
(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or
cyano, wherein R3 is preferably selected from cyclopropyl, ethyl,
ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or
(S)-tetrahydrofuran-3-yloxy; or a derivative thereof wherein one or
more hydroxyl groups of the .beta.-D-glucopyranosyl group are
acylated with groups selected from (C1-18-alkyl)carbonyl,
(C1-18-alkyl)oxycarbonyl, phenylcarbonyl and
phenyl-(C1-3-alkyl)-carbonyl; Dapagliflozin, represented by formula
(3): ##STR00025## Canagliflozin, represented by formula (4):
##STR00026## Empagliflozin, represented by formula (5):
##STR00027## Luseogliflozin, represented by formula (6):
##STR00028## Tofogliflozin, represented by formula (7):
##STR00029## Ipragliflozin, represented by formula (8):
##STR00030## Ertugliflozin, represented by formula (9):
##STR00031## Atigliflozin, represented by formula (10):
##STR00032## Remogliflozin, represented by formula (11):
##STR00033## a thiophene derivative of the formula (12)
##STR00034## wherein R denotes methoxy or trifluoromethoxy;
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene; represented by formula (13); ##STR00035## a spiroketal
derivative of the formula (14): ##STR00036## wherein R denotes
methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl;
a pyrazole-O-glucoside derivative of the formula (15) ##STR00037##
wherein R1 denotes C1-3-alkoxy, L1, L2 independently of each other
denote H or F, R6 denotes H, (C1-3-alkyl)carbonyl,
(C1-6-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or
benzylcarbonyl; a compound of the formula (16): ##STR00038##
Sergliflozin, represented by formula (17): ##STR00039## a compound
represented by formula (18): ##STR00040## wherein R3 is selected
from cyclopropyl, ethyl, ethinyl, ethoxy,
(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.
3. The method of claim 2, wherein said SGLT2 inhibitor or
pharmaceutically acceptable form thereof is selected from the group
consisting of the following compounds or pharmaceutically
acceptable forms thereof: a glucopyranosyl-substituted benzene
derivative of the formula (1) ##STR00041## wherein R1 denotes
cyano, Cl or methyl; R2 denotes H, methyl, methoxy or hydroxy; and
R3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine,
iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,
iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl,
cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl,
1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy,
difluoromethyl, trifluoromethyl, pentafluoroethyl,
2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl,
2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,
1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,
2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,
2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy,
2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl,
methlysulfonyl, ethylsulfinyl, ethyl sulfonyl, trimethylsilyl,
(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or
cyano; wherein R3 is preferably selected from cyclopropyl, ethyl,
ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or
(S)-tetrahydrofuran-3-yloxy; or a derivative thereof wherein one or
more hydroxyl groups of the .beta.-D-glucopyranosyl group are
acylated with groups selected from (C1-18-alkyl)carbonyl,
(C1-18-alkyl)oxycarbonyl, phenylcarbonyl and
phenyl-(C1-3-alkyl)-carbonyl. Dapagliflozin, represented by formula
(3): ##STR00042## Canagliflozin, represented by formula (4):
##STR00043## Empagliflozin, represented by formula (5):
##STR00044## Ertugliflozin, represented by formula (9):
##STR00045## a compound represented by formula (18): ##STR00046##
wherein: R3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy,
(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.
4. The method according to claim 1, wherein the metabolic disorder
is a clinical condition or sign associated with insulin resistance
or hyperinsulinaemia.
5. The method according to claim 1, wherein the metabolic disorder
is hyperinsulinemia and/or insulin resistance, and wherein said
hyperinsulinemia and/or insulin resistance is associated with one
or more of laminitis, vascular dysfunction, hypertension, hepatic
lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars
Intermedia Dysfunction and/or Equine Metabolic Syndrome.
6. The method according to claim 1, wherein the equine animal is a
horse or a pony.
7. The method according to claim 1, wherein the equine animal is
obese and/or exhibits regional adiposity.
8. The method according to claim 1, wherein the composition
comprises a crystalline complex of the SGLT2 inhibitor or
pharmaceutically acceptable form thereof and an amino acid, and the
amino acid is proline.
9. The method according to claim 1, wherein the SGLT2 inhibitor or
pharmaceutically acceptable form thereof is administered orally or
parenterally.
10. The method according to claim 1, wherein the SGLT2 inhibitor or
pharmaceutically acceptable form thereof is administered
orally.
11. The method according to claim 1, wherein the SGLT2 inhibitor or
pharmaceutically acceptable form thereof is administered in a range
of from 0.01 to 5 mg/kg body weight per day.
12. The method according to claim 1, wherein the SGLT2 inhibitor or
pharmaceutically acceptable form thereof is administered in a range
of from 0.02 to 1.0 mg/kg body weight per day.
13. The method according to claim 1, wherein the SGLT2 inhibitor or
pharmaceutically acceptable form thereof is administered in a range
of from 0.03 to 0.4 mg/kg body weight per day.
14. The method according to claim 1, wherein the SGLT2 inhibitor or
pharmaceutically acceptable form thereof is administered once per
day.
15. The method according to claim 1, wherein the equine animal is
not obese and/or is present with muscle wasting and/or exhibits
hyperglycemia.
16. The method of claim 1, wherein the composition comprises a
1:1:1 crystalline complex of the SGLT2 inhibitor or
pharmaceutically acceptable form thereof, L-proline and water in a
crystalline form.
17. The method according to claim 16, wherein the 1:1:1 crystalline
complex is characterized by an X-ray powder diffraction pattern
that comprises peaks at 20.28, 21.14 and 21.64 degrees 2.THETA.
(.+-.0.1 degrees 2.theta.), wherein said X-ray powder diffraction
pattern is made using CuK.sub..alpha.1 radiation.
18. The method of claim 1, wherein said laminitis, vascular
dysfunction, hypertension, hepatic lipidosis, atherosclerosis,
hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or
Equine Metabolic Syndrome is associated with insulin resistance
and/or hyperinsulinemia.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/672,705, filed Mar. 30, 2015, which claims
priority from EP 14162983.2, filed Apr. 1, 2014, and from EP
14176714.5, filed Jul. 11, 2014, and from EP 14187223.4, filed Oct.
1, 2014, the disclosures of which are incorporated herein by
reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to veterinary medicine, in
particular to the treatment and/or prevention of metabolic
disorders in equine animals.
BACKGROUND OF THE INVENTION
[0003] Equine animals, e.g., horses, are affected by various
metabolic disorders, including insulin resistance and
hyperinsulinaemia. Such insulin-related disorders in equine
animals, for example, are only rarely associated with diabetes
mellitus and hyperglycemia, as it is in humans or various other
mammals. However, in equine animals, insulin also regulates vital
metabolic functions; e.g., insulin drives glucose into tissues such
as liver, adipose, and skeletal muscle; induces vasoconstrictive
and vasodilatory pathways; and regulates protein and fat
metabolism. Insulin-related disorders thus have a severe and
life-threatening impact on the health of equine animals. They are
correlated or may be associated with a number of further equine
disorders, conditions or syndromes, including impaired glucose
tolerance, dyslipidemia, dysadipokinemia, obesity and/or regional
adiposity, subclinical inflammation or systemic inflammation, in
particular low grade systemic inflammation, which also comprises
adipose tissue, Equine Metabolic Syndrome (EMS) and/or Equine
Pituitary Pars Intermedia Dysfunction (PPID), also known as equine
Cushing's syndrome, which are characterized e.g. by laminitis,
vascular dysfunction, hypertension, hepatic lipidosis,
hyperadrenocorticism and/or atherosclerosis.
[0004] In particular, insulin resistance in equine animals may be
associated with EMS and/or PPID or may cause the development or
progression of PPID. EMS and/or PPID may become manifest e.g., in
laminitis. This devastating worldwide cause of mortality in horses
is a multifactorial condition causing structural and mechanical
changes in the supporting tissues within the hoof, resulting in
acute and chronic pain, lameness, and potentially euthanasia.
Equine laminae are highly metabolically active, and a complex
microvascular bed is present. A significant body of evidence exists
also for vascular dysfunction (endothelial cell dysfunction) during
equine laminitis (ref 1: Katz & Bailey, 2012). In vitro studies
in equine digital vessels have shown insulin resistance mediated
endothelial and/or vascular dysfunction (ref. 2: Venugopal et al.,
2011). A direct link between hyperinsulinaemia and laminitis has
been documented in naturally-occurring forms of the disease (ref.
3: Treiber et al., 2006). However, the mechanism by which insulin
resistance and/or hyperinsulinemia cause EMS and/or PPID, in
particular vascular dysfunction and/or laminitis in horses is
poorly understood.
[0005] No satisfactory treatment is currently available for
metabolic disorders such as insulin resistance, hyperinsulinaemia
and associated disorders in equine animals, such as EMS and/or in
case they are associated with or secondary to e.g., PPID, which
become manifested e.g., by laminitis, vascular dysfunction,
hypertension in equine animals. For instance, the use of Metformin
is controversially discussed (ref 4: Tinworth et al., 2012).
Similarly, treatment of equine PPID with pergolide seems to hardly
affect insulin resistance and/or hyperinsulinemia (ref 5: Gehlen,
2014).
[0006] In human medicine, insulin resistance, e.g., when manifested
as diabetes mellitus type 2, is a well-recognized condition, and
may lead in particular to hyperglycemia (pathologically increased
plasma glucose levels). Several oral antihyperglycemic drugs are
approved for human diabetes. These drugs act, e.g., by stimulating
pancreatic insulin secretion in a glucose-independent or
glucose-dependent manner (sulfonylurea/meglitinides, or DPP IV
inhibitors, respectively), by enhancing tissue sensitivity to
insulin (biguanides, thiazolidinediones), or by slowing
postprandial intestinal glucose absorption (alpha-glucosidase
inhibitors).
[0007] Other antihyperglycemic approaches have been contemplated
for treating diabetes and high blood sugar, including inhibition of
the renal sodium-dependent glucose cotransporter SGLT2. SGLT2 in
the kidney regulates glucose levels by mediating the reabsorption
of glucose back into the plasma following filtration of the blood.
SGLT2 inhibition thus induces glucosuria or glycosuria and may
reduce blood glucose levels.
[0008] SGLT2 inhibition has not previously been contemplated for
use in equine animals, in particular in insulin-resistant equine
animals. In equine animals, insulin-resistance, i.e., failure of
tissues to respond appropriately to insulin, generally becomes
manifested as hyperinsulinemia. When insulin-resistant target
tissues, e.g., skeletal muscle, have a reduced capacity for glucose
uptake, the pancreas is stimulated to release more insulin, leading
to hyperinsulinaemia. However, unlike in humans, e.g., insulin
resistance in equine animals, e.g., horses, is generally not
associated with hyperglycemia (ref. 6: Frank et al., 2011).
Insulin-resistant equine animals, e.g., horses, do not appear to
have high blood glucose. For that reason, it would appear to be
counter-intuitive to apply an approach that reduces blood glucose
by transferring glucose out of the blood into the urine, even if
this was previously known in a context of high blood glucose.
DISCLOSURE OF THE INVENTION
Summary of the Invention
[0009] The present invention has surprisingly found that inhibition
of SGLT2 is effective and safe in the treatment and/or prevention
of metabolic disorders in equine animals. The present invention
thus provides the use of one or more SGLT2 inhibitors or
pharmaceutically acceptable forms thereof in the treatment and/or
prevention of a metabolic disorder of an equine animal. Further
aspects of the invention are defined below, as well as in the
claims.
[0010] According to the invention, the metabolic disorder may be
insulin resistance, hyperinsulinemia, and/or a clinical
condition/sign associated with insulin resistance and/or
hyperinsulinemia.
[0011] The metabolic disorder, or said clinical condition/sign
associated with insulin resistance and/or hyperinsulinemia, may be
one or more disorder selected from insulin resistance,
hyperinsulinemia, impaired glucose tolerance, dyslipidemia,
dysadipokinemia, subclinical inflammation, systemic inflammation,
low grade systemic inflammation, which also comprises adipose
tissue, obesity, regional adiposity, laminitis, vascular
dysfunction, hypertension, hepatic lipidosis, atherosclerosis,
hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or
Equine Metabolic Syndrome.
[0012] According to the invention, the equine animal may be
suffering from one or more of impaired glucose tolerance,
dyslipidemia, dysadipokinemia, subclinical inflammation, systemic
inflammation, low grade systemic inflammation, which also comprises
adipose tissue, obesity, regional adiposity, laminitis, vascular
dysfunction, hypertension, hepatic lipidosis, atherosclerosis,
hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or
Equine Metabolic Syndrome.
[0013] According to the invention, impaired glucose tolerance,
dyslipidemia, dysadipokinemia, subclinical inflammation, systemic
inflammation, low grade systemic inflammation, which also comprises
adipose tissue, obesity, regional adiposity, laminitis, vascular
dysfunction, hypertension, hepatic lipidosis, atherosclerosis,
hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or
Equine Metabolic Syndrome may be associated with hyperinsulinemia
and/or insulin resistance.
[0014] According to the invention, the metabolic disorder may be
hyperinsulinemia and/or insulin resistance, and said
hyperinsulinemia or insulin resistance may optionally be associated
with one or more of impaired glucose tolerance, dyslipidemia,
dysadipokinemia, subclinical inflammation, systemic inflammation,
low grade systemic inflammation, which also comprises adipose
tissue, obesity, regional adiposity, laminitis, vascular
dysfunction, hypertension, hepatic lipidosis, atherosclerosis,
hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or
Equine Metabolic Syndrome.
[0015] The equine animal may, e.g., be a horse. The equine animal
may, e.g., be a pony. The equine animal may be obese and/or exhibit
regional adiposity. However, for instance as regards Pituitary Pars
Intermedia Dysfunction, the equine animal may also be not obese
and/or be present with muscle wasting and/or exhibit
hyperglycemia.
[0016] The pharmaceutically acceptable form of the one or more
SGLT2 inhibitors may be a crystalline complex between the one or
more SGLT2 inhibitors and one or more amino acids, e.g.,
proline.
[0017] According to the invention, the one or more SGLT2 inhibitors
or pharmaceutically acceptable forms thereof may be provided, e.g.,
for oral or parenteral administration, preferably for oral
administration.
[0018] The one or more SGLT2 inhibitors or pharmaceutically
acceptable forms thereof may be administered in dosages of 0.01 to
3.0 mg/kg body weight per day, preferably from 0.02 to 1.0 mg/kg
body weight per day, more preferably from 0.03 to 0.4 mg/kg body
weight per day. Thus, the one or more SGLT2 inhibitors or
pharmaceutically acceptable forms thereof may be prepared for the
administration of 0.01 to 3.0 mg/kg body weight per day, preferably
from 0.02 to 1.0 mg/kg body weight per day, more preferably from
0.03 to 0.4 mg/kg body weight per day.
[0019] The one or more SGLT2 inhibitors or pharmaceutically
acceptable forms thereof is preferably administered only once per
day.
[0020] According to the present invention, any SGLT2 inhibitor or
pharmaceutically acceptable form thereof may be used. In preferred
embodiments, the one or more SGLT2 inhibitors are a
glucopyranosyl-substituted benzene derivative. A number of SGLT2
inhibitors which may be used according to the invention are
described in detail below.
[0021] The present invention also provides a pharmaceutical
composition comprising one or more SGLT2 inhibitors or a
pharmaceutically acceptable form thereof, for use according to the
invention as disclosed herein.
[0022] In the examples provided herein, therapeutic and
prophylactic benefits resulting from inhibition of SGLT2 according
to the present invention are demonstrated experimentally.
Experimental data disclosed herein are intended to illustrate the
invention, but not to have any limiting effect upon the scope of
protection, which is defined herein below by the claims.
[0023] In particular, the present invention has surprisingly found
that the use of one or more SGLT2 inhibitors according to the
present invention advantageously leads to a reduction in insulin
resistance in treated, insulin resistant equine animals. That is,
equivalently, the use of one or more SGLT2 inhibitors according to
the present invention advantageously leads to increased insulin
sensitivity in treated, insulin resistant equine animals.
[0024] The use of one or more SGLT2 inhibitors according to the
present invention advantageously leads to reduced plasma insulin
levels, i.e., allows effective treatment of hyperinsulinemia. Thus,
the use of one or more SGLT2 inhibitors according to the present
invention advantageously leads to reduced baseline plasma insulin
levels, and/or a reduced insulin excursion due to a glycemic
challenge, e.g., as measured during an intravenous glucose
tolerance test (ivGTT), an oral sugar test (OST) or after any other
form of glucose intake, e.g., after a meal (postprandial insulin
excursion).
[0025] The use of one or more SGLT2 inhibitors according to the
present invention advantageously leads to a reduction in
hyperinsulinemia and surrogate markers of insulin resistance in
treated, insulin resistant equine animals.
[0026] The glucose excursion after a challenge with insulin (e.g.,
in an intravenous insulin tolerance test (ivITT)), or after a
challenge with glucose (e.g., as measured during an intravenous
glucose tolerance test (ivGTT), an oral sugar test (OST) or after
any other form of glucose intake, e.g., after a meal (postprandial
glucose excursion)), or as measured in a combined glucose-insulin
tolerance test (CGIT), of an equine animal treated in accordance
with the invention is, advantageously, also improved. That is,
after a challenge with insulin, the decrease in glucose levels is
greater and/or more rapid; or after a challenge with glucose, the
glycemic peak of the glucose excursion is lowered and/or the
duration of the glucose excursion is reduced.
[0027] The use of one or more SGLT2 inhibitors according to the
present invention thus generally leads to improved (i.e.,
increased) glucose tolerance, i.e., equivalently, reduces glucose
intolerance.
[0028] The use of one or more SGLT2 inhibitors according to the
present invention advantageously also leads to a reduction in
plasma levels of non-esterified fatty acids, or an improved
elimination of non-esterified fatty acids (NEFAs) from the
bloodstream e.g., after a challenge with insulin (e.g., as measured
during an intravenous insulin tolerance test (ivITT)), or after a
challenge with glucose (e.g., as measured during an intravenous
glucose tolerance test (ivGTT), an oral sugar test (OST) or after
any other form of glucose intake, e.g., after a meal, that
initiates a blood insulin excursion, or as measured in a combined
glucose-insulin tolerance test (CGIT).
[0029] The use of one or more SGLT2 inhibitors according to the
present invention advantageously also leads to a reduction in body
fat and improved adipokine profile, e.g., reduced blood leptin
levels. The invention is also associated with anti-obesity effects,
and/or lead to a decrease in body mass in an equine animal. In one
aspect, the invention thus allows obesity and/or obesity-related
metabolic disorders to be managed in an equine animal.
[0030] The use of one or more SGLT2 inhibitors according to the
present invention generally reduces dyslipidemia, dysadipokinemia,
obesity and/or regional adiposity. Thus, the use of SGLT2
inhibitors allows for the treatment and/or prevention of
dyslipidemia, dysadipokinemia, obesity and/or regional adiposity,
in particular when associated with insulin resistance and/or
hyperinsulinemia in equine animal.
[0031] Advantageously, the use of one or more SGLT2 inhibitors
according to the present invention does not cause hypoglycemia.
[0032] The effects of the uses according to the present invention
(i.e., the above-mentioned beneficial effects upon insulin
resistance/sensitivity, insulin excursion, second phase insulin
secretion, glucose tolerance, elimination of non-esterified fatty
acids, body fat, and/or blood leptin levels) are also advantageous
in that they allow for the prevention of complications of insulin
resistance and/or hyperinsulinemia, and the treatment, prevention
or control of further metabolic disorders, symptoms and/or clinical
conditions/signs/signs that are associated with insulin resistance
and/or hyperinsulinemia in equine animals. They thus allow the
possibility of preventing and/or delaying the onset of such
complications, further metabolic disorders, symptoms and/or
clinical condition/signs in equine animals.
[0033] The use of one or more SGLT2 inhibitors according to the
present invention also provides for treatment and/or prevention of
laminitis, i.e., leads to reduction of lameness and/or time to
recovery from a laminitis episode.
[0034] The use of one or more SGLT2 inhibitors according to the
present invention provides for treatment and/or prevention of
vascular dysfunction, i.e., improvement of altered digital
perfusion and/or improved vascular response to contractile or
dilatatory stimuli.
[0035] The use of one or more SGLT2 inhibitors according to the
present invention also provides for treatment and/or prevention of
Equine Metabolic Syndrome (EMS).
[0036] The use of one or more SGLT2 inhibitors according to the
present invention also provides for treatment and/or prevention of
Pituitary Pars Intermedia Dysfunction (PPID), for instance
prevention of the development and/or progression of Pituitary Pars
Intermedia Dysfunction (PPID) in an equine animal. That is the
onset and/or progression of Pituitary Pars Intermedia Dysfunction
(PPID) in an equine animal may be fully inhibited or delayed.
[0037] The use of one or more SGLT2 inhibitors according to the
present invention may prevent the development and/or recurrence of
laminitis in an equine animal suffering from EMS and/or PPID.
[0038] The use of one or more SGLT2 inhibitors according to the
present invention may prevent the development and/or recurrence of
vascular dysfunction in an equine animal suffering from EMS and/or
PPID.
[0039] The use of one or more SGLT2 inhibitors according to the
present invention may prevent the development and/or recurrence of
hypertension in an equine animal suffering from EMS and/or
PPID.
[0040] The use of one or more SGLT2 inhibitors according to the
present invention may prevent the development and/or recurrence of
hepatic lipidosis in an equine animal suffering from EMS and/or
PPID.
[0041] The use of one or more SGLT2 inhibitors according to the
present invention may prevent the development and/or recurrence of
regional obesitas in an equine animal suffering from EMS and/or
PPID.
[0042] A further advantage of the present invention is that the use
of SGLT2 inhibitors is effective against the metabolic disorders
alone, i.e., if desired the use of one or more SGLT2 inhibitors in
an equine animal provides a monotherapy (i.e. a stand-alone
therapy; i.e., no other medication is administered to the equine
animal for the treatment or prevention of the same metabolic
disorder). The invention also allows for the possibility for
combination therapy with another drug (e.g., a further insulin
sensitizing drug).
[0043] The effects of using one or more SGLT2 inhibitors according
to the present invention (e.g., the above-mentioned beneficial
effects upon insulin resistance/sensitivity, plasma insulin levels,
insulin excursion, glucose excursion, glucose tolerance,
elimination of non-esterified fatty acids, body fat, and/or blood
leptin levels) may be relative to the same or a comparable equine
animal prior to administration of one or more SGLT2 inhibitors
according to the present invention, and/or relative to a comparable
equine animal that has not received said treatment (e.g., a placebo
group). In either case, when a comparison is made, the comparison
may be made after a certain treatment period, e.g., 0.5, 1, 2, 3 or
4 months. Preferably the treatment period is 3 or more months.
[0044] A further advantage of the present invention is that one or
more SGLT2 inhibitors may effectively be administered to an equine
animal orally, e.g., in liquid form. Moreover, SGLT2 inhibitors
according to the present invention can be administered only once
per day. These advantages allow for optimal dosing and compliance
of the treated equine animal.
[0045] Generally, the use of SGLT2 inhibitors according to the
present invention may thus attenuate, delay or prevent the
progression of a metabolic disorder, e.g., the metabolic disorders
disclosed herein, or may delay or prevent the onset of metabolic
disorders and their complications in equine animals.
[0046] The invention also provides methods of treating or
preventing metabolic disorders in equine animals, comprising
administering to an equine animal in need of such treatment or
prevention an effective dose of one or more SGLT2 inhibitors as
described herein.
[0047] In a preferred embodiment, the present invention thus
provides the use of one or more SGLT2 inhibitors or
pharmaceutically acceptable forms thereof in the treatment and/or
prevention of recurrent laminitis associated with hyperinsulinemia
in equine animals, preferably horses, with insulin resistance.
[0048] In another preferred embodiment, the present invention thus
provides the use of one or more SGLT2 inhibitors or
pharmaceutically acceptable forms thereof in the treatment and/or
prevention of recurrent laminitis associated with Equine Metabolic
Syndrome (EMS) in equine animals, preferably horses.
[0049] In yet another preferred embodiment, the present invention
thus provides the use of one or more SGLT2 inhibitors or
pharmaceutically acceptable forms thereof in the treatment and/or
prevention of the clinical conditions/signs associated with Equine
Metabolic Syndrome (EMS) or Equine Metabolic Syndrome (EMS) in
equine animals, preferably horses, wherein preferably said clinical
conditions/signs may be one or more disorder selected from insulin
resistance, hyperinsulinemia, impaired glucose tolerance,
dyslipidemia, dysadipokinemia, subclinical inflammation, systemic
inflammation, low grade systemic inflammation, which also comprises
adipose tissue, obesity, regional adiposity, laminitis, vascular
dysfunction, hypertension, hepatic lipidosis, atherosclerosis,
hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or
Equine Metabolic Syndrome.
Definitions
[0050] All values and concentrations presented herein are subject
to inherent variations acceptable in biological science within an
error of .+-.10%. The term "about" also refers to this acceptable
variation.
[0051] Treatment effects disclosed herein (such as an improvement,
reduction or delayed onset of a disorder, disease or condition, or
the improvement, reduction, increase or delay of any effect, index,
marker level or other parameter relating to a disorder, disease or
condition) may be observed with a statistical significance of
p<0.05, preferably <0.01.
[0052] When reference is made herein to a deviation (e.g., an
increase, elevation, excess, prolongation, raise, reduction,
decrease, improvement, delay, abnormal levels, or any other change,
alteration or deviation with respect to a reference), the deviation
may be, e.g., by 5% or more, particularly 10% or more, more
particularly 15% or more, more particularly 20% or more, more
particularly 30% or more, more particularly 40% or more, or more
particularly 50% or more, with respect to the relevant reference
value, unless otherwise stated. Typically, the deviation will be by
at least 10%, i.e., 10% or more. The deviation may also be by 20%.
The deviation may also be by 30%. The deviation may also be by 40%.
The relevant reference value may be generated from a group of
reference animals which are treated with placebo instead of an
SGLT2 inhibitor.
[0053] Herein, an excursion, e.g., an insulin excursions or glucose
excursion, designates a change in concentration or level in blood
over time. The magnitude of excursions, e.g., insulin excursions or
glucose excursions may be expressed as area-under-curve (AUC)
values.
[0054] Herein, the terms "active substance" or "active ingredient"
encompass one or more SGLT2 inhibitors or any pharmaceutically
acceptable form thereof (e.g., a prodrug or a crystalline form),
for use according to the invention. In the case of a combination
with one or additional active compound, the terms "active
ingredient" or "active substance" may also include the additional
active compound.
[0055] Herein, the expression "associated with", in particular
encompasses the expression "caused by".
[0056] Herein, ivGTT refers to an intravenous glucose tolerance
test. In an ivGTT, 0.2 g dextrose per kg body mass may typically be
employed.
[0057] Herein, ivITT refers to an intravenous insulin tolerance
test. In an ivITT, 0.03 U insulin per kg body mass may typically be
employed.
[0058] Herein, CGIT refers to a combined glucose-insulin tolerance
test. In a CGIT, 0.15 mg glucose per kg body mass and 0.1 U insulin
per kg body mass may typically be employed.
[0059] Herein, OST refers to an oral sugar test. In an OST, 0.15 mL
corn syrup per kg body mass may typically be employed.
SGLT2 Inhibitors
[0060] SGLT2 inhibitors for use according to the invention include,
but are not limited to, glucopyranosyl-substituted benzene
derivatives, for example as described in WO01/27128 (ref. 7),
WO03/099836 (ref. 8), WO2005/092877 (ref. 9), WO2006/034489 (ref.
10), WO2006/064033 (ref 11), WO2006/117359 (ref 12), WO2006/117360
(ref 13), WO2007/025943 (ref 14), WO2007/028814 (ref. 15),
WO2007/031548 (ref. 16), WO2007/093610 (ref. 17), WO2007/128749
(ref. 18), WO2008/049923 (ref. 19), WO2008/055870 (ref. 20),
WO2008/055940 (ref. 21), WO2009/022020 (ref. 22) or WO2009/022008
(ref 23), all hereby incorporated by reference.
[0061] Moreover, a SGLT2 inhibitor for use according to the
invention may be selected from the group consisting of the
following compounds or pharmaceutically acceptable forms thereof:
[0062] (1) a glucopyranosyl-substituted benzene derivative of the
formula (1)
[0062] ##STR00001## [0063] wherein R.sup.1 denotes cyano, Cl or
methyl (most preferably cyano); [0064] R.sup.2 denotes H, methyl,
methoxy or hydroxy (most preferably H) and [0065] R.sup.3 denotes
cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl,
3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl,
1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl,
1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl,
trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl,
3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,
3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl,
2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,
2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,
2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy,
2-methyloxy-ethyloxy, methyl sulfanyl, methyl sulfinyl,
methlysulfonyl, ethyl sulfinyl, ethyl sulfonyl, trimethylsilyl,
(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or
cyano; [0066] wherein R3 is preferably selected from cyclopropyl,
ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or
(S)-tetrahydrofuran-3-yloxy; and most preferably R3 is cyclopropyl,
[0067] or a derivative thereof wherein one or more hydroxyl groups
of the .beta.-D-glucopyranosyl group are acylated with groups
selected from (C.sub.1-18-alkyl)carbonyl,
(C.sub.1-18-alkyl)oxycarbonyl, phenyl carbonyl and
phenyl-(C.sub.1-3-alkyl)-carbonyl; [0068] (2)
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene,
represented by formula (2):
[0068] ##STR00002## [0069] (3) Dapagliflozin, represented by
formula (3):
[0069] ##STR00003## [0070] (4) Canagliflozin, represented by
formula (4):
[0070] ##STR00004## [0071] (5) Empagliflozin, represented by
formula (5):
[0071] ##STR00005## [0072] (6) Luseogliflozin, represented by
formula (6):
[0072] ##STR00006## [0073] (7) Tofogliflozin, represented by
formula (7):
[0073] ##STR00007## [0074] (8) Ipragliflozin, represented by
formula (8):
[0074] ##STR00008## [0075] (9) Ertugliflozin, represented by
formula (9):
[0075] ##STR00009## [0076] (10) Atigliflozin, represented by
formula (10):
[0076] ##STR00010## [0077] (11) Remogliflozin, represented by
formula (11):
[0077] ##STR00011## [0078] (12) a thiophene derivative of the
formula (12)
[0078] ##STR00012## [0079] wherein R denotes methoxy or
trifluoromethoxy; [0080] (13)
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene as described in WO2005/012326, represented by formula
(13);
[0080] ##STR00013## [0081] (14) a spiroketal derivative of the
formula (14):
[0081] ##STR00014## [0082] wherein R denotes methoxy,
trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl; [0083]
(15) a pyrazole-O-glucoside derivative of the formula (15)
[0083] ##STR00015## [0084] wherein [0085] R.sup.1 denotes
C.sub.1-3-alkoxy, [0086] L.sup.1, L.sup.2 independently of each
other denote H or F, [0087] R.sup.6 denotes H,
(C.sub.1-3-alkyl)carbonyl, (C.sub.1-6-alkyl)oxycarbonyl,
phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; [0088] (16)
a compound of the formula (16):
[0088] ##STR00016## [0089] (17) and Sergliflozin, represented by
formula (17):
##STR00017##
[0090] The term "dapagliflozin" as employed herein refers to
dapagliflozin of the above structure as well as pharmaceutically
acceptable forms thereof, including hydrates and solvates thereof,
and crystalline forms thereof. The compound and methods of its
synthesis are described in WO03/099836 (ref. 8) for example.
Preferred hydrates, solvates and crystalline forms are described in
the patent applications WO2008/116179 (ref. 24) and WO2008/002824
(ref 25) for example.
[0091] The term "canagliflozin" as employed herein refers to
canagliflozin of the above structure as well as pharmaceutically
acceptable forms thereof, including hydrates and solvates thereof,
and crystalline forms thereof. The compound and methods of its
synthesis are described in WO2005/012326 (ref. 26) and
WO2009/035969 (ref. 27) for example. Preferred hydrates, solvates
and crystalline forms are described in the patent application
WO2008/069327 (ref. 28) for example.
[0092] The term "empagliflozin" as employed herein refers to
empagliflozin of the above structure as well as pharmaceutically
acceptable forms thereof, including hydrates and solvates thereof,
and crystalline forms thereof. The compound and methods of its
synthesis are described in WO2005/092877 (ref. 9), WO2006/120208
(ref. 29) and WO2011/039108 (ref. 30) for example. A preferred
crystalline form is described in the patent applications
WO2006/117359 (ref. 12) and WO2011/039107 (ref 31) for example.
[0093] The term "atigliflozin" as employed herein refers to
atigliflozin of the above structure as well as pharmaceutically
acceptable forms thereof, including hydrates and solvates thereof,
and crystalline forms thereof. The compound and methods of its
synthesis are described in WO2004/007517 (ref. 32) for example.
[0094] The term "ipragliflozin" as employed herein refers to
ipragliflozin of the above structure as well as pharmaceutically
acceptable forms thereof, including hydrates and solvates thereof,
and crystalline forms thereof. The compound and methods of its
synthesis are described in WO2004/080990 (ref. 33), WO2005/012326
(ref. 26) and WO2007/114475 (ref. 34) for example.
[0095] The term "tofogliflozin" as employed herein refers to
tofogliflozin of the above structure as well as pharmaceutically
acceptable forms thereof, including hydrates and solvates thereof,
and crystalline forms thereof. The compound and methods of its
synthesis are described in WO2007/140191 (ref 35) and WO2008/013280
(ref 36) for example.
[0096] The term "luseogliflozin" as employed herein refers to
luseogliflozin of the above structure as well as pharmaceutically
acceptable forms thereof, including hydrates and solvates thereof,
and crystalline forms thereof.
[0097] The term "ertugliflozin" as employed herein refers to
ertugliflozin of the above structure as well as pharmaceutically
acceptable forms thereof, including hydrates and solvates thereof,
and crystalline forms thereof. The compound is described for
example in WO2010/023594 (ref. 37).
[0098] The term "remogliflozin" as employed herein refers to
remogliflozin of the above structure as well as pharmaceutically
acceptable forms thereof, including prodrugs of remogliflozin, in
particular remogliflozin etabonate, including hydrates and solvates
thereof, and crystalline forms thereof. Methods of its synthesis
are described in the patent applications EP1213296 (ref. 38) and
EP1354888 (ref. 39) for example.
[0099] The term "sergliflozin" as employed herein refers to
sergliflozin of the above structure as well as pharmaceutically
acceptable forms thereof, including prodrugs of sergliflozin, in
particular sergliflozin etabonate, including hydrates and solvates
thereof, and crystalline forms thereof. Methods for its manufacture
are described in the patent applications EP1344780 (ref. 40) and
EP1489089 (ref. 41) for example.
[0100] The compound of formula (16) above and its manufacture are
described for example in WO2008/042688 (ref 42) or WO2009/014970
(ref 43).
[0101] Preferred SGLT2 inhibitors are glucopyranosyl-substituted
benzene derivatives. Optionally, one or more hydroxyl groups of the
glucopyranosyl group in such one or more SGLT2 inhibitors may be
acylated with groups selected from (C.sub.1-18-alkyl)carbonyl,
(C.sub.1-18-alkyl)oxycarbonyl, phenyl carbonyl and
phenyl-(C.sub.1-3-alkyl)-carbonyl.
[0102] More preferred are glucopyranosyl-substituted benzonitrile
derivatives of formula (1) as disclosed herein above. Yet more
preferred are glucopyranosyl-substituted benzonitrile derivatives
of formula (18):
##STR00018##
wherein R3 denotes cyclopropyl, hydrogen, fluorine, chlorine,
bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl,
sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl,
cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl,
1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl,
ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl,
2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl,
2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,
1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,
2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,
2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy,
2-methyloxy-ethyloxy, methyl sulfanyl, methylsulfinyl,
methlysulfonyl, ethyl sulfinyl, ethylsulfonyl, trimethylsilyl,
(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano
(wherein R3 is preferably selected from cyclopropyl, ethyl,
ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or
(S)-tetrahydrofuran-3-yloxy; and R3 most preferably is cyclopropyl,
or a derivative thereof wherein one or more hydroxyl groups of the
.beta.-D-glucopyranosyl group are acylated with groups selected
from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl,
phenyl carbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl.
[0103] Preferably, such SGLT2 inhibitor is
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene
as shown in formula (2) (also referred to herein as "compound A").
Optionally, one or more hydroxyl groups of the
.beta.-D-glucopyranosyl group of compound A may be acylated with
groups selected from (C.sub.1-18-alkyl)carbonyl,
(C.sub.1-18-alkyl)oxycarbonyl, phenyl carbonyl and
phenyl-(C.sub.1-3-alkyl)-carbonyl.
[0104] Thus, in preferred embodiments, a SGLT2 inhibitor according
to the present invention is a glucopyranosyl-substituted benzene
derivative SGLT2 inhibitor, preferably a SGLT2 inhibitor of formula
(1), more preferably of formula (18), or yet more preferably of
formula (2) (i.e., compound A), in each case as defined herein
above.
Metabolic Disorders
[0105] According to the invention, metabolic disorders or metabolic
diseases are all kinds of disturbances of the energy metabolism,
affecting e.g., the turnover of carbohydrates and/or of fat. It is
preferred to affect the control of the energy metabolism,
especially the glucose metabolism by influencing the responsible
regulatory network, e.g., via modulation of the activity and/or
concentrations of insulin.
[0106] The metabolic disorder may be an insulin-related disorder.
In particular, the metabolic disorder may be insulin resistance
(or, equivalently, impaired insulin sensitivity). Insulin
resistance may be associated with a further metabolic disorder or
clinical condition/sign, e.g., insulin resistance may be associated
with impaired glucose tolerance, dyslipidemia, dysadipokinemia,
subclinical inflammation, systemic inflammation, low grade systemic
inflammation, which also comprises adipose tissue, obesity and/or
regional adiposity.
[0107] Additionally or alternatively, insulin resistance may be
associated with laminitis. Additionally or alternatively, insulin
resistance may be associated with vascular dysfunction.
Additionally or alternatively, insulin resistance may be associated
with hypertension. Additionally or alternatively, insulin
resistance may be associated with hyperadrenocorticism.
Additionally or alternatively, insulin resistance may be associated
with hepatic lipidosis. Laminitis, vascular dysfunction,
hypertension, hyperadrenocorticism and/or hepatic lipidoses are
clinical condition/signs associated with EMS and/or PPID. Thus,
additionally or alternatively, insulin resistance may be associated
with EMS and/or PPID.
[0108] The metabolic disorder may be hyperinsulinemia.
Hyperinsulinemia may be associated with a further metabolic
disorder or clinical condition/sign, e.g. hyperinsulinemia may be
associated with obesity and/or regional adiposity. Additionally or
alternatively, hyperinsulinemia may be associated with laminitis.
Additionally or alternatively, hyperinsulinemia may be associated
with vascular dysfunction. Additionally or alternatively,
hyperinsulinemia may be associated with hypertension. Additionally
or alternatively, hyperinsulinemia may be associated with hepatic
lipidosis. Laminitis, vascular dysfunction, hypertension and/or
hepatic lipidoses are clinical condition/signs associated with EMS
and/or PPID. Thus or alternatively, hyperinsulinemia may be
associated with EMS and/or PPID.
[0109] In preferred embodiments, the metabolic disorder may be
insulin resistance, hyperinsulinemia and/or a clinical
condition/sign associated with insulin resistance and/or
hyperinsulinemia. Treatment or prevention of a metabolic disorder
of an equine animal in accordance with the invention may be
treatment or prevention of insulin resistance and/or
hyperinsulinemia.
[0110] Clinical conditions/signs associated with insulin resistance
and/or hyperinsulinemia are e.g., impaired glucose tolerance,
dyslipidemia, dysadipokinemia, subclinical inflammation, systemic
inflammation, low grade systemic inflammation, which also comprises
adipose tissue, obesity and/or regional adiposity. Treatment and/or
prevention of a metabolic disorder of an equine animal in
accordance with the invention may be the treatment and/or
prevention of impaired glucose tolerance, dyslipidemia,
dysadipokinemia, subclinical inflammation, systemic inflammation,
low grade systemic inflammation, which also comprises adipose
tissue, obesity and/or regional adiposity in an equine animal. That
equine animal may also suffer from laminitis, vascular dysfunction,
hypertension, hepatic lipidosis, atherosclerosis,
hyperadrenocorticism, PPID and/or EMS.
[0111] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia may be impaired
glucose tolerance. Hence, the treatment or prevention of a
metabolic disorder of an equine animal in accordance with the
invention may be the treatment or prevention of impaired glucose
tolerance, preferably associated with insulin resistance and/or
hyperinsulinemia in an equine animal. That equine animal may also
suffer from laminitis, vascular dysfunction, hypertension, hepatic
lipidosis, atherosclerosis, hyperadrenocorticism, PPID and/or
EMS.
[0112] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia may be
dyslipidemia. Hence, the treatment and/or prevention of a metabolic
disorder of an equine animal in accordance with the invention may
be the treatment and/or prevention of dyslipidemia, preferably
associated with insulin resistance and/or hyperinsulinemia in an
equine animal. That equine animal may also suffer from laminitis,
vascular dysfunction, hypertension, hepatic lipidosis,
atherosclerosis, hyperadrenocorticism, PPID and/or EMS.
[0113] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia may be
dysadipokinemia. Hence, the treatment and/or prevention of a
metabolic disorder of an equine animal in accordance with the
invention may be treatment and/or prevention of dysadipokinemia,
preferably associated with insulin resistance and/or
hyperinsulinemia in an equine animal. That equine animal may also
suffer from laminitis, vascular dysfunction, hypertension, hepatic
lipidosis, atherosclerosis, hyperadrenocorticism, PPID and/or
EMS.
[0114] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia may be subclinical
inflammation or systemic inflammation, in particular low grade
systemic inflammation, which also comprises adipose tissue. Hence,
the treatment and/or prevention of a metabolic disorder of an
equine animal in accordance with the invention may be treatment
and/or prevention of subclinical inflammation or systemic
inflammation, in particular low grade systemic inflammation, which
also comprises adipose tissue, preferably associated with insulin
resistance and/or hyperinsulinemia in an equine animal. That equine
animal may also suffer from laminitis, vascular dysfunction,
hypertension, hepatic lipidosis, atherosclerosis,
hyperadrenocorticism, PPID and/or EMS.
[0115] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia may be obesity.
Hence, the treatment and/or prevention of a metabolic disorder of
an equine animal in accordance with the invention may be treatment
and/or prevention of obesity, preferably associated with insulin
resistance and/or hyperinsulinemia in an equine animal. That equine
animal may also suffer from laminitis, vascular dysfunction,
hypertension, hepatic lipidosis, atherosclerosis,
hyperadrenocorticism, PPID and/or EMS.
[0116] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia may be regional
adiposity. Hence, the treatment and/or prevention of a metabolic
disorder of an equine animal in accordance with the invention may
be treatment and/or prevention of regional adiposity, preferably
associated with insulin resistance and/or hyperinsulinemia in an
equine animal. That equine animal may also suffer from laminitis,
vascular dysfunction, hypertension, hepatic lipidosis,
atherosclerosis, hyperadrenocorticism, PPID and/or EMS.
[0117] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia, may be laminitis.
In some embodiments, laminitis may be associated with obesity
and/or regional adiposity. In some embodiments, when a metabolic
disorder or clinical condition/sign is laminitis, the equine animal
is suffering from EMS and/or PPID. The present invention preferably
prevents the development and/or recurrence of laminitis, e.g., in
an equine animal suffering from EMS and/or PPID.
[0118] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia, may be vascular
dysfunction, e.g., vascular dysfunction in an equine animal's hoof.
In some embodiments, vascular dysfunction may be associated with
obesity and/or regional adiposity. In some embodiments, when a
metabolic disorder or clinical condition/sign is vascular
dysfunction, the equine animal is suffering from EMS and/or PPID.
The present invention preferably prevents the development and/or
recurrence of vascular dysfunction, e.g., in an equine animal
suffering from EMS and/or PPID.
[0119] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia, may be
hypertension. In some embodiments, hypertension may be associated
with regional obesity and/or regional adiposity. In some
embodiments, when a metabolic disorder or clinical condition/sign
is hypertension, the equine animal is suffering from EMS and/or
PPID. The present invention preferably prevents the development
and/or recurrence of hypertension, e.g., in an equine animal
suffering from EMS and/or PPID.
[0120] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia, may be hepatic
lipidosis. In some embodiments, hepatic lipidosis may be associated
with regional obesity and/or regional adiposity. In some
embodiments, when a metabolic disorder or clinical condition/sign
is hepatic lipidosis, the equine animal is suffering from EMS
and/or PPID. The present invention preferably prevents the
development and/or recurrence of hepatic lipidosis, e.g., in an
equine animal suffering from EMS and/or PPID.
[0121] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia, may be
atherosclerosis, In some embodiments, atherosclerosis may be
associated with systemic inflammation, subclinical inflammation,
low grade systemic inflammation, which also comprises adipose
tissue. In some embodiments, when a metabolic disorder or clinical
condition/sign is atherosclerosis, the equine animal is suffering
from EMS and/or PPID. The present invention preferably prevents the
development and/or recurrence of atherosclerosis, e.g., in an
equine animal suffering from EMS and/or PPID.
[0122] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia, may be
hyperadrenocorticism. In some embodiments, hyperadrenocorticism may
be associated with systemic inflammation, subclinical inflammation,
low grade systemic inflammation, which also comprises adipose
tissue. In some embodiments, when a metabolic disorder or clinical
condition/sign is hyperadrenocorticism, the equine animal is
suffering from EMS and/or PPID. The present invention preferably
provides for the treatment and/or prevention of
hyperadrenocorticism, i.e., it prevents the development and/or
recurrence of hyperadrenocorticism, e.g., in an equine animal
suffering from EMS and/or PPID.
[0123] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia, may be Equine
Metabolic Syndrome (EMS). In some embodiments, EMS may be
associated with obesity and/or regional adiposity.
[0124] Herein, a metabolic disorder or clinical condition/sign,
e.g., a metabolic disorder or clinical condition/sign associated
with insulin resistance and/or hyperinsulinemia, may be Equine
Pituitary Pars Intermedia Dysfunction (PPID). In some embodiments,
PPID may be associated with hyperadrenocorticism.
[0125] In some embodiments, the equine animal treated in accordance
with the invention (e.g., for hyperinsulinemia, insulin resistance,
and/or a clinical condition/sign associated with insulin resistance
and/or hyperinsulinemia) is suffering from laminitis, vascular
dysfunction, PPID and/or EMS.
[0126] In some embodiments, impaired glucose tolerance may be
associated with obesity and/or regional adiposity. Hence, the
treatment and/or prevention of a metabolic disorder of an equine
animal in accordance with the invention may be treatment and/or
prevention of impaired glucose tolerance associated with obesity
and/or regional adiposity in an equine animal.
[0127] In some embodiments, impaired glucose tolerance may be
associated with hyperadrenocorticism. Hence, the treatment and/or
prevention of a metabolic disorder of an equine animal in
accordance with the invention may be treatment and/or prevention of
impaired glucose tolerance associated with hyperadrenocorticism in
an equine animal.
[0128] Insulin resistance can be described as the condition in
which normal amounts of insulin are inadequate to produce a normal
insulin response from fat, muscle and liver cells. Insulin
resistance in fat cells reduces the effects of insulin and results
in elevated hydrolysis of stored triglycerides in the absence of
measures which either increase insulin sensitivity or which provide
additional insulin. Increased mobilization of stored lipids in
these cells elevates free fatty acids in the blood plasma. Insulin
resistance in muscle cells reduces glucose uptake (and so local
storage of glucose as glycogen), whereas insulin resistance in
liver cells results in impaired glycogen synthesis and a failure to
suppress glucose production. Elevated blood fatty acid levels,
reduced muscle glucose uptake, and increased liver glucose
production, may all contribute to elevated blood glucose levels
(hyperglycemia), although hyperglycemia is not a major issue e.g.,
in insulin-resistant horses. In the horse, when insulin-resistant
target tissues, e.g., skeletal muscle, have a reduced capacity for
glucose uptake, the pancreas is stimulated to release more insulin,
leading to hyperinsulinemia.
[0129] Surrogate indices of insulin sensitivity may be calculated
according to the QUICKI (quantitative insulin sensitivity check
index: 1/log(glucose*insulin)) for basal blood level. For dynamic
testings, e.g. during a glucose challenge a modified Belfiore Index
(1/log(.DELTA.AUC-glucose*.DELTA.AUC-insulin)) can be employed.
[0130] Insulin resistance may be present in association with
regional adiposity, e.g., cresty neck, tail fat depots, visceral
adiposity, hypertension and dyslipidemia involving elevated
triglycerides, small dense low-density lipoprotein (sdLDL)
particles, and decreased HDL cholesterol levels. With respect to
visceral adiposity, a great deal of evidence in humans suggests two
strong links with insulin resistance. First, unlike subcutaneous
adipose tissue, visceral adipose cells produce significant amounts
of proinflammatory cytokines such as tumor necrosis factor-alpha
(TNF-a), and Interleukins-1 and -6, etc. In numerous experimental
models, these proinflammatory cytokines profoundly disrupt normal
insulin action in fat and muscle cells, and may be a major factor
in causing the whole-body insulin resistance observed in human
patients with visceral adiposity. Similar, in equines the different
excessive regional fat depots contribute to low grade systemic
inflammation. Second, adiposity is related to an accumulation of
fat in the liver, a condition known as nonalcoholic fatty liver
disease (NAFLD) in humans and hepatic lipidosis in general terms,
e.g., in equines. The result of NAFLD is an excessive release of
free fatty acids into the bloodstream (due to increased lipolysis),
and an increase in hepatic glucose production, both of which have
the effect of exacerbating peripheral insulin resistance. The cause
of the vast majority of cases of insulin resistance remains
unknown. There is clearly an inherited component. However, there
are some grounds for suspecting that insulin resistance is related
to a high-carbohydrate diet. Inflammation also seems to be
implicated in causing insulin resistance.
[0131] Hyperinsulinemia may be described as a condition in which
there are excess levels, i.e., more than about 10-20 .mu.IU/mL of
insulin circulating in the blood. As mentioned, it is commonly
present in cases of, and may be a consequence of, insulin
resistance in equine animals.
[0132] Impaired glucose tolerance can be described as condition in
which the response to a after a glycemic challenge e.g., after a
meal or after a loading test (glucose tolerance test) the glycemic
peak of the glucose excursion is higher and/or the duration of the
glucose excursion is prolonged.
[0133] Dyslipidemia or hyperlipidemia is the presence of raised or
abnormal levels of lipids and/or lipoproteins in the blood. Lipid
and lipoprotein abnormalities are regarded as a highly modifiable
risk factor for cardiovascular disease due to the influence of
cholesterol, one of the most clinically relevant lipid substances,
on atherosclerosis. Glycerol is a precursor for the synthesis of
triacylglycerols (triglycerides) and of phospholipids in the liver
and adipose tissue. When the body uses stored fat as a source of
energy, glycerol and fatty acids are released into the bloodstream
after hydrolysis of the triglycerides. The glycerol component can
be converted to glucose by the liver and provides energy for
cellular metabolism. Normal levels of free fatty acids in the blood
equine animals are concentrations of 50 to 100 mg/dl (0.6 to 1.2
mmol/l). Normal levels of triglycerides are e.g., up to around 50
mg/dL. Normal levels of blood cholesterol are, e.g., around 120
mg/dl for the horse.
[0134] Dysadipokinemia can be described as a condition in which the
circulating plasma levels of biologically active substances
produced in adipose tissue that act in an autocrine/paracrine or
endocrine fashion is deviated. e.g., an elevation of leptin and/or
a reduction of adiponectin.
[0135] Subclinical inflammation or systemic inflammation, in
particular low grade systemic inflammation is characterized by
increased expression and secretion of pro-inflammatory cytokines
such as tumor necrosis factor-alpha and/or lower expression and
secretion of anti-inflammatory cytokines e.g., interleukin-10
and/or their respective receptors.
[0136] Laminitis can be described as an inflammation or edema of
the sensitive laminae of the hoof resulting e.g., in lameness. The
laminae bond the hoof wall to the pedal bone, which supports the
entire weight of the horse or equine. Severe cases of laminitis can
result in the pedal bone rotation that may progress to perforation
of the sole. Laminitis induced lameness can be graded e.g., by
visual score of behavior in standing position and moving
performance.
[0137] Vascular dysfunction can be described as impaired action of
endothelium-dependent insulin induced vasodilation, as well
alteration of direct insulin effects on vascular smooth muscles,
e.g., relaxation and reactivity to vasoconstrictor stimuli.
[0138] Equine Metabolic Syndrome is defined by the presence of
insulin resistance, obesity and/or regional adiposity. The EMS
phenotype may also comprise dyslipidemia, dyadipokinemia and/or
hypertension. The syndrome can be described as a combination of
medical disorders that increase the risk of developing associated
pathologies, e.g., laminitis. The equine metabolic syndrome might
also be associated with other disorders like hepatic lipidosis or
infertility.
[0139] Obesity can be described as a medical condition in which
excess body fat has accumulated to the extent that it may have an
adverse effect on health, leading to reduced life expectancy. In
equines e.g., during physical examination body condition scores of
equal or more than 7 (out of 9) are encountered.
[0140] Regional adiposity in equine animals can be described as a
medical condition in which body fat (adipose tissue) accumulates in
specific regions, e.g., the neck (cresty neck), either side of the
tailhead, prepuce, in fat pads in the rump area, the mammary gland
region, and/or in supraorbital fat pads. Regional adiposity also
encompasses visceral adiposity, e.g., increased omental fat.
[0141] Obesity and or regional adiposity is associated with many
other diseases, particularly heart disease, type 2 diabetes (though
this is rare in horses), certain types of cancer, osteoarthritis
and/or strangulating lipoma. Obesity is most commonly caused by a
combination of excessive dietary calories, lack of physical
activity, and genetic susceptibility, though a limited number of
cases are due to a single cause, e.g., solely to genetics.
[0142] Atherosclerosis can be described as a condition in which an
artery wall thickens as the result of a build-up of fatty materials
such as cholesterol. It is a syndrome affecting arterial blood
vessels, a chronic inflammatory response in the walls of arteries,
in large part due to the accumulation of macrophage white blood
cells and promoted by low density (especially small particle)
lipoproteins (plasma proteins that carry cholesterol and
triglycerides) without adequate removal of fats and cholesterol
from the macrophages by functional high density lipoproteins (HDL).
It is commonly referred to as a hardening or furring of the
arteries. It is caused by the formation of multiple plaques within
the arteries.
[0143] Pituitary Pars Intermedia Dysfunction (PPID) is a common
disease of older horses and ponies. Hypothalamic dopaminergic
neurodegeneration results in an elevated adrenocorticotropic
hormone (ACTH) production in the Pituitary Pars Intermedia and
leads to hyperadrenocorticism. Clinical signs include hirsutism (a
long, often curly coat that may not shed), polydipsia/polyuria,
excessive sweating, weight loss, muscle wasting, regional fat
deposits, lethargy, infections e.g., sinusitis and/or
laminitis.
[0144] Equine animals. Herein, the term "equine animal" may be used
interchangeably with the term "equine" and encompasses any member
of the genus Equus. It encompasses, e.g., any horse or pony, the
taxonomic designations Equus ferus and/or Equus caballus, and/or
the subspecies Equus ferus caballus. The equine animal may, e.g.,
be a domestic horse.
[0145] Pharmaceutically acceptable forms. Herein, references to
SGLT2 inhibitors and/or their use according to the invention
encompass pharmaceutically acceptable forms of the SGLT2
inhibitors, unless otherwise stated.
[0146] According to the invention, any pharmaceutically acceptable
form of the SGLT2 inhibitor, e.g., of formula (1), preferably
formula (18), more preferably formula (2), may be used. E.g., a
crystalline form may be used. Prodrug forms are also encompassed by
the present invention.
[0147] Prodrug forms may include, e.g., esters and/or hydrates. The
term prodrug is also meant to include any covalently bonded carrier
which releases the active compound of the invention in vivo when
the prodrug is administered to a mammalian subject. Prodrugs of a
compound of the invention may be prepared by modifying functional
groups present in the compound of the invention in such a way that
the modifications are cleaved, either in routine manipulation or in
vivo, to the parent compound of the invention.
[0148] Crystalline forms for use according to the invention include
a complex of one or more SGLT2 inhibitors with one or more amino
acids (see e.g., WO 2014/016381). An amino acid for such use may be
a natural amino acid. The amino acid may be a proteogenic amino
acid (including L-hydroxyproline), or a non-proteogenic amino acid.
The amino acid may be a D- or an L-amino acid. In some preferred
embodiments the amino acid is proline (L-proline and/or D-proline,
preferably L-proline). E.g., a crystalline complex of
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene
(formula (2); compound A) with proline (e.g. L-proline) is
preferred.
[0149] Thus, herein is disclosed a crystalline complex between one
or more natural amino acids and an SGLT2 inhibitor, e.g., a
crystalline complex between one or more natural amino acids and a
glucopyranosyl-substituted benzene derivative SGLT2 inhibitor,
preferably a SGLT2 inhibitor of formula (1), more preferably of
formula (18) or yet more preferably of formula (2) (compound A).
Thus, herein is disclosed a crystalline complex between one or more
natural amino acids and
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene
(compound A).
[0150] Further disclosed herein is the use of one or more
crystalline complexes as defined hereinbefore or hereinafter for
preparing a pharmaceutical composition which is suitable for the
treatment or prevention of diseases or conditions which can be
influenced by inhibiting sodium-dependent glucose co-transporter
SGLT, preferably SGLT2. Further disclosed herein is the use of one
or more crystalline complexes as defined hereinbefore or
hereinafter for preparing a pharmaceutical composition for
inhibiting the sodium-dependent glucose co-transporter SGLT2.
[0151] A crystalline complex between one or more natural amino
acids (e.g. proline, preferably L-proline) and an SGLT2 inhibitor,
is a preferred pharmaceutically acceptable form of a SGLT2
inhibitor for use according to the present invention. In
particular, a crystalline complex between one or more natural amino
acids (e.g. proline, preferably L-proline) and a
glucopyranosyl-substituted benzene derivative SGLT2 inhibitor,
preferably a SGLT2 inhibitor of formula (1), more preferably of
formula (18) or yet more preferably of formula (2) (compound A) is
a preferred pharmaceutically acceptable form of a SGLT2 inhibitor
for use according to the present invention. A crystalline complex
between one or more natural amino acids (e.g., proline, preferably
L-proline) and
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene
(compound A) is particularly preferred as a pharmaceutically
acceptable form of a SGLT2 inhibitor for use according to the
present invention.
[0152] Also disclosed herein is a method for making one or more
crystalline complexes as defined hereinbefore and hereinafter, said
method comprising the following steps: [0153] a. preparing a
solution of the one or more SGLT2 inhibitors (e.g., a
glucopyranosyl-substituted benzene derivative, or a SGLT2 inhibitor
of formula (1), preferably formula (18) or more preferably formula
(2), i.e., compound A) and the one or more natural amino acids in a
solvent or a mixture of solvents; [0154] b. storing the solution to
precipitate the crystalline complex out of solution; [0155] c.
removing the precipitate from the solution; and [0156] d. drying
the precipitate optionally until any excess of said solvent or
mixture of solvents has been removed.
[0157] A certain pharmaceutical activity is of course the basic
prerequisite to be fulfilled by a pharmaceutically active agent
before same is approved as a medicament on the market. However,
there are a variety of additional requirements a pharmaceutically
active agent has to comply with. These requirements are based on
various parameters which are connected with the nature of the
active substance itself. Without being restrictive, examples of
these parameters are the stability of the active agent under
various environmental conditions, its stability during production
of the pharmaceutical formulation and the stability of the active
agent in the final medicament compositions. The pharmaceutically
active substance used for preparing the pharmaceutical compositions
should be as pure as possible and its stability in long-term
storage must be guaranteed under various environmental conditions.
This is essential to prevent the use of pharmaceutical compositions
which contain, in addition to the actual active substance,
breakdown products thereof, for example. In such cases the content
of active substance in the medicament might be less than that
specified.
[0158] Uniform distribution of the medicament in the formulation is
a critical factor, particularly when the medicament has to be given
in low doses. To ensure uniform distribution, the particle size of
the active substance can be reduced to a suitable level, e.g., by
grinding. Since breakdown of the pharmaceutically active substance
as a side effect of the grinding (or micronizing) has to be avoided
as far as possible, in spite of the hard conditions required during
the process, it is essential that the active substance should be
highly stable throughout the grinding process. Only if the active
substance is sufficiently stable during the grinding process it is
possible to produce a homogeneous pharmaceutical formulation which
always contains the specified amount of active substance in a
reproducible manner.
[0159] Another problem which may arise in the grinding process for
preparing the desired pharmaceutical formulation is the input of
energy caused by this process and the stress on the surface of the
crystals. This may in certain circumstances lead to polymorphous
changes, to amorphization or to a change in the crystal lattice.
Since the pharmaceutical quality of a pharmaceutical formulation
requires that the active substance should always have the same
crystalline morphology, the stability and properties of the
crystalline active substance are subject to stringent requirements
from this point of view as well.
[0160] The stability of a pharmaceutically active substance is also
important in pharmaceutical compositions for determining the shelf
life of the particular medicament; the shelf life is the length of
time during which the medicament can be administered without any
risk. High stability of a medicament in the abovementioned
pharmaceutical compositions under various storage conditions is
therefore an additional advantage for both the patient and the
manufacturer.
[0161] The absorption of moisture reduces the content of
pharmaceutically active substance as a result of the increased
weight caused by the uptake of water. Pharmaceutical compositions
with a tendency to absorb moisture have to be protected from
moisture during storage, e.g., by the addition of suitable drying
agents or by storing the drug in an environment where it is
protected from moisture. Preferably, therefore, a pharmaceutically
active substance should be at best slightly hygroscopic.
[0162] Furthermore, the availability of a well-defined crystalline
form allows the purification of the drug substance by
recrystallization.
[0163] Apart from the requirements indicated above, it should be
generally borne in mind that any change to the solid state of a
pharmaceutical composition which is capable of improving its
physical and chemical stability gives a significant advantage over
less stable forms of the same medicament.
[0164] A crystalline complex between a natural amino acid and one
or more SGLT2 inhibitors (e.g. a glucopyranosyl-substituted benzene
derivative or a SGLT2 inhibitor of formula (1), or formula (18) or,
particularly, of formula (2), i.e. compound A) fulfills important
requirements mentioned hereinbefore.
[0165] Preferably the natural amino acid is present in either its
(D) or (L) enantiomeric form, most preferably as the (L)
enantiomer.
[0166] Furthermore those crystalline complexes according to this
invention are preferred which are formed between the one or more
SGLT2 inhibitors (e.g. of formula (1), preferably formula (18) or,
particularly, of formula (2), i.e. compound A) and one natural
amino acid, most preferably between the compound A and the (L)
enantiomer of a natural amino acid.
[0167] Preferred amino acids according to this invention are
selected from the group consisting of phenylalanine and proline, in
particular (L)-proline and (L)-phenylalanine.
[0168] According to a preferred embodiment the crystalline complex
is characterized in that the natural amino acid is proline, in
particular (L)-proline.
[0169] Preferably the molar ratio of the one or more SGLT2
inhibitors (e.g. of formula (1), preferably formula (18) or,
particularly, of formula (2), i.e. compound A) and the natural
amino acid is in the range from about 2:1 to about 1:3; more
preferably from about 1.5:1 to about 1:1.5, even more preferably
from about 1.2:1 to about 1:1.2, most preferably about 1:1. In the
following such an embodiment is referred to as "complex (1:1)" or
"1:1 complex".
[0170] Therefore a preferred crystalline complex according to this
invention is a complex (1:1) between said SGLT2 inhibitor (e.g. of
formula (1), preferably formula (18) or, particularly, of formula
(2), i.e. compound A) and proline; in particular of said SGLT2
inhibitor and L-proline.
[0171] According to a preferred embodiment the crystalline complex,
in the particular the 1:1 complex of said SGLT2 inhibitor with
L-proline, is a hydrate.
[0172] Preferably the molar ratio of the crystalline complex and
water is in the range from about 1:0 to 1:3; more preferably from
about 1:0 to 1:2, even more preferably from about 1:0.5 to 1:1.5,
most preferably about 1:0.8 to 1:1.2, in particular about 1:1.
[0173] The crystalline complex of said SGLT2 inhibitor with
proline, in particular with L-proline and water, may be identified
and distinguished from other crystalline forms by means of their
characteristic X-ray powder diffraction (XRPD) patterns.
[0174] For example, a crystalline complex of compound A with
L-proline is preferably characterized by an X-ray powder
diffraction pattern that comprises peaks at 20.28, 21.14 and 21.64
degrees 2.THETA. (.+-.0.1 degrees 2.THETA.), wherein said X-ray
powder diffraction pattern is made using CuK.sub..alpha.1
radiation.
[0175] In particular said X-ray powder diffraction pattern
comprises peaks at 4.99, 20.28, 21.14, 21.64 and 23.23 degrees
2.THETA. (.+-.0.1 degrees 2.THETA.), wherein said X-ray powder
diffraction pattern is made using CuK.sub..alpha.1 radiation.
[0176] More specifically said X-ray powder diffraction pattern
comprises peaks at 4.99, 17.61, 17.77, 20.28, 21.14, 21.64, 23.23
and 27.66 degrees 2.THETA. (.+-.0.1 degrees 2.THETA.), wherein said
X-ray powder diffraction pattern is made using CuK.sub..alpha.1
radiation.
[0177] Even more specifically said X-ray powder diffraction pattern
comprises peaks at 4.99, 15.12, 17.61, 17.77, 18.17, 20.28, 21.14,
21.64, 23.23 and 27.66 degrees 2.THETA. (.+-.0.1 degrees 2.THETA.),
wherein said X-ray powder diffraction pattern is made using
CuK.sub..alpha.1 radiation.
[0178] Even more specifically, the crystalline complex of compound
A and L-proline is characterized by an X-ray powder diffraction
pattern, made using CuK.sub..alpha.1 radiation, which comprises
peaks at degrees 2.THETA. (.+-.0.1 degrees 2.THETA.) as contained
in Table 1.
TABLE-US-00001 TABLE 1 X-ray powder diffraction pattern of the
crystalline complex of compound A and L-proline (only peaks up to
30.degree. in 2 .THETA. are listed): 2 .THETA. [.degree.] d-value
[.ANG.] Intensity I/I.sub.0 [%] 4.99 17.68 39 7.01 12.61 6 8.25
10.70 11 9.95 8.88 12 13.15 6.73 30 13.33 6.64 10 14.08 6.28 4
15.12 5.85 32 16.40 5.40 12 16.49 5.37 13 17.11 5.18 6 17.61 5.03
32 17.77 4.99 35 18.17 4.88 32 18.32 4.84 28 18.72 4.74 8 19.16
4.63 30 19.96 4.45 26 20.28 4.37 56 20.60 4.31 7 21.14 4.20 84
21.64 4.10 100 22.33 3.98 15 23.23 3.83 41 24.06 3.70 4 24.51 3.63
15 24.93 3.57 26 25.89 3.44 23 26.21 3.40 11 26.84 3.32 8 27.66
3.22 38 27.96 3.19 9 28.26 3.16 5 28.44 3.14 6 28.75 3.10 6 29.18
3.06 19
[0179] Even more specifically, said crystalline complex is
characterized by an X-ray powder diffraction pattern, made using
CuK.sub..alpha.1 radiation, which comprises peaks at degrees
2.THETA. (.+-.0.1 degrees 2.THETA. as shown in [0202].
[0180] Furthermore said crystalline complex of the compound A with
L-proline is characterized by a melting point of above 89.degree.
C., in particular in a range from about 89.degree. C. to about
115.degree. C., more preferably in a range from about 89.degree. C.
to about 110.degree. C. (determined via DSC; evaluated as
onset-temperature; heating rate 10 K/min). It can be observed that
this crystalline complex melts under dehydration. The obtained DSC
curve is shown in [0203].
[0181] Said crystalline complex of the compound A with L-proline
shows a weight loss by thermal gravimetry (TG). The observed weight
loss indicates that the crystalline form contains water which may
be bound by adsorption and/or may be part of the crystalline
lattice, i.e., the crystalline form may be present as a crystalline
hydrate. The content of water in the crystalline form lies in the
range from 0 to about 10 weight-%, in particular 0 to about 5
weight-%, even more preferably from about 1.5 to about 5 weight-%.
The dotted line depicts a weight loss of between 2.8 and 3.8% of
water. From the observed weight loss a stoichiometry close to a
monohydrate can be estimated.
[0182] Said crystalline complex has advantageous physicochemical
properties which are beneficial in the preparation of a
pharmaceutical composition. In particular the crystalline complex
has a high physical and chemical stability under various
environmental conditions and during the production of a medicament.
For example the crystals can be obtained in a shape and particle
size which are particular suitable in a production method for solid
pharmaceutical formulations. In addition the crystals show a high
mechanical stability that allows grinding of the crystals.
Furthermore the crystalline complex does not show a high tendency
to absorb moisture and is chemically stable, i.e., the crystalline
complex allows the production of a solid pharmaceutical formulation
with a long shelf life. On the other hand the crystalline complex
has a favorably high solubility over a wide pH-range which is
advantageous in solid pharmaceutical formulations for oral
administration.
[0183] The X-ray powder diffraction patterns may be recorded using
a STOE-STADI P-diffractometer in transmission mode fitted with a
location-sensitive detector (OED) and a Cu-anode as X-ray source
(CuK.sub..alpha.1 radiation, .lamda.=1.54056 .ANG., 40 kV, 40 mA).
In Table 1 the values "2.THETA.[.degree.]" denote the angle of
diffraction in degrees and the values "d [.ANG.]" denote the
specified distances in .ANG. between the lattice planes. The
intensity shown in [0202] is given in units of cps (counts per
second).
[0184] In order to allow for experimental error, the above
described 2 .THETA. values should be considered accurate to .+-.0.1
degrees 2 .THETA., in particular .+-.0.05 degrees 2 .THETA.. That
is to say, when assessing whether a given sample of crystals of the
compound A is the crystalline form in accordance with the above
described 2 .THETA. values, a 2 .THETA. value which is
experimentally observed for the sample should be considered
identical with a characteristic value described above if it falls
within .+-.0.1 degrees 2 .THETA. of the characteristic value, in
particular if it falls within .+-.0.05 degrees 2 .THETA. of the
characteristic value.
[0185] The melting point is determined by DSC (Differential
Scanning calorimetry) using a DSC 821 (Mettler Toledo). The weight
loss is determined by thermal gravimetry (TG) using a TGA 851
(Mettler Toledo).
[0186] Also disclosed herein is a method for making a crystalline
complex as defined hereinbefore and hereinafter, said method
comprising the following steps: [0187] a. preparing a solution of
one or more SGLT2 inhibitors as described herein (e.g. compound A
or another SGLT2 inhibitor described herein) and the one or more
natural amino acids in a solvent or a mixture of solvents; [0188]
b. storing the solution to precipitate the crystalline complex out
of solution; [0189] c. removing the precipitate from the solution;
and [0190] d. drying the precipitate optionally until any excess of
said solvent or mixture of solvents has been removed.
[0191] According to step (a) a solution of the one or more SGLT2
inhibitors (e.g., compound A or another SGLT2 inhibitor described
herein) and the one or more natural amino acids in a solvent or a
mixture of solvents is prepared. Preferably the solution is
saturated or at least nearly saturated or even supersaturated with
respect to the crystalline complex. In the step (a) the one or more
SGLT2 inhibitors may be dissolved in a solution comprising the one
or more natural amino acids or the one or more natural amino acids
may be dissolved in a solution comprising the SGLT2 inhibitor.
According to an alternative procedure the one or more SGLT2
inhibitors is dissolved in a solvent or mixture of solvents to
yield a first solution and the one or more natural amino acids are
dissolved in a solvent or mixture of solvents to yield a second
solution. Thereafter said first solution and said second solution
are combined to form the solution according to step (a).
[0192] Preferably the molar ratio of the natural amino acid and the
one or more SGLT2 inhibitors (e.g., compound A or any other SGLT2
inhibitor described herein) in the solution corresponds to the
molar ratio of the natural amino acid and the one or more SGLT2
inhibitors in the crystalline complex to be obtained. Therefore a
preferred molar ratio is in the range from about 1:2 to 3:1; most
preferably about 1:1.
[0193] Suitable solvents are preferably selected from the group
consisting of C.sub.1-4-alkanols, water, ethyl acetate,
acetonitrile, acetone, diethyl ether, tetrahydrofuran, and mixture
of two or more of these solvents.
[0194] More preferred solvents are selected from the group
consisting of methanol, ethanol, isopropanol, water and mixture of
two or more of these solvents, in particular mixtures of one or
more of said organic solvents with water.
[0195] Particularly preferred solvents are selected from the group
consisting of ethanol, isopropanol, water and mixtures of ethanol
and/or isopropanol with water.
[0196] In case a mixture of water and one or more
C.sub.1-4-alkanols, in particular of methanol, ethanol and/or
isopropanol, most preferably of ethanol, is taken, a preferred
volume ratio of water:the alkanol is in the range from about 99:1
to 1:99; more preferably from about 50:1 to 1:80; even more
preferably from about 10:1 to 1:60.
[0197] Preferably the step (a) is carried out at about room
temperature (about 20.degree. C.) or at an elevated temperature up
to about the boiling point of the solvent or mixture of solvents
used.
[0198] According to a preferred embodiment the starting material of
the one or more SGLT2 inhibitors (e.g., compound A or any other
SGLT2 inhibitor described herein) and/or of the one or more natural
amino acids and/or of the solvent and mixtures of solvents contain
an amount of H.sub.2O which is at least the quantity required to
form a hydrate of the SGLT2 inhibitor; in particular at least 1
mol, preferably at least 1.5 mol of water per mol of SGLT2
inhibitor. Even more preferably the amount of water is at least 2
mol of water per mol of SGLT2 inhibitor. This means that either the
one or more SGLT2 inhibitors (e.g., compound A) as starting
material or the one or more natural amino acids or said solvent or
mixture of solvents, or said compounds and/or solvents in
combination contain an amount of H.sub.2O as specified above. For
example if the starting material of the one or more SGLT2
inhibitors (e.g., compound A) or of the natural amino acid in step
(a) does contain sufficient water as specified above, a water
content of the solvent(s) is not mandatory.
[0199] In order to reduce the solubility of the crystalline complex
according to this invention in the solution, in step (a) and/or in
step (b) one or more antisolvents may be added, preferably during
step (a) or at the beginning of step (b). Water is an example of a
suitable antisolvent. The amount of antisolvent is preferably
chosen to obtain a supersaturated or saturated solution with
respect to the crystalline complex.
[0200] In step (b) the solution is stored for a time sufficient to
obtain a precipitate, i.e., the crystalline complex. The
temperature of the solution in step (b) is about the same as or
lower than in step (a). During storage the temperature of the
solution is preferably lowered, preferably to a temperature in the
range of 20.degree. C. to 0.degree. C. or even lower. The step (b)
can be carried out with or without stirring. As known to the one
skilled in the art by the period of time and the difference of
temperature in step (b) the size, shape and quality of the obtained
crystals can be controlled. Furthermore the crystallization may be
induced by methods as known in the art, for example by mechanical
means such as scratching or rubbing the contact surface of the
reaction vessel for example with a glass rod. Optionally the
(nearly) saturated or supersaturated solution may be inoculated
with seed crystals.
[0201] In step (c) the solvent(s) can be removed from the
precipitate by known methods as for example by filtration, suction
filtration, decantation or centrifugation.
[0202] In step (d) an excess of the solvent(s) is removed from the
precipitate by methods known to the one skilled in the art as for
example by reducing the partial pressure of the solvent(s),
preferably in vacuum, and/or by heating above ca. 20.degree. C.,
preferably in a temperature range below 100.degree. C., even more
preferably below 85.degree. C.
[0203] Compound A may be synthesized by methods as specifically
and/or generally described or cited in international application
WO2007/128749 (ref. 18) which in its entirety is incorporated
herein by reference, and/or in the Examples disclosed herein below.
Biological properties of the compound A may also be investigated as
is described in WO2007/128749 (ref. 18).
[0204] A crystalline complex as described herein is preferably
employed as drug active substance in substantially pure form, that
is to say, essentially free of other crystalline forms of the one
or more SGLT2 inhibitors (e.g., compound A). Nevertheless, the
invention also embraces a crystalline complex in admixture with
another crystalline form or forms. Should the drug active substance
be a mixture of crystalline forms, it is preferred that the
substance comprises at least 50%-weight, even more preferably at
least 90%-weight, most preferably at least 95%-weight of the
crystalline complex as described herein.
[0205] In view of its ability to inhibit SGLT activity, a
crystalline complex according to the invention is suitable for the
use in the treatment and/or preventive treatment of conditions or
diseases which may be affected by the inhibition of SGLT activity,
particularly SGLT-2 activity, in particular the metabolic disorders
as described herein. The crystalline complex according to the
invention is also suitable for the preparation of pharmaceutical
compositions for the treatment and/or preventive treatment of
conditions or diseases which may be affected by the inhibition of
SGLT activity, particularly SGLT-2 activity, in particular
metabolic disorders as described herein. A crystalline complex as
described herein (in particular of compound A with a natural amino
acid, e.g., proline, particularly L-proline) is also suitable for
the use in the treatment of equine.
Pharmaceutical Compositions and Formulations
[0206] SGLT2 inhibitors for use according to the invention may be
prepared as pharmaceutical compositions. They may be prepared as
solid or as liquid formulations. In either case, they are
preferably prepared for oral administration, preferably in liquid
form for oral administration. The SGLT2 inhibitors may, however,
also be prepared, e.g., for parenteral administration.
[0207] Solid formulations include tablets, granular forms, and
other solid forms such as suppositories. Among solid formulations,
tablets and granular forms are preferred.
[0208] Pharmaceutical compositions within the meaning of the
present invention may comprise one or more SGLT2 inhibitors
according to the present invention and one or more excipients. Any
excipient that allows for, or supports, the intended medical effect
may be used. Such excipients are available to the skilled person.
Useful excipients are for example anti-adherents (used to reduce
the adhesion between the powder (granules) and the punch faces and
thus prevent sticking to tablet punches), binders (solution binders
or dry binders that hold the ingredients together), coatings (to
protect tablet ingredients from deterioration by moisture in the
air and make large or unpleasant-tasting tablets easier to
swallow), disintegrants (to allow the tablet to break upon
dilution), fillers, diluents, flavors, colors, glidants (flow
regulators--to promote powder flow by reducing interparticle
friction and cohesion), lubricants (to prevent ingredients from
clumping together and from sticking to the tablet punches or
capsule filling machine), preservatives, sorbents, sweeteners,
etc.
[0209] Formulations according to the invention, e.g., solid
formulations, may comprise carriers and/or disintegrants selected
from the group of sugars and sugar alcohols, e.g., mannitol,
lactose, starch, cellulose, microcrystalline cellulose and
cellulose derivatives, e. g., methylcellulose, and the like.
[0210] Manufacturing procedures for formulations suitable for
equine animals are known to the person skilled in the art, and for
solid formulations comprise, e.g., direct compression, dry
granulation and wet granulation. In the direct compression process,
the active ingredient and all other excipients are placed together
in a compression apparatus that is directly applied to press
tablets out of this material. The resulting tablets can optionally
be coated afterwards in order to protect them physically and/or
chemically, e.g., by a material known from the state of the
art.
[0211] A unit for administration, e.g., a single liquid dose or a
unit of a solid formulation, e.g., a tablet, may comprise 5 to 2500
mg, or e.g. 5 to 2000 mg, 5 mg to 1500 mg, 10 mg to 1500 mg, 10 mg
to 1000 mg, or 10-500 mg of one or more SGLT2 inhibitors for use
according to the invention. As the skilled person would understand,
the content of the one or more SGLT2 inhibitors in a solid
formulation, or any formulation as disclosed herein for
administration to an equine animal, may be increased or decreased
as appropriate in proportion to the body weight of the equine
animal to be treated.
[0212] In one embodiment a pharmaceutical composition for use
according to the invention is designed for oral or parenteral
administration, preferably for oral administration. The oral
administration may be ameliorated by excipients which modify the
smell and/or haptic properties of the pharmaceutical composition
for the intended patient.
[0213] When the one or more SGLT2 inhibitors for use according to
the invention is formulated for oral administration, it is
preferred that excipients confer properties, e.g., palatability
and/or chewability that render the formulation suitable for
administration to an equine animal.
[0214] Also preferred are liquid formulations. Liquid formulations
may be, e.g., solutions, syrups or suspensions. They may be
administered directly to the equine animal or may be mixed with the
food and/or drink (e.g., drinking water, or the like) of the equine
animal. One advantage of a liquid formulation (similar to a
formulation in granular form), is that such a dosage form allows
precise dosing. For example, the one or more SGLT2 inhibitors may
be dosed precisely in proportion to the body mass of an equine
animal. Typical compositions of liquid formulations are known to
the person skilled in the art.
Dosing and Administration
[0215] A practitioner skilled in the art can determine suitable
doses for the uses of the present invention. Preferred units dosing
units include mg/kg, i.e., mg SGLT2 inhibitor per body mass of the
equine animal. One or more SGLT2 inhibitors of the invention may,
e.g., be administered in doses of 0.01-5 mg/kg bodyweight per day,
e.g., 0.01-4 mg/kg, e.g., 0.01-3 mg/kg, e.g., 0.01-2 mg/kg, e.g.,
0.01-1.5 mg/kg, e.g., 0.01-1 mg/kg, e.g. 0.01-0.75 mg/kg, e.g.,
0.01-0.5 mg/kg, e.g., 0.01-0.4 mg/kg, e.g., 0.01-0.4 mg/kg
bodyweight per day. Preferably the dose is 0.02-0.5 mg/kg
bodyweight per day, more preferably 0.03-0.4 mg/kg bodyweight per
day, e.g. 0.03-0.3 mg/kg bodyweight per day.
[0216] In a preferred embodiment, the one or more SGLT2 inhibitors
or a pharmaceutically acceptable form thereof may be administered
in dosages of 0.01 to 3.0 mg/kg body weight per day, preferably
from 0.02 to 1.0 mg/kg body weight per day, more preferably from
0.03 to 0.4 mg/kg body weight per day. Thus, the one or more SGLT2
inhibitors or pharmaceutically acceptable form thereof may be
prepared for the administration of 0.01 to 3.0 mg/kg body weight
per day, preferably from 0.02 to 1.0 mg/kg body weight per day,
more preferably from 0.03 to 0.4 mg/kg body weight per day.
[0217] A practitioner skilled in the art is able to prepare one or
more SGLT2 inhibitors of the invention for administration according
to a desired dose.
[0218] Preferably, according to the invention, one or more SGLT2
inhibitors is administered no more than three times per day, more
preferably no more than twice per day, most preferably only once
per day. The frequency of administration can be adapted to the
typical feeding rate of the equine animal.
[0219] According to the invention, an SGLT2 inhibitor, e.g.,
compound A, may be administered such that an appropriate blood
plasma concentration of the one or more SGLT2 inhibitors is
achieved (e.g., a maximal blood plasma concentration, or blood
plasma concentration after a given time, e.g., 4, 8, 12 or 24 hours
after oral administration, preferably about 8 hours after oral
administration). E.g., for compound A, the blood plasma
concentration (e.g., maximal blood plasma concentration or blood
plasma concentration after said given time after oral
administration) may be within the range 2 to 4000 nM, e.g. 20 to
3000 nM, or e.g., 40 to 2000 nM.
[0220] Preferably, following administration and the time required
for the one or more SGLT2 inhibitors to reach the bloodstream, such
levels are maintained in the blood over a time interval of at least
12 hours, more preferably at least 18 hours, most preferably at
least 24 h.
[0221] Preferably, according to the invention, one or more SGLT2
inhibitors is administered orally, in liquid or solid form. The one
or more SGLT2 inhibitors may be administered directly to the
animals mouth (e.g., using a syringe, preferably a
body-weight-graduated syringe) or together with the animal's food
or drink (e.g., with its drinking water or the like), in each case
preferably in liquid form. The SGLT2 inhibitors may, however, also
be administered, e.g., parenterally, or by any other route of
administration, e.g., rectally.
[0222] The one or more SGLT2 inhibitors may be used alone or in
combination with another drug. In some embodiments, the one or more
SGLT2 inhibitors are used in combination with one or more further
oral antihyperglycemic drugs. When the one or more SGLT2 inhibitors
is used in combination with a further drug, the one or more SGLT2
inhibitors and any further drug may be administered simultaneously,
sequentially (in any order), and/or according to a chronologically
staggered dosage regime. In such embodiments, when a further drug
for combined administration with the one or more SGLT2 inhibitors
is not administered simultaneously with the SGLT2 inhibitor, the
one or more SGLT2 inhibitors and any further drug are preferably
administered within a period of at least 2 weeks, 1 month, 2
months, 4 months, 6 months or longer, e.g., 12 months or more.
[0223] In some embodiments the one or more SGLT2 inhibitors
(whether used alone or in combination with another drug) is not
used in combination with
1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)--
amino-piperidin-1-yl]-xanthine or a pharmaceutically acceptable
salt thereof, i.e., the equine animal is not treated with said
compound. In some embodiments the one or more SGLT2 inhibitors is
not used in combination with a DPP-IV inhibitor, i.e., the equine
animal is not treated with a DPP-IV inhibitor.
[0224] In some embodiments, the one or more SGLT2 inhibitors are
used as a monotherapy, i.e., stand-alone therapy, i.e., no other
medication is administered to the equine animal for the treatment
or prevention of the same metabolic disorder, i.e., the metabolic
disorder for which the one or more SGLT2 inhibitors is
administered. E.g., no other medication is administered to the
equine animal for the treatment or prevention of the same metabolic
disorder within a period of at least 2, 3, or 4 weeks before and
after administration of the SGLT2 inhibitor.
BRIEF DESCRIPTION OF THE FIGURES
[0225] FIG. 1 shows that doses of 0.3 mg/kg bodyweight or 3 mg/kg
bodyweight orally, or 1 mg/kg bodyweight i.v. of compound A, all
caused prominent increases of urinary glucose concentration in
horses.
[0226] FIG. 2 shows the correlation between compound A plasma level
and urinary glucose excretion normalized to urinary creatinine
(glucose/creatinine).
[0227] FIG. 3 compares relative changes in blood glucose over a
period of 0-210 minutes (mean values; baseline as covariate) in an
oral sugar test (OST) in treated and control animals on day 28 of
the treatment period (bold lines) with the same animals on day -14
before the beginning of the treatment period (dotted lines). For
comparison the fine dotted lines depicts the time course of the
glucose excursion in the OST of a healthy glucose tolerant
horse.
[0228] FIG. 4 shows the change of plasma glucose [mM] during a time
courses after treatment with compound A or its vehicle and feeding.
For the control group individual data are given, whereas for horses
treated with compound A mean data are given for each dosing group
(0.3 mg/kg bodyweight or 3 mg/kg bodyweight orally, or 1 mg/kg
bodyweight i.v.).
[0229] FIG. 5 shows a time course of blood insulin concentrations
[.mu.IU/mL] in insulin resistant horses during an OST after 4 weeks
of treatment with compound A (solid lines) or its vehicle (dotted
lines). Mean group values are given. Bold line: 2 hours after
compound/vehicle administration; thinner line: 24 hours after last
compound/vehicle administration.
[0230] FIG. 6 shows basal plasma insulin levels [.mu.IU/mL] before
treatment (day -12), on day 14 and on day 29 of treatment with
compound A or its vehicle. Individual data (thin lines) and the
group mean values (bold lines) are given.
[0231] FIG. 7 shows the basal insulin sensitivity of treated and
control horses as expressed by the QUICKI (quantitative insulin
sensitivity check index, i.e., 1/(log(fasting insulin
pmol/L)+log(fasting glucose mmol/L)). Measurements were taken
before treatment (day -12), on day 14 and on day 29 of treatment
with compound A or its vehicle. Individual data (thin lines) and
the group mean values (bold lines) are given.
[0232] FIG. 8 shows plasma insulin AUC (area under curve) values
[.mu.IU/mL/min] (baseline as covariate) before treatment (day -12),
on day 28 (2 hours after compound/vehicle administration) and on
day 30 (24 hours after last compound/vehicle administration) of
treatment with compound A or its vehicle. Individual data (thin
lines) and the group mean values (bold lines) are given.
[0233] FIG. 9 shows the insulin sensitivity of treated and control
horses as expressed by the Belfiore insulin sensitivity index
(i.e., 1/(log(AUC.DELTA.insulin.times.AUC.DELTA., glucose)).
Measurements were taken before treatment (day -12), on day 28 (2
hours after compound/vehicle administration) and on day 30 (24
hours after last compound/vehicle administration) of treatment with
compound A or its vehicle. Individual data (thin lines) and the
group mean values (bold lines) are given.
[0234] FIG. 10A shows the time course of the elimination of
non-esterified fatty acids (NEFAs, .mu.Eq/L) from the bloodstream
as measured during an intravenous insulin tolerance test (ivITT)
prior to the treatment period. Mean group values are given of the
horses treated with compound A (solid lines) or its vehicle (dotted
lines).
[0235] FIG. 10B shows the time course of the elimination of
non-esterified fatty acids (NEFAs, .mu.Eq/L) from the bloodstream
as measured during an intravenous insulin tolerance test (ivITT)
and represent the results after 5 weeks of treatment. Mean group
values are given of the horses treated with compound A (solid
lines) or its vehicle (dotted lines).
[0236] FIG. 11 shows the basal plasma leptin levels [ng/mL] before
treatment (day -12), on day 14 and on day 29 of treatment with
compound A or its vehicle. Individual data (thin lines) and the
group mean values (bold lines) are given.
[0237] FIG. 12 shows the horses body mass [kg] before treatment
(day -12), on day 14 and on day 29 of treatment with compound A or
its vehicle. Individual data (thin lines) and the group mean values
(bold lines) are given.
[0238] FIG. 13 shows an X-ray powder diffraction pattern of a
representative batch of a crystalline complex of compound A with
L-proline (1:1).
[0239] FIG. 14 shows a DSC/TG diagram of a representative batch of
a crystalline complex of compound A with L-proline (1:1).
[0240] FIGS. 15A and 15B show the increase of plasma glucose [mM]
and insulin [.mu.IU/mL] during a glucose challenge, the delta of
time "0"--before the challenge and 120 min after the challenge is
given. Open columns represent the values before ("pre") treatment;
filled columns give the values on day 14 of treatment ("post") with
compound A (panel A) or placebo (panel B).
[0241] FIG. 16A shows relative changes (group mean values; baseline
as covariate) of blood glucose over a period of 0-240 minutes
relative to the morning feeding on day 2 of the dietary challenge.
Bold lines: horses treated with compound A (n=3), dotted lines:
untreated controls (n=8).
[0242] FIG. 16B shows relative changes (group mean values; baseline
as covariate) of insulin levels over a period of 0-240 minutes
relative to the morning feeding on day 2 of the dietary challenge.
Bold lines: horses treated with compound A (n=3), dotted lines:
untreated controls (n=8).
EXAMPLES
[0243] The following examples show the beneficial therapeutic
effects on glycemic control and/or insulin resistance, etc., of
using of SGLT2 inhibitors in equine animals, according to the
present invention. These examples are intended to illustrate the
invention in more detail without any limitation of the scope of the
claims.
Example 1: Pharmacokinetics (PK)/Pharmacodynamics (PD) of Compound
A Single Oral Dosing in Horses
[0244] Compound A was administered to overnight fasted horses. The
groups (n=3 per group) received a single oral or intravenous (i.v.)
administration of either vehicle alone (purified water, macrogol 15
hydroxystearate) or vehicle containing the one or more SGLT2
inhibitors at a dose of 0.3 mg/kg bodyweight and 3 mg/kg bodyweight
orally and 1 mg/kg bodyweight i.v. PK/PD measurements were taken
until day 3 after a single administration of compound A or its
vehicle.
TABLE-US-00002 TABLE 2 Pharmacokinetic data, single dose 1 mg/kg
0.3 mg/kg 3.0 mg/kg Parameter i.v. p.o. p.o. .sub.tmax [hour] mean
2 1 C.sub.max [nmol/L] mean 353 3867 AUC.sub.0.fwdarw..infin. [nmol
h/l] mean 41251 2869 29752 T.sub.1/2 [hour] mean 7.9 8.5 8.2
[0245] Pharmacodynamic Data: [0246] A prominent increase of urinary
glucose concentration was evident at all doses already 1 hour after
administration (mean group values: controls 0.6 mmol/L; 1 mg/kg
i.v.-253 mmol/L; 0.3 mg/kg po-103 mmol/L; 3 mg/kg po-217 mmol/L)
and was persistent for more than 24 hours (see [0189]). [0247] None
of the doses of compound A altered the basal blood glucose level in
horses as compared to normal reference values. [0248] None of the
doses of compound A altered the renal function of horses.
[0249] Urinary glucose excretion increase is clearly plasma
compound exposure dependent, as shown in [0190].
Example 2. The Effect of Compound A on Urinary and Blood Glucose as
Well as Glucose Tolerance after Repeated Dosing in Horses
[0250] Compound A was administered to freely fed normoglycemic,
hyperinsulinemic, insulin resistant, obese horses, which exhibit an
impaired glucose tolerance. The groups (n=4 per group) received a
once daily oral administration of either vehicle alone (purified
water, macrogol 15 hydroxystearate-0.2 mL/100 kg and approximately
35 mL of apple sauce) or vehicle containing the one or more SGLT2
inhibitors in increasing doses up to 1 mg/kg bodyweight for 4
weeks. The treated horses received a daily dose of compound A at
0.1 mg/kg bodyweight for the first 7 days, followed by 0.2 mg/kg
bodyweight, from day 20 the dose was increased to 1 mg/kg
bodyweight. Urinary glucose and blood glucose were measured.
Additionally, to evaluate the glucose tolerance, blood glucose was
measured during an oral sugar test (OST, corn syrup 0.15 mL/kg) was
performed. Blood was collected via jugular vein catheters. Blood
samples were taken prior and at 60, 90, 120, 150, 180, and 210 min
relative to sugar application. [0251] The urinary glucose
concentration was significantly elevated by the
treatment--controls<1 mmol/L; treated--.about.300 mmol/L. [0252]
Basal blood glucose levels remained within normal ranges in all
horses throughout the study. No hypoglycemia was observed.
[0253] FIG. 3 shows blood glucose levels over a period of 0-210
minutes in an oral sugar test (OST) in animals treated with
compound A and in control animals treated only with vehicle on day
28 of the treatment period. Mean values are shown (n=4 per
group).
[0254] Comparison of the glucose curves at the end of the study
revealed a statistically significant tendency (p=0.066) for a
reduction of the glucose AUC in the horses treated with compound A.
The plasma glucose concentration at 90 minutes after the challenge
was significantly (p=0.038) lower in the treated horses.
[0255] These data indicate that treated horses experienced a
significant improvement of their glucose tolerance.
Example 3. The Effect of Compound A on Postprandial Blood Glucose
in Horses
[0256] The following example shows the effect of compound A on
postprandial blood glucose in horses. Compound A was administered
to overnight fasted horses. The groups (n=3 per group) received a
single oral or i.v. administration of either vehicle alone
(purified water, macrogol 15 hydroxystearate) or vehicle containing
the one or more SGLT2 inhibitors at a dose of 0.3 mg/kg bodyweight
and 3 mg/kg bodyweight orally and 1 mg/kg bodyweight i.v. Two hours
after compound administration horses were fed a test meal. The
postprandial glycaemia is quantified 2 hours thereafter and
significantly blunted by all doses of compound A, as shown in
[0192]. Compound A is thus clearly capable of effectively reducing
postprandial glucose levels in horses.
[0257] The efficacy of SGLT2 inhibition in accordance with the
invention in the treatment of pathological fasting glucose and/or
insulin and/or impaired glucose tolerance can be tested using
clinical studies. In studies over a shorter or longer period (e.g.,
2-4 weeks or 1-2 years) the success of the treatment is examined by
determining the fasting glucose and insulin values and/or the
glucose values after a meal or after a loading test (oral glucose
tolerance test or food tolerance test after a defined meal) after
the end of the period of therapy for the study and comparing them
with the values before the start of the study and/or with those of
a placebo group. In addition, the fructosamine value can be
determined before and after therapy and compared with the initial
value and/or the placebo value. A significant drop in the fasting
or non-fasting glucose and/or insulin and/or fructosamine levels
demonstrates the efficacy of the treatment.
Example 4. Effect Upon Insulin Sensitivity and Plasma Insulin
Levels in Horses
[0258] The following example shows the beneficial effect of
compound A in insulin resistant obese horses. Compound A was
administered to freely fed normoglycemic, obese horses. The groups
(n=4 per group) received a once daily oral administration of either
vehicle alone (purified water, macrogol 15 hydroxystearate-0.2
mL/100 kg and approximately 35 mL of apple sauce) or vehicle
containing the one or more SGLT2 inhibitors in increasing doses up
to 1 mg/kg bodyweight for 4 weeks. The following experiment was
performed prior to treatment, and at the end of the 4 week
treatment period. The treated horses received a daily dose of
compound A at 0.1 mg/kg bodyweight for the first 7 days, followed
by 0.2 mg/kg bodyweight, until day 20 from thereon until the end of
the study the dose was increased to 1 mg/kg bodyweight. At days 28
and 30 the following experiment was performed twice, once
approximately 2 h and another time approximately 24 h after the
last administration of compound A or its vehicle.
[0259] An oral sugar test (OST, corn syrup 0.15 mL/kg) was
performed. Blood was collected via jugular vein catheters. Blood
samples were taken prior and at 60, 90, 120, 150, 180, and 210 min
relative to sugar application. Glucose and insulin excursions were
quantified by calculating the baseline corrected glucose AUC.
[0260] The significance of differences of means between groups was
evaluated by repeated-measures two-factor (time & treatment)
ANOVA and post hoc multiple comparisons versus control or the
respective baseline readings.
[0261] The baseline corrected glucose excursion during the OST did
not change during the study period or by the treatment. The insulin
excursion in control horses was not altered throughout the study
period but was significantly reduced in treated horses as compared
to pretreatment or control horses (p<0.05, see FIG. 8). [0193]
shows a time course of blood insulin concentrations [.mu.IU/mL] in
the insulin resistant obese horses during an OST after 4 weeks of
treatment with compound A or its vehicle.
[0262] Plasma insulin levels significantly decreased over the
four-week treatment period in horses treated with compound A, but
remained essentially unchanged on average in control horses given
vehicle only (see [0194]).
[0263] Insulin sensitivity was significantly increased in treated
horses as compared to pretreatment values. This was demonstrated by
determining basal insulin sensitivity values as expressed by the
QUICKY index (1/log(gluc*ins) and during the challenge (OST) by the
modified Belfiore index (1/log(.DELTA.AUC gluc*.DELTA.AUC ins). As
shown in [0195] and in [0197], in the course of the four-week
treatment period, insulin sensitivity significantly increased in
treated horses, but remained essentially unchanged in control
horses given vehicle only.
[0264] These data indicate that the insulin resistance was
significantly improved after a 2 to 4 week treatment with compound
A.
Example 5. Effect Upon Dyslipidemia, Dysadipokinemia and Body
Weight/Obesitas in Horses
[0265] The following example shows the beneficial effect of
compound A in insulin resistant obese horses. The details of the
experiments are described in example 4.
[0266] To test the effect of compound A treatment on blood lipid
handling/elimination, an intravenous insulin tolerance test (ivITT,
0.03 U insulin per kg body mass) was performed prior to start of
and on day 35 of the treatment period. The test was performed prior
to the morning feeding and approximately 24 hours after the last
administration of compound A or its vehicle (day 35 only). Blood
was collected prior to and at 15, 30, 60, 90, 120 and 150 minutes
after the insulin challenge. [0198] shows a time course of baseline
corrected blood NEFA concentrations [.mu.Eq/L] in the insulin
resistant obese horses during an ivITT.
[0267] The baseline corrected NEFA elimination curve during the ITT
was clearly not different between the groups prior to treatment
(see FIG. 10, panel A). At the end of the treatment period NEFA
elimination was significantly improved by the compound A treatment
(see FIG. 10, panel B).
[0268] The use of one or more SGLT2 inhibitors according to the
present invention advantageously also reduced blood leptin levels.
As shown in FIG. 11, in the course of the four-week treatment
period, plasma leptin concentrations significantly decreased in
treated horses, but remained essentially unchanged in control
horses given vehicle only.
[0269] Additionally, the use of one or more SGLT2 inhibitors
according to the present invention also reduced significantly the
body weight of obese horses treated with compound A (see FIG. 12)
in the course of the four-week treatment period.
[0270] These data indicate that after a 2 to 5 week treatment with
compound A obese, insulin resistant horses showed significantly
improved handling of blood lipids (elimination after a challenge)
and an improved adipokine profile with reduced blood leptin
concentrations. Additionally, the body weight was significantly
reduced by treatment with compound A and indicates the potential to
influence obesity and/or regional adiposity in horses.
[0271] The efficacy of SGLT2 inhibition in accordance with the
invention in the treatment of pathological obesity and/or regional
adiposity can be tested using clinical studies. In studies over a
shorter or longer period (e.g., 3-6 months or 1-2 years) the
success of the treatment is examined by determining e.g., body
weight, body condition scores, other morphometric measurements or
non-invasive body composition determination methods, e.g.,
ultrasound determination of fat pad dimension or deuterium oxide
dilution (heavy water) methods. A significant difference in these
values during or at the end of the study, compared with the initial
value or compared with a placebo group, or a group given a
different therapy, proves the efficacy of a pharmaceutical
composition according to the invention in the reduction of obesitas
and/or regional adipositas.
Example 6. Effects on Parameters of Inflammation
[0272] In studies in horses with metabolic disorders according to
the present invention running for different lengths of time (e.g.,
2 weeks to 12 months) the effect of the treatment with SGLT2
inhibitors according to the invention on inflammation (be it
subclinical inflammation, systemic inflammation, low grade systemic
inflammation) is evaluated by determining in the blood stream for
example the concentration of proinflammatory cytokines (e.g.,
TNF-alpha or IL-6) or acute phase proteins (e.g., serum amyloid A
or haptoglobulin). A significant fall in these values during or at
the end of the study, compared with the initial value or compared
with a placebo group, or a group given a different therapy, proves
the efficacy of a pharmaceutical composition according to the
invention in the reduction of parameters of inflammation in horses
with metabolic disorders.
Example 7. Effects on Equine Metabolic Syndrome and Associated
Diseases as Laminitis
[0273] In studies in horses with metabolic disorders according to
the present invention, particularly in studies in horses with
equine metabolic syndrome and/or pituitary pars intermedia
dysfunction and associated diseases as laminitis running for
different lengths of time (e.g., 2 weeks to 12 months) e.g., the
success of the improvement in insulin resistance can be checked
using the measurement of baseline blood glucose, blood fructosamine
and blood insulin level and there corresponding relation in the
individual horse. Also the glucose and insulin values after a meal
or after a loading test (glucose tolerance test or insulin
tolerance test) after or during a period of therapy and comparing
them with the values before the start of the study and/or with
those of a placebo group can be employed. Additionally, the
incidence of laminitis and/or the reduction of lameness and/or time
to recovery from a laminitis episode can be evaluated with respect
to the initial lameness values and the time course of lameness
throughout an observation period.
[0274] Also the comparison with a placebo group or a group given a
different therapy can prove the efficacy of a pharmaceutical
composition according to the invention.
Example 8. Effects of Compound A on Insulin Resistance and
Hyperinsulinemia in Horses Suffering from Equine Pituitary Pars
Intermedia Dysfunction (PPID)
[0275] The following example shows the beneficial effect of
compound A in an insulin resistant horse with PPID. PPID was
diagnosed based on blood ACTH values--normal ACTH being below 30
pg/mL. The respective horse exhibited an ACTH blood concentration
of 966 pg/mL, was thus clearly diagnosed to suffer from PPID.
[0276] An in-feed oral glucose challenge test was performed prior
to treatment and at the end of a 4 week treatment period. For this
test, oral dextrose powder at 1 g/kg bodyweight was dissolved in
100 ml tap water and added to 200 g to wheat bran plus lucerne
chaff. Blood was collected via the jugular vein prior to the
challenge and 2 hours thereafter.
[0277] The horse received a once daily dose of 0.3 mg/kg of
compound A dissolved in purified water, macrogol 15
hydroxystearate. Compound A was given orally with some apple sauce
for 4 weeks. Prior to the treatment there was a clear evidence of
hyperinsulinemia, the basal plasma insulin concentrations were 19
.mu.IU/mL. Treatment clearly decreased the basal hyperinsulinemia
to normal concentrations (4 .mu.IU/mL) and also clearly reduced the
rise of insulin in response to the challenge by 45%. The blood
glucose response was also slightly reduced--in consequence when
determining the insulin sensitivity values as expressed by the
QUICKY index (1/log(gluc*ins) 4 weeks of treatment increased basal
insulin sensitivity to 160% of the prevalue.
[0278] The data show that hyperinsulinemia and insulin resistance
in horses with PPID can be significantly improved by treatment with
SGLT2 inhibitors, e.g., compound A.
Example 9. Effects of Compound A in Horses with Me