U.S. patent application number 17/094591 was filed with the patent office on 2021-03-11 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.
Application Number | 20210069222 17/094591 |
Document ID | / |
Family ID | 1000005234810 |
Filed Date | 2021-03-11 |
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United States Patent
Application |
20210069222 |
Kind Code |
A1 |
REICHE; Dania Birte ; et
al. |
March 11, 2021 |
TREATMENT OF METABOLIC DISORDERS IN EQUINE ANIMALS
Abstract
A SGLT2 inhibitor or a pharmaceutically acceptable form thereof
is provided for use in the treatment and/or prevention of a
metabolic disorder of an equine animal. In particular, a SGLT2
inhibitor or a pharmaceutically acceptable form thereof is provided
for use in the treatment and/or prevention of insulin resistance,
hyperinsulinemia, impaired glucose tolerance, dyslipidemia,
dysadipokinemia, subclinical inflammation, systemic inflammation,
low grade systemic inflammation, obesity, and/or regional adiposity
in an equine animal.
Inventors: |
REICHE; Dania Birte; (Bingen
am Rhein, DE) ; JOHNSTON; Laura; (Sydney, AU)
; MOHREN; Nicole; (Jugenheim, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim Vetmedica GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
1000005234810 |
Appl. No.: |
17/094591 |
Filed: |
November 10, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15362031 |
Nov 28, 2016 |
10864225 |
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17094591 |
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14242916 |
Apr 2, 2014 |
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15362031 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/351 20130101;
C07D 309/10 20130101; C07H 15/207 20130101; A61K 9/0053 20130101;
A61K 31/7034 20130101; A61K 9/0031 20130101; A61K 9/0019 20130101;
A61K 31/7048 20130101; A61K 9/02 20130101; A61K 9/2018 20130101;
A61K 47/545 20170801; A61K 31/70 20130101; A61K 9/20 20130101; A61K
9/4866 20130101; A61K 31/7042 20130101; A61K 31/7056 20130101; A61K
9/48 20130101 |
International
Class: |
A61K 31/7034 20060101
A61K031/7034; C07H 15/207 20060101 C07H015/207; A61K 9/02 20060101
A61K009/02; A61K 9/00 20060101 A61K009/00; A61K 31/7048 20060101
A61K031/7048; A61K 9/20 20060101 A61K009/20; A61K 31/7056 20060101
A61K031/7056; A61K 31/70 20060101 A61K031/70; A61K 31/7042 20060101
A61K031/7042; A61K 9/48 20060101 A61K009/48; A61K 47/54 20060101
A61K047/54; A61K 31/351 20060101 A61K031/351; C07D 309/10 20060101
C07D309/10 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 4, 2013 |
EP |
13162408.2 |
Claims
1. An SGLT2 inhibitor or a pharmaceutically acceptable form thereof
for use in the treatment and/or prevention of a metabolic disorder
of an equine animal.
Description
FIELD OF THE INVENTION
[0001] 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
[0002] 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 hyperglycaemia 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, dyslipidaemia, dysadipokinemia, obesity and/or regional
adiposity, subclinical inflammation or systemic inflammation, in
particular low grade systemic inflammation, which also comprises
adipose tissue.
[0003] No satisfactory treatment is currently available for
metabolic disorders such as insulin resistance, hyperinsulinaemia
and associated disorders in equine animals.
[0004] In human medicine, insulin resistance, e.g. when manifest as
diabetes mellitus type 2, is a well-recognized condition, and may
lead in particular to hyperglycaemia (pathologically increased
plasma glucose levels). Several oral antihyperglycaemic 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).
[0005] Other antihyperglycaemic 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 and may reduce blood
glucose levels.
[0006] 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
manifest as hyperinsulinaemia. 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 hyperglycaemia (ref. 1: Frank et al., 2011,
incorporated by reference). 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
[0007] The present inventors have 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 an SGLT2 inhibitor or a
pharmaceutically acceptable form 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.
[0008] According to the invention, the metabolic disorder may be
insulin resistance, hyperinsulinemia, and/or a clinical condition
associated with insulin resistance and/or hyperinsulinaemia.
[0009] The metabolic disorder, or said clinical condition
associated with insulin resistance and/or hyperinsulinaemia, 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, and/or regional adiposity.
[0010] 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, and/or regional adiposity.
[0011] 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 may be associated with
hyperinsulinemia and/or insulin resistance
[0012] 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, and/or regional adiposity.
[0013] 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.
[0014] The pharmaceutically acceptable form of the SGLT2 inhibitor
may be a crystalline complex between the SGLT2 inhibitor and one or
more amino acids, e.g. proline.
[0015] According to the invention, the SGLT2 inhibitor or
pharmaceutically acceptable form thereof may be provided, e.g., for
oral or parenteral administration, preferably for oral
administration.
[0016] The SGLT2 inhibitor 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 SGLT2 inhibitor 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.
[0017] The SGLT2 inhibitor or pharmaceutically acceptable form
thereof is preferably administered only once per day.
[0018] According to the present invention, any SGLT2 inhibitor or
pharmaceutically acceptable form thereof may be used. In preferred
embodiments, the SGLT2 inhibitor is a glucopyranosyl-substituted
benzene derivative. A number of SGLT2 inhibitors which may be used
according to the invention are described in detail herein
below.
[0019] The present invention also provides a pharmaceutical
composition comprising an SGLT2 inhibitor or a pharmaceutically
acceptable form thereof, for use according to the invention as
disclosed herein.
[0020] 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.
[0021] In particular, the present inventors have surprisingly found
that the use of an SGLT2 inhibitor 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 an SGLT2 inhibitor according to the
present invention advantageously leads to increased insulin
sensitivity in treated, insulin resistant equine animals.
[0022] The use of an SGLT2 inhibitor according to the present
invention advantageously leads to reduced plasma insulin levels,
i.e. allows effective treatment of hyperinsulinaemia. Thus, the use
of an SGLT2 inhibitor 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).
[0023] The use of an SGLT2 inhibitor according to the present
invention advantageously leads to a reduction in hyperinsulinemia
and surrogate markers of insulin resistance in treated, insulin
resistant equine animals.
[0024] 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.
[0025] The use of an SGLT2 inhibitor according to the present
invention thus generally leads to improved (i.e. increased) glucose
tolerance, i.e., equivalently, reduces glucose intolerance.
[0026] The use of an SGLT2 inhibitor 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).
[0027] The use of an SGLT2 inhibitor 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.
[0028] The use of an SGLT2 inhibitor according to the present
invention generally reduces dyslipidaemia, dysadipokinemia, obesity
and/or regional adiposity. Thus, the use of SGLT2 inhibitors allow
the treatment and prevention of dyslipidaemia, dysadipokinemia,
obesity and/or regional adiposity, in particular when associated
with insulin resistance and/or hyperinsulinemia in equine
animal.
[0029] Advantageously, the use of an SGLT2 inhibitor according to
the present invention does not cause hypoglycemia.
[0030] 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 hyperinsulinaemia, and the treatment, prevention
or control of further metabolic disorders, symptoms and/or clinical
conditions that are associated with insulin resistance and/or
hyperinsulinaemia in equine animals. They thus allow the
possibility of preventing or delaying the onset of such
complications, further metabolic disorders, symptoms and/or
clinical conditions in equine animals.
[0031] 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 an SGLT2 inhibitor 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 and/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).
[0032] The effects of using an SGLT2 inhibitor 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 an SGLT2 inhibitor according to the present
invention, and/or relative to a comparable equine animal that has
not received said treatment (e.g. a placebo group).
[0033] A further advantage of the present invention is that an
SGLT2 inhibitor 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.
[0034] 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.
[0035] 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 and/or
prevention an effective dose of an SGLT2 inhibitor as described
herein.
Definitions
[0036] 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.
[0037] 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.
[0038] 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.
[0039] 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.
[0040] Herein, the terms "active substance" or "active ingredient"
encompass an SGLT2 inhibitor 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.
[0041] Herein, the expression "associated with", in particular
encompasses the expression "caused by".
[0042] Herein, ivGTT refers to an intravenous glucose tolerance
test. In an ivGTT, 0.2 g dextrose per kg body mass may typically be
employed.
[0043] Herein, ivITT refers to an intravenous insulin tolerance
test. In an ivITT, 0.03 U insulin per kg body mass may typically be
employed.
[0044] 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.
[0045] Herein, OST refers to an oral sugar test. In an OST, 0.15 mL
corn syrup per kg body mass may typically be employed.
[0046] SGLT2 Inhibitors
[0047] 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. 2),
WO03/099836 (ref. 3), WO2005/092877 (ref. 4), WO2006/034489 (ref.
5), WO2006/064033 (ref. 6), WO2006/117359 (ref 7), WO2006/117360
(ref 8), WO2007/025943 (ref 9), WO2007/028814 (ref. 10),
WO2007/031548 (ref 11), WO2007/093610 (ref. 12), WO2007/128749
(ref. 13), WO2008/049923 (ref 14), WO2008/055870 (ref. 15),
WO2008/055940 (ref 16), WO2009/022020 (ref. 17) or WO2009/022008
(ref 18), all herein incorporated by reference.
[0048] 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:
[0049] (1) a glucopyranosyl-substituted benzene derivative of the
formula (1)
[0049] ##STR00001## [0050] wherein R.sup.1 denotes cyano, Cl or
methyl (most preferably cyano); [0051] R.sup.2 denotes H, methyl,
methoxy or hydroxy (most preferably H) and [0052] 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, methylsulfanyl, methylsulfinyl,
methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl,
(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or
cyano; [0053] 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,
[0054] 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, phenylcarbonyl and
phenyl-(C.sub.1-3-alkyl)-carbonyl; [0055] (2)
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene,
represented by formula (2):
[0055] ##STR00002## [0056] (3) Dapagliflozin, represented by
formula (3):
[0056] ##STR00003## [0057] (4) Canagliflozin, represented by
formula (4):
[0057] ##STR00004## [0058] (5) Empagliflozin, represented by
formula (5):
[0058] ##STR00005## [0059] (6) Luseogliflozin, represented by
formula (6):
[0059] ##STR00006## [0060] (7) Tofogliflozin, represented by
formula (7):
[0060] ##STR00007## [0061] (8) Ipragliflozin, represented by
formula (8):
[0061] ##STR00008## [0062] (9) Ertugliflozin, represented by
formula (9):
[0062] ##STR00009## [0063] (10) Atigliflozin, represented by
formula (10):
[0063] ##STR00010## [0064] (11) Remogliflozin, represented by
formula (11):
[0064] ##STR00011## [0065] (12) a thiophene derivative of the
formula (12)
[0065] ##STR00012## [0066] wherein R denotes methoxy or
trifluoromethoxy; [0067] (13)
1-(.beta.-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethy-
l]benzene as described in WO2005/012326, represented by formula
(13);
[0067] ##STR00013## [0068] (14) a spiroketal derivative of the
formula (14):
[0068] ##STR00014## [0069] wherein R denotes methoxy,
trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl; [0070]
(15) a pyrazole-O-glucoside derivative of the formula (15)
[0070] ##STR00015## [0071] wherein [0072] R.sup.1 denotes
C.sub.1-3-alkoxy, [0073] L.sup.1, L.sup.2 independently of each
other denote H or F, [0074] R.sup.6 denotes H,
(C.sub.1-3-alkyl)carbonyl, (C.sub.1-6-alkyl)oxycarbonyl,
phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; [0075] (16)
a compound of the formula (16):
[0075] ##STR00016## [0076] (17) and Sergliflozin, represented by
formula (17):
##STR00017##
[0077] 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. 3), incorporated by
reference, for example. Preferred hydrates, solvates and
crystalline forms are described in the patent applications
WO2008/116179 (ref 19) and WO2008/002824 (ref 20), both
incorporated by reference, for example.
[0078] 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. 21) and
WO2009/035969 (ref. 22), both incorporated by reference, for
example. Preferred hydrates, solvates and crystalline forms are
described in the patent application WO2008/069327 (ref 23),
incorporated by reference for example.
[0079] 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. 4), WO2006/120208
(ref 24) and WO2011/039108 (ref 25), all incorporated by reference,
for example. A preferred crystalline form is described in the
patent applications WO2006/117359 (ref 7) and WO2011/039107 (ref
26), incorporated by reference, for example.
[0080] 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 27), incorporated by
reference, for example.
[0081] 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. 28), WO2005/012326
(ref. 21) and WO2007/114475 (ref. 29), all incorporated by
reference, for example.
[0082] 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. 30) and
WO2008/013280 (ref. 31), both incorporated by reference, for
example.
[0083] 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.
[0084] 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 32), incorporated by reference.
[0085] 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 33) and
EP1354888 (ref 34), both incorporated by reference, for
example.
[0086] 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 35) and
EP1489089 (ref. 36), both incorporated by reference, for
example.
[0087] The compound of formula (16) above and its manufacture are
described for example in WO2008/042688 (ref. 37) or WO2009/014970
(ref 38), both incorporated by reference.
[0088] Preferred SGLT2 inhibitors are glucopyranosyl-substituted
benzene derivatives. Optionally, one or more hydroxyl groups of the
glucopyranosyl group in such an SGLT2 inhibitor may be acylated
with groups selected from (C.sub.1-18-alkyl)carbonyl,
(C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and
phenyl-(C.sub.1-3-alkyl)-carbonyl.
[0089] 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, methylsulfanyl, methylsulfinyl,
methlysulfonyl, ethylsulfinyl, 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, phenylcarbonyl and
phenyl-(C.sub.1-3-alkyl)-carbonyl.
[0090] 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, phenylcarbonyl and
phenyl-(C.sub.1-3-alkyl)-carbonyl.
[0091] 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
[0092] 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.
[0093] 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, 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.
[0094] The metabolic disorder may be hyperinsulinaemia.
Hyperinsulinaemia may be associated with a further metabolic
disorder or clinical condition, e.g. hyperinsulinaemia may be
associated with obesity and/or regional adiposity.
[0095] In preferred embodiments, the metabolic disorder may be
insulin resistance, hyperinsulinemia and/or a clinical condition
associated with insulin resistance and/or hyperinsulinaemia.
Treatment and/or prevention of a metabolic disorder of an equine
animal in accordance with the invention may be treatment and/or
prevention of insulin resistance and/or hyperinsulinaemia.
[0096] Clinical conditions associated with insulin resistance
and/or hyperinsulinaemia 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.
[0097] Herein, a metabolic disorder or clinical condition, e.g. a
metabolic disorder or clinical condition associated with insulin
resistance and/or hyperinsulinaemia may be impaired glucose
tolerance. 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 impaired glucose tolerance,
preferably associated with insulin resistance and/or
hyperinsulinaemia in an equine animal.
[0098] Herein, a metabolic disorder or clinical condition, e.g. a
metabolic disorder or clinical condition associated with insulin
resistance and/or hyperinsulinaemia 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 hyperinsulinaemia in an equine animal.
[0099] Herein, a metabolic disorder or clinical condition, e.g. a
metabolic disorder or clinical condition associated with insulin
resistance and/or hyperinsulinaemia 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 hyperinsulinaemia in an equine
animal.
[0100] Herein, a metabolic disorder or clinical condition, e.g. a
metabolic disorder or clinical condition associated with insulin
resistance and/or hyperinsulinaemia 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 hyperinsulinaemia in an equine animal.
[0101] Herein, a metabolic disorder or clinical condition, e.g. a
metabolic disorder or clinical condition associated with insulin
resistance and/or hyperinsulinaemia 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 hyperinsulinaemia in an equine animal.
[0102] Herein, a metabolic disorder or clinical condition, e.g. a
metabolic disorder or clinical condition associated with insulin
resistance and/or hyperinsulinaemia 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 hyperinsulinaemia in an equine
animal.
[0103] 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.
[0104] 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
(hyperglycaemia), although hyperglycaemia 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 hyperinsulinaemia.
[0105] 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.
[0106] Insulin resistance may be present in association with
regional adiposity, e.g. cresty neck, tail fat depots, visceral
adiposity, hypertension and dyslipidaemia 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. 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.
[0107] Hyperinsulinaemia can 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.
[0108] 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.
[0109] Dyslipidaemia or hyperlipidaemia 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. 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/1). 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.
[0110] 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.
[0111] Subclinical inflammation or systemic inflammation, in
particular low grade systemic inflammation is characterized by
increased expression and secretion of proinflammatory 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.
[0112] 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 a body condition scores of
equal or more than 7 (out of 9) is encountered.
[0113] 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.
[0114] Equine Animals
[0115] 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.
[0116] Pharmaceutically Acceptable Forms
[0117] Herein, references to SGLT2 inhibitors and/or their use
according to the invention encompass pharmaceutically acceptable
forms of the SGLT2 inhibitors, unless otherwise stated.
[0118] 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.
[0119] Prodrug forms may include, e.g., esters and/or hydrates. The
term pro-drug 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. Pro-drugs
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.
[0120] Crystalline forms for use according to the invention include
a complex of an SGLT2 inhibitor with one or more amino acids (see
e.g. WO 2014/016381, incorporated by reference). 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.
[0121] 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).
[0122] 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 and/or prevention of diseases or conditions which can be
influenced by inhibiting sodium-dependent glucose cotransporter
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 cotransporter SGLT2.
[0123] 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.
[0124] Also disclosed herein is a method for making one or more
crystalline complexes as defined hereinbefore and hereinafter, said
method comprising the following steps: [0125] a. preparing a
solution of the SGLT2 inhibitor (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; [0126] b. storing the solution to precipitate the
crystalline complex out of solution; [0127] c. removing the
precipitate from the solution; and [0128] d. drying the precipitate
optionally until any excess of said solvent or mixture of solvents
has been removed.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] 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.
[0133] 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.
[0134] Furthermore, the availability of a well-defined crystalline
form allows the purification of the drug substance by
recrystallization.
[0135] 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.
[0136] A crystalline complex between a natural amino acid and an
SGLT2 inhibitor (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.
[0137] Preferably the natural amino acid is present in either its
(D) or (L) enantiomeric form, most preferably as the (L)
enantiomer.
[0138] Furthermore those crystalline complexes according to this
invention are preferred which are formed between the SGLT2
inhibitor (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.
[0139] Preferred amino acids according to this invention are
selected from the group consisting of phenylalanine and proline, in
particular (L)-proline and (L)-phenylalanine.
[0140] According to a preferred embodiment the crystalline complex
is characterized in that the natural amino acid is proline, in
particular (L)-proline.
[0141] Preferably the molar ratio of the SGLT2 inhibitor (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".
[0142] 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.
[0143] 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.
[0144] 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.
[0145] 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.
[0146] 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 (.+-.0.1 degrees 2), wherein said X-ray powder
diffraction pattern is made using CuK.sub..alpha.1 radiation.
[0147] In particular said X-ray powder diffraction pattern
comprises peaks at 4.99, 20.28, 21.14, 21.64 and 23.23 degrees 2
(.+-.0.1 degrees 2), wherein said X-ray powder diffraction pattern
is made using CuK.sub..alpha.1 radiation.
[0148] 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 (.+-.0.1 degrees 2), wherein said X-ray powder
diffraction pattern is made using CuK.sub..alpha.1 radiation.
[0149] 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 (.+-.0.1 degrees 2), wherein said
X-ray powder diffraction pattern is made using CuK.sub..alpha.1
radiation.
[0150] 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 (.+-.0.1 degrees 2) 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 are listed): 2 d-value Intensity I/I.sub.0
[.degree.] [.ANG.] [%] 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
[0151] 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
(.+-.0.1 degrees 2 as shown in 0.
[0152] 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 0.
[0153] 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.
[0154] Said crystalline complex has advantageous physico-chemical
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.
[0155] 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[.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 0 is given in units of cps (counts per second).
[0156] In order to allow for experimental error, the above
described 2 values should be considered accurate to .+-.0.1 degrees
2 , in particular .+-.0.05 degrees 2 . 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
values, a 2 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 of the
characteristic value, in particular if it falls within .+-.0.05
degrees 2 of the characteristic value.
[0157] 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).
[0158] Also disclosed herein is a method for making a crystalline
complex as defined hereinbefore and hereinafter, said method
comprising the following steps: [0159] a. preparing a solution of
an SGLT2 inhibitor 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; [0160] b. storing the
solution to precipitate the crystalline complex out of solution;
[0161] c. removing the precipitate from the solution; and [0162] d.
drying the precipitate optionally until any excess of said solvent
or mixture of solvents has been removed.
[0163] According to step (a) a solution of the SGLT2 inhibitor
(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 SGLT2 inhibitor 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 SGLT2 inhibitor 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).
[0164] Preferably the molar ratio of the natural amino acid and the
SGLT2 inhibitor (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 SGLT2 inhibitor 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.
[0165] Suitable solvents are preferably selected from the group
consisting of C.sub.1-4-alkanols, water, ethylacetate,
acetonitrile, acetone, diethylether, tetrahydrofuran, and mixture
of two or more of these solvents.
[0166] 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.
[0167] Particularly preferred solvents are selected from the group
consisting of ethanol, isopropanol, water and mixtures of ethanol
and/or isopropanol with water.
[0168] 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.
[0169] 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.
[0170] According to a preferred embodiment the starting material of
the SGLT2 inhibitor (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 SGLT2 inhibitor
(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 SGLT2 inhibitor (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.
[0171] 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.
[0172] 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.
[0173] In step (c) the solvent(s) can be removed from the
precipitate by known methods as for example filtration, suction
filtration, decantation or centrifugation.
[0174] 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.
[0175] Compound A may be synthesized by methods as specifically
and/or generally described or cited in international application
WO2007/128749 (ref 13), incorporated by reference, 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 13), incorporated by reference.
[0176] 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 SGLT2
inhibitor (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.
[0177] 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
[0178] 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.
[0179] Solid formulations include tablets, granular forms, and
other solid forms such as suppositories. Among solid formulations,
tablets and granular forms are preferred.
[0180] Pharmaceutical compositions within the meaning of the
present invention may comprise an SGLT2 inhibitor 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 antiadherents (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.
[0181] 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.
[0182] 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.
[0183] 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 an SGLT2 inhibitor for use according to
the invention. As the skilled person would understand, the content
of the SGLT2 inhibitor 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.
[0184] In one embodiment a pharmaceutical composition for use
according to the invention is designed for oral or parenteral
administration, preferably for oral administration. Especially the
oral administration is ameliorated by excipients which modify the
smell and/or haptic properties of the pharmaceutical composition
for the intended patient, e.g. as described.
[0185] When the SGLT2 inhibitor 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.
[0186] 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 SGLT2 inhibitor 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. Apart from the active substance, liquid
formulations may comprise e.g. solubilizing
Dosing and Administration
[0187] 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. An SGLT2 inhibitor 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.
[0188] In a preferred embodiment, the SGLT2 inhibitor 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 SGLT2 inhibitor 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.
[0189] A practitioner skilled in the art is able to prepare an
SGLT2 inhibitor of the invention for administration according to a
desired dose.
[0190] Preferably, according to the invention, an SGLT2 inhibitor
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.
[0191] According to the invention, an SGLT2 inhibitor, e.g.
compound A, may be administered such that an appropriate blood
plasma concentration of the SGLT2 inhibitor 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.
[0192] Preferably, following administration and the time required
for the SGLT2 inhibitor 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.
[0193] Preferably, according to the invention, an SGLT2 inhibitor
is administered orally, in liquid or solid form. The SGLT2
inhibitor 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.
[0194] The SGLT2 inhibitor may be used alone or in combination with
another drug. In some embodiments, the SGLT2 inhibitor is used in
combination with one or more further oral antihyperglycaemic drugs.
When the SGLT2 inhibitor is used in combination with a further
drug, the SGLT2 inhibitor 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 SGLT2 inhibitor
is not administered simultaneously with the SGLT2 inhibitor, the
SGLT2 inhibitor 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.
[0195] In some embodiments the SGLT2 inhibitor (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 SGLT2 inhibitor is not used in combination
with a DPP-IV inhibitor, i.e., the equine animal is not treated
with a DPP-IV inhibitor.
[0196] In some embodiments, the SGLT2 inhibitor is used as a
monotherapy, i.e. stand-alone therapy, i.e. no other medication is
administered to the equine animal for the treatment and/or
prevention of the same metabolic disorder, i.e. the metabolic
disorder for which the SGLT2 inhibitor is administered. E.g., no
other medication is administered to the equine animal for the
treatment and/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
[0197] 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.
[0198] FIG. 2 shows the correlation between compound A plasma level
and urinary glucose excretion normalized to urinary creatinine
(glucose/creatinine)
[0199] 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.
[0200] 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.).
[0201] 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 h after
compound/vehicle administration; thinner line: 24 h after last
compound/vehicle administration.
[0202] FIG. 6 shows basal plasma insulin levels [mIU/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.
[0203] 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.
[0204] FIG. 8 shows plasma insulin AUC (area under curve) values
[mIU/mL/min] (baseline as covariate) before treatment (day -12), on
day 28 (2 h after compound/vehicle administration) and on day 30
(24 h 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.
[0205] 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 h after
compound/vehicle administration) and on day 30 (24 h 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.
[0206] FIGS. 10A and 10B show 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).
Mean group values are given of the horses treated with compound A
(solid lines) or its vehicle (dotted lines). Panel A shows the
results of the ivITT prior to the treatment period, Panel B
represent the results after 5 weeks of treatment.
[0207] 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.
[0208] 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.
[0209] 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)
[0210] FIG. 14 shows a DSC/TG diagram of a representative batch of
a crystalline complex of compound A with L-proline (1:1)
EXAMPLES
[0211] The following examples show the beneficial therapeutic
effects on glycaemic 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
[0212] 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 SGLT2 inhibitor 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 Parameter
1 mg/kg i.v. 0.3 mg/kg p.o. 3.0 mg/kg 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
[0213] Pharmacodynamic Data: [0214] A prominent increase of urinary
glucose concentration was evident at all doses already 1 h after
administration (mean group values: controls 0.6 mmol/L; 1 mg/kg
iv-253 mmol/L; 0.3 mg/kgpo-103 mmol/L; 3 mg/kg po-217 mmol/L) and
was persistent for more than 24 h (see 0). [0215] None of the doses
of compound A altered the basal blood glucose level in horses as
compared to normal reference values. [0216] None of the doses of
compound A altered the renal function of horses.
[0217] Urinary glucose excretion increase is clearly plasma
compound exposure dependent, as shown in 0.
Example 2 the Effect of Compound A on Urinary and Blood Glucose as
Well as Glucose Tolerance after Repeated Dosing in Horses
[0218] 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 SGLT2
inhibitor in increasing doses up to 1 mg/kg 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. [0219] The urinary glucose concentration was
significantly elevated by the treatment--controls <1 mmol/L;
treated--.about.300 mmol/L. [0220] Basal blood glucose levels
remained within normal ranges in all horses throughout the study.
No hypoglycemia was observed.
[0221] 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).
[0222] Comparison of the glucose curves at the end of the study
revealed a statistical 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.
[0223] 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
[0224] 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 SGLT2 inhibitor at a dose of 0.3 mg/kg and 3 mg/kg
orally and 1 mg/kg 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 0. Compound A is thus clearly
capable of effectively reducing postprandial glucose levels in
horses.
[0225] 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
[0226] 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 SGLT2 inhibitor 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.
[0227] 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.
[0228] 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.
[0229] 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). 0 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.
[0230] 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 0).
[0231] 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 0 and in 0, 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.
[0232] 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
[0233] 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.
[0234] 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 h 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. 0 shows a time course of baseline
corrected blood NEFA concentrations [.mu.Eq/L] in the insulin
resistant obese horses during an ivITT.
[0235] 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).
[0236] The use of an SGLT2 inhibitor 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.
[0237] Additionally, the use of an SGLT2 inhibitor 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.
[0238] 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.
[0239] 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
[0240] In clinical 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 Preparation of
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene
(Compound A)
[0241] In the foregoing and following text, H atoms of hydroxyl
groups are not explicitly shown in every case in structural
formulae. The following example of synthesis serves to illustrate a
method of preparing
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene
(compound A). A method of preparing its crystalline complex with
L-proline is also described. It is to be regarded only as a
possible method described by way of example, without restriction of
the scope of the invention. The terms "room temperature" and
"ambient temperature" are used interchangeably and denote
temperatures of about 20.degree. C. The following abbreviations are
used:
DMF dimethylformamide NMP N-methyl-2-pyrrolidone THF
tetrahydrofuran
Preparation of 4-bromo-3-hydroxymethyl-1-iodo-benzene
[0242] Oxalyl chloride (13.0 mL) is added to an ice-cold solution
of 2-bromo-5-iodo-benzoic acid (49.5 g) in CH.sub.2Cl.sub.2 (200
mL). DMF (0.2 mL) is added and the solution is stirred at room
temperature for 6 h. Then, the solution is concentrated under
reduced pressure and the residue is dissolved in THF (100 mL). The
resulting solution is cooled in an ice-bath and LiBH.sub.4 (3.4 g)
is added in portions. The cooling bath is removed and the mixture
is stirred at room temperature for 1 h. The reaction mixture is
diluted with THF and treated with 0.1 M hydrochloric acid. Then,
the organic layer is separated and the aqueous layer is extracted
with ethyl acetate. The combined organic layers are dried
(Na.sub.2SO.sub.4) and the solvent is evaporated under reduced
pressure to give the crude product.
Yield: 47.0 g (99% of theory)
Preparation of 4-bromo-3-chloromethyl-1-iodo-benzene
[0243] Thionyl chloride (13 mL) is added to a suspension of
4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane
(100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient
temperature for 3 h. Then, the solvent and the excess reagent is
removed under reduced pressure. The residue is triturated with
methanol and dried.
Yield: 41.0 g (82% of theory)
Preparation of 4-bromo-1-iodo-3-phenoxymethyl-benzene
[0244] Phenol (13 g) dissolved in 4 M KOH solution (60 mL) is added
to 4-bromo-3-chloromethyl-1-iodo-benzene (41.0 g) dissolved in
acetone (50 mL). NaI (0.5 g) is added and the resulting mixture is
stirred at 50.degree. C. overnight. Then, water is added and the
resulting mixture is extracted with ethyl acetate. The combined
extracts are dried (Na.sub.2SO.sub.4) and the solvent is evaporated
under reduced pressure. The residue is purified by chromatography
on silica gel (cyclohexane/ethyl acetate 19:1).
Yield: 38.0 g (79% of theory)
Preparation of
1-bromo-4-(1-methoxy-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene
[0245] A 2 M solution of iPrMgCl in THF (11 mL) is added to dry
LiCl (0.47 g) suspended in THF (11 mL). The mixture is stirred at
room temperature until all the LiCl is dissolved. This solution is
added dropwise to a solution of
4-bromo-1-iodo-3-phenoxymethyl-benzene (8.0 g) in tetrahydrofuran
(40 mL) cooled to -60.degree. C. under argon atmosphere. The
solution is warmed to -40.degree. C. and then
2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (10.7 g, 90%
pure) in tetrahydrofuran (5 mL) is added. The resulting solution is
warmed to -5.degree. C. in the cooling bath and stirred for another
30 min at this temperature. Aqueous NH.sub.4Cl solution is added
and the resultant mixture is extracted with ethyl acetate. The
combined organic extracts are dried over sodium sulfate and the
solvent is removed under reduced pressure. The residue is dissolved
in methanol (80 mL) and treated with methanesulfonic acid (0.6 mL)
to produce the more stable anomer solely. After stirring the
reaction solution at 35-40.degree. C. overnight, the solution is
neutralized with solid NaHCO.sub.3 and the methanol is removed
under reduced pressure. The remainder is diluted with aqueous
NaHCO.sub.3 solution and the resulting mixture is extracted with
ethyl acetate. The combined extracts are dried over sodium sulfate
and the solvent is evaporated to yield the crude product that is
submitted to reduction without further purification.
Yield: 7.8 g (93% of theory)
Preparation of
1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)--
benzene
[0246] Boron trifluoride diethyletherate (4.9 mL) is added to a
solution of
1-bromo-4-(1-methoxy-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene
(8.7 g) and triethylsilane (9.1 mL) in dichloromethane (35 mL) and
acetonitrile (50 mL) cooled to -20.degree. C. at such a rate that
the temperature maintains below -10.degree. C. The resultant
solution is warmed to 0.degree. C. over a period of 1.5 h and then
treated with aqueous sodium hydrogen carbonate solution. The
resulting mixture is stirred for 0.5 h, the organic solvent is
removed and the residue is extracted with ethyl acetate. The
combined organic layers are dried over sodium sulfate and the
solvent is removed. The residue is taken up in dichloromethane (50
mL) and pyridine (9.4 mL), acetic anhydride (9.3 mL) and
4-dimethylaminopyridine (0.5 g) are added in succession to the
solution. The solution is stirred for 1.5 hours at ambient
temperature and then diluted with dichloromethane. This solution is
washed twice with 1 M hydrochloric acid and dried over sodium
sulfate. After the solvent is removed, the residue is
recrystallized from ethanol to furnish the product as a colorless
solid.
Yield: 6.78 g (60% of theory) Mass spectrum (ESI.sup.+):
m/z=610/612 (Br) [M+NH.sub.4].sup.+
Preparation of
2-(phenoxymethyl)-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonit-
rile
[0247] A flask charged with zinc cyanide (1.0 g), zinc (30 mg),
Pd.sub.2(dibenzylideneacetone).sub.3*CHCl.sub.3 (141 mg) and
tri-tert-butylphosphonium tetrafluoroborate (111 mg) is flushed
with argon. Then a solution of
1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)--
benzene (5.4 g) in NMP (12 mL) is added and the resulting mixture
is stirred at room temperature for 18 h. After dilution with ethyl
acetate, the mixture is filtered and the filtrate is washed with
aqueous sodium hydrogen carbonate solution. The organic phase is
dried (sodium sulfate) and the solvent is removed. The residue is
recrystallized from ethanol.
Yield: 4.10 g (84% of theory) Mass spectrum (ESI.sup.+): m/z=557
[M+NH.sub.4].sup.+
[0248] Alternatively, the compound described above is synthesized
starting from
1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymet-
hyl)-benzene using copper(I) cyanide (2 equivalents) in NMP at
210.degree. C.
Preparation of
2-bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile
[0249] A 33% solution of hydrobromic acid in acetic acid (15 mL) is
added to a solution of
2-phenyloxymethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonit-
rile (0.71 g) and acetic anhydride (0.12 mL) in acetic acid (10
ml). The resulting solution is stirred at 55.degree. C. for 6 h and
then cooled in an ice-bath. The reaction mixture is neutralized
with chilled aqueous potassium carbonate solution, and the
resultant mixture is extracted with ethyl acetate. The combined
organic extracts are dried over sodium sulfate and the solvent is
removed under reduced pressure. The residue is taken up in ethyl
acetate/cyclohexane (1:5), and the precipitate is separated by
filtration and dried at 50.degree. C. to give the pure product.
Yield: 0.52 g (75% of theory) Mass spectrum (ESI.sup.+):
m/z=543/545 (Br) [M+NH.sub.4].sup.+
Preparation of 4-cyclopropyl-phenylboronic Acid
[0250] 2.5 M solution of nButyllithium in hexane (14.5 mL) is added
dropwise to 1-bromo-4-cyclopropyl-benzene (5.92 g) dissolved in THF
(14 mL) and toluene (50 mL) and chilled to -70.degree. C. The
resultant solution is stirred at -70.degree. C. for 30 min before
triisopropyl borate (8.5 mL) is added. The solution is warmed to
-20.degree. C. and then treated with 4 M aqueous hydrochloric acid
(15.5 mL). The reaction mixture is further warmed to room
temperature and then the organic phase is separated. The aqueous
phase is extracted with ethyl acetate and the combined organic
phases are dried (sodium sulfate). The solvent is evaporated and
the residue is washed with a mixture of ether and cyclohexane to
give the product as a colorless solid.
Yield: 2.92 g (60% of theory) Mass spectrum (ESP): m/z=207 (Cl)
[M+HCOO].sup.-
Preparation of
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene
##STR00019##
[0252] An Ar filled flask is charged with
2-bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile
(1.60 g), 4-cyclopropyl-phenylboronic acid (1.0 g), potassium
carbonate (1.85 g) and a degassed 3:1 mixture of acetone and water
(22 mL). The mixture is stirred at room temperature for 5 min,
before it is cooled in an ice-bath. Then palladium dichloride (30
mg) is added and the reaction mixture is stirred for 16 hours at
ambient temperature. The mixture is then diluted with brine and
extracted with ethyl acetate. The combined extracts are dried over
sodium sulfate and the solvent is removed under reduced pressure.
The residue is dissolved in methanol (20 mL) and treated with 4 M
aqueous potassium hydroxide solution (4 mL). The resulting solution
is stirred at ambient temperature for 1 h and then neutralized with
1 M hydrochloric acid. The methanol is evaporated, and the residue
is diluted with brine and extracted with ethyl acetate. The organic
extracts collected are dried over sodium sulfate, and the solvent
is removed. The residue is chromatographed on silica gel
(dichloromethane/methanol 1:0->8:1).
Yield: 0.91 g (76% of theory) Mass spectrum (ESI.sup.+): m/z=413
[M+NH.sub.4].sup.+
Preparation of a Crystalline Complex (1:1) of Compound A with
L-Proline
[0253] L-proline (0.34 g) dissolved in 2.1 mL of a mixture of
ethanol and water (volume ratio 10:1) is added to a solution of
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene
(1.17 g, obtained as described above) dissolved in 2 mL ethanol.
The resulting solution is allowed to stand at ambient temperature.
After about 16 h the crystalline complex is isolated as white
crystals by filtration. If necessary the crystallization may be
initiated by scratching with a glass rod or metal spatula for
example or by inoculating with seed crystals. Residual solvent is
removed by storing the crystals at slightly elevated temperature
(30 to 50.degree. C.) under vacuum for about 4 h to yield 1.27 g of
the crystalline 1:1 complex of L-proline and
1-cyano-2-(4-cyclopropyl-benzyl)-4-(.beta.-D-glucopyranos-1-yl)-benzene.
[0254] Several batches of the crystalline complex according to the
above preparation are obtained. The X-ray powder diffraction
patterns coincide. The melting points are determined via DSC and
evaluated as onset-temperature. Examples of melting points are
approximately 89.degree. C., 90.degree. C., 92.degree. C.,
101.degree. C. and 110.degree. C. The X-ray powder diffraction
pattern as contained in Table 2 and as depicted in FIG. 13 and the
DSC and TG diagram in FIG. 14 correspond to a batch with a melting
point of approximately 90.degree. C.
[0255] The X-ray powder diffraction pattern of the crystalline
complex of the compound A and L-proline (peaks up to 30.degree. in
2 .THETA.) is provided above in Table 1.
Example 8 Formulations
[0256] Some examples of formulations are described in which the
term "active substance" denotes an SGLT2 inhibitor or
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 substances, the term
"active substance" may also include the additional active sub
stance.
[0257] Tablets containing 100 mg of active substance
Composition:
TABLE-US-00003 [0258] 1 tablet contains: active substance 100.0 mg
lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg
magnesium stearate 2.0 mg 220.0 mg
[0259] Method of Preparation:
[0260] The active substance, lactose and starch are mixed together
and uniformly moistened with an aqueous solution of the
polyvinylpyrrolidone. After the moist composition has been screened
(2.0 mm mesh size) and dried in a rack-type drier at 50.degree. C.
it is screened again (1.5 mm mesh size) and the lubricant is added.
The finished mixture is compressed to form tablets.
Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on
both sides and notched on one side.
[0261] Tablets containing 150 mg of active substance
Composition:
TABLE-US-00004 [0262] 1 tablet contains: active substance 150.0 mg
powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0
mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0
mg
[0263] Preparation:
[0264] The active substance mixed with lactose, corn starch and
silica is moistened with a 20% aqueous polyvinylpyrrolidone
solution and passed through a screen with a mesh size of 1.5 mm.
The granules, dried at 45.degree. C., are passed through the same
screen again and mixed with the specified amount of magnesium
stearate. Tablets are pressed from the mixture.
[0265] Weight of tablet: 300 mg
[0266] die: 10 mm, flat
[0267] Hard gelatine capsules containing 150 mg of active
substance
Composition:
1 Capsule Contains:
TABLE-US-00005 [0268] active substance 150.0 mg corn starch (dried)
approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium
stearate 3.0 mg approx. 420.0 mg
[0269] Preparation:
[0270] The active substance is mixed with the excipients, passed
through a screen with a mesh size of 0.75 mm and homogeneously
mixed using a suitable apparatus. The finished mixture is packed
into size 1 hard gelatine capsules.
[0271] Capsule filling: approx. 320 mg
[0272] Capsule shell: size 1 hard gelatine capsule.
[0273] Suppositories containing 150 mg of active substance
Composition:
1 Suppository Contains:
TABLE-US-00006 [0274] active substance 150.0 mg polyethyleneglycol
1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene
sorbitan monostearate 840.0 mg 2,000.0 mg
[0275] Preparation:
[0276] After the suppository mass has been melted the active
substance is homogeneously distributed therein and the melt is
poured into chilled molds.
[0277] Ampoules containing 10 mg active substance
Composition:
TABLE-US-00007 [0278] active substance 10.0 mg 0.01N hydrochloric
acid/NaCl q.s. double-distilled water ad 2.0 ml
[0279] Preparation:
[0280] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 2 ml ampoules.
[0281] Ampoules containing 50 mg of active substance
Composition:
TABLE-US-00008 [0282] active substance 50.0 mg 0.01N hydrochloric
acid/NaCl q.s. double-distilled water ad 10.0 ml
[0283] Preparation:
[0284] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 10 ml ampoules.
REFERENCES
[0285] All references cited herein are incorporated by reference in
their entirety. [0286] 1) Frank et al. (2011) Journal of Veterinary
Internal Medicine 24(3):467-75 [0287] 2) WO01/27128 [0288] 3)
WO03/099836 [0289] 4) WO2005/092877 [0290] 5) WO2006/034489 [0291]
6) WO2006/064033 [0292] 7) WO2006/117359 [0293] 8) WO2006/117360
[0294] 9) WO2007/025943 [0295] 10) WO2007/028814 [0296] 11)
WO2007/031548 [0297] 12) WO2007/093610 [0298] 13) WO2007/128749
[0299] 14) WO2008/049923 [0300] 15) WO2008/055870 [0301] 16)
WO2008/055940 [0302] 17) WO2009/022020 [0303] 18) WO2009/022008
[0304] 19) WO2008/116179 [0305] 20) WO2008/002824 [0306] 21)
WO2005/012326 [0307] 22) WO2009/035969 [0308] 23) WO2008/069327
[0309] 24) WO2006/120208 [0310] 25) WO2011/039108 [0311] 26)
WO2011/039107 [0312] 27) WO2004/007517 [0313] 28) WO2004/080990
[0314] 29) WO2007/114475 [0315] 30) WO2007/140191 [0316] 31)
WO2008/013280 [0317] 32) WO2010/023594 [0318] 33) EP1213296 [0319]
34) EP1354888 [0320] 35) EP1344780 [0321] 36) EP1489089 [0322] 37)
WO2008/042688 [0323] 38) WO2009/014970 [0324] 39) WO2014/016381
* * * * *