Note: Descriptions are shown in the official language in which they were submitted.
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TREATMENT OF THE INSULIN RESISTANCE SYNDROME
This invention relates to the use of selective cGMP PDE5 inhibitors and in
particular to selective cGMP PDE5 inhibitor compounds such as the compound
s sildenafil for the treatment of the Insulin Resistance Syndrome.
The Insulin Resistance Syndrome as defined herein means the
concomitant existence in a subject of two or more of: dyslipidemia,
hypertension,
type 2 diabetes mellitus or impaired glucose tolerance (IGT) or a family
history of
io type 2 diabetes mellitus, hyperuricaemia andlor gout, a pro-coagulant
state,
atherosclerosis, truncal obesity. A family history of type 2 diabetes mellitus
as
defined herein means having a first degree relation, sibling, parent or
grandparent
with type 2 diabetes mellitus. At the centre of the Insulin Resistance
Syndrome,
also known as "Syndrome X" and "Metabolic Syndrome" in the biomedical
is literature is the common feature of tissue resistance to the action of
insulin. This
impaired biological response to insulin can be -manifested in both the
metabolic
and vascular effects of insulin. Although there are monogenic syndromes of
insulin resistance (1R), in which a definite gene has been identified as the
cause of
insulin resistance (such as leprechaunism), these are relatively rare. By
contrast,
2o the more common presentation of the IRS is associated with obesity
(particularly
abdominal) and appears to be polygenic.
The early adaptive response to insulin resistance in many individuals
having the insulin resistance syndrome produces compensatory
2s hyperinsulinaemia. As subjects with the insulin resistance syndrome become
progressively insulin resistant, they manifest varying degrees of change in
clinical
parameters, including blood pressure, and/or increased levels of serum
glucose,
and/or cholesterol and/or triglycerides, and/or uric acid, and/or factors that
increase coagulation. Once these clinical parameters have changed enough, the
3o patient with the IRS may differentially manifest well-recognised clinical
conditions
or diagnoses. These conditions include:
1. Hypertension (high blood pressure);
2. Impaired Glucose Tolerance (IGT) or type 2 diabetes mellitus (DM);
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3. Hyperlipidemia or dyslipidemia, particularly (but not limited to)
hypertriglyceridemia;
4. Hyperuricemia or Gout;
5. Hypercoagulability (defined as an abnormal, increased tendency for clots to
s form, particularly inside blood vessels);
6. Atherosclerosis.
These clinical conditions are well-recognised risk factors for cardio-vascular
(coronary artery and cerebrovascular) disease.
lo
It is difficult to estimate the prevalence of the Insulin Resistance Syndrome
in the general populace due to both the diversity of the collective risk
factors
associated with the syndrome and the likelihood that many individuals affected
by
the Insulin Resistance Syndrome go undetected because they may exhibit no
is exterior symptoms and have no prior history of coronary heart disease. It
is
however possible to postulate that at a minimum the patient population at risk
for
the development of the Insulin Resistance Syndrome includes individuals with
obesity, particularly truncal (abdominal) obesity. As obesity is an extremely
common problem in the industrialized world and is associated with the clinical
ao conditions mentioned above, it is very likely that the prevalence of IRS is
very
high. Considering this potential patient group alone forms an immense
population
potentially at risk for the development of complications of the Insulin
Resistance
Syndrome. For example in the United States in 1994, 23% of the population aged
between 20 and 74 had hypertension, which accounted for 5 deaths per 100,000
25 population (1997). There will be an estimated 154,392,000 patients with
diabetes
world-wide in the year 2000. Of these, 15,000,000 will be in the US and
934,000
in the UK. The burden of disease for ischaemic heart disease for both sexes in
the WHO region estimated for 1998 was 51,948,000 with a mortality of
7,375,000,
constituting 13.7% of total mortality and ranking the highest in the mortality
score.
3o The burden of diabetes in both sexes in the WHO region estimated for 1998
was
11,668,000. Thus there exists a large medical need for an effective and safe
oral
therapy for the treatment of the Insulin Resistance Syndrome and prevention of
the development of the Insulin Resistance Syndrome and its clinical
consequences.
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Resistance to the effects of insulin can also be observed in the diminished
biological response of the endothelium to the vascular effects of insulin.
That is,
insulin promotes relaxation of blood vessels) at least in part through the
action of
s nitric oxide. Nitric oxide generated in the endothelium then stimulates cGMP
production in blood vessels and causes them to relax or dilate. This opening
of
the blood vessel allows more blood to flow, which is particularly important
when
more blood flow is needed to critical organs, like the heart. It has been
demonstrated that there is a decreased release of nitric oxide (NO) from the
to endothelium of patients with insulin resistance. This decreased release of
nitric
oxide is not only from insulin, but also from other important vasodilators
like
acetylcholine. This so-called "endothelial dysfunction" contributes to the
risk
factors for cardiovascular disease which are associated with the Insulin
Resistance Syndrome. It is thought that the vascular effect of insulin
contributes
is to the effect of insulin to regulate metabolism, particularly, but not
necessarily
limited to, glucose metabolism.
In addition to the vascular actions of nitric oxide, NO also has direct
effects
on glucose uptake by skeletal muscle. That is, treatment with a NO-donor
ao substance (nitroprusside) or an analogue of cGMP treatment in vitro
increases
glucose uptake (transport by GLUT4 glucose transporters). This vasodilation-
independent pathway is described in G. J. Etgen, D. A. Fryburg and E. M. Gibbs
in
Diabetes, 46, 1997 pp. 1915-1919 the contents of which are incorporated herein
by reference. It is proposed herein that, taken together, nitric oxide and
cGMP
2s likely have direct tissue level and vascular actions that influence,
mediate, or
mimic insulin's actions.
Further effects of impaired NO release by the endothelium include: an
increase in vascular smooth muscle cell (VSMC) growth, proliferation and
so migration which are key steps in atherosclerotic plaque formation which can
lead
to stroke; an increase in platelet aggregation and adhesiveness (these effects
on
the platelet are also cGMP driven); an increase of lipid peroxidation and an
effect
on the inhibition of cell adhesion molecule expression including vascular cell
adhesion molecule (VCAM-1 ), intracellular adhesion molecule (ICAM) and E-
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4
selectin. Impaired endothelial NO release also impacts on the activity of
inflammatory cytokines such as tumour necrosis factor-oc, and the production
of
monocyte chemoattractant factor through decreased activity of the
transcriptional
activator nuclear factor k B.
s
There are examples in which the treatment of factors contributing to IRS
(e.g., obesity) or the treatment of IRS itself, such as with troglitazone or
Rezulin,
improves many of these clinical conditions. For example, dieting alone or
pharmacotherapeutic agents that induce weight loss will decrease blood
pressure,
io blood glucose and triglycerides. Agents that are designed to improve
insulin
sensitivity can also favorably alter blood pressure, lipids, and blood
glucose.
It is proposed herein that successful diagnosis and treatment of patients
with the Insulin Resistance Syndrome (as defined above) with a selective PDE5
is inhibitor, especially sildenafil, may lead to clinically relevant
improvements in blood
pressure and/or blood sugar and/or lipids and/or uric acid, and/or
procoagulant
factors. This treatment can occur alone or in combination with other
therapeutics
that improve the IRS. Improvement in these clinical conditions should reduce
the
risk of the development of cardiovascular disease in some of these patients as
2o well as other complications of these individual disorders (including, but
not limited
to diabetic neuropathy, nephropathy, and retinopathy).
The present invention is concerned with the search for a pharmaceutical
treatment for individuals with the Insulin Resistance Syndrome as defined
2s hereinbefore.
Whilst the Insulin Resistance Syndrome has many manifestations an
important underlying mechanistic basis for the condition resides in a
resistance to
both the vascular and metabolic effects of insulin. It is also understood that
the
3o underlying pathology of vascular resistance in insulin resistance syndrome,
is a
diminished amount of NO produced by the endothelial cells in response to
insulin.
In the insulin pathway in insulin resistant individuals, there may be impaired
signalling of insulin for glucose uptake (from the phosphatidylinositol 3-
kinase,
P13K, pathway) which may lead to an inefficient GLUT-4 transport mechanism.
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Whilst not wishing to be bound by any particular theory it is proposed herein
that
the pathway for the GLUT-4 transport mechanism and the cGMP-NO mechanistic
pathway are somehow inter-linked.
s For optimal functioning of the insulin signalling pathway for glucose uptake
(via the GLUT-4 transport mechanism) it is preferable to have a normally
functioning NO-cGMP pathway.
It is further proposed herein that amplification of the cGMP signal, using
to cGMP specific PDE5 inhibitors in patients with the Insulin Resistance
Syndrome
would help to optimise the insulin glucose uptake signal and improve insulin
action
at key tissues. By making tissues more sensitive to insulin, it is thereby
also
proposed herein that improvements in the clinical parameters of the IRS would
result, including, but not limited to improvements in;
1. Blood glucose control: In patients with diabetes mellitus or impaired
glucose
tolerance (IGT), it is postulated herein that an improvement in insulin
resistance should result in a decrease in plasma glucose concentrations
(either fasting or after an oral glucose tolerance test or a meal). In a
related
2o manner, as regulated by the patient's pathophysiology, there will likely be
an
improvement in serum insulin concentrations in either the fasting state or
after
a glucose load or meal. These improvements in blood glucose control, should
the subjects have type 2 diabetes mellitus, would manifest as improvements in
measures of long-term blood glucose control, such as, but not limited to,
2s haemoglobin A1 c (glycosylated haemoglobin) or fructosamine; and/or
2. Blood pressure: It is postulated herein that an improvement in insulin
resistance may also yield improvements in both systolic and diastolic blood
pressure; and/or
3. Lipids: It is postulated herein that an improvement in insulin resistance
may
also yield improvements in serum lipids, including, but not limited to, serum
cholesterol and triglycerides; and/or
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'4. Uric Acid: It is postulated herein that an improvement in insulin
resistance may
also yield improvements in serum uric acid; and/or
5. Coagulation Factors: It is postulated herein that an improvement in insulin
s resistance would also restore, towards normal, factors that worsen the
procoagulant state.
These improvements in insulin resistance (improved sensitivity) may or may
not be accompanied by improvement in compensatory hyperinsulinaemia and
io hence improve the components of the Insulin Resistance Syndrome.
cGMP PDE 5 inhibitors prevent the effect of the phosphodiesterase 5
enzyme that converts cGMP to inactive GMP thus increasing the amount of
accumulated cGMP. This accumulation would amplify the vasodilatory, metabolic,
is and anti-atherogenic effects of the available nitric oxide and insulin. It
is
postulated herein that this amplification action (of plasma cGMP) will
mitigate the
adverse effects associated with the IRS and improve one or more of the
associated conditions.
2o Sildenafil (Viagra ~) is an orally-active, potent and selective inhibitor
of cyclic
guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDES)
which is the predominant PDE5 isoenzyme in human corpora cavernosa.
Consequently, sildenafil has been shown to be effective in the treatment of
male
erectile dysfunction. It is proposed herein that by inhibiting the cGMP to GMP
2s conversion pathway, selective cGMP PDE5 inhibitors and in particular
Sildenafil
increase the intracellular concentrations of nitric oxide (NO) derived cGMP.
This
accumulation would amplify the vasodilatory, metabolic, and anti-atheroge~nic
effects of the available nitric oxide and insulin.
3o Thus according to a first aspect of the present invention we provide a
method of treating the insulin resistance syndrome which comprises treating
the
patient with an effective amount of a selective cGMP PDE5 inhibitor or a
pharmaceutical composition thereof wherein the insulin resistance syndrome
means the concomitant existence in a subject of two or more of: dyslipidemia;
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7
hypertension; type 2 diabetes mellitus, impaired glucose tolerance (IGT) or
having
a family history of diabetes; hyperuricaemia and/or gout; a pro-coagulant
state;
atherosclerosis; or truncal obesity.
s Depending on the individual with IRS, the method may have a beneficial
effect on one or more of conditions associated with the IRS as defined herein.
Thus according to a further aspect the present invention additionally provides
a
method of treating type 2 diabetes mellitus or impaired glucose tolerance
(IGT); or
dyslipidemia, or hyperuricemia and/or gout, or the procoagulant state which
to comprises treating the patient with an effective amount of a cGMP PDE5
inhibitor
or a pharmaceutical composition thereof. According to a yet further aspect the
present invention additionally provides a method of treating type 2 diabetes
mellitus or impaired glucose tolerance (IGT) in a patient wherein the patient
does
not have other risk factors associated with the IRS which comprises treating
the
is patient with an effective amount of a selective pyrazolopyrimidinone cGMP
PDE5
inhibitor as defined hereinafter or a pharmaceutically acceptable salt or a
pharmaceutical composition thereof. According to a further aspect the present
invention additionally provides a method for the prevention of progression in
a
subject of impaired glucose tolerance (IGT) to type 2 diabetes mellitus via
a,o treatment of a patient in need of such treatment with an effective amount
of a
selective pyrazolopyrimidinone cGMP PDE5 inhibitor as defined hereinafter or a
pharmaceutically acceptable salt or a pharmaceutical composition thereof.
According to a second aspect the present invention provides a method of
2s treating the insulin resistance syndrome which comprises treating the
patient with
an effective amount of a cGMP PDE5 inhibitor or a pharmaceutical composition
thereof wherein the insulin resistance syndrome means the concomitant
existence
in a subject of three or more of: dyslipidemia; hypertension; type 2 diabetes
mellitus, impaired glucose tolerance (IGT) or having a family history of
diabetes;
3o hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis; or
truncal
obesity.
According to a third aspect the present invention provides a method of
treating the insulin resistance syndrome which comprises treating the patient
with
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8
an effective amount of a cGMP PDE5 inhibitor or a pharmaceutical composition
thereof wherein the insulin resistance syndrome means the concomitant
existence
in a subject of four or more of: dyslipidemia; hypertension; type 2 diabetes
mellitus, impaired glucose tolerance (IGT) or having a family history of
diabetes;
s hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis; or
truncal
obesity.
According to a fourth aspect the present invention provides a method of
treating the insulin resistance syndrome which comprises treating the patient
with
io an effective amount of a cGMP PDE5 inhibitor or a pharmaceutical
composition
thereof wherein the insulin resistance syndrome means the concomitant
existence
in a subject of five or more of: dyslipidemia; hypertension; type 2 diabetes
mellitus, impaired glucose tolerance (IGT) or having a family history of
diabetes;
hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis; or truncal
is obesity.
According to a fifth aspect the present invention provides a method of
treating the insulin resistance syndrome which comprises treating the patient
with
an effective amount of a cGMP PDE5 inhibitor or a pharmaceutical composition
ao thereof wherein the insulin resistance syndrome means the concomitant
existence
in a subject of : dyslipidemia; hypertension; type 2 diabetes mellitus or
impaired
glucose tolerance (IGT); and truncal obesity.
According to a sixth aspect the present invention provides a method of
2s treating the insulin resistance syndrome which comprises treating a patient
with
type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history
of
diabetes and at least one of the following conditions : dyslipidemia;
hypertension;
hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis; or truncal
obesity with an effective amount of a cGMP PDE5 inhibitor or a pharmaceutical
3o composition thereof.
According to a seventh aspect the present invention provides a method of
treating the insulin resistance syndrome which comprises treating a patient
with
type 2 diabetes mellitus, impaired glucose tolerance (GT) or a family history
of
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'diabetes and at least two of the following conditions : dyslipidemia;
hypertension;
hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis; or truncal
obesity with an effective amount of a cGMP PDE5 inhibitor or a pharmaceutical
composition thereof.
According to an eighth aspect the present invention provides a method of
treating the insulin resistance syndrome which comprises treating a patient
with
type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history
of
diabetes and at least three of the following conditions : dyslipidemia;
hypertension;
io hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis; or
truncal
obesity with an effective amount of a cGMP PDES inhibitor or a pharmaceutical
composition thereof.
According to a ninth aspect the present invention provides a method of
is treating the insulin resistance syndrome which comprises treating a patient
with
type 2 diabetes mellitus, impaired glucose tolerance (IRS) or a family history
of
diabetes and at least three of the following conditions : dyslipidemia;
hypertension;
hyperuricaemia andlor gout; a pro-coagulant state; atherosclerosis; or truncal
obesity with an effective amount of a cGMP PDES inhibitor or a pharmaceutical
2o composition thereof.
According to a tenth aspect the present invention provides a method of
treating the insulin resistance syndrome which comprises treating a patient
with
type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history
of
2s diabetes and at least four of the following conditions : dyslipidemia;
hypertension;
hyperuricaemia; a pro-coagulant state; atherosclerosis; or truncal obesity
with an
effective amount of a cGMP PDE5 inhibitor or a pharmaceutical composition
thereof.
so According to an eleventh aspect the present invention provides a method of
treating the insulin resistance syndrome which comprises treating a patient
with
type 2 diabetes mellitus, impaired glucose tolerance (1GT) or a family history
of
diabetes and at least five of the following conditions : dyslipidemia;
hypertension;
hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis; or truncal
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obesity with an effective amount of a cGMP PDE5 inhibitor or a pharmaceutical
composition thereof.
According to a further aspect the present invention additionally provides a
s method for the reduction in the risk of the development of cardiovascular
disease
in patients identified as being at risk of developing the insulin resistance
syndrome
wherein said method comprises treating the patient with an effective amount of
a
cGMP PDE5 inhibitor or a pharmaceutical composition thereof and wherein a
patient at risk of developing the insulin resistance syndrome is defined as an
to individual having at least one of the following conditions: dyslipidemia;
hypertension; type 2 diabetes mellitus, impaired glucose tolerance (IGT) or
having
a family history of diabetes; hyperuricaemia and/or gout; a pro-coagulant
state;
atherosclerosis; or truncal obesity and whom on subsequent analysis is found
to
have at least two of said conditions.
According to a further aspect the present invention provides a method for
treating the insulin resistance syndrome as defined hereinbefore in a
polygenic
insulin resistant individual which comprises treating the individual with an
effective
amount of a cGMP PDE5 inhibitor or a pharmaceutical composition thereof.
Suitable PDESi's for use in the pharmaceutical compositions according to
the present invention are the cGMP PDESi's hereinafter detailed. Particularly
preferred for use herein are potent and selective cGMP PDESi's.
2s Suitable cGMP PDE5 inhibitors for the use according to the present
invention
include:
the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756; the pyrazolo
[4,3-d]pyrimidin-7-ones disclosed in EP-A-0526004; the pyrazolo [4,3-
d]pyrimidin-
so 7-ones disclosed in published international patent application WO 93/06104;
the
isomeric pyrazolo [3,4-d]pyrimidin-4-ones disclosed in published international
patent application WO 93/07149; the quinazolin-4-ones disclosed in published
international patent application WO 93/12095; the pyrido [3,2-d]pyrimidin-4-
ones
disclosed in published international patent application WO 94/05661; the purin-
6-
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11
'ones disclosed in published international patent application WO 94/00453; the
pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international patent
application WO 98/49166; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in
published international patent application WO 99/54333; the pyrazolo [4,3-
s d]pyrimidin-4-ones disclosed in EP-A-0995751; the pyrazolo [4,3-d]pyrimidin-
7-
ones disclosed in published international patent application WO 00/24745; the
pyrazolo [4,3-d]pyrimidin-4-ones disclosed in EP-A-0995750; the compounds
disclosed in published international application W095/19978; the compounds
disclosed in published international application WO 99/24433 and the compounds
Io disclosed in published international application WO 93/07124.
The pyrazolo [4,3-d]pyrimidin-7-ones disclosed in published international
application WO 01/27112; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in
published international application WO 01/27113; the compounds disclosed in EP
is A-1092718 and the compounds disclosed in EP-A-1092719.
Preferred selective type V phosphodiesterase inhibitors for the use according
to
the present invention include:
20 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-
1,6-
dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil) also known as 1-[[3-
(6,7-
dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazoto[4,3-d]pyrimidin-5-yl)-4-
ethoxyphenyl]sulphonyl]-4-methylpiperazine (see EP-A-0463756);
2s 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-
pyrazolo[4,3-d]pyrimidin-7-one (see EP-A-0526004);
3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-
yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see W098/49166);
3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-
2-
(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see
W 099/54333);
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'(+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1 (R)-
methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-
one, also known as 3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1 R)-2-
methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazoloj4,3-
d]
s pyrimidin-7-one (see W099/54333);
5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-
methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also known as 1-
{6-
ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazo!o[4,3-
io d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine (see WO 01/27113,
Example 8);
5-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-
methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO
is 01/27113, Example 15);
5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-
2,6-
dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27113, Example 66);
20 5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-
dihydro-
7H pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27112, Example 124);
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-
7H
pyrazoio[4,3-d]pyrimidin-7-one (see WO 01!27112, Example 132);
and pharmaceutically acceptable salts, polymorphs and solvates thereof.
Thus according to a preferred aspect the present invention provides for the
use of a selective pyrazolopyrimidinone cGMP PDES inhibitor or a
pharmaceutical
3o composition thereof in the preparation of a medicament for the curative,
palliative
or prophylactic treatment of the insulin resistance syndrome in a mammal
wherein
the selective cGMP PDE5 inhibitor is selected from : sildenafil, 5-(2-ethoxy-5-
morpholinoacetylphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-
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13
propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-djpyrimidin-
7-
one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-
3-yl]-
2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-
ethoxy-
5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-
s dihydro-7H-pyrazolo[4,3-djpyrimidin-7-one and 1-[[3-(3,4-dihydro-5-methyl-4-
oxo-
7-propylimidazolo[5,1-t]-as-trizin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-
ethylpiperzine
or a pharmaceutically acceptable salt, solvate, pro-drug or polymorph thereof.
More particularly, the present invention provides a method of treating a
io patient with the insulin resistance syndrome which comprises treating the
patient
with an effective amount of a selective pyrazolopyrimidinone cGMP PDE5
inhibitor
selected from sildenafil, 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-
3-
azetidinyl)-2,6-dihydro-7H pyrazolo[4,3-d]pyrimidin-7-one or 5-[2-ethoxy-5-(4-
ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-
dihydro
is 7H-pyrazolo[4,3-d]pyrimidin-7-one or pharmaceutically acceptable salts,
solvates,
pro-drugs, polymorphs or pharmaceutical compositions thereof.
The invention also provides for the use of a selective pyrazolopyrimidinone
cGMP PDE5 inhibitor and in particular sildenafil, 5-(5-Acetyl-2-butoxy-3-
pyridinyl)-
20 3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H pyrazolo[4,3-d]pyrimidin-7-
one or 5-
[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-1-(2-
methoxyethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one for the
manufacture
of a composition for the treatment or prophylaxis of the insulin resistance
syndrome.
2s
According to a further aspect the present invention additionally provides for
the use of sildenafil or a pharmaceutically acceptable salt or of a
pharmaceutical
composition thereof for the treatment of the insulin resistance syndrome in a
subject having type 2 diabetes mellitus, impaired glucose tolerance (IGT) or
3o having a family history of diabetes and at least one of the following
conditions
dyslipidemia; hypertension; hyperuricaemia andlor gout; a pro-coagulant state;
atherosclerosis; or truncal obesity.
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14
According to a yet further aspect the present invention additionally provides
for the use of sildenafil or a pharmaceutically acceptable salt or of a
pharmaceutical composition thereof for the treatment of the insulin resistance
syndrome in a subject having type 2 diabetes mellitus, impaired glucose
tolerance
s (IGT) or having a family history of diabetes and one or more of the
following
conditions : dyslipidemia; hypertension; or truncal obesity.
According to a yet further still aspect the present invention additionally
provides for the use of sildenafil or a pharmaceutically acceptable salt or of
a
io pharmaceutical composition thereof for the treatment of the insulin
resistance
syndrome in a subject having type 2 diabetes mellitus, or impaired glucose
tolerance (IGT) or having a family history of diabetes and dyslipidemia and
hypertension and truncal obesity.
is Preferred pharmaceutically acceptable salts of sildenafil for use herein
are
sildenafil citrate and sildenafil mesylate.
The cGMP PDE5 inhibitors as defined herein and in particular potent and
selective cGMP PDE5 inhibitors and most particularly sildenafil, 5-(5-Acetyl-2-
2o butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H
pyrazolo[4,3-
dJpyrimidin-7-one or 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-
yl]-3-
ethyl-1-(2-methoxyethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one are
additionally useful for the manufacture of a composition for the treatment or
prophylaxis of endothelial dysfunction.
Further type V PDE inhibitors suitable for use herein include:
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl) -
pyrazino[2',1':6,1 ]pyrido[3,4-b]indole-1,4-dione (IC-351 ), i.e. the compound
of
3o examples 78 and 95 of published international application W~95/19978, as
well
as the compound of examples 1, 3, 7 and 8;
2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-
3H-
imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil) also known as 1-[[3-(3,4-
dihydro-5-
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methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yi)-4-ethoxyphenyl]sulphonyl]-
4-
ethylpiperazine, i.e. the compound of examples 20, 19, 337 and 336 of
published
international application W099/24433; and
s the compound of example 11 of published international application W093/07124
(EISAI); and
compounds 3 and 14 from Rotella D P, J. Med. Chem., 2000, 43, 1257.
to Still other type cGMP PDES inhibitors useful in conjunction with the
present
invention include:4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-
propoxy]-
3(2H)pyridazinone; 1-[4-[(1,3-benzodioxol-5- ylmethyl)amiono]-6-chloro-2-
quinozolinyl]-4-piperidine-carboxylic acid, monosodium salt; (+)-cis-
5,6a,7,9,9,9a-
hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-
4,5]imidazo[2,1-
is b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-
octahydrocyclopent[4,5]-imidazo[2,1-b]purin-4-one; 3-acetyl-1-(2-chlorobenzyl)-
2-
propylindole-6- carboxylate; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-
carboxylate; 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl) propoxy)-3-
(2H)pyridazinone; I-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-
1,6-dihydro- 7H-pyrazolo(4,3-d)pyrimidin-7-one; 1-[4-[(1,3-benzodioxol-5-
ylmethyl)arnino]-6-chloro-2- quinazolinyl]-4-piperidinecarboxylic acid,
monosodium
salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051
(Bayer); Pharmaprojects No. 5064 (Kyowa Hakko; see WO 96/26940);
Pharmaprojects No. 5069 (Schering Plough); GF-196960 (Glaxo Wellcome); E-
2s 8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer) and Sch-51866.
It is to be understood that the contents of the above published patent
applications,
and in particular the general formulae of the therapeutically active compounds
of
the claims and the exemplified compounds therein are incorporated herein in
their
3o entirety by reference thereto.
The suitability of any particular cGMP PDE5 inhibitor can be readily
determined by
evaluation of its potency and selectivity using literature methods followed by
evaluation of its toxicity, absorption, metabolism, pharmacokinetics, etc in
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16
accordance with standard pharmaceutical practice.
Preferably, the cGMP PDE5 inhibitors have an ICSO against the PDE5 enzyme of
less than 100 nanomolar (preferably, at less than 50 nanomolar).
s
According to a further aspect the present invention provides for the use of a
selective pyrazolopyrimidinone cGMP PDE5 inhibitor or a pharmaceutical
composition thereof in the preparation of a medicament for the curative,
palliative
or prophylactic treatment of type 2 diabetes mellitus or IGT in a mammal
wherein
io the selective cGMP PDE5 inhibitor is selected from : sildenafil, 5-(2-
ethoxy-5-
morpholinoacetylphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazo1o[4,3-
d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-
propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-
7-
one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-
3-yl]-
is 2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-
ethoxy-
5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-
dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and 1-[[3-(3,4-dihydro-5-methyl-4-
oxo-
7-propylimidazolo[5,1-t]-as-trizin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-
ethylpiperzine
or a pharmaceutically acceptable salt, solvate, pro-drug or polymorph thereof.
More particularly, the present invention provides a method of treating a
patient with type 2 diabetes mellitus, IGT or IR which comprises treating the
patient with an effective amount of a selective pyrazolopyrimidinone cGMP PDE5
inhibitor selected from sildenafil, 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-
2-(1-
2s ethyl-3-azetidinyl)-2,6-dihydro-7H pyrazolo[4,3-d]pyrimidin-7-one or 5-[2-
ethoxy-5-
(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-
dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or pharmaceutically acceptable
salts,
solvates, pro-drugs, polymorphs or pharmaceutical compositions thereof.
3o According to a further aspect still the invention also provides for the use
of a
selective pyrazolopyrimidinone cGMP PDE5 inhibitor and in particular
sildenafil, 5-
(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-
7H
pyrazolo[4,3-d]pyrimidin-7-one or 5-[2-ethoxy-5-(4-ethylpiperazin-1-
ylsulphonyl)pyridin-3-yl]-3-ethyl-1-(2-methoxyethyl)-1,6-dihydro-7H-
pyrazolo[4,3-
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17
d]pyrimidin-7-one for the manufacture of a composition for the treatment or
prophylaxis of type 2 diabetes mellitus, IGT or IR.
According to a further aspect the present invention additionally provides for
s the use of sildenafil or a pharmaceutically acceptable salt thereof or a
pharmaceutical composition thereof for the treatment of type 2 diabetes
mellitus,
IGT or IR.
1C50 values for the cGMP PDE5 inhibitors may be determined using the PDE5
io assay in the Test Methods Section hereinafter.
Preferably the cGMP PDE5 inhibitors used in the pharmaceutical compositions
according to the present invention are selective for the PDE5 enzyme.
Preferably
they have a selectivity of PDES over PDE3 of greater than 100 more preferably
is greater than 300. More preferably the PDE5 has a selectivity over both PDE3
and
PDE4 of greater than 100, more preferably greater than 300.
Selectivity ratios may readily be determined by the skilled person. 1C50
values for
the PDE3 and PDE4 enzyme may be determined using established literature
2o methodology, see S A Ballard et al, Journal of Urology, 1998, vol. 159,
pages
2164-2171 and as detailed herein after.
According to a further aspect, the invention provides the use of a
pharmaceutical medicament for use according to any aspect of the invention
2s hereinbefore or hereinafter detailed which is adapted for administration by
mouth,
said medicament comprising a PDE5 inhibitor having and IC5o of less than 100
nanomolar and a selectivity over PDE3 of greater than 100. Wherein said oral
use is for the treatment of the insulin resistance syndrome, or type 2
diabetes
mellitus or IGT or IR according to any aspect of the invention detailed herein
3o before preferably said PDE5 inhibitor is a pyrazolopyrimidinone, more
preferably
sildenafil, 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-ethyl-3-n-propyl-1,6-
dihydro-
7H-pyrazolo[4,3-d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-
ylsulphonyl)-2-
n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-
one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-
3-yl]-
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18
'2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-
ethoxy-
5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-
dihydro-7H-pyrazolo[4,3-dJpyrimidin-7-one and 1-[[3-(3,4-dihydro-5-methyl-4-
oxo-
7-propylimidazolo[5,1-t]-as-trizin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-
ethylpiperzine
s or a pharmaceutically acceptable salt, solvate, pro-drug or polymorph
thereof, and
in particular sildenafil, 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-
3-
azetidinyl)-2,6-dihydro-7H pyrazolo[4,3-d]pyrimidin-7-one or 5-[2-ethoxy-5-(4-
ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-1-(2-methoxyethyl)-1,6-
dihydro-
7H-pyrazolo[4,3-d]pyrimidin-7-one, and especially sildenafil.
io
Wherein said oral administration of a PDE5 inhibitor is for the treatment of
insulin resistance; type 2 diabetes mellitus; impaired glucose tolerance
(IGT);
dislipidemia; hyperuricemia and/or gout; or a proco-agulant state then said
PDE5
is inhibitor is a pyrazolopyrimidinone, more preferably sildenafil, 5-(2-
ethoxy-5-
morpholinoacetylphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyi)-2-n-
propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-
7-
one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-
3-yl]-
20 2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-
ethoxy-
5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-
dihydro-7H-pyrazolo[4,3-dJpyrimidin-7-one and 1-[[3-(3,4-dihydro-5-methyl-4-
oxo-
7-propylimidazolo[5,1-f]-as-trizin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-
ethylpiperzine
or a pharmaceutically acceptable salt, solvate, pro-drug or polymorph thereof,
and
2s in particular sildenafil, 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-
ethyl-3-
azetidinyl)-2,6-dihydro-7H pyrazolo[4,3-dJpyrimidin-7-one or 5-[2-ethoxy-5-(4-
ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-1-(2-methoxyethyl)-1,6-
dihydro-
7H-pyrazolo[4,3-djpyrimidin-7-one, and especially sildenafil.
3o As proposed hereinbefore amplification of the cGMP signal, using cGMP
specific PDE5 inhibitors in patients with the Insulin Resistance Syndrome
would
help to optimise the insulin glucose uptake signal and improve insulin action
at key
tissues. By making tissues more sensitive to insulin, it is thereby also
proposed
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19
herein that improvements in the clinical parameters of the IRS would result.
Thus,
according to a further aspect the present invention additionally provides a
method
for improving insulin action (treating insulin resistance) wherein said method
comprises treating a patient with the insulin resistance syndrome which
comprises
s treating a patient with underlying insulin resistance with an effective
amount of a
selective pyrazolopyrimidinone cGMP PDE5 inhibitor (as detailed hereinbefore).
Thus the present invention additionally provides a method for treating insulin
resistance which comprises treating a patient with underlying insulin
resistance
Io with an effective amount of a selective pyrazolopyrimidinone cGMP PDE5
inhibitor
selected from sildenafil, 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-
3-
azetidinyl)-2,6-dihydro-7H pyrazolo[4,3-d]pyrimidin-7-one or 5-[2-ethoxy-5-(4-
ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-
dihydro-
7H-pyrazolo[4,3-djpyrimidin-7-one or pharmaceutically acceptable salts,
solvates,
is pro-drugs, polymorphs or pharmaceutical compositions thereof.
Depending on the individual with IRS, any of the methods detailed
hereinbefore may have a beneficial effect on one or more of conditions
associated
with the IRS as defined herein. Thus according to a further aspect the present
ao invention additionally provides a method of treating type 2 diabetes
mellitus or
impaired glucose tolerance (IGT); or dyslipidemia, or hyperuricemia, or the
procoagulant state wherein said method comprises treating a patient with
underlying insulin resistance with an effective amount of a selective
pyrazolopyrimidinone cGMP PDE5 inhibitor (as detailed hereinbefore).
as
Thus the present invention additionally provides a method for treating type 2
diabetes mellitus or impaired glucose tolerance (IGT); or dyslipidemia, or
hyperuricemia, or the procoagulant state which comprises treating a patient
with
an effective amount of a selective pyrazolopyrimidinone cGMP PDE5 inhibitor
so selected from sildenafil, 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-
ethyl-3-
azetidinyl)-2,6-dihydro-7H pyrazolo[4,3-dJpyrimidin-7-one or 5-[2-ethoxy-5-(4-
ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-
dihydro-
7H-pyrazolo[4,3-d]pyrimidin-7-one or pharmaceutically acceptable salts,
solvates,
pro-drugs, polymorphs or pharmaceutical compositions thereof.
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The pharmaceutically acceptable salts of the selective cGMP PDE5
inhibitor compounds as disclosed herein for use in the treatment of the
insulin
resistance syndrome in accordance with the present invention which contain a
s basic centre are, for example, non-toxic acid addition salts formed with
inorganic
acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric
acid, with carboxylic acids or with organo-sulphonic acids. Examples include
the
HCI, HBr, HI, sulphate or bisulphate, nitrate, phosphate or hydrogen
phosphate,
acetate, benzoate, succinate, saccarate, fumarate, maleate, lactate, citrate,
io tartrate, gluconate, camsylate, methanesulphonate, ethanesulphonate,
benzene-
sulphonate, p-toluenesulphonate and pamoate salts. The selective cGMP PDE5
inhibitor compounds for use in the present invention can also provide
pharmaceutically acceptable metal salts, in particular non-toxic alkali and
alkaline
earth metal salts, with bases. Examples include the sodium, potassium,
is aluminium, calcium, magnesium, zinc and diethanolamine salts. For a review
on
suitable pharmaceutical salts see Berge et al, J. Pharm, Sci., 66, 1-19, 1977.
The cGMP PDESi compounds suitable for use in accordance with any
aspect of the present invention as disclosed herein, their pharmaceutically
2o acceptable salts, and pharmaceutically acceptable solvates of either entity
can be
administered alone but, in human therapy will generally be administered in
admixture with a suitable pharmaceutical excipient diluent or carrier selected
with
regard to the intended route of administration and standard pharmaceutical
practice.
For example, the cGMP PDESi compounds suitable for use in accordance
with the present invention or salts or solvates thereof can be administered
orally,
buccally or sublingually in the form of tablets, capsules (including soft gel
capsules), multi-particulate, gels, films, ovules, elixirs, solutions or
suspensions,
3o which may contain flavouring or colouring agents, for immediate-, delayed-,
modified-, sustained-, dual-, controlled-release or pulsatile delivery
applications.
Such compounds may also be administered via fast dispersing or fast dissolving
dosages forms or in the form of a high energy dispersion or as coated
particles.
Suitable pharmaceutical formulations may be in coated or un-coated form as
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21
'desired.
Such solid pharmaceutical compositions, for example, tablets may contain
excipients such as microcrystalline cellulose, lactose, sodium citrate,
calcium
s carbonate, dibasic calcium phosphate, glycine and starch (preferably corn,
potato
or tapioca starch), disintegrants such as sodium starch glycollate,
croscarmellose
sodium and certain complex silicates, and granulation binders such as
polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC),
hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,
io lubricating agents such as magnesium stearate, stearic acid, glyceryl
behenate
and talc may be included.
Solid compositions of a similar type may also be employed as fillers in
gelatin capsules or HPMC capsules. Preferred excipients in this regard include
is lactose, starch, a cellulose, milk sugar or high molecular weight
polyethylene
glycols. For aqueous suspensions and/or elixirs, the cGMP PDESi compounds
may be combined with various sweetening or flavouring agents, colouring matter
or dyes, with emulsifying and/or suspending agents and with diluents such as
water, ethanol, propylene glycol and glycerin, and combinations thereof.
Modified release and pulsatile release dosage forms may contain
excipients such as those detailed for immediate release dosage forms together
with additional excipients that act as release rate modifiers, these being
coated on
and/or included in the body of the device. Release rate modifiers include, but
are
2s not exclusively limited to, hydroxypropylmethyl cellulose, methyl
cellulose, sodium
carboxymefihylcellulose, ethyl cellulose, cellulose acetate, polyethylene
oxide,
Xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor
oil, carnauba wax, paraffin wax, cellulose acetate phthalate,
hydroxypropylmethyl
cellulose phthalate, methacrylic acid copolymer and mixtures thereof. Modified
3o release and pulsatile release dosage forms may contain one or a combination
of
release rate modifying excipients. Release rate modifying excipients maybe
present both within the dosage form i.e. within the matrix, and/or on the
dosage
form i.e. upon the surface or coating.
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22
Fast dispersing or dissolving dosage formulations (FDDFs) may contain the
following ingredients: aspartame, acesulfame potassium, citric acid,
croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl
cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate,
mannitol,
s methyl methacrylate, mint flavouring, polyethylene glycol, fumed silica,
silicon
dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol.
The
terms dispersing or dissolving as used herein to describe FDDFs are dependent
upon the solubility of the drug substance used i.e. where the drug substance
is
insoluble a fast dispersing dosage form can be prepared and where the drug
to substance is soluble a fast dissolving dosage form can be prepared.
The cGMP PDESi compounds suitable for use in accordance with the
present invention can also be administered parenterally, for example,
intracavernosally, intravenously, intra-arterially, intraperitonealiy,
intrathecally,
is intraventricularly, intraurethrally intrasternally, intracranially,
intramuscularly or
subcutaneously, or they may be administered by infusion or needle-free
techniques. For such parenteral administration they are best used in the form
of a
sterile aqueous solution which may contain other substances, for example,
enough salts or glucose to make the solution isotonic with blood. The aqueous
ao solutions should be suitably buffered (preferably to a pH of from 3 to 9),
if
necessary. The preparation of suitable parenteral formulations under sterile
conditions is readily accomplished by standard pharmaceutical techniques well-
known to those skilled in the art.
2s For oral and parenteral administration to human patients, the daily dosage
level of the selective cGMP PDES inhibitor compounds for use according to any
aspect of the present invention as disclosed herein or salts or solvates
thereof will
usually be from 5 to 500 mg (in single or divided doses). For the treatment of
the
Insulin Resistance Syndrome the dosage may by via single dose, divided daily
so dose, multiple daily dose, acute dosing, continuous (chronic) daily dosing
for a
specified period which may be from one to five or 5 or more, such as up to 10
or
more days. Alternatively the treatment of the Insulin Resistance Syndrome may
be affected by continuous dosing, such as for example, via a controlled
release
dosage form wherein such continuous dosage form can be administered on a
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23
daily basis for a number of days or wherein such continuous dosing can be
affected via a slow-release formulation which doses for more than one day at a
time. For chronic conditions treatment may be effected via continuous daily
dosing or via repeated regular dosing of controlled or sustained release
s formulation or such like. All references to the form of treatment may be
equally
applied to further aspects of the present invention as described herein such
as for
the treatment of type 2 diabetes mellitus, IGT or insulin resistance.
Thus, for example, tablets or capsules of the cGMP PDESi compounds
io suitable for use in accordance with the present invention or salts or
solvates
thereof may contain from 5 mg to 250 mg of active compound for administration
singly or two or more at a time, as appropriate. The physician in any event
will
determine the actual dosage which will be most suitable for any individual
patient
and it will vary with~the age, weight and response of the particular patient.
The
is above dosages are exemplary of the average case. There can, of course, be
individual instances where higher or lower dosage ranges are merited and such
are within the scope of this invention.
Example Tablet Formulation
In general a tablet formulation could typically contain between about 0.01 mg
and
500mg of selective cGMP PDES inhibitor compounds for use in accordance with
the present invention (or a salt thereof) whilst tablet fill weights may range
from
50mg to 1000mg. An example formulation for a l0mg tablet is illustrated:
Formulation 1
Ingredient %wlw
Sildenafil citrate 10.000*
Lactose 64.125
3o Starch 21.375
Croscarmellose Sodium 3.000
Magnesium Stearate 1.500
* This quantity is typically adjusted in accordance with drug activity.
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Formulation 2
A tablet is prepared using the following ingredients
s Quantity~mq/tablet~
sildenafil 250
cellulose, microcrystalline 400
silicon dioxide, fumed 10
stearic acid 5
to total 665ma
the components are blended and compressed to form tablets each weighing
665mg.
Is Formulation 3
An intravenous formulation may be prepared as follows:
sildenafil 100mg
isotonic saline 1,OOOmI
The cGMP PDESi compounds suitable for use in accordance with the present
invention can also be administered intranasally or by inhalation and are
conveniently delivered in the form of a dry powder inhaler or an aerosol spray
presentation from a pressurised container, pump, spray or nebuliser with the
use
2s of a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluoromethane,
dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-
tetrafluoroethane
(HFA 134A [trade mark] or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade
mark]), carbon dioxide or other suitable gas. In the case of a pressurised
aerosol,
the dosage unit may be determined by providing a valve to deliver a metered
3o amount. The pressurised container, pump, spray or nebuliser may contain a
solution or suspension of the active compound, e.g. using a mixture of ethanol
and the propellant as the solvent, which may additionally contain a lubricant,
e.g.
sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin)
for
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use in an inhaler or insufflator may be formulated to contain a powder mix of
a
compound of the invention and a suitable powder base such as lactose or
starch.
Aerosol or dry powder formulations are preferably arranged so that each
s metered dose or "puff" contains from 1 to 50 mg of a compound of the
invention
for delivery to the patient. The overall daily dose with an aerosol will be in
the
range of from 1 to 50 mg which may be administered in a single dose or, more
usuaNy, in divided doses throughout the day.
to The cGMP PDESi compounds suitable for use in accordance with the
present invention may also be formulated for delivery via an atomiser.
Formulations for atomiser devices may contain the following ingredients as
solubilisers, emulsifiers or suspending agents: water, ethanol, glycerol,
propylene
glycol, low molecular weight polyethylene glycols, sodium chloride,
fluorocarbons,
is polyethylene glycol ethers, sorbitan trioleate, oleic acid.
Alternatively, the cGMP PDESi compounds suitable for use in accordance
with the present invention or salts or solvates thereof can be administered in
the
form of a suppository or pessary, or they may be applied topically in the form
of a
2o gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The
cGMP
PDESi compounds suitable for use in accordance with the present invention or
salts or solvates thereof may also be dermally or transdermally administered,
for
example, by the use of a skin patch. They may also be administered by the
pulmonary or rectal routes.
The compounds may also be administered by the ocular route. For
ophthalmic use, the compounds can be formulated as micronised suspensions in
isotonic, pH adjusted, sterile saline, or, preferably, as solutions in
isotonic, pH
adjusted, sterile saline, optionally in combination with a preservative such
as a
3o benzylalkonium chloride. Alternatively, they may be formulated in an
ointment
such as petrolatum.
For application topically to the skin, the cGMP PDESi compounds suitable
for use in accordance with the present invention or salts or solvates thereof
can be
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26
formulated as a suifiable ointment containing the active compound suspended or
dissolved in, for example, a mixture with one or more of the following:
mineral oil,
liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene
polyoxypropylene compound, emulsifying wax and water. Alternatively, they can
s be formulated as a suitable lotion or cream, suspended or dissolved in, for
example, a mixture of one or more of the following: mineral oil, sorbitan
monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl
esters
wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
to The cGMP PDESi compounds suitable for use in accordance with the
present invention may also be used in combination with a cyclodextrin.
Cyclodextrins are known to form inclusion and non-inclusion complexes with
drug
molecules. Formation of a drug-cyclodextrin complex may modify the solubility,
dissolution rate, bioavailability and/or stability property of a drug
molecule. Drug-
ls cyclodextrin complexes are generally useful for most dosage forms and
administration routes. As an alternative to direct complexation with the drug
the
cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent
or
solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and
suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-
20 98/55148.
Generally, in humans, oral administration is the preferred route, being the
most convenient. In circumstances where the recipient suffers from a
swallowing
disorder or from impairment of drug absorption after oral administration, the
drug
2s may be administered parenterally, sublingually or buccally.
For veterinary use, a compound, or a veterinarily acceptable salt thereof, or
a veterinarily acceptable solvate or pro-drug thereof, is administered as a
suitably
acceptable formulation in accordance with normal veterinary practice and the
3o veterinary surgeon will determine the dosing regimen and route of
administration
which will be most appropriate for a particular animal.
Thus, for example, tablets or capsules of selective cGMP PDE5 inhibitor
compounds for use in accordance with the invention or salts or solvates
thereof
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27
may contain from 5 mg to 250 mg of active compound for administration singly
or
two or more at a time, as appropriate. The physician in any event will
determine
the actual dosage which will be most suitable for any individual patient and
it will
vary with the age, weight and response of the particular patient. The above
s dosages are exemplary of the average case. There can, of course, be
individual
instances where higher or lower dosage ranges are merited and such are within
the scope of this invention.
It is to be appreciated that all references herein to treatment include
to curative, palliative and prophylactic treatment and include acute treatment
(taken
as required) and chronic treatment (i.e. longer term continuous treatment).
The present invention additionally comprises treatment of the insulin
resistance syndrome with a combination of a cGMP PDE5 inhibitor compound as
is defined herein with one or more additional pharmaceutically active agents
such
as:
1 ) one or more naturally occurring or synthetic prostaglandins or esters
thereof. Suitable prostaglandins for use herein include compounds such as
2o alprostadil, prostaglandin El,prostaglandin Eo, 13, 14 - dihydroprosta
glandin
E1, prostaglandin E2, eprostinol, natural synthetic and semi-synthetic
prostaglandins and derivatives thereof including those described in WO-
00033825 and/or US 6,037,346 issued on 14th March 2000 all incorporated
herein by reference, PGEo, PGE~, PGAy, PGB1, PGFi a, 19-hydroxy PGA1, 19-
2s hydroxy - PGB1, PGE2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2, PGE3a,
carboprost tromethamine dinoprost, tromethamine, dinoprostone, lipo prost,
gemeprost, metenoprost, sulprostune, tiaprost and moxisylate; and/or
2) one or more a - adrenergic receptor antagonist compounds, a-blockers.
3o Suitable compounds for use herein include: the a-adrenergic receptor
blockers
as described in PCT application W099/30697 published on 14th June 1998,
the disclosures of which relating to a-adrenergic receptors are incorporated
herein by reference and include, selective a1-adrenoceptor or a2-adrenoceptor
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2~
blockers and non-selective adrenoceptor blockers, suitable ai-adrenoceptor
blockers include: phentolamine, phentolamine mesylate, trazodone, alfuzosin,
indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan,
efaraxan, yohimbine (a2-blocker), rauwolfa alkaloids, Recordati 15/2739, SNAP
s 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin, terazosin, abanoquil and
prazosin; a2-blocker blockers from US 6,037,346 [14th March 2000]
dibenarnine, tolazoline, trimazosin and dibenarnine; a-adrenergic receptors as
described in US patents: 4,188,390; 4,026,894; 3,511,836; 4,315,007;
3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and
l0 2,599,000 each of which is incorporated herein.by reference; a2-
Adrenoceptor
blockers include: clonidine, papaverine, papaverine hydrochloride, optionally
in
the presence of a cardiotonic agent such as pirxamine; and/or
3) one or more NO-donor (NO-agonist) compounds. Suitable NO-donor
is compounds for use herein include organic nitrates, such as mono- di or tri-
nitrates or organic nitrate esters including glyceryl trinitrate (also known
as
nitroglycerin), isosorbide 5-morionitrate, isosorbide dinitrate,
pentaerythritol
tetranitrate, erythrityl tetranitrate, sodium nitroprusside (SNP), 3-
morpholinosydnonimine molsidomine, S-nitroso- N-acetyl penicilliamine
20 (SNAP) S-nitroso-N-glutathione (SNO-GLU), N-hydroxy - L-arginine,
amylnitrate, linsidomine, linsidomine chlorohydrate, (SIN-1) S-nitroso - N-
cysteine, diazenium diolates,(NONOates), 1,5-pentanedinitrate, L-arginine,
ginseng, zizphi fructus, molsidomine, Re - 2047, nitrosylated maxisylyte
derivatives such as NMI-678-11 and NMI-937 as described in published PCT
2s application WO 0012075 ; andlor
4) one or more potassium channel openers or modulators. Suitable potassium
channel openers/modulators for use herein include nicorandil, cromokalim,
levcromakalim, lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin,
3o glyburide, 4-amini pyridine, BaCl2 ; and/or
5) one or more dopaminergic agents, preferably apomorphine or a selective D2,
D3 or D2/D3agonist such as, pramipexole and ropirinol (as claimed in WO-
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29
0023056),L-Dopa or carbidopa, PNU95666 (as claimed in WO-0040226);
and/or
6) one or more vasodilator agents. Suitable vasodilator agents for use herein
s include nimodepine, pinacidil, cyclandelate, isoxsuprine, chloroprumazine,
halo
peridol, Rec 15/2739, trazodone, and/or
7) one or more thromboxane A2 agonists; and/or
l0 8) one or more ergot alkoloids; Suitable ergot alkaloids are described in
US
patent 6,037,346 issued on 14th March 2000 and include acetergamine,
brazergoline, bromerguride, cianergoline, delorgotrile, disulergine,
ergonovine
maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide,
mesulergine,
metergoline, metergotamine, nicergoline, pergolide, propisergide,
proterguride,
is terguride; and/or
9) one or more compounds which modulate the action of natruretic factors in
particular atrial naturetic factor (also known as atrial naturetic peptide), B
type
and C type naturetic factors such as inhibitors of neutral endopeptidase;
and/or
10)one or more angiotensin receptor antagonists such as losartan; and/or
11)one or more substrates for NO-synthase, such as L-arginine; and/or
2s 12)one or more calcium channel blockers such as amlodipine; and/or
13)one or more antagonists of endothelin receptors and inhibitors or
endothelin-
converting enzyme; and/or
14)one or more cholesterol lowering agents such as statins (e.g. atorvastatin/
Lipitor- trade mark) and fibrates; and/or
15)one or more antiplatelet and antithrombotic agents, e.g. tPA, uPA,
warfarin,
hirudin and other thrombin inhibitors, heparin, thromboplastin activating
factor
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inhibitors; and/or
16)one or more insulin sensitising agents such as Rezulin, Avandia or Actos
and
hypoglycaemic agents such as, but not limited to, glipizide (sulfonylureas),
s metformin, or acarbose; and/or
17)one or more acetylcholinesterase inhibitors such as donezipil; and/or
18) one or more estrogen receptor modulators and/or estrogen agonists and/or
io estrogen antagonists, preferably raloxifene or lasofoxifene, (-)-cis-6-
phenyl-5-
[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-of and
pharmaceutically acceptable salts thereof (compound A below) the preparation
of which is detailed in WO 96/21656.
Compound A
23) one or more of a further PDE inhibitor, more particularly a PDE 2, 4, 7 or
8
inhibitor, preferably a PDE2 inhibitor said inhibitors preferably having an
IC50
against the respective enzyme of less than 1 OOnM: and/or
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24) one or more of an NPY (neuropeptide Y) inhibitor, more particularly NPY1
or
NPY5 inhibitor, preferably NPY1 inhibitor, preferably said NPY inhibitors
(including
NPY Y1 and NPY Y5) having an IC50 of less than 100nM , more preferably less
s than 50nM, suitable NPY and in particular NPY1 inhibitor compounds are
described in EP-A-1097718; and/or
25) one or more of vasoactive intestinal peptide (VIP), VIP mimetic, more
particularly mediated by one or more of the VIP receptor subtypes VPAC1,VPAC
io or PACAP (pituitary adenylate cyclase activating peptide), one or more of a
VIP
receptor agonist or a VIP analogue (eg Ro-125-1553) or a VIP fragment, one or
more of a a-adrenoceptor antagonist with VIP combination (eg Invicorp,
Aviptadil);
and/or
is 26) one or more of a melanocortin receptor agonist or modulator or
melanocortin
enhancer, such as melanotan II, PT-14, PT-141 or compounds claimed in WO-
09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361, WO-
00114879, WO-00113112, WO-09954358 and/or
Zo 27) one or more of a serotonin receptor agonist, antagonist or modulator,
more
particularly agonists, antagonists or modulators for 5HT1A (including VML
670),
5HT2A, 5HT2C, 5HT3 and/or 5HT6 receptors, including those described in WO-
09902159, WO-00002550 and/or WO-00028993; and/or
2s 28) one or more of a testosterone replacement agent (inc
dehydroandrostendione), testosternone (Tostrelle), dihydrotestosterone or a
testosterone implant; and/or
29) one or more of estrogen, estrogen and medroxyprogesterone or
3o medroxyprogesterone acetate (MPA) (i.e. as a combination), or estrogen and
methyl testosterone hormone replacement therapy agent (e.g. HRT especially
Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo,
Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Preempro,
Prempak, Premique, Estratest, Estratest HS, Tibolone); and /or
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32
30) one or more of a modulator of transporters for noradrenaline, dopamine
and/or serotonin, such as bupropion, GW-320659
s 31 ) one or more of a purinergic receptor agonist and/or modulator; and/or
32) one or more of a neurokinin (NK) receptor antagonist, including those
described in WO-09964008; and/or
l0 33) one or more of an opioid receptor agonist, antagonist or modulator,
preferably
agonists for the ORL-1 receptor and/or;
34) one or more of an agonist or modulator for oxytocin/vasopressin receptors,
preferably a selective oxytocin agonist or modulator and/or;
is
35) one or more modulators of cannabinoid receptors.
36) one or more CNS active agents; and/or
20 37) one or more compounds which inhibit angiotensin-converting enzyme such
as
enapril, and one or more combined inhibitors of angiotensin-converting
enzyme and neutral endopeptidase such as omapatrilat; and/or
38) L-DOPA or carbidopa; and/or
39) one or more steroidal or non-steroidal anti-inflammatory agents; and/or
40) one or more protein kinase C-(3 inhibitors such as LY333531; and/or
41) one or more activators of AMP-activated protein kinase such as 5-amino-4-
imidazolecarboxamide ribonucleoside; and/or
42) insulin; and/or
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33
43) weight loss agents such as sibutramine or orlistat; and/or
44) one or more dipeptidyl peptidase IV inhibitors such as NVP DPP728 or
P32/98; and/or
45) one or more glucagon antagonists such as NNC25-2504
46) one or more agents that inhibit PTP1 B such as PTP112; and/or
io
47) one or more agents that reduce PTP1 B levels using antisense technology;
andlor
48) one or more glycogen synthase kinase-3 inhibitors such as Chir98014;
and/or
49) one or more GLP-1 agonists such as GLP1, NN-2211 or exendin 4; and/or
50) one or more PPAR-gamma agonists such as Rezulin, Avandia, Actos or
CS011; and/or,
51 ) one or more PPAR-alpha agonists such as fenofibrate; and/or
52) one or more dual PPAR-alpha/PPAR-gamma agonists such as fargiitazar,
rosiglitasone, pioglitazone, GW1929, DRF2725, AZ242 or ICRP 297, and/or
53) one or more sorbitol dehydrogenase inhibitors such as CP-470711; and/or
54) one or more aldose reductase inhibitors such as zopolrestat, zenarestat,
or
fidarestat.
55)one or more preparations of growth hormone or growth hormone
secretagogues; and/or
56)one or more of an NEP inhibitor, preferably wherein said NEP is EC
3.4.24.11
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34
and more preferably wherein said NEP inhibitor is a selective inhibitor for EC
3.4.24.11, more preferably a selective NEP inhibitor is a selective inhibitor
for
EC 3.4.24.11, which has an ICSO of less than 100nM (e.g. ompatrilat,
sampatrilat) suitable NEP inhibitor compounds are described in EP-A-1097719
s and/or;
According to a still further aspect the present invention comprises treatment
of
type 2 diabetes mellitus or IGT or IR with a combination of a cGMP PDE5
inhibitor
compound which is a pyrazolopyrimidinone, more preferably sildenafil, 5-(2-
to ethoxy-5-morpholinoacetylphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-
pyrazolo[4,3-
d]pyrimidin-7-one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-
propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-
7-
one, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-
3-yl]
2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-
ethoxy
i5 5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-
2,6
dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-
propylimidazolo[5,1-t]-as-trizin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-
ethylpiperzine or
a pharmaceutically acceptable salt, solvate, pro-drug or polymorph thereof,
and in
particular sildenafil, 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-
2o azetidinyl)-2,6-dihydro-7H pyrazolo[4,3-dJpyrimidin-7-one or 5-[2-ethoxy-5-
(4-
ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-1-(2-methoxyethyl)-1,6-
dihydro-
7H-pyrazolo(4,3-dJpyrimidin-7-one, and especially sildenafil with one or more
additional pharmaceutically active agents wherein said additional agent
comprises
one or more agent from (1 ) to (56) as defined herein before.
?s
Preferred combinations for use according to any of the aspects of the present
invention as described herein include a combination of a cGMP PDESi, and in
particular sildenafil with one or more additional agents selected from (16),
(40),
(41 ), (42), (43), (50), (51 ), (52), (53) or (54) as detailed hereinbefore.
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PHARMACOKINETICS
BIOAVAI LABI LITY
Preferably, the PDE5 inhibitor compounds for use in the present invention (and
s combinations) are orally bioavailable. Oral bioavailablity refers to the
proportion of
an orally administered drug that reaches the systemic circulation. The factors
that
determine oral bioavailability of a drug are dissolution, membrane
permeability
and metabolic stability. Typically, a screening cascade of firstly in vitro
and then in
vivo techniques is used to determine oral bioavailablity.
to
Dissolution, the solubilisation of the drug by the aqueous contents of the
gastro-
intestinal tract (GIT), can be predicted from in vitro solubility experiments
conducted at appropriate pH to mimic the GIT. Preferably the PDE5 inhibitor
compounds for use according to the present invention have a minimum solubility
is of 50 mcg/ml. Solubility can be determined by standard procedures known in
the
art such as described in Adv. Drug Deliv. Rev. 23, 3-25, 1997.
Membrane permeability refers to the passage of the compound through the cells
of the GIT. Lipophilicity is a key property in predicting this and is defined
by in
2o vitro Log D~,4 measurements using organic solvents and buffer. Preferably
the
compounds of the invention have a Log D~,~ of -2 to +4, more preferably -1 to
+3.
The log D can be determined by standard procedures known in the art such as
described in J. Pharm. Pharmacal. 1990, 42:144.
2s Cell monolayer assays such as Caco-2 add substantially to prediction of
favourable membrane permeability in the presence of efflux transporters such
as
p-glycoprotein, so-called Caco-2 flux. Preferably, compounds for use according
to
the present invention have a Caco-2 flux of greater than 2x10-6cms~l, more
preferably greater than 5x10-6cms-1. The Caco-2 flux value can be determined
by
3o standard procedures known in the art such as described in J. Pharm. Sci,
1990,
79, 595-600
Metabolic stability addresses the ability of the GIT or the liver to
metabolise
compounds during the absorption process: the first pass effect. Assay systems
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36
such as microsomes, hepatocytes etc are predictive of metabolic liability.
Preferably the compounds of the Examples show metabolic stablity in the assay
system that is commensurate with an hepatic extraction of less then 0.5.
Examples of assay systems and data manipulation are described in Curr. Opin.
s Drug Disc. Devel., 201, 4, 36-44, Drug Met. Disp.,2000, 28, 1518-1523
Because of the interplay of the above processes further support that a drug
will be
orally bioavailable in humans can be gained by in vivo experiments in animals.
Absolute bioavailability is determined in these studies by administering the
to compound separately or in mixtures by the oral route. For absolute
determinations
(% absorbed) the intravenous route is also employed. Examples of the
assessment of oral bioavailability in animals can be found in Drug Met.
Disp.,2001, 29, 82-87; J. Med Chem , 1997, 40, 827-829, Drug Met. Disp.,1999,
27, 221-226. and as described in J. Pharm. Sci 79, 7, p595-600 (1990), and
is Pharm. Res. vol 14, no. 6 (1997).
PDE5 inhibitor - TEST METHODS
Phosphodiesterase (PDE) inhibito activity
Preferred PDE compounds suitable for use in accordance with the present
2o invention are potent and selective cGMP PDE5 inhibitors. In vitro PDE
inhibitory
activities against cyclic guanosine 3',5'-monophosphate (cGMP) and cyclic
adenosine 3',5'-monophosphate (CAMP) phosphodiesterases can be determined
by measurement of their IC5o values (the concentration of compound required
for
50% inhibition of enzyme activity).
The required PDE enzymes can be isolated from a variety of sources, including
human corpus cavernosum, human and rabbit platelets, human cardiac ventricle,
human skeletal muscle and bovine retina, essentially by the method of W.J.
Thompson and M.M. Appleman (Biochem., 1971, 10, 311 ). In particular, the
3o cGMP-specific PDE (PDES) and the cGMP-inhibited cAMP PDE (PDE3) can be
obtained from human corpus cavernosum tissue, human platelets or rabbit
platelets; the cGMP-stimulated PDE (PDE2) can be obtained from human corpus
cavernosum; the calcium/calmodulin (Ca/CAM)-dependent PDE (PDE1 ) from
human cardiac ventricle; the cAMP-specific PDE (PDE4) from human skeletal
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37
muscle; and the photoreceptor PDE (PDE6) from bovine retina.
Phosphodiesterases 7-11 can be generated from full length human recombinant
clones transfected into SF9 cells.
s Assays can be performed either using a modification of the "batch" method of
W.J. Thompson et al. (Biochem., 1979, 1 ~, 5228) or using a scintillation
proximity
assay for the direct detection of AMP/GMP using a modification of the protocol
described by Amersham plc under product code TRKQ7090/7100. In summary,
the effect of PDE inhibitors was investigated by assaying a fixed amount of
to enzyme in the presence of varying inhibitor concentrations and low
substrate,
(cGMP or cAMP in a 3:1 ratio unlabelled to [3H]-labeled at a conc ~1/3 Km)
such
that IC5o ~-_ K;. The final assay volume was made up to 100,1 with assay
buffer [20
mM Tris-HCI pH 7.4, 5 mM MgCl2, 1 mg/ml bovine serum albumin]. Reactions
were initiated with enzyme, incubated for 30-60 min at 30°C to give
<30%
is substrate turnover and terminated with 50 ~,I yttrium silicate SPA beads
(containing 3 mM of the respective unlabelled cyclic nucleotide for PDEs 9 and
11 ). Plates were re-sealed and sf~aken for 20 min, after which the beads were
allowed to settle for 30 min in the dark and then counted on a TopCount plate
reader (Packard, Meriden, CT) Radioactivity units were converted to % activity
of
2o an uninhibited control (100%), plotted against inhibitor concentration and
inhibitor
ICSO values obtained using the 'Fit Curve' Microsoft Excel extension.
Functional activity
2s This can be assessed in vitro by determining the capacity of a compound of
the
invention to enhance sodium nitroprusside-induced relaxation of pre-contracted
rabbit corpus cavernosum tissue strips, as described by S.A. Ballard et al.
(Brit. J.
Pharmacol., 1996, 118 (suppl.), abstract 153P).
3o In vivo activity
Compounds were screened in anaesthetised dogs to determine their capacity,
after i.v. administration, to enhance the pressure rises in the corpora
cavernosa of
the penis induced by intracavernosal injection of sodium nitroprusside, using
a
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38
method based on that described by Trigo-Rocha et al. (Neurourol. and Urodyn.,
1994, 13, 71 ).
Effect of Specific Selective PDE5 inhibitors on Insulin Resistance Syndrome in
s animals-Effects on Plasma Glucose and Serum Triglyceride Levels in oblob
Mice
Biological Data
Experimental Protocol
Test Compounds:
to The selective PDES inhibitor compounds to be tested were solubilized in 10%
DMSOl0.1 % pluronics and dosed via oral gavage using mouse oral feeding
needles (20 gauge, Popper & Sons, Inc., New Hyde Park, NY). A volume of 4
ml/kg weight was administered for each dose. Compounds were tested at doses
ranging from 1-50 mg/kg. Alternatively, the test selective PDE5 inhibitor
is compound was administered in the drinking water and found to produce
similar
reductions in plasma glucose and triglycerides to the reductions observed for
the
same compound when administered by oral gavage.
2o ExJaerimental Animals:
Male ~blob mice obtained from Jackson Laboratories (Bar Harbor, ME) were used
in the studies at 6 to 10 weeks of age. Mice were housed five per cage and
allowed free access to D11 mouse chow (Purina, Brentwood, MO) and water.
2s Experimental Protocol:
Mice were allowed to acclimate to the Pfizer animal facilities for 1 week
prior to the
start of the study. On day one, retro-orbital blood samples were obtained and
plasma glucose was determined as described hereinafter. Mice were then sorted
into groups of five such that mean plasma glucose concentrations for each
group
3o did not differ. On day one, mice were dosed with vehicle or a test
selective PDE5
inhibitor compound only in the afternoon. Subsequently, mice were dosed twice
a
day on day 2-4 in the morning and in the afternoon. On day 5, the mice
received
an a.m. dose and bled 3 hours later for plasma preparation for glucose and
triglyceride analysis as described below. Alternatively, test selective PDE5
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39
inhibitor compound was administered in the drinking water commencing on the
afternoon of day 1 and continuing through day 5, when mice were then bled for
plasma preparation for glucose and triglyceride analysis as described below.
Terminal plasma samples were collected on day 5 following the retro-orbital
sinus
s bleed as described below. Body weight was measured on days 1 and 5 of the
study, and food consumption was assessed over the 5 day period.
Terminal Bleed and Tissue Collection:
to On the morning of the last day of the study mice were dosed with test
compound
or vehicle at approximately 8:00 am. Three hours after dosing, 25 ~L of blood
was obtained via the retro-orbital sinus and added to 100 ~.L of 0.025
heparinized-saline in Denville Scientific microtubes. The tubes were spun at
the
highest setting in a Beckman Microfuge 12 for 2 minutes. Plasma was collected
is for plasma glucose and triglyceride determination. The mice were then
sacrificed
by decapitation and ~1 ml of blood was collected in Becton-Dickinson
Microtainer
brand plasma separator tubes with lithium heparin. The tubes were spun in a
Beckman Microfuge 12 at the maximum setting for five minutes. Plasma was
collected in 1.5 ml Eppendorf tubes and snap frozen in liquid nitrogen. Plasma
zo samples were stored at - 80° C until analyzed.
Metabolite and Hormone Anai r~ sis:
Plasma glucose and triglycerides were measured using the Alcyon Clinical
Chemistry Analyzer (Abbott Laboratories, Abbott Park, IL) using kits supplied
by
2s Abbott. Plasma cGMP was measured using the Biotrak enzyme-immunoassay
system by Amersham (Piscataway, NJ). Via a similar technique the plasma
insulin can be assessed by the Mercodia ELISA Insulin kit by ALPCO (Uppsala,
Sweden). All assays were conducted according to instructions provided by the
manufacturers.
Statistical Analysis:
Comparisons between drug treatments and appropriate vehicles were done by
Student's t-test.
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Results summary):
Selective PDE5 inhibitors have been demonstrated to reduce the plasma glucose
and serum triglyceride levels produced by ob/ob mice in accordance with the
5 biological test methods detailed hereinbefore.
Results
Table 1 illustrates the changes in plasma glucose levels over a 5 day period
io observed with selective PDE5 inhibitor compounds.
Selective PDE5 Compound A: 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-
propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-
dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
is
Selective PDES Compound B: 5-(2-ethoxy-5-morpholinoacetylphenyi)-1-
methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one
2o Table 1
Changes in Plasma
Glucose Concentrations
(mg/dl)
Vehicle -9 + 22
PDE5 A - l0mg/kg -115 34*
PDE5 A - 50 mg/kg-105 25*
PDE5 B - 25 mg/kg-97 32*
The data in Table 1 are presented as mean ~ standard error of the mean. These
numbers reflect absolute decreases in plasma glucose levels. Significant
zs differences from the Vehicle control are indicated as *p < 0.05.
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Table 2 illustrates the change in plasma cGMP and plasma triglyceride levels
in
ob/ob mice observed with the test selective PDE5 inhibitor compounds A and B.
s Table 2
Plasma cGMP LevelPlasma Triglyceride
(mg/dl) Level (mg/dl)
Vehicle 9.8 + 0.5 178 + 16
PDE5 A - 1 Omg/kg48.3 19.0~ 163 .10
PDE5 B - 25 mg/kg30.7 3.3** 143 7~
io The data in Table 2 are presented as mean ~ standard error of the mean.
Significant differences from the Vehicle control as indicated as ~p < 0.1, *p
< 0.05,
**p < 0.01.
i5 Table 3 illustrates the reduction in plasma glucose levels over a 5 day
period
observed with selective a PDE5 inhibitor compound administered in the drinking
water of the mice.
Selective PDE5 Compound C: sildenafil
Table 3
Changes in Plasma Glucose
Concentrations (mg/dl)
Vehicle 25 + 25
PDE5 C - 9 mg/kg -27 34
PDE5 C - 22 mg/kg-15 27
PDE5 C - 45 mg/kg-36 22~
The data in Table 3 are presented as mean ~ standard error of the mean.
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42
Positive values in this table reflect a decrease in plasma glucose level.
Significant
differences from the Vehicle control are indicated as ~p < 0.1.
Table 4 illustrates the triglyceride levels in ob/ob mice treated with the
test
s selective PDE5 inhibitor compound C administered in the drinking water of
the
mice.
Table 4
Plasma Triglyceride
Level (mg/dl)
Vehicle 204 + 13'
PDES C - 9 mg/kg163 14*
PDE5 C - 22 mg/kg212 20
PDE5 C - 45 mg/kg151 10**
io The data in Table 4 are presented as mean ~ standard error of the mean.
Significant differences from the Vehicle control as indicated as *p < 0.05,
**p <
0.01.
15 Taken together, these experimental results in the hyperglycemic, insulin-
resistant
olalob mouse suggest that selective PDE5 inhibition improves metabolic
parameters associated with IRS.
Further these results suggest that treatment with selective PDE5 inhibitors
can
2o result in decreases in plasma glucose concentrations. As detailed herein
before
decreases in plasma glucose concentrations are consistent with an improvement
in insulin resistance which is a clinical parameter of the IRS, and, as
further
detailed hereinbefore such improvements, in subjects with type 2 diabetes
mellitus
would manifest as improvements in for example haemoglobin A1 c.
These results also suggest that treatment with selective PDE5 inhibitors can
result
in improvements in serum lipid levels. As detailed herein before an
improvement
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43
in serum lipid levels (such as in triglyceride levels) is consistent with an
improvement in insulin resistance which is a clinical parameter of the IRS.
Such
improvements, in subjects with the IRS (as defined herein) would manifest as
improvements in for example dyslipidemia (hypertriglyceridaemia).
s
These results in the hyperglycemic, insulin-resistant oblob mouse additionally
suggest that continuous treatment with a selective PDE5 inhibitor can improve
metabolic parameters associated with IRS in 5 days or less.
io Clinical Trial Data 1
In a 28-day clinical trial with sildenafil, serum triglyceride levels were
obtained
before and at the end of dosing from non-diabetic subjects. Doses included in
the
study were l0mg, 25mg and 50gm of sildenafil or placebo, dosed once daily.
is These subjects had the insulin resistance syndrome, as defined by the risk
factors
as defined hereinbefore. Data are presented in tables 5 and 6 below to
illustrate
that subjects had evidence of the insulin resistance syndrome.
Table 5 illustrates the sub-division of the IRS components amongst the
subjects
2o studied.
Coronary artery disease (CAD) / ischaemic heart disease (IHD) is one clinical
end-
point in subjects having the Insulin Resistance Syndrome. For this reason the
presence of CAD/IHD was taken as evidence to support the existence of the
2s Insulin Resistance Syndrome in patients with only one of the defined risk
factors.
Table 5
IRS Com onent Placebo SildenafilTotal
D slipidemia (Hypertriglyceridaemia) 40 74 114
Obesit BMI>26 26 47 73
H ertension 10 12 22
Corona arte disease h/o an ina,8 5 13
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44
arrh thmia, MI, i.e., atherosclerosis
H eruricaemia 0 2 02
BMI -Body Mass Index
s Table 6 illustrates the collective totals of the number of IRS components
within the
subject group.
Table 6
1 com onent 114 T
~
2 com onent 80 73 T+O ;
4 T+H ; 3 T+I
3 com onent 24 6 T+O+I ; 14 T+O+H ; 2 T+I+H ; 2 T+O+U
4 com onent 4 T+O+I+H
to
T =Raised Triglycerides (Dyslipidemia), D = Obesity, H = Hypertension, I =
GADlIHD, U =
Hyperuricaemia
Preliminary data are presented below demonstrating reductions in serum
is triglyceride levels with sildenafil treatment. Falls in serum triclyceride
levels (in
mg/dl) of 100.3; 67.3; and 23.9 were observed for the 10, 25 and 50mg
sildenafil
groups respectively, compared to 19.9mg/dl fall in the placebo group. This
represents a fall of about 40%; 31 % and 12% fall on treatment with sildenafil
from
baseline values (mg/dl) of 255, 213 and 191 compared to 10.7% from a baseline
20 of 185mg/dl for placebo.
The reduction of serum triglycerides that was seen in the sildenafil group was
statistically significantly different compared to placebo (p= 0.0457). There
was
also a trend seen in HDL (p=0.0539). These changes, in non-diabetic subjects
2s who have many features of the IRS, are consistent with improvements in the
insulin resistance syndrome.
Further these results are consistent with improvements in insulin resistance
in
non-diabetic subjects who have many features of the IRS when treated with
3o sildenafil. Thus according to a further aspect the present invention
additionally
comprises treatment of insulin resistance with a selective pyrazolopyrimdinone
cGMP PDE5 inhibitor (as defined hereinbefore).
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4s
Clinical Trial Data 2
Adult subjects with Diabetes Mellitus were treated chronically with sildenafil
citrate
s in an out-patient, multicentre study. Subjects were taking several different
glucose-lowering agents (including, but not limited to, metformin, insulin, or
sulfonylureas) or were treated with diet alone. Glycosylated haemoglobin (HbA1
c)
was determined prior to treatment and at the end of the study. Glycosylated
haemoglobin (HbAI~) is a recognised measure of chronic glucose control. In
this
io study a significant improvement in glucose control was observed in said
subjects
with type 2 diabetes mellitus when treated with sildenafil citrate
(ViagraT"'). These
significant improvements were consistently observed across the subject group
irrespective of their background therapy.
is
These results are consistent with improvements in the IRS in adult subjects
when
treated with sildenafil. Further these results are consistent with
improvements in
glucose control in patients having type 2 diabetes mellitus when treated with
sildenafil. Thus the present invention provides a method of treatment of type
2
2o diabetes mellitus comprising treating a subject in need of such treatment
with a
selective pyrazolopyrimidinone cGMP PDE5 inhibitor (as defined hereinbefore)
and especially sildenafil. In particular said treatment is effected by the
oral route.
The results of clinical trial 2 are supporting for the use of a selective cGMP
PDE5
2s inhibitor as defined hereinbefore, and especially sildenafil for the
treatment of IGT.
Additionally these results are consistent with improvements in the IRS in
adult
subjects when treated with a combination of sildenafil and glucose-lowering
agents. Thus the present invention additionally comprises the combination of a
so selective PDE5 inhibitor and a glucose-lowering agent for the treatment of
the
IRS. In particular said combined treatment is effected by the oral route.
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46
According to a further aspect the present invention provides a combination
therapy suitable for use in the treatment of the IRS, IR, type 2 diabetes
mellitus,
s impaired glucose tolerance (IGT), hyperuricaemia and/or gout, dyslipidemia,
the
procoagulant state or truncal obesity wherein said combination comprises a
selective cGMP PDE5 inhibitor, preferably a pyrazolopyrimidinone, especially
sildenafil with an additional agent active as defined hereinbefore and
preferably
(16), (40), (41 ), (42), (50), (52), (53) and/or (54), more preferably one or
more of
to weight loss agents, sulfonyl ureas, insulin, Rezulin, Avandia, Actos,
Glipizide,
Metformin, Acarbose, rosiglitasone, pioglitazone, farglitazar, LY333531,
CS011,
PPAR-alpha agonists, andlor CP-470711.
According to a yet further aspect said combination treatments) is/are effected
Is orally and further may be in the form_of a kit.
Taken together, the results from both the animal and human trials are
consistent
2o with improvements in the IRS as well as in clinical parameters associated
with the
IRS. That is, improvements in triglycerides in both diabetic and non-diabetic
experiments as well as improvement in glucose in those with diabetes support
the
activity of PDE5 inhibitor compounds, including but not limited to sildenafil,
on the
IRS.
~s
