Filed of the Invention:
The present invention relates to a combination, such as a combined preparation or
pharmaceutical composition comprising: (a) compound of formula (I), or (II) as defined
hereinafter or a pharmaceutically acceptable salt thereof; (b) at least one therapeutic agent
selected from the group consisting of an antihypertensive agent, an antidiabetics agent, a
hypolipidemic agent, an antiplatelet agent, an antiobesity agent, an antithrombotic agent,
an agent for diabetic vascular complications, an agent for treatment of heart failure or a
pharmaceutically acceptable salts thereof, optionally in presence of a pharmaceutically
acceptable carrier for separate, simultaneous or sequential use.
Background of the Invention:
Diabetes is an important adult disease all over the world and it refers to a disease process
caused due to multiple factors and characterized by elevated levels of plasma glucose or
hyperglycemia. Worldwide, more than 171 million people have diabetes, and its
prevalence is expected to double by 2030. (Padwal R, Majumdar SR, Johnson JA, Varney
J, McAlister FA. A systematic review of drug therapy to delay or prevent type 2 diabetes.
Diabetes Care 2005;28:736-44.) Persistent or uncontrolled hyperglycemia is associated
with increased and premature morbidity and mortality. Often abnormal glucose
homeostasis is associated both directly and indirectly with alterations of the lipid,
lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic
disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk
of macrovascular and microvascular complications, including coronary heart disease,
stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and
retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism
and hypertension are critically important in the clinical management and treatment of
diabetes mellitus.
Diabetic complications, a major cause of death due to diabetes, occur by the damage of
almost all organs in the body at 10-20 years after the onset of diabetes. These diabetic
2

complications can progress even when diabetes is well controlled so as to recover the
normal blood glucose concentration. Diabetes and Hypertension frequently coexist,
leading to additive increase in the risk of life threatening cardiovascular events. It is well
known that hypertension accelerates the course of micro and macrovascular
complications of diabetes and hypertension often precedes diabetes and vice versa.( J
Cardiometab. Syndr. 2007, 2(2), 124-30) Hypertension affects 40-60% of type 2
diabetics between the ages of 40-75. Hypertension is often unrecognized, resistant to
treatment and undertreated, in spite of the fact that if hypertension is controlled this
reduces diabetes related deaths, stroke, macrovascular disease, microvascular disease and
heart failure.
People with diabetes are at increase.' sk of developing heart failure wit • he relative risk
increasing by 10-15% per unit increase in glycated haemoglobin. Conversely, heart
failure is present in 25-40% of all adults with diabetes. Moreover, people with heart
failure have worse outcomes if they also have diabetes and it ha- sen suggested that any
level of hyperglycaemia is associated with increased rates of hospital admission, even in
patients without manifest diabetes. (BMJ 2007;335:497 (8 September),
doi:10.1136/bmj.39314.620174.80 (published 30 August 2007) Diabetes mellitus is an
independent risk factor for CHF and vice versa. Apart from CHD and hypertension,
hyperglycaemia and insulin resistance are directly linked to the development of diastolic
dysfunction and to CHF. (MMW Fortschr Med. 2007 Sep 13;149(37):41-4)
Patients with signs and symptoms of heart failure and a preserved left ventricular (LV)
systolic function may have significant abnormalities in diastolic function. This condition
is called diastolic heart failure (DHF) and is observed in about 40% of patients with
chronic heart failure (CHF). Diabetes mellitus is one of the major risk factors for DHF.
Diastolic dysfunction is observed in about 40% of patients with diabetes mellitus and
correlates with poor glycemic control. Poor glycemic control is associated with a high
incidence of heart failure in diabetic patients ( Am J Cardiovasc Drugs. 2006;6(4):219-
30)
3

It has been observed that the usual treatments in heart failure have similar or lower
efficacy in the diabetic patient, and treatment intolerance is frequent. Treatments used for
diabetes often are poorly tolerated in case of heart failure (metformin, glitazones) ( Arch
Mai Coeur Vaiss. 2007 Jun-Jul;100(6-7):535-46)
Health problems such as heart disease, stroke, kidney disease, eye damage and foot
problems that can lead to amputations are far more prevalent in people with type 2
diabetes than in the general population. In USA, an estimated three out of five people
with diabetes (57.9 percent) have one or more of the complications associated with
diabetes. Cardiovascular disease is responsible for between 50% and 80% of deaths in
people with diabetes. Studies suggest that up to 50% of people with diabetes are affected
to some degree of diabetic neuropathy. Diabetic retinopathy is a leading cause of
blindness and visual disability. Research findings suggest that, after 15 years of diabetes,
approximately 2% of people become blind, while about 10% develop severe visual
handicap.
Although the underlying causes of hyperglycemia are multiple, a common thread
associated with high levels of blood sugar is the development of a range of vascular and
inflammatory complications that might seriously limit the quality and duration of life in
affected individuals (Trends Endocrinol Metab.2000 Nov;ll(9):368-75) Mediators of
vascular damage of diabetes include poor glycemic control, lipoprotein abnormalities,
hypertension, oxidative stress, inflammation and advanced glycation end-products
(AGEs). AGE accumulation causes arterial stiffening in the vessel wall,
glomerulosclerosis in the kidney, and vascular hyperpermeability in the retina. Through
their interaction with their putative receptor the so-called receptor for AGEs (RAGE),
AGEs activate endothelial cells and macrophages, generate reactive oxygen species
(ROS), induce overexpression of vascular endothelial growth factor (VEGF) and vascular
cell adhesion molecule-1 (VCAM-1), and quench nitric oxide (NO) (Curr Med Chem.
2006;13(15):1777-88).
4

Current drugs used for managing diabetes and its precursor syndromes, such as insulin
resistance, generally fall within five classes of compounds: biguanides,
thiazolidinediones, sulfonylureas, meglitinides and alpha-glucosidase inhibitors.
Treatment of diabetic complications such as diabetic macroangiopathy, diabetic
microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, foot
ulcers, myocardial infarction, or diabetic cardiomyopathy are generally treated by using
current treatment strategies directed at slowing the progression of diabetic nephropathy or
other diabetic complications using various approaches, including optimized glycemic
control (through modification of diet and/or insulin therapy) and hypertension control.
These therapeutic strategies have demonstrated varying degrees of success.
For example, both angiotensin-converting enzyme (ACE) inhibitors and angiotensin
receptor blockers (ARBs), administered to reduce hypertension, have been shown to
delay progression or development of nephropathy and macroalbuminuria. Further, while
glycemic and blood pressure control therapies significantly decrease the morbidity and
mortality associated with diabetic nephropathy by delaying progression of associated
pathologies, such conventional therapies do not adequately halt the progression of the
disease and thus fail to provide a complete therapeutic effect. In addition, administration
of ACE inhibitors or ARBs, the current standard of care, are not universally effective and
only minimally delay the progression of nephropathy.
Thus, there is a critical need for better drugs and/or combination of approach since
current treatment may have limited impact on the progressive complications.
Hypertension affects large number of population worldwide and it is estimated that by
2025 the global prevalence may set to rise to 29.2% of all adults - a total of between 1.54
and 1.58 billion individuals. Prevalence may set to increase by 24% in developed
countries and by 80% in developing countries, so that in 20 years' time, three quarters of
the world's population with hypertension would live in developing countries.
Currently available therapy includes diuretics such as hydrochlorothiazide, cicletanine,
xipamide, indapamide, clopamide, amiloride, spironolactone and canrenone; beta-
5

blockers such as propranolol, acebutolol, atenolol, nadolol, bisoprolol, metoprolol,
pindolol, oxprenolol and betaxolol; ACE inhibitors such as captopril, enalapril,
benazepril, lisinopril, quinapril, ramipril and imidapril; Angiotensin II receptor
antagonists (ARBs), such as losartan, candesartan, cilexetil, irbesartan, telmisartan, and
valsartan; calcium channel antagonists, such as nifedipine, amlodipine, felodipine,
isradipine, diltiazem, bepridil, lacidipine, nitrendipine, nicardipine and verapamil; central
anti-hypertensive agents such as clonidine, guanfacine, monoxidine, rilmenidine and a-
methyl-dopa; alpha-blockers such as prasozin, urapidil, doxazosine and terazosine;
Vasodilators such as hydralazine, dihydralazine and minoxidil.vasopeptidase inhibitors;
Endothelin antagonists and rennin inhibitors such as aliskiren.
It has generally been observed that in a long term treatment monotherapy with any of the
above drug does not adequately control the symptoms of hypertension and patients
ultimately progress toward various complication of hypertension. This happens due to the
complexity of disease process and involvement of different factors causing hypertension
The precise pathophysiological mechanisms through which elevated blood pressure leads
to cardiovascular disease, however, remain uncertain. Basic data suggest that increasing
levels of blood pressure may stimulate a proinflammatory response and that endothelial
inflammation may also herald the changes in arterial wall that characterize the
hypertensive state. (Circulation. 2003;108:2993.) . Patients with cardiovascular disease
present with increase expression and plasma concentration of inflammatory markers and
mediators, which include CRP (C-reactive protein) and adhesion molecules, such as
selectins (P-selectin, E-selectin and L-selectin), ICAM-1 (Intracellular adhesion
molecule-1) and VCAM-1 (vascular cell adhesion molecule-1). Moreover, increased
plasma levels of primary inflammatory cytokine TNF-alpha(Tumour necrosis factor-
alpha), and the secondary inflammatory cytokine IL9Interleukin)-6 as well as ICAM-1,
VCAM-1, E-selectin, vWF(von Willebrand factor) and CRP, have been demonstrated in
patients with hypertension. High levels of inflammatory mediators, particularly IL-6,
ICAM-1 and CRP, may be independent risk factors for the development of hypertension.
They may also be associated with increased risk of diabetes.(Clinical Science (2007) 112,
375-84) Clinicians normally tackle this problem using different combination of drugs. A
6

combination treatment increases the number of mechanisms potentially capable of
reducing an elevated blood pressure, future complications and reduces the rate and
magnitude of the adverse events produced by each drug. Further, the addition of one
agent may counteract some deleterious effect of the other. Additionally, a number of
patients are either nonresponsive to one or more of the available monotherapies. However
it has been observed that even after combining different drugs maintaining the
symptomatic control and preventing its complications for longer period still remains
difficult.
Congestive heart failure (CHF) is a relatively common disorder affecting approximately
five million Americans, with a mortality rate of over 80,000 per year. The prevalence of
CHF has grown to epidemic proportions as the population ages and as cardiologists have
become more successful at reducing mortality from ischemic heart disease, the most
common prelude to CHF. Roughly 4.6 million people in the United States have been
diagnosed with CHF; the incidence of such diagnosis is approaching 10 per 1000 after 65
years of age. Hospitalization for CHF is usually the result of inadequate outpatient
therapy. Hospital discharges for CHF rose from 377,000 (in 1979) to 957,000 (in 1997)
making CHF the most common discharge diagnosis in people age 65 and over. The five-
year mortality from CHF approaches 50% (Levy D. (2002) New Engl J Med.
347(18): 1442-4). Hence, while therapies for heart disease have greatly improved and life
expectancies have extended over the last several years, new and better therapies continue
to be sought, particularly for CHF.
Although, presently used treatments can alleviate symptoms of CHF and correct certain
pathophysiologic abnormalities caused by the disease process, CHF remains a
relentlessly progressive condition with a relatively high rate of mortality. In fact, relative
reductions in morbidity and mortality brought about by existing drugs are on the order of
about 10 to 25 percent. Drug therapies, using known active ingredients such as
vasodilators, angiotensin II receptor antagonists, ACE inhibitors, diuretics,
antithrombolytic agents, p-adrenergic receptor antagonists, a-adrenergic receptor
antagonists, calcium channel blockers, and the like, are available for treating heart failure
and associated diseases.
7

Accumulating evidence indicates that inflammatory mediators are important in the
pathogenesis of chronic heart failure (CHF), contributing to cardiac remodeling and
peripheral vascular disturbances. Several studies have shown increased levels of
inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin
(IL)-lbeta, and IL-6 in patients with CHF in both plasma and circulating leukocytes as
well as in the failing myocardium itself. Importantly, this increase in inflammatory
mediators does not seem to be accompanied by a corresponding increase in anti-
inflammatory cytokines, such as IL-10 and transforming growth factor-beta, resulting in
an inflammatory imbalance in the cytokine network. (Am J Cardiol. 2005 Jun
6;95(11A):17C-23C; discussion 38C-40C) Since heart failure is a clinical syndrome
arising from diverse causes and is accompanied by adverse changes in physiological
function of organs other than the heart, the appropriate selection of therapeutic agents to
yield improvements in cardiovascular morbidity and survival at the various stages of
cardiovascular disease frequently requires the concurrent administration of drugs from
several classes of therapeutic agents, such as ACE inhibitors, angiotensin-receptor
antagonists, beta-blockers, HMG CoA reductase inhibitors (statins), and aldosterone
antagonists.
These diseases are multifactorial having varied etiopathology and thus most of the time
response to monotherapy does not become sufficient and gradually diminishes.
Major advantageous of combination therapy:
1. More than one cause of action can be targeted and thus complimentary actions
can be achieved.
2. Due to synergistic effects of combination low dose of each drug can be
administered as compared to monotherapy.
3. Few side effects due to low individual dose
4. Reduces the possibilities of complications
WO 2006/002983 discloses a pharmaceutical combination comprising an ATI receptor
blocker or pharmaceutically acceptable salts thereof, particularly valsartan and a
8

compound which exhibits advanced glycosylation end product (AGE) breaking activity
(also called AGE breaker)or a pharmaceutically effective salts thereof.
However, in spite of different modalities of available treatment, there exists a need for
better therapeutic approaches, which effectively control the symptoms of these diseases
as well as reduces the possibilities or delay the complications.
R1, R2, R3, X and m of formula (I) are as defined hereinafter.
9
Inventors of present invention have found that the compounds of formula (I) or (II),
which has AGE inhibitory, AGE breaking and free radical scavenging effect, when co
used with the currently available therapy, better symptomatic control can be achieved and
quality of life can be improved which were not observed in the administration of the
respective compounds singly, and they are presently conducting further studies to
accomplish the present invention.



R1, R2, R3, R4, R5, X, Y, A and B of formula (II) as defined hereinafter
Summary of the Invention:
In one embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) at least one therapeutic agent selected from the group
consisting of an antihypertensive agent, an antidiabetic agent, a hypolipidemic agent, an
antiplatelet agent, an antiobesity agent, an antithrombotic agent, an agent for diabetic
vascular complications, an agent for treatment of heart failure or a pharmaceutically
acceptable salts thereof, optionally in presence of a pharmaceutically acceptable carrier.
In a preferred embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) at least one antihypertensive agent.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) one or more antihypertensive agent, wherein said
antihypertensive agent include but not limited to an angiotensin converting enzyme
(ACE) inhibitor, a renin inhibitor, a beta adrenergic receptor blocker, an alpha adrenergic
10

receptor blocker, a calcium channel blocker, a potassium channel activator, an
aldosterone synthase inhibitor, a neutral endopeptidase (NEP) inhibitor, a dual
angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, an
endothelin receptor antagonist, a dual angiotensin and endothelin receptor antagonist
(DARA), a diuretic or a pharmaceutically acceptable salt thereof, optionally in the
presence of a pharmaceutically acceptable carrier.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an angiotensin converting enzyme (ACE) inhibitor or a
pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a renin inhibitor or a pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a beta adrenergic receptor blocker or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an alpha adrenergic blocker or a pharmaceutically acceptable
salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a calcium channel blocker or a pharmaceutically acceptable
salt thereof.
11

In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a potassium channel activator or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a dual angiotensin and endothelin receptor antagonist (DARA)
or a pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an aldosterone synthase inhibitor or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a neutral endopeptidase (NEP) inhibitor or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an endothelin receptor antagonist or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a diuretic or a pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
12

acceptable salt thereof; (b) at least one therapeutic agent selected from the group
consisting of hypolipidemic agent.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) one or more hypolipidemic agent, wherein said hypolipidemic
agent include but not limited to an MTP inhibitor, a HMG CoA reductase inhibitor, a
squalene synthetase inhibitor, a fibric acid derivative, an ACAT inhibitor, lipoxygenase
inhibitors, a cholesterol absorption inhibitor, an ileal Na +/bile acid cotransporter
inhibitor, upregulators of LDL receptor activity, a cholesteryl ester transfer
protein(CETP) inhibitor, a bile acid sequestrant, and/or a nicotinic acid and derivative, or
a pharmaceutically acceptable salt thereof, optionally in the presence of a
pharmaceutically acceptable carrier.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an MTP inhibitor or a pharmaceutically acceptable salt
thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a HMG CoA reductase inhibitor or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (IT) as defined above or a pharmaceutically
acceptable salt thereof; (b) a squalene synthetase inhibitor or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
13

acceptable salt thereof; (b) a fibric acid derivative or a pharmaceutically acceptable salt
thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an ACAT inhibitor or a pharmaceutically acceptable salt
thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a cholesterol absorption inhibitor or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an ileal Na +/bile acid cotransporter inhibitor or a
pharmaceutically acceptable salt thereof.
La a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a cholesteryl ester transfer protein(CETP) inhibitor or a
pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a bile acid sequestrant or a pharmaceutically acceptable salt
thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
14

acceptable salt thereof; (b) a nicotinic acid and its derivative or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) at least one therapeutic agent selected from the group
consisting of antidiabetic agent.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) one or more antidiabetic agent, wherein said antidaibetic agent
include but not limited to a biguanide such as metformin, phenformin, a sulfonylurea
such as gliclazide, an alpha glucosidase inhibitor, a PPARγ agonist such as
thiazolidinediones, a PPARa agonist such as fibric acid derivatives, an alpha-amylase
inhibitor, a fatty acid oxidation inhibitor, an A2 antagonist, a PPAR8 agonist or
antagonist, a PPARa/γ dual agonist, an aP2 inhibitor, a dipeptidyl peptidase IV (DP4)
inhibitor, a SGLT2 inhibitor, a glycogen phosphorylase inhibitor, a glucagon-like
pep tide-1 (GLP-1), a glucokinase activator, a VPAC2 receptor agonist, a FTP-IB (protein
tyrosine phosphatase-lB) inhibitor, an l1-HSD 1 (11 (3-hydroxy-steroid
dehydrogenasel) inhibitor or meglitinide, as well as insulin, or a pharmaceutically
acceptable salt thereof, optionally in the presence of a pharmaceutically acceptable
carrier.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a biguanide or a pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a sulfonylurea or a pharmaceutically acceptable salt thereof.
15

In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an alpha glucosidase inhibitor or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a PPARγ agonist or a pharmaceutically acceptable salt
thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a PPARa agonist or antagonist or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a PPAR8 agonist or antagonist or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a PPARa/γ dual agonist or a pharmaceutically acceptable salt
thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an aP2 inhibitor or a pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
16

acceptable salt thereof; (b) a dipeptidyl peptidase IV (DP4) inhibitor or a
pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a SGLT2 inhibitor or a pharmaceutically acceptable salt
thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a glycogen phosphorylase inhibitor or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a glucagon-like peptide-1 (GLP-1) or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a PTP-1B (protein tyrosine phosphatase-lB) inhibitor or a
pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an 11|3-HSD 1 (11 p-hydroxy-steroid dehydrogenase 1)
inhibitor or a pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a meglitinide or a pharmaceutically acceptable salt thereof.
17

In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (D) as defined above or a pharmaceutically
acceptable salt thereof; (b) at least one therapeutic agent selected from the group
consisting of antiobesity agent.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) one or more antiobesity agent, wherein said antiobesity agent
include but not limited to a 5HT (serotonin) transporter inhibitor, a NE (norepinephrine)
transporter inhibitor, a CB-1 (cannabinoind-1 receptor) antagonist/inverse agonist, a
ghrelin antibody, a ghrelin antagonist, a H3 (histamine H3) antagonist/inverse agonist, , a
NPY1 (neuropeptide Y Yl) antagonist, a NPY2 (neuropeptide Y Y2) agonist, a NPY5
(neuropeptide Y Y5) antagonist, a leptin or its derivative, an opioid antagonist, an orexin
antagonist, a BRS3 (bombesin receptor subtype 3) agonist, a CCK-A (cholecystokinin-A)
agonist, a CNTF (ciliary neurotrophic factor), a CNTF derivative, a GHS (growth
hormone secretagogue receptor) agonist, 5HT2c (serotonin receptor 2c) agonist, a Mc3r
(melanocortin 3 receptor) agonist, a Mc4r (melanocortin 4 receptor) agonist, a
monoamine reuptake inhibitor, a p3 (beta adrenergic receptor 3) agonist, a DGAT1
(diacylglycerol acyltransferase 1) inhibitor, a DGAT2 (diacylglycerol acyltransferase 2)
inhibitor, a FAS (fatty acid synthase) inhibitor, a PDE (phosphodiesterase) inhibitor, a
thyroid hormone (3 agonist, an UCP-1 (uncoupling protein 1), 2,.or 3 activator, an acyl-
estrogen, a glucocorticoid antagonist, a SCD-1 (stearoyl-CoA desaturase-1) inhibitor, a
lipase inhibitor, a fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor, .or
a pharmaceutically acceptable salt thereof, optionally in the presence of a
pharmaceutically acceptable carrier.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a CB-1 (cannabinoind-1 receptor) antagonist/inverse agonist
or a pharmaceutically acceptable salt thereof.
18

In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a Neuropeptide (NPY1/NPY5) antagonist or a
pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a beta.3 adrenergic receptor (beta 3) agonist or a
pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a thyroid hormone beta agonist or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) at least one therapeutic agent selected from the group
consisting of antiplatelet or antithrombotic agent.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) at least one therapeutic agent selected from the group
consisting of agent for diabetic vascular complications.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) one or more agent for diabetic vascular complications,
wherein said agent include but not limited to an aldose reductase inhibitor, an AGE
19

inhibitor or an AGE breaker or a pharmaceutically acceptable salt thereof optionally in
the presence of a pharmaceutically acceptable carrier.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising; (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) at least one therapeutic agent selected from the group
consisting of agent used for the treatment of heart failure.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) one or more agent used for the treatment of heart failure, such
agent include but not limited to a digitalis glycoside, a phosphodiesterase inhibitor or a
pharmaceutically acceptable salt thereof in the presence of a pharmaceutically acceptable
carrier.
In one embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) (i) an antihypertensive agent and (ii) one or more drugs
selected from the group consisting of an antidiabetic or a hypolipidemic or an antiplatelet
or an antithrombotic agent, or a pharmaceutically acceptable salts thereof in the presence
of a pharmaceutically acceptable carrier.
In one embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) (i) an antidiabetic agent and (ii) one more drugs selected from
the group consisting of an antihypertensive or a hypolipidemic or an antiplatelet or an
antithrombotic agent, or a pharmaceutically acceptable salts thereof in the presence of a
pharmaceutically acceptable carrier.
20

In this composition components (a) and (b) can be administered together, one after the
another or separately in one combined unit dosage form or in two separate unit dosage
form. The unit dosage form may also be a fixed combination.
In another embodiment the present invention relates to method of treating or preventing
the disease condition related to diabetes and aging-related vascular complications, such as
diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy
and hypertension by administration of a therapeutically effective amount of any preferred
pharmaceutical composition according to the present invention comprising a compound
of formula (I) or (II) as defined above and at least one therapeutic agent selected from the
group consisting of an antihypertensive agent, an antidiabetics agent, a hypolipidemic
agent, an antiplatelet agent, an antiobesity agent, an antithrombotic agent, an agent for
diabetic vascular complications, an agent for treatment of heart failure or a
pharmaceutically acceptable salts thereof, optionally in the presence of a
pharmaceutically acceptable carrier to a mammal in need thereof.
In another embodiment the invention provides the use of pharmaceutical composition of
the instant invention comprising a compound of formula (I) or (II) as defined above and
at least one therapeutic agent selected from the group consisting of an antihypertensive
agent, an antidiabetic agent, a hypolipidemic agent, an antiplatelet agent, an antiobesity
agent, an antithrombotic agent, an agent for diabetic vascular complications, an agent for
treatment of heart failure or a pharmaceutically acceptable salts thereof, optionally in the
presence of a pharmaceutically acceptable carrier to a mammal in need thereof, to treat or
prevent diabetes and aging-related vascular complications, such as diabetic neuropathy,
diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy or hypertension.
In another embodiment the present invention relates to methods of treating or preventing
the disease condition selected from the group consisting of hypertension, heart failure
such as (acute and chronic) congestive heart failure, left ventricular dysfunction and
hypertrophic cardiomyopathy, diabetic cardiac myopathy, detrimental vascular
remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether
21

unstable or stable), renal insufficiency (diabetic and non- diabetic), renal failure
conditions, such as diabetic nephropathy, by administration of a therapeutically effective
amount of any preferred pharmaceutical composition according to the present invention
comprising a compound of formula (I) or (II) as defined above plus at least one
therapeutic agent selected from the group consisting of an antihypertensive agent, an
antidiabetic agent, a hypolipidemic agent, an antiplatelet agent, an antiobesity agent, an
antithrombotic agent, an agent for diabetic vascular complications, an agent for treatment
of heart failure or a pharmaceutically acceptable salts thereof, optionally in the presence
of a pharmaceutically acceptable carrier to a mammal in need thereof.
In another embodiment the invention provides the use of pharmaceutical composition of
the instant invention comprising a compound of formula (I) or (II) as defined above plus
at least one therapeutic agent selected from the group consisting of an antihypertensive
agent, an antidiabetic agent, a hypolipidemic agent, an antiplatelet agent, an antiobesity
agent, an antithrombotic agent, an agent for diabetic vascular complications, an agent for
treatment of heart failure or a pharmaceutically acceptable salts thereof, optionally in the
presence of a pharmaceutically acceptable carrier to a mammal in need thereof, to treat or
prevent the disease condition selected from the group consisting of hypertension, heart
failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction
and hypertrophic cardiomyopathy, diabetic cardiac myopathy, , detrimental vascular
remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether
unstable or stable), renal insufficiency (diabetic and non- diabetic), renal failure
conditions, such as diabetic nephropathy.
The present invention provides a kit comprising in separate containers in a single package
pharmaceutical compositions comprising in one container a pharmaceutical composition
comprising a compound of formula (I) or (II) as defined above and in a second container
a pharmaceutical composition comprising at least one therapeutic agent selected from the
group consisting of an antihypertensive agent, an antidiabetic agent, a hypolipidemic
agent, an antiplatelet agent, an antiobesity agent, an antithrombotic agent, an agent for
diabetic vascular complications, an agent for treatment of heart failure or a
22

pharmaceutically acceptable salts thereof. The kit form is particularly advantageous when
the separate components must be administered in different dosage forms or are
administered at different dosage intervals.
Detailed Description:
The present invention relates to a combination, such as a combined preparation or
pharmaceutical composition comprising: (a) compound of formula (I) or (II) as defined
above or a pharmaceutically acceptable salt thereof (b) at least one therapeutic agent
selected from the group consisting of an antihypertensive agent, an antidiabetic agent, a
hypolipidemic an agent, antiplatelet agent, an antiobesity agent, an antithrombotic agent,
an agent for diabetic vascular complications, an agent for treatment of heart failure or a
pharmaceutically acceptable salts thereof, optionally in presence of a pharmaceutically
acceptable carrier for separate, simultaneous or sequential use.

wherein
R1 is -R4-R5 or -N(R7) N (R7) R9;
R4, is selected from the group consisting of -N(R7)R6O-, -N(R7)R6N(R7)-, OR6O,
and -OR6N(R7)-, where R6 is alkyl with C2 to C8 carbon atoms; R5 is selected from the
group consisting of alkyl, aryl including heteroaryl, -COR7, SO2R-7, -C(S) NHR7, -
C(NH)NHR7, -COR10,
R7

23

-C(O)NHR7 and -N(R7) N=C
I
R10
where R7 is selected from the group consisting of H, aikyl and aryl including heteroaryl
provided R7 may be the same or different for R1 and R3 in the same compound;
R2 is selected from the group consisting of F, Cl, Br, I, OR7, NO2, alkyl, aryl including
heteroaryl, formyl, acyl, C(O)NR7R10, C(O)OR7, NR7R10, N=C(R7)(R10), SR7, SO2NH2,
SO2 alkyl and SO2aryl,
and m is 0, 1 or 2;
R3 is selected from the group consisting of R7, OR7, N(R7) (R10), N=C(R7) (R10), N(R7)
N(R7) (R10), N(R7) N=C(R7) (R10) and CH(R7)C(O)R8;
where R8 is selected from the group consisting of R7, OR7 and NR7R10;
R9 is selected from the group consisting of hydrogen, alkyl, aryl including heteroaryl,
C(0)R10, -SO2R10, -C(S)NHR10, -C(NH) NH (R1O) and -C(O) NHR10,
R10 is selected for the group consisting of H, alkyl or aryl including heteroaryl and in
each case may be the same or different from substituent R7, provided R10 may be the
same or different for R1 and R3 in the same compound;
X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate
ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite
ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF4" and PF6" or null;
with proviso that,
(i) when two alkyl groups are present on the same carbon or nitrogen, they may be
linked together to form a cyclic structure ;
(ii) the nitrogen of heteroaryl ring of R10, when present, may be quaternized;
(iii) when R3 is OR7 and R1 is -NHNH2 then R7 is not alkyl and
(iv) when R3 is OR7 , R1 is N(R7)(NR7)R9 and R9 is C(O)R10 where
R10 is alkyl, then R7 is not hydrogen.
24

As used herein, "alkyl" refers to an optionally substituted hydrocarbon group joined by
single carbon-carbon bonds and having 1 to 8 carbon atoms joined together. The alkyl
hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. The
substituents are selected from F, Cl, Br, I, N, S,0 and aryl. Preferably, no more than three
substituents are present.
As used herein "aryl" refers to an optionally substituted aromatic group with atleast one
ring having a conjugated pi- electron system, containing upto two conjugated or fused
ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of
which may be optionally substituted. The substituents are selected from F, Cl, Br, I, N, O
and straight chain or branched C1-C6 hydrocarbon.

R1 is alkyl or aryl group;
Y is selected from the group comprising of sulfur, oxygen, nitrogen, or alkylene;
A and B are independently selected from nitrogen, NH, NR6, sulfur, oxygen or carbon to
form heteroaromatic ring system;
R2, R3 and R4 are independently selected from the group consisting of F, Cl, Br, I,
OR7, NO2, alkyl, aryl including heteroaryl, formyl, acyl, C(O)NR6R7, C(0)0R6, NR6R7,
N=C(R6)(R7), SR6, S02NH2, SO2alkyl, SO2aryl; R2, R3 and R4 might be optionally joined
together to form a ring system;
R5 is independently selected for the group consisting of alkyl, aryl and null;
25

R6 is independently selected from the group consisting of H, alkyl and aryl including
heteroaryl provided R6 might be different for R2, R3 and R4 in the same compound;
R7 is independently selected from the group consisting of H, alkyl and aryl including
heteroaryl and in each case optionally different from substituent R6, provided R7 might be
different for R2, R3 and R4 in the same compound;
X is selected from group consisting of a halide ion, acetate ion, perchlorate ion, sulfonate
ion, oxalate ion, citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite
ion, phosphoric hydrogenion; phosphonate ion, phosphate ion, BF4, PF6 and null;
with proviso that when two alkyl groups are present on the same carbon or nitrogen, they
are optionally linked together to form a cyclic structure.
As used herein, "alkyl" refers to an optionally substituted hydrocarbon group joined by
single carbon-carbon bonds and having 1 to 8 carbon atoms joined to gather. The alkyl
hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. The
substituents are selected from F, Cl, Br,I, N, S,0 and aryl. Preferably, no more than three
substituents are present.
As used herein "aryl" refers to an optionally substituted aromatic group with atleast one
ring having a conjugated pi-electron system, containing upto two conjugated or fused
ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of
which may be optionally substituted. The substituents are selected from F, Cl, Br, I, N, S,
O and straight chain or branched C1-C6 hydrocarbon.
The following list of compounds provides representative compounds of the general
formula (I) and (II):
l-(2-ethoxy -2- oxoethyl) -4-(phenylsulfonyl hydrazino carbonyl) pyridinium bromide
(compound 1);
l-(2-phenylamino-2-oxoethyl)-4- (phenylsulfonyl hydrazino carbonyl) pyridinium
chloride (compound 2);
l-(2-ethoxy -2- oxoethyl) -3-(phenylsulfonyl hydrazino carbonyl) pyridinium bromide
(compound 3);
26

l-(2-(2' ,4dichlorophenyl)-2-oxoethyl)-3-(2(methoxy)ethyloxycarbonyl) pyridinium
bromide (Compound 4);
l-(2-phenylamino-2-oxoethyl)-3-((benzoyloxy)ethylaminocarbonyl) pyridinium chloride
(compound 5);
l-(2-thien-2'-yl- 2-oxoethyl)-3-(phenylaminocarbonyl hydrazinocarbonyl)pyridinium
bromide (compound 6);
l-(2-phenyl-2-oxoethyl)~3-(2-(acetoxy)ethylaminocarbonyl) pyridinium bromide
(compound 7);
l-(2-phenylamino-2-oxoethyl)-3-(phenyl sulfonyl hydrazino carbonyl) pyridinium
chloride (compound 8);
l-(2-phenylamino-2-oxoethyl)-3-((4-methylphenyl) sulfonyl hydrazino
carbonyl)pyridinium chloride (compound 9);
l-(2-phenyl-2-oxoethyl)-3-(2-(benzoyloxy)ethyloxy carbonyl) pyridinium bromide
(compound 10);
l-(2-thien-2'-yl-2-oxoethyl)-3-(phenylcarbonyl hydrazino carbonyl) pyridinium bromide
(compound 11);
1 -(2-ethoxy-2-oxoethyl)-3-((phenylmethyl)sulfonyl hydrazino carbonyl)pyridinium
bromide (compound 12);
l-(2-phenyl-2-oxoethyl)-3-((phenylmethyl)sulfonyl hydrazino carbonyl) pyridinium
bromide (compound 13);
N, N' - bis [3-carbonyl-l-(2-furan-2'-yl-2-oxoethyl) pyridinium] hydrazine dibromide.
(Compound No: 14);
N, N'-bis [3-carbonyl-l- (2-thien-2'-yl-2-oxoethyl) pyridinium] hydrazine
dichloride.(Compound No: 15);
1 -(2-thien-2'-yl-2-oxoethyl)-3-((2-( 1 -oxo-3-cyclohexyl)-propyl)-hydrazino carbonyl)-
pyridinium bromide.( Compound No: 16);
l-(2-phenylamino-2-oxo ethyl)-3-({2-(l-oxo-3-cyclohexyl)-propyl}-hydrazino-
carbonyl}-pyridinium bromide. (Compound No: 17);
l-(2-thien-2'-yl-2-oxoethyl)-3-[2-(benzoyloxy)ethylamino carbonyl]-pyridinium bromide
(Compound No: 18);
1 -(4-ethoxy-2, 4-dioxobutyl)-3-(2-(benzoyloxy)ethylamino carbonyl)-pyridinium
chloride. (Compound No: 19);
l-(2' , 4'-dichloro-phenyl-2-oxoethyl)-3-(2-methoxyethyl aminocarbonyl)-pyridinium
bromide. (Compound No: 20);
N,N'-bis-[3-carbonyl- l-(2-cyclopropylamino-2-oxoethyl) pyridinium] hydrazine
dichloride. (Compound No: 21);
l-(2-cyclopropylamino-2-oxoethyl)-3-(2-methoxyethylaminocarbonyl)-pyridinium
chloride. (Compound No: 22);
N-N'-bis [3-carbonyl-l-(2-isopropylamino-2-oxoethyl) pyridinium] hydrazine dichloride.
(Compound No: 23);
1 -(2-thien-2' yE-oxoethyl)-3-(2-(2-chloro-3-pyridoylhydrazinocarbonyl) -pyridinium
chloride. (Compound No: 24);
l-(2-isopropylamino-2-oxoethyl)-3-(2-methylsulfonylhydrazinocarbonyl) -pyridinium
chloride. (Compound No: 25);
l-(2-(l-pyrrolidinyl)-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl) pyridinium
chloride.(Compound No: 26);
27

l-(2-thien-2'-yl-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl) pyridinium
chloride. (Compound No: 27);
N,N'-bis[3-carbonyl-l-(2-hydroxy-2-oxoethyl)pyridinium]hydrazine dichloride
(Compound No: 28);
l-(2-thien-2'-yl-2-oxoethyl)-3-((2-methoxy ethyl) ammo carbonyl)-5-bromo pyridinium
chloride (Compound No: 29);
l-(2'-thien-2'-yl-2-oxoethyl)-3-[l-oxo-l-(2-methoxy carbonyl)pyridyl] hydrazino
pyridinium chloride. (Compound No: 30);
l-[l-(2-thien-2'-yl-2-oxoethyl)-6-methyl-3-carbonyl pyridinium]-2-[l-(2-Thien-2'-yl-2-
oxoethyl )-3-carbonyl pyridinium ] hydrazine dichloride(compound no: 31);
l-(2-thien-2'-yl-2-oxoethyl)-3-(isopropylsulfonyl hydrazino carbonyl) pyridinium
bromide(compound no: 32);
l-(2-(4-benzyl piperidin-l-yl)-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl)
pyridinium chloride(compound no: 33);
l-(2-(2-ethoxy carbonyl pyrrolidin-l-yl)-2-oxoethyl)-3-(methanesulfonyl hydrazino
carbonyl) pyridinium chloride, (compound no: 34);
l-(2-mien-2'-yl-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl )-5-bromo
pyridinium bromide, (compound no: 35);
l-(2-thien-2'-yl-2-oxoethyl)-3-(ethoxycarbonyl hydrazino carbonyl) pyridinium bromide.
(compound no: 36);
l-(2-(5-chloro-thien-2-yl)-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl )
pyridinium bromide (compound no: 37);
N,N'-bis[3-carbonyl-l-(2-(4-nitro-thien-2-yl)-2-oxoethyl)pyridinium] hydrazine
dichloride. (compound no: 38);
l-(2-thien-2'-yl-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl ) -6-methyl
pyridinium bromide, (compound no: 39);
N,N'-bis[3-carbonyl-1 -(2-(5-methyl-thien-2-yl)-2-oxoethyl) pyridinium] hydrazine
dichloride. (compound no: 40);
N,N'-bis[3-carbonyl-l-(2-(2-ethoxycarbonyl pyrrolidin-l-yl)-2-oxoethyl) pyridinium]
hydrazine dichloride. (compound no: 41);
l-[l-(2-thien-2'-yl-2-oxoethyl)-5-aminocarbonyl-3-carbonyl pyridinium]-2-[l-(2-Thien-
2'-yl-2-oxoethyl )-3-carbonyl pyridinium] hydrazine dichloride (compound no: 42);
l-(2-(4-carbethoxy-thiazolidin-3-yl)-2oxoethyl)-3-(methanesulfonyl hydrazino carbonyl)
pyridinium chloride (compound no: 43);
N,N'-bis[3-carbonyl-l-(2-(5-chloro-thien-2-yl)-2-oxoethyl) pyridinium] hydrazine
dichloride. (compound no: 44);
l-(2-(5-methyl-thien-2-yl)-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl)
pyridinium chloride (compound no: 45);
l-(2-(4-nitro-thien-2-yl)-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl )
pyridinium bromide, (compound no: 46);
l-(2-phenylamino-2-oxoethyl)-3-(phenyl hydrazino carbonyl) pyridinium chloride
(compound no: 47);
l-(2-phenylamino-2-oxoethyl)-4 -[2-(benzoyloxy) ethylamino carbonyl ] pyridinium
chloride (compound no: 48);
l-2-(5-nitxo-thien-2-yl)-2-oxoethyl)-3-(methanesulfonyl hydrazino carbonyl) pyridinium
chloride (compound no: 49);
28

l-(2-thien-2'-yl-2-oxoethyl)-3-(trifluoromethanesulfonyl hydrazino carbonyl)
pyridinium bromide, (compound no. 50);
l-(2-thien-2'-yl-2-oxoethyl)-3-(phenyl hydrazino carbonyl) pyridinium bromide
(compound no.51);
l-(2-thien-2'-yl-2-oxoethyl)-3-(p-methoxy phenyl sulfonyl hydrazino carbonyl)
pyridinium bromide (compound no. 52);
l-(2-ethoxy-2-oxoethyl)-3-(phenyl aminocarbonyl hydrazino carbonyl ) pyridinium
bromide (compound no. 53);
l-(2-ethoxy-2-oxoethyl)-3-(p-toluene sulfonyl hydrazino carbonyl ) pyridinium bromide
(compound no. 54);
l-(2-phenyl-2-oxoethyl)-3-(phenylamino carbonyl hydrazino carbonyl ) pyridinium
bromide (compound no. 55);
l-(2-phenylamino-2-oxoethyl)-3-(benzyl sulfonyl hydrazino carbonyl)
pyridiniumchloride. (compound no. 56);
l-(2-phenyl-2-oxoethyl)-4-(methanesulfonyl hydrazino carbonyl ) pyridinium bromide
(compound no. 57);
l-(2-phenyl-2-oxoethyl)-3-(phenyl hydrazino carbonyl) pyridinium bromide, (compound
no. 58);
l-(2-ethoxy-2-oxoethyl)-4-[2-(benzoyloxy) ethyl amino carbonyl ] pyridinium bromide
(compound no. 59);
l-(2-ethoxy-2-oxoethyl)-3-(phenyl hydrazino carbonyl ) pyridinium bromide.(compound
no. 60);
l-(2-phenyl-2-oxoethyl)-3-(p-methoxyphenyl sulfonyl hydrazino carbonyl ) pyridinium
bromide, (compound no. 61);
l-(2-phenyl-2-oxoethyl)- 4-[2-(benzoyloxy) ethyl amino carbonyl ] pyridinium bromide,
(compound no. 62);
l-(2-ethoxy-2-oxoethyl)- 4-(p-methanesulfonyl hydrazino carbonyl ) pyridinium
bromide, (compound no. 63);
N, N'-Bis [3-carbonyl-l- (2-phenyl-2-oxoethyl)-pyridinium] hydrazine dibromide
(compound 64);
N, N'-Bis [3-carbonyl-l -(2-ethoxy-2-oxoethyl) pyridinium] hydrazine dibromide
(compound 65);
N, N'-Bis [3-carbonyl-l- (2- (2, 4-dichlorophenyl)-2-oxoethyl) pyridinium] hydrazine
dibromide (compound 66);
1- (2-Ethoxy-2-oxoethyl)-3- (2- (2-pyridyl) hydrazinocarbonyl) pyridinium bromide
(compound 67);
1- (2-Thien-2'-yl-2-oxoethyl)-3- (methanesulfonyl hydrazinocarbonyl) pyridinium
bromide (compound 68);
N, N'-Bis [3-carbonyl-l- (2-thien-2'-yl-2-oxoethyl) pyridinium] hydrazine dibromide
(compound 69);
1- (2-Ethoxy-2-oxoethyl)-3- (2- (benzoyloxy) ethylaminocarbonyl) pyridinium bromide
(compound 70);
1- (2- (2,4-Dichlorophenyl)-2-oxoethyl)-3- (2-(benzoyloxy) ethylamino- carbonyl)
pyridinium bromide (compound 71);
1- (2-Thien-2'-yl-2-oxoethyl)-3- (2- (2-pyridyl) hydrazinocarbonyl) pyridinium bromide
(compound 72);
29

1- (2-Phenyl-2-oxoethyl)-3- (2- (2-pyridyl) hydrazinocarbonyl) pyridinium bromide
(compound 73);
1- (2-Phenyl-2-oxoethyl)-3- (hydrazinocarbonyl) pyridinium bromide (compound 74);
1- (2- Phenyl-2-oxoethyl)-3- (methanesulfonyl hydrazinocarbonyl) pyridinium bromide
(compound 75);
1- (2-Ethoxy-2-oxoethyl)-3- (methanesulfonyl hydrazinocarbonyl) pyridinium bromide
(compound 76);
1- (2-Phenyl-2-oxoethyl)-3- (phenylsulfonylhydrazino carbonyl) pyridinium bromide
(compound 77);
1- (2-Phenyl-2-oxoethyl)-2-chloro-3- (phenylsulfonylhydrazino carbonyl) pyridinium
bromide (compound 78);
1- (2- Phenyl-2-oxoethyl)-3- (2- (methoxy) carbonyl) ethyloxy carbonyl pyridinium
bromide (compound 79);
1- (2-Ethoxy-2-oxoethyl)-3- (2- (benzoyloxy) ethyloxy carbonyl) pyridinium bromide
(compound 80);
l-(2-Thien-2'-yl-2-oxoethyl)-4-(2-(benzoyloxy) ethylaminocarbonyl) pyridinium bromide
(compound 81);
1- (2-thien-2'-yl-2-oxoethyl)-3- [ (3-phenyl methyl)pyrazol-5-yl] pyridinium bromide
(compound 82);
l-(2-thien-2'-yl-2-oxoethyl)-3-[(3-phenyl methyl) oxazol-5-yl pyridinium bromide
(compound 83);
l-(2-thien-2'-yl-2-oxoethyl)-3-[3-{ l-(2-thien-2'-yl)-2-oxoethyl pyridinium-4 thio}
methyl-pyrazol-5-yl] pyridinium dibromide. (compound 84);
1- (2-thien-2'-yl-2-oxoethyl)-3- [3- f 1- (3, 5-dimethylpyrazol-l-yl) methyl) pyrazol-5-yl]
pyridinium bromide, (compound 85);
1- (2-thien-2'-yl-2-oxoethyl)-3- [3-phenylmethyl}-l- {2-pyridyl}-pyrazol-5-yl] -
pyridinium bromide, (compound 86);
1- (2-thien-2'-yl-2-oxoethyl)-3- [3 (3, 5-dimethylpyrazol-l-yl) methyl-1-pyridyl}
pyrazol-5-yl] pyridinium bromide, (compound 87);
1- [2- (cyclopropylamino)- 2-oxoethyl] 3- [3- (3, 5-dimethylpyrazol-l-yl) methyl}-
pyrazol-5-yl]-pyridinium bromide, (compound 88);
1- {2-(4-nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-l-yl) methyl} pyrazol-
5-yl]-pyridinium bromide, (compound 89);
1- (2-cyclopropylamino-2-oxoethyl)-3 [ (3-phenylmethyl) pyrazol-5-yl] pyridinium
chloride, (compound 90);
3,5-bis-[l-(2-thien-2'-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazole dibromide.
(compound 91);
l-(2-thien-2'-yl-2-oxoethyl)-3-l (l-phenyl-3-phenylmethyl) pyrazol-5-yl] pyridinium
chloride, (compound 92);
l-(2-(5'-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylmethyl) pyrazol-5-yl] pyridinium
chloride, (compound 93);
1- (2-thien-2'-yl-2-oxoethyl) 3- [1-phenyl, 3- { (3, 5-dimethyl pyrazol-1-yl) methyl)}
pyrazol-5-yl]-pyridinium chloride, (compound 94);
1- (2-phenyl-2-oxoethyl)-3- [ (3-phenylmethyl) pyrazol-5-yl]-pyridinium bromide,
(compound 95);
30

1- (2-cyclopropylamino- 2-oxoethyl) 3- [ (l-phenyl-3-phenylmethyl) pyrazol-5 yl]-
pyridinium chloride (compound 96);
1- (2- (4-benzyl-l-piperidinyl)-2-oxoethyl) 3- [ (3-phenoxymethyl) pyrazol-5-yl]
pyridinium bromide (compound 97);
1 (2-phenyl-2-oxoethyl)-3-[(3-(3, 5-dimethylpyrazol-l-yl) methyl) pyrazol-5 yl]-
pyridinium chloride (compound 98);
l-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3, 5-dimethylpyrazol-l-yl) methyl).
pyrazol-5-yl] pyridinium chloride (compound 99);
1- (2-phenyl-2-oxoethyl)-3- [ (l-phenyl-3-phenylmethyl) pyrazol-5-yl] pyridinium
chloride (compound 100);
1- (2- (5-methyl-2-thienyl)-2-oxoethyl)-3- [ (3 (2-cyclohexyl ethyl) pyrazol-5-yl]
pyridinium chloride (compound 101);
1- (2-cyclopropylamino-2-oxoethyl)-3- [ (3- (2-cyclohexylethyl) pyrazol-5-yl]
pyridinium chloride (compound 102);
1- (2-phenyl-2-oxoethyl)-3- [ (3- (2-cyclohexylethyl) pyrazol-5-yl] pyridinium chloride
(compound 103);
1- (2-cyclopropylamino-2-oxoethyl)-3- [ (l-cyclohexyl-3-phenylmethyl) pyrazol
5-yl] pyridinium chloride (compound 104);
1- (2-thien-2'-yl-2-oxoethyl)-3- [ (3-phenoxymethyl) pyrazol-5-yl] pyridinium chloride
(compound 105);
1- [2- (l-adamantylamino)-2-oxoethyl]-3- [ (3-phenylmethyl) pyrazol-5-yl] pyridinium
chloride (compound 106);
1- (2-phenyl-2-oxoethyl)-3- [ {3- (3, 5-dimethylpyrazol-l-yl) methyl)} 1-phenyl-
pyrazol-5-yl] pyridinium bromide (compound 107);
l-(2-(4-nitor-2-thienyl)-2-oxoethyl)-3-[(l-cyclohexyl-3-(3,5-dimethylpyrazol-l yl)-
methyl) pyrazol-5-yl] pyridinium bromide (compound 108);
1- (2- (4-nitro-2-thienyl)-2-oxoethyl)-3 [ (3- (2-cyclohexylethyl) pyrazol-5-yl]
pyridinium bromide (compound 109);
l-(2-thien-2'-yl-2-oxoethyl)-3-[(l-phenyl-3-phenoxymethyl) pyrazol-5-yl] pyridinium
chloride (compound 110);
1- (2- (4-nitro-2-thienyl)-2-oxoethyl)-3- [ (l-phenyl-3-phenylmethyl) pyrazol-5 yl]
pyridinium bromide (compound 111);
pyrazolel- (2-cyclopropylamino-2-oxoethyl)-3- [ (3-phenoxymethyl) pyrazol-5-yl]
pyridinium chloride (compound 112);
1- (2-cyclopropylamino-2-oxoethyl)-3- [ (l-cyclohexyl-3- (3, 5-dimethyl pyrazole) - 1-
yl)-5-yl] pyridinium chloride (compound 113);
1- (2- (5-chloro-2-thienyl)-2-oxoethyl)-3- [ (3-phenoxymethyl) pyrazol-5-yl] pyridinium
bromide (compound 114);
l-(2-phenyl-2-oxoethyl)-3-[(l-phenyl-3-phenoxyrnethyl) pyrazol-5-yl] pyridinium
chloride (compound 115);
1- (2-thien-2'-yl-2-oxoethyl)-3- [ (l-cyclohexyl-3- (3, 5-dimethylpyrazol-l-yl- methyl)
pyrazol-5-yl] pyridinium chloride (compound 116);
1- (2-cyclopropylamino-2-oxoethyl)-3- [ (l-phenyl-3-phenoxymethyl) pyrazol-5 yl]
pyridinium bromide (compound 117);
1- (2-thien-2'-yl-2-oxoethyl)-3- [ (l-phenyl-3- (2-cyclohexylethyl)pyrazol-5-yl]
pyridinium bromide (compound 118);
31

l-(2-thien-2'-yl-2-oxoethyl)-3-[(l-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl] pyridinium
chloride (compound 119);
3- [ (3-phenylmethyl) pyrazol-5-yl] pyridine hydrochloride (compound 120);
3- [ (3-phenoxymethyl) pyrazol-5-yl] pyridine hydrochloride (compound 121);
3- [ (3, 5-dimethylpyrazol-l-yl-methyl) pyrazol-5-yl] pyridine (compound 122);
3- [3- (2-cyclohexyl-ethyl)-pyrazol-5-yl] pyridine (compound 123);
1- (2-napthyl-2-oxo ethyl)-3 [ (3-phenoxymethyl) pyrazol-5-yl] pyridinium bromide
(compound 124);
1- (phenylmethyl)-3 [ (3-phenyl methyl)pyrazol-5-yl] pyridinium chloride (compound
125);
l-(2-thien-2'-yl-2-oxo ethyl)-3[ (3 (-1-naphthyl) pyrazol-5-yl] pyridinium chloride
(compound 126);
1- (2-phenyl-2oxoethyl)-3 [3 (thienyl-2-yl-methyl)pyrazol-5-yl] pyridinium chloride
(compound 127);
1- (2- (5-methyl-2-thienyl)-2-oxoethyl)-3- [3 (2-phenyl ethyl) pyrazol-5 yl] pyridinium
chloride (compound 128);
1- (2- (5-methyl 2-thienyl)-2-oxo ethyl)-3- [3- (3-phenoxy propyl) pyrazol-5 yl]
pyridinium chloride (compound 129);
1- (isopropyl)-3 [ (3-phenylmethyl) pyrazol-5-yl] pyridinium bromide (compound 130);
1- (2- (5-methyl-2-thienyl)-2-oxoethyl)-3- [ (3-thiophenylmethyl) pyrazol-5 yl]
pyridinium chloride (compound 131);
1- (2-thien-2'-yl-2-oxoethyl)-3 [ (3- (N-methyl-indole-3-yl methyl) pyrazol-5 yl]
pyridinium chloride (compound 132);
1- (2-napthyl-2-oxo-ethyl)-3 [ (3-methyl) pyrazol-5-yl] pyridinium bromide (compound
133);
1- (2- (1, 4 benzodioxane-6-yl-amino-2-oxoethyl)-3 [ (3-phenylmethyl) pyrazol-5-yl]
pyridinium chloride (compound 134);
1- (2-thien-2'-yl-2-oxo. ethyl)-3[ (3-phenyl) pyrazol-5-yl]-5 bromo pyridinium chloride
(compound 135);
1- (2-thien-2'-yl)-2-oxoethyl)-3 [ (3-phenyl) pyrazol-5-yl] quinolinium chloride
(compound 136) and
3- [ (3-phenyl) pyrazol-5-yl)] quinoline (compound 137).
In a preferred embodiment the present invention relates to pharmaceutical compositions
which comprise in combination compound no. 27 or 68 or a pharmaceutically acceptable
salts thereof and at least one therapeutic agent selected from the group consisting of an
antihypertensive agent, an antidiabetic agent, a hypolipidemic agent, an antiplatelet agent,
an antiobesity agent, an antithrombotic agent, an agent for diabetic vascular
complications, an agent for treatment of heart failure or a pharmaceutically acceptable
salts thereof. More preferably composition comprises in combination compound no. 27 or
a pharmaceutically acceptable salts thereof and at least one therapeutic agent selected
from the group consisting of metformin, pioglitazone. amlodipine, ramipril, atorvastatin,
32

simvastatin, nicorandil, indapamide, clopidogrel and hydrochlorothiazide or
pharmaceutically acceptable salts thereof.
The antihypertensive agent, as mentioned herein, includes but not limited to an
angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, a beta adrenergic
receptor blocker, an alpha adrenergic receptor blocker, a calcium channel blocker, a
potassium channel activator, an aldosterone synthase inhibitor, a neutral endopeptidase
(NEP) inhibitor, a dual angiotensin converting enzyme/neutral endopeptidase
(ACE/NEP) inhibitor, an endothelin receptor antagonist, a dual angiotensin and
endothelin receptor antagonist (DARA), a diuretic or a pharmaceutically acceptable salt
thereof.
The interruption of the enzymatic degradation of angiotensin I to angiotensin II with so-
called ACE-inhibitors is a successful variant for the regulation of blood pressure and also
a therapeutic method for the treatment of congestive heart failure.
Numerous ACE inhibitors have been synthesized. Most of these compounds can be
classified into three groups based on their chemical structure: (1) sulfhydryl-(also called
mercapto-) containing ACE inhibitors, including captopril and agents that are structurally
related to captopril, such as fentiapril, pivalopril, zofenopril and alacepril; (2) dicarboxyl-
containing ACE inhibitors, including enalapril and agents that are structurally related to
enalapril, such as lisinopril, benazepril, quinapril, moexipril, ramipril, spirapril,
perindopril, indolapril, pentopril, indalapril and cilazapril; and (3) phosphorus-containing
ACE inhibitors, structurally related to fosinopril.
Representative ACE inhibitors are captopril, cilazapril, delapril, enalapril, enalaprilat,
fentiapril, fosinopril, indolapril, libenzapril, rentiapril, zabicipril, moveltipril, spiraprilat,
lisinopril, perindopril, pivopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril;
particularly preferred are captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril,
and trandolapril; or in each case, a pharmaceutically acceptable salt thereof. Preferred
33

ACE inhibitors are those agents that have been marketed, most preferred are benazepril,
ramipril, lisinopril, enalapril or a pharmaceutically acceptable salt thereof.
Renin released from the kidney cleaves angiotensinogen in the circulation to form the
decapeptide angiotensin I. This is in turn cleaved by angiotensin converting enzyme in
the lungs, kidneys and other organs to form the octapeptide angiotensin II, which
increases blood pressure both directly by arterial vasoconstriction and indirectly by
liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone,
accompanied by an increase in extracellular fluid volume. Inhibitors of the enzymatic
activity of renin bring about a reduction in the formation of angiotensin I. As a result a
smaller amount of angiotensin II is produced. The reduced concentration of that active
peptide hormone is the direct cause of e.g. the antihypertensive effect of renin inhibitors.
Accordingly, renin inhibitors or salts thereof can be employed e.g. as antihypertensives or
for treating congestive heart failure.
The class of renin inhibitor comprises compounds having differing structural features.
For example, mention may be made of compounds which are selected from the group
comprising of Aliskiren, ditekiren (chemical name: [1S-[1R*,2R*,4R*(1R*,2R*)]]-1-
[(1,1 -dimethylethoxy)carbonyl]-L-proly I-L-phenylalanyl-N-[2-hydroxy-5-methyl-1 -(2-
methylpropyl)-4-[[[2-methyl-l- -[[(2-pyridinylmrthyl)amino]carbonyl]butyl] amino]
carbonyl] hexyl]-N-alfa-me- thyl-L-histidinamide), terlakiren (chemical name: [R-
(R*,S*)]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[l-(cyclohexy Imethyl)-2-
hydroxy-3-(l -methylethoxy)-3-oxopropyl]-S-methyl-L-cysteineami- de), zankiren
(chemical name: tlS-[lR*[R*(R*)],2S*,3R*]]-N-[l-(cyclohexylmethyl)-2,3-dihydroxy-
5 -methylhexyl] -alfa- [ [2- [[(4-methyl-1 -piperazinyl)sulfonyl]methyl] -1 -oxo-3-
phenylpropyl] amino]- 4thiazolepropanamide), RO 66-1132, RO-66-1168 or in each case,
a pharmaceutically acceptable salt thereof.
Especially preferred is the compound of formula chemically defined as
2(S),4(S),5(S),7(S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(l-methyle- thyl)-4-
hydroxy-5-amino-8-[4-methoxy-3(3-methoxy-propoxy)phenyl]-octanamid- e (generic
34

name: aliskiren), or a pharmaceutically acceptable salt, especially the hemi-fumarate,
thereof.
The beta adrenergic receptor blocker in said combination comprises selective or
nonselective beta blocker, preferably is a representative selected from the group
comprising of a selective beta.l-blockers, such as atenolol, bisoprolol, metoprolol,
esmolol, celiprolol, betaxololor taliprolol or a non-selective .beta.-blocker, such as
oxprenolol, pindolol, propranolol, timolol, bupranolol, penbutolol, mepindolol, carteolol
or nadolol, or a .beta.-blockers possessing also .alpha.-blocking activity such as
carvedilol or labetalol, or in each case, a pharmaceutically acceptable salt thereof.
The alpha 1 adrenergic receptor blocker in said combination preferably is a representative
selected from the group consisting of doxazosin, prazosin, terazosin or in each case, a
pharmaceutically acceptable salt thereof.
The class of calcium channel blocker (CCBs) essentially comprises dihydropyridines
(DHPs) and non-DHPs such as diltiazem-type and verapamil-type CCBs. A CCB useful
in said combination is preferably a DHP representative selected from the group
comprising of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine,
nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine,
and is preferably a non-DHP representative selected from the group comprising of
flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil
and verapamil, and in each case, a pharmaceutically acceptable salt thereof.
Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine,
nimodipine, nisoldipine, nitrendipine, and verapamil, or pharmaceutically acceptable salt
thereof. An especially preferred DHP is amlodipine or a pharmaceutically acceptable salt,
especially the besylate. An especially preferred representative of non-DHPs is diltiazem
or verapamil or a pharmaceutically acceptable salt, especially the hydrochloride.
35

Aldosterone synthase is an enzyme that converts corticosterone to aldosterone by
hydroxylating corticosterone to form 18-OH-corticosterone and 18-OH-corticosterone to
aldosterone. The term "aldosterone synthase inhibitor" denotes a compound that directly
or indirectly reduces or stops the synthesis or activity of aldosterone. The class of
aldosterone synthase inhibitors is known to be applied for the treatment of hypertension
and primary aldosteronism comprises both steroidal and non-steroidal aldosterone
synthase inhibitors, the later being most preferred.
Preference is given to commercially available aldosterone synthase inhibitors or those
aldosterone synthase inhibitors that have been approved by the health authorities.
Exemplary aldosterone synthase inhibitor of the present invention include without
limitation: Aromatase inhibitors such as R-76713, R-83842, CGS-16949A (fadrozole),
CGS-20267 (letrozole), CGS-20267, aminoglutethamide, CGS-47645, ICI-D-1033,
chromone & xanthone derivatives, and YM-511; 12-Lipoxygenase inhibitors such as
PDGF, TNF, IL-1, IL-1 beta, BW755c, phenidone, baicalein, aminoguanidine,
nordihydroguaiaretic acid (NDGA), cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate
(CDC), panaxynol, pioglitazone, and mRNA cleaving ribozyme; P450 lip inhibitors
such as 18-vinylprogesterone, and 18-ethynylprogesterone, fatty acids such as oleic acid;
18-vinyldeoxycorticosterone, ketoconazole, clotrimazole, miconazole, etomidate,
spironolactone, and 23-0586; Atrial natriuretic factors such as ANP, ANF and ANF
fragments; 17, 20 Lysase inhibitors such as YM-55208, and YM-53789; Prostaglandin
synthesis inhibitors such as indomethacin, meclofenamate, aminoglutethamide, and
aspirin; PKC inhibitors such as sphingosine, retinal, H-7, staurosporine, and
trifluoperazine; Benzodiazepines such as diazepam and midazolam; Calcium blockers
such as amlodipine, and mibefradil; Diacylglycerol lipase inhibitors such as RHC-80267
[l,6-bis-(cyclohexyloximinocarbonylamino)-hexane]; Potasium ionophores such as
valinomycin, and cromakalim; Electron transport blockers (metabolic inhibitors) such as
antimycm A, cyanide, rotenone, and amytal; Dopamine (prolactin inhibiting hormone),
Chlorbutol, 18-ethynyl-ll-deoxycorticosterone (18-EtDOC); and ethanol.
36

The terms "aldosterone antagonist" and "aldosterone receptor antagonist" denote a
compound capable of binding to an aldosterone receptor, as a competitive inhibitor of the
action of aldosterone itself at the receptor site, so as to modulate the receptor-mediated
activity of aldosterone. Such compounds are also contemplated in the present invention.
Certain compounds, for example 11 p-Hydroxy androst-4-en-3-one 17-spirolactone, act
as both an aldosterone synthase inhibitor and as an aldosterone receptor antagonist. Such
compounds are also contemplated in the present invention
The natriuretic peptides constitute a family of peptides that include the atrial (ANP),
brain-derived (BNP) and C-type natriuretic (CNP) peptides. The natriuretic peptides
affect vasodilation, natriuresis, diuresis, decreased aldosterone release, decreased cell
growth, and inhibition of the sympathetic nervous system and the renin-angiotensin-
aldosterone system indicating their involvement in the regulation of blood pressure and of
sodium and water balance. Neutral endopeptidase 24.11 (NEP) inhibitors impede
degradation of natriuretic peptides and elicit pharmacological actions potentially
beneficial in the management of several cardiovascular disorders. NEP inhibitor useful in
the said combination is an agent selected from the group represented by candoxatril,
sinorphan, SCH 34826 and SCH 42495.
Compounds having inhibitory effects on both angiotensin converting enzyme and neutral
endopetidase, so-called dual ACE/NEP inhibitors, can be used for the treatment of
cardiovascular pathologies. A preferred dual angiotensin converting enzyme/neutral
endopetidase (ACE/NEP) inhibitor is, for example, omapatrilat, fasidotril, fasidotrilat,
Z13752A or a pharmaceutically acceptable salt thereof.
Compounds having dual angiotensin and endothelin receptor antagonist (DARA) action
can be used for the treatment of cardiovascular pathologies. A preferred compound is
PS433540 and compound disclosed in international publication WO/2007/100295
Endothelin (ET) is a highly potent vasoconstrictor peptide synthesized and released by
the vascular endothelium. Endothelin (ET) exists in three isoforms (ET-1, ET-2 and ET-
37

3). (ET shall mean any or all of the isoforms of ET). Elevated levels of ET have been
reported in plasma from patients with essential hypertension. Endothelin receptor
antagonists can be used to inhibit the vasoconstrictive effects induced by ET.
The preferred endothelin antagonists are, for example, bosentan, enrasentan, atrasentan,
especially atrasentan hydrochloride, darusentan, BMS 193884, sitaxsentan, especially
sitaxsentan sodium, YM 598, S 0139, J 104132, furthermore, tezosentan, or in each case,
a pharmaceutically acceptable salt thereof.
The diuretic in this composition is selected from the group comprising of
hydrochlorothiazide (HCTZ), furosemide, altizide, trichlormethazide, triflumethazide,
bemetizide, cyclothiazide, methylchlothiazide, azosemide, chlorothiazide, butizide,
bendroflumethazide, cyclopenthiazide, benzclortriazide, polythiazide, hydroflumethazide,
benzthiazide, ethiazide, penflutazide, chlorthalidone, butazolimide, spironolactone,
amiloride and triamterene. Preferred diuretic for incorporation in this invention are
hydrochlorothiazide, trichlormethazide, furosemide, chlorthalidone, and altizide,
especially hydrochlorothiazide.
The hypolipidemic agent or lipid-lowering agent which may be employed in combination
with the compounds of formula (I) or (II) may include a MTP inhibitor, a HMG CoA
reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an ACAT
inhibitor, a lipoxygenase inhibitor, a cholesterol absorption inhibitor, an ileal Na+/bile
acid cotransporter inhibitor, an upregulator of LDL receptor activity, a cholesteryl ester
transfer protein(CETP) inhibitor, a bile acid sequestrant, and/or nicotinic acid and
derivatives or a pharmaceutically acceptable salt thereof.
The HMG-CoA reductase inhibitor used in the present invention means any drug that
inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase),
which is an enzyme in rate-determining step of cholesterol biosynthesis, and includes
without limitations atorvastatin, pravastatin, cerivastatin, simvastatin, lovastatin,
fluvastatin, mevastatin, itavastatin, rosuvastatin, pitavastatin and ZD4522; and those
disclosed in U.S. Pat. No. 4,231,938, U.S. Pat. No. 4,444,784, U.S. Pat. No. 4,739,073,
38

U.S. Pat. No. 4,346, 227; EP 491,226, and U.S. Pat. No. 4,647,576. Atorvastatin,
pravastatin, and simvastatin are preferred.
The squalene synthetase inhibitor suitable for use herein include, but are not limited to,
ER-27856, ER-28448, RPR 107393, compounds as disclosed in U.S. Pat. No. 5,712,396,
6207664, those disclosed by Biller et al., J. Med. Chem., 1988, Vol. 31, No. 10, pp.
1869-1871, including isoprenoid (phosphinyl-methyl)phosphonates as well as other
known squalene synthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.
4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M.,
and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).
Other hypolipidemic agents suitable for use herein include, but are not limited to, fibric
acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate,
clinofibrate and the like, probucol, and related compounds, probucol and gemfibrozil
being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-
Sephadex (Secholex®, Policexide®), as well as lipostabil, Eisai E-5050 (an N-substituted
ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL),
istigmastanylphos-phorylcholine, aminocyclodextrin, AJ-814 (azulene derivative),
melinamide, Sandoz 58-035, CL-277,082 and CL-283,546 (disubstituted urea
derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,
poly(diallylmethylamine) derivatives, quaternary amine poly (diallyldimethylammonium
chloride) and ionenes. The hypolipidemic agent may also be an ileal Na +/bile acid
cotransporter inhibitor such as S-8921.
The acyl coenzyme A-cholesterol acyl transferase (ACAT) inhibitor useful in the present
invention includes, but are not limited to, avasimibe, eflucimibe, KY505, SMP 797, and
the like; and those disclosed in U.S. Pat. No. 5,510,379, and International Patent
Application Nos. WO 96/26948 and WO 96/10559.
The cholesterol absorption inhibitor useful in the present invention includes, but not
limited to, stanol esters, beta-sitosterol; sterol glycosides such as tiqueside; and
39

azetidinones such as ezetimibe; and those disclosed in U.S. Pat. No. 5,846,966, U.S. Pat.
No. 5,631,365, U.S. Pat. No. 5,767,115, U.S. Pat. No. 6,133,001, U.S. Pat. No.
5,886,171, U.S. Pat. No. 5,856,473, U.S. Pat. No. 5,756,470, U.S. Pat. No. 5,739, 321,
U.S. Pat. No. 5,919,672, WO 00/63703, WO /0060107, WO 00/38725, WO 00/34240,
WO 00/20623, WO 97/45406, WO 97/16424, WO 97/16455, and WO 95/08532, the
entire contents of which are hereby incorporated by reference. An examplary cholesterol
absorption inhibitor is ezetimibe, which is l-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-(4-
fluorophenyl)propyl]-4-(S)-(4-hydroxy phenyl)-2-azetidinone. Additional examplary
hydroxy-substituted azetidinone cholesterol absorption inhibitors are specifically
described in U.S. Pat. No. 5,767,115, column 39, lines 54-61 and column 40, lines 1-51
(hereby incorporated by reference), represented by the formula as defined in column 2,
lines 20-63 (hereby incorporated by reference).
The CETP inhibitor useful in the present invention includes, but not limited to, JTT 705,
torcetrapib, CP 532,632, BAY63-2149, SC 591, SC 795, and the like, and those disclosed
in U.S. Pat. No. 5,512, 548; WO 99/20302, WO 99/14204, WO 99/41237, WO 95/04755,
WO 96/15141, WO 96/05227, EP 796846, EP818197, EP 818448, DE 19704244,
DE19741051, DE 19741399, DE 19704243, DE 19709125, DE 19627430, DE 19832159,
DE 19741400, JP 11049743, and JP 09059155; and those disclosed in J. Antibiot., 49(8):
815-816 (1996), and Bioorg. Med. Chem. Lett., 6:1951-1954 (1996).
The antidiabetic agent, as mentioned herein, includes but not limited to a PPARy agonist,
a biguanide, a protein tyrosine phosphatase-lB (PTP-1B) inhibitor, a sulfonylurea, a
meglitinide, an alpha glucoside hydrolase inhibitor, a PPARa agonist, a PPAR5 agonist
or antagonist, an alpha-amylase inhibitor, a fatty acid oxidation inhibitor, an A2
antagonist, a dipeptidyl peptidase IV (DP4) inhibitor, an aP2 inhibitor, a SGLT2
inhibitor, a glycogen phosphorylase inhibitor, a glucagon-like peptide-1 (GLP-1), an
insulin or insulin mimetic, a PPAR.alpha./gamma dual agonist, an lip-HSD 1 (110-
hydroxy-steroid dehydrogenase 1) inhibitor, other insulin sensitizing drug, a glucokinase
activator, a VPAC2 receptor agonist or a pharmaceutically acceptable salt thereof.
40

The antidiabetic agent may be an oral an antihyperglycemic agent preferably a biguanide
such as metformin or phenformin or salts thereof, preferably metformin HC1.
The other antidiabetic agent may be a sulfonylurea such as glyburide (also known as
glibenclamide), glimepiride, glipizide, gliclazide or chlorpropamide, other known
sulfonylurea or other antihyperglycemic agent which act on the ATP-dependent channel
of the p-cells, with glyburide and glipizide being preferred.
The oral antidiabetic agent may also be an alpha glucoside hydrolase inhibitor such as
acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q,
salbostatin, CKD-711, MDL-25,637, MDL-73,945, MOR 14 or a pharmaceutically
acceptable salt thereof.
The PPARy agonist may be selected from thiazolidinedione oral anti-diabetic agents or
other insulin sensitizers such as rosiglitazone, pioglitazone, MCC-555, GL-262570,
englitazone, darglitazone, isaglitazone, JTT-501, L-895645, R-l 19702, NN-2344,
balaglitazone or YM-440, preferably rosiglitazone and pioglitazone.
The compounds of formula (I) or (II) may also be employed in combination with a an
antihyperglycemic agent such as insulin or insulin mimetic like biota, LP-100, novarapid,
insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and
ultralente), Lys-Pro insulin or glucagon-like peptide-1 (GLP-1) such as GLP-l(l-36)
amide, GLP-1 (7-36) amide, GLP-1 (7-37) (as disclosed in U.S. Pat. No. 5,614,492 the
disclosure of which is incorporated herein by reference), as well as AC2993 and LY-
315902, which may be administered via injection, intranasal, inhalation or by transdermal
or buccal devices.
The other antidiabetic agent may also be a PPAR ct/y dual agonist such as CLX-0940,
GW-1536, GW1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, SB 219994,
muraglitazar, AZ-242/tesaglitazar, GW-409544, as well as those disclosed by Murakami
et al, "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation—
41

Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha
Activation on Abnormal Iipid Metabolism in Liver of Zucker Fatty Rats", Diabetes 47,
1841-1847 (1998) or the compounds (from Bristol-Myers Squibb) described in U.S. Pat.
No. 6,414,002.
The antidiabetic agent may be a SGLT2 inhibitor such as Sergliflozin, Dapagliflozin or
disclosed in WO01/27128. Preferred will be Sergliflozin. The antidiabetic agent may also
be an aP2 inhibitor. PTP1-B inhibitor can be selected from the compounds disclosed in
international publication WO/2007/32028.
The antidiabetic agent may be a DPP4 (Dipeptidyl peptidase IV) inhibitor such as,
vildagliptin, sitagliptin, saxagliptin, alogliptin or as disclosed in international applications
WO/2003/84940 and WO/2005/33106. The most preferred is vildagliptin.
The meglitinide which may be employed in combination with the compound of formula
(I) of the invention includes but not limited to repaglinide, nateglinide or KAD1229, with
repaglinide being preferred.
The Alpha-amylase inhibitor may be employed in combination include but not limited to
tendamistat, trestatin, A1-3688, and the like. The A2 antagonist can be selected from
midaglizole, isaglidole, deriglidole, idazoxan, earoxan, and fluparoxan. The fatty acid
oxidation inhibitor, which may be employed in combination, is clomoxir, etomoxir, and
the like.
The antiobesity agent, as mentioned herein, include but not limited to a 5HT (serotonin)
transporter inhibitor, a NE (norepinephrine) transporter inhibitor, a CB-1 (cannabinoind-1
receptor) antagonist/inverse agonist, a ghrelin antibody, a ghrelin antagonist, a H3
(histamine H3) antagonist/inverse agonist, , a NPY1 (neuropeptide Y Yl) antagonist, a
NPY2 (neuropeptide Y Y2) agonist, a NPY5 (neuropeptide Y Y5) antagonist, leptin or its
derivative, an opioid antagonist, an orexin antagonist, a BRS3 (bombesin receptor
subtype 3) agonist, a CCK-A (cholecystokinin-A) agonist, a CNTF (ciliary neurotrophic
42

factor), a CNTF derivative, a GHS (growth hormone secretagogue receptor) agonist,
5HT2c (serotonin receptor 2c) agonist, a Mc3r (melanocortin 3 receptor) agonist, a Mc4r
(melanocortin 4 receptor) agonist, a monoamine reuptake inhibitor, a p3 (beta adrenergic
receptor 3) agonist, a DGAT1 (diacylglycerol acyltransferase 1) inhibitor, a DGAT2
(diacylglycerol acyltransferase 2) inhibitor, a FAS (fatty acid synthase) inhibitor, a PDE
(phosphodiesterase) inhibitor, a thyroid hormone p agonist, an UCP-1 (uncoupling
protein 1), 2,.or 3 activator, an acyl-estrogen, a glucocorticoid antagonist, a SCD-1
(stearoyl-CoA desaturase-1) inhibitor, a lipase inhibitor, a fatty acid transporter inhibitor,
a dicarboxylate transporter inhibitor, or pharmaceutically acceptable salts.
The serotonin (5HT) transport inhibitor useful in this invention includes but not limited
to, paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine.
The norepinephrine (NE) transport inhibitor useful in this invention includes but not
limited to, GW 320659, despiramine, talsupram, and nomifensine.
The cannabinoid receptor 1 (CB-1) antagonist/inverse agonist useful in the present
invention includes but not limited to rimonabant, taranabant, rosonabant, CP-945598, SR-
147778, BAY 65-2520, or SLV 319.
The GLP-1 agonist useful in the present invention includes exendin-3 and exendin-4, and
those disclosed in US 2003087821 and NZ 504256.
The neuropeptide Yl (NPY1) antagonists useful in the present invention includes but not
limited to BIBP3226, J-l 15814, BIBO 3304, LY-357897, CP-671906, or GI-264879A.
The neuropeptide Y2 (NPY2) agonist useful in the present invention includes but not
limited to, peptide YY (PYY), and PYY3-36, peptide YY analogs, PYY agonists, and the
compounds disclosed in WO 03/026591, WO 03/057235, and WO 03/027637.
The neuropeptide Y5 (NPY5) antagonist useful in the present invention includes but not
limited to GW-569180A, GW-594884A, GW-587081X, GW-548118X; FR 235,208;
43

FR226928, FR 240662, FR252384; 1229U91, GI-264879A, CGP71683A, LY-377897,
LY366377, PD-160170, SR-120562A, SR-120819A, JCF-104, or H409/22.
The beta.3 adrenergic receptor (beta.3) agonist useful in the present invention includes
but not limited to AD9677/TAK677, CL-316,243, SB 418790, BRL-37344, L-796568,
BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecadrine, Zeneca
D7114, and SR59119A
The thyroid hormone beta agonist useful in the present invention includes but not limited
to MB07811 or KB-2611.
The antiplatelet agent which may be employed in combination with compounds of
formula (I) or (II) of the invention includes without limitation aspirin, clopidogrel,
ticlopidine, dipyridamole, prasugrel, abciximab, tirofiban, eptifibatide, anagrelide, and
ifetroban, with clopidogrel and aspirin being preferred.
The anti-thrombotic agent which may be employed in combination with compounds of
formula (I) or (II) of the invention includes without limitation melagatran and
ximelagatran (Exanta® Astra Zeneca), warfarin and Factor Xa inhibitors such as
razaxaban.
An agent useful for diabetic vascular complications in present invention includes without
limitation aldose reductase inhibitor, AGE inhibitor or AGE breaker. Aldose reductase
inhibitor, among those suitable for the treatment of diabetic complications, represent
those which decrease intracellular sorbitols by inhibiting aldose reductases, and said
sorbitols accumulate excessively by enhancement of a course of polyol metabolism
which is induced by continuous hyperglycemia shown in tissues developing diabetic
complication. They include, for example, epalrestat, tolrestat, fidarestat and zenerestat.
Advanced glycation end products (AGE) inhibitor, among those suitable for the treatment
of diabetic complications, represent those which alleviate cell disorders by inhibiting
production of advanced glycation endproducts which are increased by continuous
hyperglycemia in a diabetic state. NNC-39-0028 and OPB-9195 are examples thereof.
44

AGE breaker suitable for the treatment of diabetic complications, represent those which
are capable of reversing the formation of advanced glycosylation end product cross-links
responsible for the complications of aging and diabetes. Alagebrium is non limiting
example of AGE breaker.
The digitalis glycoside, which can be used in present invention includes without
limitation oleandrin, neriifolin, odoroside A and H, ouabain (G-strophantin), cymarin,
sarmentocymarin, periplocymarin, K-strophantin, thevetin A, cerberin, peruvoside,
thevetosin, thevetin B, tanghinin, deacetyltanghinin, echujin, hongheloside G, honghelin,
periplocin, strophantidol, nigrescin, uzarin, calotropin, cheiroside A, cheirotoxin,
euonoside, euobioside, euomonoside, lancetoxin A and B, kalanchoside, bryotoxin A-C,
bryophyllin B, cotiledoside, tyledoside A-D, F and G, orbicuside A-C, alloglaucotoxin,
corotoxin, coroglaucin, glaucorin, scillarene A and B, scilliroside, scilliacinoside,
scilliglaucoside, scilliglaucosidin, scillirosidin, scillirubrosidin, scillirubroside,
proscillaridin A, rubelin, convalloside, convallatoxin, bovoside A, glucobovoside A,
bovoruboside, antiarin A, helleborin, hellebrin, adonidin, adonin, adonitoxin, thesiuside,
digitoxin, gitoxin, gitalin, digoxin, F-gitonin, digitonin, lanatoside A-C, bufotalin,
bufotalinin, bufotalidin, pseudobufotalin, acetyl-digitoxin, acetyl-oleandrin, beta-
methyldigoxin or alpha-methyldigoxin. Examples of phosphodiesterase inhibitors are:
amrinone, milrinone, enoximone and bucladesine.
The compounds to be combined can be present as pharmaceutically acceptable salts. If
these compounds have, for example, at least one basic center, they can form acid addition
salts. Corresponding acid addition salts can also be formed having, if desired, an
additionally present basic center. The compounds having at least one acid group (for
example COOH) can also form salts with bases. Corresponding internal salts may
furthermore be formed, if a compound comprises, e.g., both a carboxy and an amino
group.
45

The corresponding active ingredient or a pharmaceutically acceptable salt thereof may
also be used in crystalline form, amorphous form, hydrate or include other solvents used
for crystallization.
It has been found that, a combination of compound of formula (I) or (II) and at least one
therapeutic agent selected from the group consisting of an antihypertensive agent, an
antidiabetics agent, a hypolipidemic agent, an antiplatelet agent, an antiobesity agent, an
antithrombotic agent, an agent for diabetic vascular complications, an agent for treatment
of heart failure, or a pharmaceutically acceptable salt thereof, achieves greater therapeutic
response than the either drug administered alone.
Definitions:
The use of the terms "a" and "an" and "the" and similar referents in the context of
describing the invention (especially in the context of the following claims) are to be
construed to cover both the singular and die plural, unless otherwise indicated herein or
clearly contradicted by context.
The terms "comprising", "having", "including", and "containing" are to be construed as
open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted.
The term "treatment", "treat", "treating", refer to both prophylactic or preventative
treatment as well as curative or disease modifying treatment, including treatment of
patients at risk of contracting the disease or suspected to have contracted the disease as
well as patients who are ill or have been diagnosed as suffering from a disease or medical
condition.
The term "therapeutically effective amount" refers to that amount of a compound of the
invention that is sufficient to effect treatment, as defined above, when administered to a
mammal in need of such treatment. The therapeutically effective amount will vary
depending upon the subject and disease condition being treated, the weight and age of the
46

subject, the severity of the disease condition, the manner of administration and the like,
which can readily be determined by one of ordinary skill in the art.
The term "at least one therapeutic agent" shall mean that in addition to compound of
formula (I) or (II) one or more, for example two, furthermore three, active ingredients as
specified according to the present invention can be combined.
The Agents of the invention may be present in the same pharmaceutical compositions or
in separate pharmaceutical compositions. Thus the active ingredients may be
administered at the same time (e.g. simultaneously) or at different times (e.g.
sequentially) and over different periods of time, which may be separate from one another
or overlapping. The unit dose form may also be a fixed combination.
The pharmaceutical compositions of present invention are adapted for oral, parenteral
(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion,
subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual,
or topical routes of administration and may be formulated, alone or together, in suitable
dosage unit formulations containing conventional non-toxic pharmaceutically acceptable
carriers, adjuvants and vehicles appropriate for each route of administration. The
preferred route is oral.
Typical oral formulations include tablets, capsules, syrups, elixirs and suspensions.
Typical injectable formulations include solutions and suspensions.
The pharmaceutical compositions containing the active ingredient may be in a form
suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups
or elixirs. Compositions intended for oral use may be prepared according to any method
known to the art for the manufacture of pharmaceutical compositions and such
compositions may contain one or more agents selected from the group consisting of
sweetening agents, flavoring agents, coloring agents and preserving agents in order to
47

provide pharmaceutically elegant and palatable preparations. Tablets contain the active
ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are
suitable for the manufacture of tablets. These excipients may be for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or
sodium phosphate; granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents,
for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they
may be coated by known techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over a longer period.
Pharmaceutical compositions for oral use may also be presented as hard gelatin capsules
wherein the active ingredient is mixed with an inert solid diluent, for example, calcium
carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin,
or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable
for the manufacture of aqueous suspensions. Such excipients are suspending agents, for
example sodium carboxymethylcellulose, methylcellulose, hydroxy-
propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum
acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of ethylene oxide with long
chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty acids and a hexitol such
as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with
partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring
agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose
or saccharin.
48

Oily suspensions may be formulated by suspending the active ingredients in a vegetable
oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as
liquid paraffin. The oily suspensions may contain a thickening agent, for example
beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above,
and flavoring agents may be added to provide a palatable oral preparation. These
compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by
the addition of water provide the active ingredients in admixture with a dispersing or
wetting agent, suspending agent and one or more preservatives. Suitable dispersing or
wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example sweetening, flavoring and coloring agents, may also
be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water
emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or
a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying
agents may be naturally-occurring gums, for example gum acacia or gum tragacanth,
naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial
esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate,
and condensation products of the said partial esters with ethylene oxide, for example
polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for
example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also
contain a demulcent, a preservative and flavoring and coloring agents.
Parenteral formulations are especially injectable fluids that are effective in various
manners, such as intravenously, intramuscularly, intraperitoneally, intranasally,
intradermally or subcutaneously. Such fluids are preferably isotonic aqueous solutions or
suspensions which can be prepared before use, for example from lyophilised preparations
49

which contain the active ingredient alone or together with a pharmaceutically acceptable
carrier. The pharmaceutical preparations may be sterilised and/or contain adjuncts, for
example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilisers, salts
for regulating the osmotic pressure and/or buffers.
The compounds of the present invention may also be administered in the form of
suppositories for rectal administration of the drug. These compositions can be prepared
by mixing the drug with a suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will therefore melt in the rectum to
release the drug. Such materials are cocoa butter and polyethylene glycols.
Suitable formulations for transdermal application include an effective amount of a
compound of the invention with carrier. Advantageous carriers include absorbable
pharmacologically acceptable solvents to assist passage through the skin of the host. For
example, transdermal devices are in the form of a bandage comprising a backing
member, a reservoir containing the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound of the skin of the host at a controlled and
predetermined rate over a prolonged period of time, and means to secure the device to the
skin.
Suitable formulations for topical application, e.g. to the skin and eyes, include aqueous
solutions, suspensions, ointments, creams, gels or sprayable formulations, for example,
for delivery by aerosol or the like.
Said compositions for the administration of the compounds of this invention may
conveniently be presented in dosage unit form and may be prepared by any of the
methods well known in the art of pharmacy. All methods include the step of bringing the
active ingredient into association with the carrier which constitutes one or more accessory
ingredients. In general, the pharmaceutical compositions are prepared by uniformly and
intimately bringing the active ingredient into association with a liquid carrier or a finely
divided solid carrier or both, and then, if necessary, shaping the product into the desired
50

formulation. For example using conventional mixing, granulation, coating, solubulizing
or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained
by combining the active compounds with solid excipients, if desired granulating a
mixture which has been obtained, and, if required or necessary, processing the mixture or
granulate into tablets or coated tablet cores after having added suitable auxiliary
substances.
The dosage of the active compounds can be selected based on a variety of factors, such as
mode of administration, age and/or individual condition. Preferred dosages for the active
ingredients of the pharmaceutical combination according to the present invention are
therapeutically effective dosages, especially those which are commercially available.
The following examples illustrate the above-described invention; however, it is not
intended to restrict the scope of this invention in any manner.
Examples:
Ex.1 Tablet

Active Ingredient of General formula I Therapeutically effective amount
Metformin HCL 500mg
Lactose l00mg
Microcrystaline Cellulose 51mg
Starch 60mg
Polyvinyl pyrolidone (K-30) 2mg
Magnesium Stearate lmg
Purified Water Q.S.
1. Sift active compound of formula (I), metformin HCL, starch, lactose and
microcrystalline cellulose and mix thoroughly.
2. Dissolve PVP K30 in purified water and granulate the blend of step-1 with binder
solution.
3. Dry the granules and mill them through suitable screen.
51

4. Sift magnesium stearate and mix with dried granules.
5. Compress the lubricated granules from step-4 in to tablets.
Ex. 2 Tablet

Active Ingredient of General formula I Therapeutically effective amount
Amlodipine Besylate 7mg
Calcium Hydrogen Phosphate 63mg
Microcrystaline Cellulose 124mg
Sodium Starch Glycolate 4mg
Magnesium Stearate 2mg
1. Sift active compound of formula (I), amlodipine besylate, calcium hydrogen
phosphate and microcrystalline cellulose and mix thoroughly.
2. Sift sodium starch glycolate and mix with blend of step-1.
3. Sift magnesium stearate and mix with blend of step-2.
4. Sift magnesium stearate and mix with dried granules.
5. Compress the lubricated blend from step-3 in to tablets.
Ex. 3 Film coated Tablet

Active Ingredient of General formula I Therapeutically effective amount
Atorvastatin l0mg
Calcium Carbonate 33mg
Microcrystaline Cellulose 60mg
Lactose 33mg
Crosscarmellose Sodium 9.75mg
Polysorbate 80 0.5mg
Hydroxy Propyl Cellulose 3mg
Magnesium Stearate 0.75mg
Film Coating
Opadry white 6mg
52

Simeticone emulsion 0.1
Purified Water Q.S.
1. Sift active compound of formula (I), atorvastatin, calcium carbonate,
microcrystalline cellulose, lactose and part quantity of crosscarmellose
sodium and mix thoroughly.
2. Disoolve polysorbate 80 in purified water. Add hydroxypropyl cellulose in
surfactant solution. Add this binder solution to the blend of step-1 and
granulate.
3. Dry the granules and mix them through screen.
4. Sift remaining quantity of crosscarmellose sodium ad mix with dried granules.
5. Sift magnesium stearate and mix with blend of step-4.
6. Compress the lubricated blend from step-5 in to tablets.
7. Prepare coating suspension by dispersing Opadry® white in purified water
and add simeticone emulsion. Coat the tablets with this coating suspension.
Ex. 4 Capsule

Active Ingredient of General formula I Therapeutically effective amount
Metformin HCL 500mg
Indapamide 2.5mg
Microcrystaline Cellulose 51mg
Lactose l00mg
Starch 60mg
Polyvinyl pyrolidone (K-30) 2mg
Magnesium Stearate lmg
Purified Water Q.S.
Follow the same procedure of example-1.
53

Biological Example:
Effect of compound 27 on HF as an add-on therapy
This study is a randomized, double blind, multicentric, placebo-controlled, parallel group,
study of compound 27, as an add-on to conventional treatment in definite heart failure
patients. Each patient will be evaluated for 6 months and patients showing improvement
at the end of 6 months study treatment would be offered to participate in the continuation
study. Sufficient number of patients would be recruited to ensure that about 120 patients
will be evaluated at the completion of study. Patients of either sex, aged > 45 years and
with definite chronic heart failure as measured by BHFS (Boston Heart Failure Score)
and LVEF(Left Ventricular Ejection Fraction) > 35% would be included in the study.
Study Objective:
Objective of the study is to evaluate the efficacy and safety of compound 27 in patients of
HF as an add-on therapy to existing medications, particularly one or more agent selected
from the group consisting of antihypertensive, antidiabetic, hypolipidemic,
antithrombotic, antiobesity, agent for treatment of diabetic vascular complications or
agent for treatment for HF.
Study end Points:
(a) Primary efficacy endpoints:
A mortality-adjusted composite clinical score comprised of:
• Event-free survival as measured by deducting the days of hospitalization for heart
failure from days alive.
• Improvement in NYHA (New York Heart Association).
• Improvement in LVEF as measured by echocardiography.
The composite score will be on a scale of 1-100, in which each of the 3 components will
be given equal weight. (For example, if a patient is alive and hospital free during 100 of
54

180 days of the expected duration of the study, the first component will contribute
(100/180)*33.3 to the composite score.)
(b) Secondary efficacy endpoints:
• All cause mortality
• Change in the diuretic therapy
• Change in Boston criteria for diagnosing Heart Failure Score (BHFS)
• Individual components of mortality-adjusted composite clinical score
(c) Safety endpoints:
Adverse Events (AE's) monitored on days of assessment both using the checklist and as
volunteered by the patient. These events will be categorized, summarized and reported as
appropriate.
At each scheduled clinic visit, drug safety and tolerability will be evaluated by physical
examination, including vital sign measurement and Clinical diagnostics and laboratory
measurements.
(d) Other exploratory measurements: Effect of treatment on:
• Cardiac haemodynamics at rest & during exercise as measured by ICG
(Impedence cardiography), 2DECH0 with Colour Doppler & Tissue Doppler
Imaging.
• Exercise capacity as indicated by CPET(Cardio pulmonary exercise testing)
55

The most preferred embodiments of the invention are :
56
1. A pharmaceutical combination comprising a compound represented by formula
(I) or (II) as defined above or its pharmaceutically acceptable salt thereof, and one
or more compound selected from a) antihypertensive agent b) hypolipemic agent
c) antidiabetic agent d) antiplatelet agent e) anti-thrombotic agent f) drug for
diabetic vascular complications or a pharmaceutically acceptable salts thereof,
optionally in presence of a pharmaceutically acceptable excipient.
2. A kit comprising in separate containers in a single package a pharmaceutical
compositions comprising in one container a pharmaceutical composition
comprising a compound of formula (I) or (II) as defined above or its
pharmaceutically acceptable salt thereof, and in a second container a
pharmaceutical composition comprising one or more compound selected from a)
antihypertensive agent b) hypolipemic agent c) antidiabetic agent d) antiplatelet
agent e) anti-thrombotic agent f) drug for diabetic vascular complications or a
pharmaceutically acceptable salts thereof.
3. A package comprising a compound of formula (I) or (H) as defined above or its
pharmaceutically acceptable salt thereof, together with instructions for use in
combination with one or more compound selected from a) antihypertensive agent
b) hypolipemic agent c) antidiabetic agent d) antiplatelet agent e) anti-thrombotic
agent f) drug for diabetic vascular complications or a pharmaceutically acceptable
salts thereof.

In one embodiment, the present invention relates to a pharmaceutical composition comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically acceptable salt thereof; (b) at least one therapeutic agent selected from the group consisting of an antihypertensive agent, an antidiabetic agent, a hypolipidemic agent, an antiplatelet agent, an antiobesity agent, an antithrombotic agent, an agent for diabetic vascular complications, an agent for treatment of heart failure or a pharmaceutically
acceptable salts thereof, optionally in presence of a pharmaceutically acceptable carrier.
In a preferred embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) at least one antihypertensive agent.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) one or more antihypertensive agent, wherein said
antihypertensive agent include but not limited to an angiotensin converting enzyme
(ACE) inhibitor, a renin inhibitor, a beta adrenergic receptor blocker, an alpha adrenergic
receptor blocker, a calcium channel blocker, a potassium channel activator, an aldosterone synthase inhibitor, a neutral endopeptidase (NEP) inhibitor, a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, an endothelin receptor antagonist, a dual angiotensin and endothelin receptor antagonist (DARA), a diuretic or a pharmaceutically acceptable salt thereof, optionally in the presence of a pharmaceutically acceptable carrier.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an angiotensin converting enzyme (ACE) inhibitor or a
pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a renin inhibitor or a pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a beta adrenergic receptor blocker or a pharmaceutically
acceptable salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) an alpha adrenergic blocker or a pharmaceutically acceptable
salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a calcium channel blocker or a pharmaceutically acceptable
salt thereof.
In a further embodiment, the present invention relates to a pharmaceutical composition
comprising: (a) compound of formula (I) or (II) as defined above or a pharmaceutically
acceptable salt thereof; (b) a potassium channel activator or a pharmaceutically
acceptable salt thereof.