Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ortho-hydroxybenzoic acid or derivative doai
Reexamination Certificate
2000-01-28
2001-07-03
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ortho-hydroxybenzoic acid or derivative doai
Reexamination Certificate
active
06255298
ABSTRACT:
FIELD OF INVENTION
Cardiovascular diseases are the leading cause of death in the U.S., accounting annually for more than one million deaths. Atherosclerosis is the major contributor to coronary heart disease and a primary cause of non-accidental death in Western societies. Since the prevention of atherosclerosis is an enormous unmet medical need, considerable effort has been made in defining the etiology and potential treatment of atherosclerosis and its consequences, including myocardial infarction, angina, organ failure and stroke. Despite this effort, there are many unanswered questions including how and when atherosclerotic lesions become life-threatening, the best point of intervention, and how to detect and monitor the progression of lesions.
There is widespread agreement that multiple risk factors contribute to atherosclerosis including hypertension. elevated total serum cholesterol, high levels of low density lipoprotein (“LDL”) cholesterol, low levels of high density lipoprotein (“HDL”) cholesterol, diabetes mellitus. severe obesity, and cigarette smoking. To date, treatment of atherosclerosis has been narrowly focused on treating elevated cholesterol levels and modifying lipids has become the major focus of treatment and research.
However, recent studies have indicated that 40% of deaths due to coronary disease occurred in men with total cholesterol levels of below 220 mg/dl. It is thus obvious that too great an emphasis is being placed on lipid lowering. Indeed, only 30% of patients with atherosclerosis have elevated lipid levels, indicating that other pathogenic factors are involved. A logical scenario for future therapies and preventive measures should therefore include a multidisciplinary approach consisting of diet modification, HMG-CoA reductase inhibition and novel therapies aimed directly at plaque growth and stability.
The initial lesion in atherosclerosis is the fatty streak, which arises from cholesterol esters maintained as lipid droplets inside macrophage-derived foam cells. Macrophages down-regulate their LDL receptors and instead express mRNA and undergo new protein synthesis for a novel receptor for modified LDL. This receptor recognizes all modified forms of low-density lipoprotein and has come to be known as the macrophage scavenger receptor (“MSR”). If the macrophage is present in an environment that is continually generating modified LDL, it will accumulate lipid droplets of cholesterol esters, continuing until the macrophage dies from its toxic lipid burden. The released lipid then forms the a cellular necrotic core of the atherosclerotic lesion. Subsequent recruitment of fibroblasts, vascular smooth muscle cells and circulating monocytes and T-lymphocytes complete the inflammatory response and formation of the mature atherosclerotic plaque. Macrophage-derived foam cells are concentrated in the shoulders of plaques, where their secreted proteases and collagenases may contribute to plaque rupture which may lead to a fatal thrombotic event.
Plaque regression, a function of the dynamic balance among initiation, progression, stabilization and removal of plaque constituents, has been unequivocally demonstrated in humans as well as in numerous animal models. Multiple regression studies in non-human primates have shown that even relatively advanced lesions regress over time when atherogenic dietary stimuli are discontinued or pharmacological regimens are initiated.
Inhibition of lipid accumulation within macrophage-derived foam cells by utilizing MSR antagonists is expected to prevent plaque initiation, retard plaque progression, and initiate plaque regression through the process of “reversed cholesterol transport” to acceptor HDL. Thus, MSR antagonists provide a unique approach towards the pharmacotherapy of cardiovascular diseases such as atherosclerosis, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure, and hypercholesterolemia.
SUMMARY OF THE INVENTION
The present invention involves salicylanilide derivatives represented by formula (I) hereinbelow and their use as macrophage scavenger receptor (“MSR”) antagonists which are useful in the treatment of a variety of cardiovascular diseases including but not limited to atherosclerosis, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.
The present invention further provides methods for antagonizing the macrophage scavenger receptor in animals, including humans, comprising administering to an animal in need of treatment an effective amount of a compound of Formula (I), indicated hereinbelow.
The present invention further provides methods of inhibiting lipid accumulation within macrophage-derived foam cells.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are selected from Formula (I) hereinbelow:
wherein
R
1
is independently selected from the group consisting of hydrogen, fluoroalkyl, halo, haloaryl, aryl, and alkoxy; or R
1
represents a fused ring forming a naphthalene moiety with the six membered aryl ring it substitutes;
m is an integer from 1 to 4;
R
2
is independently selected from the group consisting of R
1
-benzamido, R
1
-benzyl ether, R
1
-benzylamino, amino, halo, hydroxy, alkoxy, alkyl, fluoroalkyl, cyano, nitro, aryloxy, nitroalkyl, aryl, and 1,2-benzo; or the R
2
moiety represents a fused ring forming a napthalene ring with the six membered aryl ring it substitutes;
n is an integer from 1 to 4;
R
3
is hydrogen or methyl; and
R
4
is hydrogen or hydroxy.
Preferably, R
1
is selected from the group consisting of hydrogen, 5-trifluoromethyl, 5-chloro, 5-bromo, 3-bromo, 4-bromo, 5-bromo-3-phenyl, 5-iodo, 5-iodo-3-phenyl, 2-phenyl, 3-phenyl, 5-phenyl and 3-methoxy.
More preferably, R
1
is 5-trifluoromethyl or 5-bromo.
Preferably, any R
2
aryl substituents are selected from the group consisting of hydroxy, halo, aryl, alkyl, cyano, nitro, R
1
-benzamidyl, alkoxy and aryloxy. More preferably, R
2
is selected from the group consisting of 2-chloro, 3,4-dichloro, 2,3-dichloro, 3-methoxy, 2-isopropyl, 3-cyano, 4-butyl, 2-nitro, 2-phenoxy, 2-nitro-4-methyl, 2-phenyl, 4-phenyl, 2-benzamidyl, 1,2-benzo.
Most preferably, R
2
is 3,4-dichloro, 2-benzamidyl, 4-phenyl or 4-butyl.
Preferably, R
3
is hydrogen.
Particularly preferred compounds useful in the present invention include:
5-bromo-3′,4′-dichlorosalicylanilide;
5-bromo-2′-amino-4′,5′-dichiorosalicylanilide;
5-trifluoromethyl-4′-phenyisalicylanilide;
5-bromo-3′bromo-6′-hydroxysalicylanilide;
5-bromo-2′-benzamidyl-3′,4′-dichlorosalicylanilide and
5-bromo-4′-bromosalicylanilide.
The present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof. Pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations at which they are administered.
Pharmaceutically acceptable salts for use when basic groups are present include acid addition salts such as those containing sulfate. hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are prese
Lysko Paul G.
Weinstock Joseph
Henley III Raymond
King William T.
Kinzig Charles M.
Simon Soma G.
SmithKline Beecham Corporation
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