Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-06-12
2004-01-27
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S424000, C548S243000, C548S543000
Reexamination Certificate
active
06683104
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates generally to prevention and treatment of atherosclerosis, myocardial infarction and related conditions such as peripheral vascular disease and ischemic stroke, and specifically to drugs that increase levels of HDL.
2. Description of Related Art
Low HDL cholesterol (HDLC), or hypoalphalipoproteinemia, is a blood lipid abnormality which correlates with a high risk of cardiovascular disease (CVD), in particular coronary artery disease (CAD), but also cerebrovascular disease, coronary restenosis, and peripheral vascular disease. HDLC levels are influenced by both environmental and genetic factors.
Epidemiological studies have consistently demonstrated that plasma HDLC concentration is inversely related to the incidence of CAD. HDLC levels are a strong graded and independent cardiovascular risk factor. Protective effects of an elevated HDLC persist until 80 years of age. A low HDLC is associated with an increased CAD risk even with normal (<5.2 mmol/l) total plasma cholesterol levels. Coronary disease risk is increased by 2% in men and 3% in women for every 1 mg/dL (0.026 mmol/l) reduction in HDLC and in the majority of studies this relationship is statistically significant even after adjustment for other lipid and non-lipid risk factors. Decreased HDLC levels are the most common lipoprotein abnormality seen in patients with premature CAD. Four percent of patients with premature CAD have an isolated form of decreased HDLC levels with no other lipoprotein abnormalities while 25% have low HDLC levels with accompanying hypertriglyceridemia.
These findings have led to increased attention to HDLC levels as a focus for treatment and resulted in a recommendation of the National Cholesterol Education Program suggesting that HDLC values below 0.9 mmol/l confer a significant risk for men and women.
To provide tools that would raise the HDLC levels and thus aid in prevention and treatment of atherosclerosis, myocardial infarction and related conditions such as peripheral vascular disease and ischemic stroke, we focused out attention on urea derivatives which constitute one aspect of the present invention.
BRIEF SUMMARY OF THE INVENTION
In certain embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof:
wherein:
R
1
is
optionally mono-, di-, or tri-substituted where valence permits with halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio;
R
2
, R
3
, and R
4
are independently selected at each occurrence from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, or aminocarbonyl; and
A is -aryl-O—, -aryl-S—, or -aryl-N, optionally mono-, di-, or poly-substituted where valence permits with halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio.
In certain preferred embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
R
1
is
optionally mono-, di-, or tri-substituted where valence permits with halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio;
R
2
, R
3
, and R
4
are independently selected at each occurrence from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, or aminocarbonyl; and
A is -aryl-O—, -aryl-S—, or -aryl-N, optionally mono-, di-, or poly-substituted where valence permits with halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amninocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio.
In certain preferred embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
R
1
is
optionally mono-, di-, or tri-substituted where valence permits with halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, amninocarbonyloxy, or alkylthio;
R
2
, R
3
, and R
4
are independently hydrogen or alkyl; and
A is -aryl-O—, -aryl-S—, or -aryl-N, optionally mono-, di-, or poly-substituted where valence permits with halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio.
In certain preferred embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
R
1
is
optionally mono-, di-, or tri-substituted where valence permits with halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio;
R
2
, R
3
, and R
4
are independently hydrogen or alkyl; and
A is -aryl-O—, optionally mono-, di-, or poly-substituted where valence permits with halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio.
In certain more preferred embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
R
1
is
optionally mono-, di-, or tri-substituted where valence permits with halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio;
R
2
, R
3
, and R
4
are independently hydrogen or alkyl; and
A is
optionally mono-, di-, or poly-substituted where valence permits with halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio.
In other aspects, the invention is directed to methods of raising HDL cholesterol levels in a patient by administering the compound of formula (I) or a pharmaceutical composition thereof to said patient in the need of such treatment. “Treatment” includes both therapeutic and prophylactic effects.
In other aspects, the invention is directed to methods of treatment of hypoalphalipoproteinemia, atherosclerosis, myocardial infarction, vascular disease and ischemic stroke by administering the compound of formula (I) or a pharmaceutical composition thereof to a patient in the need of such treatment. “Treatment” includes both therapeutic and prophylactic effects.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to compounds of formula (I), which compounds raise HDLC levels in a patient. Further, this invention relates to pharmaceutical compositions comprising compounds described herein and to their use as therapeutic agents, particularly in the treatment of cardiovascular diseases and conditions.
More specifically, the compounds of this invention are useful in the treatment of hypoalphalipoproteinemia, atherosclerosis, myocardial infarction, vascular disease and ischemic stroke.
Compounds of formula (I) may be used in combination with known cholesterol reducing drugs or sequentially with known cholesterol reducing drugs when a combination formulation is inappropriate. Cholesterol reducing agents include, but are not limited to atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastati
A.P. Group Inc.
Ramsuer Robert W.
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