Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-13
2002-10-01
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S280400, C546S294000, C546S293000
Reexamination Certificate
active
06458815
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds that are sulfonamides, and to methods of treating atherosclerosis, coronary heart disease, and restenosis using the sulfonamide compounds. The invention also relates to a pharmaceutical composition that comprises a sulfonamide of the present invention.
BACKGROUND OF THE INVENTION
Vascular diseases such as coronary heart disease, atherosclerosis, stroke, restenosis, and peripheral vascular disease, remain the leading cause of death and disability throughout the world. About 1.5 million people die each year in the United States alone from myocardial infarction resulting from congestive heart failure. While diet and life style can accelerate the onset of vascular diseases, genetic predisposition leading to dyslipidemia is a significant factor in vascular-related disabilities and deaths. “Dyslipidemia” means abnormal levels of lipoproteins in blood plasma.
Several risk factors have been associated with increased risk of vascular disease. Among these are the dyslipidemias of high levels of low-density lipoprotein (LDL), and low levels of high-density lipoproteins (HDL). The ratio of HDL- to LDL-cholesterol is often used to assess the risk of vascular disease. A high ratio of HDL/LDL cholesterol is desirable. Compounds that increase this ratio by either lowering LDL or increasing HDL, or both, therefore are beneficial. Recent studies have also shown that elevated levels of lipoprotein(a), “Lp(a)”, are detrimental.
Lp(a) appears to be undesirable, since elevated levels of Lp(a) have been associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, stroke, cerebral infarction, and restenosis following balloon angioplasty. In fact, Lp(a) appears to be an excellent predictor for stroke. Accordingly, a high concentration of Lp(a) is one of the major risk factors leading to death from heart disease.
Lp(a) is composed of LDL and a high molecular weight glycoprotein called apolipoprotein(a), apo(a). Epidemiological studies show that, when present in high levels in the plasma, Lp(a) is an independent risk factor for premature atherosclerotic coronary heart disease. A concentration of 0.30 g/L in plasma is considered to double the risk of premature coronary heart disease. This concentration has been used as a clinical set point to determine what plasma concentrations of Lp(a) are considered above normal and for which treatment to lower plasma Lp(a) levels may be desirable.
SUMMARY OF THE INVENTION
The present invention provides compounds of the Formula I
wherein
R
1
is heteroaryl, substituted heteroaryl, —(CH
2
)
n
-C
3
-C
8
cycloalkyl, —(CH
2
)
n
-aryl, or —(CH
2
)
n
-substituted aryl;
R
2
is C
1
-C
6
alkyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, or
n is 0 to 4, and the pharmaceutically acceptable salts thereof.
In a preferred embodiment, R
3
is
In a preferred embodiment, R
2
is
In a preferred embodiment, R
1
is pyridyl, —CH
2
-cyclohexyl,
In a more preferred embodiment, the present invention provides compounds of the Formula I
wherein
R
1
is pyridyl, —CH
2
cyclohexyl, or -substituted pyridyl;
R
2
is -thienyl-pyridyl, -C
1
-C
6
alkyl, substituted phenyl, thienyl, or —CH
2
-phenyl;
R
3
is
and the pharmaceutically acceptable salts thereof.
In a most preferred embodiment, the present invention provides the compounds:
5-Pyridin-2-yl-thiophene-2-sulfonic acid (3,5-di-tert-butyl-4-hydroxy-benzyl)-pyridin-3-yl-amide;
(Cyclohexylmethyl-methanesulfonyl-amino)-(3,5-di-tert-butyl-4-hydroxy-phenyl)-acetic acid ethyl ester;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-methyl-N-pyridin-3-yl-benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-fluoro-N-pyridin-3-yl-benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-nitro-N-pyridin-3-yl-benzenesulfonamide;
Thiophene-2-sulfonic acid (3,5-di-tert-butyl-4-hydroxy-benzyl)-6-methoxy-pyridin-3-yl-amide;
Thiophene-2-sulfonic acid (3,5-di-tert-butyl-4-hydroxy-benzyl)-pyridin-3-yl-amide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-acetamido-N-pyridin-3-yl-benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-methoxy-N-pyridin-3-yl benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-3-nitro-N-pyridin-3-yl-benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-3-N-pyridin-3-yl-benzenesulfonamide;
N-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-N-pyridin-3-yl-methanesulfonamide;
N-(2-Chloro-pyridin-3-yl)-N-(3,5-di-tert-butyl-4-hydroxy-benzyl)-4-methyl-benzenesulfonamide;
N-(3,5-di-tert-butyl-4-hydroxybenzyl)-2-bromo-N-pyridin-3-yl-benzenesulfonamide;
N-(6-Chloro-pyridin-3-yl)-N-(3,5-di-tert-butyl-4-hydroxybenzyl)-4-methyl-benzenesulfonamide;
N-(3,5-di-tert-butyl-4-hydroxybenzyl)-2-naphthalene-N-pyridin-3-yl-sulfonamide;
N-(3,5-di-tert-butyl-4-hydroxy-benzyl)-N-(6-methoxy-pyridin-3-yl)-4-methyl-benzenesulfonamide; and
N-(3,5-di-tert-butyl-4-hydroxybenzyl)-3-bromo-N-pyridin-3-yl-benzenesulfonamide.
Also provided is a pharmaceutical composition comprising a compound of Formula I.
Also provided is a method of lowering plasma Lp(a) in a patient, the method comprising administering to a patient in need of Lp(a) lowering a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula I.
Also provided is a method of treating coronary heart disease, the method comprising administering to a patient having coronary heart disease a therapeutically effective amount of a compound of Formula 1.
Also provided is a method of treating or preventing restenosis, the method comprising administering to a patient having restenosis or at risk of having restenosis a therapeutically effective amount of a compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The term “alkyl” means a straight or branched hydrocarbon having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also be substituted with one or more of the substituents listed below for aryl.
The term “aryl” means an aromatic ring such as phenyl, 5-fluorenyl, 1-naphthyl, or 2-naphthyl group, unsubstituted or substituted by 1 to 3 substituents which can be selected from, but not limited to, —C
1
-C
6
alkyl, —O—C
1
-C
6
alkyl, and —S—C
1
-C
6
alkyl, —OH, —SH, —F, —CN, —Cl, —Br, —I, —CF
3
, —NO
2
, —CO
2
H, —CO
2
C
1
-C
6
alkyl, —NH
2
, —NHC
1
-C
6
alkyl, N(C
1
-C
6
alkyl)
2
, or
The term “heteroaryl” means an aromatic ring containing one or more heteroatoms. Examples of heteroaryl radicals include thienyl, furyl, pyrrolyl, pyridyl, imidazolyl, or indolyl group, substituted or unsubstituted by 1 or 2 substituents from the group of substituents described above for aryl. Examples of heteroatoms include nitrogen, oxygen, sulfur, and phosphorus.
The term “cycloalkyl” means a saturated hydrocarbon ring which contains from 3 to 7 carbon atoms, and includes for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like. The cycloalkyl group can be substituted with from 1 to 3 substituents from the group of substituents described above for aryl.
The symbol “−” means a bond.
The term “patient” means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
A “therapeutically effective amount” is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of or prevents atherosclerosis, coronary heart disease, or restenosis, or lowers plasma levels of Lp(a). A therapeutically effective amount of a compound of the present invention can be easily determined by one skilled in the art by administering a quantity of a compound to a patient and observing the result. In addition, those skilled in the art are familiar with identifying patients having restenosis, coronary heart disease, or atherosclerosis o
Lee Helen Tsenwhei
Ramharack Randy Ranjee
Roth Bruce David
Sexton Karen Elaine
Ashbrook Charles W.
Coppins Janet L
Rotman Alan L.
Warner-Lambert & Company
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