Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-06
2004-02-03
Morris, Patricia L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S233000
Reexamination Certificate
active
06686476
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to antiatherosclerotic agents and more specifically to compounds, compositions and methods useful for elevating HDL cholesterol concentration which may be useful in the treatment of atherosclerosis and related conditions, such as dyslipoproteinemias and coronary heart disease.
BACKGROUND OF THE INVENTION
Numerous studies have demonstrated that both the risk of coronary heart disease (CHD) in humans and the severity of experimental atherosclerosis in animals are inversely correlated with serum HDL cholesterol (HDL—C) concentrations (Russ et al.,
Am. J. Med
., 11 (1951) 480-483; Gofman et al.
Circulation
, 34 (1966), 679-697; Miller and Miller,
Lancet,
1 (1975), 16-19; Gordon et al.,
Circulation,
79 (1989), 8-15; Stampfer et al.,
N. Engl. J. Med
., 325 (1991), 373-381; Badimon et al.,
Lab. Invest
., 60 (1989), 455-461). Atherosclerosis is the process of accumulation of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral arterial vessels and subsequent myocardial infarction and stroke. Angiographic studies have shown that elevated levels of some HDL particles in humans appear to be correlated to a decreased number of sites of stenosis in the coronary arteries of humans (Miller et al.,
Br. Med. J
., 282 (1981), 1741-1744).
There are several mechanisms by which HDL may protect against the progression of atherosclerosis. Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al.,
Arteriosclerosis
, 6 (1986), 434-441). Data of this nature suggest that one antiatherogenic property of HDL may lie in its ability to deplete tissue of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset,
J. Lipi Res
., 9 (1968), 155-167). This has been supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al.,
J. Biol. Chem
., 258 (1983), 7161-7167; McKinnon et al.,
J. Biol. Chem
., 261 (1986), 2548-2552). In addition, HDL may serve as a reservoir in the circulation for apoproteins necessary for the rapid metabolism of triglyceride-rich lipoproteins (Grow and Fried,
J. Biol. Chem
., 253, (1978), 1834-1841; Lagocki and Scanu,
J. Biol. Chem
., 255 (1980), 3701-3706; Schaefer et al.,
J. Lipid Res
., 23 (1982), 1259-1273). More recently, as a possible mechanism for protection against the development of atherosclerosis, Cockerill et. al. (
Arterioscler., Thromb., Vasc. Biol
, 15, (1995), 1987-1994) have demonstrated that plasma HDL's inhibit the cytokine-induced expression of endothelial cell adhesion molecules (VCAM-1 and ICAM-1) in a concentration dependent and cell specific manner. Accordingly, it is believed that agents which increase HDL cholesterol concentration would be of utility as anti-atherosclerotic agents, useful particularly in the treatment of dyslipoproteinimias and coronary heart disease.
Ureas, thioureas and derivatives thereof are known to be useful for the treatment of various conditions. For example, the use of urea and thiourea derivatives as tyrosine kinase inhibitors, to inhibit cell proliferation and differentiation in the treatment of cancer is disclosed in WO 9640673-A1. The use of [(alkoxy) pyridinyl] amino derivatives to inhibit the secretion of gastric acid is disclosed in WO-9315055. N-phenyl thiourea derivatives and their use in the treatment of atherosclerosis is disclosed in CA-2072704. The use of bis-aryl ureas and related compounds as cardiovascular agents is disclosed in CA-2132771, while the administration of ureas and thioureas for the treatment of ischaemia, asthma, Parkinson's disease, epilepsy, and urinary incontinence is disclosed in U.S. Pat. No. 5,547,966. Substituted thioureas and isothioureas are also disclosed in U.S. Pat. No. 5,185,358.
The treatment of atherosclerosis with certain ureas, thioureas and derivatives thereof has been suggested in Japanese Patent 83-01841 (the use of ureas and thioureas as inhibitors of squalene epoxidase); U.S. Pat. No. 4,623,662 (the use of certain urea and thiourea compounds to lower serum lipids in warm-blooded animals); and U.S. Pat. Nos. 4,387,105 and 4,387,106 (the use of di(aralkyl) ureas and di(aralkyl) thioureas to inhibit fatty acyl CoA: cholesterol acyl transferase). However, the treatment of atherosclerosis, and the related cardiovascular disease and dyslipoproteinemias, through the elevation of serum HDL cholesterol concentrations with the present urea and thiourea derivatives, has heretofore not been recognized.
SUMMARY OF THE INVENTION
The present invention relates to antiatherosclerotic agents comprising 1-aryl-3-heteroaryl-thioureas and 1-aryl-3-heteroaryl-isothioureas represented by formulas I and II:
wherein
R is
wherein R
9
, R
10
, R
11
, R
12
, R
13
, and R
14
are each, independently, hydrogen or a lower alkyl of 1-6 carbon atoms;
R
6
, and R
7
are each, independently, hydrogen, lower alkyl of 1-6 carbon atoms, or CH
2
COOR
8
, where R
8
is a lower alkyl of 1-6 carbon atoms; and
X=O or S;
R
1
is hydrogen or a lower alkyl of 1-6 carbon atoms;
R
2
, R
3
, and R
4
are each, independently, hydrogen or halogen; and
R
5
is a lower alkyl of 1-6 carbon atoms;
or a pharmaceutically acceptable salt thereof.
The present invention is further directed to methods of elevating the HDL concentration and treating atherosclerosis and related coronary heart disease and dyslipoproteinemias in a mammal in need thereof, comprising administering to the mammal an effective amount of the antiatherosclerotic agents of formulas I and II:
wherein
R is
wherein R
9
, R
10
, R
11
, R
12
, R
13
, and R
14
are each, independently, hydrogen or a lower alkyl of 1-6 carbon atoms;
R
6
, and R
7
are each, independently, hydrogen, lower alkyl of 1-6 carbon atoms, or CH
2
COOR
8
, where R
8
is a lower alkyl of 1-6 carbon atoms; and
X is O or S;
R
1
is hydrogen or a lower alkyl of 1-6 carbon atoms;
R
2
, R
3
, and R
4
are each, independently, hydrogen or halogen; and
R
5
is a lower alkyl of 1-6 carbon atoms;
or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the antiatherosclerotic agents of the present invention are those represented by formulas I and II where:
R is
wherein:
R
9
, R
10
, R
11
, R
12
, R
13
, and R
14
are each, independently, hydrogen or lower alkyl of 1 to 6 carbon atoms;
R
6
and R
7
are, each independently, lower alkyl of 1 to 6 carbon atoms; and
X is O or S;
R
1
is hydrogen;
R
2
, R
3
, and R
4
are each, independently, hydrogen or halogen; and
R
5
is a lower alkyl of 1 to 6 carbon atoms;
or a pharmaceutically acceptable salt thereof.
As used in this invention, the term “lower alkyl” includes both straight chain as well as branched moieties. The terms “halo” or “halogen” includes fluorine, chlorine, bromine, and iodine.
The compounds of Formula I are known to be unstable to salt formation. Accordingly, the expression “pharmaceutically acceptable salts” as used herein should be construed as applying only to the compounds of Formula II. The pharmaceutically acceptable salts of the present compounds include those derived from organic and inorganic acids, including, but not limited to, acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methane sulfonic, toluene sulfonic and similarly known acceptable acids.
The most preferred compounds according to this invention are:
1-(5-Chloro-2-methyl-phenyl)-3-(thiazol-2-yl)-thiourea;
1-(5-Chloro-2-methyl-phenyl)-3-(4-methyl-oxazol-2-yl)-thiourea;
1-(5-Chloro-2-methyl-phenyl)-3-(5-methyl-[1,3,4]thiadiazol-2-yl)-thiourea;
1-(5-Chloro-2-methyl-phenyl)-3-(1H-pyrazol-3-yl)-thiourea;
1-(5-Chloro-2-methyl-phenyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea;
1-(5-Chloro-2-methyl-phenyl)-3-(4-methyl-thiazol-2-yl)-thiourea;
1-(5-Chloro-2-methyl-phenyl)-3-(4,5-dimethyl-thiazol-2-yl)-thiourea;
1-(5-Chloro-2-methyl-phenyl)-3-(3-methyl-isothiazol-5-yl)-thiourea;
1-(5-Chlor
Failli Amedeo A.
Steffan Robert J.
Morris Patricia L.
Nagy Michael R.
Wyeth
LandOfFree
Substituted 1-aryl-3-heteroaryl-thioureas and substituted... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted 1-aryl-3-heteroaryl-thioureas and substituted..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted 1-aryl-3-heteroaryl-thioureas and substituted... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3350368