Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-09-28
2002-10-29
Killos, Paul J. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S562000, C560S016000, C562S428000, C564S017000
Reexamination Certificate
active
06472430
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to anti-atherosclerotic agents and more specifically, to compounds, compositions and methods for treating atherosclerotic conditions, such as dyslipoproteinemias and coronary heart disease. This invention specifically relates to amino thioxomethyl amino oxyacetic acid derivatives that elevate HDL cholesterol concentration and which may be useful for the treatment of atherosclerotic conditions such as, 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 (Ross et al,
Am. J. Med.,
11 (1951) 480-493; 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. Angiographical studies have shown that elevated level of some HDL particles in humans appears 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 tissues of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (Glomset,
J. Lipid 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; MacKinnon 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). Accordingly, agents which increase HDL cholesterol concentrations are useful as anti-atherosclerotic agents, particularly in the treatment of dyslipoproteinemias and coronary heart disease.
Ureas, thiorureas and derivatives thereof are known to be useful for treating various conditions. For example, European Patent No. 528 148 A1 discloses the use of N-phenyl thiourea derivatives (1) for the treatment of atherosclerosis by elevation of HDL-C serum levels. Among the compounds disclosed is 5-chloro-2-methylphenyl thioureido acetic acid (2). In all cases, one of R
1
or R
2
is hydrogen.
U.S. Pat. No. 3,282,987 claims the use of &agr;-ureidooxy carboxylic acids (3) and their derivatives as plant growth regulators and herbicides.
where R is hydrogen, alkyl, or chlorophenyl; and R
1
is hydrogen, or alkyl of 1-12 carbons.
U.S. Pat. No. 3,625,968 discloses compounds of the formula, R
1
and R2 may be identical or different and each denotes aliphatic, araliphatic, cycloaliphatic, or aromatic; R
1
may also be hydrogen.
U.S. Pat. No. 3,438,985 discloses similar compounds where R
1
and R
2
represents hydrogen or lower alkyl.
French Patent No. 1,432,738 also discloses similar compounds where R
1
is lower alkyl and R
2
is hydrogen.
SUMMARY OF THE INVENTION
In accordance with this invention there is provided thioxomethyl aminoxy acetic acid derivatives of Formula I:
wherein
R is lower alkyl;
R
1
is hydroxy, amino, or lower alkoxy;
R
2
and R
3
are each independently hydrogen, alkyl or aryl;
Ar is phenyl, indanyl, benzhydryl, or phenyl substituted with one or more members of the group consisting of halogen, lower alkyl, perfluoroalkyl, lower alkoxy, perfluoroalkylalkoxy, dialkylamino, and aryloxy; or pharmaceutically acceptable salts thereof.
This invention also provides methods of elevating HDL concentration and treating or inhibiting atherosclerosis and related coronary heart disease or dyslipoproteinemias and increasing the HDL cholesterol concentration in a mammal in need thereof comprising administering to and said mammal an effective amount of a compound of Formula I:
wherein
R is lower alkyl;
R
1
is hydroxy, amino, or lower alkoxy,
R
2
and R
3
are each independently hydrogen, alkyl or aryl;
Ar is phenyl, indanyl, benzhydryl, or phenyl substituted with one or more members of the group consisting of halogen, lower alkyl, perfluoroalkyl, lower alkoxy, perfluoroalkylalkoxy, dialkylamino, and aryloxy; or pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the present compounds are those represented by Formula I:
wherein
R is lower alkyl;
R
1
is lower alkoxy;
R
2
and R
3
are hydrogen;
Ar is phenyl, indanyl, or phenyl substituted with one or more members selected from the group consisting of halogen, lower alkyl, lower alkoxy, and aryloxy; or pharmaceutically acceptable salts thereof.
As used in the present application, the term “lower alkyl” and “lower alkoxy” include both straight chain and branched moieties having 1-6 carbon atoms. The term “alkyl” also included branched and straight chain moieties and is not limited in carbon number. The term “aryl” includes aromatic radicals of 6-12 carbon atoms. The term “halogen” includes fluorine, chlorine, bromine and iodine.
The pharmaceutically acceptable salts of the present compounds include those derived from organic and inorganic acids such as, but not limited to: acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, hydrochloric, hydrotoronic, phosphoric, nitric, sulfuric, methanesulfonic, toluene sulfonic, and similarly known, acceptable acids. The most preferred compounds of this invention are:
Ethyl [[[[(5-Chloro-2-methylphenyl)amino]thioxomethyl]methylamino]oxy]acetate;
Ethyl [[[[(4-Chloro-2-methylphenyl)amino]thioxomethyl]methylamino]oxy]acetate;
Ethyl [[[[(2,3-dihydro-1H-inden-5-yl)amino]thioxomethyl]methylamino]oxy]acetate;
Ethyl [[methyl[[(2-(1-methylethyl)phenyl]amino]thioxomethyl]methylamino]oxy]acetate;
Ethyl [[[[(2,5-dimethylphenyl)amino]thioxomethyl]methylamino]oxy]acetate;
Ethyl [[[[(2-methylpropyl)amino]thioxomethyl]methylamino]oxy]acetate;
Ethyl [[[[(4-phenoxyphenyl)amino]thioxomethyl]methylamino]oxy]acetate;
Ethyl [[[[(4-Chloro-2-methylphenyl)amino]thioxomethyl]ethylamino]oxy]acetate.;
Ethyl [[[[(5-Chloro-2-methylphenyl)amino]thioxomethyl](1-methylethyl)amino]oxy]acetate; and
Ethyl [[[[(5-Chloro-2-methylphenyl)amino]thioxomethyl](1-methylpropyl)amino]oxy]acetate
The compounds of the invention may be prepared readily according to the following reaction scheme or modification thereof using readily available starting materials, reagents and conventional synthetic procedures. It is also possible to make use of variants of these process steps, which in themselves are known to and well within the preparatory skill of the medicinal chemist.
In reaction scheme IR is alkyl, R
1
is alkyl, alkenyl, alkynyl, benzyl, aryl or substituted aryl, R
2
and R
3
are independently hydrogen, alkyl, alkenyl, alkynyl, benzyl, aryl or substituted aryl, Ar is phenyl, indanyl, benzhydryl, or phenyl optionally substituted with one or more groups selected from halogen, lower alkyl, perfluoroalkyl, l
Elokdah Hassan M.
Sulkowski Theodore S.
Killos Paul J.
Nagy Michael R.
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