Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-28
2003-05-13
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S268000
Reexamination Certificate
active
06562814
ABSTRACT:
FIELD OF THE INVENTION
This 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 3-thioxo-[1,2,4]-oxadiazinan-5-one 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.
U.S. Pat. No. 3,438,985 discloses a process for preparing 1,2,4-oxadiazinan-3,5-diones, useful as anticonvulsants.
wherein R and R
1
represent hydrogen and alkyl. Preferred compounds are those where R
1
represents hydrogen and R represents hydrogen or lower alkyl.
U.S. Pat. No. 3,625,968 discloses the production of 1,2,4-oxadiazinan-3,5-diones useful as herbicides, diuretics and antiphlogistic pharmaceuticals,
wherein R
1
and R
2
may be different or identical and each denotes an aliphatic, araliphatic, cycloaliphatic or aromatic group. R
1
may also be hydrogen and R
2
may also denote arylsulfonyl radical or heterocyclic radical.
French Patent No. 1,432,738 also discloses a process for the preparation of 1,2,4-oxadiazinan-3,5-diones according to the following formula:
wherein R
1
and R
2
are hydrogen, alkyl, cycloalkyl, aryl, or aralkyl, same or different, the aryls optimally substituted by alkyl, halogen, nitro or amino.
The preparation of 5-thioxo-1,2,4-oxadiazinan-3-ones by treatment of 1,2,4-oxadiazin-3,5-diones with phosphorus pentasulfide is cited in Berkowitz, Phillip T. et al.,
J. Org. Chem.,
41, 3128 (1976) and
J. Med. Chem.,
20, 134 (1977). These compounds are used as intermediates in the preparation of 5-substituted amino-1,2,4-oxadiazin-3-ones useful as antibacterial agents.
SUMMARY OF THE INVENTION
In accordance with this invention there are provided substituted 3-thioxo 1,2,4-oxadiazin-5-ones of Formula I:
wherein
R is lower alkyl, alkenyl of 2-6 carbon atoms, or alkynyl of 2-6 carbon atoms;
R
1
and R
2
are each independently hydrogen alkyl, or aryl; and
Ar is phenyl, indanyl, benzhydryl, or phenyl substituted with one or more members of the group selected from the group consisting of halogen, lower alkyl, perfluoroalkyl, lower alkoxy, perfluoroalkylalkoxy, dialkylamino, and aroyloxy; or pharmaceutically acceptable salts thereto.
The present invention also provides methods of treating arteriosclerosis and related coronary heart disease or dyslipoproteinemias and improving the HDL concentration in a mammal in need thereof which comprises administering to the mammal a compound of Formula I:
wherein
R is lower alkyl, alkenyl of 2-6 carbon atoms, or alkynyl of 2-6 carbon atoms;
R
1
and R
2
are each independently hydrogen alkyl, or aryl; and
Ar is phenyl, indanyl, benzhydryl, or phenyl, substituted with one or more members of the group consisting of halogen, alkyl, perfluoroalkyl, lower alkoxy, perfluoroalkylalkoxy, dialkylamino, and aroyloxy; or pharmaceutical acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the present compounds are those represented by Formula I:
wherein
R is alkyl;
R
1
and R
2
are each hydrogen; and
Ar is phenyl, indanyl, benzhydryl, or phenyl substituted with one or more members of the group consisting of halogen, lower alkyl, lower alkoxy, and aroyloxy.
As used herein, the terms “lower alkyl” and “lower alkoxy” are meant to include both straight and branched chain moieties containing 1-6 carbon atoms. The term “aryl” is meant to include aromatic radicals of 6-12 carbon atoms. The term “halogen” is meant to include fluorine, chlorine, bromine and iodine.
The pharmaceutically acceptable salts of the present compounds include those derived from organic and inorganic acids such as acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluene sulfonic, and similarly known acceptable acids.
The most preferred compounds of this invention are:
4-(5-Chloro-2-methylphenyl)-2-methyl-3-thioxo-1,2,4-oxadiazin-5-one;
4-(5-Chloro-2-methylphenyl)-2-ethyl-3-thioxo-1,2,4-oxadiazin-5-one;
4-(4-Chloro-2-methylphenyl)-2-methyl-3-thioxo-1,2,4-oxadiazin-5-one;
4-(Indan-5-yl)-2-methyl-3-thioxo-1,2,4-oxadiazin-5-one;
4-(2,5-Dimethylphenyl)-2-methyl-3-thioxo-1,2,4-oxadiazin-5-one;
4-(6-Chloro-2-methylphenyl)-2-methyl-3-thioxo-1,2,4-oxadiazin-5-one;
4-(2-Isopropylphenyl)-2-methyl-3-thioxo-1,2,4-oxadiazin-5-one;
4-(Diphenylmethyl)-2-methyl-3-thioxo-1,2,4-oxadiazin-5-one;
4-(4-t-Butylylphenyl)-2-methyl-3-thioxo-1,2,4-oxadiazin-5-one;
4-(4-Phenoxyphenyl)-2-methyl-3-thioxo-1,2,4-oxadiazin-5-one; and
4-(5-Chloro-2-methoxyphenyl)-2-methyl-3-thioxo-1,2,4-oxadiazin-5-one.
The compounds of the invention can be readily prepared 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 the following reaction scheme R is alkyl, R
1
is alkyl, alkenyl, or alkynyl, R
2
, R
3
and R
4
are independently hydrogen, halogen, alkyl, alkenyl, etc.
The aminooxy acetate ester hydrochloride (2) was prepared by esterifying carboxymethoxyl amine hemihydrochloride (1) with the appropriate alcohol saturated with hydrogen chloride at ambient temperature for 24 hours. Reaction of 2 at ambient temperature over a period of 3-5 hours with ethyl- or methyl-chloroformate in the presence of base such as sodium bicarbonate and a solvent such as alcohol afforded the oxy-carbamate (3). Alkylation of 3 with alkyl iodides (excess) in refluxing alcohol under basic conditions over a period of 2 to 3 hours afforded 4. Hydrolysis of 4
Elokdah Hassan M.
Sulkowski Theodore S.
Ford John M.
Nagy Michael R.
Wyeth
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