Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-02
2002-01-22
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S315000
Reexamination Certificate
active
06340687
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 dyslipoproteinimias and coronary heart disease. This invention specifically relates to substituted tetrahydro-pyrimidine-2(1H)-thione derivatives that elevate HDL cholesterol (HDL-C) concentration and which may be useful for the treatment of atherosclerotic conditions 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, 480-483 (1951); Gofman et al.,
Circulation,
34, 679-697 (1966); Miller and Miller,
Lancet,
1, 16-19 (1975); Gordon et al.,
Circulation,
79, 8-15 (1989); Stampfer et al.,
N. Engl. J. Med.
325, 373-381 (1991); Badimon et al.,
Lab. Invest.,
60, 455-461 (1989)). Atherosclerosis is the process of the 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, 1741-1744 (1981)).
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, 434-441 (1986)). 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. Lipid Res.,
9, 155-167 (1968)). This has been supported by experiments showing efficient transfer of cholesterol from HDL to the liver (Glass et al.,
J. Biol. Chem.,
258 7161-7167 (1983); McKinnon et al.,
J. Biol. Chem.,
26, 2548-2552 (1986)). 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, 1834-1841 (1978); Lagocki and Scanu,
J. Biol. Chem.,
255, 3701-3706 (1980); Schaefer et al.,
J. Lipid Res.,
23, 1259-1273 (1982)). Accordingly, agents which increase HDL cholesterol concentrations would be of utility as antiatherosclerotic agents, useful particularly in the treatment of dyslipoproteinimias and coronary heart disease.
Cyclic ureas and thioureas have heretofore been used for various purposes, all of which are unrelated to their antiatherosclerotic effects.
For example, JP 3-176475 discloses the preparation of cyclic ureas and thioureas such as 1,3-disubstituted tetrahydro-pyrimidine-2-thiones and their use as herbicidal agents. European Patent Application Publication Nos. 0612741 and 0503548 disclose cyclic urea (thiourea) derivatives useful as aggregation inhibitors and inhibitors of cell-cell and cell-matrix interactions, respectively.
The
J. Chem. Soc. Perkin I,
6, 1622-1625 (1981) describes the regioselective preparation of 3,4-dihydro and 3,4,5,6-tetrahydro-pyrimidine-2(1H)-ones and the corresponding thiones useful as intermediates in the synthesis of diamines, thiazines and pyrimidine-2(1H)-ones.
Synthesis,
1175-1180 (1994) describes the synthesis of antiinflammatory pyrimidobenzimidazoles from 1-aryl-6-hydroxy-tetrahydro-pyrimidine-2-(1H)-thiones.
The use of 6-hydroxy-tetrahydro-pyrimidine-2(1H)-thiones as antiamoebic and antihelmintic agents is disclosed in
Indian Drugs,
31, 317-320 (1994). Other uses of similar compounds are disclosed in, e.g.,
Arzneim.
-
Forsch.,
40, 55-57 (1990) (1-phenyl-tetrahydro-pyrimidine-2(1H)-thione as immunomodulator agents); and
Farmakol. Toksikol.
(Moscow), 41, 494-497 (1978) (1-substituted 4-hydroxy-hexahydro-pyrimidine-2-thione derivatives as radioprotectors). The production of similar thione derivatives, without reference to a specific utility has been disclosed in
Dokl. Bolg. Akad. Nauk.,
35, 49-51 (1982) (the mass spectra of 1-substituted 2-oxo (or 2-thio)hexahydropyrimidines);
Khim. Gerotsikl. Soedin.,
1273-1278 (1983) (the mass spectra of 1-substituted 4-hydroxy-hexahydro-pyrimidine-2-thiones; and
Khim. Gerotsikl. Soedin.,
889-895 (1989) (the synthesis of 4-hydroxy-hexahydro-pyrimidine-2-thiones). None of these references disclose the use of cyclic ureas and thioureas to raise the HDL cholesterol concentrations in mammals.
SUMMARY OF THE INVENTION
In accordance with this invention, there are provided 1-(aryl-substituted)-3-substituted tetrahydro-pyrimidine-2(1H)-thiones which are useful as antiatherosclerotic agents.
More particularly, this invention provides antiatherosclerotic agents of Formula 1 having the following structure:
wherein
R
1
is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms; and
R
2
, R
3
, R
4
, R
5
, and R
6
are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, aralkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy of 6-12 carbon atoms, aralkyloxy of 7-12 carbon atoms, fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of 1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, —SCF
3
, nitro, alkylamino in which the alkylamino moiety has 1-6 carbon atoms, or dialkylamino in which each alkyl group has 1-6 carbon atoms;
or a pharmaceutically acceptable salt thereof.
This invention also provides methods of elevating the HDL concentration and treating or inhibiting atherosclerosis and related coronary heart disease, or dyslipoproteinemias, and improving the HDL/LDL cholesterol ratio in a mammal in need thereof which comprises administering to the mammal a compound of Formula 1 having the structure:
wherein
R
1
is hydrogen, alky of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or phenylalkyl of 7-10 carbon atoms; and
R
2
, R
3
, R
4
, R
5
, and R
6
are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, aralkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy of 6-12 carbon atoms, aralkyloxy of 7-12 carbon atoms, fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of 1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, —SCF
3
, nitro, alkylamino in which the alkylamino moiety has 1-6 carbon atoms, or dialkylamino in which each alkyl group has 1-6 carbon atoms;
or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
It is preferred that the compounds of the present invention are represented by the compounds of Formula 1 where R
1
is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms or cycloalkyl of 3-8 carbon atoms; and R
2
, R
3
, R
4
, R
5
, and R
6
are each, independently, hydrogen, halogen or alkyl of 1-6 carbon atoms.
More preferably, the compounds of the present invention are represented by the compounds of Formula 1 where R
1
is methyl, ethyl, isopropyl or cyclobutyl; and R
2
, R
3
, R
4
, R
5
, and R
6
are each, independently, chlorine or methyl.
As used in describing this invention, the terms “alkyl”, “alkenyl”, and “alkynyl” include both straight chain as well as branched moieties. This includes the alkyl portions of substituents such as alkoxy, thioalkyl, alkylsulfinyl, alkylsulfonyl, fluoroalkoxy, and the like. The terms “halo” and “halogen” include fluorine, chlorine, bromine, and iodine. Fluoroalkoxy includes mono-, di-, tri-, and polyfluorinated alkoxy moieties, such as —OCF
3
, —OCH
2
F, —OCHF
2
, —OCH
2
CF
3
, and the like. The term “aryl” incl
Failli Amedeo A.
Memoli Kevin A.
Shumsky Jay S.
Strike Donald P.
American Home Products Corporation
Ford John M.
Nagy Michael R.
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