Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-14
2001-07-31
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S220000
Reexamination Certificate
active
06268364
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the field of anti-atherosclerotic agents and specifically relates to compounds, compositions and methods for treating atherosclerotic conditions such as dysliproteinimias and coronary heart disease. This invention specifically relates to substituted tetrahydro-1,3,5-triazin-2[1H]-thione derivatives that elevate HDL cholesterol 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 (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. 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.,
Circulation,
66 (
Suppl.
1) (1982), 102; 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..
2, (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 would be of utility as anti-atherosclerotic agents, useful particularly in the treatment of dysliproteinimias and coronary heart disease.
PRIOR ART
U.S. Pat. No. 3,505,057 and U.S. Pat. No. 3,505,323 (E.I. DuPont de Nemours and Co, Apr. 7, 1970) disclose 1-aryl-tetrahydro-s-triazin-2[1H]-thiones and their use as herbicidal agents.
U.S. Pat. No 4,193,994 (Pfizer Inc., Mar. 18, 1980) discloses 1-(o-tolyl)-3,5-disubstituted tetrahydro-s-triazin-2[1H]-thiones and their use as acaricidal agents.
Zhurnal Obshchei Khimii,
Vol. 61, No. 8, (1991), pp. 1870-1873 , English translation (1992), pp. 1728-1730 (Plenum Publishing Co.), report the synthesis of 1-aryl-3, 5-di-(tert-butyl)-terahydro-triazin-2[1H]-thiones with no stated specific utility.
Khim. Geterotsikl, Soedin.
(1986), pp. 976-980, reports the mass spectra of 1-aryl-3,5disubstituted-tetrahydro-triazin-2[1H]-thiones with no stated specific utility.
DESCRIPTION OF THE INVENTION
In accordance with this invention, there are provided 1-(aryl substituted)-3,5-disubstituted tetrahydro-triazin-2[1H]-thiones which are useful as antiatherosclerotic agents.
More particularly, this invention provides antitherosclerotic agents of formula 1 having the structure
wherein
R
1
, R
2
, R
3
, R
4
, and R
5
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, phenylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy 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;
R
6
is hydrogen; and
R
7
is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, or arylalkyl of 7-12 carbon atoms
or a pharmaceutically acceptable salt thereof.
With respect to the above compounds, it is preferred that R
1
, R
2
, R
3
, R
4
, and R
5
are each, independently, hydrogen, halogen, or alkyl of 1-6 carbon atoms.
This invention also provides a method of treating or inhibiting atherosclerosis, cardiovascular disease, or dyslipoproteinimias, and improving the HDL/LDL cholesterol ratio in a mammal in need thereof which comprises administering a compound of formula 1 having the structure
wherein
R
1
, R
2
, R
3
, R
4
, and R
5
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, phenylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy 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;
R
6
is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, or arylalkyl of 7-12 carbon atoms; and
R
7
is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, or arylalkyl of 7-12 carbon atoms or a pharmaceutically acceptable salt thereof.
With respect to the above methods, it is preferred that R
6
is alkyl of 1-6 carbon atoms; that R
6
is alkyl of 1-6 carbon atoms, and R
1
, R
2
, R
3
, R
4
, and R
5
are each, independently, hydrogen, halogen, or alkyl of 1-6 carbon atoms. It is more preferred that R
6
is 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 term halo includes 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 aryl moiety of the arylalkyl and aryloxy substituents include radicals such as benzyl, phenyl and naphthyl.
As used in describing this invention, the term “compounds of this invention” includes the broader description encompassing the formula used in accordance with the above methods, as well as the narrower description encompassing the formula used in accordance with the above novel compounds.
The pharmaceutically acceptable salts are those derived from organic and inorganic acids such as, but not limited to: acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluenesulfonic and similarly known acceptable acids.
The 1-(aryl substituted)-3,5-disubstituted tetrahydro-triazin-2[1H]thiones of this invention are preferentially prepared by reacting an appropriately substituted aromatic thiourea with formaldehyde and an amine (Mannich reaction; see J. Marsh,
Advanced Organic Chemistry,
3
rd Ed
,, Wiley-Interscience, NY, page 800) as shown in Scheme 1.
wherein R
1
, R
2
, R
3
, R
4
, R5, R
6
, and R
7
are as described above for formula 1.
The appropriately substituted aromatic thioureas starting materials are either available commercially or are known in the art or can be prepared by procedures analogous to those in the literature for known compounds (see J. Marsh, Advanced Organic Chemistry, 3rd Ed., Wiley-Interscience, NY, page 1174).
Representative compound
Failli Amedeo A.
Memoli Kevin A.
Steffan Robert J.
Strike Donald P.
American Home Products Corporation
Balasubramanian Venkataraman
Milowsky Arnold S.
Raymond Richard L.
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