Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-11
2003-08-12
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S354000, C546S262000, C546S326000
Reexamination Certificate
active
06605624
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the field of preventing and/or treating cardiovascular disease, and specifically relates to compounds, compositions and methods for preventing and/or treating atherosclerosis and other coronary artery disease. More particularly, the invention relates to substituted pyridine compounds that inhibit cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein-I.
BACKGROUND OF THE INVENTION
Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye,
Atherosclerosis,
121, 1-12 (1996)). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.
Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society. High LDL cholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDL/LDL ratios. Inhibition of CETP by the subject compounds are shown to effectively modify plasma HDL/LDL ratios, and to check the progress and/or formation of these diseases.
CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall,
J. Lipid Res.,
34, 1255-74 (1993)). The movement of cholesteryl ester from HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy,
Medicinal Res. Revs.,
13, 139-59 (1993)). This exact phenomenon was first demonstrated by Swenson et al., (
J. Biol. Chem.,
264, 14318 (1989)) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. (
Biochim. Biophys. Acta
795, 743-480 (1984)) describes proteins from human plasma that +inhibit CETP. U.S. Pat. No. 5,519,001, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity.
There have been several reports of compounds that act as CETP inhibitors. Barrett et al. (
J. Am. Chem. Soc.,
188, 7863-63 (1996)) describes cyclopropane-containing CETP inhibitors. Pietzonka et al. (
Bioorg. Med. Chem. Lett,
6, 1951-54 (1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. (
Bioorg. Med. Chem. Lett.,
5, 605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds, as CETP inhibitors. Lee et al. (
J. Antibiotics,
49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (
Lipids,
25, 216-220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (
J. Lipid Res.,
35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP. Bisgaier et al. (
Lipids,
29, 811-8 (1994) describe 4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor.
A number of substituted pyridine compounds are known. For example, U.S. Pat. Nos. 4,609,399, 4,655,816; 4,692,184; 4,698,093; 4,789,395; 4,885,026; 4,936,905; 4,988,384; 5,037,469; 5,125,961; 5,129,943; 5,156,670; 5,169,432; and 5,260,262 each disclose novel substituted pyridines which are useful as herbicides and herbicide intermediates. No pharmacologic properties for the substituted pyridines are recited in these patents. Except as set forth below, the literature does not describe substituted pyridines as inhibitors of CETP.
Connolly et al. (
Biochem. Biophys. Res. Comm.
223, 42-47 (1996)), describe 4,4′-dithiopyridine, 2,2′-dithiopyridine, 6,6′-dithionicotinic acid and 2,2′-dithiobis (pyridine-N-oxide) as CTEP inhibitors. The isolated pyridine compounds tested by Connolly et al. were, at best, inhibitory only after a 16 hour pre-incubation period and would not be useful in situations requiring rapid and potent inhibition. Connolly et al. also neither addressed whether substitution of the reported pyridines would increase their potency nor suggested the testing or use of specific substituted pyridines.
European Patent Application 796 846 A1 describes certain 2-aryl-substituted pyridines for use in the treatment of lipoproteinaemia and hyperlipoproteinaemia.
European Patent Application 818 197 A1 describes certain 2-aryl-substituted pyridines for use in the treatment of hyperlipoproteinaemia and atherosclerosis.
U.S. Pat. No. 4,925,852 describes 3-demethylmevalonic acid derivatives for use as inhibitors of cholesterol biosynthesis.
U.S. Pat. No. 5,169,857 describes 7-(polysubstituted pyridyl)-hept-6-endates for use in the treatment of hyperproteinaemia, lipoproteinaemia or arteriosclerosis.
WO 98/04528 describes certain 4-aryl-pyridyl compounds as anti-hypercholesterolemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents.
SUMMARY OF THE INVENTION
The present invention is directed to a method for administering to a subject a therapeutically effective amount of a substituted pyridine of Formula I:
wherein:
R
2
and R
6
are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R
2
and R
6
is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
R
3
is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl,
—CHO,
—CO
2
R
7
, wherein R
7
is selected from the group consisting of hydrogen, alkyl and cyanoalkyl; and
wherein
R
15a
is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy, and
R
16a
is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsilyloxy;
R
4
is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthio
Connolly Daniel T.
Corley David G.
Flynn Daniel L.
Glenn Kevin C.
Hamme Ashton T.
Davis Zinna Northington
Harness & Dickey & Pierce P.L.C.
Pharmacia Corporation
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