Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-28
2002-09-10
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S285000, C514S292000, C514S293000, C544S252000, C546S070000, C546S082000, C546S084000
Reexamination Certificate
active
06448255
ABSTRACT:
FIELD OF THE INVENTION
The present 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 compounds which 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 (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.
SUMMARY OF THE INVENTION
In accordance with this invention there is provided compounds of formula I:
wherein:
R is hydrogen, lower alkyl, alkenyl, alkynyl, aryl, heteroaryl, or aryl or heteroaryl substituted with one or more members of the group consisting of alkyl, hydroxy, alkoxy, perfluoroalkyl, perfluoroalkoxy, alkylthio, nitro, amino, mono- or di-alkylamino, and halogen;
D is C—H, carbon bound to R
5
or nitrogen;
R
1
, R
2
, R
3
, and R
4
are each independently hydrogen, alkyl, or taken together form a ring;
R
5
is one or more groups selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, perfluoroalkyl, perfluoroalkoxy, alkylthio, nitro, amino, mono- or di-alkylamino, or halogen;
n is an integer of 0-3;
or pharmaceutically acceptable salts thereof.
The present invention is further directed to a method of treating atherosclerosis in a mammal in need thereof which comprises administering to the mammal an anti-atherosclerotic effective amount of compound of Formula I:
wherein:
R is hydrogen, lower alkyl, alkenyl, alkynyl, aryl, heteroaryl, or aryl or heteroaryl substituted with one or more members of the group consisting of alkyl, hydroxy, alkoxy, perfluoroalkyl, perfluoroalkoxy, alkylthio, nitro, amino, mono or di-alkylamino, and halogen;
D is C—H, carbon bound to R
5
or nitrogen;
R
1
, R
2
, R
3
, and R
4
are independently hydrogen, alkyl, or taken together form a ring.
R
5
is one or more groups optionally selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, perfluoroalkyl, perfluoroalkoxy, alkylthio, nitro, amino, mono or di-alkylamino, or halogen;
n is an integer of 0-3;
or pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the present invention is directed to compounds of Formula I, wherein R is aryl; D is C—H; R
1
, R
2
, R
3
, and R
4
are each independently hydrogen, alkyl, or taken together form a ring; R
5
is halogen; n is 0-1; or pharmaceutically acceptable salts thereof.
As used herein, the term “lower alkyl” refers to both straight and branched chain moieties of 1-6 carbon atoms. 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, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluene sulfonic, and similarly known, acceptable acids.
The most preferred compounds of this invention are:
10-Hydroxy-2,2-dimethyl-10-phenyl-2,10-dihydroimidazo[1,2-b]isoquinolin-5(3H)-one;
11-(4-Fluorophenyl)-11-hydroxy-2,3,4,11-tetrahydro-6H-pyrimido[1,2-b]isoquinolin-6-one;
10-(4-Fluorophenyl)-10-hydroxy-2,2-dimethyl-2,10-dihydroimidazo[1,2-b]isoquinolin-5(3H)-one;
6-(4-Fluorophenyl)-6-hydroxy-1,3,4,4a,6,12a-hexahydrobenzimidazo[1,2-b]isoquinolin-11 (2H)-one;
(2R,10S)-10-(4-Fluorophenyl)-10-hydroxy-2-methyl-2,10-dihydroimidazo[1,2-b]isoquinolin-5(3H)-one;
(2S, 10S)-10-(4-Fluorophenyl)-10-hydroxy-2-methyl-2,10-dihydroimidazo[1,2-b]isoquinolin-5(3H)-one; and
10-(4-Chlorophenyl)-10-hydroxy-2,2-dimethyl-2,10-dihydroimidazo[2,1-g][1,7]naphthyridin-5(3H)-one.
The compounds of the present 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 schemes, R is a group selected from hydrogen, lower alkyl, alkenyl, alkynyl, aryl, heteroaryl, aryl/heteroaryl optionally substituted with one or more groups selected from alkyl of 1-6 carbon atom, hydroxy, alkoxy, perfluoroalkyl, perfluoroalkoxy, alkylthio, nitro, amino, mono or di-alkylamino, or halogen; D is C—H, Carbon bound to R
5
or Nitrogen; R
1
, R
2
, R
3
, and R
4
are independently hydrogen, lower alkyl, or taken together as a ring; R
5
is one or more groups optionally selected from hydrogen, lower alkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, perfluoroalkyl, perfluoroalkoxy, alkylthio, nitro, amino, mono or di-alkylamino, or halogen, and n is an integer of 0-3.
Preparation of 3-carboxamido phthalides (VII) from o-acyl benzoic acids (II) in a 5-step process has been described in the literature (Hauser, C. R., Tetenbaum, M. T. and Hoffenberg, D. S.;
J. Org. Chem.,
23, 861 (1958)). The procedure, as outlined in scheme I, involves reduction of the o-acyl benzoic acid (II) to the lactone (III). Metalation of the 3-position of III and subsequent quenching with carbon dioxide afforded the lactone acid (V). Conversion of V to the corresponding acid chloride (VI) followed by treatment with ammonia afforded the 3-carboxamido phthalides (VII).
In the present invention, o-acyl benzoic acids (II) are converted to the corresponding 3-carboxamido phthalides (VII) in a one step process. The process is novel and widely applicable. Reaction of o-acyl benzoic acids with potassium cyanide (Scheme II) was carried out in acetic acid by heating in a steam bath for 17 to 70 hours either in a round bottom flask or in a s
Babiak John
Chai Sie-Yearl
Elokdah Hassan M.
Sulkowski Theodore S.
Nagy Michael R.
Rao Deepak R.
Wyeth
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