Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-30
2002-07-09
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S469000
Reexamination Certificate
active
06417225
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to prophylactic/therapeutic agents for atherosclerosis or xanthomatosis, more specifically, prophylactic/therapeutic agents for atherosclerosis or xanthomatosis containing a 2,6-di-t-butylphenol derivative as an active ingredient.
PRIOR ART
Oxidative denaturation of low-density lipoprotein (LDL) has been known as one of important causes of the development and progress of atherosclerosis and xanthomatosis (Steinberg, D., Parthasarathy, S., Carew, T. E., Khoo, J. C. & Witztum, J. L. Beyond Cholesterol; Modifications of low-density lipoprotein that increase its atherogenicity. N. Engl. J. Med. 320; 915-924, 1989). However, reports have shown that probucol which is an antioxidant has no therapeutic effect on atherosclerosis in clinical tests (Walldius, G., Erikson, U., Olsson, A., Bergstrand, L., Hadell, K., Johansson, J., Kaijser, L., Lassvik, C., Molgaard, J., Nilsson, S., Elinder, L. S., Stenport, G. & Holme, I. The effect of probucol on femoral atheroscleroses: the Probucol Quantitative Regression Swedish Trial (PQRST). Am. J. Cardiol. 84, 875-883, 1994).
As to therapy of arteriosclerosis, HMGCoA reductase inhibitor which is an antihyperlipidemic agent has so far been reported to inhibit the progress of arteriosclerosis (Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383-1389, 1994). However, patients to be treated with the antihyperlipidemic agent are limited to hyperlipidemic patients, and the antihyperlipidemic agent is ineffective for arterosclerosis in the patients with familial hyperlipidemia. An antihyperlipidemic agent is considered to reduce the amount of LDL exposed to oxidative modification, thus showing an antiarteriosclerotic effect.
On the other hand, antioxidants capable of directly preventing oxidation of LDL are expected as prophylactic/therapeutic agents for atherosclerosis, but any drugs including the above-mentioned probucol have not been found to have a clinically sufficient effect as a prophylactic/therapeutic agent for atherosclerosis at present.
An object of the present invention is to provide a novel prophylactic/therapeutic agent for atherosclerosis having a clinically sufficient effect.
DISCLOSURE OF THE INVENTION
As a result of extensive research to solve the above problems, we found that compounds of general formula (1):
wherein
R
1
represents a hydrogen atom, an acyl group or an arylalkoxycarbonyl group,
R
2
represents a lower alkyl group,
R
3
represents a hydrogen atom or a lower alkyl group, and
R
4
, R
5
and R
6
may be identical or different and each represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group or an optionally substituted arylalkyl group, or
R
2
and R
4
together with the oxygen atom may form a furan or dihydrofuran ring, or
R
5
and R
6
may combine to form a cycloalkyl group or a heterosubstituted cycloalkyl group in which one or more methylene groups of the cycloalkyl group are replaced by oxygen, sulfur or alkyl-substituted nitrogen atoms, provided that R
6
is absent when R
2
and R
4
together with the oxygen atom form a furan ring have a potent inhibitory effect against atherosclerosis in rabbit atherosclerosis models and murine atherosclerosis models as well as a potent inhibitory effect against xanthomas in murine xanthoma models.
Compounds of general formula (1) have been shown in JPA No. 6-206842/94. The publication contains the antioxidative data of the compounds demonstrating that they are useful as therapeutic agents for atherosclerosis, myocardial infarction and other diseases as well as that they are effective as antioxidants for ischemic organ disorders such as atherosclerosis, myocardial infarction, cerebral apoplexy, etc., but does not contain any test examples in which models are employed.
MOST PREFERRED EMBODIMENTS OF THE INVENTION
For the definition of R
1
in general formula (1), the acyl group preferably contains 1 to 10 carbon atoms, the examples of which include acetyl, formyl, propionyl and benzoyl groups. The arylalkoxycarbonyl group preferably contains 7 to 11 carbon atoms, the examples of which include a benzyloxycarbonyl group.
R
1
is preferably a hydrogen atom or an acyl group, more preferably a hydrogen atom. When R
1
is an acyl group, it is preferably an acetyl group.
The lower alkyl group for R
2
and R
3
means a straight or branched alkyl group containing 1 to 6 carbon atoms, the examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl group.
R
3
is preferably a hydrogen atom.
The alkyl group for R
4
, R
5
and R
6
means a straight or branched alkyl group preferably containing 1 to 20, more preferably 1 to 10 carbon atoms, the examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl, i-amyl, hexyl, heptyl, octyl, nonyl and decyl groups. The alkenyl group means a straight or branched alkenyl group preferably containing 2 to 20, more preferably 2 to 10 carbon atoms, the examples of which include vinyl, allyl, butenyl, pentenyl, geranyl and farnesyl groups. The alkynyl group means a straight or branched alkynyl group containing 2 to 20, preferably 2 to 10 carbon atoms, the examples of which include ethynyl, propynyl and butynyl groups. The aryl group preferably contains 6 to 20, more preferably 6 to 10 carbon atoms, the examples of which include phenyl, tolyl, xylyl, biphenyl, naphthyl, anthryl and phenanthryl groups. The arylalkyl group means an alkyl group having an aromatic hydrocarbon substituted for a hydrogen atom on the alkyl group, preferably containing 7 to 20, preferably 7 to 11 carbon atoms, the examples of which include benzyl and phenethyl groups.
The above-mentioned alkyl, alkenyl, alkynyl, aryl and arylalkyl groups may have one or more substituents selected from halogen atoms, lower alkyl, lower alkoxy, aryloxy containing 6 to 10 carbon atoms, hydroxy, amino, nitro and/or trifluoromethyl groups. Specifically, halogen atoms include chlorine, bromine, iodine and fluorine; lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl groups; alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy groups; and aryloxy groups include phenoxy, 3,5-di-t-butyl-4-hydroxy-2-methylphenoxy and naphthoxy groups.
Preferably, R
2
and R
4
together with the oxygen atom may form a furan or dihydrofuran ring, which is fused with the benzene ring of general formula (1) to form a benzofuran or dihydrobenzofuran ring, respectively. More preferably, R
2
and R
4
together with the oxygen atom form a dihydrofuran ring, and R
6
is absent when R
2
and R
4
together with the oxygen atom form a furan ring.
The cycloalkyl group formed by R
5
and R
6
is preferably a cycloalkyl group containing 3 to 8 carbon atoms, the examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. The examples of the heterosubstituted cycloalkyl group in which one or more methylene groups of the cycloalkyl group are replaced by oxygen, sulfur or C1-6 alkyl-substituted nitrogen atoms includes, for example, tetrahydrothiopyranyl, N-methylpiperidyl and tetrahydropyranyl groups. A heterosubstistituted cycloalkyl group containing one or more oxygen atoms is preferred, and a tetrahydropyranyl group is especially preferred.
Especially preferred compounds of general formula (1) having the above-defined substituents are as follows:
4,6-di-t-butyl-5-hydroxy-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-2,2-diethyl-5-hydroxy-2,3-dihydrobenzofuran;
4,6-di-t-butyl-2,2-di-n-propyl-5-hydroxy-2,3-dihydrobenzofuran;
4,6-di-t-butyl-2,2-di-n-butyl-5-hydroxy-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2-octylbenzofur
Browdy and Neimark
Chugai Seiyaku Kabushiki Kaisha
Powers Fiona T.
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