Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-05-06
2000-08-15
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514446, 514462, 514469, 514708, 514709, 514710, 514711, 514712, 514713, 514724, 514728, 514731, 514733, 514734, 514736, 514738, 514739, A01N 4312
Patent
active
061037532
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to an intimal thickening inhibitory agent and more particularly an intimal thickening inhibitory agent comprising a 2,6-di-t-butylphenol derivative as an active ingredient.
BACKGROUND OF THE INVENTION
It is known that coronary sclerosis is a primary cause of ischemic heart diseases such as angina pectoris and cardiac infarction. Narrowing of the vascular lumen resulting from arteriosclerotic thickening of the intima brings about nutrition and oxygen deficiencies in the myocardial tissues to induce the above diseases. Percutaneous transluminal coronary angioplasty (hereinafter abbreviated as "PTCA") that has recently been developed as a treatment for the ischemic heart diseases such as angina pectoris and cardiac infarction is to physically dilate a blood vessel by inflating a balloon at the stenosis region of the coronary artery. However, the problem which has been recognized from the beginning of development of this treatment is that restenosis appears at the treated region within 3 to 6 months after the angioplasty at a frequency of about 40% (see Circulation, 77, pp. 361-371 (1988)).
Up to the present time, use of anticoagulants, antiplatelet agents or drugs having an inhibitory effect on proliferation of vascular smooth muscle cells has been attempted to prevent stenosis due to arteriosclerotic intimal thickening or restenosis after PTCA. Thus, an extensive research for such drug has been conducted (see, for example, JP 2-121922 A/90, JP 3-83923 A/91, JP 3-118383 A/91, JP 4-99775 A/92, JP 4-154720 A/92, JP 6-135829 A/94, JP 6-206842 A/94, JP 7-25768 A/95, JP 7-149641 A/95 and JP 7-223958 A/95). However, there has been found no drug having clinically sufficient inhibitory effect on vascular stenosis due to arteriosclerotic intimal thickening or restenosis due to intimal thickening after PTCA (see, Nihon Rinsyo, 52 (extra ed.), pp. 869-872 (1994)).
DISCLOSURE OF THE INVENTION
As a result of an extensive research in an attempt to solve the foregoing problem, it has been found that a compound represented by formula (1): ##STR3## wherein X represents an oxygen atom or a group of formula (2); ##STR4## wherein n represents an integer of from 0 to 2; R.sub.1 represents a hydrogen atom or an acyl group; group; represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted aryl group; or heterocyclic ring derived from a cycloalkyl group by substituting any one or more methylene groups on the ring with oxygen atoms, sulfur atoms or alkyl-substituted nitrogen atoms; form a benzofuran ring, a benzo[b]thiophene ring, a benzo[b]thiophene-1-oxide ring or a benzo[b]thiophene-1,1-dioxide ring, muscle cells as well as on intimal thickening in balloon injury models.
The fact that the compound represented by formula (1) is effective in the treatment and prevention of ischemic organopathy such as arteriosclerosis, cardiac infarction and apoplexy has already been revealed (see JP 6-206842 A/94, WO 94-08930, and WO 95-27710).
BEST MODE FOR CARRYING OUT THE INVENTION
In the above formula (1), the acyl groups include an acetyl group, a formyl group, a propionyl group, a benzoyl group, a benzyloxycarbonyl group, an aminoacetyl group, an N-methylaminoacetyl group, and an N,N-dimethylaminoacetyl group. The term "lower alkyl group" means a straight- or branched-chain alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, a sec-butyl group, and a tert-butyl group. The term "lower alkenyl group" means a straight- or branched-chain alkenyl group having 2 to 6 carbon atoms, for example, a vinyl group, an allyl group, a butenyl group, and a pentenyl group.
The alkyl group represented by R.sub.4, R.sub.5, or R.sub.6 is a straight- or branched-chain alkyl group having 1 to 20 carbon atoms, for example, a methyl group, an ethyl group, a n-propyl group, an i-propyl group,
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Ferns et al., Probucol inhibits neointimal thickening and macrophage accumulation after ballon injury in the cholesterol-fed rabbit, Proc. Natl. Acad. Sci., 89:11312-11316, Dec. 1992.
Freyschuss et al., Antioxidant Treatment Inhibits the Development of Intimal Thickening after Ballon Injury of the Aorta in Hypercholesterolemic Rabbits, J. Clin. Invest., 91:1282-1288, 1993.
Godfried et al., Potentiation of atherosclerotic lesion in rabbits by a high dietary level of vitamin E, British Journal of Nutrition, 61:607-617, 1989.
DeMaio et al., Vitamin E Supplementation, Plasma Lipids and Incidence of Restenosis After Percutaneous, Transluminal Coronary Angioplasty (PTCA), Journal of the American College of Nutrition, 11:68-73, 1992.
Schneider et al., Probucol Decreases Neointimal Formation in a Swine Model of Coronary Artery Ballon Injury, Basic Science Report, 88:628-637, 1993.
Konneh et al., Vitamin E inhibirs the intimal response to Balloon catheter injury in the carotid artery of the cholesterol-fed rat, Antherosclerosis, 113:29-39, 1995.
Lafont et al., Effect of Alpha-tocopherol on Restenosis after Angioplasty in a Model Experimental Atherosclerosis, J. Clin. Invest., 95:1018-1025, 1995.
Tardif et al., Probucol and Multivitamins in the Prevention of Restenosis After Coronary Angioplasty, he New England Journal of Medicine, 320:365-372, 1997.
Cynshi Osamu
Kato Yoshiaki
Sekimori Reiko
Chugai Seiyaku Kabushiki Kaisha
Krass Frederick
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