Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-21
2004-11-30
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S161000, C548S171000
Reexamination Certificate
active
06825223
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel anilide compounds and pharmaceutical compositions comprising them. More precisely, the present invention relates to compounds of a general formula (I):
wherein Ar represents an optionally-substituted aryl group; R
4
and R
5
are the same or different, and each represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group; and R
4
and R
5
may together form a lower alkylene group of which one or more methylene moieties may optionally be substituted by oxygen and/or sulfur atoms;
X represents —NH—, or an oxygen or sulfur atom;
Y represents —NH—, an oxygen or sulfur atom, or a sulfoxide or sulfone group;
Z represents a single bond, or —NR
6
—;
R
6
represents a hydrogen atom or a lower alkylene group; and
n represents an integer of from 0 to 15;
provided that, when X and Y are sulfur atoms, R
4
and R
5
are hydrogen atoms, Z is a single bond and n is 0, then Ar must not be a phenyl or p-chlorophenyl group, when X and Y are sulfur atoms, R
4
and R
5
are hydrogen atoms,
Z is a single bond and n is 1, then Ar must not be a phenyl group, and
when X is an oxygen atom, Y is a sulfur atom, R
4
and R
5
are hydrogen atoms, Z is a single bond and n is 1, then Ar must not be a phenyl group,
their salts and solvates, and pharmaceutical compositions comprising said compounds.
BACKGROUND
With the recent change in the Japanese eating habits into Western-style ones to take high-calorie and high-cholesterol foods and drinks, which is based on the improvement in the living standard in Japan, and with the recent increase in the aged population of Japan, cases of hyperlipemia and arteriosclerotic disorders resulting from hyperlipemia are greatly increasing with bringing about one social problem in Japan. The conventional chemotherapy for cases of hyperlipemia and arteriosclerosis is essentially to lower their blood-lipid levels that participate in the disorders, but is not targeted to the focuses themselves of arteriosclerosis to cure them.
Acyl coenzyme A cholesterol acyltransferase (ACAT) is an enzyme to catalyze the transfer of cholesterol into cholesterol esters, while playing an important role in the metabolism of cholesterol and the absorption thereof through digestive systems. It is believed that the inhibition of such an ACAT enzyme that may catalyze the esterification of free cholesterol in epithelial cells in small intestines brings about the inhibition of the cholesterol absorption through intestinal tubes, while the inhibition of the formation of cholesterol esters in the liver based on the ACAT inhibition brings about the inhibition of the VLDL (very low-density lipoprotein) secretion into blood, thereby resulting in the decrease in the blood cholesterol. Many known ACAT inhibitors are expected to act on ACAT in small intestines and the liver as anti-hyperlipemic agents thereby to lower blood cholesterol.
For example, as ACAT inhibitors, U.S. Pat. No. 4,716,175 discloses 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl) dodecanamide, and European Patent 372,445 discloses N′-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptylurea. However, any known ACAT inhibitors have heretofore been specifically directed to the decrease in blood cholesterol as anti-hyperlipemic agents, and administered to patients in large amounts in order to express their effects. Therefore, in the clinical examination stage using them, many patients have experienced various side effects such as bleeding from their intestinal tubes, intestinal disorders, diarrhea and liver disorders, which have made it difficult to develop the clinical use of ACAT inhibitors.
WO92/09582 discloses compounds having a certain substituent at the 2-position of the imidazole skeleton) and EP-A 477,778 discloses compounds having certain substituents at the 4- and 5-positions of the imidazole skeleton. For example, disclosed are 5-[2-(2-(4-fluorophenyl)ethyl)-3-(1-methyl-1H-imidazol-2-yl)-2H-benzopyran-6-yl]oxy-2,2-dimethyl-N-(2,6-diisopropylphenyl)pentanamide (see WO92/09582), N-(2,6-diisopropylphenyl)-2-(tetradecylthio)acetamide (see JP 92-500533, WO92/09572), N-butyl-N′-[2-(3-(5-ethyl-4-phenyl-1-yl)propoxy)-6-methylphenyl]urea (see EP 477,778), and N-[5-(4,5-diphenyl-1H-imidazo-2-ylthio)pentyl]-N-heptyl-2-benzoxazolamine (see WO93/23392); and it is disclosed that these compounds have ACAT inhibiting activities. However, the chemical structures of these compounds are quite different from those of the compounds of the present invention.
3-(benzothiazol-2-ylthio)-N-(phenyl)propanamide, 3-(benzothiazol-2-ylthio)-N-(phenyl)ethanamide and 3-(benzothiazol-2-ylthio)-N-(p-chlorophenyl) ethanamide is reported in J. Chem. Eng. Data, 27, 207 (1982) and 3-(benzoxazol-2-ylthio)—N—(phenyl)propanamide is reported in Fungitsidy, Ed. Melnikov, N. N. Izd. Fan Uzb. SSR: Tashkent, USSR, 82-88 (1980)).
SUMMARY
Naturally, arteriosclerosis is a disorder that is characterized by the increase in the thickness of intimate and the accumulation of lipids in blood vessels. The recent studies on this disorder, arteriosclerosis have clarified that the inhibition of macrophage-derived foam cells that play the central role in the formation of focuses of arteriosclerosis is expected to reduce the focuses themselves of arteriosclerosis. In the focuses of atheromatous arteriosclerosis, seen are macrophage-derived foam cells (which have fatty drops of cholesterol esters therein), and it is said that the formation of such foam cells from macrophages has close relation to the growth of the focuses of arteriosclerosis. In addition, it has been reported that the ACAT activity in the blood vessel walls in the site with arteriosclerotic lesions is increased and that cholesterol esters are accumulated on the blood vessel walls in said site (see Gillies, P. J. et al.; Exp. Mole, Pathol., 44, 329-339 (1986)).
Since the inhibition of the esterification of cholesterol by an ACAT inhibitor produces free cholesterol in cells while the resulting free cholesterol is removed from the cells by a high-density lipoprotein (HDL) and brought to the liver (countertransference of cholesterol via HDL) and metabolized therein, it is expected that such an ACT inhibitor may inhibit the accumulation of cholesterol esters in the site of arteriosclerotic lesions. As a result, it is believed that ACAT inhibitors exhibit direct anti-arteriosclerotic effects. It has been reported that ACAT includes two sub-types, one existing in small intestines and the other existing in blood vessel walls (see Kinnunen, P. M., et al.; Biochem., 27, 7344-7350 (1988) ). Many studies on ACAT inhibitors have heretofore been made for the former sub-type of ACAT existing in small intestines and the liver (see Tomoda, H. et al.; J. Antibiotics, 47, 148-153 (1994)). Having considered that chemicals capable of selectively inhibiting the latter sub-type of ACAT existing in blood vessel walls could be medicines with few side effects for curing arteriosclerosis, as compared with ACAT inhibitors not specific organs, we, the present inventors have searched for inhibitors for ACAT of that type and have studied to synthesize such. ACAT inhibitors.
In order to attain this object, we have made various studies and, as a result, have found that compounds of a general formula (I):
wherein Ar represents an optionally-substituted aryl group;
R
4
and R
5
are the same or different, and each represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group; and R
4
and R
5
may together form a lower alkylene group of which one or more methylene Moieties may optionally be substituted by oxygen and/or sulfur atoms;
X represents —NH—, or an oxygen or sulfur atom;
Y represents —NH—, an oxygen or sulfur atom, or a sulfoxide or sulfone;
Z represents a single bond, or —NH
6
—;
R
4
represents a hydrogen atom or a lower alkylene group; and
n represents an integer of from 0 to 15;
provided that, when X and Y are sulfur atoms, R
4
and R5 are hydrogen atoms, Z is a single bond and n is 0, th
Edano Toshiyuki
Kawamine Katsumi
Sato Yukihiro
Shibuya Kimiyuki
Shiratsuchi Masami
Alexander John B.
Corless Peter F.
Edwards & Angell LLP
Kowa Company Ltd.
Stockton Laura L.
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