Anilide compounds and drugs containing the same

Details Anilide compounds and drugs containing the same Anilide compounds and drugs containing the same

2001-12-19

2004-09-28

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S302000, C514S303000, C546S113000, C546S114000, C546S115000, C546S116000, C546S118000

Reexamination Certificate

active

06797717

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel anilide compound and a pharmaceutical composition containing the same. More specifically, the invention relates to a compound represented by the general formula I:
represents a divalent residue of benzene with a substituent(s), heterocycle-condensed benzene which may or may not have a substituent, pyridine which may or may not have a substituent, cyclohexane or naphthalene
Ar represents an aryl group which may or may not have a substituent;
X represents —NH—, oxygen atom or sulfur atom;
Y represents —NR
4
—, oxygen atom, sulfur atom, sulfoxide or sulfone;
Z represents single bond or —NR
5
—;
R
4
represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent;
R
5
represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent; and
n represents an integer of 0 to 15;
a salt thereof or a solvated compound thereof and pharmaceutical compositions comprising these compounds.
BACKGROUND OF THE INVENTION
Following the transfer of the (Japanese) dietary life to European-style diets comprising high calorie and high cholesterol due to the improvement of the living standard and the increase of the ratio of aged people in the (Japanese) population, hyperlipidemia and arteriosclerotic diseases caused by hyperlipidemia have increased in number rapidly in recent years. The increase of these diseases is now one of the social problems (in Japan). Conventional pharmaceutical treatment of hyperlipidemia and arteriosclerosis has mainly targeted the reduction of lipid in blood as the etiology thereof. The treatment has never targeted arteriosclerotic lesions of themselves. Acyl coenzyme A cholesterol acyltransferase (ACAT) is the enzyme to catalyze the synthesis of cholesterol ester from cholesterol to play a significant role in the cholesterol metabolism and absorption in gastrointestinal tract. It is suggested that the inhibition of ACAT esterifying free cholesterol in the epidermal cell of small intestine works to inhibit cholesterol absorption from intestinal lumen and that the inhibition of cholesterol ester generation in liver owing to ACAT inhibition suppresses VLDL secretion from liver into blood stream, with the resultant action to decrease blood cholesterol. It is considered that many of conventional ACAT inhibitors function as anti-lipidemia agents to exert the action of decreasing blood cholesterol by allowing the inhibitors to react with the ACAT enzyme in small intestine and liver.
As ACAT inhibitors, for example, U.S. Pat. No. 4,716,175 describes 2,2 dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide; and EP 372, 445 describes N′-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptyl urea in the specification. However, many of these conventional ACAT inhibitors as anti-hyperlipidemia agents principally work to decrease blood cholesterol and are administered at large doses to permit sufficient exertion of the action. Due to the emergence of side effects including intestinal bleeding, intestinal disorders, diarrhea and liver disorders at high frequencies at clinical test stages, accordingly, the development of these agents for clinical practice has been very difficult.
Arteriosclerosis is a disease essentially involving unique features of hypertrophy of inner vascular membrane and lipid accumulation. Recent research works indicate that suppression of macrophage foaming essentially functioning for the formation of arteriosclerotic lesions possibly degenerates arteriosclerotic lesions. Macrophage-derived foam cell (storing cholesterol ester as lipid droplet inside the cell) is observed in arteriosclerotic lesions. It is indicated that macrophage foaming is deeply involved in the progress of the disease. Additionally, it is reported that ACAT activity is elevated in the wall of blood tubes in arteriosclerotic lesions, indicating that cholesterol ester is accumulated in the wall of blood tubes (Gyres, P. J. et al., Exp. Mole. Pathol., 44, 329-339 (1986)).
Due to the inhibition of cholesterol esterification by ACAT inhibitors, free cholesterol is generated inside cells and is then eliminated with high-density lipoprotein (HDL) to be transferred to and metabolized in liver (reverse transfer by HDL). It is suggested that the accumulation of cholesterol in diseased sites is thereby suppressed. Consequently, direct anti-arteriosclerotic action is exerted. A report tells that ACAT includes two sub-types, namely an ACAT type present in small intestine and an ACAT type, present in vascular wall (Quinoonen, P. M. et al., Biochem., 27, 7344-7350 (1988)). Conventional research works on ACAT inhibitors have mostly been carried out by using the ACAT type present in small intestine and liver (Tomoda, H. et al., J. Antibiotics 47, 148-153 (1994)). Based on the assumption that a pharmaceutical agent selectively inhibiting the ACAT type which presents in vascular wall may work as a therapeutic agent of arteriosclerosis with less side effects, the present inventors have synthetically produced such inhibitors and have carried out examinations on them.
DISCLOSURE OF THE INVENTION
So as to attain the object, the inventors have made investigations. Consequently, the inventors have found that a compound represented by the general formula I:
represents a divalent residue of benzene with a substituent(s), heterocycle-condensed benzene which may or may not have a substituent, pyridine which may or may not have a substituent, cyclohexane or naphthalene
Ar represents an aryl group which may or may not have a substituent;
X represents —NH—, oxygen atom or sulfur atom;
Y represents —NR
4
—, oxygen atom, sulfur atom, sulfoxide or sulfone;
Z represents single bond or —NR
5
—;
R
4
represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent;
R
5
represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent; and
n represents an integer of 0 to 15;
a salt thereof or a solvated compound thereof exerts an excellent ACAT inhibitory action. Thus, the invention has been achieved.
The inventors have found that the inventive compounds exert ACAT inhibitory actions in an organ-specific manner and an action inhibiting the transfer of intra-cellular cholesterol and that the inventive compounds are particularly useful as anti-hyperlipidemia agents with an excellent action to reduce cholesterol in blood and as a prophylactic and therapeutic agent of arteriosclerosis with an action to suppress macrophage foaming.
Thus, the compound represented by the general formula I, a salt thereof or a solvated product thereof is provided in accordance with the invention.
Additionally, the invention provides pharmaceutical compositions comprising the compound represented by the general formula I, a salt thereof or a solvated product thereof, together with carriers pharmaceutically acceptable.
Still additionally, the invention provides the compounds shown as the above formula I, salts thereof or solvated compounds thereof, and ACAT inhibitors, agents inhibiting intra-cellular cholesterol transfer, blood cholesterol-reducing agents, or macrophage foaming-suppressing agents. In other words, the invention provides therapeutic and prophylactic agents of diseases including hyperlipidemia, arteriosclerosis, arteriosclerosis of carotid and cerebral arteries, cerebrovascular diseases, ischemic cardiac diseases, coronary arteriosclerosis, nephrosclerosis, arteriosclerotic nephrosclerosis, arteriocapillary sclerotic nephrosclerosis, malignant nephrosclerosis, ischemic intestinal diseases, acute mesenteric blood tube occlusion, chronic intestinal angina, ischemic colitis, aortic aneurysm and occlusive arteriosclerosis (ASO).
As compounds similar to the compound of the formula I, 3-(benzothiazol-2-ylthio)-N-(phenyl)propanamide and 3-(benzoxazol-2-ylthio)-N-(phenyl)propanamide are di

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