JP2004051639A - Medicinal composition for treating arteriosclerosis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal composition having excellent antiarteriosclerotic action. <P>SOLUTION: The medicinal composition for preventing and treating arteriosclerosis or disease caused thereby is characterized by administrating an ADP (adenosine 5'-diphosphate) receptor antagonist and ACAT (acyl coenzyme A cholesterol acyltransferase) inhibitor simultaneously or respectively gradually. <P>COPYRIGHT: (C)2004,JPO

Description

The present invention provides an adenosine-5'-diphosphate (hereinafter abbreviated as ADP) receptor antagonist and an acyl coenzyme A. cholesterol acyl transferase (hereinafter abbreviated as ACAT) inhibitor simultaneously or for a time. The present invention relates to a pharmaceutical composition for preventing or treating (particularly, treating) arteriosclerosis or a disease derived from arteriosclerosis (particularly, arteriosclerosis), which is separately administered separately.

発 症 With the westernization of diet and the aging of the population, the incidence of atherosclerosis is increasing. Atherosclerosis is a major factor in myocardial infarction, cerebral infarction, cerebral hemorrhage or peripheral circulatory disorder, and effective prevention and treatment methods are desired. Risk factors that cause atherosclerosis include hyperlipidemia (particularly hypercholesterolemia), hypertension, and abnormal glucose metabolism based on insulin resistance. It is also believed that these risk factors often overlap and cause complications (syndrome X) {Diabetis, 37, 1595 (1988) [Diabetes, 37, 1595 (1988). )]｝.

Attempts to reduce risk factors such as hyperlipidemia (especially hypercholesterolemia), hypertension, or abnormal glucose metabolism based on insulin resistance have been made to prevent or treat atherosclerosis. It has been done. However, for example, a 3-hydroxy-3-methylglutaryl coenzyme A (hereinafter abbreviated as HMG-CoA) reductase inhibitor improves hyperlipidemia and consequently suppresses atherosclerosis. However, the effect of HMG-CoA reductase inhibitor alone in patients with severe hyperlipidemia or arteriosclerosis is not sufficient, and the development of more effective atherosclerosis preventive or therapeutic drugs Is required {Biochemical E. Biophysica Acta, Vol. 960, p. 294 (1988) [Biochim. Biophys. Acta, 960, 294 (1988)].

コ レ ス テ ロ ー ル By the way, it is known that cholesterol in food is absorbed into intestinal mucosal cells as free cholesterol, where it is esterified by ACAT, and transferred into blood as cholesterol ester. ACAT inhibitors are known to be effective against arteriosclerosis because they inhibit cholesterol esterification in foam cells, reduce cholesterol accumulation, and suppress the formation and progression of atherosclerotic lesions. I have.

On the other hand, platelets are also involved in the development of arteriosclerosis, and it is known that platelet aggregation inhibitors are effective against arteriosclerosis. Platelet activating substances important for platelet activation and aggregation include ADP released from vascular platelets and damaged blood cells, endothelium or tissues by stimulation of substances such as collagen and thrombin. Can be. ADP is also referred to as P _2T receptor, activates platelets by binding to ADP receptor. As a result, many platelets bind and stabilize into large platelet aggregates. Platelet ADP receptors that mediate aggregation are members of the _P2T receptor family that are activated by purine and / or pyrimidine nucleotides, are activated by ADP and its derivatives, and are adenosine-5'-triphosphate and its derivatives Is antagonized by Studies of human or rat genetic disorders resulting from reduced ADP release from platelets or reduced ADP receptor numbers and signaling indicate that ADP and ADP receptors play important roles in platelet aggregation. It is shown.

Here, it is known that it is effective to prescribe two or more known lipid-lowering agents in combination for hyperlipidemia and arteriosclerosis (for example, see Non-Patent Document 1). . It has also been pointed out that it is effective to formulate a lipid-lowering agent having a new mechanism of action in combination with a known drug (for example, see Non-Patent Document 2). However, much remains unknown as to which combination of drugs can be an effective and safe drug for preventing or treating hyperlipidemia or arteriosclerosis. Some drugs are highly toxic (for example, see Non-Patent Document 3), and avoiding the toxicity is also considered to be important in the combination therapy of multiple drugs. In other words, it is considered that the combination of drugs with which mechanism of action is most important in terms of both efficacy and safety. Heretofore, it has not been known that the combined use of an ADP receptor antagonist and an ACAT inhibitor is more effective in preventing or treating arteriosclerosis.
The Washington Manual of Medical Therapeutics, 29th Edition (1998) [The Washington Manual of Medical Therapeutics, 29th Edition, by Department of Medicine, Washington University School of Medicine (1998)] Diabete & Metabolisme (Paris), 21, 139 (1995) Drugs of the Future, 2000, Vol. 25, p. 171 [Drugs of the Future, 25, 171, (2000)]

The present inventors have conducted studies in consideration of the importance of prevention and treatment of arteriosclerosis. As a result, the use of a combination of an ADP receptor antagonist and an ACAT inhibitor has an effect of inhibiting arteriosclerosis in the aorta. Improves the suppressive effect of xanthomas on the limb joints and improves arteriosclerosis or diseases derived from arteriosclerosis such as ischemic heart disease, ischemic brain disease or peripheral circulatory insufficiency (particularly arteriosclerosis) ) Was found to be useful for the prevention or treatment (particularly, treatment), and the present invention was completed.

An object of the present invention is to administer an ADP receptor antagonist and an ACAT inhibitor simultaneously or separately at an interval, to achieve arteriosclerosis or ischemic heart disease, ischemic brain disease or peripheral circulatory insufficiency. It is an object of the present invention to provide a pharmaceutical composition for preventing or treating (particularly, treating) a disease derived from arteriosclerosis (particularly, arteriosclerosis).

有効 The active ingredients of the pharmaceutical composition of the present invention are an ADP receptor antagonist and an ACAT inhibitor.

An ADP receptor antagonist which is one of the active ingredients of the pharmaceutical composition of the present invention includes, for example,
5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine {5-[(2-chlorophenyl) methyl] described in USP 4,051,141 or USP 4,127,580 -4,5,6,7-tetrahydrothieno [3,2-c] pyridine｝,
N- [2- (methylthio) ethyl] -2-[(3,3,3-trifluoropropyl) described in USP 5,955,447 and Journal of Medicinal Chemistry, 1999, Vol. 42, p. Thio] -5'-adenylic acid / monoanhydride / dichloromethylenebisphosphonic acid [N- [2- (methylthio) ethyl] -2-[(3,3,3-trifluoropropyl) thio] -5'-adenylic acid, monoanhydride with dichloromethylenebisphosphonic acid],
Journal of Medicinal Chemistry, 1999, Vol. 42, pp. 213-220, 2- (propylthio) -5'-adenylic acid / monoanhydride / dichloromethylenebis (phosphonic acid) [2- ( propylthio) -5'-adenylic acid, monoanhydride with dichloromethylenebis (phosphonic acid)],
Methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate described in USP 4,529,596, USP 4,847,265 or USP 5,576,328 ｛Methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate｝,
2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine described in USP 5,288,726 or WO 02/04461 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine｝, or a pharmaceutically acceptable salt thereof,
Preferably, 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine (particularly its hydrochloride), N- [2- (methylthio) ethyl ] -2-[(3,3,3-trifluoropropyl) thio] -5'-adenylic acid / monoanhydride / dichloromethylenebisphosphonic acid, methyl (+)-(S) -α- (2- (Chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate (especially its sulfate), 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7-tetrahydrothieno [3,2-c] pyridine (particularly its hydrochloride) or a pharmaceutically acceptable salt thereof;
More preferably, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable thereof. Salts, especially the hydrochloride thereof.

Further, an ACAT inhibitor which is one of the active ingredients of the pharmaceutical composition of the present invention includes, for example,
(±) -N- (1,2-diphenylethyl) -2- (2-octyloxyphenyl) acetamide {(±) -N- (1,2-diphenylethyl) -2 described in WO 92/09561 -(2-octyloxyphenyl) acetamide｝,
2,6-bis (1-methylethyl) phenyl N-[[2,4,6-tris (1-methylethyl) phenyl] described in USP 5,491,172, USP 5,633,287, USP 6,093,719, USP 6,124,309 or USP 6,143,755 Acetyl] sulfamate {2,6-bis (1-methylethyl) phenyl N-[[2,4,6-tris (1-methylethyl) phenyl] acetyl] sulfamate}
(1S, 2S) -2- [N- (2,2-dimethylpropyl) -N-nonylcarbamoyl] aminocyclohexane-1-yl 3- [N- (2,2,5,5) described in USP 5,120,738 -Tetramethyl-1,3-dioxane-4-carbonyl) amino] propionate {(1S, 2S) -2- [N- (2,2-dimethylpropyl) -N-nonylcarbamoyl] aminocyclohexane-1-yl 3- [N -(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propionate｝,
(S) -2 ′, 3 ′, 5′-Trimethyl-4′-hydroxy-α-dodecylthio-α-phenylacetanilide {(S) -2 ′, 3 ′, 5′- described in USP 5,990,173. trimethyl-4'-hydroxy-α-dodecylthio-α-phenylacetanilide｝,
US Pat. No. 5,849,732 describes 2- [3- (2-cyclohexylethyl) -3- (4-dimethylaminophenyl) ureido] -4-methoxy-6-tert-butylphenol and its hydrochloride {2- [3- (2-cyclohexylethyl) -3- (4-dimethylaminophenyl) ureido] -4-methoxy-6-tert-butylphenol hydrochloride｝,
(-)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4,5-dimethyl-1,3-dioxolane described in WO 96/26948 -2-yl {phenylphosphate} (-)-4-[(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4,5-dimethyl-1,3-dioxolan-2 -yl] phenylphosphate｝ and its monosodium salt,
N- [2,4-bis (methylthio) -6-methyl-3-pyridyl] -2- [4- [2- (oxazolo [4,5-b] pyridin-2-ylthio described in EP 987254 ) Ethyl] piperazin-1-yl] acetamide {N- [2,4-bis (methylthio) -6-methyl-3-pyridyl] -2- [4- [2- (oxazolo [4,5-b] pyridin -2-ylthio) ethyl] piperazin-1-yl] acetamide｝,
N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide {N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide} described in USP 5,475,130
Trans-1,4-bis [[1-cyclohexyl-3- (4-dimethylaminophenyl) ureido] methyl] cyclohexane {trans-1,4-bis [[1-cyclohexyl-3-] described in USP 5,733,931 (4-dimethylaminophenyl) ureido] methyl] cyclohexane｝,
1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methylpyridin-3-yl] urea described in WO 96/10559 {1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methylpyridin-3-yl] urea｝,
N- (4,6-dimethyl-1-pentylindoline-7-yl) -2,2-dimethylpropanamide {N- (4,6-dimethyl-1-pentylindolin-) described in USP 5,990,150 or USP 6,127,403. 7-yl) -2,2-dimethylpropanamide｝,
N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide {N- (1-octyl-5) described in USP 6,063,806 or USP 6,200,988. -carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide｝ and its sulfate, or a pharmaceutically acceptable salt thereof,
Preferably, 2,6-bis (1-methylethyl) phenyl N-[[2,4,6-tris (1-methylethyl) phenyl] acetyl] sulfamate, (S) -2 ′, 3 ′, 5 '-Trimethyl-4'-hydroxy-α-dodecylthio-α-phenylacetanilide, (-)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4 , 5-Dimethyl-1,3-dioxolan-2-yl} phenyl phosphate, N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide, trans-1,4-bis [[1- Cyclohexyl-3- (4-dimethylaminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) ) -6-Methylpyridin-3-yl] urea, N- (4,6-dimethyl-1-pentylindolin-7-yl) -2,2-dimethylpropanamide, N- (1-octyl-5-carboxy) Methyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide, or a pharmaceutically acceptable salt thereof,
More preferably, (S) -2 ′, 3 ′, 5′-trimethyl-4′-hydroxy-α-dodecylthio-α-phenylacetanilide, (−)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4,5-dimethyl-1,3-dioxolan-2-yl} phenylphosphate, trans-1,4-bis [[1-cyclohexyl-3- (4-Dimethylaminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methylpyridine-3 -Yl] urea, N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide, or a pharmaceutically acceptable salt thereof. Ri,
More preferably, N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide or a pharmaceutically acceptable salt thereof,
Most preferably, it is a sulfate of N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide (particularly 1/2 sulfate). .

The ADP receptor antagonist or ACAT inhibitor, which is an active ingredient of the pharmaceutical composition of the present invention, can be converted into a pharmacologically acceptable salt, if desired, and these are also included in the present invention.

When the ADP receptor antagonist or ACAT inhibitor, which is an active ingredient of the pharmaceutical composition of the present invention, has a basic group, they can be converted into an acid addition salt according to a conventional method, if desired. For example, in a solvent (for example, ethers, esters or alcohols, preferably ethers), the mixture is treated with a corresponding acid at room temperature for 5 to 30 minutes, and the precipitated crystals are collected by filtration or It can be obtained by distilling off the solvent under reduced pressure. Such salts include, for example, mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate; Sulfonates such as sulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates or p-toluenesulfonates; fumarate, succinate, citrate, tartrate Carboxylate such as oxalate or maleate; or amino acid salt such as glutamate or aspartate. In the above acid addition salts, when the corresponding acid is a divalent acid, the ratio (molar ratio) of the ADP receptor antagonist or ACAT inhibitor to the acid is 1: 1 or 2: 1 (preferably 2: 1). 1: 1) are included in the present invention, and when the corresponding acid is a trivalent acid, any of the salts having the above ratio of 1: 1, 2: 1 or 3: 1. Included in the present invention.

When the ADP receptor antagonist or the ACAT inhibitor, which is an active ingredient of the pharmaceutical composition of the present invention, has an acidic group, they correspond to each other, if desired, by treating with a base according to a conventional method. It can be a pharmacologically acceptable salt. For example, in a solvent (for example, ethers, esters or alcohols, preferably alcohols), the mixture is treated with a corresponding base at room temperature for 5 to 30 minutes, and the precipitated crystals are collected by filtration or It can be obtained by distilling off the solvent under reduced pressure. Examples of such salts include sodium salts, potassium salts, alkali metal salts such as lithium salts, calcium earth salts, alkaline earth metal salts such as magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, and the like. Metal salts such as nickel salts and cobalt salts; inorganic base salts such as ammonium salts; or t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methyl Glucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt , Tris (Hide It can be an organic base salt such as (loxymethyl) aminomethane salt, preferably an alkali metal salt (especially a sodium or potassium salt).

The ADP receptor antagonist or the ACAT inhibitor, which is the active ingredient of the pharmaceutical composition of the present invention, may have a geometric isomer or a stereoisomer when it contains an asymmetric carbon. Alternatively, any of those mixtures is included in the present invention.

The ADP receptor antagonist or the ACAT inhibitor, which is the active ingredient of the pharmaceutical composition of the present invention, can exist as hydrates each containing various proportions of water. Both are included in the present invention.

When the ADP receptor antagonist or the ACAT inhibitor, which is the active ingredient of the pharmaceutical composition of the present invention, is administered “simultaneously”, there is no particular limitation as long as they can be administered at almost the same time, but they may be used alone. Preferably, it is administered as a single composition.

When the ADP receptor antagonist or the ACAT inhibitor, which is the active ingredient of the pharmaceutical composition of the present invention, is administered "separately at a later time", it is not particularly limited as long as it can be administered separately at different times. However, for example, the ADP receptor antagonist may be administered first, then the ACAT inhibitor may be administered after a fixed time, or the ACAT inhibitor may be administered first, then the fixed time Later, an ADP receptor antagonist may be administered.

In the pharmaceutical composition of the present invention,
Preferably,
(1) ADP receptor antagonist is 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, N- [2- (methylthio) ethyl] -2-[(3,3,3-trifluoropropyl) thio] -5'-adenylic acid / monoanhydride / dichloromethylenebisphosphonic acid, 2- (propylthio) -5'-adenylic acid / monoanhydride Dichloromethylenebis (phosphonic acid), methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate, 2- Acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, or a pharmaceutically acceptable salt thereof. Medicine composition,
(2) The ADP receptor antagonist is 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride, N- [2- (methylthio) ) Ethyl] -2-[(3,3,3-trifluoropropyl) thio] -5′-adenylic acid / monoanhydride / dichloromethylenebisphosphonic acid, methyl (+)-(S) -α- ( 2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate sulfate, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4, 5,6,7-tetrahydrothieno [3,2-c] pyridine or 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3 -c] Pharmaceutical compositions pyridine hydrochloride,
(3) A drug wherein the ADP receptor antagonist is 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmaceutically acceptable salt thereof. Composition,
(4) a pharmaceutical composition wherein the ADP receptor antagonist is 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride;
(5) The ADP receptor antagonist is N- [2- (methylthio) ethyl] -2-[(3,3,3-trifluoropropyl) thio] -5′-adenylic acid / monoanhydride / dichloromethylene A pharmaceutical composition which is bisphosphonic acid or a pharmaceutically acceptable salt thereof,
(6) The ADP receptor antagonist is methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate or its pharmacology. A pharmaceutical composition, which is an acceptable salt,
(7) The ADP receptor antagonist is methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate sulfate A pharmaceutical composition,
(8) The ADP receptor antagonist is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or its pharmacology. A pharmaceutical composition, which is an acceptable salt,
(9) The ADP receptor antagonist is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or 2- A pharmaceutical composition which is acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine.hydrochloride,
(10) The ACAT inhibitor is 2,6-bis (1-methylethyl) phenyl N-[[2,4,6-tris (1-methylethyl) phenyl] acetyl] sulfamate, (S) -2 ′, 3 ', 5'-trimethyl-4'-hydroxy-α-dodecylthio-α-phenylacetanilide, (-)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureide Methyl] -4,5-dimethyl-1,3-dioxolan-2-yl {phenylphosphate, N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide, trans-1,4-bis [[1-Cyclohexyl-3- (4-dimethylaminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4 -Bis (methylthio) -6-methylpyridin-3-yl] urea, N- (4,6-dimethyl-1-pentylindoline-7-yl) -2,2-dimethylpropanamide, N- (1-octyl) -5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide, or a pharmaceutical composition thereof, which is a pharmaceutically acceptable salt thereof;
(11) The ACAT inhibitor is (±) -N- (1,2-diphenylethyl) -2- (2-octyloxyphenyl) acetamide, 2,6-bis (1-methylethyl) phenyl N-[[ 2,4,6-tris (1-methylethyl) phenyl] acetyl] sulfamate, (1S, 2S) -2- [N- (2,2-dimethylpropyl) -N-nonylcarbamoyl] aminocyclohexane-1-yl 3- [N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propionate, (S) -2 ′, 3 ′, 5′-trimethyl-4′-hydroxy- α-dodecylthio-α-phenylacetanilide, 2- [3- (2-cyclohexylethyl) -3- (4-dimethylaminophenyl) ureido] -4-methoxy-6-tert-butylphenol Hydrochloride, (-)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4,5-dimethyl-1,3-dioxolan-2-yl} phenyl Phosphate monosodium salt, N- [2,4-bis (methylthio) -6-methyl-3-pyridyl] -2- [4- [2- (oxazolo [4,5-b] pyridin-2-ylthio ) Ethyl] piperazin-1-yl] acetamide, N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide, trans-1,4-bis [[1-cyclohexyl-3- (4-dimethyl) Aminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methylpyridine-3 Yl] urea, N- (4,6-dimethyl-1-pentylindoline-7-yl) -2,2-dimethylpropanamide or N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline- 7-yl) -2,2-dimethylpropanamide, a pharmaceutical composition which is a sulfate,
(12) The ACAT inhibitor is (S) -2 ′, 3 ′, 5′-trimethyl-4′-hydroxy-α-dodecylthio-α-phenylacetanilide, (−)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4,5-dimethyl-1,3-dioxolan-2-yl} phenyl phosphate, trans-1,4-bis [[1-cyclohexyl -3- (4-Dimethylaminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methyl Pyridin-3-yl] urea, N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide, or pharmacologically acceptable thereof Pharmaceutical compositions is a salt,
(13) A medicament wherein the ACAT inhibitor is N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide or a pharmaceutically acceptable salt thereof. Composition,
(14) The pharmaceutical composition, wherein the ACAT inhibitor is a sulfate of N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide, or
(15) The pharmaceutical composition wherein the ACAT inhibitor is N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide.1 / 2 sulfate. Can be mentioned.

Further, a pharmaceutical composition obtained by arbitrarily combining the ADP receptor antagonist selected from the above (1) to (9) and the ACAT inhibitor selected from the above (10) to (15) is also suitable. For example,
(16) The ADP receptor antagonist is 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, N- [2- (methylthio) ethyl] -2-[(3,3,3-trifluoropropyl) thio] -5'-adenylic acid / monoanhydride / dichloromethylenebisphosphonic acid, 2- (propylthio) -5'-adenylic acid / monoanhydride Dichloromethylenebis (phosphonic acid), methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate, 2- Acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, or a pharmaceutically acceptable salt thereof. ,
The ACAT inhibitor is 2,6-bis (1-methylethyl) phenyl-N-[[2,4,6-tris (1-methylethyl) phenyl] acetyl] sulfamate, (S) -2 ′, 3 ′ , 5'-Trimethyl-4'-hydroxy-α-dodecylthio-α-phenylacetanilide, (-)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4,5-dimethyl-1,3-dioxolan-2-yl} phenyl phosphate, N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide, trans-1,4-bis [[ 1-cyclohexyl-3- (4-dimethylaminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis Methylthio) -6-methylpyridin-3-yl] urea, N- (4,6-dimethyl-1-pentylindolin-7-yl) -2,2-dimethylpropanamide, N- (1-octyl-5- A pharmaceutical composition which is carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide, or a pharmaceutically acceptable salt thereof;
(17) The ADP receptor antagonist is 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride, N- [2- (methylthio) ) Ethyl] -2-[(3,3,3-trifluoropropyl) thio] -5′-adenylic acid / monoanhydride / dichloromethylenebisphosphonic acid, methyl (+)-(S) -α- ( 2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate sulfate, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4, 5,6,7-tetrahydrothieno [3,2-c] pyridine or 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3 A 2-c] pyridine hydrochloride,
The ACAT inhibitor is (±) -N- (1,2-diphenylethyl) -2- (2-octyloxyphenyl) acetamide, 2,6-bis (1-methylethyl) phenyl N-[[2,4 , 6-Tris (1-methylethyl) phenyl] acetyl] sulfamate, (1S, 2S) -2- [N- (2,2-dimethylpropyl) -N-nonylcarbamoyl] aminocyclohexane-1-yl 3- [ N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propionate, (S) -2 ', 3', 5'-trimethyl-4'-hydroxy-α-dodecylthio -Α-phenylacetanilide, 2- [3- (2-cyclohexylethyl) -3- (4-dimethylaminophenyl) ureido] -4-methoxy-6-tert-butylphenol hydrochloride (-)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4,5-dimethyl-1,3-dioxolan-2-yl} phenylphosphate. Monosodium salt, N- [2,4-bis (methylthio) -6-methyl-3-pyridyl] -2- [4- [2- (oxazolo [4,5-b] pyridin-2-ylthio) ethyl] Piperazin-1-yl] acetamide, N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide, trans-1,4-bis [[1-cyclohexyl-3- (4-dimethylaminophenyl) Ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methylpyridin-3-yl] u Rare, N- (4,6-dimethyl-1-pentylindoline-7-yl) -2,2-dimethylpropanamide or N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7- Il) a pharmaceutical composition which is a sulfate of 2,2-dimethylpropanamide;
(18) the ADP receptor antagonist is 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmaceutically acceptable salt thereof,
The ACAT inhibitor is (S) -2 ', 3', 5'-trimethyl-4'-hydroxy-α-dodecylthio-α-phenylacetanilide, (-)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4,5-dimethyl-1,3-dioxolan-2-yl} phenylphosphate, trans-1,4-bis [[1-cyclohexyl-3- (4-Dimethylaminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methylpyridine-3 -Yl] urea, N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide, or a pharmacologically acceptable thereof. Pharmaceutical compositions are,
(19) The ADP receptor antagonist is methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate or its pharmacology. Is an acceptable salt,
A pharmaceutical composition, wherein the ACAT inhibitor is N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide or a pharmaceutically acceptable salt thereof;
(20) The ADP receptor antagonist is methyl (+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate / sulfate And
A pharmaceutical composition, wherein the ACAT inhibitor is N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide or a pharmaceutically acceptable salt thereof;
(21) The ADP receptor antagonist is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or its pharmacology. Is an acceptable salt,
A pharmaceutical composition, wherein the ACAT inhibitor is N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide or a pharmaceutically acceptable salt thereof;
(22) The ADP receptor antagonist is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or 2- Acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine.hydrochloride,
A pharmaceutical composition wherein the ACAT inhibitor is N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide sulfate, or
(23) The ADP receptor antagonist is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or 2- Acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine.hydrochloride,
The pharmaceutical composition wherein the ACAT inhibitor is N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide.1 / 2 sulfate, It is suitable.

The ADP receptor antagonist which is an active ingredient of the pharmaceutical composition of the present invention includes USP 4,051,141, USP 4,127,580, USP 5,955,447, Journal of Medicinal Chemistry, 1999, Vol. 42, p.213-220, USP 5,721,219, USP 4,529,596. , USP 4,847,265, USP 5,576,328, USP 5,288,726 or WO 02/04461, or can be easily produced according to a method analogous thereto.

The ACAT inhibitor which is an active ingredient of the pharmaceutical composition of the present invention includes WO 92/09561, USP 5,491,172, USP 5,633,287, USP 6,093,719, USP 6,124,309, USP 6,143,755, USP 5,120,738, USP 5,990,173, USP 5,849,732, WO 96 / It can be easily produced according to the method described in US Pat.

The ADP receptor antagonist and the ACAT inhibitor, which are the active ingredients of the pharmaceutical composition of the present invention, can be individually prepared in separate unit dosage forms, or can be mixed and physically prepared into one unit dosage form. it can.

When the pharmaceutical composition of the present invention is used as a prophylactic or therapeutic drug for the above-mentioned diseases, the ADP receptor antagonist and the ACAT inhibitor, which are the active ingredients of the pharmaceutical composition of the present invention, are each administered by itself. Or by mixing with an appropriate pharmacologically acceptable excipient, diluent, or the like, and orally or injecting into a preparation such as a tablet, capsule, granule, powder or syrup. It can be administered parenterally in the form of preparations or suppositories.

These formulations include excipients (e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Arabic gum; dextran; organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminate; phosphates such as calcium hydrogen phosphate; calcium carbonate And inorganic excipients such as sulfates such as calcium sulfate.) Lubricants (eg, metal stearate such as stearic acid, calcium stearate, and magnesium stearate). Talc; colloidal silica; beeswax; Waxes such as wax; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; Silicates such as hydrates; and the above-mentioned starch derivatives.), Binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same as the above-mentioned excipients) And carboxymethyl; disintegrants (eg, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked sodium carboxymethylcellulose; and carboxymethyl). Examples include chemically modified starch and celluloses such as starch, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone), emulsifiers (eg, colloidal clays such as bentonite and veegum); magnesium hydroxide, aluminum hydroxide Metallic hydroxides, such as sodium lauryl sulfate, anionic surfactants, such as calcium stearate; cationic surfactants, such as benzalkonium chloride; and polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters And nonionic surfactants such as sucrose fatty acid esters.) Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenyl) Alcohols such as chill alcohol; benzalkonium chloride; phenols, phenols such as cresol; thimerosal; dehydroacetic acid; and sorbic acid and the. ), Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.) and diluents can be used in a well-known method.

The dosage and the administration ratio of the ADP receptor antagonist and the ACAT inhibitor, which are the active ingredients of the pharmaceutical composition of the present invention, may vary depending on various conditions such as the activity of each drug, the symptoms, age, and weight of the patient. .

The dose varies depending on the patient's condition, age, etc., but in the case of oral administration, the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 1000 mg (preferably 500 mg) per dose. In the case of oral administration, a lower limit of 0.01 mg (preferably 0.05 mg) and an upper limit of 100 mg (preferably 50 mg) may be administered to an adult 1 to 6 times per day, depending on the symptoms. They can be administered simultaneously or separately at intervals.

The dose of the ADP receptor antagonist when used for the prevention or treatment of arteriosclerosis in the present invention may be smaller than the dose when used as a blood coagulation inhibitor, which is an essential use. Also, the dosage may be lower due to the superior effects of the combined use with the ACAT inhibitor.

Further, the ratio of the doses of the ADP receptor antagonist and the ACAT inhibitor, which are the active ingredients of the pharmaceutical composition of the present invention, can also vary greatly, for example, in a weight ratio of 1: 10000 to 10000: 1. And preferably from 1: 1000 to 1000: 1, more preferably from 1: 100 to 100: 1.

In particular, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or 2-acetoxy-5- (α-cyclo Propylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride and N- (1-octyl-5-carboxymethyl-4,6-dimethyl The dose ratio of the sulfate of indoline-7-yl) -2,2-dimethylpropanamide (preferably 1/2 sulfate) is preferably in a weight ratio of 1: 200 to 200: 1. It is.

The pharmaceutical composition for separately or simultaneously administering the ADP receptor antagonist and the ACAT inhibitor of the present invention is excellent in suppressing arteriosclerosis in the aorta and developing xanthomas in the limb joints. Since it has an inhibitory action and has low toxicity, it is necessary to treat arteriosclerosis in warm-blooded animals (particularly humans) or diseases derived from arteriosclerosis such as ischemic heart disease, ischemic brain disease and peripheral circulatory insufficiency ( In particular, it is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for arteriosclerosis. In addition, the combined use of the ADP receptor antagonist and the ACAT inhibitor, which are the active ingredients of the present invention, shows more excellent effects than the use of each single agent.

Hereinafter, the present invention will be described in more detail with reference to Examples and Preparation Examples, but the scope of the present invention is not limited thereto.

実 験 Male New Zealand white rabbits (1.0-1.5 kg body weight) were loaded with a cholesterol diet (0.5% cholesterol, 3% peanut oil and 3% coconut oil) at the following feeding amounts for 10 weeks to conduct experiments. They were fed 40 g for the first two weeks, 50 g for the next four weeks, and 60 g for the last four weeks. Two weeks after the cholesterol diet load, a nylon thread was aseptically inserted from the right femoral artery to the vicinity of the diaphragm, causing chronic endothelial injury to the abdominal aorta and the right femoral artery. The nylon thread remained fixed at the insertion site for 8 weeks. After the operation of inserting a nylon thread, grouping was performed so that the average values of serum total cholesterol level, triglyceride level, platelet aggregation rate and body weight in each group were almost uniform, and ADP receptor antagonist and ACAT inhibitor Was orally administered alone or in combination. Eight weeks after the administration, the animals were euthanized, the right femoral artery was excised, and the area ratio of aortic sclerotic lesion was calculated. After extending the right femoral artery (1 cm from the iliac artery bifurcation), photograph using a digital camera (COOLPX990, Nikon Corporation), measure the luminal surface area and atherosclerotic lesion area using an image analyzer, The arteriosclerotic lesion area ratio to the luminal surface area was calculated. A 1 cm section was cut out from the iliac artery bifurcation to the femoral artery and fixed in methanol-Carnoy's solution to prepare a paraffin block. After slicing, Elastica Masson staining and immunostaining using an anti-human α-actin antibody (1A4) were performed, and the intimal hyperplasia and smooth muscle cell occupancy were calculated using an image analyzer.

The results are shown in Table 1. In the table, compound A refers to 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, B represents a sulfate of N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide.

　この結果より、ＡＤＰ受容体拮抗剤及びＡＣＡＴ阻害剤を組み合わせた使用は、それぞれ単独の使用より優れた動脈硬化症抑制作用（相乗効果）を示した。したがって、本発明の、ＡＤＰ受容体拮抗剤及びＡＣＡＴ阻害剤を、同時に又は時間を置いて別々に投与する為の医薬組成物は、動脈硬化症又は動脈硬化症に由来する疾患（特に、動脈硬化症）の予防薬又は治療薬（特に、治療薬）として有用である。

　（製剤例１）錠剤
　２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン（10.0mg）、Ｎ−（１−オクチル−５−カルボキシメチル−４，６−ジメチルインドリン−７−イル）−２，２−ジメチルプロパンアミドの硫酸塩（30.0mg）、乳糖（408.0mg）、トウモロコシデンプン（50.0mg）及びステアリン酸マグネシウム（2.0mg）を混合し、打錠機により打錠して、１錠 500mgの錠剤とする。この錠剤は、必要に応じて、コーティング（好適には、糖衣）を施すことができる。

From these results, the use of a combination of an ADP receptor antagonist and an ACAT inhibitor showed a superior arteriosclerosis inhibitory action (synergistic effect) compared to the use of each alone. Therefore, the pharmaceutical composition of the present invention for separately or simultaneously administering an ADP receptor antagonist and an ACAT inhibitor comprises atherosclerosis or a disease derived from atherosclerosis (particularly atherosclerosis). It is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for the disease.

(Formulation Example 1) Tablet 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine (10.0 mg), N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide sulfate (30.0 mg), lactose (408.0 mg), corn starch (50.0 mg) and Magnesium stearate (2.0 mg) is mixed, and the mixture is tableted with a tableting machine to give 500 mg tablets. The tablet can be coated (preferably sugar-coated) as necessary.

The pharmaceutical composition for separately administering the ADP receptor antagonist and the ACAT inhibitor according to the present invention simultaneously or at a certain time interval has excellent anti-arteriosclerosis action in the aorta and xanthoma in the limb joint. It has an inhibitory effect on the onset of and has low toxicity, so it is derived from arteriosclerosis in warm-blooded animals (especially humans) or arteriosclerosis such as ischemic heart disease, ischemic brain disease and peripheral circulatory insufficiency. It is useful as a prophylactic or therapeutic agent (especially a therapeutic agent) for diseases (in particular, arteriosclerosis).

Claims (13)

(4) A pharmaceutical composition for preventing or treating arteriosclerosis or a disease derived from arteriosclerosis, which comprises administering an ADP receptor antagonist and an ACAT inhibitor simultaneously or separately at an interval. The ADP receptor antagonist is 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, N- [2- (methylthio) ethyl] -2- [(3,3,3-trifluoropropyl) thio] -5'-adenylic acid / monoanhydride / dichloromethylene bisphosphonic acid, 2- (propylthio) -5'-adenylic acid / monoanhydride / dichloromethylene Bis (phosphonic acid), methyl {(+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate, 2-acetoxy-5 -(Α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, or a pharmaceutically acceptable salt thereof, The pharmaceutical composition of claim 1. The ADP receptor antagonist is 5-[(2-chlorophenyl) methyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmaceutically acceptable salt thereof. Pharmaceutical composition. The ADP receptor antagonist is N- [2- (methylthio) ethyl] -2-[(3,3,3-trifluoropropyl) thio] -5'-adenylic acid / monoanhydride / dichloromethylenebisphosphon The pharmaceutical composition according to claim 1, which is an acid or a pharmacologically acceptable salt thereof. The ADP receptor antagonist is methyl {(+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate or a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition of claim 1, which is a salt. The ADP receptor antagonist is methyl {(+)-(S) -α- (2-chlorophenyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -acetate sulfate; The pharmaceutical composition of claim 1. The ADP receptor antagonist is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition of claim 1, which is a salt. The ADP receptor antagonist is 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or 2-acetoxy-5 The pharmaceutical composition according to claim 1, which is-(α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine.hydrochloride. The ACAT inhibitor is 2,6-bis (1-methylethyl) phenyl {N-[[2,4,6-tris (1-methylethyl) phenyl] acetyl] sulfamate, (S) -2 ′, 3 ′, 5'-trimethyl-4'-hydroxy-α-dodecylthio-α-phenylacetanilide, (-)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl]- 4,5-dimethyl-1,3-dioxolan-2-yldiphenylphosphate, N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide, trans-1,4-bis [[1 -Cyclohexyl-3- (4-dimethylaminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bi (Methylthio) -6-methylpyridin-3-yl] urea, N- (4,6-dimethyl-1-pentylindoline-7-yl) -2,2-dimethylpropanamide, N- (1-octyl-5) Pharmaceutical composition according to claims 1 to 8, which is -carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide or a pharmaceutically acceptable salt thereof. The ACAT inhibitor is (±) -N- (1,2-diphenylethyl) -2- (2-octyloxyphenyl) acetamide, 2,6-bis (1-methylethyl) phenyl {N-[[2,4 , 6-Tris (1-methylethyl) phenyl] acetyl] sulfamate, (1S, 2S) -2- [N- (2,2-dimethylpropyl) -N-nonylcarbamoyl] aminocyclohexane-1-yl {3- [ N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propionate, (S) -2 ', 3', 5'-trimethyl-4'-hydroxy-α-dodecylthio -Α-phenylacetanilide, 2- [3- (2-cyclohexylethyl) -3- (4-dimethylaminophenyl) ureido] -4-methoxy-6-tert-butylphenol Acid salt, (-)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4,5-dimethyl-1,3-dioxolan-2-yl} phenyl Phosphate monosodium salt, N- [2,4-bis (methylthio) -6-methyl-3-pyridyl] -2- [4- [2- (oxazolo [4,5-b] pyridin-2-ylthio ) Ethyl] piperazin-1-yl] acetamide, N- (2,6-diisopropylphenyl) -2-tetradecylthioacetamide, trans-1,4-bis [[1-cyclohexyl-3- (4-dimethyl) Aminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methylpyridine-3-i Urea, N- (4,6-dimethyl-1-pentylindoline-7-yl) -2,2-dimethylpropanamide or N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline- The pharmaceutical composition according to claims 1 to 8, which is a sulfate of 7-yl) -2,2-dimethylpropanamide. The ACAT inhibitor is (S) -2 ', 3', 5'-trimethyl-4'-hydroxy-α-dodecylthio-α-phenylacetanilide, (-)-4-{(4R, 5R) -2- [3- (2,6-diisopropylphenyl) ureidomethyl] -4,5-dimethyl-1,3-dioxolan-2-yl} phenylphosphate, trans-1,4-bis [[1-cyclohexyl-3- (4-Dimethylaminophenyl) ureido] methyl] cyclohexane, 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- [2,4-bis (methylthio) -6-methylpyridine-3 -Yl] urea, N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide, or a pharmaceutically acceptable salt thereof. Salts, pharmaceutical composition according to claim 1 to 8. 2. The ACAT inhibitor is N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide or a pharmaceutically acceptable salt thereof. To 8. 9. The pharmaceutical composition according to claim 1, wherein the ACAT inhibitor is a sulfate of N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) -2,2-dimethylpropanamide. object.