WO2002072147A1

WO2002072147A1 - Medicinal compositions containing bile acid transporter inhibitor

Info

Publication number: WO2002072147A1
Application number: PCT/JP2002/002311
Authority: WO
Inventors: Toshimori Inaba
Original assignee: Sankyo Company, Limited
Priority date: 2001-03-14
Filing date: 2002-03-12
Publication date: 2002-09-19

Abstract

Medicinal compositions for administering an ileal bile acid transporter inhibitor and an ACAT inhibitor either at the same time or separately at a certain interval.

Description

Pharmaceutical compositions containing bile acid transporter inhibitors

The present invention relates to an ileal bile acid transport inhibitor, an enzyme

A: A pharmaceutical composition for administering cholesterol acyltransferase (hereinafter referred to as ACAT) inhibitors simultaneously or separately at an interval.

Further, the present invention provides that a pharmacologically effective amount of an ileal bile acid transporter inhibitor and an ACAT inhibitor are separately or simultaneously administered to a warm-blooded animal (particularly a human) at an interval. Accordingly, the present invention relates to a method for preventing or treating arteriosclerosis-related diseases such as hyperlipidemia, arteriosclerosis or ischemic heart disease, ischemic brain disease, and peripheral circulatory insufficiency. Technology background

Atherosclerosis is steadily increasing with the westernization of the diet and the aging population. Atherosclerosis is a major cause of ischemic heart disease (myocardial infarction, unstable angina, sudden ischemic death), ischemic brain disease (cerebral infarction, intracerebral hemorrhage, etc.), peripheral circulatory insufficiency and the like. Risk factors for atherosclerosis include hyperlipidemia (especially hypercholesterolemia), as well as hypertension and abnormal glucose metabolism due to insulin resistance. In addition, these risk factors often develop as complications (syndrome X), and it is thought that their etiologies are intertwined with each other. 88 years) [Diabetes 37 _: 1595 (1988)]} There is a need for effective preventive and therapeutic methods. Disclosure of the invention

The present inventors include an ileal bile acid transport inhibitor and an ACAT inhibitor As a result of diligent research on pharmaceutical compositions that perform the above treatments, superior lipids (cholesterol or triglyceride) can be obtained by administering the above two drugs simultaneously or separately at intervals, rather than administering each drug alone. It has a lowering effect and has an inhibitory effect on the progression of arteriosclerosis.It is a preventive agent for arteriosclerosis-related diseases such as hyperlipidemia, arteriosclerosis or ischemic heart disease, ischemic brain disease and peripheral circulatory insufficiency. Alternatively, they have found that they are useful as therapeutic agents, and have completed the present invention. Accordingly, an object of the present invention is to provide a pharmaceutical composition for administering an ileal bile acid transporter inhibitor and an ACAT inhibitor simultaneously or separately at an interval. ,

It is another object of the present invention to administer pharmacologically effective amounts of an ileal bile acid transporter inhibitor and an ACAT inhibitor to warm-blooded animals (particularly humans) simultaneously or separately at intervals. Accordingly, it is an object of the present invention to provide a method for preventing or treating arteriosclerosis-related diseases such as hyperlipidemia, arteriosclerosis or ischemic heart disease, ischemic brain disease and peripheral circulatory insufficiency. The active ingredients of the pharmaceutical composition of the present invention are an ileal bile acid transport inhibitor and an ACAT inhibitor.

An “ileal bile acid transporter inhibitor”, which is one of the active ingredients of the pharmaceutical composition of the present invention, is a drug that inhibits a bile acid transporter present in the ileum, and comprises a bile acid from the small intestine. It is used as a therapeutic agent for hyperlipidemia because it suppresses the reabsorption of cholesterol and consequently lowers cholesterol. Such ileal bile acid transporter inhibitors include, for example,

Naphthalene derivatives or pharmacologically acceptable salts thereof described in JP-A-61-267541 (EP 188248, US Pat. No. 4,771,072) [preferably TA-7522, and its chemical name Is 1- (3,4-dimethoxyphenyl) -2,3-Bis (methoxycarbonyl) _4-hydroxy-1,6,7,8_trimethoxyxinaphthylene. ],

Compounds having the general formula (I) described in WO 99/32478 (US Pat. No. 5,994,391, US Pat. No. 6,107,494, US Pat. Or a salt thereof, a solvate thereof, or a prodrug thereof. {Preferably, {1- [4_ [4 _ [(4R, 5R)]-3,3-dibutyl-17- (dimethylamino) 1-2,3 , 4,5-Tetrahydro-1-hydroxy-1,1-dioxo-1-benzopentin-5-yl] phenoxymethyl] benzyl} -1-aza-1-azodiabicyclo [2.2.2] octane Chloride, 1-{4-[4-[(4 R, 5 R) -1,3,3-dibutyl-7- (dimethylamino) -1,2,3,4,5-tetrahydro-4- 4-hydroxy_1,1-dioxo-1 1-benzocepin-5-yl] phenoxy] butyl} —4-aza—1-azoniabicyclo [2.2.2] octane methanesulfonate or {2-—2-—2-—4-[(4R, 5 R) —3,3-Dibutyl—7— (dimethylamino) —2,3,4,5-tetrahydro-14-hydroxy_1,1-dioxo-1-benzobenzoin-5-yl] phenoxy] ethoxy] ethoxy] Ethyl} triethylammonium chloride, most preferably 1- {4- [4-[(4R, 5R) -3,3-dibutyl-7- (dimethylamino) -2,3,4,5-] Tetrahydro-4-hydroxy-1,1,1-dioxo-1-benzobenzopin-5-yl] phenoxymethyl] benzyl} -4-aza-1-azoniabicyclo [2.2.2] octane chloride},

A compound having the general formula (I) described in JP-A-5-310634 (EP 597107 and EP 701991) or a pharmaceutically acceptable salt thereof [preferably, S-8921; Its chemical name is methyl-11- (3,4-dimethoxyphenyl) _3_ (3-ethylvaleryl) -1-hydroxy-6,7,8-trimethoxy-2-naphthoate. ],

Compounds having the general formula (I) described in W099 / 35135, salts thereof, Solvates or physiologically functional derivatives thereof,

A compound having the general formula (I) described in WO 99X64409 (USP 6,221, 897), a pharmacologically acceptable salt or a physiologically functional derivative thereof,

A compound having the general formula (I) described in WO 00/47568, a pharmaceutically acceptable salt thereof, a solvate thereof or a prodrug thereof,

Compounds having the general formula (I) described in WO 00/61568 (US Pat. No. 6,277,831), pharmacologically acceptable salts or physiologically functional derivatives thereof, and

The following general formula (II) described in EP 1070703

d

Inside

R ¹ is a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted with 1 to 5 groups selected from substituent groups a and b, and a group selected from substituent groups a and b. An aryl group substituted by 1 to 5 or a heterocyclic group substituted by 1 to 5 with a group selected from substituent groups a and b,

R ² is a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted by 1 to 3 groups selected from a substituent group a, a group selected from a substituent group a, and 1 to Represents a 3-substituted aryl group or a heterocyclic group substituted by 1 to 3 groups with a group selected from substituent group a,

R ³ and R ⁴ are the same or different and each represent a hydrogen atom or a group selected from substituent group a;

A is the following formula (A-1)

(Wherein, R ⁵ represents a hydrogen atom, a hydroxy group or a lower alkyl group;

R ⁶ represents a hydroxy group, a lower alkoxy group, a lower alkylthio group or an amine residue,

X and Y are the same or different and each represent an oxygen atom or a sulfur atom;

z represents a single bond or —c ₆ alkylene group. )

A group having

G is a single bond, a C ₆ alkylene group or a substituted C ₆ alkylene group (the substituent is a hydroxy group, an oxo group, a cycloalkyl group, an aryl group, a heterocyclic group, a substituent group a And b) a substituted or unsubstituted alkyl group substituted with 1 to 5 groups selected from the groups selected from a and b, an aryl group substituted with 1 to 5 groups substituted with the groups selected from the groups a and b, or is a heterocyclic group substituted by 1 to 5 groups selected from b.), and when the broken line represents a double bond, D represents a carbon atom; and E represents = N— 0— Indicates that

When the dashed line represents a single bond, D represents a group having CH or a nitrogen atom, E represents an oxygen atom, a sulfur atom, a group having —NH— or a group having one C O—,

Substituent group a is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a mono-lower alkylamino group, a g-lower alkylamino group, a cyano group and a nitro group. And the substituent group b is a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a monono lower alkyl group rubamoyl group, a G lower alkyl group rubamoyl group, a nitro group, a cycloalkyl group, an aryl group, a From cycloalkyl, arylalkyl, aryloxy, 7aralkyloxy and arylalkylthio groups substituted with 1 to 3 aryloxy groups, aralkyloxy groups, arylthio groups, and groups selected from substituent group a. Group. ]

A cyclobutene derivative having the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof (the compound having the general formula (I), a pharmaceutically acceptable salt thereof, Disclosed as esters or other derivatives thereof). In the above formula (II), RR ² , G and “cycloalkyl group” in the definition of substituent group b, “cycloalkyl group substituted with 1 to 3 groups selected from substituent group a” and “ The cycloalkyl portion of the cycloalkyl group substituted by 1 to 5 groups selected from the substituent groups a and b '' is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norpolnyl A saturated carbocyclic group having 3 to 10 carbon atoms, such as adamantyl or indanyl, and may be condensed with another cyclic group such as a benzene ring. Such a cycloalkyl group is preferably a C ₅ —〇 ₆ cycloalkyl group, and most preferably a cyclohexyl group. In the above formula (II), “aryl group”, “aryl group substituted by 1 to 3 groups selected from substituent group a” in the definition of RR ² , G and substituent group b, and “ The aryl portion of the aryl group substituted by 1 to 5 groups selected from the substituent groups a and b is, for example, a carbon number such as phenyl, indenyl, 1-naphthyl or 2-naphthyl group. 6 to 10 aromatic hydrocarbon groups. R ¹ is preferably phenyl, 1-naphthyl or 2-naphthyl group, most preferably a phenyl group, and in R ² , G and the substituent group b, preferably a phenyl group It is. In the formula (II), "heterocyclic group" in the definition of the RR ² and G, "is 1 to 3 substituted with a group selected et or Substituent group a heterocycle group" and "substituent group a and The heterocyclic group of the `` heterocyclic group substituted by 1 to 5 groups selected from b '' includes a sulfur atom, an oxygen atom And represents a 5- to 7-membered heterocyclic group containing 1 to 3 carbon atoms and / or 1 to 3 nitrogen atoms. —Aromatic heterocyclic groups such as oxaziazolyl, triazolyl, tetrazolyl, thiadiazolyl, vilanyl, pyridyl, pyridazinyl, pyrimigel, vilazinyl, and morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyridazolidinyl, imidazolidinyl Examples of such groups include partially or completely reduced groups. Further, the heterocyclic group may be condensed with another cyclic group such as a benzene ring. Groups such as sathiinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl, and isoindolinyl. In such a heterocyclic group, a 5- or 6-membered aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group condensed with a benzene ring is preferable, and chenyl, furyl and pyrrole are more preferable. A phenyl, thiazolyl, oxazolyl, imidazolyl, pyridyl or benzene ring condensed thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl or pyridyl group, more preferably a phenyl or pyridyl group; Preferably, it is a 2-phenyl or 4-pyridyl group. In the above formula (II), “lower alkyl group” in the definition of R ⁵ and the substituent group a is, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, s-butyl, t-butyl, pentyl, isopentyl , 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, Straight or branched chain having 1 to 6 carbon atoms such as 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group an alkyl group, preferably a CC ₄ alkyl group, more preferably a 〇 ₂ Arukiru group, and most preferably a methyl group. In the above formula (II), “lower alkoxy group” in the definition of R ⁶ and the substituent group a represents a group in which the above “lower alkyl group” is bonded to an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy. , Butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethyl C1-C6 linear chains such as butoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy Or a branched chain alkoxy group, preferably —c ₄ alkoxy group, more preferably one c ₂ alkoxy group. And most preferably a methoxy group. In the above formula (II), “lower alkylthio group” in the definition of R ⁶ and the substituent group a represents a group in which the above “lower alkyl group” is bonded to a sulfur atom, for example, methylthio, ethylthio, propylthio, isopropylthio , Butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, Such as 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio or 2,3-dimethylbutylthio a carbon number from 1 to 6 straight-chain or branched alkylthio group, preferably, C, one C ₄ Al A thiothio group, more preferably a C ₂ alkylthio group, and most preferably a methylthio group. In the above formula (II), the term “amine residue” in the definition of R ⁶ represents an unsubstituted or substituted amino group or a heterocycle containing a nitrogen atom. For example, amino group; hydroxyamino group; methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1 1-ethylpropylamino, hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2 1-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino, 2-ethylethylamino —Lower alkylamino group ”; methoxyamino, ethoxyamino, propoxyamino, isopropoxyamino, butoxyamino, isobutoxyamino, s-butoxyamino, t-butoxyamino, pentyloxyamino, isopentyloxyamino, 2- “Mono or di-lower” in which one or two of the above “lower alkoxy” groups such as methylbutoxyamino, neopentyloxyamino, hexyloxyamino, dimethoxyamino, and jetoxyamino are bonded to one or two amino groups. Alkoxyamino group "; dimethylamino, getylamino, N-ethyl-N-methylamino “Di-lower alkylamino group” in which two “lower alkyl groups” such as dipyramino, dibutylamino, dipentylamino, and dihexylamino groups are bonded to two amino groups; cyclopentylamino, cyclohexylamino, dicyclopentylamino Amino or dicyclohexylamino, such as aminohexylamino, wherein the above-mentioned cycloalkyl group is substituted with 1 or 2 amino groups; sulfomethylamino, 2-sulfoethylamino, 3-sulfopropylamino, Amino groups substituted by one or two "sulfo lower alkyl groups" such as 4-1-sulfoptylamino, 5-1-sulfopentylamino, 6-sulfohexylamino; carboxymethylamino, 2-hydroxylpoxylamino , 3-force propyloxyamino, 4-force oxybutylamino, 5-carboxypentylamino, 6-forceoxyhexylamino, methoxycarboxymethylamino, ethoxycarboxymethylamino, 2-methoxy Carboxyethylamino, 2-ethoxycarboxypropylamino, 3-methoxycarboxypropylamino, 3-ethoxycarboxypropylamino, 4-methoxycarboxybutylamino, 5-methoxycarboxypentylamino Carboxy or lower alkoxy radicals, such as 6-methoxycarboxyhexylamino A lower alkyl group substituted with 1 to 2 amino groups; a saturated cyclic amine residue having a nitrogen atom in the ring such as pyrrolidino, piperidino, piperazino, N-methylpiperazino, morpholino, and thiomorpholino; An aryl or aralkylamino group in which a nitrogen atom may be substituted with a "lower alkyl group", such as anilinino, benzylamino, N-methylanilino, N-methylbenzylamino; pyridylamino, N-methylpyridylamino, An amine residue such as N-ethylpyridylamino bonded by a nitrogen atom such as a heteroarylamino group which may be substituted with a “lower alkyl group” may be mentioned. An amino group, a hydroxyamino group, a mono-lower alkylamino group or a di-lower alkylamino group, An amino group in which 1 to 2 substituents are substituted by a `` lower lower alkyl group '' or an amino group in which 1 to 2 substituents are substituted by a `` lower alkyl group substituted by a carboxy or lower alkoxycarbonyl '', more preferably an amino group A hydroxyamino group, a mono-lower alkylamino group or a di-lower alkylamino group, most preferably an amino group or a hydroxy group.

'Is a group. In the above formula (II), (^ _ (: ₆ alkylene moiety in the definition of Z and G in the “C alkylene group” and the “substituted C! —C ₆ alkylene group” , Methylmethylene, ethylmethylene, ethylene, propylene, trimethylene, 1-methylethylene, dimethylmethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene, 1,1- Dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene, 1,1 dimethyliletrimethylene, 2,2-dimethyliletrimethylene, 3,3-dimethyletrimethylene Methylene, hexamethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methynolepentamethylene, 5-methylpentamethylene, 1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene Methylene, 3,3 —A linear or branched alkylene group having 1 to 6 carbon atoms, such as dimethyltetramethylene or 4,4-dimethyltetramethylene group; the, - (: ₂ Arukiren a group, the most favorable applicable, a methylene group, at G, preferably is one C ₄ alkylene group, more preferably a methylene, methylmethylene or Echirumechiren group In the above formula (II), “Halogen atom J in the definition of substituent group a is fluorine, chlorine, bromine, or iodine atom. In the above formula (II), the “halogeno lower alkyl group” in the definition of the substituent group “a” is the same as the above “lower alkyl group”. A group substituted by a gen atom, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibumomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-Promoethyl, 2-chloroethyl, 2-fluoroethyl, 2-chloroethyl, 3-chloropropyl, 4-fluorobutyl, 6-hexylhexyl or 2, One (: ₆ halogenoalkyl group such as 2-dibromoethyl group, preferably — (: ₄ halogenoalkyl group, more preferably 1 C ₂ halogenoalkyl group, most preferably In the above formula (II), the “mono-lower alkylamino group” in the definition of the substituent group a has the same meaning as described above, and is preferably a mono-C ₄ alkyl group. An alkylamino group, more preferably a mono-C ₂ alkylamino group, and most preferably a methylamino group. ”In the above formula (II),“ The “lower alkylamino group” has the same meaning as described above, and is preferably a di- (broad alkylamino group, more preferably a di-C ^ —C ₂ alkylamino group, and most preferably Has a dimethylamino group In the above formula (II), “lower alkoxycarbonyl group” in the definition of the substituent group b represents a group in which the above “lower alkoxy group” is bonded to a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, and propoxy. Luponyl, isopropoxy, luponyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxy

—C 1-6 straight-chain or straight-chain such as dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl or 2,3-dimethylbutoxycarbonyl A branched-chain alkoxycarbonyl group, preferably a C ₄ alkoxycarbonyl group, More preferably, it is a 1 c ₂ alkoxycarbonyl group, and most preferably, a methoxycarbonyl group. In the above formula (II), the “mono-lower alkyl group” in the definition of the substituent group “b” indicates a group in which the above “lower alkyl group” is bonded to a single group by a single group. For example, methylcarbamoyl, Ethyl carbamoyl, Propyl carbamoyl, Isoprop Oral pill carbamoyl, Butyl carbamoyl, Isobutyl carbamoyl, S-butyl carbamoyl, T-butyl carbamoyl, Pentyl carbamoyl, Isopentyl carbamoyl, 2-Methyl butyl carbamoyl, Neopentyl carbamoyl, 1-E A mono-C ₆ alkylcarbamoyl group, such as a propylpropyl group or a hexylcarbamoyl group, preferably a mono-C ₄ , —C ₄ alkyl group or a mono-C ₂ alkyl group; Is a radical Preferably, it is a methylcarbamoyl group. In the above formula (II), the “di-lower alkyl group rubamoyl group” in the definition of the substituent group b represents a group in which the above “Ci-C ₆ alkyl group” is bonded to two group rubamoyl groups. dimethylcarbamoyl, Jefferies Ji carbamoyl, N- Echiru N- methyl force Rubamoiru a dipropyl force Rubamoiru, dibutylcarbamoyl, di C _t one C ₆ alkyl carba model I le groups such as alkoxy carbamoyl group to dipentyl Cal Bamoiru or di, preferably a di one C ₄ alkyl force Rubamoiru group, more preferably a di c ^ - alkyl force Rubamoiru group, most preferably a dimethyl local Pamoiru group. In the above formula (II), the aryloxy portion of the “aryloxy group” in the definition of the substituent group b and the “aryloxy group substituted by 1 to 3 groups selected from the substituent group a” is the same as the above. An "aryl group" indicates a group bonded to an oxygen atom, for example, pheno It is a C ₆ -C _{1 ()} aryloxy group such as xy, 1-indenyloxy, 2-indenyloxy, 1-naphthyloxy or 2-naphthyloxy, preferably a phenoxy group. In the above formula (II), the "aralkyloxy group" in the definition of the substituent group b and the "aralkyloxy group substituted with 1 to 3 groups selected from the substituent group a" in the definition of the substituent group b are benzyl, and —Naphthylmethyl, / 3—naphthylmethyl, indenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenyl, 2-phenyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-Phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylphenyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3- Naphthyl butyl, 4-naphthyl butyl, 1-phenylpentyl, 2-phenylpentyl , 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenypentyl Hexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2 A C ₇ -C ₁₆ aralkyl group such as a 1-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-1-naphthylhexyl or 6-naphthylhexyl group, preferably a benzyloxy group is there. -In the above formula (II), the arylthio moiety of the "arylthio group" in the definition of the substituent group b and the "arylthio group substituted with 1 to 3 groups selected from the substituent group a" Indicates a group in which the above “aryl group” is bonded to a sulfur atom, and includes, for example, phenylthio, 1-indenylthio, 2-indenylthio, 3_indenylthio, and 1-naphthylthio. And a C ₆ -C _1Q arylthio group such as a 2-naphthylthio group, preferably a phenylthio group. In the above formula (II), specific examples of the "cycloalkyl group substituted by 1 to 3 groups selected from the substituent group a" in the definition of R ² include, for example, 2-fluorocyclopropyl, 2- Chlorocyclopropyl, 2- or 3-fluorocyclopentyl, 2- or 3-chlorocyclopentyl, 2-, 3- or 4-fluorocyclohexyl, 2_, 3- or 4-chlorocyclohexyl, 2 -, 3- or 4-bromocyclohexyl, 2-, 3- or 4-hydroxycyclohexyl, 2-hydroxycyclopropyl, 2- or 3-hydroxycyclopentyl, 2-, 3- or 4-hydroxy Cyclohexyl, 2-methylcyclopropyl, 2-ethylcyclopropyl, 2- or 3-methylcyclopentyl, 2- or 3-methylcyclopentyl, 21 , 3- or 4-methylcyclohexyl, 2-, 3- or 4-ethylcyclohexyl, 2-trifluoromethylcyclopropyl, 2- or 3_trifluoromethylcyclopentyl, 2-, 3- or 4- Trifluoromethylcyclohexyl, 2-methoxycyclopropyl, 2- or 3-methoxycyclopentyl, 2-, 3- or 4-methoxycyclohexyl, 21,3- or 4-ethoxycyclohexyl, 2-methylthiocyclo Propyl, 2- or 3-methylthiocyclopentyl, 2-, 3- or 4-methylthiocyclohexyl, 2-, 3_ or 4-ethylthiocyclohexyl, 2-aminocyclopropyl, 2- or 3-aminocyclopentyl, 2- , 3 _ or 4 monoaminocyclohexyl, 2-methylaminocyclopropyl , 2- or 3-methylaminocyclopentyl, 2-, 3- or 4-methylaminocyclohexyl, 2-nitrocyclopentyl, 2- or 3-nitrocyclopentyl, 2-, 3- or 4-nitrocyclo Methoxyhexyl, 2-dimethylaminocyclopropyl, 2- or 3-dimethylaminocyclopentyl, 2-, 3- or 4-dimethylamino 3,4-difluorocyclohexyl, 3,4-dichlorocyclohexyl, 2,3-dimethoxycyclohexyl, 3,4-dimethoxycyclohexyl, 3,5-dimethoxycyclohexyl or 3,4,5-tri A methoxycyclohexyl group, preferably a 1 to 3 substituted C ₅ —〇 ₆ cycloalkyl group (the substituent is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl or lower alkoxy). And most preferably a monosubstituted cyclohexyl group, wherein the substituent is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl or lower alkyl. A group selected from the group consisting of alkoxy groups.). In the above formula (II), specific examples of the “aryl group substituted by 1 to 3 groups selected from the substituent group a” in the definition of R ² include, for example, 2-, 3- or 4-fluoro Phenyl, 2-, 3- or 4-monophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-phenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-methoxyphenyl, 2- , 3- or 4- ethoxyphenyl, 2_, 3- or 4-propoxyphenyl, 2_, 3- or 4-isopropoxyphenyl, 2-, 3- or 4-methylthiophenyl, 2-, 3 1- or 4-ethylthiophenyl, 2 , 3- or 4-aminophenyl, 2,3_ or 4-methylaminophenyl, 2-, 3- or 4-dimethylaminophenyl, 2,3-1 or 412-trophenyl, 3,4-difluorophenyl, 3,4 4-dichlorophenyl, 3,4-dibromophenyl, 3,5-difluoromouth phenyl, 3,5-dichloromouth phenyl, 3,5-dibromophenyl, 2,3,4-trifluorophenyl, 2,, 3,4-monochlorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methyl-2-methoxyphenyl, 6-fluoro-4-monomethyl-12-methoxyphenyl, 5-fluoroindene-3-yl, 5-methylindene-3-yl, 5 —Methoxyindene-1-yl, 5-fluoroindene-2-yl, 5-methylindene-2-yl, 5-methylindene-2-yl, 5-methoxyindene-2-yl, 5 —2-Troindene-3-I-yl, 5-12-Troindene—2-I-yl, 5-Fluoronaphthalene-1-2-yl, 5-Methylnaphthalene-1-2-yl, 5-Methoxynaphthalene-1-2-yl 5—Fluoronaphthalene 1—yl , 5-chloronaphthalene-11-yl, 5-methylnaphthalene-111-yl, 5-methoxynaphthalene-111-yl, 512-tronaphthalene-1-1-yl or 5--2-tronaphthalene-one 2-yl group, preferably 1 to 3 substituted aryl group (the substituent is selected from the group consisting of halogen atom, hydroxy, lower alkyl, halogeno lower alkyl and lower alkoxy group) And more preferably a one-substituted aryl group (the substituent is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl or lower alkoxy group), and more preferably preferably, C ₆ which is one substituted - C _1Q Ariru group (the substituent is a halogen atom, hydroxy, lower alkyl, eight Rogeno lower alkyl or lower alkoxy group.) be Even more preferably, it is a monosubstituted phenyl group (the substituent is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl or lower alkoxy group), and most preferably, 4-fluorophenyl. A 4-phenyl, 4-methylphenyl or 4-methoxyphenyl group. In the above formula (II), specific examples of the “heterocyclic group substituted by 1 to 3 groups selected from the substituent group a” in the definition of R ² include, for example, 3-, 4- or 5-. Fluorofuran-1-yl, 2-, 4- or 5-fluorofuran-3-yl, 3 ―, 4 _ or 5-hydroxyfuran-2-yl, 2-, 4- or 5-hydroxyfuran-3-yl, 3-, 4- or 5-methylfuran-2-yl, 2-, 4- or 5-methylfuran-3-yl, 3-, 4- or 5-methoxyfuran-2-yl, 2-, 4- or 5-methoxyfuran-3-yl, 3-, 4-1 Or 5-methylthiofuran-2-yl, 21,4- or 5-methylthiofuran-3-yl, 3_, 41- or 5-fluorothiophene-2-yl, 3 —, 4-1- or 5-bromothiophen-1-yl, 3-, 4- or 5-hydroxythiophen-2-yl, 3-, 4- or 5-methylthiophen-2-yl, 2-1, 4 — Or 5-methylthiophen-1-yl, 3-, 4- or 5-ethylthiophen-2-yl, 2-, 4- or 5 —Ethylthiophene—3-yl, 3-, 4- or 5-Methoxythiophene 2-yl, 2-, 4-1 or 5-Methoxythiophene-3-yl, 3-, 4-1 or 5-Methylthiothiophene-2-yl, 2-, 4_ or 5-methylthiothiophene-3-yl, 3- or 4-fluorothiazole_5-yl, 4-hydroxythiazo 5-yl, 4-methylthiazo 5-yl, 3-, 4- or 5-fluorobenzothiophen-2-yl, 2-, 4- or 5-fluorobenzothiophene I 3-yl, 34_ or 5-bromobenzothiophene-2-yl, 2-, 4- or 5-bromobenzothiophene-3-yl, 3-, 4-mono or 5-hydroxybenzo Thiophene_2-yl, 2-, 4- or 5-hydroxybenzothiophene 3-yl, 3-, 4 _ or 5-methylbenzothiophene 1-2-yl, 2-, 4-or 5-methylbenzothiophene 1-3 -yl, 3-, 4-or 5-methoxybenzothiophene 1-2- 2-, 4- or 5-methoxybenzothiophen-3-yl, 4-, 5-, 6- or 7-methylbenzothiazole-2-yl, 2- or 4-fluoropyridine-13 2-, 3- or 4-hydroxypyridin-4-yl, 2- or 3-hydroxypyridine-4-yl, 2- or 4-methylpyridine-1-3 —Ill, 2- or 3-hydroxypyridine-1-yl, 2- or 3-methylpyridin-4-yl, 2_ or 4-methoxypyridine-14-yl, 2_ or 3-methoxypyridine-14-yl 2-, 4- or 4-methylthiopyridine-1-yl, 2- or 3-methylthiopyridine-41-yl, 3-, 4- or 5-nitrothiophene-2-yl, 2_, 4- or 5-nitrothiophene-3-yl or

A 2- or 3-nitropyridine-4-yl group, preferably a 5- or 6-membered aromatic heterocyclic group which may be condensed with a 1- or 3-substituted benzene ring; A hydrogen atom, a hydroxy, a lower alkyl, a halogeno lower alkyl and a lower alkoxy group). More preferably, it may be condensed with one substituted benzene ring. A 5- or 6-membered aromatic heterocyclic group (the substituent is a halogen atom, a hydroxy, a lower alkyl or a lower alkoxy group), and more preferably, a single-substituted chenyl group or a furyl group , A pyrrolyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group or a pyridyl group (the substituent is a halogen atom, hydroxy, lower alkyl or lower alkoxy group). Preferably,

A single-substituted phenyl or pyridyl group (the substituent is a halogen atom, a hydroxy, a lower alkyl or a lower alkoxy group), and most preferably a 2-substituted 2-thenyl Or a 4-pyridyl group (the substituent is a halogen atom, hydroxy, lower alkyl or lower alkoxy group). In the above formula (II), specific examples of the “cycloalkyl group substituted by 1 to 5 groups selected from the substituent groups a and b” in the definition of R ¹ include, for example, the aforementioned in the definition of R ² "1 to 3 substituted alkyl groups substituted with a group selected from the substituent group a", 21-hydroxypropyl, 21- or 3-isopropyloxypentyl, 2-, 3- Or 4 l-oxycarbonylcyclohexyl, 2-methoxycarbonylcyclopropyl, 21- or 3-methoxycarbonylcyclopentyl, 2 _,

3- or 4-methoxycarbonylcyclohexyl, 2-, 3- or 4-force Rubamoylcyclohexyl, 2,3- or 4-methylcarbamoylcyclohexyl, 21,3- or 4-dimethylcarbamoylcyclohexyl, 2- or 3-cyclohexylcyclopentyl, 2-, 3- Or 4-cyclohexyl cyclohexyl, 2-phenylcyclopropyl, 2- or 3-phenylcyclopentyl, 2-, 3- or 4-phenylcyclohexyl, 2-phenoxycyclopropyl, 2- or 3-phenoxy Cyclopentyl, 2—, 3—, or 4

3-pentyloxy-open-pentyl, 2-, 3- or 4-hydroxy-hexyl, 2-phenylthiocyclopropyl, 2- or 3-phenyl-thiopentyl or 2_, 3- or 4-phenyl-o-cyclopentyl A cyclohexyl group, preferably a cycloalkyl group substituted by 1 to 3 groups with a group selected from substituent groups a and b, more preferably 1 to 3 substituted groups A cycloalkyl group (the substituent is a group selected from a substituent group a, a cycloalkyl group, an aryl group, an aryloxy group, an aralkyloxy group, an arylthio group, and one to three groups selected from the substituent group a; And is a group selected from the group consisting of cycloalkyl, aryl, aryloxy, aralkyloxy and arylthio.), And more preferably 1 to 3 An individually substituted cycloalkyl group (the substituent is a group selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a nitro group); Even more preferably, 1 to 3 substituted 'C ₅ -〇 ₆ cycloalkyl groups (the substituents are a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a nitro group And most preferably a cyclohexyl group substituted by 1 to 3 groups (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower group). A group selected from the group consisting of an alkyl group, a lower alkoxy group and a nitro group.). In the above formula (II), specific examples of the “aryl group substituted with 1 to 5 groups selected from the substituent groups a and b” in the definition of R ¹ include, for example, the definition of R ² The above-mentioned “aryl group substituted by 1 to 3 groups selected from the substituent group a”, 2-, 3- or 4-methoxy phenyl, 2-, 3- or 4-methoxycarbonylphenyl, 2-, 3- Or 4-ethoxycarbonylphenyl, 2-, 3- or 4-carbamoylphenyl, 2-, 3- or 4-methylcarbamoylphenyl, 2-, 3- or 4-dimethylcarbamoylphenyl, 2-, 3- or 4-cyclopentylphenyl, 2-, 3- or 4-cyclohexylphenyl, 2-, 3- or 4-phenoxyphenyl, 2-, 3- or 4-diphenyl Nil, 2—, 3— or 4 Roxyphenyl, 3,4-dibenzyloxyphenyl, 3,5-dibenzyloxyphenyl, 2,3-, 1- or 4-phenylthiophene, 5-cyclohexylindene-3-yl, 5-phenine

One 3-yl, 5-phenoxyindene _ 3-yl, 5

3-yl, 5-phenylthioindene 3-yl, 5-

2-yl, 5-phenylindene-1-yl, 5-phenoxyindene_2-yl, 5-benzyloxyindene-1-yl, 5-phenylthioindene-2- ^ 5-yl, 5-cyclohexylnaphthalene-2-yl, 5-phenyl-2-naphthalene-12-yl, 5-phenoxynaphthalene-12-yl, 5-benzyloxynaphthalene-12-yl,

5-phenyl-2-naphthalene 2-yl, 5-cyclohexylnaphthalene 1-1yl, 5-phenylnaphthalene-11-yl, 5-phenyloxynaphthalene-11-yl, 5 A benzyloxynaphthalene-11-yl or 5-phenylthionaphthalene-11-yl group, preferably an aryl group substituted by 1 to 3 groups selected from substituent groups a and b. More preferably, 1 to 3 substituted aryl groups (the substituents are a substituent group a, a cycloalkyl group, an aryl group, an aryloxy group, an aralkyloxy group, an arylthio group, and a substituent group a Cycloalkyl, aryl, aryloxy, aralkyloxy, substituted by 1 to 3 groups selected from And a group selected from the group consisting of arylthio groups. And more preferably a substituted or unsubstituted aryl group having 1 to 3 substituents such as a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a nitro group. And still more preferably, a C ₆ -C 1 _-aryl group substituted by 1 to 3 (the substituent is a halogen atom, a hydroxy group, a lower group, An alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a nitro group), and more preferably, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl 3-Methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl or 3,3-methylphenyl 4,5-trifluorophenyl group; most preferably, 3_fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl or 3 , 5-dichlorophenyl group. In the above formula (II), specific examples of the “heterocyclic group substituted by 1 to 5 groups selected from the substituent groups a and b” in the definition of R ¹ include, for example, the aforementioned in the definition of R ² "Heterocyclic group substituted by 1 to 3 groups selected from substituent group a", 3-, 4- or 5-phenylthiophene-2-yl, 21, 41- or 5-phenyl A thiophene-3-yl or 2- or 3-phenylpyridine-14-yl group, preferably a heterocyclic ring substituted by 1 to 3 groups selected from the substituent groups a and b And more preferably a 5- or 6-membered aromatic heterocyclic group which may be condensed with 1 to 3 substituted or benzene rings, and more preferably 1 to 3 substituted benzene. A 5- or 6-membered aromatic heterocyclic group which may be condensed with a ring (the substituent is a substituent group a, a cycloalkyl group, an aryl group) , Ariruokishi group, Ararukiruokishi group, § Li one thio group, And a group selected from the group consisting of cycloalkyl, aryl, aryloxy, 7-ralkyloxy and arylthio groups substituted with 1 to 3 groups selected from the substituent group a. And more preferably, a 5- or 6-membered aromatic heterocyclic group which may be condensed with a 1- to 3-substituted benzene ring (the substituent is an octogen atom, a hydroxy group, a lower group) An alkyl group, a halogeno-lower alkyl group, a lower alkoxy group and a nitro group.), And more preferably a 1 to 3 substituted chenyl group, a furyl group and a pyrrolyl group. Group, thiazolyl group, oxazolyl group, imidazolyl group, pyridyl group or condensed with benzene ring, chenyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl or pyridyl group (the substituents are halogen atom, hydroxy group, lower alkyl, And a group selected from the group consisting of octogeno lower alkyl, lower alkoxy and nitro groups.) , 1 to 3 substituted phenyl or pyridyl groups (the substituents are groups selected from the group consisting of halogen atoms, hydroxy groups, lower alkyl, halogeno lower alkyl, lower alkoxy and nitro groups) And particularly preferably a 1 to 3 substituted 2-thenyl or 4-pyridyl group (the substituent is selected from a halogen atom, a hydroxy group, a lower alkyl, a halogeno-lower alkyl, a lower-alkoxy and a di-total group) A group selected from the group consisting of :). In the above formula (II), specific examples of “substituted C! —C ₆ alkylene group” in the definition of G include, for example, hydroxymethylene, oxomethylene, cyclopentylmethylene, cyclohexylmethylene, phenylmethylene, 1 1-naphthylmethylene, 2-naphthylmethylene, 4-fluorophenylmethylene, 4-chlorophenylmethylene, 4-hydroxyphenylmethylene, 4-methylphenylmethylene, 1-naphthylmethylene, 2-naphthylmethylene, 2-chenyl Methylene, 4-pyridylmethylene, 1-hydroxyethylene, 1-oxoethylene, 1-cyclopentylethylene, 1-cyclohexylethylene, 1-phenylethylene, 1- (1-naphthyl) ethyl 1- (2-naphthyl) ethylene, 1- (4-fluorophenyl) ethylene, 1- (4-chlorophenyl) ethylene, 1- (4-hydroxyphenyl) ethylene,

1- (4-methylphenyl) ethylene, 1- (2-Chenyl) ethylene, 1- (4-Pyridyl) ethylene, 2-hydroxyethylene, 2-oxoethylene, 2-cyclopentyl, 2-cyclohexylethylene, 2-phenylethylene, 2-

(1 _ naphthyl) ethylene, 2- (2-naphthyl) ethylene, 2- (4-fluorophenyl) ethylene, 2- (4-chlorophenyl) ethylene, 2- (4-hydroxyphenyl) ethylene, 2- ( 4-methylphenyl) ethylene, 2- (1-naphthyl) ethylene, 2- (2-naphthyl) ethylene, 2- (2-phenyl) ethylene,

2- (4-pyridyl) ethylene, 1-hydroxy-2-methylethylene, 2-methyl-1-oxoethylene, 1-cyclopentyl-2-methylethylene, 1-cyclohexyl 2-methylethylene, 2-methyl-1-phenyl Ethylene, 2-methyl-1- (1-naphthyl) ethylene, 2-methyl-1- (2-naphthyl) ethylene,

1- (4-fluorophenyl) -2-methylethylene, 1- (4-chlorophenyl) 1-2-methylethylene, 1-1 (4-hydroxyphenyl) 1-2-methylethylene, 1- (4-methylphenyl) ) _ 2-methylethylene, 2-methyl-1- (1-naphthyl) ethylene, 2-methyl-1-1 (2-naphthyl) ethylene, 2-methyl-1-1 (2_Chenyl) ethylene, 2-methyl-11 (4-pyridyl) ethylene, 1-hydroxytrimethylene, 1-year-old oxotrimethylene, 1-cyclopentyltrimethylene, 1-cyclohexyltrimethylene, 1-phenyltrimethylene, 1- (1naphthyl) ) Trimethylene, 1- (2-naphthyl) trimethylene, 1- (4-fluorophenyl) trimethylene, 1-1 (4-chlorophenyl) trimethylene, 1-1 (4-hydroxyphenyl) trimethylene, 1-1 (4-methyl) (Ruphenyl) trimethylene, 1- (1-naphthyl) trimethylene, 1- (2-naphthyl) -trimethylene, 1- (2-chenyl) -trimethylene, 1- (4-pyridyl) -trimethylene, 3-hydroxytrimethylene, 3-oxotrimethylene Methylene, 3-cyclopentyl trimethylene, 3- Cyclohexyl trimethylene, 3-pheninoletrimethylene, 3- (1-naphthinole) trimethylene, 3- (2-naphthinole) trimethylene, 3_ (4-phenolenophenyl) trimethylene, 3- (4-chlorophene) -Nore) trimethylene, 3- (4-hydroxyphenyl) trimethylene, 3- (4-methinolephenole) trimethylene, 3- (1-1 naphthyl) trimethylene, 3- (2-naphthyl) trimethylene, 3- ( 2-alkyl) trimethylene or 3- (4-pyridyl) trimethylene, preferably a monoalkylene group substituted by hydroxy, oxo or aryl, more preferably hydroxy, oxo or A Ci-C alkylene group substituted with aryl, most preferably methylene or ethyl substituted with hydroxy, oxo or aryl. It is a down group.

Specific examples of the cyclobutene derivative having the general formula (II), which is an ileal bile acid transporter inhibitor, which is an active ingredient of the pharmaceutical composition of the present invention, include, for example, those described in Tables 1 to 6 of EP 1070703. The present invention is not limited to these compounds. In the ileal bile acid transporter inhibitor as described above, preferably, TA-7522, S-8921,

• 1— {4- [ ₄ -[(4R, 5R) -1,3-dibutyl-7- (dimethylamino) —2,3,4,5-tetrahydro-1-4-hydroxy-1,1-dioxo-1 1—Benzochepin-5-inole] phenoxymethinole] benzyl} —4—aza—1-azonia bicyclo [2.2.2] octane chloride (hereinafter referred to as compound C), • 1— {4— [4-[(4R, 5R) -3,3-Diptyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxo-11-benzozopine _5-inole] phenoxy ] Puchinore) 14 1 other 1 _ azobicyclo [2.2.2] year old butane methanesulfonate (hereinafter referred to as compound D), • {2— [2— [2— [4— [(4 R, 5 R) —3,3-Diptyl- 7—

1,2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxo-1

1-Venzochepin-5-inole] phenoxy] ethoxy] ethoxy] eth ^^ triethylammonium chloride (hereinafter referred to as compound E),

• 4— {3— [(1— (3,5-difluorophenyl) ethylamino) 1- (4-methoxypheninole) methyl] phenenoamino) —3-hydroxy-3-cyclobutene—1,2-dione , Compound A.),

• 4- {3-[(1- (3,4-difluorophenyl) -ethynoleamino)-(4-methoxyphenyl) methyl] pheninoleamino) -3-hydroxy-3-cyclobutene-1,2-dione , And compound F.)

• 3- {3-[(4-Fluorophenyl) — (1- (3-fluorophenyl) ethynoleamino) methyl] phenenoleamino} —4-hydroxy-1-3-cyclobutene-1,

A compound selected from 2-dione (hereinafter, referred to as compound G) or a pharmacologically acceptable salt thereof;

TA-75 22, S—8 9 21,

• 1- {4- [4-[(4 R, 5 R) —3,3-dibutyl—7— (dimethyl / reamino) —2,3,4,5-tetrahydro-1-hydroxy-1,1-dioxo-1 1-Benzochepine-1-yl] phenoxymethyl] benzyl} —4-aza 1-azourea bicyclo [2.2.2] octane chloride (compound C),

• 4- {3-[(1- (3,5-difluorophenyl) ethylamino)-(4-methoxypheninole) methinole] pheninoleamino} -13-hydroxy-13-cyclobutene-11,2-dione (Compound A ),

• 4 -— {3 -— ((1— (3,4-diphenyl) phenylamino) -1- (4-methoxyphenyl) methynole] phenylamino) -3-hydroxy-1-cyclobutene—1,2-dione (Compound F )

• 3-{3-[(4-fluorophenyl) 1 (1- (3-fluorophenyl) ethyl Noleamino) methinole] phenylamino} —one compound selected from 4-hydroxy-13-cyclobutene-11,2-dione (compound G) or a pharmaceutically acceptable salt thereof, and more preferably, S-8921 ,

• 1— {4— [4-I [(4R, 5R) —3,3-dibutyl-7— (dimethylamino) -2,3,4,5-tetrahydro-1-hydroxy-1,1,1-dioxo-11 Benzochepine-1_ [yl] phenoxymethyl] benzyl} 1-41-azazonabicyclo [2.2.2] octane chloride (compound C),

• 4- {3-[((1- (3,5-difluorophenyl) ethylamino) -1- (4-methoxypheninole) methyl] pheninoleamino) -3-hydroxy-1-3-cyclobutene 1-1,2-dione (compound A),

• 4 -— {3-[(1— (3,4-difluorophenyl) ethylamino) -1- (4-methoxyphenyl) methyl] phenenoamino} —3-hydroxy-3-cyclobutene1-1,2-dione (compound F) and

• 3- {3-[(4-Fluorophenyl) -1- (1- (3-fluorophenyl) ethylamino) methyl] phenylamino} -4-hydroxy-13-cyclobutene-1,

A compound selected from 2-dione (compound G) or a pharmacologically acceptable salt thereof; most preferably,

• 4- {3-[((1- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenoleamino} -13-hydroxy-13-cyclobutene-11,2-dione (Compound A) or It is a pharmacologically acceptable salt.

The planar chemical structural formula of a preferred ileal bile acid transporter inhibitor is shown below.

Compound C

Compound D Compound E

Compound G An “ACAT inhibitor”, which is one of the active ingredients of the pharmaceutical composition of the present invention, is a drug that inhibits the enzyme acetyl cholesterol A: cholesterol acetyl transferase (ACAT). Rather, it acts directly on arterial sclerosis lesions on the blood vessel wall and suppresses the formation of foam cells (macrophage accumulation of cholesterol in cells) of macula phage. Or it is used as a prophylactic agent. Such ACAT inhibitors include, for example,

A compound having the general formula (I) described in WO 92/09561 [preferably FR-129169, the chemical name of which is N- (1,2-dipheninoleetinole) -2- (2-octyloxyfiel) is an acetoamide. ],

JP-A-8-510256 (WO 94/26702, USP 5,491,172), a compound having the general formula (I) or a pharmacologically acceptable salt thereof (preferably And its chemical name is 2,6-diisopropylphenyl-2-N-[(2,4,6-triisopropylphenyl) acetyl] sulfamate, and the CI-1011 of the present invention is It also contains its pharmacologically acceptable salts. ),

The compound having the general formula (I) described in EP421441 (USP 5,120, 738) or a pharmacologically acceptable salt thereof (preferably, F-1394, and its chemical name is ( IS, 2 S) — 2— [3— (2,2-dimethylpropyl) —3-nouelureido] cyclohexane-1-yl 3— [(4 R) -N- (2, 2,5,5-tetramethyl-1,3-dioxane-14-carbol) amino] propionate, and F-1394 of the present invention also contains a pharmacologically acceptable salt thereof. — The compound described in No. 500771 (WO 97/1 9918, US Pat. No. 5,990,173) or a pharmacologically acceptable salt thereof [preferably, F-12511 with the chemical name, (S) - 2,ヽ3 \ 5 one Torimechinore -4,-hydroxy one _alpha - a dodecylthio one α- phenylene Ruasetayurido, F- 1 251 1 of the present invention, its pharmacologically acceptable Also included are salts. ],

A compound having the general formula (1) described in JP-A-10-195037 (No. 790240, US Pat. No. 5,849,732) or a pharmacologically acceptable salt thereof [preferably, — 2591 and its chemical name is 1_ (3_t-butyl-1-2-hydroxy-1-5-methoxyphenyl) -1 3- (2-cyclohexylethyl) -1-3- (4-dimethinoleamino Fe-1) is rare, and T-2591 of the present invention also includes pharmacologically acceptable salts thereof (hydrochloride and the like). ],

A compound having the general formula (I) described in WO 96/26948 or a pharmacologically acceptable salt thereof {preferably FCE-28654, and its chemical name is 1- (2,6-diisopropyl) Fuel) -3-([4R, 5R) —4,5-dimethyl-2- (4-phosphonopheninole) —1,3-dioxolan-1-ylmethyl] urea and the FCE of the present invention — 28654 also includes pharmacologically acceptable salts (such as sodium salts). )},

A compound having the general formula (I) described in WO 98/54153 (EP 987254) or a pharmacologically acceptable salt thereof (preferably, K-10085, and its chemical name is N— [2,4-bis (methylthio) -1-methyl-3-pyridyl] —2— [4-1—2- (oxoxolo [4,5-b] pyridin-2-ylthio) ethyl] piperazine [111] acetoamide, and K-110085 of the present invention also contains a pharmacologically acceptable salt thereof. }, A compound having the general formula (I) described in WO92 / 095772 (EP559898, USP 5,475,130). Is HL—004 and its chemical name is N— (2,6-diisopropinolefe-norre) -1-tetradecinolethioacetamide. ],

A compound having the general formula (I) described in JP-A-7-82222 (EP 718281) or a pharmacologically acceptable salt thereof (preferably NTE-122, The chemical name is trans-1,4-bis [1-cyclohexyl-13- (4-dimethylaminophenyl) peridomethyl] cyclohexane, and NTE-122 of the present invention is pharmacologically acceptable. Salt (hydrochloride, etc.). ),

Compounds described in Japanese Patent Publication No. H10-5101012 (W096 / 15059) or a pharmacologically acceptable salt thereof (preferably, FR-1 860 54 And its chemical name is 1-benzyl-1- [3— (pyrazole-3-yl) benzyl] — 3 _

[2,4-bis (methylthio) -1-methylpyridine-13-yl] is rare, and FR-186054 of the present invention also includes pharmacologically acceptable salts thereof. ),

Compounds having the general formula (I) described in WO 96/09287 (EP 0 789 286, US Pat. No. 5,990,150) or pharmacologically acceptable thereof Salt [preferably, N- (1-pentyl-1,4,6-dimethylindoline-7-yl)]-2,2-dimethylethanamide, and the present invention relates to a pharmacologically acceptable salt thereof (salt Acid salts, etc.). ],

A compound having the general formula (I) described in WO 97/12860 (EP 0 866 559, US Pat. No. 6,063,806) or a pharmacologically acceptable salt thereof [Preferably, N- (1-octyl-5-potoxymethyl-1,4,6-dimethylindoline-17-yl) -1,2,2-dimethylpropanamide; Salts (hydrochlorides, sulfates, etc.) are also included. Suitably in such ACAT inhibitors, FR-129169, CI-10 1 1, F—1394, F—1251 1, T-12591, FCE—28654, K—10085, HL—004, NTE—122, FR—186054,

• N- (1-octy / re 5--canoleboxymethylinole-4,6-dimethinoleindoline-17-yl) -2,2-dimethylpropanamide (hereinafter referred to as Compound B) and

• N— (1-pentyl-1,4,6-dimethylindoline-1-yl) -1,2,2-dimethylethylamide (hereinafter referred to as compound H), or a pharmacologically active compound thereof. An acceptable salt, and more preferably, CI—101 1, F-12.

51 1,

• N- (1-octyl-5-propyloxymethinolate 4,6-dimethylindoline-17-yl) -1,2,2-dimethylpropanamide (Compound B) and

• N- (1-pentyl-1,4,6-dimethylindoline-7-yl) -1,2,2-dimethylethylethaneamide (Compound H) Any one compound selected from the group consisting of: Yes, and most preferably,

• N_ (1-octyl-5-carboxymethyl-4,6-dimethylindoline-17-yl) -1,2,2-dimethylpropanamide (compound B) or a pharmacologically acceptable salt thereof.

The following shows a planar chemical structural formula of a suitable ACAT inhibitor.

R- 1 291 69 C 1 01 1

CE-28654 T-2591

H L-004 NTE-1 22

R-1 86054 Compound H

Compound B

The ileal bile acid transporter inhibitor and the ACAT inhibitor, which are the active ingredients of the pharmaceutical composition of the present invention, have a basic group such as an amino group, and are reacted with an acid. When it has an acidic group such as a carboxy group, it can be converted into a salt by reacting it with a base.

The salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid Salt, phosphoric acid Inorganic acid salts such as salts; lower alkanesulfonic acid salts such as methanesulfonic acid salt, trifluoromethanesulfonic acid salt and ethanesulfonic acid salt, and arylsulfonic acid such as benzenesulfonic acid salt and p-toluenesulfonic acid salt Organic salts such as salts, acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates; and glycine salts, lysine salts , Alginate, oleutin, glutamate, and aspartate; and most preferably, a hydrohalide or an inorganic acid salt.

On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an aluminum salt, or an iron salt. Inorganic salts such as ammonium salts, octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, fucnylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guajen salts, getylamine salts, Triethylamine salt, disuccinic hexylamine salt, N, N, dibenzylethylenediamine salt, black mouth proforce salt, proforce salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine Salt ·, Tetramethylammonium salt, Tris (hydroxymethyl) Amin salts such good Una organic salts Minometan salt; and, glycine salts, lysine salts, arginine salts, Orunichi down, glutamate, Ru can be mentioned Amino acid salts such as Asuparagin acid salt. The ileal bile acid transporter inhibitor and the ACAT inhibitor, which are active ingredients of the pharmaceutical composition of the present invention, have various isomers when an asymmetric carbon atom is present in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula. Accordingly, the present invention includes all these isomers and mixtures of these isomers in any proportion.

For example, an ileal bile acid transporter inhibitor having the above general formula (II) That the cyclobutene derivatives, _ G-R ¹ group is represented by the following formula

R °

A person

If R. The group and the R ¹ group may be substituted on an asymmetric carbon atom, especially R 1. When the group is a methyl group and R ¹ is a phenyl group or a phenyl group having a substituent, a compound having an R configuration is preferable. The ileal bile acid transporter inhibitor and the ACAT inhibitor, which are the active ingredients of the pharmaceutical composition of the present invention, absorb water by leaving them in the air or by recrystallizing them. Or a hydrate, and such a hydrate is also included in the salts of the present invention. The “ester” in the above refers to the cyclobutene derivative having the general formula (II) of the present invention, which can be converted into an ester, and such an ester is mentioned as “ester of hydroxy group” and An ester in which each ester residue is a `` general protecting group '' or a `` protecting group that can be cleaved in vivo by a biological method such as hydrolysis '' can be mentioned. Say.

“General protecting group” refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.

As the “general protecting group” for the “ester of a hydroxy group”, preferably, fomilyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, pareryl, isovaleryl, octanoyl, nonanoyl, decanol, 3 -Methylnonanoyl, 8-methylnonanoyl, 3-ethylooctanoyl, 3,7-dimethylotatanyl, pendecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanol, 1-methylpentadecanol Groups such as 14-Methylpentadecanoyl, 13, 13-Dimethyltetradecanoyl, Heptadecanoyl, 15-Methylhexadedecyl, Octadecanol, 1-Methylheptadecanoyl, Nonadecanoyl, Alcosanol, Henikosanol Chloroacetylinoles, dichloroacetylinoles, 'trichloroacetylinoles, trifluroacetinoles, halogenated alkylcarboyl groups such as roacetinole, alkoxyalkylcarbonyl groups such as methoxyacetyl, acryloyl, propioloyl, methacryloyl, octanoyl, isocrotonyl, ) — A “lower aliphatic acyl group” such as an unsaturated alkylcarboyl group such as 2-methyl-2-butenoyl (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms); benzoyl, α Naphthoyl, β-naphthoyl-like arylcarboyl group, 2-promobenzoyl, 4-chlorobenzoyl halide-like arylene-carboyl group, 2,4,6-tri-methylinobenzyl, 4-toluoyl Lower alkylated arylcarbonyl groups, lower alkoxylated arylcarbonyl groups such as 4-acetyl, arylbenzenecarbonyl groups such as 4-nitrobenzoyl and 212-trobenzoyl, 2- (methoxycarbonyl) ) “Aromatic acyl groups” such as lower alkoxycarbenylated arylcarbonyl groups such as benzoinole and arylated arylcarbonyl groups such as 4-phenylbenzoyl; Carbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycanoleponinole, lower alkoxycarbonyl groups such as t-butoxycanolepo-nore, isotopoxycarbonyl, halogens such as 2,2,2-trichloromouth ethoxycarbonyl, 2-trimethylsilinoleethoxy power / repo / re / halogen or tri-lower alkyl "Alkoxycanoleboninole group" such as a lower alkoxycarbonyl group substituted with a silyl group; tetrahydropyran-1-yl, 3-bromotetrahydridopyran-1-2-isle, 4-methoxytetrahydropyran-1 4 A "tetrahydroviranyl or tetrahydrothiopyranyl group" such as 1-yl, tetrahydrothiopyran-12-yl, 4-methoxytetrahydrothiopyran-14-yl; tetrahydrofuran-12-yl, tetrahydrothiofuran-12 —Like tetrahydrofuranyl Or tetrahydrothiofuranyl group; trimethylsilyl, triethylsilyl, isol, methyldi-t-butylsilyl, tri-lower alkylsilyl groups such as triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylsoprovirsilyl, phenyldiyl "Silyl groups" such as tri-lower alkylsilyl groups substituted with one or two aryl groups such as soprovirsilyl; methoxymethyl, 1,1-dimethyl-11-methoxymethyl, ethoxymethyl, Lower alkoxymethyl groups such as propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl; lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl; 2,2,2-trichloromouth ethoxymethyl; Screw (2-black mouth "Alkoxymethyl group" such as halogeno lower alkoxymethyl such as methyl; lower alkoxylated tyl group such as 1-ethoxyxyl and 1- (isopropoxy) ethyl; halogen such as 2,2,2-trichloromethylethyl "Substituted ethyl groups" such as chemical tyl groups; such as benzinole, α-naphthylmethinole,] 3-naphthinolemethinole, diphen-noremethinole, triphenylenolemethinole, α-naphthyldiphenenolemethyl, and 9-anthrylmethyl Lower alkyl group substituted with 1 to 3 aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzinole, 4-Methoxypheninoresefene / Lemethisle, 2-Nitrobenzinole, 4-Nitrobenzile, 4-Black Benzinole, 4-Pro Aralkyl groups such as lower alkyl groups substituted with one to three aryl groups in which the aryl ring is substituted with lower alkyl, lower alkoxy, nitro, halogen, and cyano groups such as mopendinole and 4-cyanobenzinole "Arkenyloxycanoleponyl group" such as buroxycarbonyl and aryloxycarbonyl; benzyloxycarponyl, 4-methoxybenzyloxyl / reponinole, 3,4-dimethoxypentzinole The aryl group may be substituted with one or two lower alkoxy or ditro groups, such as oxycanoleboninole, 2-ditropenoxycarbonyl, 4-nitrobenzyloxycarbur, etc. Aral Kill Oxycarbyl group ".

As the “general protecting group” for the “ester of the carboxy group”, preferably, the above-mentioned “lower alkyl group”; ether, 1-propyl, 2-propyl, 1-methyl-12- 1-propeninole, 1-methinole, 1-propenile, 2-methylinole, 1-propenile, 2-methyl-12-propenyl, 2-ethyl-2-propionyl, 1-butenyl, 2-pteninole, 1-methinolene, 2-pteninole , 1-methyl-1 1-pteninole, 3-methinole 1- 2-pturn, 1-ethynorre 2-buthenore, 3-l-pteninole, 1-methyl-3-buteninole, 2-methylinole 3-pteninole, 1-ethinolen 3-buteninole Nore, 1—Pentenore,

2-pentenole, 1-methinole, 2-pentenole, 2-methinole, 2-pentenole, 3-pentenyl, 1-methinole, 3-pentenole, 2-methinole, 3-penteninole, 4-penteninole, 4-pentenole, 1 Mechinore 4 ^ integrators two Honoré, 2- Mechinore 4 one ^ ^ Nteyu / Les, Kiseninore to 1, Kiseninore to 2, Kiseninore to 3 _, lower Arukeyuru groups such as Kiseenore 4 into single Kiseninore, to 5; Etul, 2-Probul, 1-Methyl-2-Propier, 2-Petinole, 1-Methyl _2-Butur, 2-Methinole, 2-Petinole, 1-Echinolé 2-Bucnole, 3-Petinole Nore, 1—Metinore 1—3-butinole, 2—Metinore

3-Petinole, 1-Echinole 3-Butinole, 2-Pentinole, 1-Methinole 2-Pentinole, 3-Pentinole, 1-Methyl-1 3-Pentinole, 2-Methinole 3-Pentinole, 4-Pentinole A lower alkyl group such as 1-methinolle 4-pentenchole, 2-methinolle 4-pent pentinole, 2-hexynole, 3-hexynole, 4-bexynole, 5-hexynole; the above-mentioned "halogeno lower alkyl" "Hydroxy such as 2-hydroxyethyl, 2,3-dihydroxypropynole, 3-hydroxypropyl, 3,4-dihydroxybutyl, and 4-hydroxybutyl" Lower alkyl group ";" Lower fat such as acetylmethyl " Tricyclic alkyl ”;“ lower alkyl group ”; the above“ aralkyl group ”

The above-mentioned “silyl group”, preferably a lower alkyl group or an aralkyl group. "Protective group that can be cleaved in vivo by a biological method such as hydrolysis" means a protective group that is cleaved in the human body by a biological method such as hydrolysis to produce a free acid or a salt thereof. A derivative is administered by intravenous injection to a laboratory animal, such as a rat or a mouse, and then the body fluid of the animal is examined to determine whether the derivative is the original compound or a pharmacologically acceptable salt thereof. Can be determined by being able to detect

As the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a hydroxy group”, preferably, formyloxymethyl, acetooxymethyl, dimethylaminoacetoxymethyl, propionyl Oxymethyl, Butyriloxymethylinole, Pivaloyloxymethyl, Valeryloxymethyl, Isovaleryloxymethyl, Hexanoyloxymethyl, 1-Formyloxetil, 1-Acetoxicetyl, 1-Pro Pioerokisekiru, 1-butyrylokisekil, 1-Pivalolyokisekiru, 1-Valeryloquisekil, 1-Isovalerylokisekiru, 1-Hexanoyloki Shetyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-ptyriloxypro Pill, 1-pivaloyloxypropyl, 1-valerinoleoxypropyl, 1-isovaleryl-l-oxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxyptyl, 1-butyryl Oxybutyl, 1-pivalofiloxybutyl, 1-acetoxoxypentyl, 1-propionyloxypentyl, 1-peptylyl-xipentinole, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl 1 — (“lower fatty ^ acyl” oxy) “lower alkyl group”, cyclopentyl canoleponinoleoxymethylinole, cyclohexylinolenovolenoleoxymethyl, 1-cyclopentylcarboninoleoxymethyl Chill, 1—hexyl carbonylylinoleoxyethyl, 1—cyclopentylcarbonyloxypropyl, 1—cyclohexyl 1-("cycloalkyl" carberoxy) "lower alkyl", such as xylcarboxypropyl, 1-cyclopentyl carbenooxybutyl, 1-cyclohexyl phenol Methyl-like one ("Aromatic Acyle") (Lower alkyl group) such as lower alkyl group; methoxycarboxyloxymethyl, ethoxycarbonyloxymethyl, propoxyl-propyl / reoxymethyl, isopropoxyl-lpoeroxymethyl, butoxycarbonylloxymethyl , Isoptoxycarponyloxymethyl, Pentyloxycarponyloxymethyl, Hexinoleoxycanoleponinoleoxymethylinole, Cyclohexyloxycarbonyloxymethinole, Cyclohexyl / reoxycanoleponinolexy ( 1- (Methoxycarbonyloxy) ethyl, 1- (Propoxycarbonyloxy) ethyl, 1- (Isopropoxycarbonyloxy) ethyl, 1- (Methoxycarbonyloxy) ethyl, 1- (Isopropoxycarbonyloxy) ethyl, 1 -(Butoxycarbonyloxy) 1- (isobutoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (hexinoleoxycanolebonyloxy) ethyl , 1- (cyclopentyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyloxy cycanoleponinoleoxy) propyl, 1- (cyclopentyl / reoxycanolepo-noleoxy) ) Butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarboxy) propyl, 1- (methoxycarbo) (Uroxy) propyl, 1- (propoxycarbonyl) propyl, 1- (isopropoxycarboxy / reoxy) Pill, 1- (butoxycanoleponinoleoxy) propyl, 1- (isobutoxycanoleponyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) Propyl, 1- (Methoxycarbonyloxy) butyl, 1- (Ethoxycarbonyloxy) butyl, 1- (Propoxycarbonyl / reoxy) butyl, 1- (Isopropoxycarbonyloxy) butyl, 1- (Butoxycano) 1- (Methoxycarbonylyloxy) pentyl, 1- (Methoxycarbonylyloxy) pentyl, 1- (Ethoxycarboninoleoxy) pentyl, 1- (Methoxycanoleponinoleoxy) Xyl, 1- (ethoxycanoleponinoleoxy) hexyl (Lower alkoxycarbonyl) alkyl groups such as phenyl; (5-phenyl-2-oxo1-1,3-dioxolen-14-yl) methyl, [5- (4-methylphenyl) 1-2] Oxo-1,3-dioxolen-4-yl] methyl, [5_ (4-methoxyphenyl) -12-oxo-1,3,3-dioxolen-14yl] methinole, [5- (4-fluoro) Phenyl) 1-oxo-1, 3-dioxolen-1 4-inole] methyl, [5- (4-cyclohexene) 1-2 oxo-1, 3-dioxolen-14-methyl] methyl, (2-oxo-1,3-dioxolene 4-inole) Methyl, (5-methinoole _2-oxo_1,3-dioxolen-1-4-inole) Mechinore, (5-ethinole 2-two-year-old 1,3 —Dioxolen-4-yl) methyl, (5-propyl-1-2-oxo-1,3-dioxo) Methyl, (5-isopropyl-12-oxo-1,3-dioxolen-4-yl) methyl, (5-butyl-12-oxo-1,3-dioxolen-1-yl) ) Carbonyldioxyalkyl group such as methyl; carbonyloxy lower alkyl group such as phthalidyl, dimethylphthalidyl, dimethoxy phthalidyl, etc .; The “aromatic acyl group”: “half ester salt residue of succinic acid”: “phosphate ester residue”: “ester forming residue such as amino acid”: carpamoyl group: 1 to 2 lower alkyl groups And a “1- (acyloxy) alkyloxycarboyl group” such as bivaloyloxymethyloxycarbonyl. A "carbonyl O alkoxyalkyl group". On the other hand, as the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a carboxy group”, preferably, methoxyethyl, 1-ethoxyl, 1-methyl-1-methyl Methoxyxetil, 1- (isopropoxy) ethyl, 2-methoxetine, 2-ethoxyxetylene, 1,1 dimethynole 1-methoxetil, ethoxymethynole, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxy Lower alkoxy lower alkyl groups such as methyl, 2-meth Lower alkoxylated lower alkoxy lower alkyl group such as xylethoxymethyl, “aryl” oxy “lower alkyl group” such as phenoxymethyl, 2,2,2-trichloroethoxymethinole, bis (2-chloroethoxy) ) Nodulation such as methinole “Alkoxyalkyl group” such as lower alkoxy lower alkyl group; “Methoxycarbonyl” “Lower alkoxy” carbonyl “Lower alkyl group”; Cyanometyl, 21-cyanoethyl "Cyano" lower alkyl group ";""loweralkyl" thiomethyl group such as methylthiomethyl and ethylthiomethyl; "" aryl "thiomethyl group such as phenylthiomethyl and naphthylthiomethyl; 2-methanesulfonyl / reethyl, 2-trifluoromethanesulfonylethyl "Lower alkyl" which may be substituted with halogen; "sulfur" lower alkyl group "; such as" 2-arylsulfonylethyl, 2-toluenesulfurethyl "" aryl "sulfonyl" lower alkyl The above-mentioned “11- (acyloxy)“ lower alkyl group ””; the above “phthalidyl group”; the above “aryl group”; the above “lower alkyl group”; “carboxyalkyl group” such as carboxymethyl; "Amide-forming residues of amino acids" such as fenirarayun.

The “other derivative” is a cyclobutene derivative having the general formula (II) of the present invention, or a derivative other than the above “pharmacologically acceptable salt” and the above “ester thereof” when having an amino group and / or a carboxy group. Derivatives are shown below. Such derivatives include, for example, amide derivatives. The pharmaceutical composition of the present invention is a pharmaceutical composition for administering an ileal bile acid transporter inhibitor and an ACAT inhibitor simultaneously or separately at an interval.

In the present invention, "simultaneous administration" is not particularly limited as long as it can be administered at substantially the same time, but administration as a single composition is preferred.

In the present invention, "separately at different times" means to separate at different times. There is no particular limitation as long as the administration form can be administered to, for example, first, an ileal bile acid transporter inhibitor is administered, and then, after a predetermined time, an ACAT inhibitor is administered, or This refers to administering an ACAT inhibitor first, and then administering an ileal bile acid transporter inhibitor after a fixed time. The pharmaceutical composition of the present invention,

(1) a pharmaceutical composition for administering the ileal-type bile acid tranporter inhibitor and the ACAT inhibitor simultaneously or separately at an interval of time;

(2) In item (1), the ileal bile acid transporter inhibitor has the general formula (II)

(ιι)

[Where,

R ¹ is a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted by 1 to 5 groups selected from substituent groups a and b, and a group selected from substituent groups a and b An aryl group substituted with 1 to 5 or a heterocyclic group substituted with 1 to 5 groups selected from a group selected from substituent groups a and b,

A is the following formula (A-1)

Z represents a single bond or a 1 C ₆ alkylene group. )

A group having

G represents a single bond, a C ₆ alkylene group or a substituted C ₆ alkylene group (the substituent is a hydroxy group, an oxo group, a cycloalkyl group, an aryl group, a heterocyclic group, a substituent group a or b A cycloalkyl group substituted with 1 to 5 substituents, a aryl group substituted 1 to 5 with a group selected from substituent groups a and b, or a substituent group a And b is a heterocyclic group substituted with 1 to 5 groups selected from b), and when the broken line represents a double bond, D represents a carbon atom; and E represents 2 N— Represents a group having O—,

When the dashed line represents a single bond, D represents a group having C H or a nitrogen atom, E represents an oxygen atom, a sulfur atom, a group having one NH— or a group having one C O—,

Substituent group a includes a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a mono lower alkylamino group, a G lower alkylamino group, a cyano group and a nitro group. A substituent group b is a carboxy group, a lower alkoxycarbyl group, a carbamoyl group, a mono-lower alkyl rubamoyl group, a di-lower alkylcarbamoyl group, a nitro group, a cycloalkyl group, Cycloalkyl, aryloxy, aryloxy, arylalkyloxy, aryloxy, aryloxy, arylalkyloxy, arylthio, and 1 to 3 groups substituted with a group selected from substituent group a. From the luthio group Group. ]

A pharmaceutical composition which is a cyclobutene derivative having the formula: a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof;

(3) In (2),

General formula (I I) Force General formula (I I a)

[In the above formula, R ¹ R ² , R ³ , R ⁴ , A, D, E and G have the same meaning as defined in (2). ]

A cyclobutene derivative, a pharmacologically acceptable salt thereof, a pharmaceutical composition thereof which is an ester or other derivative thereof,

(4) In (2),

General formula (I I) Force General formula (l i b)

[In the above formula, RR ² , R ³ , R ⁴ , A, D, E and G have the same meaning as defined in (2). ]

A pharmaceutical composition which is a cyclobutene derivative, a pharmacologically acceptable salt thereof, an ester or other derivative thereof,

(5) In any one selected from (2) to (4),

z is a single bond or a ci one c ₂ alkylene group compound or pharmaceutical composition is a pharmacologically acceptable salt thereof, (6) In any one selected from (2) to (4),

A pharmaceutical composition wherein Z is a compound having a single bond or a methylene group or a pharmacologically acceptable salt thereof,

(7) In any one selected from (2) to (4),

Wherein Z is a compound having a single bond or a pharmacologically acceptable salt thereof,

(8) In any one selected from (2) to (7),

Compound is a R ⁵ forces a hydrogen atom or a lower alkyl group or a pharmaceutical composition which is a pharmacologically acceptable salt thereof,

(9) In any one selected from ( ² ) to (7),

Compound is a R ⁵ forces a hydrogen atom or a methyl group, or a pharmaceutical composition which is a pharmacologically acceptable salt thereof,

(10) In any one selected from (2) to (7),

A pharmaceutical composition, wherein R ⁵ is a compound or a pharmacologically acceptable salt thereof, which is a hydrogen atom;

(11) In any one selected from (2) to (10),

A pharmaceutical composition, wherein R ⁶ is a compound having a hydroxy group or an amine residue or a pharmaceutically acceptable salt thereof;

(1 2) In any one selected from (2) to (10),

R ⁶ force hydroxy group, hydroxy § amino is a group or an amino group compound or pharmaceutical composition is a pharmacologically acceptable salt thereof,

(13) In any one selected from (2) to (10),

A pharmaceutical composition wherein R ⁶ is a compound having a hydroxy group or a pharmaceutically acceptable salt thereof,

(14) In any one selected from (2) to (13),

A pharmaceutical composition, wherein X and Y are oxygen atoms or a pharmacologically acceptable salt thereof,

(1 5) In any one selected from (2) to (14), A compound which is a group having a D force CH or a nitrogen atom or a pharmacologically acceptable salt thereof,

(16) In any one selected from (2) to (14),

A pharmaceutical composition, wherein D is a compound having a group having CH or a pharmacologically acceptable salt thereof,

(17) In any one selected from (2) to (16),

A pharmaceutical composition which is a compound which is a group having an E force, an oxygen atom, a sulfur atom or one NH— or a pharmacologically acceptable salt thereof,

(18) In any one selected from (2) to (16),

A pharmaceutical composition which is a compound which is a group having E force_N H— or a pharmacologically acceptable salt thereof,

(1 9) In any one selected from (2) to (18),

A compound in which G is a C i _C ₆ alkylene group or a substituted C i _C ₆ alkylene group, or a pharmacologically acceptable salt thereof,

(20) In any one selected from (2) to (18),

G is, C "C ₆ alkylene group or a substituted Ci-Ce alkylene group (the substituent is a hydroxy group, a Okiso group or Ariru group.) Are those compounds or a pharmacologically allowable salt thereof Pharmaceutical compositions,

(21) In any one selected from (2) to (18),

G is a compound wherein the compound is a C Cs alkylene group or a pharmacologically acceptable salt thereof,

(22) In any one selected from (2) to (18),

A pharmaceutical composition wherein G is a compound having 1 C ₄ alkylene group or a pharmacologically acceptable salt thereof,

(23) In any one selected from (2) to (18),

A compound or a drug thereof, wherein G is a methylene, methylmethylene or ethylmethylene group A pharmaceutical composition which is a physiologically acceptable salt,

(24) In any one selected from (2) to (18),

G force S, a pharmaceutical composition which is a compound which is a methylmethylene group or a pharmacologically acceptable salt thereof,

(25) In any one selected from (2) to (24),

Ri force cycloalkyl group, aryl group, heterocyclic group, aryl group substituted with 1 to 3 groups selected from substituent groups a and b, or substituent group a and b A pharmaceutical composition which is a compound or a pharmacologically acceptable salt thereof, which is a heterocyclic group substituted by 1 to 3 substituents with a selected group,

(26) In any one selected from (2) to (24),

R ¹ aryl group, 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, aryl group substituted with 1 to 3 groups selected from substituent groups a and b, or A compound which is a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring and is substituted by 1 to 3 groups selected from substituent groups a and b, or a pharmaceutically acceptable salt thereof. Pharmaceutical composition,

(27) In any one selected from (2) to (24),

R ¹ may be condensed with an aryl group, a 5- to 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, or may be condensed with a 1 to 3 substituted aryl group or a benzene ring 5 to 6 Membered aromatic heterocyclic group (the substituent is a group selected from a substituent group a, a cycloalkyl group, an aryl group, an aryloxy group, an aralkyloxy group, an arylthio group, and 1 to 3 groups selected from the substituent group a A substituted or selected from the group consisting of cycloalkyl, aryl, aryloxy, aralkyloxy and arylthio groups.) Or a pharmacologically acceptable salt thereof.

(28) In any one selected from (2) to (24),

R ¹ may be condensed with a aryl group or a benzene ring, or may be condensed with a 5- or 6-membered aromatic heterocyclic group, or with a substituted or substituted aryl group or a benzene ring. 6-membered aromatic heterocyclic group (The substituent is a halogen atom, hydroxy group, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, nitro group, cycloalkyl group, aryl group, aryloxy group and aryl group. Or a pharmacologically acceptable salt thereof, or a pharmaceutical composition, which is a group selected from the group consisting of a luthio group.

(29) In any one selected from (2) to (24),

R ¹ is C ₆ —. Aryl, chelyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, or benzene ring; condensed with phenyl, phenyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl or pyridyl, or 1 And 3 substituted C ₆ —. Or a pharmacologically acceptable compound thereof, wherein the substituent is a group selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group and a dinitro group. A pharmaceutical composition, which is

(30) In any one selected from (2) to (24),

IV is phenyl, 1-naphthyl, 2-naphthyl, 3-fluorophenol, 4-phenolic phenol, 3-chlorophenol, 4-chlorophenol, 3,4-diphenylphenol, 3,4-diphenylphenol , 3,5-Diphnoleolopheninole, 3,4-Diclofene, 3,5-Dichlorophene, 3-Hydroxyphene, 4-Hydroxyphene, 3-Methynofene, 4 —Methynolephenyl, 3,4-Dimethynolephenyl, 3-Methoxyphenyl, 4-Methoxyphenyl, 3,4-Dimethoxyphenyl, 3,4,5-Trimethoxyphenyl, 3,4,5-Trifluorophenyl, A pharmaceutical composition which is a compound having a phenyl or pyridyl group or a pharmacologically acceptable salt thereof,

(31) In any one selected from (2) to (24),

R ¹ force feninole, 3-phneorolopheninole, 3 _ black phenyl, 3, 4-diph / leo phenyl, 3, 5-diphnole A pharmaceutical composition which is a compound or a pharmaceutically acceptable salt thereof, which is a 5-dichlorophenol, 2-thienyl or 4-pyridyl group, (32) In any one selected from (2) to (31),

R ² is a cycloalkyl group, an aryl group, a heterocyclic group, an aryl group substituted by 1 to 3 groups selected from substituent group a, or a group selected from substituent group a; A pharmaceutical composition which is a compound which is a 3-substituted heterocyclic group or a pharmacologically acceptable salt thereof,

(33) In any one selected from (2) to (3 1),

R ² may be condensed with an aryl group or a 5- to 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, or may be condensed with a 1 to 3 substituted aryl group or a benzene ring. A 6-membered aromatic heterocyclic group (the substituent is a group selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group) or a compound thereof; A pharmaceutical composition which is a pharmacologically acceptable salt,

(34) In any one selected from (2) to (3 1),

R ² R aryl, chenyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, or benzene ring Or a substituted aryl group (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group or a lower alkoxy group) or a pharmaceutically acceptable compound thereof. A pharmaceutical composition, which is a salt

(35) In any one selected from (2) to (31),

R ² force C ₆ — Ci. Aryl group, 2-chel group, 4-pyridyl group, or 1 substituted C ₆ —. A compound which is an aryl group (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group or a lower alkoxy group), or a pharmacologically acceptable salt thereof;

(36) In any one selected from (2) to (31),

R ² force phenyl group or 1-substituted phenyl group (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a halogeno lower alkyl group or a lower alkoxy group) It is a group. (37) A pharmaceutical composition which is a compound or a pharmacologically acceptable salt thereof, (37) in any one selected from (2) to (31),

A pharmaceutical composition wherein R ² is a compound or a pharmacologically acceptable salt thereof, in which R ² is phenyl, 4-phenyl, 4-phenyl, 4-methyl / phenyl or 4-methoxyphenyl. ,

(38) In any one selected from (2) to (37),

A pharmaceutical composition wherein R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxy group, a halogen atom, a lower alkoxy group, an amino group or a di-lower alkylamino group, or a pharmaceutically acceptable salt thereof; object,

(39) In any one selected from (2) to (37),

A pharmaceutical composition wherein R ³ and R ⁴ are the same or different and are a hydrogen atom, a hydroxy group or a lower alkoxy group, or a pharmaceutically acceptable salt thereof;

(40) In any one selected from (2) to (37),

A pharmaceutical composition wherein R ³ and R ⁴ are a hydrogen atom or a pharmacologically acceptable salt thereof,

(41) In (1), the bile acid transporter inhibitor is

4- (3-((1- (3,5-difluorophenyl) ethylamino) -1- (4-methoxypheninole) methyl] pheninoleamino} 1-3-hydroxy-1-3-cyclobutene—1,2-diene,

4- (3-[(1— (3,4-difluorophenyl) ethynoleamino)-(4-methoxypheninole) methyl] pheninoleamino) —3-hydroxy-1-3-cyclobutene1-1,2-dione and

3— {3— [(4-fluorophenyl) _ (1- (3-phenolic phenyl) ethynoleamino) methyl] phenylenamino) 1-4-Hydroxy 3-cyclobutene 1-1,2-dione A pharmaceutical composition which is one compound or a pharmacologically acceptable salt thereof, (42) In (1), the ileal bile acid transporter inhibitor is

4- {3 -— ((1- (3,5-difluorophenyl) ethylamino) -1- (4-methoxypheninole) methyl] pheninoleamino) —3-hydroxy-3-cyclobutene-11,2-dione or its pharmacological properties A pharmaceutical composition which is an acceptable salt,

(43) In (1), the ileal bile acid transporter inhibitor is TA-7522, S-8921 and

1— {4-[4-I [(4 R, 5 R) —3,3-dibutyl-1 7— (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxo-1 1-benzozopine 1-5-yl] phenoxymethyl] benzyl} —4-aza-11-azoniabicyclo [2.2.2] octane chloride,

1— {4- [4— [(4 R, 5 R) 1-3,3-dibutyl-17- (dimethylamino) —2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxo-1 1-benzozopine 1-5-yl] phenoxy] butyl}-4-aza-one

[2.2.2] Octane methanesulfonate and

{2- [2— [2-[4-I [(4 R, 5 R) —3,3_dibutyl-17- (dimethynoleamino) -2,3,4,5-tetrahydro-1-4-hydroxy] 1,1-dioxo-1-benzobenzoin-5-yl] phenoxy] ethoxy] ethoxy] ethyl} triethynoleammonium chloride

A pharmaceutical composition which is any one compound selected from or a pharmacologically acceptable salt thereof,

(44) In (1), the ileal bile acid transporter inhibitor is TA-7522, S-8921 and

1-{4-1 [4-[(4 R, 5 R) —3,3-dityl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1, 1-dioxo-1 -benzozopine 1-5-inole] phenoxymethinole] benzyl} 1 4-aza-11-azoniabicyclo [2.2.2] octane chloride Or a pharmaceutical composition which is a pharmacologically acceptable salt thereof,

(45) In (1), the ileal bile acid transporter inhibitor may be S-8921 and

1 1 {4 1 [4- [(4 R, 5 R) 1, 3,3-dibutyl-1 7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1,1-dioxo-1 1 Benzochepin-1-yl] phenoxymethyl] benzyl} —4-aza-1-1-azobicyclo [2.2.2] Any compound selected from octane chloride or a pharmaceutically acceptable salt thereof Certain pharmaceutical compositions

And more preferably,

(46) In any one selected from (1) to (45),

A CAT inhibitors are FR-129169, CI-1011, F-1394, F-251251, T-12591, FCE_28654, K-110085, HL-004, NTE-122 FR- 186054,

N— (1-octyl-5-carboxymethyl-1,4,6-dimethylindoline-17-yl) —2,2-dimethylpropaneamide and

A pharmaceutical composition which is any one compound selected from N- (1-pentyl-1,4-dimethylindoline-17-yl) -12,2-dimethylethylethaneamide or a pharmacologically acceptable salt thereof;

(47) In any one selected from (1) to (45),

A CAT inhibitor is C I _101 1, F— 1 251 1,

N- (1-octyl-5-carboxymethyl-1,4,6-dimethinoleindoline-17-yl) -1,2,2-dimethylpropanamide and

A pharmaceutical composition which is any one compound selected from N- (1-pentyl-1,4-, 6-dimethylindoline-17-yl) -12,2-dimethylethaneamide or a pharmacologically acceptable salt thereof;

(48) In any one selected from (1) to (45), A The CAT inhibitor is N- (1-octyl-5-carboxymethyl-4,6-dimethylindoline-17-yl) -1,2,2-dimethylpropaneamide or a pharmacologically acceptable salt thereof. Certain pharmaceutical compositions can be mentioned.

Also, as the pharmaceutical composition as described above,

(49) The pharmaceutical composition according to any one of (1) to (48), for preventing or treating hyperlipidemia,

(50) The pharmaceutical composition according to any one of (1) to (48), for preventing or treating arteriosclerosis,

(5 1) The pharmaceutical composition according to any one of (1) to (48), for preventing or treating ischemic heart disease,

(52) The pharmaceutical composition according to any one of (1) to (48), for preventing or treating arteriosclerosis,

(5 3) The pharmaceutical composition according to any one of (1) to (48) for prevention or treatment of ischemic brain disease.

Can be mentioned. The ileal bile acid transporter inhibitor, which is an active ingredient of the pharmaceutical composition of the present invention, is described in, for example, JP-A-61-26754-1 (EP1884882, US Pat. No. 4,771,088). Publication No. 72), WO 99/324 78 Publication (US Pat. No. 5,994,391, US Pat. No. 6,107,494, US Publication No. 200 20 13476) ), Japanese Patent Application Laid-Open No. 5-310634 (EP5991107, EP701919), WO99 / 351035, WO99 / 64409 publication (USP 6,221,897 publication), WO 00/47568 publication, WO 00/6156568 publication (USP 6,277,831 publication), EP 1 070 According to the method described in Japanese Patent No. 703, it can be easily produced. Further, the ACAT inhibitor which is an active ingredient of the pharmaceutical composition of the present invention is described in, for example, W092 / 09561, JP-A-8-510256 (WO94 / 26702, USP 5,491, 172 gazette), EP421441 gazette (USP 5,120,738 gazette), JP 2000-50771 gazette (WO 97/1 9918 gazette, USP 5,990,173 gazette), JP-A-10-195037 (EP 790240, US Pat. No. 5,849,732), WO 96/26 948, WO 98/541 53 '(EP 987254), WO 9 2/09572 publication (EP 559898 publication, US Pat. No. 5,475,130 publication), Japanese Patent Application Laid-Open No. 7-82232 (EP 718281), No. 96/10559), WO96Z09287 (EP0782986, USP5, 990, 150), WO9712860 (EP0866059, USP6, 063, 806) Publication), it can be easily produced. The invention's effect

The pharmaceutical composition of the present invention for administering the ileal bile acid transporter inhibitor and the ACAT inhibitor simultaneously or separately at an interval has an excellent lipid (cholesterol or triglyceride) lowering effect. It has an excellent inhibitory effect on the progression of arteriosclerosis and has a low toxicity. It is useful as a prophylactic or therapeutic agent (especially a therapeutic agent) for diseases (especially hyperlipidemia or arteriosclerosis). In addition, the ileal bile acid transporter inhibitor and the ACAT inhibitor of the present invention show superior effects as compared with the case where each is administered as a single agent, because they are used in combination. Industrial applicability

An ileal bile acid transporter inhibitor which is an active ingredient of the pharmaceutical composition of the present invention; The ACAT inhibitors can be prepared alone, in separate unit dosage forms, or mixed together physically in one unit dosage form.

When the pharmaceutical composition of the present invention is used as a prophylactic or therapeutic agent for the above-mentioned diseases, the ileal bile acid transporter inhibitor and the ACAT inhibitor, which are the active ingredients of the pharmaceutical composition of the present invention, are used. , Each itself or mixed with appropriate pharmacologically acceptable excipients, diluents and the like, for example, orally or injectable or suppository by tablets, capsules, granules, powders or syrups, etc. It can be administered parenterally with an agent or the like. These preparations may contain excipients (eg, lactose, sucrose, dextrose, sugar, rust conductors such as mannitol, sorbitol; corn starch, potato starch, starch derivatives such as α-starch, dextrin; Cellulose derivatives; Arabic gum; Dextran; Organic excipients such as pullulan: and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminium; Inorganic excipients such as phosphates; carbonates such as calcium carbonate; sulfates such as calcium sulfate; and lubricants (for example, stearic acid, canolecidium stearate, magnesium stearate) Pum-like metal stearates; talc; colloidal silica; Waxes such as gums and gays; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; Lauryl sulfate; silicic acid such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives.), Binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, Examples thereof include polypyrrolidone, macrogol, and the same compounds as the above-mentioned excipients), disintegrants (eg, low-substituted hydroxypropylcellulose, phenolic methoxy cellulose, carboxylate) Methylcellulose canolesum, internally cross-linked carboxymethinolate cellulose Cellulose derivatives such as © beam;. The carboxymethyl Chirusutachi, mention may be made of carboxymethyl starch sodium © beam, the chemically modified starches and celluloses such as cross-linked poly Biel pyrrolidone), stabilizers (Paroxybenzoic acid esters such as methinoleparaben and propylparaben; phenolic compounds such as chloroptanol, benzylinoleconore, and feninoleetinoleanoreconole; phenols such as benzalkonidium chloride; phenol and cresol; Thimerosal; dehydroacetic acid; and sorbic acid.), Flavoring agents (e.g., commonly used sweeteners, sour agents, flavors, etc.), addition of diluents and the like. It is manufactured by a well-known method using an agent.

The dosage and administration ratio of the ileal bile acid transporter inhibitor and the ACAT inhibitor, which are the active ingredients of the pharmaceutical composition of the present invention, depend on various conditions such as the activity of each drug, the symptoms, age, and body weight of the patient. May vary. The dosage varies depending on symptoms, 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 100 Omg (preferably 50 Omg) each time. In the case of parenteral administration, a minimum dose of 0.1 mg (preferably 0.05 mg) and a maximum dose of 10 mg (preferably 5 mg) per dose should be given to adults 1 to 6 times a day, It can be administered simultaneously or separately at intervals depending on the condition.

In addition, the ratio of the dose of the ileal bile acid transporter inhibitor, which is an active ingredient of the pharmaceutical composition of the present invention, to the amount of the ACAT inhibitor is also significantly variable, such as the ileal bile acid transporter inhibitor. The dosage ratio of ACAT inhibitor may be in the range from 1: 500 to 500: 1 by weight.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, Examples and Formulation Examples are shown, and the power of the present invention is described in more detail. The scope of the present invention is not limited thereto. Example 1

Measurement of serum triglycerides (Triglycerides)

After acclimating 24 12-week-old male Syrian golden hamsters to a powdered diet, they were divided into 4 groups so that the average values of total blood cholesterol, triglyceride (TG) and body weight were uniform. The compound A (0.03%) and the compound B (0.03%) were fed as a single agent or in combination with each other for 2 weeks. Blood was collected two weeks after administration, and the TG value in serum obtained by a standard method was measured by an enzyme method using Triglyceride E-Test II Co. (Wako Pure Chemical Industries, Ltd.). The rate of change of the TG value of the compound-administered group relative to the TG value of the control group was defined as a decrease rate. Table 1 shows the results.

[Table 1] Test compound Triglyceride reduction rate Compound A 23.3%

Compound B 14.5% Compound A + Compound B 42.7% Based on the above results, the combined use of compound A, an ileal bile acid transporter inhibitor, and compound B, an ACAT inhibitor, resulted in It is evident that it shows an excellent triglyceride lowering effect compared to administration. Formulation Example 1

Tablets

Compound A (50. Omg), Compound B (30. Omg), Lactose (368. Omg), Corn starch (50. Omg) and Magnesium stearate (2. Omg)

Mix 60 and compress with a crusher

Depending on the coating: and as ¹ coagulation ^{5 G.} This glue is indispensable

Can be applied (preferably sugar coating)

Claims

The scope of the claims

1. A pharmaceutical composition for separately administering an ileal bile acid transport inhibitor and an ACAT inhibitor simultaneously or at intervals.

2. The method of claim 1, wherein the ileal bile acid transporter inhibitor is TA-7522, S-8921,

1- {4- [4--1 [(4R, 5R) -3,3-Dibutyl-17- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1-1,1-dioxo- 1-Venzochepin-5- [Phenoxymethyl] benzyl} 1-aza 1-azoni-abicyclo [2.2.2] octane chloride,

1-1- {4- [4--1 [(4R, 5R) -1-3,3-Dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1,1-dioxo-1 1-benzozopine _ 5-yl] phenoxy] butyl} 1-aza-1 1-azoniabicyclo [2.2.2] octanemethanesulfonate,

{2— [2— [2- [4— [(4R, 5R) -1,3,3-dibutyl—7— (dimethylamino) -1,2,3,4,5-tetrahydro-1-hydroxy-1,1-dioxo -1-benzocepin 5-yl] phenoxy] ethoxy] ethoxy] ethyl} triethylammonium chloride,

4- (3-[(1- (3,5-difluorophenyl) ethylamino) 1- (4-methoxyphenyl) methyl] phenylamino} -1-hydroxy-3-cyclobutene-1,2-dione;

4- {3-[((1- (3,4-difluorophenyl) ethylamino) -1- (4-methoxyphenyl) methyl] phenylamino} -3-hydroxy-3-cyclobutene1-1,2-dione and

• 3— {3— [(4-fluorophenyl) mono (1- (3-fluorophenyl) ethyl Lamino) methyl] phenylamino} —4-Hydroxy-3-cyclobutene-1,2-dione

Or a pharmacologically acceptable salt thereof.

3. In claim 1, the ileal bile acid transporter inhibitor is TA-7522, S-8921,

1- {4- [4- [(4R, 5 R) -3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-1- 4-hydroxy-1,1-dioxo-1 —Venzochepine-15-yl] phenoxymethyl] benzyl} -1-aza—1-azazobicyclo [2.2.2] octane chloride,

4- {3- (3,5-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} -1-hydroxy-3-cyclobutene—1,2-dione,

4- (3- (3,4-Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} 1-hydroxy-3--3-cyclobutene—1,2-dione and

3- {3-((4-Fluorophenyl) -1- (1- (3-fluorophenyl) ethylamino) methyl] phenylamino} _4-Hydroxy-3-cyclobutene_1,2-dione

Or a pharmacologically acceptable salt thereof.

4. The method of claim 1, wherein the ileal bile acid transporter inhibitor is S-8921,

1- {4-1-1 [4--1 [(4R, 5R) -1-3,3-dibutyl-7- (dimethylamino ) -2,3,4,5-Tetrahydro-1-hydroxy-1,1,1-dioxo-11-benzozopine-15-yl] phenoxymethyl] benzyl} _4-aza-1-azonia bicyclo Octane chloride,

4- {3-[((1- (3,5-difluorophenyl) ethylamino) -1- (4-methoxyphenyl) methyl] phenylamino} -1-hydroxy-3--3-cyclobutene—1,2-dione

4- {3 -— [(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] phenylamino} 1-3-hydroxy-13-cyclobutene—1,2-dione and

3— {3-[(4_Fluorophenyl) one (1— (3-Fluorophenyl) ethylamino) methyl! /] Phenylamino} 1-4-hydroxy-3-cyclobutene-1,2-dione

Or a pharmacologically acceptable salt thereof.

5.In claim 1, the ileal bile acid transporter inhibitor comprises:

4-1- {3- (3,5-difluorophenyl) ethylamino) -1- (4-methoxyphenyl) methyl] phenylamino} -3-hydroxy-1-3-cyclobutene-1 1,2-dione or a pharmaceutically acceptable salt thereof Pharmaceutical composition.

6. In any one of claims 1 to 5,

AC AT inhibitor is FR-129169, CI 1011, F_1394, F-

12511, T_2591, FCE- 28654, K-1 10085, HL-004

, NTE—122, FR-186054,

N- (1 -year-old butyl-5-potoxymethyl-4,6-dimethylindoline-1-yl) -2,2-dimethylpropanamide and A pharmaceutical composition which is any one compound selected from N- (1-pentyl-4,6-dimethylindoline-1-yl) -1,2,2-dimethyleneamide or a pharmacologically acceptable salt thereof.

7. In any one of claims 1 to 5,

ACAT inhibitors are FR-129169, CI-1011,

N- (1 year old octyl-5-carboxymethyl-4,6-dimethylindoline-7-yl) 1,2,2-dimethylpropanamide and

Pharmaceutical composition which is any one compound selected from N- (1-pentyl-4,6-dimethylindoline-17-yl) -12,2-dimethylethylethaneamide or a pharmacologically acceptable salt thereof.

8. In any one of claims 1 to 5,

A CAT inhibitor

N- (1 year old octyl-5-potoxymethyl-4,6-dimethylindoline-17-yl) -a pharmaceutical composition which is 2,2-dimethylpropanamide or a pharmacologically acceptable salt thereof.

9. The pharmaceutical composition according to any one of claims 1 to 8 for preventing or treating hyperlipidemia.

10. The pharmaceutical composition according to any one of claims 1 to 8 for preventing or treating arteriosclerosis.

11. The pharmaceutical composition according to any one of claims 1 to 8 for preventing or treating ischemic heart disease.

1 2. The pharmaceutical composition according to any one of claims 1 to 8, for preventing or treating ischemic brain disease.

13. The pharmaceutical composition according to any one of claims 1 to 8 for preventing or treating peripheral circulatory insufficiency.