WO2002072147A1 - Compositions medicinales contenant un inhibiteur de transporteur d'acide biliaire - Google Patents

Compositions medicinales contenant un inhibiteur de transporteur d'acide biliaire Download PDF

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WO2002072147A1
WO2002072147A1 PCT/JP2002/002311 JP0202311W WO02072147A1 WO 2002072147 A1 WO2002072147 A1 WO 2002072147A1 JP 0202311 W JP0202311 W JP 0202311W WO 02072147 A1 WO02072147 A1 WO 02072147A1
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group
hydroxy
pharmaceutical composition
methyl
acceptable salt
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PCT/JP2002/002311
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Japanese (ja)
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Toshimori Inaba
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Sankyo Company, Limited
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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Definitions

  • compositions containing bile acid transporter inhibitors are provided.
  • the present invention relates to an ileal bile acid transport inhibitor, an enzyme
  • ACAT cholesterol acyltransferase
  • 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.
  • arteriosclerosis-related diseases such as hyperlipidemia, arteriosclerosis or ischemic heart disease, ischemic brain disease, and peripheral circulatory insufficiency.
  • 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
  • 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.
  • the active ingredients of the pharmaceutical composition of the present invention are an ileal bile acid transport inhibitor and an ACAT inhibitor.
  • 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.
  • 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. ],
  • 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. ],
  • 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.
  • 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)
  • 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.
  • 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.
  • 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. ]
  • 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
  • Such a cycloalkyl group is preferably a C 5 — ⁇ 6 cycloalkyl group, and most preferably a cyclohexyl group.
  • 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.
  • 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.
  • Aromaatic 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.
  • 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.
  • 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
  • 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.
  • 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-dimethylbut
  • amine residue in the definition of R 6 represents an unsubstituted or substituted amino group or a heterocycle containing a nitrogen atom.
  • 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-
  • 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.
  • ( ⁇ _ (: 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-
  • 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,
  • 6 halogenoalkyl group such as 2-dibromoethyl group, preferably —
  • alkylamino group more preferably a mono-C 2 alkylamino group, and most preferably a methylamino group.
  • 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
  • “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.
  • 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.
  • 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.
  • 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.
  • 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-naph
  • 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.
  • 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-trifluor
  • a monosubstituted cyclohexyl group wherein the substituent is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl or lower alkyl.
  • 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
  • a 4-phenyl, 4-methylphenyl or 4-methoxyphenyl group A 4-phenyl, 4-methylphenyl or 4-methoxyphenyl group.
  • 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-.
  • 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 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).
  • the substituent is a halogen atom, hydroxy, lower alkyl or lower alkoxy group.
  • 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).
  • 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 _,
  • 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 cycl
  • 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
  • aryl groups 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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)
  • a 1- to 3-substituted benzene ring the substituent is an octogen atom, a hydroxy group, a lower group
  • a 1 to 3 substituted chenyl group, a furyl group and a pyrrolyl group preferably a 1 to 3 substituted chenyl group, a furyl group and a pyrrolyl group.
  • 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-chloroph
  • 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,
  • 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.
  • ileal bile acid transporter inhibitor as described above, preferably, TA-7522, S-8921,
  • planar chemical structural formula of a preferred ileal bile acid transporter inhibitor is shown below.
  • 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.
  • 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. ),
  • 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). ],
  • 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.). ),
  • FR-186054 of the present invention also includes pharmacologically acceptable salts thereof.
  • 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
  • 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.
  • 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,
  • compound H (1-pentyl-1,4,6-dimethylindoline-1-yl) -1,2,2-dimethylethylamide (hereinafter referred to as compound H), or a pharmacologically active compound thereof.
  • 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.
  • 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
  • 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.
  • 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.
  • 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 (II)
  • the group and the R 1 group may be substituted on an asymmetric carbon atom, especially R 1.
  • R 1 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.
  • 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.
  • General protecting group refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.
  • 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, Octade
  • 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,
  • sil 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
  • 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-valerinole
  • 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-
  • 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 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.
  • “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.
  • “separately at different times” means to separate at different times.
  • 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
  • the ileal bile acid transporter inhibitor has the general formula (II)
  • 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,
  • 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)
  • 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 a 1 C 6 alkylene group.
  • 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
  • b is a heterocyclic group substituted with 1 to 5 groups selected from b
  • D represents a carbon atom
  • E represents 2 N— Represents a group having O—
  • 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;
  • R 1 R 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,
  • 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),
  • Z is a compound having a single bond or a pharmacologically acceptable salt thereof
  • 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,
  • Compound is a R 5 forces a hydrogen atom or a methyl group, or a pharmaceutical composition which is a pharmacologically acceptable salt thereof,
  • R 5 is a compound or a pharmacologically acceptable salt thereof, which is a hydrogen atom;
  • R 6 is a compound having a hydroxy group or an amine residue or a pharmaceutically acceptable salt thereof
  • R 6 force hydroxy group, hydroxy ⁇ amino is a group or an amino group compound or pharmaceutical composition is a pharmacologically acceptable salt thereof,
  • R 6 is a compound having a hydroxy group or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition wherein X and Y are oxygen atoms or a pharmacologically acceptable salt thereof,
  • a pharmaceutical composition wherein D is a compound having a group having CH or a pharmacologically acceptable salt thereof,
  • 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,
  • a pharmaceutical composition which is a compound which is a group having E force_N H— or a pharmacologically acceptable salt thereof,
  • G is a C i _C 6 alkylene group or a substituted C i _C 6 alkylene group, or a pharmacologically acceptable salt thereof
  • 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.
  • G is a compound wherein the compound is a C Cs alkylene group or a pharmacologically acceptable salt thereof,
  • a pharmaceutical composition wherein G is a compound having 1 C 4 alkylene group or a pharmacologically acceptable salt thereof,
  • a compound or a drug thereof, wherein G is a methylene, methylmethylene or ethylmethylene group A pharmaceutical composition which is a physiologically acceptable salt,
  • G force S a pharmaceutical composition which is a compound which is a methylmethylene group or a pharmacologically acceptable salt thereof,
  • 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,
  • 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.
  • 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.
  • 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.
  • a pharmacologically acceptable salt thereof, or a pharmaceutical composition which is a group selected from the group consisting of a luthio group.
  • R 1 is C 6 —.
  • 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.
  • 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,
  • 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,
  • 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,
  • 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
  • R 2 force C 6 — Ci.
  • 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;
  • 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.
  • a pharmaceutical composition which is a compound or a pharmacologically acceptable salt thereof, (37) in any one selected from (2) to (31),
  • 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.
  • 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,
  • 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;
  • R 3 and R 4 are a hydrogen atom or a pharmacologically acceptable salt thereof
  • the ileal bile acid transporter inhibitor is TA-7522, S-8921 and
  • a pharmaceutical composition which is any one compound selected from or a pharmacologically acceptable salt thereof,
  • the ileal bile acid transporter inhibitor is TA-7522, S-8921 and
  • the ileal bile acid transporter inhibitor may be S-8921 and
  • a CAT inhibitors are FR-129169, CI-1011, F-1394, F-251251, T-12591, FCE_28654, K-110085, HL-004, NTE-122 FR- 186054,
  • 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;
  • a CAT inhibitor is C I _101 1, F— 1 251 1,
  • 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;
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • the ileal bile acid transporter inhibitor and the ACAT inhibitor which are the active ingredients of the pharmaceutical composition of the present invention.
  • excipients eg, lactose, sucrose, dextrose, sugar, rust conductors such as mannitol, sorbitol; corn starch, potato starch, starch derivatives such as ⁇ -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;
  • 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.
  • 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.
  • 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.
  • Example 1 Example 1

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Abstract

L'invention concerne des compositions médicinales destinées à administrer un inhibiteur de transporteur d'acide biliaire et un inhibiteur d'ACAT, soit de façon simultanée, soit de façon séparée par un certain intervalle de temps.
PCT/JP2002/002311 2001-03-14 2002-03-12 Compositions medicinales contenant un inhibiteur de transporteur d'acide biliaire WO2002072147A1 (fr)

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JP2001072050 2001-03-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7012147B2 (en) * 2001-02-02 2006-03-14 Sankyo Company, Limited Indoline derivative and process for producing the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009287A1 (fr) * 1994-09-20 1996-03-28 Kyoto Pharmaceutical Industries, Ltd. Nouveaux derives heterocycliques, leur procede de production et leur utilisation medicinale
WO1997012860A1 (fr) * 1995-10-05 1997-04-10 Kyoto Pharmaceutical Industries, Ltd. Nouveaux derives heterocycliques et leur utilisation medicinale
EP1070703A1 (fr) * 1999-07-22 2001-01-24 Sankyo Company Limited Composés de cyclobutène

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009287A1 (fr) * 1994-09-20 1996-03-28 Kyoto Pharmaceutical Industries, Ltd. Nouveaux derives heterocycliques, leur procede de production et leur utilisation medicinale
WO1997012860A1 (fr) * 1995-10-05 1997-04-10 Kyoto Pharmaceutical Industries, Ltd. Nouveaux derives heterocycliques et leur utilisation medicinale
EP1070703A1 (fr) * 1999-07-22 2001-01-24 Sankyo Company Limited Composés de cyclobutène

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7012147B2 (en) * 2001-02-02 2006-03-14 Sankyo Company, Limited Indoline derivative and process for producing the same

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