WO2005113499A1 - Composés indoles - Google Patents

Composés indoles Download PDF

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Publication number
WO2005113499A1
WO2005113499A1 PCT/JP2005/009142 JP2005009142W WO2005113499A1 WO 2005113499 A1 WO2005113499 A1 WO 2005113499A1 JP 2005009142 W JP2005009142 W JP 2005009142W WO 2005113499 A1 WO2005113499 A1 WO 2005113499A1
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group
alkyl
substituent
substituted
groups
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PCT/JP2005/009142
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English (en)
Japanese (ja)
Inventor
Masami Arai
Takanori Yamazaki
Kazuhiko Tamaki
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Sankyo Company, Limited
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Publication of WO2005113499A1 publication Critical patent/WO2005113499A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides an excellent anti-arteriosclerotic action and anti-inflammatory activity by regulating the function of Liver X receptors (LXR) to improve lipid metabolism disorders or controlling the production of inflammatory mediators.
  • LXR Liver X receptors
  • the present invention relates to a novel indole compound or a pharmacologically acceptable salt or ester thereof, which has an inflammatory effect.
  • the present invention relates to a pharmaceutical composition containing an indolui conjugate or a pharmacologically acceptable salt or ester thereof as an active ingredient, preferably arteriosclerosis (arteriosclerosis).
  • arteriosclerosis arteriosclerosis due to attainable disease
  • atherosclerosis due to diabetes arteriosclerosis due to diabetes
  • hyperlipidemia hypercholesterolemia
  • lipid-related diseases rheumatoid arthritis, osteoarthritis, allergic Inflammatory diseases such as diseases, asthma, sepsis, psoriasis, osteoporosis, inflammatory diseases caused by inflammatory site forces
  • autoimmune diseases such as systemic lupus erythematosus, ulcerative colitis, Crohn's disease
  • ischemic Cardiovascular disease such as heart disease, heart failure; cerebrovascular disease; renal disease; diabetes; diabetic complications such as retinopathy, nephropathy, neuropathy, coronary artery disease; obesity; nephritis; hepatitis; cancer; Al Pharmaceutical
  • the present invention provides a pharmaceutical composition, preferably an indolui conjugate for producing a pharmaceutical composition for treating or preventing the above-mentioned diseases, or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition preferably an indolui conjugate for producing a pharmaceutical composition for treating or preventing the above-mentioned diseases, or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for treating a disease caused by administering a pharmacologically effective amount of an indolui conjugate or a pharmacologically acceptable salt or ester thereof to a warm-blooded animal (particularly a human).
  • the present invention relates to a method for producing an indolui conjugate or a pharmacologically acceptable salt or ester thereof.
  • anti-hypertensive drugs include beta- and beta-blockers, diuretics, calcium antagonists, ACE inhibitors, and A-II antagonists, and HMG-CoA reductase inhibitors as anti-hyperlipidemic drugs , Anion exchange resin, nicotinic acid derivatives, probucol, fibrates, etc., and insulin, sulfonylureas, metformin, glitazones, etc. are used as antidiabetic agents. These drugs contribute to the regulation of blood pressure and blood lipid or blood glucose levels. However, the mortality from heart disease, cerebrovascular disease and renal disease has not been greatly improved even by the use of these drugs, and the development of better therapeutic drugs for these diseases has been desired.
  • a direct risk factor for circulatory disease is arteriosclerosis accompanied by thickening of the arterial wall, and the cause of the thickening is accumulation of oxidized low-density lipoprotein cholesterol (LDL-C) in the arterial wall.
  • LDL-C oxidized low-density lipoprotein cholesterol
  • LXR nuclear receptor i8
  • LXRa is highly distributed in the liver of mammals and in small amounts in the kidney, small intestine, spleen, and adrenal gland, and LXR
  • LXR is regulated by the transcription of oxidized sterols in macrophages in the vascular wall, induces the expression of ABCA1 (ATP Binding Cassette Transpoter-1) and ApoE (Apolipoprotein E), and extracts cholesterol from the vascular wall. Promotes reverse cholesterol transfer system to liver (And u, T. T “Repa, J. J” Mangelsdorf, D. J “J. Biol. Chem., 2001, Vol. 276, p. 37735-37738) 0 LXR is also ABCA1 in the small intestine. Induces the absorption of dietary cholesterol from the gastrointestinal tract (Repa, J.
  • LXR LXR Are expected to be useful in the treatment or prevention of arteriosclerosis, atherosclerosis, arteriosclerosis due to diabetes, hyperlipidemia or lipid-related diseases.
  • Atherosclerosis is also considered to be a chronic inflammatory disease (Ross, R., N. Engl. J. Med., 1986, Vol. 314, ⁇ .488- ⁇ 00).
  • LXR has been regulated by regulating the expression of inflammatory mediators such as nitric oxide synthase (NO synthase), cyclooxygenase-12 (COX-2), and interleukin-16 (IL-6). It has been reported that it plays an important role in regulating immune function (Mangelsdorf, DJ, Tontonoz, P. et. Al., Nat. Med., 2003, Vol. 9, p. 213-219) ).
  • LXR modulators are expected to suppress the development and progression of arteriosclerosis due to their anti-inflammatory effects, in addition to improving lipid metabolism.
  • naturally occurring and synthesized LXR activators have been shown to reduce chemically induced dermatitis in animal models (Fowler, AJ, et. Al., J. Invest Dermatol. 2003, Vol. 120, p.246-255).
  • LXR modulators are expected to be useful in treating a variety of inflammatory diseases.
  • the inventors of the present invention have conducted intensive studies on the synthesis and pharmacological activity of indole conjugates in order to find a compound having excellent binding activity to LXR.
  • the present inventors have found that the compound has an excellent binding activity to LXR, and completed the present invention.
  • the present invention exhibits excellent anti-atherosclerotic and anti-inflammatory effects by regulating the action of nuclear receptor LXR to improve lipid metabolism disorders or to control the production of inflammatory mediators. And a pharmacologically acceptable salt or ester thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an indoley conjugate or a pharmacologically acceptable salt or ester thereof as an active ingredient, preferably arteriosclerosis (which can cause arteriosclerosis).
  • arteriosclerosis which can cause arteriosclerosis.
  • the present invention provides a pharmaceutical composition, preferably an indolui conjugate for producing a pharmaceutical composition for treating or preventing the above-mentioned diseases, or a pharmaceutically acceptable salt or ester thereof. Provide use.
  • the present invention relates to a disease caused by administering a pharmacologically effective amount of an indolui conjugate or a pharmacologically acceptable salt or ester thereof to a warm-blooded animal (particularly a human). And methods for treating or preventing the above diseases.
  • the present invention further provides a method for producing an indole conjugate or a pharmacologically acceptable salt or ester thereof.
  • the present invention is a.
  • a halogeno CC alkyl group (the halogeno CC alkyl group may have 1 to 7 halo groups).
  • C represents a C alkoxy group substituted with a halogeno group), C C alkylthio group, C
  • Two such alkyl groups together with the nitrogen atom of the amino group, form a 5- to 7-membered saturated heterocyclyl group containing one to three atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. May be formed), a cyano group, a nitro group, a halogeno group, or a phenyl group;
  • R 5 represents a hydrogen atom, a C 1 -C alkyl group or a halogeno group
  • R 6 is a group represented by the formula — COR 8 wherein R 8 is a C—C alkoxy group or a halogeno C—C alkoxy group
  • the halogeno C C alkoxy group is a C C substituted with 1 to 7 halogeno groups.
  • the groups are the same or different and the two alkyl groups together with the nitrogen atom of the amino group contain one to three atoms selected from the group consisting of nitrogen, oxygen and sulfur-nuclear.
  • a 7-membered saturated heterocyclyl group may be formed.
  • R 9 is a C-C alkyl group, a ferrous (C-C alkyl) group,
  • a cyclyl- (C—C alkyl) group (the substituents being the same or different, and
  • R 7 is the formula! ⁇ 1 ! ⁇ 1 , —CSN (R 1Q ) R 12 , —SO N (R 10 ) R 12 , —CONR 13 R ", —SO
  • R 12 -NR 15 R 16 , -X'NCR 1 ⁇ 11 , -X 3 N (R 10 ) R 12 ,-X 3 Z 2 N (R 1 () ) R 12 , or-
  • R 1Q represents a hydrogen atom, a C 1 -C alkyl group, (C 1 -C cycloalkyl) — (C 1 -C
  • R 11 represents a hydrogen atom, a C—C alkyl group, a substituted C—C alkyl group (the substituent is
  • a substituted C—C alkenyl group (the substituents are the same or different and are selected from substituent group ⁇
  • the two alkyl groups, together with the nitrogen atom of the amino group comprise one to three atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur-nuclear atom; (A heterocyclyl group may be formed), di (C—C-alkyl) amido
  • alkyl groups are the same or different
  • di (C-Ccycloalkyl) amino groups are the same or different
  • the cycloalkyl groups are the same or different), N— (C—C alkyl) —N— (C—C
  • R 11 is not a C—C alkoxy group when R 1Q is a hydrogen atom and Z 1 is —CO 2]
  • R 12 is a hydrogen atom, a C—C alkyl group, a substituted C—C alkyl group (the substituent is
  • R 13 and R 14 may be substituted with a nitrogen atom to which R 13 and R ′′ are bonded, and may be a 5- to 7-membered saturated heterocyclyl group (the substituents may be the same or different, and One to three groups).
  • R 15 has the same meaning as R 1Q (however, R 15 is not a hydrogen atom),
  • R 16 represents a CC alkyl group or a CC alkyl group
  • A represents a 2-oxopyrrolidine-1-yl group, a 2,5-doxopyrrolidine-1-yl group, or a 2-oxo-1,3-oxazolidine-3-yl group;
  • X 3 represents a C—C anoalkylene group
  • Z 1 represents a group having the formula CO, one CS— or so
  • z 2 represents a group having the formula CO— or so.
  • the heterocyclic group contains 2 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur nuclear atom), or a substituted 5- or 6-membered aromatic heterocyclyl group (the heterocyclyl group is a nitrogen atom).
  • Atom, oxygen atom and sulfur nuclear atom, and the substituents are the same or different and are 1 to 3 groups selected from the substituent group ⁇ ). Show;
  • X 1 represents a methylene group or a substituted methylene group (the substituent is one or two identical or different C—C alkyl groups);
  • X 2 represents a single bond, a methylene group, or a substituted methylene group (the substituent is one or two identical or different C—C alkyl groups),
  • ⁇ represents a phenyl group, a substituted phenyl group (the substituents are the same or different and is 1 to 3 groups selected from a substituent group j8), a 5- or 6-membered aromatic heterocyclyl group, or a substituted A 5- or 6-membered aromatic heterocyclyl group (the substituents are the same or different and are 1 to 3 groups selected from a substituent group ⁇ );
  • Substituent group ⁇ is a C C alkyl group, a halogeno C C alkyl group (the halogeno C
  • the 16 1 6 C alkyl group represents a C C alkyl group substituted with 1 to 7 halogeno groups.
  • the substituent group j8 includes a C C alkyl group, a halogeno C C alkyl group (the halogeno C
  • the 16 1 6 C alkyl group represents a C C alkyl group substituted with 1 to 7 halogeno groups.
  • Substituent group 0 is a hydroxyl group, C—C alkoxy group, halogeno C—C alkoxy
  • halogeno C C alkoxy group is a C 1 -C 7 substituted with 1 to 7 halogeno groups
  • the two alkyl groups, together with the nitrogen atom of the amino group comprise one to three atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur-nuclear atom; (Which may form a heterocyclyl group), di (C-Calkyl) amino
  • a carbonyl group (the alkyl groups are the same or different, and the two or more alkyl groups are taken together with the nitrogen atom of the amino group to form a nitrogen atom, an oxygen atom, and a sulfur atom; A 5- to 7-membered saturated heterocyclyl group containing an atom may be formed), and a halogeno group. Or a pharmacologically acceptable salt or ester thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof, and a carrier or diluent.
  • the present invention provides the above pharmaceutical composition for the treatment or prevention in a warm-blooded animal, wherein the warm-blooded animal is a human disease which can be treated or prevented by regulating LXR function in the warm-blooded animal.
  • the pharmaceutical composition is for treatment or prophylaxis in a warm-blooded animal, wherein the warm-blooded animal includes arteriosclerosis (including arteriosclerosis resulting from a disease that can develop arteriosclerosis); Atherosclerosis; Arteriosclerosis due to diabetes; Hyperlipidemia; Hypercholesterolemia; Lipid-related diseases; Inflammatory diseases caused by inflammatory site force-in; Autoimmune diseases; A vascular disease; cerebrovascular disease; renal disease; diabetes; diabetic complications; obesity; nephritis; hepatitis; cancer; and a human who is a disease selected from the group consisting of Alzheimer's disease.
  • arteriosclerosis including arteriosclerosis resulting from a disease that can develop arteriosclerosis
  • Atherosclerosis Arteriosclerosis due to diabetes
  • Hyperlipidemia including arteriosclerosis resulting from a disease that can develop arteriosclerosis
  • Hyperlipidemia Hypercholesterolemia
  • Lipid-related diseases Inflammatory diseases caused by inflammatory site force-in
  • the pharmaceutical composition is for treatment or prevention in a warm-blooded animal, and the warm-blooded animal is capable of treating arteriosclerosis (arteriosclerosis caused by a disease that can develop arteriosclerosis).
  • arteriosclerosis arteriosclerosis caused by a disease that can develop arteriosclerosis.
  • it may be a human who is a disease selected from the group which also has diabetic power.
  • the pharmaceutical composition is for treatment or prophylaxis in a warm-blooded animal, wherein the warm-blooded animal can be a human with arteriosclerosis.
  • the present invention also provides a compound represented by the above general formula (I) or a pharmaceutically acceptable salt or ester thereof for use as a medicament.
  • the present invention also relates to the use of one or more compounds represented by the above general formula (I) or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for treatment or prevention in a warm-blooded animal.
  • the warm-blooded animal can be a human being a disease that can be treated or prevented by modulation of LXR function in the warm-blooded animal.
  • the disease that can be treated or prevented by modulation of LXR function in a warm-blooded animal is arteriosclerosis (including arteriosclerosis due to a disease that can develop arteriosclerosis); atherosclerosis Arteriosclerosis due to diabetes; hyperlipidemia; hypercholesterolemia; lipid-related diseases; inflammatory diseases caused by inflammatory cytokines; autoimmune diseases; cardiovascular diseases; cerebrovascular diseases. Kidney disease; diabetes; diabetic complications; obesity; nephritis; hepatitis; cancer; and Alheimer's disease.
  • the disease is atherosclerosis (including arteriosclerosis due to a disease that can develop arteriosclerosis); atherosclerosis; arteriosclerosis due to diabetes; hyperlipidemia Hypercholesterolemia; lipid-related diseases; inflammatory diseases that are diseases caused by inflammatory site force-in; and diabetes.
  • arteriosclerosis including arteriosclerosis due to a disease that can develop arteriosclerosis
  • atherosclerosis including arteriosclerosis due to a disease that can develop arteriosclerosis
  • arteriosclerosis due to diabetes
  • hyperlipidemia Hypercholesterolemia lipid-related diseases
  • inflammatory diseases that are diseases caused by inflammatory site force-in
  • diabetes is arteriosclerosis.
  • the present invention provides a method for treating a warm-blooded animal by administering an effective amount of the compound represented by the general formula (I) or a pharmaceutically acceptable salt or ester thereof to the warm-blooded animal.
  • the warm-blooded animal can be a human being a disease that can be treated or prevented by modulation of LXR function in the warm-blooded animal.
  • the disease that can be treated or prevented by modulating LXR function in a warm-blooded animal is arteriosclerosis (including arteriosclerosis due to a disease that can develop arteriosclerosis); atherosclerosis Disease; arteriosclerosis due to diabetes; hyperlipidemia; hypercholesterolemia; lipid-related diseases; inflammatory diseases that are caused by inflammatory site forces; autoimmune diseases; cardiovascular diseases; Cerebrovascular disease; kidney disease; diabetes; diabetic complications; obesity; nephritis; hepatitis; cancer; and Alzheimer's disease.
  • arteriosclerosis including arteriosclerosis due to a disease that can develop arteriosclerosis
  • atherosclerosis Disease arteriosclerosis due to diabetes
  • hyperlipidemia hypercholesterolemia
  • lipid-related diseases inflammatory diseases that are caused by inflammatory site forces
  • autoimmune diseases cardiovascular diseases
  • Cerebrovascular disease kidney disease
  • diabetes diabetic complications
  • obesity nephritis
  • hepatitis cancer
  • Alzheimer's disease Alzheimer's disease.
  • the disease is atherosclerosis ( Atherosclerosis due to a disease that can develop arteriosclerosis); atherosclerosis; arteriosclerosis due to diabetes; hyperlipidemia; hypercholesterolemia; lipid-related diseases; Inflammatory disease, a disease caused by bowel force caused by sight force; and diabetic force. Most preferably, the disease is arteriosclerosis.
  • the present invention provides a compound represented by the above general formula (I) or a pharmaceutically acceptable salt or ester thereof; an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a plasma HDL-elevating agent , Cholesterol biosynthesis inhibitor, squalene epoxidase inhibitor, squalene synthetase inhibitor, therapeutic agent for hypercholesterolemia, acyl-coenzyme A, cholesteryl ester transfer protein inhibitor (hereinafter referred to as CETP inhibitor), ACAT inhibitor, probucol, cholesterol absorption inhibitor, bile acid-adsorbed ion exchange resin, fibrate, nicotinic acid derivative, niacinamide, LDL receptor inducer, vitamin B
  • Vitamin B antioxidant vitamin, angiotensin II inhibitor, angiotensin converting enzyme
  • a pharmaceutical selected from the group consisting of an inhibitor, a ⁇ -blocker, a fibrinogen inhibitor, aspirin, a diuretic, and a combination thereof; and a pharmaceutical composition comprising a carrier or a diluent.
  • a halogeno C C alkyl group (the halogeno C C alkyl group may include 1 to 5 halogeno C C alkyl groups;
  • the compound according to (1) which is a group or a bromo group
  • Fluoromethyl group chloromethyl group, difluoromethyl group, trifluoromethyl group, pentafluoroethyl group, methoxy group, ethoxy group, fluoromethoxy group, chloromethoxy group, difluoromethoxy group, trifluoromethoxy group, pentafluoroethoxy group, A methanesulfol group, an ethanesulfol group, a fluoro group, a chloro group, or a bromo group; Compound,
  • R 5 is the same or different and is a hydrogen atom, a C-C alkyl group, a trifluoromethyl group
  • R 6 is a group represented by the formula —COR 8a wherein R 8a is a C 1 -C alkoxy group, a halogeno C 2 -C alcohol
  • halogeno C C alkoxy group is a C 1 -C 5 substituted with 1 to 5 halogeno groups
  • a oxy group (the substituents are the same or different and are one or two groups selected from a substituent group
  • the two or more alkyl groups, together with the nitrogen atom of the amino group, contain one to three atoms selected from the group consisting of nitrogen, oxygen and sulfur nuclear. Or a 7-membered saturated heterocyclyl group may be formed).
  • R 9a is a C—C alkyl group, a ferrous (C—C alkyl) group,
  • a phenyl group, a substituted phenyl group (the substituents are the same or different and are one or two groups selected from substituent group j81), a 5- or 6-membered aromatic heterocyclyl group (the heterocyclyl group);
  • the group is a phenyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, or a pyridyl group, or a substituted 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group is a phenyl group, an imidazolyl group, Oxazolyl group, thiazolyl group, triazolyl group, or pyridyl group, and the substituents are the same or different and are one or two groups selected from a substituent group ⁇ 1).
  • the heterocyclyl group represents a phenyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, or a pyridyl group, and the substituents are the same or different and are 1 to 2 groups selected from the substituent group a1. Is a group);
  • Substituent group ⁇ 1 is a C C alkyl group, a halogeno C C alkyl group (the halogeno C
  • —C alkyl groups are substituted with 1 to 5 fluoro, cyclo or bromo groups.
  • C represents an alkyl group), a fluoro group, and a black group.
  • the substituent group j81 represents a C C alkyl group, a halogeno C C alkyl group (the halogeno C
  • —C alkyl groups are substituted with 1 to 5 fluoro, cyclo or bromo groups.
  • C represents an alkyl group
  • C—C alkoxy group C—C alkoxycarbonyl group
  • (1) to (6) which are a group consisting of a nitro group, a nitro group, a fluoro group, a chloro group, and a bromo group.
  • R 6 is a group represented by the formula —COR 8b wherein R 8b is a C—C alkoxy group, a halogeno C—C alcohol
  • substituents are the same or different and are one or two groups selected from substituent group ⁇ 81 1), C—C alkenyloxy group, or C—C A cycloalkyloxy group
  • R % represents a fluorine group or a substituted phenyl group (the substituents may be the same or
  • substituent group j82 are different from each other and are one or two groups selected from substituent group j82), a chel group, a pyridyl group, or a substituted chel group or a substituted pyridyl group (the substituents may be the same or different). And one or two groups selected from substituent groups) 82).
  • a benzyl group, a substituted benzyl group (the substituents are the same or different and are one or two groups selected from substituent group ⁇ 2), a pyridylmethyl group, or a substituted pyridylmethyl group ( The substituents are the same or different and are a substituent group ⁇ 1 or 2 groups selected from 2);
  • Substituent group a2 is a group consisting of a methyl group, an ethyl group, a trifluoromethyl group, a fluoro group, and
  • Substituent group j82 includes methyl, ethyl, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, methoxy, ethoxy, methoxycarbol, ethoxycarbo. , A cyano group, a nitro group, a fluoro group, and a compound according to any of (1) to (6),
  • R 6 is a compound of the formula: COR 8 wherein R & is a C—C alkoxy group or a halogeno C—C
  • halogeno C-C alkoxy group may be 1 to 5 fluoro or
  • R 6 is a group having the formula: COR 8d (wherein R 8d represents a 2-propoxy group or a 2-methyl 2-propoxy group).
  • R 7 has the formula — ⁇ ⁇ , ⁇ 1 ! ⁇ 113 -CSN (R 10a ) R 12 ⁇ —SO N (R 10a ) R 12 — CONR 13a
  • R 14a — SO R 12a , — NR 15 16a , -X 3a N (R 10a ) Z 1 R n ⁇ — X 3a N (R 1 ⁇ ) a ) R 12a , or —X
  • R 1Qa is a hydrogen atom, a C 1 -C alkyl group, a (C—C cycloalkyl) (C 1 -C
  • R lla represents a hydrogen atom, a C 1 -C alkyl group, a substituted C 1 -C alkyl group (the substituent is
  • the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group form one or two atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. May form a 5- or 7-membered saturated heterocyclyl group), di (C
  • a phenyl group or a 5- to 7-membered heterocyclyl group (the heterocyclyl group contains 1 to 2 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; Indicates a member heterocyclyl group).
  • R Ua is not a hydrogen atom -N (R 10a ) Z 1 R
  • R 1Qa is a hydrogen atom in l la and Z 1 is —CO 2
  • R Ua is a C-C alkoxy
  • R 12a represents a hydrogen atom, a C 1 -C alkyl group, a substituted C 1 -C alkyl group (the substituent is
  • a rocyclyl (CC alkyl) group (the heterocyclyl group is a nitrogen atom, an oxygen atom,
  • the substituents are the same or different and are one or two groups selected from substituent group ⁇ 1), or a C—C alkenyl group (provided that R 12a in —SO R 12a Is a hydrogen atom
  • R 13a and R 14a are, together with the nitrogen atom to which R 13a and R 14a are bonded, a 5- or 6-membered saturated heterocyclyl group which may be substituted (the heterocyclyl group is a nitrogen atom, an oxygen atom, Represents a 5- or 6-membered saturated heterocyclyl group containing 1 or 2 atoms selected from the group consisting of sulfur and nuclear, and the substituents are the same or different and are 1 to 2 selected from the group of substituents 1 Groups)), R 15a has the same meaning as R 1Qa (however, R 15a is not a hydrogen atom),
  • R 16a represents a C—C alkyl group or a C—C alkyl group
  • X 3a represents a methylene group.
  • Ryl represents an imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl group, or a substituted 5- or 6-membered aromatic heterocyclyl group
  • the heterocyclyl group represents an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, an oxadiazolyl group, or a thiadiazolyl group; the substituents may be the same or different, and 1 or 2 groups selected from ⁇ 1));
  • Substituent group 01 is a hydroxyl group, C 1 -C alkoxy group, halogeno C 1 -C alkoxy
  • the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group form one or two atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. May form a 5- or 7-membered saturated heterocyclyl group), di (C
  • alkyl groups may be the same or different and
  • the alkyl group together with the nitrogen atom of the amino group forms a 5- to 7-membered saturated heterocyclyl group containing one or two atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. May be formed), a fluoro group, a chloro group, and a bromo group.
  • R 7 is of the formula — (R 1 () b ) R 12b , or-
  • R 1Qb represents a C—C alkyl group, a cyclopropyl— (C—C alkyl) group, or Represents a c-c cycloalkyl group
  • R Ub is a hydrogen atom, a C 1 -C alkyl group, a substituted C 1 -C alkyl group (the substituent is
  • R 12b represents a hydrogen atom, a methyl group, an ethyl group, a (C—C cycloalkyl) (C 1 -C
  • R 13b and R 14b together with the nitrogen atom to which R 13b and R 14b are bonded, are optionally substituted pyrrolidyl, piberidyl, piperazyl, morpholinyl or thiomorpholinyl (
  • the substituents are the same or different and represent the substituent group ⁇ 1 to 2 groups selected from 2). ]
  • Substituent group 02 is a hydroxyl group, a methoxy group, an ethoxy group, a fluoromethoxy group, a cyclomethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a pentafluoroethoxy group, a benzyloxy group, a phenyloxy group, an amino group.
  • R 7 is a group having the formula ⁇ ⁇ ⁇ 1 ! ⁇ 1 ⁇
  • R 1Qe represents a methyl group, an ethyl group or a cyclopropyl group
  • R lle represents a C—C alkyl group or a substituted C—C alkyl group (the substituent is a substituent group ⁇ 2), cyclopropyl— (C 1 -C alkyl) group, C 1 -C 6
  • R 7 is a group having the formula —Nd ⁇ COR 11 ⁇ or—N (R 1Qd ) CSR lld
  • R 1M represents a methyl group or an ethyl group
  • R Ud represents a methyl group, an ethyl group, a 1-propyl group, a methoxymethyl group, a cyclopropylmethyl group, or a cyclopropyl group.
  • ⁇ is a phenyl group, a substituted phenyl group (the substituent is one group selected from substituent group j81), a 5- or 6-membered aromatic heterocyclyl group (the heterocyclyl group is Thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, or pyridyl), or substituted 5- or 6-membered aromatic heterocyclyl (the heterocyclyl is chenyl, imidazolyl) Oxazolyl group, thiazolyl group, triazolyl group, or pyridyl group, and the substituent is one group selected from substituent group j81).
  • Y is a phenyl group, a substituted phenyl group (the substituent is one group selected from substituent group j81), a pyridyl group, or a substituted pyridyl group (the substituent is a substituted
  • a halogeno C C alkyl group (the halogeno C C alkyl group comprises 1 to 5 halo
  • R 5 is the same or different and is a hydrogen atom, a C-C alkyl group, a trifluoromethyl group,
  • a fluoro group, a chloro group, or a bromo group A fluoro group, a chloro group, or a bromo group
  • R 6 is of the formula COR 8a wherein R 8a is a C 1 -C alkoxy group, a halogeno C 1 -C alkoxy
  • halogeno C C alkoxy group is a C.sub.C substituted with 1 to 5 halogeno groups
  • One or two or more substituents j8 is one or two groups selected from 1),
  • a xy group (the substituents are the same or different and are one or two groups selected from substituent group ⁇ 81), a C-C alkylamino group, a di (C-C alkyl) amino group (the alkyl group) Base
  • the two or more alkyl groups, together with the nitrogen atom of the amino group contain 1 to 3 atoms selected from the group consisting of nitrogen, oxygen and sulfur nuclear. Or a 7-membered saturated heterocyclyl group may be formed).
  • R 9a is a C—C alkyl group, a ferrous (C—C alkyl) group,
  • a phenyl group, a substituted phenyl group (the substituents are the same or different and are one or two groups selected from substituent group j81), a 5- or 6-membered aromatic heterocyclyl group (the heterocyclyl group);
  • the group is a phenyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, or a pyridyl group, or a substituted 5- to 6-membered aromatic heterocyclyl group (the heterocyclyl group is a phenyl group, an imidazolyl group, A oxazolyl group, a thiazolyl group, a triazolyl group, or a pyridyl group, the substituents being the same or different, and and 1 to 2 groups selected from ⁇ 1). ],
  • a fluoro (CC alkyl) group, a substituted fluoro (CC alkyl) group (substit
  • the heterocyclyl group is a phenyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, or a pyridyl group. Is a group)
  • R 7 is — CONR 13a R " a ,
  • R 1Qa a group having R 12a
  • R 1Qa is a hydrogen atom, a C 1 -C alkyl group, a (C—C cycloalkyl) (C 1 -C
  • R Ua is a hydrogen atom, a C 1 -C alkyl group, a substituted C 1 -C alkyl group (the substituent is
  • substituents are the same or different and are one or two groups selected from substituent group ⁇ 1), a CC cycloalkyl group, a substituted C cycloalkyl) group ( The substituent
  • the alkyl groups are the same or different, and the two alkyl groups together with the nitrogen atom of the amino group form one or two atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. May form a 5- or 7-membered saturated heterocyclyl group), di (C
  • a phenyl group or a 5- to 7-membered heterocyclyl group (the heterocyclyl group contains 1 to 2 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; Indicates a member heterocyclyl group).
  • R Ua is not a hydrogen atom -N (R 10a ) Z 1 R
  • R 1Qa is a hydrogen atom in l la and Z 1 is —CO 2
  • R Ua is a C-C alkoxy
  • R 12a represents a hydrogen atom, a C 1 -C alkyl group, a substituted C 1 -C alkyl group (the substituent is
  • a rocyclyl (CC alkyl) group (the heterocyclyl group is a nitrogen atom, an oxygen atom,
  • the substituents are the same or different and are one or two groups selected from substituent group ⁇ 1), or a C—C alkenyl group (provided that R 12a in —SO R 12a Is a hydrogen atom
  • R 13a and R 14a are, together with the nitrogen atom to which R 13a and R 14a are bonded, a 5- or 6-membered saturated heterocyclyl group which may be substituted (the heterocyclyl group is a nitrogen atom, an oxygen atom, Represents a 5- or 6-membered saturated heterocyclyl group containing 1 or 2 atoms selected from the group consisting of sulfur and nuclear, and the substituents are the same or different and are 1 to 2 selected from the group of substituents 1 Groups)),
  • R 15a has the same meaning as R 1Qa (however, R 15a is not a hydrogen atom),
  • R 16a represents a C—C alkyl group or a C—C alkyl group
  • X 3a represents a methylene group.
  • Ryl represents an imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl group, or a substituted 5- or 6-membered aromatic heterocyclyl group
  • the heterocyclyl group represents an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, an oxadiazolyl group, or a thiadiazolyl group; the substituents may be the same or different, and 1 or 2 groups selected from ⁇ 1)
  • X 1 is a methylene group or a substituted methylene group (the substituent is one or two same or different CC alkyl groups),
  • X 2 is a single bond, a methylene group, or a substituted methylene group (the substituent is one or two same or different CC alkyl groups),
  • ⁇ is a phenyl group, a substituted phenyl group (the substituent is one group selected from substituent group j81), a 5- or 6-membered aromatic heterocyclyl group (the heterocyclyl group is Or a substituted 5- or 6-membered aromatic heterocyclyl group (showing a phenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, or pyridyl group), or a phenyl, imidazolyl, oxazolyl, or oxazolyl group.
  • R 5 is a hydrogen atom
  • R 6 is a group represented by the formula: COR 8b wherein R 8b is a C—C alkoxy group, a halogeno C—C alkoxy
  • halogeno C-C alkoxy group is 1 to 5 fluoro, chloro or bromo
  • a group (the substituents are the same or different and are one or two groups selected from substituent group ⁇ 81), a C—C-alkoxy group, or a C—C cycloalkyloxy group .
  • R % represents a fluorine group or a substituted phenyl group (the substituents may be the same or
  • substituent group j82 are different from each other and are one or two groups selected from substituent group j82), a chel group, a pyridyl group, or a substituted chel group or a substituted pyridyl group (the substituents may be the same or different). And one or two groups selected from substituent groups) 82).
  • a benzyl group, a substituted benzyl group (the substituents are the same or different and are one or two groups selected from substituent group ⁇ 2), a pyridylmethyl group, or a substituted pyridylmethyl group (The substituents are the same or different and are a substituent group ⁇ 1 or 2 groups selected from 2),
  • R 7 is the formula -! ⁇ ⁇ ⁇ 1 ⁇ 1113 - CSN (R 10b) R 12b, -SO N (R 10b) R 12 or, -CON
  • R 1Qb represents a C—C alkyl group, a cyclopropyl— (C—C alkyl) group, or
  • R Ub represents a hydrogen atom, a C—C alkyl group, a substituted C—C alkyl group (the substituent is
  • R 12b represents a hydrogen atom, a methyl group, an ethyl group, a (C—C cycloalkyl) (C 1 -C
  • R 13b and R 14b are substituted together with the nitrogen atom to which R 13b and R 14b are attached.
  • a pyrrolidyl group, a piberidyl group, a piperazyl group, a morpholinyl group or a thiomorpholinyl group (the substituents may be the same or different, and may be 1 to 2 Is shown). ]
  • X 1 force is a methylene group
  • X 2 is a single bond
  • Y is a phenyl group, a substituted phenyl group (the substituent is one group selected from a substituent group j8 1), a pyridyl group, or a substituted pyridyl group (the substituent is a substituent group j8 A single group selected from 1), (1)
  • R 4 is the same or different and is a hydrogen atom, a trifluoromethyl group, a methoxy group, a fluoro group, or a chloro group;
  • R 5 is a hydrogen atom
  • R 6 is a group represented by the formula — COR 8e [where R & is a C—C alkoxy group or halogeno C—C
  • R 7 is a group having the formula — ⁇ ⁇ , ⁇ 1 ! ⁇
  • R 1Qe represents a methyl group, an ethyl group or a cyclopropyl group
  • R lle represents a C—C alkyl group or a substituted C—C alkyl group (the substituent is a substituent group ⁇
  • X 1 force is a methylene group
  • X 2 is a single bond
  • R 4 is the same or different and is a hydrogen atom, trifluoromethyl Group, methoxy group, fluoro group, or black group,
  • R 5 is a hydrogen atom
  • R 6 is a group having the formula: COR 8d (wherein, R 8d represents a 2-propoxy group or a 2-methyl 2-propoxy group),
  • R 7 is a group having the formula —N (R 1M ) COR lld or —N (R 1M ) CSR lld
  • R 1M represents a methyl group or an ethyl group
  • R Ud represents methyl group, Echiru group, 1-propyl group, a methoxymethyl group, a cyclopropyl methylcarbamoyl group, or a cyclopropyl group.
  • X 1 force is a methylene group
  • X 2 is a single bond
  • Y is a phenyl group, a substituted phenyl group (the substituent is one group selected from a substituent group j8 1), a pyridyl group, or a substituted pyridyl group (the substituent is a substituent group j8 A single group selected from 1), (1)
  • R 1 , And R 4 is the same or different and is a hydrogen atom, a trifluoromethyl group, a methoxy group, a fluoro group, or a chloro group;
  • R 5 is a hydrogen atom
  • R 6 is a group having the formula: COR 8d (wherein, R 8d represents a 2-propoxy group or a 2-methyl 2-propoxy group),
  • R 7 is a group having the formula —N (R 1 ⁇ ) d ) COR lld or —N (R 1 ⁇ ) d ) CSR lld
  • R 1M represents a methyl group or an ethyl group
  • R Ud represents methyl group, Echiru group, 1-propyl group, a methoxymethyl group, a cyclopropyl methylcarbamoyl group, or a cyclopropyl group.
  • X 1 force is a methylene group
  • X 2 is a single bond
  • the compound according to (1) which is a Y-phenyl group, or
  • tert-butyl 6 port 2 ( ⁇ 4- [(cyclopropylcarbol) (methyl) amino] phenoxy ⁇ methyl) 5 fluoro-1H-indole-1-carboxylate, tert-butyl 5 port 2— ( ⁇ 4 — [(cyclopropylcarbol) (methyl) amino] phenoxy ⁇ methyl) -6fluoro-1H-indole-1carboxylate and tert-butyl 2-( ⁇ — [(cyclopropylcarbol) (Methyl) amino] phenoxy ⁇ methyl) -5,6 dichloro-1H-indole-1 carboxylate
  • the compound according to (1) which is selected from the group consisting of:
  • the pharmaceutical composition comprises atherosclerosis (including arteriosclerosis caused by a disease that can develop arteriosclerosis), atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, and hypertension. Cholesterolemia, lipid-related diseases, inflammatory diseases caused by inflammatory sites, inflammatory diseases, autoimmune diseases, cardiovascular diseases, cerebrovascular diseases, renal diseases, diabetes mellitus, diabetic complications, obesity,
  • the pharmaceutical composition according to (26) which is a pharmaceutical composition for treating or preventing a disease selected from the group consisting of nephritis, hepatitis, cancer, and Alzheimer's disease,
  • the pharmaceutical composition contains atherosclerosis (including arteriosclerosis caused by a disease that can develop arteriosclerosis), atherosclerosis, arteriosclerosis caused by diabetes, hyperlipidemia, and hypertension. It is a pharmaceutical composition for treating or preventing cholesterol, a lipid-related disease, an inflammatory disease caused by inflammatory cytotoxicity, and a disease selected from the group consisting of diabetic potential (26)
  • the pharmaceutical composition according to, or,
  • composition according to (26), wherein the pharmaceutical composition is for treating or preventing a disease selected from the group consisting of arteriosclerosis, atherosclerosis, and atherosclerosis due to diabetes. Is also provided.
  • the drug is pravastatin, atornostatin or rospastatin (30) Also provided is a pharmaceutical composition as described.
  • 1-638 cycloalkyl) — (C 1 -C alkyl) group has 1 to 6 alkyl groups.
  • a straight-chain or branched-chain alkyl group having a carbon atom for example, a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, a 1-butyl group, a 2-butyl group, a 2-methyl-1-propyl group , 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl
  • Is a c-c alkyl group (especially a methyl group, an ethyl group or a propyl group),
  • it is a methinole or ethynole group, most preferably a methinole group.
  • the 14-group is a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl
  • the group may be a 2-methyl-1-propyl group or a 2-methyl-2-propyl group, preferably a C 1 -C alkyl group, more preferably a methyl group.
  • 16 16 alkyl groups such as fluoromethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, trifluoromethyl group, trichloromethyl group, 2-fluoroethyl group, 2-bromoethyl group, and 2-chloroethyl group.
  • Geno C-C alkyl groups are substituted with 1 to 5 fluoro, cyclo or bromo groups.
  • ⁇ represents a C-C alkyl group), and still more preferably a fluoromethyl group or a chloromethyl group.
  • the c-c alkoxy moiety of the (1 6 3 8 c-c alkoxy) group '' is substituted with the above c-c alkyl group.
  • Is also preferably a methoxy group.
  • the "C-C alkoxy group" for R 8 in the general formula (I) is a hydroxyl group substituted with a C-C alkyl group, and is, for example, a methoxy group, an ethoxy group, a 1-propoxy group, a 2-prop- Poxy, 1-butoxy, 2-butoxy, 2-methyl-1 propoxy, 2-methyl 2-propoxy, 1 pentyloxy, 2 pentyloxy, 3 pentyloxy, 2-methyl 2-butoxy, 3-methyl 2 Butoxy group, 2,2 dimethyl-1 propoxy group, 1 hexyloxy group, 2 hexyloxy group, 3 hexyloxy group, 2-methyl-1 pentyloxy group, 3-methyl-1 pentyloxy group, 3-methyl-3-pentyloxy group, 2 Ethyl-1 butoxy, 2,2 dimethyl-1-butoxy, 2,3 dimethyl-1 butoxy, 1-heptyloxy, 3 ethyl-3-pentyloxy 1-octyloxy or 3-
  • 1626 groups more preferably a c-c alkoxy group, even more preferably c-c
  • the ⁇ rukoxy group '' is the above C alkoxy group substituted with 1 to 7 halogeno groups below.
  • a fluoromethoxy group for example, a fluoromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a dimethoxymethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2-fluoroethoxy group, a 2-bromoethoxy group, a 2-chloroethoxy group, 2-Eodoethoxy group, 2,2-Difluoroethoxy group, 2,2,2-Trifluoroethoxy group, Trichloro mouth ethoxy group, Pentafluoroethoxy group, 3-Fluoropropoxy group, 3-Fluoro mouth It may be a propoxy group, a 4 fluorobutoxy group, a 5 fluoropentyloxy group, or a 6-fluorohexyloxy group.
  • the halogeno C—C alkoxy group at R 8 is preferably a halogeno C—C alcohol
  • halogeno C C alkoxy group is a C 1 -C 5 substituted with 1 to 5 halogeno groups
  • a halogeno C-C alkoxy group may be substituted with 1 to 5 fluoro, chloro or bromo groups.
  • it is a methinorethio group or an ethinorethio group, and most preferably, a methinorethio group.
  • Sulfonic acid group ethanesulfonic acid group, 1-propanesulfonic acid group, 2-propanesulfonic acid group, 1-butanesulfonic acid group, 2-butanesulfonic acid group, 2-methyl-1-propanesulfonic acid group, 2- Methyl 2-propanesulfyl group, 1-pentane sulfyl group, 2 pentane sulfiel group, 3 pentane sulfiel group, 2-methyl 2-butane sulfiel group, 3-methyl-2-butane sulfiel group, Hexansulfyl group, 2 Hexanesulfiel group, 3 Hexanesulfiel group, 2-Methyl-1-pentanesulfiel group, 3-Methyl-1-pentanesulfiel group, 2-Ethyl 1-Butanesulfiel group A 2,2-dimethyl-1 butanesulfier group or a 2,3 dimethyl-1 butanesulfier group,
  • a methanesulfiel group or an ethanesulfiel group and more preferably a methanesulfiel group.
  • a sulfol group (one so—) substituted with the above C C alkyl group for example, methane
  • Snorehoninole group ethaneshonolehoninole group, 1-propane snolehoninole group, 2-propane snolehonol group, 1 butanesulfol group, 2-butanesulfol group, 2-methyl-1 propane sulfol group, 2-methyl —2—propane sulfol group, 1-pentane sulfol group, 2 Pentane sulfol group, 3 Pentane sulfol group, 2-Methyl-2-butanesulfonyl group, 3-Methyl-2 butanesulfonyl group, 1 Hexanesulfol group, 2 Hexanesulfol group, 3 Hexanesulfol- 2-methyl-1 pentanesulfol group, 3-methyl-1 pentanesulfol group, 2-ethyl-1 butanesulfol group, 2,2 dimethyl-1 but
  • a methanesulfol group most preferably a methanesulfol group.
  • amino group is an amino group substituted with one of the above C C alkyl groups.
  • Tylamino group ethylamino group, propylamino group (for example, 1-propylamino group, 2-propylamino group), 1-butylamino group, 2-butylamino group, 2-methyl 1-propylamino group, 2-methyl-2-propylamino Group, 1 pentylamino group, 2-pentylamino group, 3 pentylamino group, 2-methyl-2-butylamino group, 3-methyl-2-butylamino group, 1-hexylamino group, 2-hexylamino group, 3-hexylamino group, 2-methyl It may be a tyl-1 pentylamino group, a 3-methyl-1pentylamino group, a 2-ethyl-1-butylamino group, a 2,2 dimethyl-1-butylamino group, or a 2,3 dimethyl-1-butylamino group, preferably a C—C Alkylamino group, more preferably C—C Al
  • -C alkylamino group more preferably a methylamino group or an ethylamino group.
  • Alkyl) amino group is an aryl group substituted with the same or different two C-C alkyl groups.
  • di (C-C alkyl) amino group means that two such alkyl groups are nitrogen groups of the amino group.
  • the 7-membered saturated heterocyclyl group can be, for example, an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazyl group, a morpholinyl group, a thiomorpholinyl group, or a perhydroazepyryl group, preferably a nitrogen atom,
  • the “nodrogeno group” is a fluoro group, a chloro group, a bromo group, or an odo group. And is preferably a fluoro group, a chloro group or a bromo group, more preferably a fluoro group or a chloro group, and most preferably a fluoro group.
  • —C cycloalkyl) — (C—C alkyl) group is 3 to A cyclic alkyl group having 8 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group; -C cycloalkyl group, more preferably, C -C
  • the C—C cycloalkyl moiety of the “C cycloalkyl) — (C—C alkyl) group” is 3 to 6
  • cyclopropyl group a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • a cycloalkyl group most preferably a cyclopropyl group.
  • a cyclo group or a cyclobutylmethoxy group A cyclo group or a cyclobutylmethoxy group.
  • a C alkoxy group substituted with one phenyl group for example, phenylmetholate
  • oxazolyl group isoxazolyl group, thiazolyl group, isothiazolyl group, 1,2,3-oxadiazolyl group, 1,2,3 thiadiazolyl group, triazolyl group, tetrazolyl group, vinyl group, pyridyl group, pyridazyl group , Pyrimidyl, birazinyl, azepyr, azosinyl, azoninyl, indolyl, benzofural, Unsaturated heterocyclic groups such as benzochel, benzimidazolyl, benzoisoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, and quinazolyl groups Or azetiduryl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazet
  • a hydroxyl group substituted by a C-C cycloalkyl group for example, cyclopropyl
  • the number of the "ferro- (C-C alkyl) group" in R 6 , R 9 and R 12 is one.
  • alkyl group more preferably a benzyl group or a 1-phenylethyl group.
  • the cyclyl moiety is a 5- to 6-membered aromatic heterocyclic group containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, for example, a furyl group, a phenyl group, a pyrrolyl group.
  • the "5- to 6-membered aromatic heterocyclyl group" in Y in the general formula (I) is a 5- to 6-membered aromatic heterocyclyl group containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • 6-membered aromatic heterocyclic group for example, a furyl group, a chayl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, an oxdiazolyl group, and a thiadiazolyl group , A tetrazolyl group, a bilanyl group, a pyridyl group, a pyridazyl group, a pyrimidyl group, or a birazinyl group, preferably a phenyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, or It is a pyridyl group, more preferably a chloro group or a pyridyl group, and
  • hydroxy (C-C alkyl) group for R 7 in the general formula (I) is one hydroxyl group
  • the above c-c alkyl group substituted with, for example, hydroxymethyl group, hydroxy
  • a hydroxy (c-c alkyl) group most preferably a hydroxymethyl group or 1
  • the "5- to 6-membered aromatic heterocyclyl group" for R 7 in the general formula (I) is a 5- to 6-membered aromatic heterocyclyl group containing 2 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur nuclear atom.
  • 6-membered aromatic heterocyclic group for example, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group, oxadiazolyl group, thiadiazolyl group, pyridazinyl group, pyrimidinyl group, or pyrazyl group It is preferably an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, an oxdiazolyl group, or a thiadiazolyl group, and more preferably an imidazolyl group or an oxazolyl group. , A thiazolyl group, or a triazolyl group. Preferably a Toriazoriru group.
  • C alkyl group for example, furylmethyl group, chenylmethyl group, pyrrolylmethyl group,
  • Aromatic heterocyclyl (c—C alkyl) group (the heterocyclyl group is a phenyl group,
  • cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group 1-cyclopropylethyl group, 2-cyclopropylethyl group, 2-cyclobutylethyl group 2-cyclopentylethyl group, 2-cyclohexylethyl group, 2-cycloheptylethyl group, 3-cyclopropyl-1-propyl group, 2-cyclopropyl-1-propyl group, 2-cyclopropyl-2-propyl group, 3-cyclobutyl-1-propyl group, 3-cyclopentyl-1-propyl group, 3-cyclohexyl-1-propyl group, 4-cyclopropyl-1-butyl group, 4-cyclopropyl-2-butyl group, 3-cyclopropyl-2-methyl-1-propyl group, 3 Cyclopropyl pill—2-methyl-2-propyl group,
  • Alkyl most preferably a cyclopropylmethyl group.
  • the “(C 1 -Ccycloalkyl ) (C 1 -C alkyl) group” in R 1Q of the general formula (I) includes one
  • a C C alkyl group substituted with the above C C cycloalkyl group for example,
  • the rocyclyl group is a 5- to 7-membered heterocyclyl group containing 1 to 2 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), and more preferably 5 to 6 Membered aromatic heterocyclyl (C 1 -C alkyl) group (the heterocyclyl group
  • Dazolyl pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrrolidyl, piperidinyl, pyriduryl, morpholinyl, or thiomorpholinyl).
  • alkenyl group having a bond and 2 to 7 carbon atoms for example, a vinyl group, a 2-propyl group, a 2-butenyl group, a 1,3-butadiene-1-yl group, a 2-methyl-2-propyl group; Group, 2-pentenyl group, 2-methyl-2-butenyl group, 2-hexyl group, or 2-pentynyl group, preferably a CC alkenyl group, more preferably
  • Is a C-C alkyl group most preferably a butyl group, a 2-probeyl group or
  • the “C—C-alkyl group” for R 12 and R 16 in the general formula (I) is a group having 1 to 3 carbon atoms.
  • alkenyl group having a carbon double bond and 3 to 7 carbon atoms for example, 2-propyl group, 2-butenyl group, 1,3-butadiene-1-yl group, 2-methyl-2-propyl
  • it is a C 2 C alkenyloxy group, most preferably, 2-propenyloxy.
  • the “C—C alkamine group” for R 11 in the general formula (I) is one of the above C—C alkyne groups.
  • a 2-amino group substituted with a phenyl group for example, 2-prolamino group, 2-butyramino group, 1,3 butadiene 1-ylamino group, 2-methyl-2-prolamino group, 2-pentene -A lumino group, 2-methyl 2-butyramino group, 2-hexyl-amino group or 2-heptylamino group, preferably a C-C alkenylamino group.
  • the “C—C cycloalkylamino group” for R 11 in the general formula (I) is one of the above C—C cycloalkylamino groups.
  • a cycloalkyl group for example, a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, a cyclohexylamino group, a cycloheptylamino group, or a cyclooctylamino group. And preferably a C—C cycloalkylamino
  • a C-C cycloalkylamino group most preferably a cycloalkylamino group.
  • ⁇ - ⁇ ) is an amino group.
  • R 11 of the general formula (I) may be the same or different
  • Mouth pillamino group N cyclopropyl-N cyclobutylamino group, N cyclopropyl-N cyclopentylamino group, N cyclopropyl-N cyclohexylamino group, N-cyclopropyl-N-cycloheptylamino group, N-cyclo Propyl-N-cyclooctylamino, dicyclobutylamino, N cyclobutyl-N cyclopentylamino, N cyclobutyl-N cyclohexylamino, N cyclobutyl-N cycloheptylamino, N cyclobutyl-N-cyclooctylamino, dicyclopentyl It may be an amino group, a dicyclohexylamino group, a dichloroheptylamino group, or a dicyclooctylamino group, preferably a di (C-Ccycl
  • Group is substituted with one of the above C C alkyl groups and one of the above C C alkenyl groups
  • Tyl-N- (2-probyl) amino group N-methyl-N- (2-buturyl) amino group, N-ethyl-N- (2-probyl) amino group, or N-ethyl-N — It is an (2-butyr) amino group.
  • a ⁇ no group '' is one C C alkyl group and one C C cycloalkyl group
  • a substituted amino group such as N cyclopropyl-N-methylamino group, N cyclobutyl-N-methylamino group, N cyclopentyl-N-methylamino group, N cyclohexyl N-methylamino group, N cycloheptyl-N —Methylamino group, N cyclooctyl-N—Methylamino group, N cyclopropyl Nethylamino group, N cyclobutyl Nethylamino group, N cyclopentyl N ethylamino group, N cyclohexyl N ethylamino group, N cycloheptyl-Nethylamino group, N Crooctyl-N-ethylamino group, N-cyclopropyl N- (1-propyl) amino group, N cyclobutyl-1-N- (1-propyl) amino group, N cyclopent
  • it is an N-methyl-N-cyclopropylamino group, an N-methyl-N-cyclobutylamino group, a N-ethyl-N-cyclopropylamino group, or a N-ethyl-N-cyclobutylamino group.
  • amino group refers to one of the above-mentioned C-C-alkyl groups and one of the above-mentioned C—C cycloalkyl.
  • N- (2-probyl) -N-cyclopropylamino group an N- (2-butenyl) -N-cyclopropylamino group, an N- (2-pentene) -R) -N-cyclopropylamino group, N- (2-hexyl) -N-cyclopropylamino group, N- ( 2 heptyl) N cyclopropylamino group, N— (2-probyl) N cyclobutylamino group, N— (2-butulyl) —N cyclobutylamino group, N— (2-pentyl) —N Cyclobutylamino group, N— (2-hexyl) —N Cyclobutylamino group, N— (2-hepturyl) -N-cyclobutylamino group, N— (2-probel) N cyclopentylamino, N— (2-butulyl) -N cyclopentylamino
  • N cyclopropylamino group, N— (2-probyl) -1-N cyclobutylamino group, N— (2-butenyl) -1-N cyclopropylamino group, or N— (2-butenyl) -1 N is a cyclobutylamino group.
  • a 5- to 7-membered saturated heterocyclic group for example, a pyrrolidyl group, an imidazolidyl group, a birazolidyl group, a piperidyl group, a piperazil group, a morpholinyl group, a thiomorpholyl group, or It may be a perhydroazepinyl group, preferably a 5- to 6-membered saturated heterocyclic group containing 1 to 2 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, Preferred are pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, and most preferred are pyrrolidinyl, piperid
  • the “C—C alkylene group” for X 3 in the general formula (I) has 1 to 2 carbon atoms It is an alkylene group, which can be, for example, a methylene group, an ethylene group or a methylmethylene group, preferably a methylene group or a methylmethylene group, and most preferably a methylene group.
  • -C is a carboxyl group (1-CO 2) substituted with an alkoxy group.
  • Ball group ethoxycarbol group, 1 propoxycarbol group, 2-propoxycarbol group, 1 butoxycarbol group, 2-butoxycarbol group, 2-methyl-1-ol -Methyl group, 2-methyl-2-propoxycarbol group, 1 pentyloxycarbonyl group, 2 pentyloxycarbol group, 3 pentyloxycarbol group, 2-methyl-2-butoxycarbol group, 3 —Methyl-2-butoxycarbol, 1-hexyloxycarbol, 2hexyloxycarbol, 3hexyloxycarbol, 2-methyl-1-pentyloxycarbol, It can be a 3-methyl-1-pentoxycarbol group, a 2-ethyl-1-butoxycarbol group, a 2,2-dimethyl-1-butoxycarbol group, or a 2,3-dimethyl-1-butoxycarbol group.
  • (CC Kokishi) carbo - a group more preferably a methoxide
  • a di- (C C alkyl) amino group-substituted carboyl group (one CO 2)
  • a luponyl group (the alkyl groups are the same or different and the two alkyl groups together with the nitrogen atom of the amino group are selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom; Or a 5- to 7-membered saturated heterocyclyl group containing at least one nitrogen atom), and more preferably a (dimethylamino) carbol group, a (getylamino) carbol group, or a (1 pyrrolidyl) group.
  • R 2 and R 3 are hydrogen atoms, and R 4 is not a hydrogen atom (preferably, R 4 is a fluoro group);
  • R 4 is a hydrogen atom
  • R 1 and R 2 are hydrogen atoms, and R 3 and R 4 are not hydrogen atoms (preferably, and R 4 is a fluoro group, or R 3 is a fluoro group, R 4 Is a black group);
  • R 1 and R 4 are hydrogen atoms, and R 2 and R 3 are not hydrogen atoms (preferably, R 2 and R 3 are fluoro groups); (v) R 3 and R 4 are hydrogen atoms, and R 2 is not a hydrogen atom (preferably, R 2 is a fluoro group or a cyclo group, more preferably, R 2 is a fluoro group ); Or
  • R 1 and R 3 are hydrogen atoms, and R 2 and R 4 are not hydrogen atoms (preferably, R 2 and R 4 are a fluoro group or a cyclo group, more preferably 2 and R 4 are fluoro groups).
  • the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable ester thereof When the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable ester thereof has a basic group, it can be converted to a salt by reacting with an acid, When the compound represented by the formula (I) or a pharmaceutically acceptable ester thereof has an acidic group, it can be converted to a salt by reacting with a base. If these salts are used to treat disease, they must be pharmacologically acceptable.
  • the salt formed with the basic group of the compound represented by the general formula (I) of the present invention is preferably, for example, hydrochloride, hydrobromide, hydroiodide, etc.
  • Inorganic acid salts such as hydrohalides; nitrates; perchlorates; sulfates; or phosphates; may be substituted with fluorine atoms such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate.
  • fluorine atoms such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate.
  • Fumarate succinate; citrate; tartrate; oxalate; or an organic acid salt such as maleate; or glycine, lysine, arginine, ortin, daltamate, It can be an amino acid salt such as aspartate, and more preferably a hydrohalic acid salt.
  • the salt formed with the acidic group of the compound represented by the general formula (I) of the present invention is preferably, for example, an alkali metal salt such as a sodium salt, a potassium salt, a lithium salt; a calcium salt; Magnesi Alkaline earth metal salts such as pumium salts; aluminum salts; iron salts; zinc salts; copper salts; nickel salts; or metal salts such as conorate salts; Or t-octylamine salt, dibenzylamine salt, morpholine salt, dalcosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methyldalcamine salt, guadin salt, diethylamine salt, triethylamine salt, dicyclohexane Xylamine salt, ⁇ , ⁇ '-dibenzylethylenediamine salt, clomouth proforce salt, proforce salt, diethanolamine salt, benzylphenethylamine salt,
  • the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt or ester thereof is allowed to stand in the air or to adsorb moisture during recrystallization to form a hydrate. These hydrates are also included in the present invention.
  • the compounds of the present invention may incorporate other solvents to form solvates, and these solvates are also included in the present invention.
  • optical isomers including diastereomers
  • these isomers and mixtures thereof are represented by a single compound represented by the formula (I). It is described by the formula.
  • the present invention also encompasses the deviation of each of these isomers and their mixtures (including racemates) in any proportions.
  • the present invention includes an ester of the compound represented by the general formula (I).
  • These esters are hydroxyl or carboxyl groups of the compound represented by the general formula (I), and are compounds modified with a protecting group by a method known in the art (for example, “Protective uroups”). in Organic Synthesis, Second EditioJ, Tneodora W. ureene ana Peter GM Wuts, 1991, John Wiley & Sons, Inc.).
  • the nature of the protecting group is not particularly limited. However, if the ester is to be used for the treatment of a disease, it must be pharmacologically acceptable; for example, the protecting group may be present when the compound is administered to a mammalian organism. Metabolic processes (e.g., ) To produce a compound represented by the general formula (I) or a salt thereof. That is, the pharmacologically acceptable ester is a “prodrug” of the compound represented by the general formula (I) of the present invention.
  • the ester of the compound represented by the general formula (I) of the present invention is pharmacologically acceptable is easily determined.
  • an experimental animal such as a rat or a mouse and the body fluid of the animal is examined, and the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is detected.
  • the compound is determined to be a pharmacologically acceptable ester.
  • the compound represented by the general formula (I) of the present invention can be converted into an ester, and the ester can be, for example, a compound obtained by esterifying a hydroxyl group of the compound.
  • the ester residue can be a general protecting group when the esterified compound is used as an intermediate, or when the esterified compound is pharmacologically acceptable. In such a case, it may be a protecting group that can be eliminated in a metabolic process (eg, hydrolysis) in a living body.
  • the above general protecting group is an ester protecting group that can be eliminated under chemical conditions such as hydrolysis, hydrogenolysis, electrolysis, and photolysis.
  • These general protecting groups used in the preparation of the compounds of the general formula (I) in which the hydroxyl groups have been modified may suitably be, for example,
  • Aliphatic alkyl groups such as alkyl carbyl groups, lower alkoxyalkyl carbonyl groups having 1 to 25 carbon atoms or unsaturated alkyl carbyl groups having 1 to 25 carbon atoms;
  • aryl carboyl group halogenoaryl carboyl group, lower alkyl aryl carboyl group, lower alkoxy aryl carboyl group, nitrated aryl carboyl group, lower alkoxy carboaryl carboyl group, Or, a realization An aromatic acyl group such as a bonyl group;
  • Alkoxycarbonyl groups such as 16-xy) carbonyl groups
  • a silyl group such as a (C C alkyl) silyl group
  • an alkoxy group such as a (C alkoxy) methyl group substituted with a halogeno group
  • Triphenylmethyl group which may be substituted with the above substituents, or C—C alkyl, C
  • An aralkyl group such as a benzyl group which may be substituted with a substituent
  • (X) an alkoxycarbonyl group having 3 to 6 carbon atoms
  • an aralkyloxycarbonyl group optionally substituted by one or more selected substituents, an aralkyloxycarbonyl group
  • ester group that can be eliminated in a metabolic process (e.g., hydrolysis) in a living body is eliminated in a metabolic process (e.g., hydrolysis) when administered to a living body of a mammal, and is represented by the general formula (I).
  • Such protecting groups as ester residues may suitably be, for example, the following:
  • Sodoxylenylmethyl group (the substituent is a C—C alkyl group and a C—C alkyl group)
  • a substituted or unsubstituted carboxyalkyl group such as a alkenyl group which may be substituted with a 16 16-alkyl or halogeno group;
  • (X) 1- (Asiloxy) alkoxycarbol group (the said acyloxy group represents the above-mentioned aliphatic acyloxy group or the above-mentioned aromatic acyloxy group).
  • the protecting groups that can be eliminated in metabolic processes in vivo which are used for producing a compound represented by the general formula (I) in which a hydroxyl group is modified, Aliphatic acyl groups (especially C -C alkylcarbonyl groups) and substituted carboxyloxy groups
  • Alkyl groups are preferred.
  • Suitable compounds among the compounds represented by the general formula (I) may be the compounds shown in Tables 1 and 2 below. However, the compound of the present invention is not limited to these compounds.

Abstract

L'invention fournit d'excellents régulateurs de LXR, à savoir des composés représentés par la formule générale (I) : (I) dans laquelle R1, R2, R3 et R4 sont chacun H, un alkyle, un alcoxy, un amino substitué, un halogéno ou similaire ; R5 est H, un alkyle ou un halogéno ; R6 est -COR8 (dans lequel R8 est un alcoxy, un phényloxy, un amino substitué ou similaire) ; -SO2R9 (dans lequel R9 est un alkyle, un phényle, un groupe hétérocyclique ou similaire) ou un alkyle substitué ; R7 est -N(R10)Z1R11, -CSN(R10)R12, -SO2N(R10)R12, -CONR13R14, -SO2R12, -NR15R16, -X3N(R10)Z1R11, -X3N(R10)R12, -X3Z2N(R10)R12, -X3Z2R12 ou similaire (dans lesquels R10 est H, un alkyle ou similaire ; R11 est H, un alkyle, un cycloalkyle, un alcoxy, un amino substitué ou similaire ; R12 est H, un alkyle, un cycloalkyle ou similaire ; R13 et R14 sont chacun un groupe hétérocyclique ou similaire ; R15 est tel que défini pour R10 ; R16 est un alkyle ou un alcényle ; X3 est un alkylène ; Z1 est -CO-, -CS- ou -SO2- ; Z2 est -CO- ou -SO2-) ; X1 est un méthylène ou similaire ; X2 est une liaison simple ou similaire ; et Y est un phényle, un groupe hétérocyclique ou similaire.
PCT/JP2005/009142 2004-05-20 2005-05-19 Composés indoles WO2005113499A1 (fr)

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WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
US9637481B2 (en) 2012-03-02 2017-05-02 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators for the treatment of dermal diseases, disorders and conditions
WO2017123568A2 (fr) 2016-01-11 2017-07-20 The Rockefeller University Méthodes pour le traitement de troubles associés à des cellules suppressives dérivées de cellules myéloïdes
US9981913B2 (en) 2013-09-04 2018-05-29 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators
US10047055B2 (en) 2013-09-04 2018-08-14 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators
US10392413B2 (en) 2015-12-18 2019-08-27 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
US10669296B2 (en) 2014-01-10 2020-06-02 Rgenix, Inc. LXR agonists and uses thereof
US11174220B2 (en) 2019-12-13 2021-11-16 Inspirna, Inc. Metal salts and uses thereof
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Cited By (14)

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Publication number Priority date Publication date Assignee Title
WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
US9637481B2 (en) 2012-03-02 2017-05-02 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators for the treatment of dermal diseases, disorders and conditions
US11034657B2 (en) 2013-09-04 2021-06-15 Ellora Therapeutics, Inc. Liver X receptor (LXR) modulators
US9981913B2 (en) 2013-09-04 2018-05-29 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators
US10047055B2 (en) 2013-09-04 2018-08-14 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators
US10246419B2 (en) 2013-09-04 2019-04-02 Ralexar Therapeutics, Inc. Liver X receptor (LXR) modulators
US10669296B2 (en) 2014-01-10 2020-06-02 Rgenix, Inc. LXR agonists and uses thereof
US10392413B2 (en) 2015-12-18 2019-08-27 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
US10968246B2 (en) 2015-12-18 2021-04-06 Ardelyx, Inc. Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists
WO2017123568A2 (fr) 2016-01-11 2017-07-20 The Rockefeller University Méthodes pour le traitement de troubles associés à des cellules suppressives dérivées de cellules myéloïdes
US11214536B2 (en) 2017-11-21 2022-01-04 Inspirna, Inc. Polymorphs and uses thereof
US11174220B2 (en) 2019-12-13 2021-11-16 Inspirna, Inc. Metal salts and uses thereof
US11459292B2 (en) 2019-12-13 2022-10-04 Inspirna, Inc. Metal salts and uses thereof
US11878956B2 (en) 2019-12-13 2024-01-23 Inspirna, Inc. Metal salts and uses thereof

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