JP2007284367A - LXR agonist - Google Patents

Abstract

〔式中、ＸはCH₂又は酸素原子を示し；Ｙは-C(=NOH)-R¹、-CO-R¹、-COO-R¹、-NHCO-R¹、又はアリールアミノ基を示し；R¹は水素原子又はC_1-6アルキル基を示し；ｎは１又は２の整数を示す〕で表される化合物を含むＬＸＲアゴニスト。PROBLEM TO BE SOLVED: To provide a novel LXR agonist, and a medicament for preventing and / or treating atherosclerosis, arteriosclerosis and the like containing the LXR agonist as an active ingredient.
The following general formula (1):

[In the formula, X represents CH ₂ or an oxygen atom; Y represents —C (═NOH) —R ¹ , —CO—R ¹ , —COO—R ¹ , —NHCO—R ¹ , or an arylamino group. R ¹ represents a hydrogen atom or a C _1-6 alkyl group; n represents an integer of 1 or 2, and an LXR agonist comprising the compound represented by:

Description

  The present invention relates to a novel LXR agonist having a naphthoquinone derivative as an active ingredient. The medicament containing the LXR agonist of the present invention can be used as a medicament for the prevention and / or treatment of, for example, atherosclerosis, arteriosclerosis, and hypercholesterolemia.

  Liver X receptor (LXR) has been cloned as an orphan receptor whose ligand and function are both unknown, and from subsequent studies, some oxysterols including 22-R-hydroxycholesterol may act as ligands. It is a reported nuclear receptor (Non-patent document 1, Non-patent document 2, and Non-patent document 3). LXR forms a heterodimer with RXR, the same nuclear receptor, and regulates the transcription of the target gene in a ligand-dependent manner. In mammals, there are two types of LXR genes (α and β), but their expression distribution varies greatly between the two genes. LXRα is specific to tissues involved in cholesterol metabolism such as liver, small intestine, and adipose tissue. Whereas LXRβ is expressed universally, it is expressed in almost all examined tissues (Non-patent Documents 4 and 5).

  When a high cholesterol diet is given to LXR-deficient mice, it has been reported that symptoms such as fatty liver, increased LDL cholesterol concentration in blood, and decreased HDL cholesterol concentration (Non-Patent Document 6 and Non-Patent Document 7) have been reported. Is strongly suggested to play an important role in cholesterol metabolism. In addition, by analyzing the symptoms of arteriosclerosis model mice that have normal LXRα and β functions in the liver and small intestine and LXRα and β in macrophages, the activity of LXRα and β in macrophages can be It has been clarified that it has a strong influence on morbidity (Non-patent Document 8).

  Many genes (ABCA1, ABCG1, ApoE, CETP, and LPL) among the genes identified as LXR target genes are genes involved in reverse cholesterol transport (RCT). Thus, LXR agonists increase the expression of these genes and activate the reverse cholesterol transport pathway, thereby increasing cholesterol efflux from the periphery, increasing HDL cholesterol and decreasing the cholesterol content of atherosclerotic lesions It is expected. For example, in a high-fat diet-loaded LDL receptor-deficient mouse administered with an LXR agonist, HDL cholesterol elevation, VLDL and LDL cholesterol reduction, and reduction in the area of arteriosclerotic lesions have been reported (Non-patent Document 9). In addition, involvement in diseases such as hypercholesterolemia and atherosclerosis has been reported (Patent Document 1 and Patent Document 2).

  Specific examples of LXR agonists include benzofuran-5-acetic acid derivatives (Patent Document 5), 2-aminoquinazolin-one derivatives (Patent Document 6), tetrahydroquinoline derivatives (Patent Document 7), and tetrahydrocarbazole derivatives (Patent Document 8). , Isoquinolinone derivatives (Patent Document 9), and naphthalene derivatives (Patent Document 10) are known. Further, in some compounds having an LXR agonistic action, such as GW3965 which is an aromatic amino alcohol derivative (Example 16 described in Patent Document 3) and T0901317 which is a benzenesulfonamide derivative (Example 12 described in Patent Document 4). Its usefulness as a therapeutic agent for cholesterolemia and arteriosclerosis has been reported. However, clinically developed or used LXR agonists do not yet exist, and further provision of new and useful LXR agonists is desired.

On the other hand, naphthoquinone derivatives have been reported to have an effect on proliferative diseases such as cancer (Patent Document 11), but a report on LXR agonistic action, or prevention of atherosclerosis, arteriosclerosis, and hypercholesterolemia and There are no reports on therapeutic effects.
Janowski et al., Nature, 383, pp.728-731, 1996 Lehmann et al., J. Biol. Chem., 272, pp. 3137-3140, 1997 Fu et al., J. Biol. Chem., 276, pp. 38378-38387, 2001 Auboeuf et al., Diabetes, 46, pp. 1319-1327, 1997 Lu et al., J. Biol. Chem., 276, pp. 37735-37738, 2001 Peet et al., Cell, 93, pp.693-704, 1998 Alberti et al., J. Clin. Invest., 107, pp. 565-573, 2001 Tangirala et al., Proc. Natl. Acad. Sci. USA, 99, pp. 11896-11901, 2002 Terasaka et al., FEBS Lett., 536, pp. 6-11, 2003 Levin et al., Arterioscler Thromb. Vasc. Biol., 25, pp. 135-142, 2005 Izvestiya Akademii Nauk, Seriya Khimicheskaya, 6, pp.1086-8, 1994 Sibirskii Khimicheskii Zhurnal, 2, pp.65-72, 1993 Izvestiya Sibirskogo Otdeleniya Akademii Nauk SSSR, Seriya Khimicheskikh Nauk, 3, pp.46-50, 1990 Izvestiya Sibirskogo Otdeleniya Akademii Nauk SSSR, Seriya Khimicheskikh Nauk, 5, pp.136-42, 1982 Special Table 2002-539155 Special Table 2004-509161 International Publication WO2002 / 24632 Brochure International Publication WO2000 / 54759 Brochure International Publication WO2003 / 82192 Brochure International Publication WO2004 / 24161 Pamphlet International Publication WO2004 / 72046 Pamphlet US Patent Publication 2005/215577 International Publication WO2004 / 58717 Pamphlet International Publication WO2005 / 23188 Pamphlet International Publication WO2000 / 77609 Brochure US Patent Publication No. 2003/232801 International Publication WO2002 / 077609 Brochure

An object of the present invention is to provide a novel LXR agonist.
Another subject of the present invention is a medicament comprising the above LXR agonist as an active ingredient, which is useful for the prevention and / or treatment of atherosclerosis, arteriosclerosis, hypercholesterolemia and the like. To provide medicine.

  As a result of intensive studies to solve the above problems, the present inventors have found that the naphthoquinone derivative represented by the following general formula (1) has an excellent LXR agonistic action, and completed the present invention. It came to do.

〔式中、ＸはCH₂又は酸素原子を示し；Ｙは-C(=NOH)-R¹、-CO-R¹、-COO-R¹、-NHCO-R¹、又はアリールアミノ基を示し；R¹は水素原子又はC_1-6アルキル基を示し；ｎは１又は２の整数を示す〕で表される化合物及びその塩、並びにそれらの水和物及びそれらの溶媒和物からなる群から選ばれる物質を含むＬＸＲアゴニストが提供される。 That is, according to the present invention, the following general formula (1):

[In the formula, X represents CH ₂ or an oxygen atom; Y represents —C (═NOH) —R ¹ , —CO—R ¹ , —COO—R ¹ , —NHCO—R ¹ , or an arylamino group. R ¹ represents a hydrogen atom or a C _1-6 alkyl group; n represents an integer of 1 or 2, and a salt thereof, and a group consisting of hydrates and solvates thereof; An LXR agonist comprising a substance selected from is provided.

  From another aspect, the present invention provides a medicament comprising the above-mentioned LXR agonist as an active ingredient. The medicament of the present invention is useful as a medicament for the treatment or prevention of diseases caused by abnormal cholesterol metabolism in mammals including humans, such as atherosclerosis, arteriosclerosis, or hypercholesterolemia. is there. Preferably, the medicament of the present invention is provided in the form of a pharmaceutical composition comprising the above active ingredient and one or more pharmaceutical additives.

  From still another aspect, according to the present invention, the compound represented by the above general formula (1) and the salt thereof, and the hydrate and the solvate thereof for the production of the above LXR agonist or the above medicament are provided. A method for the prevention and / or treatment of atherosclerosis, arteriosclerosis, or hypercholesterolemia, comprising the use of a substance selected from the group consisting of: Alternatively, a method is provided comprising administering a therapeutically effective amount to a mammal, including a human.

Further, according to the present invention, in the above formula (1),
A compound or a salt thereof, wherein X is an oxygen atom, Y is —C (═NOH) —R ¹ , R ¹ is a C _1-6 alkyl group (preferably a methyl group), and n is 2. A hydrate or a solvate thereof; and a compound or a salt thereof in which X is CH ₂ , Y is an arylamino group (preferably a phenylamino group), and n is 2, or a hydration thereof Or a solvate thereof.

  The LXR agonist provided by the present invention is useful as an active ingredient of a medicament for the prevention and / or treatment of diseases such as atherosclerosis, arteriosclerosis, or hypercholesterolemia.

In the general formula (1), X represents CH ₂ or an oxygen atom, but X is preferably CH ₂ .
In the general formula (1), Y 1 represents —C (═NOH) —R ¹ , —CO—R ¹ , —COO—R ¹ , —NHCO—R ¹ , or an arylamino group, and R ¹ represents a hydrogen atom or C represents a _1-6 alkyl group. R ¹ is preferably a C _1-6 alkyl group.
As the C _1-6 alkyl group R ¹ represents a linear, branched, cyclic, or may be any of C _1-6 alkyl group consisting of a combination thereof, but linear or branched A branched C _1-6 alkyl group is preferred. Examples thereof include a methyl group, an ethmethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, or a hexyl group. As the C _1-6 alkyl group represented by R ¹ , a methyl group is particularly preferable.

Examples of the arylamino group include an amino group monosubstituted by a monocyclic or condensed polycyclic aromatic group such as a phenylamino group and a naphthylamino group, and a phenylamino group is preferred.
Y is preferably —C (═NOH) —R ¹ , —CO—R ¹ , —NHCO—R ¹ , or an arylamino group, and Y is more preferably —C (═NOH) —CH ₃ , —CO —CH ₃ , an acetylamino group, or an arylamino group.
In general formula (1), n represents an integer of 1 or 2. When n is 1, the ring containing X forms a 5-membered ring, and when n is 2, the ring containing X forms a 6-membered ring.
A combination in which X is CH ₂ , Y is —C (═NOH) —R ¹ , —CO—R ¹ , or —NHCO—R ¹ , and n is an integer of 1 or 2 is preferable. In this combination, R ¹ is more preferably a C _1-6 alkyl group.

  Among the compounds represented by the general formula (1), preferable examples include 2-[[4- [1- (hydroxyimino) ethyl] phenyl] amino] -3-piperidino-1,4-benzoquinone; [[4- [1- (hydroxyimino) ethyl] phenyl] amino] -3-morpholino-1,4-benzoquinone; 2-[[4- (ethoxycarbonyl) phenyl] amino] -3-piperidino-1,4 2-benzoquinone; 2-[(4-acetylphenyl) amino] -3-piperidino-1,4-benzoquinone; 2-[(4-carboxyphenyl) amino] -3-piperidino-1,4-benzoquinone; 2- [ [4- (Phenylamino) phenyl] amino] -3-morpholino-1,4-benzoquinone; 2-[(4-acetylphenyl) amino] -3-pyrrolidino-1,4-benzoquinone; 2-[[4- [ -(Hydroxyimino) ethyl] phenyl] amino] -3-pyrrolidino-1,4-benzoquinone; 2-[[4- (acetylamino) phenyl] amino] -3-piperidino-1,4-benzoquinone; or 2- And [[4- (phenylamino) phenyl] amino] -3-piperidino-1,4-benzoquinone.

  Of these, 2-[[4- [1- (hydroxyimino) ethyl] phenyl] amino] -3-piperidino-1,4-benzoquinone; 2-[(4-acetylphenyl) amino] -3-piperidino- 1,4-benzoquinone; 2-[(4-acetylphenyl) amino] -3-pyrrolidino-1,4-benzoquinone; 2-[[4- [1- (hydroxyimino) ethyl] phenyl] amino] -3- Pyrrolidino-1,4-benzoquinone; 2-[[4- (acetylamino) phenyl] amino] -3-piperidino-1,4-benzoquinone; or 2-[[4- (phenylamino) phenyl] amino] -3 -Piperidino-1,4-benzoquinone is more preferred. But the compound contained in the LXR agonist of this invention is not limited to the specific compound illustrated above.

  The compound represented by the general formula (1) may form a salt. Although the kind of salt is not specifically limited, For example, an acid addition salt or a base addition salt etc. are mentioned, The physiologically acceptable acid addition salt or base addition salt is preferable. Examples of the salt include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; benzoate, methanesulfonate, ethanesulfonate Acid addition salts of organic acids such as benzene sulfonate, p-toluene sulfonate, oxalate, maleate, fumarate, tartrate, citrate or acetate; sodium salt, potassium salt, Examples include, but are not limited to, metal salts such as calcium salts; ammonium salts; organic amine salts such as methylamine salts, ethylamine salts, and triethylamine salts; and amino acid salts such as glycine salts.

  The compound represented by the general formula (1) or a salt thereof may exist as a hydrate or a solvate. Any hydrate or any solvate of the compound represented by the general formula (1) or a salt thereof can be used as the LXR ligand of the present invention. The type of solvent that forms the solvate is not particularly limited, but a physiologically acceptable solvent such as ethanol, acetone, ethyl acetate, tetrahydrofuran, or glycerin is preferable.

  The compound represented by the general formula (1) can be produced, for example, according to the methods described in Patent Document 12, Patent Document 13, Non-Patent Documents 11 to 14, and the like, or similar methods thereto. The obtained compound can be purified using a conventional purification means such as a recrystallization method or column chromatography, if necessary. If necessary, it can be converted into a desired acid addition salt or base addition salt according to a conventional method. Furthermore, some of the compounds represented by the general formula (1) are commercially available, and can be purchased from, for example, ChemBridge Corporation.

  The fact that the compound selected from the group consisting of the compound represented by the general formula (1) and salts thereof, and hydrates and solvates thereof has an LXR agonistic action is determined by the method shown in Test Examples in Examples. A person skilled in the art can easily confirm. As used herein, the term “LXR agonist” has the property of binding as a ligand to either or both of LXRα and LXRβ, and a target gene of LXR (for example, ABCA1, ABCG1, ApoE, CETP, and LPL). A substance having an action of increasing the expression level of at least one of the genes, activating the reverse cholesterol transport pathway, thereby increasing cholesterol efflux from the periphery, increasing HDL cholesterol and increasing arteriosclerosis Has the effect of reducing the cholesterol content of the lesion. Therefore, the LXR agonist of the present invention is an active ingredient of a medicament for treating or preventing diseases caused by abnormal cholesterol metabolism in mammals including humans, such as atherosclerosis, arteriosclerosis, or hypercholesterolemia. Useful as.

  As the medicament of the present invention, the above-mentioned LXR agonist may be used as it is. However, the medicament of the present invention is preferably a compound represented by the general formula (1) and a salt thereof, and a hydrate and a solvent thereof. It can be prepared as a pharmaceutical composition comprising one or more pharmaceutical additives together with a substance selected from the group consisting of Japanese products. The administration route of the medicament of the present invention is not particularly limited, and can be administered orally or parenterally, and can be appropriately selected depending on the purpose of treatment. For example, it may be in any form such as a solid preparation for oral administration, a liquid preparation for oral administration, an injection, a suppository, an ointment, an inhalant, an eye drop, a nasal drop, or a transdermal absorption agent. . Pharmaceutical compositions suitable for these dosage forms can be produced by known methods.

  When preparing a solid preparation for oral administration, an excipient is added to the above-mentioned substance, which is an active ingredient, and a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, or a corrigent as necessary. After adding one or more additives for pharmaceutical preparations, etc., it may be prepared as a tablet, coated tablet, granule, powder, capsule or the like by a conventional method. As an additive for formulation, what is generally used in this industry can be used, for example. More specifically, examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, or polyvinylpyrrolidone. It is done. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, or lactose. Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol. Examples of the corrigent include sucrose, orange peel, citric acid, tartaric acid and the like.

  When preparing a liquid preparation for oral administration, it is usual to add one or more additives for preparation such as a corrigent, a buffer, a stabilizer, or a corrigent to the above-mentioned substances which are active ingredients. What is necessary is just to prepare as an internal use liquid agent, a syrup agent, or an elixir by a method. As the corrigent, for example, those listed above can be used privately, and as the buffer, for example, sodium citrate can be used. Examples of the stabilizer include tragacanth, gum arabic, or gelatin.

  When preparing injections, add one or more additives for formulation such as pH adjusters, buffers, stabilizers, tonicity agents, or local anesthetics to the above substances that are active ingredients However, subcutaneous, intramuscular and intravenous injections can be produced by conventional methods. Examples of the pH adjusting agent and buffer include sodium citrate, sodium acetate, or sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, or thiolactic acid. Examples of the local anesthetic include procaine hydrochloride or lidocaine hydrochloride. Examples of the isotonic agent include sodium chloride and glucose.

  When preparing a suppository, a known suppository carrier, for example, polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, or the like is added to the above-mentioned substance, which is an active ingredient, and, if necessary, Tween (registered trademark) or the like. The surfactant can be added by a conventional method.

When preparing an ointment, one or more additives for pharmaceutical preparations such as bases, stabilizers, wetting agents, preservatives and the like that are usually used for the above-mentioned substances that are active ingredients are used as necessary. It may be added and mixed to prepare a formulation by a conventional method. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, and paraffin. Examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, and propyl p-hydroxybenzoate.
The form of the pharmaceutical composition of the present invention is not limited to the specific form described above. For example, a pharmaceutical composition in the form of an inhalant, eye drops, or nasal drops is prepared by a conventional method. You can also.

  The dosage of the pharmaceutical agent of the present invention is not particularly limited, and can be appropriately selected according to conditions such as the age and weight of the patient, the symptoms of the disease to be prevented and / or treated, the dosage form, and the number of administrations. Usually, about 1 to 1000 mg per day may be administered as the mass of the compound represented by the general formula (1) which is an active ingredient for adults. It is preferable to administer the above dose in one or several divided doses.

Among the compounds represented by the general formula (1), for example, X is an oxygen atom, Y is —C (═NOH) —R ¹ , and R ¹ is a C _1-6 alkyl group (preferably a methyl group). And a compound in which n is 2; and a compound in which X is CH ₂ , Y is an arylamino group (preferably a phenylamino group), and n is 2 is a novel compound. More specifically, 2-[[4- [1- (hydroxyimino) ethyl] phenyl] amino] -3-morpholino-1,4-benzoquinone or 2-[[4- (phenylamino) phenyl] amino] Examples thereof include compounds such as -3-piperidino-1,4-benzoquinone. These novel compounds can be produced according to the methods described above, and can also be produced according to the methods specifically described in the examples of the present specification. In addition to salts of these compounds, hydrates or solvates of these compounds or salts thereof are also encompassed within the scope of the present invention. Further, it goes without saying that these substances are included in the scope of the present invention in addition to their use as LXR agonists.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples.
Example 1: Preparation of 2-[[4- [1- (hydroxyimino) ethyl] phenyl] amino] -3-morpholino-1,4-benzoquinone 2-[[4- (Methylcarbonyl) phenyl] amino] -3 -Morpholino-1,4-benzoquinone (Sibirskii Khimicheskii Zhurnal, 2, pp.65-72, 1993) (50 mg, 0.133 mmol), hydroxylamine hydrochloride (19 mg, 0.266 mmol) and sodium acetate (37 mg, 0.452 mmol) in ethanol (4 mL) -water (0.4 mL) was heated to reflux for 9 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (developing solvent hexane: acetone = 2: 1) to give 2-[[4- [1- (hydroxyimino) ethyl] phenyl. ] Amino] -3-morpholino-1,4-benzoquinone 33 mg (yield 63%) was obtained as a dark green solid.
Melting point: 203-204 ° C
¹ H-NMR (CDCl ₃ ) δ: 2.29 (3H, s), 3.23 (4H, t, J = 5.5 Hz), 3.40 (4H, t, J = 5.5 Hz), 6.87 (2H, J = 8.5 Hz) , 7.24 (1H, s), 7.58 (2H, J = 8.5 Hz), 7.63 (1H, dt, J = 1,5, 7.6 Hz), 7.68 (1H, dt, J = 1.5, 7.6 Hz), 8.03 ( 2H, dd, J = 1.5, 7.6 Hz) 8.54 (1H, brs).

Example 2: Preparation of 2-[[4- (phenylamino) phenyl] amino] -3-piperidino-1,4-benzoquinone To piperidine (15 mL) 2-chloro-3-[[4- (phenylamino) phenyl Amino] -1,4-benzoquinone (Japanese Patent Laid-Open No. 8-113555) (1.87 g, 5.00 mmol) was added and heated at 100 ° C. overnight. The reaction solution was purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 5: 1), and 2-[[4- (phenylamino) phenyl] amino] -3-piperidino-1,4-benzoquinone 910 mg (43% yield) was obtained as a reddish brown solid.
Melting point: 162-164 ° C
¹ H-NMR (CDCl ₃ ) δ: 1.21-1.51 (6H, m), 3.00-3.23 (4H, m), 5.65 (1H, brs), 6.80-7.28 (10H, m), 7.59 (1H, dt, J = 1,6, 7.6 Hz), 7.64 (1H, dt, J = 1.6, 7.6 Hz), 8.96-8.03 (2H, m).

Test Example 1: Transcriptional promotion assay <Plasmid construction>
Expression constructs were prepared by inserting the ligand binding domains (LBD) of human LXRα and LXRβ cDNAs adjacent to the yeast GAL4 transcription factor DNA binding domain (DBD) of the mammalian expression vector pBIND (Promega), respectively, and pBIND-LXRα / GAL4 and pBIND-LXRβ / GAL4 were prepared. The GAL4 responsive reporter construct, pG5luc, is a known vector available from Promega and contains 5 copies of the GAL4 response element and luciferase reporter gene located adjacent to the promoter.

<Assay>
LOXRα / GAL4 or LXRβ / GAL4 hybrids and GAL4-responsive reporter vector stably expressing CHOK-1 cells in 10% inactivated fetal bovine serum, 100 units / ml penicillin G at 37 ° C. in a humidified atmosphere of 5% CO ₂ And 20,000 cells / well in a 96 well plate containing HAM-F12 medium containing 100 μg / ml streptomycin sulfate. After 24 hours, medium in which the test compound was dissolved over the test concentration range was added and incubated with the cells for 24 hours. The effect of the test compound on the activation of luciferase transcription via LBD of LXR was measured by measuring luciferase activity using a Bright-Glo luciferase assay substrate (Promega). The result of luciferase activity was shown as the induction ratio relative to the DMSO control group. T0901317 and GW3965 (described in Example 12 of Patent Document 4 and Example 16 of Patent Document 3) were simultaneously evaluated as comparative compounds. The results are shown in Table 1. In the table, Me represents a methyl group, and Et represents an ethyl group.

  All of the naphthoquinone derivatives of the present invention had excellent LXR agonist activity. Compounds 1, 4, 8, and 9 had stronger LXR agonist activity than controls T0901317 and GW3965, and compounds 7 and 10 had stronger LXR agonist activity than control GW3965.

Formulation Example 1 (Capsule)
30 mg of the compound of Example 1
Microcrystalline cellulose 30mg
Lactose 57mg
Magnesium stearate 3mg
Total amount 120mg
The above ingredients were mixed by a conventional method and then filled into gelatin capsules to obtain capsules.

Formulation Example 2 (tablet)
30 mg of the compound of Example 1
Starch 44mg
Starch (for paste) 5.6mg
Magnesium stearate 0.4mg
Carboxymethylcellulose calcium 20mg
Total amount 100mg
The above components were mixed by a conventional method to obtain a tablet.

Formulation Example 3 (Injection)
Injected distilled water was added to a solution obtained by dissolving the compound of Example 1 (100 mg) and sodium chloride (900 mg) in about 80 mL of distilled water for injection to make a total volume of 100 mL. This solution was sterile filtered, dispensed into 10 ampoules, and sealed to obtain a sterile injection.

Claims (12)

The following general formula (1):

[In the formula, X represents CH ₂ or an oxygen atom; Y represents —C (═NOH) —R ¹ , —CO—R ¹ , —COO—R ¹ , —NHCO—R ¹ , or an arylamino group. R ¹ represents a hydrogen atom or a C _1-6 alkyl group; n represents an integer of 1 or 2, and a salt thereof, and a group consisting of hydrates and solvates thereof; LXR agonist containing the substance chosen from. Y is -C (= NOH) -R ¹ , -CO-R ¹ , -COO-R ¹ , -NHCO-R ¹ , or a phenylamino group, and R ¹ is a C _1-6 alkyl group. 2. The LXR agonist according to 1. X is CH ₂ , Y is —C (═NOH) —R ¹ , —CO—R ¹ , or —NHCO—R ¹ , n is an integer of 1 or 2, and R ¹ is C _1— The LXR agonist according to claim 1, which is a ₆ alkyl group. The LXR agonist according to claim 2 or 3, wherein R ¹ is a methyl group. A medicament comprising the LXR agonist according to any one of claims 1 to 4 as an active ingredient. The medicament according to claim 5, which is used for prevention and / or treatment of diseases caused by abnormal cholesterol metabolism in mammals including humans. The medicine according to claim 6, wherein the disease caused by abnormal cholesterol metabolism is atherosclerosis, arteriosclerosis, or hypercholesterolemia. The medicament according to any one of claims 5 to 7, which is in the form of a pharmaceutical composition comprising the LXR according to any one of claims 1 to 4 and one or more pharmaceutical additives. The formula (1) according to claim 1, wherein X is an oxygen atom, Y is -C (= NOH) -R ¹ , and R ¹ is a C _1-6 alkyl group (preferably a methyl group). , A compound wherein n is 2, or a salt thereof, or a hydrate or a solvate thereof. 2-[[4- [1- (hydroxyimino) ethyl] phenyl] amino] -3-morpholino-1,4-benzoquinone or a salt thereof, or a hydrate or a solvate thereof. A compound or a salt thereof, or a hydrate thereof according to claim 1, wherein X is CH ₂ , Y is an arylamino group (preferably a phenylamino group), and n is 2. Or a solvate thereof. 2-[[4- (Phenylamino) phenyl] amino] -3-piperidino-1,4-benzoquinone or a salt thereof, or a hydrate or a solvate thereof.