Novel compound, method for producing same, and prophylactic or therapeutic agent for dyslipidemia or dyslipidemia-related disease

Abstract

Provided are a compound represented by a Formula (1) or a salt thereof, and a method for producing the compound represented by the Formula (1). In the formula, two R1 symbols each independently represent a hydrogen atom or an alkyl group. Two instances of the letter n each independently represent an integer of 0 or more. R3, R4, and R5 symbols each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, or the like. In addition, the present invention provides a prophylactic or therapeutic agent for dyslipidemia or dyslipidemia-related diseases, the agent including, as an active ingredient, a compound represented by Formula (1) or a salt thereof.

Description

Novel compounds and methods for producing the same, as preventive or therapeutic agents for dyslipidemia or dyslipidemia-related diseases.

[0001] The present invention relates to a novel compound, a method for producing the same, and an agent for the prevention or treatment of dyslipidemia or dyslipidemia-related diseases containing the novel compound as an active ingredient.

[0002] Dyslipidemia is a condition in which the amount of at least one of the following in the blood—LDL (low-density lipoprotein) cholesterol, HDL (high-density lipoprotein) cholesterol, and triglycerides (neutral fats)—exceeds the normal range. Because dyslipidemia can cause arteriosclerosis, heart disease (angina pectoris, myocardial infarction, etc.), cerebrovascular disease (cerebral hemorrhage, cerebral infarction, etc.), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), etc., its prevention or treatment is important.

[0003] Currently, statin drugs, which specifically inhibit hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are primarily used to treat dyslipidemia. When statin drugs are administered, HMG-CoA reductase is inhibited, resulting in a decrease in cholesterol levels in hepatocytes. This decrease in hepatocyte cholesterol levels leads to increased expression of LDL receptors in hepatocytes, increasing the uptake of LDL cholesterol from the blood into hepatocytes. As a result, blood cholesterol levels can be reduced.

[0004] Special table 2024-506848 publication Special table 2024-507810 publication

[0005] However, long-term use of statin drugs can cause adverse events such as muscle damage and liver damage, sometimes necessitating discontinuation or reduction of the dosage. This is called "statin intolerance," and it affects approximately 10% of patients. Therefore, development is underway to create drugs that can be used by patients with statin intolerance (see, for example, Patent Documents 1 and 2).

[0006] The present invention aims to provide a novel compound that can be used for the prevention or treatment of dyslipidemia or dyslipidemia-related diseases, a method for producing the same, and a preventive or therapeutic agent for dyslipidemia or dyslipidemia-related diseases containing the novel compound as an active ingredient.

[0007] Specific means for solving the above problems include the following embodiments. <1> A compound represented by the following formula (1) or a salt thereof. [In the formula, two Rs ２ , ｎ , , ,

[0010] , , １ , ２ ,

[0009] ,

[0008] each independently represents a hydrogen atom or an alkyl group. Two Rs ２ each independently represents a hydrogen atom or an alkyl group. When Rs １ and Rs ２ bonded to the same nitrogen atom are both alkyl groups, Rs １ and Rs ２ may form a monocyclic heterocyclic ring together with the nitrogen atom to which they are bonded, or together with at least one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the nitrogen atom to which they are bonded. Two ns each independently represent an integer of 0 or more. Rs ３ , Rs ４ , and Rs ５ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Two or more of the groups Rs ３ , Rs ４ , and Rs ５ may combine together to form a monocyclic or polycyclic aliphatic ring, a monocyclic or polycyclic aromatic ring, or a monocyclic or polycyclic heteroaromatic ring.

[0008] <2> The compound or a salt thereof according to <1>, wherein two ns in the formula (1) are the same.

[0009] <3> The compound or a salt thereof according to <1>, wherein two groups represented by -(CH ２ ) ｎ -NR １ R ２ in the formula (1) are the same.

[0010] <6> In the formula (1), n represents an integer of 1 to 4, and -NR１ R ２ The compound or salt thereof described in <3>, wherein the group represented by is a dimethylamino group, a diethylamino group, a 1-pyrrolidinyl group, a 1-piperidinyl group, a 1-morpholinyl group, or a 1-azepanil group.

[0011] <5> In formula (1) above, R ３ , R ４ , and R ５ However, each independently represents a hydrogen atom, an alkyl group, or an aryl group, and optionally, R ３ , R ４ , and R ５ A compound or salt thereof according to any one of items <1> to <4>, wherein two or more of the groups combine to form a monocyclic or polycyclic aliphatic ring or a monocyclic or polycyclic aromatic ring.

[0012] <6> In formula (1) above, R ３ , R ４ , and R ５ However, a compound or salt thereof described in any one of items <1> to <5> that satisfies any of the following conditions (a) to (d). (a) R ３ and R ４ However, each independently represents an alkyl group, R ５ (b) R ３ and R ４ However, each independently shows an aryl group, R ５ However, it shows a hydrogen atom. (c) R ３ However, R represents a hydrogen atom, an alkyl group, or an aryl group. ４ and R ５ However, it shows a hydrogen atom. (d) R ３ and R ４ These come together to form a monocyclic or polycyclic aliphatic ring or a monocyclic or polycyclic aromatic ring, R ５ This indicates a hydrogen atom.

[0013] <7> A method for producing a compound represented by the following formula (1), comprising the steps of: reacting a compound represented by the following formula (2) with a compound represented by the following formula (3) in the presence of a Lewis acid catalyst to obtain a compound represented by the following formula (4); and reacting a compound represented by the following formula (4) with a compound represented by the following formula (5) to obtain a compound represented by the following formula (1). [In the formula, two R １ Each of these independently represents a hydrogen atom or an alkyl group. ２ Each independently represents a hydrogen atom or an alkyl group. R bonded to the same nitrogen atom １ and R ２ If both are alkyl groups, １ and R ２ These atoms may form a monocyclic heterocycle together with the nitrogen atom to which they are bonded, or together with at least one atom selected from the group consisting of oxygen, sulfur, and nitrogen atoms, in addition to the nitrogen atom to which they are bonded. The two n's independently represent non-negative integers. R ３ , R ４ , and R ５ Each of these independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. ３ , R ４ , and R ５ Two or more of these groups may come together to form a monocyclic or polycyclic aliphatic ring, a monocyclic or polycyclic aromatic ring, or a monocyclic or polycyclic heteroaromatic ring. [In the formula, R ３ , R ４ , and R ５ This is equivalent to equation (1) above. [In the formula, X represents a halogen atom, and n is equivalent to that in formula (1) above.] [In the formula, R ３ , R ４ , R ５ , and n are equivalent to those in formula (1) above, and X is equivalent to those in formula (3) above. [In the formula, R １ and R ２This is equivalent to equation (1) above.

[0014] <8> A preventive or therapeutic agent for dyslipidemia or dyslipidemia-related diseases containing any one of the compounds described in <1> to <6> or a salt thereof as an active ingredient.

[0015] According to the present invention, it is possible to provide a novel compound that can be used for the prevention or treatment of dyslipidemia or dyslipidemia-related diseases, a method for producing the same, and a preventive or therapeutic agent for dyslipidemia or dyslipidemia-related diseases containing the novel compound as an active ingredient.

[0016] This figure shows the amount of intracellular cholesterol accumulated in human liver cancer-derived HepG2 cells when treated with 1 μM of a test compound (STA10, STB10, STC10, STD10, STE10, STF10, STG10, or STH10) in the presence of fluorescently labeled cholesterol. This figure shows the amount of intracellular cholesterol accumulated in HepG2 cells when treated with compound STD10 at various concentrations (10 nM, 100 nM, 500 nM, or 1000 nM) in the presence of fluorescently labeled cholesterol. This figure shows the amount of intracellular cholesterol accumulated in HepG2 cells when treated with 1 μM of a test compound (STD10, STD17, STD22, STD23, STD24, STD25, or STD26) in the presence of fluorescently labeled cholesterol. This figure shows the total blood cholesterol concentration (mg / dL) when compound STD10 was administered intraperitoneally to mice at a concentration of 12.5 mg / kg body weight for 3 weeks. This figure shows the total blood cholesterol concentration (mg / dL) when mice were orally administered compound STD10 at a concentration of 50 mg / kg body weight for one week. This figure shows the amount of triglycerides (neutral fats) (mg) in 1 g of liver when mice were orally administered compound STD10 at a concentration of 12.5 mg / kg body weight for three weeks. This figure shows the amount of intracellular cholesterol accumulation when HepG2 cells were treated with 1 μM of a test compound (STD10, STD1, STD2, STD3, STD14, STD16, STD51, STD52, STD53, STD54, or STD55) in the presence of fluorescently labeled cholesterol.

[0017] <Novel Compound or Salt Thereof> The compound according to this embodiment is represented by the following formula (1).

[0018]

[0019] As shown in the examples described later, the present inventors have newly discovered that the compound represented by formula (1) has effects such as lowering blood cholesterol and lowering liver triglycerides.

[0020] In the above equation (1), the two R １ Each independently represents either a hydrogen atom or an alkyl group. Also, the two R ２ Each of these independently represents either a hydrogen atom or an alkyl group.

[0021] R １ or R ２ When the alkyl group is an alkyl group, the number of carbon atoms in the alkyl group is preferably 1 to 30, more preferably 1 to 10, and even more preferably 1 to 5. The alkyl group may be linear or branched, but linear is preferred. Specific examples of alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, and the like.

[0022] R bonded to the same nitrogen atom １ and R ２ If both are alkyl groups, １ and R ２ These atoms may form a monocyclic heterocycle together with the nitrogen atom to which they are bonded, or together with at least one atom selected from the group consisting of oxygen, sulfur, and nitrogen atoms, in addition to the nitrogen atom to which they are bonded. A 5- to 7-membered ring is preferred as the monocyclic heterocycle. Specific examples of monocyclic heterocycles include pyrrolidine rings, piperidine rings, piperazine rings, morpholine rings, thiomorpholine rings, and azepane rings.

[0023] In formula (1) above, the two n's independently represent integers of 0 or greater. n is preferably an integer between 1 and 30, more preferably an integer between 1 and 10, even more preferably an integer between 1 and 4, and particularly preferably 1 or 2.

[0024] In the above formula (1), R３ , R ４ , and R ５ Each of these independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0025] R ３ , R ４ , or R ５ If the alkyl group is an alkyl group, the number of carbon atoms in the alkyl group is preferably 1 to 30, more preferably 1 to 20, and even more preferably 1 to 11. The alkyl group may be linear or branched, but linear is preferred. Specific examples of alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, and the like.

[0026] Examples of substituents that an alkyl group may have include alkoxy groups, aryl groups, heteroaryl groups, non-aromatic heterocyclic groups, acyl groups, acyloxy groups, halogen atoms (fluorine, chlorine, bromine, iodine), hydroxyl groups, carboxyl groups, amino groups, nitro groups, and cyano groups. If an alkyl group has multiple substituents, these substituents may be the same or different.

[0027] R ３ , R ４ , or R ５ When the group is an aryl group, specific examples of aryl groups include monocyclic or polycyclic groups of two to four rings, such as phenyl, naphthyl, tetrahydronaphthyl, anthryl, phenanthryl, pyrenyl, fluorenyl, indenyl, acenaphthenyl, indanyl, and acenaphthenyl groups.

[0028] R ３ , R ４ , or R ５When the group is a heteroaryl group, specific examples of heteroaryl groups include monocyclic nitrogen-containing groups such as pyrrolyl, pyridyl, imidazolyl, pyrazolyl, pyrazinyl, pyridadinyl, pyrimidinyl, triazolyl, and tetrazolyl groups; monocyclic oxygen-containing groups such as furyl groups; monocyclic sulfur-containing groups such as thienyl groups; monocyclic nitrogen- and oxygen-containing groups such as oxazolyl, isoxazolyl, and oxadiazolyl groups; monocyclic nitrogen- and sulfur-containing groups such as thiazolyl, isothiazolyl, and thiadiazolyl groups; indolyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrahydroquinolyl, quinolyl, and tetrahydroiso Examples include bicyclic nitrogen-containing groups such as quinolyl, isoquinolyl, quinolidinyl, synnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthilidinyl, pyrrolopyridyl, imidazopyridyl, pyrazolopyridyl, pyridopyradyl, purinyl, and pteridinyl groups; bicyclic oxygen-containing groups such as benzofuranyl and isobenzofuranyl groups; bicyclic sulfur-containing groups such as benzothienyl groups; bicyclic nitrogen- and oxygen-containing groups such as benzoxazolyl, benzoisoxazolyl, and benzoxadiazolyl groups; and bicyclic nitrogen- and sulfur-containing groups such as benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, and thiazolopyridyl groups.

[0029] Examples of substituents that an aryl group or heteroaryl group may have include alkyl groups, alkoxy groups, aryl groups, heteroaryl groups, non-aromatic heterocyclic groups, acyl groups, acyloxy groups, halogen atoms (fluorine, chlorine, bromine, iodine), hydroxyl groups, carboxyl groups, amino groups, nitro groups, and cyano groups. If an aryl group or heteroaryl group has multiple substituents, these substituents may be the same or different.

[0030] R ３ , R ４ , and R ５ Two or more of these groups may come together to form a monocyclic or polycyclic aliphatic ring, a monocyclic or polycyclic aromatic ring, or a monocyclic or polycyclic heteroaromatic ring.

[0031] Examples of the aliphatic ring include rings having 3 to 20 ring member carbon atoms, preferably 3 to 10 ring member carbon atoms, such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, an adamantane ring, a bicyclo[2.2.1]heptane ring, a bicyclo[2.2.2]octane ring, a bicyclo[3.2.1]octane ring, a tricyclo[2.2.1.0]heptane ring, and the like.

[0032] Examples of the aromatic ring include rings corresponding to the aryl groups described above. Examples of the heteroaromatic ring include rings corresponding to the heteroaryl groups described above.

[0033] The above-described aliphatic ring, aromatic ring, or heteroaromatic ring may have a substituent. Examples of the substituent include an alkyl group, an alkoxy group, an aryl group, a heteroaryl group, a non-aromatic heterocyclic group, an acyl group, an acyloxy group, a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), a hydroxy group, a carboxy group, an amino group, a nitro group, a cyano group, and the like. When the aliphatic ring, aromatic ring, or heteroaromatic ring has a plurality of substituents, the plurality of substituents may be the same or different.

[0034] As the compound represented by the above formula (1), those in which two n are the same are preferable, and those in which the two groups represented by -(CH ２ ) ｎ -NR １ R ２ are the same are more preferable. More preferable compounds include those in which the two groups represented by -(CH ２ ) ｎ -NR １ R ２ are the same, n represents an integer of 1 to 4, and the group represented by -NR １ R ２ [[ID=二十九]]is a dimethylamino group, a diethylamino group, a 1-pyrrolidinyl group, a 1-piperidinyl group, a 1-morpholinyl group, or a 1-azepanyl group. Specific examples of the group represented by -(CH ２ ) ｎ -NR １ R ２ include groups represented by the following formula.

[0035]

[0036] Also, as the compound represented by the above formula (1), R ３ , R ４ , and R ５ each independently represent a hydrogen atom, an alkyl group, or an aryl group, and optionally, two or more of R ３ , R ４ , and R ５ combine to form a monocyclic or polycyclic aliphatic ring or a monocyclic or polycyclic aromatic ring. More preferred compounds are those in which R ３ , R ４ , and R ５ satisfy any of the following (a) to (d). (a) R ３ and R ４ each independently represent an alkyl group, and R ５ represents a hydrogen atom or an alkyl group. (b) R ３ and R ４ each independently represent an aryl group, and R ５ represents a hydrogen atom. (c) R ３ represents a hydrogen atom, an alkyl group, or an aryl group, and R ４ and R ５ represent hydrogen atoms. (d) R ３ and R ４ combine to form a monocyclic or polycyclic aliphatic ring or a monocyclic or polycyclic aromatic ring, and R ５ represents a hydrogen atom. <00,00261> In the above preferred compounds, the alkyl group is preferably an alkyl group having 1 to 11 carbon atoms, more preferably an alkyl group having 1 to 9 carbon atoms. In particular, when R ３ , R ４ , and R ５ are all alkyl groups, an alkyl group having 1 to 6 carbon atoms is preferred, and an alkyl group having 1 to 3 carbon atoms is more preferred. The aryl group is preferably a phenyl group. As the monocyclic or polycyclic aliphatic ring that two or more of R ３ , R ４ , and R ５ can combine to form, a cyclohexane ring and an adamantane ring are preferred. Also, R３ , R ４ , and R ５ Of these, two or more groups can together form a monocyclic or polycyclic aromatic ring, and benzene rings and naphthalene rings are preferred.

[0038] If the compound represented by formula (1) has an acidic or basic functional group, the compound may be in the form of a salt. For example, if the compound represented by formula (1) has an acidic functional group, the compound may be in the form of an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, etc.), an ammonium salt, etc. Also, if the compound represented by formula (1) has a basic functional group, the compound may be in the form of a salt with an inorganic acid such as hydrochloric acid or phosphoric acid, or in the form of a salt with an organic acid such as acetic acid, fumaric acid, or methanesulfonic acid.

[0039] <Method for producing novel compounds> The compound represented by formula (1) above can be produced by a manufacturing method that includes, for example, the step of reacting a compound represented by formula (2) below with a compound represented by formula (3) below in the presence of a Lewis acid catalyst to obtain a compound represented by formula (4) below (hereinafter also referred to as the "first step"); and the step of reacting a compound represented by formula (4) below with a compound represented by formula (5) below to obtain a compound represented by formula (1) below (hereinafter also referred to as the "second step").

[0040] [In the formula, R ３ , R ４ , and R ５ This is equivalent to equation (1) above.

[0041] [In the formula, X represents a halogen atom, and n is equivalent to that in formula (1) above.]

[0042] [In the formula, R ３ , R ４ , R ５ , and n are equivalent to those in equation (1) above, and X is equivalent to those in equation (3) above.

[0043] [In the formula, R １ and R２ This is equivalent to equation (1) above.

[0044] First, in the first step, the compound represented by formula (2) and the compound represented by formula (3) are reacted in the presence of a Lewis acid catalyst to obtain the compound represented by formula (4).

[0045] As a Lewis acid catalyst, AlCl ３ AlBr ３ FeCl ３ , FeBr ３ Metal halides such as Al(OTf) ３ Examples include metal triflates such as the like.

[0046] The amounts used for the compound represented by formula (2), the compound represented by formula (3), and the Lewis acid catalyst are not particularly limited. For example, for every 1 equivalent of the compound represented by formula (2), 1 to 100 equivalents of the compound represented by formula (3) and 0.1 to 5 equivalents of the Lewis acid catalyst may be used.

[0047] The reaction temperature in the first step is preferably, for example, -78 to 50°C. The reaction time is preferably, for example, 5 to 60 minutes.

[0048] β-chlorophenetol is used as the compound represented by formula (3) above, and AlCl is used as the Lewis acid catalyst. ３ The assumed reaction mechanism when using is shown in the following equation.

[0049]

[0050] Next, in the second step, the compound represented by formula (4) and the compound represented by formula (5) are reacted to obtain the compound represented by formula (1).

[0051] The amounts of the compound represented by formula (4) and the compound represented by formula (5) used are not particularly limited. For example, the amount of the compound represented by formula (5) is 2 to 200 equivalents for every 1 equivalent of the compound represented by formula (4).

[0052] The reaction temperature in the second step is preferably, for example, 70 to 140°C. The reaction time is preferably, for example, 30 minutes to 24 hours.

[0053] <Preventive or therapeutic agent for dyslipidemia or dyslipidemia-related diseases> The preventive or therapeutic agent for dyslipidemia or dyslipidemia-related diseases according to this embodiment contains the compound represented by the above formula (1) or a salt thereof as an active ingredient.

[0054] As described above, the compound represented by formula (1) or its salt has effects such as lowering blood cholesterol and lowering liver triglycerides. For this reason, the preventive or therapeutic agent according to this embodiment is effective in preventing or treating dyslipidemia or dyslipidemia-related diseases. "Prevention" includes not only preventing the onset of the disease but also delaying the onset. "Treatment" includes not only eliminating or reducing symptoms but also suppressing the progression of symptoms.

[0055] Examples of dyslipidemia include high LDL cholesterol, high triglycerides, high chylomicronemia, low HDL cholesterol, postprandial hyperlipidemia, familial lipoprotein lipase deficiency, apolipoprotein C-II deficiency, familial hypercholesterolemia, familial apoB100 deficiency, autosomal recessive hypercholesterolemia, polygenic hypercholesterolemia, familial combined hyperlipidemia, familial type III hyperlipidemia, familial type IV hyperlipidemia, primary type V hyperlipidemia, idiopathic hypertriglycerides, secondary hypercholesterolemia, and secondary hypertriglycerides.

[0056] Examples of dyslipidemia-related diseases include arteriosclerosis, heart disease (angina pectoris, myocardial infarction, etc.), cerebrovascular disease (cerebral hemorrhage, cerebral infarction, etc.), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cancer, and diabetes.

[0057] The preventive or therapeutic agent according to this embodiment preferably contains a pharmacologically acceptable carrier in addition to the active ingredient. Examples of pharmacologically acceptable carriers include organic or inorganic carriers commonly used as pharmaceutical materials. In solid formulations, this carrier is incorporated as an excipient, lubricant, binder, disintegrant, etc., and in liquid formulations, as a solvent, solubilizer, suspending agent, isotonic agent, buffer, etc. Furthermore, the preventive or therapeutic agent according to this embodiment may also contain pharmaceutical additives such as preservatives, antioxidants, and colorants.

[0058] The dosage form of the preventive or therapeutic agent according to this embodiment is not particularly limited. Examples of dosage forms of the preventive or therapeutic agent include oral preparations such as tablets, capsules, emulsions, and suspensions; and parenteral preparations such as injections, intravenous infusions, nasal sprays, and topical preparations.

[0059] The dosage of the preventive or therapeutic agent according to this embodiment is determined appropriately depending on the target recipient, route of administration, symptoms, etc.

[0060] The present invention will be described more specifically below with reference to examples, but the present invention is not limited to these examples.

[0061] <Synthesis Example 1: Synthesis of Compound STA10> (Step 1-1: Synthesis of Compound 2)

[0062]

[0063] AlCl ３ (200 mg, 1.50 mmol), β-chlorophenethol (7.9 mL, 0.19 M), and 2-ethylbutanal (150 mg, 1.50 mmol) were added in sequence, and the mixture was stirred for 5 minutes. After 5 minutes, water was added until the reaction system became cloudy, and the reaction was stopped. Diethyl ether was added, and the organic layer was separated. The aqueous layer was then extracted with diethyl ether. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the reaction mixture. After removing β-chlorophenethol from the reaction mixture under reduced pressure, the mixture was purified by column chromatography. Recrystallization of the obtained solid in methanol solvent yielded pure crystals of compound 2 in a yield of 343.4 mg and 58%. The amount of compound 2 contained in the mother liquor was 33.9 mg and 6%.

[0064] (Step 1-2: Synthesis of Compound 2)

[0065]

[0066] FeCl ３ (243 mg, 1.50 mmol), β-chlorophenethol (7.9 mL, 0.19 M), and 2-ethylbutanal (150 mg, 1.50 mmol) were added in sequence, and the mixture was stirred for 5 minutes. After 5 minutes, water was added to stop the reaction. Diethyl ether was added to separate the organic layer, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the reaction mixture. After removing β-chlorophenethol from the reaction mixture under reduced pressure, the mixture was purified by column chromatography. Recrystallization of the obtained solid in methanol solvent yielded pure crystals of compound 2 in a yield of 398.2 mg and 67%. The amount of compound 2 contained in the mother liquor was 37.2 mg and 6%.

[0067] (Step 2: Synthesis of compound STA10)

[0068]

[0069] Compound 2 (30.8 mg, 0.0759 mmol) and a 2M methanol solution containing dimethylamine (1.9 mL, 3.79 mmol) were placed in an autoclave. The temperature was then raised to 110°C and the mixture was stirred for 8 hours. After stirring, the reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The concentrate was purified by preparative thin-layer chromatography (eluent: chloroform / methanol = 9 / 1) to obtain compound STA10 (29.8 mg, 93%). The physical properties of compound STA10 are as follows.

[0070] Compound STA10: 2,2'-(((2'''-ethylbutane-1''',1'''-diyl)bis(4'',1''-phenylene))bis(oxy))bis(N,N-dimethylethane-1-amine) 1H NMR (300 MHz, CDCl3): δ 7.20-7.11 (m, 4H, H-3''), 6.85-6.75 (m, 4H, H-2''), 4.00 (t, J = 6.0 Hz, 4H, H-2, H-2'), 3.58 (d, J = 11.4 Hz, 1H, H-1'''), 2.68 (t, J = 6.0 Hz, 4H, H-1, H-1'), 2.31 (s, 12H, NMe2), 2.17-2.02 (m, 1H, H-2'''), 1.46-1.23 (m, 2H, H-3'''), 1.32-1.07 (m, 2H, H-3'''), 0.77 (t, J = 7.5 Hz, 6H, H-4'').

[0071] <Synthesis Example 2: Synthesis of Compound STB10>

[0072]

[0073] Compound 2 (33.1 mg, 0.0837 mmol) was placed in an autoclave, followed by the addition of anhydrous ethanol (2.53 mL, 0.033 M) and pyrrolidine (0.11 mL, 1.31 mmol). The mixture was then heated to 110°C and stirred for 8 hours. After stirring, the reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The concentrate was purified by preparative thin-layer chromatography (developing solvent: chloroform / methanol = 9 / 1) to obtain 42.0 mg of crude product. The crude product was further purified by preparative thin-layer chromatography (developing solvent: chloroform / methanol / ammonia = 90 / 10 / 2) to obtain compound STB10 (34.5 mg, 89%). The physical properties of compound STB10 are as follows.

[0074] Compound STB10: 1,1'-((((2''' '-ethylbutane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dipyrrolidine 1H NMR (500 MHz, CDCl3): δ 7.18-7.11 (m, 4H, H-3'''), 6.83-6.75 (m, 4H, H-2'''), 4.04 (t, J = 6.5 Hz, 4H, H-2''), 3.58 (d, J = 10.5 Hz, 1H, H-1''' '), 2.85 (t, J = 6.5 Hz, 4H, H-1''), 2.64-2.54 (m, 8H, H-2, H-2'), 2.15-2.04 (m, 1H, H-2''' '), 1.85-1.73 (m, 8H, H-3, H-3'), 1.42-1.30 (m, 2H, H-3''' '), 1.26-1.12 (m, 2H, H-3''' '), 0.77 (t, J = 7.5 Hz, 6H, H-4''' ').

[0075] <Synthesis Example 3: Synthesis of Compound STC10>

[0076]

[0077] Compound 2 (30.5 mg, 0.0759 mmol) was placed in an autoclave, followed by the addition of anhydrous ethanol (2.53 mL, 0.030 M) and piperidine (0.13 mL, 1.31 mmol). The mixture was then heated to 110°C and stirred for 8 hours. After stirring, the reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The concentrate was purified by preparative thin-layer chromatography (developing solvent: chloroform / methanol = 9 / 1) to obtain 35.6 mg of crude product. The crude product was further purified by preparative thin-layer chromatography (developing solvent: chloroform / methanol / ammonia = 90 / 10 / 2) to obtain compound STC10 (31.0 mg, 82%). The physical properties of compound STC10 are as follows.

[0078] Compound STC10: 1,1'-((((2''' '-ethylbutane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dipiperidine 1H NMR (300 MHz, CDCl3): δ 7.19-7.09 (m, 4H, H-3'''), 6.83-6.72 (m, 4H, H-2'''), 4.03 (t, J = 6.3 Hz, 4H, H-2''), 3.58 (d, J = 11.1 Hz, 1H, H-1''' '), 2.72 (t, J = 6.3 Hz, 4H, H-1''), 2.59-2.35 (m, 8H, H-2, H-2'), 2.19-2.00 (m, 1H, H-2''' '), 1.70-1.44 (m, 8H, H-3, H-3'), 1.56-1.30 (m, 4H, H-4, H-4'), 1.46-1.24 (m, 2H, H-3''' '), 1.32-1.06 (m, 2H, H-3''' '), 0.77 (t, J = 7.5 Hz, 6H, H-4''' ').

[0079] <Synthesis Example 4: Synthesis of Compound STD10>

[0080]

[0081] Compound 2 (30.8 mg, 0.0759 mmol) was placed in an autoclave, followed by the addition of anhydrous ethanol (2.53 mL, 0.031 M) and morpholine (0.66 mL, 7.58 mmol). The mixture was then heated to 110°C and stirred for 8 hours. After stirring, the reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The concentrate was purified by preparative thin-layer chromatography (eluent: chloroform / methanol = 9 / 1) to obtain compound STD10 (35.4 mg, 98%). The physical properties of compound STD10 are as follows.

[0082] Compound STD10: 4,4'-((((2''' '-ethylbutane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (300 MHz, CDCl3): δ 7.20-7.10 (m, 4H, H-3'''), 6.83-6.73 (m, 4H, H-2'''), 4.04 (t, J = 6.0 Hz, 4H, H-2''), 3.71 (t, J = 4.8 Hz, 8H, H-2, H-2'), 3.58 (d, J = 11.1 Hz, 1H, H-1''' '), 2.76 (t, J = 6.0 Hz, 4H, H-1'), 2.55 (t, J = 4.8 Hz, 8H, H-3, H-3'), 2.20-2.01 (m, 1H, H-2''' '), 1.48-1.24 (m, 2H, H-3''' '), 1.34-1.06 (m, 2H, H-3''' '), 0.77 (t, J = 7.2 Hz, 6H, H-4''' ').

[0083] <Synthesis Example 5: Synthesis of Compound STE10>

[0084]

[0085] Compound 2 (32.8 mg, 0.0829 mmol) was placed in an autoclave, followed by the addition of anhydrous ethanol (2.53 mL, 0.033 M) and diethylamine (0.79 mL, 7.58 mmol). The mixture was then heated to 110°C and stirred for 8 hours. After stirring, the reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The concentrate was purified by preparative thin-layer chromatography (eluent: chloroform / methanol = 9 / 1) to obtain compound STE10 (23.6 mg, 61%). The physical properties of compound STE10 are as follows.

[0086] Compound STE10: 2,2'-(((2'''-ethylbutane-1''',1'''-diyl)bis(4'',1''-phenylene))bis(oxy))bis(N,N-diethylethan-1-amine) 1H NMR (500 MHz, CDCl3): δ 7.18-7.11 (m, 4H, H-3''), 6.82-6.73 (m, 4H, H-2''), 3.98 (t, J = 6.5 Hz, 4H, H-2, H-2'), 3.58 (d, J = 10.5 Hz, 1H, H-1'''), 2.83 (t, J = 6.5 Hz, 4H, H-1, H-1'), 2.61 (q, J = 7.0 Hz, 8H, N(CH2CH3)2), 2.16-2.03 (m, 1H, H-2'''), 1.42-1.30 (m, 2H, H-3'''), 1.25-1.13 (m, 2H, H-3'''), 1.05 (t, J = 7.0 Hz, 12H, N(CH2CH3)2), 0.77 (t, J = 7.5 Hz, 6H, H-4''').

[0087] <Synthesis Example 6: Synthesis of Compound STF10>

[0088]

[0089] Compound 2 (30.3 mg, 0.0759 mmol) was placed in an autoclave, followed by the addition of anhydrous ethanol (2.53 mL, 0.030 M) and azepane (0.15 mL, 1.31 mmol). The mixture was then heated to 110°C and stirred for 8 hours. After stirring, the reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The concentrate was purified by preparative thin-layer chromatography (developing solvent: chloroform / methanol = 9 / 1) to obtain 32.7 mg of crude product. The crude product was further purified by preparative thin-layer chromatography (developing solvent: chloroform / methanol / ammonia = 90 / 10 / 2) to obtain compound STF10 (29.5 mg, 74%). The physical properties of compound STF10 are as follows.

[0090] Compound STF10: 1,1'-((((2''' '-ethylbutane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))bis(azepane) 1H NMR (500 MHz, CDCl3): δ 7.18-7.10 (m, 4H, H-3'''), 6.82-6.73 (m, 4H, H-2'''), 4.00 (t, J = 6.0 Hz, 4H, H-2''), 3.58 (d, J = 11.0 Hz, 1H, H-1''' '), 2.90 (t, J = 6.0 Hz, 4H, H-1''), 2.79-2.69 (m, 8H, H-2, H-2'), 2.17-2.02 (m, 1H, H-2''' '), 1.73-1.48 (m, 16H, H-3, H-3', H-4, H-4'), 1.44-1.29 (m, 2H, H-3''' '), 1.27-1.10 (m, 2H, H-3''' '), 0.77 (t, J = 7.5 Hz, 6H, H-4''' ').

[0091] <Synthesis Example 7: Synthesis of Compound STG10>

[0092]

[0093] Compound STG10 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STG10 are as follows.

[0094] Compound STG10: 3,3'-(((2'''-ethylbutane-1''',1'''-diyl)bis(4'',1''-phenylene))bis(oxy))bis(N,N-dimethylpropan-1-amine) 1H NMR (500 MHz, CDCl3): δ 7.18-7.11 (m, 4H, H-3''), 6.81-6.75 (m, 4H, H-2''), 3.94 (t, J = 6.5 Hz, 4H, H-3, H-3'), 3.58 (d, J = 11.0 Hz, 1H, H-1'''), 2.41 (t, J = 7.5 Hz, 4H, H-1, H-1'), 2.22 (s, 12H, NMe2), 2.15-2.05 (m, 1H, H-2'''), 1.90 (tt, J = 6.5, 6.5 Hz, 4H, H-2, H-2'), 1.42-1.30 (m, 2H, H-3'''), 1.25-1.13 (m, 2H, H-3'''), 0.77 (t, J = 7.5 Hz, 6H, H-4''').

[0095] <Synthesis Example 8: Synthesis of Compound STH10>

[0096]

[0097] Compound STH10 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STH10 are as follows.

[0098] Compound STH10: 1,1'-((((2''' '-ethylbutane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(propane-3'',1''-diyl))dipyrrolidine 1H NMR (500 MHz, CDCl3): δ 7.18-7.12 (m, 4H, H-3'''), 6.82-6.73 (m, 4H, H-2'''), 3.96 (t, J = 6.5 Hz, 4H, H-3''), 3.58 (d, J = 11.0 Hz, 1H, H-1''' '), 2.58 (t, J = 7.0 Hz, 4H, H-1''), 2.55-2.45 (m, 8H, H-2, H-2'), 2.16-2.04 (m, 1H, H-2''' '), 1.96 (tt, J = 7.0, 6.5 Hz, 4H, H-2''), 1.83-1.72 (m, 8H, H-3, H-3'), 1.43-1.29 (m, 2H, H-3''' '), 1.26-1.12 (m, 2H, H-3''' '), 0.77 (t, J = 7.5 Hz, 6H, H-4''' ').

[0099] <Synthesis Example 9: Synthesis of Compound STD22>

[0100]

[0101] Compound STD22 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD22 are as follows.

[0102] Compound STD22: 4,4'-((((2''' '-propylpentane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.20-7.08 (m, 4H, H-3'''), 6.85-6.70 (m, 4H, H-2'''), 4.05 (t, J = 5.5 Hz, 4H, H-2''), 3.72 (t, J = 4.5 Hz, 8H, H-2, H-2'), 3.59 (d, J = 11.0 Hz, 1H, H-1''' '), 2.77 (t, J = 5.5 Hz, 4H, H-1''), 2.86-2.33 (m, 8H, H-3, H-3'), 2.30-2.08 (m, 1H, H-2''' '), 1.45-0.95 (m, 8H, H-3''' ', H-4''' '), 0.77 (t, J = 7.0 Hz, 6H, H-5''' ').

[0103] <Synthesis Example 10: Synthesis of Compound STD23>

[0104]

[0105] Compound STD23 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD23 are as follows.

[0106] Compound STD23: 4,4'-((((2''' '-butylhexane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.20-7.07 (m, 4H, H-3'''), 6.85-6.72 (m, 4H, H-2'''), 4.05 (t, J = 6.0 Hz, 4H, H-2''), 3.72 (t, J = 4.5 Hz, 8H, H-2, H-2'), 3.60 (d, J = 10.0 Hz, 1H, H-1''' '), 2.76 (t, J = 6.0 Hz, 4H, H-1''), 2.62-2.49 (m, 8H, H-3, H-3'), 2.25-2.09 (m, 1H, H-2''' '), 1.44-0.96 (m, 12H, H-3''' ', H-4''' ', H-5''' '), 0.80 (t, J = 7.0 Hz, 6H, H-6''' ').

[0107] <Synthesis Example 11: Synthesis of Compound STD17>

[0108]

[0109] Compound STD17 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD17 are as follows.

[0110] Compound STD17: 4,4'-((((2''' '-pentylheptane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.22-7.07 (m, 4H, H-3'''), 6.85-6.70 (m, 4H, H-2'''), 4.05 (t, J = 6.0 Hz, 4H, H-2''), 3.72 (t, J = 4.5 Hz, 8H, H-2, H-2'), 3.59 (d, J = 11.0 Hz, 1H, H-1''' '), 2.76 (t, J = 6.0 Hz, 4H, H-1''), 2.69-2.40 (m, 8H, H-3, H-3'), 2.25-2.10 (m, 1H, H-2''' '), 1.36-0.98 (m, 16H, H-3''' ', H-4''' ', H-5''' ', H-6''' '), 0.82 (t, J = 7.0 Hz, 6H, H-7''' ').

[0111] <Synthesis Example 12: Synthesis of Compound STD24>

[0112]

[0113] Compound STD24 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD24 are as follows.

[0114] Compound STD24: 4,4'-((((2''' '-hexyloctane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.19-7.08 (m, 4H, H-3'''), 6.83-6.73 (m, 4H, H-2'''), 4.05 (t, J = 5.5 Hz, 4H, H-2''), 3.72 (t, J = 4.5 Hz, 8H, H-2, H-2'), 3.59 (d, J = 10.0 Hz, 1H, H-1''' '), 2.76 (t, J = 5.5 Hz, 4H, H-1'), 2.55 (t, J = 4.5 Hz, 8H, H-3, H-3'), 2.26-2.06 (m, 1H, H-2''' ), 1.40-0.98 (m, 20H, H-3''' ', H-4''' ', H-5''' ', H-6''' ', H-7''' '), 0.84 (t, J = 6.5 Hz, 6H, H-8''' ')

[0115] <Synthesis Example 13: Synthesis of Compound STD25>

[0116]

[0117] Compound STD25 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD25 are as follows.

[0118] Compound STD25: 4,4'-((((2''' '-heptylnonane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.20-7.07 (m, 4H, H-3'''), 6.84-6.72 (m, 4H, H-2'''), 4.05 (t, J = 6.0 Hz, 4H, H-2''), 3.72 (t, J = 5.0 Hz, 8H, H-2, H-2'), 3.59 (d, J = 10.5 Hz, 1H, H-1''' '), 2.76 (t, J = 6.0 Hz, 4H, H-1''), 2.65-2.44 (m, 8H, H-3, H-3'), 2.28-2.06 (m, 1H, H-2''' '), 1.37-1.00 (m, 24H, H-3''' ', H-4''' ', H-5''' ', H-6''' ', H-7''' ', H-8''' '), 0.86 (t, J = 7.0 Hz, 6H, H-9''' ').

[0119] <Synthesis Example 14: Synthesis of Compound STD26>

[0120]

[0121] Compound STD26 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD26 are as follows.

[0122] Compound STD26: 4,4'-((((2''' '-octyldecane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.19-7.08 (m, 4H, H-3'''), 6.83-6.72 (m, 4H, H-2'''), 4.05 (t, J = 6.0 Hz, 4H, H-2''), 3.72 (t, J = 4.5 Hz, 8H, H-2, H-2'), 3.59 (d, J = 10.5 Hz, 1H, H-1''' '), 2.76 (t, J = 6.0 Hz, 4H, H-1'), 2.55 (t, J = 4.5 Hz, 8H, H-3, H-3'), 2.23-2.11 (m, 1H, H-2''' '), 1.42-1.00 (m, 28H, H-3''' ', H-4''' ', H-5''' ', H-6''' ', H-7''' ', H-8''' ', H-9''' '), 0.87 (t, J = 7.5 Hz, 6H, H-10''' ').

[0123] <Synthesis Example 15: Synthesis of Compound STD1>

[0124]

[0125] Compound STD1 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD1 are as follows.

[0126] Compound STD1: 4,4'-((((2''' '-phenylethane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.19-7.13 (m, 2H, H-3''' '', H-5''' ''), 7.14-7.09 (m, 1H, H-4''' ''), 7.12-7.03 (m, 4H, H-3''', H-5'''), 7.02-6.95 (m, 2H, H-2''' '', H-6''' ''), 6.83-6.73 (m, 4H, H-2''', H-6'''), 4.12 (t, J = 8.0 Hz, 1H, H-1''' '), 4.05 (t, J = 6.0 Hz, 4H, H-2''), 3.72 (t, J = 4.5 Hz, 8H, H-2, H-6, H-2', H-6'), 3.28 (d, J = 8.0 Hz, 2H, H-2''' '), 2.77 (t, J = 6.0 Hz, 4H, H-1''), 2.64-2.48 (m, 8H, H-3, H-5, H-3', H-5').

[0127] <Synthesis Example 16: Synthesis of Compound STD2>

[0128]

[0129] Compound STD2 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD2 are as follows.

[0130] Compound STD2: 4,4'-(((ethane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.17-7.05 (m, 4H, H-3''', H-5'''), 6.86-6.75 (m, 4H, H-2''', H-6'''), 4.06 (t, J = 6.0 Hz, 4H, H-2''), 3.79 (t, J = 8.0 Hz, 1H, H-1''' '), 3.72 (t, J = 5.0 Hz, 8H, H-2, H-6, H-2', H-6'), 2.77 (t, J = 6.0 Hz, 4H, H-1''), 2.64-2.48 (m, 8H, H-3, H-5, H-3', H-5'), 2.03–1.86 (m, 2H, H-2''' '), 1.34-1.16 (m, 2H, H-3''' '), 0.90 (t, J = 7.0 Hz, 3H, H-4''' ').

[0131] <Synthesis Example 17: Synthesis of Compound STD3>

[0132]

[0133] Compound STD3 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD3 are as follows.

[0134] Compound STD3: 4,4'-(((ethane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.16-7.04 (m, 4H, H-3''', H-5'''), 6.88-6.76 (m, 4H, H-2''', H-6'''), 4.08 (t, J = 5.5 Hz, 4H, H-2''), 4.04 (q, J = 8.0 Hz, 1H, H-1''' '), 3.73 (t, J = 5.5 Hz, 8H, H-2, H-6, H-2', H-6'), 2.78 (t, J = 5.5 Hz, 4H, H-1''), 2.64-2.48 (m, 8H, H-3, H-5, H-3', H-5'), 1.57 (d, J = 8.0 Hz, 3H, H-2''' ').

[0135] <Synthesis Example 18: Synthesis of Compound STD14>

[0136]

[0137] Compound STD14 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD14 are as follows.

[0138] Compound STD14: 4,4'-((((2''' ',2''' '-diphenylethane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.20-7.07 (m, 4H, H-2''' '', H-6''' ''), 7.16-7.04 (m, 4H, H-3''' '', H-5''' ''), 7.08-6.96 (m, 6H, H-3''', H-5''', H-4''' ''), 6.68-6.60 (m, 4H, H-2''', H-6'''), 4.66 (brs, 2H, H-1''' ', H-2''' '), 3.97 (t, J = 5.5 Hz, 4H, H-2''), 3.70 (t, J = 4.5 Hz, 8H, H-2, H-6, H-2', H-6'), 2.71 (t, J = 5.5 Hz, 4H, H-1''), 3.25-2.75 (m, 8H, H-3, H-5, H-3', H-5').

[0139] <Synthesis Example 19: Synthesis of Compound STD16>

[0140]

[0141] Compound STD16 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD16 are as follows.

[0142] Compound STD16: 4,4'-((((1''' '-cyclohexylmethane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.20-7.08 (m, 4H, H-3''', H-5'''), 6.84-6.74 (m, 4H, H-2''', H-6'''), 4.05 (t, J = 6.0 Hz, 4H, H-2''), 3.71 (t, J = 4.5 Hz, 8H, H-2, H-6, H-2', H-6'), 3.36 (d, J = 10.0 Hz, 1H, H-1''' '), 2.76 (t, J = 6.0 Hz, 4H, H-1''), 2.62-2.48 (m, 8H, H-3, H-5, H-3', H-5'), 2.08-1.90 (m, 1H, H-1''' ''), 1.74-1.56 (m, 3H, H-4''' ''(ax), H-3''' ''(eq), H-5''' ''(eq)), 1.66-1.50 (m, 2H, H-2''' ''(eq), H-6''' ''(eq)), 1.36-1.00 (m, 3H, H-4''' ''(eq), H-3''' ''(ax), H-5''' ''(ax)), 0.90-0.75 (m, 2H, H-2''' ''(ax), H-6''' ''(ax)).

[0143] <Synthesis Example 20: Synthesis of Compound STD51>

[0144]

[0145] Compound STD51 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD51 are as follows.

[0146] Compound STD51: 4,4'-((((2''' ',2''' '-dimethylpropane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.33-7.27 (m, 4H, H-3''', H-5'''), 6.83-6.77 (m, 4H, H-2''', H-6'''), 4.07 (t, J = 6.0 Hz, 4H, H-2''), 3.73 (t, J = 5.0 Hz, 8H, H-2, H-6, H-2', H-6'), 3.60 (s, 1H, H-1''' '), 2.79 (t, J = 6.0 Hz, 4H, H-1''), 2.65-2.50 (m, 8H, H-3, H-3', H-5, H-5'), 0.98 (s, 9H, C(CH3)3).

[0147] <Synthesis Example 21: Synthesis of Compound STD52>

[0148]

[0149] Compound STD52 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD52 are as follows.

[0150] Compound STD52: 4,4'-((((decane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.15-7.06 (m, 4H, H-3''', H-5'''), 6.83-6.78 (m, 4H, H-2''', H-6'''), 4.06 (t, J = 6.0 Hz, 4H, H-2''), 3.77 (t, J = 7.5 Hz, 1H, H-1''' '), 3.72 (t, J = 4.5 Hz, 8H, H-2, H-2', H-6, H-6'), 2.77 (t, J = 6.0 Hz, 4H, H-1''), 2.60-2.52 (m, 8H, H-3, H-5, H-3', H-5'), 1.94 (dt, J = 7.5, 7.5 Hz, 2H, H-2''' '), 1.35-1.15 (m, 14H, H-9''' ', H-3''' ', H-4''' ', H-5''' ', H-6''' ', H-7''' ', H-8''' '), 0.87 (t, J = 7.5 Hz, 3H, H-10''' ').

[0151] <Synthesis Example 22: Synthesis of Compound STD53>

[0152]

[0153] Compound STD53 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD53 are as follows.

[0154] Compound STD53: 4,4'-((((1''' '-(adamantane-1''' ''-yl)methane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.37-7.22 (m, 4H, H-3''', H-5'''), 6.88-6.72 (m, 4H, H-2''', H-6'''), 4.07 (t, J = 6.0 Hz, 4H, H-2''), 3.72 (t, J = 4.0 Hz, 8H, H-2, H-6, H-2', H-6'), 3.37 (s, 1H, H-1''' '), 2.77 (t, J = 6.0 Hz, 4H, H-1''), 2.63-2.47 (m, 8H, H-3, H-5, H-3', H-5'), 1.99-1.85 (m, 3H, H-3''' '', H-5''' '', H-7''' ''), 1.69-1.53 ​​(m, 3H, H-4''' '', H-6''' '', H-10''' ''); 1.65-1.54 (m, 6H, H-2''' '', H-8''' '', H-9''' ''), 1.61-1.48 (m, 3H, H-4''' '', H-6''' '', H-10''' '').

[0155] <Synthesis Example 23: Synthesis of Compound STD54>

[0156]

[0157] Compound STD54 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD54 are as follows.

[0158] Compound STD54: 4,4'-((((1''' '-phenylmethane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 7.33-7.22 (m, 2H, H-2''' '', H-6''' ''), 7.26-7.14 (m, 1H, H-4''' ''), 7.12-7.07 (m, 2H, H-3''' '', H-5''' ''), 7.06-6.94 (m, 4H, H-3''', H-5'''), 6.88-6.76 (m, 4H, H-2''', H-6'''), 5.44 (s, 1H, H-1''' '), 4.08 (t, J = 5.5 Hz, 4H, H-2''), 3.73 (t, J = 4.5 Hz, 8H, H-2, H-6, H-2', H-6'), 2.79 (t, J = 5.5 Hz, 4H, H-1''), 2.68-2.46 (m, 8H, H-3, H-5, H-3', H-5').

[0159] <Synthesis Example 24: Synthesis of Compound STD55>

[0160]

[0161] Compound STD55 was synthesized in the same manner as in Synthesis Example 1. The physical properties of compound STD55 are as follows.

[0162] Compound STD55: 4,4'-((((1''' '-(naphthalene-1''' ''-yl)methane-1''' ',1''' '-diyl)bis(4''',1'''-phenylene))bis(oxy))bis(ethane-2'',1''-diyl))dimorpholine 1H NMR (500 MHz, CDCl3): δ 8.04-7.91 (m, 1H, H-8''' ''), 7.92-7.78 (m, 1H, H-5''' ''), 7.79-7.68 (m, 1H, H-4''' ''), 7.48-7.38 (m, 1H, H-6''' ''), 7.44-7.33 (m, 1H, H-7''' ''), 7.42-7.29 (m, 3H, H-3''' ''), 7.04-6.95 (m, 4H, H-3''', H-5'''), 6.97-6.89 (m, 1H, H-2''' ''), 6.87-6.76 (m, 4H, H-2''', H-6'''), 6.16 (s, 1H, H-1''' '), 4.08 (t, J = 5.5 Hz, 4H, H-2''), 3.73 (t, J = 5.5 Hz, 8H, H-2, H-6, H-2', H-6'), 2.78 (t, J = 5.5 Hz, 4H, H-1''), 2.64-2.47 (m, 8H, H-3, H-5, H-3', H-5').

[0163] <Test Example 1: Evaluation of Cytotoxicity> 0.50 × 10 ４ 80 μL of DMEM medium containing suspensions of human liver cancer-derived HepG2 cells was dispensed into each well of a 96-well plate. Additionally, 100 μL of DMEM medium was dispensed as background. ２ The cells were incubated in an incubator for 24 hours to allow them to adhere. Then, the test compounds (STA10, STB10, STC10, STD10, STE10, STF10, STG10, or STH10) were adjusted to various concentrations and added 20 μL each to each well, followed by CO2 injection. ２ The mixture was incubated in an incubator for 23 hours. 10 μL of MTT reagent was added to each well, and the mixture was stirred with a shaker before adding CO2. ２ The cells were incubated in an incubator for one hour. The supernatant was discarded, and 100 μL of DMSO was added to each well to dissolve the purple formazan. Mitochondrial NADH levels were measured by measuring the absorbance at a wavelength of 570 nm using a microplate reader, and cell viability was quantified.

[0164] The MTT assay results for each test compound are shown in Table 1 below. As shown in Table 1, all test compounds showed low cytotoxicity. In particular, compound STD10 showed low IC50 ５０ The concentration was 13.20 μM, and its cytotoxicity was significantly lower compared to other test compounds.

[0165]

[0166] <Test Example 2: Evaluation of Intracellular Cholesterol Accumulation Ability> 1.89 × 10 ５ Three mL of DMEM medium containing suspended HepG2 cells was seeded into a glass-bottom dish. ２ The cells were incubated in an incubator for 24 hours to allow them to adhere. Then, the test compound (STA10, STB10, STC10, STD10, STE10, STF10, STG10, or STH10) was added to a concentration of 0.5 μM, and CO2 was added. ２ The samples were incubated in an incubator for 24 hours. As a control, DMEM medium was added instead of the test compound. After washing twice with PBS containing 0.5% BSA, 500 μL of 4% paraformaldehyde was added to each dish and allowed to stand at room temperature for 15 minutes. After washing twice with PBS containing 0.5% BSA, 500 μL of fluorescently labeled cholesterol solution was added to each dish and allowed to stand in the dark at 37°C for 30 minutes. The fluorescently labeled cholesterol solution was prepared by mixing 40 μL of Filipin III (Cayman Chemical), 3560 μL of PBS, and 400 μL of inactivated FBS. Next, after washing three times with PBS containing 0.5% BSA, 2000 μL of PBS containing 0.5% BSA was added to each dish, and images were taken at 60x magnification using a confocal microscope (FV10i, Olympus Corporation). The acquired images were analyzed using Image J software. After background correction, the ratio of the total cell area to the total fluorescence area (fluorescence area ratio) was calculated and quantified.

[0167] Figure 1 shows the fluorescence area ratio when each test compound is added. Figure 1 shows the relative values ​​with the fluorescence area ratio in the control group set to 1.00. As shown in Figure 1, all test compounds had a high cholesterol accumulation capacity.

[0168] <Test Example 3: Evaluation of Intracellular Cholesterol Accumulation Capacity> Intracellular cholesterol accumulation capacity was evaluated in the same manner as in Test Example 2, except that compound STD10 was added at concentrations of 10 nM, 100 nM, 500 nM, or 1000 nM. As a control, DMEM medium was added instead of compound STD10. For comparison, pitavastatin (0.5 μM), an HMG-CoA reductase inhibitor, or ezetimibe (10 μM), a small intestinal cholesterol transporter inhibitor, was added, and intracellular cholesterol accumulation capacity was evaluated in the same manner.

[0169] Figure 2 shows the fluorescence area ratio when each test compound is added. Figure 2 shows the relative values ​​with the fluorescence area ratio in the control set to 1.00. As shown in Figure 2, compound STD10 had a high cholesterol accumulation ability even at a low concentration of 10 nM.

[0170] <Test Example 4: Evaluation of Cytotoxicity> The cytotoxicity of the test compounds (STD10, STD22, STD23, STD17, STD24, STD25, or STD26) was evaluated in the same manner as in Test Example 1.

[0171] The MTT assay results for each test compound are shown in Table 2 below. As shown in Table 2, all test compounds exhibited low cytotoxicity. In particular, compound STD26 showed remarkably low cytotoxicity, with a cell viability of only 60% even at a high concentration of 100 μM.

[0172]

[0173] <Test Example 5: Evaluation of Intracellular Cholesterol Accumulation Ability> The intracellular cholesterol accumulation ability of the test compounds (STD10, STD17, STD22, STD23, STD24, STD25, or STD26) was evaluated in the same manner as in Test Example 2, except that the effective concentration of the test compound was changed to 1 μM.

[0174] Figure 3 shows the fluorescence area ratio when each test compound is added. Figure 3 shows the relative values ​​with the fluorescence area ratio in the control group set to 1.00. As shown in Figure 3, all test compounds had a high cholesterol accumulation capacity.

[0175] <Test Example 6: Evaluation of Action in Vivo> Male ICR mice aged 4-5 weeks were divided into a control group and a treatment group, and both groups were fed a high-fat diet for 10 weeks. After that, the control group was administered a citric acid aqueous solution, and the treatment group was administered compound STD10. Compound STD10 was administered in the following three ways: (1) Intraperitoneal administration of compound STD10 at a concentration of 12.5 mg / kg body weight for 3 weeks (2) Oral administration of compound STD10 at a concentration of 50 mg / kg body weight for 1 week (3) Oral administration of compound STD10 at a concentration of 12.5 mg / kg body weight for 3 weeks

[0176] When compound STD10 was administered intraperitoneally at a concentration of 12.5 mg / kg body weight for 3 weeks, the blood concentration of compound STD10 was 0.53 ± 0.02 μg / mL. Figure 4A shows the total blood cholesterol concentration (mg / dL) in each group. As shown in Figure 4A, the total blood cholesterol concentration was significantly reduced in the group administered compound STD10. ＊＊ p < 0.01; ＊＊＊＊ p<0.0001).

[0177] When compound STD10 was orally administered at a concentration of 50 mg / kg body weight for one week, the blood concentration of compound STD10 was 1.17 ± 0.14 μg / mL. Figure 4B shows the total blood cholesterol concentration (mg / dL) in each group. As shown in Figure 4B, the total blood cholesterol concentration was significantly reduced in the group administered compound STD10. ＊ p < 0.05; ＊＊ p < 0.01).

[0178] When compound STD10 was orally administered at a concentration of 12.5 mg / kg body weight for 3 weeks, the blood concentration of compound STD10 was 0.11 ± 0.10 μg / mL. Figure 4C shows the amount of triglycerides (neutral fats) per 1 g of liver in each group. As shown in Figure 4C, the amount of triglycerides in the liver was significantly reduced in the group administered compound STD10.＊＊ p < 0.01).

[0179] <Test Example 7: Evaluation of Cytotoxicity> The cytotoxicity of the test compounds (STD1, STD2, STD3, STD14, STD16, STD51, STD52, STD53, STD54, or STD55) was evaluated in the same manner as in Test Example 1.

[0180] The MTT assay results for each test compound are shown in Table 3 below. As shown in Table 3, all of the test compounds showed low cytotoxicity.

[0181]

[0182] <Test Example 8: Evaluation of Intracellular Cholesterol Accumulation Ability> The intracellular cholesterol accumulation ability of the test compounds (STD10, STD1, STD2, STD3, STD14, STD16, STD51, STD52, STD53, STD54, or STD55) was evaluated in the same manner as in Test Example 2, except that the effective concentration of the test compound was changed to 1 μM. For comparison, ezetimibe (10 μM), a small intestinal cholesterol transporter inhibitor, was added and the intracellular cholesterol accumulation ability was evaluated in the same manner.

[0183] Figure 5 shows the fluorescence area ratio when each test compound is added. Figure 5 shows the relative values ​​with the fluorescence area ratio in the control group set to 1.00. As shown in Figure 5, all test compounds had a high cholesterol accumulation capacity.

Claims

A compound represented by the following formula (1) or a salt thereof. [In the formula, two Rs １ each independently represent a hydrogen atom or an alkyl group. Two Rs ２ each independently represent a hydrogen atom or an alkyl group. When Rs １ and Rs ２ bonded to the same nitrogen atom are both alkyl groups, Rs １ and Rs ２ may form a monocyclic heterocyclic ring together with the nitrogen atom to which they are bonded, or in addition to the nitrogen atom to which they are bonded, together with at least one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Two ns each independently represent an integer of 0 or more. Rs ３ , Rs ４ , and Rs ５ each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Two or more of the groups of Rs ３ , Rs ４ , and Rs ５ may combine together to form a monocyclic or polycyclic aliphatic ring, a monocyclic or polycyclic aromatic ring, or a monocyclic or polycyclic heteroaromatic ring. 　 The compound or salt thereof according to claim 1, wherein in formula (1), the two n's are the same. 　 In the above formula (1), -(CH ２ ) ｎ -NR １ R ２ The compound or salt thereof according to claim 1, wherein the two groups represented are identical. 　 In formula (1) above, n represents an integer from 1 to 4, and -NR １ R ２ The compound or salt thereof according to claim 3, wherein the group represented by is a dimethylamino group, a diethylamino group, a 1-pyrrolidinyl group, a 1-piperidinyl group, a 1-morpholinyl group, or a 1-azepanyl group. 　 In formula (1) above, R ３ , R ４ , and R ５ However, each independently represents a hydrogen atom, an alkyl group, or an aryl group, and optionally, R ３ , R ４ , and R ５ The compound or salt thereof according to claim 1, wherein two or more of the groups combine to form a monocyclic or polycyclic aliphatic ring or a monocyclic or polycyclic aromatic ring. 　 In formula (1) above, R ３ , R ４ , and R ５ The compound or salt thereof according to claim 1, provided that any of the following conditions (a) to (d) are met. (a) R ３ and R ４ However, each independently represents an alkyl group, R ５ However, it represents a hydrogen atom or an alkyl group. (b) R ３ and R ４ However, each independently shows an aryl group, R ５ However, this indicates a hydrogen atom. (c) R ３ However, R represents a hydrogen atom, an alkyl group, or an aryl group. ４ and R ５ However, this indicates a hydrogen atom. (d) R ３ and R ４ These come together to form a monocyclic or polycyclic aliphatic ring or a monocyclic or polycyclic aromatic ring, R ５ However, this indicates a hydrogen atom. 　 A method for producing a compound represented by the following formula (1), A step of reacting a compound represented by the following formula (2) with a compound represented by the following formula (3) in the presence of a Lewis acid catalyst to obtain a compound represented by the following formula (4); and A step of reacting a compound represented by the following formula (4) with a compound represented by the following formula (5) to obtain a compound represented by the following formula (1); A manufacturing method that includes this. [In the formula, two Rs １ each independently represent a hydrogen atom or an alkyl group. Two Rs ２ each independently represent a hydrogen atom or an alkyl group. When Rs １ and Rs ２ bonded to the same nitrogen atom are both alkyl groups, Rs １ and Rs ２ may form a monocyclic heterocyclic ring together with the nitrogen atom to which they are bonded or, in addition to the nitrogen atom to which they are bonded, together with at least one atom selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. Two ns each independently represent an integer of 0 or more. Rs ３ , Rs ４ , and Rs ５ each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Two or more of the groups of Rs ３ , Rs ４ , and Rs ５ may combine together to form a monocyclic or polycyclic aliphatic ring, a monocyclic or polycyclic aromatic ring, or a monocyclic or polycyclic heteroaromatic ring. [In the formula, R ３ , R ４ , and R ５ This is equivalent to equation (1) above. [In the formula, X represents a halogen atom, and n is equivalent to that in formula (1) above.] [In the formula, R ３ , R ４ , R ５ , and n are equivalent to those in formula (1) above, and X is equivalent to those in formula (3) above. [In the formula, R １ and R ２ This is equivalent to equation (1) above. 　 An agent for the prevention or treatment of dyslipidemia or dyslipidemia-related diseases, comprising a compound or salt thereof as described in any one of claims 1 to 6 as an active ingredient.

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