JPWO2008093655A1 - Polyalcohol compounds and medicines - Google Patents

Abstract

It is an object of the present invention to provide a polyalcohol compound that can be an active ingredient of an antihyperlipidemic drug that can be easily formulated and has a high water solubility, and can reduce the required dose. . The polyalcohol compound of the present invention is represented by the following formula (I). [Wherein, R represents a residue obtained by removing a carboxyl group or an ester group from a fibrate antihyperlipidemic compound. X represents a linking group for bonding n polyalcohol moieties to R. n shows the integer of 1-8. ]

Description

  The present invention relates to a polyalcohol compound having a plurality of hydroxyl groups and a medicament containing the polyalcohol compound.

  A physiologically active peptide has low stability in blood, and there are cases in which the expected drug effect cannot be sufficiently exerted even when administered. Some physiologically active peptides and low molecular weight physiologically active substances cannot be used as injections because of their low water solubility.

  In order to solve such a problem, the present inventors have added branched glycerol (hereinafter sometimes referred to as “BGL”) for the purpose of improving the stability and water solubility of bioactive peptides and the like. Developed (Patent Document 1). In addition, the present inventors have also developed a technique in which the branched glycerol is bound to an amphiphile or the like and used as a drug carrier (Patent Document 2).

  Meanwhile, a fibrate antihyperlipidemic drug such as fenofibrate has a hydrophobic part such as a benzene ring, but has a low hydrophilic part, so its water solubility is extremely low. Therefore, water cannot be used as a solvent for fibrate antihyperlipidemic drugs, making formulation difficult. Moreover, since it must be formulated as a crystal, the intestinal absorbability is poor, and the dose must be increased. As a result, the administration conditions are severe, such as having to drink a large amount of water when taking the medicine.

In order to overcome these problems, a fibrate antihyperlipidemic drug has been devised such as micronizing the drug at the time of formulation. However, since it is impossible to miniaturize the drug to a molecular level by a physical method, the effect is insufficient. On the other hand, even if the water solubility of a fibrate antihyperlipidemic drug is simply improved to facilitate formulation, the intestinal absorbability of polar compounds is generally poor compared to fat-soluble compounds. The fundamental problem of having to take a large amount cannot be solved.
International Publication No. 2004/029018 International Publication No. 2005/023844

  As described above, fibrates are known as antihyperlipidemic drugs, but their water solubility is extremely low, making formulation difficult. As a result, the dose must be increased and the risk of side effects may be higher than the intended efficacy. In addition, there is a problem that the patient is burdened by having to drink a large amount of water when taking the medicine.

  Therefore, the problem to be solved by the present invention is to provide an antihyperlipidemic drug that is highly water-soluble and easy to formulate and that can reduce the required dose.

  The inventors of the present invention have made extensive studies to solve the above problems. As a result, binding of BGL, which was already developed by the present inventors, to a fibrate antihyperlipidemic compound not only improved its water solubility, but also the active metabolite after oral administration. It was found that the blood concentration was improved. This is considered to be a result of improved intestinal absorbability of the administered compound, but it is completely unexpected considering that the intestinal absorbability of a compound having high water solubility, ie, high polarity is generally poor. It was an effect. The present inventors have completed the present invention based on such findings.

  The polyalcohol compound of the present invention is represented by the following formula (I).

[Wherein, R represents a residue obtained by removing a carboxyl group or an ester group from a fibrate antihyperlipidemic compound. X represents a linking group for bonding n polyalcohol moieties to R. n shows the integer of 1-8. ]
Examples of R include those represented by the following formula (II).

[Wherein, R ¹ and R ² are the same or different and each represents a C ₁ -C ₆ alkyl group. R ¹ and R ² may be bonded together with the carbon atom to which they are bonded to form a cycloalkyl ring. Y represents a halogen atom group, a 2- (halogen-substituted benzoylamino) ethyl group or a halogen-substituted benzoyl group. ]
In the present invention, the “C ₁ -C ₆ alkyl group” refers to a linear or molecular chain aliphatic hydrocarbon group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. Of these, C ₁ -C ₄ alkyl are preferred, C ₁ -C ₂ alkyl is more preferable.

  Examples of the “halogen atom group” include a fluoro group, a chloro group, a bromo group, and an iodo group, preferably a chloro group or a bromo group, and more preferably a chloro group. In addition, “halogen substitution” indicates that the above halogen atom group is substituted.

Examples of the “cycloalkyl ring formed by bonding together with the carbon atom to which R ¹ and R ² are bonded” include a cycloheptane ring, a cyclohexane ring, and the like.

  Specific examples of the group represented by the above formula (II) are as follows.

  Furthermore, R is preferably a residue obtained by removing a carboxyl group or an ester group from clinofibrate, clofibrate, bezafibrate or fenofibrate. The polyalcohol compound of the present invention having a residue of these fibrate compounds exhibits an excellent antihyperlipidemic effect.

As the polyalcohol compound, those in which n is 2 ^m (wherein m represents an integer of 0 to 3 (more preferably, m is 0 or 1)) are suitable. Such compounds have the advantage that they are easier to synthesize. A polyalcohol compound in which n represents an integer of 2 or more and X has a serial branched structure (dendroidal) is also suitable. Such a compound not only has excellent water solubility, but also exhibits an antihyperlipidemic effect effectively because the active center portion of the compound is difficult to be covered with the polyalcohol structure.

  Moreover, the medicament and the antihyperlipidemic oral drug of the present invention are characterized by containing the polyalcohol compound.

  The polyalcohol compound of the present invention overcomes the disadvantage of the poor water solubility of conventional fibrate antihyperlipidemic drugs and exhibits good water solubility. Moreover, it has an excellent effect that the blood concentration of the active metabolite after oral administration is higher than that of the original fibrate antihyperlipidemic drug.

  In addition, the polyalcohol compound of the present invention had no death in animal experiments and no weight loss.

  Therefore, since the polyalcohol compound of the present invention exhibits good water solubility, it can be easily formulated, and the dose can be reduced. Furthermore, the polyalcohol compound of the present invention is extremely excellent in terms of safety and medicinal properties, and is extremely useful as a new antihyperlipidemic drug.

  The polyalcohol compound of the present invention is represented by the following formula (I).

[Wherein, R represents a residue obtained by removing a carboxyl group or an ester group from a fibrate antihyperlipidemic compound. X represents a linking group for bonding n polyalcohol moieties to R. n represents an integer of 1 to 8 (preferably n is 1 or 2). ]
A fibrate antihyperlipidemic compound generally has a benzene ring portion and a carboxyl group portion or an ester group portion as described below.

  In the polyalcohol compound of the present invention, the R group represents a residue obtained by removing a carboxyl group or an ester group from a fibrate antihyperlipidemic compound such as the above formula (II), and is mainly used for reducing blood triglyceride. Shows antihyperlipidemic effect. In addition, R group is not limited to the said residue, What is necessary is just a residue remove | excluding the carboxyl group or ester group from the fibrate antihyperlipidemic compound which has a carboxyl group or ester group.

  The X group is a linking group that binds the polyalcohol part of the compound of the present invention to the part derived from the fibrate antihyperlipidemic compound. Here, the polyalcohol moiety refers to the following structure consisting of one or more glycerin structures.

For example, since the polyalcohol compound of the present invention in which n is 1 can be synthesized by ester condensation of a carboxyl group derived from a fibrate antihyperlipidemic compound and a hydroxyl group derived from glycerin, X is a carbonyl group Can do. Of course, the present invention is not limited thereto, and in the case of the polyalcohol compound of the present invention in which n is 1, X may be a simple bond or a C ₁ -C ₆ alkylene group.

  When n is 2 or more, the X group must bind a residue of a fibrate antihyperlipidemic compound and a plurality of glycerin structures. In this case, the X group preferably has a structure in which a plurality of glycerin structures are bonded to each other by the following structure (III), and a plurality of the following structures are bonded to each other by the same structure.

[Wherein Y ¹ represents a single bond, C ₁ -C ₆ alkylene, carbonyl, carbonyloxy, amino, imino, amide, —O—, —S—, —S (═O) —, or —S (= O) _2- . Y ² represents —CH═ or —N═. Y ³ and Y ⁴ are each a single bond, C ₁ -C ₆ alkylene, carbonyl, amino, imino, amide, —O—, —S—, —S (═O) —, or —S (═O). ₂ indicates-. ]
When the X group has a serial branched structure composed of a plurality of structures (III), the polyalcohol compound of the present invention is a portion derived from a fibrate anti-antihyperlipidemic compound while having high water solubility. Is not covered by X groups, so that at least the activity is retained. Here, the serially branched structure refers to, for example, the following structure of a dendrimer type in which the structure (III) is connected in a branched manner.

“Amino” refers to —NH— or —NR ³ — (R ³ represents C ₁ -C ₆ alkyl such as methylene or ethylene). “Imino” refers to —C (═NR ⁴ ) — (R ⁴ represents a hydrogen atom, C ₁ -C ₆ alkyl such as methylene or ethylene, or a hydroxyl group). The “amide” may be either —NH—C (═O) — or —C (═O) —NH—.

  The following structure can be illustrated as specific structure (III).

  When a plurality of structures (III) are contained in X, the structures (III) may be the same as or different from each other.

  For example, in the case of the following polyalcohol compound (I ′) in which n is 2, the X group has the following structure.

  In the case of the following polyalcohol compound (I ″) where n is 4, the X group has the following structure.

  When n is 2 or more, n is preferably an even number. The upper limit is not particularly limited, but if the number of hydroxyl groups is too large, the intestinal absorptivity may be lowered. Therefore, n is preferably 1 or 2. However, n may be 3 or more in order to increase the water solubility of a highly hydrophobic fibrate antihyperlipidemic drug.

The polyalcohol compound of the present invention can be produced by combining a main part derived from a fibrate antihyperlipidemic drug and a part containing the polyalcohol part by a general method. For example, the compound (I) of the present invention can be synthesized by the following step A.
Process A :

[Wherein X ′ represents O, S or NH. Pro represents a hydroxyl-protecting group. R, X and n have the same meaning as described above. ]
The compound (1) is a hydrolyzed ester group of a fibrate antihyperlipidemic compound having a carboxyl group or a fibrate antihyperlipidemic compound having an ester group. Moreover, a compound (2) can be manufactured according to the process B mentioned later.

  The reaction conditions in the first step of the above step A are not particularly limited. For example, the carboxylic acid compound (1) and the alcohol compound (2) are reacted in a solvent in the presence of a condensing agent. As the condensing agent, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCI), 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide (EDC), or the like can be used. In this case, an additive is generally used. As an additive used in this step, dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt) can be used. The solvent used in this step is not particularly limited as long as it is inactive in this reaction. For example, halogenated hydrocarbons such as methylene chloride and chloroform can be used.

  The temperature during this reaction depends on the starting materials, the solvent, etc., but is usually room temperature. The reaction time after the addition depends on the starting materials, the solvent and the like, but is usually 1 to 24 hours.

  After the reaction, the mixture is quenched with dilute hydrochloric acid or the like, and extracted with an organic solvent that is not miscible with water, such as ethyl acetate or chloroform. The organic phase is washed with water such as saturated saline, and then the washed organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue is purified by a conventional method such as silica gel chromatography to give compound (3).

  In addition, as a reaction equivalent to the above reaction, compound (3) can also be synthesized by synthesizing an acid chloride compound from compound (1) or by reacting compound (1) with compound (2) after active esterification. Obtainable. Such a reaction is a technique well known to those skilled in the art.

  Next, compound (I) is obtained by removing the protecting group of compound (3) by a deprotection method according to the type of protecting group. For example, when an allyl group is used as a protecting group, it can be easily deprotected using a palladium catalyst. General types and deprotection conditions are described in “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS Second Edition” T.W.Green, P.G.M.Wuts, John Wiley & Sons, INC. Can be referred to.

The compound (2) used in the above step A can be produced in the following step B. In addition, the process B is an example to the last, and if it is those skilled in the art, a compound (2) can be manufactured according to the structure of X group or the structure of n with reference to the process B or a general method. .
Process B :

[In the formula, Hal represents a halogen atom such as a chlorine atom or a bromine atom, and Pro, X ′ and n have the same meaning as described above.]
In step B, epichlorohydrin or the like and an alcohol compound or glycerin and a protected compound are reacted to produce compound (4). In the reaction of epichlorohydrin or the like with an alcohol compound, a quaternary ammonium salt or a base is preferably used. Usually, a quaternary ammonium salt and a base are added using the alcohol compound itself as a solvent, and epichlorohydrin or the like is added dropwise. In the reaction between glycerin and the protected compound, it is preferable to use a base. These reaction conditions are well known to those skilled in the art.

  Next, after converting the hydroxyl group of the compound (4) into a halogen atom, the compound (6) is obtained by further reacting with glycerin. Such reaction conditions are also well known to those skilled in the art. Moreover, a compound (2) is obtained by repeating these reactions according to the value of n.

  The polyalcohol compound of the present invention has high water solubility. Therefore, since the polyalcohol compound of the present invention can be dissolved in water or the like and can be formulated using the resulting solution, a preparation in which the compound is dispersed to the molecular level can be easily produced. . Moreover, the polyalcohol compound of the present invention has a high concentration of active metabolites in blood after oral administration, despite its high water solubility. Therefore, the polyalcohol compound of the present invention is very useful as an active ingredient of an oral preparation. However, it is of course possible to use a preparation form of an injection. In addition, since the polyalcohol compound of the present invention has the main part of a fibrate antihyperlipidemic drug, it exhibits an antihyperlipidemic effect caused by the drug.

  The dosage of the polyalcohol compound of the present invention may be appropriately adjusted according to the age, symptoms, sex, etc. of the patient with reference to the dosage of the original fibrate antihyperlipidemic drug. However, since the polyalcohol compound of the present invention has high intestinal absorbability, it is considered that the polyalcohol compound exhibits an antihyperlipidemic effect at a dose lower than that of the original fibrate antihyperlipidemic drug having low water solubility.

FIG. 1 is a graph showing the blood concentration of an active metabolite (fenofibric acid) when the polyalcohol compound of the present invention is administered and when a conventional antihyperlipidemic drug is administered.

FIG. 2 is a graph showing changes in body weight of rats when the polyalcohol compound of the present invention is administered and when an aqueous sodium carboxymethyl cellulose solution is administered.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. It is also possible to implement, and they are all included in the technical scope of the present invention.

  Production Example 1 2-Hydroxyethyl 2- {4-[(4-chlorophenyl) carbonyl] phenoxy} -2-methylpropanoate

  Fenofibric acid was synthesized according to the method described in Divis et al., Synthesis, pages 1955 to 1958 (2004), and fenofibric chloride was further converted from fenofibric acid salt according to the method described in US Pat. No. 4,146,728. Was synthesized.

Phenofibril chloride (50 mg, 0.148 mmol) was added to a pyridine solution (0.5 mL) of ethylene glycol (46 mg, 0.741 mmol) at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. The reaction solution was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The obtained extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain the target compound (33.4 mg, 0.092 mmol, yield: 62%).
FT-IR (neat): 3392, 2993, 2922, 2850, 1738, 1653, 1599, 1506, 1396, 1286, 1252, 1144, 1090, 1014, 930, 854, 764 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): δ = 7.80-7.67 (m, 4H), 7.45 (d, J = 8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.30 (t, J = 4.4 Hz, 2H), 3.77 (t, J = 4.8 Hz, 2H), 1.70 (s, 6H)
¹³ C-NMR (CDCl ₃ , 100 MHz): δ = 193.9 (C), 173.7 (C), 159.3 (C), 138.2 (C), 136.0 (C), 131.9 (CH x 2), 131.0 (CH x 2 ), 130.3 (C), 128.4 (CH x 2), 117.0 (CH x 2), 79.3 (C), 66.9 (CH ₂ ), 60.7 (CH ₂ ), 25.4 (CH ₃ x 2).

  Production Example 2-1 2-Phenyl-1,3-dioxan-5-yl 2- {4-[(4-chlorophenyl) carbonyl] phenoxy} -2-methylpropanoate

2-Phenyl-1,3-dioxan-5-ol (20 mg, 0.111 mmol) was dissolved in anhydrous methylene chloride (1 mL, alcohol free). To the solution, DMAP (27.1 mg, 0.222 mmol) and phenofibril chloride (56.2 mg, 0.167 mmol) were sequentially added, followed by stirring at room temperature for 1 hour. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain the target compound (49.3 mg, 0.103 mmol, yield: 92%).
FT-IR (neat): 3392, 2993, 2922, 2850, 1738, 1653, 1599, 1506, 1396, 1286, 1252, 1144, 1090, 1014, 930, 854, 764 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): δ = 7.80-7.67 (m, 4H), 7.45 (d, J = 8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.30 (t, J = 4.4 Hz, 2H), 3.77 (t, J = 4.8 Hz, 2H), 1.70 (s, 6H)
¹³ C-NMR (CDCl ₃ , 100 MHz): δ = 193.9 (C), 173.7 (C), 159.3 (C), 138.2 (C), 136.0 (C), 131.9 (CH x 2), 131.0 (CH x 2 ), 130.3 (C), 128.4 (CH x 2), 117.0 (CH x 2), 79.3 (C), 66.9 (CH ₂ ), 60.7 (CH ₂ ), 25.4 (CH ₃ x 2).

  Production Example 2-2 2-hydroxy-1- (hydroxymethyl) ethyl 2- {4-[(4-chlorophenyl) carbonyl] phenoxy} -2-methylpropanoate

The dioxane compound (49.3 mg, 0.103 mmol) obtained in Production Example 2-1 was dissolved in an anhydrous methanol solution (1 mL). Amberlyst 15 (5.0 mg) was added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to obtain the target compound (36.1 mg, 0.092 mmol, yield: 90%). However, the obtained target compound contained a small amount of an acyl group rearranged to the 1-position hydroxyl group of glycerin.
FT-IR (neat): 3390, 2922, 2850, 1734, 1647, 1597, 1286, 1252, 1146, 930 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): δ = 7.78-7.64 (m, 4H), 7.44 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 5.00 (quint, J = 4.8 Hz, 1H), 3.80-3.67 (m, 4H), 1.70 (s, 6H)
¹³ C-NMR (CDCl ₃ , 100 MHz): δ = 194.2 (C), 173.4 (C), 159.3 (C), 138.3 (C), 135.9 (C), 131.9 (CH x 2), 131.0 (CH x 2 ), 130.3 (C), 128.4 (CH x 2), 117.0 (CH x 2), 79.5 (CH), 76.1 (C), 61.5 (CH ₂ x 2), 25.4 (CH ₃ x 2).

  Production Example 3-1 2- [2,2-dimethyl (1,3-dioxan-5-yloxy)]-1-[(2,2-dimethyl (1,3-dioxane-5-yloxy)) methyl] ethyl 2- {4-[(4-Chlorophenyl) carbonyl] phenoxy} -2-methylpropanoate

The alcohol compound (50 mg, 0.156 mmol) obtained by the method described in Patent Document 2 was dissolved in anhydrous methylene chloride (1 mL, alcohol-free). To the solution, DMAP (38.1 mg, 0.312 mmol) and phenofibril chloride (78.9 mg, 0.234 mmol) were sequentially added, followed by stirring at room temperature for 3 hours. The reaction solution was poured into a 5% aqueous copper sulfate solution and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to obtain the target compound (84.7 mg, 0.136 mmol, yield: 87%).
FT-IR (neat): 2993, 2941, 2873, 1739, 1655, 1599, 1506, 1485, 1466, 1373, 1284, 1252, 1146, 1090, 928, 854, 829, 764 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): δ = 7.77-7.68 (m, 4H), 7.45 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.19 (quint, J = 5.2 Hz, 1H), 3.95-3.83 (m, 4H), 3.70-3.58 (m, 8H), 3.37-3.30 (m, 2H), 1.68 (s, 6H), 1.37 (s, 12H)
¹³ C-NMR (CDCl ₃ , 100 MHz): δ = 193.8 (C), 172.8 (C), 159.3 (C), 138.1 (C), 136.1 (C), 131.8 (CH x 2), 130.9 (CH x 2 ), 130.2 (C), 128.3 (CH x 2), 117.2 (CH x 2), 98.0 (C x 2), 79.2 (C), 72.6 (CH), 70.8 (CH x 2), 67.0 (CH ₂ x 2), 62.2 (CH ₂ x 2), 62.1 (CH ₂ x 2), 25.3 (CH ₃ x 2), 23.8 (CH ₃ x 2), 23.1 (CH ₃ x 2).

  Production Example 3-2 2- [2-Hydroxy-1- (hydroxymethyl) ethoxy] -1-{[2-hydroxy-1- (hydroxymethyl) ethoxy] methyl} ethyl 2- {4-[(4-chlorophenyl) ) Carbonyl] phenoxy} -2-methylpropanoate

The acetal compound (100.0 mg, 0.161 mmol) obtained in Production Example 3-1 was dissolved in a mixed solvent of anhydrous methanol (0.5 mL) and anhydrous THF (0.5 mL). Amberlyst 15 (7.0 mg) was added to the solution, and the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10/1) to obtain the target compound (73.8 mg, 0.136 mmol, yield: 87%).
FT-IR (neat): 3365, 2922, 1734, 1647, 1597, 1468, 1286, 1252, 1146, 1089, 929, 854, 764 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): δ = 7.75-7.69 (m, 4H), 7.45 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.20 (quint, J = 4.8Hz, 1H), 3.83-3.51 (m, 12H), 3.44-3.36 (m, 2H), 1.69 (s, 6H)
¹³ C-NMR (CDCl ₃ , 100 MHz): δ = 194.4 (C), 173.1 (C), 159.2 (C), 138.4 (C), 135.8 (C), 131.7 (CH x 2), 131.0 (CH x 2 ), 130.3 (C), 128.4 (CH x 2), 117.2 (CH x 2), 81.0 (CH x 2), 79.3 (C), 72.9 (CH), 67.7 (CH ₂ x 2), 61.7 (CH ₂ x 2), 61.6 (CH ₂ x 2), 25.3 (CH ₃ x 2).

  Production Example 4-1 1,3-bis [2- (2-propenyloxy) -1- (2-propenyloxymethyl) ethoxy] propan-2-ol

[Wherein Allyl represents an allyl group (2-propenyl group)]
A suspension of 1,3-diallyloxy-2-propanol (1000 mg, 5.81 mmol), tetrabutylammonium bromide (140.4 mg, 0.44 mmol), and potassium hydroxide (124.6 mg, 1.89 mmol) Was stirred dropwise at room temperature, and epichlorohydrin (134.3 mg, 1.45 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 20 hours and at 80 ° C. for 24 hours. Water was then added and the suspension was extracted with ethyl acetate. The obtained extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to recover the alcohol compound (535.8 mg, 3.11 mmol, recovery rate: 54%) as the starting compound, and the target compound ( 285.0 mg, 0.71 mmol, the yield based on the conversion rate of the starting alcohol compound: 53%).
FT-IR (neat): 3456, 3080, 2866, 1647, 1458, 1101, 997, 926 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): δ = 5.97-5.83 (m, 4H), 5.32-5.13 (m, 8H), 4.07-3.90 (m, 9H), 3.78-3.45 (m, 14H)
¹³ C-NMR (CDCl ₃ , 100 MHz): δ = 134.3 (CH x 4), 116.9 (CH ₂ x 4), 78.7 (CH x 2), 72.2 (CH ₂ x 4), 71.9 (CH ₂ x 2) , 70.1, 70.0 (CH ₂ x 4), 69.7 (CH).

  Production Example 4-2 2- [2- (2-propenyloxy) -1- (2-propenyloxymethyl) ethoxy] -1-{[2- (2-propenyloxy) -1- (2-propenyloxymethyl) ) Ethoxy] methyl} ethyl 2- (4- {2-[(4-chlorophenyl) carbonylamino] ethyl} phenoxy) -2-methylpropanoate

The alcohol compound (100 mg, 0.25 mmol) obtained in Production Example 4-1 was dissolved in anhydrous methylene chloride (2 mL, alcohol-free). To the solution, a carboxylic acid compound (180.7 mg, 0.50 mmol), DMAP (15.3 mg, 0.12 mmol), and EDC (95.7 mg, 0.50 mmol) were sequentially added, followed by stirring at room temperature for 4 hours. did. The reaction solution was poured into 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The obtained extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain the target compound (124.4 mg, 0.208 mmol, yield: 83%).
FT-IR (neat): 3327, 3080, 2985, 2916, 1734, 1645, 1597, 1508, 1487, 1385, 928 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): δ = 7.63 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8 Hz, 2H), 6.84 (D, J = 8 Hz, 2H), 6.48 (t, J = 4.8 Hz, 1H), 5.97-5.79 (m, 4H), 5.34-5.09 (m, 8H), 4.04-3.38 (m, 25H), 2.83 (t, J = 6.8 Hz, 2H), 1.58 (s, 6H)
¹³ C-NMR (CDCl ₃ , 100 MHz): δ = 173.5 (C), 166.2 (C), 153.9 (C), 137.3 (C), 134.4, 134.4 (CH x 4), 132.8 (C), 132.2 (C ), 129.2 (CH x 2), 128.5 (CH x 2), 128.1 (CH x 2), 119.5 (CH x 2), 116.7, 116.7 (CH ₂ x 4), 78.9 (CH x 2), 78.4 (C ), 73.0 (CH), 72.0, 72.0 (CH ₂ x 4), 69.9 (CH ₂ x 4), 68.6 (CH ₂ x 2), 41.1 (CH ₂ ), 34.5 (CH ₂ ), 25.2 (CH ₃ x 2).

  Production Example 4-3 2- [2-hydroxy-1- (hydroxymethyl) ethoxy] -1-{[2-hydroxy-1- (hydroxymethyl) ethoxy] methyl} ethyl 2- (4- {2-[( 4-chlorophenyl) carbonylamino] ethyl} phenoxy) -2-methylpropanoate

The allyl ether compound (102 mg, 0.14 mmol) obtained in Production Example 4-2 was dissolved in methanol (2 mL). The solution was added with Pd / C (29.2 mg, 0.03 mmol) and Amberlyst 15 (3.3 mg) in this order, and then stirred at 50 ° C. for 14 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluent: ethyl acetate / methanol = 9/1) to obtain the target compound (5.6 mg, 0.010 mmol, yield: 7%).
FT-IR (neat): 3348, 2925, 1732, 1641, 1508, 1487, 1280, 1234, 1149, 1047, 972 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): δ = 7.65 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.78 (D, J = 8 Hz, 2H), 5.23 (quint, J = 4.8 Hz, 1H), 3.86-3.35 (m, 16H), 2.84 (t, J = 6.4 Hz, 2H), 1.62 (s, 6H)
¹³ C-NMR (CDCl ₃ , 100 MHz): δ = 173.9 (C), 166.6 (C), 153.5 (C), 137.3 (C), 132.6 (C), 132.6 (C), 129.4 (CH x 2), 128.5 (CH x 2), 128.3 (CH x 2), 118.4 (CH x 2), 80.9 (CH x 2), 78.7 (C), 72.6 (CH), 67.7 (CH ₂ x 2), 61.6 (CH ₂ x 4), 41.4 (CH ₂ ), 34.5 (CH ₂ ), 25.2 (CH ₃ x 2).

  Production Example 5-1 2- [2- (2-propenyloxy) -1- (2-propenyloxymethyl) ethoxy] -1-{[2- (2-propenyloxy) -1- (2-propenyloxymethyl) ) Ethoxy] methyl} ethyl 2- (4-chlorophenoxy) -2-methylpropanoate

The alcohol compound (100 mg, 0.25 mmol) obtained in Production Example 4-1 was dissolved in anhydrous methylene chloride (2 mL, alcohol-free). To the solution, a carboxylic acid compound (107.2 mg, 0.50 mmol), DMAP (15.3 mg, 0.12 mmol), and DCC (103.0 mg, 0.50 mmol) were sequentially added, followed by stirring at room temperature for 8 hours. did. The reaction solution was poured into 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The obtained extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain the target compound (124.5 mg, 0.208 mmol, yield: 83%).
FT-IR (neat): 3080, 2987, 2933, 1738, 1647, 1593, 1489, 1385, 1282, 1240, 1009, 928 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): δ = 7.18 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 5.93-5.81 (m, 4H), 5.30-5.12 ( m, 8H), 4.01-3.38 (m, 23H), 1.57 (m, 6H)
¹³ C-NMR (CDCl ₃ , 100 MHz): δ = 173.2 (C), 153.9 (C), 134.5, 134.5 (CH x 4), 128.8 (CH x 2), 126.9 (C), 120.6 (CH x 2) , 116.7 (CH ₂ x 4), 79.3 (C), 78.4 (CH x 2), 73.2 (CH), 72.1, 72.1 (CH ₂ x 4), 70.0, 70.0 (CH ₂ x 4), 67.7 (CH ₂ x 2), 25.1 (CH ₃ x 2).

  Production Example 5-2 2- [2-hydroxy-1- (hydroxymethyl) ethoxy] -1-{[2-hydroxy-1- (hydroxymethyl) ethoxy] methyl} ethyl 2- (4-chlorophenoxy) -2 -Methylpropanoate

The allyl ether compound (124.5 mg, 0.21 mmol) obtained in Production Example 5-1 was dissolved in methanol (1 mL). Pd / C (44.4 mg, 0.04 mmol) and Amberlyst 15 (5.0 mg) were sequentially added to the solution, followed by stirring at 50 ° C. for 10 hours. The reaction solution was filtered and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (eluent: ethyl acetate / methanol = 9/1) to obtain the target compound (3.7 mg, 0.008 mmol, yield: 4%).
FT-IR (neat): 3381, 2924, 1734, 1592, 1489, 1387, 1282, 1238, 1146, 971, 829 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): δ = 7.21 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 5.20 (quint, J = 4.8 Hz, 1H), 3.89 -3.43 (m, 14H), 1.59 (s, 6H)
¹³ C-NMR (CDCl ₃ , 100 MHz): δ = 173.5 (C), 153.5 (C), 129.0 (CH x 2), 127.3 (C), 120.5 (CH x 2), 80.9 (CH x 2), 79.5 (C), 72.7 (CH), 67.7 (CH ₂ x 2), 61.8, 61.7 (CH ₂ x 4), 25.2 (CH ₃ x 2).

Production Example 6-1 2- [2,2-dimethyl (1,3-dioxan-5-yloxy)]-1-{[2,2-dimethyl (1,3-dioxane-5-yloxy)] methyl} ethyl 2- (4- {2-[(4-Chlorophenyl) carbonylamino] ethyl} phenoxy) -2-methylpropanoate ( 16 )

To an anhydrous methylene chloride solution (2 mL, alcohol-free) of alcohol compound 8 (100 mg, 0.31 mmol) obtained by the method described in Patent Document 2, carboxylic acid compound 14 (225.9 mg, 0.62 mmol), DMAP (38 0.2 mg, 0.31 mmol) and EDC (119.7 mg, 0.62 mmol) were sequentially added, followed by stirring at room temperature for 1.5 hours. The reaction solution was poured into a 0.1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give the desired compound 16 (203.9 mg, 0.307 mmol, yield: 98%) was obtained.
FT-IR (neat): 2991, 2941, 2873, 1736, 1643, 1373, 1281, 1250, 914 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): d = 7.66 (d, J = 8 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8 Hz, 2H), 6.88 -6.73 (m, 3H), 5.16 (quint, J = 4.8 Hz, 1H), 3.95-3.53 (m, 14H), 3.37-3.29 (m, 2H), 2.91-2.80 (m, 2H), 1.59 (s , 6H), 1.41-1.32 (m, 12H)
¹³ C-NMR (CDCl ₃ , 100 MHz): d = 173.3 (C), 166.1 (C), 153.6, (C), 137.0 (C), 132.7 (C), 132.2 (C), 129.1 (CH x 2) , 128.3 (CH x 2), 128.1 (CH x 2), 118.6 (CH x 2), 97.8 (C x 2), 78.5 (C), 72.2 (CH), 70.5 (CH x 2), 66.8 (CH ₂ x 2), 62.0 (CH ₂ x 4), 41.2 (CH ₂ ), 34.3 (CH ₂ ), 25.0 (CH ₃ x 2), 23.8 (CH ₃ x 2), 22.8 (CH ₃ x 2).

Preparation Example 6-2 2- [2-hydroxy-1- (hydroxymethyl) ethoxy] -1-{[2-hydroxy-1- (hydroxymethyl) ethoxy] methyl} ethyl 2- (4- {2-[( 4-Chlorophenyl) carbonylamino] ethyl} phenoxy) -2-methylpropanoate ( 17 )

Amberlyst 15 (13.2 mg) was added to a solution of the ketal compound 16 (203.9 mg, 0.307 mmol) obtained in Production Example 6-1 in anhydrous methanol (2 mL), and the mixture was stirred at room temperature for 3 days. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: methanol = 85: 15) to obtain the target compound 17 (135.4 mg, 0.232 mmol, yield: 76%). It was.

Production Example 7-1 2- [2,2-dimethyl (1,3-dioxane-5-yloxy)]-1-{[2,2-dimethyl (1,3-dioxane-5-yloxy)] methyl} ethyl 2- (4-Chlorophenoxy) -2-methylpropanoate ( 20 )

To an anhydrous methylene chloride solution (2 mL, alcohol-free) of alcohol compound 8 (100 mg, 0.31 mmol) obtained by the method described in Patent Document 2, carboxylic acid compound 18 (134.0 mg, 0.62 mmol), DMAP (38 .2 mg, 0.31 mmol) and EDC (119.7 mg, 0.62 mmol) were sequentially added, followed by stirring at room temperature for 2 hours. The reaction solution was poured into a 0.1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the desired compound 20 (140.8 mg, 0.27 mmol, yield: 87%) was obtained.
FT-IR (neat): 2991, 2941, 2873, 1738, 1489, 1373, 1247, 1200, 1149, 1092, 829 cm ^-1
1 H-NMR (CDCl ₃ , 400 MHz): d = 7.20 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.16 (quint, J = 4.8 Hz, 1H), 3.95 -3.85 (m, 4H), 3.70-3.59 (m, 8H), 3.39-3.32 (m, 2H), 1.59 (s, 6H), 1.44-1.36 (m, 12H)
¹³ C-NMR (CDCl ₃ , 100 MHz): d = 173.1 (C), 153.7 (C), 128.8 (CH x 2), 126.9 (C), 120.2 (CH x 2), 98.0 (C x 2), 79.2 (C), 72.5 (CH), 70.8 (CH x 2), 66.9 (CH ₂ x 2), 62.2, 62.0 (CH ₂ x 4), 25.2 (CH ₃ x 2), 23.8, 23.0 (CH ₃ x 4 ).

Production Example 7-2 2- [2-hydroxy-1- (hydroxymethyl) ethoxy] -1-{[2-hydroxy-1- (hydroxymethyl) ethoxy] methyl} ethyl 2- (4-chlorophenoxy) -2 -Methylpropanoate ( 21 )

Amberlyst 15 (11.5 mg) was added to a solution of the ketal compound 20 (140.8 mg, 0.272 mmol) obtained in Production Example 7-1 in anhydrous methanol (2 mL), and the mixture was stirred at room temperature for 29 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1) to obtain the target compound 21 (105.8 mg, 0.242 mmol, yield: 89%). Obtained.

Production Example 8-1 2- [2-acetyloxy-1- (acetyloxymethyl) ethoxy] -1-{[2-acetyloxy-1- (acetyloxymethyl) ethoxy] methyl} ethyl acetate ( 2 )

BF ₃ · OEt ₂ (0.012 mL, 0.10 mmol) was added to an acetic anhydride solution (0.5 mL) of the alcohol compound 1 (100 mg, 0.25 mmol) obtained in Production Example 4-1, and the mixture was stirred at room temperature for 20 hours. did. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the desired compound 2 (94.4 mg, 0. 21 mmol, yield: 84%).
FT-IR (neat): 2956, 1741, 1438, 1371, 1232, 1049 cm ^-1
1 H-NMR (CDCl ₃ , 400MHz): d = 5.04 (quint, J = 4.8Hz, 1H), 4.25-4.04 (m, 8H), 3.82-3.67 (m, 6H), 2.08 (s, 15H)
¹³ C-NMR (CDCl ₃ , 100 MHz): d = 170.2 (C x 4), 169.9 (C), 75.8 (CH x 2), 71.4 (CH), 68.3 (CH ₂ x 2), 62.8, 62.8 (CH ₂ x 4), 20.8 (CH ₃ ), 20.6 (CH ₃ x 4)
ESI-HRMS: m / z ([M + Na] ⁺ ) Calcd for C ₁₉ H ₃₀ O ₁₂ Na: 473.1635, Found: 473.1636.

Production Example 8-2 2- {2-hydroxy-3- [2-hydroxy-1- (hydroxymethyl) ethoxy] propoxy} -1,3-diol ( 3 )

Sodium methoxide (1.1 mg, 0.02 mmol) was added to a methanol solution (0.5 mL) of the pentaacetyl compound 2 (94.4 mg, 0.21 mmol) obtained in Production Example 8-2, and the mixture was stirred at room temperature for 24 hours. Stir. Amberlyst 15 (20 mg) was added to the reaction solution, followed by filtration and concentration under reduced pressure to obtain the target compound 3 (50 mg, quantitative).
¹ H-NMR (CD ₃ OD, 400MHz): d = 3.91 (quint, J = 4.8Hz, 1H), 3.73-3.53 (m, 12H), 3.46-3.39 (m, 2H)
¹³ C-NMR (CD ₃ OD, 100 MHz): d = 82.6 (CH x 2), 72.5 (CH ₂ x 2), 70.8 (CH), 62.3, 62.2 (CH ₂ x 4)
ESI-HRMS: m / z ([M + Na] ⁺ ) Calcd for C ₉ H ₂₀ O ₇ Na: 263.1107, Found: 263.1104.

Test Example 1 Blood concentration of active metabolite after oral administration The polyalcohol compound produced in Production Example 3-2 (molecular weight: 540.18) was dissolved in a 1.5% by mass aqueous solution of sodium carboxymethylcellulose, and the concentration was 150 mg. / ML solution was prepared. For comparison, a solution of fenofibrate (molecular weight: 360.11) was similarly prepared. However, the concentration of the fenofibrate solution was set to 100 mg / mL in order to equalize the number of moles of fenofibrate in both solutions. Furthermore, a 15 μg / mL DMSO solution of flurbiprofen was prepared as an internal standard solution.

  Ten 7-week-old SD male rats were divided into two groups of 5 each, and the above polyalcohol compound solution and fenofibrate solution were orally administered at a rate of 1 mL / kg, respectively 1, 2, 3, 4, 6 , 8, 12, 24, 48, and 72 hours later, 100 μL of whole blood was collected from the tail vein. During this time, food was freely consumed. After adding heparin to the collected whole blood, it was centrifuged at 1500 × g for 5 minutes to obtain plasma.

  Distilled water (970 μL) was added to the obtained plasma (30 μL), and the internal standard solution (10 μL) was further added. 1M hydrochloric acid (1 mL) and diethyl ether (5 mL) were added to the mixture, and the mixture was stirred at 250 rpm for 15 minutes using a shaker manufactured by TAITEC. Next, the mixture was centrifuged at 1200 × g and 4 ° C. for 15 minutes to recover the organic layer. Furthermore, diethyl ether (5 mL) was added to the aqueous layer again, and the same treatment was performed to recover the organic phase. While heating the obtained organic phase to 40 ° C. with a heat block, ether was volatilized under a nitrogen stream. HPLC residue mobile phase solvent (acetonitrile: 0.02 M citrate buffer = 40: 60, citrate buffer pH: 3.7, 100 μL) was added to the resulting residue to dissolve the residue, and then the membrane was dissolved. The solution was filtered through a filter (Millipore, millex-LG, 0.2 μm), and 60 μL was injected into the HPLC apparatus. As the HPLC column, CAPCELL PAK C18 SG120 (4.6 × 150 mm) manufactured by Shiseido was used. The results are shown in FIG. In addition, “FA / IS” on the vertical axis in FIG. 1 is the peak area of flurbiprofen, which is an internal standard: the peak of fenofibric acid, which is a hydrolyzate of fenofibrate, relative to IS. The area: FA ratio is shown. In addition, “#” is p <0.05, “##” is p <0.01, “$” is p <0.001, and each indicates a significant difference with respect to the fenofibrate solution. .

  As shown in FIG. 1, when the polyalcohol compound of the present invention is orally administered, the blood concentration of fenofibric acid, which is an active metabolite, is significantly higher than when fenofibrate is orally administered. Moreover, when the area under the curve was compared, the area when the polyalcohol compound of the present invention was administered was 3.75 times that of the fenofibrate solution. Such a result is considered to be due to the improvement of intestinal tract absorption by modifying fenofibrate with the polyalcohol moiety according to the present invention. This is an unexpected result considering that intestinal absorbability generally decreases as water solubility improves.

  From the above results, the polyalcohol compound of the present invention can be expected to safely exhibit excellent pharmacological action with a smaller dose than conventional antihyperlipidemic drugs.

Test Example 2 Safety Test Polyalcohol part (1,3-di (1,3-dihydroxyisopropoxy) -2-propanol) of the polyalcohol compound produced in Production Example 3-2 was added to 1.5 of sodium carboxymethylcellulose. It melt | dissolved in the mass% aqueous solution, and set it as the solution of concentration: 58mg / mL. Five 10-week-old male SD rats were divided into two groups, and the solution and an aqueous sodium carboxymethyl cellulose solution as a control were orally administered once a day at a rate of 1 mL / kg for 7 days. The change in body weight is shown in FIG.

  As shown in FIG. 2, even when the polyalcohol part according to the present invention was administered, the body weight of the rats was hardly different from the control group. Thus, it was concluded that the polyalcohol moiety according to the present invention is not as toxic as it causes weight loss.

Claims (7)

A polyalcohol compound represented by the following formula (I).

[Wherein, R represents a residue obtained by removing a carboxyl group or an ester group from a fibrate antihyperlipidemic compound. X represents a linking group for bonding n polyalcohol moieties to R. n shows the integer of 1-8. ] The polyalcohol compound according to claim 1, wherein R represents a group represented by the following formula (II).

[Wherein, R ¹ and R ² are the same or different and each represents a C ₁ -C ₆ alkyl group. R ¹ and R ² may be bonded together with the carbon atom to which they are bonded to form a cycloalkyl ring. Y represents a halogen atom group, a 2- (halogen-substituted benzoylamino) ethyl group or a halogen-substituted benzoyl group. ]   The polyalcohol compound according to claim 1, wherein R represents a residue obtained by removing a carboxyl group or an ester group from clinofibrate, clofibrate, bezafibrate or fenofibrate. The polyalcohol compound according to claim 1, wherein n represents 2 ^m (where m represents an integer of 0 to 3).   The polyalcohol compound according to claim 1, wherein n represents 1 or 2.   The pharmaceutical containing the compound of any one of Claims 1-5.   An antihyperlipidemic oral drug comprising the compound according to any one of claims 1 to 5.

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