KR20100120244A - Solid medicinal preparation improved in solubility and stability and process for producing the same - Google Patents

Abstract

The present invention relates to a solid preparation having improved solubility while maintaining the stability of the preparation by adding a formulation to a poorly water-soluble chemical substance as a medicinal active ingredient. Specifically, it is a solid preparation comprising a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as a medicinal active ingredient, (1) the poorly water-soluble chemical substance forms a solid dispersion together with the water-soluble polymer substance, (2 (3) The water-soluble polymer material forming the solid dispersion is in the form of microflakes, and (3) the water-soluble polymer material in the form of the microflakes is adsorbed and / or adhered to the surface of the inorganic porous material. It is a solid formulation with improved solubility. These solid preparations can be prepared by stirring and mixing a solution obtained by dissolving a poorly water-soluble chemical substance and a water-soluble high molecular substance as a pharmaceutically active ingredient in an organic solvent, followed by granulation and drying.

Description

Solid formulations with improved solubility and stability and methods for their preparation {SOLID MEDICINAL PREPARATION IMPROVED IN SOLUBILITY AND STABILITY AND PROCESS FOR PRODUCING THE SAME}

The present invention relates to solid preparations with improved solubility and stability and methods for their preparation.

More specifically, it is a solid preparation containing a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as a medicinal active ingredient,

(1) the poorly water-soluble chemical forms a solid dispersion with the water-soluble high molecular material,

(2) The water-soluble high molecular substance which forms the said solid dispersion is a fine piece, and

(3) The present invention relates to a solid preparation having improved water solubility and a method for producing the same, wherein the fine flake water-soluble high molecular material is held in an adsorbed and / or adhered state to the surface of the inorganic porous material.

The solid preparation of the present invention is excellent in solubility, has high bioavailability (bioavailability), and can be sufficiently exerted in its original activity as a pharmaceutically active ingredient in a very small dosage. Therefore, when the solid preparation of the present invention is administered to a patient, it is possible to reduce the burden on the patient and to reduce the risk of side effects. In addition, the present solid preparations have excellent stability, and these solid preparations can be produced very efficiently and easily by the production method of the present invention.

In addition, since the solid preparation of the present invention is rapidly and completely absorbed into the body, when the technique is applied to, for example, a microsomal triglyceride transfer protein (MTP) inhibitor or the like, a simple dose reduction or By selectively inhibiting the target small intestine MTP without remaining in the effect of improving bioavailability, it can be an excellent drug for treating hyperlipidemia, atherosclerosis, coronary artery disease, obesity, diabetes or hypertension, alleviating side effects such as fatty liver.

Hereinafter, the background art regarding formulation for improving the solubility of a poorly water-soluble chemical substance as a medicinal active ingredient, and the background art regarding the MTP inhibitory substance as an example of the medicine considered to be suitable for application to the solid formulation of this invention are demonstrated. do.

1. Formulation Technology

1-1. Pharmaceutical And Solubility And Stability

In the design of pharmaceutical solid preparations, especially oral preparations, it is important to design a sufficiently high bioavailability in terms of efficacy of the drug.

Many factors influence the bioavailability of oral administration. These factors include water solubility, drug absorption in the entire digestive tract, strength of administration, and first-pass effect, but especially in poorly water-soluble chemicals, their dissolution rate is known to be a rate-limiting step of absorption. In the development of pharmaceuticals, solubility in water is the most important and high priority factor.

Unfortunately, many pharmaceutical chemicals are poorly soluble in water, and therefore have a drawback that their bioavailability is very low because only a few of the doses are transferred and absorbed into the blood even when administered orally.

The solubility test of 338 orally administered pharmaceutical compounds except for protein preparations was carried out in Japan. Solubility tests were performed to classify from `` very soluble '' to `` nearly insoluble. '' There are also reports that 150 samples of compounds having a solubility of 0.1 mg / ml or less accounted for about 40% of the total.

As a drug, in order to exert its efficacy as described above, its bioavailability, i.e., its solubility, must be high, but on the other hand, since the drug is preserved over an organ, its stability is also a very important requirement.

In general, crystals of chemicals are superior in stability to their amorphous state, but are poor in terms of solubility. Thus, the solution of stability and solution of solubility have mutually opposite relationship, and it was extremely difficult to solve the problem of stability and solubility simultaneously.

1-2. On improving solubility of poorly soluble drugs

In order to improve the solubility of these poorly soluble drugs, various formulations have been proposed, such as conversion to salt compounds, solvate formation, crystal polymorphisms, fine powdering of drugs, and mixed grinding with excipients.

However, formulation techniques such as improving solubility while maintaining stability, in particular, formulation formulations that can be applied to any drug, have not yet been found.

Solid dispersions have been widely used as a means for improving solubility of poorly soluble chemicals, and many poorly soluble chemicals have been put to practical use as solid dispersion formulations. Solid dispersions are defined as "dispersion of one or more active ingredients in a carrier or matrix thereof inert in a solid state, prepared by melting, solvent or melt-solvent methods. 1).

That is, the solid dispersion is an operation of forming a uniform liquid phase by dissolving the chemical in an organic solvent together with a carrier made of an inorganic porous material or a polymeric material to form a uniform liquid phase, or drying both the polymer material and the chemical and then solidifying it. In the solid mixture obtained by the chemical agent, the drug is uniformly dispersed in the microcrystal or the molecular size, that is, the monomolecular state, in or on the surface of the carrier matrix. Generally, amorphous is in a high energy state compared to crystal, and the dissolution rate is improved or the chemical concentration in the aqueous solution is increased. As a result, the absorption rate is increased to increase the blood concentration (for example, Patent Document 1 and 2).

1-3. About the preparation method of the solid dispersion

Although various kinds of methods have been proposed for the above-mentioned solid dispersion production method, a practical method includes a solvent method, a melting method, a spray drying method (spray drying method), a mixed grinding method and the like. Among these, the melting method and the solvent method are described below.

(A) melting method

The melting method is a method of obtaining a solid dispersion by heating and melting a carrier made of an inorganic porous material or a high molecular material and a chemical which is an active ingredient. For example, an inorganic substance selected from the group consisting of itraconazole, a triazole-based antifungal agent, calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate silicate, magnesium aluminum silicate, synthetic aluminum silicate, and hydrous silicon dioxide A method for producing a solid dispersion composed of itraconazole and an inorganic porous material has been reported, which is characterized by mixing the porous materials, then heating and melting to cool the obtained melt (see Patent Document 3, for example). Alternatively, a method of melt extruding a mixture containing itraconazole and a water-soluble polymer and then grinding the melt extruded mixture has also been reported (see Patent Document 4, for example).

(B) Solvent Method

The solvent method is a method of producing a solid dispersion by dissolving a water-soluble polymer as a drug and a carrier in a solvent such as an organic solvent and then distilling off the solvent. By dissolving poorly water-soluble chemicals in a solvent, it is thought that the chemicals can be amorphized and dispersed in a carrier in this state, thereby improving solubility and bioavailability (see Patent Document 5, for example).

As a specific example, a polymer base such as nifedipine, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and methyl cellulose, which are poorly water-soluble chemicals, is used on fine granules obtained by granulating lactose and the like into a water-soluble polymer such as hydroxypropyl cellulose. The so-called spray-drying method which sprays and dries the solution melt | dissolved with the organic solvent, and obtains a solid dispersion is known (for example, refer patent document 6 and 7).

In addition, water-soluble chemicals such as cycloheptadines and water-soluble polymers such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, and hydroxypropylcellulose are dissolved in water / alcohol, and then spray granulated in lactose to solid dispersion. It has also been reported to produce (see Patent Document 5, for example).

In addition, "For a particular poorly water-soluble chemical | medical agent, the chemical | medical agent is melt | dissolved in an organic solvent, and mixed with an inorganic porous substance or a polymeric substance, and the method of disperse | distributing a chemical | medical agent to an inorganic porous substance by distiling a solvent after that, and the method of disperse | distributing to a polymeric substance This is known. However, this method is not adaptable to all poorly soluble chemicals, and the physical properties of the poorly soluble chemicals must be examined in detail to determine the optimal one. ”(See Patent Document 8, for example.) ).

Also known are pharmaceutical compositions and methods for preparing the same, in which solubility and absorption are improved by amorphizing 3-bis (4-methoxyphenyl) methylene-2-indolinone in the presence of a polymeric material and / or an inorganic porous material, Moreover, as a specific manufacturing method thereof, the method of amorphizing TAS-301 by the heat melting method or the solvent method using an inorganic porous material, and the method of the amorphous method by the solvent method using a high molecular material are known. However, the technical significance of using both of a high molecular material and an inorganic porous material at the same time is not known at all (see Patent Document 8, for example).

(C) Carrier in solid dispersion

There are two types of carriers for solid dispersions: polymeric materials and inorganic porous materials.

As the polymer substance, those which are usually dissolved in water or weakly basic to strongly basic buffers, and pharmaceutically acceptable can be used, but the kind thereof is not particularly limited. For example, hydroxypropyl methyl cellulose (Shin-Etsu Chemical Co., Ltd .; brand name TC-5), hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, methyl cellulose, carboxymethyl ethyl cellulose, poly Vinylpyrrolidone (BASF; trade name collidone), polyethyleneglycol, ethyl acrylate methyl methacrylate copolymer, methacrylic acid copolymer or the like or a mixture thereof was used (see Patent Document 8, for example).

On the other hand, the inorganic porous material I, fine particles or powder having a large number of fine pores, and is not particularly limited as long as it is stable at the heat-melting temperature of the active ingredient, for example, calcium silicate, hard anhydrous silicic acid, magnesium silicate, anodized silicate Magnesium mate, magnesium metasilicate, magnesium aluminum silicate, synthetic aluminum silicate, hydrous silicon dioxide and the like were used. The particle diameter is 0.01 μm to 100 μm, on average 0.1 to 10 μm.

Although the amount of these polymeric substances and / or inorganic porous substances is not particularly limited, it depends on the type of drug or carrier used, but in many cases, about 0.5 to 5 times (weight ratio) relative to drug 1 is considered appropriate. See, eg, patent document 8).

Alternatively, formulations incorporating hydrophobic excipients, stabilizers and disintegrating agents are also known.

For example, (a) solid crystals of amorphous pharmaceutically active agents and pharmaceutically acceptable hydrophobic excipients which are crystalline in the state and slightly water soluble at ambient pressure and ambient temperature, (b) polyethylene glycol, sugars, sorbitol, A stabilizer consisting of mannitol, polyvinylpyrrolidone, or at least one cellulose ether, and (c) a disintegrant comprising sodium croscarmellose sodium, sodium starch glycolate, crospovidone, or crosslinked polyacrylate. Granulated particles are known (see Patent Documents 9 and 10, for example).

(D) Mixing ratio of drug and carrier in solid dispersion

For the ratio of the drug and the base (carrier) in the solid dispersion, for example, nifedipine, which is one of the calcium antagonists commonly used for the prevention and treatment of angina or hypertension, is a high-molecular substance (hydroxyl) for the drug (nifedipine). Reported that the proportion of propylmethylcellulose) is preferably 1.5 to 3 parts by weight. The reason for such a blending ratio is that when the amount of the base compounded is 1 part by weight or less with respect to 1 part by weight of nifedipine, the composition in the form of a solid dispersion is not obtained. It is because the preparation manufactured by the process becomes large and it is unpreferable (for example, refer patent document 11).

Although the technique of the said solid dispersion is an excellent technique, this solid dispersion technique is not absolute and it cannot be said that amorphous can always be obtained, As a result, the dissolution rate of a chemical | medical agent may not be increased as a result. For example, some parameters, such as the interaction of polymers with active ingredients, their proportions and the production techniques employed, influence the chemical-physical properties of the resulting solid dispersions. For this reason, it has also been reported that for each specific active ingredient, both the polymer and the operating conditions need to be selected for the preparation of the dispersion causing the conversion to the amorphous form and for the maintenance of the amorphous form of the product (for example, the patent literature) 12).

In addition, even when any of the above-mentioned melting method and solvent method were employed, the solid dispersion obtained in this manner was pulverized and sieved, and it was necessary to mix other substances to form a granule, a tablet, or the like as needed (Example See, for example, Patent Document 13). In particular, in the solvent method, a dispersion may become a film form depending on manufacturing conditions, and in this case, it was necessary to cut and refine | miniaturize the said film.

1-4. About stability

The stability of the formulation is one of the important factors for ensuring the efficacy and quality of the pharmaceutical.

Even when applying for the approval of manufacturing a drug, stability tests such as long-term preservation tests, accelerated tests, and overload tests on the original drug and its preparations are required to obtain information necessary for setting the drug storage method and shelf life. .

In general, chemicals are more stable than amorphous. However, from the standpoint of solubility, the chemicals constituting a stable crystalline form have a problem that it is difficult to dissolve.

2. About MTP

Hereinafter, a lipid absorption inhibitor, especially an MTP inhibitor, will be described as an example of a poorly water-soluble drug.

MTP is expressed in both organs of the liver and small intestine and is a transport protein that catalyzes the migration of triglycerides, cholesteryl esters and phosphatidylcholine between small monolayer vesicles, producing lipoproteins.

As such, MTP can not only lipidize APO B-100 newly synthesized in the liver, but also lipid APO B-48 newly synthesized in the intestine.

Thus, lipoparticles rich in triglycerides such as VLDL (ultra low specific lipoprotein) and chiromicron, respectively, are produced. In this way, MTP inhibitors and / or Apo B secretion inhibitors can be expected to reduce the plasma concentrations of LDL-c and triglycerides and also reduce the absorption of lipids in the intestine.

Thus, MTP inhibitors and / or Apo B secretion inhibitors may be used for non-insulin dependent diabetes mellitus, coronary heart disease, pancreatitis, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, mixed dyslipidemia, postprandial hyperlipidemia, atherosclerosis It can be used to treat sclerosis and obesity.

2-1. MTP and Apo B and Blood Lipids

Conventionally, in atherosclerosis, hyperlipidemia, diabetes mellitus, hypertension, etc. have become one of the risk factors. Hyperlipidemia refers to a state in which lipids such as cholesterol are increased in the blood, and as an adult, it is caused by genetic abnormalities such as enzymes, proteins, and lipoprotein receptors involved in the metabolism of low-weight lipoprotein (LDL). Primary hyperlipidemia, secondary hyperlipidemia resulting from various diseases or medications, and acquired hyperlipidemia based on hypertrophy.

Lipids ingested by the meal are absorbed in the small intestine by the operation of bile acids and secreted into the blood via lymphatic vessels as chiromicrons. The secreted chiromicron is decomposed into free fatty acids by triglyceride (TG) moiety by the operation of lipoprotein lipase (LPL) present in capillaries, resulting in chiromicron with high content of cholesteryl ester (CE) It is blown into the liver through its chiromicron receptor. In addition, the chiromicron taken in the liver is converted to CE and TG and associated with apolipoprotein B synthesized on the rough endoplasmic reticulum to form VLDL. The VLDL is transported to a Golgi apparatus, modified, and then secreted out of the cell to form intermediate specific gravity lipoprotein (IDL) by the operation of LPL, and converted to LDL by hepatic triglyceride lipase (HTGL), which is lipid or peripheral. Distributed to the organization.

In the formation of chiromicron in the small intestine or VLDL in the liver, the presence of a protein having TG or CE transport activity in the microsomal fraction of the small or small intestine has been pointed out previously, but in 1985 by Wetero et al. From the microsomal fraction its protein, MTP, was purified and purified from the liver and intestine (see Non-Patent Document 2). However, this MTP has been in the spotlight in the field of clinical medicine since it was reported in 1993 that the cause of β-lipoproteinemia was a deficiency of MTP. That is, this symptom shows no abnormality in the gene related to apolipoprotein B, but apolipoprotein B is hardly detected in serum, serum cholesterol is 50 mg / dL or less, and serum triglyceride is extremely low. In addition, lipoproteins containing apolipoprotein B such as chiromicron, VLDL, and LDL are not present in the blood at all. As a result, it has been disclosed that MTP is an essential protein for the association of apolipoprotein B with TG and CE, that is, the formation of VLDL and chiromicron, and has a periodic function in their secretion.

Originally, since lipids are insoluble in water, lipids in the blood are associated with hydrophilic proteins called apolipoproteins and exist as so-called lipoproteins. VLDL, IDL, LDL or chiromicron and the like regarding hyperlipidemia are all lipoproteins. MTP is present in the microsomal fractions of hepatocytes and small intestinal epithelial cells and is responsible for the transport of TG or CE within the cells. In the liver and small intestine, depending on the synthesis of apolipoprotein B (apolipoprotein B100 in the liver, apolipoprotein B48 in the small intestine), TG or CE is applied to each apolipoprotein B by the transfer action of MTP. In association, VLDL or chiromicron is formed. As a result, these lipoproteins are secreted outside the cells as VLDL in the liver and chiromicron in the small intestine.

MTP is indispensable for building this lipoprotein. In other words, by inhibiting the activity of MTP, the transfer of lipids such as TG and CE to apolipoproteins is inhibited, and the formation of lipoproteins can be inhibited.

On the other hand, in general, it has been found that LDL is closely involved in the progression of atherosclerosis, and LDL penetrates the vascular endothelium and is deposited on the intercellular matrix of the blood vessel wall, whereby oxidative degeneration occurs and lipid peroxide and denatured protein are formed. It causes a series of inflammatory reactions, resulting in macrophage invasion and lipid deposition / foaming of the blood vessel walls, suppuration and proliferation of smooth muscle cells, and an increase in the intercellular matrix, thereby forming atherosclerotic plaques. Therefore, it is thought that the reduction or LDL can prevent or treat atherosclerosis, coronary artery disease, and hypertension.

As such, MTP can not only lipidize Apo B-100 newly synthesized in the liver, but also lipid Apo B-48 newly synthesized in the small intestine.

Thus, MTP inhibitors and / or Apo B secretion inhibitors inhibit the formation of lipoproteins such as chiromicron, VLDL, LDL, thereby reducing the plasma concentrations of LDL-c and triglycerides, and also reducing lipid absorption in the intestine. It is also expected to be a drug for the prevention or treatment of a new type of hyperlipidemia, atherosclerosis, coronary artery disease, diabetes, obesity or hypertension, and also as a therapeutic or prophylactic agent for pancreatitis, hypercholesterolemia, hypertriglyceridemia and the like.

On the other hand, as the development of MTP inhibitors progresses, MTP inhibitors exert the effect of lowering lipids in the blood, but it has been pointed out that the possibility of causing fat accumulation (fatty liver) in the liver has been feared. Therefore, if only the small intestine MTP can be selectively inhibited before it reaches the liver, triglycerides and cholesterol in the blood can be significantly lowered without accompanying side effects such as fatty liver.

From this, there was a strong demand for novel MTP inhibitors and their improved preparations without side effects such as fatty liver.

2-2. MTP Inhibitors

As such MTP inhibitory substance and / or Apo B secretion inhibitory substance, especially MTP inhibitory substance, the following compounds are already known.

(A) Unexamined-Japanese-Patent No. 11-228569 describes the following 3-piperidyl-4-oxoquinazolin derivatives (refer patent document 14).

Wherein R is formula (i)

[Wherein, R ¹ and R ² may be the same or different and each represents a hydrogen atom; Lower alkyl groups having 1 to 4 carbon atoms; Aralkyl group; Benzoyl group; Cycloalkyl groups having 3 to 7 carbon atoms; Aryl group; Or a heteroaryl group containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom (where these cycloalkyl groups, aryl groups or heteroaryl groups are halogen atoms; lower alkyl groups having 1 to 4 carbon atoms; 1 carbon atom) 1 to 3 lower haloalkyl groups; nitro groups; 1 to 4 carbon atoms lower alkoxy groups; amino groups; amino groups substituted with 1 to 4 carbon atoms lower alkyl groups; hydroxyl groups; phenoxy groups; and 1 to 3 substituents selected from sulfo groups May be substituted) and also R ¹ or R ² At least one of which is not a hydrogen atom] or formula (ii)

[Wherein, A and B may be the same or different and include an aromatic hydrocarbon ring; Aromatic heterocycles containing 1 to 3 hetero atoms selected from nitrogen, sulfur and oxygen atoms; Cycloalkane ring having 3 to 7 carbon atoms; Or a cycloalkene ring having 5 to 7 carbon atoms (where these aromatic hydrocarbon ring, aromatic heterocycle, cycloalkane ring or cycloalkene ring is a halogen atom; lower alkyl group having 1 to 4 carbon atoms; lower haloalkyl group having 1 to 4 carbon atoms; hydroxyl group; nitro group) A lower alkoxy group having 1 to 4 carbon atoms, an amino group substituted with an amino group substituted with a lower alkyl group having 1 to 4 carbon atoms, and a 1-3 substituent selected from a sulfo group), and X is a single bond; Linear or branched lower alkylene groups having 1 to 4 carbon atoms; Linear or branched lower alkenylene groups having 2 to 4 carbon atoms, wherein these lower alkylene groups or lower alkenylene groups are selected from halogen atoms; hydroxyl groups; nitro groups; lower alkoxy groups having 1 to 4 carbon atoms; amino groups; and sulfo groups May be substituted with a group); Oxygen atom; Sulfur atom; An imino group which may be substituted with a lower alkyl group having 1 to 4 carbon atoms; Carbonyl group; -OZ-; -ZO-; -SZ-; -ZS-; -NH-Z-; -NR ⁵ -Z-; -Z-NH-; Or -Z-NR ^5- , wherein Z is a lower alkylene group having 1 to 4 carbon atoms; or a carbonyl group, R ⁵ is a lower alkyl group having 1 to 4 carbon atoms, and Y is a single bond; Linear or branched lower alkylene groups having 1 to 4 carbon atoms; Or a carbonyl group, n is an integer selected from 1 to 4, R ³ and R ⁴ may be the same or different, and a hydrogen atom; Lower alkyl groups having 1 to 4 carbon atoms; Halogen atom; Lower haloalkyl groups having 1 to 4 carbon atoms; Hydroxyl group; Amino group; Or nitro group.}

(B) Japanese Patent Publication No. 2004-514676 (WO2002 / 042291) describes an MTP inhibitory substance consisting of a benzamide compound having a piperidine ring as follows (see Patent Document 15).

(Wherein,

Z represents a biphenyl optionally substituted with one or more substituents selected from trihalomethyl and trihalomethoxy in the 2 ', 3', 4 ', 5' and 6 'positions. Het represents halo, cyano, nitro, (C ₁ to C ₆ ) alkyl, (C ₆ to C ₁₂ ) aryl, (C ₁ to C ₆ ) alkoxy, hydroxyl, (C ₁ to C ₆ ) thioalkoxy Quinolyl or quinoxalyl or pyridyl optionally substituted with one or a plurality of substituents selected from carboxyl and (C ₁ to C ₆ ) alkoxycarbonyl.)

(C) Japanese Patent Publication No. 2003-535900 (WO01 / 097810) describes an MTP inhibitory substance consisting of a benzamide derivative represented by the following formula (see Patent Document 16).

[Wherein A is N or CH;

X is the following group; (i) one or two double bonds while also containing a further one or more hydroxy, C _{1 - 6} alkyl, C _{1 - 6} alkoxy, C _{1 - 6} acyl, or C _{1 - 6} acyl group optionally substituted -C ₁ also _in-6 alkylene -, (ii) oxo, sulfonyl, thioxo, (iii) -C _{1 - 6} alkylene-carbonyl -, -C _{1 - 6} alkyl sulfonyl rensul -, -C _{1 - 6} alkyl Lenti-oxo _{-, (iv) -C 2 -} 6 alkylene _-, -C ₂ - ₆ alkylene-thio _-, -C ₂ - ₆ alkylene group (NH or NC _{1 - 6} alkyl) amino -, (v ) -C _{1 - 6} alkylene carboxy _-, -C ₁ - ₆ alkylene thioamide _-, -C ₁ - ₆ alkylene group (NH or NC _{1 - 6} alkyl) carboxamide, and (vi) -C _{2 - 6} alkylene-carbonyl _-, -C ₂ - ₆ alkylene thiocarbonyl _-, -C ₂ - ₆ alkylene group (NH or NC _{1 - 6} alkyl) aminocarbonyl-is selected from the group consisting of;

Z is while also contain a direct bond or or one double bond, and one or more hydroxy, C _{1 - 6} alkyl, C _{1 - 6} alkoxy, C _{1 - 6} acyl, or C _{1 - 6} substituted with an acyloxy , which may be -C _{1 - 6} alkylene-an;

R ¹ is selected from the following group: (i) hydrogen, C _{1 - 3} perfluoroalkyl, (ii) C _{6 - 10} aryl, C _{3 - 8} cycloalkyl, and their fused benz derivatives thereof, C _{7 - 10} poly cycloalkyl, C _{4 - 8} cycloalkenyl, C _{7 - 10} poly cycloalkenyl, (iii) a heterocyclyl selected from monocyclic and fused polycyclic part, wherein said part containing a total of 5 to 14 ring atoms Wherein the portion contains a total of 1 to 4 heterocyclic atoms independently selected from oxygen, nitrogen and sulfur, and the individual rings of the portion may be independently saturated, partially unsaturated or aromatic and also (iv) X is C _{1 - 6} alkylene, or Z is a direct link, or Z is a C _{1 -} For ₆ to alkyl any of the alkylene, R ¹ is additionally halogen, cyano, nitro or C _{1 - 6} acyl be date and;

Wherein, if R ¹ contains one or more rings, the rings may each independently have 0 to 4 substituents independently selected from the following groups: (i) halogen, hydroxy, cyano, nitro , formyl, C _{1 - 6} alkylsulfonylamino, (ii) C _1-6 alkyl, C _{3 - 8} cycloalkyl, C _{1 - 3} alkyl, (iii) a perfluoroalkyl C _{1 - 6} alkoxy, methylenedioxy , C _{1 - 3} perfluoro alkoxy, C _{1 - 6} alkylthio, (iv) amino, C _{1 - 6} alkylamino, di -C _{1 - 6} alkyl, amino, (v) phenyl, phenoxy, phenylthio, halo phenylthio, benzyl, benzyloxy, (vi) hydroxy-carbonyl, C _{1 - 6} alkoxycarbonyl, (vii) aminocarbonyl, C _{1 - 6} alkyl-aminocarbonyl, di -C _{1 - 6} alkyl, aminocarbonyl di -C _{1 - 6} alkyl, aminocarbonyl-C _{1 - 6} alkoxy, C _{1 - 3} perfluoroalkyl-aminocarbonyl, (viii) C _{1 - 6} acyl, C _{1 - 6} acyloxy, C _{1 - 6} acyl oxy-C _{1 - 6} alkyl, C _{1 - 6} acylamino, and (ix) an aromatic heterocyclyl consisting of monocyclic part, where total is the portion for containing, and wherein the part is independently selected from oxygen, nitrogen and sulfur to 6 ring atoms of 5 to 1 to 4 one containing a hetero ring atom, and wherein said heterocyclyl groups are each halogen, C _{1 - 4} alkyl, C _{1 - 4} alkoxy, C _{1 - 3} perfluoroalkyl and C _{1 -} to _{3-perfluoroalkyl} group independently selected from alkoxy May be substituted by one or more groups, which are;

Y is a direct bond or oxy, -C _{1 - 6} alkylene -, - oxy-C _{1 - 6} alkylene-or a heterocyclyl consisting of monocyclic portion, wherein the portion containing 5 ring atoms, wherein the part of the It contains a total of 1 to 4 heterocyclic atoms independently selected from oxygen, nitrogen and sulfur, which rings may be independently saturated, partially unsaturated or aromatic;

R ² is phenyl, C _{3 - 8} cycloalkyl, or a heterocyclyl consisting of monocyclic part, wherein the part contains at 6 ring atoms of 5 to gun in which the part is independently selected from oxygen, nitrogen and sulfur 1 to 4 may be a heterocycle saturated with the ring independently containing, and the atom, and may be a partially unsaturated be either or an aromatic, R ² are each halogen, C _{1 - 4} alkyl, C _{1 - 4} alkoxy, C _{3 -} from ₄ alkyl aminosulfonyl _{- 8} cycloalkyl, C _{1 -} to ₃ perfluoroalkoxy, hydroxy-carbonyl, C _{1 - - 3} alkyl, C ₁ perfluoroalkyl ₆ alkoxycarbonyl, cyano, nitro, C ₁ May be substituted by one or more groups selected independently;

Means a group ₃ is independently selected from alkoxy perfluoroalkyl one or more of the _- R ³ is hydrogen, a halogen, C _{1 - 4} alkyl, C _{1 - 4} alkoxy, C _{1 - 3} perfluoroalkyl or C ₁ .]

(D) Japanese Patent Publication No. 2003-521484 (WO01 / 047898) describes an MTP inhibitory substance consisting of a substituted piperazine derivative represented by the following chemical formula (see Patent Document 17).

[Wherein m represents the number 2 or 3, n represents the number 1, 2, 3, 4 or 5 ”and X represents a carbon-carbon bond, an oxygen atom, a methylene group, a methylene group, an imine group or an N— ( C _{1 -3} -alkyl) -imino group, R _a is a dinuclear or trinuclear aromatic hydrocarbon (an internuclear methine group may be substituted by a nitrogen atom), a dinuclear or trinuclear heteroaromatic bound to a piperazino group via a carbon atom 5-membered heteroaryl rings containing a cyclopentadienyl ring condensed through one or two nitrogen atoms and a vinylene group (methine groups may be further substituted by nitrogen atoms, and / or internuclear methine groups are nitrogen atoms May be substituted by C _{1 -3} -alkyl group, phenyl-C _{1 -3} -alkyl group, phenyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group as necessary. Imino groups, or oxygen atoms or sulfur And a phenyl ring or a 6-membered heteroaryl ring condensed through one or two available vinylene groups (including one, two or three nitrogen atoms, the condensed rings of which may be the same or different) Or a 5-membered heteroaryl ring containing a naphthyl ring condensed through one of two available vinylene groups (in the bicyclic or tricyclic groups thus formed, the internuclear carbon atoms may be further substituted by nitrogen atoms) Yes), or if necessary C _{1 -3} - alkyl, phenyl -C _{1 -3} - alkyl group, a phenyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl groups optionally substituted imino group, or by in 5 including a phenyl ring, a naphthyl ring, a pyridine ring, a pyridazine ring, a pyrimidine ring or a pyrazine ring condensed through an oxygen atom or a sulfur atom, and one or two nitrogen atoms and an available vinylene group Heteroaryl ring (an internuclear carbon atom may be substituted by a nitrogen atom), 1, 2 or 3 nitrogen atoms, and pyridinyl ring, pyridazinyl ring, pyrimidinyl ring or pyran condensed through a vinylene group Naphthyl ring or 6-membered heteroaryl ring containing a genyl ring (nuclear carbon atoms may be substituted by nitrogen atoms), or 6-membered heteroaryl condensed through a phenyl ring and 1 or 2 available vinylene groups Rings (comprising one, two or three nitrogen atoms) (these condensed rings may be identical or different, and among the bicyclic or tricyclic groups thus formed, the internuclear carbon atoms may be further substituted by nitrogen atoms) Or a phenyl ring or 6-membered heteroaryl ring (including one, two or three nitrogen atoms) condensed through a pyridine ring, a pyrazine ring or a pyridazine ring and two available vinylene groups ( S may be the same ring is condensed and may also be different, thus formed tricyclic dishes from internuclear carbon atoms which may be further substituted by a nitrogen atom) in yirueojim] a show, the affected tableware and tricyclic tableware said to R _a is fluorine atom, chlorine atom, bromine atom or iodine atom in the carbon skeleton, C _{1 -3} - alkyl, hydroxy, C _{1 -3} - alkoxy group, a carboxy group, C _{1 -3} - alkoxycarbonyl group, aminocarbonyl group, C _{1 -3} - alkylamino group or an N, N- di - (C _{1 -3-alkyl)} - may be further mono- or disubstituted by an aminocarbonyl group, these substituents may be the same and may also be different, and the alkyl part and hydrogen atoms in the alkoxy moiety may be substituted in whole or in part by a fluorine atom, R _b and R _c is a hydrogen atom or a C _{1 -3} in each case independently of one another - or the group Out, (which may be the same, they may also be different), R _f and R _g is a hydrogen atom or a C _{1 -6} - (with its hydrogen atom may be substituted in whole or in part by fluorine atoms) alkyl group, C _{3 - 7-cycloalkyl} group, a phenyl group, C _{1 -3-alkoxy-carbonyl} -C _{1 -2} - alkyl group, a carboxy -C _{1 - 2} alkyl, methoxy -C _{2 -3} - alkyl group, a heteroaryl group, a phenyl -C _{1 -3-alkyl} or heteroaryl ₁ -C ₃ - alkyl group, the phenyl and heteroaryl groups in the carbon skeleton fluorine atom, a chlorine atom or a bromine atom, a C ₁ - ₃ - alkyl group or a C ₁ - ₃ - alkoxy group (with its hydrogen atom may be substituted in whole or in part by a fluorine atom), a hydroxy group, a carboxy group, C _{1 -3-alkoxycarbonyl} group, aminocarbonyl group, C _{1 -3-alkyl-aminocarbonyl} group, N, N- di- ( C _{1 -3-alkyl)} - aminocarbonyl group, N, N- di - (C _{1 -3-alkyl)} - amino group, a nitro group or an amino To an optionally substituted, may be substituted di or tri, these substituents may be the same or may also be different, and / or a hydrogen atom bonded to the nitrogen atom of the heteroaryl group are C _{1 -3} - alkyl group (whose hydrogen atoms may be substituted in whole or in part by fluorine atoms), C _{1 -3-alkyl-carbonyl} or C _{1 - 4} alkoxy-may be replaced by a carbonyl group, or R _f and R _g are nitrogen therebetween Together with the atoms form a 3- to 7-membered cycloalkyleneimino group, and the methylene group at the 4-position of the 6- or 7-membered cycloalkyleneimino group is an oxygen atom or a sulfur atom, a sulfinyl group, a sulfonyl group, an imino group or an N- (C _{1 -3-alkyl)} - and already may be further substituted by a group, the general formula (I) of the tricyclic dishes may be mono- or disubstituted by a fluorine atom or a chlorine atom, a methyl group or a methoxy group, and these substituents Is It may work and may also be different.]

(E) Japanese Patent Publication No. 2003-520270 (WO01 / 053260) discloses an MTP inhibitory substance consisting of a benzamide derivative represented by the following chemical formula (see Patent Document 18).

[Wherein, R ₂ -C, R ₃ -C, R ₄ -C or R ₅ -C may be substituted with N;

In addition, n is 1, 2 or 3;

R ₁ is aryl, heteroaryl or (aryl or heteroaryl) -lower alkoxy;

R ₂ , R ₃ , R ₄ and R ₅ are independently hydrogen, lower alkyl, lower alkoxy, halo, trifluoromethyl or cyano;

R ₆ is

m is 1, 2 or 3;

R ₇ is hydrogen, lower alkyl, (aryl or heteroaryl) -lower alkyl, lower alkoxy, (aryl or heteroaryl) -lower alkoxy, hydroxy, oxo, lower alkylenedioxy or lower alkanoyloxy;

W is O, S or NR ₈ ;

R ₈ is -COR _a ,

-COOR _d , -SO ₂ R _e , hydrogen, lower alkyl, aryl, heteroaryl (or aryl or heteroaryl) -lower alkyl, which may be optionally substituted;

R _a , R _d and R _e are independently lower alkyl, cycloalkyl, adamantyl, aryl, heteroaryl or (aryl or heteroaryl) -lower alkyl which may be optionally substituted;

R _b and R _c are independently hydrogen, cycloalkyl, lower alkyl, aryl, heteroaryl or (aryl or heteroaryl) -lower alkyl, which may be optionally substituted; Or R _b and R _c together form a lower alkylene.

(F) Japanese Patent Publication No. 2003-519131 (WO01 / 047899) describes an MTP inhibitory substance consisting of a substituted piperazine derivative represented by the following chemical formula (see Patent Document 19).

??? in which, n is the number 2, 3, 4 or 5 a represents, X is a carbon-carbon bond, an oxygen atom, a methylene, ethylene, imino or N- (C _{1 -3-alkyl)} - an imino group represents, Y _a represents a carbonyl group or a sulfonyl group, Y _b is a group - (CH _{2) m} - (wherein m represents the number 2 or 3, hydrogen atoms are C _{1 -3} - may be substituted by an alkyl group and, or a methylene group bonded to the nitrogen atom denotes a may be substituted) by a carbonyl group, R is _a C _{1 -6} - alkoxy group, a phenyl -C _{1 -3} - alkoxy group or an amino group (the amino group is a C _{1 - 3-alkyl} group, a phenyl -C _{1 -4} - may be mono- or disubstituted by an alkyl group or a phenyl group, the substituents may be the same and may also be different), a phenyl group, a naphthyl group, a tetrahydronaphthyl group, a phenoxy group, or a heteroaryl group, if necessary a hydroxy group, C _{1 -3} - alkoxy group, C _{1 -4} - alkoxycarbonyl or C _{1 - 4-alkyl-carbonyloxy} groups C _{1 -9} alkyl group which may be substituted (this alkyl moiety is from the C _{1 -3-alkyl} group, one or two phenyl group, a naphthyl group, a fluorenyl group, a phenoxy group, heteroaryl group Group or C _{3-7 -cycloalkyl} group), or C _{3-7 -cycloalkyl} group, phenylcarbonyl group, naphthylcarbonyl group, tetrahydronaphthyl-carbonyl group, phenoxycarbonyl group or hetero substituted by phenyl group arylcarbonyl, C _{1 -9} - alkylcarbonyl group (which is in the alkyl portion by one or two phenyl group, a naphthyl group, a fluorenyl group, a phenoxy group, a heteroaryl group or C _{3 -7} - may be substituted by a cycloalkyl group ), or a phenyl group substituted by a C _{3 -7} - represents a cycloalkyl group, and any phenyl moiety as described in the preceding R _a, naphthyl and heteroaryl portion of aryl portion may be substituted with a group R ₁ and R ₂ And, R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, a cyano group, C _1-3 - alkyl, C _{2 -4} - alkenyl group, a phenyl group, a hydroxy group, C _{1 -4} - alkoxy group, a phenyl -C _1-3 - alkoxy group, a carboxy group, C _1-3 - alkoxycarbonyl group, aminocarbonyl group, C _1-3 - alkylamino group, N, N- di - (C _1-3-alkyl) -amino group, a nitro group, amino group, C _{1 -3-alkylamino,} di - (C _1-3 - alkyl) - amino group, a phenyl -C _{1 -3-alkylamino} group, an N- (C _{1 -3-alkyl)} -phenyl -C _{1 -3} -Alkylamino group, C _{1 -3} -alkylcarbonylamino group, N- (C _{1 -3} -alkyl) -C _{1 -3} -alkylcarbonylamino group, C _{1 -3} -alkylsulfonylamino group or N- (C _{1 -3-alkyl)} -C _{1 -3} - alkyl alcohol represents a sulfonyl group, and R ₂ is a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, a C ₁ - ₃ - alkyl group, a hydroxy group or a C _1-4 alkoxy group represents an , a group of the alkyl moiety and the alkoxy moiety of the R ₁ and R ₂ Standing, a hydrogen atom may be substituted in whole or in part by fluorine, or R ₁ and R ₂ together form a methylene-dioxy, or any phenyl moiety of the a R _a is three chlorine atom or a bromine atom, or It may be substituted by 3 to 5 fluorine atoms, R _b is a carboxy group, C _{1 -6} - alkoxycarbonyl, C _{1 -6} - alkoxycarbonyl -C _{1 -3} - alkyl group, C _{3 -7} - cycloalkoxy A carbonyl group or a phenyl-C _{1-3 -alkoxycarbonyl} group or a R ₃ NR ₄ -CO group, wherein R ₃ and R ₄ (which may be the same and may be different) are hydrogen atoms, C _{1-6 -alkyl} groups (its a hydrogen atom may be substituted in whole or in part by fluorine atoms, and C _{1 -3-C 1 -3} alkyl amino-alkyl moiety is a carboxyl group or a C _{1 -3} - it may be substituted by an alkoxycarbonyl group, or a Army also in 2 position or 3 position Group, C _{1 -3-alkylamino} or di - (C _{1 -3-alkyl)} may be substituted by amino), C _{3 -7-cycloalkyl,} pyridyl, pyridinyl -C _{1 -3} - alkyl a phenyl group, a naphthyl group or a phenyl -C _{1 -3} - represents an alkyl group, the phenyl group is a fluorine atom, a chlorine atom or a bromine atom, a C _{1 -3} in each case - in whole or by an alkyl group (its hydrogen atom may be replaced by fluorine atom some may be substituted), a hydroxyl group, C _{1 -3} - alkoxy group, a carboxy group, C _{1 -3} - alkoxycarbonyl group, aminocarbonyl group, C _1-3 - alkylamino group, N, N- di - (C _{1 -3} -alkyl) -amino group or N, N- di - (C _{1 -3} alkyl) - may be substituted by amino, or R ₃ and R ₄ are 3- to 7-membered cycloalkyl together with the nitrogen atom between them The methylene group of the 4-position of a 6- or 7-membered cycloalkyleneimino group, which forms a lenimino group, and an oxygen atom or a sulfur atom, a sulfinyl group, In the alkyl group, the general formula (I) - Four group, an imino group or N- (C _{1 -3-alkyl)} while already it may be further substituted by the group, and R _c is a hydrogen atom or a C _{1 -3} The tricyclic group may be further mono- or di-substituted by a fluorine atom or a chlorine atom, a methyl group or a methoxy group, and these substituents may be the same or different, and the heteroaryl group is one, two or three nitrogens. 6-membered heteroaryl group containing an atom, or, if necessary C _{1 -3} - which may be substituted by an alkyl group already in accordance with the group, oxygen atom or sulfur atom or a C _{1 -3} required - which may be substituted by an alkyl group Means a 5-membered heteroaryl group containing an imino group and one or two nitrogen atoms or an oxygen atom or a sulfur atom and a nitrogen atom, and a phenyl ring may be condensed to the heteroaryl group via a vinylene group And furthermore, the carboxyl groups described in the definition of the above groups may be substituted by groups which can be converted to carboxyl groups in vivo or by groups which are negatively charged under physiological conditions, and all of the above saturated alkyls containing more than two carbon atoms Moieties and alkoxy moieties may be straight or branched unless otherwise specified.]

(G) Japanese Patent Publication No. 2003-509505 and WO01 / 021604 disclose an MTP inhibitory substance consisting of a substituted piperazine derivative represented by the following formula (see Patent Document 20).

(Wherein n represents number 1, 2, 3, 4 or 5, m represents number 2 or 3, X represents a carbon-carbon bond, an oxygen atom, a methylene group, an ethylene group, an imino group or N- ( C _{1 -3} -alkyl) -imino group, R _a represents a phenyl group or heteroaryl group substituted by groups R ₁ and R ₂ , R ₁ represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, C _1-3 - alkyl group (whose hydrogen atom may then be fully or partially substituted by fluorine atoms), hydroxy, C _{1 -4} - (in his hydrogen atom may be in fully or partially substituted by a fluorine atom), an alkoxy group, a phenoxy group, heteroaryloxy group, phenyl -C _{1 -3} - alkoxy group, a carboxy group, C _{1 -3} - alkoxycarbonyl group, aminocarbonyl group, C _{1 -3} - alkylamino group, N, N- di _- (C ₁ - _3-alkyl) -amino group, a nitro group, an amino group, C _{1 -3-alkylamino,} di - (C _{1 -3} alkyl) - amino group, a phenyl -C _{1 -3} - Al Kill amino, N- (C _{1 -3-alkyl)} -phenyl -C _{1 -3-alkylamino} group, C _{1 -3-alkyl-carbonyl} amino, N- (C _{1 -3} - alkyl) -C _{1 -3} - alkylcarbonyl group, a C _{1 -3} - alkylsulfonylamino group or N- (C _{1 -3} - alkyl) -C _{1 -3} - alkylsulfonyl, an amino group, the phenyl portion or heteroaryl portion of the group R ₁ is 1 to 5 fluorine, chlorine or bromine atom, a C _{1 -3} - alkyl group (whose hydrogen atoms may also be fully or partially substituted by fluorine atoms), a hydroxy group, or C _{1 -4} - alkoxy group (whose hydrogen while atoms may be substituted by that full or part may be substituted), a fluorine atom, and R ₂ is a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, a C _{1 -3} - alkyl group (whose hydrogen atom is fluorine atom in full or in part may be substituted) by, or C _{1 -4} - alkoxy group (whose hydrogen atoms are completely or in part by fluorine atoms Represents may be substituted), or R ₁ and R ₂ together form a methylene-dioxy, or R _a is substituted by a monocyclic heteroaryl group or a phenyl group (this phenyl group or a stage in each case the cyclic heteroaryl The phenyl group and the heteroaryl group in each case a fluorine atom, a chlorine atom or a bromine atom, a C _1-3 -alkyl group (its hydrogen atom may be completely or partially substituted by a fluorine atom), a hydroxy group, C _{1 -3-alkoxy} group, a carboxy group, C _{1 -3-alkoxycarbonyl} group, aminocarbonyl group, C _{1 -3-alkylamino} group or an N, N- di - (C _{1 -3-alkyl)} - aminocarbonyl group substituted by a may be, R _b and R _c are independently hydrogen atom or C _{1 -3} each other represents an alkyl group, and R _f and R _g (which may be the same and may also be different) is hydrogen atom, C _{1 - 6-alkyl} group (whose Bovine atoms that may be fully or partially substituted by fluorine atoms), C _{3 -7} - cycloalkyl group, a phenyl group, a heteroaryl group, a phenyl -C _{1 -3} - alkyl or heteroaryl -C _1-3 - alkyl group in group (its hydrogen atom may be substituted completely or partially by fluorine atoms, the phenyl and heteroaryl groups in each case one to three fluorine, chlorine or bromine atom, one to three C _{1 -3} ), 1 to 3 hydroxy groups, one to three C _{1 -3} - alkoxy group (with its hydrogen atom may be in fully or partially substituted by fluorine atoms), or carboxyl group, C _{1 -3} - an alkoxycarbonyl group, an aminocarbonyl group , C _{1 -3-alkylamino} group, N, N- di - (C _{1 -3-alkyl)} - aminocarbonyl group, N, N- di - (C _{1 -3-alkyl)} - amino group, a nitro group or an amino group It may be substituted by, or in conjunction with R _f and R _g is a nitrogen atom between them 3 to 7-membered cycloalkylene, and already formed a group, 6-, or 7-membered cycloalkylene group is a methylene group in the 4-position of the already oxygen atom or a sulfur atom, a sulfinyl group, a sulfonyl group, an imino group or N- (C _{1 -} It may be further substituted by a ₃ -alkyl) -imino group, the tricyclic group in the formula (I) may be mono- or di-substituted by a fluorine atom or a chlorine atom, a methyl group or a methoxy group, and these substituents may be the same It may also be different and the heteroaryl group may include a six-membered heteroaryl group containing one, two or three nitrogen atoms, or 1 to 4 hetero atoms, for example nitrogen, oxygen and sulfur It means a 5-membered heteroaryl, and a hydrogen atom bonded to the nitrogen which may have C _{1 -3,} if necessary - can be substituted by an alkyl group).

(H) Japanese Patent Publication No. 2003-505373 (WO01 / 005762) describes an MTP inhibitory substance consisting of a benzamide derivative (biphenylamide derivative) represented by the following chemical formula (see Patent Document 21).

[Wherein, n is 1, 2, 3, 4, or a number of from 5, R _a and R _b may be different may be the same and each represent a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, a C _{1 - 3} alkyl group (where hydrogen atoms are all or some of the fluorine atoms may be substituted), a hydroxyl group, C _1-3 alkoxy, amino, C _{1 - 3} alkyl group or a di (C _1-3 alkyl) amino group, R _c is hydrogen atom, C _{1 - 10} alkyl, C _{3 - 7} cycloalkyl or C _{3 - 7} cycloalkyl, -C _{1 -} (where there may be substituted in each case, hydrogen atoms are all or some of the fluorine atoms) ₃ alkyl group, a fluorine atom, , a chlorine atom or a bromine atom, C _{1 - 3} alkyl (where that hydrogen atoms are all or may be partially substituted with a fluorine atom), a hydroxy group, C _{1 - 3} alkoxy groups, C _{1 - 3} alkoxycarbonyl group, aminocarbonyl group, C _{1 - 3-amino-alkyl} group or N, N- di (C _1-3 alkyl) aminocarbonyl , A 3 to 7 membered cycloalkyleneimino group (wherein the methylene group at the 4 position in the 6 or 7 membered cycloalkyleneimino group may be further substituted by an oxygen atom or a sulfur atom), a sulfinyl group, sulfonyl group, imino group or N- (C _{1 - 3} alkyl) imino group, a nitro group, an amino group, C _{1 - 3} alkyl group, a di (C _1-3 alkyl) amino group, C _{1 - 3} alkylcarbonyl group, an N- (C _{1 - 3} alkyl) -C _{1 - 3} alkyl-carbonyl group, C _{1 - 3} alkylsulfonyl group or a N- (C _{1 - 3} alkyl) -C _{1 - 3} alkylsulfonyl which may be substituted with an amino group, a naphthyl group or a monocyclic 5 or a 6-membered heteroaryl group, wherein the 6-membered heteroaryl groups having one nitrogen atom, 2 or 3, 5-membered heteroaryl groups are C _{1 -} imino group with _three alkyl groups, may be oxygen or sulfur atoms, or C _{1 - 3} alkyl group and an oxygen atom or a sulfur atom or one or two nitrogen atoms may be substituted Already has a group that, also phenyl ring 2 may be condensed monocyclic heterocyclic group with the by a carbon atom, R _d is a fluorine atom, a chlorine atom or a bromine atom, a C _{1 - 3} alkyl group (wherein the hydrogen atoms are wholly or that part may be substituted with a fluorine atom), a hydroxy group, C _{1 - 3} alkoxy group, a carboxy group, C _{1 - 3} alkoxycarbonyl group, aminocarbonyl group, C _{1 - 3} alkylamino group or an N, N- di (C _1-3 alkyl ) Aminocarbonyl group, 3- to 7-membered cycloalkyleneimino group (wherein the methylene group at the 4-position in the 6- or 7-membered cycloalkyleneimino group may be further substituted with an oxygen atom or a sulfur atom), sulfinyl group, sulfonyl group, imino group or N- (C _{1 - 3} alkyl) imino group, a nitro group, an amino group, C _{1 - 3} alkyl group, a di (C _1-3 alkyl) amino group, C _{1 - 3} alkylcarbonyl group, an N- (C _{1 - 3} alkyl) -C _{1 - 3} alkyl-carbonyl group, C _{1 - 3} Alkylsulfonyl group or a N- (C _1-3 alkyl) -C _{1 - 3} alkylsulfonyl, and optionally substituted by an amino group, a naphthyl group or a monocyclic 5 or 6 membered heteroaryl group, wherein the 6-membered heteroaryl groups having one nitrogen atom, 2 or 3, 5-membered heteroaryl groups are C _{1 - 3} alkyl group, an imino group, which may be oxygen or sulfur atoms, or C _{1 - 3} alkyl group and an oxygen atom or a sulfur atom or a or 2 with the imino group which may be substituted by nitrogen atoms, and also phenyl ring two adjacent may be single condensed polycyclic heterocyclic group, and wherein by a carbon atom, R _e is a carboxy group, C _{1 - 6} alkoxycarbonyl group or C _{3 -7} cycloalkoxy group (wherein the alkyl part or cycloalkyl part from the second position relative to the oxygen atom in each case is C _{1 - 3} alkoxy group, amino group, C _{1 - 3} alkylamino or di (C _1-3 alkyl) Mino group, a phenyl -C _{1 - 3} alkoxycarbonyl group or a heteroaryl group -C _{1 - 3} alkoxy group may be substituted with a carbonyl group, the heteroaryl part being as defined above), and, R _f represents a hydrogen atom, C _{1 - 3} alkyl group phenyl or -C _{1 - 3} alkyl group, R _g is hydrogen atom or C _{1 - 3} alkyl group is.

(I) Japanese Patent Publication 2000-510483, WO98 / 47875 discloses benzamide derivatives represented by the following formulae, specifically 4'-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4 MTP inhibitors are described which comprise -tetrahydro-isoquinolin-6-yl) -amide as an active ingredient (see Patent Document 22).

(J) Japanese Patent Laid-Open No. 2001-172180 discloses an MTP inhibitory substance consisting of benzamide derivatives (biphenylamide derivatives) represented by the following (i), (ii), (iii) and (iv): (See Patent Document 23).

(i) Formula (1)

Wherein L is (A) XYZ, wherein X is a moiety selected from the group consisting of CH ₂ , CO, CS or SO ₂ ; Y is a direct bond; Up to 20 carbons that may be monosubstituted with hydroxy, (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₁₀ ) acyl, (C ₁ -C ₁₀ ) acyloxy or (C ₆ -C ₁₀ ) aryl Aliphatic hydrocarbylene groups having an atom; NH; And O, provided that X is CH _2, then Y is a direct bond; And Z is a part selected from the group consisting of the following groups; (1) hydrogen, halogen, cyano, (2) hydroxy, (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₁₀ ) alkylthio, (C ₁ -C ₁₀ ) acyl, thiophenylcarbonyl, ( C ₁ -C ₁₀ ) alkoxycarbonyl, (3) (C ₁ -C ₁₀ ) alkylamino, di (C ₁ -C ₁₀ ) alkylamino, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₁₀ ) alkyl Amino, provided that Y is not 0 or NH, and (4) unsubstituted vinyl, (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl and their condensed benz derivatives, (C ₇ -C ₁₀ ) Polycycloalkyl, (C ₄ -C ₈ ) cycloalkenyl, (C ₇ -C ₁₀ ) polycycloalkenyl, (5) (C ₆ -C ₁₀ ) aryloxy, (C ₆ -C ₁₀ ) arylthio, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₁₀ ) alkoxy, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₁₀ ) alkylthio, (C ₃ -C ₈ ) cycloalkyloxy, (C _4- C ₈ ) cycloalkenyloxy, (6) a heterocyclic group selected from the group consisting of a monocyclic group and a condensed polycyclic group, the group comprising a total of 5 to 14 ring atoms and independently selected from oxygen, nitrogen and sulfur 1 to 4 total Is selected from the ring the individual rings, and to be a saturated, partially unsaturated or aromatic independently, a terminal of the group comprising a heteroatom, X is CH _2, Z is either H or a group (4) and (6), Wherein when Z comprises one or more rings, the rings are each halo, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy , (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₁₀ ) alkoxycarbonyl, (C ₁ -C ₁₀ ) alkylthio, (C ₁ -C ₁₀ ) alkylamino, (C ₁ -C ₁₀ ) alkylaminocarbonyl, di (C ₁ -C ₁₀ ) alkylamino, di (C ₁ -C ₁₀ ) alkylaminocarbonyl, di (C ₁ -C ₁₀ ) alkylamino (C _1- C ₁₀ ) alkoxy, (C ₁ -C ₃ ) perfluoroalkyl, (C ₁ -C ₃ ) perfluoroalkoxy, (C ₁ -C ₁₀ ) acyl, (C ₁ -C ₁₀ ) acyloxy, (C 0 to 4 independently selected from ₁ -C ₁₀ ) acyloxy (C ₁ -C ₁₀ ) alkyl and pyrrolidinyl Or may independently include a substituent; Or (B) G, wherein G is selected from the group consisting of: (a) phenyl or a heterocyclic ring containing from 3 to 14 ring atoms in total, said heterocyclic ring comprising a total of 1 to 4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, each of which is a heterocyclic ring The ring of may be independently saturated, partially saturated or aromatic, and each phenyl or heterocyclic ring is halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl , Benzyloxy, (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkoxy, (C _1- C ₁₀ ) alkoxycarbonyl, (C ₇ -C ₁₀ ) alkylthio, (C ₁ -C ₁₀ ) alkylamino, di (C ₁ -C ₁₀ ) alkylamino, (C ₁ -C ₁₀ ) alkylaminocarbonyl, Di (C ₁ -C ₁₀ ) alkylaminocarbonyl, (C ₁ -C ₁₀ ) acyl, (C ₁ -C ₄ ) perfluoroacyl, (C ₁ -C ₁₀ ) acyloxy, (C ₁ -C ₆ ) acylamino, and (C ₁ -C ₆₎ perfluoroalkyl acyl From the furnace, and also contain one to four substituents independently selected; (b) -CH ₂ CN, (c)

(d) (C ₂ -C ₁₂ ) alkyl or (C ₂ -C ₁₂ ) perfluoroalkyl which may be substituted with 1 to 3 substituents independently selected from the following substituents: (1) phenyl, halogen, nitro, Cyano, hydroxy, -NR ¹ R ² , -OCOR ³ , (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₄ ) thioalkoxy or (C ₁ -C ₄₎ perfluoroalkyl thioalkoxy, wherein R ¹ and R ² in -NR ¹ R ² are each hydrogen, formyl, phenyl, benzyl, benzoyl, (C ₃ -C ₈₎ cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₁₀ ) alkoxycarbonyl, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆₎ perfluoroalkyl acyl, aminocarbonyl, (C ₁ -C ₁₀₎ alkyl-aminocarbonyl, di (C ₁ -C ₁₀₎ alkyl, aminocarbonyl, aminosulfonyl, (C ₁ -C ₄₎ alkyl Aminosulfonyl, di (C ₁ -C ₄ ) alkylaminosulfonyl, (C ₁ -C ₄ ) perfluoroalkylaminosulfonyl, di (C ₁ -C ₄ ) perfluoroalkylaminosulfonyl, (C _One -C ₄ ) alkylsulfonyl and (C ₁ -C ₄ ) perfluoroalkylsulfonyl are independently selected, or R ¹ and R ² together with the nitrogen atom to which they are attached are saturated, partially saturated or aromatic heterocyclic To form a ring, wherein the heterocyclic ring includes a total of 3 to 14 ring atoms, and may further include 1 to 4 ring heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclic ring is halogen, Hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₄ ) perfluor Roalkyl, (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₁₀ ) alkoxycarbonyl, (C ₁ -C ₁₀ ) alkylthio, (C ₁ -C ₁₀ ) alkylamino, di (C ₁ -C ₁₀ ) alkylamino, (C ₁ -C ₁₀ ) alkylaminocarbonyl, di (C ₁ -C ₁₀ ) alkylaminocarbonyl, (C ₁ -C ₁₀ ) acyl, (C ₁ -C ₁₀ ) Perfluoroalkyl acyl, (C ₁ -C ₁₀₎ acylamino, and (C ₁ -C ₁₀₎ may include 1 to 4 substituents independently selected from acyloxy, R ³ is -NR a -OCOR ^{3 1} R ² , phenyl, (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₀ ) perfluoroalkyl, (C ₁ -C ₆ ) alkoxy and (C ₁ -C ₆ ) perfluoroalkoxy , (2) (C ₃ -C ₈ ) cycloalkyl or (C ₃ -C ₈ ) cycloalkenyl, wherein each of the (C ₃ -C ₈ ) cycloalkyl or (C ₃ -C ₈ ) cycloalkenyl is Halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₄ ) Perfluoroalkyl, (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₁₀ ) alkoxycarbonyl, (C ₁ -C ₁₀ ) alkylthio, (C ₁ -C ₁₀ ) alkylamino, di (C ₁ -C ₁₀ ) alkylamino, (C ₁ -C ₁₀ ) alkylaminocarbonyl, di (C ₁ -C ₁₀ ) alkylaminocarbonyl, (C ₁ -C ₁₀ Independently from acyl, (C ₁ -C ₁₀ ) perfluoroacyl, (C ₁ -C ₁₀ ) acylamino, (C ₁ -C ₁₀ ) perfluoroacylamino and (C ₁ -C ₁₀ ) acyloxy May comprise 1 to 4 substituents selected, and (3) saturated, partially saturated or aromatic heterocyclic rings comprising a total of 3 to 14 ring atoms, wherein said heterocyclic ring is independently selected from oxygen, nitrogen and sulfur Wherein the heterocyclic ring comprises halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy , (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkoxy, (C ₁ -C ₁₀ ) Alkoxycarbonyl, (C ₁ -C ₁₀ ) alkylthio, (C ₁ -C ₁₀ ) alkylamino, di (C ₁ -C ₁₀ ) alkylamino, (C ₁ -C ₁₀ ) alkylaminocarbonyl, di (C ₁ -C ₁₀ ) alkylaminocarbo Neyl, (C ₁ -C ₁₀ ) acyl, (C ₁ -C ₁₀ ) perfluoroacyl, (C ₁ -C ₁₀ ) acylamino, (C ₁ -C ₁₀ ) perfluoroacylamino and (C _{1- 10} C) may include 1 to 4 substituents independently selected from _{acyloxy, (e) (C 3 -C} 8) cycloalkyl or (C ₃ -C ₈₎ cycloalkenyl, wherein said (C ₃ Each of -C ₈ ) cycloalkyl and (C ₃ -C ₈ ) cycloalkenyl is halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl , Benzyloxy, (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₁₀ ) alkoxy, (C ₁ -C ₄ ) perfluoroalkoxy, (C _1- C ₁₀ ) alkoxycarbonyl, (C ₁ -C ₁₀ ) alkylthio, (C ₁ -C ₁₀ ) alkylamino, di (C ₁ -C ₁₀ ) alkylamino, (C ₁ -C ₁₀ ) alkylaminocarbonyl, Di (C ₁ -C ₁₀ ) alkylaminocarbonyl, (C ₁ -C ₁₀ ) acyl, (C ₁ -C ₁₀ ) perfluoroacyl, (C ₁ -C ₁₀ ) acylamino, (C ₁ -C ₁₀ Perfluoro Room amino and (C ₁ -C ₁₀₎ may include 1 to 4 substituents independently selected from _{acyloxy, (f) - (CH 2} ) n COR 4, wherein - a (CH _{2) n} COR ⁴ R ⁴ is hydroxy, phenyl, -NR ¹ R ² , (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) perfluoroalkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) Perfluoroalkoxy, (C ₃ -C ₈ ) cycloalkyl and (C ₃ -C ₈ ) cycloalkenyl, n is an integer from 1 to 4.

(ii) BMS-197636 (9- [4- [4- (2,3-dihydro-1-oxo-1H-isoindol-2-yl) -1-piperidinyl] butyl] -N-propyl- 9H-fluorene-9-carboxamide) and pharmaceutically acceptable salts thereof.

(iii) compound BMS-200150 (2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-1H-isoindol-1-one) and pharmaceuticals thereof Acceptable salts.

(iv) compound BMS-201038 (9- [4- (4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl) butyl] -N-2,2,2-tri Fluoroethyl) -9H-fluorene-9-carboxamide) and pharmaceutically acceptable salts thereof.

In addition, Patent Document 23 describes specific examples of the following compounds.

4′-trifluoromethyl-biphenyl-2-carboxylic acid- (2-butyl-1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,

4′-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,

9- [4- [4- (2,3-dihydro-1-oxo-1H-isoindol-2-yl) -1-piperidinyl] butyl] -N-propyl-9H-fluorene-9 Carboxamide,

2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-1H-isoindol-1-one,

(K) Japanese Unexamined Patent Application Publication No. 2000-169395 discloses an MTP inhibitory substance consisting of a benzamide derivative as follows (see Patent Document 24).

4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (1H- [1,2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydro Isoquinolin-6-yl] -amide,

4′-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] -amide,

9- (4- [4- [4'-trifluoromethyl-biphenyl-2-carbonyl) amino] -piperidin-1-yl} butyl) -9H-fluorene-9-carboxylic acid -(2,2,2-trifluoroethyl) -amide,

9- [4- [4- (2-benzothiazol-2-yl-benzoylamino) piperidin-1-yl] butyl] -9H-fluorene-9-carboxylic acid- (2,2, 2-trifluoroethyl) amide,

[11a-R] -8-[(4-cyanophenyl) methoxy] -2-cyclopentyl-7- (prop-2-enyl) -2,3,11,11a-tetrahydro-6H- Pyrazino [1,2b] isoquinoline-1,4-dione,

[11a-R] -2-cyclopentyl-7- (prop-2-enyl) -8-[(pyridin-2-yl) methoxy] -2,3,11,11a-tetrahydro-6H- Pyrazino [1,2b] isoquinoline-1,4-dione,

2-cyclopentyl-2- [4- (2,4-dimethylpyrid [2,3-b] indol-9-ylmethyl) phenyl] -N- (2-hydroxy-1-phenylethyl) acet amides,

2-cyclopentyl-N- (2-hydroxy-1-phenylethyl) -2- [4- (quinolin-2-ylmethoxy) -phenyl] acetamide.

2-3. Challenges in MTP Inhibitors

Here, as described above, various MTP inhibitors have been known, but on the other hand, as the development of inhibitors of MTP progresses, MTP inhibitors exert a lowering effect on lipids in the blood, but cause fat accumulation in the liver (fatty liver). It was pointed out that it was possible to worry about liver toxicity (see Patent Document 25).

For this reason, new MTP inhibitors are strongly desired for sufficient preventive and therapeutic effects without side effects such as fatty liver.

(L) In recent years, studies have been actively conducted on compounds that selectively inhibit small intestine MTP, and Japanese Patent Laid-Open No. 2003-321424 has also reported a compound for inhibiting small intestine selective MTP represented by the following general formula (1) ( See patent document 26).

Formula (1)

[In the formula, R ¹ and R ² are hydrogen atoms, C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl, C _{1 - 6} alkoxy group, a halo-C _{1 - 6} alkyl group, a halo-C _{1 - 6} alkyloxy group, a substituted which may be C _{6 - 14} aryl group, an optionally substituted C ₁₆ aralkyl group, optionally substituted C _{6 - 14} with an aryloxy group, an optionally substituted C _{7 - 16} aralkyl kilok group, an optionally substituted C _{6 - 13} aryl group, optionally substituted heterocyclic group, C _{2 - 7} alkoxycarbonyl group, a halogen atom, C _{2 - 6} alkenyl ^{group, -N (R 40) (R} 41) ( wherein R ⁴⁰ and R ⁴¹ are the same or or different C ₆ which may be a hydrogen atom or a _{substituted-aryl} group _14), and; Ring A is a C _6-14 aryl group, heterocyclic group, or

ego; X is -COO- (CH ₂ ) _n- , -CON (R ¹⁰ )-(CH ₂ ) _n -or -N (R ¹⁰ ) -CO- (CH ₂ ) _n- (where R ¹⁰ is a hydrogen atom, C _{1 - 6} alkyl or C _{3 - 7} cycloalkyl group and, n is an integer of 0 or 1 to 3) and; R ³ and R ⁴ are the same or different C ₁₆ alkyl, C ₁₆ alkoxy group, a halo-C ₁₆ alkyl group with a hydrogen atom, a hydroxyl group, a halogen atom, may be substituted, C _{7 - 16} aralkyl kilok group, C _{1 - 6} acyl group, an optionally substituted heterocyclic ^{group, -CON (R 11) (R} 12) ( wherein R ¹¹ and R ¹² are the same or different hydrogen atom, C _{1 - 6} alkyl, optionally substituted C _{6 - 14} aryl group, an optionally substituted C _{7 -16} aralkyl groups, C ₁ with ₆ alkoxy group, or combine together with the nitrogen atom to which

(Where p is 0 or an integer from 1 to 2),-(CH ₂ ) _q -N (R ¹³ ) (R ¹⁴ ), where R ¹³ and R ¹⁴ are the same or different and represent a hydrogen atom, C _{1 - 6} alkyl, C _{2 - 7} alkoxycarbonyl group, C _{1 - 6} acyl, and or together with the nitrogen atom to which

May form a (where p is the Same as the above), q is an integer of 0 or 1 to 3) or -CO (R ¹⁵⁾ (wherein R ¹⁵ is a hydroxy group, C _{1 - 6} alkoxy group, optionally substituted C _{6 - 14} aryloxy group, optionally substituted C _{7 - 16} aralkyl group or a kilok C ₁₆ alkyl group) and; Ring B is

(Where K is 0 or an integer of 1 to 2), or ring B is combined with a nitrogen atom to which R ³ , R ¹⁰ and R ¹⁰ are bonded

May form; Alk1 ¹ is alkanediyl or alkendiyl; Alk1 ² is alkanediyl or alkenediyl; l is 0 or an integer of 1 to 3; m is 0 or an integer of 1 to 3; D is C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 7} alkoxycarbonyl ^{group, -N (R 42) -CO (} R 43) ( wherein R ⁴² is a hydrogen atom or a C _{1 - 6} alkyl group, R ⁴³ is a C _{6 - 14} aryl group or C _{7 - 16} aralkyl group), or to

Chemical formula;

(Wherein, R ^5, R ⁶ and R ⁷ are the same or different and a hydrogen atom, C _{1 - 6} alkyl, C _{1 - 6} alkoxy group, C _{2 - 7} alkoxycarbonyl group, a carboxyl group, a halogen atom, a cyano group, a nitro group , halo-C ₁₆ alkyl, C ₁₆ Ah, which group, a hydroxyl group, an amino group, an optionally substituted C _{6 - 14} aryl group, or _{- (CH 2) r -CON (} R 16) (R 17) ( where R ¹⁶ and r ¹⁷ are the same or different and a hydrogen atom, C _{1 - 6} alkyl or halo C _{1 -} and ₆ alkyl, r is an integer of 0 or 1 to 3 shown below); ring C is C _{6 - 14} aryl group, C _{7 - 15} arylcarbonyl group, a C _{8 - 17} aralkyl-carbonyl group, a heterocycle residue, C _{3 - 7} cycloalkyl, C _{7 - 16} aralkyl group, or ring C, and R ⁷ and R ⁸ are together

May form; R ⁸ And R ⁹ are the same or different hydrogen atom, C _{1 - 6} alkyl, optionally substituted C _{6 - 14} aryl group, a hydroxy C _{1 - 6} alkyl ^{group, -CON (R 18) (R} 19) ( where R ¹⁸ and R ¹⁹ are the same or different hydrogen atom, C _{1 - 6} alkyl group, a C _3-7 cycloalkyl group, a halo-C _{1 - 6} alkyl, C _{2 -} C ₆ alkoxyalkyl group or may be substituted with _{12 - 14} aryl group), -COO (R ²⁰⁾ or _{- (CH 2) s -OCO (} R 20) ( wherein R ²⁰ is a hydrogen atom, C _{1 - 6} alkyl group or C _3-7 cycloalkyl group, s is an integer of 0 or 1 to 3 ^{), -N (R 21) (} R 22) ( wherein R ²¹ and R ²² are the same or different hydrogen atom, C _{1 - 6} alkyl, C _{1 - 6} acyl, C _{1 - 6} alkylsulfonyl, or R ^With nitrogen atoms to which ²¹ and R ²² are bonded

And that the can) is formed, or R ⁸ and R ⁹ together are C _{3 - 7} may form a cycloalkyl group; an ester compound or a prodrug thereof, or pharmaceutically acceptable salts thereof represented by the following.

Moreover, the following compound is described in the patent document as a specific compound.

2- (2- {3-methyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di Ethyl ester,

2- (2- {4- [Methyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester ,

2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,

2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisopropyl ester,

2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid dimethyl ester,

2-cyclopentyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,

2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid dicyclohexyl ester,

2-benzyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,

2- (2- {2-methyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di Ethyl ester,

2-cyclohexyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,

2-phenyl-2- (2- {2-trifluoromethyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,

2-pyridin-2-yl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid di Ethyl ester,

2-pyridin-3-yl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid di Ethyl ester,

2-phenyl-2- (2- {3-trifluoromethyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- Malonic acid diethyl ester,

2- (2- {4-[(4'-Methyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(4'-methoxy-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2-phenyl-2- (2- {4-[(3'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diethyl ester,

2- (2- {4- [isopropyl- (4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {4- [Cyclohexyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid dipropyl ester,

2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisobutyl ester,

2- (2- {4- [ethyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester ,

2- (2- {3-ethyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di Ethyl ester,

2- (2- {3-isopropyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-isobutyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-chloro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di Ethyl ester,

2- (2- {3-bromo-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid diethyl ester,

2- (2- {3-diethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl Malonic acid diethyl ester,

2- (2- {3-Diisopropylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,

2- (2- {3- (ethyl-methylcarbamoyl) -4-[(4'trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2 -Phenyl-malonic acid diethyl ester,

{3- (ethyl-methylcarbamoyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetic acid 2,2-bis-ethylcarba Moyl-2-phenyl-ethyl ester,

{3- (Pyrrolidine-1-carbonyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetic acid 2,2-bis-ethyl Carbamoyl-2-phenyl-ethyl ester,

2-phenyl-2- (2- {3- (pyrrolidine-1-carbonyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2-phenyl-2- (2- {3- (piperidine-1-carbonyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- [2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -ethyl] 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-fluoro-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {4-[(4'-Bromo-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid dimethyl ester,

2-cyclopentyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) Malonic acid diethyl ester,

2-cyclohexyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) Malonic acid diethyl ester,

2- (2- {4-[(4'-Chloro-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid di Ethyl ester,

2- (2- {4-[(4'-acetyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid di Ethyl ester,

2- (2- {4-[(4'-Cyano-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- [3- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -propyl] 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid di 2,2,2-trifluoroethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(2'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- (2- {5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-bromo-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-Chloro-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(3'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(3'-Chloro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5 -Nitro-pyridin-2-yl) -malonic acid diethyl ester,

2- (5-Amino-pyridin-2-yl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino ] -Phenyl} -acetoxymethyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-pyridine- 2-yl-malonic acid diethyl ester,

2- (2- {3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl}- Acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-o- Tolyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-m- Tolyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-p- Tolyl-malonic acid diethyl ester,

2- (2-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (3-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (4-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Succinic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (2 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (4 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {4-[(5,4'-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- [2- (2- {3-dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy ) -Ethyl] -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-ethoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-isopropoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- [2- (2- {4-[(5,4'-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxy ) -Ethyl] -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(3-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- {2- [4- (2,4-bis-trifluoromethyl-benzoylamino) -3-dimethylcarbamoyl-phenyl] -acetoxymethyl} -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-methyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di Ethyl ester,

2- (2- [3-dimethylcarbamoyl-4- (2-ethyl-4-trifluoromethyl-benzoylamino) -phenyl] -acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-ethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di Ethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-isopropenyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-mal Lonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-isopropyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-thiophene -2-yl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-thiophene 3-yl-malonic acid diethyl ester,

2- (2- {4-dimethylcarbamoyl-5-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -pyridin-2-yl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3 -Methyl-thiophen-2-yl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5 -Methyl-thiophen-2-yl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-thiazole -2-yl-malonic acid diethyl ester,

2- (2- {3-ethoxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-methoxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-isopropoxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-mal Lonic acid diethyl ester,

2- (2- {3-benzyloxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester.

2- (2- {3-hydroxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2-phenyl-2- (2- {3-piperidin-1-yl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy Methyl) -malonic acid diethyl ester,

2-phenyl-2- (2- {3-pyrrolidin-1-yl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy Methyl) -malonic acid diethyl ester,

2- (2- {3-dimethylamino-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-morpholin-4-yl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- Phenyl-malonic acid diethyl ester,

2- (2- {3-diethylamino-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-mal Lonic acid diethyl ester,

2- (2- {2-chloro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -benzoyloxy} -ethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {3-ethoxycarbonyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid diethyl ester,

2- (3- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -propionyloxymethyl) -2-phenyl Malonic acid diethyl ester,

2- (2- {3-benzyloxycarbonyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid diethyl ester,

2- (2- {3-carboxy-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid di Ethyl ester,

2- (2- {3-isopropoxycarbonyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl Malonic acid diethyl ester,

2- (2- {3-methoxycarbonyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid diethyl ester,

2- (2- {3-acetylamino-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-methoxycarbonylamino-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl Malonic acid diethyl ester,

2- (2- {3- (4-Methyl-thiazol-2-yl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -ace Methoxymethyl) -2-phenyl-malonic acid diethyl ester,

2-phenyl-2- (2- {6-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -biphenyl-3-yl} -acetoxymethyl) -malonic acid Diethyl ester,

2- (2- {3-formyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid Diethyl ester,

2- (2- {3-dimethylaminomethyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-mal Lonic acid diethyl ester,

2- (2- {3- (methoxy-methylcarbamoyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-isobutyryl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-mal Lonic acid diethyl ester and

2- (2- {3- (1-hydroxy-2-methyl-propyl) -4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -ace Methoxymethyl) -2-phenyl-malonic acid diethyl ester.

Among the above compound groups, particularly representative biphenylamide derivatives are as follows.

2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisobutyl ester,

2- (2- {4- [ethyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester ,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid dimethyl ester,

2-cyclopentyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) Malonic acid diethyl ester,

2-cyclohexyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) Malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- [3- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -propyl] 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid di 2,2,2-trifluoroethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(2'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- (2- {5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-bromo-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-Chloro-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(3'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(3'-Chloro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5 -Nitro-pyridin-2-yl) -malonic acid diethyl ester,

2- (5-Amino-pyridin-2-yl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino ] -Phenyl} -acetoxymethyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-pyridine- 2-yl-malonic acid diethyl ester,

2- (2- {3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl}- Acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-o- Tolyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-m- Tolyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-p- Tolyl-malonic acid diethyl ester,

2- (2-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (3-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (4-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Succinic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (2 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (4 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {4-[(5,4'-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- [2- (2- {3-dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy ) -Ethyl] -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-ethoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-isopropoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- [2- (2- {4-[(5,4'-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxy ) -Ethyl] -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester and

2- (2- {3-dimethylcarbamoyl-4-[(3-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester

Patent document 1; Japanese Patent Laid-Open No. 2000-281561

Patent document 2; Japanese Patent Laid-Open No. 9-309834

Patent document 3; Japanese Patent Laid-Open No. 2004-10575

Patent document 4; Japanese Patent Publication No. 11-509238

Patent document 5; Japanese Patent Laid-Open No. 2003-73261

Patent document 6; Japanese Patent Publication No. 3-1288

Patent document 7; Japanese Patent Application Laid-Open No. 3-28404

Patent document 8; Japanese Patent Laid-Open No. 11-246404

Patent document 9; Japanese Patent Publication No. 2003-531099

Patent document 10; WO00 / 056726 Publication

Patent document 11; Japanese Patent Publication No. 08-208476

Patent document 12; WO2002 / 051385 publication

Patent document 13; Japanese Patent Laid-Open No. 9-59159

Patent document 14; Japanese Patent Publication No. 11-228569

Patent document 15; Japanese Patent Publication No. 2004-514676 (WO2002 / 042291)

Patent document 16; Japanese Patent Publication No. 2003-535900 (WO01 / 097810)

Patent document 17; Japanese Patent Publication No. 2003-521484 (WO01 / 047898)

Patent document 18; Japanese Patent Publication No. 2003-520270 (WO01 / 053260)

Patent document 19; Japanese Patent Publication No. 2003-519131 (WO01 / 047899)

Patent document 20; Japanese Patent Publication No. 2003-509505 (WO01 / 021604)

Patent document 21; Japanese Patent Publication No. 2003-505373 (WO01 / 005762)

Patent document 22; Japanese Patent Publication No. 2000-510483 (WO98 / 47875)

Patent document 23; Japanese Patent Laid-Open No. 2001-172180

Patent document 24; Japanese Patent Laid-Open No. 2000-169395

Patent document 25; Japanese Patent Laid-Open No. 2002-220345

Patent document 26; Japanese Patent Laid-Open No. 2003-321424

Non Patent Literature 1; W. L. Chiou and S. Riegelman; Pharmaceutical application of solid dispersion systems, J. Pharm. Sci. ”(Vol. 60, 1281-1302,1971)

Non Patent Literature 2; `` Chem. Of Weterau and Zirvasmit. Phys. Lipids ”( 38 , 205-222 pages, 1985)]

<Start of invention>

Drugs required sufficient effectiveness from their original purpose and also required high stability in terms of their safety. In terms of efficacy, ie drug efficacy, it is important to design bioavailability sufficiently high in the design of medicinal solid preparations, especially oral preparations. As mentioned above, the factors affecting the bioavailability include water solubility, drug absorption in the entire digestive tract, administration strength and first-pass effect, but especially in poorly water-soluble drugs, the rate of dissolution is known to be a rate-limiting step of absorption. Solubility in water is the most important and high priority factor in the development of pharmaceuticals.

Unfortunately, many pharmaceutical chemicals are poorly soluble in water, and therefore have a drawback that their bioavailability is very low because only a few of the doses are transferred and absorbed into the blood even by oral administration.

The same can be said for the MTP inhibitor. In addition, many conventional MTP inhibitors have the drawback that they do not act selectively in the small intestine and also act in the liver, which is suspected of causing side effects such as fatty liver.

Moreover, also about the manufacturing method of a solid dispersion, when a solvent method is employ | adopted, since a solid dispersion may become a film form depending on manufacturing conditions as mentioned above, the process of cutting this precisely is necessary, When employ | adopted, since the solid dispersion obtained becomes a pellet form, further processing, such as grinding | pulverization, was needed. In addition, when the spray drying method is adopted, a large amount of solvent is required, and since the inside of the obtained granules is hollow, the volume becomes large, resulting in poor handleability, and a specific gravity difference between different compounding agents. It had such drawbacks that it could not be maintained.

Accordingly, an object of the present invention is to improve the solubility and improve the bioavailability and excellent high stability by adding a formulation to the poorly water-soluble chemicals (eg, lipid absorption inhibitors such as MTP inhibitors) as active ingredients. It is to provide a novel solid preparation and an effective method for preparing the same.

The inventors of the present invention have studied more intensively in terms of preparations in order to provide a drug such as an MTP inhibitor having excellent dissolution properties, that is, high bioavailability and excellent stability. As a result, a poorly water-soluble chemical substance (e.g., an MTP inhibitory substance) as an active ingredient and a water-soluble high molecular substance such as polyvinylpyrrolidone or hydroxypropyl cellulose are dissolved in an organic solvent, and the solution and the inorganic porous substance are stirred. After mixing, the solid formulation obtained by granulating and drying found that it had the outstanding solubility and the outstanding stability, and completed this invention.

The present invention is specifically as follows.

1.A solid formulation containing a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as a medicinal active ingredient,

(1) the poorly water-soluble chemical forms a solid dispersion with the water-soluble high molecular material,

(2) The water-soluble high molecular substance which forms the said solid dispersion is a fine piece, and

(3) The water-soluble solid preparation having improved water solubility, wherein the microflake-like water-soluble high molecular material is kept adsorbed and / or adhered to the surface of the inorganic porous material.

2. The solid preparation according to 1 above, wherein the water-soluble high molecular material is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, agar, dextrin, gelatin or mixtures thereof.

3. The solid preparation according to 2 above, wherein the water-soluble high molecular material is polyvinylpyrrolidone or hydroxypropyl cellulose.

4. The solid preparation according to any one of 1 to 3, wherein the water-soluble polymer substance is 3 to 100 times by weight based on the poorly water-soluble chemical substance as a pharmaceutically active ingredient.

5. The solid preparation according to 4 above, wherein the water-soluble high molecular material is polyvinylpyrrolidone and the polyvinylpyrrolidone is 3 to 50 times by weight relative to the poorly water-soluble chemical substance as a pharmaceutically active ingredient.

6. The solid preparation according to 4 above, wherein the water-soluble high molecular substance is hydroxypropyl cellulose and the hydroxypropyl cellulose is 6 to 15 times by weight with respect to the poorly water-soluble chemical substance as a pharmaceutically active ingredient.

7. The inorganic porous material according to any one of the above 1 to 6, wherein the inorganic porous material is calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate silicate, magnesium aluminum silicate, synthetic aluminum silicate, hydrous silicon dioxide, Or a mixture thereof.

8. The solid preparation according to the above 7, wherein the inorganic porous material is hard silicic anhydride.

9. The solid preparation according to any one of 1 to 8, wherein the inorganic porous material is 4 to 14 times by weight relative to the poorly water-soluble chemical as a pharmaceutically active ingredient.

10. The solid preparation according to any one of 1 to 9, wherein the poorly water-soluble chemical as a pharmaceutically active ingredient is a lipid absorption inhibitor.

11. The solid preparation according to the above 10, wherein the lipid absorption inhibitor is an apolipoprotein B (Apo B) secretion inhibitor, a triglyceride (TG) transport protein inhibitor or a cholesteryl ester transport protein (CETP) inhibitor.

12. The solid preparation according to the above 10, wherein the lipid absorption inhibitor is an MTP inhibitor, a lipase inhibitor or an ACAT inhibitor.

13. The solid preparation according to 12 above, wherein the lipid absorption inhibitor is an MTP inhibitor.

14. The solid preparation according to 13 above, wherein the MTP inhibitor is a substituted piperazine derivative or a salt thereof.

15. The solid preparation according to the above 13, wherein the MTP inhibitor is a benzamide derivative or a salt thereof.

16. The solid preparation according to item 15 above, wherein the MTP inhibitor is a benzamide derivative or salt thereof selected from the following.

4′-trifluoromethyl-biphenyl-2-carboxylic acid- (2-butyl-1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,

4′-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,

9- [4- [4- (2,3-dihydro-1-oxo-1H-isoindol-2-yl) -1-piperidinyl] butyl] -N-propyl-9H-fluorene-9 Carboxamide,

2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-1H-isoindol-1-one,

9- [4- (4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl) butyl] -N-2,2,2-trifluoroethyl) -9H- Fluorene-9-carboxamide,

4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (1H- [1,2,4] triazol-3-ylmethyl) -1,2,3.4-tetrahydroisoquinoline -6-yl] -amide,

4′-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] -amide,

9H- (4- [4- [4'-trifluoromethyl-biphenyl-2-carbonyl) amino] -piperidin-1-yl} butyl) -9H-fluorene-9-carboxylic acid -(2,2,2-trifluoroethyl) -amide,

9- [4- [4- (2-benzothiazol-2-yl-benzoylamino) piperidin-1-yl] butyl] -9H-fluorene-9-carboxylic acid- (2,2, 2-trifluoroethyl) amide,

[11a-R] -8-[(4-cyanophenyl) methoxy] -2-cyclopentyl-7- (prop-2-enyl) -2,3,11,11a-tetrahydro-6H- Pyrazino [1,2b] isoquinoline-1,4-dione,

[11a-R] -2-cyclopentyl-7- (prop-2-enyl) -8-[(pyridin-2-yl) methoxy] -2,3,11,11a-tetrahydro-6H- Pyrazino [1,2b] isoquinoline-1,4-dione,

2-cyclopentyl-2- [4- (2,4-dimethylpyrid [2,3-b] indol-9-ylmethyl) phenyl] -N- (2-hydroxy-1-phenylethyl) acet Amides and

2-cyclopentyl-N- (2-hydroxy-1-phenylethyl) -2- [4- (quinolin-2-ylmethoxy) -phenyl] acetamide.

17. The solid preparation according to the above 15, wherein the benzamide derivative is a compound represented by the following Chemical Formula 1, wherein X represents -CON (R ¹⁰ )-(CH ₂ ) _n- .

<Formula 1>

[In the formula, R ¹ and R ² are hydrogen atoms, C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl, C _{1 - 6} alkoxy group, a halo-C _{1 - 6} alkyl group, a halo-C _{1 - 6} alkyloxy group, a substituted which may be C _{6 - 14} aryl group, an optionally substituted C _{7 - 16} aralkyl group, optionally substituted C _{6 - 14} aryloxy group, optionally substituted C _{7 - 16} aralkyl kilok group, an optionally substituted C _{6 - 13} aryl group, optionally substituted heterocyclic group, C _{2 - 7} alkoxycarbonyl group, a halogen atom, C _{2 - 6} alkenyl ^{group, -N (R 40) (R} 41) ( wherein R ⁴⁰ and R ⁴¹ are the same or or different C ₆ which may be a hydrogen atom or a _{substituted-aryl} group _14), and; Ring A is a C _6-14 aryl group, heterocyclic group, or

ego; X is ^{-CON (R 10) - (CH} 2) n - , and (wherein R ¹⁰ is a hydrogen atom, C _{1 - - 6} alkyl or C _{3 7} cycloalkyl group and, n is an integer of 0 or 1 to 3); R ³ and R ⁴ are the same or different C ₁₆ alkyl group which a hydrogen atom, a hydroxyl group, a halogen atom, may be substituted, C ₁₆ alkoxy group, a halo C _1-6 alkyl group, C _{7 - 16} aralkyl kilok group, C _{1 - 6} acyl group, an optionally substituted heterocyclic ^{group, -CON (R 11) (R} 12) ( wherein R ¹¹ and R ¹² are the same or different hydrogen atom, C _{1 - 6} alkyl, optionally substituted C _{6 - 14} aryl group, an optionally substituted C _{7 - 16} aralkyl group, C ₁₆ alkoxy group, or combine together with the nitrogen atom to which

(Where p is 0 or an integer from 1 to 2),-(CH ₂ ) _q -N (R ¹³ ) (R ¹⁴ ), where R ¹³ and R ¹⁴ are the same or different and represent a hydrogen atom, C _{1 - 6} alkyl, C _{2 - 7} alkoxycarbonyl group, C _{1 - 6} acyl, and or together with the nitrogen atom to which

May form a (where p is the Same as the above), q is an integer of 0 or 1 to 3) or -CO (R ¹⁵⁾ (wherein R ¹⁵ is a hydroxy group, C _{1 - 6} alkoxy group, optionally substituted C _{6 - 14} aryloxy group, optionally substituted C _{7 - 16} aralkyl group or a kilok C ₁₆ alkyl group) and; Ring B is

(Where K is 0 or an integer of 1 to 2), or ring B is combined with a nitrogen atom to which R ³ , R ¹⁰ and R ¹⁰ are bonded

May form; Alk1 ¹ is alkanediyl or alkendiyl; Alk1 ² is alkanediyl or alkenediyl; l is 0 or an integer of 1 to 3; m is 0 or an integer of 1 to 3; D is C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 7} alkoxycarbonyl ^{group, -N (R 42) -CO (} R 43) ( wherein R ⁴² is a hydrogen atom or a C _{1 - 6} alkyl group, R ⁴³ is a C _{6 - 14} aryl group or C _{7 - 16} aralkyl group) or the following general formula;

(Wherein, R ^5, R ⁶ and R ⁷ are the same or different and a hydrogen atom, C _{1 - 6} alkyl, C _{1 - 6} alkoxy group, C _{2 - 7} alkoxycarbonyl group, a carboxyl group, a halogen atom, a cyano group, a nitro group , halo-C ₁₆ alkyl, C ₁₆ Ah, which group, a hydroxyl group, an amino group, an optionally substituted C _{6 - 14} aryl group, or _{- (CH 2) r -CON (} R 16) (R 17) ( where R ¹⁶ and r ¹⁷ are the same or different and a hydrogen atom, C _{1 - 6} alkyl or halo C _{1 -} and ₆ alkyl, r is an integer of 0 or 1 to 3 shown below); ring C is C _{6 - 14} aryl group, C _{7 - 15} arylcarbonyl group, a C _{8 - 17} aralkyl-carbonyl group, a heterocycle residue, C _{3 - 7} cycloalkyl, C _{7 - 16} aralkyl group, or ring C, and R ⁷ and R ⁸ are together

May form; R ⁸ And R ⁹ are the same or different hydrogen atom, C _{1 - 6} alkyl, optionally substituted C _{6 - 14} aryl group, a hydroxy C _{1 - 6} alkyl ^{group, -CON (R 18) (R} 19) ( where R ¹⁸ and R ¹⁹ are the same or different hydrogen atom, C _{1 - 6} alkyl group, a C _3-7 cycloalkyl group, a halo-C _{1 - 6} alkyl, C _{2 -} C ₆ alkoxyalkyl group or may be substituted with _{12 - 14} aryl group), -COO (R ²⁰⁾ or _{- (CH 2) s -OCO (} R 20) ( wherein R ²⁰ is a hydrogen atom, C _{1 - 6} alkyl group or C _3-7 cycloalkyl group, s is an integer of 0 or 1 to 3 ^{), -N (R 21) (} R 22) ( wherein R ²¹ and R ²² are the same or different hydrogen atom, C _{1 - 6} alkyl, C _{1 - 6} acyl, C _{1 - 6} alkylsulfonyl, or R ^With nitrogen atoms to which ²¹ and R ²² are bonded

And that the can) is formed, or R ⁸ and R ⁹ together are C _{3 - 7} may form a cycloalkyl group; an ester compound or a prodrug thereof, or pharmaceutically acceptable salts thereof represented by the following.

18. The method according to the above 15, wherein the benzamide derivative is

2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisobutyl ester,

2- (2- {4- [ethyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester ,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid dimethyl ester,

2-cyclopentyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) Malonic acid diethyl ester,

2-cyclohexyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) Malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- [3- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -propyl] 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid di 2,2,2-trifluoroethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(2'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- (2- {5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-bromo-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-Chloro-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(3'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(3'-Chloro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5 -Nitro-pyridin-2-yl) -malonic acid diethyl ester,

2- (5-Amino-pyridin-2-yl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino ] -Phenyl} -acetoxymethyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-pyridine- 2-yl-malonic acid diethyl ester,

2- (2- {3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl}- Acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-o- Tolyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-m- Tolyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-p- Tolyl-malonic acid diethyl ester,

2- (2-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (3-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (4-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Succinic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (2 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (4 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {4-[(5,4'-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- [2- (2- {3-dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy ) -Ethyl] -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-ethoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-isopropoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- [2- (2- {4-[(5,4'-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxy ) -Ethyl] -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester and

2- (2- {3-dimethylcarbamoyl-4-[(3-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester

Solid formulation, which is a compound selected from.

19. A poorly water-soluble chemical substance as a medicinal active ingredient, characterized by stirring and mixing a solution obtained by dissolving a poorly water-soluble chemical substance and a water-soluble high molecular substance as an active ingredient in an organic solvent, followed by granulation and drying, Solid preparation comprising a water-soluble high molecular material and an inorganic porous material,

(1) the poorly water-soluble chemical forms a solid dispersion with the water-soluble high molecular material,

(2) The water-soluble high molecular substance which forms the said solid dispersion is a fine piece, and

(3) A method for producing a solid formulation having improved water solubility, wherein the microflake-like water-soluble high molecular material is maintained adsorbed and / or adhered to the surface of the inorganic porous material.

20. The preparation of a solid preparation according to 19 above, wherein the water soluble high molecular material is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, agar, dextrin, gelatin or mixtures thereof. Way.

21. The method for producing a solid preparation according to item 20, wherein the water-soluble high molecular material is polyvinylpyrrolidone or hydroxypropyl cellulose.

22. The method for producing a solid preparation according to any one of 19 to 21, wherein the water-soluble polymer substance is 3 to 100 times by weight relative to the poorly water-soluble chemical substance as a pharmaceutically active ingredient.

23. The method for producing a solid preparation according to the above 22, wherein the water-soluble high molecular material is polyvinylpyrrolidone and the polyvinylpyrrolidone is 3 to 50 times by weight relative to the poorly water-soluble chemical substance as a medicinal active ingredient.

24. The method for producing a solid preparation according to item 22, wherein the water-soluble high molecular substance is hydroxypropyl cellulose and the hydroxypropyl cellulose is 6 to 15 times by weight relative to the poorly water-soluble chemical substance as a medicinal active ingredient.

25. The inorganic porous material according to any one of 19 to 24, wherein the inorganic porous material is calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate silicate, magnesium aluminum silicate, synthetic aluminum silicate, hydrous silicon dioxide, Or a mixture thereof.

26. The method for producing a solid preparation according to 25 above, wherein the inorganic porous material is hard silicic anhydride.

27. The method for producing a solid preparation according to any one of 19 to 26, wherein the inorganic porous material is 4 to 14 times by weight relative to the poorly water-soluble chemical as a pharmaceutically active ingredient.

28. The method for producing a solid preparation according to any one of 19 to 27, wherein the amount of organic solvent is 1 to 2 times by weight of the water-soluble high molecular material.

29. The method for producing a solid preparation according to any one of 19 to 28, wherein the poorly water-soluble chemical as a pharmaceutically active ingredient is a lipid absorption inhibitor.

30. The method for producing a solid preparation according to 29 above, wherein the lipid absorption inhibitor is an inhibitor of apolipoprotein B (Apo B) secretion, a triglyceride (TG) transport protein inhibitor or a cholesteryl ester transport protein (CETP) inhibitor.

31. The method for producing a solid preparation according to 29 above, wherein the lipid absorption inhibitor is an MTP inhibitor, a lipase inhibitor or an ACAT inhibitor.

32. The method for producing a solid preparation according to 31 above, wherein the lipid absorption inhibitor is an MTP inhibitor.

The solid preparation of the present invention having excellent solubility was particularly improved in bioavailability, and was able to sufficiently and effectively exhibit the function originally possessed by the medicine in a very small dosage, and also had excellent stability. In addition, since the solubility improvement effect of this invention is thought not to originate from the chemical characteristic inherent to a chemical | medical agent, but to a physical effect, application to various wide range of pharmaceutical products can be expected.

For example, when the present technology is applied to MTP inhibitors and / or Apo B secretion inhibitors, they can be rapidly and completely dissolved in the body after administration, so that not only can the dose be reduced, but a small amount of the drug It can also be expected to reduce the risk of excess MTP inhibitors reaching the liver and causing side effects such as fatty liver or unexpected side effects by acting quickly. Therefore, the MTP inhibitor to which the technique of the present invention is applied may be an excellent therapeutic agent or prophylactic agent of hyperlipidemia, atherosclerosis, coronary artery disease, obesity, diabetes mellitus or hypertension.

These solid preparations maintain a state in which a chemical substance as an active ingredient forms a microparticulate solid dispersion together with a water-soluble high molecular substance, and the microparticulate water-soluble high molecular substance is adsorbed and / or adhered to the surface of the inorganic porous material. It is estimated that it contributes to the improvement of solubility.

In addition, since the solid dispersion obtained by the production method of the present invention is finely shaped and bulky and heavy (high density), it is not necessary to cut or crush the solid dispersion obtained as in the solvent method or the melting method. Even under the drying operation, the granules do not adhere to or scatter in the container, have excellent handleability, easily obtain content uniformity as compared with the granules obtained by the spray drying method, and can be filled or tableted into a hard capsule as it is.

Since the solid preparation of the present invention surprisingly has not only dissolution properties but also excellent stability, and is simple and effective in manufacturing, the solid preparation can be widely applied to poorly water-soluble drugs which have been difficult to practically use.

Therefore, when the solid preparation technology of the present invention is applied to lipid absorption inhibitors such as MTP inhibitors and Apo B secretion inhibitors, for example, there is no fear of fatty liver or unexpected side effects. , Arteriosclerosis, coronary artery disease, obesity, diabetes or hypertension can be a therapeutic or prophylactic.

1 is a graph showing the dissolution test results of the solid preparations obtained in Example 1. (Example 2)
2 is a graph showing a powder X-ray diffraction pattern of the amorphous solid preparation obtained in Example 3-2. (Example 5)

Best Mode for Carrying Out the Invention

The meaning of each term in this invention is as follows.

"Solid dispersion" means the solid mixture in which the chemical substance as an active ingredient is disperse | distributed in a high molecular substance in the monomolecular form, an amorphous state (the presence of some crystal | crystallization is permissible).

"Water poorly soluble" means a state in which the drug is poorly soluble in water and cannot be used as a drug by a conventional formulation method, and specifically, it is required to dissolve 1 g of the drug within 30 minutes at about 20 ° C. It can be indicated by the amount of water being added.

In general, when the amount of water required to dissolve 1 g of a drug is 100 mL or more and less than 1000 mL, it is said to be difficult to dissolve, and the amount of water required to dissolve it is more than 1000 mL and less than 10000 mL. When it is 10000 mL or more, it is said that it is hardly melted. The term "water poorly soluble" refers to the above-mentioned "difficult to melt", "very hard to melt" and "almost hard to melt", and "a very hard to melt" and "almost hard to melt" in consultation.

"Improved water solubility" means that the poorly water-soluble drug improves the water solubility as described above and thus becomes a state that can be used as a medicine by a conventional formulation method. Specifically, the solubility in water at about 20 DEG C is improved to about 5 times, preferably about 10 times, more preferably 100 times or more.

"Amorphous" is the term opposite to "crystal", and the molecular size, that is, the monomolecular state (some crystals) in a carrier matrix in which a chemical substance as an active ingredient in a solid dispersion, for example, an MTP inhibitory substance, is composed of a water-soluble high molecular substance. The presence of is allowed) means a state that is uniformly dispersed.

Whether it is amorphous or not can be confirmed by powder X-ray diffraction or differential scanning calorimetry (hereinafter, referred to as DSC) which is an ordinary means of analysis.

The term “solid preparation” is the term as opposed to a liquid preparation, an injection, and the like, and means a preparation in solid form. There is no restriction | limiting in particular if it is a solid formulation, According to a conventional method, it cannot convert into various formulations, such as powder, a granule, a granule, a pill, a tablet, and can use.

A "water-soluble high molecular substance" is a high molecular substance for forming a solid dispersion with a chemical substance as an active ingredient, for example, an MTP inhibitor, and / or an Apo B secretion inhibitor. The water-soluble high molecular substance is not particularly limited as long as it can form a solid dispersion with these chemicals. Specific examples include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, agar, dextrin, gelatin or mixtures thereof. It is preferably polyvinylpyrrolidone or hydroxypropyl cellulose, and particularly preferably polyvinylpyrrolidone. Povidone K30 is preferred in grades.

These water-soluble high molecular materials, in particular polyvinylpyrrolidone, are also known as binders and stabilizers, and are believed to not only form solid dispersions but also contribute to stabilization of chemical substances present as amorphous molecules in the solid dispersions.

In order to effectively achieve the object of the present invention, these water-soluble polymers are preferably 3 to 100 weight times, particularly 3 to 50 weight times, based on poorly water-soluble chemicals (eg, MTP inhibitors, Apo B secretion inhibitors). Do. When polyvinylpyrrolidone is used as the water-soluble high molecular material, it can be preferably used in the range of 3 to 50 weight times, particularly preferably 3 to 20 weight times, and more preferably 8 to 12 weight times. If it is out of this range, sufficient formulation effects, for example, proper dosage and proper dissolution properties, cannot be obtained.

When hydroxypropyl cellulose is used as the water-soluble high molecular material, it can be preferably used in the range of 6 to 15 times by weight. If the weight is less than 6 times, the stability is somewhat inferior.

The "organic solvent" for producing a solid dispersion is not particularly limited as long as it can dissolve both a chemical substance (for example, an MTP inhibitor, an Apo B secretion inhibitor) and a water-soluble polymer substance such as PVP as an active ingredient. It is preferable to use a solvent having a relatively low boiling point. For example, Alcohol, such as methanol, ethanol, propanol, isopropyl alcohol, butanol, monomethoxy ethanol, ethylene glycol monomethyl ether; Ethers such as diethyl ether, dibutyl ether, diisobutyl ether, dioxane, tetrahydrofuran and ethylene glycol; aliphatic hydrocarbons such as n-hexane, cyclohexane, n-heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; Nitriles such as acetonitrile; Organic acids such as acetic acid and propionic acid; Esters such as ethyl acetate, aliphatic halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; Ketones such as acetone and methyl ketone; Amides such as dimethylformamide and dimethylacetamide; Or mixed liquids of these suitable ratios. Especially, low boiling point solvents, such as ketones, such as acetone, and alcohols, such as anhydrous ethanol, are preferable, and acetone and anhydrous ethanol are especially preferable.

An "excipient" is generally a pharmaceutical additive that is appropriately added in the formulation of solid preparations such as powders and granules and tablets suitably molded, and increases the volume of the powder or tablets of the powder or promotes compressibility or solubility. Or it can use when expecting an inhibitory effect.

The "inorganic porous substance" is an inorganic substance having a plurality of fine pores, and is not particularly limited, but for example, calcium silicate, hard anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate silicate, magnesium aluminum silicate, Synthetic aluminum silicates, hydrous silicon dioxide or mixtures thereof. Preference is given to calcium silicate or hard silicic anhydride, in particular hard silicic anhydride. Here, the type of calcium silicate or hard silicic anhydride is not particularly limited, but the calcium silicate is preferably described in the pharmaceutical additive specification (1998), and the hard silicic anhydride is preferably described in the Japanese Pharmacy (14th Amendment). Regarding the particle size, from the object of the present invention, it is preferable that 70% or more, preferably 80% or more falls within the range of 0.01 μm to 100 μm, and optimally 70% or more thereof, and preferably 80% or more is 0.1 to 10%. It is preferable to fall in the range of μ.

Although the weight ratio of these inorganic porous materials and the chemical substance (for example, MTP inhibitor, Apo B secretion inhibitor) as an active ingredient is not specifically limited, The compounding ratio of the inorganic porous material in the solid dispersion of this invention is used as an excipient | filler. In order to acquire sufficient effect, 4-100 times is preferable by weight ratio with respect to the chemical substance as an active ingredient, 6-50 times is more preferable, It is especially preferable that it is 7-20 times. If the amount of the inorganic porous material is less than 4 with respect to the amount of the chemical substance as the active ingredient, it is not preferable because the desired effective solid dispersion cannot be obtained. If the amount of the inorganic porous substance is greater than 100 with respect to the amount 1 of the chemical substance as an active ingredient, although the solid dispersion can be obtained, the amount of therapeutically necessary MTP inhibitor and / or Apo B secretion inhibitor is obtained. This is undesirable because it inevitably increases the amount of the solid dispersion to be used, which leads to an increase in the dose per dose when administered to a patient.

The "fine flake shape" means a substantially flat and fine piece, that is, a fine flake. However, spherical or filamentous things are not excluded, and 70% or more, preferably 80% or more thereof may correspond to the flaky pieces as described above. In addition, the size thereof is generally 0.01 to 100 times, particularly 0.1 to 10 times, the particle size of the inorganic porous material, and 70% or more, preferably 80% or more of the microflakes is 0.01 μm to 100 μm, particularly 0.1 It is preferred to fall within the range of μ to 10 μ.

“Keeping adsorbed and / or adhered state” means that both of the microflake-like water-soluble polymer material and inorganic porous material forming a solid dispersion are not simply present in a mixed state, but are adsorbed and / or adhered to each other. It means that it is kept in a state.

The formation of the fine pieces and the realization of the adsorption and adhesion state are achieved by stirring, mixing and drying a solution in which the active ingredient and the water-soluble polymer material are dissolved together with an inorganic porous material.

The term "water poorly soluble" in the term "water poorly soluble chemical substance as a medicinal active ingredient" is as defined above. "Chemical substance as a pharmaceutical active ingredient" is a chemical substance which comprises the main component for exhibiting an effect | action as a pharmaceutical. The chemical substance here includes natural substances in addition to the substance obtained by chemical synthesis.

As for the "solid preparation" of the present invention, the definition thereof is as described above, but other "excipient", "lubricant", "binder", "disintegrant", "surfactant", "preservative", Formulation additives, such as an "antioxidant", a "coloring agent", and a "sweetening agent", can also be used. Suitable examples of other “excipients” include, for example, lactose, white sugar, D-mannitol, starch, crystalline cellulose, starch, mannitol, calcium silicate (trade name; Flowlite RE), magnesium aluminate silicate (trade name; noicillin), White sugar, starch spherical granules (trade name; Nonparel), crystalline cellulose, carboxymethyl cellulose (trade name; Avicel RC), hydroxypropyl starch and the like are used. As a preferable example of a "lubricant", crystalline cellulose, magnesium stearate, calcium stearate, talc, colloidal silica, corn starch, magnesium oxide, etc. are mentioned, for example. Preferred examples of other "binders" include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and the like. As a preferable example of a "disintegrant", for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, methyl cellulose (trade name: Metros SM), croscarmellose sodium, carmellose Calcium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, partially alphaated starch and the like are used. Especially preferably, it is carboxymethyl cellulose calcium. As the "surfactant", for example, polyoxyethylene polyoxypropylene glycol (trade name; Pluronic), glycerin fatty acid ester, sucrose fatty acid ester, polyoxyethylene hardened castor oil, polysorbate 80, cetanol, and the like are used. do. As a preferable example of a "preservative", paraoxy benzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. are used, for example. As a preferable example of an "antioxidant", sulfite, ascorbic acid, etc. are used, for example. These additives can also be used individually or in mixture of 2 or more types.

The "lipid absorption inhibitor" in the present invention is not particularly limited as long as it is a chemical agent (a chemical substance as an active ingredient or a natural product) that inhibits or inhibits absorption of lipids regardless of the mechanism of action. Specifically, a lipid absorption inhibitor selected from the group consisting of inhibitors of apolipoprotein B (Apo B) secretion, triglyceride (TG) transport protein inhibitors and cholesteryl ester transport protein (CETP) '' inhibitors, and MTP inhibitors and lipases And lipid absorption inhibitors selected from the group consisting of inhibitors and ACAT inhibitors.

The "MTP inhibitor" (MTP inhibitor) and "Apo B secretion inhibitor (Apo B secretion inhibitor)" in this invention are the substances which have MTP inhibitory effect, Apo B secretion inhibitory effect, especially the chemically synthesized substance, It means a hydrate or solvate thereof, a prodrug thereof, or a salt thereof, and is not particularly limited, and means any MTP inhibitory substance or Apo B secretion inhibitory substance.

In the present invention, "the MTP inhibitory substance is 3-piperidyl-4-oxoquinazolin derivative or salt thereof" means a compound and salts thereof as defined above and / or by the following general formula (A).

In this invention, "the MTP inhibitory substance is a substituted piperazine derivative or its salt" means the compound defined by the said Formula (D), (F) and / or (G), and its salt.

In the present invention, "the MTP inhibitory substance is a benzamide derivative or a salt thereof" means the above formulas (B), (C), (E), (H), (I), (J), and (K). And / or benzamide derivatives or salts thereof as defined by (L).

The "MTP inhibitory substance" of these (A)-(L) is as follows specifically.

(A) 3-piperidyl-4-oxoquinazolin derivatives described and defined in Japanese Patent Laid-Open No. 11-228569 (see (A) and Patent Document 14 above).

(B) A group of compounds having a piperidine skeleton described and defined in Japanese Patent Publication No. 2004-514676 (WO2002 / 042291) (see (B) and Patent Document 15, above).

(C) Benzamide derivatives described and defined in Japanese Patent Publication No. 2003-535900 (WO01 / 097810) (see (C) and Patent Document 16 above).

(D) Substituted piperazine derivatives described and defined in Japanese Patent Publication No. 2003-521484 (WO01 / 047898) (see (D) and Patent Document 17, above).

(E) Benzamide derivatives described and defined in Japanese Patent Publication No. 2003-520270 (WO01 / O53260) (see (E) and Patent Document 18, above).

(F) Substituted piperazine derivatives described and defined in Japanese Patent Publication No. 2003-519131 (WO01 / 047899) (see (F) and Patent Document 19, above).

(G) Substituted piperazine derivatives described and defined in Japanese Patent Publication No. 2003-509505 and WO01 / 021604 (see (G) and Patent Document 20 above).

(H) Benzamide derivatives (biphenylamide derivatives) described and defined in Japanese Patent Publication No. 2003-505373 (WO01 / OO5762) (see (H) and Patent Document 21 above).

(I) Benzamide derivatives described and defined in Japanese Patent Publication No. 2000-510483, WO98 / 47875, for example 4'-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4- Tetrahydro-isoquinolin-6-yl) -amide (see (I) above and Patent Document 22).

(J) Benzamide derivatives (biphenylamide derivatives) described in (i), (ii), (iii) and (iv) of Japanese Patent Laid-Open No. 2001-172180 (the above (J) and patent documents) 23).

(K) A benzamide derivative described in Japanese Unexamined Patent Publication No. 2000-169395 (see (K) and Patent Document 24).

(L) Benzamide derivatives described and defined in Japanese Patent Laid-Open No. 2003-321424 (see the above (L) and Patent Document 26).

In addition, the following specific compounds are also included in the present invention.

The following compound (refer patent document 23) described in Unexamined-Japanese-Patent No. 2001-172180.

4′-trifluoromethyl-biphenyl-2-carboxylic acid- (2-butyl-1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,

4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1.2,3,4-tetrahydroisoquinolin-6-yl) -amide,

9- [4- [4- (2,3-dihydro-1-oxo-1H-isoindol-2-yl) -1-piperidinyl] butyl] -N-propyl-9H-fluorene-9 Carboxamide,

2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-1H-isoindol-1-one,

9- [4- (4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl) butyl] -N-2,2,2-trifluoroethyl) -9H- Fluorene-9-carboxamide.

The following compound (refer patent document 23) described in Unexamined-Japanese-Patent No. 2001-172180.

4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (1H- [1,2,4] triazol-3-ylmethyl) -1,2,3.4-tetrahydroisoquinoline -6-yl] -amide,

4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1.2,3,4-tetrahydroisoquinolin-6-yl] -amide,

9- (4- [4- [4'-trifluoromethyl-biphenyl-2-carbonyl) amino] -piperidin-1-yl} butyl) -9H-fluorene-9-carboxylic acid -(2,2,2-trifluoroethyl) -amide,

9- [4- [4- (2-benzothiazol-2-yl-benzoylamino) piperidin-1-yl] butyl] -9H-fluorene-9-carboxylic acid- (2,2, 2-trifluoroethyl) amide,

[11a-R] -8-[(4-cyanophenyl) methoxy] -2-cyclopentyl-7- (prop-2-enyl) -2,3,11,11a-tetrahydro-6H- Pyrazino [1,2b] isoquinoline-1,4-dione,

[11a-R] -2-cyclopentyl-7- (prop-2-enyl) -8-[(pyridin-2-yl) methoxy] -2,3,11,11a-tetrahydro-6H- Pyrazino [1,2b] isoquinoline-1,4-dione,

2-cyclopentyl-2- [4- (2,4-dimethylpyrid [2,3-b] indol-9-ylmethyl) phenyl] -N- (2-hydroxy-1-phenylethyl) acet amides,

2-cyclopentyl-N- (2-hydroxy-1-phenylethyl) -2- [4- (quinolin-2-ylmethoxy) -phenyl] acetamide.

In addition to the above, BAY13-9952, CP-10447, R1037570 or WM-1159 are also included in the present invention.

Particularly preferred "MTP inhibitory substances" include compounds in which X is -CON (R ¹⁰ )-(CH ₂ ) _n -among the compounds described in the above item (L). In addition, when the compound described in these (L) is enumerated by more specific compound name, the following compound is mentioned.

2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisobutyl ester,

2- (2- {4- [ethyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester ,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid dimethyl ester,

2-cyclopentyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) Malonic acid diethyl ester,

2-cyclohexyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) Malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- [3- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -propyl] 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid di 2,2,2-trifluoroethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(2'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- (2- {5-Dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-bromo-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-chloro-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-phenyl} -acetoxymethyl) -2-phenyl-malonic acid di Ethyl ester,

2- (2- {3-dimethylcarbamoyl-4 '-[(3'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy Methyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(3'-Chloro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5 -Nitro-pyridin-2-yl) -malonic acid diethyl ester,

2- (5-Amino-pyridin-2-yl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino ] -Phenyl} -acetoxymethyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-pyridine- 2-yl-malonic acid diethyl ester,

2- (2- {3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl}- Acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-o- Tolyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-m- Tolyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-p- Tolyl-malonic acid diethyl ester,

2- (2-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (3-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (4-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Succinic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (2 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (4 -Methoxy-phenyl) -malonic acid diethyl ester,

2- (2- {4-[(5,4'-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {4-[(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- [2- (2- {3-dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy ) -Ethyl] -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-ethoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(5-isopropoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,

2- [2- (2- {4-[(5,4'-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxy ) -Ethyl] -2-phenyl-malonic acid diethyl ester,

2- (2- {3-dimethylcarbamoyl-4-[(6-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester and

2- (2- {3-dimethylcarbamoyl-4-[(3-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester

Moreover, as a salt of the compound which comprises MTP inhibitor and Apo B secretion inhibitor, a pharmaceutically acceptable salt is preferable, For example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, an organic acid And salts thereof, and salts with basic or acidic amino acids. As a preferable example of a salt with an inorganic base, For example, alkali metal salts, such as a sodium salt and potassium salt; Alkaline earth metal salts such as calcium salts and magnesium salts; Aluminum salts; Ammonium salt etc. are mentioned. Preferred examples of salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like. Can be mentioned. As a preferable example of a salt with an inorganic acid, salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. are mentioned, for example. Preferred examples of salts with organic acids include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Can be. Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.

The manufacturing method of the solid preparation of this invention is as follows.

1. Assembly process

(1) An appropriate amount of poorly water-soluble chemicals, such as MTP inhibitors, as the active ingredient is dissolved in a suitable organic solvent such as acetone, anhydrous ethanol, or a mixed solvent thereof. The organic solvent is in an amount sufficient to dissolve the polymer material added in the subsequent process. However, when an excessively large amount of solvent is used, the amount of the solvent used is suitably 1 to 2 times by weight of the polymeric material, since subsequent operations are complicated and adversely affect the formulation. Stir-dissolution can be performed by using a propeller mixer, for example.

(2) A water-soluble high molecular substance is added to an organic solvent in which an appropriate amount of chemical substance is dissolved, and further stirred and mixed to sufficiently dissolve both chemical and water-soluble high molecular substances. At this time, the solvent may be heated as necessary to promote dissolution.

(3) In contrast, an inorganic porous material such as hard silicic anhydride as an excipient and a disintegrating agent such as carboxymethyl cellulose calcium are stirred and mixed as necessary as an excipient.

(4) Next, a mixture of the inorganic porous material and disintegrating agent prepared in the above (3) and the solution obtained by dissolving both the chemical material and the high molecular material obtained in (2) are mixed and granulated according to a conventional method.

From the viewpoint of operability, it is preferable to add and mix the solution of (2) with respect to the mixture obtained in (3), but it is not particularly limited, and the mixture of (3) is added and mixed in the solution of (2). You may.

(5) Next, this is granulated, and the organic solvent is distilled off under reduced pressure or normal pressure by vacuum drying or the like, and then dried.

(6) Finally, the dry granulated product is established using a sieve or the like.

The organic solvent used in the above operation (1) is not particularly limited as long as it can dissolve poorly water-soluble or insoluble chemical substances (for example, MTP inhibitors and / or Apo B secretion substances) and polymer substances as active ingredients. Alcohols such as methanol, ethanol, propanol, isopropyl alcohol, butanol, monomethoxyethanol and ethylene glycol monomethyl ether; Ketones, such as acetone and methyl ketone, or these liquid mixtures, etc. can be used. Low boiling solvents, such as ketones, such as acetone, and alcohols, such as anhydrous ethanol, are preferable, and acetone, anhydrous ethanol, or a mixture thereof is especially preferable. Water may be added as needed.

2. Tableting process

When purification is desired, further, disintegrating agents such as carboxymethyl cellulose calcium and crosslinked polyvinyl polydone and lubricants such as magnesium stearate are added to the granulated particles obtained in the granulation step and mixed uniformly. Tableting can be obtained by tableting.

The amount of the chemical substance as an active ingredient to be contained in the solid preparation varies depending on the dosage form, the administration method, the carrier, or the donor's age, weight, and the like, and can be determined depending on the respective conditions and circumstances, and is not particularly limited. In the case of the MTP inhibitory substance, it is usually 0.1 to 20% (w / w), preferably 1 to 8% (w / w) based on the total amount of the preparation. If it is 0.1% (w / w) or less, an effect as a chemical | medical agent cannot be anticipated, and when it is 20% (w / w) or more, sufficient effect as a solid dispersion cannot be exhibited.

In order to obtain a sufficient effect as a solid dispersion, the compounding quantity of the water-soluble high molecular substance in the solid preparation of this invention is 3-100 times by weight ratio with respect to the chemical substance (for example, MTP inhibitor, Apo B secretion inhibitor) as an active ingredient. , Preferably 3 to 50 times, more preferably 3 to 20 times, and in the case of polyvinylpyrrolidone, 3 to 20 times by weight, more preferably 8 to 12 times by weight, and hydroxypropyl In the case of cellulose, it is particularly preferably 6 to 15 times.

In order to obtain a sufficient effect as the solid preparation of the present invention, the inorganic porous material is preferably 4 to 14 times by weight with respect to the chemical substance (for example, MTP inhibitor, Apo B secretion inhibitor) as an active ingredient, and 6 to It is more preferable that it is 13 times, and it is especially preferable that it is 7 to 11 times.

In order to obtain a sufficient effect as the solid preparation of the present invention, the disintegrant is preferably 1 to 10 times by weight relative to the chemical substance (for example, MTP inhibitor, Apo B secretion inhibitor) as the active ingredient, 3 to 7 It is especially preferable that it is a doubled amount. Preferred disintegrants are also crosslinked polyvinylpyrrolidone (crospovidone).

The "solid preparation" thus obtained is heavy (high density) and can be used as a pharmaceutical preparation for oral administration in addition to tablets. Moreover, according to a conventional method, it can also be set as pharmaceutical formulations, such as a fine granule, a fine granule, a granule, a capsule, a liquid preparation. When preparations such as powders, granules, capsules and the like are desired, the pharmaceutical particles obtained by the above method can be easily obtained by adding appropriate excipients, disintegrants, lubricants, surfactants and the like according to the conventional method, if necessary. have. Methods for producing these formulations are well known and commonly used by those skilled in the art, and it is possible to employ appropriate methods depending on the form of the formulation.

In addition, when dragees or the like are desired, the surface of the formulation may be coated with a suitable coating composition.

Generally, chemical substances (eg, MTP inhibitors and Apo B secretion inhibitors) as medicinal active ingredients are poorly water-soluble or insoluble, and when orally administered, their bioavailability is low because of the small percentage of the dose actually absorbed into the blood. Had a low defect. However, the solid preparations of the present invention have excellent solubility, oral absorption and water absorption in the blood, and thus the bioavailability of the chemical substance having poor water solubility has been drastically improved.

In addition, the solid formulations of the present invention not only improved solubility but also maintained excellent stability.

The solid preparation of the present invention can be used in combination with other pharmaceutical preparations. For example, the solid preparation of the present invention containing an MTP inhibitor or an Apo B secretion inhibitor as an active ingredient can be used in combination with another antihyperlipidemic drug. In this case, a solid preparation of an MTP inhibitor or an Apo B secretion inhibitor and another antihyperlipidemic drug may be used, or both may be integrated and used as a mixture.

<Examples>

Example 1

Although an Example and a test example demonstrate this invention in detail below, this invention is not limited to this.

In the examples below, 2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl), which is a MTP inhibitory substance consisting of benzamide derivatives, is a poorly water-soluble chemical substance as an active ingredient. 2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester (hereinafter, simply referred to as "MTP inhibitory compound") was used.

1. assembly;

(1) dissolution of chemicals as active ingredients;

To the acetone / anhydrous ethanol mixed solution obtained by injecting 418.5 g of acetone and 46.5 g of anhydrous ethanol (weight ratio; 9: 1) into a propeller mixer and stirring and mixing, 30.0 g of the MTP inhibitory compound was added as a poorly water-soluble chemical. It was dissolved sufficiently.

(2) dissolution of the polymeric material;

In the solvent in which the MTP inhibitory compound was dissolved, 300.0 g of polyvinylpyrrolidone (Popidone K30) was gradually added as a water-soluble high molecular material, and further stirred and mixed to dissolve.

(3) preparation of excipients;

Separately, a mixing stirrer was used and uniformly stirred and mixed using 239.1 g of hard silicic anhydride as an excipient and 150.0 g of carboxymethylcellulose calcium mixed stirring granulator as a disintegrating agent.

(4) mixing excipients and polymer solution;

The organic mixed solvent in which the MTP inhibitory compound prepared in the step (2) and the polyvinylpyrrolidone solution were added was slowly added to the hard anhydrous silicic acid mixture prepared in the step (3) and mixed and stirred until homogeneous.

(5) bath assembly;

The mixture obtained in the above (4) was granulated according to a conventional method and then dried in a vacuum dryer.

(6) formulation;

In addition, in order to make a particle size uniform, the sizing operation was performed in accordance with a conventional method using the sieve of 600 micrometers.

2. tableting;

The granulation process was repeated twice, and 150.0 g of cross-linked polyvinylpyrrolidone (crospovidone) as a disintegrating agent and 7.8 g of magnesium stearate as a lubricant were added to 1438.2 g of the resulting granules, using a W-type mixer. After mixing uniformly, tableting using a rotary tableting machine produced about 133 mg of tablets (about 5 mg / tablet of MTP inhibitory compound as an active ingredient) per tablet.

Example 2

Dissolution test;

The dissolution test was carried out using a 0.1 w / v% sodium lauryl sulfate solution (900 mL, 37 ° C.) degassed according to the No. 1 dissolution test method No. 2 (puddle method, 50 rpm). The tablet (133.00 mg / tablet; containing 5 mg of raw medicine) prepared in Example 1 was directly added to the test solution. As a comparative control, the original drug consisting of crystals was added to the test solution as it was. The temperature was adjusted to 37 ± 0.1 ° C. The result was as shown in FIG.

As shown in FIG. 1, the compound (crystal) of the comparative control did not dissolve even after 60 minutes, whereas 95.45% of the solid preparation of the present invention dissolved after only 15 minutes.

Considering that the foods eaten by mouth or the like reach the small intestine after about 15 to 30 minutes, the preparation of the present invention is completely dissolved at the time of reaching the small intestine and is absorbed into the small intestine very efficiently. It can be said that it is ideal as a medicine to say.

In addition, since the solubility is excellent, the dose of the drug can be reduced, that is, the minimum required dose can be administered, and the solubility is improved, thereby making it possible to effectively increase the amount of drug to be transferred into the blood. This prevents the use of non-degradable drugs in the blood to move to the liver, resulting in risks derived from the drug (for example, liver fat caused by MTP inhibitors), and sometimes unexpected risks. It was possible to prevent in advance.

Moreover, the effect of these solubility improvement does not originate from the chemical property of an active ingredient compound, but the chemical substance as an active ingredient forms a microflake-like solid dispersion with a water-soluble polymer material, and the said microflake-like water-soluble polymer material is It is presumed to contribute to the improvement of solubility by remaining adsorbed and / or adhered to the surface of the inorganic porous material.

Therefore, the formulation technology of the present invention can be applied to a wide range of drug compounds without depending on the chemical properties of the drug as an active ingredient.

Example 3

Formulations for stability tests and identification tests for amorphous;

In order to confirm the stability and amorphousness of the present solid formulation, a test formulation was prepared according to the following method.

In addition, since it is thought that the main cause on stability and crystallinity depends on the combination of a water-soluble high molecular substance and a poorly water-soluble chemical substance, the solid dispersion which consists of these two materials was made into the test formulation. In addition, the MTP inhibitory compound was used as a poorly water-soluble chemical.

The test formulation was prepared by adding an appropriate amount of MTP inhibitory compound to a suitable and appropriate amount of solvent as described below, further adding a high molecular substance to be tested and gradually dissolving it, followed by spray drying.

Example 3-1

A powder was obtained by dissolving 5 g of MTP inhibitory compound and 15 g of polyvinylpyrrolidone (Collidon 30, manufactured by BASF) in a mixed solvent of 108 g of acetone and 72 g of water, followed by spray drying.

Example 3-2

5 g of MTP inhibitory compound and 50 g of polyvinylpyrrolidone (Collidon 30, manufactured by BASF) were dissolved in a mixed solvent of 270 g of acetone and 180 g of water, and a powder was obtained by spray drying.

Example 3-3

A powder was obtained by dissolving 5 g of MTP inhibitory compounds and 15 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nihon Soda) in 180 g of acetone, followed by spray drying.

Example 3-4

5 g of MTP inhibitory compound and 50 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nihon Soda) were dissolved in 450 g of acetone, and a powder was obtained by spray drying.

Example 3-5

5 g of MTP inhibitory compound and 15 g of hydroxypropylmethylcellulose (TC-5EW, manufactured by Shin-Etsu Chemical Co., Ltd.) were dissolved in a mixed solvent of 135 g of acetone and 60 g of water, and a powder was obtained by spray drying.

Example 3-6

5 g of MTP inhibitory compound and 50 g of hydroxypropylmethylcellulose (TC-5EW, manufactured by Shin-Etsu Chemical Co., Ltd.) were dissolved in a mixed solvent of 375 g of acetone and 150 g of water, and a powder was obtained by spray drying.

Example 4

Stability test under warm conditions;

Each powder obtained in Example 3 was tested under the heating condition of 80 degreeC. Purity was measured by high performance liquid chromatography (measured wavelength; 242 nm). In addition, the crystallization state was confirmed by powder X-ray diffraction. The results were as shown in Table 1 below.

In addition, although the term "maximum" in Table 1 showed the highest peak among 1 or more impurities, it means the percentage, and "total" means the total percentage of all impurities.

As can be seen from Table 1, the formulation of the present invention remained in an amorphous state and stability even at the initial stage of formulation and under heating conditions of 80 ° C.

Example 5

Identification of amorphous;

In order to observe the amorphous state of the formulation obtained in Example 3-2, immediately after formulation and at 40 ° C., 1 month, under various humidity conditions (11%, 32%, 53%, 75%), powder X It measured by the line diffraction method. The test was carried out by placing a sample dose into an aluminum cell having a depth of 0.2 mm and measuring the powder X-ray diffraction pattern at a scanning speed of 5 ° per minute. The results are shown in FIG.

As is apparent from FIG. 2, the formulation of the present invention had a good amorphous state and excellent stability even under such conditions.

Example 6

Stability tests under humidified conditions;

Each formulation obtained in Example 3 was tested under 40 degreeC and humidification conditions. The results were as shown in Table 2 below.

As can be seen from Table 2, polyvinylpyrrolidone and hydroxypropyl cellulose, in particular polyvinylpyrrolidone, showed excellent stability even under various humidity conditions.

As can be seen from the results of the stability test, the solid preparations of the present invention, in particular, polyvinylpyrrolidone or hydroxypropyl cellulose, particularly preferably polyvinylpyrrolidone, are used as the polymer material, and these polymer materials are effective. About 3 to 100 weight times, preferably about 3 to 20 weight times, particularly preferably about 8 to 12 weights, based on chemicals as components (e.g., MTP inhibitors or Apo B secretion inhibitors) In the case of pears and also HPCs, the solid formulations applied in the range of 6 to 15 weight folds had excellent water solubility properties and also excellent stability.

As described above, the solid preparation of the present invention has excellent water solubility characteristics, and thus high utilization rate can be realized. This fact has three important meanings. Firstly, the high utilization rate enables practical application of many poorly soluble chemicals as active ingredients, for example, MTP inhibitors and / or Apo B secretion inhibitors, and secondly, since they dissolve rapidly, It is rapidly absorbed by the small intestine, which is an absorption site, and especially, a drug that targets the small intestine selectively acts on the small intestine, and thirdly, because of its improved solubility, the dosage is significantly smaller than before, This reduces the burden of side effects, such as side effects, such as fatty liver or unexpected side effects are reduced.

In addition, the production method itself is also very simple and effective.

As described above, the solid preparation of the present invention surprisingly has not only dissolution characteristics but also excellent stability, and is simple and effective in manufacturing, and thus can be widely applied to a poorly water-soluble drug which has been difficult to practically use.

Therefore, when the solid preparation technology of the present invention is applied to lipid absorption inhibitors such as MTP inhibitors and Apo B secretion inhibitors, for example, there is no fear of fatty liver or unexpected side effects. , Arteriosclerosis, coronary artery disease, obesity, diabetes or hypertension can be a therapeutic or prophylactic.

Claims (32)

It is a solid preparation containing a poorly water-soluble chemical substance, a water-soluble polymer substance and an inorganic porous substance as a medicinal active ingredient,
(1) the poorly water-soluble chemical forms a solid dispersion with the water-soluble high molecular material,
(2) The water-soluble high molecular substance which forms the said solid dispersion is a fine piece, and
(3) The water-soluble solid preparation having improved water solubility, wherein the microflake-like water-soluble high molecular material is kept adsorbed and / or adhered to the surface of the inorganic porous material. The solid preparation according to claim 1, wherein the water-soluble high molecular material is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, agar, dextrin, gelatin or mixtures thereof. The solid preparation according to claim 2, wherein the water soluble high molecular material is polyvinylpyrrolidone or hydroxypropyl cellulose. The solid preparation according to any one of claims 1 to 3, wherein the water-soluble polymer substance is 3 to 100 times by weight based on the poorly water-soluble chemical substance as a pharmaceutically active ingredient. The solid preparation according to claim 4, wherein the water-soluble high molecular material is polyvinylpyrrolidone and the polyvinylpyrrolidone is 3 to 50 times by weight relative to the poorly water-soluble chemical substance as a medicinal active ingredient. The solid preparation according to claim 4, wherein the water-soluble high molecular substance is hydroxypropyl cellulose and the hydroxypropyl cellulose is 6 to 15 times by weight based on the poorly water-soluble chemical substance as a pharmaceutically active ingredient. The inorganic porous material according to any one of claims 1 to 6, wherein the inorganic porous material is calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate silicate, magnesium aluminum silicate, synthetic aluminum silicate, hydrous silicon dioxide , Or a mixture thereof. 8. The solid preparation of claim 7, wherein the inorganic porous material is hard silicic anhydride. The solid preparation according to any one of claims 1 to 8, wherein the inorganic porous material is 4 to 100 times by weight based on the poorly water-soluble chemical as a medicinal active ingredient. The solid preparation according to any one of claims 1 to 9, wherein the poorly water-soluble chemical as a pharmaceutically active ingredient is a lipid absorption inhibitor. The solid formulation of claim 10, wherein the lipid absorption inhibitor is an apolipoprotein B (Apo B) secretion inhibitor, a triglyceride (TG) transport protein inhibitor, or a cholesteryl ester transport protein (CETP) inhibitor. The solid formulation of claim 10, wherein the lipid absorption inhibitor is an MTP inhibitor, a lipase inhibitor, or an ACAT inhibitor. The solid formulation of claim 12, wherein the lipid absorption inhibitor is an MTP inhibitor. The solid preparation according to claim 13, wherein the MTP inhibitor is a substituted piperazine derivative or a salt thereof. The solid preparation of claim 13, wherein the MTP inhibitor is a benzamide derivative or salt thereof. The solid preparation according to claim 15, wherein the MTP inhibitor is a benzamide derivative or a salt thereof selected from the following.
4′-trifluoromethyl-biphenyl-2-carboxylic acid- (2-butyl-1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,
4′-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -amide,
9- [4- [4- (2,3-dihydro-1-oxo-1H-isoindol-2-yl) -1-piperidinyl] butyl] -N-propyl-9H-fluorene-9 Carboxamide,
2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-1H-isoindol-1-one,
9- [4- (4- [2- (4-trifluoromethylphenyl) benzoylamino] piperidin-1-yl) butyl] -N-2,2,2-trifluoroethyl) -9H- Fluorene-9-carboxamide,
4'-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (1H- [1,2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydro Isoquinolin-6-yl] -amide,
4′-trifluoromethyl-biphenyl-2-carboxylic acid- [2- (2-acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] -amide,
9H- (4- [4- [4'-trifluoromethyl-biphenyl-2-carbonyl) amino] -piperidin-1-yl} butyl) -9H-fluorene-9-carboxylic acid -(2,2,2-trifluoroethyl) -amide,
9- [4- [4- (2-benzothiazol-2-yl-benzoylamino) piperidin-1-yl] butyl] -9H-fluorene-9-carboxylic acid- (2,2, 2-trifluoroethyl) amide,
[11a-R] -8-[(4-cyanophenyl) methoxy] -2-cyclopentyl-7- (prop-2-enyl) -2,3,11,11a-tetrahydro-6H- Pyrazino [1,2b] isoquinoline-1,4-dione,
[11a-R] -2-cyclopentyl-7- (prop-2-enyl) -8-[(pyridin-2-yl) methoxy] -2,3,11,11a-tetrahydro-6H- Pyrazino [1,2b] isoquinoline-1,4-dione,
2-cyclopentyl-2- [4- (2,4-dimethylpyrido [2,3-b] indol-9-ylmethyl) phenyl] -N- (2-hydroxy-1-phenylethyl) acet Amides and
2-cyclopentyl-N- (2-hydroxy-1-phenylethyl) -2- [4- (quinolin-2-ylmethoxy) -phenyl] acetamide. The solid preparation according to claim 15, wherein the benzamide derivative is a compound represented by the following Chemical Formula 1, wherein X means -CON (R ¹⁰ )-(CH ₂ ) _n- .
<Formula 1>

[In the formula, R ¹ and R ² are hydrogen atoms, C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl, C _{1 - 6} alkoxy group, a halo-C _{1 - 6} alkyl group, a halo-C _{1 - 6} alkyloxy group, a substituted which may be C _{6 - 14} aryl group, an optionally substituted C _{7 - 16} aralkyl group, optionally substituted C _{6 - 14} aryloxy group, optionally substituted C _{7 - 16} aralkyl kilok group, an optionally substituted C _{6 - 13} aryl group, optionally substituted heterocyclic group, C _{2 - 7} alkoxycarbonyl group, a halogen atom, C _{2 - 6} alkenyl ^{group, -N (R 40) (R} 41) ( wherein R ⁴⁰ and R ⁴¹ are the same or or different C ₆ which may be a hydrogen atom or a _{substituted-aryl} group _14), and; Ring A is a C _6-14 aryl group, heterocyclic group, or

ego; X is ^{-CON (R 10) - (CH} 2) n - , and (wherein R ¹⁰ is a hydrogen atom, C _{1 - - 6} alkyl or C _{3 7} cycloalkyl group and, n is an integer of 0 or 1 to 3); R ³ and R ⁴ are the same or different C ₁₆ alkyl group which a hydrogen atom, a hydroxyl group, a halogen atom, may be substituted, C ₁₆ alkoxy group, a halo C _1-6 alkyl group, C _{7 - 16} aralkyl kilok group, C _{1 - 6} acyl group, an optionally substituted heterocyclic ^{group, -CON (R 11) (R} 12) ( wherein R ¹¹ and R ¹² are the same or different hydrogen atom, C _{1 - 6} alkyl, optionally substituted C _{6 - 14} aryl group, an optionally substituted C _{7 - 16} aralkyl group, C ₁₆ alkoxy group, or combine together with the nitrogen atom to which

(Where p is 0 or an integer from 1 to 2),-(CH ₂ ) _q -N (R ¹³ ) (R ¹⁴ ), where R ¹³ and R ¹⁴ are the same or different and represent a hydrogen atom, C _{1 - 6} alkyl, C _{2 - 7} alkoxycarbonyl group, C _{1 - 6} acyl, and or together with the nitrogen atom to which

May form a (where p is the Same as the above), q is an integer of 0 or 1 to 3) or -CO (R ¹⁵⁾ (wherein R ¹⁵ is a hydroxy group, C _{1 - 6} alkoxy group, optionally substituted C _{6 - 14} aryloxy group, optionally substituted C _{7 - 16} aralkyl group or a kilok C ₁₆ alkyl group) and; Ring B is

(Where K is 0 or an integer of 1 to 2), or ring B is combined with a nitrogen atom to which R ³ , R ¹⁰ and R ¹⁰ are bonded

May form; Alk1 ¹ is alkanediyl or alkendiyl; Alk1 ² is alkanediyl or alkenediyl; l is 0 or an integer of 1 to 3; m is 0 or an integer of 1 to 3; D is C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 7} alkoxycarbonyl ^{group, -N (R 42) -CO (} R 43) ( wherein R ⁴² is a hydrogen atom or a C _{1 - 6} alkyl group, R ⁴³ is a C _{6 - 14} aryl group or C _{7 - 16} aralkyl group) or the following general formula;

(Wherein, R ^5, R ⁶ and R ⁷ are the same or different and a hydrogen atom, C _{1 - 6} alkyl, C _{1 - 6} alkoxy group, C _{2 - 7} alkoxycarbonyl group, a carboxyl group, a halogen atom, a cyano group, a nitro group , halo-C ₁₆ alkyl, C ₁₆ Ah, which group, a hydroxyl group, an amino group, an optionally substituted C _{6 - 14} aryl group, or _{- (CH 2) r -CON (} R 16) (R 17) ( where R ¹⁶ and r ¹⁷ are the same or different and a hydrogen atom, C _{1 - 6} alkyl or halo C _{1 -} and ₆ alkyl, r is an integer of 0 or 1 to 3 shown below); ring C is C _{6 - 14} aryl group, C _{7 - 15} arylcarbonyl group, a C _{8 - 17} aralkyl-carbonyl group, a heterocycle residue, C _{3 - 7} cycloalkyl, C _{7 - 16} aralkyl group, or ring C, and R ⁷ and R ⁸ are together

May form; R ⁸ And R ⁹ are the same or different hydrogen atom, C _{1 - 6} alkyl, optionally substituted C _{6 - 14} aryl group, a hydroxy C _{1 - 6} alkyl ^{group, -CON (R 18) (R} 19) ( where R ¹⁸ and R ¹⁹ are the same or different hydrogen atom, C _{1 - 6} alkyl group, a C _3-7 cycloalkyl group, a halo-C _{1 - 6} alkyl, C _{2 -} C ₆ alkoxyalkyl group or may be substituted with _{12 - 14} aryl group), -COO (R ²⁰⁾ or _{- (CH 2) s -OCO (} R 20) ( wherein R ²⁰ is a hydrogen atom, C _{1 - 6} alkyl group or C _3-7 cycloalkyl group, s is an integer of 0 or 1 to 3 ^{), -N (R 21) (} R 22) ( wherein R ²¹ and R ²² are the same or different hydrogen atom, C _{1 - 6} alkyl, C _{1 - 6} acyl, C _{1 - 6} alkylsulfonyl, or R ^With nitrogen atoms to which ²¹ and R ²² are bonded

And that the can) is formed, or R ⁸ and R ⁹ together are C _{3 - 7} may form a cycloalkyl group; an ester compound or a prodrug thereof, or pharmaceutically acceptable salts thereof represented by the following. The method of claim 15, wherein the benzamide derivative is
2-phenyl-2- (2- {4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -malonic acid diisobutyl ester,
2- (2- {4- [ethyl- (4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl-malonic acid diethyl ester ,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid dimethyl ester,
2-cyclopentyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) Malonic acid diethyl ester,
2-cyclohexyl-2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) Malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,
2- [3- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy) -propyl] 2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(5-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,
2- (2- {4-[(5-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Malonic acid di 2,2,2-trifluoroethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(2'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,
2- (2- {5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,
2- (2- {3-bromo-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,
2- (2- {3-Chloro-5-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(3'-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,
2- (2- {4-[(3'-Chloro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (5 -Nitro-pyridin-2-yl) -malonic acid diethyl ester,
2- (5-Amino-pyridin-2-yl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino ] -Phenyl} -acetoxymethyl) -malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-pyridine- 2-yl-malonic acid diethyl ester,
2- (2- {3-chloro-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl}- Acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-bromo-5-dimethylcarbamoyl-2-fluoro-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-o- Tolyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-m- Tolyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-p- Tolyl-malonic acid diethyl ester,
2- (2-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,
2- (3-chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,
2- (4-Chloro-phenyl) -2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -Acetoxymethyl) -malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2-phenyl- Succinic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (2 -Methoxy-phenyl) -malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (3 -Methoxy-phenyl) -malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) -2- (4 -Methoxy-phenyl) -malonic acid diethyl ester,
2- (2- {4-[(5,4'-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,
2- (2- {4-[(6-chloro-4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-fluoro-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,
2- [2- (2- {3-dimethylcarbamoyl-4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxy ) -Ethyl] -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(5-ethoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(5-isopropoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl ) -2-phenyl-malonic acid diethyl ester,
2- [2- (2- {4-[(5,4'-bis-trifluoromethyl-biphenyl-2-carbonyl) -amino] -3-dimethylcarbamoyl-phenyl} -acetoxy ) -Ethyl] -2-phenyl-malonic acid diethyl ester,
2- (2- {3-dimethylcarbamoyl-4-[(6-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl) 2-phenyl-malonic acid diethyl ester and
2- (2- {3-dimethylcarbamoyl-4-[(3-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -phenyl} -acetoxymethyl)- 2-phenyl-malonic acid diethyl ester
Solid formulation, which is a compound selected from. Poorly soluble chemicals and water-soluble polymers as medicinal active ingredients are characterized by stirring and mixing a solution obtained by dissolving a poorly water-soluble chemical substance and a water-soluble high molecular substance as an active ingredient, and an inorganic porous substance, followed by granulation and drying. Solid preparations comprising materials and inorganic porous materials,
(1) the poorly water-soluble chemical forms a solid dispersion with the water-soluble high molecular material,
(2) The water-soluble high molecular substance which forms the said solid dispersion is a fine piece, and
(3) The method for producing a solid preparation having improved water solubility, wherein the microflake-like water-soluble high molecular material is kept adsorbed and / or adhered to the surface of the inorganic porous material. 20. The method of claim 19, wherein the water soluble high molecular material is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, agar, dextrin, gelatin or mixtures thereof. . The method for producing a solid preparation according to claim 20, wherein the water soluble high molecular material is polyvinylpyrrolidone or hydroxypropyl cellulose. 22. The method for producing a solid preparation according to any one of claims 19 to 21, wherein the water-soluble polymer substance is 3 to 100 times by weight relative to the poorly water-soluble chemical substance as a pharmaceutically active ingredient. The method for producing a solid preparation according to claim 22, wherein the water-soluble high molecular material is polyvinylpyrrolidone and the polyvinylpyrrolidone is 3 to 50 times by weight relative to the poorly water-soluble chemical substance as a medicinal active ingredient. The method for producing a solid preparation according to claim 22, wherein the water-soluble high molecular substance is hydroxypropyl cellulose and the hydroxypropyl cellulose is 6 to 15 times by weight based on the poorly water-soluble chemical substance as a medicinal active ingredient. The inorganic porous material according to any one of claims 19 to 24, wherein the inorganic porous material is calcium silicate, light anhydrous silicic acid, magnesium silicate, magnesium aluminate silicate, magnesium aluminate silicate, magnesium aluminum silicate, synthetic aluminum silicate, hydrous silicon dioxide. Or a mixture thereof. The method for producing a solid preparation according to claim 25, wherein the inorganic porous material is hard silicic anhydride. 27. The method for producing a solid preparation according to any one of claims 19 to 26, wherein the inorganic porous material is 4 to 100 times by weight based on the poorly water-soluble chemical as a pharmaceutically active ingredient. The method for producing a solid preparation according to any one of claims 19 to 27, wherein the amount of organic solvent is 1 to 2 times by weight of the water-soluble high molecular material. 29. The method for producing a solid preparation according to any one of claims 19 to 28, wherein the poorly water-soluble chemical as a pharmaceutically active ingredient is a lipid absorption inhibitor. 30. The method of claim 29, wherein the lipid absorption inhibitor is an inhibitor of Apo B secretion, a triglyceride (TG) transport protein inhibitor, or a cholesteryl ester transport protein (CETP) inhibitor. The method of claim 29, wherein the lipid absorption inhibitor is an MTP inhibitor, a lipase inhibitor, or an ACAT inhibitor. 32. The method of claim 31, wherein the lipid absorption inhibitor is an MTP inhibitor.

Images