TW202408497A - Solid dispersion, pharmaceutical preparation containing solid dispersion, and methods respectively for producing these products - Google Patents

Abstract

Provided are: a solid dispersion comprising at least one compound selected from the group consisting of a hetero ring derivative represented by general formula [1], a tautomer of the hetero ring derivative, and a pharmaceutically acceptable salt of the hetero ring derivative or the tautomer, and a pharmaceutically acceptable polymer; and a pharmaceutical preparation containing the solid dispersion.

Description

Solid dispersions, preparations containing solid dispersions, and methods of manufacturing the same

The present invention relates to a solid dispersion, a preparation containing the solid dispersion, and a manufacturing method thereof.

Membrane-bound prostaglandin E synthase-1 (mPGES-1) has been shown to be associated with pathological progression in various inflammations. In addition, mPGES-1 inhibitors only inhibit cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production, and are therefore expected to be highly safe anti-inflammatory agents (for example, Patent Document 1). As a compound having mPGES-1 inhibitory activity, Patent Document 1 discloses a novel heterocyclic derivative, a pharmaceutically acceptable salt thereof, and preparation examples thereof.

However, Patent Document 1 does not describe the solubility of the above-mentioned heterocyclic derivatives and their pharmaceutically acceptable salts, and also does not describe the oral absorbability of the above-mentioned heterocyclic derivatives and their pharmaceutically acceptable salts. [Prior technical literature] [Patent Document]

[Patent Document 1] International Publication No. 2013/024898

[The problem the invention is trying to solve]

The purpose of the present invention is to provide a solid dispersion that is effectively used as a pharmaceutical containing a compound having mPGES-1 inhibitory activity, a preparation that is effectively used as a pharmaceutical containing the solid dispersion, and a method for producing the same. [Technical means for solving the problem]

The inventors of the present invention have found that the following is selected from the general formula [1]: The present inventors have found that a solid dispersion containing at least one compound selected from the group consisting of the heterocyclic derivatives represented by the above general formula, their tautomeric isomers, and their pharmaceutically acceptable salts in an amorphous state obtained by using a pharmaceutically acceptable polymer can solve the above problem. It has also been found that a preparation using the solid dispersion is excellent as a pharmaceutical product.

The present invention is based on the novel findings, and relates to, for example, the inventions described in (Item 1) to (Item 38) below.

(Item 1) A solid dispersion comprising at least one compound selected from the group consisting of a heterocyclic derivative represented by the following general formula [1], its tautomeric isomers, and its pharmaceutically acceptable salts, and a pharmaceutically acceptable polymer. [Chemistry 2] In the general formula [1], ring A represents a group represented by the following general formula [2], [3] or [4]. [In the general formulae [2], [3] and [4], ^X1 represents NH, N-alkyl or O; ^A1 represents hydrogen or alkyl; ^A2 represents i) hydrogen, ii) halogen, iii) alkyl which may be substituted by 1 to 3 groups selected from the group consisting of halogen, amino, monoalkylamino, dialkylamino, aminoformyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy and alkylcarbonyloxy, iv) cycloalkyl which may be substituted by alkyl, which may be substituted by 1 to 3 halogens, v) alkoxy, vi) saturated heterocyclic which may be substituted by alkyl, alkoxycarbonyl, alkylcarbonyl or pendoxy, vii) alkylthio, viii) alkylsulfonyl, ix) alkylsulfinyl, x) a group represented by the following general formula [5], [Chemistry 4] (In the general formula [5], ^R3 and ^R4 are the same or different and represent a) hydrogen, b) an alkyl group which may be substituted by a group selected from the group consisting of a monoalkylamino group, a dialkylamino group, a saturated cyclic amine group which may be substituted by an alkyl group, a saturated heterocyclic group which may be substituted by an alkyl group, an alkoxy group, a hydroxycarbonyl group, a hydroxy group, an alkoxycarbonyl group, and an alkylthio group, or c) a cycloalkyl group) or ix) a saturated cyclic amine group which may be substituted by an alkyl group, an amino group, a monoalkylamino group, a dialkylamino group, an alkoxy group, or a hydroxy group]. ^R1 represents phenyl, benzyl, naphthyl, cycloalkyl, cycloalkylmethyl, heteroaryl, heteroarylmethyl, 1,2,3,4-tetrahydronaphthalene-5-yl, 1,2,3,4-tetrahydronaphthalene-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutylbenzene-3-yl, 1,2-dihydrocyclobutylbenzene-4-yl or alkyl, and the phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl may be selected from i) halogen, ii) alkyl substituted by 1 to 3 groups selected from the group consisting of halogen, hydroxyl, and phenyl, iii) alkoxy, ^R2 represents a phenyl group or a pyridyl group, and the phenyl group or the pyridyl group may be substituted by one to three groups selected from the group consisting of i) a halogen, ii) an alkylsulfonyl group, iii) an alkoxy group which may be substituted by one to three halogens or alkoxy groups, iv) an alkynyl group which may be substituted by an alkoxyalkyl group or a cycloalkyl group, and v) an alkyl group which may be substituted by one to three groups selected from the group consisting of an alkoxy group, an alkoxyalkoxy group, a cycloalkyl group, a phenyl group, and a halogen. (Item 2) A solid dispersion as described in (Item 1), wherein the compound is selected from N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride, At least one selected from the group consisting of N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide sulfuric acid. (Item 3) A solid dispersion as described in (Item 1) or (Item 2), wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of cellulose polymers, acrylic polymers, vinyl polymers, and polyethylene glycol polymers. (Item 4) A solid dispersion as described in (Item 3), wherein the pharmaceutically acceptable polymer is an acrylic polymer. (Item 5) A solid dispersion as described in (Item 3) or (Item 4), wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of methacrylic acid copolymers, aminoalkyl methacrylate copolymers, ammonium alkyl methacrylate copolymers, and ethyl acrylate-methyl methacrylate copolymers. (Item 6) A solid dispersion as described in any one of (Items 3) to (Item 5), wherein the pharmaceutically acceptable polymer is a methacrylic acid copolymer. (Item 7) A solid dispersion as described in any one of (Item 3) to (Item 6), wherein the pharmaceutically acceptable polymer is a methacrylic acid copolymer soluble at a pH of 5.5 or above. (Item 8) A solid dispersion as described in any one of (Item 3) to (Item 7), wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of methacrylic acid/methyl methacrylate copolymers and methacrylic acid/ethyl acrylate copolymers. (Item 9) A solid dispersion as described in any one of (Item 3) to (Item 8), wherein the pharmaceutically acceptable polymer is a methacrylic acid/methyl methacrylate copolymer. (Item 10) A solid dispersion as described in any one of (Item 3) to (Item 9), wherein the pharmaceutically acceptable polymer is a methacrylic acid copolymer L. (Item 11) A solid dispersion as described in any one of (Item 3) to (Item 10), wherein the pharmaceutically acceptable polymer is Eudragit (registered trademark) L100. (Item 12) A solid dispersion as described in any one of (Item 3) to (Item 8), wherein the pharmaceutically acceptable polymer is a methacrylic acid/ethyl acrylate copolymer. (Item 13) A solid dispersion as described in any one of (Item 3) to (Item 8) and (Item 12), wherein the pharmaceutically acceptable polymer is a dry methacrylic acid copolymer LD. (Item 14) A solid dispersion as described in any one of (Item 3) to (Item 8), (Item 12) and (Item 13), wherein the pharmaceutically acceptable polymer is Eudragit (registered trademark) L100-55. (Item 15) The solid dispersion as described in (Item 3), wherein the pharmaceutically acceptable polymer is a cellulose polymer. (Item 16) The solid dispersion as described in (Item 3) or (Item 15), wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, ethyl cellulose, and hydroxyethyl cellulose. (Item 17) The solid dispersion as described in any one of (Item 3), (Item 15) and (Item 16), wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose and hydroxypropyl methylcellulose acetate succinate. (Item 18) A solid dispersion as described in any one of (Item 3) and (Item 15) to (Item 17), wherein the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose. (Item 19) A solid dispersion as described in any one of (Item 3) and (Item 15) to (Item 17), wherein the pharmaceutically acceptable polymer is hydroxypropyl methylcellulose acetate succinate. (Item 20) A solid dispersion as described in any one of (Item 3), (Item 15) to (Item 17) and (Item 19), wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of HPMCAS-M and HPMCAS-H. (Item 21) A solid dispersion as described in (Item 3), wherein the pharmaceutically acceptable polymer is an ethylene polymer. (Item 22) A solid dispersion as described in (Item 3) or (Item 21), wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of polyvinyl pyrrolidone, carboxyvinyl polymer, vinyl pyrrolidone-vinyl acetate copolymer, and polyvinyl alcohol-polyethylene glycol graft copolymer. (Item 23) A solid dispersion as described in any one of (Item 3), (Item 21) and (Item 22), wherein the pharmaceutically acceptable polymer is PVP/VA64. (Item 24) A solid dispersion as described in (Item 3), wherein the pharmaceutically acceptable polymer is a combination of methacrylic acid copolymer L and hydroxypropyl methylcellulose, or a combination of methacrylic acid copolymer L and PVP/VA64. (Item 25) A solid dispersion as described in any one of (Item 1) to (Item 24), further comprising a surfactant. (Item 26) A solid dispersion as described in (Item 25), wherein the pharmaceutically acceptable polymer is methacrylic acid copolymer L, and the solid dispersion contains sodium lauryl sulfate or poloxamer 188 as a surfactant. (Item 27) A solid dispersion as described in (Item 25), wherein the pharmaceutically acceptable polymer is HPMCAS-M, and the solid dispersion contains sodium lauryl sulfate or poloxamer 188 as a surfactant. (Item 28) A solid dispersion as described in (Item 25), wherein the pharmaceutically acceptable polymer is PVP/VA64, and the solid dispersion contains sodium lauryl sulfate or poloxamer 188 as a surfactant. (Item 29) A solid dispersion as described in any one of (Item 1) to (Item 28), wherein the pharmaceutically acceptable polymer is soluble at a pH value exceeding 5.0, for example, the solubility is 1 mg/mL or more, preferably 1 to 3 mg/mL. (Item 30) A solid dispersion as described in any one of (Item 1) to (Item 29), wherein the pharmaceutically acceptable polymer is soluble in the second solution of the dissolution test of the 18th revised edition of the Japanese Pharmacopoeia, for example, the solubility is 1 mg/mL or more, preferably 1 to 3 mg/mL. (Item 31) A solid dispersion as described in any one of (Item 1) to (Item 30), wherein the solubility of the solid dispersion in the second solution of the dissolution test of the 18th revised edition of the Japanese Pharmacopoeia is greater than the solubility of the heterocyclic derivative represented by the general formula [1], its tautomeric isomers, and its pharmaceutically acceptable salts. (Item 32) A solid dispersion as described in any one of (Item 1) to (Item 31), wherein the solubility of the solid dispersion transferred to artificial intestinal fluid is greater than the solubility of the heterocyclic derivative represented by the general formula [1], its tautomeric isomers, and its pharmaceutically acceptable salts. (Item 33) A solid dispersion as described in any one of (Item 1) to (Item 32), wherein the amount of the compound relative to the total mass of the solid dispersion is 1 to 98 mass %. (Item 34) A preparation comprising a solid dispersion as described in any one of (Item 1) to (Item 33). (Item 35) A preparation as described in (Item 34), wherein the solubility of the preparation in the second solution of the dissolution test of the 18th revised edition of the Japanese Pharmacopoeia is greater than the solubility of the heterocyclic derivative represented by the above general formula [1], its tautomer, and its pharmaceutically acceptable salt. (Item 36) A preparation as described in (Item 34) or (Item 35), which is for oral administration. (Item 37) A preparation as described in any one of (Item 34) to (Item 36), which is in the form of a tablet. (Item 38) A method for producing a solid dispersion, comprising the following steps: spray drying a solution prepared by dissolving at least one compound selected from the group consisting of a heterocyclic derivative represented by the general formula [1], its tautomers, and its pharmaceutically acceptable salts, and a pharmaceutically acceptable polymer in a solvent. [Effects of the Invention]

According to the present invention, it is possible to provide a solid dispersion effectively used as a pharmaceutical containing a compound having mPGES-1 inhibitory activity, a preparation effectively used as a pharmaceutical containing the solid dispersion, and a method for producing the same. Furthermore, according to the present invention, the solubility and/or oral absorbability of the compound having mPGES-1 inhibitory activity can be improved.

Hereinafter, the method for implementing the present invention will be described in detail. However, the present invention is not limited to the following implementation method.

(Compound) The compound of this embodiment is selected from the group consisting of heterocyclic derivatives represented by the following general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof (hereinafter, Also known as the above compounds, etc.). [Chemistry 5]

In the general formula [1], ring A represents a group represented by the following general formula [2], [3] or [4]. [In the general formulae [2], [3] and [4], ^X1 represents NH, N-alkyl or O; ^A1 represents hydrogen or alkyl; ^A2 represents i) hydrogen, ii) halogen, iii) alkyl which may be substituted by 1 to 3 groups selected from the group consisting of halogen, amino, monoalkylamino, dialkylamino, aminoformyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy and alkylcarbonyloxy, iv) cycloalkyl which may be substituted by alkyl, which may be substituted by 1 to 3 halogens, v) alkoxy, vi) saturated heterocyclic which may be substituted by alkyl, alkoxycarbonyl, alkylcarbonyl or pendoxy, vii) alkylthio, viii) alkylsulfonyl, ix) alkylsulfinyl, x) a group represented by the following general formula [5], [Chemistry 7] (In the general formula [5], ^R3 and ^R4 are the same or different and represent a) hydrogen, b) an alkyl group substituted by a group selected from the group consisting of a monoalkylamino group, a dialkylamino group, a saturated cyclic amine group which may be substituted by an alkyl group, a saturated heterocyclic group which may be substituted by an alkyl group, an alkoxy group, a hydroxycarbonyl group, a hydroxy group, an alkoxycarbonyl group, and an alkylthio group, or c) a cycloalkyl group) or ix) a saturated cyclic amine group which may be substituted by an alkyl group, an amine group, a monoalkylamino group, a dialkylamino group, an alkoxy group, or a hydroxy group]. ^R1 represents phenyl, benzyl, naphthyl, cycloalkyl, cycloalkylmethyl, heteroaryl, heteroarylmethyl, 1,2,3,4-tetrahydronaphthalene-5-yl, 1,2,3,4-tetrahydronaphthalene-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutylbenzene-3-yl, 1,2-dihydrocyclobutylbenzene-4-yl or alkyl, and the phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl may be selected from i) halogen, ii) alkyl substituted by 1 to 3 groups selected from the group consisting of halogen, hydroxyl, and phenyl, iii) alkoxy, ^R2 represents a phenyl group or a pyridyl group, and the phenyl group or the pyridyl group may be substituted by one to three groups selected from the group consisting of i) a halogen, ii) an alkylsulfonyl group, iii) an alkoxy group which may be substituted by one to three halogens or alkoxy groups, iv) an alkynyl group which may be substituted by an alkoxyalkyl group or a cycloalkyl group, and v) an alkyl group which may be substituted by one to three groups selected from the group consisting of an alkoxy group, an alkoxyalkoxy group, a cycloalkyl group, a phenyl group, and a halogen.

Examples of "halogen" include fluorine, chlorine, bromine, and iodine. Examples of "alkyl" include linear or branched groups with 1 to 8 carbon atoms, specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, iso-hexyl, n-heptyl, iso-heptyl, and n-octyl. Among them, an alkyl group with 1 to 6 carbon atoms is preferred, and an alkyl group with 1 to 3 carbon atoms is more preferred. Examples of the alkyl moiety of "monoalkylamino", "dialkylamino", "monoalkylaminocarbonyl", "dialkylaminocarbonyl", "alkylcarbonyloxy", "alkoxycarbonyl", "alkylcarbonyl", "alkylthio", "alkylsulfonyl", "alkylsulfinyl", "alkoxyalkyl", and "alkoxyalkylamino" include the same as the above-mentioned "alkyl". Examples of the "alkoxy" include linear or branched carbon number 1 to 8 groups, specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, n-heptyloxy, and n-octyloxy. Examples of the alkoxy moiety of "alkoxyalkoxy", "alkoxyalkyl", and "alkoxyalkylamino" include the same as the above-mentioned "alkoxy". Examples of the "heteroaryl group" include 1-2 cyclic aromatic rings having 1-3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Specifically, for example, furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isozolyl, 4-isozolyl, 5-isozolyl), oxadiazolyl (e.g. 1,3,4-oxadiazol-2-yl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl (e.g. 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl), isothiazolyl (e.g. 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrimidinyl (e.g. 2-pyrimidinyl), benzothiadiazolyl (e.g., 1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl,), benzothiazolyl (e.g., benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl,), indolyl (e.g., indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl,), benzothiophenyl (e.g., 1-benzothiophene-2-yl, 1-benzothiophene-3-yl, 1-benzothiophene-4-yl, 1-benzothiophene-5-yl, 1-benzothiophene-7-yl,), -6-yl, 1-benzothiophene-7-yl,), 1,1-dioxo-1-benzothiophenyl (e.g. 1,1-dioxo-1-benzothiophene-2-yl, 1,1-dioxo-1-benzothiophene-3-yl, 1,1-dioxo-1-benzothiophene-4-yl, 1,1-dioxo-1-benzothiophene-5-yl, 1,1-dioxo-1-benzothiophene-6-yl, 1,1-dioxo-1-benzothiophene-7-yl), quinolyl (quinolyl-2-yl, quinolyl-3-yl, quinolyl-4-yl, quinolyl-5-yl, quinolyl-6-yl, quinolyl-7-yl, quinolyl-8-yl), 1,3-benzoxazol-2-yl. As the heteroaryl moiety of the "heteroarylmethyl group", the same ones as the above-mentioned "heteroaryl group" can be exemplified. As the "saturated cyclic amino group", for example, a 4- to 7-membered saturated cyclic amino group which may have 1 O or S and 1 or 2 N as a ring constituent atom can be exemplified, and specifically, 1-azacyclobutyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidinyl, 1-piperazinyl, 1-tetrahydropyrimidinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-homopiperazinyl, and oxazolidin-3-yl can be exemplified. As the saturated cyclic amino moiety of the "saturated cyclic aminocarbonyl group", the same ones as the above-mentioned "saturated cyclic amino group" can be exemplified. Examples of the "saturated heterocyclic group" include 4-membered or 6-membered saturated heterocyclic groups having one N or O as a ring-constituting atom, and specifically include 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-oxacyclobutyl, 3-oxacyclobutyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl. Examples of the "cycloalkyl group" include groups having 3 to 8 carbon atoms, and specifically include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of the cycloalkyl part of the "cycloalkylmethyl group" include the same groups as those for the above-mentioned "cycloalkyl group". Examples of "naphthyl" include 1-naphthyl and 2-naphthyl. Examples of "pyridyl" include 2-pyridyl, 3-pyridyl and 4-pyridyl. Examples of "alkynyl" include linear or branched alkynyl groups having 2 to 6 carbon atoms. Specifically, examples include ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl and 4-pentynyl.

The compound of this embodiment is preferably a compound described in (A), (B) or (C) below. (A) In the general formula [1], ring A is a group represented by the general formula [4], and X ¹ is a heterocyclic derivative of NH, its tautomer, and a pharmaceutically acceptable salt thereof. (B) In the general formula [1], R ¹ is phenyl, 1,2,3,4-tetralin-5-yl, 1,2,3,4-tetralin-6-yl, 2, 3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutylbenzene-3-yl or 1,2-dihydrocyclobutanyl Phenyl-4-yl, and the phenyl group may be selected from the group consisting of i) halogen, ii) alkyl group that may be substituted by 1 to 3 halogens, iii) alkoxy group, and iv) cyano group Heterocyclic derivatives substituted with 1 to 3 groups, their tautomers, and their pharmaceutically acceptable salts. (C) R ² is phenyl, and the phenyl group may be selected from i) halogen, ii) alkylsulfonyl, iii) alkoxy which may be substituted by alkoxy, and iv) which may be substituted by alkoxy Alkynyl substituted by alkyl or cycloalkyl, v) may be substituted by 1 to 3 groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl, and phenyl Heterocyclic derivatives substituted with 1 to 3 groups of alkyl groups, their tautomers, and their pharmaceutically acceptable salts.

In the compound of the present embodiment, it is more preferred that ring A is a group represented by the general formula [4], ^X1 is NH, ^A2 is i) hydrogen, ii) an alkyl group which may be substituted by a group selected from the group consisting of a halogen, a monoalkylamino group, a dialkylamino group, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group, a saturated cyclic aminocarbonyl group, an alkoxy group, an alkoxyalkoxy group, and an alkylcarbonyloxy group, iii) a cycloalkyl group which may be substituted by an alkyl group, the alkyl group may be substituted by 1 to 3 halogen groups, iv) an alkoxy group, v) a saturated heterocyclic group which may be substituted by an alkyl group or an alkoxycarbonyl group, vi) an alkylthio group, vii) an alkylsulfonyl group, viii) an alkylsulfinyl group, ix) an alkyl-substituted amino group which is substituted by a group selected from the group consisting of a monoalkylamino group, a dialkylamino group, a saturated cyclic amino group which is substituted by an alkyl group, a tetrahydrofuranyl group, a morpholinyl group, an alkoxy group, a hydroxycarbonyl group, a hydroxyl group, and an alkylthio group, x) an amino group which is substituted by a cycloalkyl group, or xi) a saturated cyclic amino group which is substituted by an alkyl group, a dialkylamino group, an alkoxy group, or a hydroxyl group, ^R1 is i) a phenyl group which is substituted by 1 to 3 groups selected from the group consisting of a halogen, an alkyl group which is substituted by 1 to 3 halogens, an alkoxy group, and a cyano group, ii) 1,2,3,4-tetrahydronaphthalen-5-yl group, iii) 2,3-dihydro-1H-inden-5-yl group, iv) benzyl which may be substituted by halogen or alkyl which may be substituted by 1 to 3 halogens, v) cycloalkyl, vi) cycloalkylmethyl, vii) naphthyl, viii) pyridylmethyl which may be substituted by alkyl which may be substituted by 1 to 3 halogens, ix) thienyl, x) thienylmethyl, xi) benzothiazolyl, xii) benzothiadiazolyl, xiii) indolyl or xiv) alkyl, ^R2 represents phenyl or pyridyl, and the phenyl may be substituted by 1 to 3 groups selected from the group consisting of i) halogen, ii) alkylsulfonyl, iii) alkoxy which may be substituted by alkoxy, iv) alkynyl which may be substituted by alkoxyalkyl or cycloalkyl, and v) alkyl which may be substituted by 1 to 3 groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl and phenyl, The pyridyl group may be substituted with a halogen, a heterocyclic derivative, a tautomer and a pharmaceutically acceptable salt thereof.

Furthermore, as the compound of this embodiment, it is more preferable that ring A is a group represented by general formula [4], X ¹ is NH, and A ² is an alkyl group substituted with an alkoxy group, a dialkylamino group, or tetrahydrofuran group, tetrahydrofurylmethyl, alkoxyalkylamino, or unsubstituted or cycloalkyl substituted by an alkyl group which may be substituted by 1 to 3 halogens, R ¹ is substituted by 1 halogen, and 1 Methyl-substituted phenyl, R ² is a heterocyclic derivative of phenyl which may be substituted by 1 trifluoromethyl or 2 halogens, and its tautomers, as well as its pharmaceutically acceptable salts.

Moreover, as the compound of this embodiment, the heterocyclic derivative described in any one of the following (1) to (239), its tautomer, and its pharmaceutically acceptable salt are particularly preferred. (1) N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxylic acid amine (2) N-cyclohexyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (3) N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxylic acid amine (4) N-[(1-hydroxycyclohexyl)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (5) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino}-2,3-dihydro-1-benzene Furan-7-methamide (6) N-cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-2,3-dihydro-1-benzofuran-7-methamide (7) N-(3-chloro-2-methylphenyl)-5-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-2,3-dihydro-1-benzene Furan-7-methamide (8) N-cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-indazole-7-carboxamide (9) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-indazole-7-carboxamide (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (11) 2-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (12) N-Cyclohexyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (13) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (14) N-Cyclopentyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (15) N-cyclobutyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (16) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (17) N-cyclohexyl-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (18) 2-ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (19) N-cyclohexyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxylic acid amine (20) 2-(methoxymethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (21) 2-(methoxymethyl)-N-(2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzo Imidazole-4-methamide (22) 2-(methoxymethyl)-N-(4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzo Imidazole-4-methamide (23) N-(2-chlorobenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (24) 2-(methoxymethyl)-N-(4-methylbenzyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzo Imidazole-4-methamide (25) N-(4,4-difluorocyclohexyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H- Benzimidazole-4-methamide (26) N-(4-tert-butylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H- Benzimidazole-4-methamide (27) 2-(methoxymethyl)-N-[4-(trifluoromethyl)phenyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (28) N-(2,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H -Benzimidazole-4-methamide (29) N-(2-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (30) N-(3,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H -Benzimidazole-4-methamide (31) N-(3-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (32) N-(2,3-dihydro-1H-inden-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl} Amino)-1H-benzimidazole-4-methamide (33) 2-(methoxymethyl)-N-(5,6,7,8-tetralin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl }Amino)-1H-benzimidazole-4-methamide (34) N-(2-fluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (35) 2-(methoxymethyl)-N-(2-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-phenyl imidazole-4-methamide (36) 2-(methoxymethyl)-N-(4-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-phenyl imidazole-4-methamide (37) N-(3-bromo-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (38) N-(3-chloro-2-methylbenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (39) N-(2,6-difluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H- Benzimidazole-4-methamide (40) N-(3-cyano-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine) -1H-benzimidazole-4-methamide (41) 2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-N-{[3-(trifluoromethyl)pyridine-2 -yl]methyl}-1H-benzimidazole-4-methamide (42) N-(2-chloro-6-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (43) 2-(2-Amino-2-side oxyethyl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl ]carbonyl}amino)-1H-benzimidazole-4-methamide (44) 2-(2-Amino-2-side oxyethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl ]carbonyl}amino)-1H-benzimidazole-4-methamide (45) N-(3-chloro-2-methylphenyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (46) N-Cyclohexyl-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (47) 1-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (48) N-(3-chloro-2-methylphenyl)-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (49) N-cyclohexyl-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (50) 1-ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (51) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzene Triazole-4-methamide (52) 2-methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1,3-benzene Triazole-4-methamide (53) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-phenyl Triazole-4-methamide (54) N-(3-chloro-2-methylphenyl)-2-ethoxy-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzo Imidazole-4-methamide (55) 2-ethoxy-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzo Imidazole-4-methamide (56) N-(3-chloro-2-methylphenyl)-2-(1-chloro-2-methylpropan-2-yl)-6-({[2-(trifluoromethyl)benzene base]carbonyl}amino)-1H-benzimidazole-4-carboxamide (57) N-(3-chloro-2-methylphenyl)-2-[(dimethylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl} Amino)-1H-benzimidazole-4-methamide (58) N-(3-chloro-2-methylphenyl)-2-(2-methylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine) -1H-benzimidazole-4-methamide (59) 2-(2-methylpropyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine) -1H-benzimidazole-4-methamide (60) 3-{4-[(3-chloro-2-methylphenyl)aminomethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H -Benzimidazole-2-yl}azetidine-1-carboxylic acid tert-butyl ester (61) N-(3-chloro-2-methylphenyl)-2-[(methylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine base)-1H-benzimidazole-4-methamide (62) {4-[(3-chloro-2-methylphenyl)aminomethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzene Imidazol-2-yl}methylacetate (63) N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl} Amino)-1H-benzimidazole-4-methamide (64) 2-[(2R)-Tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl} Amino)-1H-benzimidazole-4-methamide (65) N-(3-chloro-2-methylphenyl)-2-[(2S)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl} Amino)-1H-benzimidazole-4-methamide (66) 2-[(2S)-Tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl} Amino)-1H-benzimidazole-4-methamide (67) 2-(1-acetyl azobutin-3-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl] Carbonyl}amine)-1H-benzimidazole-4-carboxamide (68) (2S)-2-{4-[(3-chloro-2-methylphenyl)aminemethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine tert-butyl)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylate (69) (2R)-2-{4-[(3-chloro-2-methylphenyl)aminemethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine tert-butyl)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylate (70) N-(3-chloro-2-methylphenyl)-2-[(2S)-pyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl }Amino)-1H-benzimidazole-4-methamide (71) N-(3-chloro-2-methylphenyl)-2-[(2S)-1-methylpyrrolidin-2-yl]-6-({[2-(trifluoromethyl) Phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (72) 2-[(2S)-1-acetylpyrrolidin-2-yl]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (73) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethoxy)methyl]-6-({[2-(trifluoromethyl)phenyl ]carbonyl}amino)-1H-benzimidazole-4-methamide (74) N-(3-chloro-2-methylphenyl)-2-(1-methoxy-2-methylpropan-2-yl)-6-({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (75) 2-tert-Butyl-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-phenyl imidazole-4-methamide (76) 2-tert-Butyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-N-{[3-(trifluoromethyl)pyridin-2-yl] Methyl}-1H-benzimidazole-4-methamide (77) N-(3-chloro-2-methylphenyl)-2-(2-ethoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine )-1H-benzimidazole-4-methamide (78) N-(3-chloro-2-methylphenyl)-2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (79) 2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-N-{[3-(trifluoromethyl)pyridine-2 -yl]methyl}-1H-benzimidazole-4-methamide (80) N-(3-chloro-2-methylphenyl)-2-(2-methoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine )-1H-benzimidazole-4-methamide (81) N-(3-chloro-2-methylphenyl)-2-(2,2-dimethylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl} Amino)-1H-benzimidazole-4-methamide (82) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzo Imidazole-4-methamide (83) N-(3-chloro-2-methylphenyl)-2-(2-methylpentan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl }Amino)-1H-benzimidazole-4-methamide (84) N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine )-1H-benzimidazole-4-methamide (85) 2-tert-Butyl-N-(3-chloro-4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-phenyl imidazole-4-methamide (86) 2-tert-Butyl-N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole -4-methamide (87) 2-tert-Butyl-N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole -4-methamide (88) N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl] Carbonyl}amine)-1H-benzimidazole-4-carboxamide (89) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl }Amino)-1H-benzimidazole-4-methamide (90) N-(2-chlorobenzyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (91) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H -Benzimidazole-4-methamide (92) 6-{[(2-chloro-4-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-methoxymethyl-1H-benzene imidazole-4-methamide (93) 6-{[(2-chloro-5-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H -Benzimidazole-4-methamide (94) N-(3-chloro-2-methylphenyl)-6-{[(2-chlorophenyl)carbonyl]amine}-2-(methoxymethyl)-1H-benzimidazole -4-methamide (95) N-(3-chloro-2-methylphenyl)-6-{[(2-chloropyridin-3-yl)carbonyl]amine}-2-(methoxymethyl)-1H- Benzimidazole-4-methamide (96) 6-{[(2-bromophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole -4-methamide (97) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amine}-2-(methoxymethyl)-1H- Benzimidazole-4-methamide (98) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amine}-2-(methoxymethyl)-1H- Benzimidazole-4-methamide (99) 6-{[(2-chloro-3-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H -Benzimidazole-4-methamide (100) 6-{[(2-chloro-3,6-difluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl )-1H-benzimidazole-4-methamide (101) 6-{[(2-Bromo-6-chlorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H -Benzimidazole-4-methamide (102) 6-{[(2-Bromo-6-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H -Benzimidazole-4-methamide (103) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-6-methylphenyl)carbonyl]amine}-2-(methoxymethyl)- 1H-benzimidazole-4-methamide (104) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-4-methylphenyl)carbonyl]amine}-2-(methoxymethyl)- 1H-benzimidazole-4-methamide (105) 6-{[(5-bromo-2-chlorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H -Benzimidazole-4-methamide (106) 6-{[(2-Bromo-5-chlorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H -Benzimidazole-4-methamide (107) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-5-methylphenyl)carbonyl]amine}-2-(methoxymethyl)- 1H-benzimidazole-4-methamide (108) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[5-methyl-2-(trifluoromethyl)phenyl]carbonyl }Amino)-1H-benzimidazole-4-methamide (109) 6-({[2,5-bis(trifluoromethyl)phenyl]carbonyl}amine)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl base)-1H-benzimidazole-4-methamide (110) 6-({[2,4-bis(trifluoromethyl)phenyl]carbonyl}amine)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl base)-1H-benzimidazole-4-methamide (111) N-(3-chloro-2-methylphenyl)-6-({[5-fluoro-2-(trifluoromethyl)phenyl]carbonyl}amine)-2-(methoxy Methyl)-1H-benzimidazole-4-methamide (112) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}amine)-2-(methoxy Methyl)-1H-benzimidazole-4-methamide (113) N-(3-chloro-2-methylphenyl)-6-[({2-chloro-5-[2-(propan-2-yloxy)ethoxy]phenyl}carbonyl) Amino]-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (114) 6-({[2-chloro-5-(2-ethoxyethoxy)phenyl]carbonyl}amine)-N-(3-chloro-2-methylphenyl)-2- (Methoxymethyl)-1H-benzimidazole-4-methamide (115) 6-({[2-chloro-5-(3-methoxypropyl)phenyl]carbonyl}amine)-N-(3-chloro-2-methylphenyl)-2-( Methoxymethyl)-1H-benzimidazole-4-methamide (116) 6-({[5-(3-tert-butoxy-1-propyn-1-yl)-2-chlorophenyl]carbonyl}amine)-N-(3-chloro-2- Methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (117) 6-({[5-(3-tert-butoxypropyl)-2-chlorophenyl]carbonyl}amine)-N-(3-chloro-2-methylphenyl)-2 -(methoxymethyl)-1H-benzimidazole-4-methamide (118) 6-({[2-chloro-5-(3-hydroxy-3-methylbutyl)phenyl]carbonyl}amine)-N-(3-chloro-2-methylphenyl)- 2-(methoxymethyl)-1H-benzimidazole-4-methamide (119) 6-({[2-chloro-5-(ethoxymethyl)phenyl]carbonyl}amine)-N-(3-chloro-2-methylphenyl)-2-(methoxy (Methyl)-1H-benzimidazole-4-methamide (120) 6-[({2-chloro-5-[(2-ethoxyethoxy)methyl]phenyl}carbonyl)amino]-N-(3-chloro-2-methylphenyl )-2-(methoxymethyl)-1H-benzimidazole-4-methamide (121) 6-({[2-chloro-5-(2-cyclopropylethyl)phenyl]carbonyl}amine)-N-(3-chloro-2-methylphenyl)-2-( Methoxymethyl)-1H-benzimidazole-4-methamide (122) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(2-phenylethyl)phenyl]carbonyl}amine)-2-(methyl Oxymethyl)-1H-benzimidazole-4-methamide (123) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzo Imidazole-4-methamide (124) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole- 4-methamide (125) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-cyclopentyl-1H-benzimidazole -4-methamide (126) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2- base]-1H-benzimidazole-4-methamide (127) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amine}-2-[(2R)-tetrahydrofuran-2-yl ]-1H-benzimidazole-4-methamide (128) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amine}-2-[(2R)-tetrahydrofuran-2-yl ]-1H-benzimidazole-4-methamide (129) N-(3-chloro-2-methylphenyl)-2-[(2S)-5-pentanoxypyrrolidin-2-yl]-6-({[2-(trifluoromethyl) Phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (130) N-(3-chloro-2-methylphenyl)-2-[(2R)-5-pyrrolidin-2-yl]-6-({[2-(trifluoromethyl) Phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (131) N-(3-chloro-2-methylphenyl)-2-[2-side oxy-2-(pyrrolidin-1-yl)ethyl]-6-({[2-(tri Fluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (132) N-(3-chloro-2-methylphenyl)-2-[2-(dimethylamino)-2-side oxyethyl]-6-({[2-(trifluoro Methyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (133) N-(3-chloro-2-methylphenyl)-2-[2-(methylamino)-2-side oxyethyl]-6-({[2-(trifluoromethyl base)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (134) 2-Chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole- 4-methamide (135) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl] Carbonyl}amine)-1H-benzimidazole-4-carboxamide (136) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl} Amino)-1H-benzimidazole-4-methamide (137) N-(3-chloro-2-methylphenyl)-2-(methylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H -Benzimidazole-4-methamide (138) N-(3-chloro-2-methylphenyl)-2-(ethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H -Benzimidazole-4-methamide (139) N-(3-chloro-2-methylphenyl)-2-[(2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)benzene base]carbonyl}amino)-1H-benzimidazole-4-carboxamide (140) N-(3-chloro-2-methylphenyl)-2-(cyclopentylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (141) N-(3-chloro-2-methylphenyl)-2-(piperidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine) -1H-benzimidazole-4-methamide (142) N-(3-chloro-2-methylphenyl)-2-(4-methylpiperidine-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl }Amino)-1H-benzimidazole-4-methamide (143) 2-[Bis(2-hydroxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl }Amino)-1H-benzimidazole-4-methamide (144) N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)- 1H-benzimidazole-4-methamide (145) N-(3-chloro-2-methylphenyl)-2-{[2-(𠰌lin-4-yl)ethyl]amino}-6-({[2-(trifluoromethyl base)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (146) N-(3-chloro-2-methylphenyl)-2-{[2-(dimethylamino)ethyl]amino}-6-({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (147) N-(3-chloro-2-methylphenyl)-2-(3-hydroxyazetidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl }Amino)-1H-benzimidazole-4-methamide (148) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-({[2-( Trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (149) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-6-({[2-(trifluoromethyl)benzene base]carbonyl}amino)-1H-benzimidazole-4-carboxamide (150) N-(3-chloro-2-methylphenyl)-2-{[2-(diethylamino)ethyl]amino}-6-({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (151) N-(3-chloro-2-methylphenyl)-2-{[2-(pyrrolidin-1-yl)ethyl]amino}-6-({[2-(trifluoromethyl base)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (152) N-(3-chloro-2-methylphenyl)-2-{[3-(dimethylamino)propyl]amino}-6-({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (153) N-(3-chloro-2-methylphenyl)-2-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-6-({ [2-(Trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (154) N-(3-chloro-2-methylphenyl)-2-{[2-(dipropan-2-ylamino)ethyl]amino}-6-({[2-(tri Fluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (155) N-(3-chloro-2-methylphenyl)-2-(𠰌lin-4-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine) -1H-benzimidazole-4-methamide (156) 2-Amino-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (157) N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoro Methyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (158) N-(3-chloro-2-methylphenyl)-2-{[(3-methyloxetan-3-yl)methyl]amino}-6-({[2 -(Trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (159) N-{4-[(3-chloro-2-methylphenyl)aminemethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H -Benzimidazole-2-yl}glycinate tert-butyl ester (160) N-{4-[(3-chloro-2-methylphenyl)aminemethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H -Benzimidazol-2-yl}glycine (161) N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1-methyl-6-({[ 2-(Trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (162) N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)amino]-6-({[2-( Trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (163) N-(3-chloro-2-methylphenyl)-2-(pyrrolidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine) -1H-benzimidazole-4-methamide (164) 2-(azetidin-1-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine )-1H-benzimidazole-4-methamide (165) N-(3-chloro-2-methylphenyl)-2-(3-methoxyazetidin-1-yl)-6-({[2-(trifluoromethyl)phenyl ]carbonyl}amino)-1H-benzimidazole-4-methamide (166) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxy-2-methylpropyl)amine]-6-({[2-(trifluoromethyl) Phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (167) N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amine}-6-({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (168) N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amine}-6-({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (169) N-(3-chloro-2-methylphenyl)-2-{[(2S)-1-hydroxy-3-methylbutan-2-yl]amino}-6-({[ 2-(Trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (170) N-(3-chloro-2-methylphenyl)-2-{[(2R)-1-hydroxy-3-methylbutan-2-yl]amino}-6-({[ 2-(Trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (171) N-(3-chloro-2-methylphenyl)-2-{[(2S)-1-hydroxy-3,3-dimethylbutan-2-yl]amino}-6- ({[2-(Trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (172) N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-6-({ [2-(Trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (173) N-(3-chloro-2-methylphenyl)-2-[(3-methoxypropyl)amino]-6-({[2-(trifluoromethyl)phenyl] Carbonyl}amine)-1H-benzimidazole-4-carboxamide (174) N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)ethyl]amino}-6-({[2-(trifluoro Methyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (175) 2-[(2-tert-butoxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)benzene base]carbonyl}amino)-1H-benzimidazole-4-carboxamide (176) N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl base)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (177) N-(3-chloro-2-methylphenyl)-2-{[2-(methylthio)ethyl]amine}-6-({[2-(trifluoromethyl) Phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide (178) N-(3-chloro-2-methylphenyl)-2-(methylthio)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H -Benzimidazole-4-methamide (179) N-(3-chloro-2-methylphenyl)-2-(methylsulfonyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)- 1H-benzimidazole-4-methamide (180) N-(3-chloro-2-methylphenyl)-2-(methylsulfenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine) -1H-benzimidazole-4-methamide (181) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H -Benzimidazole-4-methamide (182) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H- Benzimidazole-4-methamide (183) N-(3-chloro-2-methylphenyl)-6-{[(2,4-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H- Benzimidazole-4-methamide (184) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H- Benzimidazole-4-methamide (185) 6-{[(2-Bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H -Benzimidazole-4-methamide (186) 6-{[(2-Bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H -Benzimidazole-4-methamide (187) 6-({[2-chloro-5-(cyclopropylethynyl)phenyl]carbonyl}amine)-N-(3-chloro-2-methylphenyl)-2-(dimethyl methylamine)-1H-benzimidazole-4-methamide (188) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amine}-2-[(3-hydroxy-2,2- Dimethylpropyl)amino]-1H-benzimidazole-4-methamide (189) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amine}-2-[(3-methoxy-2, 2-Dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (190) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amine}-2-[(2-hydroxy-2-methyl Propyl)amino]-1H-benzimidazole-4-carboxamide (191) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amine}-2-[(2-methoxy-2- Methylpropyl)amino]-1H-benzimidazole-4-methamide (192) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amine}-2-{[2-(propan-2-yl) Oxy)ethyl]amino}-1H-benzimidazole-4-methamide (193) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-{[2-(propane-2- (oxy)ethyl]amino}-1H-benzimidazole-4-carboxamide (194) 2-[(2-tert-butoxyethyl)amino]-6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2 -methylphenyl)-1H-benzimidazole-4-methamide (195) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2 ,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (196) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2 -Methylpropyl)amino]-1H-benzimidazole-4-methamide (197) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2 -methyl]amino}-1H-benzimidazole-4-methamide (198) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2 -methyl]amino}-1H-benzimidazole-4-methamide (199) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2 -Dimethylpropyl)amino]-1H-benzimidazole-4-methamide (200) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-{[(2S)-1-hydroxy -3-Methylbutan-2-yl]amino}-1H-benzimidazole-4-carboxamide (201) N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)- 1H-benzimidazole-4-methamide (202) N-(4-tert-butylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H- Benzimidazole-4-methamide (203) N-(2,3-dihydro-1H-inden-5-yl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl} Amino)-1H-benzimidazole-4-methamide (204) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-1H -Benzimidazole-4-methamide (205) N-(3-chloro-4-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H- Benzimidazole-4-methamide (206) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H- Benzimidazole-4-methamide (207) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amine}-1H-benzimidazole- 4-methamide (208) N-(3-chloro-4-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amine}-1H-benzimidazole- 4-methamide (209) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amine}-2-(1-methylcyclopropyl)- 1H-benzimidazole-4-methamide (210) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amine}-2-(1-methylcyclopropyl)- 1H-benzimidazole-4-methamide (211) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(methylsulfonyl)phenyl]carbonyl}amine) -1H-benzimidazole-4-methamide (212) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(2-methoxyethyl)- 1H-benzimidazole-4-methamide (213) 2-(methoxymethyl)-N-phenyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxylic acid amine (214) 2-(methoxymethyl)-N-propyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxylic acid amine (215) 2-(methoxymethyl)-N-(pyridin-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (216) N-Benzyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxylic acid amine (217) N-(cyclohexylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole- 4-methamide (218) 2-(methoxymethyl)-N-(naphth-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (219) 2-(methoxymethyl)-N-(thiophen-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole -4-methamide (220) N-(2,1,3-benzothiadiazol-4-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl }Amino)-1H-benzimidazole-4-methamide (221) N-(1,1-dioxide-1-benzothiophen-6-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl ]carbonyl}amino)-1H-benzimidazole-4-methamide (222) 2-(methoxymethyl)-N-(thiophen-2-ylmethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzene imidazole-4-methamide (223) N-(1H-indol-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H- Benzimidazole-4-methamide (224) N-(1,3-benzothiazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine) -1H-benzimidazole-4-methamide (225) N-(2,2-dimethylpropyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H -Benzimidazole-4-methamide (226) 2-(methoxymethyl)-N-(thiophen-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole -4-methamide (227) N-(5-chloro-1,3-benzoethazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl] Carbonyl}amine)-1H-benzimidazole-4-carboxamide (228) N-(2-benzylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzo Imidazole-4-methamide (229) 2-(methoxymethyl)-N-(quinolin-8-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzo Imidazole-4-methamide (230) N-(cycloheptylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole -4-methamide (231) N-(1,3-benzoethazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine )-1H-benzimidazole-4-methamide (232) N-(6-chloro-1,3-benzoethazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl] Carbonyl}amine)-1H-benzimidazole-4-carboxamide (233) N-[3-chloro-2-(hydroxymethyl)phenyl]-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine base)-1H-benzimidazole-4-methamide (234) N-(3-chloro-2-methylphenyl)-6-{[(3-fluoropyridin-2-yl)carbonyl]amine}-2-(methoxymethyl)-1H- Benzimidazole-4-methamide (235) N-(3-chloro-2-methylphenyl)-6-{[(3-chloropyridin-4-yl)carbonyl]amine}-2-(methoxymethyl)-1H- Benzimidazole-4-methamide (236) N-(3-chloro-2-methylphenyl)-6-{[(3,5-dichloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl) -1H-benzimidazole-4-methamide (237) 6-{[(5-butoxy-2-chlorophenyl)carbonyl]amine}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl) -1H-benzimidazole-4-methamide (238) 6-({[2-chloro-5-(2,2-difluoroethoxy)phenyl]carbonyl}amine)-N-(3-chloro-2-methylphenyl)-2 -(methoxymethyl)-1H-benzimidazole-4-methamide (239) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]carbonyl}amine) -2-(methoxymethyl)-1H-benzimidazole-4-methamide

Some of the compounds of the present embodiment have asymmetric carbons, but each optical isomer and a mixture thereof are included in the compounds of the present embodiment.

The heterocyclic derivatives of the present embodiment that can form tautomers, each tautomer and mixtures thereof are all included in the compounds of the present embodiment. For example, a heterocyclic derivative represented by the general formula [1] in which ring A is a group represented by the general formula [4] and ^X1 is NH (i.e., a heterocyclic derivative represented by the following general formula (1X)) can form a heterocyclic derivative represented by the general formula [1XA]. [Chemistry 8] In the general formulae [1X] and [1XA], R ¹ , R ² and A ² have the same meanings as in the general formula [1].

Examples of pharmaceutically acceptable salts of the heterocyclic derivatives of the present embodiment and their tautomers include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, acetic acid, citric acid, tartaric acid, cis Salts of organic acids such as butenedioic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, etc.

The compound of the present embodiment can be produced, for example, by the production method described in Patent Document 1.

The compound of this embodiment can be selected from N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride, At least one of the group consisting of N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide sulfuric acid .

The compound of this embodiment may be used individually by 1 type, or in combination of 2 or more types.

(solid dispersion) The solid dispersion system of this embodiment is composed of an amorphous drug dispersed in an inactive carrier base. The drug mentioned here is the compound of this embodiment mentioned above. In addition, the carrier base is a pharmaceutically acceptable polymer. In the solid dispersion of this embodiment, the above-mentioned compounds and the like are contained in a pharmaceutically acceptable polymer in an amorphous state.

(Medically acceptable polymer) The pharmaceutically acceptable polymer of the present embodiment preferably contains the above-mentioned compounds in an amorphous state, and preferably contains N-(3-chloro-2-methylbenzene having the following structure) in an amorphous state. base)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amine)-1H-benzimidazole-4-carboxamide 4-methyl Benzenesulfonate.

[Chemistry 9]

The pharmaceutically acceptable polymer of the present embodiment is soluble at a pH value exceeding 5.0, preferably soluble at 1 mg/mL or more, and more preferably soluble at 1-3 mg/mL. The pharmaceutically acceptable polymer of the present embodiment is soluble at a pH value exceeding 5.5, preferably soluble at 1 mg/mL or more, and more preferably soluble at 1-3 mg/mL. The pharmaceutically acceptable polymer of the present embodiment is, for example, soluble at a pH value exceeding 6.0, preferably soluble at 1 mg/mL or more, and more preferably soluble at 1-3 mg/mL. The pharmaceutically acceptable polymer of the present embodiment is soluble in the second solution of the dissolution test of the 18th revision of the Japanese Pharmacopoeia, preferably in the second solution of the dissolution test of the 18th revision of the Japanese Pharmacopoeia after stirring at room temperature of 25°C for 12 hours.

The pharmaceutically acceptable polymer of the present embodiment is, for example, at least one selected from the group consisting of acrylic polymers, vinyl polymers, cellulose polymers and polyethylene glycol polymers, preferably at least one selected from the group consisting of methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid aminoalkyl ester copolymer E, polyvinyl pyrrolidone and hydroxypropyl methylcellulose.

The pharmaceutically acceptable polymer of this embodiment is, for example, an acrylic polymer, for example, selected from the group consisting of methacrylic acid copolymers (for example, methacrylic acid/methyl methacrylate copolymer, methacrylic acid/ethyl acrylate copolymer). ), at least one of the group consisting of aminoalkyl methacrylate copolymer, ammonium alkyl methacrylate copolymer, and ethyl acrylate-methyl methacrylate copolymer.

The ratio of the structural units derived from methacrylic acid to the structural units derived from methyl methacrylate of the methacrylic acid/methyl methacrylate copolymer of this embodiment (structural units derived from methacrylic acid: derived from methane The structural unit of methyl acrylate) can be 30:70～70:30, can be 35:65～65:35, can be 40:60～60:40, can be 45:55～55:45.

The methacrylic acid/methyl methacrylate copolymer of this embodiment is dissolved, for example, at 1 mg/mL or more, preferably at 1 to 3 mg/mL. The methacrylic acid/methyl methacrylate copolymer of this embodiment is, for example, dissolved in the second liquid of the Japanese Pharmacopoeia 18th revised edition dissolution test, preferably dissolved in the Japanese Pharmacopoeia after stirring for 12 hours at room temperature of 25°C. In the second solution of the dissolution test of the 18th revised edition of the Pharmacopoeia.

As the methacrylic acid/methyl methacrylate copolymer in this embodiment, for example, methacrylic acid copolymer L (for example, Eudragit (registered trademark) L100 (manufactured by EVONIK)) or methacrylic acid copolymer S can be used. Furthermore, Eudragit (registered trademark) L100 dissolves at a pH value of 6.0 or higher. In other words, Eudragit (registered trademark) L100 is an example of a methacrylic acid copolymer that dissolves at a pH value of 6.0 or higher, and is an example of a methacrylic acid/methyl methacrylate copolymer that dissolves at a pH value of 6.0 or higher.

The ratio of the structural units derived from methacrylic acid to the structural units derived from ethyl acrylate in the methacrylic acid/ethyl acrylate copolymer of the present embodiment (structural units derived from methacrylic acid:structural units derived from ethyl acrylate) may be 30:70 to 70:30, 35:65 to 65:35, 40:60 to 60:40, or 45:55 to 55:45.

The methacrylic acid/ethyl acrylate copolymer of the present embodiment is soluble, for example, at 1 mg/mL or more. The methacrylic acid/ethyl acrylate copolymer of the present embodiment is soluble, for example, in the second solution of the dissolution test of the 18th revision of the Japanese Pharmacopoeia, preferably in the second solution of the dissolution test of the 18th revision of the Japanese Pharmacopoeia after stirring at room temperature of 25°C for 12 hours.

As the methacrylic acid/ethyl acrylate copolymer of the present embodiment, for example, a dry methacrylic acid copolymer LD (e.g., Eudragit (registered trademark) L100-55 (manufactured by EVONIK)) or a methacrylic acid copolymer LD can be used. Furthermore, Eudragit (registered trademark) L100-55 is soluble at a pH value of 5.5 or higher. In other words, Eudragit (registered trademark) L100-55 is an example of a methacrylic acid copolymer soluble at a pH value of 5.5 or higher, and is an example of a methacrylic acid/ethyl acrylate copolymer soluble at a pH value of 5.5 or higher.

As the aminoalkyl methacrylate copolymer of this embodiment, for example, aminoalkyl methacrylate copolymer E (Eudragit (registered trademark) EPO (manufactured by EVONIK)) can be used. As the ethyl acrylate-methyl methacrylate copolymer in this embodiment, for example, an ethyl acrylate-methyl methacrylate copolymer dispersion (Eudragit (registered trademark) NE30D (manufactured by EVONIK)) can be used.

The acrylic polymer of this embodiment is preferably at least one selected from the group consisting of methacrylic acid copolymer L, dry methacrylic acid copolymer LD, and methacrylic acid aminoalkyl ester copolymer E. In other words, the acrylic polymer is preferably a methacrylic acid copolymer (for example, methacrylic acid copolymer L, dry methacrylic acid copolymer LD), methacrylic acid aminoalkyl ester copolymer (methacrylic acid aminoalkyl ester copolymer) Ester copolymer E). The acrylic polymer is more preferably a methacrylic acid copolymer (for example, methacrylic acid copolymer L, dry methacrylic acid copolymer LD), and further preferably a methacrylic acid/methyl methacrylate copolymer (methacrylic acid copolymer) Object L).

The pharmaceutically acceptable polymer of the present embodiment is, for example, a vinyl polymer, for example, at least one selected from the group consisting of polyvinyl pyrrolidone, carboxyvinyl polymer, vinyl pyrrolidone-vinyl acetate copolymer, and polyvinyl alcohol-polyethylene glycol graft copolymer, preferably at least one selected from the group consisting of polyvinyl pyrrolidone, carboxyvinyl polymer, and vinyl pyrrolidone-vinyl acetate copolymer. More preferably, it is a vinyl pyrrolidone-vinyl acetate copolymer, such as PVP/VA64.

The pharmaceutically acceptable polymer of the present embodiment is, for example, a cellulose-based polymer, for example, at least one selected from the group consisting of hydroxypropyl methylcellulose (e.g., HPMC E3LV), hydroxypropyl methylcellulose acetate succinate (e.g., HPMCAS-M, HPMCAS-H, HPMCAS-L), hydroxypropyl methylcellulose phthalate (e.g., HPMCP-HP55, HPMCP-HP55S, HPMCP-HP50), hydroxypropyl cellulose, ethyl cellulose, and hydroxyethyl cellulose, preferably at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, and hydroxypropyl methylcellulose phthalate, and more preferably hydroxypropyl methylcellulose.

The pharmaceutically acceptable polymer of the present embodiment is, for example, a polyethylene glycol-based polymer, for example, at least one selected from the group consisting of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 20000 and polyethylene oxide.

The pharmaceutically acceptable polymers of this embodiment may be used alone or in combination of two or more. For example, in this embodiment, acrylic acid polymers, vinyl polymers, cellulose polymers, and polyethylene glycol polymers may be used in any combination.

As an example, in this embodiment, an acrylic polymer and an ethylene polymer may be combined. As the acrylic polymer, a methacrylic acid copolymer is preferred, a methacrylic acid/methyl methacrylate copolymer is more preferred, and a methacrylic acid copolymer L (for example, Eudragit (registered trademark) L100 (EVONIK) Manufacturing)). As the vinyl polymer, polyvinylpyrrolidone, carboxyvinyl polymer, and vinylpyrrolidone-carboxyvinyl polymer (PVP/VA64) are preferred, and PVP/VA64 is more preferred. Furthermore, the weight ratio of Eudragit (registered trademark) L100 to PVP/VA64 is 1:9 to 9:1, and preferably the weight ratio of Eudragit (registered trademark) L100 to PVP/VA64 is 9:1.

Furthermore, in this embodiment, an acrylic polymer and a cellulose polymer may be used in combination. As the acrylic polymer, a methacrylic acid copolymer is preferred, a methacrylic acid/methyl methacrylate copolymer is more preferred, and a methacrylic acid copolymer L (for example, Eudragit (registered trademark) L100 (EVONIK) Manufacturing)). As the cellulose-based polymer, hypromellose or hypromellose acetate succinate is preferred, and hypromellose (for example, HPMC) is more preferred. Furthermore, the weight ratio of Eudragit (registered trademark) L100 to HPMC is 1:9 to 9:1, and preferably the weight ratio of Eudragit (registered trademark) L100 to HPMC is 9:1.

Furthermore, in this embodiment, a vinyl polymer and a cellulose polymer may be used in combination. Specifically, the vinyl polymer may be selected from the group consisting of polyvinylpyrrolidone, carboxyvinyl polymer, and vinylpyrrolidone-vinyl acetate copolymer (such as PVP/VA64) At least one of them is combined with at least one selected from the group consisting of HPMC, HPMCAS-M, HPMCAS-H, HPMCAS-L, HPMCP-HP55, HPMCP-HP55S and HPMCP-HP50 as the cellulosic polymer. use. It is also better to use HPMC in combination with PVP/VA64. Furthermore, the weight ratio of HPMC to PVP/VA64 is 1:9 to 9:1.

[Surfactant] The pharmaceutically acceptable polymer of this embodiment can also be used in combination with a surfactant depending on the situation, for example, it can be used in combination with sodium lauryl sulfate or poloxamer 188. That is, the solid dispersion of this embodiment may further contain a surfactant.

The surfactant in this embodiment may be an ionic surfactant, a nonionic surfactant, or a combination thereof. The ionic surfactant in this embodiment may be an anionic surfactant, a cationic surfactant or an amphoteric surfactant, or a combination of two or more types selected from these. The surfactant in this embodiment may be an anionic surfactant and/or a nonionic surfactant, for example. Examples of the anionic surfactant include carboxylates (such as calcium stearate, magnesium stearate), sulfonates (such as linear alkyl benzene sulfonic acid (LAS), α-sulfo fatty acid methyl ester salts) (MES), α-olefin sulfonate (AOS)), sulfate ester salts (such as alkyl sulfate salts (such as sodium lauryl sulfate), alkyl sulfate ester salts (AS), polyoxyethylene alkyl sulfate ester salts ( AES)). Examples of the cationic surfactant include amine salt type and quaternary ammonium salt type (for example, benzalkonium chloride, benzethonium chloride). Examples of amphoteric surfactants include alkyl betaine type (such as lauryldimethylaminoacetate betaine, stearyldimethylaminoacetate betaine, dodecylaminomethyldimethyldimethyl Sulfopropyl betaine, octadecylaminomethyldimethylsulfopropyl betaine), fatty amide propyl betaine types (such as cocamidopropyl betaine, coconut amide propyl hydroxysulfobetaine), alkyl imidazole type (such as 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine), amino acid type (such as lauryl glutamine Sodium phosphate, potassium lauryl glutamate, lauryl methyl-β-alanine), amine oxide type (such as lauryldimethylamine N-oxide, oleyldimethylamine N-oxide). Examples of the nonionic surfactant include ester type (for example, glycerin fatty acid ester (for example, glyceryl monostearate), sorbitan fatty acid ester (for example, sesquioleic acid sorbitan)), Ether type (such as polyoxyethylene alkyl ether (such as polyoxyethylene lauryl ether), polyoxyethylene hydrogenated castor oil (such as polyoxyethylene hydrogenated castor oil 60)), ester-ether type (such as polyoxyethylene sorbitan) Fatty acid esters (e.g. polysorbate 80), poloxamer (e.g. poloxamer 188)). Specific examples of the surfactant in this embodiment include alkyl sulfate and/or poloxamer, and more specifically, sodium lauryl sulfate and/or poloxamer 188. For example, the methacrylic acid copolymer L (for example, Eudragit (registered trademark) L100 (manufactured by EVONIK)) can be used in combination with sodium lauryl sulfate, or the methacrylic acid copolymer L (for example, Eudragit (registered trademark) L100 (manufactured by EVONIK)) can be used together. )) used together with poloxamer 188. In addition, HPMCAS-M and sodium lauryl sulfate can be used together, and HPMCAS-M and poloxamer 188 can also be used together. Furthermore, PVP/VA64 and sodium lauryl sulfate can be used together, or PVP/VA64 and poloxamer 188 can be used together. Furthermore, it is preferable to use Eudragit (registered trademark) L100 in combination with sodium lauryl sulfate or to use Eudragit (registered trademark) L100 in combination with poloxamer 188.

[Solid dispersion] The solid dispersion of this embodiment contains at least one compound selected from the group consisting of heterocyclic derivatives represented by the above general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof, and the above-mentioned pharmaceutically acceptable polymers. The solid dispersion of this embodiment contains the compound in an amorphous (amorphous) state, and the compound in the amorphous state is dispersed in the polymer.

The solid dispersion of the present embodiment can be used as long as the solubility concentration of the solid dispersion in the second solution of the dissolution test of the 18th revision of the Japanese Pharmacopoeia is greater than the solubility concentration of at least one compound (the above-mentioned compound, etc.) selected from the group consisting of the heterocyclic derivative represented by the above general formula [1], its tautomer, and its pharmaceutically acceptable salt. For example, the solid dispersion is added to 250 mL of the second solution of the dissolution test of the 18th revision of the Japanese Pharmacopoeia in such a manner that 100 mg of compound A is calculated. At this time, the mixture obtained by physical mixing in such a manner that the weight ratio of the solid dispersion: L-HPC: sorbitol = 1:2:2 is used for the test. Stirring is performed at 37°C and a paddle speed of 200 rpm, and the solubility concentration is measured from 0 to 120 minutes after the start of the test. At any time between 0 and 120 minutes from the start of the test, the solubility concentration of the solid dispersion is greater than the maximum solubility concentration of the above-mentioned compound, etc. It is more preferred that the solubility concentration between 0 and 90 minutes from the start of the test is greater than the solubility concentration of the above-mentioned compound, etc. It is more preferred that the maximum solubility concentration of the solid dispersion between 0 and 90 minutes from the start of the test is compared with the solubility concentration of the solid dispersion 120 minutes from the start of the test, and the reduction rate of the solubility concentration is 70% or less.

In addition, the solid dispersion of the present embodiment can be transferred to artificial intestinal fluid if the solubility of the solid dispersion is greater than that of the heterocyclic derivative represented by the above general formula [1], its tautomers, and its pharmaceutically acceptable The solubility of the salt is sufficient. Here, the artificial intestinal fluid is, for example, FaSSIF (Fasted State Simulated Intestinal Fluid, fasted state simulated intestinal fluid) or FeSSIF (Fed State Simulated Intestinal Fluid, fed state simulated intestinal fluid). The test liquid that simulates the pH environment in the stomach is, for example, 0.1 N hydrochloric acid. For example, in a dissolution test in which the test solution was converted from 0.1 N hydrochloric acid to FaSSIF 30 minutes after the start of the test, the maximum value of the dissolved concentration of the solid dispersion from the start of the test to 210 minutes before was greater than the value selected from the above general formula [1] The maximum value of the dissolved concentration of at least one compound (the above-mentioned compound, etc.) in the group consisting of the heterocyclic derivatives, their tautomers, and their pharmaceutically acceptable salts is sufficient. Preferably, the dissolved concentration of the solid dispersion 35 minutes after the start of the test is greater than the group selected from the group consisting of heterocyclic derivatives represented by the above general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof The dissolved concentration of at least one compound (the above-mentioned compound, etc.) is sufficient.

(Weight ratio of compound to pharmaceutically acceptable polymer) The ratio of the compound to the pharmaceutically acceptable polymer in the solid dispersion of the present embodiment is the weight of the compound relative to the total weight of the solid dispersion, for example, 1 to 98 weight%, preferably 10 to 98 weight%, further preferably 20 to 40 weight%, further preferably 25 to 35 weight%, further preferably 30%.

(Method for producing solid dispersion) The solid dispersion of the present invention can be produced, for example, using a spray dry method or a melting method.

That is, the method for producing a solid dispersion of the present embodiment includes the step of spray-drying the compound of the present embodiment (selected from the group consisting of heterocyclic derivatives represented by general formula [1], tautomers thereof, and A solution obtained by dissolving at least one compound in the group consisting of a pharmaceutically acceptable salt) and the polymer of the present embodiment (for example, a pharmaceutically acceptable methacrylic acid/methyl methacrylate copolymer) in a solvent Carry out the spray drying step.

The solvent only needs to be one that can dissolve the compound and polymer of the present embodiment. For example, methanol, methylene chloride, acetone, tetrahydrofuran, mixed solvents of two or more of these, and mixed solvents of these and water can be used. In terms of efficiently obtaining the solid dispersion of the present embodiment, preferred solvents are methanol, methylene chloride, tetrahydrofuran, mixed solvents of two or more of these, and mixed solvents of these and water. , more preferably a mixed solvent of methanol and methylene chloride, and a mixed solvent of tetrahydrofuran and water, further preferably a mixed solvent of methylene chloride and methanol (methylene chloride/methanol=9/1~7/3), and A mixed solvent of tetrahydrofuran and water (tetrahydrofuran/water=90/10~99/1), especially a mixed solvent of methylene chloride and methanol (methylene chloride/methanol=8/2), and a mixed solvent of tetrahydrofuran and water (Tetrahydrofuran/water=95/5).

Spray drying by spray drying can be carried out according to conventional methods. Specifically, it can be implemented using a commercially available spray drying device (for example, Spray Dryer B-290, manufactured by BUCHI).

The temperature during spray drying can be, for example, 40 to 140°C, 60 to 120°C, or 80 to 110°C. The time for spray drying can be, for example, 30 minutes to 72 hours, or 18 hours to 50 hours.

In addition, when the sample obtained by spray drying contains residual solvent, a step of removing the solvent such as drying under reduced pressure may also be included as a post-processing.

[Preparation] The formulation of this embodiment contains the solid dispersion of the present invention. The preparation of this embodiment may contain only the solid dispersion of this embodiment, or may contain the solid dispersion of this embodiment and other pharmaceutically acceptable ingredients.

(Other ingredients) Examples of other ingredients include excipients, binders, disintegrants, lubricants, fluidizers, colorants, etc.

Examples of the excipient include D-mannitol, potato starch, lactose hydrate, corn starch, calcium hydrogen phosphate hydrate, magnesium carbonate, calcium carbonate, and crystalline cellulose.

Examples of the binder include hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, polyvinyl alcohol, and methylcellulose.

Examples of the disintegrating agent include calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, light silicic anhydride, calcium silicate, low-substituted hydroxypropylcellulose, and agar. Powder, crospovidone, lactose hydrate.

Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, and stearic acid.

Examples of the fluidizing agent include light silicic anhydride, titanium oxide, stearic acid, colloidal silica, talc, starch, and aluminum magnesium silicate.

Examples of the coloring agent include titanium oxide, yellow ferric oxide, and ferric oxide.

(Polymer content in the preparation) The polymer content in the preparation of this embodiment can be arbitrarily set according to the dosage form, usage and dosage of the preparation, for example, relative to the total mass of the total mass of the preparation, it can be 10% to 90%, 20% to 80%, or 30% to 60%.

The preparation of this embodiment is selected from at least one compound selected from the group consisting of heterocyclic derivatives represented by the above-mentioned general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof, as listed in the Japanese Pharmacopoeia The dissolved concentration in the second solution of the 18th revised edition dissolution test is, for example, 1 μg/mL or more. Preferably, 100 mg of the above compound or the like is added to 250 mL of the second solution of the 18th revised edition of the Japanese Pharmacopoeia dissolution test at 37°C. , when measuring the dissolved concentration when testing at a propeller speed of 200 rpm, it showed a dissolved concentration of 1 μg/mL or more.

(Dosage form) The dosage form of the preparation of this embodiment is not particularly limited, and may be, for example, tablets, capsules, powders, granules, or fine granules.

(Manufacturing method of preparation) The preparation of this embodiment can be manufactured according to conventional methods according to the dosage form, etc. For example, when the preparation of this embodiment is a tablet, it can be manufactured by granulation, crushing (such as dry crushing, wet crushing), granulation, tableting, film coating and other steps.

(Dosage) The preparation of this embodiment can be administered orally or parenterally. Therefore, the preparation of this embodiment can be used for oral administration or parenteral administration. The dosage of the preparation of this embodiment is preferably adjusted taking into consideration the patient's condition such as age, weight, type and degree of disease, route of administration, type of compound of this embodiment, etc. Generally, for adults, this dosage is used. When administered orally, the active ingredient amount of the compound of the embodiment is preferably in the range of 0.01 mg to 5 g/adult per day, preferably in the range of 1 mg to 500 mg/adult. Depending on the situation, an amount below this range may be sufficient, and sometimes an amount above this range may be required. In the case of normal administration once a day or in divided doses or intravenous administration, the administration may be rapid or continuous within 24 hours.

(Medical Use) The compounds of this embodiment show mPGES-1 inhibitory activity. Therefore, the preparations of this embodiment can be used, for example, as inflammatory enteritis, allergic bowel syndrome, migraine, headache, back pain, lumbar spinal stenosis, spondylosis, palatine arthritis, cervical shoulder-wrist syndrome, cervical spondylosis, endometriosis, adenomyosis, premature birth, urgent premature birth, menstrual disorders, overactive bladder, frequent urination at night, interstitial cystitis, neurodegenerative diseases (such as Alzheimer's disease, multiple sclerosis), psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, fascial injury, viral infections (such as influenza, colds, herpes zoster, AIDS (Acquired immunodeficiency syndrome), bacterial infection, fungal infection, burns, inflammation after surgery, trauma and tooth extraction, pain, malignant tumors (e.g. leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, duodenal cancer, colon cancer, rectal cancer, liver cancer, gallbladder-bile duct cancer, bile duct cancer, pancreatic cancer, thyroid cancer, breast cancer, lung cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer, ureteral-ureteral cancer, urothelial cancer, penile cancer, prostate cancer, testicular tumor, bone - Soft tissue sarcoma, malignant bone tumor, skin cancer, thymoma, mesothelioma, and unknown primary cancer, etc.), arteriosclerosis, cerebral stroke, gout, arthritis, deforming arthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ligament ossification, systemic lupus erythematosus, vasoconstriction, pancreatitis, nephritis, chronic prostatitis, chronic pelvic pain syndrome, conjunctivitis, iritis, sclerositis, uveitis, trauma treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial colorectal adenomatosis, scleroderma, bursitis, uterine sarcoma, cancer pain preventive or therapeutic agents.

By using the compound of the present embodiment in combination with an immune checkpoint inhibitor, the anti-tumor activity is synergistically enhanced. Therefore, the preparation of the present embodiment can be used in combination with an immune checkpoint inhibitor for cancer (e.g., leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder-choledochal cancer, biliary cancer, pancreatic cancer, thyroid cancer, The invention relates to a preventive and/or therapeutic agent for the treatment of various cancers, including prostate cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer, ureteral cancer, urothelial cancer, penile cancer, prostate cancer, testicular tumor, bone-soft tissue sarcoma, malignant bone tumor, skin cancer, thymoma, mesothelioma, and cancer of unknown primary, etc. In addition, the immune checkpoint inhibitor is not particularly limited, as long as it is a substance that can inhibit the function (signal) of the immune checkpoint molecule or an inhibitory drug of the immune checkpoint molecule. Furthermore, the immune checkpoint molecule means a molecule that exerts an immunosuppressive function by transmitting a co-inhibitory signal.

Examples of immune checkpoint molecules include adenosine A2A receptor, adenosine A2B receptor, 5'-nucleotidase (NT5E, CD73), CD134 (OX40), CD154 (CD40L), CD223 (LAG-3: Lymphocyte Activation Gene 3 Protein, lymphocyte activation gene 3), anti-CD27, anti-CD276 antigen (anti-B7-H3), anti-CD70, CTLA-4: Cytotoxic T-Lymphocyte Protein 4 (cytotoxic T lymphocyte-associated antigen 4) (anti- CD152), DLL1: delta-Like Protein 1 (Delta-like protein 1), ENTPD1 (CD39), ILDR2: Immunoglobulin-Like Domain-Containing Receptor 2 (immunoglobulin-like domain receptor 2) (C1orf32), PD-1 , PD-L1 (CD274), PVRIG: Transmembrane protein (transmembrane protein) PVRIG, TGFβ2: Transforming Growth Factor beta-2 (Transforming Growth Factor β2), TIM3: Hepatitis A Virus Cellular Receptor 2 (Hepatitis A Virus Cellular Receptor 2 2), VISTA: V-Type Immunoglobulin Domain-Containing Suppressor of T-cell Activation (T cell activation immunoglobulin inhibiting V-type domain), VTCN1 (anti-B7-H4, Ovr110), CD47/SIRPalpha (Tyrosine-Protein Phosphatase Non-receptor Type Substrate 1, tyrosine protein phosphatase non-receptor type substrate 1), tryptophan-2,3-dioxygenase: TDO, and tubulin, preferably CTLA-4, PD -1. PD-L1 (programmed cell death-ligand 1, programmed cell death-ligand 1), PD-L2 (programmed cell death-ligand 2, programmed cell death-ligand 2), LAG-3 (Lymphocyte activation gene 3. Lymphocyte activating gene 3), TIM3 (T cell immunoglobulin and mucin-3, T cell immunoglobulin mucin-3), BTLA (B and T lymphocyte attenuator, B and T lymphocyte attenuator), B7H3, B7H4 , CD160, CD39, CD73, A2aR (adenosine A2a receptor, adenosine A2A receptor), KIR (killer inhibitory receptor, killer cell inhibitory receptor), VISTA (V-domain Ig-containing suppressor of T cell activation, V domain Immunoglobulin T cell activation inhibitory factor), IDO1 (Indoleamine 2,3-dioxygenase, indoleamine-pyrrole 2,3-dioxygenase), ArginaseI, TIGIT (T cell immunoglobulin and ITIM domain, T cell immunoglobulin and ITIM domain), CD115, are not particularly limited as long as they are equivalent to molecules that exert immunosuppressive functions by transmitting co-inhibitory signals.

Examples of immune checkpoint inhibitory drugs include those selected from the group consisting of adenosine A2A receptor antagonists, adenosine A2B receptor antagonists, anti-5'-nucleotidase (anti-NT5E, anti-CD73), and anti-CD134 (anti-CD134). OX40), anti-CD154 (anti-CD40L), anti-CD223 (anti-LAG-3), anti-CD27, anti-CD276 antigen (anti-B7-H3), anti-CD70, anti-CTLA4 (anti-CD152), anti-DLL1, anti-ENTPD1 (anti-CD39 ), anti-ILDR2 (anti-C1orf32), anti-PD-1, anti-PD-L1 (anti-CD274), anti-PVRIG, anti-TGFβ2, anti-TIM3, anti-VISTA, anti-VTCN1 (anti-B7-H4, anti-Ovr110), CD47/SIRPalpha Immune checkpoint inhibitors that act in the group consisting of interaction inhibition, tryptophan-2,3-dioxygenase: TDO inhibition, and tubulin polymerization inhibition, preferably one selected from the group consisting of anti-CTLA -4. Anti-PD-1, anti-PD-L1, anti-PD-L2, anti-LAG-3, anti-TIM3, anti-BTLA, anti-B7H3, anti-B7H4, anti-CD160, anti-CD39, anti-CD73, anti-A2aR, anti-KIR, Immune checkpoint inhibitors acting in the group consisting of anti-VISTA, anti-IDO1, anti-ArginaseI, anti-TIGIT and anti-CD115. [Example]

Hereinafter, the present invention will be described in more detail based on examples. However, the present invention is not limited to the following examples.

[Test Example 1: Preparation of Compound A and Compound B] With reference to the description of Example 239 and Example 89 of International Publication No. 2013/024898, Compound A: N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate and Compound B: N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide were prepared and used (hereinafter, also referred to as Compound A and Compound B).

Furthermore, the structure of compound A is as follows. [Chemical 10]

[Test Example 2: Preparation of solid dispersion by spray drying method] (Example 1) 12 parts by weight of Compound A produced in Test Example 1 and 28 parts by weight of Eudragit (registered trademark) L100 (manufactured by EVONIK, methacrylic acid copolymer L) (weight ratio 30:70) were dissolved in a mixture of methylene chloride and methanol. In solvent (dichloromethane/methanol=8/2). The obtained solution was spray-dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying is carried out under the conditions of inlet temperature: 75-90°C and spray speed: 12-20 mL/min. After spray drying, a dryer was used to dry at 40° C. for 24 hours, and then further dried at 50° C. for 21 hours to obtain the solid dispersion of Example 1.

(Example 2) 12 parts by weight of compound A produced in Test Example 1 and 28 parts by weight of Eudragit (registered trademark) L100-55 (manufactured by EVONIK, dry methacrylic acid copolymer LD) (weight ratio 30:70) were dissolved in methylene chloride and In a mixed solvent of methanol (dichloromethane/methanol = 8/2). The obtained solution was spray-dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying is carried out under the conditions of inlet temperature: 75-90°C and spray speed: 12-20 mL mL/minute. After spray drying, a dryer was used for additional drying at 40° C. for 12 hours to obtain the solid dispersion of Example 2.

(Example 3) 12 parts by weight of compound A produced in Test Example 1 and 28 parts by weight of Eudragit (registered trademark) EPO (manufactured by EVONIK, aminoalkyl methacrylate copolymer E) (weight ratio 30:70) were dissolved in dichloro In a mixed solvent of methane and methanol (dichloromethane/methanol = 8/2). The obtained solution was spray-dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying is carried out under the conditions of inlet temperature: 75-90°C and spray speed: 12-20 mL/minute. After spray drying, the dryer was used for additional drying at 40° C. for 12 hours to obtain the solid dispersion of Example 3.

(Example 4) 12 parts by weight of Compound A produced in Test Example 1 and 28 parts by weight of PVP/VA64 (manufactured by BASF, a copolymer of vinylpyrrolidone and vinyl acetate) (weight ratio 30:70) were dissolved in methylene chloride and In a mixed solvent of methanol (dichloromethane/methanol = 8/2). The obtained solution was spray-dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying is carried out under the conditions of inlet temperature: 81-84°C and spray speed: 18-20 mL/min. After spray drying, a dryer was used for additional drying at 40° C. for 24 hours to obtain the solid dispersion of Example 4.

(Example 5) 8 parts by weight of the compound A prepared in Test Example 1 and 32 parts by weight of hydroxypropylmethylcellulose (HPMC, manufactured by DUPONT) (weight ratio 20:80) were dissolved in a mixed solvent of tetrahydrofuran and water (tetrahydrofuran/water = 95/5). The obtained solution was spray dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying was performed under the conditions of inlet temperature: 102-104°C and spray rate: 18-20 mL/min. After spray drying, additional drying was performed at 40°C for 24 hours using a dryer to obtain the solid dispersion of Example 5.

(Example 6) 12 parts by weight of Compound A produced in Test Example 1 and 28 parts by weight of HPMCAS-H (manufactured by Shin-Etsu Chemical Industry) (weight ratio 30:70) were dissolved in a mixed solvent of methylene chloride and methanol (methylene chloride/methanol = 8/2). The obtained solution was spray-dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying is carried out under the conditions of inlet temperature: 84-86°C and spray speed: 18-20 mL/min. After spray drying, the dryer was used for additional drying at 40° C. for 24 hours to obtain the solid dispersion of Example 6.

(Example 7) 12 parts by weight of the compound A prepared in Experimental Example 1 and 28 parts by weight of HPMCAS-M (manufactured by Shin-Etsu Chemical Co., Ltd.) (weight ratio 30:70) were dissolved in a mixed solvent of dichloromethane and methanol (dichloromethane/methanol = 8/2). The obtained solution was spray dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying was performed under the conditions of inlet temperature: 83-88°C and spray rate: 18-20 mL/min. After spray drying, additional drying was performed at 40°C for 24 hours using a dryer to obtain the solid dispersion of Example 7.

(Example 8-1) The solid dispersion of Example 1 and the solid dispersion of Example 5 were physically mixed at a weight ratio of 1:9 to obtain the solid dispersion of Example 8-1.

(Example 8-2) The solid dispersion of Example 1 and the solid dispersion of Example 5 were physically mixed at a weight ratio of 9:1 to obtain the solid dispersion of Example 8-2.

(Example 9-1) The solid dispersion of Example 1 and the solid dispersion of Example 4 were physically mixed at a weight ratio of 1:9 to obtain the solid dispersion of Example 9-1.

(Example 9-2) The solid dispersion of Example 1 and the solid dispersion of Example 4 were physically mixed at a weight ratio of 9:1 to obtain the solid dispersion of Example 9-2.

(Example 10-1) The solid dispersion of Example 5 and the solid dispersion of Example 4 were physically mixed at a weight ratio of 1:9 to obtain the solid dispersion of Example 10-1.

(Example 10-2) The solid dispersion of Example 5 and the solid dispersion of Example 4 were physically mixed at a weight ratio of 9:1 to obtain the solid dispersion of Example 10-2.

(Example 11) 12 parts by weight of the compound A prepared in Experimental Example 1, 26 parts by weight of Eudragit (registered trademark) L100 (manufactured by EVONIK, methacrylic acid copolymer L), and 2 parts by weight of Kolliphor P188 (manufactured by BASF, poloxamer 188) (weight 30:65:5) were dissolved in a mixed solvent of dichloromethane and methanol (dichloromethane/methanol = 8/2). The obtained solution was spray dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying was carried out under the conditions of inlet temperature: 91-92°C and spray rate: 18-20 mL/min. After spray drying, use a dryer to dry at 40°C for 24 hours to obtain the solid dispersion of Example 11.

(Example 12) 12 parts by weight of compound A produced in Test Example 1, 26 parts by weight of Eudragit (registered trademark) L100 (manufactured by EVONIK, methacrylic acid copolymer L), and 2 parts by weight of Kolliphor SLS (manufactured by BASF, sodium lauryl sulfate) were mixed 30:65:5) is dissolved in a mixed solvent of dichloromethane and methanol (dichloromethane/methanol=8/2). The obtained solution was spray-dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying is carried out under the conditions of inlet temperature: 83-85°C and spray speed: 18-20 mL/min. After spray drying, use a dryer to dry at 40°C for 24 hours to obtain the solid dispersion of Example 12.

(Example 13) 12 parts by weight of Compound A produced in Test Example 1, 26 parts by weight of HPMCAS-M (manufactured by Shin-Etsu Chemical Industry) and 2 parts by weight of Kolliphor P188 (manufactured by BASF, poloxamer 188) (weight 30:65:5) were dissolved In a mixed solvent of dichloromethane and methanol (dichloromethane/methanol = 8/2). The obtained solution was spray-dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying is carried out under the conditions of inlet temperature: 88-92°C and spray speed: 18-20 mL/min. After spray drying, use a dryer to dry at 40° C. for 24 hours to obtain the solid dispersion of Example 13.

(Example 14) 12 parts by weight of the compound A prepared in Experimental Example 1, 26 parts by weight of HPMCAS-M (manufactured by Shin-Etsu Chemical Co., Ltd.), and 2 parts by weight of Kolliphor SLS (manufactured by BASF, sodium lauryl sulfate) (weight 30:65:5) were dissolved in a mixed solvent of dichloromethane and methanol (dichloromethane/methanol = 8/2). The obtained solution was spray dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying was performed under the conditions of inlet temperature: 88-90°C and spray speed: 18-20 mL/min. After spray drying, the solid dispersion of Example 14 was obtained by drying at 40°C for 24 hours using a dryer.

(Example 15) 12 parts by weight of the compound A prepared in Experimental Example 1, 26 parts by weight of PVP/VA64 (manufactured by BASF, a copolymer of vinyl pyridone and vinyl acetate), and 2 parts by weight of Kolliphor P188 (manufactured by BASF, poloxamer 188) (weight 30:65:5) were dissolved in a mixed solvent of dichloromethane and methanol (dichloromethane/methanol = 8/2). The obtained solution was spray dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying was performed under the conditions of an inlet temperature of 86-90°C and a spray rate of 18-20 mL/min. After spray drying, the solid dispersion of Example 15 was obtained by drying at 40°C for 24 hours using a dryer.

(Example 16) 12 parts by weight of the compound A prepared in Experimental Example 1, 26 parts by weight of PVP/VA64 (manufactured by BASF, a copolymer of vinyl pyridone and vinyl acetate), and 2 parts by weight of Kolliphor SLS (manufactured by BASF, sodium lauryl sulfate) (weight 30:65:5) were dissolved in a mixed solvent of dichloromethane and methanol (dichloromethane/methanol = 8/2). The obtained solution was spray dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying was performed under the conditions of an inlet temperature of 86-88°C and a spray rate of 18-20 mL/min. After spray drying, the solid dispersion of Example 16 was obtained by drying at 40°C for 24 hours using a dryer.

(Reference Example 1) Tablets of compound A were prepared according to the formula listed in the table below. The ingredients used were those listed in or in accordance with the 18th revised edition of the Japanese Pharmacopoeia, the Standard for Pharmaceutical Additives, European Pharmacopoeia 9.0, THE UNITED STATES PHAMACOPEIA 41, and THE NATIONAL FORMULARY 36. [Table 1] Element Mixing amount (weight parts) Bare Tablet Compound A prepared in Experimental Example 1 25.0 Lactose hydrate 143.0 Crystalline cellulose 28.8 Low-substituted hydroxypropyl cellulose 19.2 Cross-linked polyvinylpyrrolidone 9.6 Hydroxypropyl cellulose 7.2 Light Silicic Anhydride 4.8 Magnesium stearate 2.4 Painting Hydroxypropyl methylcellulose 3.9 Titanium oxide 1.0 Yellow ferric oxide 0.05 Ferrous Oxide 0.05

Compound A produced in Test Example 1, lactose hydrate, crystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, and light silicic anhydride were mixed, and then wetted with an adhesive liquid of hydroxypropyl cellulose. After formula granulation, crush, dry and whole granulate. The obtained granulated material is mixed with magnesium stearate to prepare tablet granules. Beat the ingot particles to obtain bare ingots. The coating solution prepared using hypromellose, titanium oxide, yellow ferric oxide, ferric oxide and purified water was sprayed onto the bare tablets to form a film coating, and the tablets of Reference Example 1 were obtained.

[Test Example 3: Evaluation of solid dispersion] (Powder X-ray diffraction) The crystal state of the solid dispersions of Examples 1 to 5 immediately after production was evaluated using a powder X-ray diffraction device. The measurement conditions of powder X-ray diffraction are as follows. Measurement device: SmartLab 9 kW (Rigaku) Tube voltage: 45 V Tube current: 200 mA Measurement range: 5 to 40 deg

The results of powder X-ray diffraction showed that the crystal peaks derived from compound A in the solid dispersions of Examples 1 to 5 all disappeared, showing a halo pattern ( FIG. 1 : Example 1). That is, it was confirmed that compound A was contained in an amorphous state.

(Dissolution test) The solid dispersions of Examples 1 to 3 were subjected to a dissolution test using the first liquid of the Japanese Pharmacopoeia 18th revised edition dissolution test at 37°C. Add so that the test liquid volume is 250 mL, the propeller rotation speed is 200 rpm, and the input amount is 100 mg based on Compound A. The results are shown in Table 2. [Table 2] 10 minutes 20 minutes 30 minutes 60 minutes 90 minutes 120 minutes Example 1 10 twenty four 15 18 twenty three 13 Example 2 twenty one twenty four 26 31 32 33 Example 3 259 292 292 237 252 247 Unit: μg/mL

The solid dispersions of Examples 1 to 3 were subjected to a dissolution test using the second liquid of the Japanese Pharmacopoeia 18th revised edition dissolution test at 37°C. Add so that the test liquid volume is 250 mL, the propeller rotation speed is 200 rpm, and the input amount is 100 mg based on Compound A. The results are shown in Table 3 and Table 4. [table 3] 10 minutes 20 minutes 30 minutes 60 minutes 90 minutes 120 minutes Example 1 111 118 113 121 106 101 Example 2 307 318 321 286 93 33 Example 3 0 0 0 0 0 0 Unit: μg/mL

[Table 4] 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes Example 8-1 (Eudragit L-100+HPMC) 11 11 11 8 10 8 Example 8-2 (Eudragit L-100+HPMC) 50 92 60 64 62 51 Example 9-1 (Eudragit L-100+PVP/VA64) 4 6 4 4 6 5 Example 9-2 (Eudragit L-100+PVP/VA64) 59 68 55 59 57 43 Example 10-1 (PVP/VA64+HPMC) 3 3 3 5 5 4 Example 10-2 (PVP/VA64+HPMC) 7 3 3 5 5 4 Unit: μg/mL

According to the conditions shown in Table 5 below, the Japanese Pharmacopoeia 18th revised edition dissolution test (liquid covering method) was performed using two test solutions in sequence. The results are shown in Table 6.

[table 5] Time elapsed after the test started 0～30 minutes 30～210 minutes Test solution 0.1 N HCl FaSSIF temperature 37±0.5℃ 37±0.5℃ Paddle speed 100 rpm 100 rpm Input amount (concentration) 2.0 mg/mL 1.0 mg/mL

[Table 6] 10 minutes 25 minutes 35 minutes 50 minutes 70 minutes 120 minutes 210 minutes Example 4 (PVP/VA64) 183 173 104 97 148 180 212 Example 5 (HPMC) 164 185 126 19 15 twenty one 15 Example 6 (HPMCAS-H) 145 156 101 85 68 48 48 Example 7 (HPMCAS-M) 148 191 108 60 50 56 59 Example 11 (Eudragit L-100 + Poloxamer 188) 98 111 550 429 316 203 130 Example 12 (Eudragit L-100 + sodium lauryl sulfate) 44 60 957 74 55 57 64 Example 13 (HPMCAS-M + Poloxamer 188) 69 77 113 56 36 31 33 Example 14 (HPMCAS-M + sodium lauryl sulfate) 113 101 65 47 48 62 71 Example 15 (PVP/VA64+Poloxamer 188) 151 140 118 82 119 154 203 Example 16 (PVP/VA64 + sodium lauryl sulfate) 81 72 93 96 169 203 230 Unit: μg/mL

(Canine PK test (fed condition)) Using the administration samples obtained by placing the solid dispersions of Examples 1 to 5 and 5 in capsules and the administration sample of Reference Example 1, the administration dose was changed to a dose in which Compound A became 100 mg, and a canine PK test was performed under the following conditions. Under fed conditions, any of the administration samples was orally administered to beagles (5 to 6 dogs, weighing 9 to 14 kg) in a dose in which Compound A became 100 mg. Blood (approximately 0.6 mL) was collected from the radial cutaneous vein without anesthesia at 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 24 hours after administration, and sodium heparin (6 μL) was added and then ice-cooled. The collected blood was centrifuged (3,000×g, 10 minutes, 4°C) and plasma was recovered. The plasma concentration of compound A was measured by LC-MS/MS (Liquid Chromatography Mass Spectrometry/Mass Spectrometry). Based on the obtained plasma concentration transition, the maximum plasma concentration (C _max ), the time to reach the maximum plasma concentration (T _max ), the area under the plasma concentration-time curve from the last blood collection time (AUC _0→last ) to 0 and the actual data, the area under the plasma concentration-time curve from 0 to ∞ time (AUC _0→∞ ) was calculated. The results are shown in Table 7. Furthermore, AUC _0→last is the AUC up to the last valid blood sampling time. Here, the data of the sampling point after the time of fecal ingestion is set as invalid. These values are set as reference values because the time range of the AUC calculation object is different including individuals. In addition, AUC _0→∞ is the AUC calculated based on actual data until infinity, which is considered to be a relatively useful value. [Table 7] Parameters Reference Example 1 (Tablet) Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 5 Methacrylic acid copolymer L Dry Methacrylic Acid Copolymer LD Aminoalkyl methacrylate copolymer E HPMC C _max (ng/mL) 518 844 321 349 565 _{AUC last (} ng·hr/mL) 3200 6640 2460 2550 Undetermined AUC _{0→ ∞} (ng·hr/mL) 4580 9040 4640 3210 5540

Furthermore, under fasting conditions, the same canine PK test was performed using the administration samples of Examples 11 and 12 and Reference Example 1, changing the administration dosage to a dosage of 25 mg of Compound A, and the results obtained are shown in Table 8.

[Table 8] parameters Reference example 1 (tablet) Example 11 Example 12 Eudragit L-100+poloxamer 188 Eudragit L-100+sodium lauryl sulfate C _max (ng/mL) 130 189 168 AUC _{0→ ∞} (ng·hr/mL) 2130 2210 1880

[Preparation example 1] Preparation Example 1 uses additives listed in or based on the 18th revised edition of the Japanese Pharmacopoeia, Standards for Pharmaceutical Additives, European Pharmacopoeia 9.0, THE UNITED STATES PHAMACOPEIA 41, and THE NATIONAL FORMULARY 36. The solid dispersion of Example 1 was mixed with corn starch, D-mannitol, croscarmellose sodium, light silicic anhydride, crospovidone and magnesium stearate in the formula ratio of Table 9, using a beating method. The ingot is loaded with 500 kgf and punched with a 16×8 mm pestle, so that the mass becomes 660 mg. Furthermore, the obtained tablets can be made into film-coated tablets if necessary.

[Table 9] Ratio(mass%) Compound A produced in Test Example 1 15 methacrylic acid copolymer 35 corn starch 10 D-Mannitol twenty two Croscarmellose sodium 10 Light silicic anhydride 1 Magnesium stearate 2 Crospovidone 5 Total bare ingots 100

[Preparation Example 2] Preparation Example 2 uses additives included in or based on the 18th revised edition of the Japanese Pharmacopoeia, the Standard for Pharmaceutical Additives, European Pharmacopoeia 9.0, THE UNITED STATES PHAMACOPEIA 41, and THE NATIONAL FORMULARY 36. The solid dispersion of Example 1 is mixed with D-mannitol, sodium cross-linked carboxymethyl cellulose, light silicic anhydride, crystalline cellulose, and sodium stearyl fumarate in the formula ratio shown in Table 10, and the tablets are made using a pestle with a tablet load of 500 kgf and 16×8 mm to a mass of 660 mg. Furthermore, the obtained tablets can be made into film-coated tablets as needed.

[Table 10] Ratio(mass%) Compound A prepared in Experimental Example 1 15 Methacrylic acid copolymer 35 D-Mannitol 19 Crystalline cellulose 19 Cross-linked sodium carboxymethyl cellulose 10 Light Silicic Anhydride 1 Sodium stearyl fumarate 1 Bare Tablets Total 100

Test method: Japanese Pharmacopoeia 18th revised edition dissolution test (liquid covering method) Add 100 mg of Compound A or 1 tablet of Preparation Examples 1 and 2 into 250 mL of the second solution of the Japanese Pharmacopoeia 18th revised edition dissolution test at 37°C, conduct the test at a paddle speed of 200 rpm, and show the results of the process of measuring the dissolved concentration. in Table 11.

[Table 11] 10 minutes 20 minutes 30 minutes 60 minutes 90 minutes 120 minutes Compound A powder 0 0 0 0 0 0 Preparation of Preparation Example 1 116 128 127 124 117 106 Preparation Example 2 Preparation 59 65 66 57 58 54 Unit: μg/mL

Figure 1 is the powder X-ray diffraction spectrum of the solid dispersion of Example 1.

Claims (15)

A solid dispersion comprising at least one compound selected from the group consisting of a heterocyclic derivative represented by the following general formula [1], its tautomeric isomers, and its pharmaceutically acceptable salts, and a pharmaceutically acceptable polymer, In the general formula [1], ring A represents a group represented by the following general formula [2], [3] or [4], [Chemical 2] [In the general formulae [2], [3] and [4], ^X1 represents NH, N-alkyl or O; ^A1 represents hydrogen or alkyl; ^A2 represents i) hydrogen, ii) halogen, iii) alkyl which may be substituted by 1 to 3 groups selected from the group consisting of halogen, amino, monoalkylamino, dialkylamino, aminoformyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy and alkylcarbonyloxy, iv) cycloalkyl which may be substituted by alkyl, which may be substituted by 1 to 3 halogens, v) alkoxy, vi) saturated heterocyclic which may be substituted by alkyl, alkoxycarbonyl, alkylcarbonyl or pendoxy, vii) alkylthio, viii) alkylsulfonyl, ix) alkylsulfinyl, x) a group represented by the following general formula [5], [Chemical 3] (In the general formula [5], ^R3 and ^R4 are the same or different and represent a) hydrogen, b) an alkyl group which may be substituted by a group selected from the group consisting of a monoalkylamino group, a dialkylamino group, a saturated cyclic amine group which may be substituted by an alkyl group, a saturated heterocyclic group which may be substituted by an alkyl group, an alkoxy group, a hydroxycarbonyl group, a hydroxy group, an alkoxycarbonyl group, and an alkylthio group, or c) a cycloalkyl group) or ix) a saturated cyclic amine group which may be substituted by an alkyl group, an amine group, a monoalkylamino group, a dialkylamino group, an alkoxy group, or a hydroxy group] R ¹ represents phenyl, benzyl, naphthyl, cycloalkyl, cycloalkylmethyl, heteroaryl, heteroarylmethyl, 1,2,3,4-tetrahydronaphthalene-5-yl, 1,2,3,4-tetrahydronaphthalene-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutylbenzene-3-yl, 1,2-dihydrocyclobutylbenzene-4-yl or alkyl, and the phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl may be selected from i) halogen, ii) alkyl which may be substituted by 1 to 3 groups selected from the group consisting of halogen, hydroxyl, and phenyl, iii) alkoxy, ^R2 represents a phenyl group or a pyridyl group, and the phenyl group or the pyridyl group may be substituted by one to three groups selected from the group consisting of i) a halogen, ii) an alkylsulfonyl group, iii) an alkoxy group which may be substituted by one to three halogens or alkoxy groups, iv) an alkynyl group which may be substituted by an alkoxyalkyl group or a cycloalkyl group, and v) an alkyl group which may be substituted by one to three groups selected from the group consisting of an alkoxy group, an alkoxyalkoxy group, a cycloalkyl group, a phenyl group, and a halogen. The solid dispersion of claim 1, wherein the compound is selected from the group consisting of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride, At least one of the group consisting of N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide sulfuric acid . The solid dispersion of claim 1 or 2, wherein the pharmaceutically acceptable polymer is selected from the group consisting of cellulose polymers, acrylic polymers, ethylene polymers and polyethylene glycol polymers. At least 1 of them. The solid dispersion of claim 3, wherein the pharmaceutically acceptable polymer is selected from the group consisting of methacrylic acid copolymer, aminoalkyl methacrylate copolymer, ammonium alkyl methacrylate copolymer, and At least one of the group consisting of ethyl acrylate-methyl methacrylate copolymer. The solid dispersion of claim 3 or 4, wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of methacrylic acid/methyl methacrylate copolymers and methacrylic acid/ethyl acrylate copolymers. The solid dispersion of claim 3, wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, ethyl cellulose, and hydroxyethyl cellulose. The solid dispersion of claim 3, wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of polyvinyl pyrrolidone, carboxyvinyl polymer, vinyl pyrrolidone-vinyl acetate copolymer, and polyvinyl alcohol-polyethylene glycol graft copolymer. The solid dispersion of any one of claims 3 to 7, further comprising a surfactant. The solid dispersion of claim 3, wherein the pharmaceutically acceptable polymer is soluble at a pH value exceeding 5.0. For example, the solid dispersion of claim 1 or 2, wherein the solubility of the solid dispersion in the second liquid of the Japanese Pharmacopoeia 18th revised edition dissolution test is greater than that of the heterocyclic derivative represented by the above general formula [1], and its tautology structure, and the solubility of its pharmaceutically acceptable salts. The solid dispersion of claim 9 or 10, wherein the above compound is 1 to 98% by mass relative to the total mass of the above solid dispersion. A preparation comprising the solid dispersion of any one of claims 1 to 11. The preparation of claim 12, wherein the solubility of the preparation in the second solution of the dissolution test of the 18th revised edition of the Japanese Pharmacopoeia is greater than the solubility of the heterocyclic derivative represented by the above general formula [1], its tautomerism, and its pharmaceutically acceptable salt. The preparation of claim 13 is for oral administration. Such as the preparation of claim 14, which is in the form of a tablet.