RU2836236C1 - Preventive and/or therapeutic agent for chronic prostatitis/chronic pelvic pain syndrome - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical industry, namely to use of mPGES-1 inhibitor for preparing a drug for preventing and/or treating chronic prostatitis/chronic pelvic pain syndrome. Disclosed is the use of the mPGES-1 inhibitor for the manufacture of a medicinal agent for preventing and/or treating chronic prostatitis/chronic pelvic pain syndrome, where the mPGES-1 inhibitor is: compound selected from a group consisting of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide and N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide or a tautomer of a compound, or a pharmaceutically acceptable salt thereof; N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzene sulphonate; N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide.

EFFECT: described above mPGES-1 inhibitors are effective for preparing a drug for preventing and/or treating chronic prostatitis/chronic pelvic pain syndrome.

3 cl, 1 dwg, 1 tbl, 8 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0001] The present invention relates to a prophylactic and/or therapeutic agent for chronic prostatitis/chronic pelvic pain syndrome, comprising an mPGES-1 inhibitor as an active ingredient.

LEVEL OF TECHNOLOGY

[0002] Prostatitis is classified by the US NIH into four categories (acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis/chronic pelvic pain syndrome, and asymptomatic inflammatory prostatitis) (Non-Patent Literature 1). Category I is acute bacterial prostatitis associated with systemic symptoms such as urinary symptoms, pain, and fever caused by bacterial infection. Category II is chronic bacterial prostatitis, which is the chronic form of Category I, and symptoms of recurrent bacterial infection are recognized. Category III is chronic prostatitis/chronic pelvic pain syndrome and is classified as a disease accompanied by pain and discomfort in the pelvic part such as the perineal part, testicular part, penile part, and lower abdomen, and urinary symptoms such as residual urine sensation and pollakiuria as the main symptoms. In addition, Category IV asymptomatic inflammatory prostatitis is an asymptomatic disease; however, inflammatory phenomena are recognized in prostate biopsy tissue samples or in prostatic fluid and semen. In addition, it has been reported that the expression of IL-1β is significantly increased in the seminal plasma of patients with chronic prostatitis, and the expression of MIP-1α and MCP-1 is significantly increased in the prostatic fluid of patients with chronic prostatitis (Non-Patent Literature 2 and 3).

[0003] However, unlike Category I acute bacterial prostatitis and Category II chronic bacterial prostatitis, the etiology of Category III chronic prostatitis/chronic pelvic pain syndrome is unknown and therefore effective therapeutic methods have not been found.

[0004] Regarding PGE2 synthase (PGES), it is known that there are three subtypes, such as membrane-bound prostaglandin E synthase-1 (mPGES-1), mPGES-2, and cytoplasmic PGES (cPGES) (Non-Patent Literatures 4 to 6). mPGES-1, like COX-2, is mainly induced during inflammation and plays a major role in the production of PGE2 in inflammatory lesions. In addition, mPGES-1 is known to be involved in malignancies (e.g., colon cancer, breast cancer, lung cancer, and prostate cancer) (see Non-Patent Literature 7, Non-Patent Literature 8, and Non-Patent Literature 9).

[0005] Patent Literature 1 discloses that a heterocyclic derivative represented by General Formula [1] or a tautomer of the derivative or a pharmaceutically acceptable salt thereof has mPGES-1 inhibitory activity. In addition, Patent Literatures 2 and 3 disclose small molecules having mPGES-1 inhibitory activity. Non-Patent Literature 10 discloses that CANEFRON (registered trademark) N contains a component of plant origin and has mPGES-1 inhibitory activity.

[0006] However, until now, nothing has been reported about the relationship between chronic prostatitis and the mPGES-1 signaling pathway.

list of contrasting materials

PATENT LITERATURE

[0007] Patent Literature 1: WO 2013/024898,

Patent Literature 2: WO 2011/023812,

Patent Literature 3: WO 2017/073709.

NON-PATENT LITERATURE

[0008] Non-Patent Literature 1: JAMA. 1999 Jul. 21; 282(3): 236-7,

Non-Patent Literature 2: Int. J. Urol. 2001 Sep; 8(9): 495-499,

Non-Patent Literature 3: J. Urol. 2008 May; 179(5): 1857-1862,

Non-patent literature 4: Jakobsson, et al., Proc. Natl. Acad. Sci. USA, 1999, 96, 7220-7225,

Non-patent literature 5: Biochem. Biophys. Res. Commun., 2002, 291, 884-889,

Non-patent literature 6: J. Biol. Chem., 2000, 275, 32775-32782,

Non-patent literature 7: J. Biol. Chem., 2003, 278(21), 19396-19405,

Non-patent literature 8: Oncogene, 2012, 31(24), 2943-2952,

Non-Patent Literature 9: Cancer Res., 2008, 68(9), 3251-3259,

Non-patent literature 10: j. phymed. 2019, 60, 152987,

ESSENCE OF THE INVENTION

TECHNICAL TASK

[0009] The aim to be achieved by the present invention is to create a prophylactic and/or therapeutic agent against chronic prostatitis/chronic pelvic pain syndrome.

SOLUTION TO THE PROBLEM

[0010] The present inventors aimed to elucidate the pathophysiology of chronic prostatitis/chronic pelvic pain syndrome and found that the mPGES-1 pathway is involved in chronic prostatitis/chronic pelvic pain syndrome. In addition, the present inventors found that pain and inflammation in animal models of chronic prostatitis can be reduced by an mPGES-1 inhibitor, thus completing the invention.

[0011] The invention relates to the following.

[0012] (1) A prophylactic and/or therapeutic agent for chronic prostatitis/chronic pelvic pain syndrome, containing an mPGES-1 inhibitor as an active ingredient.

(2) The prophylactic and/or therapeutic agent against chronic prostatitis/chronic pelvic pain syndrome according to the above item (1),

wherein the mPGES-1 inhibitor is a compound of Formula [1] (hereinafter also referred to as the compound of the present invention), or a tautomer of the compound, or a pharmaceutically acceptable salt thereof, and

The compound of Formula [1] looks like this:

Formula [1]:

[Chemical formula 1]

,

in which

ring A is a group represented by Formula [2], [3], or [4]:

[Chemical formula 2]

,

in which

X ¹ is NH, N-alkyl or O;

A ¹ is hydrogen or alkyl;

A ² represents:

i) hydrogen,

ii) halogen,

iii) alkyl which may be substituted with one to three groups selected from the group consisting of halogen, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy and alkylcarbonyloxy,

iv) cycloalkyl which may be substituted by alkyl, in which said alkyl may be substituted by one to three halogens,

v) alkoxy,

vi) a saturated heterocyclic group which may be substituted by alkyl, alkyloxycarbonyl, alkylcarbonyl or oxo,

vii) alkylthio,

viii) alkylsulfonyl,

ix) alkylsulfinyl,

x) Formula [5]:

[Chemical formula 3]

,

in which R ³ and R ⁴ are the same or different and each represents:

a) hydrogen,

b) alkyl which may be substituted by a group selected from the group consisting of monoalkylamino, dialkylamino, saturated cyclic amino optionally substituted by alkyl, saturated heterocyclic group optionally substituted by alkyl, alkoxy, hydroxycarbonyl, hydroxyl, alkyloxycarbonyl and alkylthio, or

c) cycloalkyl,

or

xi) saturated cyclic amino which may be substituted by alkyl, amino, monoalkylamino, dialkylamino, alkoxy or hydroxyl;

R ¹ is phenyl, benzyl, naphthyl, cycloalkyl, cycloalkylmethyl, heteroaryl, heteroarylmethyl, 1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutabenzen-3-yl, 1,2-dihydrocyclobutabenzen-4-yl or alkyl, wherein said phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl and heteroarylmethyl may be substituted with one to three groups selected from the group consisting of:

i) halogen,

ii) alkyl which may be substituted by one to three groups selected from the group consisting of halogen, hydroxy and phenyl,

iii) alkoxy,

iv) hydroxy

v) cyano;

R ² is phenyl or pyridyl, wherein said phenyl and pyridyl may be substituted with one to three groups selected from the group consisting of:

i) halogen,

ii) alkylsulfonyl,

iii) alkoxy which may be substituted by one to three halogens or alkoxy,

iv) alkynyl which may be substituted by alkoxyalkyl or cycloalkyl, and

v) alkyl which may be substituted by one to three groups selected from the group consisting of alkoxy, alkoxyalkoxy, cycloalkyl, phenyl and halogen.

(3) The prophylactic and/or therapeutic agent against chronic prostatitis/chronic pelvic pain syndrome as described in (2) above,

in which ring A is a group represented by Formula [4], and X ¹ is NH.

(4) A prophylactic and/or therapeutic agent for chronic prostatitis/chronic pelvic pain syndrome according to item (2) or (3) above,

in which R ¹ is phenyl, 1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutabenzen-3-yl or 1,2-dihydrocyclobutabenzen-4-yl, wherein said phenyl may be substituted with one to three groups selected from the group consisting of:

i) halogen,

ii) alkyl which may be substituted by one to three halogens,

iii) alkoxy and

iv) cyano.

(5) A prophylactic and/or therapeutic agent against chronic prostatitis/chronic pelvic pain syndrome according to any one of the above items (2) to (4),

in which R ² is phenyl and

said phenyl may be substituted by one to three 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 one to three groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl and phenyl.

(6) A prophylactic and/or therapeutic agent against chronic prostatitis/chronic pelvic pain syndrome according to any one of the above items (2) to (5),

in which ring A is a group represented by General Formula [4];

X ¹ represents NH;

A ² represents:

i) hydrogen,

ii) alkyl which may be substituted by a group selected from the group consisting of halogen, monoalkylamino, dialkylamino, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy and alkylcarbonyloxy,

iii) cycloalkyl which may be substituted by alkyl optionally substituted by one to three halogens,

iv) alkoxy,

v) a saturated heterocyclic group which may be substituted by alkyl or alkyloxycarbonyl,

vi) alkylthio,

vii) alkylsulfonyl,

viii) alkylsulfinyl,

ix) amino substituted with alkyl which may be substituted with a group selected from the group consisting of monoalkylamino, dialkylamino, saturated cyclic amino optionally substituted with alkyl, tetrahydrofuryl, morpholino, alkoxy, hydroxycarbonyl, hydroxyl and alkylthio,

x) amino substituted with cycloalkyl, or

xi) saturated cyclic amino which may be substituted by alkyl, dialkylamino, alkoxy or hydroxyl;

R ¹ represents:

i) phenyl which may be substituted with one to three groups selected from the group consisting of halogen, alkyl optionally substituted with one to three halogens, alkoxy and cyano,

ii) 1,2,3,4-tetrahydronaphthalene-5-yl,

iii) 2,3-dihydro-1H-inden-5-yl,

iv) benzyl which may be substituted by halogen or alkyl optionally substituted by one to three halogens,

v) cycloalkyl,

vi) cycloalkylmethyl,

vii) naphthyl,

viii) pyridylmethyl which may be substituted by alkyl optionally substituted by one to three halogens,

ix) thienyl,

x) thienylmethyl,

xi) benzothiazolyl,

xii) benzothiadiazolyl,

xiii) indolyl or

xiv) alkyl and

R ² is phenyl or pyridyl,

wherein said phenyl may be substituted by one to three 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 one to three groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl and phenyl, and

the said pyridyl may be substituted by halogen.

(7) A prophylactic and/or therapeutic agent against chronic prostatitis/chronic pelvic pain syndrome according to any one of the above items (2) to (6),

in which ring A is a group represented by General Formula [4];

X ¹ represents NH;

A ² is an alkoxy-substituted alkyl, dialkylamino, tetrahydrofuryl, tetrahydrofurylmethyl, alkoxyalkylamino or cycloalkyl which may be substituted by unsubstituted alkyl or alkyl substituted by one to three halogens;

R ¹ is phenyl substituted by one halogen and one methyl, and

R ² is phenyl which may be substituted by one trifluoromethyl or two halogens.

(8) A prophylactic and/or therapeutic agent against chronic prostatitis/chronic pelvic pain syndrome according to any one of the above items (2) to (7),

wherein the mPGES-1 inhibitor is a compound selected from the group consisting of:

(1) N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(2) N-cyclohexyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(3) N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(4) N-[(1-hydroxycyclohexyl)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(5) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino}-2,3-dihydro-1-benzofuran-7-carboxamide,

(6) N-cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxamide,

(7) N-(3-chloro-2-methylphenyl)-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxamide,

(8) N-cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-indazole-7-carboxamide,

(9) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-indazole-7-carboxamide,

(10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(11) 2-methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(12) N-cyclohexyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(13) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(14) N-cyclopentyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(15) N-cyclobutyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(16) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(17) N-cyclohexyl-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(18) 2-ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(19) N-cyclohexyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(20) 2-(methoxymethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(21) 2-(methoxymethyl)-N-(2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(22) 2-(methoxymethyl)-N-(4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(23) N-(2-chlorobenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(24) 2-(methoxymethyl)-N-(4-methylbenzyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(25) N-(4,4-difluorocyclohexyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(26) N-(4-tert-butylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(27) 2-(methoxymethyl)-N-[4-(trifluoromethyl)phenyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(28) N-(2,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(29) N-(2-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(30) N-(3,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(31) N-(3-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(32) N-(2,3-dihydro-1H-inden-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(33) 2-(methoxymethyl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(34) N-(2-fluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(35) 2-(methoxymethyl)-N-(2-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(36) 2-(methoxymethyl)-N-(4-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(37) N-(3-bromo-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(38) N-(3-chloro-2-methylbenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(39) N-(2,6-difluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(40) N-(3-cyano-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(41) 2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide,

(42) N-(2-chloro-6-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(43) 2-(2-amino-2-oxoethyl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(44) 2-(2-amino-2-oxoethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(45) N-(3-chloro-2-methylphenyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(46) N-cyclohexyl-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(47) 1-methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(48) N-(3-chloro-2-methylphenyl)-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(49) N-cyclohexyl-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(50) 1-ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(51) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzoxazole-4-carboxamide,

(52) 2-methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzoxazole-4-carboxamide,

(53) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzoxazole-4-carboxamide,

(54) N-(3-chloro-2-methylphenyl)-2-ethoxy-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(55) 2-ethoxy-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(56) N-(3-chloro-2-methylphenyl)-2-(1-chloro-2-methylpropan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(57) N-(3-chloro-2-methylphenyl)-2-[(dimethylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(58) N-(3-chloro-2-methylphenyl)-2-(2-methylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(59) 2-(2-methylpropyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(60) tert-butyl-3-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}azetidin-1-carboxylate,

(61) N-(3-chloro-2-methylphenyl)-2-[(methylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(62) {4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}methyl acetate,

(63) N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(64) 2-[(2R)-tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(65) N-(3-chloro-2-methylphenyl)-2-[(2S)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(66) 2-[(2S)-tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(67) 2-(1-acetylazetidin-3-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(68) tert-butyl-(2S)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylate,

(69) tert-butyl-(2R)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-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-carboxamide,

(71) N-(3-chloro-2-methylphenyl)-2-[(2S)-1-methylpyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-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-carboxamide,

(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}amino)-1H-benzimidazole-4-carboxamide,

(76) 2-tert-butyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide,

(77) N-(3-chloro-2-methylphenyl)-2-(2-ethoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(78) N-(3-chloro-2-methylphenyl)-2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(79) 2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide,

(80) N-(3-chloro-2-methylphenyl)-2-(2-methoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(81) N-(3-chloro-2-methylphenyl)-2-(2,2-dimethylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(82) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(83) N-(3-chloro-2-methylphenyl)-2-(2-methylpentan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(84) N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(85) 2-tert-butyl-N-(3-chloro-4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(86) 2-tert-butyl-N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide,

(87) 2-tert-butyl-N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide,

(88) N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(89) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(90) N-(2-chlorobenzyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(91) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(92) 6-{[(2-chloro-4-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-methoxymethyl-1H-benzimidazole-4-carboxamide,

(93) 6-{[(2-chloro-5-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(94) N-(3-chloro-2-methylphenyl)-6-{[(2-chlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(95) N-(3-chloro-2-methylphenyl)-6-{[(2-chloropyridin-3-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(96) 6-{[(2-bromophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(97) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(98) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(99) 6-{[(2-chloro-3-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(100) 6-{[(2-chloro-3,6-difluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(101) 6-{[(2-bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(102) 6-{[(2-bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(103) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-6-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(104) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-4-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(105) 6-{[(5-bromo-2-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(106) 6-{[(2-bromo-5-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(107) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-5-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(108) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[5-methyl-2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(109) 6-({[2,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(110) 6-({[2,4-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(111) N-(3-chloro-2-methylphenyl)-6-({[5-fluoro-2-(trifluoromethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(112) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(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}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(115) 6-({[2-chloro-5-(3-methoxypropyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(116) 6-({[5-(3-tert-butoxyprop-1-yn-1-yl)-2-chlorophenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(117) 6-({[5-(3-tert-butoxypropyl)-2-chlorophenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(118) 6-({[2-chloro-5-(3-hydroxy-3-methylbutyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(119) 6-({[2-chloro-5-(ethoxymethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(120) 6-[({2-chloro-5-[(2-ethoxyethoxy)methyl]phenyl}carbonyl)amino]-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(121) 6-({[2-chloro-5-(2-cyclopropylethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(122) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(2-phenylethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(123) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(124) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide,

(125) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-cyclopentyl-1H-benzimidazole-4-carboxamide,

(126) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide,

(127) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide,

(128) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide,

(129) N-(3-chloro-2-methylphenyl)-2-[(2S)-5-oxopyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(130) N-(3-chloro-2-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(131) N-(3-chloro-2-methylphenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(132) N-(3-chloro-2-methylphenyl)-2-[2-(dimethylamino)-2-oxoethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(133) N-(3-chloro-2-methylphenyl)-2-[2-(methylamino)-2-oxoethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(134) 2-chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(135) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(136) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(137) N-(3-chloro-2-methylphenyl)-2-(methylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(138) N-(3-chloro-2-methylphenyl)-2-(ethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(139) N-(3-chloro-2-methylphenyl)-2-[(2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(140) N-(3-chloro-2-methylphenyl)-2-(cyclopentylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(141) N-(3-chloro-2-methylphenyl)-2-(piperidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(142) N-(3-chloro-2-methylphenyl)-2-(4-methylpiperazin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(143) 2-[bis(2-hydroxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(144) N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(145) N-(3-chloro-2-methylphenyl)-2-{[2-(morpholin-4-yl)ethyl]amino}-6-({[2-(trifluoromethyl)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-carboxamide,

(148) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(149) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-6-({[2-(trifluoromethyl)phenyl]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)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-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(155) N-(3-chloro-2-methylphenyl)-2-(morpholin-4-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(156) 2-amino-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(157) N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)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}amino)-1H-benzimidazole-4-carboxamide,

(159) tert-butyl-N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycinate,

(160) N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-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}amino)-1H-benzimidazole-4-carboxamide,

(163) N-(3-chloro-2-methylphenyl)-2-(pyrrolidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(164) 2-(azetidin-1-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(165) N-(3-chloro-2-methylphenyl)-2-(3-methoxyazetidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(166) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(167) N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(168) N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-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}amino)-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}amino)-1H-benzimidazole-4-carboxamide,

(174) N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(175) 2-[(2-tert-butoxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(176) N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(177) N-(3-chloro-2-methylphenyl)-2-{[2-(methylsulfanyl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(178) N-(3-chloro-2-methylphenyl)-2-(methylsulfanyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(179) N-(3-chloro-2-methylphenyl)-2-(methylsulfonyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(180) N-(3-chloro-2-methylphenyl)-2-(methylsulfinyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(181) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

(182) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

(183) N-(3-chloro-2-methylphenyl)-6-{[(2,4-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

(184) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

(185) 6-{[(2-bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

(186) 6-{[(2-bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

(187) 6-({[2-chloro-5-(cyclopropylethynyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

(188) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide,

(189) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide,

(190) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2-hydroxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide,

(191) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2-methoxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide,

(192) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-{[2-(propan-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide,

(193) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)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-carboxamide,

(195) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide,

(196) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide,

(197) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-1H-benzimidazole-4-carboxamide,

(198) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-1H-benzimidazole-4-carboxamide,

(199) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide,

(200) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-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-carboxamide,

(202) N-(4-tert-butylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(203) N-(2,3-dihydro-1H-inden-5-yl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(204) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

(205) N-(3-chloro-4-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

(206) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

(207) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide,

(208) N-(3-chloro-4-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide,

(209) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(1-methylcyclopropyl)-1H-benzimidazole-4-carboxamide,

(210) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(1-methylcyclopropyl)-1H-benzimidazole-4-carboxamide,

(211) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(methylsulfonyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(212) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(2-methoxyethyl)-1H-benzimidazole-4-carboxamide,

(213) 2-(methoxymethyl)-N-phenyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(214) 2-(methoxymethyl)-N-propyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(215) 2-(methoxymethyl)-N-(pyridin-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-4-carboxamide,

(216) N-benzyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(217) N-(cyclohexylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(218) 2-(methoxymethyl)-N-(naphthalene-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-4-carboxamide,

(219) 2-(methoxymethyl)-N-(thiophen-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-4-carboxamide,

(220) N-(2,1,3-benzothiadiazol-4-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(221) N-(1,1-dioxido-1-benzothiophen-6-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(222) 2-(methoxymethyl)-N-(thiophen-2-ylmethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-4-carboxamide,

(223) N-(1H-indol-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(224) N-(1,3-benzothiazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(225) N-(2,2-dimethylpropyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(226) 2-(methoxymethyl)-N-(thiophen-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-4-carboxamide,

(227) N-(5-chloro-1,3-benzoxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-4-carboxamide,

(228) N-(2-benzylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(229) 2-(methoxymethyl)-N-(quinolin-8-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-4-carboxamide,

(230) N-(cycloheptylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(231) N-(1,3-benzoxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(232) N-(6-chloro-1,3-benzoxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-4-carboxamide,

(233) N-[3-chloro-2-(hydroxymethyl)phenyl]-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

(234) N-(3-chloro-2-methylphenyl)-6-{[(3-fluoropyridin-2-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(235) N-(3-chloro-2-methylphenyl)-6-{[(3-chloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(236) N-(3-chloro-2-methylphenyl)-6-{[(3,5-dichloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(237) 6-{[(5-butoxy-2-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

(238) 6-({[2-chloro-5-(2,2-difluoroethoxy)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide and

(239) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide,

or a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(9) A prophylactic and/or therapeutic agent for chronic prostatitis/chronic pelvic pain syndrome in accordance with the above items (2) to (8),

wherein the mPGES-1 inhibitor is a compound 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,

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 sulfate,

or a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(10) A pharmaceutical composition for the prevention and/or treatment of chronic prostatitis/chronic pelvic pain syndrome, containing an mPGES-1 inhibitor and its pharmaceutically acceptable carrier.

(11) An mPGES-1 inhibitor for use in the prevention and/or treatment of chronic prostatitis/chronic pelvic pain syndrome.

(12) Use of an mPGES-1 inhibitor for the manufacture of a medicinal product for the prevention and/or treatment of chronic prostatitis/chronic pelvic pain syndrome.

(13) A method for the prevention and/or treatment of chronic prostatitis/chronic pelvic pain syndrome, comprising administering an mPGES-1 inhibitor to a subject in need of administration of an mPGES-1 inhibitor.

[0013] Each of the above elements can be arbitrarily selected and combined.

BENEFICIAL EFFECTS OF THE INVENTION

[0014] The therapeutic and/or curative agent of the present invention exhibits a therapeutic and/or prophylactic effect on chronic prostatitis/chronic pelvic pain syndrome and is therefore suitable for the treatment and/or prophylaxis of chronic prostatitis/chronic pelvic pain syndrome.

BRIEF DESCRIPTION OF DRAWINGS

[0015] The Figure shows the results of the evaluation of the analgesic effect of the studied compounds 1-5 on the model of autoimmune chronic prostatitis.

DESCRIPTION OF IMPLEMENTATION OPTIONS

[0016] Embodiments of the invention are described below.

[0017] According to an aspect of the invention, there is provided a prophylactic and/or therapeutic agent for chronic prostatitis/chronic pelvic pain syndrome, the agent comprising an mPGES-1 inhibitor as an active ingredient.

[0018] According to an aspect of the invention, a commercially available compound and/or a compound that can be obtained by a standard method in the field of synthetic organic chemistry can be used in relation to the mPGES-1 inhibitor.

[0019] According to an aspect of the invention, the mPGES-1 inhibitor can be used as a drug, but it can also be used in the form of its pharmaceutically acceptable salt in a known manner. Examples of such a salt include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and salts of organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid.

For example, mPGES-1 inhibitor hydrochloride can be prepared by dissolving mPGES-1 inhibitor in an alcohol solution, an ethyl acetate solution, or a solution of hydrogen chloride in diethyl ether.

[0020] According to an aspect of the invention, the mPGES-1 inhibitor may have an asymmetric carbon, and each of the optical isomers and mixtures thereof can be used as a preventive and/or therapeutic agent of the invention. The optical isomer can be obtained, for example, by optical resolution of a racemate obtained in the same manner as in the Examples described below, using the basicity of the racemate and using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, or the like), or can be obtained using an optically active compound that has been prepared in advance as a starting material. In addition, the optical isomer can also be obtained by optical resolution using a chiral column or by asymmetric synthesis.

In addition, among the mPGES-1 inhibitors capable of forming tautomers, each of the tautomers and mixtures thereof can be used as a prophylactic and/or therapeutic agent of the invention.

[0021] According to an aspect of the invention, the mPGES-1 inhibitor is, for example, the above-described compound of Formula [I] (the present compound) or a pharmaceutically acceptable salt thereof. The present compound can be obtained from a known compound and/or an intermediate that can be easily synthesized according to the method described in WO 2013/024898 and/or a known method.

[0022] With respect to the compound of Formula [I] (the present compound), examples of each substituent are as follows.

Examples of "halogen" include fluorine, chlorine, bromine, and iodine.

Examples of "alkyl" include linear or branched alkyl having 1 to 8 carbon atoms, and specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl and n-octyl. Among these, preferred is alkyl having 1 to 6 carbon atoms, and more preferred is alkyl having 1 to 3 carbon atoms.

Examples of the alkyl moiety "monoalkylamino", "dialkylamino", "monoalkylaminocarbonyl", "dialkylaminocarbonyl", "alkylcarbonyloxy", "alkyloxycarbonyl", "alkylcarbonyl", "alkylthio", "alkylsulfonyl", "alkylsulfinyl", "alkoxyalkyl" and "alkoxyalkylamino" include compounds similar to the above-described "alkyl".

Examples of the alkoxy moiety "alkoxy" include linear or branched alkoxy containing from 1 to 8 carbon atoms, and specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy and n-octyloxy.

Examples of the alkoxy moiety "alkoxyalkoxy", "alkoxyalkyl" and "alkoxyalkylamino" include moieties similar to "alkoxy" described above.

"Heteroaryl" may be a monocyclic or bicyclic aromatic ring containing one to three heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom as constituent atoms. Specific examples thereof include furyl (e.g. 2-furyl or 3-furyl), thienyl (e.g. 2-thienyl or 3-thienyl), pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl or 4-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl or 4-pyrazolyl), triazolyl (e.g. 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl or 1,2,4-triazol-4-yl), tetrazolyl (e.g. 1-tetrazolyl, 2-tetrazolyl or 5-tetrazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl or 5-oxazolyl), isoxazolyl (for example, 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl), oxadiazolyl (for example, 1,3,4-oxadiazol-2-yl), thiazolyl (for example, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl), thiadiazolyl (for example, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl or 1,2,3-thiadiazolyl), isothiazolyl (e.g. 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl), pyridazinyl (e.g. 3-pyridazinyl or 4-pyridazinyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl), pyrazinyl (e.g. 2-pyrazinyl), benzothiadiazolyl (e.g. 1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-4-yl or 2,1,3-benzothiadiazol-5-yl), benzothiazolyl (e.g. benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl or benzothiazol-7-yl), indolyl (e.g. indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), benzothiophenyl (e.g. 1-benzothiophen-2-yl, 1-benzothiophen-3-yl, 1-benzothiophen-4-yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl or 1-benzothiophen-7-yl), 1,1-dioxo-1-benzothiophenyl (e.g. 1,1-dioxo-1-benzothiophen-2-yl, 1,1-dioxo-1-benzothiophen-3-yl, 1,1-dioxo-1-benzothiophen-4-yl, 1,1-dioxo-1-benzothiophen-5-yl, 1,1-dioxo-1-benzothiophen-6-yl or 1,1-dioxo-1-benzothiophen-7-yl), quinolyl (quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl or quinolin-8-yl) and 1,3-benzoxazol-2-yl.

Examples of the heteroaryl moiety "heteroarylmethyl" include moieties similar to the "heteroaryl" described above.

Examples of the "saturated cyclic amino" include a 4- to 7-membered saturated cyclic amino group containing one or two N atoms, wherein the cyclic amino group optionally contains one O or S as a ring constituting atom, and is optionally substituted with oxo, and specific examples thereof include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, 4-morpholino, 4-thiomorpholino, 1-homopiperazinyl and 2-oxo-oxazolidin-3-yl.

Examples of the saturated cyclic amino moiety of the "saturated cyclic aminocarbonyl" include those of the above-described "saturated cyclic amino".

Examples of the "saturated heterocyclic group" include a 4- to 6-membered saturated heterocyclic group containing one N or O as a ring constituting atom, and specific examples thereof include 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl.

Examples of "cycloalkyl" include cycloalkyl having from 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Examples of the cycloalkyl moiety "cycloalkylmethyl" include those described above as "cycloalkyl".

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 containing from 2 to 6 carbon atoms. Specific 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.

[0023] According to an aspect of the invention, the mPGES-1 inhibitor is, for example, each of the above-described compounds (1) to (239), or a tautomer of the compound, or a pharmaceutically acceptable salt thereof, and the mPGES-1 inhibitor is preferably

N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-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, or

N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

or a pharmaceutically acceptable salt thereof, and more preferably

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 4-methylbenzenesulfonate,

N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride or

N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride.

[0024] When the present compound or a pharmaceutically acceptable salt thereof is administered as a drug, the present compound or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition containing the present compound or a pharmaceutically acceptable salt thereof in pure form or in a pharmaceutically acceptable non-toxic and inert carrier, for example, in a proportion of from 0.001% to 99.5% and preferably from 0.1% to 90% to a mammal including a human.

[0025] One or more types of diluents, fillers and other excipients for the composition, which are solid, semi-solid or liquid, are used as a carrier. It is desirable that the pharmaceutical composition according to the invention is administered in the form of a unit dosage form. The pharmaceutical composition can be administered by interstitial administration, oral administration, intravenous administration, local administration (transdermal administration, administration through the eyes, intraperitoneal, intrapleural and the like) or transrectally. In addition, the pharmaceutical composition should be administered in a dosage form suitable for these administration methods.

[0026] It is desirable to adjust the dosage of the drug after administration in consideration of the patient's condition such as age, body weight, type and severity of the disease, route of administration, type of the compound of the invention, whether or not it is a salt, type of salt and the like; however, in general, as an amount of the compound of the invention as an active ingredient for an adult in the case of oral administration, the dosage is suitably in the range of 0.01 mg to 5 g/adult, and preferably in the range of 1 mg to 500 mg/adult per day. In some cases, a dosage equal to or less may be sufficient, or, on the contrary, a higher dosage may be required. Generally, the compound or its pharmaceutically acceptable salt may be administered once or in several divided doses per day, or in the case of intravenous administration, the compound or its pharmaceutically acceptable salt may be administered rapidly, or may be administered continuously for 24 hours.

EXAMPLES

[0027] The present invention will now be described in more detail by means of Reference Examples, Examples, Research Examples and Production Examples; however, the invention is not limited thereto.

[0028] The test compounds used in Study Examples 1 and 2 are as follows.

In accordance with the description of Examples 1-249 of WO 2013/024898, the compounds used in Study Examples 1 and 2 were prepared and used. The activity data of the compounds used in Study Examples 1 and 2 are as described in Tables 1-17 of WO 2013/024898.

[0029] Study Example 1: Study of mPGES-1 Inhibitory Activity

The mPGES-1 microsome was prepared from CHO-K1 cells transiently transfected with a plasmid encoding human mPGES-1 cDNA. The mPGES-1 microsome was diluted in potassium phosphate buffer pH 7.4 containing reduced glutathione, a solution of the test compound in DMSO or DMSO alone (final DMSO concentration 1% in both cases) was added to it, and the mixture was incubated at 4°C for 20 min. Then, a solution prepared by dissolving the PGH2 substrate to a final concentration of 1 μM was added to the mixture to initiate the enzymatic reaction, and the mixture was incubated at 4°C for 60 s. Ferric chloride and citrate solutions (final concentrations of 1 mg/mL and 50 mM, respectively) were added to the mixture to complete the reaction. The PGE2 thus formed was quantified using the HTRF kit (Cisbio International Product Catalog #62P2APEC). A solution without the test compound was used as a positive control, and a solution without the test compound and the microsome were used as a negative control. 100% activity was defined as the PGE2 production in the positive control minus the PGE2 production in the negative control. The IC50 value was then calculated using a standard method.

[0030] Study Example 2: Study of Inhibition of PGE2 and PGF2α Production in A549 Cells

Human A549 cells were seeded at 2× ¹⁰⁴ cells in 100 μl/well (96-well plate) and the cells were incubated overnight. After removing the medium, the cells were washed with phosphate-buffered saline and then the culture medium was replaced with RPMI medium containing 3% PBS containing a solution of the test compound in DMSO or DMSO alone (final DMSO concentration 0.1% in both cases). The cells were incubated for 60 min, then IL-1β (5 ng/well) was added and the cells were incubated at 37°C for 24 h. Then, PGE2 in the medium was measured using an HTRF kit (Cisbio International Product Catalog #62P2APEC) and PGF2α was measured using an EIA kit (Cayman Chemical Company Product Catalog #516011). A solution without test compound was used as a positive control and a solution without test compound and IL-1β were used as a negative control. 100% activity was defined as the production of PGE2 and PGF2α in the positive control minus the production of PGE2 and PGF2α in the negative control. The IC50 value was then measured using a standard method.

[0031] The test compounds used in Study Examples 3-8 are as follows.

[0032] Test Compound 1 and Test Compound 2:

According to the description of Example 239 and Example 89 of WO 2013/024898, the compounds of test compound 1: N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate and test compound 2: 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 test compound 1 and test compound 2).

Test compound 3:

In accordance with the description of Example 9 of WO 2011/023812, test compound 3: N-cyclopentyl-1-(1-isopropyl-5,6-dimethyl-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared and used.

Test compound 4:

In accordance with the description of Example 2 of WO 2017/073709, the test compound 4: N-[4-chloro-3-(5-cyano-6-oxo-4-thiophen-3-yl-1,6-dihydropyrimidin-2-yl)benzyl]-2,2-dimethylpropionamide was obtained and used.

In relation to KANEFRON (registered trademark) N, a commercially available product was purchased and used.

[0033] <Study Example 3: Evaluation of Analgesic Effect in Autoimmune Chronic Prostatitis Model>

The analgesic effect of the studied compounds 1-4 was assessed in the following manner using the autoimmune chronic prostatitis model (experimental autoimmune prostatitis; EAP), which is commonly used as a model of chronic prostatitis.

1. Method for obtaining prostate-specific antigen (prostate-specific antigen; PAg)

The prostate was extracted from a 14-week-old male Wistar rat (manufactured by Japan SLC, Inc.), and the prostate was homogenized in PBS (Cat. No. 045-29795, manufactured by FUJIFILM Wako Pure Chemical Corporation) prepared by adding cOmplete (registered trademark) Mini, EDTA-free (Cat. No. 11836170001, manufactured by Roche Diagnostics GmbH) and cooling with ice using a portable microhomogenizer (NS-310E, manufactured by Microtec Co., Ltd.), and then the resulting product was centrifuged at 10,000×g at 4°C for 30 minutes using a centrifuge (Allegra X-30R, manufactured by Beckman Coulter, Inc.) to collect the supernatant. The protein concentration was measured using a DC (trade mark) protein assay kit (Cat. No. 500-0112, manufactured by BIO-RAD Laboratories, Inc.) and a SpectraMax (registered trademark) M5 microplate reader (manufactured by Molecular Devices, LLC.), and then the supernatant was stored at -20°C.

2. Method for obtaining the EAP model

PAg and Freund's complete adjuvant (Cat. No. 263810, manufactured by Becton, Dickinson and Company) were mixed in equal amounts to prepare an emulsion with a PAg protein concentration of 5 mg/250 μl. Under isoflurane anesthesia, the initial immunization was performed by subcutaneously injecting 250 μl of the resulting emulsion per rat into the soles and ridges of both hind limbs of 9-week-old male Wistar rats (manufactured by Japan SLC, Inc.). The same treatment as booster immunization was performed 28 days after the initial immunization. In the placebo treatment group, an emulsion prepared by mixing saline (Cat. No. 35081517, manufactured by Otsuka Pharmaceutical Factory, Inc.) and complete Freund's adjuvant in equal amounts was administered (see Prostate, 2018 Nov.; 78(15): 1157-1165).

3. Method of grouping

At 37 days after the initial immunization, the pretest value was measured using the following pain assessment method and grouping was performed such that there was no significant difference in either the pain response rate or the AUC at each stimulus intensity. Grouping was performed by stratified random sampling using SAS version 9.3 and EXSUS version 8.1.

4. Method of pain assessment

Forty-two days after the initial immunization, the test substance was prepared using 0.5% aqueous methylcellulose as the vehicle to a concentration of 100 mg/kg based on the free substance, the test substance was administered orally at a rate of 10 ml/kg, and pain assessment was performed 4 hours after administration. Rats were placed on a wire mesh for 30 minutes before assessment and acclimatized. Three kinds of von Frey threads of 0.4 g, 1 g or 4 g (Touch Test (registered trademark), Cat. No. NC12775-06, NC12775-08, NC12775-11, manufactured by North Coast Medical, Inc.) with different stimulus intensities were pressed for 1-2 seconds on the lower abdomen of rats from under the wire mesh, and thereby the presence or absence of an escape response (escaping, licking the stimulation site, etc.) was observed. Stimulation was performed five times at each stimulus intensity in order from the thread with the lowest stimulus intensity, the proportion showing the escape response was calculated as the escape response ratio (%), and the area under the curve (AUC) was calculated from the linear graph plotted based on the stimulus intensity and the escape response ratio.

5. Statistical analysis

Calculation of summary statistics and statistical analysis were performed using Microsoft Office Excel 2016 (registered trademark), SAS version 9.3 and EXSUS version 8.1. The mean and standard error of AUC for each group were determined and Student's t-test was performed between the placebo group and the EAP model medium group and between the EAP model medium group and the EAP model drug group.

6. Research results

The analgesic effect of the studied compounds 1-5 on the EAP model is shown in the Figure.

[0034] <Study Example 4: Evaluation of Anti-inflammatory Effect in Normal Human Prostate Stromal Cells>

1. Cell culture

Normal human prostate stromal cells (WPMY-1 cells, Cat. No. CRL-2854 (trademark)) purchased from ATCC (registered trademark) were subcultured using culture medium under conditions of 37°C and 5% _CO2 . DMEM (Cat. No. 08458-45, manufactured by NACALAI TESQUE, INC.) containing inactivated fetal bovine serum (Cat. No. SH30910, manufactured by GE Healthcare) at a final concentration of 5%, as well as penicillin at a final concentration of 20 U/mL and streptomycin at a final concentration of 20 μg/mL (mixed penicillin-streptomycin solution, Cat. No. 26253-84, manufactured by NACALAI TESQUE, INC.) were used as the culture medium.

2. Cell seeding and drug treatment

One day before treatment with each test compound, WPMY-1 cells were suspended in the growth medium and the cells were seeded at 57,000 cells/well in a 12-well Falcon (registered trademark) cell culture multiwell plate (Cat. No. 353043, manufactured by Corning, Incorporated). The WPMY-1 cells seeded in the 12-well plate were cultured overnight under the conditions of 37°C and 5% CO ₂ .

The day after seeding, each test substance was processed. First, a 10 mM solution of drug in DMSO was prepared using DMSO (Cat. No. 13445-74, NACALAI TESQUE, INC.) and the solution was diluted to 10 μM using assay medium. A 1000 mg/mL solution of CANEFRON in DMSO was prepared and diluted to 1000 μg/mL using assay medium. As the assay medium, DMEM (Cat. No. 08458-45, manufactured by NACALAI TESQUE, INC.) containing inactivated fetal bovine serum (Cat. No. SH30910, manufactured by GE Healthcare) at a final concentration of 2%, as well as penicillin at a final concentration of 20 U/mL and streptomycin at a final concentration of 20 μg/mL (penicillin-streptomycin mixed solution, Cat. No. 26253-84, manufactured by NACALAI TESQUE, INC.) were used. The culture medium was removed, the medium was replaced with the assay medium containing each test substance, and then the cells were cultured for 24 hours under the conditions of 37°C and 5% _CO2 .

3. Cytokine stimulation

Cytokine stimulation was performed 24 hours after treatment with each test substance. Assay medium each containing 1 ng/mL IL-17 (Cat. No. 200-17, PeproTech, Inc.), TNF-α (Cat. No. 300-01A, PeproTech, Inc.), and IFN-γ (Cat. No. 300-02, PeproTech, Inc.) were prepared and used as cytokine stimulation medium. Each test substance was diluted in a similar manner to that used with the cytokine stimulation medium the day before, and the cells were treated with each test substance and cytokine. The cells were cultured for 5 hours under the conditions of 37°C and 5% _CO2, and the cells were harvested.

4. Gene expression analysis

Total RNA was extracted from the cells according to the manufacturer's protocol using RNeasy Mini Kit (registered trademark) (Cat. No. 74106, manufactured by QIAGEN), and the RNA concentration was measured using NanoDrop (trade name) ONE (Cat. No. ND-ONE-W, manufactured by Thermo Scientific, Inc.). 500 ng of RNA was reverse transcribed using ReverTra Ace (registered trademark), qPCR RT Master Mix (Cat. No. FSQ-201, manufactured by TOYOBO CO., LTD.), and Biometra Tadvanced 96SG (manufactured by BM Equipment Co., Ltd.). cDNA obtained by reverse transcription, TB Green (registered trademark) Premix Ex Taq II (Cat. No. RR820, manufactured by Takara Bio Inc.) and LightCycler (registered trademark) 480 Real-Time PCR System (manufactured by Roche Diagnostics GmbH) were used to evaluate the expression level of CCL2 gene. For CCL2 primers, Fw: AGCAGCAAGTGTCCCAAAGA and Rv: GGTGGTCCATGGAATCCTGA were used.

The ratio of mRNA level of each treated group to that of NT (untreated) group was calculated using the Δ threshold cycle (Ct) method (2-ΔΔCt) to calculate the rate of change. All data were corrected with GAPDH. For PCR conditions, the system was maintained at 95°C for 10 minutes and then repeated 45 cycles of maintaining at 95°C for 15 seconds and 60°C for 1 minute.

5. Research results

The studied compounds suppressed the expression of inflammatory cytokine/chemokine (CCL2) in normal human prostate stromal cells (WPMY-1 cells) and exhibited an anti-inflammatory effect (Table 1).

[Table 1]

Compound under study CCL2 expression level when the vehicle expression level was taken as 1 1 0.6792 2 0.7813 3 1,0119 4 1,2215 KANEFRON® N 0.9571

[0035] <Study Example 5: Evaluation of Anti-inflammatory Effect in Autoimmune Chronic Prostatitis Model>

1. Obtaining a protein solution

The EAP model rat was prepared in a manner similar to Study Example 1, and the test substance was administered for 42 days after the initial immunization. At 42 days after the initial immunization, the ventral lobe of the prostate gland was collected, placed in a 2 ml tube, frozen with liquid nitrogen, and then stored at -80°C.

The protein solution was prepared by adding T-PER (Cat. No. 78510, manufactured by Thermo Scientific, Inc.) containing cOmplete (trade name) Mini, EDTA-free, into a 2 mL tube containing the prostate gland in an amount of 1 mL relative to 100 mg of prostate tissue weight, homogenizing the prostate gland using a hand-held microhomogenizer (NS-310E, manufactured by Microtec Co., Ltd.), centrifuging the resulting product at 14,000×g and 4°C for 30 minutes using himac (registered trademark) CT15RE (manufactured by Koki Holdings Co., Ltd.), and collecting the supernatant.

2. Measurement of cytokine/chemokine levels

The amounts of 23 kinds of cytokines/chemokines were measured according to the manufacturer's protocol using a cytokine assay kit (Rat 23-plex panel) and a Bio-Plex system (manufactured by Bio-RAD Laboratories, Inc.). In addition, the total amount of protein was measured using a DC (trade mark) protein assay kit (Cat. No. 500-0112, manufactured by BIO-RAD Laboratories, Inc.) and a SpectraMax (registered trademark) M5 microplate reader (manufactured by BIO-RAD LaboratoriesMolecular Devices, LLC.), and then the concentration of cytokines/chemokines per 1 mg of total protein was calculated.

2. Research results

The studied compounds suppressed the expression of inflammatory cytokines/chemokines (IL-1β, CCL2, CCL3 and CCL5) in the EAP model and exhibited an anti-inflammatory effect.

[0036] <Study Example 6: Evaluation of Analgesic Effect in a Hormone-Induced Chronic Prostatitis (HCP) Model (HCP)>

1. Method for obtaining the GKP model

Under isoflurane anesthesia, resting male Wistar rats (Charles River Laboratories Japan, Inc.) were surgically castrated, and 0.25 mg/kg 17β-estradiol (Cat. No. 14541-61, NACALAI TESQUE, INC.) was subcutaneously administered to the rats at 2 ml/kg once a day for 30 days from the day of surgery using sesame oil (Cat. No. S3547, Sigma-Aldrich). The placebo treatment group underwent placebo surgery and was similarly administered sesame oil as a vehicle (see Prostate, 2019 Apr; 79(5): 446-453).

2. Treatment with medicinal products

The test substance was administered for 30 days from the date of surgery.

3. Method of pain assessment

The assessment was carried out in a manner similar to that in Example Research 3.

4. Statistical analysis

The assessment was carried out in a manner similar to that in Example Research 3.

5. Research results

The studied compounds exhibited analgesic effect in the GPC model.

[0037] <Study Example 7: Evaluation of Analgesic Effect in a Formalin-Induced Prostatitis Model>

1. Method for obtaining a model of formalin-induced prostatitis

Under isoflurane anesthesia, a midline incision was made in the lower abdomen of a 7-week-old male SD rat (purchased from Japan SLC, Inc.) to expose the prostate, 25 μl of each 5% formalin solution prepared by mixing 10% neutral buffered formalin solution (Cat. No. 062-01661, manufactured by FUJIFILM Wako Pure Chemical Corporation) and normal saline (Cat. No. 35081517, manufactured by Otsuka Pharmaceutical Factory, Inc.) in equal amounts were injected into the right and left ventral lobes of the prostate gland, then the lower abdomen was sutured and the antibiotic substance cephalexin (Cat. No. 034-11052, manufactured by FUJIFILM Wako Pure Chemical Corporation) was subcutaneously injected at a rate of 15 mg/kg. In the placebo treatment group, 25 μl of saline was injected into the right and left ventral lobes of the prostate gland (see Int Neurourol J. 2018 Jun; 22(2): 90–98).

2. Treatment with medicinal products

The test substance was administered twice daily for 7 days from the date of receipt of the model.

3. Method of pain assessment

The evaluation was carried out in a manner similar to that in Example Study 1, 7 days after receiving the model.

4. Statistical analysis

The assessment was carried out in a manner similar to that in Example Research 3.

5. Research results

The studied compounds exhibited an analgesic effect in a formalin-induced prostatitis model.

[0038] <Study Example 8: Evaluation of PGE2 Production in Prostate Epithelial Cells Obtained from a Patient with Benign Prostatic Hyperplasia>

1. Cell culture

Prostate epithelial cells obtained from a patient with benign prostatic hyperplasia (BPH-1 cells, Cat. No. ACC143) purchased from DSMZ were passaged using growth medium under conditions of 37°C and 5% CO ₂ . The culture medium used was RPMI-1640 (Cat. No. 189-02025, manufactured by FUJIFILM Wako Pure Chemical Corporation) containing inactivated fetal bovine serum (Cat. No. SH30910, manufactured by GE Healthcare) at a final concentration of 20%, testosterone (Cat. No. 32811-61, manufactured by NACALAI TESQUE, INC.) at a final concentration of 20 ng/mL, as well as recombinant human insulin at a final concentration of 4.2 μg/mL, human transferrin at a final concentration of 3.8 μg/mL, and sodium selenite at a final concentration of 5 ng/mL (insulin-transferrin-sodium selenite medium supplement, Cat. No. I1884, manufactured by Sigma-Aldrich).

2. Cell seeding and drug treatment

One day before treatment with each test compound, BPH-1 cells were suspended in growth medium and the cells were seeded at 9600 cells/well in a Falcon (registered trademark) 96-well multiwell cell culture plate (Cat. No. 353072, Corning, Incorporated). Control wells were seeded with control medium. RPMI-1640 (Cat. No. 189-02025, manufactured by FUJIFILM Wako Pure Chemical Corporation) containing inactivated fetal bovine serum (Cat. No. SH30910, manufactured by GE Healthcare) at a final concentration of 2%, testosterone (Cat. No. 32811-61, manufactured by NACALAI TESQUE, INC.) at a final concentration of 20 ng/mL, as well as recombinant human insulin at a final concentration of 4.2 μg/mL, human transferrin at a final concentration of 3.8 μg/mL, and sodium selenite at a final concentration of 5 ng/mL (insulin-transferrin-sodium selenite medium supplement, Cat. No. I1884, manufactured by Sigma-Aldrich) were used as the control medium. BPH-1 cells seeded in 96-well plate were cultured overnight at 37°C and 5% CO ₂ .

The next day after seeding, each test substance was treated. First, 10 mM DMSO solution was prepared using DMSO (Cat. No. 13445-74, manufactured by NACALAI TESQUE, INC.), and the DMSO solution was diluted to 10, 1, or 0.1 μM using the culture medium. The culture medium or control medium was removed, the medium in the culture medium wells containing each test substance or control wells was replaced with the control medium, and then the cells were cultured for 48 hours under the conditions of 37°C and 5% _CO2 , and the supernatant was collected.

3. Measuring the amount of PGE2

The amount of PGE2 in the cell culture supernatant was measured according to the manufacturer's protocol using prostaglandin E2 kits (Cat. No. 62P2APEG, manufactured by Cisbio) and a SpectraMax (registered trademark) M5 microplate reader (manufactured by Molecular Devices, LLC).

4. Research results

The studied compounds suppressed PGE2 production in BPH-1 cells.

[0039] Example of obtaining 1

Tablet (tablet for internal use)

One 80 mg tablet contains:

Compound under study 5.0 mg Cornstarch 46.6 mg Crystalline cellulose 24.0 mg Methylcellulose 4.0 mg Magnesium stearate 0.4 mg

The mixed powder of these ratios was tabletted in a standard manner to obtain tablets for internal use.

INDUSTRIAL APPLICABILITY

[0040] The present invention relates to a preventive and/or therapeutic agent for chronic prostatitis/chronic pelvic pain syndrome containing an mPGES-1 inhibitor as an active ingredient, and the invention has industrial applicability.

Claims (6)

1. Use of an mPGES-1 inhibitor for the manufacture of a medicinal product for the prevention and/or treatment of chronic prostatitis/chronic pelvic pain syndrome, wherein the mPGES-1 inhibitor is a compound selected from the group consisting of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide and N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, or a tautomer of the compound, or a pharmaceutically acceptable salt thereof. 2. Use of an mPGES-1 inhibitor for the manufacture of a medicinal product for the prevention and/or treatment of chronic prostatitis/chronic pelvic pain syndrome, wherein the mPGES-1 inhibitor is N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate. 3. Use of an mPGES-1 inhibitor for the manufacture of a medicinal product for the prevention and/or treatment of chronic prostatitis/chronic pelvic pain syndrome, wherein the mPGES-1 inhibitor is N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide.

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