Prophylactic and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome

Abstract

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

Description

[0001] This application is a divisional application of the Chinese invention application "Preventive and / or therapeutic agents for chronic prostatitis / chronic pelvic pain syndrome" with an application date of December 24, 2020 and application number 202080090316.8. Technical Field

[0002] 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 effective ingredient. Background Art

[0003] Prostatitis is classified into 4 categories (acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis / chronic pelvic pain syndrome, asymptomatic inflammatory prostatitis) by the U.S. NIH (non-patent literature 1). Category I is an acute bacterial prostatitis with systemic symptoms such as urination symptoms, pain, and fever due to bacterial infection. Category II is chronic bacterial prostatitis, which is a chronic form of category I, and is confirmed to have symptoms of recurrent bacterial infection. Category III is chronic prostatitis / chronic pelvic pain syndrome, which is classified as a disease with urination symptoms such as pain / discomfort in the pelvic parts such as perineum, testicles, penis, and lower abdomen, and residual urine, frequent urination, etc. as the main symptoms. It should be noted that although the asymptomatic inflammatory prostatitis of category IV is asymptomatic, inflammation can be confirmed in prostate biopsy tissue specimens, prostate squeezed fluid / 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 express of patients with chronic prostatitis (Non-Patent Documents 2 and 3).

[0004] However, unlike category I acute bacterial prostatitis and category II chronic bacterial prostatitis, category III chronic prostatitis / chronic pelvic pain syndrome has no known cause and therefore no effective treatment has been found.

[0005] PGE2 synthase (PGES) is known to have the existence (non-patent literature 4~6) of these 3 kinds of hypotypes of membrane-bound prostaglandin E synthase-1 (mPGES-1), mPGES-2 and cytoplasmic type PGES (cPGES).MPGES-1 is the same as COX-2, and is mainly induced when inflammation, participates in the PGE2 production of inflammatory lesions.In addition, known mPGES-1 is relevant to malignant tumor (for example, colon cancer, breast cancer, lung cancer, prostate cancer etc.) (with reference to non-patent literature 7, non-patent literature 8, non-patent literature 9).

[0006] Patent Document 1 states that a heterocyclic derivative represented by the general formula [1], or a tautomer thereof, or a pharmaceutically acceptable salt thereof, has mPGES-1 inhibitory activity. In addition, Patent Documents 2 and 3 state low molecular weight compounds having mPGES-1 inhibitory activity. Non-Patent Document 10 states that Canephron (registered trademark) N contains plant-derived ingredients and has mPGES-1 inhibitory activity.

[0007] However, to date, the relationship between chronic prostatitis and the mPGES-1 pathway has not been reported.

[0008] Prior art literature

[0009] Patent Literature

[0010] Patent Document 1: WO2013 / 024898

[0011] Patent Document 2: WO2011 / 023812

[0012] Patent Document 3: WO2017 / 073709

[0013] Non-patent literature

[0014] Non-patent literature 1: JAMA. 1999 Jul. 21; 282(3): 236-7.

[0015] Non-patent document 2: Int. J. Urol. 2001 Sep; 8(9): 495-499

[0016] Non-patent document 3: J. Urol. 2008 May; 179(5): 1857-1862.

[0017] Non-patent document 4: Jakobsson et al., Proc. Natl. Acad. Sci. USA, 1999, 96, 7220-7225

[0018] Non-patent document 5: Biochem. Biophys. Res. Commun., 2002, 291, 884-889

[0019] Non-patent document 6: J. Biol. Chem., 2000, 275, 32775-32782

[0020] Non-patent document 7: J. Biol. Chem., 2003, 278(21), 19396-19405

[0021] Non-patent document 8: Oncogene, 2012, 31(24), 2943-2952

[0022] Non-patent document 9: Cancer Res., 2008, 68(9), 3251-3259

[0023] Non-patent literature 10: J. Phymed. 2019, 60, 152987 Summary of the invention

[0024] Problems to be solved by the invention

[0025] The problem to be solved by the present invention is to provide a preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome.

[0026] Solution to the problem

[0027] The present inventors set out to clarify the condition of chronic prostatitis / chronic pelvic pain syndrome and found that the mPGES-1 pathway is related to chronic prostatitis / chronic pelvic pain syndrome. In addition, the present inventors found that the pain and inflammation of chronic prostatitis in animal models can be reduced by using mPGES-1 inhibitors, thereby completing the present invention.

[0028] The present invention relates to the following aspects. (1)

[0030] A preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome, comprising an mPGES-1 inhibitor as an active ingredient. (2)

[0032] The preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to (1) above,

[0033] The mPGES-1 inhibitor is a compound of formula [1] (hereinafter also referred to as the present compound), or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein:

[0034] The compound of formula [1] is represented by the following formula [1],

[0035] [Chemical formula 1]

[0036]

[0037] In formula [1],

[0038] Ring A is a group represented by formula [2], [3] or [4],

[0039] [Chemical formula 2]

[0040]

[0041] (Where,

[0042] X 1 is NH, N-alkyl, or O,

[0043] A 1 is hydrogen or an alkyl group,

[0044] A 2 for:

[0045] i) Hydrogen;

[0046] ii) halogen;

[0047] iii) an alkyl group optionally substituted by 1 to 3 groups selected from halogen, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy, and alkylcarbonyloxy;

[0048] iv) a cycloalkyl group optionally substituted by an alkyl group, wherein the alkyl group is optionally substituted by 1 to 3 halogen groups;

[0049] v) alkoxy;

[0050] vi) a saturated heterocyclic group optionally substituted by an alkyl group, an alkyloxycarbonyl group, an alkylcarbonyl group, or an oxygen group;

[0051] vii) alkylthio;

[0052] viii) alkylsulfonyl;

[0053] ix) alkylsulfinyl;

[0054] x) a group represented by the formula [5],

[0055] [Chemical formula 3]

[0056]

[0057] (Where R 3 , R 4 Same or different, as:

[0058] a) Hydrogen;

[0059] b) an alkyl group optionally substituted by a group selected from the group consisting of a monoalkylamino group, a dialkylamino group, a saturated cyclic amino group optionally substituted by an alkyl group, a saturated heterocyclic group optionally substituted by an alkyl group, an alkoxy group, a hydroxycarbonyl group, a hydroxy group, an alkyloxycarbonyl group, and an alkylthio group; or

[0060] c) cycloalkyl); or

[0061] xi) a saturated cyclic amino group optionally substituted by an alkyl group, an amino group, a monoalkylamino group, a dialkylamino group, an alkoxy group, or a hydroxy group,

[0062] 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-dihydrocyclobutylbenzen-3-yl, 1,2-dihydrocyclobutylbenzen-4-yl, or alkyl, and the phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl are optionally selected from

[0063] i) Halogen,

[0064] ii) an alkyl group optionally substituted by 1 to 3 groups selected from halogen, hydroxyl, and phenyl,

[0065] iii) alkoxy,

[0066] iv) hydroxyl groups, and

[0067] v) Cyano

[0068] 1 to 3 groups are substituted,

[0069] R 2 is phenyl or pyridyl, the phenyl or pyridyl group is optionally selected from

[0070] i) Halogen,

[0071] ii) alkylsulfonyl,

[0072] iii) an alkoxy group optionally substituted by 1 to 3 halogen or alkoxy groups,

[0073] iv) an alkynyl group optionally substituted by an alkoxyalkyl group or a cycloalkyl group, and

[0074] v) an alkyl group optionally substituted by 1 to 3 groups selected from alkoxy, alkoxyalkoxy, cycloalkyl, phenyl, and halogen

[0075] 1~3 groups are substituted]. (3)

[0077] The preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to (2) above, wherein

[0078] Ring A is a group represented by formula [4], X 1 For NH. (4)

[0080] The preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to (2) or (3) above, wherein

[0081] 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-dihydrocyclobutane-3-yl, or 1,2-dihydrocyclobutane-4-yl, the phenyl being optionally selected from

[0082] i) Halogen,

[0083] ii) an alkyl group optionally substituted with 1 to 3 halogens,

[0084] iii) alkoxy, and

[0085] iv) Cyano

[0086] 1 to 3 groups are substituted. (5)

[0088] The preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (4) above, wherein

[0089] R 2 is phenyl,

[0090] The phenyl group is optionally selected from

[0091] i) Halogen,

[0092] ii) alkylsulfonyl,

[0093] iii) an alkoxy group optionally substituted by an alkoxy group,

[0094] iv) an alkynyl group optionally substituted by an alkoxyalkyl group or a cycloalkyl group, and

[0095] v) an alkyl group optionally substituted by 1 to 3 groups selected from halogen, alkoxy, alkoxyalkoxy, cycloalkyl, and phenyl

[0096] 1 to 3 groups are substituted. (6)

[0098] The preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (5) above, wherein

[0099] Ring A is a group represented by the general formula [4], X 1 For NH,

[0100] A 2 for:

[0101] i) Hydrogen;

[0102] ii) an alkyl group optionally substituted by a group selected from halogen, monoalkylamino, dialkylamino, monoalkylaminocarbonyl, dialkylaminocarbonyl, a saturated cyclic aminocarbonyl, an alkoxy group, an alkoxyalkoxy group, and an alkylcarbonyloxy group;

[0103] iii) a cycloalkyl group optionally substituted by an alkyl group, wherein the alkyl group is optionally substituted by 1 to 3 halogen groups;

[0104] iv) alkoxy;

[0105] v) a saturated heterocyclic group optionally substituted by an alkyl group or an alkyloxycarbonyl group;

[0106] vi) alkylthio;

[0107] vii) alkylsulfonyl;

[0108] viii) alkylsulfinyl;

[0109] ix) an amino group optionally substituted by an alkyl group, the alkyl group optionally substituted by a group selected from a monoalkylamino group, a dialkylamino group, a saturated cyclic amino group optionally substituted by an alkyl group, a tetrahydrofuranyl group, a morpholinyl group, an alkoxy group, a hydroxycarbonyl group, a hydroxy group, and an alkylthio group;

[0110] x) amino optionally substituted by cycloalkyl; or

[0111] xi) a saturated cyclic amino group optionally substituted by an alkyl group, a dialkylamino group, an alkoxy group, or a hydroxy group,

[0112] R 1 for:

[0113] i) phenyl optionally substituted by 1 to 3 groups selected from halogen, alkyl optionally substituted by 1 to 3 halogens, alkoxy, and cyano;

[0114] ii) 1,2,3,4-tetrahydronaphthalen-5-yl;

[0115] iii) 2,3-dihydro-1H-inden-5-yl;

[0116] iv) benzyl optionally substituted by halogen or alkyl, the alkyl optionally substituted by 1 to 3 halogens;

[0117] v) cycloalkyl;

[0118] vi) cycloalkylmethyl;

[0119] vii) naphthyl;

[0120] viii) pyridylmethyl optionally substituted by alkyl, wherein the alkyl is optionally substituted by 1 to 3 halogens;

[0121] ix) thienyl;

[0122] x) thienylmethyl;

[0123] xi) benzothiazolyl;

[0124] xii) benzothiadiazolyl;

[0125] xiii) indolyl; or

[0126] xiv) an alkyl group,

[0127] R 2 represents a phenyl group or a pyridyl group,

[0128] The phenyl group is optionally selected from

[0129] i) Halogen,

[0130] ii) alkylsulfonyl,

[0131] iii) an alkoxy group optionally substituted by an alkoxy group,

[0132] iv) an alkynyl group optionally substituted by an alkoxyalkyl group or a cycloalkyl group, and

[0133] v) an alkyl group optionally substituted by 1 to 3 groups selected from halogen, alkoxy, alkoxyalkoxy, cycloalkyl, and phenyl

[0134] 1 to 3 groups are substituted,

[0135] The pyridyl group is optionally substituted by halogen. (7)

[0137] The preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (6) above, wherein

[0138] Ring A is a group represented by the general formula [4], X 1 For NH,

[0139] A 2 is an alkyl group substituted by an alkoxy group, a dialkylamino group, a tetrahydrofuranyl group, a tetrahydrofuranylmethyl group, an alkoxyalkylamino group, or a cycloalkyl group which is unsubstituted or optionally substituted by 1 to 3 halogen-substituted alkyl groups,

[0140] R 1 is a phenyl group substituted with one halogen and one methyl group,

[0141] R 2 is phenyl which is optionally substituted by 1 trifluoromethyl or 2 halogens. (8)

[0143] The preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (7) above, wherein

[0144] The mPGES-1 inhibitor is a compound selected from the following, or a tautomer thereof or a pharmaceutically acceptable salt thereof,

[0145] (1) N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0146] (2) N-cyclohexyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0147] (3) N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0148] (4) N-[(1-Hydroxycyclohexyl)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0149] (5) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino}-2,3-dihydro-1-benzofuran-7-carboxamide

[0150] (6) N-cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxamide

[0151] (7) N-(3-chloro-2-methylphenyl)-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxamide

[0152] (8) N-cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-indazole-7-carboxamide

[0153] (9) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-indazole-7-carboxamide

[0154] (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0155] (11) 2-methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0156] (12) N-cyclohexyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0157] (13) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0158] (14) N-cyclopentyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0159] (15) N-cyclobutyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0160] (16) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0161] (17) N-cyclohexyl-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0162] (18) 2-ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0163] (19) N-cyclohexyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0164] (20) 2-(Methoxymethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0165] (21) 2-(Methoxymethyl)-N-(2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0166] (22) 2-(Methoxymethyl)-N-(4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0167] (23) N-(2-chlorobenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0168] (24) 2-(Methoxymethyl)-N-(4-methylbenzyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0169] (25) N-(4,4-difluorocyclohexyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0170] (26) N-(4-tert-butylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0171] (27) 2-(Methoxymethyl)-N-[4-(trifluoromethyl)phenyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0172] (28) N-(2,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0173] (29) N-(2-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0174] (30) N-(3,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0175] (31) N-(3-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0176] (32) N-(2,3-dihydro-1H-inden-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0177] (33) 2-(Methoxymethyl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0178] (34) N-(2-fluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0179] (35) 2-(Methoxymethyl)-N-(2-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0180] (36) 2-(Methoxymethyl)-N-(4-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0181] (37) N-(3-bromo-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0182] (38) N-(3-chloro-2-methylbenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0183] (39) N-(2,6-difluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0184] (40) N-(3-cyano-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0185] (41) 2-(Methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide

[0186] (42) N-(2-chloro-6-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0187] (43) 2-(2-amino-2-oxoethyl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0188] (44) 2-(2-amino-2-oxoethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0189] (45) N-(3-chloro-2-methylphenyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0190] (46) N-cyclohexyl-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0191] (47) 1-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0192] (48) N-(3-chloro-2-methylphenyl)-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0193] (49) N-cyclohexyl-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0194] (50) 1-ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0195] (51) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzo Azole-4-carboxamide

[0196] (52) 2-methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzo Azole-4-carboxamide

[0197] (53) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzo Azole-4-carboxamide

[0198] (54) N-(3-chloro-2-methylphenyl)-2-ethoxy-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0199] (55) 2-Ethoxy-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0200] (56) N-(3-chloro-2-methylphenyl)-2-(1-chloro-2-methylpropane-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0201] (57) N-(3-chloro-2-methylphenyl)-2-[(dimethylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0202] (58) N-(3-chloro-2-methylphenyl)-2-(2-methylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0203] (59) 2-(2-methylpropyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0204] (60) tert-butyl 3-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}azetidine-1-carboxylate

[0205] (61) N-(3-chloro-2-methylphenyl)-2-[(methylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0206] (62) {4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}methyl acetate

[0207] (63) N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0208] (64) 2-[(2R)-tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0209] (65) N-(3-chloro-2-methylphenyl)-2-[(2S)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0210] (66) 2-[(2S)-Tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0211] (67) 2-(1-acetylazetidin-3-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0212] (68) (2S)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylic acid tert-butyl ester

[0213] (69) (2R)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylic acid tert-butyl ester

[0214] (70) N-(3-chloro-2-methylphenyl)-2-[(2S)-pyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0215] (71) N-(3-chloro-2-methylphenyl)-2-[(2S)-1-methylpyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0216] (72) 2-[(2S)-1-acetylpyrrolidin-2-yl]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0217] (73) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethoxy)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0218] (74) N-(3-chloro-2-methylphenyl)-2-(1-methoxy-2-methylpropane-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0219] (75) 2-tert-Butyl-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0220] (76) 2-tert-butyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide

[0221] (77) N-(3-chloro-2-methylphenyl)-2-(2-ethoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0222] (78) N-(3-chloro-2-methylphenyl)-2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0223] (79) 2-(Ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide

[0224] (80) N-(3-chloro-2-methylphenyl)-2-(2-methoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0225] (81) N-(3-chloro-2-methylphenyl)-2-(2,2-dimethylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0226] (82) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0227] (83) N-(3-chloro-2-methylphenyl)-2-(2-methylpentan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0228] (84) N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0229] (85) 2-tert-Butyl-N-(3-chloro-4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0230] (86) 2-tert-Butyl-N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide

[0231] (87) 2-tert-Butyl-N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide

[0232] (88) N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0233] (89) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0234] (90) N-(2-chlorobenzyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0235] (91) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0236] (92) 6-{[(2-chloro-4-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-methoxymethyl-1H-benzimidazole-4-carboxamide

[0237] (93) 6-{[(2-chloro-5-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0238] (94) N-(3-chloro-2-methylphenyl)-6-{[(2-chlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0239] (95) N-(3-chloro-2-methylphenyl)-6-{[(2-chloropyridin-3-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0240] (96) 6-{[(2-bromophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0241] (97) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0242] (98) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0243] (99) 6-{[(2-chloro-3-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0244] (100) 6-{[(2-chloro-3,6-difluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0245] (101) 6-{[(2-bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0246] (102) 6-{[(2-bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0247] (103) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-6-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0248] (104) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-4-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0249] (105) 6-{[(5-bromo-2-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0250] (106) 6-{[(2-bromo-5-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0251] (107) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-5-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0252] (108) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[5-methyl-2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0253] (109) 6-({[2,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0254] (110) 6-({[2,4-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0255] (111) N-(3-chloro-2-methylphenyl)-6-({[5-fluoro-2-(trifluoromethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0256] (112) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0257] (113) N-(3-chloro-2-methylphenyl)-6-[({2-chloro-5-[2-(propan-2-yloxy)ethoxy]phenyl}carbonyl)amino]-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0258] (114) 6-({[2-chloro-5-(2-ethoxyethoxy)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0259] (115) 6-({[2-chloro-5-(3-methoxypropyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0260] (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

[0261] (117) 6-({[5-(3-tert-butoxypropyl)-2-chlorophenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0262] (118) 6-({[2-chloro-5-(3-hydroxy-3-methylbutyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0263] (119) 6-({[2-chloro-5-(ethoxymethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0264] (120) 6-[({2-chloro-5-[(2-ethoxyethoxy)methyl]phenyl}carbonyl)amino]-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0265] (121) 6-({[2-chloro-5-(2-cyclopropylethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0266] (122) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(2-phenylethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0267] (123) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0268] (124) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide

[0269] (125) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-cyclopentyl-1H-benzimidazole-4-carboxamide

[0270] (126) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide

[0271] (127) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide

[0272] (128) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide

[0273] (129) N-(3-chloro-2-methylphenyl)-2-[(2S)-5-oxopyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0274] (130) N-(3-chloro-2-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0275] (131) N-(3-chloro-2-methylphenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0276] (132) N-(3-chloro-2-methylphenyl)-2-[2-(dimethylamino)-2-oxoethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0277] (133) N-(3-chloro-2-methylphenyl)-2-[2-(methylamino)-2-oxoethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0278] (134) 2-Chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0279] (135) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0280] (136) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0281] (137) N-(3-chloro-2-methylphenyl)-2-(methylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0282] (138) N-(3-chloro-2-methylphenyl)-2-(ethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0283] (139) N-(3-chloro-2-methylphenyl)-2-[(2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0284] (140) N-(3-chloro-2-methylphenyl)-2-(cyclopentylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0285] (141) N-(3-chloro-2-methylphenyl)-2-(piperidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0286] (142) N-(3-chloro-2-methylphenyl)-2-(4-methylpiperazin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0287] (143) 2-[Bis(2-hydroxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0288] (144) N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0289] (145) N-(3-chloro-2-methylphenyl)-2-{[2-(morpholin-4-yl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0290] (146) N-(3-chloro-2-methylphenyl)-2-{[2-(dimethylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0291] (147) N-(3-chloro-2-methylphenyl)-2-(3-hydroxyazetidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0292] (148) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0293] (149) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0294] (150) N-(3-chloro-2-methylphenyl)-2-{[2-(diethylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0295] (151) N-(3-chloro-2-methylphenyl)-2-{[2-(pyrrolidin-1-yl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0296] (152) N-(3-chloro-2-methylphenyl)-2-{[3-(dimethylamino)propyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0297] (153) N-(3-chloro-2-methylphenyl)-2-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0298] (154) N-(3-chloro-2-methylphenyl)-2-{[2-(dipropan-2-ylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0299] (155) N-(3-chloro-2-methylphenyl)-2-(morpholin-4-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0300] (156) 2-amino-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0301] (157) N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0302] (158) N-(3-chloro-2-methylphenyl)-2-{[(3-methyloxetan-3-yl)methyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0303] (159) N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycine tert-butyl ester

[0304] (160) N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycine

[0305] (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

[0306] (162) N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0307] (163) N-(3-chloro-2-methylphenyl)-2-(pyrrolidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0308] (164) 2-(azetidin-1-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0309] (165) N-(3-chloro-2-methylphenyl)-2-(3-methoxyazetidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0310] (166) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0311] (167) N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0312] (168) N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0313] (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

[0314] (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

[0315] (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

[0316] (172) N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0317] (173) N-(3-chloro-2-methylphenyl)-2-[(3-methoxypropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0318] (174) N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0319] (175) 2-[(2-tert-Butoxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0320] (176) N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0321] (177) N-(3-chloro-2-methylphenyl)-2-{[2-(methylthio)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0322] (178) N-(3-chloro-2-methylphenyl)-2-(methylthio)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0323] (179) N-(3-chloro-2-methylphenyl)-2-(methylsulfonyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0324] (180) N-(3-chloro-2-methylphenyl)-2-(methylsulfinyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0325] (181) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0326] (182) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0327] (183) N-(3-chloro-2-methylphenyl)-6-{[(2,4-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0328] (184) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0329] (185) 6-{[(2-bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0330] (186) 6-{[(2-bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0331] (187) 6-({[2-chloro-5-(cyclopropylethynyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0332] (188) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0333] (189) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0334] (190) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2-hydroxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0335] (191) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2-methoxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0336] (192) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-{[2-(propan-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide

[0337] (193) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide

[0338] (194) 2-[(2-tert-Butoxyethyl)amino]-6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-1H-benzimidazole-4-carboxamide

[0339] (195) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0340] (196) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0341] (197) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-1H-benzimidazole-4-carboxamide

[0342] (198) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-1H-benzimidazole-4-carboxamide

[0343] (199) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0344] (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

[0345] (201) N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0346] (202) N-(4-tert-butylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0347] (203) N-(2,3-dihydro-1H-inden-5-yl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0348] (204) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0349] (205) N-(3-chloro-4-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0350] (206) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0351] (207) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide

[0352] (208) N-(3-chloro-4-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide

[0353] (209) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(1-methylcyclopropyl)-1H-benzimidazole-4-carboxamide

[0354] (210) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(1-methylcyclopropyl)-1H-benzimidazole-4-carboxamide

[0355] (211) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(methylsulfonyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0356] (212) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(2-methoxyethyl)-1H-benzimidazole-4-carboxamide

[0357] (213) 2-(Methoxymethyl)-N-phenyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0358] (214) 2-(Methoxymethyl)-n-propyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0359] (215) 2-(Methoxymethyl)-N-(pyridin-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0360] (216) N-Benzyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0361] (217) N-(cyclohexylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0362] (218) 2-(Methoxymethyl)-N-(naphthalen-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0363] (219) 2-(Methoxymethyl)-N-(thiophen-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0364] (220) N-(2,1,3-Benzothiadiazole-4-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0365] (221) N-(1,1-dioxide-1-benzothiophen-6-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0366] (222) 2-(Methoxymethyl)-N-(thiophen-2-ylmethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0367] (223) N-(1H-indol-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0368] (224) N-(1,3-Benzothiazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0369] (225) N-(2,2-dimethylpropyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0370] (226) 2-(Methoxymethyl)-N-(thiophen-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0371] (227) N-(5-chloro-1,3-benzo oxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0372] (228) N-(2-benzylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0373] (229) 2-(Methoxymethyl)-N-(quinolin-8-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0374] (230) N-(Cycloheptylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0375] (231) N-(1,3-Benzo[2-(4-(4-nitro-1-yl)-1-nitropropene) oxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0376] (232) N-(6-chloro-1,3-benzo oxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0377] (233) N-[3-chloro-2-(hydroxymethyl)phenyl]-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0378] (234) N-(3-chloro-2-methylphenyl)-6-{[(3-fluoropyridin-2-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0379] (235) N-(3-chloro-2-methylphenyl)-6-{[(3-chloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0380] (236) N-(3-chloro-2-methylphenyl)-6-{[(3,5-dichloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0381] (237) 6-{[(5-Butoxy-2-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0382] (238) 6-({[2-chloro-5-(2,2-difluoroethoxy)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide, and

[0383] (239) N-(3-Chloro-2-methylphenyl)-6-({[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide. (9)

[0385] The preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (8) above, wherein

[0386] The mPGES-1 inhibitor is a compound selected from the following, or a tautomer or a pharmaceutically acceptable salt thereof:

[0387] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

[0388] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride,

[0389] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate,

[0390] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate,

[0391] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate,

[0392] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

[0393] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride,

[0394] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate,

[0395] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate,

[0396] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate,

[0397] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

[0398] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride,

[0399] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide methanesulfonate,

[0400] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and

[0401] N-(3-Chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide sulfate.

[0402] (10) A pharmaceutical composition for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome, comprising an mPGES-1 inhibitor and a pharmaceutically acceptable carrier.

[0403] (11) An mPGES-1 inhibitor for use in the prevention and / or treatment of chronic prostatitis / chronic pelvic pain syndrome.

[0404] (12) Use of an mPGES-1 inhibitor in the manufacture of a medicament for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome.

[0405] (13) A method for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome, the method comprising:

[0406] An mPGES-1 inhibitor is administered to a subject in need thereof.

[0407] The above-mentioned structures can be arbitrarily selected and combined.

[0408] Effects of the Invention

[0409] The therapeutic and / or treatment agent of the present invention shows a therapeutic and / or preventive effect on chronic prostatitis / chronic pelvic pain syndrome, and is therefore useful for the treatment and / or prevention of chronic prostatitis / chronic pelvic pain syndrome. BRIEF DESCRIPTION OF THE DRAWINGS

[0410] Figure 1 The results of evaluating the analgesic effects of test compounds 1 to 5 in the autoimmune chronic prostatitis model are shown. DETAILED DESCRIPTION

[0411] Embodiments of the present invention will be described.

[0412] In one embodiment of the present invention, a preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome containing an mPGES-1 inhibitor as an active ingredient is provided.

[0413] In one embodiment of the present invention, the mPGES-1 inhibitor may be a commercially available inhibitor and / or an inhibitor that can be produced by a conventional method in the field of organic synthetic chemistry.

[0414] In one embodiment of the present invention, the mPGES-1 inhibitor can be used directly as a pharmaceutical, or can be used in the form of a pharmaceutically acceptable salt by a known method. Such salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, 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.

[0415] For example, the hydrochloride of the mPGES-1 inhibitor can be obtained by dissolving the mPGES-1 inhibitor in a hydrogen chloride alcohol solution, an ethyl acetate solution or a diethyl ether solution.

[0416] In one embodiment of the present invention, mPGES-1 inhibitor can have chiral carbon, and each optical isomer and their mixture can be used for the prevention and / or therapeutic agent of the present invention.For optical isomer, for example, its alkalescence can be utilized, optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) can be used to carry out optical resolution from the racemate obtained as described later by known method, or optically active compound prepared in advance can be used to manufacture in raw material.In addition, optical resolution, asymmetric synthesis using chiral column can also be manufactured.

[0417] In addition, among mPGES-1 inhibitors, for inhibitors that can form tautomers, each tautomer and a mixture thereof can be used in the preventive and / or therapeutic agent of the present invention.

[0418] In one embodiment of the present invention, the mPGES-1 inhibitor is, for example, a compound of formula [I] (the present compound) or a pharmaceutically acceptable salt thereof. The present compound can be prepared from known compounds and / or easily synthesized intermediates based on the methods described in WO2013 / 024898 and / or known methods.

[0419] In the compound of the above formula [I] (the present compound), each substituent is exemplified as follows.

[0420] Examples of the "halogen" include fluorine, chlorine, bromine and iodine.

[0421] The "alkyl group" includes, for example, a linear or branched alkyl group having 1 to 8 carbon atoms, and specifically includes, for example, 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 them, an alkyl group having 1 to 6 carbon atoms is preferred, and an alkyl group having 1 to 3 carbon atoms is more preferred.

[0422] Examples of the alkyl part of “monoalkylamino”, “dialkylamino”, “monoalkylaminocarbonyl”, “dialkylaminocarbonyl”, “alkylcarbonyloxy”, “alkyloxycarbonyl”, “alkylcarbonyl”, “alkylthio”, “alkylsulfonyl”, “alkylsulfinyl”, “alkoxyalkyl” and “alkoxyalkylamino” include the same groups as mentioned above for the “alkyl”.

[0423] The alkoxy moiety of the "alkoxy" is, for example, a linear or branched alkoxy group having 1 to 8 carbon atoms, and specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, n-heptyloxy and n-octyloxy.

[0424] Examples of the alkoxy moiety of the "alkoxyalkoxy group", "alkoxyalkyl group" and "alkoxyalkylamino group" include the same groups as those mentioned above for the "alkoxy group".

[0425] Examples of the "heteroaryl group" include 1-2-ring aromatic rings having 1-3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms as constituent atoms. Specifically, examples thereof include 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), Azolyl (e.g., 2- Azolyl, 4- Azolyl, 5- oxazolyl), iso Azolyl (e.g., 3-iso Azolyl, 4-iso Azolyl, 5-iso Azolyl), Oxazolyl (e.g., 1,3,4- The invention also includes 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), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., , 2-pyrimidinyl, 4-pyrimidinyl, 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, 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), benzothiophene (e.g., 1-benzothiophene-2-yl, 1-benzothiophene-3-yl, 1-benzothiophene-4-yl, 1-benzothiophene-5-yl, 1-benzothiophene-6-yl, 1-benzothiophene-7-yl), 1,1-dioxo-1-benzothiophene (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 (quinol-2-yl, quinol-3-yl, quinol-4-yl, quinol-5-yl, quinol-6-yl, quinol-7-yl, quinol-8-yl), 1,3-benzo Oxazol-2-yl.

[0426] Examples of the heteroaryl moiety of the "heteroarylmethyl group" include the same groups as those mentioned above for the "heteroaryl group".

[0427] Examples of the “saturated cyclic amino group” include a 4- to 7-membered saturated cyclic amino group having one or two N atoms, which may be substituted with oxygen and may have one O or S atom as a ring atom. Specific examples include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-homopiperazinyl, 2-oxomorpholinyl, Oxazolidin-3-yl.

[0428] Examples of the saturated cyclic amino moiety of the "saturated cyclic aminocarbonyl group" include the same groups as those mentioned above for the "saturated cyclic amino group".

[0429] The “saturated heterocyclic group” includes, for example, a 4- to 6-membered saturated heterocyclic group having one N or O as a ring atom, and specifically includes, for example, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl.

[0430] Examples of the "cycloalkyl group" include a group having 3 to 8 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

[0431] Examples of the cycloalkyl moiety of the "cycloalkylmethyl group" include the same groups as mentioned above in the "cycloalkyl group".

[0432] Examples of the "naphthyl group" include 1-naphthyl and 2-naphthyl.

[0433] Examples of the "pyridyl group" include 2-pyridyl, 3-pyridyl and 4-pyridyl.

[0434] Examples of the “alkynyl group” include linear or branched alkynyl groups having 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.

[0435] In one embodiment of the present invention, the mPGES-1 inhibitor is, for example, the above-mentioned compounds (1) to (239), or tautomers thereof or pharmaceutically acceptable salts thereof, preferably

[0436] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

[0437] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, or

[0438] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide or a pharmaceutically acceptable salt thereof,

[0439] More preferably

[0440] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

[0441] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride,

[0442] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate,

[0443] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, or

[0444] N-(3-Chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride.

[0445] When the present compound or a pharmaceutically acceptable salt thereof is administered in the form of a medicine, the present compound or a pharmaceutically acceptable salt thereof can be administered directly or in the form of a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%, of the compound or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable nontoxic and inactive carrier and administered to mammals including humans.

[0446] As a carrier, one or more of a solid, semi-solid, or liquid diluent, filler, and other prescription adjuvants can be used. The pharmaceutical composition of the present invention is preferably administered in the form of a dosing unit. The pharmaceutical composition can be administered by intra-tissue administration, oral administration, intravenous administration, topical administration (transdermal administration, eye drops, intraperitoneal, intrathoracic, etc.) or rectal administration. Of course, it can also be administered by a dosage form suitable for these administration methods.

[0447] As the dosage of pharmaceuticals, it is preferred to consider the patient's state, route of administration, type of the compound of the present invention, whether it is a salt, type of salt, etc., taking into account age, weight, type of disease, degree, etc., and adjust on the basis of the salt, usually, as the active ingredient amount of the compound of the present invention or its pharmaceutically allowed salt for adults, in the case of oral administration, it is appropriate to be within the range of 0.01mg~5g / adult per day on average, preferably within the range of 1mg~500mg / adult. Depending on the circumstances, it is sometimes sufficient to be below the above range, and sometimes the dosage above the above range is required. Usually, it can be administered once a day or divided into several times, or in the case of intravenous administration, it can be administered quickly or continuously within 24 hours.

[0448] Example

[0449] Hereinafter, the present invention will be described in more detail with reference to reference examples, examples, test examples and preparation examples, but the present invention is not limited thereto.

[0450] The test compounds used in Test Examples 1 and 2 are as follows.

[0451] The compounds used in Test Examples 1 and 2 were prepared and used according to Examples 1 to 249 of WO2013 / 024898. The activity data of the compounds used in Test Examples 1 and 2 are shown in Tables 1 to 17 of WO2013 / 024898.

[0452] Test Example 1 mPGES-1 inhibitory activity test

[0453] mPGES-1 microsomal samples were prepared from CHO-K1 cells transiently transfected with a plasmid encoding human mPGES-1 cDNA. mPGES-1 microsomal samples were diluted in potassium phosphate buffer pH 7.4 containing reduced glutathione, and a DMSO solution of the test compound or DMSO (final DMSO concentration of 1%) was added and incubated at 4°C for 20 minutes. The enzyme reaction was then initiated by adding a solution of PGH2 substrate adjusted to a final concentration of 1 μM and incubated at 4°C for 60 seconds. The reaction was terminated by adding ferric chloride and citrate solutions (final concentrations of 1 mg / mL and 50 mM, respectively). The PGE2 formed was quantified using an HTRF kit (Cisbio International catalog #62P2APEC). A solution without the test compound was used as a positive control, and a solution without the test compound and microsomal sample was used as a negative control. 100% activity was defined as the PGE2 produced in the positive control minus the PGE2 produced in the negative control. Next, IC50 values ​​were determined using standard methods.

[0454] Test Example 2 PGE2 and PGF2α production inhibition test using A549 cells

[0455] 2×10 human A549 cells were inoculated at 100 μL / well (96-well plate). 4, incubate overnight. Then, remove the culture medium, wash with phosphate buffered saline solution, and replace with 3% FBS-containing DMSO solution or DMSO (DMSO final concentration is 0.1%) RPMI culture medium. After incubation for 60 minutes, add IL-1β (5ng / well) and incubate at 37°C for 24 hours. Then, use the HTRF kit (Cisbio International product catalog #62P2APEC) to quantify PGE2 in the culture medium, and use the EIA kit (Cayman chemical company product catalog #516011) to quantify PGF2α. Use a solution without the test compound as a positive control, and a solution without the test compound and IL-1β as a negative control. 100% activity is defined as the amount of PGE2 and PGF2α produced in the positive control after subtracting the amount of PGE2 and PGF2α produced in the negative control. Then, the IC50 value was determined using a standard method.

[0456] The test compounds used in Test Examples 3 to 8 are as follows.

[0457] Test compound 1 and test compound 2:

[0458] According to the description of Example 239 and Example 89 of WO2013 / 024898, 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 (hereinafter also referred to as test compound 1 and test compound 2) were prepared and used.

[0459] Test compound 3:

[0460] Test compound 3: N-cyclopentyl-1-(1-isopropyl-5,6-dimethyl-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared and used according to the description of Example 9 of WO2011 / 023812.

[0461] Test compound 4:

[0462] Test compound 4: N-[4-chloro-3-(5-cyano-6-oxo-4-thiophen-3-yl-1,6-dihydropyrimidin-2-yl)benzyl]-2,2-dimethylpropanamide was prepared and used according to the description of Example 2 of WO2017 / 073709.

[0463] Canephron (registered trademark) N was purchased from the market and used.

[0464] <Test Example 3: Evaluation of analgesic effect in autoimmune chronic prostatitis model>

[0465] As a chronic prostatitis model, a commonly used model, ie, an experimental autoimmune prostatitis (EAP) model was used, and the analgesic effects of the test compounds 1 to 4 were evaluated according to the following method.

[0466] 1. Preparation method of prostate specific antigen (PAg)

[0467] The prostate of male Wistar rats aged 14 weeks (manufactured by Japan SLC) was removed, cOmplete (trademark) Mini, EDTA-free (Cat. No. 11836170001, manufactured by Roche Diagnostics GmbH) was added, and homogenized in ice-cold PBS (Cat. No. 045-29795, manufactured by FUJIFILM Wako Chemicals) using a handheld microhomogenizer (NS-310E, manufactured by MICROTEC), and then centrifuged at 10000×g and 4°C for 30 minutes using a centrifuge (Allegra X-30R, manufactured by Beckman Coulter), and the supernatant was recovered. The protein concentration was quantified using a DC (trademark) protein assay kit (Cat. No. 500-0112, manufactured by BIO-RAD Laboratories) and an ELISA reader SpectraMax (registered trademark) M5 (manufactured by Molecular Devices), and then stored at -20°C.

[0468] 2. EAP model preparation method

[0469] PAg was mixed with complete Freund's adjuvant (Complete Freund's adjuvant, Cat. No. 263810, manufactured by Becton Dickinson) in equal amounts to prepare an emulsion with a PAg protein concentration of 5 mg / 250 μL. Under isoflurane anesthesia, 250 μL of the emulsion prepared above was intradermally administered to the soles of both hind limbs and the base of the tail of 9-week-old male Wistar rats (manufactured by Japan SLC) for primary immunization. 28 days after the primary immunization, the same treatment was performed as a booster immunization. The sham treatment group was administered an emulsion prepared by mixing equal amounts of physiological saline solution (Cat. No. 35081517, manufactured by Otsuka Pharmaceutical Co., Ltd.) and complete Freund's adjuvant (reference: Prostate. 2018 Nov; 78 (15): 1157-1165.).

[0470] 3. Grouping method

[0471] 37 days after the first immunization, the pre value was measured using the following pain evaluation method, and the groups were divided so that there were no significant differences in the pain response rate and AUC at each stimulation intensity. The groups were divided by stratified random allocation using SAS version 9.3 and EXSUS version 8.1.

[0472] 4. Pain assessment method

[0473] After 42 days from the initial immunization, the test substance was prepared into 100 mg / kg as a free body with 0.5% methylcellulose aqueous solution as a medium, and was orally administered with 10 mL / kg. Pain evaluation was performed 4 hours after administration. Before evaluation, rats were placed on a wire mesh for 30 minutes to adapt. From the bottom of the wire mesh, 0.4, 1, 4g of these 3 von Frey fibers (Touch Test (registered trademark), Cat.No.NC12775-06, NC12775-08, NC12775-11, North Coast Medical company system) with different stimulation intensities were pressed to the lower abdomen of the rat for 1 to 2 seconds to observe whether there was an escape reaction (escape, licking the stimulation site, etc.). From the fiber with weak stimulation intensity, 5 stimulations were performed successively under each stimulation intensity, and the ratio of escape reaction was calculated, as the escape reaction rate (%), and the area under the curve (AUC) was calculated according to the line graph made by the stimulation intensity and the escape reaction rate.

[0474] 5. Statistical Analysis

[0475] Summary statistics calculation 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 calculated, and Student's t-test was performed between the Sham group and the EAP model-vehicle administration group, and between the EAP model-vehicle administration group and the EAP model-drug administration group.

[0476] 6. Test results

[0477] The analgesic effects of test compounds 1 to 5 in the EAP model are shown in Figure 1 .

[0478] <Test Example 4: Evaluation of the anti-inflammatory effect of normal human prostate stromal cells>

[0479] 1. Cell Culture

[0480] Normal human prostate stromal cells (WPMY-1 cells, Cat. No. CRL-2854 (trademark)) purchased from ATCC (registered trademark) were subcultured using a proliferation medium at 37°C and 5% CO2. As a proliferation medium, DMEM (Cat. No. 08458-45, Nacalai Tesque) containing a final concentration of 5% inactivated fetal bovine serum (Cat. No. SH30910, manufactured by GE Healthcare), a final concentration of 20 U / mL of penicillin and 20 μg / mL of streptomycin (penicillin-streptomycin mixed solution, Cat. No. 26253-84, manufactured by Nacalai Tesque) was used.

[0481] 2. Cell seeding and drug treatment

[0482] One day before treatment with each test compound, WPMY-1 cells were suspended in a proliferation medium and seeded in a Falcon (registered trademark) cell culture 12-well multiwell plate (Cat. No. 353043, manufactured by Corning) at a density of 57,000 cells / well. The WPMY-1 cells seeded in the 12-well plate were cultured overnight at 37°C and 5% CO2.

[0483] On the day after inoculation, each test substance was treated. First, DMSO (Cat. No13445-74, Nacalai Tesque) was used to prepare a 10mM DMSO solution, which was diluted to 10μM using an analysis medium. Among them, Canephron prepared a 1000mg / mL DMSO solution and diluted it to 1000μg / mL with an analysis medium. As an analysis medium, DMEM (Cat. No. 08458-45, Nacalai Tesque) containing a final concentration of 2% inactivated fetal bovine serum (Cat. No. SH30910, GE Healthcare), a final concentration of 20U / mL penicillin and 20μg / mL streptomycin (penicillin-streptomycin mixed solution, Cat. No. 26253-84, Nacalai Tesque) was used. After removing the proliferation medium and replacing it with an analysis medium containing each test substance, it was cultured for 24 hours at 37°C and 5% CO2.

[0484] 3. Cytokine stimulation

[0485] After 24 hours of treatment with each test substance, cytokine stimulation was performed. Prepare an analysis medium containing 1 ng / mL of IL-17 (Cat.No.200-17, Pepro Tech), TNF-α (Cat.No.300-01A, Pepro Tech), and IFN-γ (Cat.No.300-02, Pepro Tech) as a cytokine stimulation medium. Using a cytokine stimulation medium, each test substance was diluted by the same method as the previous day, and the cells were treated with each test substance and cytokine. The cells were cultured for 5 hours at 37 ° C and 5% CO2, and the cells were recovered.

[0486] 4. Gene Expression Analysis

[0487] Total RNA was extracted from cells using RNeasy (registered trademark) Mini Kit (Cat. No. 74106, manufactured by Qiagen) according to the manufacturer's protocol, and the RNA concentration was measured using NanoDrop (trademark) ONE (Cat. No. ND-ONE-W, manufactured by Thermoscientific). 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). The gene expression level of CCL2 was evaluated using cDNA obtained by reverse transcription and TB Green (registered trademark) Premix Ex TaqII (Cat. No. RR820, manufactured by Takara Bio) and LightCycler (registered trademark) 480 Real-Time PCR System (manufactured by Roche Diagnostics GmbH). Primers used for CCL2 were: Fw: AGCAGCAAGTGTCCCAAAGA and Rv: GGTGGTCCATGGAATCCTGA.

[0488] The change rate was calculated by calculating the ratio of the mRNA level of each treatment group to the value of the NT (no treatment) group using the Δ threshold cycle (Ct) method (2-ΔΔCt). All data were corrected by GAPDH. The PCR conditions were 95°C for 10 minutes, followed by 45 cycles of 95°C for 15 seconds and 60°C for 1 minute.

[0489] 5. Test results

[0490] The test compound inhibited the expression of inflammatory cytokines / chemokines (CCL2) in normal human prostate stromal cells (WPMY-1 cells), showing anti-inflammatory effects (Table 1).

[0491]

[0492] <Test Example 5: Evaluation of anti-inflammatory effects in autoimmune chronic prostatitis model>

[0493] 1. Protein Solution Preparation

[0494] EAP model rats were prepared in the same manner as in Test Example 1, and the test substance was administered 42 days after the first immunization. 42 days after the first immunization, the ventral lobe of the prostate was collected, placed in a 2 mL tube, frozen with liquid nitrogen, and stored at -80°C.

[0495] To a 2 mL tube containing the prostate was added cOmplete (trademark) Mini, EDTA-free T-PER (Cat. No. 78510, manufactured by Thermo Scientific) based on the weight of 100 mg of prostate tissue, and the mixture was homogenized using a handheld microhomogenizer (NS-310E, manufactured by MICROTEC). The mixture was centrifuged at 14,000 × g and 4°C for 30 minutes using himac (registered trademark) CT15RE (manufactured by Koki Holdings), and the supernatant was recovered to prepare a protein solution.

[0496] 2. Cytokine / Chemokine Quantification

[0497] Cytokine detection kit (Rat 23-plex panel) and Bio-Plex system (Bio-Rad) were used to measure the amount of 23 cytokines / chemokines according to the manufacturer's protocol. In addition, the total protein amount was quantified using DC (trademark) proteinassay kit (Cat.No.500-0112, BIO-RAD Laboratories) and microplate reader SpectraMax (registered trademark) M5 (BIO-RAD Laboratories Molecular Devices), and then the cytokine / chemokine concentration per 1 mg of total protein was calculated.

[0498] 2. Test results

[0499] The test compound inhibited the expression of inflammatory cytokines / chemokines (IL-1β, CCL2, CCL3, CCL5) in the EAP model, showing an anti-inflammatory effect.

[0500] <Test Example 6: Evaluation of analgesic effect in hormone / castration-induced prostatitis (HCP) model>

[0501] 1.HCP model preparation method

[0502] Retired male Wistar rats (manufactured by Charles River Laboratories Japan) were castrated under isoflurane anesthesia, and 17β-estradiol (Cat. No. 14541-61, manufactured by Nacalai Tesque) was subcutaneously administered at 2 mL / kg using sesame oil (Cat. No. S3547, manufactured by Sigma-Aldrich) as a medium, once a day for 30 days from the day of surgery. The sham treatment group underwent sham surgery and was similarly administered with sesame oil as a medium (reference: Prostate. 2019 Apr; 79(5): 446-453.).

[0503] 2. Drug disposal

[0504] The test substances were administered for 30 days starting from the day of surgery.

[0505] 3. Pain assessment method

[0506] Evaluation was performed by the same method as in Test Example 3.

[0507] 4. Statistical Analysis

[0508] Evaluation was performed by the same method as in Test Example 3.

[0509] 5. Test results

[0510] The test compounds showed analgesic effects in the HCP model.

[0511] <Test Example 7: Evaluation of analgesic effect in formalin-induced prostatitis model>

[0512] 1. Preparation of formalin-induced prostatitis model

[0513] Under isoflurane anesthesia, the lower abdomen of 7-week-old male SD rats (manufactured by Japan SLC) was incised midline to expose the prostate, and 25 μL of a 5% formalin solution prepared by mixing equal amounts of 10% neutral buffered formalin solution (Cat. No. 062-01661, manufactured by FUJIFILM Wako Chemicals) and physiological saline solution (Cat. No. 35081517, manufactured by Otsuka Pharmaceutical Co., Ltd.) was injected into each of the left and right ventral lobes of the prostate. The rats were then sutured and 15 mg / kg of the antibiotic cephalexin (Cat. No. 034-11052, manufactured by FUJIFILM Wako Chemicals) was subcutaneously administered. In the sham-treated group, 25 μL of physiological saline solution was injected into each of the left and right ventral lobes of the prostate (reference: Int Neurourol J. 2018 Jun; 22(2): 90-98.).

[0514] 2. Drug disposal

[0515] The test substance was administered twice a day for 7 days starting from the day of model preparation.

[0516] 3. Pain assessment method

[0517] Evaluation was performed by the same method as in Test Example 1 7 days after the model preparation.

[0518] 4. Statistical Analysis

[0519] Evaluation was performed by the same method as in Test Example 3.

[0520] 5. Test results

[0521] The test compound showed analgesic effect in the formalin-induced prostatitis model.

[0522] Test Example 8: Evaluation of PGE2 production in prostate epithelial cells derived from patients with prostatic hypertrophy

[0523] 1. Cell Culture

[0524] At 37°C, 5% CO2, prostate epithelial cells (BPH-1 cells, Cat. No. ACC143) derived from patients with prostatic hypertrophy purchased from DSMZ were subcultured using proliferation culture medium. As proliferation culture medium, RPMI-1640 (Cat. No. 189-02025, FUJIFILM Wako Chemicals) containing 20% ​​inactivated fetal bovine serum (Cat. No. SH30910, GE Healthcare), 20 ng / mL testosterone (Cat. No. 32811-61, Nacalai Tesque), 4.2 μg / mL recombinant human insulin, 3.8 μg / mL human transferrin, and 5 ng / mL sodium selenite (insulin-transferrin-sodium selenite culture medium supplement, Cat. No. 11884, Sigma-Aldrich) was used.

[0525] 2. Cell seeding and drug treatment

[0526] One day before treatment with each test compound, BPH-1 cells were suspended in a growth medium and seeded in a Falcon (registered trademark) cell culture 96-well multiwell plate (Cat. No. 353072, manufactured by Corning) at a density of 9,600 cells / well. Control wells were seeded with cells using a control medium. As control culture medium, RPMI-1640 (Cat. No. 189-02025, FUJIFILM Wako Chemicals) 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) at a final concentration of 20 ng / mL, 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 (insulin-transferrin-sodium selenite culture medium supplement, Cat. No. 11884, manufactured by Sigma-Aldrich) at a final concentration of 5 ng / mL was used. BPH-1 cells seeded in 96-well plates were cultured overnight at 37° C., 5% CO2.

[0527] On the day after inoculation, each test substance was treated. First, 10 mM DMSO solution was prepared using DMSO (Cat. No13445-74, manufactured by Nacalai Tesque) and diluted to 10, 1, and 0.1 μM using a proliferation medium. The proliferation medium or control medium was removed, and the proliferation medium containing each test substance or the control well was replaced with a control medium not containing the test substance, and then cultured for 48 hours at 37 ° C and 5% CO2, and the supernatant was recovered.

[0528] 3. PGE2 Amount Determination

[0529] The amount of PGE2 in the cell culture supernatant was measured using Prostaglandin E2 kits (Cat. No. 62P2APEG, manufactured by Cisbio) and microplate reader SpectraMax (registered trademark) M5 (manufactured by Molecular Devices) according to the manufacturer's protocol.

[0530] 4. Test results

[0531] The test compounds inhibited the production of PGE2 in BPH-1 cells.

[0532] Preparation Example 1

[0533] Tablets (oral tablets)

[0534] In prescription 1 tablet 80 mg

[0535] Test compound 5.0 mg

[0536] Corn starch 46.6mg

[0537] Crystalline cellulose 24.0 mg

[0538] Methylcellulose 4.0mg

[0539] Magnesium stearate 0.4mg

[0540] The mixed powder of this ratio is compressed into tablets by a common method to prepare oral tablets.

[0541] Industrial Applicability

[0542] The present invention relates to a method for preventing and treating chronic prostatitis / chronic pelvic pain syndrome containing an mPGES-1 inhibitor as an effective ingredient.

[0543] Preventive and / or therapeutic agent with industrial applicability.

Claims

1. Use of an mPGES-1 inhibitor in the manufacture of a pharmaceutical product for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome, wherein: The mPGES-1 inhibitor is selected from the following compounds, or tautomers thereof or pharmaceutically acceptable salts thereof: (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and (88) N-(3-Chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide.

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