AGONIST EP4

Abstract

A compound represented by general formula (I) (wherein all symbols have the same meanings as the symbols described in the specification) or a pharmaceutically acceptable salt thereof is useful as an EP4 agonist, particularly has an EP4 agonistic activity, has selectivity for other PGE receptor subtypes, and has a smaller risk of toxicity to the circulatory system. Therefore, the compound or the pharmaceutically acceptable salt thereof is useful as a medicinal ingredient in the prevention and / or treatment of diseases associated with EP4 receptors.

Description

EP4 agonist

[0001] The present disclosure relates to a compound having EP4 agonistic activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical containing the compound or a salt thereof as an active ingredient.

[0002] (wherein all symbols have the same meaning as defined below), or a pharmaceutically acceptable salt thereof (hereinafter referred to as the disclosed compound), and a pharmaceutical composition containing the same as an active ingredient.

[0003] Prostaglandin E2 (abbreviated as PGE2) is known as a metabolic product in the arachidonic acid cascade, and its effects are known to be cytoprotective, uterine contractile, analgesic, promoting peristalsis of the digestive tract, stimulating, inhibiting gastric acid secretion, lowering blood pressure, and diuretic.

[0004] It is known that there are subtypes of PGE receptors, each with a different role, and the currently known subtypes are roughly divided into four, called EP1, EP2, EP3, and EP4 (Non-Patent Document 1).

[0005] The EP4 receptor is thought to be involved in the suppression of TNF-α production and the enhancement of IL-10 production, and therefore compounds that bind to the EP4 receptor are thought to be useful for the prevention and / or treatment of diseases such as immune diseases (autoimmune diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, and systemic lupus erythematosus, and rejection after organ transplantation), asthma, neuronal cell death, arthritis, lung injury, pulmonary fibrosis, emphysema, bronchitis, chronic obstructive respiratory disease, liver injury, acute hepatitis, nephritis (acute nephritis, chronic nephritis), renal failure, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis, hemophagocytic syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burns, systemic granuloma, inflammatory bowel diseases (ulcerative colitis, Crohn's disease, etc.), hypercytokinemia during dialysis, multiple organ failure, and shock. Furthermore, the EP4 receptor is also involved in mucosal protective action (Non-Patent Document 2), and is thought to be useful in the prevention and / or treatment of gastrointestinal ulcers such as gastric ulcers and duodenal ulcers, and stomatitis.

[0006] Compounds that selectively bind to EP4 do not cause pain thought to be caused by EP1 or uterine contraction thought to be caused by EP3, and are therefore thought to be drugs that do not affect these.

[0007] Many compounds with EP4 agonist activity have been discovered to date, but when administered systemically, such as orally or intravenously, there are concerns that they may have effects on the circulatory system, such as lowering blood pressure and increasing heart rate (Non-Patent Document 3).

[0008] On the other hand, Patent Document 1 describes that a compound represented by the following general formula (A) is a compound having EP4 agonist activity.

[0009] General formula (A) is (In the formula, Q Ａ is CH ２ or an oxygen atom; B Ａ Ha-CH ２ - group, -(CH ２ ) ２ - group, -(CH ２ ) ３ - group, -(CH ２ ) ４ - group, -(CH ２ ) ５ - group, -CH=CH- group, -CH ２ -CH=CH- group, CH=CH-CH ２ - group, or -CH ２ -CH=CH-CH ２ - group, provided that B Ａ is a -CH=CH- group or a -CH=CH-CH ２ When Q is a - group, Ａ Ha-CH ２ - group; X Ａ is -NR ａＡ - group (where R ａＡ is a hydrogen atom, a halogen atom, an alkyl group or an acyl group), an —O— group, an —S— group, an —SO— group, an —SO ２ - group or a single bond, provided that X Ａ When Q is a single bond, Ａ is an oxygen atom; J Ａ is -(CR ｂＡ RｃＡ ) ｎＡ - group (where nA is an integer from 1 to 4 and R ｂＡ and R ｃＡ are both hydrogen atoms, or R ｂＡ and R ｃＡ one or both of R are lower alkyl groups and the rest are hydrogen atoms, or R ｂＡ and R ｃＡ when attached to the same atom, form a C2-C5-polymethylene group), or —CH ２ A is a —CH═CH— group; Ａ is -CH ２ -CH ２ - group, -CH=CH- group, or -C≡C- group; Z Ａ is CH ２ OH group, -C(O)OR' group, -C(O)NR'R'' group, -C(O)NSO ２ R' group, -P(Cl-C6) alkyl(O)(OR') group, (-PO(OR') ２ or a tetrazol-5-yl group, where R′ and R″ are each independently a hydrogen atom or an alkyl group; nA is 1, 2, 3, or 4; R １Ａ is -(CH ２ ) ｐＡ R ７Ａ group or -(CH ２ ) ｑＡ OR ８Ａ group, where R ７Ａ and R ８Ａ are each independently an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; pA and qA are each independently 0, 1, 2, 3, 4, or 5; R ２Ａ is a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group; R ３Ａ , R ４Ａ , R ５Ａ and R ６Ａ and each independently represent a hydrogen atom or an alkyl group.

[0010] Furthermore, Patent Document 2 discloses that the compound represented by the following general formula (B) has EP4 agonistic activity.

[0011] General formula (B) is (In the formula, R １９－３Ｂ and R ２０－３Ｂ each independently represents a hydrogen atom, an alkyl group, or a halogen atom; T ３Ｂ represents an oxygen atom or a sulfur atom, X ３Ｂ is -CH ２ represents a — group, an —O— group, or an —S— group; ３Ｂ A １－３Ｂ or A ２－３Ｂ represents, １－３Ｂ represents an alkylene group, an alkenylene group, or an alkynylene group which may be substituted with an alkyl group; A ２－３Ｂ Ha-G １－３Ｂ -G ２－３Ｂ -G ３－３Ｂ represents a - group, １－３Ｂ represents an alkylene group or the like, G ２－３Ｂ is -Y ３Ｂ - group, -(ring1 ３Ｂ )-group, -Y ３Ｂ - (ring 1 ３Ｂ )- group, etc., and Y ３Ｂ represents an -S- group, etc., ３－３Ｂ represents a single bond, an alkylene group, an alkenylene group, an alkynylene group, or the like; D ３Ｂ is D １－３Ｂ or D ２－３Ｂ represents D １－３Ｂ represents a —COOH group, —COOR ２－３Ｂ group, a tetrazol-5-yl group, or CONR ３－３Ｂ SO ２ R ４－３Ｂ represents a group, and D ２－３Ｂ is -CH ２ OH group, -CH ２ OR ５－３Ｂ group, hydroxyl group, -OR ５－３Ｂ group, formyl group, -CONR ６－３Ｂ R ７－３Ｂ group, -CONR ６－３Ｂ SO ２ R ８－３Ｂrepresents a group, etc., ３Ｂ Is E １－３Ｂ or E ２－３Ｂ represents E １－３Ｂ is a cycloalkyl group, or ring 3 ３Ｂ represents E ２－３Ｂ is a cycloalkyl group, ring 4 ３Ｂ , or ring5 ３Ｂ represents ring1 ３Ｂ , and ring5 ３Ｂ is R ２１－３Ｂ and / or R ２２－３Ｂ ring3 may be substituted with ３Ｂ is R ２１－３Ｂ ring4 may be substituted with ３Ｂ There must be one R ２２－３Ｂ and further substituted with R ２１－３Ｂ and / or R ２２－３Ｂ may be substituted with R ２１－３Ｂ represents an alkyl group, an alkoxy group, a halogen atom, a phenyl group, or the like; R ２２－３Ｂ represents an alkenyl group, an alkynyl group, an alkylthio group, a hydroxyl group, -NR ２４－３Ｂ R ２５－３Ｂ group, an alkyl group substituted with an alkoxy group, an alkyl group substituted with an alkoxy group substituted with a halogen atom, —NR ２４－３Ｂ R ２５－３Ｂ an alkyl group substituted with a group, ring6 ３Ｂ , -O-ring7 ３Ｂ , ring7 ３Ｂ an alkyl group substituted with ３Ｂ an alkoxy group substituted with —O-ring7 ３Ｂ an alkyl group substituted with —COOR ２６－３Ｂ ring1 represents a group, etc. ３Ｂ , ring5 ３Ｂ , ring 6 ３Ｂ , and ring7 ３Ｂrepresents a C3-15 monocyclic, bicyclic or tricyclic carbocyclic aryl which may be partially or fully saturated, or a 3-15 membered monocyclic, bicyclic or tricyclic heterocyclic aryl which contains 1 to 4 heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms and which may be partially or fully saturated, ３Ｂ and ring 4 ３Ｂ represents a thienyl group, a phenyl group, or a furyl group. (Partial excerpts of the group definitions are given below.)

[0012] Furthermore, Patent Document 3 discloses that the compound represented by the following general formula (C) is a compound having EP2 and EP4 agonist activity.

[0013] General formula (C) is (In the formula, T Ｃ represents an oxygen atom or a sulfur atom, X Ｃ is -CH ２ represents a — group, an —O— group, or an —S— group; Ｃ is A １Ｃ or A ２Ｃ represents, １Ｃ represents an alkylene group, an alkenylene group, or an alkynylene group which may be substituted with an alkyl group; A ２Ｃ Ha-G １Ｃ -G ２Ｃ -G ３Ｃ represents a - group, １Ｃ represents an alkylene group or the like; G ２Ｃ is -Y Ｃ - group, - ring 1 Ｃ - group, -Y Ｃ - Ring 1 Ｃ - group, etc., and Y Ｃ represents an —S— group, etc., and G ３Ｃ represents a single bond, an alkylene group, an alkenylene group, an alkynylene group, or the like; D Ｃ is D １Ｃ or D ２Ｃ represents D １Ｃ represents a —COOH group, —COOR ２Ｃ group, a tetrazol-5-yl group, or a -CONR ３Ｃ SO ２ R ４Ｃ represents a group, and D２Ｃ is -CH ２ OH group, -CH ２ OR ５Ｃ group, hydroxyl group, -OR ５Ｃ group, formyl group, -CONR ６Ｃ R ７Ｃ group, -CONR ６Ｃ SO ２ R ８Ｃ represents a group, etc., Ｃ Is E １Ｃ or E ２Ｃ represents E １Ｃ teeth represents R １１Ｃ represents an alkyl group, an alkylthio group, an alkyl group substituted with a cycloalkyl group, a ring 2 Ｃ an alkyl group substituted with -W １Ｃ -W ２Ｃ - Ring 2 Ｃ represents an alkyl group substituted with W １Ｃ represents an —O— group, an —S— group, an —SO— group, or an —SO ２ - group, -NR １１－１Ｃ - group, carbonyl group, -NR １１－１Ｃ SO ２ represents a - group, a carbonylamino group, or an aminocarbonyl group; W ２Ｃ represents a single bond or an optionally substituted alkyl group, and Ring 1 Ｃ , or ring 2 Ｃ is 1 to 5 R Ｃ and R Ｃ represents an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, a halogen atom, a hydroxyl group, a nitro group, -NR １５Ｃ R １６Ｃ group, an alkyl group substituted with an alkoxy group, an alkyl group substituted with a halogen atom, an alkyl group substituted with an alkoxy group substituted with a halogen atom, —NR １５Ｃ R １６Ｃ alkyl group substituted with a group, ring 5 Ｃ group, -O- ring 5 Ｃ group, ring 5 Ｃ alkyl group substituted with a group, ring 5 Ｃ Alkenyl group substituted with a group, ring 5 Ｃ Alkynyl group substituted with a group, ring 5Ｃ an alkoxy group substituted with a group, —O-ring 5 Ｃ an alkyl group substituted with a COOR group; １７Ｃ a group, an alkoxy group substituted with a halogen atom, a formyl group, an alkyl group substituted with a hydroxy group, or an acyl group; Ｃ may be substituted with a substituent selected from the following: an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkyl group substituted with an alkoxy group, a halogen atom, a hydroxyl group, an alkyl group substituted with a halogen atom, or an alkyl group substituted with an alkoxy group substituted with a halogen atom; Ｃ , ring 2 Ｃ , and ring 5 Ｃ each independently represents (1) a C3-15 monocyclic, bicyclic, or tricyclic carbocyclic aryl which may be partially or fully saturated, or (2) a 3-15-membered monocyclic, bicyclic, or tricyclic heterocyclic aryl which may be partially or fully saturated and contains heteroatoms selected from 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms, and / or 1 to 2 sulfur atoms (the definition of the group is partially excerpted).

[0014] Furthermore, Patent Document 4 describes that the compound represented by the following general formula (D) is a compound having EP2 and EP4 agonist activity.

[0015] General formula (D) is (In the formula, D Ｄ Ha-COOR １Ｄ or a tetrazolyl group, R １Ｄ represents a hydrogen atom or an alkyl group, G Ｄ is ring A Ｄ or an alkylene group; Ｄ teeth (In the formula, R ２Ｄ represents a halogen atom, an alkyl group, or an alkoxy group; Ｄ represents a bond or -S-, T Ｄ represents an oxygen atom or a sulfur atom, and X Ｄ Ha-CH ２ represents -, -O- or -S-; ring B Ｄrepresents an optionally substituted C3-7 cycloalkyl group, (In the formula, R ３Ｄ represents a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxy group which may be substituted by a halogen atom, an alkyl group substituted by an alkoxy group, a phenyl group, or a 3- to 15-membered monocyclic, bicyclic, or tricyclic heterocyclic ring which may be partially or completely saturated; R ３Ｄ The phenyl group or heterocyclic ring in the formula (I) may be substituted with a halogen atom, an alkyl group, an alkoxy group, and / or a nitro group. ), and nD represents an integer of 1 to 4. (Partial excerpt of the definition of the group.)

[0016] Furthermore, Patent Document 5 describes that the compound represented by the following general formula (E) is a compound having EP4 agonist activity.

[0017] The general formula (E) is (In the formula, L １Ｅ represents a) an alkylene group, an alkenylene group, or an alkynylene group, wherein the alkylene group, alkenylene group, or alkynylene group is optionally substituted with 1 to 4 fluorine substituents; b) —(CH ２ ) ｔＥ -G Ｅ - (CH ２ ) ｐＥ -, where tE represents 0 to 2, pE represents 0 to 3, and tE + pE = 0 to 4, or c) -(CH ２ ) ｎＥ -G １Ｅ - (CH ２ ) ｐＥ -, -(CH ２ ) ｎＥ -G ２Ｅ - (CH ２ ) ｐＥ -, -(CH ２ ) ｎＥ -C≡C-G ２Ｅ - or -(CH ２ ) ｎＥ -C(R １２Ｅ ) = C(R １２Ｅ )-G ２Ｅ-, where nE represents 1 to 5, pE represents 0 to 3, and nE+pE=1 to 6; G Ｅ teeth G １Ｅ O, CO, S, SO, SO ２ , or NR ７Ｅ represents ２Ｅ teeth Here, G ２Ｅ may be optionally substituted with 1 to 3 substituents selected from the group consisting of an alkyl group, a haloalkyl group, a cyano group, a halogen atom, an alkoxy group, and a haloalkoxy group; R １Ｅ is COOR ９Ｅ Group, CONR ９Ｅ R １０Ｅ Group, CH ２ OR ９Ｅ Group, SO ３ R ９Ｅ Group, SO ２ NR ９Ｅ R １０Ｅ group, PO(OR ９Ｅ ) ２ group or a tetrazol-5-yl group; L ３Ｅ Ha-C(R ２Ｅ ) ２ -C(R ３Ｅ ) ２ - group, -C(R ２Ｅ ) = C(R ３Ｅ )- group, a -C≡C- group, or represents R ４Ｅ and R ５Ｅ each independently represents H or an alkyl group, or R ４Ｅ and R ５Ｅ may form a cycloalkyl group together with the carbon atom to which they are attached, L ２Ｅ represents an alkylene group or an alkenylene group, wherein the alkylene group and alkenylene group may be optionally substituted with 1 to 4 fluorine substituents; R ６Ｅrepresents an aryl group or a heteroaryl group, wherein the aryl group or heteroaryl group may be optionally substituted with 1 to 4 substituents selected from the group consisting of an alkyl group, a haloalkyl group, a cyano group, a halogen atom, an alkoxy group, a haloalkoxy group, and an -alkylene-alkoxy group, and rE represents 0 or 1. (This is an excerpt from the definition of the group.)

[0018] International Publication No. 2003 / 007941 Pamphlet International Publication No. 2003 / 009872 Pamphlet International Publication No. 2003 / 074483 Pamphlet International Publication No. 2004 / 065365 Pamphlet International Publication No. 2014 / 144610 Pamphlet

[0019] J. Lipid Mediators Cell Signaling, 379-391 (1995) The Journal of Clinical Investigation, 883-893 (2002) International Heart Journal, 107-114 (2017)

[0020] The objectives of the present disclosure include providing a compound useful as an EP4 agonist, in particular a compound having EP4 agonist activity, selectivity over other PGE receptor subtypes, and a reduced risk of cardiovascular toxicity.

[0021] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors have found that the compound represented by the general formula (I) described below is useful as an EP4 agonist, and that despite having particularly potent EP4 agonist activity, it has excellent selectivity for the large intestine and therefore has the property of having a low risk of toxicity to the circulatory system.

[0022] In one aspect, the present disclosure provides a compound comprising: [1] a compound of general formula (I): (In the formula, R １ (1) -OH group, (2) -NHCH ２ CH ２ SO ３ H group, (3)-NHCH ２ COOH group, or (4) —NHCH(COOH)CH ２ CH ２ represents a COOH group, L１ represents (1) a thiazole ring, or (2) a C1-4 alkylene; ２ represents (1) a C3-5 alkylene or (2) a benzene ring; X represents (1) -CO-, (2) -NR Ｘ -, or (3) represents a sulfur atom, R Ｘ represents (1) a hydrogen atom or (2) a C1-4 alkyl group; ２ is (1) a methyl group, (2) a benzene ring, (3) a 5- to 10-membered heterocycle, or (4) -COR ２－１ (5) a —CO— (benzene ring) group, (6) a —CO— (5- to 10-membered heterocyclic) group, (7) a —NH— (benzene ring) group, or (8) a —OH group; R ２ represents a benzene ring, a 5- to 10-membered heterocyclic ring, a —CO— (benzene ring) group, a —CO— (5- to 10-membered heterocyclic ring) group, or a —NH— (benzene ring) group, the benzene ring or the 5- to 10-membered heterocyclic ring may be selected from the group consisting of 1 to 5 R ２－２ and R ２－１ represents (1) a C1-4 alkyl group optionally substituted with a C1-4 alkoxy group, or (2) a —NH—(C1-4 alkyl) group; R ２－２ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a C1-4 haloalkoxy group, or (6) a benzene ring.) or a pharmaceutically acceptable salt thereof, [2] a pharmaceutical composition comprising the compound according to [1] above or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutically acceptable carrier, [3] the pharmaceutical composition according to [2] above, which is an EP4 agonist, etc.

[0023] The disclosed compound is useful as an EP4 agonist, and in particular has EP4 agonist activity and selectivity for other PGE receptor subtypes. Furthermore, the disclosed compound has excellent colon selectivity, so there is little risk of circulatory system toxicity. The disclosed compound can be used as an active ingredient of a preventive and / or therapeutic agent for diseases related to the EP4 receptor.

[0024] The present disclosure will be described in detail below.

[0025] As used herein, halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

[0026] In this specification, C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl groups.

[0027] In the present specification, C3-5 alkyl groups include propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl groups, and isomers thereof.

[0028] In this specification, C1-4 alkylene includes methylene, ethylene, propylene (trimethylene), butylene (tetramethylene), isopropylene, isobutylene, and isomers thereof.

[0029] In this specification, C3-5 alkylene includes propylene (trimethylene), butylene (tetramethylene), pentylene (pentamethylene), isopropylene, isobutylene, isopentylene, and isomers thereof.

[0030] In the present specification, the term "C1-4 haloalkyl group" means, for example, an alkyl group substituted by one or more halogen atoms, and specific examples thereof include a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a pentafluoroethyl group, a 1-fluoropropyl group, a 2-chloropropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 4,4,4-trifluorobutyl group, a 4-bromobutyl group, and isomers thereof.

[0031] In this specification, C1-4 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy groups.

[0032] In the present specification, the term "C1-4 haloalkoxy group" means, for example, an alkoxy group substituted with one or more halogen atoms, and specific examples thereof include a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, an iodomethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1-fluoroethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a pentafluoroethoxy group, a 1-fluoropropoxy group, a 2-chloropropoxy group, a 3-fluoropropoxy group, a 3-chloropropoxy group, a 4,4,4-trifluorobutoxy group, a 4-bromobutoxy group, and isomers thereof.

[0033] In the present specification, the 5- or 6-membered heterocycle may be a non-aromatic heterocycle or an aromatic heterocycle. The 5- or 6-membered heterocycle may have, for example, at least one heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom as a ring-constituting atom. Examples of the 5- or 6-membered heterocycle include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, and tetrahydrothiophene. Examples of such an anthraquinone ring include phene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, and dithiane rings.

[0034] In this specification, the 5- to 10-membered heterocycle may be a non-aromatic heterocycle or an aromatic heterocycle. The 5- to 10-membered heterocycle may be a monocyclic heterocycle or a fused heterocycle such as a dicyclic or tetracyclic heterocycle. The 5- to 10-membered heterocycle may have, for example, at least one heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom as a ring-constituting atom. Examples of the 5-10 membered heterocycle include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydropyridine, Thiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane, azepine, diazepine, oxepin, thiepin, oxazepine,Oxadiazepine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, dihydroazepine, tetrahydroazepine, perhydroazepine , dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, i Indolin, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthalazine Phthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole,Perhydrobenzimidazole, dioxaindane, benzodioxane, chroman, benzodithiolane, benzodithiane, azaspiro[4.4]nonane, oxazaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiaspiro[4.5]decane, dithiaspiro[4.5]decane, dioxaspiro[4.5]decane, oxazaspiro[4.5]decane, azabicyclo[3.2.1]octane, oxabicyclo[3.2.1]octane, thieno[3,2-c]pi thieno[2,3-c]pyrazole, thieno[2,3-d]thiazole, thieno[2,3-d][1.2.3]triazole, dihydropyrano[3,4-d]thiazole, dihydrothieno[2,3-b]pyran, dihydrothieno[3,2-c]pyran, dihydrothieno[3,2-b]pyran, dihydrothieno[3,2-c]thiopyran, tetrahydrothieno[3,2-b]pyridine, tetrahydrothieno[3,2-c]pyridine, and thieno[3,2-c]pyridine rings.

[0035] In this disclosure, R １ is an —OH group, —NHCH ２ CH ２ SO ３ H group, -NHCH ２ COOH group, or -NHCH(COOH)CH ２ CH ２ represents a COOH group. １ is preferably an —OH group, —NHCH ２ CH ２ SO ３ H group, or -NHCH(COOH)CH ２ CH ２ A COOH group, more preferably a —OH group or —NHCH ２ CH ２ SO ３ It is an H group.

[0036] In the present disclosure, L １ represents a thiazole ring or a C1-4 alkylene. １ is preferably a thiazole ring, and the substitution pattern of the thiazole ring is preferably

[0037] (In the formula, * represents the bonding site with the sulfur atom, and ** represents -COR １ represents the binding site with .

[0038] In the present disclosure, L ２ represents a C3-5 alkylene or a benzene ring. ２ is preferably propylene (trimethylene), butylene (tetramethylene), pentylene (pentamethylene), or a benzene ring, and more preferably butylene (tetramethylene) or a benzene ring.

[0039] In the present disclosure, X is —CO—, —NR Ｘ X preferably represents -NR Ｘ - or a sulfur atom, more preferably a sulfur atom.

[0040] In this disclosure, R Ｘ represents a hydrogen atom or a C1-4 alkyl group. Ｘ is preferably a hydrogen atom or a methyl group.

[0041] In this disclosure, R ２ represents a methyl group, a benzene ring, a 5- to 10-membered heterocycle, -COR ２－１ R represents a —CO— (benzene ring) group, a —CO— (5- to 10-membered heterocyclic ring) group, a —NH— (benzene ring) group, or a —OH group. ２ is preferably a benzene ring, a 5- to 10-membered heterocycle, or —COR ２－１group, a —CO—(benzene ring) group, a —CO—(5-10 membered heterocyclic ring) group, or a —NH—(benzene ring) group, more preferably a benzene ring, a 5-10 membered heterocyclic ring, a —CO—(benzene ring) group, or a —CO—(5-10 membered heterocyclic ring) group, even more preferably a benzene ring, a 5-6 membered heterocyclic ring, a —CO—(benzene ring) group, or a —CO—(5-6 membered heterocyclic ring) group, still more preferably a benzene ring, a pyridine ring, a pyrazine ring, a pyrazole ring, an imidazole ring, a thiazole ring, a triazole ring, a tetrazole ring, a quinoline ring, a —CO—(benzene ring) group, a —CO—(pyridine ring) group, a —CO—(pyrazine ring) group, or a —CO—(furan ring) group, and particularly preferably a benzene ring, a pyridine ring, a pyrazine ring, or a —CO—(benzene ring) group.

[0042] R ２ is preferably selected depending on the type of X. For example, when X is —CO—, R ２ is preferably a methyl group, a benzene ring, a 5- to 10-membered heterocycle, an —NH— (benzene ring) group, or an —OH group, and more preferably an —NH— (benzene ring) group. Ｘ -, then R ２ represents a methyl group, a benzene ring, a 5- to 10-membered heterocycle, -COR ２－１ group, —CO— (benzene ring) group, or —CO— (5- to 10-membered heterocyclic ring) group is preferred, and a benzene ring, —COR ２－１ A —CO— (benzene ring) group, or a —CO— (5- to 10-membered heterocyclic ring) group is more preferred, and a benzene ring, —COCH ２ OCH ３ group, -CONHCH ２ CH ３ It is more preferable that X is a —CO— (benzene ring) group, a —CO— (pyridine ring) group, a —CO— (pyrazine ring) group, or a —CO— (furan ring) group. ２is preferably a methyl group, a benzene ring, or a 5- to 10-membered heterocycle, more preferably a benzene ring or a 5- to 10-membered heterocycle, even more preferably a 5- to 10-membered heterocycle, and even more preferably a pyridine ring, a pyrazine ring, a pyrazole ring, a thiazole ring, an imidazole ring, a triazole ring, a tetrazole ring, or a quinoline ring.

[0043] In the present disclosure, the 5- to 10-membered heterocycle is preferably a pyridine ring, a pyrazine ring, a pyrazole ring, a pyrimidine ring, an imidazole ring, a thiazole ring, a triazole ring, a tetrazole ring, a furan ring, or a quinoline ring, more preferably a pyridine ring, a pyrazine ring, a pyrimidine ring, an imidazole ring, a thiazole ring, a triazole ring, a tetrazole ring, a furan ring, or a quinoline ring, and even more preferably a pyridine ring or a pyrazine ring.

[0044] In this disclosure, R ２－１ represents a C1-4 alkyl group optionally substituted with a C1-4 alkoxy group, or an —NH—(C1-4 alkyl) group. ２－１ is preferably a C1-4 alkyl group substituted with a C1-4 alkoxy group, or a —NH—(C1-4 alkyl) group, and more preferably —CH ２ OCH ３ group, or -NHCH ２ CH ３ It is the base.

[0045] In this disclosure, R ２－２ represents a halogen atom, a C1-4 alkyl group, a C1-4 haloalkyl group, a C1-4 alkoxy group, a C1-4 haloalkoxy group, or a benzene ring. ２－２ is preferably a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkoxy group, or a benzene ring, more preferably a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a difluoromethoxy group, or a benzene ring, and even more preferably a fluorine atom, a methyl group, or a methoxy group.

[0046] In the present disclosure, the compound represented by general formula (I) is preferably a compound represented by general formula (I-1): (In the formula, R ３ represents (1) a benzene ring, (2) a pyridine ring, (3) a pyrazine ring, (4) a pyrimidine ring, (5) an imidazole ring, (6) a thiazole ring, (7) a triazole ring, (8) a tetrazole ring, (9) a furan ring, (10) a quinoline ring, or (11) a pyrazole ring; R ３ is 1 to 5 R ３－１ and R ３－１ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a C1-4 haloalkoxy group, or (6) a benzene ring; X １ is (1)-NR Ｘ -, or (2) a sulfur atom, and the other symbols have the same meanings as above.), and more preferably a compound represented by general formula (I-2): (wherein all symbols have the same meanings as defined above), and more preferably a compound represented by general formula (I-3): (In the formula, R ３ａ represents (1) a pyridine ring or (2) a pyrazine ring, and R ３ａ is 1 to 3 R ３－１ and the other symbols have the same meanings as above.

[0047] In this disclosure, R ３ is preferably a benzene ring, a pyridine ring, a pyrazine ring, a pyrazole ring, a thiazole ring, an imidazole ring, a triazole ring, a tetrazole ring, or a quinoline ring, more preferably a benzene ring, a pyridine ring, or a pyrazine ring, and even more preferably a pyridine ring or a pyrazine ring.

[0048] In this disclosure, R ３－１ is preferably a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkoxy group, or a benzene ring, more preferably a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a difluoromethoxy group, or a benzene ring, and even more preferably a fluorine atom, a methyl group, or a methoxy group.

[0049] In the present disclosure, another embodiment of the compound represented by general formula (I) is preferably a compound represented by general formula (I-4): (In the formula, R ４ is (1)-COR ４－１ (1) a -CO- (benzene ring) group, (2) a -CO- (pyridine ring) group, (3) a -CO- (pyrazine ring) group, (4) a -CO- (furan ring) group, (5) a -CO- (furan ring) group, (6) a -NH- (benzene ring) group, or (7) a -OH group; R ４ represents a -CO- (benzene ring) group, a -CO- (pyridine ring) group, a -CO- (pyrazine ring) group, a -CO- (furan ring) group, or a -NH- (benzene ring) group, the benzene ring, the pyridine ring, the pyrazine ring, or the furan ring may be joined by 1 to 5 R ４－２ and R ４－１ represents (1) a C1-4 alkyl group optionally substituted with a C1-4 alkoxy group, or (2) a —NH—(C1-4 alkyl) group; R ４－２ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a C1-4 haloalkoxy group, or (6) a benzene ring; X ２ is (1) -CO-, or (2) -NR Ｘ -, and other symbols have the same meanings as above), and is a compound represented by the general formula (I-5): (wherein all symbols have the same meanings as above)

[0050] In this disclosure, R ４ is preferably a —CO— (benzene ring) group, a —CO— (pyridine ring) group, or a —CO— (pyrazine ring) group, more preferably a —CO— (benzene ring) group or a —CO— (pyridine ring) group, and even more preferably a —CO— (benzene ring) group.

[0051] In this disclosure, R ４－２ is preferably a C1-4 alkyl group or a C1-4 alkoxy group, more preferably a methyl group or a methoxy group.

[0052] In the present disclosure, the compound represented by general formula (I) is preferably a compound represented by the above-mentioned R １ , R ２ , L １ , L ２ and each of the preferred definitions of X.

[0053] In the present disclosure, another embodiment of the compound represented by general formula (I) is most preferably an example compound described in the examples below, or a pharmaceutically acceptable salt thereof.

[0054] In this disclosure, all isomers are encompassed unless otherwise specified. For example, alkyl groups, alkoxy groups, and alkylene groups include both straight-chain and branched-chain isomers. Furthermore, isomers (E, Z, cis, trans isomers) in double bonds, rings, and fused rings; isomers due to the presence of asymmetric carbons (R, S isomers, α, β isomers, enantiomers, diastereomers); optically active isomers with optical rotation (D, L, d, l isomers); polar isomers (high polarity, low polarity) obtained by chromatographic separation; equilibrium compounds; rotational isomers; mixtures of these in any proportion; and racemic mixtures are all encompassed in this disclosure. Furthermore, all isomers due to tautomerism are also encompassed in this disclosure.

[0055] In this disclosure, unless otherwise specified, symbols that will be apparent to those skilled in the art are used. represents bonding beyond the plane of the paper (i.e., α-configuration), indicates that the bond is on the front side of the paper (i.e., β-configuration), represents an arbitrary mixture of α- and β-configurations.

[0056] [Salts] The compound represented by formula (I) can be converted into a salt by a known method.

[0057] The salt is a pharmaceutically acceptable salt.

[0058] The salt is preferably water-soluble.

[0059] Pharmaceutically acceptable salts include, for example, acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts.

[0060] Acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or organic acid salts such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, or gluconate.

[0061] Examples of alkali metal salts include potassium salts and sodium salts.

[0062] Alkaline earth metal salts include, for example, calcium salts and magnesium salts.

[0063] Examples of ammonium salts include tetramethylammonium salts.

[0064] Examples of amine salts include triethylamine salts, methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts, tris(hydroxymethyl)aminomethane salts, lysine salts, arginine salts, and N-methyl-D-glucamine salts.

[0065] The compound represented by formula (I) can be converted into an N-oxide by any method. The N-oxide refers to a compound in which the nitrogen atom of the compound represented by formula (I) is oxidized.

[0066] The compound represented by general formula (I) and its pharmaceutically acceptable salts may exist in a non-solvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. The solvate is preferably a hydrate. The compound represented by general formula (I) and its pharmaceutically acceptable salts may be converted into a solvate.

[0067] The compound of formula (I) can form a co-crystal with a suitable co-crystal former. The co-crystal is preferably a pharmaceutically acceptable co-crystal former. A co-crystal is typically defined as a crystal formed by two or more different molecules through intermolecular interactions other than ionic bonding. A co-crystal may also be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, such as melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers include those described in WO 2006 / 007448.

[0068] In this disclosure, all references to the disclosed compounds include a compound represented by general formula (I), a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate (e.g., hydrate) thereof, or a co-crystal thereof, or an N-oxide of a pharmaceutically acceptable salt of a compound represented by general formula (I), a solvate (e.g., hydrate) thereof, or a co-crystal thereof.

[0069] [Prodrug] A prodrug of the compound represented by formula (I) refers to a compound that is converted into the compound represented by formula (I) in vivo by a reaction catalyzed by an enzyme, gastric acid, or the like. Examples of the prodrug of the compound represented by general formula (I) include, when the compound represented by general formula (I) has an amino group, compounds in which the amino group has been acylated, alkylated or phosphorylated (for example, compounds in which the amino group of the compound represented by general formula (I) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated or tert-butylated); when the compound represented by general formula (I) has a hydroxyl group, compounds in which the hydroxyl group has been acylated, alkylated, phosphorylated or borated (for example, compounds in which the hydroxyl group of the compound represented by general formula (I) has been acetylated, palmitoylated, propanoylated, pivaloylated, succinylated or furanyl). When the compound represented by general formula (I) has a carboxy group, examples thereof include compounds in which the carboxy group is esterified or amidated (for example, compounds in which the carboxy group of the compound represented by general formula (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, 1-{(ethoxycarbonyl)oxy}ethyl-esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl-esterified, methylamidated, and compounds in which the carboxy group of the compound represented by general formula (I) is amidated with an amino acid (for example, taurine, glutamic acid, etc.)). These compounds can be produced by known methods. Furthermore, the prodrug of the compound represented by general formula (I) may be either a hydrate or a non-hydrate. Furthermore, the prodrug of the compound represented by general formula (I) may be one that is converted into the compound represented by general formula (I) under physiological conditions, as described in "Drug Development," Vol. 7, "Molecular Design," pp. 163-198, Hirokawa Publishing, 1990.

[0070] Furthermore, each atom constituting the compound represented by general formula (I) may contain its isotope (e.g., ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １６ N. １７ O. １８ O. １８ F. ３５ S. ３６ Cl, ７７ Br, １２５ I, etc.) may be substituted.

[0071] As used herein, colon selectivity means the ratio of the colon concentration to the plasma concentration at the time of compound administration (colon concentration / plasma concentration).

[0072] [Method for Producing Compounds of the Present Disclosure] The compounds of the present disclosure can be produced by appropriately modifying and combining known methods, such as the methods shown below, methods similar thereto, the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc., 2018), or the methods shown in the Examples. A salt may be used as the starting material. The order of carrying out each reaction can be appropriately changed depending on the protecting groups introduced and the reaction conditions.

[0073] Furthermore, a compound having an amino group, a carboxyl group, or a hydroxyl group can be produced, if necessary, by using a compound protected with a protecting group commonly used for these groups, for example, a protecting group described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, and then carrying out a known deprotection reaction after an appropriate reaction step.

[0074] Examples of the protective group for a carboxyl group include methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, and 2-chlorotrityl.

[0075] Examples of protecting groups for amino groups or tetrazolyl groups include benzyloxycarbonyl groups, tert-butoxycarbonyl groups, allyloxycarbonyl (Alloc) groups, 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) groups, trifluoroacetyl groups, 9-fluorenylmethoxycarbonyl groups, benzyl (Bn) groups, p-methoxybenzyl groups, benzyloxymethyl (BOM) groups, and 2-(trimethylsilyl)ethoxymethyl (SEM) groups.

[0076] Examples of the protecting group for a hydroxyl group or hydroxamic acid include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), and the like.

[0077] The deprotection reaction is known and can be carried out by the following methods, for example: (1) deprotection reaction by alkaline hydrolysis, (2) deprotection reaction under acidic conditions, (3) deprotection reaction by hydrogenolysis, (4) deprotection reaction of a silyl group, (5) deprotection reaction using a metal, (6) deprotection reaction using a metal complex, etc.

[0078] These methods will be specifically described below. (1) The deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g., methanol, tetrahydrofuran (hereinafter, THF), dioxane, etc.) using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide, etc.) or a carbonate (e.g., sodium carbonate, potassium carbonate, etc.), or an aqueous solution thereof, or a mixture thereof, at 0 to 40°C.

[0079] (2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole, etc.), in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), in the presence or absence of 2,2,2-trifluoroethanol, at 0 to 100°C.

[0080] (3) The deprotection reaction by hydrogenolysis is carried out, for example, in a solvent (e.g., an ether (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), an alcohol (e.g., methanol, ethanol, etc.), a benzene (e.g., benzene, toluene, etc.), a ketone (e.g., acetone, methyl ethyl ketone, etc.), a nitrile (e.g., acetonitrile, etc.), an amide (e.g., N,N-dimethylformamide (hereinafter, DMF), etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, etc.), in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.), under normal pressure or elevated pressure in a hydrogen atmosphere or in the presence of ammonium formate, at 0 to 200°C.

[0081] (4) The deprotection reaction of the silyl group is carried out, for example, using tetrabutylammonium fluoride in a water-miscible organic solvent (e.g., THF, acetonitrile, etc.) at 0 to 40° C. Alternatively, the reaction is carried out, for example, in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.) at −10 to 100° C.

[0082] (5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (e.g., acetic acid, a buffer solution of pH 4.2 to 7.2, or a mixture of such a solution with an organic solvent such as THF) in the presence of zinc powder at 0 to 40°C, if necessary, with ultrasonication.

[0083] (6) The deprotection reaction using a metal complex is carried out, for example, in an organic solvent (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, or the like), water, or a mixed solvent thereof, in the presence of a trapping reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, or the like), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, or the like) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, or the like), in the presence or absence of a phosphine reagent (e.g., triphenylphosphine, or the like), using a metal complex (e.g., tetrakistriphenylphosphinepalladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, or the like), at 0 to 40°C.

[0084] The compound of formula (I) can be prepared by reaction scheme 1.

[0085] (In reaction scheme 1, R １ａ is -NHCH ２ CH ２ SO ３ H group, -NHCH ２ COOH group, or -NHCH(COOH)CH ２ CH ２represents a COOH group, and the other symbols have the same meanings as above.)

[0086] In reaction scheme 1, reaction 1-1 is known and can be carried out, for example, by reacting a compound represented by general formula 1a with a compound represented by general formula 1b in an organic solvent (e.g., tetrahydrofuran (THF), dimethylformamide (DMF), dimethoxyethane (DME), dioxane, acetonitrile, ethanol, dichloromethane, etc.), in water, or in a mixture thereof, in the presence of a base (e.g., sodium hydride, sodium hydroxide, potassium hydroxide, potassium phosphate, potassium tert-butoxide, potassium carbonate, a tertiary amine and lithium chloride, etc.) at a temperature of −20 to 70° C.

[0087] In Reaction Scheme 1, Reaction 1-2 is known and can be carried out by reacting the compound represented by general formula 1c obtained in Reaction 1-1 in an organic solvent (e.g., THF, DME, toluene, dichloromethane, diethyl ether, dioxane, etc.) with a reducing agent (e.g., sodium borohydride, zinc borohydride, etc.) in the presence or absence of cerium chloride at −20 to 50° C. Alternatively, when selectively producing only one stereoisomer, the reaction can be carried out at −100 to 50° C. using an asymmetric reducing agent (e.g., chlorodiisopinocamphenylborane, etc.) or a combination of an asymmetric auxiliary and a reducing agent ((R)-2-methyl-CBS-oxazaborolidine and boron hydride-tetrahydrofuran complex or borane dimethyl sulfide complex, (S)-(−)-binaphthol and lithium aluminum hydride, etc.).

[0088] In reaction scheme 1, reactions 1-3 are deprotection reactions, which are carried out under the same conditions as the above-mentioned deprotection reactions.

[0089] In Reaction Scheme 1, Reactions 1-4 are amidation reactions. Amidation reactions are known, and examples thereof include: (1) a method using an acid halide; (2) a method using a mixed acid anhydride; and (3) a method using a condensing agent.

[0090] These methods will be specifically described as follows: (1) A method using an acid halide is carried out by, for example, reacting a carboxylic acid with an acid halide-forming agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or without a solvent at −20° C. to reflux temperature, and then reacting the resulting acid halide with an amine in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) at a temperature of 0 to 40° C. Alternatively, the resulting acid halide can also be reacted with an amine in an organic solvent (dioxane, THF, etc.) using an alkaline aqueous solution (sodium bicarbonate solution, sodium hydroxide solution, etc.) at 0 to 40° C.

[0091] (2) The method using a mixed acid anhydride is carried out, for example, by reacting a carboxylic acid with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or without a solvent at 0 to 40°C, and then reacting the resulting mixed acid anhydride with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) at 0 to 40°C.

[0092] (3) The method using a condensing agent involves, for example, reacting a carboxylic acid and an amine in an organic solvent (chloroform, dichloromethane, DMF, diethyl ether, THF, etc.) or without a solvent, in the presence or absence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), with a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, 1-propylphosphonic acid cyclic anhydride (1-propanephosphonic acid cyclic anhydride, etc.)). anhydride, PPA, etc.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), in the presence or absence of 1-hydroxybenztriazole (HOBt), at 0 to 40°C.

[0093] It is desirable that the reactions (1), (2) and (3) are all carried out under an inert gas (argon, nitrogen, etc.) atmosphere and under anhydrous conditions.

[0094] In Reaction Scheme 1, Reactions 1-4 can be omitted as appropriate depending on the compound to be obtained and the intermediate to be used.

[0095] In addition, among the compounds represented by the general formula (1c), X is X １ Compounds which are: can also be prepared by Scheme 2.

[0096] (In Reaction Scheme 2, all symbols have the same meanings as above.)

[0097] In Reaction Scheme 2, Reaction 2-1 is known and can be carried out under the same conditions as in Reaction 1-1.

[0098] In Reaction Scheme 2, Reaction 2-2 is known and can be carried out by reacting p-toluenesulfonyl chloride in an organic solvent (e.g., dichloromethane, diethyl ether, THF, acetonitrile, benzene, toluene) in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at a temperature of 0 to 100°C.

[0099] In Reaction Scheme 2, Reaction 2-3 is known and can be carried out, for example, by reacting in an organic solvent (dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.) in the presence of an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate, etc.), an aqueous solution thereof, or a mixture thereof, at 0 to 100°C.

[0100] In each reaction in the present specification, the compounds represented by general formula 1a, general formula 1b, general formula 2a, and general formula 2d used as starting materials are either known or can be easily produced by a combination of known methods, such as those described in WO2003007941 (Patent Document 1), Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc., 2018), or methods in which known methods are partially modified.

[0101] Among the compounds disclosed herein, optically active compounds can be produced using optically active starting materials or reagents, or by optically resolving a racemic production intermediate and then leading to the compound disclosed herein, or by optically resolving a racemic compound disclosed herein.

[0102] This optical resolution is well known, and examples thereof include a method in which a salt or complex is formed with another optically active compound, and the target compound is then isolated after recrystallization, or directly separated using a chiral column or the like.

[0103] In each reaction herein, reactions involving heating can be carried out using a water bath, oil bath, sand bath or microwave, as will be apparent to those skilled in the art.

[0104] In each reaction herein, a solid-phase-supported reagent supported on a high molecular weight polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

[0105] In each reaction in this specification, the reaction product can be purified by a conventional purification method, for example, distillation under atmospheric pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, scavenger resin, or column chromatography, washing, recrystallization, etc. Purification may be carried out for each reaction or after completion of several reactions.

[0106] [Toxicity] The compounds of the present disclosure have low toxicity and can therefore be used safely as pharmaceuticals.

[0107] [Application to Pharmaceuticals] The compound of the present disclosure has agonistic activity against the EP4 receptor and may therefore be useful for the prevention and / or treatment of diseases associated with the EP4 receptor, such as immune diseases (autoimmune diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjogren's syndrome, rheumatoid arthritis, and systemic lupus erythematosus, and rejection after organ transplantation), asthma, neuronal cell death, arthritis, lung injury, pulmonary fibrosis, emphysema, bronchitis, chronic obstructive respiratory disease, liver injury, acute hepatitis, nephritis (acute nephritis, chronic nephritis), renal failure, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis, hemophagocytic syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burns, systemic granuloma, inflammatory bowel diseases (ulcerative colitis, Crohn's disease, etc.), hypercytokinemia during dialysis, multiple organ failure, and shock. Furthermore, the EP4 receptor is also involved in mucosal protective action, and the compounds of the present disclosure may be useful in the prevention and / or treatment of gastrointestinal ulcers such as gastric ulcers and duodenal ulcers, and stomatitis.

[0108] A compound that selectively binds to EP4 does not cause pain thought to be caused by EP1 or uterine contraction thought to be caused by EP3, and therefore the compound of the present disclosure can be a drug that does not have the side effects caused by these.

[0109] To use the disclosed compounds for the prevention and / or treatment of the above-mentioned diseases, the active ingredient is typically formulated with a pharmaceutically acceptable carrier, such as various additives or solvents, and then administered systemically or locally, orally or parenterally. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient that is generally used in pharmaceutical formulations. Pharmaceutically acceptable carriers are preferably those that do not exhibit pharmacological activity at the dosage of the formulation, are harmless, and do not interfere with the therapeutic effect of the active ingredient. Pharmaceutically acceptable carriers can also be used for purposes such as enhancing the usefulness of the active ingredient and formulation, facilitating formulation, stabilizing quality, or improving usability. Specifically, substances such as those described in the 2021 "Dictionary of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association) published by Yakuji Nipposha, etc., can be selected appropriately according to the purpose.

[0110] The disclosed compounds are administered to a mammal, preferably a human, more preferably a human patient, in a pharmaceutically effective amount.

[0111] The dosage of the disclosed compound will inevitably vary depending on age, body weight, symptoms, desired therapeutic effects, route of administration, duration of treatment, etc. Generally, it is administered orally in the range of 0.1 ng to 1000 mg per patient per dose, or parenterally in the range of 0.01 ng to 100 mg per patient per dose, or by continuous intravenous administration.

[0112] Of course, as mentioned above, the dosage varies depending on various conditions, so in some cases a smaller dosage than the above may be sufficient, and in other cases a dosage exceeding the range may be necessary.

[0113] Examples of dosage forms used for administration include oral preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semisolids, mouthwashes, etc.), injectable preparations (e.g., injectable preparations, etc.), dialysis preparations (e.g., dialysis preparations, etc.), inhalation preparations (e.g., inhalants, etc.), ophthalmic preparations (e.g., eye drops, eye ointments, etc.), otic preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semisolids, enteral injections, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological preparations (e.g., solid preparations for topical application, liquid preparations for topical application, sprays, ointments, creams, gels, patches, etc.).

[0114] [Oral Formulations] Oral formulations include, for example, tablets, capsules, granules, powders, oral liquids, syrups, and oral jellies. Oral formulations include rapidly disintegrating formulations in which the release of the active ingredient from the formulation is not specifically controlled, and modified-release formulations, such as enteric-coated formulations and sustained-release formulations, in which the release is controlled according to the purpose through a specific formulation design and manufacturing method. Enteric-coated formulations are designed to release the active ingredient primarily in the small intestine rather than in the stomach, for purposes such as preventing the active ingredient from being decomposed in the stomach or reducing the irritating effect of the active ingredient on the stomach. They are typically prepared by coating with an acid-insoluble enteric base. Sustained-release formulations are formulations in which the release rate, release time, and release site of the active ingredient from the formulation are controlled for purposes such as reducing the frequency of administration or reducing side effects. They are typically prepared by using an appropriate sustained-release agent. Among preparations for oral administration, capsules, granules, tablets, etc. may be coated with an appropriate coating agent such as a sugar, sugar alcohol, or polymer compound for the purpose of facilitating administration or preventing decomposition of the active ingredient.

[0115] (1) Tablets Tablets are solid preparations having a certain shape that are administered orally, and include those generally called tablets, such as plain tablets, film-coated tablets, sugar-coated tablets, multi-layer tablets, and dry-coated tablets, as well as orally rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets. When manufacturing plain tablets, the following methods (a), (b), or (c) are usually used: (a) Additives such as excipients, binders, and disintegrants to the active ingredient and mix to form a homogeneous mixture, then granulate using a suitable method using water or a solution containing a binder, then add lubricants and mix, and then compress; (b) Additives such as excipients, binders, and disintegrants to the active ingredient and mix to form a homogeneous mixture, and then directly compress; or Additives such as excipients and binders to granules prepared in advance with additives, then mix to form a homogeneous mixture, and then compress; (c) Additives such as excipients and binders to the active ingredient and mix to form a homogeneous mixture, then wet the mixture with a solvent and pour it into a mold, then mold, and then dry it using a suitable method. Film-coated tablets can usually be produced by coating plain tablets with a thin coating of an appropriate coating agent such as a polymer compound. Sugar-coated tablets can usually be produced by coating plain tablets with a coating agent containing sugars or sugar alcohols. Multilayer tablets can be produced by stacking powders of different compositions in layers and compressing them using an appropriate method. Dry-coated tablets can be produced by coating an inner core tablet with an outer layer of different composition. Tablets can also be made into enteric-coated or sustained-release tablets using appropriate known methods. Orally rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that have unique functions imparted to them by appropriate selection of additives, and can be produced in accordance with the manufacturing methods for the aforementioned tablets. Orally rapidly disintegrating tablets are tablets that can be taken by quickly dissolving or disintegrating in the oral cavity; chewable tablets are tablets that are taken by chewing; effervescent tablets are tablets that dissolve or disperse in water while rapidly effervescent; dispersible tablets are tablets that are taken by dispersing in water; and dissolving tablets are tablets that are taken by dissolving in water. Effervescent tablets can be produced by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives.

[0116] (2) Capsules Capsules are preparations filled into capsules or encapsulated with a capsule base, and include hard capsules, soft capsules, etc. Hard capsules can be produced by mixing the active ingredient with additives such as excipients to form a homogeneous mixture, or by forming a granular or shaped product using an appropriate method, and then filling the mixture directly into a capsule or by lightly shaping it. Soft capsules can be produced by encapsulating the active ingredient with additives and encapsulating it into a specific shape using an appropriate capsule base such as gelatin whose plasticity has been increased by adding glycerin, D-sorbitol, etc. Capsules can also be made into enteric capsules or sustained-release capsules using appropriate known methods, and coloring agents, preservatives, etc. can also be added to the capsule base.

[0117] (3) Granules Granules are formulations granulated into a granular form, and include not only those commonly referred to as granules but also effervescent granules. Granules are typically produced using one of the following methods (a), (b), or (c): (a) adding excipients, binders, disintegrants, or other additives to a powdered active ingredient, blending them to homogenize, and then granulating them by an appropriate method; (b) adding excipients or other additives to a pre-granulated active ingredient, blending them to homogenize; (c) adding excipients or other additives to a pre-granulated active ingredient, blending them, and then granulating them by an appropriate method. Granules can be coated as needed, and can also be made into enteric-coated or sustained-release granules using known appropriate methods. Effervescent granules can be produced by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives. Effervescent granules refer to granules that rapidly effervescently dissolve or disperse in water. Granules can also be made into fine granules by adjusting the particle size.

[0118] (4) Powders Powders are powdered preparations, and can usually be produced by adding excipients or other additives to the active ingredient, mixing them together, and making them homogeneous.

[0119] (5) Oral Liquids Oral liquids are liquid or fluid, viscous gel-like preparations, and include those commonly referred to as oral liquids, as well as elixirs, suspensions, emulsions, and lemonades. Oral liquids are typically prepared by adding additives and purified water to the active ingredient, mixing to form a homogeneous solution, or emulsifying or suspending the mixture, and filtering as needed. Elixirs are clear, liquid oral liquids containing sweet and aromatic ethanol. They are typically prepared by dissolving a solid active ingredient or its extract in ethanol, purified water, flavoring agents, and sucrose, other sugars, or sweeteners, and then filtering or otherwise preparing a clear liquid. Suspensions are oral liquids in which the active ingredient is finely and homogeneously suspended. They are typically prepared by adding a suspending agent or other additives and purified water or oil to the solid active ingredient, suspending the mixture in an appropriate manner, and homogenizing the entire mixture. An emulsion is an oral liquid preparation in which the active ingredient is finely and homogeneously emulsified, and can usually be produced by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it in an appropriate manner, and making the whole homogeneous. Meanwhile, a lemonade is a clear, liquid oral preparation with a sweet and sour taste.

[0120] (6) Syrups Syrups are viscous liquid or solid preparations containing sugars or sweeteners, including syrup preparations. Syrups can typically be prepared by adding an active ingredient to a solution of sucrose, other sugars, or sweeteners, or to a simple syrup, dissolving, mixing, suspending, or emulsifying the mixture, boiling the mixture as needed, and then filtering it while hot. Syrup preparations refer to granular or powder preparations that become syrups upon addition of water, and are sometimes referred to as dry syrups. Syrup preparations can typically be prepared using sugars or sweeteners as additives, following the manufacturing methods for the granules or powders described above.

[0121] (7) Oral Jelly Preparations Oral jellies are formulations in the form of a molded gel with no fluidity, and can usually be produced by adding an additive and a polymer gel base to the active ingredient, mixing them, gelling them using an appropriate method, and molding them into a specific shape.

[0122] [Injectable Preparations] (1) Injectable Preparations Injectable preparations are solutions, suspensions, or emulsions, or solid sterile preparations that are dissolved or suspended immediately before use and are administered subcutaneously, intramuscularly, or directly into body tissues or organs such as blood vessels. In addition to what is generally called an injectable preparation, these include freeze-dried injectable preparations, powder injectable preparations, pre-filled syringes, cartridges, infusion solutions, implantable injectable preparations, and sustained-release injectable preparations. Injectable preparations are usually produced using the following methods (a) or (b): (a) the active ingredient, either as it is or with additives added, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents to form a homogeneous mixture, which is then filled into an injectable container, sealed, and sterilized; (b) the active ingredient, either as it is or with additives added, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents to form a homogeneous mixture, which is then sterile-filtered, or a homogeneous mixture prepared aseptically is filled into an injectable container, and sealed; Freeze-dried injections can typically be produced by dissolving the active ingredient directly or with additives such as excipients in water for injection, sterile filtering, and filling into an injection container followed by freeze-drying, or by freeze-drying in a dedicated container and then filling directly into a container. Powder injections can typically be produced by processing through sterile filtration, followed by crystallization to obtain a powder, or by adding sterilized additives to the powder, and then filling into an injection container. Pre-filled syringes can typically be produced by filling a syringe with the active ingredient directly, or by preparing a solution, suspension, or emulsion using the active ingredient and additives. Cartridges refer to injections that are used by placing a cartridge filled with a drug solution into a dedicated syringe. Cartridges filled with a drug solution can typically be produced by filling the cartridge with the active ingredient directly, or by preparing a solution, suspension, or emulsion using the active ingredient and additives. Infusion solutions refer to injections that are typically 100 mL or more and are administered intravenously. An implantable injection is a solid or gel-like injection that is administered subcutaneously, intramuscularly, etc. using an implantation device or by surgery, with the aim of releasing the active ingredient over a long period of time.An implantable injection can usually be produced by using a biodegradable polymer compound and forming it into pellets, microspheres, or gels. A sustained-release injection is an injection that is administered intramuscularly or the like for the purpose of releasing the active ingredient over a long period of time, and can usually be produced by dissolving or suspending the active ingredient in vegetable oil or the like, or by forming it into a suspension of microspheres using a biodegradable polymer compound.

[0123] The disclosed compounds may be administered as a combination agent in combination with other drugs to: 1) complement and / or enhance the prophylactic and / or therapeutic effects of the compound; 2) improve the kinetics and absorption of the compound, reduce the dosage, and / or 3) reduce the side effects of the compound.

[0124] A combination of a compound of the present disclosure and another drug may be administered in the form of a combined preparation in which both components are combined in a single preparation, or in the form of separate preparations. Administration in these separate preparations includes simultaneous administration and administration at different times. Furthermore, administration at different times may involve administering the compound of the present disclosure first and the other drug later, or administering the other drug first and the compound of the present disclosure later. The respective administration methods may be the same or different.

[0125] There are no particular limitations on the diseases for which the above-mentioned combination drug can exert a preventive and / or therapeutic effect, as long as the preventive and / or therapeutic effect of the compound of the present disclosure can be complemented and / or enhanced.

[0126] For example, other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of the compound represented by general formula (I) on inflammatory bowel diseases include, for example, 5-aminosalicylic acid preparations, steroids, immunomodulators, immunosuppressants, anti-TNF-α antibodies, anti-α4β7 integrin antibodies, JAK inhibitors, etc.

[0127] Examples of 5-aminosalicylic acid preparations include salazosulfapyridine and mesalazine.

[0128] Examples of steroids include prednisolone, betamethasone, budesonide, and cortisol.

[0129] Immunomodulators include azathioprine, 6-mercaptopurine, and the like.

[0130] Immunosuppressants include tacrolimus, cyclosporine, and the like.

[0131] Examples of anti-TNF-α antibodies include infliximab, adalimumab, and golimumab.

[0132] Examples of anti-α4β7 integrin antibodies include vedolizumab.

[0133] Examples of JAK inhibitors include tofacitinib.

[0134] The weight ratio of the compound represented by formula (I) to the other drug is not particularly limited.

[0135] Any two or more of the other drugs may be administered in combination.

[0136] Furthermore, other drugs that complement and / or enhance the preventive and / or therapeutic effects of the compounds of the present disclosure include not only those that have been discovered so far but also those that will be discovered in the future, based on the above-mentioned mechanisms.

[0137] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0138] Furthermore, the contents of all patent and non-patent literature or references explicitly cited in this specification may be incorporated herein by reference in their entirety.

[0139] In one aspect, the present disclosure provides the following embodiment: [1] General formula (I): (In the formula, R １ (1) -OH group, (2) -NHCH ２ CH ２ SO ３ H group, (3)-NHCH ２ COOH group, or (4) —NHCH(COOH)CH ２ CH ２ represents a COOH group, L １represents (1) a thiazole ring, or (2) a C1-4 alkylene; ２ represents (1) a C3-5 alkylene or (2) a benzene ring; X represents (1) -CO-, (2) -NR Ｘ -, or (3) represents a sulfur atom, R Ｘ represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R ２ is (1) a methyl group, (2) a benzene ring, (3) a 5- to 10-membered heterocycle, or (4) -COR ２－１ (5) a —CO— (benzene ring) group, (6) a —CO— (5- to 10-membered heterocyclic) group, (7) a —NH— (benzene ring) group, or (8) a —OH group; R ２ represents a benzene ring, a 5- to 10-membered heterocyclic ring, a —CO— (benzene ring) group, a —CO— (5- to 10-membered heterocyclic ring) group, or a —NH— (benzene ring) group, the benzene ring or the 5- to 10-membered heterocyclic ring may be selected from the group consisting of 1 to 5 R ２－２ and R ２－１ represents (1) a C1-4 alkyl group optionally substituted with a C1-4 alkoxy group, or (2) a —NH—(C1-4 alkyl) group; R ２－２ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a C1-4 haloalkoxy group, or (6) a benzene ring, or a pharmaceutically acceptable salt thereof;

[0140] [2] L １ is a thiazole ring, and the thiazole ring is (In the formula, * represents the bonding site with the sulfur atom, and ** represents -COR １ The compound according to the above [1], or a pharmaceutically acceptable salt thereof,

[0141] [3] R ２the compound according to [1] or [2] above, wherein the 5- to 10-membered heterocycle is a heterocycle selected from the group consisting of (1) a pyridine ring, (2) a pyrazine ring, (3) a pyrimidine ring, (4) an imidazole ring, (5) a thiazole ring, (6) a triazole ring, (7) a tetrazole ring, (8) a furan ring, (9) a quinoline ring, and (10) a pyrazole ring, or a pharmaceutically acceptable salt thereof;

[0142] [4] General formula (I-1): (In the formula, R ３ represents (1) a benzene ring, (2) a pyridine ring, (3) a pyrazine ring, (4) a pyrimidine ring, (5) an imidazole ring, (6) a thiazole ring, (7) a triazole ring, (8) a tetrazole ring, (9) a furan ring, (10) a quinoline ring, or (11) a pyrazole ring; R ３ is 1 to 5 R ３－１ and R ３－１ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a C1-4 haloalkoxy group, or (6) a benzene ring; X １ is (1)-NR Ｘ -, or (2) a sulfur atom, and other symbols have the same meanings as those in [1] or [2] above.), or a pharmaceutically acceptable salt thereof,

[0143] [5] General formula (I-2): (wherein all symbols have the same meanings as those in [4] above), or a pharmaceutically acceptable salt thereof.

[0144] [6] General formula (I-3): (In the formula, R ３ａ represents (1) a pyridine ring or (2) a pyrazine ring, and R ３ａ is 1 to 3 R ３－１ and other symbols have the same meanings as those of the symbols described in any one of [1] to [5] above, or a pharmaceutically acceptable salt thereof;

[0145] [7] General formula (I-4): (In the formula, R ４ is (1)-COR ４－１ (1) a -CO- (benzene ring) group, (2) a -CO- (pyridine ring) group, (3) a -CO- (pyrazine ring) group, (4) a -CO- (furan ring) group, (5) a -CO- (furan ring) group, (6) a -NH- (benzene ring) group, or (7) a -OH group; R ４ represents a -CO- (benzene ring) group, a -CO- (pyridine ring) group, a -CO- (pyrazine ring) group, a -CO- (furan ring) group, or a -NH- (benzene ring) group, the benzene ring, the pyridine ring, the pyrazine ring, or the furan ring may be joined by 1 to 5 R ４－２ and R ４－１ represents (1) a C1-4 alkyl group optionally substituted with a C1-4 alkoxy group, or (2) a —NH—(C1-4 alkyl) group; R ４－２ represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a C1-4 haloalkoxy group, or (6) a benzene ring; X ２ is (1) -CO-, or (2) -NR Ｘ -, and other symbols have the same meanings as the symbols in [1] or [2] above.), or a pharmaceutically acceptable salt thereof according to [1] or [2] above.

[0146] [8] The compound represented by the general formula (I) is (1) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid, (2) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid, (3) 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid, (4) 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methoxy-2-pyrazinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid, (5) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-9-(2-pyridinylthio)-1-nonen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid, (6) 4-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoic acid, (7) 2-[({2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazol-4-yl}carbonyl)amino]ethanesulfonic acid, (8) 2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methoxy-2-pyrazinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazol-4-yl]carbonyl}amino)ethanesulfonic acid, and (9) 2-{[4-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoyl]amino}ethanesulfonic acid, or a pharmaceutically acceptable salt thereof,

[0147] [9] A pharmaceutical composition comprising the compound according to any one of [1] to [8] above or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutically acceptable carrier.

[0148]

[10] The pharmaceutical composition according to [9] above, which is an EP4 agonist.

[0149]

[11] The pharmaceutical composition according to [9] above, which is a therapeutic and / or preventive agent for a disease associated with the EP4 receptor.

[0150]

[12] The pharmaceutical composition according to

[11] above, wherein the disease associated with the EP4 receptor is immune disease, asthma, neuronal cell death, arthritis, lung injury, pulmonary fibrosis, emphysema, bronchitis, chronic obstructive respiratory disease, liver injury, acute hepatitis, nephritis, renal failure, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis, hemophagocytic syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burns, systemic granulomatosis, inflammatory bowel disease, hypercytokinemia during dialysis, multiple organ failure, or shock.

[0151]

[13] The pharmaceutical composition according to

[11] above, wherein the disease associated with the EP4 receptor is inflammatory bowel disease.

[0152]

[14] The pharmaceutical composition according to

[11] above, wherein the disease associated with the EP4 receptor is inflammatory bowel disease, and the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0153]

[15] A therapeutic and / or preventive agent for a disease associated with the EP4 receptor, comprising the compound according to any one of [1] to [8] above or a pharmaceutically acceptable salt thereof.

[0154]

[16] A method for preventing and / or treating a disease associated with the EP4 receptor, comprising administering to a patient in need of the prevention and / or treatment of the disease associated with the EP4 receptor the compound according to any one of [1] to [8] above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or salt thereof as an active ingredient and further containing a pharmaceutically acceptable carrier.

[0155]

[17] The compound according to any one of [1] to [8] above, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of a disease associated with the EP4 receptor.

[0156]

[18] Use of the compound according to any one of [1] to [8] above, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the prophylaxis and / or treatment of a disease associated with the EP4 receptor.

[0157] The disclosed compounds will be described in detail below based on examples, but the disclosed compounds are not limited to these examples.

[0158] [Synthesis Examples] The solvents in parentheses shown in chromatographic separations and TLCs indicate the eluting or developing solvents used, and the ratios are by volume.

[0159] The solvent in parentheses shown in the NMR section indicates the solvent used in the measurement.

[0160] The compound names used in this specification are generally determined using ACD / Name (registered trademark), a computer program that performs naming in accordance with IUPAC rules, or Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft), or are determined in accordance with IUPAC nomenclature.

[0161] LC-MS / ELSD was performed under the following conditions: Column: YMC Triart C １８ (particle size: 1.9 x 10 －６m; column length: 30 x 2.0 mm ID); flow rate: 1.0 mL / min; column temperature: 30°C; mobile phase (A): 0.1% trifluoroacetic acid aqueous solution; mobile phase (B): 0.1% trifluoroacetic acid-acetonitrile solution; gradient (ratio of mobile phase (A): mobile phase (B) is described): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.6 min] 5:95; detector: UV (PDA), ELSD, MS.

[0162] Unless otherwise specified, the HPLC retention time indicates the retention time under the conditions described in the LC-MS / ELSD. The description in parentheses next to the HPLC retention time indicates the measurement conditions.

[0163] Reference Example 1: Dimethyl phosphonate (7-hydroxy-2-oxoheptyl) To a solution of dimethyl methylphosphonate (CAS number: 756-79-6, 18 g) in tetrahydrofuran (hereinafter referred to as THF) (120 mL), a 1.59 M n-hexane solution of n-butyllithium (CAS number: 109-72-8, 100 mL) was added dropwise at −78°C, and the mixture was stirred at −78°C for 1 hour. A solution of epsilon-caprolactone (CAS number: 502-44-3, 8.3 g) in THF (20 mL) was added dropwise at −78°C, and the mixture was stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (16.7 g, purity 79%) having the following physical properties: TLC: Rf 0.31 (ethyl acetate:methanol=19:1).

[0164] Reference Example 2: Ethyl 2-[(2-{(2R)-2-[(1E)-8-hydroxy-3-oxo-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylate To a solution of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylate (CAS number: 1355026-69-5, 10 g) in THF (210 mL) were added the compound produced in Reference Example 1 (7.2 g), lithium chloride (3.9 g), and triethylamine (11 mL), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate:methanol=50:50:0→0:100:0→0:90:10) to give the title compound (9.1 g) having the following physical properties: TLC: Rf 0.2 (ethyl acetate).

[0165] Reference Example 3: Ethyl 2-[(2-{(2R)-2-[(1E)-8-{[(4-methylphenyl)sulfonyl]oxy}-3-oxo-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylate To a solution of the compound (8 g) produced in Reference Example 2 in dichloromethane (56 mL), trimethylamine hydrochloride (694 mg), triethylamine (7.6 mL), and p-toluenesulfonyl chloride (4.5 g) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80→0:100) to give the title compound (9.3 g) having the following physical properties: HPLC retention time (min): 1.17.

[0166] Reference Example 4: Ethyl 2-[(2-{(2R)-2-[(1E)-3-hydroxy-8-{[(4-methylphenyl)sulfonyl]oxy}-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylate To a solution of the compound prepared in Reference Example 3 (2.5 g) in THF (18 mL) were added a 1 M toluene solution of (R)-(+)-2-methyl-CBS-oxazaborolidine (5 mL) and N,N-diethylanilineborane (0.86 mL) at −15° C., and the mixture was stirred at −15° C. for 4 hours. Water and a 1 N aqueous hydrochloric acid solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→90:10) to give the title compound (1.86 g) as a diastereomeric mixture having the following physical data: TLC: Rf 0.2 (ethyl acetate).

[0167] Reference Example 5: Ethyl 2-[(2-{(2R)-2-[(1E)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylate To a solution of the compound produced in Reference Example 4 (120 mg) in acetonitrile (2.4 mL), potassium carbonate (42 mg), sodium iodide (45 mg), and 2-mercaptopyridine (CAS number: 2637-34-5, 34 mg) were added, and the mixture was stirred at 60°C for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol = 100:0 → 90:10) to give the title compound (87 mg) as a diastereomeric mixture having the following physical properties: HPLC retention time (min): 0.94.

[0168] Example 1: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid To a solution of the compound prepared in Reference Example 5 (86 mg) in dimethoxyethane (0.8 mL)-methanol (0.8 mL), 2N aqueous sodium hydroxide solution (0.34 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography to separate the two diastereomers, yielding the less polar form (70 mg). HPLC retention time (min): 0.83; １ H-NMR (CD ３ OD): δ 8.35, 8.23, 7.57-7.62, 7.25, 7.06, 5.74, 5.45-5.52, 4.29-4.35, 3.97-4.03, 3.79, 3.32-3.51, 3.24-3.29, 3.07-3.14, 2.18-2.43, 1.58-1.81, 1.24-1.50.

[0169] Examples 1-1 to 1-16: The following example compounds were obtained by subjecting the compounds to the same procedures as in Reference Example 5→Example 1, except that the corresponding thiol compounds were used in place of 2-mercaptopyridine.

[0170] Example 1-1: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyrazinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.923; １ H-NMR (DMSO-d ６ ): δ 8.56, 8.47, 8.30, 5.66, 5.38, 4.10-4.23, 3.88, 3.67, 3.06-3.23, 2.55, 2.34-2.47, 2.07-2.32, 1.51-1.68, 1.15-1.39.

[0171] Example 1-2: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(6-methyl-2-pyrazinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.956; １ H-NMR (DMSO-d ６): δ 8.34, 8.26, 8.19, 5.67, 5.39, 4.06-4.19, 3.88, 3.61-3.73, 3.08-3.18, 2.41-2.47, 2.07-2.30, 1.48-1.68, 1.15-1.40.

[0172] Example 1-3: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(6-methyl-2-pyridinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.827; １ H-NMR (CD ３ OD): δ 8.22, 7.49, 7.04, 6.92, 5.74, 5.48, 4.28-4.35, 4.01, 3.78, 3.32-3.51, 3.24-3.30, 3.08, 2.45, 2.15-2.43, 1.60-1.81, 1.23-1.52.

[0173] Example 1-4: 2-({2-[(2R)-2-{(1E,3S)-8-[(3-chloro-2-pyridinyl)thio]-3-hydroxy-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 1.064; １ H-NMR (DMSO-d ６ ): δ 8.43, 8.31, 7.83, 7.16, 5.66, 5.39, 4.72, 3.99-4.23, 3.88, 3.67, 3.07-3.22, 2.04-2.31, 1.46-1.74, 1.17-1.42.

[0174] Example 1-5: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(4-methyl-2-pyridinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.834; １ H-NMR (DMSO-d ６): δ 8.26, 7.09, 6.91, 5.65, 5.31-5.47, 4.62-4.87, 4.15, 3.87, 3.54-3.76, 2.98-3.21, 2.03-2.28, 1.50-1.68, 1.14-1.39.

[0175] Example 1-6: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methyl-2-pyridinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 1.011; １ H-NMR (DMSO-d ６ ): δ 8.24-8.34, 7.48, 7.02, 5.66, 5.39, 4.72, 4.09-4.20, 3.79-3.94, 3.63-3.72, 3.08-3.19, 2.05-2.31, 1.48-1.70, 1.16-1.43.

[0176] Example 1-7: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methoxy-2-pyridinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.984; １ H-NMR (DMSO-d ６ ): δ 12.50-13.46, 8.33, 8.03, 7.24, 7.08, 5.65, 5.38, 4.70, 4.10-4.20, 4.05-4.24, 3.85-3.92, 3.79-3.84, 3.63-3.73, 3.36-3.41, 2.98-3.23, 2.06-2.34, 1.44-1.70, 1.16-1.42.

[0177] Example 1-8: 2-({2-[(2R)-2-{(1E,3S)-8-[(5,6-difluoro-2-pyridinyl)thio]-3-hydroxy-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 1.049;１ H-NMR (DMSO-d ６ ): δ 8.33, 7.82, 6.94, 5.66, 5.39, 4.72, 4.08-4.20, 3.89, 3.67, 3.03-3.24, 2.06-2.32, 1.53-1.69, 1.16-1.39.

[0178] Example 1-9: 2-({2-[(2R)-2-{(1E,3S)-8-[(3-fluoro-2-pyridinyl)thio]-3-hydroxy-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 1.018; １ H-NMR (DMSO-d ６ ): δ 8.33, 7.53-7.66, 7.20, 5.65, 5.39, 4.71, 4.00-4.23, 3.88, 3.67, 3.08-3.21, 2.04-2.32, 1.47-1.75, 1.16-1.42.

[0179] Example 1-10: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(3-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.829; １ H-NMR (DMSO-d ６ ): δ 8.50, 8.29-8.41, 7.76, 7.33, 5.65, 5.38, 4.71, 4.01-4.24, 3.83-3.91, 3.61-3.72, 3.08-3.17, 2.94-3.01, 2.06-2.34, 1.45-1.69, 1.12-1.39.

[0180] Example 1-11: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(1H-1,2,4-triazol-3-ylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.813; １H-NMR (DMSO-d ６ ): δ 8.31, 5.65, 5.38, 4.71, 4.09-4.20, 3.87, 3.62-3.73, 3.00-3.08, 2.06-2.32, 1.47-1.69, 1.20-1.41.

[0181] Example 1-12: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(1H-pyrazol-3-ylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.882; １ H-NMR (DMSO-d ６ ): δ 8.31, 7.66, 6.25, 5.65, 5.38, 4.71, 3.99-4.27, 3.83-3.92, 3.66, 3.09-3.22, 2.82, 2.06-2.32, 1.58-1.69, 1.41-1.56, 1.10-1.36.

[0182] Example 1-13: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(1-phenyl-1H-tetrazol-5-yl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 1.008; １ H-NMR (DMSO-d ６ ): δ 8.30, 7.59-7.71, 5.65, 5.38, 4.72, 4.00-4.24, 3.87, 3.62-3.71, 3.11-3.19, 2.05-2.30, 1.58-1.80, 1.16-1.41.

[0183] Example 1-14: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(8-quinolinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.969; １ H-NMR (DMSO-d ６): δ 8.88, 8.28-8.38, 7.70, 7.49-7.60, 5.66, 5.38, 4.73, 4.00-4.24, 3.90, 3.62-3.71, 3.09-3.19, 2.97-3.04, 2.04-2.30, 1.52-1.77, 1.21-1.48.

[0184] Example 1-15: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(1H-imidazol-2-ylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.721; １ H-NMR (DMSO-d ６ ): δ 8.33, 7.03, 5.63, 5.38, 4.55-4.90, 4.09-4.18, 3.81-3.89, 3.66, 3.07-3.14, 2.93, 2.06-2.30, 1.55-1.70, 1.39-1.55, 1.21-1.35.

[0185] Example 1-16: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(1,3-thiazol-2-ylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.947; １ H-NMR (DMSO-d ６ ): δ 12.77-13.47, 8.35, 7.71, 7.64, 5.65, 5.39, 4.71, 4.11-4.19, 3.83-3.92, 3.65-3.72, 3.08-3.21, 2.53-2.60, 2.05-2.31, 1.54-1.73, 1.15-1.40.

[0186] Example 2: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid The title compound having the following physical properties was obtained by the same procedure as in Reference Example 5→Example 1, except that N-methylaniline was used instead of 2-mercaptopyridine: TLC: Rf 0.69 (chloroform:methanol=4:1); １ H-NMR (CD ３ OD): δ 8.14, 7.14-7.21, 6.75-6.80, 6.68, 5.67-5.77, 5.39-5.51, 4.26-4.34, 3.98, 3.72-3.81, 3.39-3.48, 2.91, 2.16-2.40, 1.69-1.80, 1.35-1.55, 1.21-1.35.

[0187] Reference Example 6: Ethyl 2-[(2-{(2R)-2-[(1E,3S)-8-(acetylthio)-3-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylate To a solution of the compound prepared in Reference Example 4 (133 mg) in DMF (2.6 mL), imidazole (23 mg) and t-butyldimethylsilyl chloride (37 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. Potassium thioacetate (CAS number: 10387-40-3, 28 mg) was added to a solution of the obtained residue in dimethylacetamide (1.3 mL), and the mixture was stirred at 60°C for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give the title compound (91 mg) having the following physical properties. HPLC retention time (min): 1.491.

[0188] Example 3: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methoxy-2-pyrazinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid To a solution of the compound prepared in Reference Example 6 (30 mg) in ethanol (0.9 mL), triphenylphosphine (14 mg), potassium carbonate (10 mg), and 2-bromo-3-methoxypyrazine (CAS number: 1209905-41-8, 10 mg) were added, and the mixture was stirred at 60°C for one day. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in THF (0.2 mL), a 1N solution of tetrabutylammonium fluoride (0.2 mL) was added, and the mixture was stirred for one day at room temperature. Methanol (0.5 mL) and a 2N aqueous solution of sodium hydroxide (0.2 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reverse-phase column chromatography to separate the two diastereomers, and the less polar form (17 mg) was obtained. HPLC retention time (min): 1.01; １ H-NMR (CDCl ３ ): δ 8.09, 7.94, 7.75, 5.76, 5.58, 4.10-4.17, 4.02, 3.78, 3.41-3.55, 3.29-3.36, 3.13-3.18, 2.19-2.57, 1.74, 1.34-1.54.

[0189] Example 3-1: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(6-methoxy-2-pyrazinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid The title compound having the following physical properties was obtained by the same procedure as in Example 3, except that 2-bromo-6-methoxypyrazine was used instead of 2-bromo-3-methoxypyrazine. HPLC retention time (min): 0.476; １ H-NMR (DMSO-d ６ ): δ 8.24-8.35, 8.11, 7.95, 5.66, 5.38, 4.06-4.23, 3.86-3.94, 3.50-3.77, 2.97-3.24, 2.65, 2.06-2.33, 1.51-1.69, 1.14-1.40.

[0190] Reference Example 7: Dimethyl (6-hydroxy-2-oxohexyl) phosphonate Using delta valerolactone (CAS number: 542-28-9) instead of epsilon-caprolactone, the title compound having the following physical properties was obtained by the same procedure as in Reference Example 1. TLC: Rf 0.3 (ethyl acetate:methanol=20:1).

[0191] Examples 4-1 to 4-4: The following example compounds were obtained by using the compound produced in Reference Example 7 instead of the compound produced in Reference Example 1, and the corresponding thiol compound instead of 2-mercaptopyridine, and by subjecting the compounds to the same procedures as in Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Example 1.

[0192] Example 4-1: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-7-(2-pyridinylthio)-1-hepten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid TLC: Rf 0.29 (methanol:chloroform:acetic acid = 1:8:0.1); １ H-NMR (CD ３ OD): δ 8.52, 8.25, 8.15, 7.76, 7.58-7.46, 5.74, 5.50, 4.36-4.25, 4.10-3.97, 3.87-3.73, 3.46, 3.40-3.20, 2.48-2.13, 1.87-1.64, 1.63-1.37.

[0193] Example 4-2: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-7-[(5-methyl-2-pyrazinyl)thio]-1-hepten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.91; １ H-NMR (CDCl ３): δ 8.38, 8.27, 8.01, 5.81, 5.54, 4.08-4.19, 3.63-3.73, 3.35-3.50, 3.27, 3.04-3.15, 2.49, 2.28-2.47, 2.19-2.27, 1.57-1.82, 1.33-1.56, 0.96.

[0194] Example 4-3: 2-[(2-{(2R)-2-[(1E,3S)-7-{[6-(difluoromethoxy)-2-pyridinyl]thio}-3-hydroxy-1-hepten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 1.04; １ H-NMR (CD ３ OD): δ 7.92, 7.28-7.75, 7.02, 6.58-6.61, 5.73, 5.43-5.52, 4.58, 4.29-4.42, 3.95-4.08, 3.73-3.88, 3.40-3.52, 3.33-3.36, 2.10-2.42, 1.58-1.78, 1.37-1.55, 1.29.

[0195] Example 4-4: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-7-[(5-methyl-2-pyridinyl)thio]-1-hepten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.894; １ H-NMR (CD ３ OD): δ 8.23, 8.21, 7.46, 7.16, 5.73, 5.48, 4.28-4.34, 4.01, 3.80, 3.39-3.54, 3.32-3.37, 3.07, 2.17-2.43, 1.60-1.81, 1.35-1.54.

[0196] Reference Example 8 Dimethyl Phosphonate (8-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-2-oxooctyl) Using methyl 7-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}heptanoate (CAS number: 181274-06-6) instead of epsilon-caprolactone, the title compound having the following physical properties was obtained by the same procedure as in Example 1. TLC: Rf 0.4 (ethyl acetate).

[0197] Reference Example 9: Ethyl 2[(2-{(2R)-2-[(1E)-9-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-3-hydroxy-1-nonen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylate Using the compound prepared in Reference Example 8 instead of the compound prepared in Reference Example 1, and subjecting to the same procedures as in Reference Example 2 → Reference Example 4, the title compound having the following physical properties was obtained. HPLC retention time (min): 1.413.

[0198] Reference Example 10: Ethyl 2-[(2-{(2R)-2-[(1E)-3-acetoxy-9-hydroxy-1-nonen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylate To a solution of the compound prepared in Reference Example 9 (360 mg) in pyridine (3.6 mL), N,N-dimethyl-4-aminopyridine (7.7 mg) and acetic anhydride (77 mg) were added, and the reaction mixture was stirred at room temperature for one day. To the reaction mixture was added a 1N aqueous solution of hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in ethanol (3.6 mL), and p-toluenesulfonic acid monohydrate (17 mg) was added at 0°C, and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=50:50→0:100) to give the title compound (265 mg) having the following physical properties: HPLC retention time (min): 1.091.

[0199] Example 5: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-9-(2-pyridinylthio)-1-nonen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid The compound prepared in Reference Example 10 was used instead of the compound prepared in Reference Example 2, and the same procedures as in Reference Example 3, Reference Example 5, and Example 1 were carried out to obtain the title compound having the following physical properties: HPLC retention time (min): 0.985; １ H-NMR (DMSO-d ６ ): δ 8.41, 8.30, 7.59-7.64, 7.26, 7.08, 5.65, 5.38, 4.71, 4.09-4.20, 3.78-3.94, 3.67, 3.06-3.17, 2.05-2.31, 1.53-1.67, 1.13-1.38.

[0200] Example 6: 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid Using butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoate (CAS number: 1365393-21-0) instead of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylate, the same procedures as in Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Example 1 were carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 0.84; １ H-NMR (CDCl ３ ): δ 8.43-8.46, 7.51, 7.21, 7.01, 5.76, 5.54, 4.10-4.21, 3.53-3.65, 3.12-3.23, 2.64-2.72, 2.34-2.62, 2.19-2.30, 1.86-1.94, 1.70-1.78, 1.40-1.60.

[0201] Example 7: 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-7-(2-pyridinylthio)-1-hepten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid Using butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoate (CAS number: 1365393-21-0) instead of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylate and using the compound prepared in Reference Example 7 instead of the compound prepared in Reference Example 1, the same procedures as in Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Example 1 were carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 0.817; １ H-NMR (CDCl ３ ): δ 8.45, 7.51, 7.21, 7.02, 5.75, 5.53, 4.09-4.22, 3.66, 3.07-3.20, 2.70, 2.34-2.63, 2.20-2.29, 1.85-2.02, 1.71-1.81, 1.42-1.65.

[0202] Reference Example 11: Methyl [3-(2-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}ethyl)phenyl]acetate Imidazole (490 mg) and t-butyldimethylsilyl chloride (1.05 g) were added to a solution of methyl 2-(3-(hydroxyethyl)phenyl)acetate (CAS number: 1260900-49-9, 1 g) in DMF (10 mL), and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→10:90) to give the title compound (1.5 g) having the following physical properties. TLC: Rf 0.5 (hexane:ethyl acetate=90:10).

[0203] Reference Example 12: Dimethyl phosphonate {3-[3-(2-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}ethyl)phenyl]-2-oxopropyl} phosphonate. The title compound (1g) having the following physical properties was obtained by using the compound (1g) prepared in Reference Example 11 instead of epsilon-caprolactone and subjecting it to the same procedure as in Reference Example 1. TLC: Rf 0.43 (hexane:ethyl acetate=33:67);

[0204] Reference Example 13: 4-({2-[(2R)-2-{(1E,3S)-3-hydroxy-4-[3-(2-hydroxyethyl)phenyl]-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoate

[0111] Using butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoate instead of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylate and the compound prepared in Reference Example 12 instead of the compound prepared in Reference Example 1, the same procedures as in Reference Example 2 → Reference Example 4 → Reference Example 10 → Example 1 were carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 0.824; １ H-NMR (CDCl ３ ): δ 7.27-7.31, 7.06-7.14, 5.81, 5.58, 4.36-4.47, 4.05-4.17, 3.87, 3.46-3.57, 3.10, 2.83-2.91, 2.73-2.82, 2.60-2.69, 2.31-2.58, 2.18-2.28, 1.87, 1.67-1.79, 1.13-1.34, 0.73-0.94.

[0205] Reference Example 14: 3-{2-[methoxy(methyl)amino]-2-oxoethyl}-N-phenylbenzamide To a solution of [3-(phenylcarbamoyl)phenyl]acetic acid (CAS number: 50961-58-5, 1.1 g) in acetonitrile (35 mL), EDCI-HCl (1 g), N,O-dimethylhydroxylamine hydrochloride (526 mg), and triethylamine (1.3 mL) were added and stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20 → 34:66) to give the title compound (750 mg) having the following physical properties. HPLC retention time (min): 0.974.

[0206] Reference Example 15: Dimethyl phosphonate {2-oxo-3-[3-(phenylcarbamoyl)phenyl]propyl} Using the compound prepared in Reference Example 14 instead of the compound prepared in Reference Example 1, and subjecting to the same procedures as in Reference Example 1, the title compound having the following physical properties was obtained. HPLC retention time (min): 0.923.

[0207] Example 8: 4-({2-[(2R)-2-{(1E,3S)-3-hydroxy-4-[3-(phenylcarbamoyl)phenyl]-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoic acid The title compound having the following physical properties was obtained by carrying out the same procedures as in Reference Example 2, Reference Example 4, and Example 1, using butyl 4-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoate instead of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylate and the compound prepared in Reference Example 15 instead of the compound prepared in Reference Example 1. HPLC retention time (min): 0.939; １ H-NMR (CD ３OD): δ 7.73-7.85, 7.66-7.72, 7.40-7.49, 7.33-7.40, 7.12-7.17, 5.74-5.83, 5.38-5.46, 4.90-5.07, 4.38-4.45, 4.13-4.22, 4.10, 3.43-3.65, 3.32-3.41, 2.85-3.07, 2.70-2.82, 2.44-2.67, 2.17-2.41, 2.00, 1.76-1.87, 1.58-1.74, 1.21-1.36, 0.93.

[0208] Reference Example 16: Dimethyl [3-(3-nitrophenyl)-2-oxopropyl]phosphonate Using N-methoxy-N-methyl-2-(3-nitrophenyl)acetamide (CAS number: 1036397-64-4) instead of epsilon-caprolactone, the title compound having the following physical properties was obtained by the same procedure as in Reference Example 1. TLC: Rf 0.39 (ethyl acetate).

[0209] Reference Example 17: Butyl 4-[(2-{(2R)-2-[(1E)-3-hydroxy-4-(3-nitrophenyl)-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoate

[0123] By subjecting the compound prepared in Reference Example 16 to the same procedures as in Reference Example 2 and then Reference Example 4, but using butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoate instead of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylate and the compound prepared in Reference Example 16 instead of the compound prepared in Reference Example 1, the title compound having the following physical properties was obtained. HPLC retention time (minutes): 1.137.

[0210] Reference Example 18: Butyl 4-[(2-{(2R)-2-[(1E)-3-acetoxy-4-(3-nitrophenyl)-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoate To a solution of the compound prepared in Reference Example 17 (260 mg) in dichloromethane (2.7 mL) were added acetyl chloride (86 mg), triethylamine (0.23 mL), and N,N-dimethyl-4-aminopyridine (6.6 mg), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80) to give the title compound (200 mg) having the following physical properties. TLC: Rf 0.33 (hexane:ethyl acetate=20:80).

[0211] Reference Example 19: Butyl 4-[(2-{(2R)-2-[(1E)-3-acetoxy-4-(3-aminophenyl)-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoate To a solution of the compound produced in Reference Example 18 (278 mg) in methanol (11 mL), water (1 mL), THF (2.1 mL), ammonium chloride (500 mg), and zinc powder (611 mg) were added, and the mixture was stirred at 65°C for 15 hours. The reaction mixture was filtered, and water was added to the filtrate, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate:methanol=80:20:0→0:100:0→0:90:10). The resulting crude product was purified by reverse phase chromatography to give the title compound (32 mg) having the following physical properties: TLC: Rf 0.22 (hexane:ethyl acetate=20:80).

[0212] Example 9: 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-4-{3-[(5-methyl-2-furoyl)amino]phenyl}-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid To a solution of the compound prepared in Reference Example 19 (25 mg) in DMF (0.2 mL) were added 5-methyl-2-furancarboxylic acid (CAS number: 1917-13-2, 9.6 mg), triethylamine (0.014 mL), and HATU (25 mg), and the mixture was stirred at room temperature for 2 hours. 2N aqueous sodium hydroxide solution (0.13 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. 2N aqueous hydrochloric acid solution (0.25 mL) and dimethyl sulfoxide (0.1 mL) were added to the reaction mixture. The reaction mixture was purified by reverse-phase column chromatography to separate the two diastereomers, and the less polar form (16 mg) was obtained. HPLC retention time (min): 0.908; １ H-NMR (DMSO-d ６ ): δ 9.91, 7.54-7.61, 7.19-7.27, 6.91, 6.31, 5.64-5.78, 5.31, 5.02, 4.17-4.27, 4.04, 2.74-2.83, 2.58-2.72, 2.42-2.47, 2.36-2.41, 2.07-2.29, 1.69, 1.41-1.62.

[0213] Example 10: 4-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoic acid The title compound was obtained by the same procedure as in Example 9, except that benzoic acid was used instead of 5-methyl-2-furancarboxylic acid, and the following physical properties were obtained: HPLC retention time (min): 0.929; １ H-NMR (DMSO-d ６ ): δ 11.92-12.33, 10.17, 7.93-7.97, 7.50-7.66, 7.24, 6.94, 5.69, 5.32, 5.02, 4.23, 4.00-4.07, 2.74-2.83, 2.60-2.74, 2.37-2.48, 2.07-2.33, 1.52-1.76.

[0214] Examples 10-1 to 10-4: The following example compounds were obtained by the same procedures as in Reference Example 17 → Reference Example 18 → Reference Example 19 → Example 9, using ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylate instead of butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoic acid and using a corresponding carboxylic acid compound instead of 5-methyl-2-furancarboxylic acid.

[0215] Example 10-1: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-4-{3-[(methoxyacetyl)amino]phenyl}-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.812; １ H-NMR (CD ３ OD): δ 8.21, 7.42-7.47, 7.22, 6.93, 5.69, 5.29-5.37, 4.27-4.35, 4.15-4.26, 3.98-4.04, 3.70-3.77, 3.52-3.63, 3.43-3.46, 2.82-2.95, 2.65, 2.11-2.36, 1.84-1.89, 1.62-1.72.

[0216] Example 10-2: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-4-{3-[(2-pyridinylcarbonyl)amino]phenyl}-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.903; １ H-NMR (CD ３ OD): δ 8.66, 8.16-8.20, 7.99, 7.63-7.67, 7.57, 7.29, 6.98, 5.74, 5.32-5.40, 4.32-4.39, 4.19-4.27, 3.52-3.65, 2.88-3.01, 2.72, 2.11-2.35, 1.64-1.72.

[0217] Example 10-3: 2-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.943; １ H-NMR (CDCl ３ ): δ 8.32, 8.08, 8.02, 7.87-7.94, 7.82, 7.44-7.57, 7.27-7.37, 6.94-7.00, 5.76-5.87, 5.51, 4.43, 4.08-4.17, 3.57-3.68, 3.14-3.42, 3.06-3.12, 2.75-2.90, 2.28-2.44, 2.15-2.25, 1.68-1.77, 1.49-1.67, 1.26-1.37.

[0218] Example 10-4: 2-[(2-{(2R)-2-[(1E,3S)-4-{3-[(ethylcarbamoyl)amino]phenyl}-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid HPLC retention time (min): 0.943; １ H-NMR (CDCl ３ ): δ 8.32, 8.08, 8.02, 7.87-7.94, 7.82, 7.44-7.57, 7.27-7.37, 6.94-7.00, 5.76-5.87, 5.51, 4.43, 4.08-4.17, 3.57-3.68, 3.14-3.42, 3.06-3.12, 2.75-2.90, 2.28-2.44, 2.15-2.25, 1.68-1.77, 1.49-1.67, 1.26-1.37.

[0219] Example 11: 2-[({2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazol-4-yl}carbonyl)amino]ethanesulfonic acid To a solution of the compound prepared in Example 1 (27 mg) in DMF (0.3 mL) were added triethylamine (0.02 mL), taurine (CAS number: 107-35-7, 10 mg), and HATU (22 mg), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reverse-phase column chromatography to give the title compound (14 mg) having the following physical properties: HPLC retention time (min): 0.786; １ H-NMR (D ２ O): δ 8.27-8.47, 8.01, 7.54-7.72, 7.33-7.51, 5.50, 5.43, 4.22-4.34, 3.88-4.02, 3.67-3.73, 3.53-3.66, 3.31, 3.04-3.16, 2.02-2.41, 1.15-1.77, 1.07.

[0220] Example 12: 2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methoxy-2-pyrazinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazol-4-yl]carbonyl}amino)ethanesulfonic acid To a solution of the compound prepared in Example 3 (540 mg) in DMF (5.4 mL) were added triethylamine (0.56 mL), taurine (188 mg), and HATU (419 mg), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography to give the title compound (210 mg) having the following physical properties: HPLC retention time (min): 0.844; １ H-NMR (D ２ O): δ 7.96, 7.85, 7.67, 5.55, 5.41, 4.23-4.29, 3.95-4.01, 3.88, 3.70, 3.59, 3.26, 3.07-3.15, 2.96, 2.24-2.37, 2.10-2.20, 1.63-1.73, 1.40-1.56, 1.23-1.37, 1.05.

[0221] Examples 12-1 to 12-6: The following example compounds were obtained by carrying out the same operations as in Example 11, using the corresponding example compounds described above instead of the compound prepared in Example 1. Example 12-1: 2-[({2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyrazinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazol-4-yl}carbonyl)amino]ethanesulfonic acid HPLC retention time (min): 0.855; １ H-NMR (D ２ O): δ 8.27-8.47, 8.01, 7.54-7.72, 7.33-7.51, 5.50, 5.43, 4.22-4.34, 3.88-4.02, 3.67-3.73, 3.53-3.66, 3.31, 3.04-3.16, 2.02-2.41, 1.15-1.77, 1.07.

[0222] Example 12-2: 2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-7-[(5-methyl-2-pyridinyl)thio]-1-hepten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazol-4-yl]carbonyl}amino)ethanesulfonic acid HPLC retention time (min): 0.801; １ H-NMR (D ２ O): δ 8.20, 8.00, 7.84, 7.46, 5.49-5.57, 5.40, 4.27, 3.97, 3.62-3.74, 3.34, 3.13-3.24, 2.99-3.11, 2.21-2.38, 2.04-2.17, 1.50-1.71, 1.44, 1.11-1.32.

[0223] Example 12-3: 2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazol-4-yl]carbonyl}amino)ethanesulfonic acid HPLC retention time (min): 0.745; １H-NMR (D ２ O): δ 7.99, 7.51, 7.44, 5.44, 5.35, 4.20-4.30, 3.81-3.92, 3.66-3.72, 3.56-3.65, 3.44, 3.24-3.33, 2.95-3.16, 2.25, 2.03-2.16, 1.59-1.71, 1.30, 1.04-1.16, 0.82-1.00.

[0224] Example 12-4: 2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(6-methyl-2-pyridinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazol-4-yl]carbonyl}amino)ethanesulfonic acid HPLC retention time (min): 0.755; １ H-NMR (D ２ O): δ 7.95-8.03, 7.46, 7.28, 5.52, 5.41, 4.27, 3.97, 3.70, 3.56-3.65, 3.31, 3.05-3.17, 2.53, 2.22-2.39, 2.12, 1.69, 1.55, 1.36-1.46, 1.16-1.36, 1.01-1.11.

[0225] Example 12-5: 2-{[4-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoyl]amino}ethanesulfonic acid HPLC retention time (min): 0.81; １ H-NMR (D ２ O): δ 7.81, 7.54-7.62, 7.47-7.53, 7.31-7.39, 7.07, 5.65, 5.31, 4.39, 4.09, 3.42, 3.22-3.29, 2.99-3.07, 2.94, 2.73, 2.51-2.58, 2.25-2.36, 2.03-2.20, 1.44-1.67.

[0226] Example 12-6: 2-({[2-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazol-4-yl]carbonyl}amino)ethanesulfonic acid HPLC retention time (min): 0.836; １ H-NMR (D ２ O): δ 7.89, 7.71, 7.49-7.52, 7.41, 7.28-7.34, 6.98-7.05, 5.55-5.64, 5.23-5.33, 4.31-4.43, 4.06-4.18, 3.63, 3.39-3.50, 3.11, 3.03, 2.59-2.75, 2.13-2.35, 1.97-2.10, 1.53-1.69.

[0227] Example 13: (2S)-2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazol-4-yl]carbonyl}amino)pentanedioic acid The same procedure as in Example 11 was carried out using the compound prepared in Example 2 instead of the compound prepared in Example 1 and L-glutamic acid instead of taurine to obtain the title compound having the following physical properties: HPLC retention time (min): 0.808; １ H-NMR (CD ３ OD): δ 8.03-8.11, 7.17, 6.76, 6.66, 5.66-5.74, 5.49, 4.60, 4.24-4.31, 4.01, 3.86, 3.42-3.51, 2.86-2.92, 2.28-2.48, 2.14-2.26, 1.75, 1.34-1.62, 1.22-1.34.

[0228] Example 14: (2R)-2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazol-4-yl]carbonyl}amino)pentanedioic acid The same procedure as in Example 11 was carried out using the compound prepared in Example 2 instead of the compound prepared in Example 1 and D-glutamic acid instead of taurine to obtain the title compound having the following physical properties: HPLC retention time (min): 0.802; １ H-NMR (CD ３ OD): δ 8.10, 8.03-8.07, 7.17, 6.73-6.78, 6.66, 5.68-5.75, 5.48, 4.60, 4.25-4.32, 4.00, 3.85, 3.40-3.53, 2.89-2.92, 2.27-2.48, 2.14-2.25, 1.75, 1.34-1.60, 1.22-1.33.

[0229] Pharmacological Example 1 Measurement of Agonistic Activity Against Various Human Prostanoid Receptors Using CHO cells or Chem1 cells (EP1-CHO, EP2-CHO, EP3-Chem1, EP4-CHO, and IP-CHO) in which various human prostanoid receptors were forcibly expressed, the agonistic activity of test compounds against various prostanoid receptors was investigated using intracellular calcium concentration for EP1 and EP3, and intracellular cyclic AMP (hereinafter abbreviated as cAMP) production for EP2, EP4, and IP as indicators.

[0230] <Compound Treatment> The test compounds and control substances (PGE2 and iloprost) were dissolved in dimethyl sulfoxide (DMSO) to prepare 10 mmol / L solutions. The prepared 10 mmol / L solution was thawed at the time of use, serially diluted with DMSO, and then diluted with measurement buffer solution 1 (Hank's balanced salt solution (Thermofischer Scientific) containing 1 w / v% human serum albumin (Sigma), 2 μmol / L indomethacin (Sigma), 2.5 mmol / L probenecid, and 10 mmol / L HEPES-NaOH (pH 7.4)) or measurement buffer solution 2 (D-PBS (Nacalai Tesque) containing 0.1 w / v% human serum albumin, 2 μmol / L diclofenac (Sigma), and 1 mmol / L 3-isobutyl-1-methylxanthine (Sigma)) for use in the experiment.

[0231] <Agonist Activity Measurement> (1) EP1 and EP3 Activity Measurement (Intracellular Calcium Concentration Measurement) Intracellular calcium concentration was measured using a Calcium 6 Assay Kit (Molecular Devices). EP1-CHO and EP3-Chem1 were prepared by thawing frozen cells the day before the measurement, inactivating them (56°C, 30 minutes), and suspending them in Ham's F-12 medium (Thermofischer Scientific) containing 9.8 vol% FBS (Thermofischer Scientific) and penicillin-streptomycin (Nacalai Tesque). The cells were then placed in a 96-well UV plate at 1.0 x 10 cells per well. ５ The cells were seeded at a density of 1000 cells / ml and incubated in 5% CO ２The cells were cultured statically at 37°C in the presence of 1000 kJ / ml. On the day of measurement, the medium was removed, and 120 μL of calcium indicator solution dissolved in measurement buffer 1 was added, followed by incubation for approximately 1 hour at room temperature in the dark. After 1 hour of incubation, the 96-well UV plate was placed in a fluorescence spectrophotometer (FDSS-7000, Hamamatsu Photonics), and the intracellular calcium concentration was measured. 30 μL of measurement buffer 1 containing various concentrations of agonist was added and allowed to react. Intracellular calcium concentration was measured by irradiating the cells with 480 nm excitation light and measuring the fluorescence intensity at 540 nm.

[0232] (2) Measurement of EP2, EP4, and IP agonist activity (measurement of cAMP concentration) For EP2-CHO, EP4-CHO, and IP-CHO, on the day of measurement, frozen cells were thawed and suspended in D-PBS containing 2 μmol / L diclofenac, centrifuged at 500 g for 3 minutes at room temperature, and the supernatant was removed. The cells were then suspended in measurement buffer solution 2 and plated at 2.0 × 10 per well in a 384-well plate. ５ pieces (EP2), 5.0×10 ４ (EP4) and 1.0 x 10 ５ 10 μL aliquots were dispensed to achieve a cell count of 1 / 100 (IP). 20 μL of measurement buffer solution 2 containing various concentrations of agonist was added, and the mixture was incubated at room temperature for 1 hour. cAMP concentration was measured using a cAMP HTRF HiRange kit (CIS bio International). Following the two-step protocol in the kit's instructions, 5 μL each of cAMP-D2 and cryptase diluted with lysis buffer was added, and the mixture was incubated at room temperature for 1 hour. After 1 hour of incubation, time-resolved fluorescence was measured at 620 nm and 660 nm when excited at 340 nm using Synergy Neo (Bio Teck), and the ratio (TRF ratio) was calculated to calculate the cAMP concentration from the calibration curve.

[0233] <Results> Using the above method, the agonist activity of the compounds of the present disclosure against various prostanoid receptors was measured. ５０The results of the measurement of agonist activity (EC value) for EP1, EP2, EP3 and IP receptors are shown in Table 1. ５０ The measurement results of the EP4 receptor agonist activity (value) are shown in Table 2. The compounds of the present disclosure listed in the table were confirmed to have potent EP4 receptor agonist activity and selectivity for EP1, EP2, EP3 and IP.

[0234]

[0235]

[0236] Pharmacological Example 2: Calculation of Colon Selectivity by Mouse PK Test compounds were dissolved in 0.5% methylcellulose solution and orally administered to C57BL / 6 mice at 1, 3, or 10 mg / kg. Blood samples were collected at various time points (0.5, 1, 2, 4, 7, or 9 hours) after administration and centrifuged at 12,000 rpm for 5 minutes to collect plasma. The colons were collected, washed with saline, and homogenized in a 4-fold volume of purified water per colon weight. Plasma and colon concentrations of the test compounds were determined by LC / MS / MS analysis. Colon selectivity was determined as the ratio of the maximum colon concentration to the maximum plasma concentration. For example, the compounds prepared in Examples 1, 2, 3, and 10 exhibited colon selectivity of 302-fold, 440-fold, 391-fold, and 620-fold, respectively. Furthermore, when the compounds prepared in Example 11, Example 12-3, and Example 12-5 were administered, the carboxylic acid forms (the compounds prepared in Example 1, Example 2, and Example 10, respectively) exhibited large intestine selectivity of 248-fold, 318-fold, and 395-fold, respectively. On the other hand, when the large intestine selectivity of the compound of Example 6 (22) described in Patent Document 3 (Comparative Compound A) and the compound of Example 6 (92) described in Patent Document 3 (Comparative Compound B), which have the following structures, were measured as comparative compounds, the large intestine selectivity was 20-fold and 133-fold, respectively.

[0237]

[0238] Pharmacological Example 3: DSS (Dextran Sodium Sulfate)-Induced Ulcerative Colitis Mouse Model Adult C57BL / 6 mice were used in this assay. Day 0 was the day the mice began drinking 2% DSS water. Ulcerative colitis was induced by placing the DSS solution in a clear plastic water bottle and allowing free access through a metal nozzle from Day 0 to Day 7. The test substance was orally administered at a dose of 10 mL / kg once daily for 7 days from Day 0 to Day 6. Fecal status was observed daily from Day 0 to Day 7, and the disease activity index (DAI) was evaluated according to a standard score (diarrhea score: 0, normal stool; 1, loose stool; 2, diarrheal stool; 3, watery stool; bloody stool score: 0, normal stool; 1, brownish, mildly bloody stool; 2, reddish stool; 3, bloody stool). The DAI score = diarrhea score + bloody stool score, or the sum of both scores. Compounds of the present disclosure were tested in this assay. Efficacy in this model is evidenced by a reduction in the DAI score compared to the score of vehicle-treated animals (control group). The compounds of Example 1 (0.3 mpk), Example 2 (0.3 mpk), Example 10 (1 mpk), Example 11 (0.3 mpk), Example 12 (3 mpk), Example 12-3 (0.3 mpk), and Example 12-5 (3 mpk) showed a 50% inhibition of the control group score in the DSS colitis mouse model at doses of 0.3, 1, or 3 mg / kg.

[0239] Pharmacological Example 4: Calculation of Concentration for Cardiovascular Effects Using Mouse Tail Cuff and Calculation of Safety Margin The cardiovascular effects in awake mice can be evaluated by the tail cuff method using a non-heated, non-invasive sphygmomanometer (MK-2000). A cuff pulse sensor is attached to the tail of a mouse previously acclimatized to the measurement procedure, and systolic blood pressure calculated from the pulse wave of the tail artery is measured. Measurements are performed consecutively multiple times, and the average value is used. The test substance is orally administered once at a dose of 10 mL / kg. Blood pressure is measured before and a specified time after administration of the test substance. A change of 10% or more in post-administration systolic blood pressure compared to pre-administration systolic blood pressure is considered to be a cardiovascular effect. Blood is drawn immediately after blood pressure measurement, and the plasma concentration of the test substance at the time of cardiovascular effects is considered to be the concentration for cardiovascular effects. The safety margin can be calculated by comparing the test substance concentration with the concentration at which a significant anti-colitis effect was observed in a mouse model of DSS-induced colitis.

[0240] Pharmacological Example 5: Calculation of Safety Margin in Rat Po Cardiovascular Evaluation Test To evaluate the cardiovascular effects in unrestrained, conscious rats, a single oral dose of the test substance was administered to Crl:CD (SD) male rats (4 rats / group) implanted with a telemetry transmitter (HD-S10, DSI) or with a catheter placed in the left carotid artery, and blood pressure (systolic, diastolic, and mean blood pressure) and heart rate were continuously measured. Evaluation was performed at pre-administration and 0.5, 1, 2, 3, 4, 7, 12, or 24 hours after administration, and the average value over 10 seconds at each evaluation time point was analyzed.

[0241] As a result of testing the compounds of the present disclosure in this assay, the no-effect dose on the rat circulatory system (blood pressure and heart rate) was 30 mg / kg for all of the compounds of Examples 11, 12, 12-3, and 12-5. Compared with the effective dose at which a significant anti-colitis effect was observed in the mouse model of DSS-induced colitis described in Pharmacological Example 3, the safety margin (dose-based) of the compounds of the present disclosure was calculated to be 100-fold for the compound of Example 11, 10-fold for the compound of Example 12, 100-fold for the compound of Example 12-3, and 10-fold for the compound of Example 12-5. From these results, and based on the safety margin obtained by comparing the no-effect dose on the rat circulatory system with the effective dose in the mouse model, the compounds of the present disclosure were considered to be compounds with a low risk of toxicity to the cardiovascular system.

[0242] Pharmacological Example 6: Calculation of Safety Margin by Monkey Po Telemetry Test To examine the effects on the monkey's cardiovascular system in unrestrained, conscious animals, a single dose of the test substance was orally administered to male cynomolgus monkeys (2 monkeys / dose) implanted with a telemetry transmitter (M11, Data Sciences International), and blood pressure (systolic, diastolic, and mean blood pressure) and heart rate were continuously measured. Evaluation was performed at pre-administration and 0.5, 1, 2, 4, 8, 10, 12, 16, or 24 hours after administration, and the average values ​​over 1 minute at each evaluation time point were analyzed.

[0243] When the compounds of the present disclosure were tested in this assay, the no-effect dose on monkey cardiovascular system (blood pressure and heart rate) was 0.3 mg / kg for the compound of Example 11, 30 mg / kg for the compound of Example 12, and 3 mg / kg for the compound of Example 12-3. Compared with the effective dose at which a significant anti-colitis effect was observed in the mouse model of DSS-induced colitis described in Pharmacological Example 3, the safety margin (dose-based) of the compounds of the present disclosure was calculated to be 1-fold for the compound of Example 11, 10-fold for the compound of Example 12, and 10-fold for the compound of Example 12-3.

[0244] On the other hand, when comparative compound B was evaluated using the same method, the no-effect dose on the monkey circulatory system (blood pressure and heart rate) was found to be less than 0.01 mg / kg, and the safety margin (on a dosage basis) compared to the effective dose at which a significant anti-colitis effect was observed in the mouse model of DSS-induced colitis described in Pharmacological Example 3 was calculated to be less than 0.03 times. From these results, the safety margin obtained by comparing the no-effect dose on the monkey circulatory system with the effective dose in the mouse model showed that the compound of the present disclosure had a wider safety margin than comparative compound B.

[0245] [Formulation Example] Formulation Example The following ingredients are mixed by a conventional method and then compressed into tablets to obtain approximately 10,000 tablets, each containing 10 mg of the active ingredient. 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid …… 100 g Calcium carboxymethylcellulose (disintegrant) …… 20 g Magnesium stearate (lubricant) …… 10 g Microcrystalline cellulose …… 870 g

[0246] The disclosed compounds are useful as EP4 agonists, and in particular have EP4 agonist activity and selectivity for other subtypes. Furthermore, the disclosed compounds have excellent colon selectivity and therefore have a low risk of circulatory system toxicity, and therefore can be used as active ingredients in preventive and / or therapeutic agents for diseases associated with the EP4 receptor.

Claims

1. A compound represented by the general formula (I) , Where R 1 represents (1) an -OH group, (2) an -NHCH2CH2SO3H group, (3) an -NHCH2COOH group, or (4) an -NHCH(COOH)CH2CH2COOH group; L 1 represents (1) a thiazole ring or (2) C1-4 alkylene; L 2 represents (1) a C3-5 alkylene or (2) a benzene ring; X is (1) -CO-, (2) -NR X - or (3) a sulfur atom; R X represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R 2 represents (1) a methyl group, (2) a benzene ring, (3) a 5-10-membered heterocyclic ring, (4) a -COR group 2-1 , (5) a -CO- group (benzene ring), (6) a -CO- group (5-10-membered heterocyclic ring), (7) a -NH- group (benzene ring), or (8) an -OH group; when R 2is a benzene ring, a 5- to 10-membered heterocyclic ring, a -CO- group (benzene ring), a -CO- group (5- to 10-membered heterocyclic ring) or an -NH- group (benzene ring), the benzene ring or the 5- to 10-membered heterocyclic ring may be substituted with 1 to 5 substituents R 2-2 ; R 2-1 represents (1) a C1-4 alkyl group which may be substituted with a C1-4 alkoxy group, or (2) an -NH-(C1-4 alkyl) group; and R 2-2 represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a C1-4 haloalkoxy group, or (6) a benzene ring; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where L 1 is a thiazole ring, and the thiazole ring is represented by the formula , where * represents the binding site with the sulfur atom and ** represents the binding site with -COR 1 .

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the 5-10-membered heterocyclic ring in R 2 is a heterocyclic ring selected from the group consisting of (1) a pyridine ring, (2) a pyrazine ring, (3) a pyrimidine ring, (4) an imidazole ring, (5) a thiazole ring, (6) a triazole ring, (7) a tetrazole ring, (8) a furan ring, (9) a quinoline ring, and (10) a pyrazole ring.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, represented by the general formula (I-1) , where R 3is (1) a benzene ring, (2) a pyridine ring, (3) a pyrazine ring, (4) a pyrimidine ring, (5) an imidazole ring, (6) a thiazole ring, (7) a triazole ring, (8) a tetrazole ring, (9) a furan ring, (10) a quinoline ring, or (11) a pyrazole ring; R 3 can be substituted with 1-5 substituents R 3-1 ; R 3-1 represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a C1-4 haloalkoxy group, or (6) a benzene ring; X 1 represents (1) -NR X - or (2) a sulfur atom; and other symbols have the same meaning as the symbols described in paragraph 1.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, represented by the general formula (I-2) , where all symbols have the same meaning as the symbols described in paragraph 4.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, represented by the general formula (I-4) , where R 4 represents (1) the -COR group 4-1 , (2) a -CO- group (benzene ring), (3) a -CO- group (pyridine ring), (4) a -CO- group (pyrazine ring), (5) a -CO- group (furan ring), (6) a -NH- group (benzene ring), or (7) an -OH group; when R 4 represents a -CO- group (benzene ring), a -CO- group (pyridine ring), a -CO- group (pyrazine ring), a -CO- group (furan ring) or a -NH- group (benzene ring), the benzene ring, pyridine ring, pyrazine ring or furan ring may be substituted with 1 to 5 substituents R 4-2 ; R 4-1 represents (1) a C1-4 alkyl group which may be substituted with a C1-4 alkoxy group, or (2) an -NH-(C1-4 alkyl) group; R 4-2represents (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a C1-4 haloalkoxy group, or (6) a benzene ring; X 2 represents (1) -CO- or (2) -NR X -; And other symbols have the same meaning as the symbols described in paragraph 1.

7. The compound according to claim 1, wherein the compound represented by the general formula (I) is a compound selected from the group consisting of (1) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid; (2) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyrazinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid; (3) 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid; (4) 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methoxy-2-pyrazinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazole-4-carboxylic acid; (5) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-9-(2-pyridinylthio)-1-nonen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid; (6) 4-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoic acid; (7) 2-[({2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazol-4-yl}carbonyl)amino]ethanesulfonic acid; (8) 2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methoxy-2-pyrazinyl)thio]-1-octen-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazol-4-yl]carbonyl}amino)ethanesulfonic acid; And (9) 2-{[4-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)butanoyl]amino}ethanesulfonic acid; or a pharmaceutically acceptable salt thereof.

8. A compound which is 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

9. A compound which is 2-[({2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazol-4-yl}carbonyl)amino]ethanesulfonic acid or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, which is an EP4 agonist.

12. The pharmaceutical composition according to claim 10, which is a therapeutic and / or prophylactic agent for a disease associated with the EP4 receptor.

13. The pharmaceutical composition of claim 10, wherein the EP4 receptor-associated disease is an immune disease, asthma, neuronal cell death, arthritis, lung injury, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver injury, acute hepatitis, nephritis, renal failure, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis, hemophagocytic syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn injury, systemic granuloma, inflammatory bowel disease, hypercytokinemia during dialysis, multiple organ failure, and / or shock.

14. The pharmaceutical composition of claim 12, wherein the EP4 receptor-associated disease is an inflammatory bowel disease, and the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

15. A therapeutic and / or prophylactic agent for a disease associated with the EP4 receptor, wherein the therapeutic and / or prophylactic agent comprises a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

16. A method for the prevention and / or treatment of a disease associated with the EP4 receptor, wherein the method comprises administering a compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof as an active ingredient, as well as a pharmaceutically acceptable carrier, to a patient in need of the prevention and / or treatment of a disease associated with the EP4 receptor.

17. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of a disease associated with the EP4 receptor.

18. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the manufacture of a prophylactic and / or therapeutic agent for the treatment of a disease associated with the EP4 receptor.