Ep4 agonists

Abstract

The present application relates to a compound represented by the general formula (I) (where all symbols represent the same meanings as those described in the specification) or a pharmaceutically acceptable salt thereof, which is useful as an EP4 agonist, and in particular, which has EP4 agonist activity, is selective to other PGE receptor subtypes, and has a low risk of toxicity to the circulatory system, and thus is useful as an active ingredient for preventing and / or treating diseases associated with the EP4 receptor.

Description

Technical Field

[0001] This invention relates to compounds having EP4 agonist activity or pharmaceutically permissible salts thereof, and to pharmaceuticals containing them as active ingredients. Specifically, this disclosure relates to compounds represented by general formula (I):

[0002]

[0003] (where all symbols represent the same meaning as described below) or their pharmaceutically permissible salts (hereinafter referred to as compounds of this disclosure), and pharmaceutical compositions containing them as active ingredients. Background Technology

[0004] Prostaglandin E2 (abbreviated as PGE2) is known to be a metabolite in the arachidonic acid cascade, and its functions are known to include cell protection, uterine contraction, pain production, promotion of gastrointestinal motility, arousal, inhibition of gastric acid secretion, lowering blood pressure, and diuresis.

[0005] It is known that there are subtypes of PGE receptors, each with different functions, and there are currently about four known subtypes, which are referred to as EP1, EP2, EP3 and EP4 (Non-Patent Literature 1).

[0006] Because the EP4 receptor is believed to be involved in inhibiting TNF-α production and enhancing IL-10 production, compounds that bind to the EP4 receptor are considered 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; organ transplant rejection, etc.), asthma, neuronal death, arthritis, lung injury, pulmonary fibrosis, emphysema, bronchitis, chronic obstructive pulmonary 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, burn injury, systemic granuloma, inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), hypercytokineemia during dialysis, multiple organ failure, and shock. EP4 receptors are also associated with mucosal protection (non-patent literature 2) and are thought to be useful for the prevention and / or treatment of gastrointestinal ulcers, such as gastric ulcers, duodenal ulcers, and stomatitis.

[0007] Compounds that selectively bind to EP4 are not considered to have the pain-producing effect caused by EP1, the uterine contraction effect caused by EP3, etc., and are therefore considered to be drugs that have no effect on these pain-producing and uterine contraction effects.

[0008] To date, many compounds with EP4 agonist activity have been discovered, and there are concerns about their effects on the circulatory system, such as decreased blood pressure and increased heart rate, when administered systemically, such as orally or intravenously (Non-Patent Literature 3).

[0009] On the other hand, Patent Document 1 describes the following general formula (A) as a compound having EP4 agonist activity.

[0010] General formula (A) is

[0011]

[0012] Q A It is CH2 or oxygen atom;

[0013] B A It is a -CH2- group, -(CH2)2- group, -(CH2)3- group, -(CH2)4- group, -(CH2)5- group, -CH=CH- group, -CH2-CH=CH- group, CH=CH-CH2- group, or -CH2-CH=CH-CH2- group, provided that B is a -CH2- group, -(CH2)2- group, -(CH2)3- group, -(CH2)4- group, -(CH2)5- group, -CH=CH-CH2- group, -CH=CH=CH=CH2- group, or -CH2-CH=CH-CH2- group, provided that B is a -CH2- group, -(CH2)2- group, -(CH2)3- group, -(CH2)4- group, -(CH2)5- group, -CH=CH- group, -CH2-CH=CH=CH- group, CH=CH-CH2- group, or -CH2-CH=CH-CH2- A When it is a -CH=CH- group or a -CH=CH-CH2- group, Q A It is a -CH2- group;

[0014] X A Yes -NR aA - group (where R) aA It can be a hydrogen atom, a halogen atom, an alkyl group or an acyl group), an -O- group, a -S- group, a -SO- group, a -SO2- group or a single bond, provided that X is a hydrogen atom, a halogen atom, an alkyl group or an acyl group, an -O- group, an -S- group, an -SO ... -SO2- group or a single bond. A When it is a single key, Q A It is an oxygen atom;

[0015] J A Yes - (CR) bA R cA ) nA - Group (where nA is an integer from 1 to 4, R bA and R cA All are hydrogen atoms, or R bA and R cA One or two of them are lower alkyl groups, and the rest are hydrogen atoms, or R bA and R cAWhen bonded to the same atom, it forms a C2-C5-polymethylene group or a -CH2-CH=CH- group;

[0016] A A It is a -CH2-CH2- group, a -CH=CH- group, or a -C≡C- group;

[0017] Z A It is a CH2OH group, a -C(O)OR' group, a -C(O)NR'R” group, a -C(O)NSO2R' group, a -P(Cl-C6)alkyl(O)(OR') group, a (-PO(OR')2 group or a tetrazol-5-yl group, wherein R' and R” are each independently a hydrogen atom or an alkyl group;

[0018] nA is 1, 2, 3, or 4;

[0019] R 1A It is -(CH2) pA R 7A Group or -(CH2) qA OR 8A Group, wherein R 7A and R 8A Each group is independently an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;

[0020] pA and qA are each independently 0, 1, 2, 3, 4 or 5;

[0021] R 2A It is a hydrogen atom, alkyl group, alkenyl group, or alkynyl group; and

[0022] R 3A R 4A R 5A and R 6A Each can independently represent a hydrogen atom or an alkyl group.

[0023] In Patent Document 2, the compound represented by the following general formula (B) is described as a compound having EP4 agonist activity.

[0024] General formula (B) is

[0025]

[0026] Where R 19-3B and R 20-3B Each can independently represent a hydrogen atom, an alkyl group, or a halogen atom;

[0027] T 3B Represents an oxygen atom or a sulfur atom;

[0028] X 3BRepresents a -CH2- group, a -O- group, or a -S- group;

[0029] A 3B Representing A 1-3B Or A 2-3B ;

[0030] A 1-3B Represents an alkylene group, an alkenylene group, or an alkyne group, which may be substituted by an alkyl group, and A 2-3B Representative - G 1-3B -G 2-3B -G 3-3B -group;

[0031] G 1-3B G represents alkylene groups, etc. 2-3B Representative-Y 3B -group, -(ring 1) 3B - group, -Y 3B -(Ring 1) 3B )- groups, etc., and Y 3B Represents -S- groups, etc.;

[0032] G 3-3B Represents single bonds, alkylene groups, alkenylene groups, ynylene groups, etc.

[0033] D 3B Represents D 1-3B Or D 2-3B ;

[0034] D 1-3B Represents -COOH group, -COOR 2-3B Group, tetrazol-5-yl group or CONR 3-3B SO2R 4-3B Group, and D 2-3B Represents -CH2OH group, -CH2OR 5-3B Group, hydroxyl group, -OR 5-3B Group, formyl group, -CONR 6-3B R 7-3B Group, -CONR 6-3B SO2R 8-3B Groups, etc.;

[0035] E 3B E 1-3B or E 2-3B ;

[0036] E 1-3B Represents a cycloalkyl group or a cyclo3 3B And E 2-3B Represents cycloalkyl groups, cyclo4 3B Or ring 5 3B ;

[0037] Ring 1 3B and Ring 5 3B Can be R 21-3B and / or R 22-3B replace;

[0038] Ring 3 3B Can be R 21-3B replace;

[0039] Ring 4 3B Must be an R 22-3B Replace, and can be further replaced by R 21-3B and / or R 22-3B replace;

[0040] R 21-3B Represents alkyl groups, alkoxy groups, halogen atoms, phenyl groups, etc.

[0041] R 22-3B Represents alkenyl groups, alkynyl groups, alkylthio groups, hydroxyl groups, and -NR. 24-3B R 25-3B Alkyl groups substituted with alkoxy groups, alkyl groups substituted with alkoxy groups substituted with halogen atoms, and alkyl groups substituted with -NR 24-3B R 25-3B Substituted alkyl groups, cyclohexane 6 3B -O-ring 7 3B , 7 3B Substituted alkyl groups, cyclopentadienyl groups 3B Substituted alkoxy groups, -O-ring 7 3B Substituted alkyl groups, -COOR 26-3B Groups, etc.;

[0042] Ring 1 3B Ring 5 3B Ring 6 3B and Ring 7 3B represent

[0043] C3-15 monocyclic, bicyclic, or tricyclic carbocyclic aryl groups, which may be partially or fully saturated, or

[0044] A 3- to 15-membered monocyclic, bicyclic, or tricyclic heterocyclic aryl group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, which may be partially or fully saturated; and

[0045] Ring 3 3B And Ring 4 3B Represents a thiophene group, a phenyl group, or a furanyl group (partial definition of the group is excerpted).

[0046] In Patent Document 3, compounds represented by the following general formula (C) are described as compounds having EP2 and EP4 agonist activities.

[0047] General formula (C) is

[0048]

[0049] Where T C Represents an oxygen atom or a sulfur atom;

[0050] X C Represents a -CH2- group, a -O- group, or a -S- group;

[0051] A C Representing A 1C Or A 2C ;

[0052] A 1C Represents an alkylene group, an alkenylene group, or an alkyne group, which may be substituted by an alkyl group, and A 2C Representative - G 1C -G 2C -G 3C -group;

[0053] G 1C G represents alkylene groups, etc. 2C Representative-Y C -group, -ring 1 C -group, -Y C -Ring 1 C - Groups, etc., Y C Represents -S- groups, etc., G 3C Represents single bonds, alkylene groups, alkenylene groups, ynylene groups, etc.

[0054] D C Represents D 1C Or D 2C ;

[0055] D 1C Represents -COOH group, -COOR 2C Group, tetrazol-5-yl group or -CONR 3C SO2R 4C Group, and D 2C Represents -CH2OH group, -CH2OR 5C Group, hydroxyl group, -OR 5C Group, formyl group, -CONR 6C R 7C Group, -CONR 6C SO2R 8C Groups, etc.;

[0056] E C E 1C or E 2C ;

[0057] E 1C represent

[0058] ;

[0059] R 11C Represents alkyl groups, alkylthio groups, alkyl groups substituted with cycloalkyl groups, and cyclo-substituted alkyl groups. C Substituted alkyl groups or -W 1C -W 2C - Ring 2 C Substituted alkyl groups;

[0060] W 1C Represents -O- group, -S- group, -SO- group, -SO2- group, -NR group 11-1C -group, carbonyl group, -NR 11- 1C SO2- group, carbonylamino group or aminocarbonyl group, W 2C Represents a single bond or a substituted alkyl group;

[0061] Ring 1 C Or ring 2 C Can be 1 to 5 R C replace;

[0062] R C Represents alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, halogen atoms, hydroxyl groups, nitro groups, and -NR. 15C R 16C Alkyl groups substituted with alkoxy groups, alkyl groups substituted with halogen atoms, alkyl groups substituted with alkoxy groups substituted with halogen atoms, and alkyl groups substituted with -NR 15C R 16C alkyl groups substituted with groups, cyclopentadienyl groups, cyclic 5 C Groups, -O-rings 5 C Group, Cyclic 5 C Alkyl groups substituted with groups, cyclopentadienyl groups C Substituted alkenyl groups, cyclopentadienyl groups C Substituted alkynyl group, cyclopentadienyl group C Substituted alkoxy groups, -O-ring 5 C Alkyl groups substituted with groups, COOR 17C Groups, alkoxy groups substituted with halogen atoms, formyl groups, alkyl groups substituted with hydroxyl groups, or acyl groups;

[0063] Ring 5 C It can be substituted by substituents selected from the following;

[0064] Alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkyl groups substituted with alkoxy groups, halogen atoms, hydroxyl groups, alkyl groups substituted with halogen atoms, and alkyl groups substituted with alkoxy groups substituted with halogen atoms.

[0065] Ring 1 C Ring 2 C and Ring 5 C Each represents independently

[0066] (1) A C3-15 monocyclic, bicyclic or tricyclic carbocyclic aryl group, which may be partially or fully saturated, or (2) a 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic aryl group containing heteroatoms selected from 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms, which may be partially or fully saturated (partial definition of the group is excerpted).

[0067] In Patent Document 4, compounds represented by the following general formula (D) are described as compounds having EP2 and EP4 agonist activities.

[0068] General formula (D) is

[0069]

[0070] Where D D Representative - COOR 1D Or a tetrazolium group, R 1D G represents a hydrogen atom or an alkyl group. D Represents ring A D or alkylene groups, and cyclic A D represent

[0071]

[0072] (where R) 2D (Representing a halogen atom, alkyl group, or alkoxy group), Y D Represents a key or -S-, T D X represents an oxygen atom or a sulfur atom. D Representing -CH2-, -O-, or -S-, ring B D This represents a C3-7 cycloalkyl group that may have the following substituents:

[0073]

[0074] (where R) 3DRepresents a halogen atom, an alkyl group that can be substituted by a halogen atom, an alkoxy group that can 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 heterocycle (which may be partially or fully saturated), and R 3D The phenyl group or heterocycle in the symbol may be replaced by a halogen atom, an alkyl group, an alkoxy group and / or a nitro group, and nD represents an integer from 1 to 4 (partial definition of the group is excerpted).

[0075] In Patent Document 5, compounds represented by the following general formula (E) are described as compounds having EP4 agonist activity.

[0076] General formula (E) is

[0077]

[0078] Where L 1E represent

[0079] a) An alkylene group, an alkenylene group, or an alkynylene group, wherein the alkylene group, alkenylene group, or alkynylene group may optionally be substituted with 1 to 4 fluorine substituents;

[0080] b) -(CH2) tE -G E -(CH2) pE -, where tE represents 0 to 2, pE represents 0 to 3, and tE + pE = 0 to 4; or

[0081] c) -(CH2) nE -G 1E -(CH2) pE -、-(CH2) nE -G 2E -(CH2) pE -、-(CH2) nE -C≡CG 2E -or-(CH2) 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;

[0082] G E represent

[0083]

[0084] G 1E Represents O, CO, S, SO, SO2, or NR 7E ;

[0085] G 2E represent

[0086]

[0087] Among them G 2E It may optionally be substituted by one to three substituents selected from alkyl groups, haloalkyl groups, cyano groups, halogen atoms, alkoxy groups and haloalkoxy groups;

[0088] R 1E Represents COOR 9E Group, CONR 9E R 10E Group, CH2OR 9E Group, SO3R 9E Group, SO2NR 9E R 10E Group, PO (OR) 9E )2 group or tetrazol-5-yl group;

[0089] L 3E Representative -C(R) 2E )2-C(R 3E )2-group, -C(R 2E )=C(R 3E - group, -C≡C- group, or ;

[0090] R 4E and R 5E Each independently represents an H or alkyl group, or an R 4E and R 5E They can form cycloalkyl groups together with the carbon atoms they are attached to;

[0091] L 2E Represents an alkylene group or an alkenylene group, wherein the alkylene group and the alkenylene group may optionally be substituted by 1 to 4 fluorine substituents;

[0092] R 6E Representing an aryl group or a heteroaryl group, wherein the aryl group or the heteroaryl group may optionally be substituted by one to four substituents selected from alkyl groups, haloalkyl groups, cyano groups, halogen atoms, alkoxy groups, haloalkoxy groups, and -alkylene-alkoxy groups; and

[0093] rE represents 0 or 1 (partial definition of the group is excerpted).

[0094] Reference List

[0095] Patent documents

[0096] Patent Document 1: WO 2003 / 007941 A

[0097] Patent Document 2: WO 2003 / 009872 A

[0098] Patent Document 3: WO 2003 / 074483 A

[0099] Patent Document 4: WO 2004 / 065365 A

[0100] Patent Document 5: WO 2014 / 144610 A

[0101] Non-patent literature

[0102] Non-patent literature 1: J. Lipid Mediators Cell Signaling, 379-391 (1995)

[0103] Non-patent literature 2: The Journal of Clinical Investigation, 883-893 (2002)

[0104] Non-patent literature 3: International Heart Journal, 107-114 (2017) Summary of the Invention

[0105] Technical issues

[0106] The purpose of this disclosure includes providing compounds that can be used as EP4 agonists, particularly compounds that have EP4 agonist activity, selectivity for other PGE receptor subtypes, and low risk of toxicity to the circulatory system.

[0107] Solution to the problem

[0108] To address the aforementioned problems, the inventors conducted in-depth research and discovered that the compounds represented by general formula (I) described below can be used as EP4 agonists, especially as they have low toxicity to the circulatory system because they possess both potent EP4 agonist activity and excellent colonic selectivity.

[0109] In one aspect, this disclosure provides the following implementation schemes:

[0110] [1] A compound or a pharmaceutically permissible salt thereof, said compound being represented by general formula (I):

[0111]

[0112] in

[0113] R 1The group represents (1)-OH group, (2)-NHCH2CH2SO3H group, (3)-NHCH2COOH group or (4)-NHCH(COOH)CH2CH2COOH group;

[0114] L 1 It indicates (1) a thiazole ring or (2) a C1-4 alkylene ring;

[0115] L 2 It indicates (1) a C3-5 alkylene group or (2) a benzene ring;

[0116] X represents (1)-CO-, (2)-NR X - or (3) sulfur atoms;

[0117] R X It represents (1) a hydrogen atom or (2) a C1-4 alkyl group;

[0118] R 2 This indicates (1) a methyl group, (2) a benzene ring, (3) a 5- to 10-membered heterocycle, and (4) -COR. 2-1 Group, (5)-CO-(benzene ring) group, (6)-CO-(5 to 10 membered heterocyclic ring) group, (7)-NH-(benzene ring) group, or (8)-OH group;

[0119] In R 2 When representing a benzene ring, a 5-10 membered heterocycle, a -CO- (benzene ring) group, a -CO- (5- to 10-membered heterocycle) group, or a -NH- (benzene ring) group, the benzene ring or the 5- to 10-membered heterocycle may be represented by 1 to 5 R groups. 2-2 replace;

[0120] R 2-1 This refers to (1) a C1-4 alkyl group that can be substituted by a C1-4 alkoxy group, or (2) a -NH-(C1-4 alkyl) group; and

[0121] R 2-2 It 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;

[0122] [2] A pharmaceutical composition comprising, as an active ingredient, a compound according to [1] or a pharmaceutically permissible salt thereof, and further comprising a pharmaceutically permissible carrier;

[0123] [3] The pharmaceutical composition according to [2] is an EP4 agonist; etc.

[0124] Advantages of the invention

[0125] The compounds disclosed herein can be used as EP4 agonists, particularly those exhibiting EP4 agonist activity and selectivity for other PGE receptor subtypes. Furthermore, the compounds disclosed herein exhibit excellent selectivity for the large intestine and therefore pose a low risk of toxicity to the circulatory system; thus, the compounds disclosed herein can be used as preventative and / or therapeutic agents for diseases related to the EP4 receptor.

[0126] Description of the implementation plan

[0127] This disclosure will now be described in detail.

[0128] In this specification, examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

[0129] Examples of C1-4 alkyl groups in this specification include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0130] Examples of C3-5 alkyl groups in this specification include propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, and neopentyl, and their isomers.

[0131] In this specification, examples of C1-4 alkylenes include methylene, ethylene, propylene (trimethylene), butylene (tetramethylene), isopropylene, isobutylene, and their isomers.

[0132] In this specification, examples of C3-5 alkylenes include propylene (trimethylene), butylene (tetramethylene), pentamethylene (pentamethylene), isopropylene, isobutylene, isopentylene, and their isomers.

[0133] In this specification, C1-4 haloalkyl groups refer to alkyl groups, for example, those substituted with one or more halogen atoms, and specific examples include fluoromethyl groups, chloromethyl groups, bromomethyl groups, iodomethyl groups, difluoromethyl groups, trifluoromethyl groups, 1-fluoroethyl groups, 2-fluoroethyl groups, 2-chloroethyl groups, pentafluoroethyl groups, 1-fluoropropyl groups, 2-chloropropyl groups, 3-fluoropropyl groups, 3-chloropropyl groups, 4,4,4-trifluorobutyl groups, 4-bromobutyl groups, and their isomers.

[0134] Examples of C1-4 alkoxy groups in this specification include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy groups.

[0135] In this specification, C1-4 haloalkoxy groups refer to alkoxy groups, for example, those substituted with one or more halogen atoms, and specific examples include fluoromethoxy groups, chloromethoxy groups, bromomethoxy groups, iodomethoxy groups, difluoromethoxy groups, trifluoromethoxy groups, 1-fluoroethoxy groups, 2-fluoroethoxy groups, 2-chloroethoxy groups, pentafluoroethoxy groups, 1-fluoropropoxy groups, 2-chloropropoxy groups, 3-fluoropropoxy groups, 3-chloropropoxy groups, 4,4,4-trifluorobutoxy groups, 4-bromobutoxy groups, and their isomers.

[0136] In this specification, the 5- or 6-membered heterocycle can be a non-aromatic or aromatic heterocycle. The 5- or 6-membered heterocycle may have, for example, at least one heteroatom selected from oxygen, sulfur, and nitrogen atoms as ring-forming atoms. Examples of 5- to 6-membered heterocycles include pyrrole, imidazole, triazole, tetraazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiaran, oxazole, isoxazole, thiazole, isothiazole, furazine, oxadiazole, oxazine, oxadiazine, thiazine, thiazine, thiazine, pyrrolidone, pyrrolidine, imidazoline, imidazoline, triazoline, triazoline, tetraazoline, tetraazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene. Tetrahydrothiophene, dihydrothiaran, tetrahydrothiaran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidin), dihydroisothiazole, tetrahydroisothiazole (isothiazolidin), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrothiadiazole (thiazolidin), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiazolidin), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazole, tetrahydrothiadiazole, morpholine, thiomorpholine, oxothiocyclohexane, dioxane, dithiocyclopentane, and dithiazane ring.

[0137] In this specification, the 5- to 10-membered heterocycle can be a non-aromatic heterocycle or an aromatic heterocycle. The 5- to 10-membered heterocycle can be a monocyclic heterocycle or a fused-ring heterocycle, such as a 2- to 4-ring heterocycle. The 5- to 10-membered heterocycle may have, for example, at least one heteroatom selected from oxygen, sulfur, or nitrogen atoms as a ring-forming atom. Examples of 5- to 10-membered heterocycles include: pyrrole, imidazole, triazole, tetraazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiaran, oxazole, isoxazole, thiazole, isothiazole, furazine, oxadiazole, oxazine, oxadiazine, thiazine, thiazine, thiazine, pyrrolidine, pyrrolidine, imidazoline, imidazoline, triazoline, triazoline, tetraazoline, tetraazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiaran, tetrahydropyran, tetrahydropyran Hydrothionane, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidin), dihydroisothiazole, tetrahydroisothiazole (isothiazolidin), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrothiadiazole, tetrahydrothiadiazole (thiazolidin), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiazolidin), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazole, tetrahydrothiadiazole, morpholine, thiomorpholine, oxothiocyclohexane, dioxane, dithiocyclopentane, dithiazane, azirheptatriene, diazirheptatriene, oxocycloheptatriene, thiocycloheptatriene Oxaazacycloheptatriene, oxazacycloheptatriene, thiaazacycloheptatriene, thiaazacycloheptatriene, indole, isoindole, indazine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithionaphthalene, indazole, quinoline, isoquinoline, quinazine, purine, phthalazine, pterin, naphthidine, quinoxaline, quinazoline, cinnaphthalene, benzoxazole, benzothiazolium, benzo[a]furazan, benzo[a]thiadiazole, benzo[a]triazole, dihydroazacycloheptatriene, tetrahydroazacycloheptatriene, perhydroazacycloheptatriene, dihydrodiazacycloheptatriene, tetrahydrodiazacycloheptatriene, perhydrodiazacycloheptatriene, dihydrooxocycloheptatriene, tetrahydrooxocycloheptatriene, perhydrooxocycloheptatriene Cycloheptatriene, dihydrothioheptatriene, tetrahydrothioheptatriene, perhydrothioheptatriene, dihydrooxazaheptatriene, tetrahydrooxazaheptatriene, perhydrooxazaheptatriene, dihydrooxazadiaheptatriene, tetrahydrooxazadiaheptatriene, perhydrooxazadiaheptatriene, dihydrothioheptatriene, tetrahydrothioheptatriene, perhydrothioheptatriene, dihydrothioheptatriene, tetrahydrothioheptatriene, perhydrothioheptatriene, dihydrothioheptatriene, tetrahydrothioheptatriene, perhydrothioheptatriene, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiopheneDihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthidine, tetrahydronaphthidine, perhydronaphthidine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, tetrahydroquinoxaline, tetrahydroquinoxaline , perhydroquinazoline, dihydrobenzoline, tetrahydrobenzoline, perhydrobenzoline, benzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazolium, perhydrobenzothiazolium, dihydrobenzimidazole, perhydrobenzimidazole, dioxane, benzodioxane, benzodioxane, benzodithiacyclopentane, benzodithiazide, azaspiro[4.4]nonane, oxane[4.4]nonane. Nonane, dioxazolo[4.4]nonane, azirasolo[4.5]decane, thiazospiro[4.5]decane, dithiazospiro[4.5]decane, dioxazolo[4.5]decane, azirasolo[4.5]decane, azirasbicyclo[3.2.1]octane, azirasbicyclo[3.2.1]octane, thieno[3,2-c]pyrazole, thieno[2,3-c]pyrazole, thieno[2,3-d]thiazole Thiophene[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]thiuran, tetrahydrothieno[3,2-b]pyridine, tetrahydrothieno[3,2-c]pyridine, and the thieno[3,2-c]pyridine ring.

[0138] In this disclosure, R 1 Represents -OH group, -NHCH2CH2SO3H group, -NHCH2COOH group, or -NHCH(COOH)CH2CH2COOH group. R 1 Preferably, it is a -OH group, a -NHCH2CH2SO3H group, or a -NHCH(COOH)CH2CH2COOH group, and more preferably a -OH group or a -NHCH2CH2SO3H group.

[0139] In this disclosure, L 1 Represents a thiazole ring or a C1-4 alkylene ring. L 1 Preferably, it is a thiazole ring, and the substitution mode of the thiazole ring is preferably...

[0140]

[0141] In the formula Represents the bonding site with the sulfur atom, and Representative and -COR 1 The bonding sites.

[0142] In this disclosure, L 2 Represents a C3-5 alkylene group or a benzene ring. L 2 Preferably, it is propylene (trimethylene), butylene (tetramethylene), pentamethylene (pentamethylene) or a benzene ring, and more preferably butylene (tetramethylene) or a benzene ring.

[0143] In this disclosure, X represents -CO-, -NR X -or sulfur atom. X is preferably -NR. X - or sulfur atom, and more preferably sulfur atom.

[0144] In this disclosure, R X Represents a hydrogen atom or a C1-4 alkyl group. R X Preferably, it contains hydrogen atoms or methyl groups.

[0145] In this disclosure, R 2 Represents methyl groups, benzene rings, 5- to 10-membered heterocycles, and -COR. 2-1 Groups, -CO- (benzene ring) groups, -CO- (5- to 10-membered heterocyclic) groups, -NH- (benzene ring) groups, or -OH groups. R 2 Preferably, it is a benzene ring, a 5- to 10-membered heterocycle, or -COR. 2-1 The group is a -CO- (benzene ring) group, a -CO- (5 to 10 membered heterocyclic) group, or a -NH- (benzene ring) group, more preferably a benzene ring or a 5 to 10 membered heterocyclic ring. The -CO- (benzene ring) group or the -CO- (5 to 10 membered heterocyclic) group is even more preferably a benzene ring, a 5 to 6 membered heterocyclic ring, a -CO- (benzene ring) group, or a -CO- (5 to 6 membered heterocyclic) group, even more preferably a benzene ring, a pyridine ring, a pyrazine ring, a pyrazole ring, an imidazole ring, a thiazole ring, a triazole ring, a tetraazole 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 is particularly preferred to be a benzene ring, a pyridine ring, a pyrazine ring, or a -CO- (benzene ring) group.

[0146] R 2 Alternatively, it can be selected based on the type of X. For example, when X is -CO-, R 2 Preferably, it is a methyl group, a benzene ring, a 5- to 10-membered heterocycle, a -NH- (benzene ring) group, or an -OH group, and more preferably a -NH- (benzene ring) group. When X is -NR X - At that time, R 2 Preferably, the group consists of a methyl group, a benzene ring, a 5- to 10-membered heterocycle, or -COR. 2-1 Group, -CO- (benzene ring) group or -CO- (5 to 10 membered heterocyclic) group, more preferably benzene ring, -COR 2-1The group, -CO- (benzene ring) group, or -CO- (5 to 10 membered heterocyclic) group, and more preferably a benzene ring, -COCH2OCH3 group, -CONHCH2CH3 group, -CO- (benzene ring) group, -CO- (pyridine ring) group, -CO- (pyrazine ring) group, or -CO- (furan ring) group. When X is a sulfur atom, R 2 Preferably, it is 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 tetrazolium ring, or a quinoline ring.

[0147] In this 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 tetrazolium ring, a furan ring, or a quinoline ring, more preferably a pyridine ring or a pyrazine ring, a pyrimidine ring, an imidazole ring, a thiazole ring, a triazole ring, a tetrazolium ring, a furan ring, or a quinoline ring, and even more preferably a pyridine ring or a pyrazine ring.

[0148] In this disclosure, R 2-1 Represents a C1-4 alkyl group, which may be substituted with a C1-4 alkoxy group or a -NH-(C1-4 alkyl) group. R 2-1 Preferably, it is a C1-4 alkyl group substituted with a C1-4 alkoxy group or a -NH-(C1-4 alkyl) group (and more preferably a -CH2OCH3 group or a -NHCH2CH3 group).

[0149] 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. R 2-2 Preferably, it is a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkoxy group, or a benzene ring; more preferably, it is a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a difluoromethoxy group, or a benzene ring; and even more preferably, it is a fluorine atom, a methyl group, or a methoxy group.

[0150] In this disclosure, compounds represented by general formula (I) are preferably compounds represented by general formula (I-1):

[0151]

[0152] Where R 3 Represents (1) benzene ring, (2) pyridine ring, (3) pyrazine ring, (4) pyrimidine ring, (5) imidazole ring, (6) thiazole ring, (7) triazole ring, (8) tetrazolium ring, (9) furan ring, (10) quinoline ring, or (11) pyrazole ring;

[0153] R3 Can be 1 to 5 R 3-1 replace;

[0154] R 3-1 Represents (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 haloalkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkoxy group, or (6) benzene ring;

[0155] X 1 Representative (1)-NR X - or (2) sulfur atom; and

[0156] Other symbols represent the same meanings as above; more preferably, compounds are represented by the general formula (I-2):

[0157]

[0158] All symbols represent the same meaning as described above; and more preferably, compounds represented by general formula (I-3):

[0159]

[0160] Where R 3a Represents (1) a pyridine ring or (2) a pyrazine ring, R 3a Can be 1 to 3 R 3-1 Replace, and other symbols represent the same meaning as above.

[0161] In this disclosure, R 3 Preferably, it is a benzene ring, pyridine ring, pyrazine ring, pyrazole ring, thiazole ring, imidazole ring, triazole ring, tetrazolium ring, or quinoline ring; more preferably, it is a benzene ring, pyridine ring, or pyrazine ring; and even more preferably, it is a pyridine ring or pyrazine ring.

[0162] In this disclosure, R 3-1 Preferably, it is a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkoxy group, or a benzene ring; more preferably, it is a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a difluoromethoxy group, or a benzene ring; and even more preferably, it is a fluorine atom, a methyl group, or a methoxy group.

[0163] In this disclosure, another aspect of the compounds represented by general formula (I) is preferably compounds represented by general formula (I-4):

[0164]

[0165] Where R 4 Representative (1)-COR 4-1(2)-CO-(benzene ring) group, (3)-CO-(pyridine ring) group, (4)-CO-(pyrazine ring) group, (5)-CO-(furan ring) group, (6)-NH-(benzene ring) group, or (7)-OH group;

[0166] When R 4 When representing 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, pyridine ring, pyrazine ring, or furan ring can be represented by 1 to 5 R groups. 4-2 replace;

[0167] R 4-1 Represents (1) a C1-4 alkyl group that can be substituted by a C1-4 alkoxy group or (2) a -NH-(C1-4 alkyl) group;

[0168] R 4-2 Represents (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 haloalkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkoxy group, or (6) benzene ring;

[0169] X 2 Represents (1)-CO- or (2)-NR X -;and

[0170] Other symbols represent the same meanings as above, or compounds represented by the general formula (I-5):

[0171]

[0172] All the symbols represent the same meaning as described above.

[0173] In this disclosure, R 4 Preferably, it is 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.

[0174] In this disclosure, R 4-2 Preferably, it is a C1-4 alkyl group or a C1-4 alkoxy group, and more preferably a methyl group or a methoxy group.

[0175] In this disclosure, the compound represented by general formula (I) is preferably the above-described R. 1 R 2 L 1 L 2 The combination of the preferred definition of X.

[0176] In this disclosure, another aspect of the compounds represented by general formula (I) is more preferably the example compounds described in the embodiments described below or their pharmaceutically permissible salts.

[0177] In this disclosure, all isomers are included unless otherwise stated. For example, alkyl groups, alkoxy groups, alkylene groups, etc., include straight-chain groups and branched groups. In addition, isomers in double bonds, rings, and fused rings (E, Z, cis, and trans forms); isomers due to the presence of asymmetric carbons (R and S forms, α and β forms, enantiomers, diastereomers); optically active substances having optical rotation (D, L, d, and l forms); polar substances obtained by chromatographic separation (highly polar substances, lowly polar substances); equilibrium compounds; rotational isomers; mixtures of these in any proportion; and racemic mixtures are all included in this disclosure. Furthermore, this disclosure also includes all tautomers.

[0178] In this disclosure, unless otherwise stated, as will be apparent to those skilled in the art, symbols

[0179]

[0180] Indicates bonding to the other side of the paper surface (i.e., α configuration), symbol

[0181]

[0182] This indicates front-side bonding with the paper surface (i.e., β configuration), and the symbol...

[0183]

[0184] Represents any mixture of α and β configurations.

[0185] [Salt]

[0186] Compounds represented by general formula (I) are converted into salts by known methods.

[0187] This salt is a pharmaceutically permissible salt.

[0188] The salt is preferably water-soluble.

[0189] Examples of pharmaceutically permissible salts include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, and amine salts.

[0190] Examples of acid addition salts include inorganic acid salts, such as hydrochlorides, hydrobroms, hydroiodates, sulfates, phosphates, and nitrates; and organic acid salts, such as acetates, lactates, tartrates, benzoates, citrates, methanesulfonates, ethanesulfonates, trifluoroacetates, benzenesulfonates, toluenesulfonates, hydroxyethylsulfonates, glucuronates, and gluconates.

[0191] Examples of alkali metal salts include potassium and sodium salts.

[0192] Examples of alkaline earth metal salts include calcium and magnesium salts.

[0193] Examples of ammonium salts include tetramethylammonium salt.

[0194] 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-glucosamine salts.

[0195] Compounds represented by general formula (I) can be converted into N-oxides by any method. N-oxides represent compounds obtained by oxidizing the nitrogen atom of a compound represented by general formula (I).

[0196] Compounds represented by general formula (I) and their pharmaceutically permissible salts may exist in a non-solventized form or in a solvated form with a pharmaceutically permissible solvent, such as water or ethanol. The solvate is preferably a hydrate. Compounds represented by general formula (I) and their pharmaceutically permissible salts may be converted into solvates.

[0197] Compounds represented by general formula (I) can form cocrystals with suitable cocrystal forming agents. The cocrystal is preferably a pharmaceutically permissible cocrystal formed by a pharmaceutically permissible cocrystal forming agent. A cocrystal is generally defined as a crystal in which two or more different molecules are formed through intermolecular interactions other than ionic bonds. The cocrystal can be a complex of a neutral molecule and a salt. The cocrystal can be prepared by known methods, such as by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable cocrystal forming agents include those described in WO 2006 / 007448 A.

[0198] In this disclosure, all references to compounds include compounds represented by general formula (I), pharmaceutically permissible salts thereof, their N-oxides, their solvates (e.g., hydrates), or eutectic forms thereof of pharmaceutically permissible salts of compounds represented by general formula (I); or N-oxides thereof, their solvates (e.g., hydrates), or eutectic forms thereof of pharmaceutically permissible salts of compounds represented by general formula (I).

[0199] [Prodrug]

[0200] A prodrug of a compound represented by general formula (I) is a compound that is converted into a compound represented by general formula (I) through a reaction in vivo with enzymes, gastric acid, etc. Examples of prodrugs of compounds represented by general formula (I) include compounds in which, when the compound represented by general formula (I) has an amino group, that amino group is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of the compound represented by general formula (I) is eicosanolylated, alaninolylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxopenten-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, neopentyloxymethylated, acetoxymethylated, tert-butylated, etc.); and compounds in which, when the compound represented by general formula (I) has a hydroxyl group, that hydroxyl group is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of the compound represented by general formula (I) is acetylated, Compounds palmitoylated, propionylated, neopentanoylated, succinylated, fumarylated, alanine-acylated, dimethylaminomethylcarbonylated, etc.; and compounds in which, when a compound represented by general formula (I) has a carboxyl group, that carboxyl group is esterified or amidated (e.g., compounds in which the carboxyl group of a compound represented by general formula (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, neopentanoyloxymethyl-esterified, 1-{(ethoxycarbonyl)oxy}ethyl-esterified, phthaloyl-esterified, (5-methyl-2-oxo-1,3-dioxopenten-4-yl)methyl-esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl-esterified or methylamidated, and compounds amidated with amino acids (e.g., taurine, glutamic acid, etc.). These compounds can be produced by methods known per se. The prodrug of a compound represented by general formula (I) can be a hydrate or a non-hydrated product. Furthermore, the prodrug of a compound represented by general formula (I) can be converted into a prodrug of a compound represented by general formula (I) under the physiological conditions described in "Pharmaceutical Research and Development", published by Hirokawa Shoten Co. in 1990, Vol. 7, "Molecular Design", pp. 163-198.

[0201] Furthermore, each atom constituting a compound represented by general formula (I) can be replaced by its isotopes (e.g., 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 16 N, 17 O, 18 O, 18 F, 35 S, 36Cl, 77 Br, 125 (e.g., I) etc., are replaced.

[0202] In this specification, colonic selectivity refers to the ratio of colonic concentration to plasma concentration at the time of compound administration (colonic concentration / plasma concentration).

[0203] [Method for manufacturing the disclosed compound]

[0204] The compounds disclosed herein can be prepared by known methods with appropriate modifications, such as the methods shown below, equivalent methods, methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), methods shown in the examples, and combinations thereof. Salts can be used as starting materials. The order of the reactions can be appropriately modified depending on the introduced protecting groups and reaction conditions.

[0205] Furthermore, if desired, compounds protected by a protecting group commonly used for these groups (e.g., the protecting group described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014) can be used to prepare compounds having amino, carboxyl, or hydroxyl groups by a known deprotection reaction following an appropriate reaction step.

[0206] Examples of protecting groups for carboxyl groups include methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), benzoylmethyl, p-methoxybenzyl, triphenylmethyl, and 2-chlorotriphenylmethyl.

[0207] Examples of protecting groups for amino or tetrazolium groups include benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluorenemethoxycarbonyl, benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM), and 2-(trimethylsilyl)ethoxymethyl (SEM).

[0208] Examples of protecting groups for hydroxyl groups or hydroxamic acids include methyl, triphenylmethyl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), neopentanoyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), and 2,2,2-trichloroethoxycarbonyl (Troc).

[0209] Deprotection reactions are known and can be carried out by the following methods. For example, an exemplary method is:

[0210] (1) Deprotection reaction via alkaline hydrolysis

[0211] (2) Deprotection reaction under acidic conditions,

[0212] (3) Through the deprotection reaction of hydrogenolysis

[0213] (4) Deprotection reaction of silyl groups

[0214] (5) Using metal deprotection reactions,

[0215] (6) Deprotection reactions using metal complexes, etc.

[0216] These methods are described in detail below:

[0217] (1) The deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g., methanol, tetrahydrofuran (THF), dioxane, etc.) using alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (e.g., barium hydroxide, calcium hydroxide, etc.), carbonates (e.g., sodium carbonate, potassium carbonate, etc.), their aqueous solutions, or mixtures thereof at 0 to 40°C.

[0218] (2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropanol, THF, anisole, etc.), in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), with or without 2,2,2-trifluoroethanol, at 0 to 100 °C.

[0219] (3) The deprotection reaction by hydrogenolysis is carried out, for example, in a solvent (e.g., ether-based solvents (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based solvents (e.g., methanol, ethanol, etc.), benzene-based solvents (e.g., benzene, toluene, etc.), ketone-based solvents (e.g., acetone, methyl ethyl ketone, etc.), nitrile-based solvents (e.g., acetonitrile, etc.), amide-based solvents (e.g., N,N-dimethylformamide (DMF), etc.), water, ethyl acetate, acetic acid, or mixtures of two or more of these solvents), in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium-carbon hydroxide, platinum oxide, Raney nickel, etc.), in a hydrogen atmosphere at atmospheric or pressurized pressure, or in the presence of ammonium formate at 0 to 200 °C.

[0220] (4) The deprotection reaction of the silyl group is carried out, for example, in an organic solvent miscible with water (e.g., THF, acetonitrile, etc.) using tetrabutylammonium fluoride at 0 to 40 °C. It is also carried out, for example, in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic 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.

[0221] (5) The deprotection reaction using metal is carried out, for example, in an acidic solvent (e.g., acetic acid, a buffer solution with pH 4.2 to 7.2, or a mixture of these solutions with an organic solvent (e.g., THF), in the presence of powdered zinc, while simultaneously applying ultrasound (if necessary), at 0 to 40°C.

[0222] (6) The deprotection reaction using metal complexes is carried out, for example, in an organic solvent (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixture thereof, in the presence of a capturing reagent (e.g., tributyltin hydride, triethylsilane, dimethyl ketone, morpholine, diethylamine, pyrrolidine, etc.), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), with or without a phosphine reagent (e.g., triphenylphosphine, etc.), using a metal complex (e.g., tetra(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, rhodium(I) tri(triphenylphosphine) chloride, etc.) at 0 to 40 °C.

[0223] Compounds represented by general formula (I) can be prepared by reaction scheme 1.

[0224]

[0225] (In reaction scheme 1, R) 1a(This represents the -NHCH2CH2SO3H group, the -NHCH2COOH group, or the -NHCH(COOH)CH2CH2COOH group, and other symbols represent the same meaning as above.)

[0226] In reaction scheme 1, reaction 1-1 is known and is carried out, for example, by reacting a compound represented by general formula 1a with a compound represented by general formula 1b in the presence of an organic solvent (e.g., tetrahydrofuran (THF), dimethylformamide (DMF), dimethoxyethane (DME), dioxane, acetonitrile, ethanol, and dichloromethane), water, or a mixture thereof, at a temperature of -20 to 70°C in the presence of an alkaline substance (e.g., sodium hydride, sodium hydroxide, potassium hydroxide, potassium phosphate, potassium tert-butoxide, potassium carbonate, tertiary amine + lithium chloride, etc.).

[0227] In reaction scheme 1, reactions 1-2 are known and are carried out by reacting the compound represented by general formula 1c obtained in reaction 1-1 with a reducing agent (e.g., sodium borohydride, zinc borohydride, etc.) in an organic solvent (e.g., THF, DME, toluene, dichloromethane, diethyl ether, dioxane, etc.), with or without cerium chloride, at -20 to 50 °C. When only one stereoisomer is selectively generated, the reaction is carried out using an asymmetric reducing agent (e.g., dichloroisobornenylborane, etc.) or a combination of chiral auxiliaries and reducing agents ((R)-2-methyl-CBS-oxonitroborane and borohydride / tetrahydrofuran complex or borane dimethyl sulfide complex; (S)-(-)-binaphthol and lithium aluminum hydride; etc.) at a temperature of -100 to 50 °C.

[0228] In reaction scheme 1, reactions 1-3 are deprotection reactions, and are carried out under the same conditions as the deprotection reactions described above.

[0229] In reaction scheme 1, reactions 1-4 are amidation reactions. Amidation reactions are known, and examples include:

[0230] (1) Using acyl halides

[0231] (2) The method using mixed acid anhydrides, and

[0232] (3) The method of using condensing agents.

[0233] These methods are described in detail below:

[0234] (1) Methods using acyl halides include, for example, reacting a carboxylic acid with an acyl halide forming agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or, in the absence of a solvent, at -20°C to reflux temperature, and reacting the resulting acyl halide with an amine in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at a temperature of 0 to 40°C. Alternatively, the method may involve reacting the resulting acyl halide 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.

[0235] (2) The method of using mixed acid anhydrides is, for example, by reacting a carboxylic acid with an acyl halide (neopentyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at 0 to 40 °C in an organic solvent (chloroform, dichloromethane, diethyl ether, THF, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) in the absence of a solvent, 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.

[0236] (3) The method of using condensing agents is, for example, to react carboxylic acids with amines in the presence or absence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) in an organic solvent (chloroform, dichloromethane, DMF, diethyl ether, THF, etc.), or in the absence of a solvent, using condensing agents (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, 1-propylphosphonic anhydride (1-propanephosphonic anhydride, PPA), etc.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate (HATU), in the presence or absence of 1-hydroxybenzotriazole (HOBt), at 0 to 40 °C.

[0237] All of these reactions (1), (2) and (3) are ideally carried out under anhydrous conditions in an inert gas atmosphere (argon, nitrogen, etc.).

[0238] 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.

[0239] In compounds represented by the general formula (1c), where X is X 1 The compound can also be prepared by reaction scheme 2.

[0240]

[0241] (In reaction scheme 2, all symbols have the same meaning as above)

[0242] In reaction scheme 2, reaction 2-1 is known and can be carried out under the same conditions as in reaction 1-1 above.

[0243] 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.

[0244] In reaction scheme 2, reactions 2-3 are known and are carried out, for example, by reacting in an organic solvent (dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, etc.) in the presence of alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.), carbonates (sodium carbonate, potassium carbonate, etc.), aqueous solutions thereof, or mixtures thereof, at 0 to 100°C.

[0245] In each reaction of this specification, the compounds used as starting materials, represented by general formula 1a, general formula 1b and general formula 2a, and the compounds represented by general formula 2d, are known, or can be readily prepared by combining and using the methods described in WO 2003007941 A (Patent Document 1), Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), etc., or by methods obtained by partially modifying known methods.

[0246] In the compounds disclosed herein, optically active compounds can be prepared by using optically active starting materials or reagents; optically resolving racemic intermediates to obtain the compounds of the present disclosure; or by optically resolving racemic compounds of the present disclosure.

[0247] Such optical separation is known, and examples include methods such as forming a salt, complex, etc. with another optically active compound, recrystallizing, and then separating the target compound, or using direct separation methods such as chiral columns.

[0248] In each reaction described herein, the reaction involving heating may be carried out using a water bath, oil bath, sand bath, or microwave oven, as will be apparent to those skilled in the art.

[0249] In each reaction described herein, a solid-phase loaded reagent supported on a macromolecular polymer (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be appropriately used.

[0250] In each reaction described herein, the reaction products can be purified by conventional purification methods, such as distillation under normal or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion exchange resins, scavenging resins or column chromatography, or washing, recrystallization, etc. Purification can be performed for each reaction or after certain reactions have been completed.

[0251] [toxicity]

[0252] Because the compounds disclosed herein have low toxicity, they can be used safely.

[0253] [Pharmaceutical Compositions]

[0254] Because the compounds disclosed herein have agonist activity against the EP4 receptor, they can be used to prevent and / or treat diseases associated with the EP4 receptor, such as immune diseases (autoimmune diseases, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjögren's syndrome, chronic rheumatoid arthritis, and systemic lupus erythematosus; organ transplant rejection, etc.), asthma, neuronal death, arthritis, lung injury, pulmonary fibrosis, emphysema, bronchitis, chronic obstructive pulmonary 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 granulomatosis, inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), hypercytokineemia during dialysis, multiple organ failure, shock, etc. The EP4 receptor is also associated with mucosal protection, and the compounds disclosed herein may be used to prevent and / or treat gastrointestinal ulcers, such as gastric ulcers, duodenal ulcers, and stomatitis.

[0255] Compounds that selectively bind to EP4 are not considered to have pain-producing effects caused by EP1, uterine contraction effects caused by EP3, etc., and therefore, due to these pain-producing and uterine contraction effects, the compounds disclosed herein can be drugs without side effects.

[0256] For the purpose of using the compounds of this disclosure for the prevention and / or treatment of the aforementioned diseases, the compound, as the active ingredient, is typically formulated together with a pharmaceutically permissible carrier (e.g., various additives or solvents) and then administered systemically or locally, orally or parenterally. Here, a pharmaceutically permissible carrier refers to a substance other than the active ingredient, which is commonly used in pharmaceutical formulations. Preferably, the pharmaceutically permissible carrier does not exhibit pharmacological effects at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. The pharmaceutically permissible carrier may also be used for purposes such as enhancing the efficacy of the active ingredient and the formulation, facilitating formulation, stabilizing quality, or improving usability. Specifically, substances described in the "Japanese Pharmaceutical Excipients Directory," published in 2021 by Yakuji Nippo, Limited (edited by the International Pharmaceutical Excipients Council Japan), may be appropriately selected according to the purpose.

[0257] The compounds disclosed herein can be administered to mammals (preferably humans, more preferably human patients) in pharmaceutically effective amounts.

[0258] The dosage of the compounds disclosed herein depends on age, weight, symptoms, desired therapeutic effect, route of administration, duration of treatment, etc., and therefore inevitably varies. Typically, the compounds disclosed herein are 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 continuously intravenously.

[0259] Of course, as mentioned above, since dosages vary depending on the circumstances, a dosage less than the above may be sufficient, or it may be necessary to administer a dose beyond the range.

[0260] Examples of dosage forms include oral formulations (e.g., tablets, capsules, granules, powders, oral solutions, syrups, oral gels, etc.), oral formulations (e.g., oral tablets, oral sprays, oral semi-solids, oral lavages, etc.), injectable formulations (e.g., injections, etc.), dialysis formulations (e.g., dialysate, etc.), inhalation formulations (e.g., inhalers, etc.), ophthalmic formulations (e.g., eye drops, eye ointments, etc.), otological formulations (e.g., ear drops, etc.), nasal formulations (e.g., nasal drops, etc.), rectal formulations (e.g., suppositories, rectal semi-solids, enteric-coated formulations, etc.), vaginal formulations (e.g., vaginal tablets, vaginal suppositories, etc.), and skin formulations (e.g., topical solids, topical liquids, sprays, ointments, creams, gels, patches, etc.).

[0261] [Formulations for oral administration]

[0262] Examples of formulations intended for oral administration include tablets, capsules, granules, powders, oral solutions, syrups, and oral gels. Examples of formulations intended for oral administration include rapidly disintegrating formulations (where the releaseability of the active ingredient from the formulation is not specifically regulated) and modified-release formulations (e.g., enteric-coated and sustained-release formulations, where releaseability is regulated according to purpose through unique formulation design and manufacturing methods). Enteric-coated formulations are designed to release the active ingredient primarily in the small intestine, not in the stomach, to prevent degradation of the active ingredient in the stomach or to reduce gastric irritation, and are typically prepared by coating with an acid-insoluble enteric matrix. Sustained-release formulations are formulations where the release rate, release time, and release site of the active ingredient from the formulation are regulated to reduce administration frequency or side effects, and are typically prepared by using a suitable sustained-release agent. In formulations intended for oral administration, capsules, granules, tablets, etc., can be coated with appropriate coating agents, such as sugars, sugar alcohols, or polymer compounds, for purposes such as promoting the uptake of the active ingredient or preventing its degradation.

[0263] (1) Tablets

[0264] Tablets are solid dosage forms administered orally and having a defined shape. Examples include those commonly referred to as tablets, such as uncoated tablets, film-coated tablets, sugar-coated pills, multilayer tablets, and dry-coated tablets, as well as orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and instant-dissolving tablets. When producing uncoated tablets, the following methods (a), (b), or (c) are typically used:

[0265] (a) Adding additives such as excipients, binders or disintegrants to the active ingredient and mixing to homogenize the mixture, and using water or a solution containing binders to form the mixture into particles by appropriate methods, then adding lubricants, etc. to the mixture, mixing the mixture, and compressing it.

[0266] (b) Adding additives such as excipients, binders or disintegrants to the active ingredient and mixing to homogenize the mixture, and then directly compressing the mixture; or adding the active ingredient, lubricant, etc. to granules prepared in advance with additives and mixing to homogenize the mixture, and then compressing the mixture.

[0267] (c) Adding additives, such as excipients or binders, to the active ingredient and mixing to homogenize the mixture, pouring the solvent-wetted mixture into a mold and shaping it, and then drying it by an appropriate method.

[0268] Film-coated tablets are typically made by thinly coating uncoated tablets with a suitable coating agent (e.g., a polymer compound). Sugar-coated pills are typically made by coating uncoated tablets with a coating agent containing sugars or sugar alcohols. Multilayer tablets are made by layering powder particles of different compositions using a suitable method, followed by compression molding of the powder particles. Dry-coated tablets are made by covering an inner chip agent with an outer layer of different compositions. Tablets can also be made into enteric-coated tablets or sustained-release tablets using known suitable methods. Orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and instant-dissolving tablets are those tablets that acquire unique functions through the appropriate selection of additives and can be made according to the methods used to prepare the tablets. Orally disintegrating tablets are tablets that can be taken by rapidly dissolving or disintegrating in the mouth; chewable tablets are tablets that are taken by chewing; effervescent tablets are tablets that rapidly produce foam while dissolving or dispersing in water; dispersible tablets are tablets that are taken by dispersing in water; and instant-dissolving tablets are tablets that are taken by dissolving in water. Effervescent tablets can be made by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives.

[0269] (2) Capsules

[0270] Capsules are formulations filled in capsules or encapsulated in a capsule matrix, examples of which include hard capsules and soft capsules. Hard capsules can be manufactured by adding additives such as excipients to the active ingredient and mixing to homogenize the mixture, or by forming granules or molded products by appropriate methods and filling the mixture, granules, or molded products into capsules as is, or by slightly shaping the mixture or granules before filling them into capsules. Soft capsules can be manufactured by encapsulating a mixture of active ingredients and additives in a suitable capsule matrix in a given shape, for example by adding gelatin with increased plasticity, such as glycerin or D-sorbitol. Capsules can also be made into enteric-coated capsules or sustained-release capsules using known appropriate methods, and colorants, preservatives, etc., can be added to the capsule matrix.

[0271] (3) Granules

[0272] Granules are formulations granulated into granule form. Examples include effervescent granules, in addition to those commonly referred to as granules. When producing granules, the following methods (a), (b), or (c) are typically used:

[0273] (a) Adding excipients, binders, disintegrants or other additives to the powdered active ingredient to homogenize the mixture, and then forming the mixture into granules by appropriate methods;

[0274] (b) Adding additives, such as excipients, to the pre-granulated active ingredient and mixing to homogenize the mixture;

[0275] (c) Adding an additive, such as an excipient, to the active ingredient that has been pre-granulated and mixing it, and then forming the mixture into granules by an appropriate method.

[0276] Granules can be coated as needed and can also be formulated into enteric-coated granules or sustained-release granules using known suitable methods. Effervescent granules can be prepared by using appropriate acidic substances, carbonates, bicarbonates, etc., as additives. Effervescent granules are granules that rapidly effervesce while dissolving or dispersing in water. Granules can also be made into fine granules by adjusting their size.

[0277] (4) Powder

[0278] The powder is a powdered formulation and is typically made by adding excipients or other additives to the active ingredient and mixing them to homogenize the mixture.

[0279] (5) Oral solution

[0280] Oral solutions are liquid or flowable viscous gel-like preparations, examples of which include those commonly referred to as oral solutions, as well as elixirs, suspensions, emulsions, and lemonade. Oral solutions are typically prepared by adding additives and purified water to the active ingredient, mixing them to homogeneously dissolve, emulsify, or suspend them, and filtering as needed. Emulsions are clear liquid oral solutions containing sweet and aromatic ethanol, and are typically prepared by adding ethanol, purified water, flavoring agents, white sugar, and other sugars or sweeteners to a solid active ingredient or its extract, and dissolving it by filtration or other methods to form a clear liquid. Suspensions are oral solutions in which the active ingredient is finely and homogeneously suspended, and are typically prepared by adding a suspending agent or other additives and purified water or oil to a solid active ingredient, suspending the mixture by appropriate methods, and homogenizing the entire mixture. Emulsions are oral solutions in which the active ingredient is finely and homogeneously emulsified, and are typically prepared by adding an emulsifier and purified water to a liquid active ingredient, emulsifying the mixture by appropriate methods, and homogenizing the entire mixture. Lemonade is a clear, liquid oral solution with a sweet and sour taste.

[0281] (6) Syrup

[0282] Syrups are viscous liquid or solid preparations containing sugars or sweeteners, and examples include syrup formulations. Syrups are typically prepared by adding an active ingredient to a solution of granulated sugar, other sugars, or a sweetener, or to a single syrup; dissolving, mixing, suspending, or emulsifying the mixture; boiling the mixture if necessary; and then filtering the mixture while heating. Syrup formulations refer to granular or powdered preparations that become syrup when water is added; they are also called dry syrups. Syrup formulations are typically manufactured using sugars or sweeteners as additives, following methods for manufacturing granules or powders.

[0283] (7) Oral gel

[0284] Oral gels are molded gel-like formulations that are not fluid and are typically manufactured by adding additives and a polymer gel matrix to the active ingredients, mixing them, gelling them using appropriate methods, and molding them into a specific shape.

[0285] [Preparations for injection]

[0286] (1) Injectable

[0287] Injectable preparations are solid, sterile formulations administered subcutaneously, intramuscularly, or directly to body tissues such as blood vessels or organs. They are used as solutions, suspensions, or emulsions, or by dissolving or suspending during use, and examples include those commonly referred to as injections, as well as lyophilized injections, powdered injections, pre-filled syringes, cartridge formulations, infusions, implantable injections, and long-acting injections. When manufacturing injections, the following methods (a) or (b) are typically used:

[0288] (a) A solution obtained by dissolving, suspending or emulsifying the mixture obtained by adding an additive to the active ingredient in water for injection, another aqueous solvent, a non-aqueous solvent, etc., and homogenizing the mixture, is filled into a container for injection, and the container is sealed and sterilized.

[0289] (b) A solution obtained by dissolving, suspending or emulsifying the mixture, either as is or by adding an additive to the active ingredient, in water for injection, another aqueous solvent, a non-aqueous solvent, etc., to homogenize the mixture, is sterilely filtered or sterilely prepared to homogenize the mixture, filled into a container for injection, and the container is sealed.

[0290] Lyophilized injections are typically prepared by dissolving the active ingredient, either as is or with additives such as excipients, in water for injection; sterile filtration of the solution; filling the solution into a container for injection; and then lyophilizing the solution, or by lyophilizing the solution in a dedicated container and then filling the solution into a direct container. Powder injections are typically prepared by sterile filtration of the powder followed by crystallization, or by adding sterile additives to the powder and filling the powder into a container for injection. Prefilled syringes are typically prepared by preparing a solution, suspension, or emulsion containing the active ingredient, either as is or with additives, and filling the solution, suspension, or emulsion into a syringe cartridge. Cartridge formulations are injections used by placing a cartridge filled with liquid medication into a dedicated syringe, and cartridges filled with liquid medication are typically prepared by preparing a solution, suspension, or emulsion containing the active ingredient, either as is or with additives, and filling the solution, suspension, or emulsion into a cartridge. Infusions are injections typically administered intravenously in volumes of 100 mL or more. Implantable injectables are solid or gel-like injectables administered via implantation or surgical procedures, such as subcutaneous or intramuscular injections, with the aim of releasing active ingredients over a prolonged period. Implantable injectables are typically made using biodegradable polymer compounds and forming them into microspheres, spheres, or gels. Long-acting injectables are injectables administered intramuscularly or similarly, with the aim of releasing active ingredients over a prolonged period. They are typically made by dissolving or suspending the active ingredient in substances such as vegetable oils, or by preparing a suspension of microspheres using biodegradable polymer compounds.

[0291] The compounds disclosed herein may be administered in combination with other pharmaceuticals for the following purposes:

[0292] 1) To supplement and / or enhance the preventive and / or therapeutic effects of the compound.

[0293] 2) Improve the kinetics and absorption of the compound, reduce the dosage of the compound, and / or

[0294] 3) Reduce the side effects of this compound.

[0295] The compounds disclosed herein, in combination with other drugs, can be administered as a compound formulation, wherein the two components are combined in one formulation, or as a single formulation. Such administration as a single formulation includes simultaneous administration and administration at time intervals. Furthermore, for administration at time intervals, the compound disclosed herein may be administered first, followed by another drug, or vice versa. The respective administration methods may be the same or different.

[0296] There are no particular limitations on the diseases for which the above-described combination of drugs exerts preventive and / or therapeutic effects, as long as the preventive and / or therapeutic effects of the disclosed compounds are supplemented and / or enhanced.

[0297] Examples of other medicines used to supplement and / or enhance the preventive and / or therapeutic effects of compounds represented by general formula (I) on inflammatory bowel disease include 5-aminosalicylic acid preparations, steroids, immunomodulators, immunosuppressants, anti-TNF-α antibodies, anti-α4β7 integrin antibodies, and JAK inhibitors.

[0298] Examples of 5-aminosalicylic acid formulations include sulfasalazine and mesalazine.

[0299] Examples of steroids include prednisolone, betamethasone, budesonide, and cortisol.

[0300] Examples of immunomodulators include azathioprine and 6-mercaptopurine.

[0301] Examples of immunosuppressants include tacrolimus and cyclosporine.

[0302] Examples of anti-TNF-α antibodies include infliximab, adalimumab, and golimumab.

[0303] Examples of anti-α4β7 integrin antibodies include vedolizumab.

[0304] Examples of JAK inhibitors include tofacitinib.

[0305] There are no particular restrictions on the weight ratio of compounds represented by general formula (I) to other drugs.

[0306] In addition, any two or more other drugs may be administered in combination.

[0307] In addition, other drugs that supplement and / or enhance the preventive and / or therapeutic effects of the compounds disclosed herein include not only those drugs that have been discovered to date, but also those drugs that will be discovered in the future based on the above-described mechanisms.

[0308] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[0309] Furthermore, all contents of all patent documents, non-patent documents, or references expressly cited in this specification may be incorporated herein as part of this specification.

[0310] In one aspect, this disclosure provides the following implementation scheme.

[0311] [1] A compound or a pharmaceutically permissible salt thereof, said compound being represented by general formula (I):

[0312]

[0313] in

[0314] R 1 It represents (1)-OH group, (2)-NHCH2CH2SO3H group, (3)-NHCH2COOH group, or (4)-NHCH(COOH)CH2CH2COOH group;

[0315] L 1 Represents (1) a thiazole ring or (2) a C1-4 alkylene ring;

[0316] L 2 Represents (1) a C3-5 alkylene group or (2) a benzene ring;

[0317] X represents (1)-CO-, (2)-NR X - or (3) sulfur atom;

[0318] R X Represents (1) a hydrogen atom or (2) a C1-4 alkyl group;

[0319] R 2 Represents (1) a methyl group, (2) a benzene ring, (3) a 5- to 10-membered heterocycle, and (4) -COR 2-1 Groups, (5)-CO- (benzene ring) group, (6)-CO- (5 to 10 membered heterocyclic ring) group, (7)-NH- (benzene ring) group, or (8)-OH group;

[0320] When R 2 When representing a benzene ring, a 5- to 10-membered heterocycle, a -CO- (benzene ring) group, a -CO- (5- to 10-membered heterocycle) group, or a -NH- (benzene ring) group, the benzene ring or the 5- to 10-membered heterocycle may be represented by 1 to 5 R groups. 2-2 replace;

[0321] R 2-1 Represents (1) a C1-4 alkyl group that can be substituted with a C1-4 alkoxy group, or (2) a -NH-(C1-4 alkyl) group; and

[0322] R 2-2 It 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.

[0323] [2] According to the compound described in [1] or its pharmaceutically permissible salt, wherein L 1 It is a thiazole ring, and the thiazole ring is represented by the following formula:

[0324]

[0325] in This indicates the bonding site with the sulfur atom, and Indicates -COR 1 The bonding sites.

[0326] [3] The compound according to [1] or [2], or a pharmaceutically permissible salt thereof, wherein R 2 The 5- to 10-membered heterocycles are selected from the following heterocycles: (1) pyridine ring, (2) pyrazine ring, (3) pyrimidine ring, (4) imidazole ring, (5) thiazole ring, (6) triazole ring, (7) tetrazolium ring, (8) furan ring, (9) quinoline ring, and (10) pyrazole ring.

[0327] [4] The compound according to [1] or [2], or a pharmaceutically permissible salt thereof, is represented by the general formula (I-1):

[0328]

[0329] Where R 3 Represents (1) benzene ring, (2) pyridine ring, (3) pyrazine ring, (4) pyrimidine ring, (5) imidazole ring, (6) thiazole ring, (7) triazole ring, (8) tetrazolium ring, (9) furan ring, (10) quinoline ring, or (11) pyrazole ring;

[0330] R 3 Can be 1 to 5 R 3-1 replace;

[0331] R 3-1 Represents (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 haloalkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkoxy group, or (6) benzene ring;

[0332] X 1 Representative (1)-NR X - or (2) sulfur atom; and

[0333] Other symbols represent the same meaning as the symbols described in [1] or [2].

[0334] [5] The compound described in [4] or its pharmaceutically permissible salt is represented by the general formula (I-2):

[0335]

[0336] All of these symbols represent the same meaning as those described in [4].

[0337] [6] A compound according to any one of [1] to [5], or a pharmaceutically permissible salt thereof, is represented by the general formula (I-3):

[0338]

[0339] Where R 3a Represents (1) a pyridine ring or (2) a pyrazine ring, R 3a Can be 1 to 3 R 3-1 Replace, and other symbols represent the same meaning as any one of [1] to [5].

[0340] [7] The compound according to [1] or [2], or a pharmaceutically permissible salt thereof, is represented by the general formula (I-4):

[0341]

[0342] Where R 4 Representative (1)-COR 4-1 (2)-CO-(benzene ring) group, (3)-CO-(pyridine ring) group, (4)-CO-(pyrazine ring) group, (5)-CO-(furan ring) group, (6)-NH-(benzene ring) group, or (7)-OH group;

[0343] When R 4 When representing 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, pyridine ring, pyrazine ring, or furan ring may be represented by 1 to 5 R groups. 4-2 replace;

[0344] R 4-1 Represents (1) a C1-4 alkyl group that can be substituted by a C1-4 alkoxy group or (2) a -NH-(C1-4 alkyl) group;

[0345] R 4-2 Represents (1) halogen atom, (2) C1-4 alkyl group, (3) C1-4 haloalkyl group, (4) C1-4 alkoxy group, (5) C1-4 haloalkoxy group, or (6) benzene ring;

[0346] X 2 Represents (1)-CO- or (2)-NR X -;and

[0347] Other symbols represent the same meaning as the symbols described in [1] or [2].

[0348] [8] The compound according to [1] or its pharmaceutically permissible salt, wherein the compound represented by general formula (I) is selected from the group consisting of:

[0349] (1) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazolyl-4-carboxylic acid;

[0350] (2) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyrazinylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazolyl-4-carboxylic acid;

[0351] (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-thiazolyl-4-carboxylic acid;

[0352] (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-thiazolyl-4-carboxylic acid;

[0353] (5) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-9-(2-pyridylthio)-1-nonen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazolyl-4-carboxylic acid;

[0354] (6) 4-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)butyric acid;

[0355] (7) 2-[({2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazolyl-4-yl}carbonyl)amino]ethanesulfonic acid;

[0356] (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-thiazolyl-4-yl]carbonyl}amino)ethanesulfonic acid; and

[0357] (9) 2-{[4-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)butyryl]amino}ethanesulfonic acid.

[0358] [9] A pharmaceutical composition comprising a compound according to any one of [1] to [8] or a pharmaceutically permissible salt thereof as an active ingredient, and further comprising a pharmaceutically permissible carrier.

[0359]

[10] The pharmaceutical composition according to [8] is an EP4 agonist.

[0360]

[11] The pharmaceutical composition according to [8] is a therapeutic and / or preventive agent for diseases associated with the EP4 receptor.

[0361]

[12] According to the pharmaceutical composition described in

[11] , the diseases associated with the EP4 receptor are immune diseases, asthma, neuronal death, arthritis, lung injury, pulmonary fibrosis, 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, burns, systemic granulomatosis, inflammatory bowel disease, hypercytokineemia during dialysis, multiple organ dysfunction syndrome and / or shock.

[0362]

[13] The pharmaceutical composition according to

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

[0363]

[14] According to the pharmaceutical composition of

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

[0364]

[15] Therapeutic and / or preventive agents for diseases associated with the EP4 receptor, said therapeutic and / or preventive agents containing a compound according to any one of [1] to [8] or a pharmaceutically permissible salt thereof.

[0365]

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

[0366]

[17] The compound of any one of [1] to [8] or its pharmaceutically permissible salt, used for the prevention and / or treatment of diseases associated with the EP4 receptor.

[0367]

[18] The use of any compound of any one of [1] to [8] or a pharmaceutically permissible salt thereof in the manufacture of a preventive and / or therapeutic agent for diseases associated with the EP4 receptor.

[0368] The compounds of this disclosure are described in detail below based on the following embodiments; however, the compounds of this disclosure are not limited to these embodiments.

[0369] [Synthesis Example]

[0370] In the sections on separation by chromatography and TLC, the solvents indicated in parentheses represent the elution or developing solvents used, and the proportions represent volume ratios.

[0371] The solvent shown in parentheses in the NMR section indicates the solvent used for the measurement.

[0372] The compound names used in this specification are named using ACD / Name (registered trademark) or Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft Corporation), which is a computer program that typically names compounds according to IUPAC rules; or according to IUPAC nomenclature.

[0373] LC-MS / ELSD analysis was performed under the following conditions.

[0374] condition;

[0375] Column: YMC Triart C 18 (Particle size: 1.9 x 10) -6 m; 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 (describing the ratio of mobile phase (A): mobile phase (B): [0 min] 95 : 5; [0.1 min] 95 : 5; [1.2 min] 5 : 95; [1.6 min] 5 : 95; Detector: UV (PDA), ELSD, MS.

[0376] Unless otherwise specified, HPLC retention times refer to the retention times under the conditions described in the LC-MS / ELSD. The descriptions in parentheses within the HPLC retention time section indicate the measurement conditions.

[0377] Reference Example 1: Dimethyl (7-hydroxy-2-oxohepyl)phosphonate

[0378] A 1.59 M n-butyllithium solution in n-hexane (CAS No. 109-72-8, 100 mL) was added dropwise to a solution of dimethyl methylphosphonate (CAS No. 756-79-6, 18 g) in tetrahydrofuran (THF) (120 mL) at -78 °C, and the mixture was stirred at -78 °C for 1 hour. A 20 mL solution of ε-caprolactone (CAS No. 502-44-3, 8.3 g) in THF 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 filtered. The filtrate was concentrated under reduced pressure to give the title compound (16.7 g, 79% purity) with the following physical properties.

[0379] TLC: Rf 0.31 (ethyl acetate:methanol = 19:1).

[0380] Reference Example 2: 2-[(2-{(2R)-2-[(1E)-8-hydroxy-3-oxo-1-octen-1-yl]-5-oxo-1- [Pyrrolidinyl]ethyl[1,3-thiazolyl]ethyl 1,3-thiazolyl-4-carboxylate

[0381] The compound (7.2 g) produced in Example 1, lithium chloride (3.9 g), and triethylamine (11 mL) were added to a THF (210 mL) solution of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolyl]ethyl}thio)-1,3-thiazolyl-4-carboxylate (CAS No.: 1355026-69-5, 10 g), 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, filtered, and 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) with the following physical properties.

[0382] TLC: Rf 0.2 (ethyl acetate).

[0383] Reference Example 3: 2-[(2-{(2R)-2-[(1E)-8-{[(4-methylphenyl)sulfonyl]oxy}-3-oxo- 1-Octen-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]-1,3-thiazolyl-4-carboxylic acid ethyl ester

[0384] Trimethylamine hydrochloride (694 mg), triethylamine (7.6 mL), and p-toluenesulfonyl chloride (4.5 g) were added to a solution of the compound (8 g) produced in Reference Example 2 in dichloromethane (56 mL), and the mixture was stirred overnight at room temperature. 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, 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) with the following physical properties.

[0385] HPLC retention time (min): 1.17.

[0386] Reference Example 4: 2-[(2-{(2R)-2-[(1E)-3-hydroxy-8-{[(4-methylphenyl)sulfonyl]oxy}- 1-Octen-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]-1,3-thiazolyl-4-carboxylic acid ethyl ester

[0387] A 1M toluene solution (5 mL) of (R)-(+)-2-methyl-CBS-oxazolborane and 0.86 mL of N,N-diethylanilineborane were added to a THF (18 mL) solution of the compound (2.5 g) produced in Reference Example 3 at -15 °C, and the mixture was stirred at -15 °C for 4 hours. Water and 1N hydrochloric acid aqueous 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, 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 (1.86 g), which is a diastereomer mixture with the following physical properties.

[0388] TLC: Rf 0.2 (ethyl acetate).

[0389] Reference Example 5: 2-[(2-{(2R)-2-[(1E)-3-hydroxy-8-(2-pyridylthio)-1-octen-1-yl]- 5-O-1-pyrrolyl[ethyl]thio[-1,3-thiazolyl-4-carboxylic acid ethyl ester

[0390] Potassium carbonate (42 mg), sodium iodide (45 mg), and 2-mercaptopyridine (CAS No.: 2637-34-5, 34 mg) were added to a 2.4 mL solution of the compound (120 mg) produced in Reference Example 4, 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, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol = 100:0 → 90:10) to give the title compound (87 mg), which is a diastereomer mixture with the following physical properties.

[0391] HPLC retention time (min): 0.94.

[0392] Example 1: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridylthio)-1-octen-1-yl]- 5-O-1-pyrrolidinyl[ethyl]thio[-1,3-thiazolyl-4-carboxylic acid]

[0393]

[0394] To a solution of the compound (86 mg) produced in Reference Example 5 in dimethoxyethane (0.8 mL)-methanol (0.8 mL), 0.34 mL of 2 N sodium hydroxide aqueous solution was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reversed-phase column chromatography to separate the two diastereomers, thereby yielding a low-polarity substance (70 mg).

[0395] HPLC retention time (min): 0.83;

[0396] 1 H-NMR (CD3OD): 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.

[0397] Examples 1-1 to 1-16:

[0398] The compounds of the following examples were obtained by performing a procedure similar to that of Reference Example 5 → Example 1 using a corresponding thiol compound instead of 2-mercaptopyridine.

[0399] Example 1-1: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyrazinylthio)-1-octene-1- [[5-oxo-1-pyrrolidinyl]ethyl]thio]-1,3-thiazolyl-4-carboxylic acid

[0400]

[0401] HPLC retention time (min): 0.923;

[0402] 1 H-NMR (DMSO-d6): 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.

[0403] Examples 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-thiazolyl-4-carboxylic acid

[0404]

[0405] HPLC retention time (min): 0.956;

[0406] 1 H-NMR (DMSO-d6): 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.

[0407] Examples 1-3: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(6-methyl-2-pyridyl)thio]-1- Octen-1-yl-5-oxo-1-pyrrolidinyl[ethyl]thio)-1,3-thiazolyl-4-carboxylic acid

[0408]

[0409] HPLC retention time (min): 0.827;

[0410] 1 H-NMR (CD3OD): 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.

[0411] Examples 1-4: 2-({2-[(2R)-2-{(1E,3S)-8-[(3-chloro-2-pyridyl)thio]-3-hydroxy-1-octyl) [Alken-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]thio)-1,3-thiazolyl-4-carboxylic acid

[0412]

[0413] HPLC retention time (min): 1.064;

[0414] 1 H-NMR (DMSO-d6): 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.

[0415] Examples 1-5: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(4-methyl-2-pyridyl)thio]-1- Octen-1-yl-5-oxo-1-pyrrolidinyl[ethyl]thio)-1,3-thiazolyl-4-carboxylic acid

[0416]

[0417] HPLC retention time (min): 0.834;

[0418] 1 H-NMR (DMSO-d6): 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.

[0419] Examples 1-6: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methyl-2-pyridyl)thio]-1- Octen-1-yl-5-oxo-1-pyrrolidinyl[ethyl]thio)-1,3-thiazolyl-4-carboxylic acid

[0420]

[0421] HPLC retention time (min): 1.011;

[0422] 1 H-NMR (DMSO-d6): 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.

[0423] Examples 1-7: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methoxy-2-pyridyl)thio]- 1-Octen-1-yl-5-oxo-1-pyrrolidinyl[ethyl]thio)-1,3-thiazolyl-4-carboxylic acid

[0424]

[0425] HPLC retention time (min): 0.984;

[0426] 1 H-NMR (DMSO-d6): 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.

[0427] Examples 1-8: 2-({2-[(2R)-2-{(1E,3S)-8-[(5,6-difluoro-2-pyridyl)thio]-3-hydroxy- 1-Octen-1-yl-5-oxo-1-pyrrolidinyl[ethyl]thio)-1,3-thiazolyl-4-carboxylic acid

[0428]

[0429] HPLC retention time (min): 1.049;

[0430] 1H-NMR (DMSO-d6): 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.

[0431] Examples 1-9: 2-({2-[(2R)-2-{(1E,3S)-8-[(3-fluoro-2-pyridyl)thio]-3-hydroxy-1-octyl) [Alken-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]thio)-1,3-thiazolyl-4-carboxylic acid

[0432]

[0433] HPLC retention time (min): 1.018;

[0434] 1 H-NMR (DMSO-d6): 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.

[0435] Examples 1-10: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(3-pyridylthio)-1-octene-1- [[5-oxo-1-pyrrolidinyl]ethyl]thio]-1,3-thiazolyl-4-carboxylic acid

[0436]

[0437] HPLC retention time (min): 0.829;

[0438] 1 H-NMR (DMSO-d6): 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.

[0439] Examples 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-thiazolyl-4-carboxylic acid

[0440]

[0441] HPLC retention time (min): 0.813;

[0442] 1H-NMR (DMSO-d6): 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.

[0443] Examples 1-12: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(1H-pyrazol-3-ylthio)-1-octyl] [Alken-1-yl]-5-oxo-1-pyrrolidinyl]-ethyl)thio]-1,3-thiazolyl-4-carboxylic acid

[0444]

[0445] HPLC retention time (min): 0.882;

[0446] 1 H-NMR (DMSO-d6): 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.

[0447] Examples 1-13: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(1-phenyl-1H-tetrazole-5-yl)thio] [[1-octen-1-yl]-5-oxo-1-pyrrolyl]ethyl]thio)-1,3-thiazolyl-4-carboxylic acid

[0448]

[0449] HPLC retention time (min): 1.008;

[0450] 1 H-NMR (DMSO-d6): 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.

[0451] Examples 1-14: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(8-quinolinylthio)-1-octene-1- [[5-oxo-1-pyrrolidinyl]ethyl]thio]-1,3-thiazolyl-4-carboxylic acid

[0452]

[0453] HPLC retention time (min): 0.969;

[0454] 1H-NMR (DMSO-d6): 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.

[0455] Examples 1-15: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(1H-imidazol-2-ylthio)-1-octene- 1-yl]-5-oxo-1-pyrrolidinyl]ethyl)thio]-1,3-thiazolyl-4-carboxylic acid

[0456]

[0457] HPLC retention time (min): 0.721;

[0458] 1 H-NMR (DMSO-d6): 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.

[0459] Examples 1-16: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(1,3-thiazolyl-2-ylthio)-1-octyl] [Alken-1-yl]-5-oxo-1-pyrrolidinyl]-ethyl)thio]-1,3-thiazolyl-4-carboxylic acid

[0460]

[0461] HPLC retention time (min): 0.947;

[0462] 1 H-NMR (DMSO-d6): 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.

[0463] Example 2: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octene-1- [5-oxo-1-pyrrolidinyl]ethyl[thio]-1,3-thiazolyl-4-carboxylic acid

[0464]

[0465] By using N-methylaniline instead of 2-mercaptopyridine, a procedure similar to that in Reference Example 5 → Example 1 was performed to obtain the title compound having the following physical property values.

[0466] TLC: Rf 0.69 (chloroform:methanol = 4:1);

[0467] 1 H-NMR (CD3OD): 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.

[0468] Reference Example 6: 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-thiazolyl- Ethyl 4-formate

[0469] Imidazole (23 mg) and tert-butyldimethylchlorosilane (37 mg) were added to a DMF (2.6 mL) solution of the compound (133 mg) produced in Reference Example 4, 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, filtered, and the filtrate was concentrated under reduced pressure. Potassium thioacetate (CAS No.: 10387-40-3, 28 mg) was added to a dimethylacetamide (1.3 mL) solution of the resulting residue, 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, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50) to give the title compound (91 mg) with the following physical properties.

[0470] HPLC retention time (min): 1.491.

[0471] 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-thiazolyl-4-carboxylic acid

[0472]

[0473] Triphenylphosphine (14 mg), potassium carbonate (10 mg), and 2-bromo-3-methoxypyrazine (CAS No.: 1209905-41-8, 10 mg) were added to an ethanol (0.9 mL) solution of the compound (30 mg) produced in Reference Example 6, and the mixture was stirred at 60 °C throughout the day and night. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. A solution of 1N tetrabutylammonium fluoride (0.2 mL) was added to a THF (0.2 mL) solution of the resulting residue, and the mixture was stirred at room temperature throughout the day and night. Methanol (0.5 mL) and 2N sodium hydroxide aqueous solution (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 reversed-phase column chromatography to separate the two diastereomers, yielding a low-polarity substance (17 mg).

[0474] HPLC retention time (min): 1.01;

[0475] 1 H-NMR (CDCl3): 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.

[0476] 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-thiazolyl-4-carboxylic acid

[0477]

[0478] By using 2-bromo-6-methoxypyrazine instead of 2-bromo-3-methoxypyrazine, a procedure similar to that in Example 3 was performed to obtain the title compound having the following physical property values.

[0479] HPLC retention time (min): 0.476;

[0480] 1 H-NMR (DMSO-d6): 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.

[0481] Reference Example 7: Dimethyl (6-hydroxy-2-oxohexyl)phosphonate

[0482] By using δ-valerolactone (CAS No.: 542-28-9) instead of ε-caprolactone, a procedure similar to that in Reference Example 1 was performed to obtain the title compound having the following physical property values.

[0483] TLC: Rf 0.3 (ethyl acetate:methanol = 20:1).

[0484] Examples 4-1 to 4-4:

[0485] The following compound examples were obtained by using the compound produced in Reference Example 7 instead of the compound produced in Reference Example 1 and by using the corresponding thiol compound instead of 2-mercaptopyridine in a procedure similar to that of Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Example 1.

[0486] Example 4-1: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-7-(2-pyridylthio)-1-heptene-1- [[5-oxo-1-pyrrolidinyl]ethyl]thio]-1,3-thiazolyl-4-carboxylic acid

[0487]

[0488] TLC: Rf 0.29 (methanol:chloroform:acetic acid = 1:8:0.1);

[0489] 1 H-NMR (CD3OD): 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.

[0490] 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-thiazolyl-4-carboxylic acid

[0491]

[0492] HPLC retention time (min): 0.91;

[0493] 1 H-NMR (CDCl3): 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.

[0494] Example 4-3: 2-[(2-{(2R)-2-[(1E,3S)-7-{[6-(difluoromethoxy)-2-pyridyl]thio}-3- [Hydroxy-1-hepten-1-yl]-5-oxo-1-pyrrolidinyl]-ethyl]thio]-1,3-thiazolyl-4-carboxylic acid

[0495]

[0496] HPLC retention time (min): 1.04;

[0497] 1 H-NMR (CD3OD): 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.

[0498] Example 4-4: 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-7-[(5-methyl-2-pyridyl)thio]-1- Hepten-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]thio)-1,3-thiazolyl-4-carboxylic acid

[0499]

[0500] HPLC retention time (min): 0.894;

[0501] 1 H-NMR (CD3OD): 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.

[0502] Reference Example 8: (8-{[dimethyl(2-methyl-2-propyl)silyl]oxy}-2-oxooctyl)phosphine dimethyl ester

[0503] The title compound having the following physical properties was obtained by using methyl 7-{[dimethyl(2-methyl-2-propyl)silyl]oxy}heptanoate (CAS No.: 181274-06-6) instead of ε-caprolactone in a procedure similar to that in Example 1.

[0504] TLC: Rf 0.4 (ethyl acetate).

[0505] Reference Example 9: 2[(2-{(2R)-2-[(1E)-9-{[dimethyl(2-methyl-2-propyl)silyl]oxy] [3-hydroxy-1-nonen-1-yl]-5-oxo-1-pyrrolyl]ethyl]thio]-1,3-thiazolyl-4-carboxylic acid ethyl ester

[0506] By using the compound produced in Reference Example 8 instead of the compound produced in Reference Example 1, a procedure similar to that of Reference Examples 2 to 4 was performed to obtain the title compound having the following physical property values.

[0507] HPLC retention time (min): 1.413.

[0508] Example 10: 2-[(2-{(2R)-2-[(1E)-3-acetoxy-9-hydroxy-1-nonen-1-yl]-5-oxo-1- [Pyrrolidinyl]ethyl[1,3-thiazolyl]ethyl 1,3-thiazolyl-4-carboxylate

[0509] N,N-dimethyl-4-aminopyridine (7.7 mg) and acetic anhydride (77 mg) were added to a pyridine (3.6 mL) solution of the compound (360 mg) produced in Reference Example 9, and the reaction mixture was stirred at room temperature throughout the day and night. 1N hydrochloric acid aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was dissolved in ethanol (3.6 mL), and p-toluenesulfonic acid monohydrate (17 mg) was added to it at 0°C. The reaction mixture was then stirred at room temperature for 1 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) with the following physical properties.

[0510] HPLC retention time (minutes): 1.091.

[0511] Example 5: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-9-(2-pyridylthio)-1-nonen-1-yl]- 5-O-1-pyrrolidinyl[ethyl]thio[-1,3-thiazolyl-4-carboxylic acid]

[0512]

[0513] By using the compound produced in Reference Example 10 instead of the compound produced in Reference Example 2, a procedure similar to that of Reference Example 3 → Reference Example 5 → Example 1 was performed to obtain the title compound having the following physical property values.

[0514] HPLC retention time (min): 0.985;

[0515] 1 H-NMR (DMSO-d6): 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.

[0516] Example 6: 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridylthio)-1-octen-1-yl]- 5-O-1-pyrrolidinyl[ethyl]thio[butyric acid]

[0517]

[0518] The title compound having the following physical properties was obtained by using butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butyrate (CAS No.: 1365393-21-0) instead of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazolyl-4-carboxylate in a procedure similar to that of Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Example 1.

[0519] HPLC retention time (min): 0.84;

[0520] 1 H-NMR (CDCl3): 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.

[0521] Example 7: 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-7-(2-pyridylthio)-1-heptene-1-yl]- 5-O-1-pyrrolidinyl[ethyl]thio[butyric acid]

[0522]

[0523] By using butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butyrate (CAS No.: 1365393-21-0) instead of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazolyl-4-carboxylate, and by using the compound produced in Reference Example 7 instead of the compound produced in Reference Example 1, a procedure similar to that of Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Example 1 was performed to obtain the title compound having the following physical properties.

[0524] HPLC retention time (min): 0.817;

[0525] 1 H-NMR (CDCl3): 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.

[0526] Reference Example 11: [3-(2-{[dimethyl(2-methyl-2-propyl)silyl]oxy}ethyl)phenyl] Methyl acetate

[0527] Imidazole (490 mg) and tert-butyldimethylchlorosilane (1.05 g) were added to a DMF (10 mL) solution of methyl 2-(3-(hydroxyethyl)phenyl)acetate (CAS No.: 1260900-49-9, 1 g), 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, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 → 10:90) to give the title compound (1.5 g) with the following physical properties.

[0528] TLC: Rf 0.5 (hexane:ethyl acetate = 90:10).

[0529] Reference Example 12: {3-[3-(2-{[dimethyl(2-methyl-2-propyl)silyl]oxy}ethyl)benzene [2-oxopropyl]phosphonate dimethyl ester

[0530] By using the compound (1 g) produced in Reference Example 11 instead of ε-caprolactone, a procedure similar to that in Reference Example 1 was performed to obtain the title compound (1 g), which has the following physical property values.

[0531] TLC: Rf 0.43 (hexane:ethyl acetate = 33:67);

[0532] 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)butyric acid

[0533] By using butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butyrate instead of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazolyl-4-carboxylate, and by using the compound produced in Reference Example 12 instead of the compound produced in Reference Example 1, a procedure similar to that of Reference Example 2 → Reference Example 4 → Reference Example 10 → Example 1 was performed to obtain the title compound having the following physical properties.

[0534] HPLC retention time (min): 0.824;

[0535] 1H-NMR (CDCl3): 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.

[0536] Reference Example 14: 3-{2-[methoxy(methyl)amino]-2-oxoethyl}-N-phenylbenzamide

[0537] To a solution of [3-(phenylcarbamoyl)phenyl]acetic acid (CAS No.: 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 the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20 → 34:66) to give the title compound (750 mg) with the following physical properties.

[0538] HPLC retention time (min): 0.974.

[0539] Reference Example 15: Dimethyl 2-oxo-3-[3-(phenylcarbamoyl)phenyl]propyl}phosphonate

[0540] By using the compound produced in Reference Example 14 instead of the compound produced in Reference Example 1, a procedure with a similar purpose to that of Reference Example 1 was performed, resulting in the title compound having the following physical property values.

[0541] HPLC retention time (min): 0.923.

[0542] Example 8: 4-({2-[(2R)-2-{(1E,3S)-3-hydroxy-4-[3-(phenylcarbamoyl)phenyl]-1-butanediol) [Alken-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]thio)butyric acid

[0543]

[0544] By using butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butyrate instead of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazolyl-4-carboxylate, and by using the compound produced in Reference Example 15 instead of the compound produced in Reference Example 1, a procedure similar to that of Reference Example 2 → Reference Example 4 → Example 1 was performed to obtain the title compound having the following physical property values.

[0545] HPLC retention time (min): 0.939;

[0546] 1 H-NMR (CD3OD): 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.

[0547] Reference Example 16: Dimethyl [3-(3-nitrophenyl)-2-oxopropyl]phosphonate

[0548] The title compound having the following physical properties was obtained by using N-methoxy-N-methyl-2-(3-nitrophenyl)acetamide (CAS No.: 1036397-64-4) instead of ε-caprolactone in a procedure similar to that in Reference Example 1.

[0549] TLC: Rf 0.39 (ethyl acetate).

[0550] Reference Example 17: 4-[(2-{(2R)-2-[(1E)-3-hydroxy-4-(3-nitrophenyl)-1-buten-1-yl]- 5-O-1-pyrrolidinyl[ethyl]thio[butyl]butyrate

[0551] By using butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butyrate instead of ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazolyl-4-carboxylate, and by using the compound produced in Reference Example 16 instead of the compound produced in Reference Example 1, a procedure similar to that of Reference Examples 2 → 4 was performed to obtain the title compound having the following physical property values.

[0552] HPLC retention time (min): 1.137.

[0553] Reference Example 18: 4-[(2-{(2R)-2-[(1E)-3-acetoxy-4-(3-nitrophenyl)-1-butene-1- [[5-oxo-1-pyrrolidinyl]ethyl(thio]butyrate butyl ester]

[0554] Acetyl chloride (86 mg), triethylamine (0.23 mL), and N,N-dimethyl-4-aminopyridine (6.6 mg) were added to a solution of the compound (260 mg) produced in Reference Example 17 in dichloromethane (2.7 mL), 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, 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.

[0555] TLC: Rf 0.33 (hexane:ethyl acetate = 20:80).

[0556] Reference Example 19: 4-[(2-{(2R)-2-[(1E)-3-acetoxy-4-(3-aminophenyl)-1-butene-1- [[5-oxo-1-pyrrolidinyl]ethyl(thio]butyrate butyl ester]

[0557] Water (1 mL), THF (2.1 mL), ammonium chloride (500 mg), and zinc powder (611 mg) were added to a methanol (11 mL) solution of the compound (278 mg) produced in Reference Example 18, and the mixture was stirred at 65 °C for 15 hours. The reaction mixture was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, 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 reversed-phase chromatography to give the title compound (32 mg) with the following physical properties.

[0558] TLC: Rf 0.22 (hexane:ethyl acetate = 20:80).

[0559] Example 9: 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-4-{3-[(5-methyl-2-furanoyl)amino] [Phenyl]-1-buten-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]thio]butyric acid

[0560]

[0561] 5-Methyl-2-furancarboxylic acid (CAS No.: 1917-13-2, 9.6 mg), triethylamine (0.014 mL), and HATU (25 mg) were added to a DMF (0.2 mL) solution of the compound (25 mg) produced in Reference Example 19, and the mixture was stirred at room temperature for 2 hours. 2N aqueous sodium hydroxide solution (0.13 mL) was added to the reaction solution, and the mixture was stirred at room temperature throughout the day and night. 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 reversed-phase column chromatography to separate the two diastereomers, yielding a low-polarity substance (16 mg).

[0562] HPLC retention time (min): 0.908;

[0563] 1 H-NMR (DMSO-d6): 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.

[0564] Example 10: 4-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy-1-butanediol) [Alken-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]thio)butyric acid

[0565]

[0566] By using benzoic acid instead of 5-methyl-2-furan carboxylic acid, a procedure similar to that in Example 9 was performed to obtain the title compound having the following physical property values.

[0567] HPLC retention time (min): 0.929;

[0568] 1 H-NMR (DMSO-d6): 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.

[0569] Examples 10-1 to 10-4:

[0570] The compounds of the following examples were obtained by using ethyl 2-({2-[(2R)-2-(formyl)-5-oxo-1-pyrrolidinyl]ethyl}thio)-1,3-thiazolyl-4-carboxylate instead of butyl 4-({2-[(2R)-2-formyl-5-oxo-1-pyrrolidinyl]ethyl}thio)butyrate and by using the corresponding carboxylic acid compound instead of 5-methyl-2-furan carboxylic acid in a procedure similar to that of Reference Examples 17 → 18 → 19 → 9.

[0571] Example 10-1: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-4-{3-[(methoxyacetyl)amino]benzene] [1-Buten-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]thio]-1,3-thiazolyl-4-carboxylic acid

[0572]

[0573] HPLC retention time (min): 0.812;

[0574] 1 H-NMR (CD3OD): 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.

[0575] Example 10-2: 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-4-{3-[(2-pyridylcarbonyl)amino]benzene] [1-Buten-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]thio]-1,3-thiazolyl-4-carboxylic acid

[0576]

[0577] HPLC retention time (min): 0.903;

[0578] 1 H-NMR (CD3OD): 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.

[0579] 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-thiazolyl-4-carboxylic acid

[0580]

[0581] HPLC retention time (min): 0.943;

[0582] 1 H-NMR (CDCl3): 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.

[0583] 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-thiazolyl-4-carboxylic acid

[0584]

[0585] HPLC retention time (min): 0.943;

[0586] 1 H-NMR (CDCl3): 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.

[0587] Example 11: 2-[({2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridylthio)-1-octene- [1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazo-4-yl}carbonyl)amino]ethanesulfonic acid

[0588]

[0589] Triethylamine (0.02 mL), taurine (CAS No.: 107-35-7, 10 mg), and HATU (22 mg) were added to a DMF (0.3 mL) solution of the compound (27 mg) produced in Example 1, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reversed-phase column chromatography to give the title compound (14 mg) with the following physical properties.

[0590] HPLC retention time (min): 0.786;

[0591] 1H-NMR (D2O): 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.

[0592] Example 12: 2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(3-methoxy-2-pyrazinyl)thio] [[1-octen-1-yl]-5-oxo-1-pyrrolyl]ethyl]thio]-1,3-thiazolyl]carbonyl]amino]ethanesulfonic acid

[0593]

[0594] Triethylamine (0.56 mL), taurine (188 mg), and HATU (419 mg) were added to a DMF (5.4 mL) solution of the compound (540 mg) produced in Example 3, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reversed-phase column chromatography to give the title compound (210 mg) with the following physical properties.

[0595] HPLC retention time (min): 0.844;

[0596] 1 H-NMR (D2O): 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.

[0597] Examples 12-1 to 12-6:

[0598] By using the corresponding compound from the above examples instead of the compound produced in Example 1, and performing a procedure similar to that in Example 11, the following compound examples were obtained.

[0599] Example 12-1: 2-[({2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyrazinylthio)-1-octyl] [Alken-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazo-4-yl}carbonyl)amino]ethanesulfonic acid

[0600]

[0601] HPLC retention time (min): 0.855;

[0602] 1H-NMR (D2O): 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.

[0603] Example 12-2: 2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-7-[(5-methyl-2-pyridyl)thio] [[-1-hepten-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]thio]-1,3-thiazolyl-4-yl]carbonyl]amino]ethanesulfonic acid

[0604]

[0605] HPLC retention time (min): 0.801;

[0606] 1 H-NMR (D2O): 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.

[0607] Examples 12-3: 2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octyl] [Alken-1-yl]-5-oxo-1-pyrrolidinyl]ethyl]thio]-1,3-thiazo-4-yl]carbonyl]amino]ethanesulfonic acid

[0608]

[0609] HPLC retention time (min): 0.745;

[0610] 1 H-NMR (D2O): 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.

[0611] Examples 12-4: 2-({[2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[(6-methyl-2-pyridyl)thio] [[1-octen-1-yl]-5-oxo-1-pyrrolyl]ethyl]thio]-1,3-thiazolyl]carbonyl]amino]ethanesulfonic acid

[0612]

[0613] HPLC retention time (min): 0.755;

[0614] 1 H-NMR (D2O): 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.

[0615] Examples 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)butyryl]amino]ethanesulfonic acid

[0616]

[0617] HPLC retention time (min): 0.81;

[0618] 1 H-NMR (D2O): 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.

[0619] Examples 12-6: 2-({[2-({2-[(2R)-2-{(1E,3S)-4-[3-(benzoylamino)phenyl]-3-hydroxy [1-Buten-1-yl]-5-oxo-1-pyrrolyl]ethyl]thio]-1,3-thiazolyl]carbonyl]amino]ethanesulfonic acid

[0620]

[0621] HPLC retention time (min): 0.836;

[0622] 1 H-NMR (D2O): 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.

[0623] 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-thiazo-4-yl]carbonyl]amino)glutaric acid

[0624]

[0625] By using the compound produced in Example 2 instead of the compound produced in Example 1, and by using L-glutamic acid instead of taurine, a procedure similar to that in Example 11 was performed to obtain the title compound having the following physical property values.

[0626] HPLC retention time (min): 0.808;

[0627] 1 H-NMR (CD3OD): 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.

[0628] 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-thiazo-4-yl]carbonyl]amino)glutaric acid

[0629]

[0630] By using the compound produced in Example 2 instead of the compound produced in Example 1, and by using D-glutamic acid instead of taurine, a procedure similar to that in Example 11 was performed to obtain the title compound having the following physical property values.

[0631] HPLC retention time (min): 0.802;

[0632] 1 H-NMR (CD3OD): 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.

[0633] Pharmacological Example 1: Determination of the activity of agonists on various human prostaglandin receptors

[0634] Using CHO cells or Chem1 cells (EP1-CHO, EP2-CHO, EP3-Chem1, EP4-CHO, and IP-CHO) that are forcibly expressing various human prostaglandin receptors, the agonist activity of the test compounds on various prostaglandin receptors was detected using intracellular calcium concentration (for EP1 and EP3) and intracellular cyclic AMP (hereinafter referred to as cAMP) production (for EP2, EP4, and IP) as indicators.

[0635] <Compound Therapy>

[0636] The test compound and control substances (PGE2 and iloprost) were dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mmol / L solution. Thaw the prepared 10 mmol / L solution before use, perform serial dilutions with DMSO, and then dilute with either the buffer solution for Measurement 1 (Hank's balanced salt solution (Thermo Fischer Scientific, Inc.) containing 1 w / v% human serum albumin (Sigma-Aldrich Co. LLC), 2 μmol / L indomethacin (Sigma-Aldrich Co. LLC), 2.5 mmol / L probenecid and 10 mmol / L HEPES-NaOH (pH 7.4)) or the buffer solution for Measurement 2 (D-PBS (Nacalai Tesque Inc.) containing 0.1 w / v% human serum albumin, 2 μmol / L diclofenac (Sigma-Aldrich Co. LLC) and 1 mmol / L 3-isobutyl-1-methylxanthine (Sigma-Aldrich Co. LLC)) and perform the experiments.

[0637] <Measurement of agonist activity>

[0638] (1) Measurement of EP1 and EP3 activity (measurement of intracellular calcium concentration)

[0639] Intracellular calcium concentration was measured using the Calcium 6 Assay Kit (Molecular Devices). For EP1-CHO and EP3-Chem1, frozen cells were thawed the day before measurement and resuspended in Ham's F-12 medium (Thermo Fischer Scientific, Inc.) containing inactivated (56°C, 30 min) 9.8 vol% FBS (Thermo Fischer Scientific, Inc.) and penicillin-streptomycin (Nacalai Tesque Inc.). Cells were then seeded in 96-well UV plates at 1.0 × 10⁶ cells per well. 5Cells were cultured statically at 37°C in the presence of 5% CO2. On the day of measurement, the culture medium was removed, and 120 μL of calcium indicator solution dissolved in the buffer solution of Measurement 1 was added. The mixture was incubated at room temperature in the dark for approximately 1 hour. After 1 hour of incubation, a 96-well UV plate was placed in a fluorescence spectrophotometer (FDSS-7000, Hamamatsu Photonics KK), and intracellular calcium concentration was measured. 30 μL of the buffer solution of Measurement 1 containing different concentrations of agonist was added, and the mixture was 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.

[0640] (2) Measurement of EP2, EP4 and IP agonist activities (measurement of cAMP concentration)

[0641] For EP2-CHO, EP4-CHO, and IP-CHO, on the day of measurement, frozen cells were thawed and resuspended in D-PBS containing 2 μmol / L diclofenac. The cells were then centrifuged at 500g for 3 minutes at room temperature, and the supernatant was removed. Cells were resuspended in the buffer solution for Measurement 2, and 10 μL of each suspension was dispersed into 384-well plates to achieve a cell count of 2.0 × 10⁶ cells per well. 5 (EP2), 5.0 × 10 4 (EP4) and 1.0 × 10 5 (IP). Add 20 μL of buffer containing different concentrations of agonist for Measurement 2 and incubate the mixture at room temperature for 1 hour. Measure cAMP concentration using the cAMP HTRF HiRange kit (CIS BioInternational SA). Following the two-step protocol in the kit instructions, add 5 μL of each cAMP-D2 and trypsin (cryptase) diluted with lysis buffer and incubate the mixture at room temperature for 1 hour. After 1 hour of incubation, measure the time-resolved fluorescence at 620 nm and 660 nm when excited at 340 nm using a Synergy Neo (Bio teck) and determine the ratio (TRF ratio) to calculate the cAMP concentration based on the calibration curve.

[0642] <Results>

[0643] The agonist activities of the disclosed compounds against various prostaglandin receptors were measured using the methods described above. Table 1 shows the agonist activities against the EP4 receptor (ECG). 50 The results of the measurements (values) are shown in Table 2, which presents the agonist activity (EC50) against the EP1, EP2, EP3, and IP receptors. 50The values ​​are measured. The compounds described in the table are shown to have potent EP4 receptor agonist activity and selectivity for EP1, EP2, EP3 and IP.

[0644] [Table 1]

[0645]

[0646] [Table 2]

[0647]

[0648] Pharmacological Example 2: Calculation of Colonic Selectivity by Mouse PK

[0649] The test compound was dissolved in a 0.5% aqueous solution of methylcellulose and administered orally to C57BL / 6 mice at doses of 1, 3, or 10 mg / kg. Blood samples were collected at various time points after administration (0.5, 1, 2, 4, 7, or 9 hours later) and centrifuged at 12,000 rpm for 5 minutes to collect plasma. The colon was collected, rinsed with physiological saline, and homogenized with 4 times the weight of the colon in purified water. The plasma and colon concentrations of the test compound were determined by LC / MS / MS analysis. Colonic selectivity was determined as the ratio of the highest colonic concentration to the highest plasma concentration. For example, the compounds produced in Examples 1, 2, 3, and 10 exhibited colonic selectivity of 302, 440, 391, and 620 times, respectively. Furthermore, when the compounds produced in Examples 11, 12-3, and 12-5 were administered, their carboxylic acid forms (the compounds produced in Examples 1, 2, and 10, respectively) exhibited colonic selectivity of 248, 318, and 395 times, respectively.

[0650] On the other hand, when the colonic selectivity of compound (22) (comparative compound A) of Example 6 described in Patent Document 3 and compound (92) (comparative compound B) of Example 6 described in Patent Document 3, which have the following structures, was measured, their colonic selectivity was 20 times and 133 times, respectively.

[0651]

[0652] Pharmacological Example 3: Dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis

[0653] Adult C57BL / 6 mice were used in this assay. Day 0 was defined as the day 2% DSS was started in drinking water. The DSS solution was placed in a clear plastic bottle, and mice were allowed free access to the solution via a metal nozzle from day 0 to day 7 to induce ulcerative colitis. The test substance was administered orally once daily at a dose of 10 mL / kg for 7 days, from day 0 to day 6. Fecal samples were observed daily from day 0 to day 7, and the Disease Activity Index (DAI) was assessed according to a reference score (diarrhea score: 0: normal stool, 1: loose stool, 2: diarrheal stool, 3: watery stool; bloody stool score: 0: normal stool, 1: brownish, slightly bloody stool, 2: slightly reddish stool, 3: black stool); DAI score = diarrhea score + bloody stool score plus the sum of both scores.

[0654] The compounds disclosed herein were tested in this assay. The reduction in DAI scores compared to vector-treated animals (control group) indicates the efficacy of the model. The compounds of Examples 1 (0.3 mpk), 2 (0.3 mpk), 10 (1 mpk), 11 (0.3 mpk), 12 (3 mpk), 12-3 (0.3 mpk), and 12-5 (3 mpk) showed 50% inhibition of control scores in the DSS colitis mouse model at doses of 0.3, 1, or 3 mg / kg.

[0655] Pharmacological Example 4: Calculation of the concentration of action on circulating organs using the mouse tail cuff method, and calculation of its safety margin.

[0656] The effects on the circulatory organs in awake mice can be assessed using the tail-cuff method with a non-invasive, preheat-free blood pressure monitor (MK-2000). A cuff-type pulse sensor is attached to the tail of a mouse pre-adapted for measurement, and systolic blood pressure is measured from the pulse wave of the tail artery. Multiple measurements are taken consecutively, and the average value is recorded. The test substance is administered orally once at a dose of 10 mL / kg. Blood pressure is measured before administration of the test substance and at certain time intervals after administration, and an effect on the circulatory organs is defined as a change of 10% or more in systolic blood pressure after administration compared to before administration. Blood is collected immediately after blood pressure measurement, and the concentration of the test substance in plasma at which the effect on the circulatory organs is achieved is defined as the concentration at which the effect on the circulatory organs is achieved. The safety margin can be calculated by comparing it with the concentration of the test substance that has shown a significant anti-colitis effect in a mouse model of DSS-induced colitis.

[0657] Pharmacological Example 5: Calculation of safety margin through oral (po) circulation organ evaluation test in rats

[0658] To investigate the effects on the circulatory system in rats under unrestricted and conscious conditions, the test substance was administered orally once to male CR1:CD (SD) rats (n=4 per group) implanted with a telemetry transmitter (HD-S10, Data Sciences International, Inc.) or cannulated in the left carotid artery. Blood pressure (systolic, diastolic, and mean blood pressure) and heart rate were continuously measured. Assessment time points were set before administration and at 0.5, 1, 2, 3, 4, 7, 12, or 24 hours after administration, and the average value for 10 seconds at each assessment time point was analyzed.

[0659] As a result of testing the compounds of this disclosure in this assay, the level of no observed effect on rat circulatory organs (blood pressure and heart rate) was 30 mg / kg for all compounds of Examples 11, 12, 12-3, and 12-5. The safety margin (dose-based) of the compounds of this disclosure was calculated to be 100 times that of the compound of Example 11, 10 times that of the compound of Example 12, 100 times that of the compound of Example 12-3, and 10 times that of the compound of Example 12-5, compared to the effective dose observed in a mouse model of DSS-induced colitis as described in Pharmacological Example 3. Based on the above results, the compounds of this disclosure are considered to be compounds with low toxicity risk to the circulatory system, based on the safety margin where the level of no observed effect on rat circulatory organs was compared to the effective dose in a mouse model.

[0660] Pharmacological Example 6: Calculation of safety margin via monkey oral remote testing

[0661] Regarding the effects on the circulatory system in monkeys under unrestricted and conscious conditions, the test substance was administered orally once to male cynomolgus monkeys (2 animals / dose) implanted with a telemetry transmitter (M11, Data Sciences International, Inc.), and blood pressure (systolic, diastolic, and mean blood pressure) and heart rate were continuously measured. Assessment time points were set before administration, and 0.5, 1, 2, 4, 8, 10, 12, 16, or 24 hours after administration, with the average value analyzed for 1 minute at each assessment time point.

[0662] As a result of testing the compounds of this disclosure in this assay, the levels of no observed effect on the monkey circulatory organs (blood pressure and heart rate) were: 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 compounds of Examples 12-3. The safety margin (dose-based) of the compounds of this 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 compounds of Examples 12-3, compared to the effective dose observed in a mouse model of DSS-induced colitis as described in pharmacological Example 3.

[0663] On the other hand, as a result of evaluating the comparative compound B using the same method, the level of no observed effect on the monkey circulatory organs (blood pressure and heart rate) was less than 0.01 mg / kg, and its safety margin (dose baseline) was calculated to be less than 0.03 times compared to the effective dose observed in the mouse model of DSS-induced colitis described in Pharmacological Example 3. Based on the above results, it was found that the safety margin of the disclosed compound (determined by comparing the level of no observed effect on the monkey circulatory system with the effective dose in the mouse model) is increased compared to the comparative compound B.

[0664] [Formulation Examples]

[0665] Formulation Examples

[0666] The following ingredients are mixed and compressed using conventional methods to obtain approximately 10,000 tablets, each containing 10 mg of the active ingredient.

[0667] 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octen-1-yl}-5-oxo-1-pyrrolyl]ethyl}thio)-1,3-thiazolyl-4-carboxylic acid……100 g

[0668] Carboxymethyl cellulose calcium (disintegrant)......20 g

[0669] Magnesium stearate (lubricant)......10 g

[0670] Microcrystalline cellulose......870 g

[0671] Industrial applicability

[0672] The compounds disclosed herein can be used as EP4 agonists, and in particular, they possess EP4 agonist activity and are selective for other subtypes. Furthermore, the compounds disclosed herein exhibit excellent selectivity for the large intestine and therefore pose a low risk of toxicity to the circulatory system; thus, the compounds disclosed herein, as active ingredients, can be used as preventative and / or therapeutic agents for diseases associated with the EP4 receptor.

Claims

1. A compound or a pharmaceutically permissible salt thereof, The compound is represented by general formula (I). In the formula, R 1 This represents (1)-OH group, (2)-NHCH2CH2SO3H group, (3)-NHCH2COOH group, or (4)-NHCH(COOH)CH2CH2COOH group. L 1 It indicates (1) a thiazole ring, or (2) a C1-4 alkylene ring. L 2 It indicates (1) a C3-5 alkylene group or (2) a benzene ring. X represents (1)-CO-, (2)-NR X - or (3) sulfur atom, R X It represents (1) a hydrogen atom or (2) a C1-4 alkyl group. R 2 This indicates (1) methyl, (2) benzene ring, (3) 5-10 membered heterocycle, and (4) -COR 2-1 (5)-CO-(benzene ring) group, (6)-CO-(5-10 membered heterocyclic) group, (7)-NH-(benzene ring) group, or (8)-OH group, In R 2 When representing a benzene ring, a 5-10 membered heterocycle, a -CO-(benzene ring) group, a -CO-(5-10 membered heterocycle) group, or a -NH-(benzene ring) group, the benzene ring or the 5-10 membered heterocycle may be optionally surrounded by 1 to 5 R groups. 2-2 replace, R 2-1 This indicates (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 It represents (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 haloalkyl, (4) C1-4 alkoxy, (5) C1-4 haloalkoxy, or (6) benzene ring.

2. The compound according to claim 1, or a pharmaceutically permissible salt thereof, wherein, L 1 The ring is a thiazole ring, which is represented by the following formula. In the formula, Indicates the bonding site with the sulfur atom. Indicates -COR 1 The bonding sites.

3. The compound according to claim 1, or a pharmaceutically permissible salt thereof, wherein... R 2 The 5-10 member heterocycles are selected from (1) pyridine ring, (2) pyrazine ring, (3) pyrimidine ring, (4) imidazole ring, (5) thiazole ring, (6) triazole ring, (7) tetrazolium ring, (8) furan ring, (9) quinoline ring, and (10) pyrazole ring.

4. The compound according to claim 1, or a pharmaceutically permissible salt thereof, wherein the compound is represented by general formula (I-1). In the formula, R 3 This indicates (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 tetrazolium ring, (9) a furan ring, (10) a quinoline ring, or (11) a pyrazole ring. R 3 Choose any 1~5 Rs 3-1 replace, R 3-1 This indicates (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 Indicates (1)-NR X - or (2) sulfur atom, Other symbols have the same meaning as those described in claim 1.

5. The compound according to claim 4, or a pharmaceutically permissible salt thereof, wherein the compound is represented by general formula (I-2). In the formula, all symbols have the same meaning as those in claim 4.

6. The compound according to claim 1, or a pharmaceutically permissible salt thereof, wherein the compound is represented by general formula (I-4). In the formula, R 4 (1)-COR 4-1 (2)-CO-(phenyl ring) group, (3)-CO-(pyridine ring) group, (4)-CO-(pyrazine ring) group, (5)-CO-(furan ring) group, (6)-NH-(phenyl ring) group or (7)-OH group, In R 4 When representing -CO-(benzene ring) group, -CO-(pyridine ring) group, -CO-(pyrazine ring) group, -CO-(furan ring) group, or -NH-(benzene ring) group, the benzene ring, pyridine ring, pyrazine ring, or furan ring is optionally surrounded by 1 to 5 R groups. 4-2 replace, R 4-1 This indicates (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 This indicates (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 This indicates (1)-CO- or (2)-NR. X -, Other symbols have the same meaning as those described in claim 1.

7. The compound according to claim 1, or a pharmaceutically permissible salt thereof, wherein, Compounds represented by general formula (I) are selected from the following: (1) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazolyl-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-thiazolyl-4-carboxylic acid, (3) 2-({2-[(2R)-2-{(1E,3S)-3-hydroxy-8-[methyl(phenyl)amino]-1-octen-1-yl}-5-oxo-1-pyrrolyl]ethyl}thio)-1,3-thiazolyl-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-thiazolyl-4-carboxylic acid, (5) 2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-9-(2-pyridylthio)-1-nonen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazolyl-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)butyric acid, (7) 2-[({2-[(2-{(2R)-2-[(1E,3S)-3-hydroxy-8-(2-pyridylthio)-1-octen-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]-1,3-thiazo-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-thiazo-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-pyrrolyl]ethyl}thio)butyryl]amino}ethanesulfonic acid.

8. A pharmaceutical composition comprising, as an active ingredient, any one of claims 1 to 7, a compound or a pharmaceutically permissible salt thereof, and a pharmaceutically permissible carrier.

9. The pharmaceutical composition according to claim 8, wherein it is an EP4 agonist.

10. The pharmaceutical composition according to claim 8, which is a therapeutic and / or preventive agent for diseases related to the EP4 receptor.

11. The pharmaceutical composition according to claim 10, wherein, Diseases associated with the EP4 receptor include immune disorders, asthma, neuronal death, arthritis, lung injury, pulmonary fibrosis, 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, burns, systemic granulomatosis, inflammatory bowel disease, hypercytokineemia during dialysis, multiple organ dysfunction syndrome, and / or shock.

12. The pharmaceutical composition according to claim 10, wherein, Diseases associated with the EP4 receptor include inflammatory bowel disease, which is also known as ulcerative colitis or Crohn's disease.

13. A therapeutic and / or preventive agent for diseases associated with the EP4 receptor, comprising any one of claims 1 to 7 or a pharmaceutically permissible salt thereof.

14. A method for the prevention and / or treatment of EP4 receptor-related diseases, comprising: A pharmaceutical composition comprising, for administration to patients requiring prevention and / or treatment of diseases related to the EP4 receptor, any compound of any one of claims 1 to 7 or a pharmaceutically permissible salt thereof, or a pharmaceutical composition containing any one of claims 1 to 7 or a pharmaceutically permissible salt thereof as an active ingredient and further comprising a pharmaceutically permissible carrier.

15. The compound according to any one of claims 1 to 7, or a pharmaceutically permissible salt thereof, for the prevention and / or treatment of diseases associated with the EP4 receptor.

16. Use of any compound of claims 1 to 7 or a pharmaceutically permissible salt thereof in the manufacture of a preventive and / or therapeutic agent for diseases associated with the EP4 receptor.

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