RU2803243C2 - Dp antagonist - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a DP receptor antagonist which is a compound of general formula (I), where R¹, R² -R⁶, R¹¹, R¹², L, J, m, n are defined in the claims, or a pharmaceutically acceptable salt thereof. The compounds are highly safe and can be used as active pharmaceutical ingredients in DP receptor mediated diseases.

EFFECT: compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof also have a good ability to penetrate into the central nervous system, and thus are particularly useful as a prophylactic and/or therapeutic agent for diseases associated with DP receptors present in the central nervous system, in particular disturbances in sleep and wakefulness.

14 cl, 2 tbl, 22 ex

Description

TECHNICAL FIELD

[0001]

This patent application claims priority to Japanese Patent Application No. 2018-175758, the entire contents of which are incorporated herein by reference.

The present invention relates to a compound having DP receptor antagonistic activity, a pharmaceutically acceptable salt thereof and a drug containing the same as an active ingredient. In more detail, to the compound represented by the general formula (I),

[Chemical formula 1]

(wherein all symbols have the meanings described below) or a pharmaceutically acceptable salt thereof (hereinafter referred to as a compound of the present invention) and a medicament containing them as active ingredients.

BACKGROUND OF THE INVENTION

[0002]

Prostaglandin D2 (abbreviated PGD2) is known as a metabolite of the arachidonic acid cascade and is known to be involved in allergic diseases, sleep, hormone secretion, pain, platelet aggregation, glycogen metabolism, intraocular pressure regulation and the like (Non-Patent Literature 1-11). It is known that DP receptors and CRTH2 receptors are represented as PGD2 receptors, and of these, DP receptors present in the brain, especially in the subarachnoid space in the ventral region of the rostral basal forebrain, are known to be associated with the sleep-inducing effects of PGD2 (Non-Patent Literature 12 ). That is, in order to inhibit the sleep-inducing effect of PGD2 and be used as a therapeutic drug for sleep-wake disorders, it is necessary to have a drug having not only DP antagonistic activity, but also the ability to penetrate the central nervous system.

[0003]

On the other hand, Patent Literature 1 discloses that the compound represented by the following general formula (A) specifically binds to and antagonizes the DP receptor.

[Chemical formula 2]

where R ^1A represents (1) a hydrogen atom, (2) a C1-4 alkyl group, etc., E ^A represents -C(=O)-, etc., R ^2A represents (1) atom halogen, (2) C1-6 alkyl group, etc., R ^3A represents (1) a halogen atom, 2) C1-6 alkyl group, etc., W ^A represents a C5-12 monocyclic or bicyclic carbocycle or a 5-12 membered monocyclic or bicyclic heterocycle, R ^4A represents (1) a hydrogen atom, (2) a C1-6 alkyl group, etc., R ^5A represents a C1-6 alkyl group, etc., (1) G ^A represents (1) a C1-6 alkylene group containing 0-2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, J ^A represents a C5-12 monocyclic or bicyclic carbocycle or a 5-12 membered monocyclic or bicyclic heterocycle, mA is an integer 0 or 1-4, nA is an integer 0 or 1-4, and iA is an integer 0 or 1-11.

[0004]

Moreover, Patent Literature 2 describes that the compound represented by the following general formula (B) is a compound that specifically binds to and antagonizes the DP receptor.

[Chemical formula 3]

where R ^1B represents (1) a hydrogen atom, (2) a C1-4 alkyl group, etc., E ^B represents a -CO- group, etc., R ^2B represents (1) a halogen atom, ( 2) C1-6 alkyl group, etc., R ^3B represents (1) a halogen atom, (2) C1-6 alkyl group, etc., R ^4B represents (1) a hydrogen atom, (2) C1-6 alkyl group, etc., R ^5B is a C1-6 alkyl group, etc., W ^B is a C5-12 monocyclic or bicyclic carbocycle or a 5-12 membered monocyclic or bicyclic heterocycle, G ^B is (1) a C1-6 alkylene group containing 0-2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, J ^B is a C5-12 monocyclic or bicyclic carbocycle or a 5-12 membered monocyclic or bicyclic heterocycle, mB is the integer 0 or 1-4, nB is the integer 0 or 1-4, iB is the integer 0 or 1-11, and R ^12B and R ^13B each independently represent (1) a C1-4 alkyl group , which can be oxidized, (2) a hydrogen atom, etc.

However, these prior art documents do not describe or suggest anything that would be capable of penetrating the central nervous system.

LIST OF REFERENCES CITED

Patent literature

[0005]

Patent Literature 1: WO 2003/078409 A

Patent Literature 2: WO 2005/028455 A

Non-patent literature

[0006]

Non-patent literature 1: The NEW ENGLAND JOURNAL of MEDICINENE, Vol. 303, 1400-1404, 1980

Non-Patent Literature 2: American Review of Respiratory Disease, Vol. 128, 597-602, 1983

Non-Patent Literature 3: The Journal of Allergy and Clinical Immunology, Vol. 88, 33-42, 1991

Non-Patent Literature 4: Archives of Otolaryngology-Head and Neck Surgery, Vol. 113, 179-83, 1987

Non-Patent Literature 5: The Journal of Allergy and Clinical Immunology, Vol. 82, 869-77, 1988

Non-Patent Literature 6: The Journal of Immunology, Vol. 146, 671-676, 1991

Non-Patent Literature 7: The Journal of Allergy and Clinical Immunology, Vol. 83, 905-912, 1989

Non-Patent Literature 8: The NEW ENGLAND JOURNAL OF MEDICINENE, Vol. 315, 800-804, 1986

Non-Patent Literature 9: American Review of Respiratory Disease, Vol. 142, 126-132, 1990

Non-Patent Literature 10: The Journal of Allergy and Clinical Immunology, Vol. 87, 540-548, 1991

Non-Patent Literature 11: The Journal of Allergy and Clinical Immunology, Vol. 78, 458-461, 1986

Non-Patent Literature 12: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, 11674-11679, 2001

SUMMARY OF THE INVENTION

TECHNICAL CHALLENGES

[0007]

The purpose of the present invention is to develop a compound having both strong antagonistic activity against DP receptors and good ability to penetrate into the CNS, and to provide a compound that can be used as a prophylactic and/or therapeutic agent for diseases caused by activation of the DP receptor , in particular, a therapeutic agent for sleep-wake disorder.

PROBLEM SOLVING

[0008]

As a result of intensive research, the inventors of the present invention discovered that the compound represented by the general formula (I) described below solves the above-mentioned objects, and as a result of further research, they created the present invention.

Thus, the present invention, in one aspect, provides

[1] The compound represented by the general formula (I):

[Chemical formula 4]

,

where R ¹ represents a hydrogen atom, a C1-4 alkyl or benzyl group,

R ² , R ³ and R ⁴ each independently represent (1) a halogen atom, (2) a C1-4 alkyl group, optionally substituted by a halogen atom, or (3) a C1-4 alkoxy group, optionally substituted by a halogen atom,

when there are several of R2 or R4, they may be the same or different,

J represents a bond, -O- or -S-,

L represents a bond, a C1-6 alkylene, a C2-6 alkenylene or a C2-6 alkynylene group,

R ⁵ represents a hydrogen atom, a C3-10 carbocycle or a 3-10 membered heterocycle,

The C3-10 carbocycle and the 3-10 membered heterocycle in ^R5 can be 1-6 substituted with ^R7 ,

provided that when L is a bond, ^R5 is not a hydrogen atom,

R ⁷ represents (1) a halogen atom, (2) a C1-4 alkyl group, optionally substituted by a halogen atom, or (3) a C1-4 alkoxy group, optionally substituted by a halogen atom,

when there are several R ⁷ , they can be the same or different,

Q represents an oxygen atom or a sulfur atom,

with the proviso that when Q represents an oxygen atom, (1) L represents a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene group and R ⁵ represents a C3-8 monocyclic carbocycle or a 3-8 membered monocyclic heterocycle, or (2) L represents a bond and R ⁵ represents a C3-10 carbocycle or a 3-10 membered heterocycle,

R ⁶ represents a hydrogen atom or a C1-4 alkyl group,

R ¹¹ represents a hydrogen atom, a halogen atom or a C1-4 alkyl group, optionally substituted with a halogen atom,

R ¹² represents a hydrogen atom, a halogen atom or a C1-4 alkyl group, optionally substituted with a halogen atom,

R ¹¹ and R ¹² can be taken together with the carbon atom to which they are attached to form a C3-6 saturated carbocycle,

n denotes an integer from 0 to 4, and

m denotes an integer from 0 to 3, or

its pharmaceutically acceptable salt,

[2] A compound according to [1] above, in which Q represents a sulfur atom, or a pharmaceutically acceptable salt thereof,

[3] A compound according to [1] or [2] above, represented by the general formula (I-1):

[Chemical formula 5]

where R ⁵¹ represents a C3-10 carbocycle or a 3-10 membered heterocycle, J ¹ represents a bond or -O-, and other symbols have the same meanings as described in [1] above, or a pharmaceutically acceptable salt thereof,

[4] A compound according to [3] above, wherein R ⁵¹ is a C3-8 monocyclic carbocycle or a 3-8 membered monocyclic heterocycle, or a pharmaceutically acceptable salt thereof,

[5] A compound according to [3] above, wherein R ⁵¹ is a 3-8 membered saturated monocyclic heterocycle, or a pharmaceutically acceptable salt thereof,

[6] A compound according to [1] above, in which Q represents an oxygen atom, R ⁵ represents a C3-8 monocyclic carbocycle or a 3-8 membered monocyclic heterocycle, or a pharmaceutically acceptable salt thereof,

[7] A connection according to [1] above, in which the connection is

(1) (4-chloro-3-{4-[2-(oxan-2-yl)ethoxy]-2-(trifluoromethyl)benzamide}phenyl)acetic acid,

(2) {4-chloro-3-[4-(2-cyclohexylethoxy)-2-(trifluoromethyl)benzamide]phenyl}acetic acid,

(3) {4-chloro-3-[4-(2-phenylethoxy)-2-(trifluoromethyl)benzamide]phenyl}acetic acid,

(4) {4-chloro-3-[4-(2-cyclopropylethoxy)-2-(trifluoromethyl)benzamide]phenyl}acetic acid,

(5) (4-chloro-3-{2,6-dimethyl-4-[2-(oxan-2-yl)ethoxy]benzamide}phenyl)acetic acid,

(6) {4-chloro-3-[4-(2-cyclohexylethoxy)-2,6-dimethylbenzamide]phenyl}acetic acid,

(7) {4-chloro-3-[4-(2-cyclopropylethoxy)-2,6-dimethylbenzamide]phenyl}acetic acid,

(8) (3-{4-[(2,3-Dihydro-1H-inden-2-yl)oxy]-2,6-dimethylbenzamide}-4-fluorophenyl)acetic acid,

(9) {4-chloro-3-[4-(3-cyclohexylprop-1-yn-1-yl)-2,6-dimethylbenzamide]phenyl}acetic acid,

(10) (4-chloro-3-{4-[(1E)-3-cyclohexylprop-1-en-1-yl]-2,6-dimethylbenzamide}phenyl)acetic acid,

(11) (4-chloro-3-{[4-(2-cyclohexylethoxy)-2,6-dimethylbenzene-1-carbothioyl]amino}phenyl)acetic acid,

(12) [4-chloro-3-({4-[2-(oxan-2-yl)ethoxy]-2-(trifluoromethyl)benzene-1-carbothioyl}amino)phenyl]acetic acid,

(13) (4-chloro-3-{[4-(2-cyclohexylethoxy)-2-(trifluoromethyl)benzene-1-carbothioyl]amino}phenyl)acetic acid,

(14) (4-chloro-3-{[4-(2-phenylethoxy)-2-(trifluoromethyl)benzene-1-carbothioyl]amino}phenyl)acetic acid,

(15) (4-chloro-3-{[4-(2-cyclopropylethoxy)-2-(trifluoromethyl)benzene-1-carbothioyl]amino}phenyl)acetic acid,

(16) [4-chloro-3-({2,6-dimethyl-4-[2-(oxan-2-yl)ethoxy]benzene-1-carbothioyl}amino)phenyl]acetic acid,

(17) {4-chloro-3-[(2,6-dimethyl-4-{2-[(2R)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}acetic acid,

(18) {4-chloro-3-[(2,6-dimethyl-4-{2-[(2S)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}acetic acid,

(19) 2-{3-[({2,6-Dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]-4-fluorophenyl}propionic acid,

(20) 1-{3-[({2,6-Dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]-4-fluorophenyl}cyclopropanecarboxylic acid,

(21) 2-{4-chloro-3-[({2,6-dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]phenyl}-2- methylpropionic acid,

(22) 2-{4-chloro-3-[(2,6-dimethyl-4-{2-[(2S)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}-2 -methylpropionic acid,

(23) 2-{4-chloro-3-[(2,6-dimethyl-4-{2-[(2R)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}-2 -methylpropionic acid,

(24) 2-{3-[({2,6-Dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]-4-fluorophenyl}-2-methylpropionic acid or

(25) 2-(4-chloro-3-{[(2,6-dimethyl-4-{2-[(2R)-tetrahydro-2H-pyran-2-yl]ethoxy}phenyl)carbothioyl]amino}phenyl )propionic acid,

or a pharmaceutically acceptable salt thereof,

[8] A pharmaceutical composition containing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

[9] A pharmaceutical composition according to [8] above, which is a DP receptor antagonist,

[10] A pharmaceutical composition according to [9] above, which is a prophylactic and/or therapeutic agent for a DP receptor-mediated disease,

[11] The pharmaceutical composition according to [10] above, wherein the DP receptor mediated disease is an allergic disease, systemic mastocytosis, systemic mast cell activation disorder, anaphylactic shock, airway constriction, urticaria, eczema, acne, allergic bronchopulmonary aspergillosis, sinusitis, migraine, nasal polyps, hypersensitivity vasculitis, eosinophilia, contact dermatitis, pruritus disease, disease secondary to pruritus, flushing disease, inflammation, chronic obstructive pulmonary disease, ischemia-reperfusion injury, cerebrovascular accident, autoimmune disease, cerebral injury, liver dysfunction, transplant rejection, rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, interstitial cystitis, muscular dystrophy, polymyositis, malignancy, leukemia, viral infection, multiple sclerosis, sleep-wake disturbance or platelet aggregation,

[12] The pharmaceutical composition according to [11] above, wherein the DP receptor mediated disease is a sleep-wake disorder,

[13] The pharmaceutical composition according to [12] above, wherein the sleep-wake disorder is a disease based on hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep-wake disorder, hypersomnia associated with a neurodegenerative disease, hypersomnia associated with mental illness, or pathological daytime sleep apnea,

[14] A method for preventing and/or treating a DP receptor-mediated disease, comprising administering to a mammal an effective amount of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to [1] above,

[15] The compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof according to [1] above, which is used for the prevention and/or treatment of a disease mediated by the DP receptor,

[16] Use of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to [1] above in the manufacture of a prophylactic and/or therapeutic agent for use in a DP receptor mediated disease,

[17] A prophylactic and/or therapeutic agent used for a DP receptor-mediated disease, containing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to [1] above, and the like.

POSITIVE EFFECT OF THE INVENTION

[0009]

Since the compound of the present invention has a strong DP receptor antagonistic activity and also has good CNS penetration ability, it can be used as a prophylactic and/or therapeutic agent for diseases caused by DP receptor activation, particularly as a therapeutic agent for sleep disorders and wakefulness. Moreover, the compound of the present invention is excellent in terms of safety because it selectively antagonizes the DP receptor.

DESCRIPTION OF IMPLEMENTATION OPTIONS

[0010]

Next, the present invention will be described in detail.

As used herein, the C1-4 alkyl group includes methyl, ethyl, propyl and butyl groups and their isomers.

[0011]

As used herein, the C1-4 alkoxy group includes methoxy, ethoxy, propoxy and butoxy groups and their isomers.

[0012]

In the present specification, examples of the C1-6 alkylene group include methylene, ethylene, propylene, butylene, pentylene, hexylene groups and isomers thereof.

[0013]

As used herein, a C2-6 alkenylene group means, for example, a C2-6 alkenylene group having one or two double bonds, and particularly includes ethenylene, propenylene, butenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene groups and isomers thereof .

[0014]

As used herein, a C2-6 alkynylene group means, for example, a C2-6 alkynylene group having one or two triple bonds, and particularly includes ethynylene, propynylene, butynylene, butadiinylene, pentynylene, pentadiinylene, hexynylene, hexadinylene groups and isomers thereof .

[0015]

As used herein, the halogen atom includes fluorine, chlorine, bromine and iodine atoms.

[0016]

In the present specification, a C3-10 carbocycle is a monocyclic or bicyclic C3-10 carbocycle, and examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, benzene, cycloheptane, cycloheptane, cycloheptadiene, cyclooctane, cyclooctene, cyclooctadiene , cyclononane, cyclononene, cyclononadiene, cyclodecane, cycldecene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene and perhydronaphthalene rings and the like.

[0017]

In the present specification, 3 to 10 membered heterocycle means a 3 to 10 membered monocyclic or bicyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom, and examples thereof include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrole, imidazole, triazole, tetrazole, pyrazole, furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, furazan, oxadiazole, thiadiazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazole, triaz olidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isooxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroiso thiazole (isothiazolidine), dihydrofurazole, tetrahydrofurazole, dihydrooxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydrothiadiazole , tetrahydrothiadiazole (thiadiazolidine), dioxolane, dithiolane, pyridine, pyrazine, pyrimidine, pyridazine, pyran, thiopyran, oxazine, oxadiazine, thiazine, thiadiazine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetra hydropyrimidine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydropyran, tetrahydropyran, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazine, tetrahydroxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiazine, tetrahydrooxadiazine, dihydrothiazine, tetrahydrothia zine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathian, dioxane, dithian, azabicyclo[2.2.1]heptane, oxabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[2.2.2]octane, diazabicyclo[2.2.2]octane, azepine, diazepine, oxepine, thiepine, oxazepine, oxadiazepine, thiazepine, thiadiazepine, dihydro azepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydroxade iazepine, tetrahydroxadiazepine, perhydrooxadiazepine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, azabicyclo[3.2. 1]octane, oxabicyclo[3.2.1]octane, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, purine, benzoxazole, benzothiazole, benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, indoline, isoindoline, dihydroline benzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimide ash, perhydrobenzimidazole, dioxaindane, benzodithiolane, azaspiro[4.4]nonane, oxazaspiro[4.4]nonane, dioxaspiro[4.4]nonane, dithianaphthalene, quinoline, isoquinoline, quinolysine, phthalaine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, chromene, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline , dihydrophthalaic, tetrahydrophthalaic, perhydrophthalaic, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzooxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, benzodioxane, chromane, benzodithiane, azaspiro[4.5]decane ovoe, thiaspiro[4.5]decane, dithiaspiro[4.5]decane, dioxaspiro[4.5] decane and oxazaspiro[4.5]decane rings and the like.

[0018]

As used herein, the C3-8 monocyclic carbocycle includes cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, benzene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene and cyclooctadiene rings and the like.

[0019]

As used herein, the C3-6 saturated carbocycle includes cyclopropane, cyclobutane, cyclopentane and cyclohexane.

[0020]

In the present specification, 3 to 8 membered monocyclic heterocycle refers to a 3 to 8 membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom, and examples thereof include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrole, imidazole, triazole, tetrazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, thiadiazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazole, triaz olidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isooxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroiso thiazole (isothiazolidine), dihydrofurazole, tetrahydrofurazole, dihydrooxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydrothiadiazole , tetrahydrothiadiazole (thiadiazolidine), dioxolane, dithiolane, pyridine, pyrazine, pyrimidine, pyridazine, pyran, thiopyran, oxazine, oxadiazine, thiazine, thiadiazine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetra hydropyrimidine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydropyran, tetrahydropyran, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazine, tetrahydroxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothia diazine, morpholine, thiomorpholine, oxathian, dioxane, dithian, azepine, diazepine, oxepine, thiepine, oxazepine, oxadiazepine, thiazepine, thiadiazepine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothepine, tetrahydrothepine, perhydrothiepine, dihydrooxazepine, tetrahydroxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydroxadiazepine, perhydrooxadiazepine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine and perhydrothiadiazepine rings and the like.

[0021]

As used herein, the 3-8 membered saturated monocyclic heterocycle includes aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydrooxazole (oxazolidine), tetrahydroisox ash (isooxazolidine), tetrahydrothiazole ( thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofurazole, tetrahydroxadiazole (oxadiazolidine), tetrahydrothiadiazole (thiadiazolidine), dioxolane, dithiolane, piperidine, piperazine, perhydropyrimidine, perhydropyridazine, tetrahydropyran, tetrahydrote iopyran, tetrahydrooxazine, tetrahydroxadiazine, tetrahydrothiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathian, dioxane, dithiano, perhydroazepine, perhydrodiazepine, perhydrooxepine, perhydrothiepine, perhydrooxazepine, perhydrooxadiazepine, perhydrothiazepine and perhydrothiadiazepine rings and the like.

[0022]

In this description, the symbol

[Chemical formula 6]

means that it is attached to the other side of a piece of paper (i.e. α-configuration), the symbol

[Chemical formula 7]

indicates that it is attached to the front of the paper (i.e. β configuration), and the symbol

[Chemical formula 8]

denotes the α-configuration, β-configuration, or a mixture thereof in any ratio.

[0023]

Of the compounds represented by the general formula (I), preferred options are, for example, those represented by the general formula (I-a):

[Chemical formula 9]

(where L ¹ represents a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene group, R ⁵² represents a C3-8 monocyclic carbocycle or a 3-8 membered monocyclic heterocycle, and other symbols have the same meanings as described above) and pharmaceutically acceptable salts thereof, other preferred embodiments are those represented by the general formula (Ib):

[Chemical formula 10]

(wherein all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof, and particularly preferred embodiments are those represented by the general formula (I-c-0):

[Chemical formula 11]

(where R ^1c represents a hydrogen atom or a methyl group, R ^2c represents a fluorine atom or a chlorine atom, R ^3c represents a methyl group or trifluoromethyl group and R ^4c represents a hydrogen atom, methyl group or trifluoromethyl group, and, when-L ^c -J ^c - represents -O-, R ⁵⁴ represents

[Chemical formula 12]

or, when -L ^c -J ^c - represents

[Chemical formula 13]

R ⁵⁴ is

[Chemical formula 14]

and other symbols have the same meanings as described above), and their pharmaceutically acceptable salts.

[0024]

Other particularly preferred options are the compounds represented by the general formula (I-c):

[Chemical formula 15]

(wherein all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof.

[0025]

In the general formula (I), other preferred options are the compounds represented by the general formula (I-d):

[Chemical formula 16]

(wherein all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof. More preferred embodiments are the compounds represented by the general formula (I-1):

[Chemical formula 17]

(wherein all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof, and even more preferred embodiments are the compounds represented by the general formula (I-2-0):

[Chemical formula 18]

(wherein all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof, and other more preferred embodiments are the compounds represented by the general formula (I-2):

[Chemical formula 19]

(wherein all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof. The most preferred embodiments are those represented by the general formula (I-3-0):

[Chemical formula 20]

(wherein R ⁵³ represents a 3-8 membered saturated monocyclic heterocycle, and other symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof. Other most preferred options are the compounds represented by the general formula (I-3):

[Chemical formula 21]

(wherein all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof.

Alternatively, the most preferred embodiments are those represented by the general formula (I-4):

[Chemical formula 22]

(wherein all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof.

[0026]

In any of the general formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) and ( I-3) R ¹ preferably represents a hydrogen atom or a C1-4 alkyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.

[0027]

Also in any of the general formulas (Ic-0), (Ic) and (I-4), R ^1c preferably represents a hydrogen atom.

[0028]

In any of the general formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) and ( I-3) R ² is preferably a halogen atom, more preferably a fluorine atom or a chlorine atom, and especially preferably a chlorine atom.

[0029]

Also, in any of the general formulas (Ic-0), (Ic) and (I-4), R ^2c preferably represents a chlorine atom.

[0030]

In any of the general formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) and ( I-3) R ³ is preferably a C1-4 alkyl group, which may be substituted by a halogen atom, and is particularly preferably a methyl group or a trifluoromethyl group.

[0031]

In any of the general formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) and ( I-3) R ⁴ is preferably a C1-4 alkyl group, which may be substituted by a halogen atom, more preferably a methyl group or a trifluoromethyl group, and particularly preferably a methyl group.

[0032]

In the general formula (Ic-0), (Ic) or (I-4), R ^4c preferably represents a hydrogen atom or a methyl group.

[0033]

Also in any of the general formulas (I), (I-a), (I-b) and (I-d), J is preferably a bond or -O-, and more preferably -O-.

[0034]

In any of the general formulas (I-1), (I-2-0), (I-2), (I-3-0) and (I-3), J ¹ preferably represents -O-.

[0035]

In the general formula (I) or (Id), R ⁵ is preferably a C3-10 carbocycle or a 3-10 membered heterocycle, more preferably a C3-8 monocyclic carbocycle or a 3-8 membered monocyclic heterocycle, and further , preferably a 3-8 membered saturated monocyclic heterocycle. Alternatively, in general formula (I) or (Id), R ⁵ is preferably a cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene or tetrahydropyran ring, more preferably a cyclohexane, benzene, cyclopropane or tetrahydropyran ring, and most preferably a tetrahydropyran ring. Moreover, preferably, R ⁵ may be substituted with (preferably 1 to 3) R ⁷ .

[0036]

In the general formula (Ib) or (I-1), R ⁵¹ is preferably a C3-8 monocyclic carbocycle or a 3-8 membered monocyclic heterocycle, and more preferably a 3-8 membered saturated monocyclic heterocycle. Alternatively, in general formula (Ib) or (I-1), R ⁵¹ is preferably a cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene or tetrahydropyran ring, more preferably a cyclohexane, benzene, cyclopropane or tetrahydropyran ring, and most preferably , tetrahydropyran ring.

[0037]

In the general formula (Ia), (I-2-0) or (I-2), R ⁵² is preferably a 3-8 membered saturated monocyclic heterocycle. Alternatively, in general formula (Ia), (I-2-0) or (I-2), R ⁵² is preferably a cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene or tetrahydropyran ring, more preferably a cyclopropane, cyclohexane, benzene or a tetrahydropyran ring, and most preferably a tetrahydropyran ring.

[0038]

In the general formula (I-3-0) or (I-3), R ⁵³ is preferably a tetrahydropyran ring.

[0039]

In the general formula (Ic-0), (Ic) or (1-4), R ⁵⁴ is preferably a tetrahydropyran ring.

[0040]

In the general formula (I), Q preferably represents a sulfur atom.

[0041]

In any of the general formulas (I), (I-d), (I-1), (I-2-0), (I-2), (I-3-0) and (I-3), L is preferably is a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene group, more preferably an ethylene, propenylene or propynylene group, and more preferably an ethylene group.

[0042]

In the general formula (Ia), L ¹ is preferably an ethylene, propenylene or propynylene, and more preferably an ethylene group.

[0043]

In the general formula (I), (Ia), (Id), (I-1), (I-2-0), (I-2), (I-3-0) or (I-3) -LJ -, -L ¹ -J- or -LJ ¹ - is preferably -O-,

[0043]

[Chemical formula 23]

and, more preferably,

[Chemical formula 24]

[0044]

In any of the general formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) and ( I-3) R ⁶ is preferably a hydrogen atom.

[0045]

In any of the general formulas (I), (Ia), (Ib), (Ic), (Id), (I-1), (I-2-0), (I-3-0) and (I- 4) R ¹¹ is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.

[0046]

In any of the general formulas (I), (Ia), (Ib), (Ic), (Id), (I-1), (I-2-0), (I-3-0) and (I- 4) R ¹² preferably represents a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.

[0047]

In any of the general formulas (I), (Ia), (Ib), (Ic), (Id), (I-1), (I-2), (I-3) and (I-4) R ¹¹ and R ¹² can be taken together with the carbon atoms to which they are attached to form a C3-6 saturated carbocycle, and the C3-6 membered saturated carbocycle is preferably a cyclopropane ring.

[0048]

In any of the general formulas (I), (I-a), (I-b), (I-d) and (I-1), n is preferably 1.

[0049]

In any of the general formulas (I), (I-a), (I-b), (I-d), (I-1), (I-2-0), (I-2), (I-3-0) and ( I-3) m is preferably 0 or 1, and more preferably 1.

[0050]

As the compound represented by the general formula (I), compounds in which some or all of the above preferred R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , J, L, Q, n and m combined are preferred.

[0051]

As a compound represented by the general formula (Ia), compounds in which some or all of the above preferred R ¹ , R ² , R ³ , R ⁴ , R ⁵² , R ⁶ , R ¹¹ , R ¹² , J, L ¹ , n and m combined are preferred.

[0052]

As a compound represented by the general formula (Ib), compounds in which some or all of the above preferred R ¹ , R ² , R ³ , R ⁴ , R ⁵¹ , R ⁶ , R ¹¹ , R ¹² , J, n and m combined are preferred.

[0053]

As a compound represented by the general formula (Ic-0), compounds in which some or all of the above preferred R ^1c , R ^2c , R ^3c , R ^4c , R ¹¹ , R ¹² , J ^c , L ^c and R ⁵⁴ combined are preferred.

[0054]

As the compound represented by the general formula (Ic), compounds in which some or all of the above-mentioned preferred R ^1c , R ^2c , R ^3c , R ^4c , J ^c , L ^c and R ⁵⁴ are combined are preferred.

[0055]

As a compound represented by the general formula (Id), compounds in which some or all of the above preferred R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , J, L, n and m combined are preferred.

[0056]

As a compound represented by the general formula (I-1), compounds in which some or all of the above preferred R ¹ , R ² , R ³ , R ⁴ , R ⁵¹ , R ⁶ , R ¹¹ , R ¹² , J ¹ , L, n and m combined are preferred.

[0057]

As a compound represented by the general formula (I-2-0), compounds in which some or all of the above preferred R ¹ , R ² , R ³ , R ⁴ , R ⁵² , R ⁶ , R ¹¹ , R ¹² , J ¹ , L and m combined are preferred.

[0058]

As a compound represented by the general formula (I-2), compounds in which some or all of the above preferred R ¹ , R ² , R ³ , R ⁴ , R ⁵² , R ⁶ , J ¹ , L and m are combined, are preferred.

[0059]

As a compound represented by the general formula (I-3-0), compounds in which some or all of the above preferred R ¹ , R ² , R ³ , R ⁴ , R ⁵³ , R ⁶ , R ¹¹ , R ¹² , J ¹ , L and m combined are preferred.

[0060]

As a compound represented by the general formula (I-3), compounds in which some or all of the above preferred R ¹ , R ² , R ³ , R ⁴ , R ⁵³ , R ⁶ , J ¹ , L and m are combined, are preferred.

[0061]

As a compound represented by the general formula (I-4), compounds in which some or all of the above preferred R ^1c , R ^2c , R ^3c , R ^4c , J ^c , L ^c , R ¹¹ , R ¹² and R ⁵⁴ combined are preferred.

[0062]

In the present specification, another embodiment of the general formula (I) is most preferably a compound of the present invention described in the examples below, or a pharmaceutically acceptable salt thereof.

[0063]

[Isomer]

In the present invention, unless otherwise indicated, all isomers are covered. For example, alkyl groups, alkoxy groups, alkylene groups and the like include straight and branched chain groups. Also covered by the present invention are isomers (E, Z, cis, trans) at a double bond, ring or fused ring, isomers due to the presence of asymmetric carbon, or the like (R-, S-form, α-, β-configuration, enantiomers, diastereomers), optically active substances with racemic properties (D, L, d, l-forms), polar compounds obtained by chromatographic separation (high-polarity compounds, low-polarity compounds), equilibrium compounds, rotational isomers and mixtures in any ratios and their racemic mixtures in any ratio. Moreover, the present invention also covers all isomers formed due to tautomerism.

In the present invention, all references to a compound of the present invention include the compounds represented by the general formula (I), pharmaceutically acceptable salts thereof, N-oxides thereof, solvates thereof, or co-crystals thereof.

[0064]

[Salt]

The compound represented by the general formula (I) is converted into a salt in a known manner.

The salt is a pharmaceutically acceptable salt.

Preferably the salt is water soluble.

Examples of the pharmaceutically acceptable salt include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts and the like.

Examples of acid addition salts include salts of inorganic acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates and nitrates, and salts of organic acids such as acetates, lactates, tartrates, benzoates, citrates, methanesulfonates, ethanesulfonates, trifluoroacetates, benzenesulfonates, toluenesulfonates , isethionates, glucuronates and gluconates.

Examples of the alkali metal salt include potassium salts, sodium salts and the like.

Examples of the alkaline earth metal salt include calcium salts, magnesium salts and the like.

Examples of the ammonium salt include tetramethylammonium salts and the like.

Examples of the amine salt 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, N-methyl-D salts -glucamine and the like.

[N-oxide]

The compound represented by the general formula (I) can be converted into N-oxide by any method. N-oxide is a compound in which a nitrogen atom in the compound represented by the general formula (I) is oxidized. The N-oxide of the compound represented by the general formula (I) may be a salt.

[0066]

[Solvate]

The compound represented by the general formula (I), its pharmaceutically acceptable salt and its N-oxide may exist in an unsolvated form or may exist in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. The compound represented by the general formula (I), its pharmaceutically acceptable salt and its N-oxide can be converted into a solvate in a known manner.

The solvate is preferably non-toxic and water soluble. Examples of suitable solvate include solvates like hydrates or with alcohol solvents (eg ethanol, etc.).

[0067]

[Cocrystal]

The compound represented by the general formula (I), its pharmaceutically acceptable salt and its N-oxide can form cocrystals with a suitable cocrystal-forming agent. The cocrystal-forming agent is preferably pharmaceutically acceptable. A cocrystal is usually defined as a crystal in which two or more different molecules are formed by intermolecular interactions that are distinct from ionic bonds. Additionally, the cocrystal may be a complex of a neutral molecule and a salt. The composition of the cocrystal can be controlled by known methods, such as melt crystallization, recrystallization from a solvent, or physical grinding of the components together. Suitable cocrystal forming agents include those described in WO 2006/007448 A.

[0068]

[Prodrug]

The compound represented by the general formula (I) can be administered as a prodrug. A prodrug of a compound represented by the general formula (I) refers to a compound that is converted to the compound represented by the general formula (I) by in vivo interaction with an enzyme, gastric acid or the like. Examples of a prodrug of the compound represented by the general formula (I) include those in which the compound represented by the general formula (I) has a carboxyl group, compounds in which the carboxyl group is esterified or amidated (for example, compounds in which the carboxyl group of the compound represented by the general formula (I), is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, 1 -{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, methylamidated, etc.) and the like. These compounds can be prepared in a known manner. In addition, the prodrug of the compound represented by the general formula (I) can be replaced by the compound represented by the general formula (I) under physiological conditions described in the review “Development of Drug” published in 1990 by Hirokawa Shoten, vol. 7, “ Molecular Design", pp. 163-198. A prodrug of the compound represented by general formula (I) may be a salt or solvate, or may form a co-crystal with a suitable co-crystal-forming agent.

[0069]

[Tagged connection]

The compound of the present invention also includes so-called labeled compounds in which some or all of their constituent atoms are replaced by their isotopes. These labeled compounds can be prepared in a known manner. As isotopes used for labeling, for example, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁷ O, ^{18 O, 18 F} , ³⁵ S, ³⁶ Cl can be suitably used , ⁷⁷ Br, ¹²⁵ I and the like, but this is not limited to.

[0070]

[Production method of the compound of the present invention]

The compound of the present invention represented by the general formula (I) can be prepared by a known method, for example, by the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, ^2nd Edition (Richard C. Larock, John Wiley & Sons Inc , 2018), the method shown below, the method equivalent to them, or the method shown in the examples. In each of the following preparation methods, the starting compound may be used in salt form. As such a salt, preferred are those described as pharmaceutically acceptable salts of the compound of the present invention represented by the general formula (I).

[0071]

Of the compounds represented by the general formula (I), the compound in which R ¹ represents a hydrogen atom, J represents -O- or -S- and Q represents an oxygen atom, that is, the compound represented by the general formula (Ia):

[Chemical formula 25]

(where J ^a represents -O- or -S-, and the other symbols have the same meanings as above)

can be prepared according to the following reaction step scheme A.

[Chemical formula 26]

Scheme A of reaction stages

(where P represents a protecting group for the carboxy group and the other symbols have the same meanings as described above)

That is, the compound represented by the general formula (IIa) and the compound represented by the general formula (IIIa) are subjected to a Mitsunobu reaction to obtain the compound represented by the general formula (IVa), and then a carboxyl group deprotection reaction is carried out, whereby it can the compound represented by the general formula (Ia) is obtained.

[0072]

The Mitsunobu reaction is known and is carried out, for example, by reacting an alcohol with a phenol derivative or a thiophenol derivative at a temperature of 0 to 60°C in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.) in the presence of a combination Mitsunobu's reagent (diazo compound (diethyl azodicarboxylic acid (DEAD), diisopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, 1,1'-azobis(N,N-dimethylformamide), etc.) and phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-based triphenylphosphine, etc.) or ylide reagent (cyanomethylenetrimethylphosphorane (CMMP), cyanomethylenetributylphosphorane (CMBP), etc.).

[0073]

The compound represented by the general formula (IVa) can also be obtained by subjecting the compound represented by the general formula (Va) to an alkylation reaction:

[Chemical formula 27]

(where X represents a leaving group such as a halogen atom, a tosyloxy group (TsO-) or a mesyloxy group (MsO-), and other symbols have the same meanings as described above) and a compound represented by the general formula (IIIa).

This alkylation reaction is known and is carried out at a temperature of 0 to 100°C, for example, in an organic solvent (dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, etc.), in the presence of hydroxide alkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or their aqueous solution, or mixtures thereof.

[0074]

In reaction step diagram A, the deprotection reaction of the carboxy group is known and can be carried out as follows.

Examples of the protecting group for the carboxy group include a methyl group, an ethyl group, an allylic group, a tert-butyl group, a trichloroethyl group, a benzyl (Bn) group, a phenacyl group and the like. The protecting group for the carboxy group is not particularly limited as long as it is a group that can be easily and selectively cleaved off other than those described above. For example, the groups described by Peter G. M. Wuts, Green's Protective Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014, are used.

The carboxy deprotection reaction is well known and examples include:

(1) alkaline hydrolysis,

(2) deprotection reaction under acidic conditions,

(3) deprotection reaction by hydrogenation,

(4) silyl group deprotection reaction,

(5) metal deprotection reaction,

(6) deprotection reaction using a metal complex and the like.

These methods are specifically described below.

(1) The alkaline hydrolysis deprotection reaction is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.), using an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide alkaline earth metal (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at a temperature of 0 to 60°C.

(2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, anisole, etc.), in an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid etc.) or inorganic acid (hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (hydrogen bromide/acetic acid, etc.) at a temperature of 0 to 100°C.

(3) The deprotection reaction by hydrogenation is carried out, for example, in a solvent (ethers (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (methanol, ethanol, etc.), benzenes (benzene, toluene etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixture of two or more of these, etc.) in the presence of a catalyst (palladium on carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.) in a hydrogen atmosphere at normal or elevated pressure or in the presence of ammonium formate at a temperature from 0 up to 200°C.

(4) The silyl group deprotection reaction is carried out, for example, in a water-miscible organic solvent (tetrahydrofuran, acetonitrile, etc.) using tetrabutylammonium fluoride at a temperature of 0 to 40°C.

(5) The metal deprotection reaction is carried out, for example, in an acidic solvent (acetic acid, a buffer with a pH of 4.2 to 7.2, or a mixed solution thereof with an organic solvent such as tetrahydrofuran) in the presence of zinc powder, if necessary , using ultrasound, at temperatures from 0 to 40°C.

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

In addition to the above, the deprotection reaction can be carried out in a manner described, for example, by Peter G. M. Wuts, Green's Protective Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014.

It will be readily apparent to those skilled in the art that the target compound of the present invention can be easily prepared by proper use of these deprotection reactions.

[0075]

Of the compounds represented by the general formula (I), the compound in which R ¹ represents a hydrogen atom, Q represents an oxygen atom, J represents a bond and L represents an alkynylene group, that is, the compound represented by the general formula (Ib):

[Chemical formula 28]

(where nb denotes an integer from 0 to 4, and other characters have the same meanings as above),

can be obtained by coupling the compound represented by the general formula (IIIb):

[Chemical formula 29]

(where X represents a halogen atom or a trifluoromethanesulfonyloxy group (TfO-), and other symbols have the same meanings as described above) and a compound represented by the general formula (Vb):

[Chemical formula 30]

(where all characters have the same meanings as above),

and then deprotection reactions from the carboxy group. This coupling reaction is known, and a compound can be prepared by reacting a compound represented by the general formula (IIIb) and a compound represented by the general formula (Vb), for example, in an organic solvent (for example, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, etc.). etc.) in the presence of a palladium catalyst (bistriphenylphosphine palladium (II) chloride, etc.), in the presence of a copper catalyst (copper (I) iodide, etc.) and in the presence of a base (triethylamine, etc.) at a temperature from room temperature to boiling temperature.

[0076]

Of the compounds represented by the general formula (I), a compound in which R ¹ represents a hydrogen atom, Q represents an oxygen atom, J represents a bond, and L represents an alkenylene or alkylene group can be prepared by subjecting the compound represented by the general formula (Ib), reduction reactions.

The reduction reaction is known and is carried out, for example, under a hydrogen atmosphere in an organic solvent (for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, 1,2-dimethoxyethane or a solvent obtained by appropriately mixing these organic solvents, etc.) or in a mixed solvent of organic solvents and water in the presence of a palladium catalyst (eg, palladium on carbon, palladium hydroxide, Lindlar catalyst, etc.) at a temperature from room temperature to about 80°C.

[0077]

Of the compounds represented by the general formula (I), the compound in which R ¹ represents a hydrogen atom and Q represents a sulfur atom, that is, the compound represented by the general formula (Ic):

[Chemical formula 31]

(where all symbols have the same meanings as described above) can be prepared according to the following reaction step scheme C.

[Chemical formula 32]

Scheme C of reaction stages

(where all characters have the same meanings as above).

That is, the compound represented by the general formula (IVa) is subjected to a thiolation reaction to obtain the compound represented by the general formula (Vc), and then a carboxy group deprotection reaction is carried out, whereby the compound represented by the general formula (Ic) can be obtained.

[0078]

In reaction step scheme C, the thiolation reaction is known and the compound can be prepared by reacting the amide compound in an organic solvent (e.g., tetrahydrofuran, toluene, benzene, acetonitrile, dichloromethane, pyridine, etc.) in the presence or absence of a base (bicarbonate sodium, etc.) in the presence or absence of a thiolation reagent (e.g. Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide), tetraphosphorus decasulfide , diphosphorus pentasulfide, hydrogen sulfide, sulfur, etc.) and phosphine reagent (for example, trichlorophosphate, etc.) at a temperature from room temperature to reflux temperature.

[0079]

In each of the above reactions, the compound used as a starting material is known or can be easily prepared by a known method.

For example, a compound represented by the general formula (IIIa):

[Chemical formula 33]

(where all symbols have the same meaning as described above) can be obtained by carrying out the deprotection/deprotection reaction, if necessary, according to the following reaction step scheme D.

[Chemical formula 34]

Scheme of reaction stages D

(where ^P2 represents a protecting group for a hydroxyl group or a thiol group and the other symbols have the same meanings as described above)

That is, the compound represented by the general formula (VId) is subjected to a protecting reaction for a hydroxyl group or a thiol group to obtain the compound represented by the general formula (VIId), and then subjected to an amidation reaction with the compound represented by the general formula (VIIId), whereby the compound represented by the general formula (VIIId) can the compound represented by the general formula (IXd) is obtained. Then, the compound represented by the general formula (IXd) is subjected to a deprotection reaction of a hydroxyl group or a thiol group, whereby the compound represented by the general formula (IIIa) can be obtained.

[0080]

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

Examples of the protecting group for the thiol group include a benzyl group, a methoxybenzyl group, a methoxymethyl (MOM) group, a 2-tetrahydropyranyl (THP) group, a diphenylmethyl group, and an acetyl (Ac) group.

[0081]

The protecting group for the hydroxyl group or the thiol group is not particularly limited as long as it is a group that can be easily and selectively cleaved off other than those described above. For example, the groups described by Peter G. M. Wuts, Green's Protective Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014, are used.

[0082]

In Reaction Step Scheme D, the amidation reaction is known and examples include:

(1) acid halide method,

(2) method using mixed acid anhydride,

(3) a method using a condensing agent and the like.

These methods are specifically described below.

(1) The acid halide method is carried out, for example, by reacting a carboxylic acid with an acidic halogenating agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or in the absence solvent at a temperature from -20°C to reflux temperature and the reaction of the resulting acid halide with an amine in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) at temperatures from 0 to 80°C. Alternatively, the reaction can also be carried out by reacting the resulting acid halide with an amine in an organic solvent (dioxane, tetrahydrofuran, etc.) using an alkaline aqueous solution (sodium bicarbonate solution, sodium hydroxide solution, etc.) at a temperature of 0 to 40 °C.

(2) The mixed acid anhydride method is carried out, for example, by reacting a carboxylic acid with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) at a temperature of 0 to 40 °C in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or in the absence of a solvent and reacting the resulting mixed acid anhydride with amine at temperatures from 0 to 40°C in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.).

(3) The method using a condensing agent is carried out, for example, by reacting a carboxylic acid with an amine in an organic solvent (chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or in the absence of a solvent at a temperature of 0 to 80°C in the presence or absence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide ( EDC), 1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propylphosphonic acid cyclic anhydride (1-propanephosphonic acid cyclic anhydride, T ₃ P), etc.) presence or absence 1-hydroxybenztriazole (HOBt).

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

[0083]

The deprotection reaction of the hydroxyl group or thiol group in the reaction step of formula D is known and can be carried out in the same manner as the deprotection reaction of the carboxy group in reaction step scheme A.

It will be readily apparent to those skilled in the art that the target compound of the present invention can be easily prepared by proper use of these deprotection reactions.

[0084]

Compounds used as other starting materials and compounds used as reagents are known in themselves or can be easily prepared using methods in combination with a known method, for example, the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, ^2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018).

[0085]

In the reactions described herein, each group can be protected when protection is required, and the compound with the protected protecting group can be suitably subjected to a known deprotection reaction.

[0086]

The reactions described herein, involving heating, can be carried out, as will be apparent to those skilled in the art, using a water bath, oil bath, sand bath or microwave oven.

[0087]

The reactions described herein may use a supported solid phase reagent that is supported on a high molecular weight polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.).

[0088]

In the reactions described herein, the reaction products can be purified in accordance with conventional purification methods such as distillation under normal or reduced pressure, high performance liquid chromatography using silica gel, magnesium silicate and the like, thin layer chromatography, ion exchange resins, resins- absorbents or column chromatography, or washing and recrystallization. Purification can be done after each reaction or after several reactions.

[0089]

[Toxicity]

The compound of the present invention has very low toxicity and is safe enough for use as a drug.

[0090]

[Pharmaceutical Applications]

Since the compound of the present invention has excellent DP receptor antagonistic activity, it can be used for the treatment of DP receptor mediated disease such as allergic disease, systemic mastocytosis, systemic mast cell activation disorder, anaphylactic shock, airway constriction, urticaria, eczema, acne, allergic bronchopulmonary aspergillosis, sinusitis, migraine, nasal polyps, hypersensitivity vasculitis, eosinophilia, contact dermatitis, pruritic disease, disease secondary to pruritic disease, skin erythema, inflammation, chronic obstructive pulmonary disease, ischemic -reperfusion injury, cerebrovascular accident, autoimmune disease, cerebral injury, liver disease, graft rejection, rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, interstitial cystitis, muscular dystrophy, polymyositis, malignancy, leukemia, viral infection, multiple sclerosis, sleep disturbance or platelet aggregation. In addition, since the compound of the present invention has excellent ability to penetrate into the central nervous system, it is particularly useful in sleep-wake disorders such as hypersomnia (for example, narcolepsy, sudden hypersomnia, recurrent hypersomnia and Kleine-Levin syndrome, etc.) , insomnia, residual sleepiness of sleep apnea syndrome, sleep-wake circadian rhythm disorder (eg, shift work circadian rhythm disorder, irregular sleep-wake rhythm disorder, etc.), hypersomnia associated with a neurodegenerative disease (eg, Parkinson's disease, dementia with Lewy bodies, Alzheimer's dementia, etc.), hypersomnia associated with mental illness (eg, depression, bipolar disorder, etc.) and pathological daytime sleep apnea.

[0091]

The compound of the present invention can be combined with another drug to be administered as a concomitant drug to:

1) complement and/or enhance the preventive and/or therapeutic effect of the compound;

2) improve kinetics and absorption and reduce the dose of the compound; and/or

3) reduce the side effect of the compound.

[0092]

The concomitant drug of a compound of the present invention and another drug may be administered in the form of a combination agent containing both components in a single preparation, or may be administered as separate preparations. When administered as separate preparations, simultaneous administration and staged administration are included. In addition, for sequential administration, the compound of the present invention may be administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later. All routes of administration may be the same or different.

[0093]

The disease on which the concomitant drug has a prophylactic and/or therapeutic effect is not particularly limited, but may be any disease in which the prophylactic and/or therapeutic effect of the compound of the present invention is complemented and/or enhanced.

[0094]

Examples of other drug for complementing and/or enhancing the preventive and/or therapeutic effects of the compounds of the present invention on sleep-wake disorders include psychostimulants (e.g., modafinil, methylphenidate (hydrochloride), methamphetamine (hydrochloride), pemoline, etc.), drugs for the treatment of narcolepsy (eg, gamma-hydroxybutyric acid, clomipramine, etc.), acetylcholinesterase inhibitors (eg, donepezil (hydrochloride), physostigmine, rivastigmine (tartrate), galantamine (hydrobromide), zanapezil (fumarate); TAK-147 , tacrine, metrifonate, etc.), NMDA receptor antagonists (e.g. ketamine, memantine, dextromethorphan hydrobromide, etc.), dopamine receptor agonists (e.g. levodopa, bromocriptine, pergolide, talipexole, pramipexole (hydrochloride) (hydrate ), cabergoline, amantadine (hydrochloride), etc.), tricyclic antidepressants (for example, amitriptyline hydrochloride, imipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (for example, paroxetine, escitalopram, etc.), drugs for the treatment of mania (for example, lithium carbonate, etc.), antipsychotics (for example, clofectone, spiperon, sulpiride, zotepine, timiperon, haloperidol decanoate, haloperidol, pimozide, propericiazine, bromperidol, perphenazine, levomepromazine maleate, chlorpromazine hydrochloride, thioridazine hydrochloride, trazodone hydrochloride, mosapramine hydrochloride, risperidone, olanzapine, etc.), norepinephrine reuptake inhibitors (for example, atomoxetine, etc.) and the like.

[0095]

The weight ratio of the compound of the present invention to another drug is not particularly limited.

Another drug may be administered in combination of two or more types.

[0096]

Moreover, other agent that complements and/or enhances the prophylactic and/or therapeutic effect of the compound of the present invention includes those that have been discovered so far based on the above mechanism, as well as those that will be discovered in the future.

[0097]

In order to use the compound of the present invention as a single agent or in combination with another agent as a concomitant drug for the purpose of preventing and/or treating the above diseases, the substance as an active ingredient is usually formulated with various additives or pharmaceutically acceptable carriers such as a diluent , and then they are administered systemically or locally in oral or parenteral form. As used herein, a pharmaceutically acceptable carrier means a substance other than an active ingredient that is typically used in the manufacture of pharmaceuticals. The pharmaceutically acceptable carrier preferably has no pharmacological effect at the dose of the drug, is harmless and does not interfere with the therapeutic effect of the active ingredient. In addition, a pharmaceutically acceptable carrier may also be used to enhance the utility of the active ingredient and the drug, simplify formulation, stabilize quality, improve usability, or the like. In particular, substances such as those described in the "Encyclopedia of Pharmaceutical Additives" (edited by the International Council of Pharmaceutical Excipients of Japan) published in 2016 by Yakuji Nippo, Limited can be selected appropriately according to the purpose.

[0098]

Examples of the dosage form used for administration include oral preparations (eg, tablets, capsules, granules, powders, oral liquids and solutions, syrups, oral jelly, etc.), mucosal preparations oral preparations (e.g. oral tablets, oral sprays, semi-solid oral preparations, rinses, etc.), dialysis preparations (e.g. dialysis agents etc.), preparations for inhalation (for example, volatile preparation, etc.), preparations for ophthalmic use (for example, ophthalmic liquids and solutions, ophthalmic ointments, etc.), preparations for ear applications (for example, ear preparations, etc.), preparations for nasal use (for example, nasal preparations, etc.), preparations for rectal use (for example, suppositories for rectal use, semi-solid preparations for rectal use, enemas for rectal use, etc.). etc.), preparations for vaginal use (e.g. vaginal tablets, vaginal suppositories, etc.), preparations for cutaneous use (e.g. solid preparations for cutaneous use, liquids and solutions for cutaneous use, sprays for cutaneous use, ointments, creams, gels, patches, etc.) and the like.

[0099]

[Oral preparations]

Examples of oral preparations include tablets, capsules, granules, powders, oral liquids and solutions, syrups, oral jellies and the like. In addition, oral formulations include rapidly disintegrating formulations, in which the release of the active ingredient(s) from the formulation is not specifically controlled, and controlled-release formulations, in which the release is controlled according to purpose through a uniquely designed formulation and manufacturing method, e.g. enteric-coated drugs, sustained-release drugs, and the like. An enteric-coated formulation refers to a formulation formulated such that the active ingredient(s) are released primarily in the small intestine rather than in the stomach to prevent degradation of the active ingredient(s) in the stomach or to reduce the irritant effect of the active ingredient(s). ov) on the stomach, and can usually be prepared by film application using an acid-insoluble enteric base. A sustained release formulation refers to a formulation in which the release rate, release time and site of release of the active ingredient(s) from the formulation are controlled to reduce the number of administrations, reduce side effects or the like, and can generally be prepared using a suitable sustained release agent. release. Oral preparations, capsules, granules, tablets, etc. may also be coated with suitable coating agents, such as sugars, sugar alcohols or polymeric compounds, to facilitate administration or prevent degradation of the active ingredient.

[0100]

(1) Tablets

Tablets are solid preparations of a specific shape and size intended for oral administration, as well as oral tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets and the like, in addition to those commonly referred to as tablets such as Uncoated tablets, film-coated tablets, sugar-coated tablets, multilayer tablets and dry-coated tablets. Uncoated tablets are usually prepared using the following methods (a), (b) or (c):

(a) Homogeneously mixing the active ingredient(s) with additives such as excipients, binders and disintegrants, granulating the mixture with water or a solution containing the binder in a suitable manner, then mixing with a lubricant and the like and molding the mixture under pressure;

(b) Homogeneously mixing the active ingredient(s) with additives such as excipients, binders and disintegrants, and directly molding the mixture by compression molding, or homogeneously mixing granules preformed with additives with the active ingredient(s), lubricant and the like, and then pressing the mixture; And

(c) Homogeneously mixing the active ingredient(s) with additives such as excipients and binders, pouring the solvent-wet mixed product into a specified mold for molding, and then drying the molded product by a suitable method.

Film-coated tablets can generally be prepared by coating uncoated tablets with thin films using suitable coating agents such as polymer compounds. Sugar-coated tablets can generally be prepared by coating uncoated tablets using coating agents including sugar or sugar alcohols. Multilayer tablets can be made by stacking particles having different compositions into layers and compressing them accordingly. Dry-coated tablets can be prepared by coating tablets with an inner core with outer layers having different compositions. In addition, the tablets can also be prepared as enteric-coated tablets or sustained-release tablets using a suitable known method. Intraoral disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets and dissolving tablets are tablets that have been given unique functions by appropriate selection of additives and can be manufactured in accordance with the tablet manufacturing method described above. Orally disintegrating tablets refer to tablets that can dissolve or disintegrate quickly in the mouth and be taken; Chewable tablets are tablets that you chew and take; Effervescent tablets refer to tablets that dissolve or disperse with vigorous release of gas bubbles in water; dispersible tablets refer to tablets that are dispersible in water and taken; and soluble tablets refer to tablets that are dissolved in water and taken. Effervescent tablets can be prepared by using a suitable acidic substance, carbonate, hydrogen carbonate or the like as additives.

[0101]

(2) Capsules

Capsules are preparations filled into capsules or encapsulated with capsule bases, which include hard capsules, soft capsules and the like. Hard capsules can be prepared by a process in which a homogeneous mixture obtained by mixing the active ingredient(s) with additives such as excipients, or granules or a molded product obtained by a suitable process is filled into a capsule as such or after slight molding. Soft capsules can be prepared by a process in which the mixture obtained by adding additives to the active ingredient(s) is formed into capsules in a specific form with suitable capsule bases such as gelatin plasticized by adding glycerin, D-sorbitol or the like. Capsules may be prepared as enteric-coated capsules or sustained-release capsules using a suitable known method, and a colorant, preservative or the like may also be added to the capsule base.

[0102]

(3) Granules

Granules are preparations granulated into granules, and in addition to those commonly called granules, effervescent granules and the like are included. Granules are usually produced using the following method (a), (b) or (c):

(a) Homogeneously mixing the particulate active ingredient(s) with filler, binder, disintegrant or other additives and then granulating the mixture in an appropriate manner;

(b) Homogeneous mixing of the active ingredient(s), previously prepared in granules, with additives such as excipients; And

(c) Mixing the active ingredient(s), previously prepared in granules, with additives such as excipients and granulating the mixture by a suitable method.

If necessary, the granules can also be coated and can also be manufactured as enteric coated granules or sustained release granules using a suitable known method. Effervescent granules can be obtained using a suitable acidic substance, carbonate, hydrogen carbonate or the like as additives. Effervescent granules refer to granules that dissolve or disperse with vigorous release of gas bubbles in water. The granules can also be produced in the form of fine granules by adjusting the particle size.

[0103]

(4) Powders

Powders are preparations in powder form and can usually be prepared by mixing homogeneously the active ingredient(s) with an excipient or other additives.

[0104]

(5) Liquids and solutions for oral administration

Liquids and solutions for oral administration are liquid or flowable, viscous and gel-like preparations, as well as elixirs, suspensions, emulsions, lemonades and the like, in addition to those commonly referred to as oral solutions. Liquids and solutions for oral administration can generally be prepared by mixing the active ingredient(s) with additives and purified water, homogeneously dissolving, emulsifying or suspending the mixture, and, if necessary, filtering the mixture. Elixirs refer to clear, sweetened and flavored liquids and solutions for oral administration in liquid form containing ethanol and can generally be prepared by adding ethanol, purified water, flavoring agent and sucrose, other sugars or sweeteners to the solid active ingredient(s) or its exudate and dissolving them, and clarifying the solution by filtration or other methods. Suspensions refer to liquids and solutions for oral administration of finely and uniformly suspended active ingredient(s) and can usually be prepared by adding a suspending agent or other additives and purified water or oil to the solid active ingredient(s) and suspending them by a suitable method of homogenizing the entire suspensions. Emulsions refer to liquids and solutions for oral administration of active ingredient(s) finely and homogeneously emulsified, and can generally be prepared by adding an emulsifying agent and purified water to the liquid active ingredients and emulsifying them in a manner consistent with homogenizing the entire suspension. In addition, sweet and sour, clear liquids and solutions for oral administration in liquid form include lemonades.

[0105]

(6) Syrups

Syrups are viscous liquid or solid preparations containing sugars or sweetening agents, and preparations for syrups, etc. Syrups can generally be prepared by adding the active ingredient(s) to a solution of syrup, other sugars or sweeteners, or simple syrup and dissolving , mixing, suspending or emulsifying them and, if necessary, boiling and then filtering the mixture while hot. Syrup preparations refer to preparations in the form of granules or powders that are converted into syrups when water is added and can also be called dry syrups. Syrup preparations can generally be prepared using sugars or sweeteners as additives in accordance with the granule or powder production method.

[0106]

(7) Oral jelly

Oral jellies are non-flowing molded gel preparations and can generally be prepared by mixing the active ingredient(s) with additives and a polymeric gel base, and gelling and molding the mixture into a specific shape in a suitable manner.

[0107]

[Injection drugs]

(1) Injections

Injections are sterile preparations for subcutaneous, intramuscular, intra-articular administration or directly into tissues or organs of the body, such as blood vessels, in the form of a solution, suspension or emulsion, or a solid that must be dissolved or suspended before use, and lyophilized injections, powders injections, pre-filled injection syringes, injection cartridges, parenteral infusions, implants/pellets, sustained release injections and the like. Injections are usually given in the following way (a) or (b):

(a) Homogeneously dissolving, suspending or emulsifying the active ingredient(s) as is or adding with additives into water for injection, other aqueous solvent or non-aqueous solvent or the like, filling the injection container with the mixture, sealing and sterilization; And

(b) Homogeneously dissolving, suspending or emulsifying the active ingredient(s) as is or adding with additives to water for injection, other aqueous solvent or non-aqueous solvent or the like, and aseptically filtering the mixture or preparing aseptically homogeneous liquid, pouring the mixture into the injection container and sealing.

Lyophilized injections can usually be prepared by dissolving the active ingredient(s) as is, or the active ingredient(s) with additives such as excipients, in water for injection, filtering the solution aseptically, filling the filtrate into an injection container, and then subjecting it to lyophilization, or by lyophilizing the filtrate in special containers and then filling it into individual injection containers. Powders for injection can generally be prepared by filtering the aseptically active ingredient(s), adding powders obtained by crystallization or powders added with sterilized additives, and filling the powders into an injection container. Prefilled injection syringes can generally be made by filling the syringes with the active ingredient(s) as is, or a solution, suspension or emulsion prepared using the active ingredient(s) and additives. Injection cartridges refer to injections used by fixing a cartridge filled with a chemical solution in an injector for exclusive use. A chemical solution filled cartridge can typically be made by filling the cartridge with the active ingredient(s) as is, or a solution, suspension or emulsion prepared using the active ingredient(s) and additives. Parenteral infusions generally refer to injections of 100 mL or more intended for intravenous administration. Implants/pellets refer to solid or gel-like injections administered subcutaneously, intramuscularly, etc. using an implant or through surgical treatment to release the active ingredient(s) over a long period of time. Implants/beads can usually be manufactured in the form of granules, microspheres or gel using biodegradable polymer compounds. Sustained release injections refer to injections that are administered intramuscularly or intraarticularly for the purpose of releasing the active ingredient(s) over an extended period of time, and can generally be prepared by dissolving or suspending the active ingredient(s) in a vegetable oil or the like, or by preparing a suspension microspheres using biodegradable polymer compounds.

[0108]

The dosage of a compound of the present invention or a concomitant drug with a compound of the present invention and another drug varies depending on age, weight, symptom, therapeutic effect, route of administration, treatment time and the like. However, a compound of the present invention or a concomitant drug with a compound of the present invention and another drug is administered orally, typically in the range of 1 ng to 1000 mg at a time for an adult, one to several times per day, or administered parenterally in the range of 0 .1 ng to 100 mg at a time for an adult, one to several times per day, or administered continuously intravenously over a range of 1 to 24 hours per day. As described above, since the dose varies depending on various conditions, a dose less than that stated above may be sufficient or may need to be administered outside the range.

[0109]

Unless otherwise specified, all technical terms, scientific terms and abbreviated terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention relates.

In addition, the contents of all patent literature and non-patent literature or references specifically cited herein may be incorporated herein in their entirety as part of this specification.

EXAMPLES

[0110]

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to them.

[Synthesis example]

The solvents given in parentheses in the Chromatographic Separations and TLC section indicate the elution solvents or developing solvents used, and the ratio is the volume ratio.

The solvent given in parentheses in the NMR section indicates the solvent used in the measurement.

The names of compounds used in this specification are given by a computer program that usually assigns names in accordance with IUPAC, ACD/Name (registered trademark) or Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft) rules, or compounds are named according to with IUPAC nomenclature.

LC-MS/ELSD was performed under the following conditions.

Column: Waters Triart C ₁₈ (particle diameter: 1.9×10 ^-6 m; column length: 30×2.0 mm internal diameter); flow rate: 1.0 ml/min; column temperature: 30°C; mobile phase (A): 0.1% aqueous trifluoroacetic acid; mobile phase (B): 0.1% trifluoroacetic acid-acetonitrile solution; gradient (mobile phase (A) to mobile phase (B) ratio): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.4 min] 5:95; [1.41 min] 95:5; [1.5 min] 95:5; detectors: UV (PDA), ELSD, MS.

HPLC retention times refer to retention times under LC-MS/ELSD conditions unless otherwise stated.

Supercritical liquid chromatography (SFC) was carried out under the following conditions.

Column: CHIRALPAK IC/SFC (Daicel Corporation), internal diameter 20 mm x length 250 mm, particle diameter 5 µm; flow rate: 100 ml/min: co-solvent/CO ₂ =12/88: ISOCRATIC 21 min (co-solvent: MeCN/MeOH=9/1); Back pressure: 120 bar.

[0111]

Reference Example 1: 4-(Acetoxy)-2-(trifluoromethyl)benzoic acid

To a solution of 4-hydroxy-2-(trifluoromethyl)benzoic acid (registration no. 320-32-1, 500 mg) in ethyl acetate (7.5 ml), pyridine (0.392 ml) and acetic anhydride (0.573 ml) were added and the mixture was stirred in during the night. Water and dilute hydrochloric acid were added to the reaction mixture, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (528 mg) having the following physical properties.

¹ H-NMR (DMSO-d ₆ ): δ 2.34, 7.56, 7.70, 7.91, 13.66.

[0112]

Reference Example 2: 4-(Chlorocarbonyl)-3-(trifluoromethyl)phenyl acetate

To a toluene (1.6 ml)-acetonitrile (0.26 ml) solution of the compound (1.0 g) obtained in Reference Example 1 was added thionyl chloride (0.17 ml), and the mixture was stirred at 60°C in within 4 hours. The compound obtained by concentrating the reaction solution under reduced pressure was used in the next reaction without purification.

[0113]

Reference Example 3: Methyl {3-[4-(acetoxy)-2-(trifluoromethyl)benzamide]-4-chlorophenyl}acetate

To a toluene (1.6 ml)-acetonitrile (1.6 ml) solution of the compound obtained in Reference Example 2 was added pyridine (0.342 ml) and methyl 2-(3-amino-4-chlorophenyl) acetate (Registration No. 59833-69-1, 422 mg) 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 organic layer was washed successively with 1 mol/L hydrochloric acid, water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30) to obtain the title compound (715 mg) having the following physical properties.

¹ H-NMR (CDCl ₃ ): δ 2.37, 3.68, 3.72, 7.07, 7.37, 7.43, 7.53, 7.71, 7.93, 8.45.

[0114]

Reference Example 4: Methyl {4-chloro-3-[4-hydroxy-2-(trifluoromethyl)benzamide]phenyl}acetate

To a solution of the compound (1.75 g) obtained in Reference Example 3 in methanol (8.8 ml)-tetrahydrofuran (8.8 ml) was added potassium carbonate (404 mg) and the mixture was stirred at room temperature for 2 hours . Water and 1 mol/L hydrochloric acid were added to the reaction mixture, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (1.36 g) having the following physical properties.

TLC: Rf 0.55 (hexane:ethyl acetate=1:1);

¹ H-NMR (CDCl ₃ ): δ 3.63, 3.75, 7.12-7.16, 7.19, 7.49, 7.52, 7.59, 10.07, 10.52.

[0115]

Example 1: Methyl (4-chloro-3-{4-[2-(oxan-2-yl)ethoxy]-2-(trifluoromethyl)benzamide}phenyl)acetate

[Chemical formula 35]

To a solution in toluene (5 ml) of the compound (500 mg) obtained in Reference Example 4, 2-(tetrahydropyran-2-yl)ethanol (CAS No. 38786-79-7, 218 mg), was added cyanomethylene triphenylphosphine (0.507 ml) and the mixture was stirred overnight at 60°C. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (564 mg) having the following physical properties.

HPLC retention time (min): 1.15;

¹ H-NMR (CDCl ₃ ): δ 1.37, 1.47-1.68, 1.86, 1.94, 3.40-3.53, 3.67, 3.72, 3.98, 4.13, 4.20, 7.04, 7.13, 7.29, 7.36, 7.62, 7.93, 8.47.

[0116]

Example 2: (4-Chloro-3-{4-[2-(oxan-2-yl)ethoxy]-2-(trifluoromethyl)benzamide}phenyl)acetic acid

[Chemical formula 36]

To a dimethoxyethane (0.4 ml) solution of the compound (40.0 mg) obtained in Example 1, 2 mol/L lithium hydroxide aqueous solution (0.12 ml) was added, and the mixture was stirred at room temperature for 1 hour. After adding 1 mol/L hydrochloric acid to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (29 mg) having the following physical properties.

HPLC retention time (min): 1.03;

¹ H-NMR (DMSO-d ₆ ): δ 1.25, 1.41-1.53, 1.63, 1.77, 1.83-1.89, 3.45, 3.63, 3. 88, 4.14-4.23, 7.19, 7.32, 7.35, 7.48, 7.51, 7.68, 10.14, 12.46.

[0117]

Examples 2-1 to 2-3

The same operations as Example 1 and Example 2 were performed using the appropriate alcohol form instead of 2-(tetrahydro-2H-pyran-2-yl)ethanol to obtain the title compound having the following physical properties.

Example 2-1: {4-Chloro-3-[4-(2-cyclohexylethoxy)-2-(trifluoromethyl)benzamide]phenyl}acetic acid

[Chemical formula 37]

TLC: Rf 0.60 (ethyl acetate:methanol=9:1);

¹ H-NMR (CDCl ₃ ): δ 0.85-1.10, 1.13-1.35, 1.52, 1.63-1.83, 3.71, 4.08, 7.05, 7.10, 7.38, 7.62, 7.94, 8.49.

Example 2-2: {4-Chloro-3-[4-(2-phenylethoxy)-2-(trifluoromethyl)benzamide]phenyl}acetic acid

[Chemical formula 38]

HPLC retention time (min): 1.07;

¹ H-NMR (DMSO-d ₆ ): δ 3.09, 3.63, 4.36, 7.18, 7.24, 7.31-7.37, 7.48, 7.51, 7, 68, 10.14, 12.45.

Example 2-3: {4-Chloro-3-[4-(2-cyclopropylethoxy)-2-(trifluoromethyl)benzamide]phenyl}acetic acid

[Chemical formula 39]

HPLC retention time (min): 1.05;

¹ H-NMR (DMSO-d ₆ ): δ -0.02-0.01, 0.28-0.32, 0.70, 1.51, 3.48, 4.02, 7.03, 7 ,16, 7.20, 7.33, 7.36, 7.53, 9.99, 12.29.

[0118]

Example 3: Methyl (4-chloro-3-{2,6-dimethyl-4-[2-(oxan-2-yl)ethoxy]benzamide}phenyl)acetate

[Chemical formula 40]

The same reaction as Example 1 was carried out using methyl {4-chloro-3-[(4-hydroxy-2,6-dimethylbenzoyl)amino]phenyl}acetate (CAS no. 1351163-96-6, Bioorganic & Medicinal Chemistry 19 (2011) 6935-6948, compound 44) instead of the compound obtained in Reference Example 4 to obtain the title compound having the following physical properties.

TLC: Rf 0.75 (hexane:ethyl acetate=1:1);

¹ H-NMR (CDCl ₃ ): δ 1.33, 1.51, 1.63, 1.85, 1.91, 2.38, 3.43, 3.50, 3.68, 3.73, 3.97, 4.08, 6.63, 7.03, 7.35, 7.74, 8.49.

[0119]

Example 3-1: Methyl {4-chloro-3-[4-(2-cyclohexylethoxy)-2,6-dimethylbenzamide]phenyl}acetate

[Chemical formula 41]

The same reaction as in Example 1 was carried out using methyl {4-chloro-3-[(4-hydroxy-2,6-dimethylbenzoyl)amino]phenyl}acetate instead of the compound obtained in Reference Example 4 and using 2 -cyclohexylethanol (CAS No. 28438-52-0) instead of 2-(tetrahydro-2H-pyran-2-yl)ethanol to give the title compound having the following physical properties.

TLC: Rf 0.68 (ethyl acetate:hexane=2:1);

¹ H-NMR (CDCl ₃ ): δ 0.80-1.05, 1.10-1.35, 1.40-1.55, 1.65-1.80, 2.35, 3.53, 3.68, 3.73, 4.00, 4.19, 6.61, 7.04, 7.36, 7.74, 8.50.

[0120]

Example 4: (4-Chloro-3-{2,6-dimethyl-4-[2-(oxan-2-yl)ethoxy]benzamide}phenyl)acetic acid

[Chemical formula 42]

The same reaction as in Example 2 was carried out using the compound obtained in Example 3 instead of the compound obtained in Example 1 to obtain the title compound having the following physical properties.

HPLC retention time (min): 1.02;

¹ H-NMR (DMSO-d ₆ ): δ 1.16-1.83, 2.32, 3.39, 3.61, 3.86, 4.02, 6.66, 7.15, 7, 45, 7.49, 9.95, 12.44.

[0121]

Examples 4-1 and 4-2:

The same operations as in Example 1 and Example 2 were performed using the appropriate alcohol form instead of 2-(tetrahydro-2H-pyran-2-yl)ethanol and using methyl {4-chloro-3-[(4-hydroxy- 2,6-dimethylbenzoyl)amino]phenyl}acetate in place of the compound obtained in Reference Example 4 to obtain the title compound having the following physical properties.

Example 4-1: {4-Chloro-3-[4-(2-cyclohexylethoxy)-2,6-dimethylbenzamide]phenyl}acetic acid

[Chemical formula 43]

TLC: Rf 0.27 (hexane:ethyl acetate=1:2);

¹ H-NMR (CD ₃ OD): δ 0.83-1.08, 1.13-1.38, 1.42-1.59, 1.60-1.91, 2.41, 3.64 , 4.01, 6.65, 7.19, 7.43, 7.72.

Example 4-2: {4-Chloro-3-[4-(2-cyclopropylethoxy)-2,6-dimethylbenzamide]phenyl}acetic acid

[Chemical formula 44]

HPLC retention time (min): 1.05;

MS (ESI, positive): 402 (M+H) ⁺ ;

[0122]

Example 5: (3-{4-[(2,3-Dihydro-1H-inden-2-yl)oxy]-2,6-dimethylbenzamide}-4-fluorophenyl)acetic acid

[Chemical formula 45]

The same reactions as in Reference Example 1→Reference Example 2→Reference Example 3→Reference Example 4→Example 1→Example 2 were carried out using methyl 2-(3-amino-4-fluorophenyl) acetate (CAS No. 257632 -77-2) instead of methyl 2-(3-amino-4-chlorophenyl) acetate, using 4-hydroxy-2,6-dimethylbenzoic acid (CAS no. 75056-97-2) instead of 4-hydroxy-2-( trifluoromethyl)benzoic acid and using 2-indanol (CAS No. 4254-29-9) instead of 2-(tetrahydro-2H-pyran-2-yl)ethanol to obtain the title compound having the following physical properties.

HPLC retention time (min): 1.02;

¹ H-NMR (DMSO-d ₆ ): δ 2.29, 3.02, 3.39, 3.60, 5.27, 6.70, 7.13-7.28, 7.57, 10, 07, 12.38.

[0123]

Reference Example 5: Methyl (4-chloro-3-{2,6-dimethyl-4-[(trifluoromethanesulfonyl)oxy]benzamide}phenyl)acetate

To a solution of methyl [4-chloro-3-(4-hydroxy-2,6-dimethylbenzamide)phenyl]acetate (1.00 g) in dichloromethane (15 ml) was added triethylamine (0.52 ml) and N,N-bis (trifluoromethylsulfonyl)aniline (1.23 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 organic layer was washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to obtain the title compound (1.38 g) having the following physical properties.

TLC: Rf 0.39 (hexane:ethyl acetate=2:1);

¹ H-NMR (CDCl ₃ ): δ 1.55, 2.45, 3.69, 3.73, 7.02, 7.08, 7.37, 7.40, 7.73, 8.43.

[0124]

Example 6: Methyl {4-chloro-3-[4-(3-cyclohexylprop-1-yn-1-yl)-2,6-dimethylbenzamide]phenyl}acetate

[Chemical formula 46]

To a solution in N,N-dimethylformamide (12 ml) of the compound (1.38 g) obtained in Reference Example 5, 3-cyclohexyl-1-propyne (1.26 ml) and triethylamine (8.1 ml) and atmosphere were added replaced by an argon atmosphere. Copper iodide (55 mg) and bis(triphenylphosphine)palladium(II) dichloride (204 mg) were added and the mixture was stirred overnight at 50°C. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate/hexane. The organic layer was washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to obtain the title compound (1.46 g) having the following physical properties.

TLC: Rf 0.45 (hexane:ethyl acetate=4:1);

¹ H-NMR (CDCl ₃ ): δ 0.95-1.40, 1.45-1.78, 1.85-1.90, 2.30, 2.37, 3.68, 3.73, 7.05, 7.14, 7.35, 7.38, 7.71, 8.47.

[0125]

Example 7: {4-Chloro-3-[4-(3-cyclohexylprop-1-yn-1-yl)-2,6-dimethylbenzamide]phenyl}acetic acid

[Chemical formula 47]

The same reaction as in Example 2 was carried out using the compound obtained in Example 6 instead of the compound obtained in Example 1 to obtain the title compound having the following physical properties.

TLC: Rf 0.61 (ethyl acetate:methanol=9:1);

¹ H-NMR (CDCl ₃ ): δ 0.98-1.35, 1.56, 1.65-1.80, 1.82-1.90, 2.30, 2.38, 3.72, 7.06, 7.14, 7.36, 7.39, 7.71, 8.48.

[0126]

Example 8: (4-Chloro-3-{4-[(1E)-3-cyclohexylprop-1-en-1-yl]-2,6-dimethylbenzamide}phenyl)acetic acid

[Chemical formula 48]

To a dioxane (12 ml) solution of the compound (1000 mg) obtained in Reference Example 5 was added 2-[(E)-3-Cyclohexylpropen-3-yl]-4,4,5,5-tetramethyl-1,3 ,2-dioxaborolane (626 mg), potassium phosphate (884 mg) and [1,1ʼ-bis(diphenylphosphino)ferrocene]palladium(II) dichloride adduct and dichloromethane and the mixture was stirred at 50°C for 18 hours. Water and ethyl acetate were added to the reaction mixture, then the mixture was filtered through Celite (trade name). The filtrate was extracted with ethyl acetate, the organic layer was washed with water and brine, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a methyl ester derivative (533 mg) of the title compound. Using the resulting methyl ester derivative, the same reaction as Example 2 was carried out to obtain the title compound having the following physical properties.

TLC: Rf 0.38 (hexane:ethyl acetate:acetic acid=14:5:1);

HPLC retention time (min): 1.31;

MS (ESI, positive): 440 (M+H) ⁺ .

[0127]

Example 9: Methyl [4-chloro-3-({2,6-dimethyl-4-[2-(oxan-2-yl)ethoxy]benzene-1-carbothioyl}amino)phenyl]acetate

[Chemical formula 49]

To a toluene (0.4 ml) solution of the compound (40 mg) obtained in Example 3 was added Lawesson's reagent (CAS No. 19172-47-5, 21 mg) and the mixture was stirred at 100°C for 24 hours . The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→4:1) to obtain the title compound (40 mg) having the following physical properties.

TLC: Rf 0.50 (hexane:ethyl acetate=2:1);

¹ H-NMR (DMSO-d ₆ ): δ 1.25, 1.46, 1.62, 1.81, 2.37, 3.44, 3.64, 3.80, 3.87, 4, 02, 6.68, 7.30, 7.42, 7.55, 11.74.

[0128]

Example 10: [4-Chloro-3-({2,6-dimethyl-4-[2-(oxan-2-yl)ethoxy]benzene-1-carbothioyl}amino)phenyl]acetic acid

[Chemical formula 50]

The same reaction as in Example 2 was carried out using the compound obtained in Example 9 instead of the compound obtained in Example 1 to obtain the title compound having the following physical properties.

TLC: Rf 0.28 (dichloromethane:methanol=9:1);

¹ H-NMR (DMSO-d ₆ ): δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6, 68, 7.29, 7.39, 7.54, 11.74, 12.46.

[0129]

Examples from 10-1 to 10-5:

The same operations as in Example 9→Example 2 were carried out using the compounds obtained in Example 1 and Example 3-1 and the methyl ester derivatives of the compounds obtained in Examples 2-1 to 2-3 instead of the compound obtained in Example 3 to obtain the title compound having the following physical properties.

Example 10-1: (4-Chloro-3-{[4-(2-cyclohexylethoxy)-2,6-dimethylbenzene-1-carbothioyl]amino}phenyl)acetic acid

[Chemical formula 51]

TLC: Rf 0.46 (ethyl acetate:methanol=9:1);

¹ H-NMR (DMSO-d ₆ ): δ 0.85-1.02, 1.10-1.30, 1.43, 1.55-1.75, 2.35, 3.65.3, 99, 6.67, 7.28, 7.36, 7.51, 7.54, 11.71, 12.44.

Example 10-2: [4-Chloro-3-({4-[2-(oxan-2-yl)ethoxy]-2-(trifluoromethyl)benzene-1-carbothioyl}amino)phenyl]acetic acid

[Chemical formula 52]

HPLC retention time (min): 1.05;

¹ H-NMR (DMSO-d ₆ ): δ 1.25, 1.42-1.51, 1.63, 1.77, 1.83-1.89, 3.45, 3.67, 3. 88, 4.12-4.21, 7.25, 7.29-7.32, 7.35, 7.47, 7.55, 11.90, 12.46.

Example 10-3: (4-Chloro-3-{[4-(2-cyclohexylethoxy)-2-(trifluoromethyl)benzene-1-carbothioyl]amino}phenyl)acetic acid

[Chemical formula 53]

HPLC retention time (min): 1.21;

¹ H-NMR (DMSO-d ₆ ): δ 0.92-1.02, 1.13-1.29, 1.49, 1.63-1.77, 3.66, 4.14, 7. 24, 7.29-7.32, 7.34, 7.46, 7.54, 11.89, 12.46.

Example 10-4: (4-Chloro-3-{[4-(2-phenylethoxy)-2-(trifluoromethyl)benzene-1-carbothioyl]amino}phenyl)acetic acid

[Chemical formula 54]

HPLC retention time (min): 1.09;

¹ H-NMR (DMSO-d ₆ ): δ 3.08, 3.66, 4.34, 7.23-7.27, 7.29-7.37, 7.46, 7.55, 11, 90, 12.50.

Example 10-5: (4-Chloro-3-{[4-(2-cyclopropylethoxy)-2-(trifluoromethyl)benzene-1-carbothioyl]amino}phenyl)acetic acid

[Chemical formula 55]

HPLC retention time (min): 1.06;

¹ H-NMR (DMSO-d ₆ ): δ -0.02-0.01, 0.28-0.32, 0.70, 1.51, 3.50, 4.00, 7.08, 7 ,13-7.18, 7.31, 7.38, 11.74, 12.30.

[0130]

Example 11:

Using the compound obtained in Example 9, optical separation was carried out using supercritical liquid chromatography (SFC) to obtain the title compound having the following physical properties.

Example 11-1: Methyl {4-chloro-3-[(2,6-dimethyl-4-{2-[(2R)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}acetate

[Chemical formula 56]

HPLC retention time (min): 13.2 (CHIRAL PAK IC, hexane:isopropanol=70:30);

Example 11-2: Methyl {4-chloro-3-[(2,6-dimethyl-4-{2-[(2S)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}acetate

[Chemical formula 57]

HPLC retention time (min): 11.8 (CHIRAL PAK IC, hexane:isopropanol=70:30);

[0131]

Example 12: {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}acetic acid

[Chemical formula 58]

The same reaction as in Example 2 was carried out using the compound obtained in Example 11-1 instead of the compound obtained in Example 1 to obtain the title compound having the following physical properties.

TLC: Rf 0.28 (dichloromethane:methanol=9:1);

HPLC retention time (min): 1.05;

MS (ESI, positive): 462(M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6, 68, 7.29, 7.39, 7.54, 11.74, 12.46.

[0132]

Example 13: {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}acetic acid

[Chemical formula 59]

The same reaction as in Example 2 was carried out using the compound obtained in Example 11-2 instead of the compound obtained in Example 1 to obtain the title compound having the following physical properties.

TLC: Rf 0.28 (dichloromethane:methanol=9:1);

HPLC retention time (min): 1.05;

MS (ESI, positive): 462(M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6, 68, 7.29, 7.39, 7.54, 11.74, 12.46.

[0133]

Reference Example 6: Methyl 2-(3-amino-4-fluorophenyl)propanoate

A solution in acetic acid (5 ml) of methyl 2-(4-fluoro)-3-nitrophenyl)propanoate (CAS no. 1428790-43-5, 3.9 g) prepared by the method described in WO 2013/045451 was added to a mixture obtained by adding iron powder (4.8 g) to acetic acid (34 ml) and water (4.0 ml) and heating to a temperature of 65°C, and the reaction mixture was stirred at a temperature of 65°C for 30 minutes. The reaction mixture was cooled to room temperature and then filtered through Celite (trade name) and the filtrate was cooled to 0°C. Then 2N aqueous sodium hydroxide solution (345 ml) was added and the mixture was again filtered through Celite (trade name). The filtrate was extracted twice with tert-butyl methyl ether, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1→65:35) to obtain the title compound (3.4 g) having the following physical properties.

¹ H-NMR (CDCl ₃ ): δ 1.45, 3.60, 3.63, 3.71, 6.60, 6.73, 6.91.

[0134]

Example 14: 2-{3-[({2,6-Dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]-4-fluorophenyl}propionic acid

[Chemical formula 60]

The same reactions as in Reference Example 2→Reference Example 3→Reference Example 4→Example 1→Example 9→Example 2 were carried out using the compounds obtained in Reference Example 6 instead of methyl 2-(3-amino-4- chlorophenyl)acetate and 4-acetoxy-2,6-dimethylbenzoic acid (CAS number 1351163-93-3), prepared by the method described in Bioorganic & Medicinal Chemistry, vol. 19, 6935-6948, 2011, instead of the compound obtained in Reference Example 1, to obtain the title compound having the following physical property values.

HPLC retention time (min): 1.07;

MS (ESI, positive, 20 V): 460 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 1.18, 1.19-1.29, 1.38, 1.39-1.55, 1.62, 1.71-1.87, 2. 32, 3.26-3.52, 3.77, 3.87, 4.04, 6.69, 7.26-7.43, 11.64, 12.44.

[0135]

Example 15: 1-{3-[({2,6-Dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]-4-fluorophenyl}cyclopropanecarboxylic acid

[Chemical formula 61]

The same reactions as in Reference Example 6→Reference Example 2→Reference Example 3→Reference Example 4→Example 1→Example 9→Example 2 were carried out using methyl 1-(4-fluoro-3-nitrophenyl)cyclopropane-1 -carboxylate (CAS number, 2260554-65-0) obtained by the method described in WO 2019/003143 A, and 4-acetoxy-2,6-dimethylbenzoic acid instead of the compound obtained in reference example 1, obtaining specified in header of a connection having the following physical characteristic values.

HPLC retention time (min): 1.09;

MS (ESI, positive, 20 V): 472 (M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 1.12-1.31, 1.38-1.54, 1.61, 1.71-1.86, 2.32, 3.27-3, 47, 3.87, 4.03, 6.68, 7.26, 7.36, 7.43, 11.64, 12.42.

[0136]

Example 16: Methyl 2-[4-chloro-3-({2,6-dimethyl-4-[2-(oxan-2-yl)ethoxy]benzene-1-carbothioyl}amino)phenyl]-2-methylpropanoate

[Chemical formula 62]

The same reactions as in Reference Example 2→Reference Example 3→Reference Example 4→Example 1→Example 9 were carried out using methyl 2-(3-amino-4-chlorophenyl)-2-methylpropanoate (CAS no. 343326 -75-0), obtained by the method described in Bioorganic Medicinal Chemistry, 2011, vol. 19, 6935-6948, and 4-acetoxy-2,6-dimethylbenzoic acid instead of the compound obtained in Reference Example 1, to obtain the title compound having the following physical characteristics.

¹ H-NMR (DMSO-d ₆ ): δ 1.20-1.28, 1.42-1.50, 1.53, 1.58-1.65, 1.72-1.85, 2. 36, 3.28-3.48, 3.61, 3.85-3.90, 4.00-4.08, 6.68, 7.35, 7.43, 7.58 11.75.

[0137]

Example 17: 2-{4-Chloro-3-[({2,6-dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]phenyl}-2- methylpropionic acid

[Chemical formula 63]

Using the compound obtained in Example 16, the same reaction as in Example 2 was carried out to obtain the title compound having the following physical properties.

HPLC retention time (min): 1.14;

MS (ESI, positive, 20 V): 490(M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 1.20-1.25, 1.43-1.49, 1.49, 1.58-1.65, 2.36, 3.26-3, 48, 3.77, 4.00-4.08, 6.68, 7.38, 7.46, 7.58 11.74, 12.57.

[0138]

Example 18: Methyl 2-{4-chloro-3-[(2,6-dimethyl-4-{2-[(2S)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}- 2-methylpropanoate and methyl 2-{4-chloro-3-[(2,6-dimethyl-4-{2-[(2R)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl} -2-methylpropanoate

Using the compound obtained in Example 16, optical separation was carried out using supercritical liquid chromatography (SFC) to obtain the title compound having the following physical properties.

Separation conditions, column: CHIRALPAK IC 5 µm 20 mm×250 (manufactured by Daicel Corporation); CO ₂ : (ethyl acetate/methanol=9/1)=78/22

Example 18-1: (first peak)

SFC retention time (min): 3.69 (CHIRALPAK IC 5 µm 20 mm×250 (manufactured by Daicel Corporation); CO ₂ : (ethyl acetate/methanol=9:1)=78:22)

Example 18-2: (second peak)

SFC retention time (min): 5.32 (CHIRALPAK IC 5 µm 20 mm×250 (manufactured by Daicel Corporation); CO ₂ : (ethyl acetate/methanol=9:1)=78:22)

[0139]

Example 19: 2-{4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}-2 -methylpropionic acid and 2-{4-chloro-3-[(2,6-dimethyl-4-{2-[(2R)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}- 2-methylpropionic acid

Using the compound obtained in Example 18-1 or Example 18-2, the same reaction as in Example 2 was carried out to obtain the title compound having the following physical characteristics.

Example 19-1: (Compound prepared using the compound prepared in Example 18-1)

HPLC retention time (min): 1.14;

MS (ESI, positive, 20 V): 490(M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 1.20-1.25, 1.43-1.49, 1.49, 1.58-1.65, 2.36, 3.26-3, 48, 3.77, 4.00-4.08, 6.68, 7.38, 7.46, 7.58 11.74, 12.57.

Example 19-2: (Compound prepared using the compound prepared in Example 18-2)

HPLC retention time (min): 1.14;

MS (ESI, positive, 20 V): 490(M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 1.20-1.25, 1.43-1.49, 1.49, 1.58-1.65, 2.36, 3.26-3, 48, 3.77, 4.00-4.08, 6.68, 7.38, 7.46, 7.58 11.74, 12.57.

[0140]

Example 20: 2-{3-[({2,6-Dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]-4-fluorophenyl}-2-methylpropionic acid

[Chemical formula 64]

The same reactions as in Reference Example 6→Reference Example 2→Reference Example 3→Reference Example 4→Example 1→Example 9→Example 2 were carried out using methyl 2-(4-fluoro-3-nitrophenyl)-2- methyl propanoate obtained by the method described in WO 2018/116107 A, and 4-acetoxy-2,6-dimethylbenzoic acid instead of the compound obtained in Reference Example 1, to obtain the title compound having the following physical characteristics.

HPLC retention time (min): 1.09;

MS (ESI, positive, 20 V): 474(M+H) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 1.25, 1.41-1.48, 1.49, 1.62, 1.71-1.85, 2.31, 3.32, 3, 43, 3.87, 3.99-4.08, 6.68, 7.31, 7.38, 7.44, 11.65, 12.51.

[0141]

Example 21: 2-(4-Chloro-3-{[(2,6-dimethyl-4-{2-[(2R)-tetrahydro-2H-pyran-2-yl]ethoxy}phenyl)carbothioyl]amino}phenyl )-propionic acid

[Chemical formula 65]

To a dichloromethane (25 ml) solution of the compound (1200 mg) obtained in Example 11-1 at 0°C, DIPEA (2.2 ml) and methoxymethyl chloride (0.57 ml) were added and the reaction mixture was stirred at room temperature within 1 hour. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→35:65) to obtain crude product (1300 mg). Cesium carbonate (4.1 g) and methyl iodide (0.78 ml) were added to a dimethylacetamide (10 ml) solution of the crude product and the reaction mixture was stirred at 35°C for 16 hours. The reaction mixture was cooled to room temperature and then an aqueous solution of ammonium chloride was added. The mixture was extracted twice with tert-butyl methyl ether, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→0:100) to obtain crude product (410 mg). To a dioxane solution (10 ml) of the crude product was added 5 mol/L aqueous hydrochloric acid solution (5 ml) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted twice with tert-butyl methyl ether, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→0:100) to obtain crude product (320 mg). To a tetrahydrofuran (4 ml) solution of the crude product, methanol (4 ml) and 2 mol/L aqueous sodium hydroxide solution (4 ml) were added, and the reaction mixture was stirred at room temperature for 3 hours. 2 mol/L aqueous hydrochloric acid was added to the reaction mixture, the mixture was extracted with tert-butyl methyl ether twice, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→0:100) to obtain the title compound (275 mg) having the following physical properties.

HPLC retention time (min): 1.10;

MS (ESI, positive, 20 V): 476(M+H) ⁺ ;

¹ H-NMR (CDCl ₃ ): δ 0.78-0.84, 1.30-1.90, 2.17-2.25, 2.39, 3.39-3.60, 3.90- 4.12, 4.54, 6.37, 6.52-6.65, 7.01-7.04, 7.25-7.30, 7.42-7.45, 8.71, 8, 88, 9.70.

[0142]

Example 22: [4-Chloro-3-({[4-(2-cyclohexylethoxy)-2,6-dimethylphenyl]carbothioyl}amino)phenyl]sodium acetate

[Chemical formula 66]

To a dioxane (2 ml) solution of the compound (60 mg) obtained in Example 10-1 was added 1 mol/L sodium hydroxide aqueous solution (0.13 ml), and then the mixture was lyophilized to obtain the title compound (49 mg) , having the following values of physical characteristics.

HPLC retention time (min): 1.38;

MS (ESI, positive, 20 V): 460 (M+H-Na) ⁺ ;

¹ H-NMR (DMSO-d ₆ ): δ 0.87-1.02, 1.10-1.28, 1.47, 1.67-1.79, 2.36, 3.26, 3. 99, 6.65, 7.12-7.28, 7.38, 11.70.

[0143]

[Pharmacological examples]

Biological Example 1: Determination of DP Receptor Antagonism Activity Using Cells Expressing the Human DP Receptor

To determine the antagonistic activity of the DP receptor, a cAMP-HTRF kit (SCETI MEDICAL LABO K.K., 62AM6PEJ) was used. 10 μl/well of the compound of the present invention prepared at various concentrations and prostaglandin D2 (final concentration 10 nmol/l) were added to a 384-well plate. Cells expressing the human DP receptor were suspended in phosphate buffer containing 2 μl/L diclofenac and 1 mmol/L IBMX (3-isobutyl-1-methylxanthine) and seeded to 5000 cells/10 μl/well. After cell seeding, cells were incubated at room temperature for 1 hour. Thereafter, anti-cAMP-cryptate conjugate and cAMP-d2 solution were added according to the measurement kit method, and the mixture was incubated at room temperature for 1 hour, then the concentration of cAMP in the sample was determined.

The intensity of the antagonistic activity of the compounds of the present invention on the DP receptor was represented by the IC ₅₀ value (the concentration of the compound of the present invention required to inhibit 50% of cAMP production in the absence of the compound of the present invention), calculated from the inhibition ratio to cAMP production increased upon stimulation with prostaglandin D2 by 10 nmol/l. Table 1 shows the antagonistic activity of the compounds of the present invention against the DP receptor.

[Table 1]

Example number Antagonistic activity of DP
IC ₅₀ (µm) 2-1 0.034 4 0.058 4-1 0.011 5 0.010 7 0.016 8 0.0037 10 0.0096 10-1 0.0017 10-4 0.0051 12 0.0048 20 0.035 21 0.0078

The compounds of the present invention exhibited potent antagonistic activity against DP receptors.

[0144]

Pharmacokinetic test 1. Determination of the concentration of the compound of the present invention in the cerebrospinal fluid (hereinafter, CSF).

(1) CSF collection

The five test substances were mixed and a test substance solution was prepared so that the dose of each test substance was 3 mg/5 ml/kg. The medium used was 5% DMSO, 20% coliphor HS15/propylene glycol (7:3). The solution of the test substance was administered orally to male Wistar rats aged 8-10 weeks, purchased from Charles River Japan. Three hours after administration, rats were anesthetized and cerebrospinal fluid (CSF) was collected by cisternal puncture. The same amount of ethanol (wako) as CSF was taken with the syringe used for collection, and the compound adsorbed on the syringe was isolated by washing.

(2) Measurement

Candesartan (TRC) was used as an internal standard substance, 40 μL of acetonitrile and 160 μL of candesartan-containing acetonitrile/ethanol (7:3) were added to 10 μl of the resulting CSF sample, and the mixture was stirred. To construct a calibration curve, 40 μl of compound solution and 160 μl of candesartan-containing acetonitrile/ethanol (7:3) were added to 10 μl of plasma and the mixture was mixed. The entire amount of each solution was transferred to a deproteinization filter plate and filtered under vacuum. The resulting filtrate was suitably diluted with acetonitrile/water (1:1) and used for measurement. During the measurement, standard samples for the calibration curve were prepared in the same matrix and analyzed in the same way. The measurement was carried out under the following conditions.

Liquid Chromatography System: Prominence UFLC _XR (Shimadzu Corporation),

Column: Shim-pack XR-ODSII 2.0mm ID×75mm (Shimadzu Corporation),

Column temperature: 40°C,

Mobile phase: A: 0.2% formic acid, 5 mmol/L aqueous ammonium acetate, B: acetonitrile,

Gradient program:

Time (mobile phase B (%)): 0 min (10)→1.5 min (90)→3.0 min (90)→3.1 min (10)→4 min (10),

Flow rate: 0.5ml/min

Mass spectrometry system: API4000, API5000 (AB SCIEX)

(3) Analysis

The regression equation was calculated based on the peak area ratio (peak area of the test substance/peak area of the internal standard substance) obtained by measuring standard samples for the calibration curve using analysis software Analyst ver. 1.5.2 (AB SCIEX). The regression equation was calculated. The peak area ratio was also obtained for the measured sample and substituted into the regression equation to calculate the quantitative value. When calculating the mean and standard deviation, points below the lower limit of quantification were calculated as 0.

The results are presented in Table 2.

[Table 2]

Example number Compound concentration in CSF (ng/ml) 4-1 29 7 45 8 28 10 43 10-1 36 10-2 55 10-4 34 12 48 20 52 21 66

Using the compound described in Example 13-24 in Patent Literature 2 of the prior art document as a reference compound, the concentration of the compound in CSF was determined to be 4.8 ng/ml. The CSF concentration of the compounds of the present invention was higher than that of the reference compound and showed good ability to penetrate into the central nervous system.

[0145]

Biological Example 2: Effect of Prolonging the Normal Wake Time of a Rat

Chronic electrodes were placed into the rats' brains and neck muscles to prepare the rats for electroencephalogram and electromyogram measurements. After a recovery period of one week or more in a protective box that blocked out sound and electrical noise, a biological signal amplifier was attached to the rat. After acclimatization in the measuring cage for 1 hour or more, the rats were orally administered various doses of the compound of the present invention as a single dose, and electroencephalogram and electromyogram were recorded 6 hours after oral administration. After completion of the measurement, rats were returned to the breeding cage each time and vehicle and each compound were assessed with a washout period of one week or more.

The recorded electroencephalogram and electromyogram were analyzed using SleepSign Ver. 3 and divided into periods every 10 seconds, and the stages of awakening, slow-wave sleep or REM sleep were determined with reference to the characteristics of the electroencephalogram and electromyogram, as well as the results of spectral analysis of each frequency component of the brain wave. The stage was defined as “awake” when a high amplitude electromyogram was observed, “non-REM sleep” when a high amplitude slow wave and low amplitude electromyogram were observed, and “REM sleep” when a low amplitude electroencephalogram was observed including the theta wave component and electrocardiogram with low amplitude. A period whose stage was difficult to determine due to noise, etc. was based on the result of determining the previous era.

After determining the sleep-wake state, the difference between the total wake-up time of 6 hours after administration of the compound to the group receiving the compound of the present invention and the total wake-up time of 6 hours after administration to the vehicle-administered group was expressed as the wake-time prolongation effect index.

As a result of evaluating the effect of prolonging the awakening time, the compounds of the present invention, for example, the compound of Example 8 and the compound of Example 12 showed the effects of prolonging the awakening time by 48 minutes and 60 minutes at a dose of 3 mg/kg, respectively, and it was shown that the compound of the present The invention can be used as a therapeutic agent for disorders of sleep and wakefulness.

[0146]

[Composition example]

A typical example of a composition used in the present invention is shown below.

{4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}acetic acid (100 g), calcium carboxymethylcellulose (20 g), magnesium stearate (10 g) and microcrystalline cellulose (870 g) are mixed in the usual way and then compressed to obtain about 10,000 tablets containing 10 mg of active ingredient per tablet.

INDUSTRIAL APPLICABILITY

[0147]

Since the compound of the present invention has strong DP receptor antagonistic activity and excellent ability to penetrate into the central nervous system, it can be used as a prophylactic and/or therapeutic agent for DP receptor-mediated diseases, in particular sleep-wake disorders.

Claims (55)

1. The compound represented by the general formula (I): [Chemical formula 1] , where R ¹ represents a hydrogen atom, a C1-4 alkyl or benzyl group, R ² , R ³ and R ⁴ each independently represent (1) a halogen atom, (2) a C1-4 alkyl group, optionally substituted by a halogen atom, or (3) a C1-4 alkoxy group, optionally substituted by a halogen atom, when there are several of R2 or R4, they may be the same or different, J represents a bond, -O- or -S-, L represents a bond, a C1-6 alkylene, a C2-6 alkenylene or a C2-6 alkynylene group, R ⁵ represents a hydrogen atom, a C3-10 carbocycle or a 3-10 membered monocyclic or bicyclic heterocycle containing from 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, The C3-10 carbocycle and 3-10 membered heterocycle in R ⁵ may be substituted with 1-6 R ⁷ provided that when L is a bond, ^R5 is not a hydrogen atom, R ⁷ represents (1) a halogen atom, (2) a C1-4 alkyl group, optionally substituted by a halogen atom, or (3) a C1-4 alkoxy group, optionally substituted by a halogen atom, when there are several R ⁷ , they can be the same or different, Q represents a sulfur atom, R ⁶ represents a hydrogen atom or a C1-4 alkyl group, R ¹¹ represents a hydrogen atom, a halogen atom or a C1-4 alkyl group, optionally substituted with a halogen atom, R ¹² represents a hydrogen atom, a halogen atom or a C1-4 alkyl group, optionally substituted with a halogen atom, R ¹¹ and R ¹² can be taken together with the carbon atom to which they are attached to form a C3-6 saturated carbocycle, n denotes an integer from 0 to 4 and m denotes an integer from 0 to 3, or its pharmaceutically acceptable salt. 2. A compound according to claim 1, represented by the general formula (I-1): [Chemical formula 2] , where R ⁵¹ represents a C3-10 carbocycle or a 3-10 membered monocyclic or bicyclic heterocycle containing from 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, J ¹ represents a bond or -O-, and others the symbols have the same meaning as stated in claim 1, or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2, wherein R ⁵¹ is a 3-8 membered saturated monocyclic heterocycle containing 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, or a pharmaceutically acceptable salt thereof. 4. The connection according to claim 1, where the connection is (11) (4-chloro-3-{[4-(2-cyclohexylethoxy)-2,6-dimethylbenzene-1-carbothioyl]amino}phenyl)acetic acid, (12) [4-chloro-3-({4-[2-(oxan-2-yl)ethoxy]-2-(trifluoromethyl)benzene-1-carbothioyl}amino)phenyl]acetic acid, (13) (4-chloro-3-{[4-(2-cyclohexylethoxy)-2-(trifluoromethyl)benzene-1-carbothioyl]amino}phenyl)acetic acid, (14) (4-chloro-3-{[4-(2-phenylethoxy)-2-(trifluoromethyl)benzene-1-carbothioyl]amino}phenyl)acetic acid, (15) (4-chloro-3-{[4-(2-cyclopropylethoxy)-2-(trifluoromethyl)benzene-1-carbothioyl]amino}phenyl)acetic acid, (16) [4-chloro-3-({2,6-dimethyl-4-[2-(oxan-2-yl)ethoxy]benzene-1-carbothioyl}amino)phenyl]acetic acid, (17) {4-chloro-3-[(2,6-dimethyl-4-{2-[(2R)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}acetic acid, (18) {4-chloro-3-[(2,6-dimethyl-4-{2-[(2S)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}acetic acid, (19) 2-{3-[({2,6-dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]-4-fluorophenyl}propionic acid, (20) 1-{3-[({2,6-dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]-4-fluorophenyl}cyclopropanecarboxylic acid, (21) 2-{4-chloro-3-[({2,6-dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]phenyl}-2- methylpropionic acid, (22) 2-{4-chloro-3-[(2,6-dimethyl-4-{2-[(2S)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}-2 -methylpropionic acid, (23) 2-{4-chloro-3-[(2,6-dimethyl-4-{2-[(2R)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl}-2 -methylpropionic acid, (24) 2-{3-[({2,6-dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]phenyl}carbothioyl)amino]-4-fluorophenyl}-2-methylpropionic acid or (25) 2-(4-chloro-3-{[(2,6-dimethyl-4-{2-[(2R)-tetrahydro-2H-pyran-2-yl]ethoxy}phenyl)carbothioyl]amino}phenyl )propionic acid, or its pharmaceutically acceptable salt. 5. A pharmaceutical composition which is a DP receptor antagonist, containing an effective amount of a compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof according to claim 1. 6. The pharmaceutical composition according to claim 5, which is a prophylactic and/or therapeutic agent for a disease mediated by the DP receptor. 7. The pharmaceutical composition according to claim 6, wherein the DP receptor-mediated disease is an allergic disease, systemic mastocytosis, systemic mast cell activation disorder, anaphylactic shock, airway constriction, urticaria, eczema, acne, allergic bronchopulmonary aspergillosis, sinusitis, migraine , nasal polyps, hypersensitivity vasculitis, eosinophilia, contact dermatitis, pruritic disease, disease secondary to pruritic disease, flushing disease, inflammation, chronic obstructive pulmonary disease, ischemia-reperfusion injury, cerebrovascular accident, autoimmune disease, cerebral injury, liver disease, transplant rejection, rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, interstitial cystitis, muscular dystrophy, polymyositis, malignancy, leukemia, viral infection, multiple sclerosis, sleep disturbance and wakefulness or platelet aggregation. 8. The pharmaceutical composition according to claim 7, wherein the DP receptor-mediated disease is a sleep-wake disorder and the sleep-wake disorder is a disease based on hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep disorder and wakefulness, hypersomnia associated with a neurodegenerative disease, hypersomnia associated with a mental illness, or pathological daytime sleep apnea. 9. A method for preventing and/or treating a DP receptor-mediated disease, comprising administering an effective amount of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 to a patient in need of preventing and/or treating a DP receptor-mediated disease . 10. The compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof according to claim 1, which is used for the prevention and/or treatment of a disease mediated by the DP receptor. 11. Use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a prophylactic and/or therapeutic agent for use in a DP receptor-mediated disease. 12. A compound which is {4-chloro-3-[(2,6-dimethyl-4-{2-[(2R)-oxan-2-yl]ethoxy}benzene-1-carbothioyl)amino]phenyl} acetic acid or a pharmaceutically acceptable salt thereof. 13. A compound represented by the following structural formula: . 14. A pharmaceutically acceptable salt of the compound represented by the following structural formula: .