JP2007023028A - Therapeutic agent for internal ear disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a prophylactic, a therapeutic agent and/or a symptom progress inhibitor for internal ear disease represented by sudden deafness, etc. <P>SOLUTION: The therapeutic agent for internal ear disease comprises one or more kinds of compounds having PGE receptor binding activity selected from EP2 agonist, EP4 agonist, EP1 antagonist and EP3 antagonist. Especially EP2 agonist has HGF production enhancing action besides vasodilator action, EP2 agonist is useful for preventing and/or treating internal ear disease and/or suppressing various symptom progresses following internal ear disease. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to prophylaxis, treatment and / or symptom progression of inner ear diseases comprising a compound having one or more PGE receptor binding activities selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists useful as pharmaceuticals. Relates to inhibitors.

  Inner ear diseases include inner ear vertigo disease caused by damage to the vestibular part consisting of the semicircular canal, oval sac, ball-type sac, and vestibular nerve responsible for balance, and the cochlea and auditory nerve parts involved in hearing. There is deaf inner ear deafness. These diseases are considered to be caused by, for example, viruses, drug addiction, vascular disorders (emboli, thrombus, bleeding), etc., which affect the above nerves and sensory organs, and their functions disappear, decrease, and react abnormally. It has been.

  These diseases not only impair hearing (equilibrium), but also symptoms such as hearing loss associated with inner ear disorders, tinnitus, dizziness, nystagmus, lightheadedness, nausea, ear pain, ear closure, self-emphasis, hypersensitivity, and ear leakage In spite of a serious disease that significantly lowers the patient's QOL due to the occurrence of the disease, drugs for administration of antiviral drugs, anticoagulants, cardiovascular drugs, steroid drugs, etc. according to the cause of the disease are used for the treatment. Currently, there are only symptomatic treatments of therapies, stellate ganglion block (SGB), hyperbaric oxygen therapy (OHP), LDL adsorption therapy (LDL-Apheresis: LDL-A) and combinations thereof.

  Prostaglandin E1 (PGE1) is a prostanoid having various physiological activities such as a vasodilatory action, a platelet aggregation inhibitory action, and a cytoprotective action, and is used as a circulation improving drug. Therefore, it has been examined whether or not the PGE1 preparation can be used as a therapeutic agent for sudden deafness (for example, see Non-Patent Documents 1 and 2). Furthermore, it is known that prostaglandin E2 (PGE2) has an effect of increasing the blood flow of the cochlea (see, for example, Non-Patent Document 3).

  On the other hand, among compounds having specific binding activity to each subtype of the PGE receptor, EP2 agonists in particular are retinal nerves such as immune diseases, asthma, bone dysplasia, nerve cell death, liver injury, premature birth, miscarriage, glaucoma and the like. It is disclosed that it is useful for treatment of disorders, bone diseases, allergic diseases and the like (see, for example, Patent Documents 1 and 2). It is also known that EP2 agonists have an effect of promoting endogenous repair factor production and are useful for the treatment of various organ disorders (see, for example, Patent Document 3).

  However, these documents do not examine which subtypes of PGE receptors are important in the inner ear, and that EP2 agonists are useful as therapeutic agents for inner ear diseases such as hearing loss. There is no description or suggestion that it is useful for improving symptoms associated with inner ear diseases.

European Patent Application Publication No. 860430 International Publication No. 03/074483 Pamphlet International Publication No. 04/032965 Pamphlet Otolaryngology, Vol. 91, No. 6, pp. 567-573, 1998 Otology & Neurotology, Volume 23, pages 665-668, 2002 European archives of otorhinolaryngology, 256, 479-483, 1999

  Although inner ear diseases such as sudden deafness and Meniere's disease are serious diseases that impair hearing and balance, no effective treatment other than symptomatic treatment has yet been found.

  In view of such problems in the treatment of inner ear diseases, it is an object of the present invention to provide an agent for preventing and treating inner ear diseases and / or a symptom progression inhibitor that is excellent in effectiveness.

  As a result of intensive studies to achieve the above object, the present inventors have surprisingly found (1) one or more PGE receptor binding activities selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists. (2) In particular, EP2 agonists prevent, treat and / or suppress symptom progression of inner ear diseases. It was also found useful, and the present invention was completed.

That is, the present invention
[1] Prevention, treatment and / or symptom progression inhibitor of inner ear disease comprising a compound having PGE receptor binding activity,
[2] The agent according to the above [1], wherein the compound having PGE receptor binding activity is at least one selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists,
[3] The agent according to the above [2], wherein the compound having PGE receptor binding activity is an EP2 agonist and / or an EP4 agonist,
[4] The agent according to [1], wherein the inner ear disease is inner ear vertigo disease or inner ear deafness,
[5] The agent according to the above [4], wherein the inner ear vertigo disease is Meniere's disease, vestibular neuritis or benign paroxysmal positional vertigo,
[6] The agent according to the above [4], wherein the inner ear deafness is deafness, sudden deafness or senile deafness caused by addictive inner ear disorder,
[7] The symptom of inner ear disease is one or more selected from hearing loss, tinnitus, dizziness, nystagmus, lightheadedness, nausea, ear pain, ear closure, voice enhancement, hypersensitivity, and otorrhea Agent,
[8] One or more compounds selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists, and anticholinergic agents, antihistamines, antiviral agents, leukotriene receptor antagonists, anticoagulants, vasodilators A drug for the prevention, treatment and / or suppression of symptom progression of inner ear diseases, comprising a combination of one or more drugs selected from steroid drugs, thrombolytic drugs, vitamin B and its derivatives and inner ear circulation improving drugs,
[9] The EP2 agonist is represented by the general formula (I)

[Wherein, T represents an oxygen atom, a sulfur atom, a methylene group, a halogen atom or an optionally substituted acyloxy group, R ¹ represents a hydrogen atom, a hydroxyl group, a C1-6 alkyloxy group or C1. Represents an acyloxy group, E represents a carbon atom or a nitrogen atom, X represents a methylene group, an oxygen atom, a sulfur atom or an optionally substituted nitrogen atom, and A represents a main chain atom. Represents a spacer of formula 1 to 8, D represents an optionally protected acidic group, G represents a spacer of a main chain of 1 to 8 atoms, and R ² may have a substituent. Represents an aliphatic hydrocarbon group which may have a good cyclic group or substituent,

Represents a single bond or a double bond, but two do not represent a double bond at the same time,

Represents the α-configuration or β-configuration or a mixture of any proportions thereof. Or a salt thereof, a solvate thereof, or a prodrug thereof, or an agent according to the above [2], which is a cyclodextrin inclusion compound thereof,
[10] The EP2 agonist is represented by the general formula (IA)

[Wherein R ^A represents a carboxyl group or a hydroxymethyl group,
R ^1A represents an oxygen atom, a methylene group or a halogen atom,
R ^2A represents a hydrogen atom, a hydroxyl group, or a C1-4 alkoxy group,
R ^3A is substituted with a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, or 1 to 3 of the following groups (1) to (5): Represents a C1-8 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group: (1) a halogen atom, (2) a C1-4 alkoxy group, (3) a C3-7 cycloalkyl group, (4) a phenyl group, or (5) a phenyl group substituted with 1 to 3 halogen atoms, a C1-4 alkyl group, a C1-4 alkoxy group, a nitro group or a trifluoromethyl group;
nA represents 0-4,

Represents a single bond or a double bond,

Represents a double bond or a triple bond,

Represents a single bond, a double bond or a triple bond,

Represents binding to the α configuration,

Represents binding to the β configuration. Or a salt thereof, a solvate thereof or a prodrug thereof, or an agent according to the above [9], which is a cyclodextrin inclusion compound thereof,
[11] The EP2 agonist is represented by the general formula (IB)

[Wherein T ^B represents (1) an oxygen atom or (2) a sulfur atom,
X ^B represents (1) —CH ₂ — group, (2) —O— group, or (3) —S— group,
A ^B represents A ^1B or A ^2B ;
A ^1B is (1) a linear C2-8 alkylene group optionally substituted with 1 to 2 C1-4 alkyl groups, (2) substituted with 1 to 2 C1-4 alkyl groups. An optionally linear C2-8 alkenylene group, or (3) a linear C2-8 alkynylene group optionally substituted by 1 to 2 C1-4 alkyl groups,
A ^2B represents a -G ^1B -G ^2B -G ^3B -group,
G ^1B is (1) a linear C1-4 alkylene group which may be substituted with 1 to 2 C1-4 alkyl groups, and (2) 1 to 2 C1-4 alkyl groups. An optionally linear C2-4 alkenylene group, or (3) a linear C2-4 alkynylene group optionally substituted by 1 to 2 C1-4 alkyl groups,
G ^2B is, (1) -Y ^B - group, (2) - Ring ^{1 B} - group, (3) -Y ^B - Ring ^{1 B} - group, (4) - Ring ¹ B -Y ^B - group, or, ⁽⁵⁾ -Y B -C1~4 alkylene - ring ^{1 B} - represents a group,
Y ^B is, (1) -S- group, (2) -SO- group, (3) -SO ₂ - group, wherein - group, (4) -O- group, or (5) ^{-NR 1B,}
R ^1B represents (1) a hydrogen atom, (2) a C1-10 alkyl group, or (3) a C2-10 acyl group,
G ^3B is (1) a single bond, (2) a linear C1-4 alkylene group optionally substituted with 1-2 C1-4 alkyl groups, and (3) 1-2 C1-4. A linear C2-4 alkenylene group optionally substituted with an alkyl group, or (4) a linear C2-4 alkynylene group optionally substituted with 1 to 2 C1-4 alkyl groups,
D ^{B represents D 1B} or ^{D 2B,}
D ^1B represents (1) —COOH group, (2) —COOR ^2B group, (3) tetrazol-5-yl group, or (4) —CONR ^3B SO ₂ R ^4B group,
R ^2B represents (1) a C1-10 alkyl group, (2) a phenyl group, (3) a C1-10 alkyl group substituted with a phenyl group, or (4) a biphenyl group,
R ^3B represents (1) a hydrogen atom, or (2) a C1-10 alkyl group,
R ^4B represents (1) a C1-10 alkyl group, or (2) a phenyl group,
D ^2B is (1) —CH ₂ OH group, (2) —CH ₂ OR ^5B group, (3) hydroxyl group, (4) —OR ^5B group, (5) formyl group, (6) —CONR ^6B R ^7B Group, (7) -CONR ^6B SO ₂ R ^8B group, (8) -CO- (NH-amino acid residue-CO) _mB -OH group, (9) -O- (CO-amino acid residue-NH) _mB -H group, (10) -COOR ^9B group, (11) -OCO-R ^10B group, (12) -COO-Z ^1B -Z ^2B -Z ^3B group, or (13)

Represents
R ^5B represents a C1-10 alkyl group,
R ^6B and R ^7B each independently represent (1) a hydrogen atom, or (2) a C1-10 alkyl group,
R ^8B represents a C1-10 alkyl group substituted with a phenyl group,
R ^9B is (1) a C1-10 alkyl group substituted with a biphenyl group optionally substituted with 1 to 3 substituents selected from a C1-10 alkyl group, a C1-10 alkoxy group, and a halogen atom. Or (2) a biphenyl group substituted with 1 to 3 substituents selected from a C1-10 alkyl group, a C1-10 alkoxy group, and a halogen atom,
R ^10B represents (1) a phenyl group, or (2) a C1-10 alkyl group,
mB represents 1 or 2,
Z ^1B represents (1) a C1-15 alkylene group, (2) a C2-15 alkenylene group, or (3) a C2-15 alkynylene group,
Z ^2B is (1) —CO— group, (2) —OCO— group, (3) —COO— group, (4) —CONR ^Z1B — group, (5) —NR ^Z2B CO— group, (6) -O- group, (7) -S- group, (8) -SO ₂ - ^{_{group, (9) -SO 2 -NR Z2B}} - _{^{group, (10) -NR Z2B SO 2}} - group, (11) -NR ^Z3b - represents a group or (15) -OCOO- group, - ^{group, (12) -NR Z4B CONR Z5B} - group, ^{(13) -NR} Z6B COO- group, (14) -OCONR ^Z7B
Z ^3B is (1) a hydrogen atom, (2) a C1-15 alkyl group, (3) a C2-15 alkenyl group, (4) a C2-15 alkynyl group, (5) a ring Z ^B , or (6) C1— represents a group or C1-10 alkyl group substituted by ring ^{Z B,,} - 10 alkoxy group, C1-10 alkylthio group, C1-10 alkyl ^{-NR Z8B}
Ring Z ^B represents (1) a carbocycle or (2) a heterocycle,
R ^Z1B , R ^Z2B , R ^Z3B , R ^Z4B , R ^Z5B , R ^Z6B , R ^Z7B , and R ^Z8B each independently represent a hydrogen atom or a C1-15 alkyl group,
R ^Z1B and Z ^3B groups, together with the nitrogen atom to which they are attached, may represent a 5- to 7-membered nitrogen-containing heterocycle, which further includes an oxygen atom, nitrogen atom, and sulfur May contain one heteroatom selected from atoms,
The 5- to 7-membered nitrogen-containing heterocyclic ring represented together with the ring Z ^B and the nitrogen atom to which R ^Z1B and Z ^3B are bonded is selected from the following (1) to (4): May be substituted with ~ 3 groups;
(1) C1-15 alkyl group, (2) C2-15 alkenyl group, (3) C2-15 alkynyl group, (4) C1-10 alkoxy group, C1-10 alkylthio group, or C1-10 alkyl-NR ^Z9B A C1-10 alkyl group substituted by a group;
R ^Z9B represents a hydrogen atom or a C1-10 alkyl group,
E ^B represents E ^1B or E ^2B ,
E ^1B is

Represents
R ^11B is, (1) C1-10 alkyl, (2) C1-10 alkylthio group, (3) C3-8 cycloalkyl C1-10 alkyl group substituted with a group is substituted with (4) the ring ^{2 B} and C1~10 alkyl or ^{(5) -W 1B -W 2B,} - represents a C1~10 alkyl group substituted with the ring ^{2 B,}
W ^1B represents (1) —O— group, (2) —S— group, (3) —SO— group, (4) —SO ₂ — group, (5) —NR ^11-1B — group, (6 ) ^{Represents a} carbonyl group, (7) —NR ^11-1B SO ₂ — group, (8) carbonylamino group, or (9) aminocarbonyl group,
R ^11-1B represents (1) a hydrogen atom, (2) a C1-10 alkyl group, or (3) a C2-10 acyl group,
W ^2B represents (1) a single bond, or (2) a C1-8 alkyl group optionally substituted with a C1-4 alkyl group, a halogen atom, or a hydroxyl group,
E ^2B represents (1) a U ^1B -U ^2B -U ^3B group, or (2) a ring 4 ^B group,
U ^1B is (1) a C1-4 alkylene group, (2) a C2-4 alkenylene group, (3) a C2-4 alkynylene group, (4) -ring 3 ^B -group, (5) C1-4 alkylene group- ring ^{3 B} - represents a group, - group, (6) C2-4 alkenylene group - ring ^{3 B} - group, or (7) C2-4 alkynylene group, - ring ^{3 B}
U ^2B represents (1) a single bond, (2) —CH ₂ — group, (3) —CHOH— group, (4) —O— group, (5) —S— group, (6) —SO— group. , (7) —SO ₂ — group, (8) —NR ^12B — group, (9) carbonyl group, (10) —NR ^12B SO ₂ — group, (11) carbonylamino group, or (12) aminocarbonyl group Represents
R ^12B represents (1) a hydrogen atom, (2) a C1-10 alkyl group, or (3) a C2-10 acyl group,
U ^3B is, (1) C1-10 alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, may be substituted with 1 to 3 substituents selected from alkylthio groups, and ^NR 13B ^{R 14B} group C1~8 C2-8 which may be substituted with 1 to 3 substituents selected from alkyl group, (2) C1-10 alkyl group, halogen atom, hydroxyl group, alkoxy group, alkylthio group, and —NR ^13B R ^14B group C2-8 which may be substituted with 1 to 3 substituents selected from an alkenyl group, (3) a C1-10 alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, an alkylthio group, and a —NR ^13B R ^14B group An alkynyl group, (4) a C1-8 alkyl group substituted with a ring 4 ^B group, or (5) a ring 4 ^B group,
R ^13B and R ^14B each independently represent (1) a hydrogen atom, or (2) a C1-10 alkyl group,
Ring 1 ^B , Ring 2 ^B , Ring 3 ^B , or Ring 4 ^B may be substituted with 1 to 5 R ^B ,
R ^B is, (1) C1-10 alkyl, (2) C2~10 alkenyl group, (3) C2~10 alkynyl group, (4) C1-10 alkoxy, (5) C1-10 alkylthio group, ( 6) halogen atom, (7) hydroxyl group, (8) nitro group, (9) -NR ^15B R ^16B group, (10) C1-10 alkyl group substituted with C1-10 alkoxy group, (11) 1-3 number of C1~10 alkyl group substituted with a halogen atom, (12) 1-3 C1~10 alkyl group substituted with substituted C1~10 alkoxy group with a halogen atom, ^{(13) -NR 15B} R ^16B C1-10 alkyl group substituted with a group, (14) the ring ^{5 B} group, (15) -O- ring ^{5 B} group, (16) the ring ^{5 B} C1-10 alkyl group substituted with a group, (17 ) substituted by the ring ^{5 B} group C2~10 Alkenyl group, (18) the ring ^{5 B C2~10} alkynyl group substituted with a group, (19) the ring ^{5 B} C1-10 alkoxy group substituted with a group, is substituted with (20) -O- ring ^{5 B} group C1-10 alkyl group, (21) COOR ^17B group, (22) C1-10 alkoxy group substituted with 1-4 halogen atoms, (23) formyl group, (24) C1 substituted with hydroxy group Represents a 10 alkyl group, or (25) a C2-10 acyl group,
R ^15B , R ^16B and R ^17B each independently represent (1) a hydrogen atom, or (2) a C1-10 alkyl group,
Ring 5 ^B may be substituted with 1-3 substituents selected from (1) to (9);
(1) C1-10 alkyl group, (2) C2-10 alkenyl group, (3) C2-10 alkynyl group, (4) C1-10 alkoxy group, (5) C1-10 substituted with C1-10 alkoxy group 10 alkyl groups, (6) halogen atoms, (7) hydroxyl groups, (8) C1-10 alkyl groups substituted with 1 to 3 halogen atoms, (9) C1 substituted with 1 to 3 halogen atoms A C1-10 alkyl group substituted with 10 alkoxy groups;
Ring 1 ^B , Ring 2 ^B , Ring 3 ^B , Ring 4 ^B , and Ring 5 ^B each independently represent (1) a carbocycle or (2) a heterocycle. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or an inclusion compound thereof according to the above [9],
[12] EP2 agonist is (1) (5Z) -7-{(1R, 2R, 3R, 5R) -2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybuta -1-enyl] -5-chloro-3-hydroxycyclopentyl} hept-5-enoic acid, and (2) (5Z) -7-{(1R, 2R, 3R, 5R) -2-[(1E, 4S ) -4- (1-allylcyclobutyl) -4-hydroxybut-1-enyl] -5-chloro-3-hydroxycyclopentyl} hept-5-enoic acid, salt, solvate thereof Or a prodrug thereof, or an agent according to the above [10], which is a cyclodextrin inclusion compound thereof,
[13] EP2 agonist is (1) 2-[(2-{(2R) -2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybut-1-enyl]- 5-oxopyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, (2) 2-[(2-{(2R) -2-[(3,5-dichlorophenoxy) Methyl] -5-oxopyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, (3) 2-{[2-((5R) -2-oxo-5-{[ 3-trifluoromethoxy) phenoxy] methyl} pyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, and (4) 2-[(2-{(2R) -2- [ (Heptylamino) methyl] -5-oxopi A lysine-1-yl} ethyl) thio] -1,3-thiazole-4-carboxylic acid, a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin inclusion compound thereof. The agent according to [11],
[14] The agent according to the above [9], wherein the EP2 agonist is limaprost,
[15] The EP4 agonist is (1) 11α, 15α-dihydroxy-9-oxo-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-3,7-dithiaprost-13E-enoic acid (2) (11α, 13E, 15α) -9-oxo-11,15-dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost-13-enoic acid Methyl ester and (3) (15α, 13E) -9-oxo-15-hydroxy-16- (4-fluorophenyl) -17,18,19,20-tetranor-5-thia-8-azaprost-13 A compound selected from enoic acid, a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin inclusion compound thereof The agent according to [2] above,
[16] EP1 antagonist is (1) 6-[(2S, 3S) -3- (4-chloro-2-methylphenylsulfonylaminomethyl) bicyclo [2.2.2] octan-2-yl] -5Z -Hexenoic acid and (2) 4- [2- (N-isobutyl-2-furanylsulfonylamino) -5-trifluoromethylphenoxymethyl] cinnamic acid, its salts, solvates thereof or The agent according to the above [2], which is a prodrug thereof or a cyclodextrin inclusion compound thereof,
[17] EP3 antagonist is 2- (2-((4-methyl-2- (naphthalen-1-yl) pentanoyl) amino) -4- (pyrazol-1-ylmethyl) benzyl) benzoic acid, a salt thereof, The agent according to the above [2], which is a solvate or a prodrug thereof, or a cyclodextrin inclusion compound thereof;
[18] A nerve regeneration and / or neuroprotective agent for inner ear nerves comprising one or more compounds selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists, and [19] EP2 agonists are (1 ) (5Z) -7-{(1R, 2R, 3R, 5R) -2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybut-1-enyl] -5-chloro -3-hydroxycyclopentyl} hept-5-enoic acid, (2) 2-[(2-{(2R) -2-[(3,5-dichlorophenoxy) methyl] -5-oxopyrrolidin-1-yl} Ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, and (3) a compound selected from limaprost, a salt thereof, a solvate thereof, or a prodo thereof Tsu grayed or the [18] agent according a cyclodextrin clathrates thereof about.

  In the present specification, a compound having PGE receptor binding activity binds to EP1, EP2, EP3 and / or EP4 receptor among the receptor subtypes of prostaglandin E (PGE) and exhibits agonistic or antagonistic activity. Any compound may be used, and not only compounds having known PGE receptor binding activity but also all compounds having PGE receptor binding activity to be found in the future are included. In addition, such a compound may be one that binds to a plurality of receptors (for example, a dual agonist or the like), or two or more compounds each independently bind to a different receptor. It may be one that exhibits binding activity of more than one receptor. Furthermore, the compound having PGE receptor binding activity of the present invention may have an IP agonistic action.

  Examples of the compound having PGE receptor binding activity in the present invention include EP1 agonist, EP1 antagonist, EP2 agonist, EP2 antagonist, EP3 agonist, EP3 antagonist, EP4 agonist, EP4 antagonist and the like. Preferably, they are EP1 antagonist, EP2 agonist, EP3 antagonist, EP4 agonist. More preferred are EP2 agonists and EP4 agonists. Particularly preferred is an EP2 agonist.

  In the present specification, the IP agonistic action refers to an action of binding to an IP receptor which is a receptor for prostaglandin I2 (PGI2) and exhibiting agonist activity. In the present invention, a compound having an IP agonist action, that is, an IP agonist may be used as a concomitant drug described later. Examples of such IP agonist include Japanese Patent Publication No. 3117800 and International Publication No. 04/032965. The compounds described in the pamphlet of No. are listed.

  Agonists as used herein include full agonists and partial agonists.

  The EP2 agonist in the present invention may have an EP4 agonist action, and includes those known to date or those to be found in the future. Examples of the EP2 agonist used in the present invention include, for example, the general formula (I)

[Wherein, T represents an oxygen atom, a sulfur atom, a methylene group, a halogen atom or an optionally substituted acyloxy group, R ¹ represents a hydrogen atom, a hydroxyl group, a C1-6 alkyloxy group or C1. Represents an acyloxy group, E represents a carbon atom or a nitrogen atom, X represents a methylene group, an oxygen atom, a sulfur atom or an optionally substituted nitrogen atom, and A represents a main chain atom. Represents a spacer of formula 1 to 8, D represents an optionally protected acidic group, G represents a spacer of a main chain of 1 to 8 atoms, and R ² may have a substituent. Represents an aliphatic hydrocarbon group which may have a good cyclic group or substituent,

Represents a single bond or a double bond, provided that when two do not represent a double bond at the same time and T represents a halogen atom or E represents a nitrogen atom, the symbol represents a single bond,

Represents the α-configuration or β-configuration or a mixture of any proportions thereof. ] The compound shown by this is mentioned.

In the present specification, examples of the “cyclic group” in the “cyclic group optionally having substituent (s)” represented by R ² include a carbocycle or a heterocycle.

  Examples of the carbocycle include C3-15 carbocycle. C3-15 carbocycles include C3-15 monocyclic or polycyclic carbocycles, carbocycles partially or fully saturated, spiro-bonded polycyclic carbocycles and bridged polycyclic carbons. Includes a ring. For example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, Cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, 6,7- Dihydro-5H-benzo [7] annulene, 5H-benzo [7] annulene, heptalene, perhydroheptalene, Phenylene, as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene, phenalene, phenanthrene, anthracene, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] undecane, bicyclo [2. 2.1] heptane, bicyclo [2.2.1] hept-2-ene, bicyclo [3.1.1] heptane, bicyclo [3.1.1] hept-2-ene, bicyclo [2.2. 2] Octane, bicyclo [2.2.2] oct-2-ene, adamantane, noradamantane ring and the like. Among these, examples of the C6-10 aromatic carbocycle include benzene, azulene, naphthalene rings and the like.

  Examples of the heterocyclic ring include a 3- to 15-membered heterocyclic ring containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and / or a sulfur atom. The 3- to 15-membered heterocycle containing 1 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms includes 1 to 5 heterocycles selected from oxygen, nitrogen and sulfur atoms. Included are 3-15 membered monocyclic or polycyclic heterocycles containing atoms, which may be partially or fully saturated, spiro-bonded polycyclic heterocycles and bridged polycyclic heterocycles. For example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadi Azole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithiaphthalene, indazole, quinoline, isoquinoline, Quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoly , Cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzoxepin, benzoxazepine, benzoxiazepine, benzothiepine, benzothiazepine, benzothiazepine, benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, Carbazole, β-carboline, acridine, phenazine, dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine, phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidine, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline , Triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine , Dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, Tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, Dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothi Pin, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydro Furazane, Tetrahydrofurazan, Dihydrooxadiazole, Tetrahydrooxadiazole (oxadiazolidine), Dihydrooxazine, Tetrahydrooxazine, Dihydrooxadiazine, Tetrahydrooxadiazine, Dihydrooxazepine, Tetrahydrooxazepine, Perhydrooxa Zepin, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadia Pin, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydro Thiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzo Thiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetra Hydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, Dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzooxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydro Benzothiazole, perhydrobenzothiazole, dihydrobenzo Midazole, perhydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzoazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine , Tetrahydroacridine, perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane, dithiolane, dithiane, dioxaindane, benzodioxane, chromene, chroman, benzodithiolane , Benzo Thiane, azaspiro [4.4] nonane, oxazaspiro [4.4] nonane, dioxaspiro [4.4] nonane, azaspiro [4.5] decane, thiaspiro [4.5] decane, dithiaspiro [4.5] decane, Dioxaspiro [4.5] decane, oxazaspiro [4.5] decane, azaspiro [5.5] undecane, oxaspiro [5.5] undecane, dioxaspiro [5.5] undecane, azabicyclo [2.2.1] heptane, Oxabicyclo [2.2.1] heptane, azabicyclo [3.1.1] heptane, azabicyclo [3.2.1] octane, azabicyclo [2.2.2] octane, diazabicyclo [2.2.2] octane Oxaazaspiro [2.5] octane, 1,3,8-triazaspiro [4.5] decane, 2,7-diaza Examples include spiro [4.5] decane, 1,4,9-triazaspiro [5.5] undecane, azabicyclo [2.1.1] hexane ring, and the like.

Examples of the “substituent” in the “cyclic group optionally having substituent (s)” represented by R ² include (a) an alkyl group optionally having substituent (s) and (b) having a substituent. An alkenyl group that may have a substituent, (c) an alkynyl group that may have a substituent, (d) a carbocyclic group that may have a substituent, and (e) a substituent that has a substituent. A good heterocyclic group, (f) a hydroxyl group optionally having a substituent, (g) a thiol group optionally having a substituent, (h) an amino group optionally having a substituent, ( i) an optionally substituted carbamoyl group, (j) an optionally substituted sulfamoyl group, (k) a carboxyl group, (l) an alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, C1-6 alkoxycarbonyl such as t-butoxycarbonyl Group), (m) sulfo group (—SO ₃ H), (n) sulfino group (—SO ₂ H), (o) phosphono group (—PO (OH) ₂ ), (p) nitro group, (q ) Oxo group, (r) thioxo group, (s) cyano group, (t) amidino group, (u) imino group, (v) -B (OH) ₂ group, (w) halogen atom (fluorine, chlorine, bromine) , Iodine), (x) alkylsulfinyl groups (for example, C1-6 alkylsulfinyl groups such as methylsulfinyl and ethylsulfinyl), (y) arylsulfinyl groups (for example, C6-10 arylsulfinyl groups such as phenylsulfinyl) (Z) an alkylsulfonyl group (for example, a C1-6 alkylsulfonyl group such as methylsulfonyl or ethylsulfonyl), (aa) an arylsulfonyl group (for example, phenylsulfonyl group) And (bb) acyl groups (for example, C1-10 alkanoyl groups such as formyl, acetyl, propanoyl, and pivaloyl, and C6-10 arylcarbonyl groups such as benzoyl). These optional substituents may be substituted at 1 to 5 substitutable positions.

  Examples of the “alkyl group” in the “optionally substituted alkyl group” as a substituent include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, Examples thereof include linear or branched C1-15 alkyl groups such as neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl groups. Here, examples of the substituent of the alkyl group include (a) hydroxyl group, (b) amino group, (c) carboxyl group, (d) cyano group, (e) nitro group, (f) mono- or di-C1- 10 alkylamino groups (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), (g) C1-10 alkoxy groups (for example, methoxy, ethoxy, propoxy, isopropoxy, t-butoxy, hexyloxy, octyloxy) , Decanyloxy, etc.), (h) C1-6 acyloxy groups (for example, acetyloxy, ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy groups, etc.), (i) C1-10 alkylcarbonyl Oxy groups (eg acetoxy, ethylcarbonyloxy, etc.), (j) substitution A carbocyclic group (which has the same meaning as described above), (k) a heterocyclic group which may have a substituent (which has the same meaning as described above), ( l) a halogen atom (representing the same meaning as described above), (m) a C1-10 alkoxy group substituted with 1 to 3 halogen atoms (for example, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy) Group, etc.), (n) -O-carbocycle (represents the same meaning as the carbocycle in the "cyclic group" in the "cyclic group optionally having substituents"), (o) -O -Heterocycles (representing the same meaning as the heterocyclic ring in the “cyclic group” in the “cyclic group optionally having substituents”), etc., and these optional substituents can be substituted 1-4 may be substituted at the position.

  Examples of the “alkenyl group” in the “optionally substituted alkenyl group” as a substituent include ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, heptadienyl, octenyl, octadienyl, Examples thereof include linear or branched C2-15 alkenyl groups such as nonenyl, nonadienyl, decenyl, decadienyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl and pentadecenyl groups. Here, the substituent of the alkenyl group has the same meaning as the substituent in the aforementioned “alkyl group optionally having substituent (s)”.

  As the `` alkynyl group '' in the `` alkynyl group optionally having substituent '' as a substituent, for example, ethynyl, propynyl, butynyl, butadiynyl, pentynyl, pentadiynyl, hexynyl, hexadiynyl, heptynyl, heptadiynyl, octynyl, octadiynyl, Examples thereof include linear or branched C2-15 alkynyl groups such as noninyl, nonadiynyl, decynyl, decadiynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl group and the like. Here, the substituent of the alkynyl group has the same meaning as the substituent in the aforementioned “alkyl group optionally having substituent (s)”.

  The carbocyclic ring in the “carbocyclic group which may have a substituent” as the substituent is the same as the carbocyclic ring in the “cyclic group” in the “cyclic group which may have a substituent”. Represents meaning. Here, as the substituent of the carbocycle, for example, (a) a linear or branched C1-15 alkyl group (having the same meaning as the alkyl group in the above-mentioned “alkyl group optionally having substituents”). ), (B) linear or branched C2-15 alkenyl group (the same meaning as the alkenyl group in the above-mentioned "alkenyl group optionally having substituents"), (c) linear Or branched C2-15 alkynyl group (the same meaning as the alkynyl group in the above-mentioned "alkynyl group optionally having substituents"), (d) hydroxyl group, (e) C1-6 alkoxy group ( For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butoxy, pentyloxy, hexyloxy, etc.), (f) thiol group, (g) C1-6 alkylthio group ( For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, etc.), (h) amino group, (i) mono- or di-C1-6 alkylamino group (for example, methylamino) Ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, N-methyl-N-ethylamino, etc.), (j) Halogen atoms (representing the same meaning as described above), (k) cyano group, (l) nitro group, (m) trifluoromethyl group, (n) trifluoromethoxy group, and the like. 1-5 substituents are substituted at substitutable positions. Good.

  The heterocyclic ring in the “optionally substituted heterocyclic group” as the substituent is the same as the heterocyclic ring in the “cyclic group” in the aforementioned “optionally substituted cyclic group”. Represents meaning. Here, the heterocyclic substituent has the same meaning as the substituent in the above-mentioned “carbocyclic group optionally having substituent (s)”.

  As a “substituent” in “an optionally substituted hydroxyl group”, “an optionally substituted thiol group” and “an optionally substituted amino group” as a substituent Is, for example, (i) an alkyl group which may have a substituent (having the same meaning as described above), (ii) an alkenyl group which may have a substituent (having the same meaning as described above). ), (Iii) an alkynyl group which may have a substituent (having the same meaning as described above), and (iv) a carbocyclic group which may have a substituent (described above) ), (V) an optionally substituted heterocyclic group (having the same meaning as described above), (vi) an acyl group (for example, formyl, acetyl, propanoyl, pivaloyl) , C1-6 alkals such as butanoyl, pentanoyl, hexanoyl (Vii) a carbamoyl group (which has the same meaning as described later), which may have a substituent, (Ii group or an isomer group thereof or a C6-10 aromatic carbocyclic carbonyl such as benzoyl). viii) alkylsulfonyl groups (for example, C1-6 alkylsulfonyl groups such as methylsulfonyl and ethylsulfonyl), (ix) arylsulfonyl groups (for example, C6-10 arylsulfonyl groups such as phenylsulfonyl) and the like.

  Examples of the “optionally substituted carbamoyl group” as the substituent include an unsubstituted carbamoyl group, N-mono-C 1-6 alkylcarbamoyl (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N- N-mono-C6 such as propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N- (tert-butyl) carbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl) and N-phenylcarbamoyl To 10 arylcarbamoyl, N, N-diC1-6 alkylcarbamoyl (for example, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, N, N -Dipentylcarbamoyl, N, N Dihexylcarbamoyl, N-methyl-N-ethylcarbamoyl, etc.), N, N-diphenylcarbamoyl, etc., N-di-C6-10 arylcarbamoyl, N-C6-10 aryl-N-C1-6 alkylcarbamoyl (eg, N -Phenyl-N-methylcarbamoyl, N-phenyl-N-ethylcarbamoyl, N-phenyl-N-propylcarbamoyl, N-phenyl-N-butylcarbamoyl, N-phenyl-N-pentylcarbamoyl, N-phenyl-N- Hexylcarbamoyl etc.).

  Examples of the “optionally substituted sulfamoyl group” as the substituent include an unsubstituted sulfamoyl group, N-mono-C1-6 alkylsulfamoyl (for example, N-methylsulfamoyl, N-ethyl). Sulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, N-isobutylsulfamoyl, N- (tert-butyl) sulfamoyl, N-pentylsulfamoyl, N- Hexylsulfamoyl etc.), N-mono-C6-10 arylsulfamoyl such as N-phenylsulfamoyl, N, N-diC1-6 alkylsulfamoyl (eg N, N-dimethylsulfamoyl) N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, , N-dipentylsulfamoyl, N, N-dihexylsulfamoyl, N-methyl-N-ethylsulfamoyl, etc.), N, N-diphenylsulfamoyl etc. Moyl, N-C6-10 aryl-N-C1-6 alkylsulfamoyl (eg, N-phenyl-N-methylsulfamoyl, N-phenyl-N-ethylsulfamoyl, N-phenyl-N-propyl) Sulfamoyl, N-phenyl-N-butylsulfamoyl, N-phenyl-N-pentylsulfamoyl, N-phenyl-N-hexylsulfamoyl, etc.).

In the present specification, the “aliphatic hydrocarbon group which may have a substituent” represented by R ² includes, for example, an alkyl group which may have a substituent and a substituent. Represents an alkynyl group which may have an alkynyl group which may have a substituent or an alkynyl group which may have a substituent, and an “alkenyl group which may have a substituent” or “an alkenyl group which may have a substituent” ”Or“ optionally substituted alkynyl group ”is defined as the“ optionally substituted alkyl group ”or“ substituted group ”defined in the above-mentioned substituents in the cyclic group. The same meaning as “an alkenyl group that may be substituted” or “an alkynyl group that may be substituted” is used.

In the present specification, examples of the “C1-6 alkyloxy group” represented by R ¹ include a methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy group and the like.

In the present specification, examples of the “C1-6 acyloxy group” represented by R ¹ include acetyloxy, ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, and hexanoyloxy groups. .

  In the present specification, the “halogen atom” represented by T represents the same meaning as described above.

In the present specification, examples of the “acyloxy group” in the “acyloxy group optionally having substituents” represented by T include acetyloxy, ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, and the like. C1-10 alkanoyloxy groups such as hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, pivaloyloxy and the like. The “substituent” in the “acyloxy group optionally having substituent (s)” represented by T is the substituent in the “alkyl group optionally having substituent (s)” defined in R ² described above. Represents the same meaning.

In the present specification, the “substituent” in the “nitrogen atom which may have a substituent” represented by X is “an alkyl group which may have a substituent” or “having a substituent. The “optionally substituted cyclic group” or the “optionally substituted cyclic group” is the “substituted group” defined in R ² . The same meaning as “an alkyl group which may have a group” or “a cyclic group which may have a substituent” is represented.

  In the present specification, the “spacer having 1 to 8 atoms in the main chain” represented by A or G means an interval in which 1 to 8 atoms are connected. Here, the “number of main chain atoms” is counted so that the main chain atoms are minimized. For example, the number of 1,4-phenylene atoms is four and the number of 1,3-phenylene atoms is three. Examples of the “spacer having 1 to 8 atoms in the main chain” include C1-8 alkylene, C2-8 alkenylene group, C2-8 alkynylene group, cyclic group (described above The same meaning as the “cyclic group” in the “cyclic group optionally having a group”, and the like, and these carbon atoms are in an oxygen atom, nitrogen atom, sulfur atom at a structurally possible position. , A carbonyl group, a thiocarbonyl group, a sulfinyl group, a sulfonyl group, a sulfamoyl group, a carbonylamino group, and an aminocarbonyl group may be substituted. Examples of the C1-8 alkylene group include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene group and the like. Examples of the C2-8 alkenylene group include ethenylene, propenylene, butenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, heptenylene, heptadienylene, octenylene, octadiylene group and the like. Examples of the C2-8 alkynylene group include ethynylene, propynylene, butynylene, butadinylene, pentynylene, pentadiinylene, hexynylene, hexadiinylene, heptynylene, heptadinylene, octynylene, octadiinylene group and the like. The “substituent” represented by the “spacer having 1 to 8 atoms in the main chain” has the same meaning as the “substituent” in the aforementioned “alkyl group optionally having substituent (s)”. These optional substituents may be substituted at 1 to 10, preferably 1 to 5, more preferably 1 to 3 substituents at substitutable positions.

In the present specification, the “optionally protected acidic group” represented by D represents an “acidic group” protected by a “protecting group”, and examples of the “acidic group” include (a) a hydroxyl group , (B) formyl group (—CHO), (c) alkoxy group, (d) carboxyl group (—COOH), (e) sulfo group (—SO ₃ H), (f) sulfonamide (—SO ₂ NH ₂₎ Or —NR ¹⁰¹ SO ₃ H (R ¹⁰¹ is a hydrogen atom or an alkyl group which may have a substituent (the same meaning as the “alkyl group which may have a substituent” defined in R ² described above) )), (G) phosphono group (—PO (OH) ₂ ), (h) phenol (—C ₆ H ₄ OH), (i) —CONR ¹⁰¹ SO ₃ R ¹⁰¹ (R ¹⁰¹ Represents the same meaning as described above.), (J) a De various types of Brønsted acid nitrogen-containing ring residue such as having (-CONH ₂₎ or (k) a hydrogen atom which can be deprotonated. “Bronsted acid” refers to a substance that gives hydrogen ions to other substances. As the “nitrogen-containing ring residue having a hydrogen atom that can be deprotonated”, for example,

Etc. Preferred “acidic groups” include carboxyl groups and hydroxyl groups. More preferably, a carboxyl group is mentioned.

As the “protecting group” in the “optionally protected acidic group” represented by D, (a) an aliphatic hydrocarbon group which may have a substituent (the “substitution defined in R ² described above”) The same meaning as the “optionally substituted aliphatic hydrocarbon group”), (b) the optionally substituted cyclic group (having the “substituent” defined in R ² described above. The same meaning as “optionally cyclic group”), (c) an amino group which may have a substituent (an “amino group which may have a substituent” defined in R ² described above) And (d) an amino acid, (e) an acyl group which may have a substituent, and the like. The “acyl group” in the “acyl group optionally having substituent (s)” herein has the same meaning as the “acyl group” defined in R ² described above, The “substituent” in the “good acyl group” has the same meaning as the substituent in the “alkyl group optionally having substituent (s)” defined in R ² described above. As used herein, the term “amino acid” means an amino acid residue of a natural amino acid or an unnatural amino acid, and the natural amino acid or abnormal amino acid includes, for example, glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, Methionine, proline, asparagine, glutamine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, lysine, arginine, histidine, β-alanine, cystathionine, cystine, homoserine, isoleucine, lanthionine, norleucine, norvaline, ornithine, sarcosine, thyronine, etc. Can be mentioned. In addition, when this amino acid contains an amino group, those in which the amino group is substituted with a substituent of the amino group described above are also included.

  More specifically, examples of the EP2 agonist used in the present invention include compounds described in the following (A) to (M). Moreover, the compound represented by the general formula (I) as the EP2 agonist used in the present invention includes the general formulas (IA), (IB), ( IC) and (ID).

  (A) European Patent Application No. 860430 describes that a compound represented by the following general formula (IA) has an EP2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (IA) is described in detail in European Patent Application Publication No. 860430. Therefore, the EP2 agonist of the present invention has the general formula (IA)

[Wherein R ^A represents a carboxyl group or a hydroxymethyl group,
R ^1A represents an oxygen atom, a methylene group or a halogen atom,
R ^2A represents a hydrogen atom, a hydroxyl group, or a C1-4 alkoxy group,
R ^3A is substituted with a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, or 1 to 3 of the following groups (1) to (5): Represents a C1-8 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group: (1) a halogen atom, (2) a C1-4 alkoxy group, (3) a C3-7 cycloalkyl group, (4) a phenyl group, or (5) a phenyl group substituted with 1 to 3 halogen atoms, a C1-4 alkyl group, a C1-4 alkoxy group, a nitro group or a trifluoromethyl group;
nA represents 0-4,

Represents a single bond or a double bond,

Represents a double bond or a triple bond,

Represents a single bond, a double bond or a triple bond.
However, (1) when the 5-6 position represents a triple bond, the 13-14 position does not represent a triple bond. (2) When the 13-14 position represents a double bond, the double bond represents an E-form, a Z-form or a mixture of EZ-forms. (3) R ^A represents a carboxyl group, R ^2A represents a hydroxyl group, R ^3A represents an ethyl group, nA represents 1, and

Represents a single bond, and

Represents a double bond, and

When R represents a double bond, R ^1A does not represent a chlorine atom. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (B) In the pamphlet of International Publication No. 03/074483, it is described that the compound represented by the following general formula (IB) has an EP2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (IB) is described in detail in International Publication No. 03/074483 pamphlet. Therefore, the EP2 agonist of the present invention has the general formula (IB)

[Wherein T ^B represents (1) an oxygen atom or (2) a sulfur atom,
X ^B represents (1) —CH ₂ — group, (2) —O— group, or (3) —S— group,
A ^B represents A ^1B or A ^2B ;
A ^1B is (1) a linear C2-8 alkylene group optionally substituted with 1 to 2 C1-4 alkyl groups, (2) substituted with 1 to 2 C1-4 alkyl groups. An optionally linear C2-8 alkenylene group, or (3) a linear C2-8 alkynylene group optionally substituted by 1 to 2 C1-4 alkyl groups,
A ^2B represents a -G ^1B -G ^2B -G ^3B -group,
G ^1B is (1) a linear C1-4 alkylene group which may be substituted with 1 to 2 C1-4 alkyl groups, and (2) 1 to 2 C1-4 alkyl groups. An optionally linear C2-4 alkenylene group, or (3) a linear C2-4 alkynylene group optionally substituted by 1 to 2 C1-4 alkyl groups,
G ^2B is, (1) -Y ^B - group, (2) - Ring ^{1 B} - group, (3) -Y ^B - Ring ^{1 B} - group, (4) - Ring ¹ B -Y ^B - group, or, ⁽⁵⁾ -Y B -C1~4 alkylene - ring ^{1 B} - represents a group,
Y ^B is, (1) -S- group, (2) -SO- group, (3) -SO ₂ - group, wherein - group, (4) -O- group, or (5) ^{-NR 1B,}
R ^1B represents (1) a hydrogen atom, (2) a C1-10 alkyl group, or (3) a C2-10 acyl group,
G ^3B is (1) a single bond, (2) a linear C1-4 alkylene group optionally substituted with 1-2 C1-4 alkyl groups, and (3) 1-2 C1-4. A linear C2-4 alkenylene group optionally substituted with an alkyl group, or (4) a linear C2-4 alkynylene group optionally substituted with 1 to 2 C1-4 alkyl groups,
D ^{B represents D 1B} or ^{D 2B,}
D ^1B represents (1) —COOH group, (2) —COOR ^2B group, (3) tetrazol-5-yl group, or (4) —CONR ^3B SO ₂ R ^4B group,
R ^2B represents (1) a C1-10 alkyl group, (2) a phenyl group, (3) a C1-10 alkyl group substituted with a phenyl group, or (4) a biphenyl group,
R ^3B represents (1) a hydrogen atom, or (2) a C1-10 alkyl group,
R ^4B represents (1) a C1-10 alkyl group, or (2) a phenyl group,
D ^2B is (1) —CH ₂ OH group, (2) —CH ₂ OR ^5B group, (3) hydroxyl group, (4) —OR ^5B group, (5) formyl group, (6) —CONR ^6B R ^7B Group, (7) -CONR ^6B SO ₂ R ^8B group, (8) -CO- (NH-amino acid residue-CO) _mB -OH group, (9) -O- (CO-amino acid residue-NH) _mB -H group, (10) -COOR ^9B group, (11) -OCO-R ^10B group, (12) -COO-Z ^1B -Z ^2B -Z ^3B group, or (13)

Represents
R ^5B represents a C1-10 alkyl group,
R ^6B and R ^7B each independently represent (1) a hydrogen atom, or (2) a C1-10 alkyl group,
R ^8B represents a C1-10 alkyl group substituted with a phenyl group,
R ^9B is (1) a C1-10 alkyl group substituted with a biphenyl group optionally substituted with 1 to 3 substituents selected from a C1-10 alkyl group, a C1-10 alkoxy group, and a halogen atom. Or (2) a biphenyl group substituted with 1 to 3 substituents selected from a C1-10 alkyl group, a C1-10 alkoxy group, and a halogen atom,
R ^10B represents (1) a phenyl group, or (2) a C1-10 alkyl group,
mB represents 1 or 2,
Z ^1B represents (1) a C1-15 alkylene group, (2) a C2-15 alkenylene group, or (3) a C2-15 alkynylene group,
Z ^2B is (1) —CO— group, (2) —OCO— group, (3) —COO— group, (4) —CONR ^Z1B — group, (5) —NR ^Z2B CO— group, (6) -O- group, (7) -S- group, (8) -SO ₂ - ^{_{group, (9) -SO 2 -NR Z2B}} - _{^{group, (10) -NR Z2B SO 2}} - group, (11) -NR ^Z3b - represents a group or (15) -OCOO- group, - ^{group, (12) -NR Z4B CONR Z5B} - group, ^{(13) -NR} Z6B COO- group, (14) -OCONR ^Z7B
Z ^3B is (1) a hydrogen atom, (2) a C1-15 alkyl group, (3) a C2-15 alkenyl group, (4) a C2-15 alkynyl group, (5) a ring Z ^B , or (6) C1— represents a group or C1-10 alkyl group substituted by ring ^{Z B,,} - 10 alkoxy group, C1-10 alkylthio group, C1-10 alkyl ^{-NR Z8B}
Ring Z ^B represents (1) a carbocycle or (2) a heterocycle,
R ^Z1B , R ^Z2B , R ^Z3B , R ^Z4B , R ^Z5B , R ^Z6B , R ^Z7B , and R ^Z8B each independently represent a hydrogen atom or a C1-15 alkyl group,
R ^Z1B and Z ^3B groups, together with the nitrogen atom to which they are attached, may represent a 5- to 7-membered nitrogen-containing heterocycle, which further includes an oxygen atom, nitrogen atom, and sulfur May contain one heteroatom selected from atoms,
The 5- to 7-membered nitrogen-containing heterocyclic ring represented together with the ring Z ^B and the nitrogen atom to which R ^Z1B and Z ^3B are bonded is selected from the following (1) to (4): May be substituted with ~ 3 groups;
(1) C1-15 alkyl group, (2) C2-15 alkenyl group, (3) C2-15 alkynyl group, (4) C1-10 alkoxy group, C1-10 alkylthio group, or C1-10 alkyl-NR ^Z9B A C1-10 alkyl group substituted by a group;
R ^Z9B represents a hydrogen atom or a C1-10 alkyl group,
E ^B represents E ^1B or E ^2B ,
E ^1B is

Represents
R ^11B is, (1) C1-10 alkyl, (2) C1-10 alkylthio group, (3) C3-8 cycloalkyl C1-10 alkyl group substituted with a group is substituted with (4) the ring ^{2 B} and C1~10 alkyl or ^{(5) -W 1B -W 2B,} - represents a C1~10 alkyl group substituted with the ring ^{2 B,}
W ^1B represents (1) —O— group, (2) —S— group, (3) —SO— group, (4) —SO ₂ — group, (5) —NR ^11-1B — group, (6 ) ^{Represents a} carbonyl group, (7) —NR ^11-1B SO ₂ — group, (8) carbonylamino group, or (9) aminocarbonyl group,
R ^11-1B represents (1) a hydrogen atom, (2) a C1-10 alkyl group, or (3) a C2-10 acyl group,
W ^2B represents (1) a single bond, or (2) a C1-8 alkyl group optionally substituted with a C1-4 alkyl group, a halogen atom, or a hydroxyl group,
E ^2B represents (1) a U ^1B -U ^2B -U ^3B group, or (2) a ring 4 ^B group,
U ^1B is (1) a C1-4 alkylene group, (2) a C2-4 alkenylene group, (3) a C2-4 alkynylene group, (4) -ring 3 ^B -group, (5) C1-4 alkylene group- ring ^{3 B} - represents a group, - group, (6) C2-4 alkenylene group - ring ^{3 B} - group, or (7) C2-4 alkynylene group, - ring ^{3 B}
U ^2B represents (1) a single bond, (2) —CH ₂ — group, (3) —CHOH— group, (4) —O— group, (5) —S— group, (6) —SO— group. , (7) —SO ₂ — group, (8) —NR ^12B — group, (9) carbonyl group, (10) —NR ^12B SO ₂ — group, (11) carbonylamino group, or (12) aminocarbonyl group Represents
R ^12B represents (1) a hydrogen atom, (2) a C1-10 alkyl group, or (3) a C2-10 acyl group,
U ^3B is, (1) C1-10 alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, may be substituted with 1 to 3 substituents selected from alkylthio groups, and ^NR 13B ^{R 14B} group C1~8 C2-8 which may be substituted with 1 to 3 substituents selected from alkyl group, (2) C1-10 alkyl group, halogen atom, hydroxyl group, alkoxy group, alkylthio group, and —NR ^13B R ^14B group C2-8 which may be substituted with 1 to 3 substituents selected from an alkenyl group, (3) a C1-10 alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, an alkylthio group, and a —NR ^13B R ^14B group An alkynyl group, (4) a C1-8 alkyl group substituted with a ring 4 ^B group, or (5) a ring 4 ^B group,
R ^13B and R ^14B each independently represent (1) a hydrogen atom, or (2) a C1-10 alkyl group,
Ring 1 ^B , Ring 2 ^B , Ring 3 ^B , or Ring 4 ^B may be substituted with 1 to 5 R ^B ,
R ^B is, (1) C1-10 alkyl, (2) C2~10 alkenyl group, (3) C2~10 alkynyl group, (4) C1-10 alkoxy, (5) C1-10 alkylthio group, ( 6) halogen atom, (7) hydroxyl group, (8) nitro group, (9) -NR ^15B R ^16B group, (10) C1-10 alkyl group substituted with C1-10 alkoxy group, (11) 1-3 number of C1~10 alkyl group substituted with a halogen atom, (12) 1-3 C1~10 alkyl group substituted with substituted C1~10 alkoxy group with a halogen atom, ^{(13) -NR 15B} R ^16B C1-10 alkyl group substituted with a group, (14) the ring ^{5 B} group, (15) -O- ring ^{5 B} group, (16) the ring ^{5 B} C1-10 alkyl group substituted with a group, (17 ) substituted by the ring ^{5 B} group C2~10 Alkenyl group, (18) the ring ^{5 B C2~10} alkynyl group substituted with a group, (19) the ring ^{5 B} C1-10 alkoxy group substituted with a group, is substituted with (20) -O- ring ^{5 B} group C1-10 alkyl group, (21) COOR ^17B group, (22) C1-10 alkoxy group substituted with 1-4 halogen atoms, (23) formyl group, (24) C1 substituted with hydroxy group Represents a 10 alkyl group, or (25) a C2-10 acyl group,
R ^{15B, R 16B} and ^{R 17B,} are each independently, represent (1) hydrogen atom or (2) C1-10 alkyl,
Ring 5 ^B may be substituted with 1-3 substituents selected from (1) to (9);
(1) C1-10 alkyl group, (2) C2-10 alkenyl group, (3) C2-10 alkynyl group, (4) C1-10 alkoxy group, (5) C1-10 substituted with C1-10 alkoxy group 10 alkyl groups, (6) halogen atoms, (7) hydroxyl groups, (8) C1-10 alkyl groups substituted with 1 to 3 halogen atoms, (9) C1 substituted with 1 to 3 halogen atoms A C1-10 alkyl group substituted with 10 alkoxy groups;
Ring 1 ^B , Ring 2 ^B , Ring 3 ^B , Ring 4 ^B , and Ring 5 ^B each independently represent (1) a carbocycle or (2) a heterocycle.
However, 1) ^{E B} represents ^{E 2B, E 2B} represents a ^U 1B ^-U 2B ^{-U 3B} group, and when ^{the U 1B} represents a C2 alkylene group or C2 alkenylene ^group, a ^{U 2B} is -CHOH- group Not
2) When U ^3B represents a C1-8 alkyl group substituted by at least one hydroxyl group, U ^1B -U ^2B does not represent a C2 alkylene group or a C2 alkenylene group,
3) When A ^B represents A ^1B and D ^B represents D ^1B , E ^B does not represent E ^1B ;
4) ^{T B} represents an oxygen atom, ^{X B} is -CH ₂ - represents a group, ^{D B} represents ^{D 1B, D 1B} represents a COOH group, ^{A B} represents ^{A 1B, A 1B} is a linear the C2-8 alkylene group, ^{E B} represents ^{E 2B, E 2B} represents a ^{U 1B -U 2B -U 3B, U} 1B represents a C1~4 alkylene group, and ^{U 3B} is C1~8 alkyl When representing a group, U ^2B does not represent a single bond, —CH ₂ — group, —NR ^12B — group, or carbonyl group,
5) ^{T B} represents an oxygen atom, ^{X B} is -CH ₂ - represents a group, ^{D B} represents ^{D 1B, D 1B} represents a COOH group, ^{A B} represents ^{A 2B, G 1B} is C1~ 4 represents an alkylene ^{group, G 2B} is -O- group or ^{-NR 1B} - represents a ^{group, G 3B} represents a single bond or C1~4 alkylene group, ^{E B} represents ^{E 2B, E 2B} is ^{U 1B} - U ^2B represents U ^3B , U ^1B represents a C1-4 alkylene group, and U ^3B represents a C1-8 alkyl group, U ^2B represents a single bond, —CH ₂ — group, —NR ^12B — group, Or does not represent a carbonyl group,
6) ^{T B} represents an oxygen atom, ^{X B} is -CH ₂ - represents a group, ^{D B} represents ^{D 1B, E B} represents ^{E 2B, E 2B} represents a ^U 1B ^-U 2B ^{-U 3B} , When U ^1B represents a C2 alkylene group or a C2 alkenylene group and U ^2B represents a —CO— group, A ^B does not represent A ^1B ;
7) 4-[(2-{(2R) -2-[(1E, 3S) -3-hydroxy-oct-1-enyl] -5-oxo-pyrrolidin-1-yl} ethyl) thio] butanoic acid and 4- {2-[(R) -2-((E) -3-hydroxy-oct-1-enyl) -5-oxo-pyrrolidin-1-yl] -ethyl} -benzoic acid is excluded. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (C) In the pamphlet of International Publication No. 99/033794, it is described that the compound represented by the following general formula (IC) has an EP2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (IC) is described in detail in International Publication No. 99/033794 pamphlet. Therefore, the EP2 agonist of the present invention has the general formula (IC)

Wherein, ^{A C} represents benzene, thiophene or furan ring,
R ^1C is a group represented by a hydroxyl group, a C1-6 alkoxy group, or NR ^10C R ^11C (wherein R ^10C and R ^11C independently represent a hydrogen atom or a C1-4 alkyl group). Represent,
R ^2C represents a C1-4 alkylene group, a C2-4 alkenylene group, a —S—C1-4 alkylene group, a —S—C2-4 alkenylene group or a C1-4 alkylene-S— group,
R ^3C represents an oxo group, a methylene group, a halogen atom, or R ^32C —COO— (wherein R ^32C represents a C1-4 alkyl group, a C1-4 alkoxy group, a phenyl group, or a phenyl-C1-4 alkyl group). A group, an R ^33C -OOC-C1-4 alkyl group or an R ^33C -OOC-C2-4 alkenyl group (wherein R ^33C represents a hydrogen atom or a C1-4 alkyl group). Represents the group shown,
R ^4C represents a hydrogen atom, a hydroxyl group or a C1-4 alkoxy group,
R ^5C is a ^C 1-8 alkyl group substituted with a ^C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, 1 to 3 groups (1) to (5) below. Represents an alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group:
(1) a halogen atom,
(2) a C1-4 alkoxy group,
(3) a C3-7 cycloalkyl group,
(4) a phenyl group, or (5) a phenyl group substituted with 1 to 3 halogen atoms, a C1-4 alkyl group, a C1-4 alkoxy group, a nitro group or a trifluoromethyl group,
nC represents 0 to 4,

Represents a single bond or a double bond, but two do not represent a double bond at the same time.

However, when the 8-9 position represents a double bond, R ^3C is a group represented by the formula R ^32C —COO— (wherein R ^32C represents the same meaning as described above), and R ^1C is C1. Represents -6 alkoxy. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (D) European Patent Application Publication No. 974580 describes that a compound represented by the following general formula (ID) has an EP2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (ID) is described in detail in European Patent Application Publication No. 974580. Therefore, the EP2 agonist of the present invention has the general formula (ID)

[Wherein, R ^1D represents a hydroxy group, a C1-6 alkoxy group, or an NR ^11D R ^12D group (wherein R ^11D and R ^12D independently represent a hydrogen atom or a C1-6 alkyl group. )
X ^D represents a chlorine atom or a fluorine atom,
R ^2D is a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, or C1 substituted with 1 to 3 groups (1) to (5) below: Represents an -8 alkyl group, a C2-8 alkenyl group, or a C2-8 alkynyl group; (1) a halogen atom, (2) a C1-4 alkoxy group, (3) a C3-7 cycloalkyl group, (4) a phenyl group, or (5) a phenyl group substituted with 1 to 3 halogen atoms, a C1-4 alkyl group, a C1-4 alkoxy group, a nitro group, or a trifluoromethyl group,
nD represents 0 or an integer of 1 to 4,

Represents a single bond or a double bond, but two do not represent a double bond at the same time,

Represents a single bond, a double bond or a triple bond. Or a salt thereof, an N-oxide or a solvate thereof, or a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (E) In the pamphlet of International Publication No. 95/019964, it is described that a compound represented by the following general formula (IE) has an EP2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (IE) is described in detail in International Publication No. 95/019964 pamphlet. Therefore, the EP2 agonist of the present invention has the general formula (IE)

[Wherein, R ^E represents a C1-20 saturated or unsaturated acyclic hydrocarbon, or — (CH ₂ ) _mE R ^1E (in the group, mE is 0 to 10, and R ^1E is C3 Represents an aliphatic ring of ˜7, an aryl consisting of C4-10 or a heterocyclic aryl (wherein the heteroatom is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom);

Represents a single bond or a double bond. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (F) In US Pat. No. 6,376,533, it is described that a compound represented by the following general formula (IF) has an EP2 agonistic action. The definition of each group of the compound represented by the general formula (IF) is described in detail in US Pat. No. 6,376,533. Accordingly, the EP2 agonist of the present invention includes the general formula (IF)

[Wherein R ^3F represents a heteroaryl or substituted heteroaryl group,
R ^1F and R ^2F are independently selected from the group consisting of a hydrogen atom, lower alkyl up to C6, lower acyl up to C6;
R ^F is CO ₂ R ^4F , CONR ^4F ₂ , CH ₂ OR ^4F , CONR ^4F SO ₂ R ^4F , P (O) (OR ^4F ) and

(In the group, R ^4F is selected from the group consisting of a hydrogen atom, phenyl, C 1-6 lower alkyl),
nF represents 0 or an integer of 1 to 4,

Represents a double bond or a single bond. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (G) In the pamphlet of International Publication No. 04/078103, it is described that a compound represented by the following general formula (IG) has an EP2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (IG) is described in detail in International Publication No. 04/078103 pamphlet. Therefore, the EP2 agonist of the present invention has the general formula (IG)

Wherein, ^{A G} is, C1 -4 alkyl, aryl, heteroaryl, selected from C3~6 cycloalkyl and C3~6 heterocycloalkyl;
B ^G represents C (O) Z ^G (in the group, Z ^G represents hydroxy, alkoxy, C 1-6 alkyl C 1-6 heteroalkyl and NR ^1G R ^2G (in the group, R ^1G and R ^2G represent Independently represents a hydrogen atom, C3-6 cycloalkyl, C3-6 heterocycloalkyl, aryl C1-6 alkyl and heteroaryl C1-6 alkyl.));
D ^G is selected from a hydrogen atom, a halogen atom and C1~6 alkyl;
E ^G is selected from a hydrogen atom and ^C 1-6 alkyl;
G ^G is a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, aryl C1-6 alkyl , heteroaryl C1~6 alkyl, aryl, and heteroaryl; or E ^G and G ^G together with the carbon atoms to which they are attached form a C3~6 cycloalkyl ring;
J ^{G, K G} and ^{L G} are independently a hydrogen atom, a halogen atom, selected from C1~6 alkyl, aryl and heteroaryl;
^MG is selected from a hydroxyl group and a hydrogen atom;
nG represents an integer selected from 0 to 1;
The double bond of (a) ^G and (b) ^G can independently be in Z or E configuration. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (H) In the pamphlet of International Publication No. 05/012322, it is described that a compound represented by the following general formula (IH) has an EP2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (IH) is described in detail in International Publication No. 05/012322. Therefore, the EP2 agonist of the present invention has the general formula (IH)

Wherein A ^H is selected from C 3-8 cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
B ^H is selected from C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene;
R ^1H is selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocycloalkyl, aryl C 1-6 alkyl, heteroaryl C 1-6 alkyl, aryl and heteroaryl. Selected;
R ^2H and R ^3H are independently selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
R ^4H is selected from a hydrogen atom and C 1-6 alkyl;
R ^5H is a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, aryl C 1-6 alkyl, Selected from heteroaryl C1-6 alkyl, aryl and heteroaryl;
nH represents an integer selected from 1, 2, 3, 4, 5 and 6. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (J) In the pamphlet of WO 98/028264, it is described that a compound represented by the following general formula (IJ) has a PGE2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (IJ) is described in detail in International Publication No. 98/028264 pamphlet. In the present invention, the PGE2 agonist can also be used as an EP2 agonist. Therefore, the EP2 agonist of the present invention has the general formula (IJ)

[Wherein (i) B ^J represents a nitrogen atom,
A ^J represents C1-6 alkylsulfonyl, C3-7 cycloalkylsulfonyl, C3-7 cycloalkyl C1-6 alkylsulfonyl (part of ^AJ is independently hydroxy, C1-4 alkyl or halogen atom) May be mono-, di-, or tri-substituted on the carbon atom by
Q ^J is -C2～6 alkylene ^-W J ^-C1~3 alkylene -, - C3-8 alkylene (wherein C3-8 alkylene is 1-4 selected independently from a fluorine atom or a C1~4 alkyl substituents may be ^{substituted), -.} X J ^-C1~5 alkylene -, - C1-5 alkylene ^-X J -, - ^C1~3 alkylene ^-X J ^-C1~3 alkylene -, - C2~ 4 alkylene ^-W J ^-X J ^-C0~3 alkylene -, - C0~4 alkylene ^-X J ^-W J ^-C1~3 alkylene -, - C2-5 alkylene ^-W J ^-X J ^-W J ^-C1~ (wherein, the two ^{W J} are each independently.) - - 3 alkylene C1 -4 alkylene - ethenylene -C1~4 alkylene -, - C1 -4 alkylene - ethenylene -C0~2 alkylene ^-X J -C0 ~ Alkylene -, - C1 -4 alkylene - ethenylene -C0~2 alkylene ^-X J ^-W J ^-C1~3 alkylene -, C1 -4 alkylene - ethynylene -C1~4 alkylene -, or -C1~4 alkylene - ethynylene - X ^J —C 0-3 alkylene-
W ^J is oxygen atom, sulfur atom, sulfino, sulfonyl, aminosulfonyl, -mono-N-C1-4alkyleneaminosulfonyl-, sulfonylamino, N-C1-4alkylenesulfonylamino, carboxamide, N-C1-4alkylene. Represents carboxamide, carboxamidooxy, N-C1-4alkylenecarboxamidooxy, carbamoyl, -mono-N-C1-4alkylenecarbamoyl, carbamoyloxy, or -mono-N-C1-4alkylenecarbamoyloxy (in the group, the W The alkyl group of ^J may be substituted with 1 to 3 fluorine atoms on the carbon).
X ^J represents a 5- to 6-membered aromatic ring optionally having 1 to 2 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom (the ring is independently And may be mono- or di-substituted with a halogen atom, C1-3 alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxy, C1-4 alkoxy, or carbamoyl).
Z ^J represents carboxyl, Cl to 6 alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, C1 -4 alkylsulfonylcarbamoyl, or phenyl sulfonylcarbamoyl,
K ^J represents a single bond, C1-8 alkylene, thio C1-4 alkylene or oxy C1-4 alkylene (the C1-8 alkylene may be monounsaturated, and in the group, K ^J is independently And may be mono-, di-, or tri-substituted with a fluorine atom, methyl, or chlorine atom)
M ^J represents —Ar ^J , —Ar ^1J —V ^J —Ar ^2J , —Ar ^1J —S—Ar ^2J or —Ar ^1J —O—Ar ^2J (in the group, Ar ^J , Ar ^1J , Ar ^2J represents Each independently having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen atoms, partially saturated, fully saturated or fully unsaturated 5 Partially saturated, fully saturated, or fully unsaturated, which may have an 8-membered ring, or 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen Represents a bicyclic ring consisting of two condensed 5- to 6-membered rings),
A part of said Ar ^J , Ar ^1J and Ar ^2J may be on one ring if some are monocyclic, on one or both rings if some are bicyclic, R ^1J , Optionally substituted on carbon by up to three substituents independently selected from R ^2J and R ^3J (wherein R ^1J , R ^2J and R ^3J are hydroxy, nitro, halogen atoms, C1-6 alkoxy, C1-4 alkoxy C1-4 alkyl, C1-4 alkoxycarbonyl, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alkyl, C3-7 cycloalkyl C1-4 alkanoyl , Formyl, C1-8 alkanoyl, C1-6 alkanoyl C1-6 alkyl, C1-4 alkanoylamino, C1-4 alkoxycarbonylamino, sulfonamide, C1-4alkylsulfonamide, amino, mono-N- or di-N, N-C1-4alkylamino, carbamoyl, mono-N- or di-N, N-C1-4alkylcarbamoyl, cyano, thiol, C1 Represents -6 alkylthio, C1-6 alkylsulfinyl, C1-4 alkylsulfonyl or mono-N- or di-N, N-C1-4 alkylaminosulfinyl).
R ^1J , R ^2J and R ^3J may be independently mono-, ^di- or tri-substituted on the carbon by a halogen atom or hydroxy, and V ^J is a single bond or independently by a hydroxy or fluorine atom Represents C1-3 alkylene which may be mono- or disubstituted.
However, ^{K J} is a C2~4 alkylene, ^{M J} is Ar ^J, Ar ^J is is cyclopent-1-yl, cyclohex-1-yl, cyclohepta-1-yl or cyclooct-1-yl When the C5-8 cycloalkyl substituent is not substituted in the 1-position with hydroxy,
Or
(ii):
B ^J represents a nitrogen atom,
A ^J represents C 1-6 alkanoyl, or C 3-7 cycloalkyl C 1-6 alkanoyl (a portion of the A ^J is independently mono-, di- or tri-substituted on the carbon by hydroxy or halogen atoms. You may)
Q ^J represents —C 2-6 alkylene-W ^J —C 1-3 alkylene-, —C 4-8 alkylene- (wherein the —C 4-8 alkylene- is independently selected from a fluorine atom or C 1-4 alkyl 4 the substituents of up pieces, optionally ^{substituted), -.} X J ^-C2~5 alkylene -, - C1-5 alkylene ^-X J -, - C1 -3 alkylene ^-X J ^-C1~3 alkylene - , -C2~4 alkylene ^-W J ^-X J ^-C0~3 alkylene -, - C0~4 alkylene ^-X J ^-W J ^-C1~3 alkylene -, - C2~5 alkylene ^-W J ^-X J ^-W (wherein, the two ^{W J} are each independently.), - - ^J -C1~3 alkylene C1 -4 alkylene - ethenylene -C1~4 alkylene -, - C1 -4 alkylene - ethenylene -C0~2 alkylene X ^J -C0~5 alkylene -, - C1 -4 alkylene - ethenylene -C0~2 alkylene ^-X J ^-W J ^-C1~3 alkylene -, - C1 -4 alkylene - ethynylene -C1~4 alkylene or-C1, to 4 alkylene - ethynylene ^-X J ^-C0~3 alkylene - represents the,
W ^J is oxygen atom, sulfur atom, sulfino, sulfonyl, aminosulfonyl-, -mono-N-C1-4alkyleneaminosulfonyl-, sulfonylamino, N-C1-4alkylenesulfonylamino, carboxamide, N-C1-4. Represents an alkylenecarboxamide, carboxamidooxy, N-C1-4alkylenecarboxamidooxy, carbamoyl, -mono-N-C1-4alkylenecarbamoyl, carbamoyloxy, or -mono-N-C1-4alkylenecarbamoyloxy (in the group, W ^J represents an alkyl group which may be substituted on carbon with 1 to 3 fluorine atoms).
X ^J represents a 5- to 6-membered aromatic ring which may have 1 to 2 heteroatoms independently selected from an oxygen atom, a nitrogen atom or a sulfur atom (the ring is independently May be mono- or di-substituted by halogen atom, C1-3 alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxy, C1-4 alkoxy, or carbamoyl).
Z ^J represents carboxyl, Cl to 6 alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, a C1~4 alkylsulfonylcarbamoyl or phenyl sulfonylcarbamoyl,
K ^J represents C 1-8 alkylene, thio C 1-4 alkylene or oxy C 1-4 alkylene (in the group, the C 1-8 alkylene may be monounsaturated, and K ^J is independently fluorine May be mono-, di- or tri-substituted by atoms, methyl or chlorine atoms),
M ^J represents -Ar ^J , -Ar ^1J -V ^J -Ar ^2J , -Ar ^1J -S-Ar ^2J or -Ar ^1J -O-Ar ^2J (in the group, Ar ^J , Ar ^1J and Ar ^2J represent Each independently having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen atoms, partially saturated, fully saturated or fully unsaturated 5 Partially saturated, fully saturated, or fully unsaturated, which may have an 8-membered ring, or 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen Represents a bicyclic ring consisting of two condensed 5- to 6-membered rings),
A part of said Ar ^J , Ar ^1J and Ar ^2J may be on one ring if some are monocyclic, on one or both rings if some are bicyclic, R ^1J , Optionally substituted on the carbon by up to three substituents independently selected from R ^2J and R ^3J (wherein R ^1J , R ^2J and R ^3J are a hydrogen atom, hydroxy, nitro, Halogen atom, C1-6 alkoxy, C1-4 alkoxy C1-4 alkyl, C1-4 alkoxycarbonyl, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alkyl, C3-7 cycloalkyl C1 -4 alkanoyl, formyl, C1-8 alkanoyl, C1-6 alkanoyl C1-6 alkyl, C1-4 alkanoylamino, C1-4 alkoxycarbonylamino, sulfo Amide, C1-4alkylsulfonamide, amino, mono-N- or di-N, N-C1-4alkylamino, carbamoyl, mono-N- or di-N, N-C1-4alkylcarbamoyl, cyano, thiol , C1-6 alkylthio, C1-6 alkylsulfinyl, C1-4 alkylsulfonyl or mono-N- or di-N, N-C1-4 alkylaminosulfinyl).
R ^1J , R ^2J and R ^3J may be mono-, ^di- or tri-substituted on the carbon independently by a halogen atom or hydroxy,
V ^J is by a single bond or independently hydroxy or fluorine atom, one or two optionally substituted C1~3 alkylene.
However, ^{K J} is a C2~4 alkylene, ^{M J} is Ar ^J, Ar ^J is a cyclopent-1-yl, cyclohex-1-yl, cyclohepta-1-yl or cyclooct-1-yl When the C5-8 cycloalkyl substituent is not substituted in the 1-position with hydroxy,
However, 6-[(3-phenyl-propyl)-(2-propyl-pentanoyl) -amino] hexanoic acid and its ethyl ester are not included.
Or
(iii)
B ^J is C (H),
A ^J represents C 1-6 alkanoyl, or C 3-7 cycloalkyl C 1-6 alkanoyl (a part of the A is independently mono-, di- or tri-substituted on the carbon by hydroxy or halogen atoms; May be good),
Q ^J represents —C 2-6 alkylene-W ^J —C 1-3 alkylene-, —C 4-8 alkylene- (wherein the —C 4-8 alkylene- is independently selected from a fluorine atom or C 1-4 alkyl 4 the substituents of up to pieces, which may be ^{substituted), -.} X J ^-C1~5 alkylene -, - C1-5 alkylene ^-X J -, - C1 -3 alkylene ^-X J ^-C1~3 alkylene - , -C2~4 alkylene ^-W J ^-X J ^-C0~3 alkylene -, - C0~4 alkylene ^-X J ^-W J ^-C1~3 alkylene -, - C2~5 alkylene ^-W J ^-X J ^-W (wherein, the two ^{W J} are each independently.), - - ^J -C1~3 alkylene C1 -4 alkylene - ethenylene -C1~4 alkylene -, - C1 -4 alkylene - ethenylene -C0~2 alkylene X ^J -C0~5 alkylene -, - C1 -4 alkylene - ethenylene -C0~2 alkylene ^-X J ^-W J ^-C1~3 alkylene -, - C1 -4 alkylene - ethynylene -C1~4 alkylene or-C1, to 4 alkylene - ethynylene ^-X J ^-C0~3 alkylene - represents the,
W ^J is oxygen atom, sulfur atom, sulfino, sulfonyl, aminosulfonyl-, -mono-N-C1-4alkyleneaminosulfonyl-, sulfonylamino, N-C1-4alkylenesulfonylamino, carboxamide, N-C1-4. Represents an alkylenecarboxamide, carboxamidooxy, N-C1-4alkylenecarboxamidooxy, carbamoyl, -mono-N-C1-4alkylenecarbamoyl, carbamoyloxy, or -mono-N-C1-4alkylenecarbamoyloxy (in the group, W ^J represents an alkyl group which may be substituted on carbon with 1 to 3 fluorine atoms).
X ^J represents a 5- to 6-membered aromatic ring which may have 1 to 2 heteroatoms independently selected from an oxygen atom, a nitrogen atom or a sulfur atom (the ring is independently May be mono- or di-substituted by halogen atom, C1-3 alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxy, C1-4 alkoxy, or carbamoyl).
Z ^J represents carboxyl, Cl to 6 alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, a C1~4 alkylsulfonylcarbamoyl or phenyl sulfonylcarbamoyl,
K ^J represents a single bond, C1-8 alkylene, thio C1-4 alkylene, C4-7 cycloalkyl C1-6 alkylene or oxy C1-4 alkylene (in the group, the C1-8 alkylene is monounsaturated). And K ^J may be mono-, di- or tri-substituted independently by fluorine, methyl or chlorine atoms).
M ^J represents -Ar ^J , -Ar ^1J -V ^J -Ar ^2J , -Ar ^1J -S-Ar ^2J or -Ar ^1J -O-Ar ^2J (in the group, Ar ^J , Ar ^1J and Ar ^2J represent Each independently having 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen atoms, partially saturated, fully saturated or fully unsaturated 5 Partially saturated, fully saturated, or fully unsaturated, which may have an 8-membered ring, or 1-4 heteroatoms independently selected from nitrogen, sulfur, and oxygen Represents a bicyclic ring consisting of two condensed 5- to 6-membered rings),
A part of said Ar ^J , Ar ^1J and Ar ^2J may be on one ring if some are monocyclic, on one or both rings if some are bicyclic, R ^1J , Optionally substituted on the carbon by up to three substituents independently selected from R ^2J and R ^3J (wherein R ^1J , R ^2J and R ^3J are a hydrogen atom, hydroxy, nitro, Halogen atom, C1-6 alkoxy, C1-4 alkoxy C1-4 alkyl, C1-4 alkoxycarbonyl, C1-7 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alkyl, C3-7 cycloalkyl C1 -4 alkanoyl, formyl, C1-8 alkanoyl, C1-6 alkanoyl C1-6 alkyl, C1-4 alkanoylamino, C1-4 alkoxycarbonylamino, sulfo Amide, C1-4alkylsulfonamide, amino, mono-N- or di-N, N-C1-4alkylamino, carbamoyl, mono-N- or di-N, N-C1-4alkylcarbamoyl, cyano, thiol , C1-6 alkylthio, C1-6 alkylsulfinyl, C1-4 alkylsulfonyl or mono-N- or di-N, N-C1-4 alkylaminosulfinyl).
R ^1J , R ^2J and R ^3J may be mono-, ^di- or tri-substituted on the carbon independently by a halogen atom or hydroxy,
V ^J represents a single bond or C 1-3 alkylene which may be independently mono- or disubstituted with a hydroxy or fluorine atom.
However, ^{K J} is a C2~4 alkylene, ^{M J} is Ar ^J, Ar ^J is is cyclopent-1-yl, cyclohex-1-yl, cyclohepta-1-yl or cyclooct-1-yl Sometimes the C5-8 cycloalkyl substituent is not substituted in position 1 with hydroxy. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (K) In the pamphlet of International Publication No. 99/19300, it is described that a compound represented by the following general formula (IK) has a PGE2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (IK) is described in detail in International Publication No. 99/19300. In the present invention, the PGE2 agonist can also be used as an EP2 agonist. Therefore, the EP2 agonist of the present invention has the general formula (IK)

Wherein, ^{A K} represents SO ₂ or CO,
Amino, oxy Cl to 6 alkylene, Ar ^K - G ^{K is, Ar K, Ar 1K -V K} -Ar 2K, Ar K -C1~6 ^alkylene, Ar K -CONH-Cl to 6 ^{alkylene, R} 1K ^{R 2K} Represents a substituted amino, or an amino substituted with Ar ^K C1-4 alkylene and R ^11K (wherein R ^11K represents a hydrogen atom or C1-8 alkyl, R ^1K and R ^2K are independently and independently Or R ^1K and R ^2K together with the nitrogen atom of the amino group may form a 5-6 membered azacycloalkyl (the aza Cycloalkyls may contain oxygen atoms and are independently one or two by up to two oxygen atoms, hydroxy, C1-4 alkyl, fluorine atoms or chlorine atoms. Others may be tri-substituted.).),
B ^K represents a nitrogen atom or CH,
Q ^K is -C2～6 alkylene ^-W K ^-C1~3 alkylene - (the alkylene may be substituted by substituents of up to 4 substituents selected independently from a fluorine atom or a C1~4 alkyl good), -. C4~8 alkylene - (said alkylene, with up to four substituent groups independently selected from fluorine atom or a C1~4 alkyl optionally substituted), ^-. X K-C1 5 alkylene - (said alkylene, with up to four substituent groups independently selected from fluorine atom or a C1~4 alkyl optionally substituted.), - C1-5 alkylene -X ^K - (wherein alkylene may be substituted with up to four substituent groups independently selected from fluorine atom or C1~4 alkyl), -. C1 -3 alkylene ^-X K ^-C1~3 alkylene - (該A Killen is with up to four substituent groups independently selected from fluorine atom or a C1~4 alkyl optionally substituted), -. C2-4 alkylene ^-W K ^-X K ^-C0~3 alkylene - (the alkylene, with up to four substituent groups independently selected from fluorine atom or a C1~4 alkyl optionally substituted.), - C0~4 alkylene ^-X K ^-W K ^-C1~3 Alkylene- (the alkylene may be substituted with up to 4 substituents independently selected from a fluorine atom or C1-4 alkyl), -C2-5alkylene-W ^K -X ^K -W ^K -C1～3 alkylene - in (groups, the two W ^K are each independently, it said alkylene is substituted with up to four substituent groups independently selected from fluorine atom or C1~4 alkyl Moyo ), -C1-4alkylene-ethenylene-C1-4alkylene- (the alkylene may be substituted with up to 4 substituents independently selected from a fluorine atom or C1-4alkyl). ,-C1-4 alkylene - ethenylene -C0~2 alkylene ^-X K ^-C0~5 alkylene - (the alkylene may be substituted with up to four substituent groups independently selected from fluorine atom or C1~4 alkyl even though it may), -. C1 -4 alkylene - ethenylene -C0~2 alkylene ^-X K ^-W K ^-C1~3 alkylene - (said alkylene is independently selected from a fluorine atom or a C1 -4 alkyl Optionally substituted with up to 4 substituents), -C1-4alkylene-ethynylene-C1-4alkylene (the alkylene is independently a fluorine atom) Alternatively, it may be substituted with up to 4 substituents selected from C1-4 alkyl. ), Or -C1~4 alkylene - ethynylene ^-X K ^-C0~3 alkylene - a represents (said alkylene is substituted with up to four substituent groups independently selected from fluorine atom or C1~4 alkyl You may)
Z ^K is carboxyl, Cl to 6 alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiazolyl, C1 -4 alkyl Represents sulfonylcarbamoyl or phenylsulfonylcarbamoyl,
K ^K is a single bond, C1～9 alkylene, thio C1 -4 alkylene, C1 -4 alkylenethio C1 -4 alkylene, a C1 -4 alkyleneoxy C1 -4 alkylene or oxy C1 -4 alkylene represents (the C1～9 alkylene may be a monounsaturated, when K ^K do not represent a single bond, K ^K is a chlorine atom is independently a fluorine atom, one hydroxyl or methyl, it may be di- or trisubstituted ),
M ^K is -Ar ^3K , -Ar ^4K -V ^1K -Ar ^5K , -Ar ^4K -S-Ar ^5K , -Ar ^4K -SO-Ar ^5K , -Ar ^4K -SO ₂ -Ar ^5K or -Ar ^{4K- Represents} O-Ar ^5K ,
Ar ^K is a partially saturated or fully unsaturated 5- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from an oxygen atom, a sulfur atom, and a nitrogen atom, Or a partially saturated, fully saturated or fully unsaturated 5- to 6-membered ring which may independently have 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom A bicyclic ring consisting of two fused or a partially saturated, complete, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen atoms Represents a tricyclic ring consisting of a tricyclic ring in which a saturated or incompletely saturated 5- to 6-membered ring is independently fused (the partially saturated or fully saturated ring is Substituted with two oxo groups or additionally 1-2 oxo groups on the sulfur atom Ar ^K is a 5-7 membered fully saturated ring having 1-2 heteroatoms independently selected from oxygen, sulfur and nitrogen atoms. Represent,
Ar ^1K and Ar ^2K are each independently a partially saturated, fully saturated, optionally having 1 to 4 heteroatoms independently selected from an oxygen atom, a sulfur atom, and a nitrogen atom, Or a fully unsaturated 5-8 membered ring, or a partially saturated, fully saturated optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen Or a bicyclic ring formed by condensing two fully unsaturated 5- to 6-membered rings, or 1 to 4 heteroatoms independently selected from a nitrogen atom, a sulfur atom and an oxygen atom Represents a tricyclic ring consisting of three rings which are optionally fused, partially saturated, fully saturated or incompletely saturated 5-6 membered rings (the partially saturated, or Fully saturated rings are further substituted on the carbon with 1-2 oxo groups. Or on a sulfur atom may be further substituted with one to two oxo groups.),
A part of the Ar ^K , Ar ^1K and Ar ^2K is ^{1 to 2 when} a part is a monocyclic ring and a part is a bicyclic ring on one ring. A part of which is a tricyclic ring, on one to three rings by up to three substituents selected from R ^3K , R ^4K and R ^5K It may be substituted on the above carbon atom or nitrogen atom (wherein R ^3K , R ^4K and R ^5K are independently a hydroxyl group, nitro, halogen atom, carboxyl, C1-7 alkoxy, C1-4 Alkoxy C1-4 alkyl, C1-4 alkoxycarbonyl, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alkyl, C3-7 cycloalkyl C1 4 alkanoyl, Rumyl, C1-8 alkanoyl, C1-6 alkanoyl C1-6 alkyl, C1-4 alkanoylamino, C1-4 alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N, N-, di- Aminocarbonylamino, sulfonamide, C1-4 alkylsulfonamide, amino, mono-N- or di-N-C1- substituted with N, N'- or tri-N, N, N'-C1-4alkyl 4-alkylamino, carbamoyl, mono-N- or di-N-C1-4alkylcarbamoyl, cyano, thiol, C1-6alkylthio, C1-6alkylsulfinyl, C1-4alkylsulfonyl or mono-N- or di-N , N-C1-4 alkylaminosulfinyl).
W ^K is oxygen atom, sulfur atom, sulfino, sulfonyl, aminosulfonyl-, -mono-N-C1-4alkyleneaminosulfonyl-, sulfonylamino, N-C1-4alkylenesulfonylamino, carboxamide, N-C1-4. Represents an alkylenecarboxamide, carboxamidooxy, N-C1-4alkylenecarboxamidooxy, carbamoyl, -mono-N-C1-4alkylenecarbamoyl, carbamoyloxy, or -mono-N-C1-4alkylenecarbamoyloxy (in the group, W ^K represents an alkyl group which may be substituted on carbon with 1 to 3 fluorine atoms).
X ^K represents a 5- to 6-membered aromatic ring which may have 1 to 2 heteroatoms independently selected from an oxygen atom, a nitrogen atom or a sulfur atom (the ring is independently May be mono-, di- or tri-substituted with a halogen atom, C 1-3 alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxy, C 1-4 alkoxy, or carbamoyl).
R ^1K , R ^2K , R ^3K , R ^4K , R ^5K , R ^11K , R ^31K , R ^41K and R ^51K are independently halogen atoms or hydroxy on the carbon when containing an alkyl, alkylene, alkenylene or alkynylene moiety. May be mono-, di- or tri-substituted, and V ^K and V ^1K are each independently a single bond, thio C1-4 alkylene, C1-4 alkylenethio, C1-4 alkyleneoxy, oxy C1-4 Represents alkylene or, independently, C1-3 alkylene optionally mono-, di- or trisubstituted with hydroxy or fluorine atoms.
However,
a. When K ^K is a C2~4 alkylene, M ^K is ^{Ar 3K, Ar 3K} is cyclopent-1-yl, cyclohex-1-yl, cyclohepta-1-yl or cyclooct-1-yl, The C5-8 cycloalkyl substituent is not substituted in the 1-position with hydroxy; and b. K ^K represents a single bond, ^{G K} is phenyl, phenylmethyl, represent a substituted phenyl or substituted phenylmethyl, ^{Q K} represents C3~8 alkylene, ^{M K} is ^{Ar 3K} or ^Ar 4K ^{-Ar 5K} when referring to, ^{a K} is a sulfonyl. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (L) In European Patent Application No. 0911321, it is described that a compound represented by the following general formula (IL) has a PGE2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (IL) is described in detail in European Patent Application No. 0911321. In the present invention, the PGE2 agonist can also be used as an EP2 agonist. Therefore, the EP2 agonist of the present invention has the general formula (IL)

[In the formula, B ^L represents a nitrogen atom or C (Q ^1L ) (in the group, Q ^1L represents a hydrogen atom or a C1-3 alkyl group),
L ^L is, n- propylenyl -X ^L - or CH ₂ - (in groups, ^{X L} represents furanyl, thienyl, thiazolyl or tetrahydrofuranyl group.) Metaphenylene -CH ₂ a represents, the CH ₂ - metaphenylene -CH ₂ or X ^L are independently 1 to 3 chlorine atoms, fluorine atom, methoxy, difluoromethoxy, trifluoromethoxy, by trifluoromethyl or a methyl group, one on a carbon of the aromatic di- or tri May be replaced,
R ^L represents a carboxyl, C1-6 alkoxycarbonyl, tetrazolyl, 5-oxo-1,2,4-thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, C1-4 alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl group. Represent,
R ^1L represents a hydrogen atom, a methyl, ethyl or propyl group,
R ^2L represents a hydrogen atom or a C2-5 alkanoyl group,
R ^3L independently represents a hydrogen atom, a fluorine atom or a methyl group,
R ^4L may be a hydrogen atom, C 1-7 alkyl, or R ^4L and R ^1L may together form a 5-9 membered carbocycle, which may be monounsaturated Independently may be mono-, di- or tri-substituted by 1 to 3 fluorine atoms, chlorine atoms, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl groups;
R ^5L may be independently mono-, di- or tri-substituted by 1 to 3 hydroxyl groups, fluorine atom, chlorine atom, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl group, C1 -6 alkylsulfonyl, C3-7 cycloalkylsulfonyl, C3-7 cycloalkyl C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C3-7 cycloalkyl C1-6 alkylcarbonyl, C1-6 Alkylcarbonyl, C3-7 alkylsulfonyl, C3-7 cycloalkylsulfonyl, C3-7 cycloalkyl C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C3-7 cycloalkylcarbonyl, C3-7 cycloalkyl C1-6 alkylcarbonyl Table group And
Z ^L represents a methylene, ethylene, propylene or ethenylene group,
G ^L is Ar ^L , Ar ^1L -V ^L -Ar ^2L , Ar ^L- (C1-6) alkylene, Ar ^L -CONH-C1-6 alkylene, R ^12L R ^13L -amino, oxy C1-6 alkylene, Ar ^L represents an amino group substituted with ^L , Ar ^L C1-4 alkylene and an amino group substituted with R ^11L (in the group, R ^11L represents a hydrogen atom or C1-8 alkyl, and R ^12L and R ^13L represent Independently selected from a hydrogen atom and C 1-8 alkyl, or R ^12L and R ^13L together with the nitrogen atom to which they are attached form a 5-6 membered azacycloalkyl group. The azacycloalkyl group may contain an oxygen atom, and is substituted with up to two groups by oxo, hydroxyl group, C1-4 alkyl, fluorine atom or chlorine atom. May be.),
Ar ^L is a partially saturated or fully unsaturated 5- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from an oxygen atom, a sulfur atom, and a nitrogen atom, Or a partially saturated, fully saturated or fully unsaturated 5- to 6-membered ring which may independently have 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom A bicyclic ring consisting of two fused or a partially saturated, complete, optionally having 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen atoms Represents a tricyclic ring consisting of a tricyclic ring in which a saturated or incompletely saturated 5- to 6-membered ring is independently fused (the partially saturated or fully saturated ring, bicyclic ring or tricyclic ring). Cyclic rings are further substituted on the carbon with 1-2 oxo groups or on sulfur atoms Further optionally substituted with 1-2 oxo groups), or Ar ^L has 1-2 heteroatoms independently selected from oxygen, sulfur and nitrogen atoms Represents a 5-7 membered fully saturated ring,
Ar ^1L and Ar ^2L are each independently a partially saturated, fully saturated group that may have 1 to 4 heteroatoms independently selected from an oxygen atom, a sulfur atom, and a nitrogen atom, Or a fully unsaturated 5 to 8 membered ring or a partially saturated and fully saturated group which may independently have 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms Or a bicyclic ring formed by condensing two fully unsaturated 5- to 6-membered rings, or 1 to 4 heteroatoms independently selected from a nitrogen atom, a sulfur atom and an oxygen atom Represents a tricyclic ring consisting of three rings which are optionally fused, partially saturated, fully saturated or incompletely saturated 5-6 membered rings (the partially saturated, or Fully saturated rings are further substituted on the carbon with 1-2 oxo groups. Or on a sulfur atom may be further substituted with one to two oxo groups.),
A part of Ar ^L , Ar ^1L, and Ar ^2L is 1 to 2 when a part is a monocyclic ring, and a part is a bicyclic ring on one ring. A part of which is a tricyclic ring, on one to three rings by up to three substituents selected from R ^14L , R ^15L and R ^16L May be substituted on the above carbon atom or nitrogen atom (wherein R ^14L , R ^15L and R ^16L are independently hydroxyl group, nitro, halogen atom, carboxyl, C1-7 alkoxy, C1-4 Alkoxy C1-4 alkyl, C1-4 alkoxycarbonyl, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alkyl, C3-7 cycloalkyl C1 4 a Canoyl, formyl, C1-8 alkanoyl, C1-6 alkanoyl C1-6 alkyl, C1-4 alkanoylamino, C1-4 alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N, N-, Aminocarbonylamino, sulfonamide, C1-4 alkylsulfonamide, amino, mono-N- or di-N, substituted with di-N, N′- or tri-N, N, N′-C1-4 alkyl, N-C1-4alkylamino, carbamoyl, mono-N- or di-N, N-C1-4alkylcarbamoyl, cyano, thiol, C1-6alkylthio, C1-6alkylsulfinyl, C1-4alkylsulfonyl or mono- N- or di-N, N-C1-4 alkylaminosulfinyl). And V ^L represent a single bond, thio (C1-4) alkylene, C1-4alkylenethio, C1-4alkyleneoxy, oxyC1-4alkylene or C1-3alkylene. When V ^L is not a single bond, it may be independently mono-, di- or tri-substituted by a hydroxyl group or a fluorine atom. Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  (M) In the pamphlet of WO 98/058911, it is described that the compound represented by the following general formula (IM) has a PGE2 agonistic action. In addition, the definition of each group of the compound represented by the general formula (IM) is described in detail in International Publication No. 98/058911 pamphlet. In the present invention, the PGE2 agonist can also be used as an EP2 agonist. Therefore, the EP2 agonist of the present invention has the general formula (IM)

[Wherein, A ^M represents a hydrogen atom or a hydroxyl group;
B ^M represents propylene, propenylene or propynylene;
Q ^M represents propylene, —CH ₂ OCH ₂ —, thiazolyl, pyridyl, phenyl or thienyl;
Z ^M represents carboxyl, Cl to 6 alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl or 5-oxo-1,2,4-oxadiazolyl group;
K ^M represents ethylene or ethynylene;
L ^M represents a single bond or —CO—;
M ^{M is, -Ar M, -Ar 1M, -V} M -Ar 2M, -Ar 1M -S-Ar represents a ^2M or ^-Ar 1M ^{-O-Ar 2M} (in groups, Ar ^M and ^{Ar 1M} are below Represents either (1) or (2)
(1) 5 to 8 membered fully unsaturated ring optionally having 1 to 4 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom, or a nitrogen atom, Optionally having 1 to 4 heteroatoms independently selected from sulfur and oxygen atoms, partially saturated, fully saturated or incompletely saturated 5 and / or 6 membered rings independently A bicyclic ring group consisting of two condensed rings, or 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen atoms, partially saturated, fully saturated Represents a tricyclic cyclic group consisting of a tricyclic ring in which 5 or / and 6-membered rings independently or partially saturated are independently fused, wherein the partially saturated or fully saturated ring is further One or more oxo groups may be substituted), or
(2) Each independently represents a fully saturated 5- to 8-membered ring. ),;
Ar ^2M is a 5- to 8-membered fully unsaturated ring optionally having 1 to 4 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom, or a nitrogen atom, a sulfur atom and an oxygen atom Optionally having from 1 to 4 heteroatoms independently selected from the atoms, partially saturated, fully saturated or incompletely saturated 5 and / or 6 membered rings independently fused A bicyclic cyclic group consisting of a ring or 1 to 4 heteroatoms independently selected from a nitrogen atom, a sulfur atom and an oxygen atom, partially saturated, fully saturated or unsaturated Represents a tricyclic cyclic group consisting of a tricyclic ring in which a fully saturated 5- and / or 6-membered ring is independently fused (the partially saturated or fully saturated ring represents one or more oxo Group may be substituted),
When a part of the Ar ^M and Ar ^1M is a fully unsaturated 5- to 8-membered monocyclic, bicyclic or tricyclic cyclic group, and a part of the Ar ^2M is independently When a part thereof is a monocyclic cyclic group, it may have a substituent on carbon or on the ring, and when a part thereof is a bicyclic cyclic group, 1 to 2 rings When a part thereof is a tricyclic cyclic group, it may have 1 to 3 cyclic substituents, and these are R ^1M , R ^2M And optionally substituted with up to three substituents selected from R ^3M (wherein R ^1M , R ^2M and R ^3M are independently a hydroxyl group, nitro, halogen atom, C 1-7 alkoxy, C1-4 alkoxy C1-4 alkyl, C1-4 alkoxycarbonyl, C1-7 alkyl, C2-7 alkenyl, 2-7 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-4 alkyl, C3-7 cycloalkyl C1-4 alkanoyl, formyl, C1-8 alkanoyl, C1-6 alkanoyl C1-6 alkyl, aminocarbonylamino Or aminocarbonylamino substituted with mono-N-, di-N, N-, di-N, N'- or tri-N, N, N'-C1-4 alkyl, C1-4 alkanoylamino, C1 4 alkoxycarbonylamino, sulfonamide, hydroxysulfonyl, C1-4 alkylsulfonamide, amino, mono-N- or di-N-C1-4 alkylamino, carbamoyl, mono-N- or di-N-C1-4 alkyl Carbamoyl, cyano, thiol, C1-6 alkylthio, C1-6 alkylsulfinyl C1 -4 alkylsulfonyl or mono -N- or di -N, representing the N-C1 -4 alkylamino alkylsulfinyl).;
R ^1M , R ^2M and R ^3M may be linear or branched when containing an alkyl, alkenyl, alkylene or alkenylene moiety and independently have 1 to 3 halogen atoms or hydroxyl groups on carbon may be substituted; the and V ^M, represents a single bond, -CO- or independently hydroxyl group or a fluorine atom is one to two substituents to be C1~3 alkylene group.
However, (1) when ^{L M} is -CO-, ^{A M} represents a hydroxyl group, and (2) when ^{L M} is a single bond and ^{M M} is phenyl, said ^phenyl, R ^{1M, R 2M} and ^{R 3M} Substituted with 1 to 3 substituents selected from Or a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof.

  EP2 agonists used in the present invention further include butaprost, rioprostil, misoprostol, limaprost, AH-13205, CP-533536, AY23626, and the like.

  Limaprost as an EP2 agonist used in the present invention may be used as an α-cyclodextrin inclusion compound, ie, limaprost alfadex.

  As the EP2 agonist of the present invention, the general formula (I)

[Wherein all symbols have the same meaning as described above. , Compounds represented by the above general formulas (IA) to (IM), butaprost, rioprostil, misoprostol, limaprost, AH-13205, CP- Each of 533536 and AY23626 is preferred, more preferably a compound represented by formula (I), formulas (IA) to (IM) and limaprost, and more preferably formula (IA), A compound represented by (IB) and limaprost.

  As a particularly preferable compound, in the compound represented by the general formula (IA), for example, (1) (5Z) -7-{(1R, 2R, 3R, 5R) -2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybut-1-enyl] -5-chloro-3-hydroxycyclopentyl} hept-5-enoic acid, (2) (5Z) -7-{(1R, 2R, 3R , 5R) -2-[(1E, 4S) -4- (1-allylcyclobutyl) -4-hydroxybut-1-enyl] -5-chloro-3-hydroxycyclopentyl} hept-5-enoic acid Examples of the compound represented by the general formula (IB) include (1) 2-[(2-{(2R) -2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4]. -Hydroxybut-1-enyl] -5-oxopyrrolidine 1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, (2) 2-[(2-{(2R) -2-[(3,5-dichlorophenoxy) methyl] -5- Oxopyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, (3) 2-{[2-((5R) -2-oxo-5-{[3-trifluoromethoxy] ) Phenoxy] methyl} pyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, (4) 2-[(2-{(2R) -2-[(heptylamino) methyl] -5-oxopyrrolidin-1-yl} ethyl) thio] -1,3-thiazole-4-carboxylic acid, and limaprost.

  EP1 agonists used in the present invention include those known to date or those found in the future. Examples of EP1 agonists known to date include compounds described in JP-A-11-322709. Preferably, (13E)-(11α, 15S, 17S) -2,5-ethano-6,9-dioxo-11,15-dihydroxy-17,20-dimethylprosta-13-enoic acid is used.

  EP1 antagonists used in the present invention include those known to date or those found in the future. EP1 antagonists known to date include, for example, European Patent Application Publication No. 878465, International Publication No. WO98 / 027053, International Publication No. 92/19617, International Publication No. WO02 / 072564. And compounds described in International Publication No. 03/084917 pamphlet. Preferable examples include compounds described in European Patent Application Publication No. 878465 and International Publication No. WO98 / 027053, and more preferably 6-[(2S, 3S) -3- (4- Chloro-2-methylphenylsulfonylaminomethyl) bicyclo [2.2.2] octan-2-yl] -5Z-hexenoic acid, 4- [2- (N-isobutyl-2-furanylsulfonylamino) -5 Trifluoromethylphenoxymethyl] cinnamic acid and the like.

  EP3 agonists used in the present invention include those known to date or those found in the future. Examples of EP3 agonists known so far include compounds described in JP-A-07-215929, JP-A-08-239356, and WO98 / 34916. . Preferably, the compound etc. which are described in the international publication 98/34916 pamphlet are mentioned, More preferably, 11 (alpha), 15 (alpha) -dimethoxy-9-oxoprosta-5Z, 13E-dienoic acid etc. are mentioned.

  EP3 antagonists used in the present invention include those known to date or those to be found in the future. EP3 antagonists known to date include, for example, WO02 / 016311 pamphlet, WO02 / 020462 pamphlet, WO03 / 016254 pamphlet, WO04 / 069788 pamphlet, Examples include compounds described in International Publication No. 04/058751 pamphlet, International Publication No. 06/044000 pamphlet, International Publication No. 06/044405 pamphlet, International Publication No. 06/0444415 pamphlet, and the like. Preferable examples include compounds described in WO 03/016254 pamphlet, and more preferable is 2- (2-((4-methyl-2- (naphthalen-1-yl) pentanoyl) amino). -4- (pyrazol-1-ylmethyl) benzyl) benzoic acid and the like.

  EP4 agonists used in the present invention include those known to date or those found in the future. EP4 agonists known to date include, for example, WO 03/009872 pamphlet, WO 00/003980 pamphlet, European Patent Application Publication No. 855389, and JP 2000-001472 A. International Publication No. 00/015608, International Publication No. 01/149661, International Publication No. 01/166518, International Publication No. 04/0665365, International Publication No. 02/024647, International Publication No. 02 / 042268 pamphlet, WO 03/008377 pamphlet, WO 03/035064 pamphlet, WO 03/053923 pamphlet, WO 03/103664 pamphlet, International public No. 03/007941 pamphlet, WO 03/074483 pamphlet, US Patent Application Publication No. 2005/0049227, WO 04/085430 pamphlet, WO 04/085431 pamphlet, International publication No. 04. / 063158 pamphlet, and the like. Preferable examples include compounds described in JP 2000-001472 A, WO 00/003980 pamphlet, WO 03/009872 pamphlet, and more preferably 11α, 15α-dihydroxy- 9-oxo-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-3,7-dithiaprost-13E-enoic acid, (11α, 13E, 15α) -9-oxo-11,15 -Dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost-13-enoic acid methyl ester, (15α, 13E) -9-oxo-15-hydroxy-16 -(4-Fluorophenyl) -17,18,19,20-tetranor-5-thia-8-azapro Str-13-enoic acid and the like.

  EP4 antagonists used in the present invention include those known to date or those to be found in the future. EP4 antagonists known to date include, for example, WO 01/62708 pamphlet, WO 02/016311 pamphlet, WO 02/020462 pamphlet, WO 03/016254 pamphlet. Examples include the compounds described. Preferable examples include compounds described in WO 02/016311 pamphlet, and more preferable is 4- [4-cyano-2- [2- (4-fluoro-1-naphthyl) propanoylamino. ] Phenyl] butanoic acid and the like.

  In this specification, the inner ear nerve includes, for example, the vestibular nerve, the cochlear nerve and the like.

  In the present specification, the nerve regeneration agent for the inner ear nerve means an agent having an effect of increasing the number of nerve cells of the inner ear nerve constituting the inner ear.

  In the present specification, the neuroprotective agent for the inner ear nerve means an agent having an effect of repairing or suppressing neuropathy of the inner ear nerve.

[Isomer]
In the present invention, all isomers are included unless otherwise specified. For example, alkyl group, alkenyl group, alkynyl group, alkyloxy group, alkoxy group, alkenyloxy group, alkynyloxy group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, alkylene group, alkenylene group, alkynylene group, acyl group and acyloxy Groups include straight-chain and branched groups. Furthermore, isomers in double bonds, rings and condensed rings (E-form, Z-form, cis-form, trans-form), isomers due to the presence of asymmetric carbon, etc. (R-form, S-form, α-configuration, β-configuration, enantiomers) , Diastereomers), optically active substances having optical activity (D-form, L-form, d-form, l-form), polar bodies (high polar bodies, low polar bodies) by chromatographic separation, equilibrium compounds, rotamers, Any mixtures of these and any proportions, racemic mixtures are also included in the present invention. Moreover, in this invention, all the isomers by a tautomer are also included.

  Moreover, the optically active compound in the present invention may contain not only 100% pure but also other optical isomers of less than 50%.

  In the present invention, unless otherwise specified, symbols will be apparent to those skilled in the art.

Represents binding to the α configuration,

Represents binding to the β configuration,

Represents an α configuration, a β configuration or a mixture of any ratio thereof,

Represents a mixture of α configuration and β configuration.

[Salts and solvates]
Salts of the compounds represented by the general formula (I) include all pharmacologically acceptable salts. The pharmacologically acceptable salt is preferably water-soluble with little toxicity. Suitable salts include, for example, alkali metal (potassium, sodium, lithium, etc.) salts, alkaline earth metal (calcium, magnesium, etc.) salts, ammonium salts (tetramethylammonium salts, tetrabutylammonium salts, etc.), organic Salts of amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl-D-glucamine, etc.) Acid adduct salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salts (acetate, trifluoroacetate, lactate, Tartrate, oxalate, fumarate, maleate, benzoic acid , Citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.), etc.).

Further, the salt includes a quaternary ammonium salt. The quaternary ammonium salt represents a compound in which the nitrogen atom of the compound represented by the general formula (I) is quaternized with an R ⁰ group. The R ⁰ group represents a C 1-8 alkyl group substituted by a C 1-8 alkyl group or a phenyl group.

  As a suitable solvate of the compound represented by the general formula (I), for example, solvates such as water and alcohol solvents (for example, methanol, ethanol and the like) can be mentioned. The solvate is preferably non-toxic and water-soluble. The solvates of the compounds of the present invention also include solvates of the alkali (earth) metal salts, ammonium salts, organic amine salts, and acid adduct salts of the compounds of the present invention.

  The compound of the present invention can be converted into the above salt and the above solvate by a known method.

[Cyclodextrin inclusion compound]
The compound of the present invention represented by the general formula (I) can be obtained by using α-, β- or γ-cyclodextrin, or a mixture thereof, Japanese Patent Publication No. 50-3362, 52-31404 or 61-52146 By using the method described in the specification, it can be converted into a cyclodextrin inclusion compound. Conversion to a cyclodextrin inclusion compound increases the stability and increases the water solubility, which is advantageous when used as a drug.

[Prodrug]
The prodrug of the compound of the present invention refers to a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid or the like in a living body. As the prodrug of the compound of the present invention, for example, when the compound of the present invention has an amino group, the amino group is acylated, alkylated or phosphorylated (for example, the amino group of the compound of the present invention is eicosanoylated, alanyl , Pentylaminoaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation , Tert-butylated compounds, etc.); when the compound of the present invention has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, the hydroxyl group of the compound of the present invention is acetylated, palmitoyl) , Propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylation A compound in which the present compound has a carboxyl group, the compound in which the carboxyl group is esterified or amidated (for example, the carboxyl group in the compound of the present invention is ethyl esterified or phenyl esterified). Carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl ) Methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.); These compounds can be produced by a method known per se. The prodrug of the compound of the present invention may be either a hydrate or non-hydrate. The prodrug of the compound of the present invention changes to the compound of the present invention under physiological conditions as described in Yodogawa Shoten, 1990, “Drug Development”, Volume 7, “Molecular Design”, pages 163-198. There may be. Furthermore, the compound of the present invention may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

  The compound of the present invention represented by the general formula (I), a salt thereof, an N-oxide or a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof (hereinafter sometimes abbreviated as a compound of the present invention). .) Is excellent in solubility, absorbability and metabolic stability, has long-lasting pharmacological activity (PGE receptor binding activity), has low inhibition of drug-metabolizing enzymes, and has low toxicity such as effects on the cardiovascular system. A compound. These properties are the most important physical, chemical, and pharmaceutical properties required for development as pharmaceuticals, and the compounds of the present invention satisfy these conditions and have the potential to become very excellent pharmaceuticals. [The Merck Manual of Diagnostics and Therapy (17th edition), Merck & Co. See publication (The Merck Manual of Diagnosis and Therapy (17th Ed.), Merck & Co.). ].

  Usefulness of the compound of the present invention as a pharmaceutical product can be evaluated by the following experimental systems, methods described in biological examples, and methods that can be carried out by appropriately modifying them. In addition, the fact that the compound of the present invention is kinetically superior in terms of, for example, blood half-life length, gastrointestinal stability, oral absorption, bioavailability, and the like is known methods such as “ Drug bioavailability (evaluation and improvement science) ”, Hyundai Medical Co., Ltd., issued July 6, 1998, etc., can be easily evaluated.

[Method for producing compound of the present invention]
The compound of the present invention can be obtained by a known method, for example, European Patent Application Publication No. 860430, International Publication No. 03/074483, International Publication No. 99/033794, European Patent Application Publication No. 974580, International Publication No. 95/019964, U.S. Patent Application No. 6376533, International Publication No. 04/0778103, International Publication No. 05/012322, International Publication No. 98/028264, International Publication No. 19300 pamphlet, European Patent Application Publication No. 0911321, International Publication No. WO 98/058911 pamphlet, European Patent Application Publication No. 878465, International Publication No. WO 98/027053 pamphlet, International Publication No. 92/19617 Pan. Let, International Publication No. 02/072564, International Publication No. 03/084917, International Publication No. 02/016311, International Publication No. 02/020462, International Publication No. 03/016254, International Publication No. 04/069788 pamphlet, WO 04/058751 pamphlet, WO 03/009872 pamphlet, WO 00/003980 pamphlet, European Patent Application No. 855389, JP 2000-001472 A , International Publication No. 00/015608, International Publication No. 01/149661, International Publication No. 01/166518, International Publication No. 04/066535, International Publication 02/024647 pamphlet, WO02 / 042268 pamphlet, WO03 / 008377 pamphlet, WO03 / 035064 pamphlet, WO03 / 053923 pamphlet, WO03 / 103664 pamphlet International Publication No. 03/007941, International Publication No. 03/074483, US Patent Application Publication No. 2005/0049227, International Publication No. 04/085430, International Publication No. 04/085431, Pamphlet, International JP 04/063158, JP 11-322709, JP 07-215929, JP 08-239356, WO 98/34916 , WO 01/62708 pamphlet, Japanese Patent Application Laid-Open No. 55-100300, or a similar method. For example, (5Z) -7-{(1R, 2R, 3R, 5R) -2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybuta-] listed as a preferred EP2 agonist 1-enyl] -5-chloro-3-hydroxycyclopentyl} hept-5-enoic acid, and (5Z) -7-{(1R, 2R, 3R, 5R) -2-[(1E, 4S) -4- (1-allylcyclobutyl) -4-hydroxybut-1-enyl] -5-chloro-3-hydroxycyclopentyl} hept-5-enoic acid is obtained by the method described in EP-A-860430. Can be manufactured. Also, for example, 2-[(2-{(2R) -2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybut-1-enyl] listed as a preferred EP2 agonist] -5-oxopyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, 2-[(2-{(2R) -2-[(3,5-dichlorophenoxy) methyl] -5-oxopyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, 2-{[2-((5R) -2-oxo-5-{[3-trifluoromethoxy] ) Phenoxy] methyl} pyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, and 2-[(2-{(2R) -2-[(heptylamino) methyl] -5 -Oxo Roridin-1-yl} ethyl) thio] -1,3-thiazole-4-carboxylic acid can be prepared by the methods described in WO 03/074483 pamphlet. Furthermore, limaprost can be produced by the method described in JP-A-55-130030.

[toxicity]
The toxicity of the compound of the present invention was very low, and it was confirmed that the compound was sufficiently safe for use as a medicine.

[Application to pharmaceutical products]
One or more PGE receptor-binding compounds selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists, in particular EP2 agonists, in addition to vasodilatory action, hepatocyte growth factor (HGF) Since it has an effect of enhancing production, it is considered to have an effect of increasing blood flow in the inner ear and a nerve regeneration action and / or a neuroprotective action of the inner ear nerve. ), Cattle, horses, dogs, cats, rabbits, rats, mice, etc.)), and the like.

  Here, the inner ear disease includes all diseases caused by disorders of organs, tissues, nerves and the like constituting the inner ear, and is not limited by the pathogenesis. The inner ear diseases are roughly classified into inner ear dizziness diseases whose main symptoms are dizziness and inner ear deafness whose main symptoms are deafness. Inner ear vertigo diseases include, for example, perilymphatic fistula, perilymph leak, Meniere's disease, delayed internal lymphoma, acoustic nerve tumor, benign paroxysmal positional vertigo, vestibular neuritis, purulent inner earitis, motion sickness, brain Examples include dizziness associated with vascular disorders. Inner ear deafness includes hearing loss caused by inner ear malformation, hearing loss caused by vestibular aqueduct, hearing loss caused by otosclerosis, hearing loss caused by addictive inner ear disorder (for example, analgesics include (E.g., aspirin, fentanyl, morphine, etc.), aminoglycoside antibiotics (e.g., streptomycin, kanamycin, neomycin, amikacin, biomycin, gentamicin, sisomycin, netilmycin, micronomycin, astromycin, tobramycin, dibekacin, isepamicin, Arbekacin, fradiomycin, etc.), other antibiotics (eg, chloramphenicol, enviomycin, colistin, polymyxin B, minomycin, erythromycin, vancomycin, etc.), anticancer agents (eg, cisplatin, carboplatin, nay) Rogen mustard, etc.), loop diuretics (eg, furosemide, ethacrylic acid, bumetanide, torasemide, etc.), anesthetics (eg: nodocaine, cocaine, etc.), antimalarials (eg, quinine, chloroquine, etc.), carbon monoxide, Heavy metals, alcohol, etc.), deafness caused by head and neck trauma (for example, inner ear shaking, temporal bone fracture, etc.), deafness caused by kidney disorders (the kidney disorders include dialysis, diabetes and the like). ), Deafness caused by autoimmune diseases (for example, rheumatoid arthritis, systemic lupus erythematosus, Paget's disease, polyarteritis nodosa), sudden deafness (as causes thereof) , For example, viral infection of the inner ear (eg, mumps hearing loss (parotiditis), rubella, herpes zoster, influenza, mononucleosis, cytomegalo ), Inner ear bacterial infection (eg, syphilis, etc.), inner ear circulation disorder, inner ear ischemic disorder, endolymphatic hydrops, inner ear window membrane rupture, etc.), noise-induced hearing loss (eg, acute noise-induced hearing loss, Chronic noise deafness, headphone deafness, etc., senile deafness, congenital deafness (eg, familial inner ear deafness, hereditary deafness (eg Pandred syndrome, connexin 26 gene deafness, Alport syndrome, Usher syndrome, Van der Hoeve syndrome) Alstrom syndrome, Hallgren syndrome, Laurence-Moon-Biedl-Bardet syndrome, Refsum syndrome, etc.)), acute bass disorder type sensorineural hearing loss, and the like. In the present invention, the inner ear disease preferably includes Meniere's disease, vestibular neuritis, benign paroxysmal positional vertigo and the like in inner ear vertigo disease. In inner ear deafness, deafness and abruptness caused by addictive inner ear disorder. Sexual deafness, senile deafness and the like.

  In addition, for the sake of convenience, the inner ear diseases are broadly classified as described above, but the organs responsible for hearing and balance are mixed in the inner ear, and the organs and nerves responsible for either sensation are not limitedly damaged. Therefore, in any disease, symptoms appearing with the inner ear disease are common. Symptoms resulting from such inner ear diseases include, for example, hearing loss, tinnitus, dizziness, nystagmus, lightheadedness, nausea, ear pain, ear closure, voice enhancement, auditory hypersensitivity, and ear leakage.

  One or more compounds having PGE receptor binding activity selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists (hereinafter referred to as the present invention), which are agents for preventing, treating and / or symptom progression of inner ear diseases of the present invention. May be abbreviated as a drug.) 1) Complementation and / or enhancement of the therapeutic effect of inner ear disease, 2) Improvement of kinetics / absorption of the drug of the present invention, reduction of dosage, and / or 3) the book In order to reduce the side effects of the drug of the invention, it may be administered as a concomitant drug in combination with other drugs.

  The concomitant drug of the drug of the present invention and another drug may be administered in the form of a combined preparation in which both components are mixed in one preparation, or may be administered in separate preparations. When administered as separate preparations, simultaneous administration and administration by time difference are included. In addition, administration by the time difference may be performed by administering the drug of the present invention first and administering the other drug later, or administering the other drug first and administering the drug of the present invention later. Each administration method may be the same or different.

  The other drug may be a low molecular weight compound, and may be a high molecular protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, or vaccine. Also good. The dose of the other drug can be appropriately selected based on the clinically used dose. The mixing ratio of the drug of the present invention and other drugs can be appropriately selected depending on the age and weight of the administration subject, the administration method, the administration time, and the like. For example, 0.01 to 100 parts by weight of another drug may be used with respect to 1 part by weight of the drug of the present invention. Two or more other drugs may be administered in combination at an appropriate ratio. In addition, other drugs that complement and / or enhance the therapeutic effect of the inner ear disease of the present invention include not only those that have been found so far, but also those that will be found in the future based on the mechanism described below. .

  Examples of other drugs include anticholinergic drugs, antihistamines, antiviral drugs, leukotriene receptor antagonists, anticoagulants, antithrombin drugs, antiplatelet drugs, thrombolytic drugs, antithrombotic drugs, factor Xa inhibitors , Factor VIIa inhibitor, activated protein C preparation, vasodilator, steroid, vitamin B and its derivatives, vitamin E and its derivatives, inner ear circulation improving drug, prostaglandins, radical scavenger, anti-vertigo, anxiolytic Drugs, antiemetics, contrast agents and the like can be mentioned.

  Examples of the anticholinergic agent include trihexyphenidyl hydrochloride, biperidene hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, cimetropium bromide, temiverine, tiotropium bromide, levatropeto (UK) -112166).

  Antihistamines include, for example, ketotifen fumarate, mequitazine, azelastine hydrochloride, oxatomide, terfenadine, emedastine fumarate, epinastine hydrochloride, astemizole, ebastine, cetirizine besylate, bepotastine besylate, fexofenadine, loratadine, desloratadine hydrochloride, olopatadine hydrochloride , TAK-427, ZCR-2060, NIP-530, mometasone furoate, mizolastine, BP-294, andlast, auranofin, acribastine, levocabastine hydrochloride, niporazine, diphenhydramine hydrochloride, meclizine hydrochloride, cyclidine and the like.

  Antiviral agents include, for example, acyclovir, ganciclovir, phosphonomernote, idoxyuridine, amantadine hydrochloride, ribavirin, vidarabine, zanamivir hydrate, oseltamivir phosphate, cidofovir, famciclovir, fomivirsen, foscalnet, penciclovir, hydrochloric acid Examples include valaciclovir.

  Examples of leukotriene receptor antagonists include pranlukast hydrate, montelukast sodium, zafirlukast, abrukast, povirukast, sulfast, irarukast sodium, berlukast, little cast, cinalukast, pyrodomast, tomerukast, doqualast, and the like.

  Examples of the anticoagulant include warfarin potassium, heparin sodium, daltevaline sodium and the like.

  Examples of the antithrombin drug include gabexate mesylate, nafomostat mesylate, and argatroban.

  Examples of the antiplatelet drug include dipyridamole, ticlopine hydrochloride, acetylsalicylic acid, cilostazol, beraprost sodium, alprostadil alphadex, alprostadil, ozagrel sodium, salvogrelate hydrochloride and the like.

  Examples of the thrombolytic agent include urokinase, alteplase, and monteplase.

  Examples of the antithrombotic agent include t-PA.

  Examples of the factor Xa inhibitor include BAY59-7939, YM150 and the like.

  Examples of the vasodilator include, for example, diltiazem hydrochloride, trimetazidine hydrochloride, dipyridamole, dirazep, hydrochloride, trapidil, nicorandil, beraprost sodium, alprostadil alphadex, alprostadil, rimaprost alphadex, rimaprostat, epoprostenol sodium , Hepronicart, isoxpurine hydrochloride, tolazoline hydrochloride, dipyridamole release agent and the like.

  Examples of the steroid drug include amsinonide, difluprednate, betamethasone dipropionate, dexamethasone, triamcinolone, triamcinolone acetonide, hydrocortisone, mometasone furanate, fluocinonide, prednisolone, clobetasol propionate, dexamethasone propionate, propionate, propionate, propionate , Dexamethasone sodium metasulfobenzoate, methylprednisolone, dexamethasone sodium phosphate, betamethasone sodium phosphate, betamethasone valerate, diflorazone acetate, dexamethasone acetate, parameterzone acetate, betamethasone acetate / sodium betamethasone phosphate, methylprednisolone acetate, prednisolone succinate for injection Sodium, butyric acid propionate Dzong, and the like.

  Examples of vitamin B and derivatives thereof include pyridoxine hydrochloride, pyridoxal cyanocobalamin phosphate, hydroxocobalamin acetate, and mecobalamin.

  Examples of vitamin E and derivatives thereof include dl-α-tocopherol, dl-α-tocopherol acetate, and calcium tocopherol succinate.

  Examples of the inner ear circulation improving drug include betahistine mesylate, diphenidol hydrochloride, adenosine triphosphate (ATP), cardinogenase, nicergoline, ibudilast, nicotinamide, and papaverine hydrochloride.

  Examples of prostaglandins (hereinafter abbreviated as PG) include, for example, PGE1 preparations (eg: alprostadil alphadex, alprostadil etc.), PGI2 preparations (eg: beraprost sodium etc.), PG receptor agonists, Examples thereof include PG receptor antagonists. Examples of PG receptors include PGE receptors (EP1, EP2, EP3, EP4), PGD receptors (DP, CRTH2), PGF receptors (FP), PGI2 receptors (IP), TX receptors (TP) and the like. Can be mentioned.

  Examples of the radical scavenger include edaravone and the like.

  Examples of the anti-vertigo drug include sodium hydrogen carbonate solution, betahistine mesylate, diphenhydramine salicylate, diphenidol hydrochloride, chlorpromazine hydrochloride, perphenazine, diprofilin, scopolamine hydrobromide, and the like.

  Examples of the anxiolytic drugs include chlordiazepoxide, oxazolam, diazepam, bromazepam, ethyl loflazepate, and alprazolam.

  Examples of the antiemetic include metoclopramide hydrochloride, domperidone, perphenazine maleate, hydroxyzine hydrochloride, prochlorperazine maleate, thiethylperazine malate, chlorpromazine and the like.

  Examples of the contrast agent include amidotrizoic acid (urogurafine).

  In order to use the drug of the present invention or the combination drug of the present invention and another drug for the above-mentioned purpose, it is usually administered systemically or locally in an oral or parenteral form.

  The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered once to several times a day in the range of 0.1 ng to 1000 mg per adult per person. Or administered parenterally once or several times a day in the range of 0.1 ng to 1000 mg per adult or continuously intravenously in the range of 1 hour to 24 hours per day Or administered topically in the range of 1 to 3 months.

  Of course, as described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, or administration may be necessary beyond the range.

  When administering the drug of the present invention or a combination drug of the drug of the present invention and other drugs, a solid preparation for internal use for oral administration, a liquid for internal use, an injection for parenteral administration, and an external preparation , Suppositories, eye drops, inhalants and the like.

  Examples of the solid preparation for internal use for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules. Tablets include sublingual tablets, buccal adhesive tablets, buccal quick disintegrating tablets and the like.

  In such solid preparations for internal use, one or more active substances are left as they are, or excipients (lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, polyvinylpyrrolidone, Mixed with magnesium metasilicate aluminate, etc.), disintegrating agents (such as calcium calcium glycolate), lubricants (such as magnesium stearate), stabilizers, solubilizing agents (such as glutamic acid, aspartic acid), etc. Used by formulating. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Also included are capsules of absorbable substances such as gelatin.

  Sublingual tablets are produced and prepared according to known methods. For example, one or more active substances, excipients (lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binders (hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegration Agents (starch, L-hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, calcium calcium glycolate, etc.), lubricants (magnesium stearate, etc.), swelling agents (hydroxypropylcellulose, hydroxypropylmethylcellulose, carbopol, Carboxymethylcellulose, polyvinyl alcohol, xanthan gum, guar gum, etc.), swelling aids (glucose, fructose, mannitol, xylitol, erythritol, Luteose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine, etc.), stabilizer, solubilizer (polyethylene glycol, propylene glycol, glutamic acid, aspartic acid, etc.), flavoring (orange, strawberry) , Mint, lemon, vanilla, etc.) and the like, and formulated into a conventional method. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Moreover, additives such as preservatives, antioxidants, colorants, sweeteners and the like that are commonly used can be added as necessary.

  The intraoral patch is manufactured and prepared according to a known method. For example, one or more active substances, excipients (lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binders (hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegration Agents (starch, L-hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, calcium calcium glycolate, etc.), lubricants (magnesium stearate, etc.), adhesives (hydroxypropylcellulose, hydroxypropylmethylcellulose, carbopol, Carboxymethylcellulose, polyvinyl alcohol, xanthan gum, guar gum, etc.), adhesion aids (glucose, fructose, mannitol, xylitol, erythritol, Luteose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine, etc.), stabilizer, solubilizer (polyethylene glycol, propylene glycol, glutamic acid, aspartic acid, etc.), flavoring (orange, strawberry) , Mint, lemon, vanilla, etc.) and the like, and formulated into a conventional method. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Moreover, additives such as preservatives, antioxidants, colorants, sweeteners and the like that are commonly used can be added as necessary.

  The intraoral quick disintegrating tablet is produced and prepared according to a known method. For example, one or more active substances can be used as is, or a coating agent (ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, acrylic acid / methacrylic acid copolymer, etc.) suitable for raw powder or granulated raw powder, plasticizer (polyethylene glycol). , Triethyl citrate, etc.) active substance coated with excipients (lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binders (hydroxypropylcellulose, polyvinylpyrrolidone, aluminate metasilicate) Magnesium acid, etc.), disintegrating agents (starch, L-hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, calcium calcium glycolate, etc.), lubricant (magnesium stearate) Dispersion agents (glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine, etc.), stabilizers, solubilizers (polyethylene) Glycol, propylene glycol, glutamic acid, aspartic acid, etc.), flavoring agents (orange, strawberry, mint, lemon, vanilla, etc.), etc. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Moreover, additives such as preservatives, antioxidants, colorants, sweeteners and the like that are commonly used can be added as necessary.

  Liquid preparations for internal use for oral administration include pharmaceutically acceptable solutions, suspensions / emulsions, syrups, elixirs and the like. In such a solution, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (purified water, ethanol or a mixture thereof). Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

  Examples of external dosage forms for parenteral administration include ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, eye drops, ear drops and Nasal drops and the like are included. These contain one or more active substances and are produced and prepared by known methods or commonly used formulations.

  The ointment is produced by a known or commonly used formulation. For example, it is manufactured and prepared by grinding or melting one or more active substances in a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acid or higher fatty acid ester (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (honey beeswax) , Whale wax, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (dimethylpolysiloxane, etc.), hydrocarbons ( Hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol etc.), vegetable oil (castor oil, olives) , Sesame oil, turpentine oil, etc.), animal oils (mink oil, yolk oil, squalane, squalene, etc.), water, absorption accelerator, used alone or in combination of two or more kinds chosen from irritation inhibitor. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like may be included.

  The gel is produced by a known or commonly used formulation. For example, it is produced and prepared by melting one or more active substances in a base. The gel base is selected from known or commonly used ones. For example, lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, etc.), neutralizing agents (triethanolamine, diisopropanolamine, etc.), surfactants (monostearin) Acid polyethylene glycol, etc.), gums, water, absorption promoters, anti-rash agents, or a mixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The cream is produced by a known or commonly used formulation. For example, it is produced and prepared by melting or emulsifying one or more active substances in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (polyoxyethylene alkyl ethers, fatty acids) Esters etc.), water, absorption promoters, anti-rash agents, or a mixture of two or more of them may be used. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, and applying it as a kneaded product on a support. The poultice base is selected from known or commonly used ones. For example, thickeners (polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium, magnesium, etc.) ), Water, a solubilizing agent, a tackifier, and a rash prevention agent, or a mixture of two or more thereof. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base and spreading and coating them on a support. The base for patch is selected from known or commonly used ones. For example, those selected from a polymer base, fats and oils, higher fatty acids, tackifiers and anti-rash agents may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The liniment is produced by a known or commonly used formulation. For example, one or more active substances are dissolved, suspended in or singly selected from water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifier, suspending agent, etc. Produced and prepared by emulsification. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  Sprays, inhalants, and sprays are commonly used diluents such as sodium bicarbonate, sodium citrate or citric acid to provide isotonicity with stabilizers such as sodium bisulfite. Such an isotonic agent may be contained.

  Inhalants for parenteral administration include aerosols, inhalable powders or inhalable solutions, which are used by dissolving or suspending them in water or other suitable media at the time of use. It may be.

  These inhalants are produced according to known methods.

  For example, in the case of inhalation solutions, preservatives (benzalkonium chloride, parabens, etc.), coloring agents, buffering agents (sodium phosphate, sodium acetate, etc.), isotonic agents (sodium chloride, concentrated glycerin, etc.) , And thickeners (such as cariboxyvinyl polymer) and absorption accelerators are appropriately selected as necessary.

  In the case of powders for inhalation, lubricants (stearic acid and its salts), binders (starch, dextrin, etc.), excipients (lactose, cellulose, etc.), colorants, preservatives (benzalkonium chloride) , Parabens, etc.), absorption promoters and the like are appropriately selected as necessary.

  A nebulizer (atomizer or nebulizer) is usually used when administering an inhalation solution, and an inhalation administration device for powder medicine is usually used when administering an inhalable powder.

  Examples of the injection for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use. An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Furthermore, this injection may contain a stabilizer, a solubilizer (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative, and the like. . These are sterilized in the final process or manufactured and prepared by aseptic manipulation. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use. In addition, gel preparations that are directly administered to the inner ear are also included as injections. Examples of the base of such a gel preparation include gelatin, hyaluronic acid, polypeptide, cholesterol pullulan and the like.

  Other compositions for parenteral administration include suppositories for rectal administration and pessaries for intravaginal administration, which contain one or more active substances and are prescribed by conventional methods.

  One or more PGE receptor-binding compounds selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists, in particular EP2 agonists, have an action of enhancing HGF production in addition to a vasodilatory action. Useful for prevention, treatment and / or suppression of symptom progression.

  It was proved by the following experiment that a compound having at least one PGE receptor binding activity selected from an EP2 agonist, an EP4 agonist, an EP1 antagonist and an EP3 antagonist, particularly an EP2 agonist, exhibits the effect of the present invention. Although an experimental method is shown below, it is not limited to this.

[Biological Example]
Biological Example 1: Measurement of in vitro HGF production action Using human lung fibroblasts (HFL-1, American Type Culture Collection: ATCC, CCL-153 ^™ ), hepatocyte growth factor (Hepatocyte Growth) of the test compound Factor: The effect on HGF production was evaluated. HFL-1 cells were cultured at a cell density of 1.0 × 10 ⁴ cells / 0.5 mL / well on a 24-well culture plate using DMEM medium (GIBCO BRL) containing 10% fetal calf serum (FCS). Seeding and culturing at 37 ° C. for 6 days. Thereafter, the medium was replaced with a DMEM medium not containing FCS, a test compound was added, and the cells were further cultured under the same conditions for 3 days. After completion of the culture, the HGF concentration in the culture supernatant was measured according to the manual of a human hepatocyte growth factor quantification kit (human HGF ELISA kit, Cat. No. KAC2212, R & D SYSTEMS). Moreover, (5Z) -7-{(1R, 2R, 3R, 5R) -5-chloro-2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4 which is an EP2 agonist as a test compound -Hydroxybut-1-enyl] -3-hydroxycyclopentyl} hept-5-enoic acid (hereinafter sometimes abbreviated as Compound 1), 2-[(2-{(2R) -2-[(3 , 5-dichlorophenoxy) methyl] -5-oxopyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid (hereinafter sometimes abbreviated as compound 2) and an EP4 agonist. Certain methyl 4-{[2-((1R, 2R, 3R) -3-hydroxy-2-{(1E, 3S) -3-hydroxy-4- [3- (methoxymethyl) phenyl] but-1-enyl } -5-o Xocyclopentyl) ethyl] sulfanyl} butanoate (hereinafter sometimes abbreviated as compound 3) was used. Dimethylsulfoxide (DMSO) was used as the solvent. As experimental groups, a medium group, a control group (0.01% DMSO added), a compound 1 added group (1 nM, 10 nM, 100 nM, 1000 nM), a compound 2 added group (1 nM, 10 nM, 100 nM, 1000 nM) and a compound 3 added group (1 nM, 10 nM, 100 nM, 1000 nM) was set.

[result]
The effect of the test compound on HGF production in HFL-1 cells is shown in FIG. 1 and FIG. (Experimental groups in FIG. 1 are 1: medium group, 2: control group, 3-6: compound 1 added group (1 nM, 10 nM, 100 nM, 1000 nM from the left), 7-10: compound 3 added group (from the left 2 represents 1 experimental group, 1: medium group, 2: control group, 3-6: compound 2 added group (from the left: 1 nM, 10 nM, 100 nM, 1000 nM). Represents.)
Compared to the control group, compounds 1, 2 and 3 were observed to increase the HGF concentration in the culture supernatant according to the added concentration, and thus EP2 agonist and EP4 agonist have an HGF production enhancing action. I found out.
Biological Example 2: Measurement of rat skin blood flow The effect of a test compound on skin blood flow was evaluated using CD (SD) IGS male rats (Nippon Charles River Co., Ltd., 6 weeks old). Rats were anesthetized with 25% urethane, a C3 catheter for blood pressure measurement was inserted into the right carotid artery, placed in a prone position and placed on a constant temperature mat at 37 ° C. A 25 gauge winged injection needle (Terumo Corporation) for administration of the test compound was inserted into the tail vein of the rat. After blood pressure, heart rate and blood flow were stabilized, compound 1 (1 μg / kg / min), compound as a test compound was administered intravenously (administration rate: 4 mL / kg / hr) through the winged needle described above. 2 (10 μg / kg / min) and Compound 3 (100 ng / kg / min) were administered. The skin blood flow was measured using a laser blood flow meter (FLO-N1; Omega Wave Co., Ltd.) by bringing a non-contact type probe for blood flow measurement close to the right sole. Skin blood flow was expressed as a relative value during or after administration, with the value before administration being 100%. The skin blood flow was measured over time for 30 minutes or more, and the maximum amount of change during monitoring was obtained.

[result]
The effect of each test compound on the maximum change in skin blood flow in rats is shown in FIG.

  In each test compound, the maximum blood flow increased from the value before administration. In particular, since compounds 2 and 3 were observed to increase blood flow by a maximum of 1.5 times compared to before administration, it was found that EP2 agonists and EP4 agonists have an effect of increasing blood flow.

[Formulation example]
Formulation Example 1
(5Z) -7-{(1R, 2R, 3R, 5R) -5-chloro-2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybut-1-enyl]- 3-hydroxycyclopentyl} hept-5-enoic acid (5 g), carboxymethylcellulose calcium (15.0 g), magnesium stearate (10.0 g) and lactose (970 g) were mixed by a conventional method and then compressed into tablets. 10000 tablets having a diameter of 6.5 mm, a thickness of 3 mm and a weight of 100 mg containing 0.5 mg of the active ingredient were obtained.

Formulation Example 2
(5Z) -7-{(1R, 2R, 3R, 5R) -5-chloro-2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybut-1-enyl]- 3-Hydroxycyclopentyl} hept-5-enoic acid (2.8 g) and maltose (400 g) were dissolved in distilled water, 20 g of disodium hydrogen phosphate 12 hydrate was added, and the total volume was adjusted to 4000 mL with distilled water. . After dust-proofing with a dust filter, the solution was sterilized using a 0.2 μm sterilizing filter, and 1 mL was filled into ampoules to obtain 4000 injections containing 0.7 mg of active ingredient in 1 ampule.

Formulation Example 3
(5Z) -7-{(1R, 2R, 3R, 5R) -5-chloro-2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybut-1-enyl]- 3-Hydroxycyclopentyl} hept-5-enoic acid (5.6 g) and maltose (400 g) were dissolved in distilled water, 20 g of disodium hydrogen phosphate dodecahydrate was added, and the total volume was adjusted to 4000 mL with distilled water. . After removing the dust with a filter, the solution is sterilized using a 0.2 μm sterilizing filter, filled into vials 1 mL each, freeze-dried by a conventional method, and 4000 injections containing 1.4 mg of active ingredient in one vial. Obtained.

  A compound having at least one PGE receptor binding activity selected from an EP2 agonist, an EP4 agonist, an EP1 antagonist, and an EP3 antagonist is useful as a pharmaceutical in the following respects. One or more compounds having PGE receptor binding activity selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists, in particular EP2 agonists, have an action of enhancing HGF production in addition to a vasodilatory action, so For example, prevention and / or treatment of Meniere's disease, vestibular neuritis, benign paroxysmal positional vertigo, deafness due to addictive inner ear disorder, sudden hearing loss or senile deafness, and / or various types associated with inner ear disease It is also useful for suppressing the progression of symptoms such as deafness, tinnitus, dizziness, nystagmus, lightheadedness, nausea, ear pain, ear closure, voice enhancement, hypersensitivity, and ear leakage.

HGF production of human lung fibroblasts in experimental group 1 (medium group), experimental group 2 (control group), experimental groups 3-6 (compound 1 added group) and experimental groups 7-10 (compound 3 added group) It is a graph to show. It is a graph which shows the HGF production amount of the human lung fibroblast in the experimental group 1 (medium group), the experimental group 2 (control group), and the experimental groups 3-6 (compound 2 addition group). It is a graph which shows the maximum variation | change_quantity of the rat skin blood flow rate in each test compound.

Claims (19)

A prophylactic, therapeutic and / or symptom progression inhibitor for inner ear diseases comprising a compound having PGE receptor binding activity. The agent according to claim 1, wherein the compound having PGE receptor binding activity is at least one selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists. The agent according to claim 2, wherein the compound having PGE receptor binding activity is an EP2 agonist and / or an EP4 agonist. The agent according to claim 1, wherein the inner ear disease is inner ear vertigo disease or inner ear deafness. The agent according to claim 4, wherein the inner ear vertigo disease is Meniere's disease, vestibular neuritis or benign paroxysmal positional vertigo. The agent according to claim 4, wherein the inner ear deafness is deafness, sudden deafness or presbycusis due to addictive inner ear disorder. The agent according to claim 1, wherein the symptom of the inner ear disease is one or more selected from hearing loss, tinnitus, dizziness, nystagmus, lightheadedness, nausea, ear pain, ear closure, voice emphasis, hypersensitivity and otorrhea. One or more compounds selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists, anticholinergic drugs, antihistamines, antiviral drugs, leukotriene receptor antagonists, anticoagulants, vasodilators, steroid drugs , A drug for prevention, treatment and / or suppression of symptom progression of inner ear diseases, comprising a combination of one or more drugs selected from thrombolytic drugs, vitamin B and derivatives thereof, and inner ear circulation improving drugs. EP2 agonists have the general formula (I)

[Wherein, T represents an oxygen atom, a sulfur atom, a methylene group, a halogen atom or an optionally substituted acyloxy group, R ¹ represents a hydrogen atom, a hydroxyl group, a C1-6 alkyloxy group or C1. Represents an acyloxy group, E represents a carbon atom or a nitrogen atom, X represents a methylene group, an oxygen atom, a sulfur atom or an optionally substituted nitrogen atom, and A represents a main chain atom. Represents a spacer of formula 1 to 8, D represents an optionally protected acidic group, G represents a spacer of a main chain of 1 to 8 atoms, and R ² may have a substituent. Represents an aliphatic hydrocarbon group which may have a good cyclic group or substituent,

Represents a single bond or a double bond, but two do not represent a double bond at the same time,

Represents the α-configuration or β-configuration or a mixture of any proportions thereof. Or a salt, a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof. EP2 agonist is represented by the general formula (IA)

[Wherein R ^A represents a carboxyl group or a hydroxymethyl group,
R ^1A represents an oxygen atom, a methylene group or a halogen atom,
R ^2A represents a hydrogen atom, a hydroxyl group, or a C1-4 alkoxy group,
R ^3A is substituted with a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, or 1 to 3 of the following groups (1) to (5): Represents a C1-8 alkyl group, a C2-8 alkenyl group or a C2-8 alkynyl group: (1) a halogen atom, (2) a C1-4 alkoxy group, (3) a C3-7 cycloalkyl group, (4) a phenyl group, or (5) a phenyl group substituted with 1 to 3 halogen atoms, a C1-4 alkyl group, a C1-4 alkoxy group, a nitro group or a trifluoromethyl group;
nA represents 0-4,

Represents a single bond or a double bond,

Represents a double bond or a triple bond,

Represents a single bond, a double bond or a triple bond,

Represents binding to the α configuration,

Represents binding to the β configuration. ] The agent of Claim 9 which is the compound shown by these, its salt, its solvate, those prodrugs, or those cyclodextrin inclusion compounds. EP2 agonist is represented by the general formula (IB)

[Wherein T ^B represents (1) an oxygen atom or (2) a sulfur atom,
X ^B represents (1) —CH ₂ — group, (2) —O— group, or (3) —S— group,
A ^B represents A ^1B or A ^2B ;
A ^1B is (1) a linear C2-8 alkylene group optionally substituted with 1 to 2 C1-4 alkyl groups, (2) substituted with 1 to 2 C1-4 alkyl groups. An optionally linear C2-8 alkenylene group, or (3) a linear C2-8 alkynylene group optionally substituted by 1 to 2 C1-4 alkyl groups,
A ^2B represents a -G ^1B -G ^2B -G ^3B -group,
G ^1B is (1) a linear C1-4 alkylene group which may be substituted with 1 to 2 C1-4 alkyl groups, and (2) 1 to 2 C1-4 alkyl groups. An optionally linear C2-4 alkenylene group, or (3) a linear C2-4 alkynylene group optionally substituted by 1 to 2 C1-4 alkyl groups,
G ^2B is, (1) -Y ^B - group, (2) - Ring ^{1 B} - group, (3) -Y ^B - Ring ^{1 B} - group, (4) - Ring ¹ B -Y ^B - group, or, ⁽⁵⁾ -Y B -C1~4 alkylene - ring ^{1 B} - represents a group,
Y ^B is, (1) -S- group, (2) -SO- group, (3) -SO ₂ - group, wherein - group, (4) -O- group, or (5) ^{-NR 1B,}
R ^1B represents (1) a hydrogen atom, (2) a C1-10 alkyl group, or (3) a C2-10 acyl group,
G ^3B is (1) a single bond, (2) a linear C1-4 alkylene group optionally substituted with 1-2 C1-4 alkyl groups, and (3) 1-2 C1-4. A linear C2-4 alkenylene group optionally substituted with an alkyl group, or (4) a linear C2-4 alkynylene group optionally substituted with 1 to 2 C1-4 alkyl groups,
D ^{B represents D 1B} or ^{D 2B,}
D ^1B represents (1) —COOH group, (2) —COOR ^2B group, (3) tetrazol-5-yl group, or (4) —CONR ^3B SO ₂ R ^4B group,
R ^2B represents (1) a C1-10 alkyl group, (2) a phenyl group, (3) a C1-10 alkyl group substituted with a phenyl group, or (4) a biphenyl group,
R ^3B represents (1) a hydrogen atom, or (2) a C1-10 alkyl group,
R ^4B represents (1) a C1-10 alkyl group, or (2) a phenyl group,
D ^2B is (1) —CH ₂ OH group, (2) —CH ₂ OR ^5B group, (3) hydroxyl group, (4) —OR ^5B group, (5) formyl group, (6) —CONR ^6B R ^7B Group, (7) -CONR ^6B SO ₂ R ^8B group, (8) -CO- (NH-amino acid residue-CO) _mB -OH group, (9) -O- (CO-amino acid residue-NH) _mB -H group, (10) -COOR ^9B group, (11) -OCO-R ^10B group, (12) -COO-Z ^1B -Z ^2B -Z ^3B group, or (13)

Represents
R ^5B represents a C1-10 alkyl group,
R ^6B and R ^7B each independently represent (1) a hydrogen atom, or (2) a C1-10 alkyl group,
R ^8B represents a C1-10 alkyl group substituted with a phenyl group,
R ^9B is (1) a C1-10 alkyl group substituted with a biphenyl group optionally substituted with 1 to 3 substituents selected from a C1-10 alkyl group, a C1-10 alkoxy group, and a halogen atom. Or (2) a biphenyl group substituted with 1 to 3 substituents selected from a C1-10 alkyl group, a C1-10 alkoxy group, and a halogen atom,
R ^10B represents (1) a phenyl group, or (2) a C1-10 alkyl group,
mB represents 1 or 2,
Z ^1B represents (1) a C1-15 alkylene group, (2) a C2-15 alkenylene group, or (3) a C2-15 alkynylene group,
Z ^2B is (1) —CO— group, (2) —OCO— group, (3) —COO— group, (4) —CONR ^Z1B — group, (5) —NR ^Z2B CO— group, (6) -O- group, (7) -S- group, (8) -SO ₂ - ^{_{group, (9) -SO 2 -NR Z2B}} - _{^{group, (10) -NR Z2B SO 2}} - group, (11) -NR ^Z3b - represents a group or (15) -OCOO- group, - ^{group, (12) -NR Z4B CONR Z5B} - group, ^{(13) -NR} Z6B COO- group, (14) -OCONR ^Z7B
Z ^3B is (1) a hydrogen atom, (2) a C1-15 alkyl group, (3) a C2-15 alkenyl group, (4) a C2-15 alkynyl group, (5) a ring Z ^B , or (6) C1— represents a group or C1-10 alkyl group substituted by ring ^{Z B,,} - 10 alkoxy group, C1-10 alkylthio group, C1-10 alkyl ^{-NR Z8B}
Ring Z ^B represents (1) a carbocycle or (2) a heterocycle,
R ^Z1B , R ^Z2B , R ^Z3B , R ^Z4B , R ^Z5B , R ^Z6B , R ^Z7B , and R ^Z8B each independently represent a hydrogen atom or a C1-15 alkyl group,
R ^Z1B and Z ^3B groups, together with the nitrogen atom to which they are attached, may represent a 5- to 7-membered nitrogen-containing heterocycle, which further includes an oxygen atom, nitrogen atom, and sulfur May contain one heteroatom selected from atoms,
The 5- to 7-membered nitrogen-containing heterocyclic ring represented together with the ring Z ^B and the nitrogen atom to which R ^Z1B and Z ^3B are bonded is selected from the following (1) to (4): May be substituted with ~ 3 groups;
(1) C1-15 alkyl group, (2) C2-15 alkenyl group, (3) C2-15 alkynyl group, (4) C1-10 alkoxy group, C1-10 alkylthio group, or C1-10 alkyl-NR ^Z9B A C1-10 alkyl group substituted by a group;
R ^Z9B represents a hydrogen atom or a C1-10 alkyl group,
E ^B represents E ^1B or E ^2B ,
E ^1B is

Represents
R ^11B is, (1) C1-10 alkyl, (2) C1-10 alkylthio group, (3) C3-8 cycloalkyl C1-10 alkyl group substituted with a group is substituted with (4) the ring ^{2 B} and C1~10 alkyl or ^{(5) -W 1B -W 2B,} - represents a C1~10 alkyl group substituted with the ring ^{2 B,}
W ^1B represents (1) —O— group, (2) —S— group, (3) —SO— group, (4) —SO ₂ — group, (5) —NR ^11-1B — group, (6 ) ^{Represents a} carbonyl group, (7) —NR ^11-1B SO ₂ — group, (8) carbonylamino group, or (9) aminocarbonyl group,
R ^11-1B represents (1) a hydrogen atom, (2) a C1-10 alkyl group, or (3) a C2-10 acyl group,
W ^2B represents (1) a single bond, or (2) a C1-8 alkyl group optionally substituted with a C1-4 alkyl group, a halogen atom, or a hydroxyl group,
E ^2B represents (1) a U ^1B -U ^2B -U ^3B group, or (2) a ring 4 ^B group,
U ^1B is (1) a C1-4 alkylene group, (2) a C2-4 alkenylene group, (3) a C2-4 alkynylene group, (4) -ring 3 ^B -group, (5) C1-4 alkylene group- ring ^{3 B} - represents a group, - group, (6) C2-4 alkenylene group - ring ^{3 B} - group, or (7) C2-4 alkynylene group, - ring ^{3 B}
U ^2B represents (1) a single bond, (2) —CH ₂ — group, (3) —CHOH— group, (4) —O— group, (5) —S— group, (6) —SO— group. , (7) —SO ₂ — group, (8) —NR ^12B — group, (9) carbonyl group, (10) —NR ^12B SO ₂ — group, (11) carbonylamino group, or (12) aminocarbonyl group Represents
R ^12B represents (1) a hydrogen atom, (2) a C1-10 alkyl group, or (3) a C2-10 acyl group,
U ^3B is, (1) C1-10 alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, may be substituted with 1 to 3 substituents selected from alkylthio groups, and ^NR 13B ^{R 14B} group C1~8 C2-8 which may be substituted with 1 to 3 substituents selected from alkyl group, (2) C1-10 alkyl group, halogen atom, hydroxyl group, alkoxy group, alkylthio group, and —NR ^13B R ^14B group C2-8 which may be substituted with 1 to 3 substituents selected from an alkenyl group, (3) a C1-10 alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, an alkylthio group, and a —NR ^13B R ^14B group An alkynyl group, (4) a C1-8 alkyl group substituted with a ring 4 ^B group, or (5) a ring 4 ^B group,
R ^13B and R ^14B each independently represent (1) a hydrogen atom, or (2) a C1-10 alkyl group,
Ring 1 ^B , Ring 2 ^B , Ring 3 ^B , or Ring 4 ^B may be substituted with 1 to 5 R ^B ,
R ^B is, (1) C1-10 alkyl, (2) C2~10 alkenyl group, (3) C2~10 alkynyl group, (4) C1-10 alkoxy, (5) C1-10 alkylthio group, ( 6) halogen atom, (7) hydroxyl group, (8) nitro group, (9) -NR ^15B R ^16B group, (10) C1-10 alkyl group substituted with C1-10 alkoxy group, (11) 1-3 number of C1~10 alkyl group substituted with a halogen atom, (12) 1-3 C1~10 alkyl group substituted with substituted C1~10 alkoxy group with a halogen atom, ^{(13) -NR 15B} R ^16B C1-10 alkyl group substituted with a group, (14) the ring ^{5 B} group, (15) -O- ring ^{5 B} group, (16) the ring ^{5 B} C1-10 alkyl group substituted with a group, (17 ) substituted by the ring ^{5 B} group C2~10 Alkenyl group, (18) the ring ^{5 B C2~10} alkynyl group substituted with a group, (19) the ring ^{5 B} C1-10 alkoxy group substituted with a group, is substituted with (20) -O- ring ^{5 B} group C1-10 alkyl group, (21) COOR ^17B group, (22) C1-10 alkoxy group substituted with 1-4 halogen atoms, (23) formyl group, (24) C1 substituted with hydroxy group Represents a 10 alkyl group, or (25) a C2-10 acyl group,
R ^{15B, R 16B} and ^{R 17B,} are each independently, represent (1) hydrogen atom or (2) C1-10 alkyl,
Ring 5 ^B may be substituted with 1-3 substituents selected from (1) to (9);
(1) C1-10 alkyl group, (2) C2-10 alkenyl group, (3) C2-10 alkynyl group, (4) C1-10 alkoxy group, (5) C1-10 substituted with C1-10 alkoxy group 10 alkyl groups, (6) halogen atoms, (7) hydroxyl groups, (8) C1-10 alkyl groups substituted with 1 to 3 halogen atoms, (9) C1 substituted with 1 to 3 halogen atoms A C1-10 alkyl group substituted with 10 alkoxy groups;
Ring 1 ^B , Ring 2 ^B , Ring 3 ^B , Ring 4 ^B , and Ring 5 ^B each independently represent (1) a carbocycle or (2) a heterocycle. Or a salt thereof, an N-oxide thereof, a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof. EP2 agonist is (1) (5Z) -7-{(1R, 2R, 3R, 5R) -2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybut-1- Enyl] -5-chloro-3-hydroxycyclopentyl} hept-5-enoic acid, and (2) (5Z) -7-{(1R, 2R, 3R, 5R) -2-[(1E, 4S) -4 -(1-allylcyclobutyl) -4-hydroxybut-1-enyl] -5-chloro-3-hydroxycyclopentyl} hept-5-enoic acid, its salt, its solvate or their The agent according to claim 10, which is a prodrug or a cyclodextrin inclusion compound thereof. The EP2 agonist is (1) 2-[(2-{(2R) -2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybut-1-enyl] -5-oxo. Pyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, (2) 2-[(2-{(2R) -2-[(3,5-dichlorophenoxy) methyl]- 5-oxopyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, (3) 2-{[2-((5R) -2-oxo-5-{[3-tri Fluoromethoxy) phenoxy] methyl} pyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid, and (4) 2-[(2-{(2R) -2-[(heptylamino) ) Methyl] -5-oxopyrrolidine 1-yl} ethyl) thio] -1,3-thiazole-4-carboxylic acid, a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin inclusion compound thereof 11. The agent according to 11. The agent according to claim 9, wherein the EP2 agonist is limaprost. The EP4 agonist is (1) 11α, 15α-dihydroxy-9-oxo-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-3,7-dithiaprost-13E-enoic acid, (2 ) (11α, 13E, 15α) -9-oxo-11,15-dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost-13-enoic acid methyl ester And (3) (15α, 13E) -9-oxo-15-hydroxy-16- (4-fluorophenyl) -17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid Or a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin inclusion compound thereof. Item 3. The agent according to Item 2. EP1 antagonist is (1) 6-[(2S, 3S) -3- (4-chloro-2-methylphenylsulfonylaminomethyl) bicyclo [2.2.2] octan-2-yl] -5Z-hexenoic acid And (2) a compound selected from 4- [2- (N-isobutyl-2-furanylsulfonylamino) -5-trifluoromethylphenoxymethyl] cinnamic acid, its salt, its solvate or their pro The agent according to claim 2, which is a drug or a cyclodextrin inclusion compound thereof. EP3 antagonist is 2- (2-((4-methyl-2- (naphthalen-1-yl) pentanoyl) amino) -4- (pyrazol-1-ylmethyl) benzyl) benzoic acid, salt thereof, solvate thereof The agent according to claim 2, which is a prodrug or a cyclodextrin inclusion compound thereof. A nerve regeneration and / or neuroprotective agent for inner ear nerves comprising at least one compound selected from EP2 agonists, EP4 agonists, EP1 antagonists and EP3 antagonists. The EP2 agonist is (1) (5Z) -7-{(1R, 2R, 3R, 5R) -2-[(1E, 4S) -4- (1-ethylcyclobutyl) -4-hydroxybut-1- Enyl] -5-chloro-3-hydroxycyclopentyl} hept-5-enoic acid, (2) 2-[(2-{(2R) -2-[(3,5-dichlorophenoxy) methyl] -5-oxo Pyrrolidin-1-yl} ethyl) sulfanyl] -1,3-thiazole-4-carboxylic acid and (3) a compound selected from limaprost, a salt thereof, a solvate thereof or a prodrug thereof, or a cyclo thereof The agent according to claim 18, which is a dextrin inclusion compound.

Images