JP2021151996A - Pharmaceutical composition containing phenylacetic acid compound - Google Patents

Abstract

To provide a pharmaceutical composition useful for the treatment of DP receptor-mediated diseases.SOLUTION: A pharmaceutical composition containing a compound of general formula (I-d) or a pharmaceutically acceptable salt thereof is useful as an agent for treatment of DP receptor-mediated diseases, or an agent for prevention and/or treatment of a disease mediated by a DP receptor at the center of the brain, namely the sleep arousal disorder, among the DP receptor-mediated diseases. The compound is, for example, (4-chloro-3-{[4-(2-cyclohexyl ethoxy)-2,6-dimethyl benzene-1-carbothioyl]amino}phenyl) acetic acid or the like.SELECTED DRAWING: None

Description

（式中、全ての記号は後記と同じ意味を表す。）で示される化合物またはその薬学的に許容される塩（以下、本開示化合物という。）を有効成分として含有する医薬組成物に関する。 The present disclosure relates to a pharmaceutical composition containing a compound having DP receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient. For details, see the general formula (I).

(In the formula, all symbols have the same meanings as described below.) The present invention relates to a pharmaceutical composition containing the compound represented by (hereinafter, the same as described below) or a pharmaceutically acceptable salt thereof (hereinafter referred to as the disclosed compound) as an active ingredient.

Prostaglandin D2 (abbreviated as PGD2) is known as a metabolite of arachidonic acid cascade and is involved in allergic diseases, sleep, hormone secretion, pain, platelet aggregation, glycogen metabolism, tonometry, etc. It is known that (Non-Patent Documents 1 to 11). It is known that DP receptors and CRTH2 receptors are present as PGD2 receptors, among which DP receptors are present in the brain, especially in the subliminal space of the rostral ventral part of the basal forebrain. Is known to be associated with the sleep-inducing action of PGD2 (Non-Patent Document 12). That is, in order to inhibit the sleep-inducing action of PGD2 and make it a therapeutic drug for sleep-wake disorders, it is necessary to have a drug having not only DP antagonistic activity but also transferability to the central nervous system.

（式中、Ｒ^１Ａは、（１）水素原子、（２）Ｃ１〜４アルキル基などを表し、Ｅ^Ａは、−Ｃ（＝Ｏ）−などを表し、Ｒ^２Ａは、（１）ハロゲン原子、（２）Ｃ１〜６アルキル基などを表し、Ｒ^３Ａは、（１）ハロゲン原子、（２）Ｃ１〜６アルキル基などを表し、Ｗ^Ａは、Ｃ５〜１２の単環もしくは二環の炭素環、または５〜１２員の単環もしくは二環の複素環を表し、Ｒ^４Ａは、（１）水素原子、（２）Ｃ１〜６アルキル基などを表し、Ｒ^５Ａは、Ｃ１〜６アルキル基などを表し、（１）Ｇ^Ａは、（１）窒素原子、酸素原子および硫黄原子から選ばれる０〜２個のヘテロ原子を含むＣ１〜６のアルキレン基などを表し、Ｊ^Ａは、Ｃ５〜１２の単環もしくは二環の炭素環、または５〜１２員の単環もしくは二環の複素環を表し、ｍＡは、０または１〜４の整数を表し、ｎＡは、０または１〜４の整数を表し、ｉＡは、０または１〜１１の整数を表す。） On the other hand, Patent Document 1 describes that the compound represented by the following general formula (A) specifically binds to and antagonizes the DP receptor.

^{(Wherein, R 1A} is (1) a hydrogen atom, and (2) C1 -4 alkyl group, ^{E A} is, -C (= O) - represents ^{like, R 2A} is (1) a halogen atom , (2) Cl to 6 represent an alkyl ^{group, R 3A} is (1) halogen atom, (2) Cl to 6 represent an alkyl group, ^{W a} is a carbon monocyclic or bicyclic C5~12 A ring or a 5- to 12-membered monocyclic or bicyclic heterocycle is represented, R ^4A represents (1) a hydrogen atom, (2) a C1 to 6 alkyl group, and the like, and R ^5A represents a C1 to 6 alkyl group. It represents like, (1) ^{G a} represents and alkylene group C1~6 containing 0-2 heteroatoms selected from (1) a nitrogen atom, an oxygen atom and a sulfur atom, ^{J a} is C5～ Represents 12 monocyclic or bicyclic carbocycles, or 5-12 membered monocyclic or bicyclic heterocycles, mA represents an integer of 0 or 1-4, and nA represents 0 or 1-4. Represents an atom, iA represents an atom of 0 or 1-11.)

（式中、Ｒ^１Ｂは、（１）水素原子、（２）Ｃ１〜４アルキル基などを表し、Ｅ^Ｂは、−ＣＯ−基などを表し、Ｒ^２Ｂは、（１）ハロゲン原子、（２）Ｃ１〜６アルキル基などを表し、Ｒ^３Ｂは、（１）ハロゲン原子、（２）Ｃ１〜６アルキル基などを表し、Ｒ^４Ｂは、（１）水素原子、（２）Ｃ１〜６アルキル基などを表し、Ｒ^５Bは、Ｃ１〜６アルキル基などを表し、Ｗ^Ｂは、Ｃ５〜１２の単環もしくは二環の炭素環、または５〜１２員の単環もしくは二環の複素環を表し、Ｇ^Ｂは、（１）窒素原子、酸素原子および硫黄原子から選ばれる０〜２個のヘテロ原子を含むＣ１〜６のアルキレン基などを表し、Ｊ^Ｂは、Ｃ５〜１２の単環もしくは二環の炭素環、または５〜１２員の単環もしくは二環の複素環を表し、ｍＢは、０または１〜４の整数を表し、ｎＢは、０または１〜４の整数を表し、ｉＢは、０または１〜１１の整数を表し、Ｒ^１２ＢおよびＲ^１３Ｂは、それぞれ独立して（１）酸化されていてもよいＣ１〜４アルキル基、（２）水素原子などを表す。）
しかし、これら先行技術文献には、中枢への移行性について何ら記載も示唆もされていない。 Further, Patent Document 2 describes that the compound represented by the following general formula (B) is a compound that specifically binds to and antagonizes the DP receptor.

^{(Wherein, R 1B} is (1) a hydrogen atom, and (2) C1 -4 alkyl group, ^{E B} represents the like -CO- ^{group, R 2B} is (1) halogen atom, (2 ) C1-6 alkyl groups and the like, R ^3B represents (1) halogen atoms, (2) C1-6 alkyl groups and the like, R ^4B represents (1) hydrogen atoms, (2) C1-6 alkyl groups and the like. represents like, ^{R 5B} represents such C1~6 alkyl group, ^{W B} represents a monocyclic or bicyclic heterocyclic monocyclic or bicyclic carbon ring of C5~12 or 5- to 12-membered, , ^{G B} is (1) a nitrogen atom, such as alkylene group C1~6 containing 0-2 hetero atoms selected from oxygen atom and sulfur atom, ^{J B} is mono- or bicyclic of C5~12 The carbocycle of the ring, or a 5- to 12-membered monocyclic or bicyclic heterocycle, mB represents an integer of 0 or 1-4, nB represents an integer of 0 or 1-4, and iB represents an integer of 0 or 1-4. , 0 or an integer of 1 to 11, and R ^12B and R ^13B represent (1) C1 to 4 alkyl groups which may be independently oxidized, (2) a hydrogen atom, and the like.)
However, these prior art documents do not describe or suggest any transition to the central nervous system.

International Publication No. 2003/078409 Pamphlet International Publication No. 2005/028455 Pamphlet

The New England Journal of Medicine (The NEW ENGLAND JOURNAL of MEDICINE), Vol. 303, 1400-1404, 1980 American Review of Respiratory Disease, Vol. 128,597-602,1983 The Journal of Allergy and Clinical Immunology, Vol. 88,33-42,1991 Archives of Otorhinolaryngology-Head and Neck Surgery, Vol. 113,179-83,1987 The Journal of Allergy and Clinical Immunology, Vol. 82,869-77,1988 The Journal of Immunology, Vol. 146,671-676, 1991 The Journal of Allergy and Clinical Immunology, Vol. 83,905-912,1989 The New England Journal of Medicine (The NEW ENGLAND JOURNAL of MEDICINE), Vol. 315,800-804,1986 American Review of Respiratory Disease, Vol. 142, 126-132, 1990 The Journal of Allergy and Clinical Immunology, Vol. 87,540-548,1991 The Journal of Allergy and Clinical Immunology, Vol. 78,458-461,1986 Proceedings of the National Academy of Sciences of the United States of America, Vol. 98,11674-11679,2001

An object of the present disclosure is to provide a pharmaceutical composition containing a prophylactic and / or therapeutic agent for a disease caused by activation of DP receptors, particularly a compound useful as a therapeutic agent for sleep-wake disorders.

（式中、Ｒ^１は、水素原子、Ｃ１−４アルキル、またはベンジル基を表し、
Ｒ^２、Ｒ^３、およびＲ^４は、それぞれ独立して、（１）ハロゲン原子、（２）ハロゲン原子で置換されていてもよいＣ１−４アルキル、または（３）ハロゲン原子で置換されていてもよいＣ１−４アルコキシ基を表し、
Ｒ^２またはＲ^４がそれぞれ複数存在する場合は、それぞれ同じでも異なっていてもよく、
Ｊは、結合手、−Ｏ−、または−Ｓ−を表し、
Ｌは、結合手、Ｃ１−６アルキレン、Ｃ２−６アルケニレン、またはＣ２−６アルキニレン基を表し、
Ｒ^５は、水素原子、Ｃ３−１０炭素環、または３−１０員ヘテロ環を表し、
Ｒ^５中のＣ３−１０炭素環および３−１０員ヘテロ環は、１−６個のＲ^７で置換されていてもよく、
但し、Ｌが結合手の場合、Ｒ^５は水素原子ではなく、
Ｒ^７は、（１）ハロゲン原子、（２）ハロゲン原子で置換されていてもよいＣ１−４アルキル、または（３）ハロゲン原子で置換されていてもよいＣ１−４アルコキシ基を表し、
Ｒ^７が複数存在する場合は、それぞれ同じでも異なっていてもよく、
Ｑは、酸素原子、または硫黄原子を表し、
但し、Ｑが酸素原子の場合、（１）ＬがＣ１−６アルキレン、Ｃ２−６アルケニレン、またはＣ２−６アルキニレン基であり、且つＲ^５はＣ３−８単環炭素環または３−８員単環ヘテロ環、または（２）Ｌは結合手であり、且つＲ^５はＣ３−１０炭素環または３−１０員ヘテロ環であり
Ｒ^６は、水素原子またはＣ１−４アルキル基を表し、
Ｒ^１１は、水素原子、ハロゲン原子、またはハロゲン原子で置換されていてもよいＣ１−４アルキル基を表し、
Ｒ^１２は、水素原子、ハロゲン原子、またはハロゲン原子で置換されていてもよいＣ１−４アルキル基を表し、
Ｒ^１１とＲ^１２は、それらが結合している炭素原子と一緒になってＣ３−６飽和炭素環を形成してもよく、
ｎは、０−４の整数を表し、
ｍは、０−３の整数を表す。）で示される化合物、またはその薬学的に許容される塩を含有してなる医薬組成物、
〔２〕 一般式（Ｉ）で示される化合物が、一般式（Ｉ−ｄ）：

（式中、すべての記号は前記〔１〕と同じ意味を表す。）で示される化合物である、前記〔１〕記載の医薬組成物、
〔３〕 一般式（Ｉ）で示される化合物が、一般式（Ｉ−１）：

（式中、Ｒ^５１はＣ３−１０炭素環、または３−１０員ヘテロ環を表し、Ｊ^１は結合手、または−Ｏ−を表し、その他の記号は前記〔１〕記載の記号と同じ意味を表す。）で示される化合物である、前記〔１〕または〔２〕記載の医薬組成物、
〔４〕 Ｒ^５１が、Ｃ３−８単環炭素環または３−８員単環ヘテロ環である、前記〔３〕記載の医薬組成物、
〔５〕 Ｒ^５１が、３−８員飽和単環ヘテロ環である、前記〔３〕記載の医薬組成物、
〔６〕 Ｑが酸素原子であり、Ｒ^５がＣ３−８単環炭素環または３−８員単環ヘテロ環である、前記〔１〕記載の医薬組成物、
〔７〕 一般式（Ｉ）で示される化合物が、（１）（４−クロロ−３−｛４−［２−（オキサン−２−イル）エトキシ］−２−（トリフルオロメチル）ベンズアミド｝フェニル）酢酸、
（２）｛４−クロロ−３−［４−（２−シクロヘキシルエトキシ）−２−（トリフルオロメチル）ベンズアミド］フェニル｝酢酸、
（３）｛４−クロロ−３−［４−（２−フェニルエトキシ）−２−（トリフルオロメチル）ベンズアミド］フェニル｝酢酸、
（４）｛４−クロロ−３−［４−（２−シクロプロピルエトキシ）−２−（トリフルオロメチル）ベンズアミド］フェニル｝酢酸、
（５）（４−クロロ−３−｛２，６−ジメチル−４−［２−（オキサン−２−イル）エトキシ］ベンズアミド｝フェニル）酢酸、
（６）｛４−クロロ−３−［４−（２−シクロヘキシルエトキシ）−２，６−ジメチルベンズアミド］フェニル｝酢酸、
（７）｛４−クロロ−３−［４−（２−シクロプロピルエトキシ）−２，６−ジメチルベンズアミド］フェニル｝酢酸、
（８）（３−｛４−［（２，３−ジヒドロ−１Ｈ−インデン−２−イル）オキシ］−２，６−ジメチルベンズアミド｝−４−フルオロフェニル）酢酸、
（９）｛４−クロロ−３−［４−（３−シクロヘキシルプロプ−１−イン−１−イル）−２，６−ジメチルベンズアミド］フェニル｝酢酸、
（１０）（４−クロロ−３−｛４−［（１Ｅ）−３−シクロヘキシルプロプ−１−エン−１−イル］−２，６−ジメチルベンズアミド｝フェニル）酢酸、
（１１）（４−クロロ−３−｛［４−（２−シクロヘキシルエトキシ）−２，６−ジメチルベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（１２）［４−クロロ−３−（｛４−［２−（オキサン−２−イル）エトキシ］−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル｝アミノ）フェニル］酢酸、
（１３）（４−クロロ−３−｛［４−（２−シクロヘキシルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（１４）（４−クロロ−３−｛［４−（２−フェニルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（１５）（４−クロロ−３−｛［４−（２−シクロプロピルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（１６）［４−クロロ−３−（｛２，６−ジメチル−４−［２−（オキサン−２−イル）エトキシ］ベンゼン−１−カルボチオイル｝アミノ）フェニル］酢酸、
（１７）｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｒ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝酢酸、
（１８）｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｓ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝酢酸、
（１９）２−｛３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］−４−フルオロフェニル｝プロパン酸、
（２０）１−｛３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］−４−フルオロフェニル｝シクロプロパンカルボン酸、
（２１）２−｛４−クロロ−３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］フェニル｝−２−メチルプロパン酸、
（２２）２−｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｓ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝−２−メチルプロパン酸、
（２３）２−｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｒ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝−２−メチルプロパン酸、
（２４）２−｛３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］−４−フルオロフェニル｝−２−メチルプロパン酸、または、
（２５）２−（４−クロロ−３−｛［（２，６−ジメチル−４−｛２−［（２Ｒ）−テトラヒドロ−２Ｈ−ピラン−２−イル］エトキシ｝フェニル）カルボチオイル］アミノ｝フェニル）プロパン酸である、前記〔１〕記載の医薬組成物、
〔８〕一般式（Ｉ-ｄ）で示される化合物が、
（１）（４−クロロ−３−｛［４−（２−シクロヘキシルエトキシ）−２，６−ジメチルベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（２）［４−クロロ−３−（｛４−［２−（オキサン−２−イル）エトキシ］−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル｝アミノ）フェニル］酢酸、
（３）（４−クロロ−３−｛［４−（２−シクロヘキシルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（４）（４−クロロ−３−｛［４−（２−フェニルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（５）（４−クロロ−３−｛［４−（２−シクロプロピルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（６）［４−クロロ−３−（｛２，６−ジメチル−４−［２−（オキサン−２−イル）エトキシ］ベンゼン−１−カルボチオイル｝アミノ）フェニル］酢酸、
（７）｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｒ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝酢酸、
（８）｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｓ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝酢酸、
（９）２−｛３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］−４−フルオロフェニル｝プロパン酸、
（１０）１−｛３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］−４−フルオロフェニル｝シクロプロパンカルボン酸、
（１１）２−｛４−クロロ−３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］フェニル｝−２−メチルプロパン酸、
（１２）２−｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｓ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝−２−メチルプロパン酸、
（１３）２−｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｒ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝−２−メチルプロパン酸、
（１４）２−｛３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］−４−フルオロフェニル｝−２−メチルプロパン酸、または、
（１５）２−（４−クロロ−３−｛［（２，６−ジメチル−４−｛２−［（２Ｒ）−テトラヒドロ−２Ｈ−ピラン−２−イル］エトキシ｝フェニル）カルボチオイル］アミノ｝フェニル）プロパン酸である、前記〔２〕記載の医薬組成物、
〔９〕 ＤＰ受容体拮抗剤である、前記〔１〕〜〔８〕のいずれかに記載の医薬組成物、
〔１０〕 ＤＰ受容体介在性疾患の予防および／または治療剤である、前記〔１〕〜〔９〕のいずれかに記載の医薬組成物、
〔１１〕 ＤＰ受容体介在性疾患が、アレルギー性疾患、炎症、自己免疫疾患、癌、神経疾患、筋疾患、睡眠覚醒障害、虚血再灌流障害、ウイルス感染、ストレス疾患、肝障害または血小板凝集である、前記〔１０〕記載の医薬組成物、
〔１２〕 ＤＰ受容体介在性疾患が、睡眠覚醒障害である、前記〔１１〕記載の医薬組成物、
〔１３〕 睡眠覚醒障害が、過眠症、不眠症、睡眠時無呼吸症候群の残遺眠気、概日リズム睡眠−覚醒障害、神経変性疾患に随伴する過眠症状、精神疾患に随伴する過眠症状、昼間の病的な眠気を基礎症状とする疾患である、前記〔１２〕記載の医薬組成物、
〔１４〕 前記〔１〕記載の一般式（Ｉ）で示される化合物、またはその薬学的に許容される塩を含有するＤＰ受容体介在性疾患の予防および／または治療剤、
〔１５〕 前記〔２〕記載の一般式（Ｉ-ｄ）で示される化合物、またはその薬学的に許容される塩を含有するＤＰ受容体介在性疾患の予防および／または治療剤、
〔１６〕 一般式（Ｉ-ｄ）で示される化合物が、
（１）（４−クロロ−３−｛［４−（２−シクロヘキシルエトキシ）−２，６−ジメチルベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（２）［４−クロロ−３−（｛４−［２−（オキサン−２−イル）エトキシ］−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル｝アミノ）フェニル］酢酸、
（３）（４−クロロ−３−｛［４−（２−シクロヘキシルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（４）（４−クロロ−３−｛［４−（２−フェニルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（５）（４−クロロ−３−｛［４−（２−シクロプロピルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸、
（６）［４−クロロ−３−（｛２，６−ジメチル−４−［２−（オキサン−２−イル）エトキシ］ベンゼン−１−カルボチオイル｝アミノ）フェニル］酢酸、
（７）｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｒ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝酢酸、
（８）｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｓ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝酢酸、
（９）２−｛３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］−４−フルオロフェニル｝プロパン酸、
（１０）１−｛３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］−４−フルオロフェニル｝シクロプロパンカルボン酸、
（１１）２−｛４−クロロ−３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］フェニル｝−２−メチルプロパン酸、
（１２）２−｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｓ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝−２−メチルプロパン酸、
（１３）２−｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｒ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝−２−メチルプロパン酸、
（１４）２−｛３−［（｛２，６−ジメチル−４−［２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エトキシ］フェニル｝カルボチオイル）アミノ］−４−フルオロフェニル｝−２−メチルプロパン酸、または、
（１５）２−（４−クロロ−３−｛［（２，６−ジメチル−４−｛２−［（２Ｒ）−テトラヒドロ−２Ｈ−ピラン−２−イル］エトキシ｝フェニル）カルボチオイル］アミノ｝フェニル）プロパン酸である、前記〔１５〕記載の剤、
〔１７〕 ＤＰ受容体介在性疾患が、アレルギー性疾患、炎症、自己免疫疾患、癌、神経疾患、筋疾患、睡眠覚醒障害、虚血再灌流障害、ウイルス感染、ストレス疾患、肝障害または血小板凝集である、前記〔１４〕〜〔１６〕のいずれかに記載の剤、
〔１８〕 ＤＰ受容体介在性疾患が、睡眠覚醒障害である、前記〔１７〕記載の剤、
〔１９〕 睡眠覚醒障害が、過眠症、不眠症、睡眠時無呼吸症候群の残遺眠気、概日リズム睡眠−覚醒障害、神経変性疾患に随伴する過眠症状、精神疾患に随伴する過眠症状、昼間の病的な眠気を基礎症状とする疾患である、前記〔１８〕記載の剤、
〔２０〕 ｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｒ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝酢酸またはその薬学的に許容される塩を含有してなる医薬組成物、
〔２１〕 （４−クロロ−３−｛４−［（１Ｅ）−３−シクロヘキシルプロプ−１−エン−１−イル］−２，６−ジメチルベンズアミド｝フェニル）酢酸またはその薬学的に許容される塩を含有してなる医薬組成物、
〔２２〕 ＤＰ受容体介在性疾患の予防および／または治療剤である、前記〔２０〕または〔２１〕記載の医薬組成物、
〔２３〕 ＤＰ受容体介在性疾患が、アレルギー性疾患、炎症、自己免疫疾患、癌、神経疾患、筋疾患、睡眠覚醒障害、虚血再灌流障害、ウイルス感染、ストレス疾患、肝障害または血小板凝集である、前記〔２２〕記載の医薬組成物、
〔２４〕 ＤＰ受容体介在性疾患が、睡眠覚醒障害である、前記〔２３〕記載の医薬組成物、
〔２５〕 睡眠覚醒障害が、過眠症、不眠症、睡眠時無呼吸症候群の残遺眠気、概日リズム睡眠−覚醒障害、神経変性疾患に随伴する過眠症状、精神疾患に随伴する過眠症状、昼間の病的な眠気を基礎症状とする疾患である、前記〔２４〕記載の医薬組成物、
〔２６〕 ｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｒ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝酢酸またはその薬学的に許容される塩を含有するＤＰ受容体介在性疾患の予防および／または治療剤、
〔２７〕 （４−クロロ−３−｛４−［（１Ｅ）−３−シクロヘキシルプロプ−１−エン−１−イル］−２，６−ジメチルベンズアミド｝フェニル）酢酸またはその薬学的に許容される塩を含有するＤＰ受容体介在性疾患の予防および／または治療剤、
〔２８〕 ＤＰ受容体介在性疾患が、アレルギー性疾患、炎症、自己免疫疾患、癌、神経疾患、筋疾患、睡眠覚醒障害、虚血再灌流障害、ウイルス感染、ストレス疾患、肝障害または血小板凝集である、前記〔２６〕または〔２７〕記載の剤、
〔２９〕 ＤＰ受容体介在性疾患が、睡眠覚醒障害である、前記〔２８〕記載の剤、
〔３０〕 睡眠覚醒障害が、過眠症、不眠症、睡眠時無呼吸症候群の残遺眠気、概日リズム睡眠−覚醒障害、神経変性疾患に随伴する過眠症状、精神疾患に随伴する過眠症状、昼間の病的な眠気を基礎症状とする疾患である、前記〔２９〕記載の剤、等に関する。 As a result of diligent studies, the present inventors have found that a pharmaceutical composition containing a compound represented by the general formula (I) described later solves the above-mentioned problems.
That is, in one aspect, the present disclosure [1] General formula (I):

(In the formula, R ¹ represents a hydrogen atom, a C1-4 alkyl, or a benzyl group.
R ² , R ³ , and R ⁴ are independently substituted with (1) a halogen atom, (2) a C1-4 alkyl optionally substituted with a halogen atom, or (3) a halogen atom. Represents a good C1-4 alkoxy group,
If there are multiple R ² or R ⁴ , they may be the same or different.
J represents a bond, -O-, or -S-
L represents a bond, C1-6 alkylene, C2-6 alkenylene, or C2-6 alquinylene group.
R ⁵ represents a hydrogen atom, a C3-10 carbocycle, or a 3-10-membered heterocycle.
C3-10 carbocyclic and 3-10 membered heterocyclic ring in R ⁵ may be substituted with 1-6 ^{R 7,}
However, when L is a bond, R ⁵ is not a hydrogen atom and is not a hydrogen atom.
R ⁷ represents (1) a halogen atom, (2) a C1-4 alkyl optionally substituted with a halogen atom, or (3) a C1-4 alkoxy group optionally substituted with a halogen atom.
If R ⁷ there is a plurality, it may be the same or different,
Q represents an oxygen atom or a sulfur atom,
However, when Q is an oxygen atom, (1) L is a C1-6 alkylene, C2-6 alkaneylene, or C2-6 alkynylene group, and R ⁵ is a C3-8 monocyclic carbocycle or a 3-8 member. ring heterocyclic or (2) L, it is a bond, and ^{R 5} is a C3-10 carbon ring or 3-10 membered heterocycle ^{R 6} represents a hydrogen atom or a C1-4 alkyl group,
R ¹¹ represents a C1-4 alkyl group optionally substituted with a hydrogen atom, a halogen atom, or a halogen atom.
R ¹² represents a C1-4 alkyl group optionally substituted with a hydrogen atom, a halogen atom, or a halogen atom.
R ¹¹ and R ¹² may be combined with the carbon atoms to which they are bonded to form a C3-6 saturated carbon ring.
n represents an integer of 0-4
m represents an integer of 0-3. ), Or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof,
[2] The compound represented by the general formula (I) is the general formula (Id):

The pharmaceutical composition according to the above [1], which is a compound represented by (all symbols in the formula have the same meaning as the above [1]).
[3] The compound represented by the general formula (I) is the general formula (I-1) :.

(In the formula, R ⁵¹ represents a C3-10 carbocycle or a 3-10-membered heterocycle, J ¹ represents a bond or −O−, and other symbols have the same meanings as those described in [1] above. The pharmaceutical composition according to the above [1] or [2], which is a compound represented by (1) or [2].
[4] The pharmaceutical composition according to the above [3], wherein ^{R 51 is a C3-8 monocyclic carbocycle or a 3-8 member monocyclic heterocycle.}
[5] The pharmaceutical composition according to [3] above, wherein ^{R 51 is a 3-8-membered saturated monocyclic heterocycle.}
[6] Q is an oxygen atom, R ⁵ is C3-8 monocyclic carbocyclic or 3-8 membered monocyclic hetero ring, wherein (1) a pharmaceutical composition according,
[7] The compound represented by the general formula (I) is (1) (4-chloro-3- {4- [2- (oxan-2-yl) ethoxy] -2- (trifluoromethyl) benzamide} phenyl. ) Acetic acid,
(2) {4-Chloro-3- [4- (2-cyclohexylethoxy) -2- (trifluoromethyl) benzamide] phenyl} acetic acid,
(3) {4-Chloro-3- [4- (2-phenylethoxy) -2- (trifluoromethyl) benzamide] phenyl} acetic acid,
(4) {4-Chloro-3- [4- (2-cyclopropylethoxy) -2- (trifluoromethyl) benzamide] phenyl} acetic acid,
(5) (4-Chloro-3- {2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzamide} phenyl) acetic acid,
(6) {4-Chloro-3- [4- (2-cyclohexylethoxy) -2,6-dimethylbenzamide] phenyl} acetic acid,
(7) {4-Chloro-3- [4- (2-cyclopropylethoxy) -2,6-dimethylbenzamide] phenyl} acetic acid,
(8) (3- {4-[(2,3-dihydro-1H-indene-2-yl) oxy] -2,6-dimethylbenzamide} -4-fluorophenyl) acetic acid,
(9) {4-Chloro-3- [4- (3-cyclohexylprop-1-in-1-yl) -2,6-dimethylbenzamide] phenyl} acetic acid,
(10) (4-Chloro-3- {4-[(1E) -3-cyclohexylprop-1-ene-1-yl] -2,6-dimethylbenzamide} phenyl) acetic acid,
(11) (4-Chloro-3-{[4- (2-cyclohexylethoxy) -2,6-dimethylbenzene-1-carbotioil] amino} phenyl) acetic acid,
(12) [4-Chloro-3-({4- [2- (oxan-2-yl) ethoxy] -2- (trifluoromethyl) benzene-1-carbotioil} amino) phenyl] acetic acid,
(13) (4-Chloro-3-{[4- (2-cyclohexylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(14) (4-Chloro-3-{[4- (2-phenylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(15) (4-Chloro-3-{[4- (2-cyclopropylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(16) [4-Chloro-3- ({2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzene-1-carbotioil} amino) phenyl] acetic acid,
(17) {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid,
(18) {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid,
(19) 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} propanoic acid,
(20) 1- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carbotioil) amino] -4-fluorophenyl} cyclopropanecarboxylic acid,
(21) 2- {4-Chloro-3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] phenyl} -2- Methylpropanoic acid,
(22) 2- {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carboti oil) amino] phenyl} -2 -Methylpropanoic acid,
(23) 2- {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} -2 -Methylpropanoic acid,
(24) 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} -2- Methylpropanoic acid, or
(25) 2- (4-Chloro-3-{[(2,6-dimethyl-4-{2-[(2R) -tetrahydro-2H-pyran-2-yl] ethoxy} phenyl) carbotie oil] amino} phenyl ) The pharmaceutical composition according to the above [1], which is propanoic acid.
[8] The compound represented by the general formula (Id) is
(1) (4-Chloro-3-{[4- (2-cyclohexylethoxy) -2,6-dimethylbenzene-1-carbotioil] amino} phenyl) acetic acid,
(2) [4-Chloro-3-({4- [2- (oxan-2-yl) ethoxy] -2- (trifluoromethyl) benzene-1-carbotioil} amino) phenyl] acetic acid,
(3) (4-Chloro-3-{[4- (2-cyclohexylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(4) (4-Chloro-3-{[4- (2-phenylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(5) (4-Chloro-3-{[4- (2-cyclopropylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(6) [4-Chloro-3- ({2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzene-1-carbotioil} amino) phenyl] acetic acid,
(7) {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid,
(8) {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid,
(9) 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} propanoic acid,
(10) 1- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} cyclopropanecarboxylic acid,
(11) 2- {4-Chloro-3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] phenyl} -2- Methylpropanoic acid,
(12) 2- {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carboti oil) amino] phenyl} -2 -Methylpropanoic acid,
(13) 2- {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carboti oil) amino] phenyl} -2 -Methylpropanoic acid,
(14) 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} -2- Methylpropanoic acid, or
(15) 2- (4-Chloro-3-{[(2,6-dimethyl-4-{2-[(2R) -tetrahydro-2H-pyran-2-yl] ethoxy} phenyl) carbotie oil] amino} phenyl ) The pharmaceutical composition according to [2] above, which is propanoic acid.
[9] The pharmaceutical composition according to any one of [1] to [8] above, which is a DP receptor antagonist.
[10] The pharmaceutical composition according to any one of [1] to [9] above, which is a prophylactic and / or therapeutic agent for DP receptor-mediated diseases.
[11] DP receptor-mediated diseases include allergic diseases, inflammation, autoimmune diseases, cancer, neurological diseases, muscle diseases, sleep-wake disorders, ischemia-reperfusion disorders, viral infections, stress disorders, liver disorders or platelet aggregation. The pharmaceutical composition according to the above [10].
[12] The pharmaceutical composition according to the above [11], wherein the DP receptor-mediated disease is a sleep-wake disorder.
[13] Sleep-wake disorders include hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep-wake disorder, hypersomnia associated with neurodegenerative diseases, and hypersomnia associated with mental illness. The pharmaceutical composition according to the above [12], which is a disease based on symptoms and daytime morbid sleep apnea.
[14] A prophylactic and / or therapeutic agent for DP receptor-mediated diseases containing the compound represented by the general formula (I) described in the above [1] or a pharmaceutically acceptable salt thereof.
[15] A prophylactic and / or therapeutic agent for DP receptor-mediated diseases containing the compound represented by the general formula (Id) described in [2] above, or a pharmaceutically acceptable salt thereof.
[16] The compound represented by the general formula (Id) is
(1) (4-Chloro-3-{[4- (2-cyclohexylethoxy) -2,6-dimethylbenzene-1-carbotioil] amino} phenyl) acetic acid,
(2) [4-Chloro-3-({4- [2- (oxan-2-yl) ethoxy] -2- (trifluoromethyl) benzene-1-carbotioil} amino) phenyl] acetic acid,
(3) (4-Chloro-3-{[4- (2-cyclohexylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(4) (4-Chloro-3-{[4- (2-phenylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(5) (4-Chloro-3-{[4- (2-cyclopropylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(6) [4-Chloro-3- ({2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzene-1-carbotioil} amino) phenyl] acetic acid,
(7) {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid,
(8) {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid,
(9) 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} propanoic acid,
(10) 1- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} cyclopropanecarboxylic acid,
(11) 2- {4-Chloro-3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] phenyl} -2- Methylpropanoic acid,
(12) 2- {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carboti oil) amino] phenyl} -2 -Methylpropanoic acid,
(13) 2- {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carboti oil) amino] phenyl} -2 -Methylpropanoic acid,
(14) 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} -2- Methylpropanoic acid, or
(15) 2- (4-Chloro-3-{[(2,6-dimethyl-4-{2-[(2R) -tetrahydro-2H-pyran-2-yl] ethoxy} phenyl) carbotie oil] amino} phenyl ) The agent according to [15] above, which is propanoic acid.
[17] DP receptor-mediated diseases include allergic diseases, inflammation, autoimmune diseases, cancer, neurological diseases, muscle diseases, sleep-wake disorders, ischemia-reperfusion disorders, viral infections, stress disorders, liver disorders or platelet aggregation. The agent according to any one of the above [14] to [16].
[18] The agent according to [17] above, wherein the DP receptor-mediated disease is sleep-wake disorder.
[19] Sleep-wake disorders include hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep-wake disorder, hypersomnia associated with neurodegenerative diseases, and hypersomnia associated with mental illness. Symptoms, the agent according to the above [18], which is a disease based on daytime morbid sleep apnea.
[20] {4-Chloro-3-[(2,6-dimethyl-4- {2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid or its pharmacy A pharmaceutical composition comprising a pharmaceutically acceptable salt,
[21] (4-Chloro-3- {4-[(1E) -3-cyclohexylprop-1-ene-1-yl] -2,6-dimethylbenzamide} phenyl) acetic acid or pharmaceutically acceptable thereof Pharmaceutical composition comprising salt,
[22] The pharmaceutical composition according to the above [20] or [21], which is a prophylactic and / or therapeutic agent for DP receptor-mediated diseases.
[23] DP receptor-mediated diseases include allergic diseases, inflammation, autoimmune diseases, cancer, neurological diseases, muscle diseases, sleep-wake disorders, ischemia-reperfusion disorders, viral infections, stress disorders, liver disorders or platelet aggregation. The pharmaceutical composition according to the above [22].
[24] The pharmaceutical composition according to the above [23], wherein the DP receptor-mediated disease is a sleep-wake disorder.
[25] Sleep-wake disorders include hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep-wake disorder, hypersomnia associated with neurodegenerative diseases, and hypersomnia associated with mental illness. The pharmaceutical composition according to the above [24], which is a disease based on symptoms and daytime morbid sleep apnea.
[26] {4-chloro-3-[(2,6-dimethyl-4- {2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid or its pharmacy Prophylactic and / or Therapeutic Agents for DP Receptor-mediated Diseases, Containing Salts Tolerable
[27] (4-Chloro-3- {4-[(1E) -3-cyclohexylprop-1-ene-1-yl] -2,6-dimethylbenzamide} phenyl) acetic acid or its pharmaceutically acceptable Prophylactic and / or therapeutic agents for salt-containing DP receptor-mediated diseases,
[28] DP receptor-mediated diseases include allergic diseases, inflammation, autoimmune diseases, cancer, neurological diseases, muscle diseases, sleep-wake disorders, ischemia-reperfusion disorders, viral infections, stress disorders, liver disorders or platelet aggregation. The agent according to the above [26] or [27],
[29] The agent according to [28] above, wherein the DP receptor-mediated disease is sleep-wake disorder.
[30] Sleep-wake disorders include hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep-wake disorder, hypersomnia associated with neurodegenerative diseases, and hypersomnia associated with mental illness. The present invention relates to the agent according to the above [29], which is a disease having a symptom, morbid sleep apnea in the daytime as a basic symptom, and the like.

Since the disclosed compound has a strong antagonistic activity against the DP receptor and also has good central migration, the pharmaceutical composition containing the disclosed compound is used for diseases caused by the activation of the DP receptor. It is useful as a prophylactic and / or therapeutic agent, especially as a therapeutic agent for sleep-wake disorders.

Hereinafter, the present disclosure will be described in detail.
In the present specification, the C1-4 alkyl group is a methyl, ethyl, propyl, butyl group, and isomers thereof.

In the present specification, the C1-4 alkoxy group is methoxy, ethoxy, propoxy, butoxy group, and isomers thereof.

In the present specification, the C1-6 alkylene group is, for example, methylene, ethylene, propylene, butylene, pentylene, hexylene group, and isomers thereof.

In the present specification, the C2-6 alkenylene group means, for example, a C2-6 alkenylene group having one or two double bonds, and specifically, ethenylene, propenylene, butenylene, butazienylene, pentenylene, pentadienylene, hexenylene. , Hexadienylene groups, and their isomers.

In the present specification, the C2-6 alkynylene group means, for example, a C2-6 alkynylene group having one or two triple bonds, and specifically, ethynylene, propynylene, butynylene, butaziinylene, pentynylene, pentadiinylene, hexynylene, and the like. Hexadinirene groups and their isomers.

In the present specification, the halogen atom is a fluorine, chlorine, bromine, and iodine atom.

In the present specification, the C3-10 carbocycle is a monocyclic or bicyclic C3-10 carbocycle, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene. , Benzene, cycloheptane, cycloheptane, cycloheptadiene, cyclooctane, cyclooctane, cyclooctadiene, cyclononane, cyclononene, cyclononadene, cyclodecane, cyclodecene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroinden , Indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene rings.

In the present specification, the 3-10-membered heterocycle is a 3-10-membered monocyclic or bicyclic heterocycle containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. Means, for example, aziridine, oxylan, thiirane, azetidine, oxetane, thietan, pyrrol, imidazole, triazole, tetrazole, pyrazole, furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, flazan, oxazole, thiadiazol, pyrrolin. , Pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isooxazolidine) ), Dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydroflazan, tetrahydroflazan, dihydrooxazole, tetrahydrooxazole (oxadiazolidine), dihydrothiazol, tetrahydrothiazol (Thiaziazolidine), dioxolane, dithiolane, pyridine, pyrazine, pyrimidine, pyridazine, pyran, thiopyran, oxazine, oxadiazine, thiazine, thiadiadin, dihydropyridine, tetrahydropyridine, piperidine, dihydropyranin, tetrahydropyran, piperazin, dihydropyrimidine, tetrahydropyramidine , Perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydropyran, tetrahydropyran, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiazine, tetrahydro Thiadin, dihydrothiasidin, tetrahydropyranidin, morpholine, thiomorpholin, oxathian, dioxane, dithian, azabicyclo [2.2.1] heptane, oxabicyclo [2.2.1] heptane, azabicyclo [3.1] .1] Heptane, Azabicyclo [2.2.2] Octane, Diazabicyclo [2.2.2] Octane, Azepi , Diazepine, Oxepin, Thiepin, Oxazepine, Oxdiazepine, Thiazepine, Thiasiazepine, Dihydroazepine, Tetrahydroazepine, Perhydroazepine, Dihydrodiazepine, Tetrahydrodiazepine, Perhydrodiazepine, Dihydrooxepin, Tetrahydrooxepin, Par Hydrooxepine, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, Dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, azabicyclo [3.2.1] octane, oxabicyclo [3.2.1] octane, Indole, Isoindole, Indridin, Benzofuran, Isobenzofuran, Benzothiophene, Isobenzothiophene, Indazole, Purine, Benzothiophene, Benzothiazole, Benzimidazole, Benzofrazan, Benzothiazol, Benzotriazol, Indolin, Isoindrin, Dihydrobenzofuran, Par Hydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydrobenzazole, perhydroindazole, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzo Thiazol, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzoimidazole, dioxaindane, benzodithiophene, azaspiro [4.4] nonan, oxazaspiro [4.4] nonan, dioxaspiro [4.4] nonan, dithianaphthalene, quinoline , Isoquinolin, quinolidine, phthalazine, pteridine, naphthylidine, quinoxaline, quinazoline, cinnoline, chromen, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinolin, perhydroisoquinolin, dihydrophthalazine, tetrahydrophthalazine, perhydrophthala Razine, dihydronaphthylidine, tetrahydronaphthylidine, perhydronaphthylidine, dihydroquinoxalin, tet Lahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathian, dihydrobenzoxazine, dihydrobenzothiazine, pyradinomorpholine, benzodioxan , Chromane, benzoditian, azaspiro [4.5] decane, thiaspiro [4.5] decane, dithiaspiro [4.5] decane, dioxaspiro [4.5] decane, and oxazaspiro [4.5] decane ring.

In the present specification, the C3-8 monocyclic carbocycles are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, benzene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclo. Octene, cyclooctane ring, and the like.

In the present specification, the C3-6 saturated carbocycle is cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

In the present specification, the 3-8 member monocyclic heterocycle is a 3-8 member monocyclic heterocycle containing 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. For example, aziridine, oxylan, thiirane, azetidine, oxetane, thietan, pyrrole, imidazole, triazole, tetrazazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, flazan, oxazole, thiazazole, pyrrolin, pyrrolidine, Imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolysin, pyrazoline, pyrazolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isooxazolidine), dihydro Thiazol, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydroflazan, tetrahydroflazan, dihydrooxazole, tetrahydrooxazole (oxadiazolidine), dihydrothiazol, tetrahydrothiazol (thiazizole) Lysine), dioxolane, dithiolane, pyridine, pyrazine, pyrimidine, pyridazine, pyran, thiopyran, oxazole, oxadiazine, thiazine, thiadiadin, dihydropyridine, tetrahydropyran, piperidine, dihydropyran, tetrahydropyran, piperazin, dihydropyrimidine, tetrahydropyranidin, perhydro Pyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydropyran, tetrahydropyran, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazine, tetrahydrooxazine, dihydrooxadiadin, tetrahydrooxadiazine, dihydrothiazine, tetrahydrothiazine, Dihydrothiasidine, tetrahydropyranidine, morpholine, thiomorpholin, oxatian, dioxane, dithian, azepine, diazepine, oxepine, thiepin, oxazepine, oxadiazepine, thiazepin, thiadiazepine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine , Tetrahydropyran , Perhydrodiazepine, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxase With pins, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothia azepine, tetrahydrothia azepine, and perhydrothia azepine rings, etc. be.

In the present specification, the 3-8-membered saturated monocyclic heterocycle refers to azidine, oxylan, thiirane, azetidine, oxetane, thietan, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, pyrazolidine, tetrahydrofuran, tetrahydropyran, tetrahydroxazole (oxazolidine). , Tetrahydroisoxazole (isooxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), tetrahydrofrazan, tetrahydroxaziazole (oxadiazolidine), tetrahydropyranizole (thiadiazolidine), dioxoran, dithiolane, piperidine, Piperazine, perhydropyrimidine, perhydropyrandazine, tetrahydropyran, tetrahydropyran, tetrahydropyran, tetrahydrooxadiadin, tetrahydrothiazine, tetrahydrothiasidine, morpholin, thiomorpholin, oxatian, dioxane, dithian, perhydroazepine, par Tetrahydropyran, perhydrooxepin, perhydrothiepine, perhydrooxazepine, perhydrooxadizepine, perhydrothiazepine, and perhydrothia azepine rings.

は紙面の向こう側（すなわちα−配置）に結合していることを表し、

は紙面の手前側（すなわちβ−配置）に結合していることを表し、

はα−配置、β−配置、またはそれらの任意の割合の混合物であることを表す。 In this specification,

Indicates that it is connected to the other side of the paper (that is, α-arrangement).

Indicates that it is connected to the front side of the paper (that is, β-arrangement).

Represents an α-configuration, a β-configuration, or a mixture thereof in any proportion.

（式中、Ｌ^１は、Ｃ１−６アルキレン、Ｃ２−６アルケニレン、またはＣ２−６アルキニレン基を表し、Ｒ^５２は、Ｃ３−８単環炭素環または３−８員単環ヘテロ環を表し、その他の記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩であり、好ましい別の態様としては、一般式（Ｉ−ｂ）：

（式中、すべての記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩であり、特に好ましい態様としては、一般式（Ｉ−ｃ−０）：

（式中、Ｒ^１ｃは、水素原子またはメチル基であり、Ｒ^２ｃは、フッ素原子または塩素原子であり、Ｒ^３ｃは、メチル基、またはトリフルオロメチル基であり、Ｒ^４ｃは、水素原子、メチル基、またはトリフルオロメチル基であり、−Ｌ^ｃ−Ｊ^ｃ−が−Ｏ−の場合、Ｒ^５４は、

であり、または、−Ｌ^ｃ−Ｊ^ｃ−が、

の場合、Ｒ^５４は、

であり、その他の記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩である。 Among the compounds represented by the general formula (I), a preferred embodiment is, for example,
General formula (I-a):

(In the formula, L ¹ represents a C1-6 alkylene, C2-6 alkenylene, or C2-6 alquinylene group, and R ⁵² represents a C3-8 monocyclic carbocycle or a 3-8 member monocyclic heterocycle. Other symbols represent the same meanings as described above), and pharmaceutically acceptable salts thereof. In another preferred embodiment, the general formula (Ib):

(In the formula, all symbols have the same meanings as described above.) A compound represented by the above, and a pharmaceutically acceptable salt thereof.

(In the formula, R ^1c is a hydrogen atom or a methyl group, R ^2c is a fluorine atom or a chlorine atom, R ^3c is a methyl group or a trifluoromethyl group, and R ^4c is a hydrogen atom. If it is a methyl group or a trifluoromethyl group and -L ^c- J ^c- is -O-, then R ⁵⁴ is

Or -L ^c -J ^c- ,

In the case of, R ⁵⁴

And the other symbols have the same meanings as described above. ), And a pharmaceutically acceptable salt thereof.

（式中、すべての記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩である。 As another particularly preferable embodiment, the general formula (Ic):

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

（式中、すべての記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩である。より好ましい態様としては、一般式（Ｉ−１）：

（式中、すべての記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩であり、さらに好ましい態様としては、一般式（Ｉ−２−０）：

（式中、すべての記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩であり、さらに好ましい別の態様としては、一般式（Ｉ−２）：

（式中、すべての記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩である。最も好ましい態様としては、一般式（Ｉ−３−０）:

（式中、Ｒ^５３は３−８員飽和単環ヘテロ環であり、その他の記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩である。最も好ましい別の態様としては、一般式（Ｉ−３）:

（式中、すべての記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩である。
または、最も好ましい態様は、一般式（Ｉ−４）:

（式中、すべての記号は前記と同じ意味を表す。）で示される化合物、およびその薬学的に許容される塩である。 In the general formula (I), as another preferable embodiment, the general formula (Id):

(In the formula, all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof. In a more preferable embodiment, the general formula (I-1):

(In the formula, all symbols have the same meanings as described above.) A compound represented by the above, and a pharmaceutically acceptable salt thereof, and more preferably, the general formula (I-2-0):

(In the formula, all symbols represent the same meanings as described above.) A compound represented by the above, and a pharmaceutically acceptable salt thereof, and still more preferably, the general formula (I-2):

(In the formula, all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof. In the most preferable embodiment, the general formula (I-3-0):

(In the formula, R ⁵³ is a 3-8 member saturated monocyclic heterocycle, and other symbols have the same meanings as described above), and a pharmaceutically acceptable salt thereof. In another most preferred embodiment, the general formula (I-3):

(In the formula, all symbols have the same meanings as described above), and pharmaceutically acceptable salts thereof.
Alternatively, the most preferred embodiment is the general formula (I-4) :.

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

General formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) ), or (I-3) in any of the, preferably as R ¹ is a hydrogen atom or a C1-4 alkyl group, more preferably a hydrogen atom or a methyl group, particularly preferably a hydrogen atom.

In any of the general formulas (I-c-0), (I-c), or (I-4), R ^1c is preferably a hydrogen atom.

General formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) ) Or (I-3), R ² is preferably a halogen atom, more preferably a fluorine atom or a chlorine atom, and particularly preferably a chlorine atom.

In any of the general formulas (I-c-0), (I-c), or (I-4), R ^2c is preferably a chlorine atom.

General formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) ), or (I-3) in any preferred as R ³ is optionally substituted C1-4 alkyl group with a halogen atom, particularly preferably a methyl group or a trifluoromethyl group.

General formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) ), or (I-3) in any of the, preferably as R ⁴ is optionally substituted C1-4 alkyl group with a halogen atom, more preferably a methyl group or a trifluoromethyl group, especially It is preferably a methyl group.

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

In any of the general formulas (I), (Ia), (Ib), or (Id), J is preferably a bond or -O-, and more preferably -O-. be.

Formula (I-1), (I -2-0), (I-2), (I-3-0), or (I-3) in any of the, preferably by -O- as ^{J 1} be.

In the general formula (I) or (I-d), preferably as ^{R 5} is C3-10 carbocyclic or 3-10 membered heterocyclic ring, and more preferably, C3-8 monocyclic carbocyclic or 3-8 membered It is a monocyclic heterocycle, more preferably a 3-8 member saturated monocyclic heterocycle. Alternatively, in the general formula (I) or (I-d), preferably as R ⁵ is cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene or tetrahydropyran ring, more preferably cyclohexane, benzene, cyclopropane, or, It is a tetrahydropyran ring, most preferably a tetrahydropyran ring. Further, the above-mentioned preferable R ⁵ may be replaced with (preferably 1 to 3) R ^7.

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

Formula (I-a), in (I-2-0), or (I-2), preferably as ^{R 52} is 3-8 membered saturated monocyclic heterocycle. Alternatively, formula (I-a), a (I-2-0), or in ^(I-2), preferably cyclopropane as ^{R 52,} cyclobutane, cyclopentane, cyclohexane, benzene or tetrahydropyran ring, More preferably, it is a cyclopropane, cyclohexane, benzene, or tetrahydropyran ring, and most preferably a tetrahydropyran ring.

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

Formula (I-c-0), in (I-c) or (1-4) ^is preferably an ^{R 54,} a tetrahydropyran ring.

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

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

In the general formula (Ia), ethylene, propenylene, or propynylene is preferable as ^{L 1, and an ethylene group is more preferable.}

であり、より好ましくは

である。 General formulas (I), (Ia), (Id), (I-1), (I-2-0), (I-2), (I-3-0), or (I-) 3) Among them, -L-J-, -L ^1- J- or -L-J ^1- is preferably -O-,

And more preferably

Is.

General formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) ), or in any of (I-3), preferably as ^{R 6} is hydrogen atom.

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

General formulas (I), (Ia), (Ib), (Ic), (Id), (I-1), (I-2-0), (I-3-0) ) Or (I-4), R ¹² is preferably a hydrogen atom, a methyl group, or an ethyl group, more preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.

General formulas (I), (Ia), (Ib), (Ic), (Id), (I-1), (I-2), (I-3), or ( In any of I-4), R ¹¹ and R ¹² may form a C3-6-membered saturated carbon ring together with the carbon atom to be bonded, and the C3-6-membered saturated carbocycle is cyclopropane. Rings are preferred.

In any of the general formulas (I), (Ia), (Ib), (Id), or (I-1), 1 is preferable as n.

General formulas (I), (Ia), (Ib), (Id), (I-1), (I-2-0), (I-2), (I-3-0) ) Or (I-3), 0 or 1 is preferable as m, and 1 is more preferable.

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

Examples of the compound represented by the general formula (Ia) include the above-mentioned preferable compounds R ¹ , R ² , R ³ , R ⁴ , R ⁵² , R ⁶ , R ¹¹ , R ¹² , J, L ¹ , n and m. , Partially or all combined compounds are preferred.

The compounds represented by the general formula (I-b) include some of the above-mentioned preferable compounds R ¹ , R ² , R ³ , R ⁴ , R ⁵¹ , R ⁶ , R ¹¹ , R ¹² , J, n and m. Alternatively, a compound in which all are combined is preferable.

Some of the compounds represented by the general formula (I-c-0) include the above-mentioned preferable R ^1c , R ^2c , R ^3c , R ^4c , R ¹¹ , R ¹² , J ^c , L ^c , and R ⁵⁴ . Alternatively, a compound in which all are combined is preferable.

As the compound represented by the general formula (Ic), a compound obtained by partially or all ^{of the above-mentioned preferable compounds of R 1c} , R ^2c , R ^3c , R ^4c , J ^c , L ^c , and R ^{54 is preferable.}

Examples of the compound represented by the general formula (Id) include the above-mentioned preferable compounds R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , J, L, n and m. Compounds in which some or all are combined are preferable.

Examples of the compound represented by the general formula (I-1) include the above-mentioned preferable compounds R ¹ , R ² , R ³ , R ⁴ , R ⁵¹ , R ⁶ , R ¹¹ , R ¹² , J ¹ , L, n and m. , Partially or all combined compounds are preferred.

Examples of the compound represented by the general formula (I-2-0) include the above-mentioned preferable R ¹ , R ² , R ³ , R ⁴ , R ⁵² , R ⁶ , R ¹¹ , R ¹² , J ¹ , L, and m. , A part or all of the compounds are preferable.

As the compound represented by the general formula (I-2) ^{, some or all of the above-mentioned preferable compounds R 1} , R ² , R ³ , R ⁴ , R ⁵² , R ⁶ , J ¹ , L, and m are combined. Compounds are preferred.

Examples of the compound represented by the general formula (I-3-0) include the above-mentioned preferable R ¹ , R ² , R ³ , R ⁴ , R ⁵³ , R ⁶ , R ¹¹ , R ¹² , J ¹ , L, and m. , A part or all of the compounds are preferable.

As the compound represented by the general formula (I-3) ^{, some or all of the above-mentioned preferable compounds R 1} , R ² , R ³ , R ⁴ , R ⁵³ , R ⁶ , J ¹ , L, and m are combined. Compounds are preferred.

Examples of the compound represented by the general formula (I-4) include some or all ^{of the above-mentioned preferred R 1c} , R ^2c , R ^3c , R ^4c , J ^c , L ^c , R ¹¹ , R ¹² and R ^54. Combined compounds are preferred.

In the present specification, the most preferable as another embodiment of the general formula (I) is the disclosed compound described in Examples described later, or a pharmaceutically acceptable salt thereof.

[Isomer]
In the present disclosure, isomers include all of them unless otherwise specified. For example, alkyl groups, alkoxy groups, alkylene groups and the like include linear and branched chains. Furthermore, isomers (E, Z, cis, trans isomers) in double bonds, rings, fused rings, isomers due to the presence of asymmetric carbons (R, S isomers, α, β isomers, enantiomers, diastereomers) , Optically active substances with optical rotation (D, L, d, l), polar bodies by chromatographic separation (high polar and low polar), equilibrium compounds, rotational isomers, mixtures of any proportions thereof, All racemic mixtures are included in this disclosure. In addition, all isomers due to tautomerism are also included in the present disclosure.
In the present disclosure, all references to the disclosed compounds refer to the compounds represented by the general formula (I), their pharmaceutically acceptable salts, their N-oxides, their solvates, or their co-crystals. Include.

[salt]
The compound represented by the general formula (I) is converted into a salt by a known method.
The salt is a pharmaceutically acceptable salt.
The salt is preferably water-soluble.
Pharmaceutically acceptable salts include, for example, acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, amine salts and the like.
Acid addition salts include, for example, hydrochlorides, hydrobromates, hydroiodide, sulfates, phosphates, inorganic acid salts such as nitrates, or acetates, lactates, tartrates, benzoic acids. Organic acid salts such as salts, citrates, methanesulfonates, ethanesulfonates, trifluoroacetates, benzenesulfonates, toluenesulfonates, ISEthionates, glucronates, or gluconates Can be mentioned.
Examples of the alkali metal salt include potassium salt and sodium salt.
Examples of the alkaline earth metal salt include calcium salt and magnesium salt.
Examples of the ammonium salt include tetramethylammonium salt and the like.
Examples of amine salts include triethylamine salts, methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts, tris (hydroxymethyl) aminomethane salts, and lysine. Examples include salts, arginine salts, and N-methyl-D-glucamine salts.

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

[Solvate]
The compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and their N-oxides may exist in an unsolvated form, or may be present in a pharmaceutically acceptable form such as water or ethanol. It may be present in a solvated form with an acceptable solvent. The compounds represented by the general formula (I), their pharmaceutically acceptable salts, and their N-oxides can be converted to solvates by known methods.
The solvate is preferably non-toxic and water-soluble. Suitable solvates include, for example, hydrates or solvates such as alcoholic solvents (eg, ethanol).

[Co-crystal]
The compounds represented by the general formula (I), their pharmaceutically acceptable salts, and their N-oxides can form a co-crystal with a suitable co-crystal forming agent. The co-crystal forming agent is preferably one that is pharmaceutically acceptable. A co-crystal is typically defined as a crystal in which two or more different molecules are formed by an intramolecular interaction different from an ionic bond. Further, the co-crystal may be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, such as by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal forming agents include those described in Pamphlet 2006/007448.

[Prodrug]
The compound represented by the general formula (I) can be administered as a prodrug. The prodrug of the compound represented by the general formula (I) refers to a compound that is converted into the compound represented by the general formula (I) by a reaction with an enzyme, gastric acid, or the like in vivo. As a prodrug of the compound represented by the general formula (I), for example, when the compound represented by the general formula (I) has a carboxy group, the compound in which the carboxy group is esterified or amidated (for example, the general formula). The carboxy group of the compound represented by (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl) oxy} ethyl esterified. , Phtalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, 1-{[(cyclohexyloxy) carbonyl] oxy} ethyl esterification, methylamided compound Etc.) and so on. These compounds can be produced by methods known per se. Further, the prodrug of the compound represented by the general formula (I) has a general formula under physiological conditions as described in Hirokawa Shoten 1990, "Drug Development", Vol. 7, "Molecular Design", pp. 163 to 198. It may be changed to the compound represented by (I). The prodrug of the compound represented by the general formula (I) may be a salt or a solvate, or may form a co-crystal with a suitable co-crystal forming agent.

[Labeling compound]
The disclosed compounds also include so-called labeled compounds in which some or all of the atoms constituting them are replaced by their isotopes. These labeled compounds can be produced by a method known per se. Isotopes used for labeling are not limited to, for example, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁷ O, ¹⁸ O, ¹⁸ F, ^35. S, ³⁶ Cl, ⁷⁷ Br, ¹²⁵ I and the like can be preferably used.

[Method for producing the disclosed compound]
The disclosed compounds represented by the general formula (I) are prepared by known methods, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Second Edition [Comprehensive Organic Transformations]. : A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018)] Can be done. In each of the following production methods, the raw material compound may be used as a salt. As such a salt, those described as pharmaceutically acceptable salts of the disclosed compound represented by the general formula (I) are preferable.

（式中、J^aは、−Ｏ−または−Ｓ−を表し、その他の記号は前記と同じ意味を表す。）
で示される化合物は、以下の反応工程式Ａに準じて製造することができる。

（式中、Ｐはカルボキシ基の保護基を表し、その他の記号は前記と同じ意味を表す。）
すなわち、一般式（ＩＩａ）で示される化合物と一般式（ＩＩＩａ）で示される化合物を光延反応に付すことにより一般式（ＩＶａ）で示される化合物を製造し、その後、カルボキシ基の脱保護反応を行うことにより、一般式（Ｉａ）で示される化合物を製造することができる。 Among the compounds represented by the general formula (I), a compound in which R ¹ is a hydrogen atom, J is -O- or -S-, and Q is an oxygen atom, that is, the general formula (Ia):

(Wherein, J ^a represents -O- or -S-, and other symbols represent the same meanings as defined above.)
The compound represented by (1) can be produced according to the following reaction process formula A.

(In the formula, P represents a protecting group of a carboxy group, and other symbols have the same meanings as described above.)
That is, a compound represented by the general formula (IIa) and a compound represented by the general formula (IIIa) are subjected to a Mitsunobu reaction to produce a compound represented by the general formula (IVa), and then a deprotection reaction of a carboxy group is carried out. By doing so, the compound represented by the general formula (Ia) can be produced.

The Mitsunobu reaction is known, and for example, alcohol is mixed in an organic solvent (dimethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.) with a Mitsunobu reagent (diazo compound (diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1). , 1'-(azodicarbonyl) dipiperidin, 1,1'-azobis (N, N-dimethylformamide), etc.) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer support triphenylphosphine, etc.) It is carried out in combination or by reacting with a phenol derivative or a thiophenol derivative at 0 to 60 ° C. in the presence of an ilide reagent (cyanomethylenetrimethylphosphorane (CMMP), cyanomethylenetributylphosphoran (CMBP), etc.).

（式中、Ｘはハロゲン原子、トシルオキシ基（ＴｓＯ−）、メシルオキシ基（ＭｓＯ−）などの脱離基を表し、その他の記号は前記と同じ意味を表す。）で示される化合物と、一般式（ＩＩＩａ）で示される化合物をアルキル化反応に付すことにより製造することもできる。
このアルキル化反応は公知であり、例えば有機溶媒（ジメチルホルムアミド、ジメチルスルホキシド、クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン、メチル ｔ−ブチル エーテル等）中、アルカリ金属の水酸化物（水酸化ナトリウム、水酸化カリウム、水酸化リチウム等）、アルカリ土類金属の水酸化物（水酸化バリウム、水酸化カルシウム等）もしくは炭酸塩（炭酸ナトリウム、炭酸カリウム等）またはその水溶液あるいはこれらの混合物の存在下、０〜１００℃で反応させることにより行なわれる。 Further, the compound represented by the general formula (IVa) is a compound represented by the general formula (Va) :.

(In the formula, X represents a leaving group such as a halogen atom, a tosyloxy group (TsO-), and a mesyloxy group (MsO-), and other symbols have the same meanings as described above.) It can also be produced by subjecting the compound represented by (IIIa) to an alkylation reaction.
This alkylation reaction is known, for example, in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.) and an alkali metal hydroxide (sodium hydroxide, hydroxide). Potassium, lithium hydroxide, etc.), alkali earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or aqueous solutions thereof, or a mixture thereof, 0 to 0 It is carried out by reacting at 100 ° C.

In the reaction step formula A, the deprotection reaction of the carboxy group is known and can be carried out as follows.
Examples of the carboxy group protecting group include a methyl group, an ethyl group, an allyl group, a t-butyl group, a trichloroethyl group, a benzyl (Bn) group, a phenacyl group and the like. The protecting group for the carboxy group is not particularly limited as long as it is a group that can be easily and selectively eliminated other than the above. For example, those described in Peter GM Wuts, Green's Protective Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014 are used.
The deprotection reaction of carboxy groups is well known, for example.
(1) Alkaline hydrolysis,
(2) Deprotection reaction under acidic conditions,
(3) Deprotection reaction by hydrogenolysis,
(4) Deprotection reaction of silyl group,
(5) Deprotection reaction using metal,
(6) Examples thereof include a deprotection reaction using a metal complex.
To explain these methods in detail,
(1) The deprotection reaction by alkaline hydrolysis is performed, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.), an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth. It is carried out at a temperature of 0 to 60 ° C. using a metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof, or a mixture thereof.
(2) The deprotection reaction under acid conditions is carried out, for example, in an organic solvent (dioxide, chloroform, dioxane, ethyl acetate, anisole, etc.) and an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosyl acid, etc.). ), Or an inorganic acid (hydrochloride, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide / acetic acid, etc.) at a temperature of 0 to 100 ° C.
(3) The deprotection reaction by hydrogenation is, for example, a solvent (ether type (tetrahexyl, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol type (methanol, ethanol, etc.), benzene type (benzene, toluene, etc.), ketone. In a system (acetone, methyl ethyl ketone, etc.), a nitrile system (acetoyl, etc.), an amide system (dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof), a catalyst (palladium-carbon, palladium black, etc.) It is carried out at a temperature of 0 to 200 ° C. in the presence of palladium hydroxide, platinum oxide, lane nickel, etc.), in a hydrogen atmosphere under normal pressure or pressure, or in the presence of ammonium formate.
(4) The deprotection reaction of the silyl group is carried out at a temperature of 0 to 40 ° C. using, for example, tetrabutylammonium fluoride in an organic solvent (tetrahydrofuran, acetonitrile, etc.) miscible with water.
(5) The deprotection reaction using a metal is carried out in, for example, in an acidic solvent (acetic acid, a buffer solution having a pH of 4.2 to 7.2 or a mixed solution of a solution thereof and an organic solvent such as tetrahydrofuran) in the presence of powdered zinc. If necessary, it is carried out at a temperature of 0 to 40 ° C. while applying ultrasonic waves.
(6) The deprotection reaction using a metal complex is carried out in, for example, an organic solvent (dimethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof, and a trap reagent (tributyltin hydride, Of triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or organic acid salts (sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.) In the presence, in the presence or absence of phosphine reagents (triphenylphosphine, etc.), metal complexes (tetrakistriphenylphosphine palladium (0), bis (triphenylphosphine) palladium (II), palladium acetate (II) , Triphenylphosphine chloride (triphenylphosphine) rhodium (I), etc.) at a temperature of 0-40 ° C.
In addition to the above, the deprotection reaction can be carried out by, for example, the method described in Peter GM Wuts, Green's Protective Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014.
As can be easily understood by those skilled in the art, the target disclosed compound can be easily produced by properly using these deprotection reactions.

（式中、ｎｂは、０−４の整数を表し、その他の記号は前記と同じ意味を表す。）
で示される化合物は、一般式（ＩＩＩｂ）：

（式中、Ｘはハロゲン原子、またはトリフルオロメタンスルホニルオキシ基（ＴｆＯ−）を表し、その他の記号は前記と同じ意味を表す。）で示される化合物と、一般式（Ｖｂ）で示される化合物：

（式中、全ての記号は前記と同じ意味を表す。）
とを、カップリング反応に付した後、カルボキシ基の脱保護反応を行うことにより製造することができる。このカップリング化反応は公知であり、一般式（ＩＩＩｂ）で示される化合物と一般式（Ｖｂ）で示される化合物を、例えば有機溶媒（例えば、テトラヒドロフラン、Ｎ、Ｎ−ジメチルホルムアミド、アセトニトリルなど）中、パラジウム触媒（ビストリフェニルホスフィンパラジウム（II） クロリド、など）の存在下、および銅触媒（ヨウ化銅（I）など）存在下、塩基（トリエチルアミンなど）の存在下、室温〜還流温度で反応させることにより製造することができる。 Among the compounds represented by the general formula (I), R ¹ is a hydrogen atom, Q is an oxygen atom, J is a bond, and L is an alkynylene group, that is, the general formula (Ib) :.

(In the formula, nb represents an integer of 0-4, and other symbols have the same meanings as described above.)
The compound represented by the general formula (IIIb):

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

(In the formula, all symbols have the same meaning as above.)
Can be produced by subjecting to a coupling reaction and then carrying out a deprotection reaction of a carboxy group. This coupling reaction is known, and the compound represented by the general formula (IIIb) and the compound represented by the general formula (Vb) are mixed in, for example, an organic solvent (for example, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, etc.). , Palladium catalyst (bistriphenylphosphine palladium (II) chloride, etc.), copper catalyst (copper iodide (I), etc.), base (triethylamine, etc.), and react at room temperature to reflux temperature. It can be manufactured by.

Among the compounds represented by the general formula (I), the compound in which R ¹ is a hydrogen atom, Q is an oxygen atom, J is a bond, and L is an alkaneylene or an alkylene group is the general formula (Ib). It can be produced by subjecting the compound represented by (1) to a reduction reaction.
The reduction reaction is known, for example, in a hydrogen atmosphere, an organic solvent (for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, 1,2-dimethoxyethane, or a solvent obtained by appropriately mixing these organic solvents, etc.) or these. It is carried out at a temperature of room temperature to about 80 ° C. in the presence of a palladium catalyst (for example, palladium-carbon, palladium hydroxide, Lindlar's catalyst, etc.) in a mixed solvent of organic solvent and water.

（式中、全ての記号は前記と同じ意味を表す。）で示される化合物は、以下の反応工程式Ｃに準じて製造することができる。

（式中、全ての記号は前記と同じ意味を表す。）
すなわち、一般式（ＩＶa）で示される化合物をチオ化反応に付すことにより一般式（Ｖｃ）で示される化合物を製造し、その後カルボキシ基の脱保護反応を行うことにより、一般式（Ｉｃ）で示される化合物を製造することができる。 Among the compounds represented by the general formula (I), a compound in which R ¹ is a hydrogen atom and Q is a sulfur atom, that is, the general formula (Ic):

(In the formula, all symbols have the same meanings as described above.) The compound represented by the above can be produced according to the following reaction process formula C.

(In the formula, all symbols have the same meaning as above.)
That is, the compound represented by the general formula (IVa) is subjected to a thiolation reaction to produce the compound represented by the general formula (Vc), and then the deprotection reaction of the carboxy group is carried out to obtain the compound represented by the general formula (Ic). The compounds shown can be produced.

In the reaction process formula C, the thiolation reaction is known, and the amide compound is contained in an organic solvent (for example, tetrahydrofuran, toluene, benzene, acetonitrile, dichloromethane, pyridine, etc.) in the presence or absence of a base (sodium hydrogen carbonate, etc.). Below, a thiolation reagent (eg, Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosfetan-2,4-disulfide), tetraphosphoras decasulfide, It can be produced by reacting diphosphoras pentasulfide, hydrogen sulfide, sulfur, etc.) with a phosphine reagent (for example, trichlorophosphate, etc.) at room temperature to reflux temperature in the presence or absence.

（式中、全ての記号は前記と同じ意味を表す。）で示される化合物は、以下の反応工程式Ｄに準じ、必要に応じて保護・脱保護反応を行なうことによって製造することができる。

（式中、Ｐ^２は水酸基またはチオール基の保護基を表し、その他の記号は前記と同じ意味を表す。）
すなわち、一般式（ＶＩｄ）で示される化合物を水酸基またはチオール基の保護反応に付すことにより一般式（ＶＩＩｄ）で示される化合物を製造し、その後一般式（ＶＩＩＩｄ）で示される化合物とアミド化反応に付すことにより、一般式（ＩＸｄ）で示される化合物が製造できる。その後、一般式（ＩＸｄ）で示される化合物を水酸基またはチオール基の脱保護反応に付すことにより、一般式（ＩＩＩａ）で示される化合物を製造することができる。 In each of the above reactions, the compound used as a starting material is known or can be easily produced by a known method.
For example, the compound represented by the general formula (IIIa):

(In the formula, all the symbols have the same meanings as described above.) The compound represented by the above can be produced by carrying out a protection / deprotection reaction as necessary according to the following reaction step formula D.

(In the formula, P ² represents a protecting group for a hydroxyl group or a thiol group, and other symbols have the same meanings as described above.)
That is, the compound represented by the general formula (VId) is subjected to a protection reaction of a hydroxyl group or a thiol group to produce a compound represented by the general formula (VIId), and then an amidation reaction with the compound represented by the general formula (VIIId). The compound represented by the general formula (IXd) can be produced by subjecting to. Then, the compound represented by the general formula (IXd) can be subjected to a deprotection reaction of a hydroxyl group or a thiol group to produce a compound represented by the general formula (IIIa).

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

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

In the reaction process formula D, the amidation reaction is known, for example,
(1) Method using acid halide,
(2) Method using mixed acid anhydride,
(3) Examples include a method using a condensing agent.
To explain these methods in detail,
(1) In the method using acid halide, for example, the carboxylic acid is mixed with an acid halide agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent, and -20. The reaction was carried out at ° C to reflux temperature, and the obtained acid halide was subjected to an amine and an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.). It is carried out by reacting at a temperature of 0 to 80 ° C. It can also be carried out by reacting the obtained acid halide with an amine in an organic solvent (dioxane, tetrahydrofuran, etc.) with an alkaline aqueous solution (sodium bicarbonate solution, sodium hydroxide solution, etc.) at 0 to 40 ° C.
(2) In the method using a mixed acid anhydride, for example, the carboxylic acid is used in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or in the absence of a solvent, and the base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropyl, etc.) is used. In the presence of (ethylamine, etc.), the mixture was obtained by reacting with an acid halide (pivaloyl chloride, tosilk lolide, mesil chloride, etc.) or an acid derivative (ethyl chloroate, isobutyl chlorogeate, etc.) at 0 to 40 ° C. This is done by reacting the acid anhydride with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) at 0-40 ° C.
(3) In the method using a condensing agent, for example, carboxylic acid and amine are mixed in an organic solvent (chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or in a solvent-free base (pyridine, triethylamine, dimethylaniline, etc.). In the presence or absence of (dimethylaminopyridine, etc.), condensing agents (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC), 1,1' - carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propyl phosphonic acid cyclic anhydride _{(1-propanephosphonic acid cyclic anhydride,} T 3 P) used, etc.), 1-hydroxybenztriazole (HOBt ) In the presence or absence of), the reaction is carried out at 0 to 80 ° C.
It is desirable that all of the reactions (1), (2) and (3) be carried out under anhydrous conditions under an atmosphere of an inert gas (argon, nitrogen, etc.).

The deprotection reaction of a hydroxyl group or a thiol group in the reaction step formula D is known, and can be carried out in the same manner as the deprotection reaction of a carboxy group in the reaction step formula A.
As can be easily understood by those skilled in the art, the target disclosed compound can be easily produced by properly using these deprotection reactions.

Other compounds used as starting materials and compounds used as reagents are known in their own right or by known methods, such as Comprehensive Organic Transformations: A Guide to Functional Group. -Easy to use in combination with the methods described in Preparations, Second Edition [Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018)] Can be manufactured.

In each reaction herein, each group may be protected if protection is required, and the compound protected by the protecting group can be subjected to a known deprotection reaction as appropriate.

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

In each reaction in the present specification, a solid-phase supporting reagent supported on a high molecular polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

In each reaction herein, the reaction product is prepared by conventional purification means, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. , Scavenger resin or column chromatography or purification by methods such as washing and recrystallization. Purification may be performed on a reaction-by-reaction basis or after several reactions have been completed.

[toxicity]
The toxicity of the disclosed compounds is very low and is safe enough for pharmaceutical use.

[Application to pharmaceutical products]
The compounds of the present disclosure are suitable for the prevention and / or treatment of DP receptor-mediated diseases.
The compounds of the present disclosure can be used to prevent and / or treat DP receptor-mediated diseases. Examples of such diseases include allergic diseases, inflammation, autoimmune diseases, cancer, neurological diseases, muscle diseases, sleep-wake disorders, ischemia-reperfusion disorders, viral infections, stress diseases, liver disorders, platelet aggregation and the like. ..
Allergic diseases include allergic bronchopulmonary aspergillosis, systemic mastocytosis, systemic mast cell activation disorder, anaphylactic shock, urticaria, eczema, eosinophilia, itchy disease, and flushing. Diseases and the like can be mentioned.
Inflammation includes airway contraction, acne, sinusitis, nasal polyps, irritable vasculitis, contact dermatitis, diseases secondary to itchy behavior, chronic obstructive pulmonary disease, pleural inflammation, and osteoarthritis. ,
Examples include ulcerative colitis and interstitial cystitis.
Examples of autoimmune diseases include rheumatoid arthritis, polymyositis, graft rejection, multiple sclerosis, Crohn's disease and the like.
Cancers include all malignant tumors, including, for example, cancers involving the cerebral nerve (eg, pediatric brain tumors (eg, neuroblastoma, medullary blastoma, stellate tumor (juvenile hair-like stellate tumor), coat). Tumors, cranopharyngeal tumors, embryonic cell tumors, optic gliomas, choroidal papillomas, brain stem gliomas), adult brain tumors (eg, adult astrocytoma, adult malignant astrocytoma, adult glioma, adult ventricle) Upper garment tumor, adult malignant ventricular upper garment tumor, adult malignant oligodendroglioma, adult myeloma, adult medulla, adult malignant meningitis), glioma (eg, stellate cell tumor, oligodendroglioma, upper garment) Tumor, brain stem glioma), pituitary adenoma, acoustic nerve sheath tumor, retinal blastoma, malignant melanoma of the vine, etc.), respiratory cancer (eg, pharyngeal cancer (eg, nasopharyngeal cancer, mesopharyngeal cancer, hypopharyngeal cancer)) , Laryngeal cancer, sinus cancer, lung cancer (eg small cell cancer, non-small cell cancer), thoracic adenoma, mesopharyngeal tumor, etc. Colon cancer, rectal cancer, anal cancer, etc.), oral cancer (eg, gingival cancer, tongue cancer, salivary adenocarcinoma, etc.), urinary cancer (eg, penis cancer, renal pelvis / urinary tract cancer, renal cell cancer, testis (testicle)) Tumors, prostate cancer, bladder cancer, etc.), cancers related to women (eigen cancer, uterine cancer (eg cervical cancer, uterine body cancer (endometrial cancer)), uterine sarcoma, choriocarcinoma (eg cystic dysplasia) Fetal, chorionic villi cancer, placental villous tumor, surviving chorionic villi), vaginal cancer, breast cancer, breast sarcoma, ovarian cancer, ovarian germ cell tumor, etc.), skin cancer (eg, melanoma (malignant melanoma) (eg, malignant melanoma) Type melanoma, superficial dilated melanoma, nodular melanoma, terminal lentigo melanoma, erosive melanoma), mycobacterial sarcoma, spinous cell carcinoma, basal cell carcinoma, skin cancer precursor / endodermal cancer (Example: Nikko keratosis, Bowen's disease, Paget's disease), lymphoma-like scab, skin CD30-positive cell undifferentiated large cell lymphoma, Cesarly syndrome, skin B-cell lymphoma, etc.), bone / muscle cancer (eg) , Osteosarcoma, soft sarcoma, rhombic sarcoma, synovial sarcoma, liposarcoma, etc.), thyroid cancer, cartinoid, liver cancer (hepatocellular carcinoma), hepatoblastoma, bile duct cancer, bile sac cancer, pancreatic cancer, pancreatic endocrine tumor (For example, insulinoma, gastrinoma, VIP-producing adenomas, etc.), cancers of unknown primary origin, hereditary tumors / familial tumors (eg, hereditary non-polyposis colon cancer, familial colon polyposis, hereditary breast cancer, ovarian cancer syndrome, Lee Fraumeni Syndrome, hereditary melanoma, Wilms tumor, hereditary papillary renal cell carcinoma, von Hippel-Lindau syndrome, multiple endocrine neoplasia, etc.), leukemia (eg, acute myeloid leukemia, acute lymphocytic leukemia, myelodystrophy) Syndrome, chronic myeloid leukemia / chronic myeloid proliferative disease, Adult T-cell leukemia lymphoma, chronic lymphocytic leukemia / small cell lymphoma, etc.), multiple myeloma, primary macroglobulinemia, malignant lymphoma (eg, hodgkin lymphoma, non-hodgkin lymphoma (middle-high grade lymphoma, Berkit lymphoma) , Lymphomacytic lymphoma, follicular lymphoma, mantle cell lymphoma, MALT (Mucosa-Associated Lymphoid Tissue) lymphoma, NK (natural killer) cell lymphoma, etc.)) and the like.
Neurological disorders include migraine, cerebrovascular accidents, brain trauma and the like.
Examples of muscle diseases include muscular dystrophy and sarcopenia.
Sleep-wake disorders include hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep-wake disorder, hypersomnia associated with neurodegenerative diseases, and hypersomnia associated with mental illness. Diseases based on daytime morbid sleep apnea can be mentioned.
Hypersomnia includes narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome and the like.
Circadian rhythm sleep-wake disorders include shift work type circadian rhythm disorders, irregular sleep / wake rhythm disorders, and the like.
Neurodegenerative diseases include Parkinson's disease, Lewy body dementias, Alzheimer's disease and the like.
Mental illnesses include depression and bipolar disorder.
Examples of the ischemia-reperfusion disorder include heart disease, cerebrovascular disorder, renal disease, liver disease, lung disease, pancreatic disease and the like, or ischemia-reperfusion disorder at the time of organ transplantation.
Viral infections include human hepatitis virus (eg, hepatitis B, hepatitis C, hepatitis A and hepatitis E, etc.), human retrovirus, human immunodeficiency virus (eg, HIV1 and HIV2, etc.), human T-cell leukemia. Virus or human T lymphotrophic virus (eg, HTLV1 and HTLV2, etc.), simple herpesvirus type 1 or 2, Epstein bar (EB) virus, cytomegalovirus, varicella-herpes zoster virus, human herpesvirus (eg, eg) Human herpesvirus 6 etc.), poliovirus, measles virus, ruin virus, Japanese encephalitis virus, mumps virus, influenza virus, cold virus (eg adenovirus, enterovirus, rhinovirus, etc.), severe acute respiratory syndrome (SARS) Onset virus, Ebola virus, West Nile virus, Flavi virus, Echo virus, Coxsackie virus, Corona virus, Respiratory polynuclear (symbol) virus, Rotavirus, Norovirus, Sapovirus, Parvovirus, Wakusina virus, HTL virus, Dengvirus , Hapillomavirus, soft tumor virus, mad dog disease virus, JC virus, arbovirus, encephalitis virus, hunter virus, ebora virus and the like.
Stress disorders include irritable bowel syndrome, functional gastroenteropathy, atopic dermatitis, bronchial asthma (adult or childhood), tension headache, chronic pain, migraine, school refusal with psychosomatic complaints, eating disorders, etc. Examples include diabetes, high blood pressure, and menopause.
Examples of liver disorders include drug-induced liver disorders and alcoholic liver disorders.
Drug-induced liver injury includes toxic liver injury, allergic liver injury and the like.
Examples of platelet aggregation include thrombotic thrombocytopenic purpura, EDTA-dependent thrombocytopenia, and the like.

The compounds of the present disclosure are preferably suitable for the prevention and / or treatment of sleep-wake disorders.
The compounds of the present disclosure are more preferably suitable for the prevention and / or treatment of hypersomnia.
The disclosed compound is
1) Complementing and / or enhancing the prophylactic and / or therapeutic effect of the compound,
2) It may be administered as a concomitant drug in combination with other drugs for improving the dynamics / absorption of the compound, reducing the dose, and / or 3) reducing the side effects of the compound.

The concomitant drug of the disclosed compound and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be administered in the form of separate preparations. When administered as these separate formulations, simultaneous administration and staggered administration are included. Further, for administration with a time lag, the disclosed compound may be administered first and another drug may be administered later, or the other drug may be administered first and the disclosed compound may be administered later. Each administration method may be the same or different.

The disease that exerts a prophylactic and / or therapeutic effect by the above-mentioned concomitant agent is not particularly limited, and any disease that complements and / or enhances the prophylactic and / or therapeutic effect of the disclosed compound may be used.

Other agents for complementing and / or enhancing the prophylactic and / or therapeutic effect of the disclosed compounds on sleep-wake disorders include, for example, psychostimulants (eg, modafinyl, methylphenidate (hydrochloride), methanephenidate (hydrochloride)). , Pemorin, etc.), Narcolepsy therapeutics (eg, γ-hydroxybutyric acid, chlorpromazine, etc.), Acetylcholine esterase inhibitors (eg, (hydrochloride) donepezil, physostigmine, (tartrate) rivastigmin, (hydrobromide) galantamine, (fumaric acid) Xanapezil; TAK-147, taclin, methylphenidate, etc.), NMDA receptor antagonists (eg, ketamine, memantin, dextrometholphan hydrobromide, etc.), dopamine receptor agonists (eg, levodopa, bromocryptin, pergolide, talipexol, etc.) (Hydrogen) pramipexosole (hydrate), cabergolin, (hydrochloride) amantazine, etc.), tricyclic antidepressants (eg, amitryptrin hydrochloride, imipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (eg, paroxetin, etc.) Escitaloplum, etc.), mania treatments (eg, lithium carbonate, etc.), antipsychotics (eg, chlorpromazine, spiperon, sulfirido, zotepine, thimiperone, haloperidol decanoate, fluphenazine decanoate, haloperidol, pimodide, propericazine, bromperi Examples include dol, perphenazine, levomepromazine maleate, chlorpromazine hydrochloride, thioridazine hydrochloride, trazodon hydrochloride, mosapramine hydrochloride, lisperidone, olanzapine, etc., and noradrenaline reuptake inhibitors (eg, atomoxetine, etc.).

The mass ratio of the disclosed compound to other agents is not particularly limited.
Other drugs may be administered in any combination of two or more.

In addition, other agents that complement and / or enhance the prophylactic and / or therapeutic effects of the disclosed compounds include those found to date as well as those found in the future based on the mechanisms described above. Is done.

In order to use the disclosed compound as a single agent or in combination with other agents as a concomitant agent for the purpose of prevention and / or treatment of the above-mentioned diseases, the substance which is an active ingredient is usually used as various additives or various additives. After being formulated with a pharmaceutically acceptable carrier such as a solvent, it is administered systemically or topically in an oral or parenteral form. Here, the pharmaceutically acceptable carrier means a substance other than the active ingredient, which is generally used in the preparation of a pharmaceutical product. The pharmaceutically acceptable carrier preferably has no pharmacological action at the dose of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. In addition, the pharmaceutically acceptable carrier can be used for the purpose of enhancing the usefulness of the active ingredient and the preparation, facilitating the formulation, stabilizing the quality, improving the usability, and the like. Specifically, substances such as those described in Yakuji Nippo's 2016 "Encyclopedia of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association) may be appropriately selected according to the purpose.

Examples of the dosage form used for administration include oral preparations (eg, tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, etc.), oral preparations (eg, oral tablets, etc.). Oral sprays, oral semi-solids, mouthwashes, etc.), injection formulations (eg, injections, etc.), dialysis preparations (eg, dialysis agents, etc.), inhalation preparations (eg, inhalants, etc.), Ophthalmic preparations (eg, eye drops, eye ointments, etc.), otologic preparations (eg, ear drops, etc.), nasal preparations (eg, nasal drops, etc.), rectal preparations (eg, suppositories, etc.) Semi-solids for the rectal, enteric injections, etc.), vaginal preparations (eg vaginal tablets, vaginal suppositories, etc.), and skin preparations (eg, external solids, external liquids, sprays, ointments, creams, etc.) , Gel agent, patch, etc.) and the like.

[Preparation for oral administration]
The orally-administered preparation includes, for example, tablets, capsules, granules, powders, oral solutions, syrups, oral jellies and the like. In addition, the orally-administered preparation includes a fast-disintegrating preparation in which the release of the active ingredient from the preparation is not particularly adjusted, and an enteric-coated preparation in which the release is adjusted according to the purpose by a unique preparation design and manufacturing method, for example. There are release-regulated preparations such as preparations and sustained-release preparations. Enteric-coated preparations are designed so that the active ingredient is not released in the stomach but mainly in the small intestine for the purpose of preventing the decomposition of the active ingredient in the stomach or reducing the irritating effect of the active ingredient on the stomach. It refers to the prepared product, and can usually be produced by applying a film using an acid-insoluble enteric base. Sustained release preparation refers to a preparation in which the release rate, release time, and release site of the active ingredient from the preparation are adjusted for the purpose of reducing the number of administrations or side effects, and is usually an appropriate sustained release agent. Can be produced by using. Of the orally-administered preparations, capsules, granules, tablets, etc. are coated with appropriate coating agents such as sugars, sugar alcohols, and polymer compounds for the purpose of facilitating administration or preventing decomposition of the active ingredient. It is also possible to apply a skin.

(1) Tablets Tablets are solid formulations having a certain shape that are orally administered, and are generally called tablets such as uncoated tablets, film-coated tablets, sugar-coated tablets, multi-layer tablets, and nucleated tablets. In addition, oral quick-disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, dissolving tablets and the like are included. When producing an uncoated tablet, the following method (a), (b), or (c) is usually used:
(A) Additives such as excipients, binders and disintegrants are added to the active ingredient to make them homogeneous, granulated by an appropriate method using water or a solution containing the binder, and then a lubricant. Etc. are added and mixed, and compression molding is performed;
(B) Additives such as excipients, binders and disintegrants are added to the active ingredient and mixed to make it homogeneous, which is then directly compression-molded or granules prepared with the additive in advance with the active ingredient and slippery material. Add a swamp, etc., mix and homogenize, and then compress mold;
(C) Additives such as excipients and binders are added to the active ingredient to make them homogeneous, and the kneaded product moistened with a solvent is poured into a certain mold to form the mixture, and then dried by an appropriate method. ;
Is used. The film-coated tablet can usually be produced by applying a thin coating agent such as a polymer compound to the uncoated tablet. Sugar-coated tablets can usually be produced by applying a coating agent containing sugars or sugar alcohols to uncoated tablets. The multi-layer tablet can be produced by stacking powders and granules having different compositions in layers and compression molding by an appropriate method. The nucleated tablet can be produced by covering the inner core tablet with an outer layer having a different composition. The tablets can also be enteric-coated or sustained-release tablets using suitable known techniques. Oral quick-disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, and dissolving tablets are tablets that have been given unique functions by appropriate selection of additives, and should be manufactured according to the above-mentioned tablet manufacturing method. Can be done. An intraoral rapid-disintegrating tablet is a tablet that can be rapidly dissolved or disintegrated in the oral cavity and taken; a chewable tablet is a tablet that is chewed and taken; Dissolved or dispersed tablets; Dispersed tablets are tablets that are dispersed in water and taken; Dissolved tablets are tablets that are dissolved and taken in water. The effervescent tablet can be produced by using an appropriate acidic substance, carbonate, hydrogen carbonate or the like as an additive.

(2) Capsules Capsules are formulations that are filled in capsules or encapsulated with a capsule base, and include hard capsules, soft capsules, and the like. Hard capsules are made by adding additives such as excipients to the active ingredient and mixing them to make them homogeneous, or granules or molded products by an appropriate method, and then filling the capsules as they are or by lightly molding them. Can be manufactured by Soft capsules are manufactured by encapsulating a soft capsule with an additive added to an active ingredient and using an appropriate capsule base such as gelatin with increased plasticity by adding glycerin, D-sorbitol, etc. to a certain shape. can do. Capsules can be enteric-coated capsules or sustained-release capsules using suitable known techniques, or colorants, preservatives, etc. can be added to the capsule base.

(3) Granules Granules are preparations that are granulated into granules, and include those generally called granules, as well as effervescent granules and the like. When producing granules, the following method (a), (b), or (c) is usually used:
(A) Excipients, binders, disintegrants, or other additives are added to the powdered active ingredient and mixed to homogenize, and then granulated by an appropriate method;
(B) Add an additive such as an excipient to the active ingredient prepared in the form of granules in advance and mix them to make them homogeneous;
(C) Additives such as excipients are added to the active ingredient prepared in advance into granules and mixed, and granulated by an appropriate method;
Is used. If necessary, the granules can be coated with a skin, or can be made into enteric-soluble granules or sustained-release granules by using an appropriate known method. Effervescent granules can be produced by using an appropriate acidic substance, carbonate, hydrogen carbonate or the like as an additive. The effervescent granule refers to a granule that dissolves or disperses while rapidly foaming in water. The granules can also be made into fine granules by adjusting the size of the particles.

(4) Powder The powder is a powdery preparation, and can usually be produced by adding an excipient or other additive to the active ingredient and mixing them to make them homogeneous.

(5) Oral solution Oral solution is a liquid or fluid viscous gel-like preparation, which is generally called an oral solution, as well as an elixir agent, a suspending agent, an emulsion, a limonade agent, etc. included. Oral solutions can usually be produced by adding an additive and purified water to the active ingredient, mixing and uniformly dissolving, emulsifying or suspending, and filtering if necessary. Elixirs are clear liquid oral solutions containing sweet and aromatic ethanol, usually in solid active ingredients or exudates thereof, with ethanol, purified water, flavoring agents, and sucrose, other sugars, or It can be produced by adding a sweetener and dissolving it to make a clear liquid by filtration or other methods. A suspending agent is an oral solution in which the active ingredient is finely and homogeneously suspended. Usually, a suspending agent or other additive and purified water or oil are added to a solid active ingredient and suspended by an appropriate method. , Can be manufactured by homogenizing the whole. An emulsion is an oral solution in which the active ingredient is finely and homogeneously emulsified. Usually, it can be produced by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it by an appropriate method, and homogenizing the whole. .. The limonade agent is a clear liquid oral liquid agent having a sweet and sour taste.

(6) Syrup agent The syrup agent is a viscous liquid or solid preparation containing a saccharide or a sweetening agent, and includes an agent for syrup and the like. Syrups are usually dissolved, mixed, suspended, or emulsified by adding the active ingredient to a solution of white sugar, other sugars, or sweeteners, or a simple syrup, and if necessary, the mixture is boiled and then heated. It can be produced by filtering. The syrup preparation refers to a granular or powdery preparation that becomes a syrup when water is added, and is sometimes referred to as a dry syrup. The syrup preparation can usually be produced by using a saccharide or a sweetening agent as an additive according to the method for producing granules or powders.

(7) Oral Jelly Agent An oral jelly agent is a non-fluid, molded gel-like preparation, which is usually mixed with an additive and a polymer gel base by adding an additive and a polymer gel base to the active ingredient, and gelled by an appropriate method. It can be manufactured by molding into a certain shape.

[Injectable product]
(1) Injections Injections are solutions, suspensions, emulsions, or solids that are dissolved or suspended before use, which are directly administered to internal tissues or organs such as subcutaneous, intramuscular, or blood vessels. In addition to lyophilized injections, powder injections, filled syringes, cartridges, infusions, implantable injections, and persistent injections, in addition to the sterile preparations of Is done. When producing an injectable preparation, the following method (a) or (b) is usually used:
(A) The active ingredient as it is, or the active ingredient with an additive added, is dissolved in water for injection, another aqueous solvent, a non-aqueous solvent, etc., suspended, or emulsified to make it homogeneous for injection. Fill the container, seal and sterilize;
(B) The active ingredient as it is, or the active ingredient with an additive added, is dissolved in water for injection, another aqueous solvent, a non-aqueous solvent, etc., suspended, or emulsified to homogenize it, and then sterile filtered. Alternatively, aseptically prepared and homogenized, filled in a container for injection and sealed;
Is used. Lyophilized injections are usually lyophilized as is, or by dissolving the active ingredient and additives such as excipients in water for injection, filtering aseptically, filling in a container for injection and then lyophilizing. It can be manufactured by freeze-drying in a special container and then filling the container directly. The powder injection can be usually produced by treating the powder by aseptic filtration, adding the powder obtained by crystallization or a sterilized additive to the powder, and filling the container for the injection. Filled syringes can usually be produced by preparing a solution, suspension, or emulsion with the active ingredient as is or with the active ingredient and additives and filling the syringe barrel. A cartridge agent is an injection that is used by putting a cartridge filled with a chemical solution into a dedicated injector, and a cartridge filled with a chemical solution is usually a solution containing the active ingredient as it is or using an active ingredient and an additive. It can be produced by preparing a suspension or an emulsion and filling it in a cartridge. The infusion solution refers to an injection usually administered intravenously in an amount of 100 mL or more. Implantable injection refers to a solid or gel-like injection applied subcutaneously, intramuscularly, etc. using an implantable device or by surgery for the purpose of releasing the active ingredient for a long period of time. Implantable injections can usually be prepared by using biodegradable polymer compounds and pelletizing, microspheres, or gelling. A long-acting injection is an injection that is applied intramuscularly for the purpose of releasing the active ingredient over a long period of time. Usually, the active ingredient is dissolved or suspended in vegetable oil or the like, or a biodegradable polymer compound. It can be produced by preparing a suspension of microspheres using.

The dose of the disclosed compound or a concomitant drug of the disclosed compound and another drug varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually 1 ng per adult. Orally administered in the range of to 1000 mg once to several times daily, or parenterally administered in the range of 0.1 ng to 100 mg once to several times daily per adult. It is continuously administered intravenously for 1 to 24 hours a day. Of course, as described above, since the dose varies depending on various conditions, an amount smaller than the above dose may be sufficient, or administration beyond the range may be necessary.

Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art of the present disclosure.
In addition, all patent documents and non-patent documents or references explicitly cited herein may be cited herein as part of this specification.

Hereinafter, the present disclosure will be described in detail by way of examples, but the present disclosure is not limited thereto.
[Synthesis Example]
The location of the separation by chromatography and the solvent in parentheses shown on the TLC indicate the elution solvent or developing solvent used, and the ratio represents the volume ratio.
The solvent in parentheses shown in the NMR section indicates the solvent used for the measurement.
As the compound names used in the present specification, a computer program, ACD / Name (registered trademark), which is generally named according to the IUPAC rules, is used, or Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft). Or named according to the IUPAC nomenclature.
LC-MS / ELSD was performed under the following conditions.
Column: Waters Triart C ₁₈ (particle size: 1.9 x 10 ^-6 m; column length: 30 x 2.0 mm ID); flow velocity: 1.0 mL / min; column temperature: 30 ° C.; mobile phase (A): 0.1 % Trifluoroacetic acid aqueous solution; mobile phase (B): 0.1% trifluoroacetic acid-acetoform solution; gradient (state the ratio of mobile phase (A): mobile phase (B)): [0 min] 95: 5; [0.1 min] 95: 5; [1.2 min] 5:95; [1.4 min] 5:95; [1.41 min] 95: 5; [1.5 min] 95: 5; Detector: UV (PDA), ELSD, MS.
The HPLC retention time indicates the retention time under the conditions described in the LC-MS / ELSD unless otherwise specified.
Supercritical fluid chromatography (SFC) was performed under the following conditions.
Column: CHIRALPAK IC / SFC (Daicel), inner diameter 20 mm x length 250 mm, particle size 5 μm; flow velocity: 100 mL / min: Co-solvent / CO ₂ = 12/88: ISOCLATIC 21 min (Co-solvent: MeOH = 9) / 1); Back pressure: 120 bar.

Reference Example 1: 4- (acetoxy) -2- (trifluoromethyl) benzoic acid 4-hydroxy-2- (trifluoromethyl) benzoic acid (CAS. No. 320-32-1, 500 mg) ethyl acetate (7) Pyridine (0.392 mL) and acetic anhydride (0.573 mL) were added to the .5 mL) solution, and the mixture was stirred overnight. Water and dilute hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (528 mg) having the following physical properties.
^{1 1} H-NMR (DMSO-d ₆ ): δ 2.34, 7.56, 7.70, 7.91, 13.66.

Reference Example 2: 4- (Chlorocarbonyl) -3- (Trifluoromethyl) Phenyl Acetate Chloride in a toluene (1.6 mL) -acetonitrile (0.26 mL) solution of the compound (1.0 g) prepared in Reference Example 1. Thionyl (0.17 mL) was added, and the mixture was stirred at 60 ° C. for 4 hours. The compound obtained by concentrating the reaction solution under reduced pressure was used for the next reaction without purification.

Reference Example 3: Methyl {3- [4- (acetoxy) -2- (trifluoromethyl) benzamide] -4-chlorophenyl} acetate Toluene (1.6 mL) -acetonitrile (1.6 mL) of the compound produced in Reference Example 2. ) Solution was added pyridine (0.342 mL) and methyl 2- (3-amino-4-chlorophenyl) acetonitrile (CAS. No. 59833-69-1, 422 mg), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30) to give the title compound (715 mg) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 2.37, 3.68, 3.72, 7.07, 7.37, 7.43, 7.53, 7.71, 7.93, 8.45.

Reference Example 4: Methyl {4-chloro-3- [4-hydroxy-2- (trifluoromethyl) benzamide] phenyl} acetate Methanol (8.8 mL) -tetrahydrofuran of the compound (1.75 g) prepared in Reference Example 3. Potassium carbonate (404 mg) was added to the (8.8 mL) solution, and the mixture was stirred at room temperature for 2 hours. Water and 1 mol / L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.36 g) having the following physical properties.
TLC: Rf 0.55 (Hexane: Ethyl acetate = 1: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 3.63, 3.75, 7.12-7.16, 7.19, 7.49, 7.52, 7.59, 10.07, 10.52.

参考例４で製造した化合物（５００ｍｇ）、２−（テトラヒドロピラン−２−イル）エタノール（ＣＡＳ．Ｎｏ．３８７８６−７９−７、２１８ｍｇ）のトルエン（５ｍＬ）溶液に、シアノメチレントリフェニルホスフィン（０．５０７ｍＬ）を加え、６０℃で一晩撹拌した。反応液を減圧濃縮後，得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）にて精製することにより、以下の物性値を有する標題化合物（５６４ｍｇ）を得た。
HPLC保持時間（分）：1.15；
¹H-NMR(CDCl₃)：δ 1.37, 1.47-1.68, 1.86, 1.94, 3.40-3.53, 3.67, 3.72, 3.98, 4.13, 4.20, 7.04, 7.13, 7.29, 7.36, 7.62, 7.93, 8.47。 Example 1: Methyl (4-chloro-3-{4- [2- (oxan-2-yl) ethoxy] -2- (trifluoromethyl) benzamide} phenyl) acetate

Cyanomethylenetriphenylphosphine (0) in a toluene (5 mL) solution of the compound (500 mg), 2- (tetrahydropyran-2-yl) ethanol (CAS. No. 38786-79-7, 218 mg) prepared in Reference Example 4. .507 mL) was added, and the mixture was stirred at 60 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (564 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.15;
^{1 1} H-NMR (CDCl ₃ ): δ 1.37, 1.47-1.68, 1.86, 1.94, 3.40-3.53, 3.67, 3.72, 3.98, 4.13, 4.20, 7.04, 7.13, 7.29, 7.36, 7.62, 7.93, 8.47.

実施例１で製造した化合物（４０．０ｍｇ）のジメトキシエタン（０．４ｍＬ）溶液に、２ｍｏｌ／Ｌ水酸化リチウム水溶液（０．１２ｍＬ）を加え、室温で１時間撹拌した。反応混合物に１ｍｏｌ／Ｌ塩酸を加えた後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮することにより、以下の物性値を有する標題化合物（２９ｍｇ）を得た。
HPLC保持時間（分）：1.03；
¹H-NMR(DMSO-d₆)：δ 1.25, 1.41-1.53, 1.63, 1.77, 1.83-1.89, 3.45, 3.63, 3.88, 4.14-4.23, 7.19, 7.32, 7.35, 7.48, 7.51, 7.68, 10.14, 12.46。 Example 2: (4-chloro-3-{4- [2- (oxan-2-yl) ethoxy] -2- (trifluoromethyl) benzamide} phenyl) acetic acid

A 2 mol / L lithium hydroxide aqueous solution (0.12 mL) was added to a dimethoxyethane (0.4 mL) solution of the compound (40.0 mg) prepared in Example 1, and the mixture was stirred at room temperature for 1 hour. After adding 1 mol / L hydrochloric acid to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (29 mg) having the following physical properties.
HPLC retention time (minutes): 1.03;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.25, 1.41-1.53, 1.63, 1.77, 1.83-1.89, 3.45, 3.63, 3.88, 4.14-4.23, 7.19, 7.32, 7.35, 7.48, 7.51, 7.68, 10.14, 12.46.

TLC：Rf 0.60（酢酸エチル：メタノール＝９：１）；
¹H-NMR(CDCl₃)：δ 0.85-1.10, 1.13-1.35, 1.52, 1.63-1.83, 3.71, 4.08, 7.05, 7.10, 7.38, 7.62, 7.94, 8.49。
実施例２−２：｛４−クロロ−３−［４−（２−フェニルエトキシ）−２−（トリフルオロメチル）ベンズアミド］フェニル｝酢酸

HPLC保持時間（分）：1.07；
¹H-NMR(DMSO-d₆)：δ 3.09, 3.63, 4.36, 7.18, 7.24, 7.31-7.37, 7.48, 7.51, 7.68, 10.14, 12.45。
実施例２−３：｛４−クロロ−３−［４−（２−シクロプロピルエトキシ）−２−（トリフルオロメチル）ベンズアミド］フェニル｝酢酸

HPLC保持時間（分）：1.05；
¹H-NMR(DMSO-d₆)：δ −0.02-0.01, 0.28-0.32, 0.70, 1.51, 3.48, 4.02, 7.03, 7.16, 7.20, 7.33, 7.36, 7.53, 9.99, 12.29。 Examples 2-1 to 2-3:
By performing the same operation as in Example 1 → Example 2 using an alcoholic substance corresponding to 2- (tetrahydro-2H-pyran-2-yl) ethanol, the title compound having the following physical property values can be obtained. Obtained.
Example 2-1: {4-chloro-3- [4- (2-cyclohexylethoxy) -2- (trifluoromethyl) benzamide] phenyl} acetic acid

TLC: Rf 0.60 (ethyl acetate: methanol = 9: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 0.85-1.10, 1.13-1.35, 1.52, 1.63-1.83, 3.71, 4.08, 7.05, 7.10, 7.38, 7.62, 7.94, 8.49.
Example 2-2: {4-chloro-3- [4- (2-phenylethoxy) -2- (trifluoromethyl) benzamide] phenyl} acetic acid

HPLC retention time (minutes): 1.07;
^{1 1} H-NMR (DMSO-d ₆ ): δ 3.09, 3.63, 4.36, 7.18, 7.24, 7.31-7.37, 7.48, 7.51, 7.68, 10.14, 12.45.
Example 2-3: {4-chloro-3- [4- (2-cyclopropylethoxy) -2- (trifluoromethyl) benzamide] phenyl} acetic acid

HPLC retention time (minutes): 1.05;
^{1 1} H-NMR (DMSO-d ₆ ): δ −0.02-0.01, 0.28-0.32, 0.70, 1.51, 3.48, 4.02, 7.03, 7.16, 7.20, 7.33, 7.36, 7.53, 9.99, 12.29.

参考例４で製造した化合物の代わりに、メチル ｛４−クロロ−３−［（４−ヒドロキシ−２，６−ジメチルベンゾイル）アミノ］フェニル｝アセタート（ＣＡＳ Ｎｏ．１３５１１６３−９６−６、Bioorganic & Medicinal Chemistry 19 (2011) 6935-6948, Compound 44）を用いて、実施例１と同様の反応を行うことにより以下の物性を有する標題化合物を得た。
TLC：Rf 0.75（ヘキサン：酢酸エチル＝１：１）；
¹H-NMR(CDCl₃)：δ1.33, 1.51, 1.63, 1.85, 1.91, 2.38, 3.43, 3.50, 3.68, 3.73, 3.97, 4.08, 6.63, 7.03, 7.35, 7.74, 8.49。 Example 3: Methyl (4-chloro-3- {2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzamide} phenyl) acetate

Instead of the compound prepared in Reference Example 4, methyl {4-chloro-3-[(4-hydroxy-2,6-dimethylbenzoyl) amino] phenyl} acetate (CAS No. 1351163-96-6, Bioorganic & Medicinal) Using Chemistry 19 (2011) 6935-6948, Compound 44), the same reaction as in Example 1 was carried out to obtain a title compound having the following physical characteristics.
TLC: Rf 0.75 (Hexane: Ethyl acetate = 1: 1);
^{1 1} H-NMR (CDCl ₃ ): δ1.33, 1.51, 1.63, 1.85, 1.91, 2.38, 3.43, 3.50, 3.68, 3.73, 3.97, 4.08, 6.63, 7.03, 7.35, 7.74, 8.49.

参考例４で製造した化合物の代わりに、メチル ｛４−クロロ−３−［（４−ヒドロキシ−２，６−ジメチルベンゾイル）アミノ］フェニル｝アセタートを用いて、２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エタノールの代わりに２−シクロヘキシルエタノール（ＣＡＳ Ｎｏ．２８４３８−５２−０）を用いて、実施例１と同様の操作を行うことにより、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.68（酢酸エチル：ヘキサン＝２：１）；
¹H-NMR(CDCl₃)：δ0.80-1.05, 1.10-1.35, 1.40-1.55, 1.65-1.80, 2.35, 3.53, 3.68, 3.73, 4.00, 4.19, 6.61, 7.04, 7.36,7.74，8.50。 Example 3-1: Methyl {4-chloro-3- [4- (2-cyclohexylethoxy) -2,6-dimethylbenzamide] phenyl} acetate

2- (Tetrahydro-2H-pyran- By performing the same operation as in Example 1 using 2-cyclohexylethanol (CAS No. 28438-52-0) instead of 2-yl) ethanol, a title compound having the following physical property values was obtained.
TLC: Rf 0.68 (ethyl acetate: hexane = 2: 1);
^{1 1} H-NMR (CDCl ₃ ): δ0.80-1.05, 1.10-1.35, 1.40-1.55, 1.65-1.80, 2.35, 3.53, 3.68, 3.73, 4.00, 4.19, 6.61, 7.04, 7.36, 7.74, 8.50.

実施例１で製造した化合物の代わりに、実施例３で製造した化合物を用いて、実施例２と同様の反応を行うことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間（分）：1.02；
¹H-NMR(DMSO-d₆)：δ 1.16-1.83, 2.32, 3.39, 3.61, 3.86, 4.02, 6.66, 7.15, 7.45, 7.49, 9.95, 12.44。 Example 4: (4-chloro-3- {2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzamide} phenyl) acetic acid

By carrying out the same reaction as in Example 2 using the compound produced in Example 3 instead of the compound produced in Example 1, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.02;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.16-1.83, 2.32, 3.39, 3.61, 3.86, 4.02, 6.66, 7.15, 7.45, 7.49, 9.95, 12.44.

TLC：Rf 0.27（ヘキサン：酢酸エチル＝１：２）；
¹H-NMR(CD₃OD)：δ 0.83-1.08, 1.13-1.38, 1.42-1.59, 1.60-1.91, 2.41, 3.64, 4.01, 6.65, 7.19, 7.43, 7.72。
実施例４−２：｛４−クロロ−３−［４−（２−シクロプロピルエトキシ）−２，６−ジメチルベンズアミド］フェニル｝酢酸

HPLC保持時間（分）：1.05；
MS(ESI, Pos.)：402 (M+H)⁺； Examples 4-1 to 4-2:
Instead of the compound prepared in Reference Example 4, methyl {4-chloro-3-[(4-hydroxy-) was used instead of 2- (tetrahydro-2H-pyran-2-yl) ethanol. By performing the same operation as in Example 1 → Example 2 using 2,6-dimethylbenzoyl) amino] phenyl} acetate, a title compound having the following physical property values was obtained.
Example 4-1: {4-chloro-3- [4- (2-cyclohexylethoxy) -2,6-dimethylbenzamide] phenyl} acetic acid

TLC: Rf 0.27 (Hexane: Ethyl acetate = 1: 2);
^{1 1} H-NMR (CD ₃ OD): δ 0.83-1.08, 1.13-1.38, 1.42-1.59, 1.60-1.91, 2.41, 3.64, 4.01, 6.65, 7.19, 7.43, 7.72.
Example 4-2: {4-Chloro-3- [4- (2-cyclopropylethoxy) -2,6-dimethylbenzamide] phenyl} acetic acid

HPLC retention time (minutes): 1.05;
MS (ESI, Pos.): 402 (M + H) ⁺ ;

メチル ２−（３−アミノ−４−クロロフェニル）アセタートの代わりに、メチル ２−（３−アミノ−４−フルオロフェニル）アセタート（ＣＡＳ Ｎｏ．２５７６３２−７７−２）を用いて、４−ヒドロキシ−２−（トリフルオロメチル）安息香酸の代わりに、４−ヒドロキシ−２，６−ジメチル安息香酸（ＣＡＳ Ｎｏ．７５０５６−９７−２）を用いて、２−（テトラヒドロ−２Ｈ−ピラン−２−イル）エタノールの代わりに、２−インダノール（ＣＡＳ Ｎｏ．４２５４−２９−９）を用いて、参考例１→参考例２→参考例３→参考例４→実施例１→実施例２と同様の操作を行うことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間（分）：1.02；
¹H-NMR(DMSO-d₆)：δ 2.29, 3.02, 3.39, 3.60, 5.27, 6.70, 7.13-7.28, 7.57, 10.07, 12.38。 Example 5: (3- {4-[(2,3-dihydro-1H-inden-2-yl) oxy] -2,6-dimethylbenzamide} -4-fluorophenyl) acetic acid

4-Hydroxy-2 using methyl 2- (3-amino-4-fluorophenyl) acetate (CAS No. 257632-77-2) instead of methyl 2- (3-amino-4-chlorophenyl) acetate. 2- (Tetrahydro-2H-pyran-2-yl) using 4-hydroxy-2,6-dimethylbenzoic acid (CAS No. 75056-97-2) instead of- (trifluoromethyl) benzoic acid Using 2-indanol (CAS No. 4254-29-9) instead of ethanol, perform the same operation as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Example 1 → Example 2. By doing so, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.02;
^{1 1} H-NMR (DMSO-d ₆ ): δ 2.29, 3.02, 3.39, 3.60, 5.27, 6.70, 7.13-7.28, 7.57, 10.07, 12.38.

Reference Example 5: Methyl (4-chloro-3- {2,6-dimethyl-4-[(trifluoromethanesulfonyl) oxy] benzamide} phenyl) acetate methyl [4-chloro-3- (4-hydroxy-2,6) -Dimethylbenzamide) Phenyl] To a solution of acetate (1.00 g) in dichloromethane (15 mL), add triethylamine (0.52 mL) and N, N-bis (trifluoromethylsulfonyl) aniline (1.23 g), and add 4 at room temperature. Stirred for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 7: 3) to give the title compound (1.38 g) having the following physical property values.
TLC: Rf 0.39 (Hexane: Ethyl acetate = 2: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 1.55, 2.45, 3.69, 3.73, 7.02, 7.08, 7.37, 7.40, 7.73, 8.43.

参考例５で製造した化合物（１．３８ｇ）のＮ，Ｎ−ジメチルホルムアミド（１２ｍＬ）溶液に、３−シクロヘキシル−1−プロピン（１．２６ｍL）、トリエチルアミン（８．１ｍＬ）を加えアルゴン雰囲気下とした。ヨウ化銅（５５ｍｇ）およびビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロライド（２０４ｍｇ）を加え、５０℃で終夜撹拌した。反応混合物に水を加え、酢酸エチル/ヘキサン混合溶媒で抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：０→７：３）によって精製することにより、以下の物性値を有する標題化合物（１．４６ｇ）を得た。
TLC：Rf 0.45 （ヘキサン：酢酸エチル＝４：１）；
¹H-NMR(CDCl₃)：δ 0.95−1.40，1.45-1.78, 1.85-1.90, 2.30, 2.37, 3.68, 3.73, 7.05, 7.14, 7.35, 7.38, 7.71, 8.47。 Example 6: Methyl {4-chloro-3- [4- (3-cyclohexylprop-1-in-1-yl) -2,6-dimethylbenzamide] phenyl} acetate

To a solution of the compound (1.38 g) prepared in Reference Example 5 in N, N-dimethylformamide (12 mL), 3-cyclohexyl-1-propyne (1.26 mL) and triethylamine (8.1 mL) were added under an argon atmosphere. bottom. Copper iodide (55 mg) and bis (triphenylphosphine) palladium (II) dichloride (204 mg) were added and stirred at 50 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate / hexane. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 7: 3) to give the title compound (1.46 g) having the following physical characteristics.
TLC: Rf 0.45 (Hexane: Ethyl acetate = 4: 1);
^{1 1} H-NMR (CDCl ₃ ): δ 0.95-1.40, 1.45-1.78, 1.85-1.90, 2.30, 2.37, 3.68, 3.73, 7.05, 7.14, 7.35, 7.38, 7.71, 8.47.

実施例１で製造した化合物の代わりに、実施例６で製造した化合物を用いて、実施例２と同様の操作を行うことにより、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.61（酢酸エチル：メタノール＝９：１）；
¹H-NMR(CDCl₃)：δ0.98-1.35, 1.56, 1.65-1.80, 1.82-1.90, 2.30, 2.38, 3.72, 7.06, 7.14, 7.36, 7.39, 7.71, 8.48。 Example 7: {4-chloro-3- [4- (3-cyclohexylprop-1-in-1-yl) -2,6-dimethylbenzamide] phenyl} acetic acid

By performing the same operation as in Example 2 using the compound produced in Example 6 instead of the compound produced in Example 1, a title compound having the following physical property values was obtained.
TLC: Rf 0.61 (ethyl acetate: methanol = 9: 1);
^{1 1} H-NMR (CDCl ₃ ): δ0.98-1.35, 1.56, 1.65-1.80, 1.82-1.90, 2.30, 2.38, 3.72, 7.06, 7.14, 7.36, 7.39, 7.71, 8.48.

参考例５で製造した化合物（１０００ｍｇ）のジオキサン（１２ｍＬ）溶液に、２−[(E)−３−シクロヘキシルプロペン−３−イル] −４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン（６２６ｍｇ），リン酸カリウム（８８４ｍｇ），［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド ジクロロメタン付加物を加え、５０℃で１８時間撹拌した。反応混合物に水、酢酸エチルを加えた後、セライト（商品名）濾過した。濾液を酢酸エチルで抽出後、有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残さをシリカゲルカラムクロマトグラフィーによって精製することにより、標題化合物のメチルエステル体（５３３ｍｇ）を得た。得られたメチルエステル体を用いて、実施例２と同様の操作を行うことにより、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.38（ヘキサン：酢酸エチル：酢酸＝１４：５：１）；
HPLC保持時間（分）：1.31；
MS(ESI, Pos.)：440 (M+H)⁺。 Example 8: (4-chloro-3-{4-[(1E) -3-cyclohexylprop-1-ene-1-yl] -2,6-dimethylbenzamide} phenyl) acetic acid

In a dioxane (12 mL) solution of the compound (1000 mg) prepared in Reference Example 5, 2-[(E) -3-cyclohexylpropene-3-yl] -4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane (626 mg), potassium phosphate (884 mg), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct was added, and the mixture was stirred at 50 ° C. for 18 hours. After adding water and ethyl acetate to the reaction mixture, the mixture was filtered through Celite (trade name). The filtrate was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a methyl ester compound (533 mg) of the title compound. Using the obtained methyl ester compound, the same operation as in Example 2 was carried out to obtain a title compound having the following physical property values.
TLC: Rf 0.38 (Hexane: Ethyl acetate: Acetic acid = 14: 5: 1);
HPLC retention time (minutes): 1.31;
MS (ESI, Pos.): 440 (M + H) ⁺ .

実施例３で製造した化合物（４０ｍｇ）のトルエン（０．４ｍＬ）溶液にローソン試薬（ＣＡＳ Ｎｏ．１９１７２−４７−５、２１ｍｇ）を加え、１００℃で２４時間撹拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１→４：１）によって精製することにより、以下の物性値を有する標題化合物（４０ｍｇ）を得た。
TLC：Rf 0.50 （ヘキサン：酢酸エチル＝２：１）；
¹H-NMR(DMSO-d₆)：δ 1.25, 1.46, 1.62, 1.81, 2.37, 3.44, 3.64, 3.80, 3.87, 4.02, 6.68, 7.30, 7.42, 7.55, 11.74。 Example 9: Methyl [4-chloro-3-({2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzene-1-carbotioil} amino) phenyl] acetylate

Lawesson's reagent (CAS No. 19172-47-5, 21 mg) was added to a toluene (0.4 mL) solution of the compound (40 mg) prepared in Example 3, and the mixture was stirred at 100 ° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 4: 1) to give the title compound (40 mg) having the following physical characteristics. ..
TLC: Rf 0.50 (Hexane: Ethyl acetate = 2: 1);
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.25, 1.46, 1.62, 1.81, 2.37, 3.44, 3.64, 3.80, 3.87, 4.02, 6.68, 7.30, 7.42, 7.55, 11.74.

実施例１で製造した化合物の代わりに、実施例９で製造した化合物を用いて、実施例２と同様の操作を行うことにより、以下の物性値を有する標題化合物を得た。
TLC：Rf 0.28 （ジクロロメタン：メタノール＝９：１）；
¹H-NMR(DMSO-d₆)：δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6.68, 7.29, 7.39, 7.54, 11.74, 12.46。 Example 10: [4-chloro-3-({2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzene-1-carbotioil} amino) phenyl] acetic acid

By performing the same operation as in Example 2 using the compound produced in Example 9 instead of the compound produced in Example 1, a title compound having the following physical property values was obtained.
TLC: Rf 0.28 (dichloromethane: methanol = 9: 1);
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6.68, 7.29, 7.39, 7.54, 11.74, 12.46.

TLC：Rf 0.46（酢酸エチル：メタノール＝９：１）；
¹H-NMR(DMSO-d₆)：δ 0.85-1.02, 1.10-1.30, 1.43, 1.55-1.75, 2.35, 3.65,3.99, 6.67, 7.28, 7.36, 7.51, 7.54, 11.71, 12.44。
実施例１０−２：［４−クロロ−３−（｛４−［２−（オキサン−２−イル）エトキシ］−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル｝アミノ）フェニル］酢酸

HPLC保持時間（分）：1.05；
¹H-NMR(DMSO-d₆)：δ 1.25, 1.42-1.51, 1.63, 1.77, 1.83-1.89, 3.45, 3.67, 3.88, 4.12-4.21, 7.25, 7.29-7.32, 7.35, 7.47, 7.55, 11.90, 12.46。
実施例１０−３：（４−クロロ−３−｛［４−（２−シクロヘキシルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸

HPLC保持時間（分）：1.21；
¹H-NMR(DMSO-d₆)：δ 0.92-1.02, 1.13-1.29, 1.49, 1.63-1.77, 3.66, 4.14, 7.24, 7.29-7.32, 7.34, 7.46, 7.54, 11.89, 12.46。
実施例１０−４：（４−クロロ−３−｛［４−（２−フェニルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸

HPLC保持時間（分）：1.09；
¹H-NMR(DMSO-d₆)：δ 3.08, 3.66, 4.34, 7.23-7.27, 7.29-7.37, 7.46, 7.55, 11.90, 12.50。
実施例１０−５：（４−クロロ−３−｛［４−（２−シクロプロピルエトキシ）−２−（トリフルオロメチル）ベンゼン−１−カルボチオイル］アミノ｝フェニル）酢酸

HPLC保持時間（分）：1.06；
¹H-NMR(DMSO-d₆)：δ −0.02-0.01, 0.28-0.32, 0.70, 1.51, 3.50, 4.00, 7.08, 7.13-7.18, 7.31, 7.38, 11.74, 12.30。 Examples 10-1 to 10-5:
In place of the compound produced in Example 3, methyl esters of Examples 1, the compound produced in Example 3-1 and the compound produced in Examples 2-1 to 2-3 were used, and Example 9 → By performing the same operation as in Example 2, a title compound having the following physical property values was obtained.
Example 10-1: (4-chloro-3-{[4- (2-cyclohexylethoxy) -2,6-dimethylbenzene-1-carbotioil] amino} phenyl) acetic acid

TLC: Rf 0.46 (ethyl acetate: methanol = 9: 1);
^{1 1} H-NMR (DMSO-d ₆ ): δ 0.85-1.02, 1.10-1.30, 1.43, 1.55-1.75, 2.35, 3.65, 3.99, 6.67, 7.28, 7.36, 7.51, 7.54, 11.71, 12.44.
Example 10-2: [4-chloro-3-({4- [2- (oxan-2-yl) ethoxy] -2- (trifluoromethyl) benzene-1-carbotioil} amino) phenyl] acetic acid

HPLC retention time (minutes): 1.05;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.25, 1.42-1.51, 1.63, 1.77, 1.83-1.89, 3.45, 3.67, 3.88, 4.12-4.21, 7.25, 7.29-7.32, 7.35, 7.47, 7.55, 11.90, 12.46.
Example 10-3: (4-chloro-3-{[4- (2-cyclohexylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid

HPLC retention time (minutes): 1.21;
^{1 1} H-NMR (DMSO-d ₆ ): δ 0.92-1.02, 1.13-1.29, 1.49, 1.63-1.77, 3.66, 4.14, 7.24, 7.29-7.32, 7.34, 7.46, 7.54, 11.89, 12.46.
Example 10-4: (4-chloro-3-{[4- (2-phenylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid

HPLC retention time (minutes): 1.09;
^{1 1} H-NMR (DMSO-d ₆ ): δ 3.08, 3.66, 4.34, 7.23-7.27, 7.29-7.37, 7.46, 7.55, 11.90, 12.50.
Example 10-5: (4-chloro-3-{[4- (2-cyclopropylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid

HPLC retention time (minutes): 1.06;
^{1 1} H-NMR (DMSO-d ₆ ): δ −0.02-0.01, 0.28-0.32, 0.70, 1.51, 3.50, 4.00, 7.08, 7.13-7.18, 7.31, 7.38, 11.74, 12.30.

HPLC保持時間（分）：13.2（ＣＨＩＲＡＬ ＰＡＫ ＩＣ， ヘキサン：イソプロパノール＝７０：３０）；
実施例１１−２：メチル ｛４−クロロ−３−［（２，６−ジメチル−４−｛２−［（２Ｓ）−オキサン−２−イル］エトキシ｝ベンゼン−１−カルボチオイル）アミノ］フェニル｝アセタート

HPLC保持時間（分）：11.8（ＣＨＩＲＡＬ ＰＡＫ ＩＣ， ヘキサン：イソプロパノール＝７０：３０）； Example 11:
The compound produced in Example 9 was subjected to optical resolution by supercritical fluid chromatography (SFC) to obtain a title compound having the following physical property values.
Example 11-1: Methyl {4-chloro-3-[(2,6-dimethyl-4- {2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} Acetate

HPLC retention time (minutes): 13.2 (CHIRAL PAK IC, hexane: isopropanol = 70:30);
Example 11-2: Methyl {4-chloro-3-[(2,6-dimethyl-4- {2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} Acetate

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

実施例１で製造した化合物の代わりに、実施例１１−１で製造した化合物を用いて実施例２と同様の操作を行うことにより以下の物性値を有する標題化合物を得た。
TLC：Rf 0.28 （ジクロロメタン：メタノール＝９：１）；
HPLC保持時間（分）：1.05；
MS(ESI, Pos.)：462(M+H)⁺；
¹H-NMR(DMSO-d₆)：δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6.68, 7.29, 7.39, 7.54, 11.74, 12.46。 Example 12: {4-chloro-3-[(2,6-dimethyl-4- {2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid

By performing the same operation as in Example 2 using the compound produced in Example 11-1 instead of the compound produced in Example 1, a title compound having the following physical property values was obtained.
TLC: Rf 0.28 (dichloromethane: methanol = 9: 1);
HPLC retention time (minutes): 1.05;
MS (ESI, Pos.): 462 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6.68, 7.29, 7.39, 7.54, 11.74, 12.46.

実施例１で製造した化合物の代わりに、実施例１１−２で製造した化合物を用いて実施例２と同様の操作を行うことにより以下の物性値を有する標題化合物を得た。
TLC：Rf 0.28 （ジクロロメタン：メタノール＝９：１）；
HPLC保持時間（分）：1.05；
MS(ESI, Pos.)：462(M+H)⁺；
¹H-NMR(DMSO-d₆)：δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6.68, 7.29, 7.39, 7.54, 11.74, 12.46。 Example 13: {4-chloro-3-[(2,6-dimethyl-4- {2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid

By performing the same operation as in Example 2 using the compound produced in Example 11-2 instead of the compound produced in Example 1, a title compound having the following physical property values was obtained.
TLC: Rf 0.28 (dichloromethane: methanol = 9: 1);
HPLC retention time (minutes): 1.05;
MS (ESI, Pos.): 462 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.25, 1.47, 1.62, 1.80, 2.37, 3.42, 3.67, 3.87, 4.04, 6.68, 7.29, 7.39, 7.54, 11.74, 12.46.

Reference Example 6: Methyl 2- (3-amino-4-fluorophenyl) propanoate Acetic acid (34 mL), iron powder (4.8 g) was added to water (4.0 mL), and the mixture was heated to 65 ° C. and released internationally. A solution of methyl 2- (4-fluoro-3-nitrophenyl) propanoate (CAS No. 1428790-43-5, 3.9 g) prepared by the method described in 2013/045451 pamphlet was added with an acetic acid (5 mL) solution. The reaction mixture was stirred at 65 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, filtered through Celite (trade name), the filtrate was cooled to 0 ° C., a 2N aqueous sodium hydroxide solution (345 mL) was poured, and the mixture was filtered through Celite (trade name) again. The filtrate was extracted twice with tert-butyl methyl ether, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 99: 1 → 65: 35) to give the title compound (3.4 g) having the following physical characteristics.
^{1 1} H-NMR (CDCl ₃ ): δ 1.45, 3.60, 3.63, 3.71, 6.60, 6.73, 6.91.

メチル ２−（３−アミノ−４−クロロフェニル）アセタートの代わりに参考例６で製造した化合物を、参考例１で製造した化合物の代わりにＢｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ， ｖｏl．１９， ６９３５−６９４８， ２０１１に記載の方法で製造した４−アセトキシ−２，６−ジメチル安息香酸（ＣＡＳ Ｎｏ．１３５１１６３−９３−３）を用いて、参考例２→参考例３→参考例４→実施例１→実施例９→実施例２と同様の操作を行うことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間（分）： 1.07；
MS(ESI, Pos., 20V)：460 (M + H)⁺；
¹H-NMR(DMSO-d₆)：δ 1.18, 1.19-1.29, 1.38, 1.39-1.55, 1.62, 1.71-1.87, 2.32, 3.26-3.52, 3.77, 3.87, 4.04, 6.69, 7.26-7.43, 11.64, 12.44。 Example 14: 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} propanoic acid

Bioorganic & Medicinal Chemistry, vol. The compound prepared in Reference Example 6 instead of methyl 2- (3-amino-4-chlorophenyl) acetate was used in place of the compound prepared in Reference Example 1. Reference Example 2 → Reference Example 3 → Reference Example 4 using 4-acetoxy-2,6-dimethylbenzoic acid (CAS No. 1351163-93-3) produced by the method described in 19, 6935-6948, 2011. → Example 1 → Example 9 → The title compound having the following physical property values was obtained by performing the same operation as in Example 2.
HPLC retention time (minutes): 1.07;
MS (ESI, Pos., 20V): 460 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.18, 1.19-1.29, 1.38, 1.39-1.55, 1.62, 1.71-1.87, 2.32, 3.26-3.52, 3.77, 3.87, 4.04, 6.69, 7.26-7.43, 11.64, 12.44.

国際公開第２０１９／００３１４３号パンフレットに記載の方法により製造したメチル １−（４−フルオロ−３−ニトロフェニル）シクロプロパン−１−カルボキシラート（ＣＡＳ Ｎｏ．、２２６０５５４−６５−０）、参考例１で製造した化合物の代わりに４−アセトキシ−２，６−ジメチル安息香酸を用いて、参考例６→参考例２→参考例３→参考例４→実施例１→実施例９→実施例２と同様の操作を行うことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間（分）： 1.09；
MS(ESI, Pos., 20V)：472 (M + H)⁺；
¹H-NMR(DMSO-d₆)：δ 1.12-1.31, 1.38-1.54, 1.61, 1.71-1.86, 2.32, 3.27-3.47, 3.87, 4.03, 6.68, 7.26, 7.36, 7.43, 11.64, 12.42。 Example 15: 1- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboty oil) amino] -4-fluorophenyl} cyclopropane carboxylic acid

Methyl 1- (4-fluoro-3-nitrophenyl) cyclopropane-1-carboxylate (CAS No., 2260554-65-0) produced by the method described in International Publication No. 2019/003143, Reference Example 1. Using 4-acetoxy-2,6-dimethylbenzoic acid instead of the compound produced in the above, Reference Example 6 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Example 1 → Example 9 → Example 2 By performing the same operation, a title compound having the following physical property values was obtained.
HPLC retention time (minutes): 1.09;
MS (ESI, Pos., 20V): 472 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.12-1.31, 1.38-1.54, 1.61, 1.71-1.86, 2.32, 3.27-3.47, 3.87, 4.03, 6.68, 7.26, 7.36, 7.43, 11.64, 12.42.

Ｂｉｏｏｒｇａｎｉｃ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ， ２０１１， ｖｏｌ．１９， ６９３５−６９４８に記載の方法により製造したメチル２−（３−アミノ−４−クロロフェニル）−２−メチルプロパノアート（ＣＡＳ Ｎｏ． ３４３３２６−７５−０）と参考例１で製造した化合物の代わりに４−アセトキシ−２，６−ジメチル安息香酸を用いて、参考例２→参考例３→参考例４→実施例１→実施例９と同様の操作を行うことにより、以下の物性値を有する標題化合物を得た。
¹H-NMR(DMSO-d₆)：δ1.20-1.28, 1.42-1.50, 1.53, 1.58-1.65, 1.72-1.85, 2.36, 3.28-3.48, 3.61, 3.85-3.90, 4.00-4.08, 6.68, 7.35, 7.43, 7.58 11.75。 Example 16: Methyl 2- [4-chloro-3-({2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzene-1-carbotioil} amino) phenyl] -2-methyl Propano art

Bioorganic Medicinal Chemistry, 2011, vol. 19, 6935-6948 Methyl 2- (3-amino-4-chlorophenyl) -2-methylpropanoate (CAS No. 343326-75-0) prepared by the method described and the compound prepared in Reference Example 1. By using 4-acetoxy-2,6-dimethylbenzoic acid instead and performing the same operation as in Reference Example 2 → Reference Example 3 → Reference Example 4 → Example 1 → Example 9, the following physical property values can be obtained. The title compound to have was obtained.
^{1 1} H-NMR (DMSO-d ₆ ): δ1.20-1.28, 1.42-1.50, 1.53, 1.58-1.65, 1.72-1.85, 2.36, 3.28-3.48, 3.61, 3.85-3.90, 4.00-4.08, 6.68, 7.35 , 7.43, 7.58 11.75.

実施例１６で製造した化合物を用いて、実施例２と同様の操作を行うことにより以下の物性値を有する標題化合物を得た。
HPLC保持時間（分）： 1.14；
MS(ESI, Pos., 20V)：490(M+H)⁺；
¹H-NMR(DMSO-d₆)：δ1.20-1.25, 1.43-1.49, 1.49, 1.58-1.65, 2.36, 3.26-3.48, 3.77, 4.00-4.08, 6.68, 7.38, 7.46, 7.58 11.74, 12.57。 Example 17: 2- {4-chloro-3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] phenyl} -2 -Methylpropanoic acid

Using the compound produced in Example 16, the same operation as in Example 2 was carried out to obtain a title compound having the following physical characteristic values.
HPLC retention time (minutes): 1.14;
MS (ESI, Pos., 20V): 490 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ1.20-1.25, 1.43-1.49, 1.49, 1.58-1.65, 2.36, 3.26-3.48, 3.77, 4.00-4.08, 6.68, 7.38, 7.46, 7.58 11.74, 12.57.

Example 18: Methyl 2- {4-chloro-3-[(2,6-dimethyl-4- {2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} -2-Methylpropanoate and methyl 2- {4-chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) ) Amino] phenyl} -2-methylpropanoart Using the compound prepared in Example 16, optical resolution was performed by supercritical fluid chromatography (SFC) to obtain the title compound having the following physical property values. rice field.
Separation conditions Column: CHIRALPAK IC 5 μm 20 mm × 250 (manufactured by Daicel); CO ₂ : (ethyl acetate / methanol = 9/1) = 78/22
Example 18-1: (first peak)
SFC retention time (minutes): 3.69 (CHIRALPAK IC 5 μm 20 mm × 250 (manufactured by Daicel); CO ₂ : (ethyl acetate / methanol = 9: 1) = 78:22)
Example 18-2: (second peak)
SFC retention time (minutes): 5.32 (CHIRALPAK IC 5 μm 20 mm × 250 (manufactured by Daicel); CO ₂ : (ethyl acetate / methanol = 9: 1) = 78:22)

Example 19: 2- {4-chloro-3-[(2,6-dimethyl-4- {2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl}- 2-Methylpropanoic acid, and 2- {4-chloro-3-[(2,6-dimethyl-4- {2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] Phenyl} -2-methylpropanoic acid Using the compound obtained in Example 18-1 or Example 18-2, the same operation as in Example 2 was carried out to obtain a title compound having the following physical property values. rice field.
Example 19-1: (Compound produced using the compound produced in Example 18-1)
HPLC retention time (minutes): 1.14;
MS (ESI, Pos., 20V): 490 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ1.20-1.25, 1.43-1.49, 1.49, 1.58-1.65, 2.36, 3.26-3.48, 3.77, 4.00-4.08, 6.68, 7.38, 7.46, 7.58 11.74, 12.57.
Example 19-2: (Compound produced using the compound produced in Example 18-2)
HPLC retention time (minutes): 1.14;
MS (ESI, Pos., 20V): 490 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ1.20-1.25, 1.43-1.49, 1.49, 1.58-1.65, 2.36, 3.26-3.48, 3.77, 4.00-4.08, 6.68, 7.38, 7.46, 7.58 11.74, 12.57.

国際公開第２０１８／１１６１０７号パンフレットに記載の方法で製造したメチル ２−（４−フルオロ−３−ニトロフェニル）−２−メチルプロパノアートと参考例１で製造した化合物の代わりに４−アセトキシ−２，６−ジメチル安息香酸を用いて、参考例６→参考例２→参考例３→参考例４→実施例１→実施例９→実施例２と同様の操作を行うことにより、以下の物性値を有する標題化合物を得た。
HPLC保持時間（分）： 1.09；
MS(ESI, Pos., 20V)：474(M+H)⁺；
¹H-NMR(DMSO-d₆)：δ 1.25, 1.41-1.48, 1.49, 1.62, 1.71-1.85, 2.31, 3.32, 3.43, 3.87, 3.99-4.08, 6.68, 7.31, 7.38, 7.44, 11.65, 12.51。 Example 20: 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} -2 -Methylpropanoic acid

Methyl 2- (4-fluoro-3-nitrophenyl) -2-methylpropanoate prepared by the method described in WO 2018/116107 and 4-acetoxy-instead of the compound prepared in Reference Example 1. Using 2,6-dimethylbenzoic acid, the following physical properties can be obtained by performing the same operations as in Reference Example 6 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Example 1 → Example 9 → Example 2. The title compound having a value was obtained.
HPLC retention time (minutes): 1.09;
MS (ESI, Pos., 20V): 474 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 1.25, 1.41-1.48, 1.49, 1.62, 1.71-1.85, 2.31, 3.32, 3.43, 3.87, 3.99-4.08, 6.68, 7.31, 7.38, 7.44, 11.65, 12.51.

実施例１１−１で製造した化合物（1200ｍｇ）のジクロロメタン（25ｍＬ）溶液に、DIPEA（2.2ｍＬ）およびメトキシメチルクロリド（0.57ｍＬ）を０℃で加え、反応混合物を室温で１時間撹拌した。反応液をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→３５：６５）によって精製することにより、粗精製物（1300ｍｇ）を得た。この粗精製物のジメチルアセトアミド（10ｍＬ）溶液に、炭酸セシウム（4.1g）およびヨウ化メチル（0.78ｍＬ）を加え、反応混合物を３５℃で１６時間撹拌した。反応混合物を室温に冷却後、塩化アンモニウム水溶液を注ぎ、ｔｅｒｔ−ブチルメチルエーテルで２回抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→０：１００）によって精製することにより、粗精製物（410ｍｇ）を得た。この粗精製物のジオキサン（10ｍＬ）溶液に５ｍｏｌ／Ｌ塩酸水溶液（5ｍＬ）を加え、反応混合物を室温で１時間撹拌した。反応混合物をｔｅｒｔ−ブチルメチルエーテルで２回抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→０：１００）によって精製することにより、粗精製物（320ｍｇ）を得た。この粗精製物のテトラヒドロフラン（4ｍＬ）溶液にメタノール（4ｍＬ）と２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（4ｍＬ）を加え、反応混合物を室温で３時間撹拌した。反応混合物に２ｍｏｌ／Ｌ塩酸水溶液を加え、ｔｅｒｔ−ブチルメチルエーテルで２回抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→０：１００）によって精製することにより、以下の物性値を有する標題化合物（275ｍｇ）を得た。
HPLC保持時間（分）： 1.10；
MS(ESI, Pos., 20V)：476(M+H)⁺；
¹H-NMR(CDCl₃)：δ 0.78-0.84, 1.30-1.90, 2.17-2.25, 2.39, 3.39-3.60, 3.90-4.12, 4.54, 6.37, 6.52-6.65, 7.01-7.04, 7.25-7.30, 7.42-7.45, 8.71, 8.88, 9.70。 Example 21: 2- (4-chloro-3-{[(2,6-dimethyl-4- {2-[(2R) -tetrahydro-2H-pyran-2-yl] ethoxy} phenyl) carbotioil] amino} Phenyl) propanoic acid

DIPEA (2.2 mL) and methoxymethyl chloride (0.57 mL) were added to a solution of compound (1200 mg) prepared in Example 11-1 in dichloromethane (25 mL) at 0 ° C., and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 35: 65) to obtain a crude product (1300 mg). Cesium carbonate (4.1 g) and methyl iodide (0.78 mL) were added to a solution of this crude product in dimethylacetamide (10 mL), and the reaction mixture was stirred at 35 ° C. for 16 hours. The reaction mixture was cooled to room temperature, an aqueous ammonium chloride solution was poured, the mixture was extracted twice with tert-butyl methyl ether, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 → 0: 100) to obtain a crude product (410 mg). A 5 mol / L hydrochloric acid aqueous solution (5 mL) was added to a solution of the crude product in dioxane (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted twice with tert-butyl methyl ether, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 → 0: 100) to obtain a crude product (320 mg). Methanol (4 mL) and a 2 mol / L sodium hydroxide aqueous solution (4 mL) were added to a solution of the crude product in tetrahydrofuran (4 mL), and the reaction mixture was stirred at room temperature for 3 hours. A 2 mol / L hydrochloric acid aqueous solution was added to the reaction mixture, the mixture was extracted twice with tert-butyl methyl ether, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 → 0: 100) to give the title compound (275 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.10;
MS (ESI, Pos., 20V): 476 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 0.78-0.84, 1.30-1.90, 2.17-2.25, 2.39, 3.39-3.60, 3.90-4.12, 4.54, 6.37, 6.52-6.65, 7.01-7.04, 7.25-7.30, 7.42- 7.45, 8.71, 8.88, 9.70.

実施例１０−１で製造した化合物（60ｍｇ）のジオキサン（2ｍＬ）溶液に、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（0.13ｍＬ）を加えた後、凍結乾燥することにより、以下の物性値を有する標題化合物（49ｍｇ）を得た。
HPLC保持時間（分）： 1.38；
MS(ESI, Pos., 20V)： 460(M+H-Na)⁺；
¹H-NMR(DMSO-d₆)：δ 0.87-1.02, 1.10-1.28, 1.47, 1.67-1.79, 2.36, 3.26, 3.99, 6.65, 7.12-7.28, 7.38, 11.70。 Example 22: [4-Chloro-3-({[4- (2-cyclohexylethoxy) -2,6-dimethylphenyl] carbotie oil} amino) phenyl] sodium acetate

The title compound having the following physical properties is obtained by adding a 1 mol / L sodium hydroxide aqueous solution (0.13 mL) to a dioxane (2 mL) solution of the compound (60 mg) prepared in Example 10-1 and then freeze-drying. (49 mg) was obtained.
HPLC retention time (minutes): 1.38;
MS (ESI, Pos., 20V): 460 (M + H-Na) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 0.87-1.02, 1.10-1.28, 1.47, 1.67-1.79, 2.36, 3.26, 3.99, 6.65, 7.12-7.28, 7.38, 11.70.

本開示化合物は、ＤＰ受容体に対し強力な拮抗活性を示した。 [Pharmacology Examples]
Biological Example 1: Measurement of DP receptor antagonism using human DP receptor-expressing cells A cAMP-HTRF kit (Seti Medical Lab, 62AM6PEJ) was used to measure DP receptor antagonism. To the 384-well plate, 10 μL / well of the disclosed compound prepared at various concentrations and prostaglandin D2 (final concentration of 10 nmol / L) was added. Human DP receptor-expressing cells were suspended in phosphate buffer containing 2 μmo L / L diclofenac and 1 mmol / L IBMX (3-Isobutyl-1-methylxantine) and seeded to 5000 cells / 10 μL / well. After cell seeding, the cells were incubated at room temperature for 1 hour. Then, anti-cAMP Cryptate conjugate and cAMP-d2 solutions were added according to the method of the measurement kit, and the mixture was incubated at room temperature for 1 hour, and then the cAMP concentration in the sample was quantified.
Strength of DP receptor antagonistic activity according to the present disclosure compound, 10 nmol / L prostaglandin D2 _{IC 50} value calculated from the inhibition rate on cAMP production amount which increases stimulation (the cAMP production in the presently disclosed compounds in the absence 50 % Concentration of the disclosed compound required for inhibition). Table 1 shows the DP receptor antagonistic activity of the disclosed compounds.

The disclosed compounds showed strong antagonistic activity against DP receptors.

比較化合物として、先行技術文献の特許文献２中の実施例１３―２４に記載の化合物を用い、ＣＳＦ中化合物濃度を測定したところ、４．８ｎｇ／ｍＬであった。本開示化合物のＣＳＦ中化合物濃度は比較化合物よりも高く、良好な中枢移行性を示した。 Pharmacokinetic test 1: Measurement of concentration of the disclosed compound in cerebrospinal fluid (hereinafter referred to as CSF) (1) Collection of CSF Mix 5 test substances so that the dose of each test substance is 3 mg / 5 mL / kg. A test substance solution was prepared. The medium used was 5% DMSO 20% colifol HS15 / propylene glycol (7: 3). The test substance solution was orally administered to male Wistar rats aged 8 to 10 weeks purchased from Charles River Japan. Three hours after administration, the rats were anesthetized and CSF was collected by cisterna magna puncture. The same amount of ethanol (wako) as CSF was taken with the syringe used for collection, and the compound adsorbed on the syringe was recovered by washing.
(2) Measurement Using Candesartan (TRC) as an internal standard substance, 40 μL of acetonitrile and 160 μL of Candesartan-containing acetonitrile / ethanol (7: 3) were added to 10 μL of the obtained CSF sample, and the mixture was stirred. To prepare a calibration curve, 40 μL of the compound solution and 160 μL of Candesartan-containing acetonitrile / ethanol (7: 3) were added to 10 μL of plasma, and the mixture was stirred. The entire amount of each solution was transferred to a deproteinization filter plate and suction filtered. The obtained filtrate was appropriately diluted with acetonitrile / water (1: 1) and used for measurement. In the measurement, standard samples for calibration curves were prepared in the same matrix and analyzed in the same manner. The measurement was performed under the following conditions.
Liquid Chromatography System: Prominence UFLC _XR (Shimadzu Corporation),
Column: Sim-pack XR-ODSII 2.0 mm ID x 75 mm (Shimadzu Corporation),
Column temperature: 40 ° C,
Mobile phase: A: 0.2% formic acid 5 mmol / L ammonium acetate aqueous solution, B: acetonitrile,
Gradient Program:
Time (mobile phase B (%)): 0 minutes (10) → 1.5 minutes (90) → 3.0 minutes (90) → 3.1 minutes (10) → 4 minutes (10),
Flow rate: 0.5 mL / min
Mass spectrometry system: API4000, API5000 (AB SCIEX)
(3) Analysis From the peak area ratio (peak area of the test substance / peak area of the internal standard substance) obtained by measuring the standard sample for the calibration curve using the analysis software Analyst ver. 1.5.2 (AB SCIEX). The regression equation was calculated. The peak area ratio was also obtained for the measurement sample and substituted into the regression equation to calculate the quantitative value. In the calculation of the average value and standard deviation, points below the lower limit of quantification were calculated as 0.
The results are shown in Table 2.

As a comparative compound, the compound described in Example 13-24 in Patent Document 2 of the prior art document was used, and the compound concentration in CSF was measured and found to be 4.8 ng / mL. The compound concentration in the CSF of the disclosed compound was higher than that of the comparative compound, and showed good central transferability.

Biological Example 2: Normal rat Awakening time prolonging action Chronic electrodes were placed in the brain and cervical muscles of rats to prepare rats capable of measuring electroencephalogram and electromyogram. After a recovery period of one week or longer, the rat and the biological signal amplifier were connected in a shield box that blocked sound and electrical noise. After acclimatization in the measurement cage for 1 hour or more, various doses of the disclosed compounds were orally administered to rats in a single dose, and electroencephalogram and electromyogram were recorded 6 hours after the oral administration. After the measurement was completed, the rats were returned to the breeding cage each time, and the vehicle and each compound were evaluated with a drug holiday of one week or more.
The recorded electroencephalogram and electromyogram are shown in SleepSign Ver. Analyze using 3 and divide into epochs every 10 seconds, and stage to any of awakening, non-REM sleep, and REM sleep with reference to the characteristics of EEG and EMG and the spectral analysis results of each frequency component of EEG. Judged. Stage judgment is "awakening" when high-amplitude electroencephalogram is observed, "non-rem sleep" when high-amplitude slow wave and low-amplitude electroencephalogram are observed, low-amplitude electroencephalogram including theta wave component, and If a low-amplitude electrocardiogram was observed, it was judged to be "REM sleep". The epoch whose stage is difficult to judge due to noise etc. is based on the judgment result of the previous epoch.
After determining the sleep / wakefulness state, the difference between the total wakefulness time of 6 hours after administration of the disclosed compound administration group and the total wakefulness time of 6 hours after administration of the vehicle administration group was expressed as an index of the wakefulness prolonging action.
As a result of evaluating the wake-up time prolonging effect of the disclosed compounds, for example, Example Compound 8 (Example 8) and Example Compound 12 (Example 12) have wake-up times of 48 minutes and 60 minutes at a dose of 3 mg / kg, respectively. It showed a prolonging effect, and the disclosed compound was shown to be useful as a therapeutic agent for sleep-wake disorders.

[Formulation example]
Examples of typical formulations used in the present disclosure are shown below.
{4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid (100 g), carboxymethyl cellulose By mixing calcium (20 g), magnesium stearate (10 g) and microcrystalline cellulose (870 g) by a conventional method and then tableting, about 10,000 tablets containing 10 mg of the active ingredient in one tablet can be obtained. ..

Since the disclosed compound has strong DP receptor antagonistic activity and excellent central migration, the pharmaceutical composition containing the disclosed compound may be used for DP receptor-mediated diseases, particularly sleep wakefulness. It is useful as a preventive and / or therapeutic agent for disorders.

Claims (14)

General formula (Id):

(In the formula, R ¹ represents a hydrogen atom, a C1-4 alkyl, or a benzyl group.
R ² , R ³ , and R ⁴ are independently substituted with (1) a halogen atom, (2) a C1-4 alkyl optionally substituted with a halogen atom, or (3) a halogen atom. Represents a good C1-4 alkoxy group,
If there are multiple R ² or R ⁴ , they may be the same or different.
J represents a bond, -O-, or -S-
L represents a bond, C1-6 alkylene, C2-6 alkenylene, or C2-6 alquinylene group.
R ⁵ represents a hydrogen atom, a C3-10 carbocycle, or a 3-10-membered heterocycle.
C3-10 carbocyclic and 3-10 membered heterocyclic ring in R ⁵ may be substituted with 1-6 ^{R 7,}
However, when L is a bond, R ⁵ is not a hydrogen atom and is not a hydrogen atom.
R ⁷ represents (1) a halogen atom, (2) a C1-4 alkyl optionally substituted with a halogen atom, or (3) a C1-4 alkoxy group optionally substituted with a halogen atom.
If R ⁷ there is a plurality, it may be the same or different,
R ⁶ represents a hydrogen atom or a C1-4 alkyl group.
R ¹¹ represents a C1-4 alkyl group optionally substituted with a hydrogen atom, a halogen atom, or a halogen atom.
R ¹² represents a C1-4 alkyl group optionally substituted with a hydrogen atom, a halogen atom, or a halogen atom.
R ¹¹ and R ¹² may be combined with the carbon atoms to which they are bonded to form a C3-6 saturated carbon ring.
n represents an integer of 0-4
m represents an integer of 0-3. ), Or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof. The compound represented by the general formula (Id) is the general formula (I-1) :.

(In the formula, R ⁵¹ represents a C3-10 carbocycle or a 3-10-membered heterocycle, J ¹ represents a bond or −O−, and the other symbols have the same meanings as those according to claim 1. The pharmaceutical composition according to claim 1, which is a compound represented by (represented). The pharmaceutical composition according to claim 2, wherein R ^{51 is a 3-8-membered saturated monocyclic heterocycle.} The compound represented by the general formula (Id) is
(1) (4-Chloro-3-{[4- (2-cyclohexylethoxy) -2,6-dimethylbenzene-1-carbotioil] amino} phenyl) acetic acid,
(2) [4-Chloro-3-({4- [2- (oxan-2-yl) ethoxy] -2- (trifluoromethyl) benzene-1-carbotioil} amino) phenyl] acetic acid,
(3) (4-Chloro-3-{[4- (2-cyclohexylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(4) (4-Chloro-3-{[4- (2-phenylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(5) (4-Chloro-3-{[4- (2-cyclopropylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(6) [4-Chloro-3- ({2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzene-1-carbotioil} amino) phenyl] acetic acid,
(7) {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid,
(8) {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid,
(9) 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} propanoic acid,
(10) 1- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} cyclopropanecarboxylic acid,
(11) 2- {4-Chloro-3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] phenyl} -2- Methylpropanoic acid,
(12) 2- {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carboti oil) amino] phenyl} -2 -Methylpropanoic acid,
(13) 2- {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carboti oil) amino] phenyl} -2 -Methylpropanoic acid,
(14) 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} -2- Methylpropanoic acid, or
(15) 2- (4-Chloro-3-{[(2,6-dimethyl-4-{2-[(2R) -tetrahydro-2H-pyran-2-yl] ethoxy} phenyl) carbotie oil] amino} phenyl ) The pharmaceutical composition according to claim 1, which is propanoic acid. {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid or its pharmaceutically acceptable A pharmaceutical composition comprising the salt to be produced. The pharmaceutical composition according to any one of claims 1 to 5, which is a DP receptor antagonist. The pharmaceutical composition according to any one of claims 1 to 6, which is a prophylactic and / or therapeutic agent for DP receptor-mediated diseases. DP receptor-mediated disorders are allergic disorders, inflammation, autoimmune disorders, cancer, neurological disorders, muscle disorders, sleep-wake disorders, ischemia-reperfusion disorders, viral infections, stress disorders, liver disorders or platelet aggregation, The pharmaceutical composition according to claim 7. DP receptor-mediated disease is sleep-wake disorder, which is associated with hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep-wake disorder, and neurodegenerative disease. The pharmaceutical composition according to claim 8, which is a disease based on hypersomnia, hypersomnia associated with mental illness, and daytime morbid insomnia. A prophylactic and / or therapeutic agent for a DP receptor-mediated disease containing the compound represented by the general formula (Id) according to claim 1 or a pharmaceutically acceptable salt thereof. The compound represented by the general formula (Id) is
(1) (4-Chloro-3-{[4- (2-cyclohexylethoxy) -2,6-dimethylbenzene-1-carbotioil] amino} phenyl) acetic acid,
(2) [4-Chloro-3-({4- [2- (oxan-2-yl) ethoxy] -2- (trifluoromethyl) benzene-1-carbotioil} amino) phenyl] acetic acid,
(3) (4-Chloro-3-{[4- (2-cyclohexylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(4) (4-Chloro-3-{[4- (2-phenylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(5) (4-Chloro-3-{[4- (2-cyclopropylethoxy) -2- (trifluoromethyl) benzene-1-carbotioil] amino} phenyl) acetic acid,
(6) [4-Chloro-3- ({2,6-dimethyl-4- [2- (oxan-2-yl) ethoxy] benzene-1-carbotioil} amino) phenyl] acetic acid,
(7) {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid,
(8) {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid,
(9) 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} propanoic acid,
(10) 1- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} cyclopropanecarboxylic acid,
(11) 2- {4-Chloro-3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] phenyl} -2- Methylpropanoic acid,
(12) 2- {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2S) -oxan-2-yl] ethoxy} benzene-1-carboti oil) amino] phenyl} -2 -Methylpropanoic acid,
(13) 2- {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carboti oil) amino] phenyl} -2 -Methylpropanoic acid,
(14) 2- {3-[({2,6-dimethyl-4- [2- (tetrahydro-2H-pyran-2-yl) ethoxy] phenyl} carboti oil) amino] -4-fluorophenyl} -2- Methylpropanoic acid, or
(15) 2- (4-Chloro-3-{[(2,6-dimethyl-4-{2-[(2R) -tetrahydro-2H-pyran-2-yl] ethoxy} phenyl) carbotie oil] amino} phenyl ) The agent according to claim 10, which is propanoic acid. {4-Chloro-3-[(2,6-dimethyl-4-{2-[(2R) -oxan-2-yl] ethoxy} benzene-1-carbotioil) amino] phenyl} acetic acid or its pharmaceutically acceptable A prophylactic and / or therapeutic agent for DP receptor-mediated diseases containing salts. DP receptor-mediated disorders are allergic disorders, inflammation, autoimmune disorders, cancer, neurological disorders, muscle disorders, sleep-wake disorders, ischemia-reperfusion disorders, viral infections, stress disorders, liver disorders or platelet aggregation, The agent according to any one of claims 10 to 12. DP receptor-mediated disease is sleep-wake disorder, which is associated with hypersomnia, insomnia, residual sleepiness of sleep apnea syndrome, circadian rhythm sleep-wake disorder, and neurodegenerative disease. The agent according to claim 13, which is a disease based on hypersomnia, hypersomnia associated with mental illness, and daytime morbid sleepiness.