JP2019189588A - AGENT FOR TREATING AND/OR PREVENTING SYNUCLEINOPATHY, AND α-SYNUCLEIN ACCUMULATION INHIBITOR - Google Patents

Abstract

To provide an agent for treating and/or preventing synucleinopathy, and an α-synuclein accumulation inhibitor.SOLUTION: An agent for treating and/or preventing synucleinopathy and an α-synuclein accumulation inhibitor comprise an S1Preceptor agonist being a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to a therapeutic and / or prophylactic agent for synucleinopathies, and an α-synuclein accumulation inhibitor.

  A group of neurodegenerative diseases characterized by abnormal accumulation of α-synuclein aggregates in nerve cells, nerve fibers, or glial cells is known as synucleinopathy. Synucleinopathies include Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. A method for treating synucleinopathies using an anti-α-synuclein antibody is known (Patent Document 1). There is a further desire to develop therapeutic and / or prophylactic agents for synucleinopathies.

International Publication No. 2012/177972 International Publication No. 2016/088884 International Publication No. 2017/036978

The Journal of Neuroscience, Vol. 25, No. 6, pp. 1459-1469, 2005 The FASEB Journal, Vol. 21, pages 1503-1514, 2007

  An object of the present invention is to provide a therapeutic and / or prophylactic agent for synucleinopathy, and an α-synuclein accumulation inhibitor.

The present inventors surprisingly have sphingosine-1-phosphate [(2S, 3R, 4E) -2-amino-3-hydroxyoctadec-4-enyl-1-phosphate; hereinafter abbreviated as S1P. There is. The present inventors have found that α-synuclein accumulation in the brain can be inhibited by agonists of the S1P ₅ (EDG-8) receptor, which is one of the receptor subtypes.

S1P is a lipid synthesized by intracellular sphingolipid turnover and extracellular secretory sphingosine kinase, and is proposed to act as an intercellular signal transmitter and intracellular secondary signal transmitter. ing. With respect to S1P ₅ receptor which is one of the S1P receptor subtypes are known to be highly expressed in oligodendrocytes (oligodendrocytes) and oligodendrocyte precursor cells, S1P ₅ receptor It has been clarified that activation activates oligodendrocyte progenitor cells to differentiate into oligodendrocytes (see Non-Patent Documents 1 and 2). Oligodendrocytes are a type of glial cell that binds to nerve cell axons to form myelin sheaths (myelin). Therefore, the S1P ₅ receptor agonist promotes the regeneration of myelin (demyelination) that has disappeared in nerve cells, and is thus considered useful for the treatment of demyelinating diseases such as multiple sclerosis.

［式中、
Ｒ¹は、Ｃ１〜４アルキル基、ハロゲン原子、Ｃ１〜４ハロアルキル基、またはＣ１〜４アルコキシ基を表し、
Ｒ²は、Ｃ１〜４アルキル基、ハロゲン原子、Ｃ１〜４ハロアルキル基、またはＳＦ₅基を表し、
Ｒ³は、Ｃ１〜４アルキル基を表し、
Ｌは、結合手、−ＣＨ₂−、または−Ｏ−を表し、
Ｚは、Ｃ１〜８アルキル基で置換されていてもよい酸性基を表し、
ｒｉｎｇ１は、３〜１０員の環状基を表し、
ｒｉｎｇ２は、３〜７員の含窒素ヘテロ環を表し、
ｍは、０〜６の整数を表し、
ｎは、０〜５の整数を表し、
ｐは、０〜５の整数を表し、
ｍが２以上のとき、複数のＲ¹は同じでも異なっていてもよく、
ｎが２以上のとき、複数のＲ²は同じでも異なっていてもよく、
ｐが２以上のとき、複数のＲ³は同じでも異なってもよい。］
で示される化合物が知られている（特許文献２）。 As an S1P ₅ receptor agonist, the general formula (I)

[Where:
R ¹ represents a C1-4 alkyl group, a halogen atom, a C1-4 haloalkyl group, or a C1-4 alkoxy group,
R ² represents C1 -4 alkyl group, a halogen atom, C1 -4 haloalkyl group, or an SF ₅ group,
R ³ represents a C1-4 alkyl group,
L represents a bond, —CH ₂ —, or —O—,
Z represents an acidic group which may be substituted with a C1-8 alkyl group,
ring1 represents a 3- to 10-membered cyclic group,
ring2 represents a 3- to 7-membered nitrogen-containing heterocycle;
m represents an integer of 0 to 6;
n represents an integer of 0 to 5,
p represents an integer of 0 to 5;
when m is 2 or more, the plurality of R ¹ may be the same or different;
when n is 2 or more, the plurality of R ² may be the same or different;
When p is 2 or more, the plurality of R ³ may be the same or different. ]
Is known (Patent Document 2).

［式中、
Ｘ、Ｙ及びＺは、独立してＮ及びＣＲ５であり、
ｍは０、１又は２であり、
ｎは１、２又は３であり、
ただしｍ＋ｎは１、２又は３であり、
Ｒ１は−（Ｃ１−６）アルキレン−Ｒ６などであり、
Ｒ６は−ＣＯＯＨなどであり、
Ｒ２は存在しないか、または１もしくは２以上の置換基であり、
Ｌ１は存在しないか、またはフェニレンなどであり、
Ｒ３はＬ２−Ｒ４であり、
Ｌ２は存在しないか、または−Ｗ−（ＣＨ２）ｐ−Ｔ−であり、
ＷはＬ１と連結し、結合または−Ｏ−などであり、
ｐは０〜１０の整数であり、
Ｔは存在しないか、あるいはＲ４と連結して、結合または−Ｏ−などであり、
Ｒ４はフェニルなどである。］
で示される化合物が知られている（特許文献３）。 Further, as the SlP ₅ receptor agonist, the general formula (II)

[Where:
X, Y and Z are independently N and CR5;
m is 0, 1 or 2;
n is 1, 2 or 3,
However, m + n is 1, 2 or 3,
R1 is-(C1-6) alkylene-R6 or the like;
R6 is —COOH or the like;
R2 is absent or is one or more substituents,
L1 is absent or is phenylene or the like,
R3 is L2-R4,
L2 is absent or is -W- (CH2) p-T-
W is linked to L1 and is a bond or —O—, etc.
p is an integer of 0 to 10,
T is absent or linked to R4 and is a bond or -O-, etc.
R4 is phenyl or the like. ]
Is known (Patent Document 3).

However, it has not been known so far that S1P ₅ (EDG-8) receptor agonists can inhibit α-synuclein accumulation in the brain.

［式中、
Ｒ¹は、Ｃ１〜４アルキル基、ハロゲン原子、Ｃ１〜４ハロアルキル基、またはＣ１〜４アルコキシ基を表し、
Ｒ²は、Ｃ１〜４アルキル基、ハロゲン原子、Ｃ１〜４ハロアルキル基、またはＳＦ₅基を表し、
Ｒ³は、Ｃ１〜４アルキル基を表し、
Ｌは、結合手、−ＣＨ₂−、または−Ｏ−を表し、
Ｚは、Ｃ１〜８アルキル基で置換されていてもよい酸性基を表し、
ｒｉｎｇ１は、３〜１０員の環状基を表し、
ｒｉｎｇ２は、３〜７員の含窒素ヘテロ環を表し、
ｍは、０〜６の整数を表し、
ｎは、０〜５の整数を表し、
ｐは、０〜５の整数を表し、
ｍが２以上のとき、複数のＲ¹は同じでも異なっていてもよく、
ｎが２以上のとき、複数のＲ²は同じでも異なっていてもよく、
ｐが２以上のとき、複数のＲ³は同じでも異なってもよい。］
で示される化合物またはその薬学的に許容される塩である、シヌクレイノパチーの治療および／または予防剤。
＜２＞
一般式（Ｉ）において、Ｚが、（１）Ｃ１〜８アルキル基で置換されていてもよいカルボキシル基、（２）Ｃ１〜８アルキル基で置換されていてもよい水酸基、（３）Ｃ１〜８アルキル基で置換されていてもよいヒドロキサム酸基、（４）Ｃ１〜８アルキル基で置換されていてもよいスルホン酸基、（５）Ｃ１〜８アルキル基で置換されていてもよいボロン酸基、（６）Ｃ１〜８アルキル基で置換されていてもよいカルバモイル基、（７）Ｃ１〜８アルキル基で置換されていてもよいスルファモイル基、（８）Ｃ１〜８アルキル基で置換されていてもよいスルホキシイミン基、または（９）テトラゾリル基である、＜１＞に記載の剤。
＜３＞
一般式（Ｉ）において、Ｚが、Ｃ１〜８アルキル基で置換されていてもよいカルボキシル基である、＜１＞または＜２＞に記載の剤。
＜４＞
一般式（Ｉ）において、ｒｉｎｇ１が５〜７員の環状基である、＜１＞〜＜３＞のいずれか１項に記載の剤。
＜５＞
一般式（Ｉ）において、ｒｉｎｇ１が、（１）シクロペンタン、（２）シクロヘキサン、（３）シクロヘプタン、（４）シクロペンテン、（５）ベンゼン、（６）ピリジン、（７）ナフタレン、（８）インドール、または（９）ジヒドロインドールである、＜１＞〜＜４＞のいずれか１項に記載の剤。
＜６＞
一般式（Ｉ）において、ｍが１〜２の整数である、＜１＞〜＜５＞のいずれか１項に記載の剤。
＜７＞
Ｓ１Ｐ₅受容体作動薬が、一般式（Ｉ−１）

［式中、
Ｒ^1-1は、Ｃ１〜４アルキル基、またはハロゲン原子を表し、
Ｒ^2-1は、Ｃ１〜３アルキル基、ハロゲン原子、またはＣ１〜３ハロアルキル基を表し、
ｒｉｎｇ１−１は、５〜７員の環状基を表し、
ｒｉｎｇ２−１は、４〜７員の含窒素飽和ヘテロ環を表し、
ｍ−１は、１〜２の整数を表し、
ｍ−１が２のとき、複数のＲ^1-1は同じでも異なっていてもよく、
ｎが２以上のとき、複数のＲ^2-1は同じでも異なっていてもよく、
その他の記号は＜１＞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である、＜１＞に記載の剤。
＜８＞
Ｓ１Ｐ₅受容体作動薬が、１−｛［６−（４−フルオロフェノキシ）−１−メチル−３，４−ジヒドロ−２−ナフタレニル］メチル｝−３−アゼチジンカルボン酸またはその薬学的に許容される塩である、＜１＞に記載の剤。
＜９＞
シヌクレイノパチーが、パーキンソン病、多系統萎縮症またはレビー小体型認知症である、＜１＞〜＜８＞のいずれか１項に記載の剤。
＜１０＞
Ｓ１Ｐ₅受容体作動薬を含む、α−シヌクレイン蓄積阻害剤であって、前記Ｓ１Ｐ₅受容体作動薬が、一般式（Ｉ）：

［式中、すべての記号は＜１＞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である、α−シヌクレイン蓄積阻害剤。
＜１１＞
シヌクレイノパチーの治療および／または予防剤である、＜１０＞に記載の剤。
＜１２＞
Ｓ１Ｐ₅受容体作動薬を、シヌクレイノパチーの治療および／または予防を必要とする哺乳動物に投与することを含む、シヌクレイノパチーの治療および／または予防方法であって、
前記Ｓ１Ｐ₅受容体作動薬が、一般式（Ｉ）：

［式中、すべての記号は＜１＞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である、方法。
＜１３＞
Ｓ１Ｐ₅受容体作動薬を、α−シヌクレインの蓄積の阻害を必要とする哺乳動物に投与することを含む、α−シヌクレインの蓄積を阻害するための方法であって、
前記Ｓ１Ｐ₅受容体作動薬が、一般式（Ｉ）：

［式中、すべての記号は＜１＞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である、方法。
＜１４＞
シヌクレイノパチーの治療および／または予防剤を製造するための、Ｓ１Ｐ₅受容体作動薬の使用であって、
前記Ｓ１Ｐ₅受容体作動薬が、一般式（Ｉ）：

［式中、すべての記号は＜１＞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である、使用。
＜１５＞
α−シヌクレイン蓄積阻害剤を製造するための、Ｓ１Ｐ₅受容体作動薬の使用であって、
前記Ｓ１Ｐ₅受容体作動薬が、一般式（Ｉ）：

［式中、すべての記号は＜１＞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である、使用。
＜１６＞
シヌクレイノパチーを治療および／または予防するための
一般式（Ｉ）：

［式中、すべての記号は＜１＞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である、Ｓ１Ｐ₅受容体作動薬。
＜１７＞
α−シヌクレインの蓄積を阻害するための
一般式（Ｉ）：

［式中、すべての記号は＜１＞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である、Ｓ１Ｐ₅受容体作動薬。 One or more embodiments of the present invention include:
<1>
Including SlP ₅ receptor agonist, a therapeutic and / or prophylactic agent for synucleinopathies, the SlP ₅ receptor agonist has the general formula (I):

[Where:
R ¹ represents a C1-4 alkyl group, a halogen atom, a C1-4 haloalkyl group, or a C1-4 alkoxy group,
R ² represents C1 -4 alkyl group, a halogen atom, C1 -4 haloalkyl group, or an SF ₅ group,
R ³ represents a C1-4 alkyl group,
L represents a bond, —CH ₂ —, or —O—,
Z represents an acidic group which may be substituted with a C1-8 alkyl group,
ring1 represents a 3- to 10-membered cyclic group,
ring2 represents a 3- to 7-membered nitrogen-containing heterocycle;
m represents an integer of 0 to 6;
n represents an integer of 0 to 5,
p represents an integer of 0 to 5;
when m is 2 or more, the plurality of R ¹ may be the same or different;
when n is 2 or more, the plurality of R ² may be the same or different;
When p is 2 or more, the plurality of R ³ may be the same or different. ]
A therapeutic and / or prophylactic agent for synucleinopathy, which is a compound represented by the formula: or a pharmaceutically acceptable salt thereof.
<2>
In the general formula (I), Z is (1) a carboxyl group which may be substituted with a C1-8 alkyl group, (2) a hydroxyl group which may be substituted with a C1-8 alkyl group, (3) C1— Hydroxamic acid group optionally substituted with 8 alkyl groups, (4) Sulfonic acid group optionally substituted with C1-8 alkyl groups, (5) Boronic acid optionally substituted with C1-8 alkyl groups A group, (6) a carbamoyl group optionally substituted with a C1-8 alkyl group, (7) a sulfamoyl group optionally substituted with a C1-8 alkyl group, and (8) substituted with a C1-8 alkyl group. The agent according to <1>, which may be a sulfoximine group or (9) a tetrazolyl group.
<3>
In general formula (I), the agent as described in <1> or <2> whose Z is the carboxyl group which may be substituted by the C1-8 alkyl group.
<4>
The agent according to any one of <1> to <3>, wherein in the general formula (I), ring1 is a 5- to 7-membered cyclic group.
<5>
In general formula (I), ring1 is (1) cyclopentane, (2) cyclohexane, (3) cycloheptane, (4) cyclopentene, (5) benzene, (6) pyridine, (7) naphthalene, (8) The agent according to any one of <1> to <4>, which is indole or (9) dihydroindole.
<6>
The agent according to any one of <1> to <5>, wherein m is an integer of 1 to 2 in the general formula (I).
<7>
The S1P ₅ receptor agonist has the general formula (I-1)

[Where:
R ^1-1 represents a C1-4 alkyl group or a halogen atom,
R ^2-1 represents a C1-3 alkyl group, a halogen atom, or a C1-3 haloalkyl group,
ring1-1 represents a 5- to 7-membered cyclic group;
ring2-1 represents a 4- to 7-membered nitrogen-containing saturated heterocyclic ring;
m-1 represents an integer of 1 to 2,
When m-1 is 2, a plurality of R ^1-1 may be the same or different,
when n is 2 or more, the plurality of R ^2-1 may be the same or different;
Other symbols have the same meaning as <1>. ]
<1> or a pharmaceutically acceptable salt thereof.
<8>
S1P ₅ receptor agonist is 1-{[6- (4-fluorophenoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid or a pharmaceutically acceptable salt thereof The agent according to <1>, which is a salt obtained.
<9>
The agent according to any one of <1> to <8>, wherein the synucleinopathy is Parkinson's disease, multiple system atrophy, or Lewy body dementia.
<10>
Including SlP ₅ receptor agonist, a α- synuclein accumulation inhibitor, the SlP ₅ receptor agonist has the general formula (I):

[Wherein all symbols have the same meanings as <1>. ]
An α-synuclein accumulation inhibitor, which is a compound represented by the formula: or a pharmaceutically acceptable salt thereof.
<11>
The agent according to <10>, which is a therapeutic and / or prophylactic agent for synucleinopathy.
<12>
A method of treating and / or preventing synucleinopathies comprising administering an S1P ₅ receptor agonist to a mammal in need of treatment and / or prevention of synucleinopathies, comprising:
The S1P ₅ receptor agonist is represented by the general formula (I):

[Wherein all symbols have the same meanings as <1>. ]
Or a pharmaceutically acceptable salt thereof.
<13>
A method for inhibiting α-synuclein accumulation comprising administering an S1P ₅ receptor agonist to a mammal in need of inhibition of α-synuclein accumulation comprising:
The S1P ₅ receptor agonist is represented by the general formula (I):

[Wherein all symbols have the same meanings as <1>. ]
Or a pharmaceutically acceptable salt thereof.
<14>
Use of an S1P ₅ receptor agonist for the manufacture of a therapeutic and / or prophylactic agent for synucleinopathy comprising:
The S1P ₅ receptor agonist is represented by the general formula (I):

[Wherein all symbols have the same meanings as <1>. ]
Or a pharmaceutically acceptable salt thereof.
<15>
Use of an S1P ₅ receptor agonist for the manufacture of an α-synuclein accumulation inhibitor comprising:
The S1P ₅ receptor agonist is represented by the general formula (I):

[Wherein all symbols have the same meanings as <1>. ]
Or a pharmaceutically acceptable salt thereof.
<16>
General formula (I) for treating and / or preventing synucleinopathies:

[Wherein all symbols have the same meanings as <1>. ]
Or a pharmaceutically acceptable salt thereof, an S1P ₅ receptor agonist.
<17>
General formula (I) for inhibiting α-synuclein accumulation:

[Wherein all symbols have the same meanings as <1>. ]
Or a pharmaceutically acceptable salt thereof, an S1P ₅ receptor agonist.

  According to the present invention, it is possible to treat and / or prevent synucleinopathies by inhibiting α-synuclein accumulation in the brain.

FIG. 1 shows the results of evaluation of α-synuclein accumulation inhibitory action in a mouse brain primary culture system. The ratio of the compound 1 treatment group when the DMSO treatment group is 100% is shown (mean ± SE). Comparison between the DMSO treatment group and the Compound 1 treatment group was performed by Student-t test. FIG. 2 shows the results of latency time in a rotarod test using mice overexpressing human A53T mutant α-synuclein. Fifteen cases were used for each group. Data are expressed as mean + SE. FIG. 3 shows the results of collecting mouse brain after rotarod test using mice overexpressing human A53T mutant α-synuclein and evaluating α-synuclein accumulation in the cortex by immunohistochemical staining. Eight cases for each group were used for tissue evaluation. Data are expressed as mean + SE. +: P <0.05 vs medium, one-way ANOVA. FIG. 4 shows the results of collecting mouse brain after rotarod test using mice overexpressing human A53T mutant α-synuclein and evaluating α-synuclein accumulation in the hippocampus by immunohistochemical staining. Eight cases for each group were used for tissue evaluation. Data are expressed as mean + SE. +: P <0.05 vs medium, one-way ANOVA.

In the present invention, the “S1P ₅ receptor agonist” is a compound that binds to the S1P ₅ receptor in vivo and in vitro and activates the receptor to exert its physiological function. is there. As described in Patent Document 2 (International Publication No. 2016/088884), the receptor is activated by using intracellular AMP using CHO cells overexpressing the human S1P ₅ (EDG-8) gene. This can be confirmed by monitoring the production concentration. EC50 values of SlP ₅ receptor agonist, for SlP ₅ receptor used in the present invention, preferably, not more than 1000 nM, more preferably, at 100nM or less. The S1P ₅ receptor agonist used in the present invention is preferably a S1P ₅ receptor selective agonist, more preferably selectivity for the S1P ₅ receptor (EC50 value for S1P ₁ receptor / S1P ₅ EC50 values for receptors) are S1P ₅ receptor selective agonists with> 30.

As S1P ₅ receptor agonists, in addition to the compounds described in Patent Documents 2 and 3, International Publication No. 2011/017561, International Publication No. 2011/023795, International Publication No. 2012/004373, International Publication No. 2012 / And compounds described in International Publication No. 2012/004378 and International Publication No. 2017/109095.

［式中、
Ｒ¹は、Ｃ１〜４アルキル基、ハロゲン原子、Ｃ１〜４ハロアルキル基、またはＣ１〜４アルコキシ基を表し、
Ｒ²は、Ｃ１〜４アルキル基、ハロゲン原子、Ｃ１〜４ハロアルキル基、またはＳＦ₅基を表し、
Ｒ³は、Ｃ１〜４アルキル基を表し、
Ｌは、結合手、−ＣＨ₂−、または−Ｏ−を表し、
Ｚは、Ｃ１〜８アルキル基で置換されていてもよい酸性基を表し、
ｒｉｎｇ１は、３〜１０員の環状基を表し、
ｒｉｎｇ２は、３〜７員の含窒素ヘテロ環を表し、
ｍは、０〜６の整数を表し、
ｎは、０〜５の整数を表し、
ｐは、０〜５の整数を表し、
ｍが２以上のとき、複数のＲ¹は同じでも異なっていてもよく、
ｎが２以上のとき、複数のＲ²は同じでも異なっていてもよく、
ｐが２以上のとき、複数のＲ³は同じでも異なってもよい。］
で示される化合物またはその薬学的に許容される塩が好ましい。 The S1P ₅ receptor agonist used in the present invention has the general formula (I):

[Where:
R ¹ represents a C1-4 alkyl group, a halogen atom, a C1-4 haloalkyl group, or a C1-4 alkoxy group,
R ² represents C1 -4 alkyl group, a halogen atom, C1 -4 haloalkyl group, or an SF ₅ group,
R ³ represents a C1-4 alkyl group,
L represents a bond, —CH ₂ —, or —O—,
Z represents an acidic group which may be substituted with a C1-8 alkyl group,
ring1 represents a 3- to 10-membered cyclic group,
ring2 represents a 3- to 7-membered nitrogen-containing heterocycle;
m represents an integer of 0 to 6;
n represents an integer of 0 to 5,
p represents an integer of 0 to 5;
when m is 2 or more, the plurality of R ¹ may be the same or different;
when n is 2 or more, the plurality of R ² may be the same or different;
When p is 2 or more, the plurality of R ³ may be the same or different. ]
Or a pharmaceutically acceptable salt thereof is preferred.

  In the present invention, the “halogen atom” means fluorine, chlorine, bromine or iodine.

  In the present invention, the “C1-8 alkyl group” includes a linear or branched C1-8 alkyl group. For example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, 1 Methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylbutyl, 2-methyl-3-hexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1-ethyl -1-methylbutyl, 1-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1,1-dimethylpentyl, 1,1,3-trimethylbutyl, 1,1-diethyl Propyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 3-ethylpentyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methyl Heptyl, 6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 1 Propylpentyl, 2-propylpentyl, 1,5-dimethylhexyl, 1-ethyl-4-methylpentyl, 1-propyl-3-methylbutyl, 1,1-dimethylhexyl, 1-ethyl-1-methylpentyl, or 1 , 1-diethylbutyl group.

  In the present invention, the “C1-4 alkyl group” includes a linear or branched C1-4 alkyl group such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, A tert-butyl group is mentioned.

  In the present invention, the “C1-3 alkyl group” includes a linear or branched C1-4 alkyl group, and examples thereof include a methyl, ethyl, propyl, and isopropyl group.

  In the present invention, the “C1-4 haloalkyl group” means a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, 2 -Means chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 4-bromobutyl To do.

  In the present invention, the “C1-3 haloalkyl group” means a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, 2 -A chloroethyl group, a pentafluoroethyl group, a 1-fluoropropyl group, a 2-chloropropyl group, a 3-fluoropropyl group, or a 3-chloropropyl group.

  In the present invention, examples of the “C1-4 alkoxy group” include a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, or tert-butoxy group.

  In the present invention, the “acidic group” means, for example, a carboxyl group, a hydroxyl group, a hydroxamic acid group, a sulfonic acid group, a boronic acid group, a carbamoyl group, a sulfamoyl group, a sulfoximine group (—SH (═O) (═NH)). Or a tetrazolyl group.

  In the present invention, “3 to 10-membered cyclic group” means a C3 to 10-membered carbon ring or a 3 to 10-membered heterocycle.

  In the present invention, the “C3-10 carbocycle” refers to a C3-10 monocyclic or bicyclic carbocycle, which may be partially or fully saturated. For example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, par Hydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene.

  In the present invention, the “3- to 10-membered heterocycle” means a partially or fully saturated 3- to 10-membered hetero atom containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. Monocyclic or bicyclic heterocycle. For example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadi Azole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithiaphthalene, indazole, quinoline, isoquinoline, Quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoly Cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydro Pyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, Perhydrodiazepine, Xylan, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydro Thiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole ( Isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazo , Tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydro Oxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazole Azepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline, Soindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline Perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline Tetrahydroquinazoline, Hydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzooxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole , Dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane, dioxaindane, benzodioxane, chroman, benzodithiolane, or benzodithian ring.

  In the present invention, the “5- to 7-membered cyclic group” means a C 5-7 carbocyclic ring or a 5- to 7-membered heterocyclic ring.

  In the present invention, the “C5-7 carbocycle” means a C5-7 monocyclic carbocycle which may be partially or wholly saturated, such as cyclopentane. , Cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, or a benzene ring.

  In the present invention, the “5- to 7-membered heterocycle” includes a 5- to 7-membered unsaturated heterocycle or a 5- to 7-membered saturated heterocycle. Examples of the 5- to 7-membered heterocycle include pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine , Tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydro Pyran, dihydrooxepin, tetrahydrooxepin, perhydroox Pin, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepin, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), Dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydro Oxadiazine, tetrahydrooxadiazine, dihydrooxazepine Tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine , Tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiazepine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane, Pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, Examples include pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, or thiazepine ring.

  In the present invention, the “3- to 7-membered nitrogen-containing heterocycle” means an unsaturated or saturated 3- to 7-membered single atom containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. Of the ring heterocycles, those that always contain one or more nitrogen atoms. For example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, oxazepine, oxadiazepine, thiazepine, thiadiazepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, Oxadiazine, thiadiazole, thiazine, thiadiazine, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine , Tetrahydropyrimidine, p Hydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (Isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thia Diazolidine), dihydrothiazine, Trahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxazepine, tetrahydrooxa Zepin, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, or per A hydrothiadiazepine ring is mentioned.

  In the present invention, the “4- to 7-membered nitrogen-containing saturated heterocycle” means a partially or fully saturated 4- to 5-containing heteroatom selected from an oxygen atom, a nitrogen atom and a sulfur atom. Of 7-membered monocyclic heterocycles, it always includes one or more nitrogen atoms. For example, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, Dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, didihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (Isoxazolidine), Hydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydro Oxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidines ), Dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihi Rochiazepin, tetrahydrothienyl azepine, perhydro thiazepine, dihydrothienyl azide azepine, tetrahydrothienyl azide azepine, perhydro Ji azide azepine, morpholine or thiomorpholine etc., can be mentioned.

In the compound of the general formula (I), R ¹ is preferably a C1-4 alkyl group or a halogen atom, more preferably a C1-4 group, and particularly preferably a methyl group.

In the compound of the general formula (I), R ² is preferably a C1-3 alkyl group, a halogen atom, or a C1-3 haloalkyl group.

  In the compound of the general formula (I), Z is substituted with a carboxyl group which may be substituted with a C1-8 alkyl group, a hydroxyl group which may be substituted with a C1-8 alkyl group, or a C1-8 alkyl group. Hydroxamic acid group which may be substituted, sulfonic acid group which may be substituted with C1-8 alkyl group, boronic acid group which may be substituted with C1-8 alkyl group, substituted with C1-8 alkyl group Preferred are a carbamoyl group, a sulfamoyl group optionally substituted with a C1-8 alkyl group, a sulfoxyimine group optionally substituted with a C1-8 alkyl group, and a tetrazolyl group, preferably substituted with a C1-8 alkyl group. The carboxyl group which may be sufficient is more preferable.

  In the compound of the general formula (I), ring1 is preferably a 5- to 7-membered cyclic group.

  In the compound of the general formula (I), ring1 is preferably cyclopentane, cyclohexane, cycloheptane, cyclopentene, benzene, pyridine, naphthalene, indole, or dihydroindole.

  In the compound of the general formula (I), the ring 2 is preferably a 4- to 7-membered nitrogen-containing saturated heterocyclic ring, more preferably azetidine, pyrrolidine, piperidine or perhydroazepine.

  In the compound of the general formula (I), m is preferably an integer of 1 to 2.

［式中、
Ｒ^1-1は、Ｃ１〜４アルキル基、またはハロゲン原子を表し、
Ｒ^2-1は、Ｃ１〜３アルキル基、ハロゲン原子、またはＣ１〜３ハロアルキル基を表し、
ｒｉｎｇ１−１は、５〜７員の環状基を表し、
ｒｉｎｇ２−１は、４〜７員の含窒素飽和ヘテロ環を表し、
ｍ−１は、１〜２の整数を表し、
ｍ−１が２のとき、複数のＲ^1-1は同じでも異なっていてもよく、
ｎが２以上のとき、複数のＲ^2-1は同じでも異なっていてもよく、
その他の記号は前記と同じ意味を表す。］
で示される化合物がより好ましい。 As a compound of general formula (I), general formula (I-1)

[Where:
R ^1-1 represents a C1-4 alkyl group or a halogen atom,
R ^2-1 represents a C1-3 alkyl group, a halogen atom, or a C1-3 haloalkyl group,
ring1-1 represents a 5- to 7-membered cyclic group;
ring2-1 represents a 4- to 7-membered nitrogen-containing saturated heterocyclic ring;
m-1 represents an integer of 1 to 2,
When m-1 is 2, a plurality of R ^1-1 may be the same or different,
when n is 2 or more, the plurality of R ^2-1 may be the same or different;
Other symbols have the same meaning as described above. ]
The compound shown by is more preferable.

In the general formula (I-1), examples of R ^1-1, preferably C1~4 alkyl group, more preferably a methyl group.

  In the general formula (I-1), the 5- to 7-membered cyclic group represented by ring1-1 is preferably cyclopentane, cyclohexane, cycloheptane, cyclopentene, benzene, or pyridine.

  In general formula (I-1), ring1-1 may be cyclopentane, cyclohexane, cycloheptane, cyclopentene, benzene, pyridine, naphthalene, indole, or dihydroindole.

  In the general formula (I-1), the 4- to 7-membered nitrogen-containing saturated heterocyclic ring represented by ring 2-1 is preferably azetidine, pyrrolidine, piperidine, or perhydroazepine.

  In the compound of the general formula (I), all isomers are included unless otherwise specified. For example, alkyl groups include straight chain and branched chain. Furthermore, geometric isomers in double bonds, rings and condensed rings (E-form, Z-form, cis-form, trans-form), optical isomers due to the presence of asymmetric carbon atoms, etc. (R, S-form, α, β configuration, Enantiomers, diastereomers), optically active substances having optical activity (D, L, d, l form), polar forms (high polar form, low polar form) by chromatographic separation, equilibrium compounds, rotamers, these Any ratio of mixtures, racemic mixtures are all included in the present invention. Moreover, in this invention, all the isomers by a tautomer are also included.

  Moreover, the optical isomers in the compound of the general formula (I) may include not only 100% pure but also other optical isomers of less than 50%.

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比率の混合物であることを表す。 In the compound of the general formula (I), unless otherwise specified, the symbol

Indicates that it is connected to the other side of the page (ie α configuration),

Represents binding to the front side of the paper (that is, β arrangement),

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

  The compound represented by the general formula (I) can be converted into a corresponding pharmaceutically acceptable salt by a known method. The pharmaceutically acceptable salt is preferably water-soluble. Suitable pharmaceutically acceptable salts include alkali metal (potassium, sodium, etc.) salts, alkaline earth metal (calcium, magnesium etc.) salts, ammonium salts, pharmaceutically acceptable organic amines (tetramethyl). Salts of ammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.) Acid adduct salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salts (acetate, trifluoroacetate, lactate, Tartrate, oxalate, fumarate, maleate, benzoate, citrate, Tan, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, and gluconate, etc.), etc.) and the like.

  In addition, the compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof may be a solvate or a solvate. The solvate is preferably low toxic and water soluble. Suitable solvates include, for example, solvates with water and alcohol solvents (for example, ethanol). The compounds of the present invention and pharmaceutically acceptable salts thereof can be converted into the corresponding solvates by known methods.

  Further, the compound represented by the general formula (I) in the free form may be a co-crystal formed with an appropriate co-crystal former. Here, the co-crystal is a crystal in which two or more different molecules are formed by an intermolecular interaction different from an ionic bond. 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 formers include those described in WO 2006/007448.

  The compound represented by the general formula (I) can be produced according to the method described in Patent Document 2 (International Publication No. 2016/088884).

<Therapeutic and / or preventive agent for synucleinopathy and α-synuclein accumulation inhibitor>
The therapeutic and / or prophylactic agent for synucleinopathy of the present invention and the α-synuclein accumulation inhibitor (both collectively referred to below as “the agent of the present invention”) include an S1P ₅ receptor agonist.

  In the present invention, “synucleinopathy” refers to a group of neurodegenerative diseases characterized by abnormal accumulation of α-synuclein aggregates in nerve cells, nerve fibers, or glial cells. The synucleinopathies are, for example, Parkinson's disease (PD), Parkinson's dementia (PDD), multiple system atrophy (MSA), Lewy body dementia (DLB), juvenile-onset pervasive neuroaxonal dystrophy (Hallafor) Denschpatz (Hallervorden-Spatz disease), pure autonomic ataxia (PAF), neurodegeneration type 1 (NBIA-I) with brain iron deposition, Gaucher disease and Tay-Sachs Including lysosomal diseases, including Alzheimer's disease, and Alzheimer-type dementia (AD). Clinically, these diseases are characterized by a chronic and progressive decline in motor function, cognitive function, behavioral function and autonomic function, depending on the distribution of lesions.

  The therapeutic and / or prophylactic agent for synucleinopathies of the present invention is preferably used for the treatment of Parkinson's disease, multiple system atrophy or Lewy body dementia. Parkinson's disease and Lewy body dementia are neurodegenerative diseases characterized by accumulation of α-synuclein in nerve cells, and can be treated by inhibiting α-synuclein accumulation in nerve cells. For Parkinson's disease, it has been reported that oligodendrocytes are less involved. (For example, see Movement Disorders, Vol 26, Issue 1, pages 6-17 (2011).) Multiple system atrophy is a neurodegenerative disease characterized by the accumulation of α-synuclein mainly in oligodendrocytes. Can be treated by inhibiting α-synuclein accumulation in oligodendrocytes.

  The α-synuclein of the present invention includes phosphorylated α-synuclein.

  The agents of the present invention can be administered to mammals in need of treatment and / or prevention of synucleinopathies and to mammals in need of inhibition of α-synuclein accumulation. Mammals include, but are not limited to, primates (humans, monkeys, etc.), rodents (mouse, rats, guinea pigs, etc.), cats, dogs, rabbits, sheep, pigs, cows, horses, donkeys, goats. And ferrets. Preferably, it is a human.

The agent of the present invention is
1) To supplement and / or enhance the therapeutic effect of the agent of the present invention,
2) To improve the kinetics / absorption of the agent of the present invention, to reduce the dose, and / or 3) To reduce the side effects of the agent of the present invention,
It may be administered as a concomitant drug in combination with other drugs.

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

  Further, the concomitant drugs combined with the agent of the present invention include not only those found so far but also those found in the future.

  The agent of the present invention is usually administered systemically or locally in an oral or parenteral form. Examples of oral preparations include liquids for internal use (for example, elixirs, syrups, pharmaceutically acceptable solutions, suspensions, emulsions), solid preparations for internal use (for example, tablets (sublingual tablets, buccal cavity) Disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, and troches. Examples of parenteral agents include liquids (eg, injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drops, etc.), eye drops (eg, aqueous eye drops (aqueous eye drops) Liquid, aqueous suspension ophthalmic solution, viscous ophthalmic solution, solubilized ophthalmic solution, etc.), non-aqueous ophthalmic solution (non-aqueous ophthalmic solution, non-aqueous suspension ophthalmic solution, etc.)), etc. Etc.), ear drops and the like. These preparations may be release control agents such as immediate-release preparations and sustained-release preparations. These preparations can be produced by a known method, for example, a method described in the Japanese Pharmacopoeia.

  The liquid for internal use as an oral preparation is produced, for example, by dissolving, suspending or emulsifying the active ingredient in a diluent (for example, purified water, ethanol or a mixture thereof) generally used. Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

  The solid preparation for internal use as an oral preparation includes, for example, an active ingredient as an excipient (eg, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), a binder (eg, hydroxypropylcellulose, polyvinylpyrrolidone, aluminum metasilicate). Magnesium oxide, etc.), disintegrating agents (eg, calcium calcium glycolate), lubricants (eg, magnesium stearate), stabilizers, solubilizing agents (glutamic acid, aspartic acid, etc.), etc. According to the formulation. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers.

  An external preparation as a parenteral preparation is produced by a known method or a commonly used formulation. For example, an ointment is manufactured by kneading or melting an active ingredient in a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (E.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene) Recall, macrogol, etc.), vegetable oil (eg, castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oil (eg, mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancer, anti-rash agent Can be used alone or in admixture of two or more. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like may be included.

  The parenteral injection includes solutions, suspensions, emulsions and solid injections used by dissolving or suspending in a solvent when used. An injection is used, for example, by dissolving, suspending or emulsifying an active ingredient in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Furthermore, this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative and the like. Also good. These are sterilized in the final process or manufactured by aseptic manipulation. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.

  In order to use the agent of the present invention or a combination drug of the agent of the present invention and another drug for the above-mentioned purpose, it is usually administered systemically or locally in an oral or parenteral form. The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered once to several times a day in the range of 1 ng to 1000 mg per adult per dose. Or administered parenterally once or several times a day in the range of 0.1 ng to 10 mg per adult, or continuously administered intravenously in the range of 1 hour to 24 hours per day. The Of course, as described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, or administration may be necessary beyond the range.

  The toxicity of the agent of the present invention is sufficiently low and can be used safely as a pharmaceutical product.

  Hereinafter, although an example explains the present invention in detail, the present invention is not limited to these.

The following compounds were used as S1P ₅ receptor agonists.
1-{[6- (4-Fluorophenoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid (Compound 1)

  Compound 1 is the compound described in Example 11 of Patent Document 2 (International Publication No. 2016/088884), and was produced according to the method described in Patent Document 2.

Biological Experiment Example 1 : Measurement of Compound Inhibitory Effect on Binding of [ ³³ P] -S1P to S1P ₅ (EDG-8) Chinese Hamster Overly (CHO) Cell Membrane Overexpressed Human S1P ₅ Gene Using the fraction, the membrane fraction was reacted in a 96-well assay plate using 1 mg protein / mL. Vehicle (DMSO) solution diluted with Binding Buffer (50 mmol / L, Tris pH 7.5, 5 mmol / L, MgCl ₂ , 0.5% BSA, Complete EDTA free (1 tablet / 50 mL)) or double concentration of ligand in each well (Compound 1) 100 μL of the solution and 50 μL of 0.16 nmol / L [ ³³ P] -S1P (American Radiolabeled Chemicals) diluted with Binding Buffer were added, and then the membrane fraction solution (50 μL) was added for 60 minutes at room temperature. Reacted. After the reaction, the solution was suction filtered using a 96-hole UNIFILTER, washed with a washing buffer (50 mmol / L, Tris pH 7.5, 0.5% BSA) (150 mL), and then dried at 60 ° C. for 45 minutes. MicroScint (trade name) 20 (50 μL / well) was added, the plate was covered with TopSeal-A, and then the radioactivity was measured with TopCount (Perkin Elmer).

[result]
Compound 1 showed an inhibition activity (IC50 value) of 1.8 nM for the binding of [ ³³ P] -S1P to S1P ₅ .

Biological Example 2 : Evaluation of S1P receptor agonist activity of compounds by monitoring intracellular cyclic AMP production concentration Overexpression of human S1P ₁ (EDG-1) or S1P ₅ (EDG-8) genes, respectively The selected CHO cells were cultured in Ham's F12 medium (GIBCO BRL) containing 10% FBS (fetal bovine serum), penicillin / streptomycin and geneticin (0.25 mg / mL). The medium is removed from the cultured cells, washed once with phosphate buffered saline, and Hanks' balanced salt solution containing Buffer (20 mmol / L HEPES, 0.1 or 0.2% BSA, 1 mmol / L IBMX and 50 μmol / L forskolin). The vehicle (DMSO) solution or the Compound 1 solution diluted in (1) was treated at 37 ° C. for 30 minutes. Thereafter, the cells were washed once with phosphate buffered saline, and cell lysis and the cyclic AMP concentration in the lysate were measured using a cAMP measurement kit (GE Healthcare).

[result]
The EC50 value for the S1P ₁ receptor of Compound 1 was> 10000 nM. On the other hand, EC50 values for SlP ₅ receptor Compound 1 was 1.7 nM.

Biological Example 3 : Evaluation of α-synuclein accumulation inhibitory action in primary mouse brain culture system A cerebrum was collected from a transgenic mouse (CNP-α-syn Tg mouse) forcibly expressing human α-synuclein in oligodendrocytes. Cells containing neurons and glial cells were prepared. The cells were cultured at a concentration of 1 × 10 ⁵ cells / cm ² on a cover glass having a diameter of 15 mm coated with 0.1% polyethylenimine (Sigma Aldrich). For culture, Dulbecco's modified Eagle's medium (Wako) and B27 / neurobasal medium are mixed 1: 1, and 5% calf serum, 50 U / ml penicillin, 50 μg / ml streptomycin, 1 mmol / L L-glutamine, and 50 μg A solution to which / ml insulin (Sigma-Aldrich) was added was used. Culture was performed for 30 days (DIV 30). Treatment with 3 μM (final concentration) of Compound 1 from DIV 2 to DIV 9 for 7 days. The DMSO treatment group was used as a control. The cover glass with the cultured cells attached thereto was fixed with 4% paraformaldehyde, treated with methanol, and permeabilized with 0.5% TritonX-100 / PBS. Pre-treatment with PBS containing 2% bovine serum albumin and 2% goat serum. After reacting with an antibody that specifically recognizes mouse α-synuclein and anti-beta-III tubulin antibody as the primary antibody, fluorescent substance Immunofluorescence double staining was performed with a secondary antibody marked with. The staining results were observed at 10 sites with a 200 × field using a Leica DMI 6000 B microscope, and the α-synuclein positive rate in nerve axons and cell bodies was calculated.

[result]
The results are shown in FIG. Compound 1 treatment reduced the alpha-synuclein positive rate in nerve axons.

Biological Example 4 : Efficacy test using mice overexpressing human A53T mutant α-synuclein
Male and female mice (A53T α-Syn Tg mice) overexpressing 5-month-old human A53T mutant α-synuclein were randomly assigned to have 15 animals in each group (male and female in each group). 7-8 each). Water for injection or Compound 1 (3, 30 mg / kg) was orally administered once daily for 16 weeks in a volume of 10 mL / kg. The body weight of the mice was measured once a week, and the dose was calculated based on the latest body weight. After the final administration of the compound, the rotarod test was evaluated to examine the motor function of the mice. The test assesses coordination by placing the animal on a rotating rod that moves at a constant or accelerated rate. When the mouse lost balance and fell to the underlying platform, the rod stopped automatically and the time to fall was measured as latency time (seconds). Prior to the test session, the mice were accustomed to the test system by staying on the rod at a constant speed of 2 rpm for 60 seconds. In the evaluation, the initial speed was increased from 2 rpm to 20 rpm, and the mouse was left on the lot for 180 seconds. If the mouse falls, the session is over and the timer is stopped. This test was performed twice for each animal, and the average was taken as the latency time.

  In addition, after the behavioral test, mouse brains were collected (8 mice in each group), and α-synuclein accumulation was evaluated by immunohistochemical staining. The right hemicerebral spinal cord was fixed by penetrating 4% paraformaldehyde / PBS (pH = 7.4) for 2 hours at room temperature. The hemisphere was then immersed overnight in 15% sucrose PBS solution, after which the sample was transferred to a 30% sucrose-PBS solution for cryoprotection. Phosphorylated α-synuclein in the cortex and hippocampus was quantified using a rabbit monoclonal antibody against Ab-synuclein phosphorylated with Ser129 (Abcam). Data were performed in a one-way ANOVA.

[result]
Compound 1 administration prolonged the latency (seconds) in the rotarod test and improved the motor function of the mice (FIG. 2). Compound 1 administration also reduced the proportion of phosphorylated α-synuclein in the cortex and hippocampus (FIGS. 3 and 4).

[Formulation example]
Formulation Example 1
The following components are mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 10 mg of the active ingredient.
1-{[6- (4-Fluorophenoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid ... 100 g
・ Carboxymethylcellulose calcium (disintegrant): 20g
・ Magnesium stearate (lubricant): 10g
・ Microcrystalline cellulose: 870 g

Formulation Example 2
The following components are mixed by a conventional method, filtered through a dust filter, filled in 5 ml aliquots, and heat sterilized in an autoclave to obtain 10,000 ampoules containing 20 mg of active ingredient in one ampule.
1-{[6- (4-Fluorophenoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid ... 200 g
・ Mannitol: 20g
・ Distilled water: 50L

  By using the agent of the present invention, it is possible to inhibit α-synuclein accumulation and effectively treat and prevent synucleinopathies.

Claims (10)

Including SlP ₅ receptor agonist, a therapeutic and / or prophylactic agent for synucleinopathies, the SlP ₅ receptor agonist has the general formula (I):

[Where:
R ¹ represents a C1-4 alkyl group, a halogen atom, a C1-4 haloalkyl group, or a C1-4 alkoxy group,
R ² represents C1 -4 alkyl group, a halogen atom, C1 -4 haloalkyl group, or an SF ₅ group,
R ³ represents a C1-4 alkyl group,
L represents a bond, —CH ₂ —, or —O—,
Z represents an acidic group which may be substituted with a C1-8 alkyl group,
ring1 represents a 3- to 10-membered cyclic group,
ring2 represents a 3- to 7-membered nitrogen-containing heterocycle;
m represents an integer of 0 to 6;
n represents an integer of 0 to 5,
p represents an integer of 0 to 5;
when m is 2 or more, the plurality of R ¹ may be the same or different;
when n is 2 or more, the plurality of R ² may be the same or different;
When p is 2 or more, the plurality of R ³ may be the same or different. ]
A therapeutic and / or prophylactic agent for synucleinopathy, which is a compound represented by the formula: or a pharmaceutically acceptable salt thereof.   In the general formula (I), Z is (1) a carboxyl group which may be substituted with a C1-8 alkyl group, (2) a hydroxyl group which may be substituted with a C1-8 alkyl group, (3) C1— Hydroxamic acid group optionally substituted with 8 alkyl groups, (4) Sulfonic acid group optionally substituted with C1-8 alkyl groups, (5) Boronic acid optionally substituted with C1-8 alkyl groups A group, (6) a carbamoyl group optionally substituted with a C1-8 alkyl group, (7) a sulfamoyl group optionally substituted with a C1-8 alkyl group, and (8) substituted with a C1-8 alkyl group. The agent according to claim 1, which may be a sulfoximine group or (9) a tetrazolyl group.   The agent according to claim 1 or 2, wherein, in the general formula (I), Z is a carboxyl group which may be substituted with a C1-8 alkyl group.   The agent according to any one of claims 1 to 3, wherein in the general formula (I), ring1 is a 5- to 7-membered cyclic group.   In general formula (I), ring1 is (1) cyclopentane, (2) cyclohexane, (3) cycloheptane, (4) cyclopentene, (5) benzene, (6) pyridine, (7) naphthalene, (8) The agent according to any one of claims 1 to 4, which is indole or (9) dihydroindole.   The agent of any one of Claims 1-5 whose m is an integer of 1-2 in general formula (I). The S1P ₅ receptor agonist has the general formula (I-1)

[Where:
R ^1-1 represents a C1-4 alkyl group or a halogen atom,
R ^2-1 represents a C1-3 alkyl group, a halogen atom, or a C1-3 haloalkyl group,
ring1-1 represents a 5- to 7-membered cyclic group;
ring2-1 represents a 4- to 7-membered nitrogen-containing saturated heterocyclic ring;
m-1 represents an integer of 1 to 2,
When m-1 is 2, a plurality of R ^1-1 may be the same or different,
when n is 2 or more, the plurality of R ^2-1 may be the same or different;
Other symbols represent the same meaning as in claim 1. ]
The agent of Claim 1 which is a compound shown by these, or its pharmaceutically acceptable salt. S1P ₅ receptor agonist is 1-{[6- (4-fluorophenoxy) -1-methyl-3,4-dihydro-2-naphthalenyl] methyl} -3-azetidinecarboxylic acid or a pharmaceutically acceptable salt thereof The agent according to claim 1, which is a salt to be prepared.   The agent according to any one of claims 1 to 8, wherein the synucleinopathy is Parkinson's disease, multiple system atrophy, or Lewy body dementia. Including SlP ₅ receptor agonist, a α- synuclein accumulation inhibitor, the SlP ₅ receptor agonist has the general formula (I):

[Wherein all symbols have the same meaning as in claim 1.] ]
An α-synuclein accumulation inhibitor, which is a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

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