JP2010047517A - Treating or preventing agent for disease associated with activity of neurotropic factor, and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a low-molecular weight compound effective for treatment, prevention and the like of a disease associated with activity of a neurotropic factor. <P>SOLUTION: The treating or preventing agent for a disease associated with activity of a neurotropic factor comprises as an effective ingredient a compound represented by general formula Ia or Ib [wherein A<SB>1</SB>is a ring optionally substituted with at least one Y<SB>a</SB>; A<SB>2</SB>is an alkylene chain; A<SB>3</SB>is an aromatic group optionally substituted with at least one Y<SB>b</SB>; A<SB>4</SB>is a hydrogen atom or an alkyl group, or may be linked to one Y<SB>a</SB>to form a bivalent chain group; X<SB>1</SB>is S, SO, SO<SB>2</SB>, NH or O; n1 is an integer of 0-4; Y<SB>1</SB>'s and Y<SB>b</SB>'s are each independently a hydroxy group or the like in each appearance; and Y<SB>a</SB>'s are each independently a hydroxy group or the like in each appearance], a pharmacologically acceptable salt thereof, or a hydrate thereof. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a therapeutic or prophylactic agent for diseases associated with neurotrophic factor activity, and a method for producing the same.

Neurotrophic factors such as BDNF and NGF are proteins that play an important role in central and peripheral nervous system cell differentiation, functional maintenance, synaptogenesis, and regeneration and repair upon injury, such as neurodegenerative diseases, diabetic Effective for the treatment of neuropathy, amyotrophic side sclerosis, multiple sclerosis, cerebral ischemic disease, Alzheimer's disease, Parkinson's disease, Huntington's chorea, depression, and peripheral neuropathy caused by cancer chemotherapy, etc. (Non-Patent Documents 2, 3, 4, and 5). However, a neurotrophic factor is a high molecular weight protein having a molecular weight of 10,000 or more, and it is known that when such a high molecular weight protein is used as a therapeutic agent, there are restrictions on the administration method and safety problems (non-patented). From the references 6 and 7), there is an urgent need to provide a low molecular weight compound that enhances the action of a neurotrophic factor with few side effects.
On the other hand, it is known that the expression of certain transcriptional regulatory factors is controlled by neurotrophic factors (see Non-Patent Document 1), and one of the transcriptional regulatory factors whose expression is controlled by neurotrophic factors. NXF is known (see Patent Document 1).
In addition, in mice lacking NXF, symptom of neurodegenerative disease appears serious when glutamate toxicity, which is considered as one of the causes of neurodegenerative disease, is induced, so NXF is important for neuroprotective action. It is known to have a role (see Patent Document 2).

JP 2007-282502 A JP 2007-282501 A Nature, 322, 1986, p. 552-555 The Journal of the American Society for Experimental NeuroTherapeutics, vol. 2, 2005, p. 120-128 Annual review of neuroscience, 24, 2001, p. 1217-1281 Brain research reviews, 30, 1999, p. 176-188 Progress in brain research, 146, 2004, p. 387-401 “Latest Medicine” Vol. 54, No. 7, 1999, pp. 88-94 “Intervention Stroke Studies (Revised 2nd Edition)-From Hyperacute to Prevention of Recurrence”, 2006, pp. 649-654

  As described above, development and provision of low molecular weight compounds that enhance the activity of neurotrophic factors are eagerly desired.

［式中、
Ａ_１は、
１個以上のＹ_ａで置換されていてもよい環を表し；
Ａ_２は、
アルキレン鎖を表し；
Ａ_３は、
１個以上のＹ_ｂで置換されていてもよい芳香族基を表し；
Ａ_４は、
水素原子またはアルキル基を表すか、あるいは１個のＹ_ａと結合して２価の鎖状基を形成してもよく；
Ｘ₁は、
Ｓ、ＳＯ、ＳＯ_２、ＮＨまたはＯを表し；
ｎ１は、
０から４の整数を表し；
Ｙ_１、Ｙ_ａおよびＹ_ｂは、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子、
3)カルボキシ基、
4)ニトロ基、
5)シアノ基、
6)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基、
7)アリール基、または
8)Ｒ^１−Ｚ_２−Ｚ_１−
（式中、
Ｒ^１は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ_２は、−Ｓ（Ｏ）ｑ−、−Ｏ−、−Ｓ−、−ＮＲ^２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ^２−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ−ＮＨ−、−Ｓ（Ｏ）ｑ−ＮＨ−または−ＮＲ^２−Ｓ（Ｏ）ｑ−（ｑは０〜２の整数を、Ｒ^２は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ_１は結合手またはアルキレン鎖を表す。）を表し；
また、
隣接する２個のＹ_ａが、これらが結合している２個の原子と一緒になって、１個以上のＹａ’で置換されていてもよい環を形成してもよく、および
１個の炭素原子上の２個のＹ_ａが、該炭素原子と一緒になって、カルボニル基またはチオカルボニル基を形成してもよい；
Ｙａ’は、各出現において、それぞれ独立して、
水酸基、
ハロゲン原子、
カルボキシ基、
ニトロ基、
アルキル基、
シクロアルキル基または
アルコキシ基
を表し、また１個の炭素原子上の２個のＹａ’が、該炭素原子と一緒になって、カルボニル基を形成してもよい。］
で示される化合物、薬学的に許容される塩、またはその水和物を有効成分として含有する、神経栄養因子の活性が関与する疾患の治療または予防剤。
［２］
神経栄養因子の活性が関与する疾患が、脳卒中、脳虚血性疾患、多発性脳梗塞性認知症、ビンスワンガー型白質脳症、アルツハイマー病、ダウン症、パーキンソン病、筋萎縮性側索硬化症または網膜変性疾患である上記［１］に記載の剤。 Thus, the inventors searched for compounds that enhance the activity of neurotrophic factor using NXF expression inducing ability as an index, and as a result, condensed 6-membered ring having a specific structure or a salt thereof enhanced the activity of neurotrophic factor. In addition, the present inventors have found that it has a protective effect on nerve cells and has reached the present invention.
That is, the present invention provides the following [1] to [23] and the like.
[1]
General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A ₂ is,
Represents an alkylene chain;
A ₃ is,
Represents an aromatic group optionally substituted by one or more Y _b ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
X ₁ is
Represents S, SO, SO ₂ , NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ , Y _a and Y _b are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. );
Also,
Two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and one Two Y _a on a carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A therapeutic or prophylactic agent for a disease involving the activity of neurotrophic factor, comprising as an active ingredient a compound represented by the formula:
[2]
Diseases involving neurotrophic factor activity are stroke, cerebral ischemic disease, multiple cerebral infarction dementia, binswanger leukoencephalopathy, Alzheimer's disease, Down's syndrome, Parkinson's disease, amyotrophic lateral sclerosis or retinal degenerative disease The agent according to [1] above.

［式中、
Ａ_１は、
１個以上のＹ_ａで置換されていてもよい環を表し；
Ａ_２は、
アルキレン鎖を表し；
Ａ_３は、
１個以上のＹ_ｂで置換されていてもよい芳香族基を表し；
Ａ_４は、
水素原子またはアルキル基を表すか、あるいは１個のＹ_ａと結合して２価の鎖状基を形成してもよく；
Ｘ₁は、
Ｓ、ＮＨまたはＯを表し；
ｎ１は、
０から４の整数を表し；
Ｙ_１、Ｙ_ａおよびＹ_ｂは、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子、
3)カルボキシ基、
4)ニトロ基、
5)シアノ基、
6)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基、
7)アリール基、または
8)Ｒ^１−Ｚ_２−Ｚ_１−
（式中、
Ｒ^１は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ_２は、−Ｓ（Ｏ）ｑ−、−Ｏ−、−Ｓ−、−ＮＲ^２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ^２−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ−ＮＨ−、−Ｓ（Ｏ）ｑ−ＮＨ−または−ＮＲ^２−Ｓ（Ｏ）ｑ−（ｑは０〜２の整数を、Ｒ^２は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ_１は結合手またはアルキレン鎖を表す。）を表し
（但し、Ｘ₁がＯのとき、Ｙ_１は水酸基ではない）；
また、隣接する２個のＹ_ａが、これらが結合している２個の原子と一緒になって、１個以上のＹａ’で置換されていてもよい環を形成してもよく、および
１個の炭素原子上の２個のＹ_ａが、該炭素原子と一緒になって、カルボニル基またはチオカルボニル基を形成してもよい；
Ｙａ’は、各出現において、それぞれ独立して、
水酸基、
ハロゲン原子、
カルボキシ基、
ニトロ基、
アルキル基、
シクロアルキル基または
アルコキシ基
を表し、また１個の炭素原子上の２個のＹａ’が、該炭素原子と一緒になって、カルボニル基を形成してもよい。］
で示される化合物
（ただし、
１，２，３，４−テトラヒドロ−２−（２−ピリジルメチル）−３−（２，４−ジオキソ−６−メチルピラン−３−イリデン）−キノキサリン、
１，２，３−４−テトラヒドロ−２−（２−ピリジルメチル）−３−（２，４−ジオキソ−６−メチルピラン−３−イリデン）−６，７−ジメチル−キノキサリン、
２，３−ジヒドロ−２−（４−ピリジルメチル）−３−（２，４−ジオキソ−６−メチルピラン−３−イリデン）−ベンゾ［１，４］チアジン、
２，３−ジヒドロ−２−（２−ニトロフェニルメチル）−３−（２，４−ジオキソ−６−メチルピラン−３−イリデン）−ベンゾ［１，４］チアジンおよび
２，３−ジヒドロ−２−（４−ニトロフェニルメチル）−３−（２，４−ジオキソ−６−メチルピラン−３−イリデン）−ベンゾ［１，４］チアジン
は除く。）
、薬学的に許容される塩、またはその溶媒和物。 [3]
General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A ₂ is,
Represents an alkylene chain;
A ₃ is,
Represents an aromatic group optionally substituted by one or more Y _b ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
X ₁ is
Represents S, NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ , Y _a and Y _b are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group);
And two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and 1 Two Y _a on one carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A compound represented by (however,
1,2,3,4-tetrahydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -quinoxaline,
1,2,3-4-tetrahydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -6,7-dimethyl-quinoxaline,
2,3-dihydro-2- (4-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine,
2,3-dihydro-2- (2-nitrophenylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine and 2,3-dihydro-2- (4-Nitrophenylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine is excluded. )
, A pharmaceutically acceptable salt, or a solvate thereof.

［式中、
Ｘ_２１、Ｘ_２２、Ｘ_２３およびＸ_２４は、
それぞれ独立して、Ｎ、Ｃ−ＨまたはＣ−Ｙ_ａを表し（但し、Ｘ_２１、Ｘ_２２、Ｘ_２３およびＸ_２４の２つ以上がＣ−ＨまたはＣ−Ｙ_ａである）;
Ａ_４は、
水素原子またはアルキル基を表すか、あるいはＸ_２１上のＹ_ａと結合して−Ｘ_２−（ＣＨ_２）_ｍ−（Ｘ_２はＯまたはＳを表し、ｍは０〜２の整数を表す）で表される２価の鎖状基を形成してもよく；および
その他の記号は前記と同一の意味を表す。
］
で示される化合物である、上記［３］に記載の化合物。 [4]
The compound represented by the general formula (Ia) or (Ib)
formula

[Where:
X ₂₁ , X ₂₂ , X ₂₃ and X ₂₄ are
Each independently represents N, C—H or C—Y _a where two or more of X ₂₁ , X ₂₂ , X ₂₃ and X ₂₄ are C—H or C—Y _a ;
A ₄ is,
Represent hydrogen atom or an alkyl group, or combine with _{Y a} on _{X 21 -X 2 - (CH 2} ) m - (X 2 represents O or S, m is an integer of 0 to 2) And other symbols represent the same meaning as described above.
]
The compound according to [3] above, which is a compound represented by the formula:

［式中、
Ｘ_３１はＮ−Ｙ_ｃまたはＯを表し；
Ｘ_３２およびＸ_３３は、それぞれ独立して、Ｃ−Ｈ、Ｃ−Ｙ_ａまたはＮを表し（但し、Ｘ_３２およびＸ_３３のうち少なくとも１つは、Ｃ−ＨまたはＣ−Ｙ_ａである。）；
Ｙ_ｃは
1)水素原子
2)ハロゲン原子、
3)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基
4)アリール基
5)Ｒ１’−Ｚ２’−Ｚ１’−
（式中、
Ｒ１’は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ２’は、−Ｓ（Ｏ）ｑ’−、−Ｏ−、−Ｓ−、−ＮＲ２’−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ２’−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ’−ＮＨ−、−Ｓ（Ｏ）ｑ’−ＮＨ−または−ＮＲ２’−Ｓ（Ｏ）ｑ’−（ｑ’は０〜２の整数を、Ｒ２’は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ１’はアルキレン鎖を表す。）、または
6)Ｒ１’’−Ｚ２’’−
（式中、
Ｒ１’’は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ２’’は、−ＣＯ−、−Ｏ−ＣＯ−、−ＮＲ２’’−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ’’−、または−Ｓ（Ｏ）ｑ’’−（ｑ’’は０〜２の整数を、Ｒ２’’は水素原子、アルキル基またはシクロアルキル基を表す。）を表す。）を表し；および
その他の記号は前記と同一の意味を表す。］
で示される化合物である、上記［３］に記載の化合物。 [5]
The compound represented by the general formula (Ia) or (Ib)
formula

[Where:
X ₃₁ represents N—Y _c or O;
X ₃₂ and X ₃₃ each independently represent C—H, C—Y _a or N (provided that at least one of X ₃₂ and X ₃₃ is C—H or C—Y _a ). );
Y _c is
1) Hydrogen atom
2) a halogen atom,
3) An acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group
4) Aryl group
5) R1'-Z2'-Z1'-
(Where
R1 ′ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z2 ′ is —S (O) q′—, —O—, —S—, —NR2′—, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH. -, -NH-CO-NH-, -NR2'-CO-, -NH-S (O) q'-NH-, -S (O) q'-NH- or -NR2'-S (O) q '-(Q' represents an integer of 0 to 2, R2 'represents a hydrogen atom, an alkyl group or a cycloalkyl group),
Z1 ′ represents an alkylene chain. ), Or
6) R1 "-Z2"-
(Where
R1 ″ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z2 ″ is —CO—, —O—CO—, —NR2 ″ —CO—, —NH—S (O) q ″ —, or —S (O) q ″ — (q ″ is An integer of 0 to 2, R2 ″ represents a hydrogen atom, an alkyl group or a cycloalkyl group. And other symbols have the same meaning as described above. ]
The compound according to [3] above, which is a compound represented by the formula:

［式中、
Ｘ_４１およびＸ_４３は、
それぞれ独立して、ＣＨ_２、ＣＨ−Ｙ_ａ、Ｃ（Ｙ_ａ）_２またはＮ−Ｙ_ｃを表し；
Ｘ_４２は、ＣＨ_２、ＣＨ−Ｙ_ａまたはＣ（Ｙ_ａ）_２を表し；
ｎ２は０〜４の整数を表し、
Ｙ_ｃは
1)水素原子
2)ハロゲン原子、
3)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基
4)アリール基
5)Ｒ１’−Ｚ２’−Ｚ１’−
（式中、
Ｒ１’は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ２’は、−Ｓ（Ｏ）ｑ’−、−Ｏ−、−Ｓ−、−ＮＲ２’−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ２’−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ’−ＮＨ−、−Ｓ（Ｏ）ｑ’−ＮＨ−または−ＮＲ２’−Ｓ（Ｏ）ｑ’−（ｑ’は０〜２の整数を、Ｒ２’は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ１’はアルキレン鎖を表す。）、または
6)Ｒ１’’−Ｚ２’’−
（式中、
Ｒ１’’は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ２’’は、−ＣＯ−、−Ｏ−ＣＯ−、−ＮＲ２’’−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ’’−、または−Ｓ（Ｏ）ｑ’’−（ｑ’’は０〜２の整数を、Ｒ２’’は水素原子、アルキル基またはシクロアルキル基を表す。）を表す。）を表し；および
その他の記号は前記と同一の意味を表す。］
で示される化合物である、上記［３］に記載の化合物。 [6]
The compound represented by the general formula (Ia) or (Ib) is

[Where:
X ₄₁ and X ₄₃ are
Each _{independently} represents _{CH 2, CH-Y a,} C (Y a) 2 or _{N-Y c;}
X _{42 represents} CH 2, _{CH-Y a} or _{C (Y a) 2;}
n2 represents an integer of 0 to 4,
Y _c is
1) Hydrogen atom
2) a halogen atom,
3) An acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group
4) Aryl group
5) R1'-Z2'-Z1'-
(Where
R1 ′ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z2 ′ is —S (O) q′—, —O—, —S—, —NR2′—, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH. -, -NH-CO-NH-, -NR2'-CO-, -NH-S (O) q'-NH-, -S (O) q'-NH- or -NR2'-S (O) q '-(Q' represents an integer of 0 to 2, R2 'represents a hydrogen atom, an alkyl group or a cycloalkyl group),
Z1 ′ represents an alkylene chain. ), Or
6) R1 "-Z2"-
(Where
R1 ″ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z2 ″ is —CO—, —O—CO—, —NR2 ″ —CO—, —NH—S (O) q ″ —, or —S (O) q ″ — (q ″ is An integer of 0 to 2, R2 ″ represents a hydrogen atom, an alkyl group or a cycloalkyl group. And other symbols have the same meaning as described above. ]
The compound according to [3] above, which is a compound represented by the formula:

（Ａ３’は、１個以上のＹ_ｂで置換されていてもよい）で示される、含窒素ヘテロアリール基である、上記［８］に記載の化合物。
［１０］
Ａ_４が水素原子である上記［３］〜［９］のいずれかに記載の化合物。
［１１］
Ｘ₁がＳである上記［３］〜［１０］のいずれかに記載の化合物。 [7]
A ₂ is a methylene chain said [3] to a compound according to any one of [6].
[8]
A compound according to any one of A ₃ is one or more Y _b in optionally substituted heteroaryl group above [3] to [7].
[9]
A ₃ has the formula

The compound according to [8] above, which is a nitrogen-containing heteroaryl group represented by (A3 ′ may be substituted with one or more Y _b ).
[10]
A ₄ is a hydrogen atom the [3] The compound according to any one of - [9].
[11]
The compound according to any one of the above [3] to [10], wherein X ₁ is S.

［式中、
Ａ_１は、
１個以上のＹ_ａで置換されていてもよい環を表し；
Ａ_４は、
水素原子またはアルキル基を表すか、あるいは１個のＹ_ａと結合して２価の鎖状基を形成してもよく；
Ｘ₁は、
Ｓ、ＮＨまたはＯを表し；
ｎ１は、
０から４の整数を表し；
Ｙ_１およびＹ_ａは、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子、
3)カルボキシ基、
4)ニトロ基、
5)シアノ基、
6)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基、
7)アリール基、または
8)Ｒ^１−Ｚ_２−Ｚ_１−
（式中、
Ｒ^１は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ_２は、−Ｓ（Ｏ）ｑ−、−Ｏ−、−Ｓ−、−ＮＲ^２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ^２−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ−ＮＨ−、−Ｓ（Ｏ）ｑ−ＮＨ−または−ＮＲ^２−Ｓ（Ｏ）ｑ−（ｑは０〜２の整数を、Ｒ^２は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ_１は結合手またはアルキレン鎖を表す。）を表し
（但し、Ｘ₁がＯのとき、Ｙ_１は水酸基ではない）；
また、
隣接する２個のＹ_ａが、これらが結合している２個の原子と一緒になって、１個以上のＹａ’で置換されていてもよい環を形成してもよく、および
１個の炭素原子上の２個のＹ_ａが、該炭素原子と一緒になって、カルボニル基またはチオカルボニル基を形成してもよい；
Ｙａ’は、各出現において、それぞれ独立して、
水酸基、
ハロゲン原子、
カルボキシ基、
ニトロ基、
アルキル基、
シクロアルキル基または
アルコキシ基
を表し、また１個の炭素原子上の２個のＹａ’が、該炭素原子と一緒になって、カルボニル基を形成してもよい。］
で示される化合物、薬学的に許容される塩、またはその溶媒和物と、
一般式
Ｘａ−Ａ_２−Ａ_３
［式中、
Ａ_２は、
アルキレン鎖を表し；
Ａ_３は、
１個以上のＹ_ｂで置換されていてもよい芳香族基を表し；
Ｙ_ｂは、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子、
3)カルボキシ基、
4)ニトロ基、
5)シアノ基、
6)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基、
7)アリール基、または
8)Ｒ^１−Ｚ_２−Ｚ_１−
（式中、
Ｒ^１は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ_２は、−Ｓ（Ｏ）ｑ−、−Ｏ−、−Ｓ−、−ＮＲ^２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ^２−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ−ＮＨ−、−Ｓ（Ｏ）ｑ−ＮＨ−または−ＮＲ^２−Ｓ（Ｏ）ｑ−（ｑは０〜２の整数を、Ｒ^２は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ_１は結合手またはアルキレン鎖を表す。）を表し；
Ｘａは、
脱離基を表す。］
で表される化合物、薬学的に許容される塩、またはその溶媒和物とを反応させることを特徴とする、
一般式

（式中の記号は前記と同一の意味を表す。）で示される化合物、薬学上許容される塩またはその溶媒和物の製造方法。 [12]
General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
X ₁ is
Represents S, NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ and Y _a are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group);
Also,
Two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and one Two Y _a on a carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof,
Formula _Xa-A 2 -A ₃
[Where:
A ₂ is,
Represents an alkylene chain;
A ₃ is,
Represents an aromatic group optionally substituted by one or more Y _b ;
Y _b is independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. );
Xa is
Represents a leaving group. ]
A compound represented by the formula: pharmaceutically acceptable salt, or a solvate thereof,
General formula

(The symbols in the formula represent the same meaning as described above.) A method for producing a compound, a pharmaceutically acceptable salt or a solvate thereof.

［式中、
Ａ_１は、
１個以上のＹ_ａで置換されていてもよい環を表し；
Ａ_４は、
水素原子またはアルキル基を表すか、あるいは１個のＹ_ａと結合して２価の鎖状基を形成してもよく；
Ｘ₁は、
Ｓ、ＮＨまたはＯを表し；
ｎ１は、
０から４の整数を表し；
Ｙ_１およびＹ_ａは、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子、
3)カルボキシ基、
4)ニトロ基、
5)シアノ基、
6)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基、
7)アリール基、または
8)Ｒ^１−Ｚ_２−Ｚ_１−
（式中、
Ｒ^１は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ_２は、−Ｓ（Ｏ）ｑ−、−Ｏ−、−Ｓ−、−ＮＲ^２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ^２−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ−ＮＨ−、−Ｓ（Ｏ）ｑ−ＮＨ−または−ＮＲ^２−Ｓ（Ｏ）ｑ−（ｑは０〜２の整数を、Ｒ^２は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ_１は結合手またはアルキレン鎖を表す。）を表し
（但し、Ｘ₁がＯのとき、Ｙ_１は水酸基ではない）；
また、
隣接する２個のＹ_ａが、これらが結合している２個の原子と一緒になって、１個以上のＹａ’で置換されていてもよい環を形成してもよく、および
１個の炭素原子上の２個のＹ_ａが、該炭素原子と一緒になって、カルボニル基またはチオカルボニル基を形成してもよい；
Ｙａ’は、各出現において、それぞれ独立して、
水酸基、
ハロゲン原子、
カルボキシ基、
ニトロ基、
アルキル基、
シクロアルキル基または
アルコキシ基
を表し、また１個の炭素原子上の２個のＹａ’が、該炭素原子と一緒になって、カルボニル基を形成してもよい。］
で示される化合物
（ただし、
１，２−ジヒドロ−３−（２−ヒドロキシ−３，５−ジクロロフェニル）−キノキサリン、
３−（２−ヒドロキシフェニル）−２Ｈ−ベンゾ［１，４］チアジン、
３−（２，５−ジヒドロキシフェニル）−２Ｈ−ベンゾ［１，４］チアジン、および
２，３−ジヒドロ−３−（５−オキソ−２−フェニル−４Ｈ−オキサゾール−４−イリデン）−ベンゾ［１，４］オキサジン
は除く。）
、薬学的に許容される塩、またはその溶媒和物。
［１４］
Ｘ₁がＳである、上記［１３］に記載の化合物。 [13]
General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
X ₁ is
Represents S, NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ and Y _a are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group);
Also,
Two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and one Two Y _a on a carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A compound represented by (however,
1,2-dihydro-3- (2-hydroxy-3,5-dichlorophenyl) -quinoxaline,
3- (2-hydroxyphenyl) -2H-benzo [1,4] thiazine,
3- (2,5-dihydroxyphenyl) -2H-benzo [1,4] thiazine and 2,3-dihydro-3- (5-oxo-2-phenyl-4H-oxazol-4-ylidene) -benzo [ 1,4] oxazine is excluded. )
, A pharmaceutically acceptable salt, or a solvate thereof.
[14]
The compound according to [13] above, wherein X ₁ is S.

［式中、
Ａ_１は、
１個以上のＹ_ａで置換されていてもよい環を表し^{；
Ａ３’}は、
１個以上のＹ_ｂで置換されていてもよい含窒素ヘテロアリール基を表し；
Ａ_４は、
水素原子またはアルキル基を表すか、あるいは１個のＹ_ａと結合して２価の鎖状基を形成してもよく；
Ｙ_ａおよびＹ_ｂは、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子、
3)カルボキシ基、
4)ニトロ基、
5)シアノ基、
6)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基、
7)アリール基、または
8)Ｒ^１−Ｚ_２−Ｚ_１−
（式中、
Ｒ^１は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ_２は、−Ｓ（Ｏ）ｑ−、−Ｏ−、−Ｓ−、−ＮＲ^２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ^２−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ−ＮＨ−、−Ｓ（Ｏ）ｑ−ＮＨ−または−ＮＲ^２−Ｓ（Ｏ）ｑ−（ｑは０〜２の整数を、Ｒ^２は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ_１は結合手またはアルキレン鎖を表す。）を表し；
また、
隣接する２個のＹ_ａが、これらが結合している２個の原子と一緒になって、１個以上のＹａ’で置換されていてもよい環を形成してもよく、および
１個の炭素原子上の２個のＹ_ａが、該炭素原子と一緒になって、カルボニル基またはチオカルボニル基を形成してもよい；
Ｙａ’は、各出現において、それぞれ独立して、
水酸基、
ハロゲン原子、
カルボキシ基、
ニトロ基、
アルキル基、
シクロアルキル基または
アルコキシ基
を表し、また１個の炭素原子上の２個のＹａ’が、該炭素原子と一緒になって、カルボニル基を形成してもよい。］
で示される化合物、薬学的に許容される塩、またはその溶媒和物と、
一般式

［式中、
ｎ１は、
０から４の整数を表し；
Ｘ₁は、
Ｓ、ＮＨまたはＯを表し；
Ｙ_１は、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子、
3)カルボキシ基、
4)ニトロ基、
5)シアノ基、
6)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基、
7)アリール基、または
8)Ｒ^１−Ｚ_２−Ｚ_１−
（式中、
Ｒ^１は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ_２は、−Ｓ（Ｏ）ｑ−、−Ｏ−、−Ｓ−、−ＮＲ^２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ^２−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ−ＮＨ−、−Ｓ（Ｏ）ｑ−ＮＨ−または−ＮＲ^２−Ｓ（Ｏ）ｑ−（ｑは０〜２の整数を、Ｒ^２は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ_１は結合手またはアルキレン鎖を表す。）を表す
（但し、Ｘ₁がＯのとき、Ｙ_１は水酸基ではない）。］
で示される化合物、薬学的に許容される塩、またはその溶媒和物とを反応させることを特徴とする一般式

（式中の記号は、上記と同一の意味を表す。）
で表される化合物、薬学的に許容される塩またはその溶媒和物の製造方法。
［１６］
Ｘ_１がＳである上記［１２］または［１５］に記載の製造方法。 [15]
General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ^{;
A3 '}
Represents a nitrogen-containing heteroaryl group optionally substituted by one or more Y _b ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
Y _a and Y _b are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. );
Also,
Two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and one Two Y _a on a carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof,
General formula

[Where:
n1 is
Represents an integer from 0 to 4;
X ₁ is
Represents S, NH or O;
Y ₁ is independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted with one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group). ]
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(The symbols in the formula have the same meaning as above.)
Or a pharmaceutically acceptable salt or solvate thereof.
[16]
The production method according to the above [12] or [15], wherein X ₁ is S.

［式中、
Ａ_１は、
１個以上のＹ_ａで置換されていてもよい環を表し；
Ａ３’は、
１個以上のＹ_ｂで置換されていてもよい含窒素ヘテロアリール基を表し；
Ｙ_１、Ｙ_ａおよびＹ_ｂは、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子、
3)カルボキシ基、
4)ニトロ基、
5)シアノ基、
6)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基、
7)アリール基、または
8)Ｒ^１−Ｚ_２−Ｚ_１−
（式中、
Ｒ^１は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ_２は、−Ｓ（Ｏ）ｑ−、−Ｏ−、−Ｓ−、−ＮＲ^２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ^２−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ−ＮＨ−、−Ｓ（Ｏ）ｑ−ＮＨ−または−ＮＲ^２−Ｓ（Ｏ）ｑ−（ｑは０〜２の整数を、Ｒ^２は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ_１は結合手またはアルキレン鎖を表す。）を表し
（但し、Ｘ₁がＯのとき、Ｙ_１は水酸基ではない）；
また、隣接する２個のＹ_ａが、これらが結合している２個の原子と一緒になって、１個以上のＹａ’で置換されていてもよい環を形成してもよく、および
１個の炭素原子上の２個のＹ_ａが、該炭素原子と一緒になって、カルボニル基またはチオカルボニル基を形成してもよい；
Ｙａ’は、各出現において、それぞれ独立して、
水酸基、
ハロゲン原子、
カルボキシ基、
ニトロ基、
アルキル基、
シクロアルキル基または
アルコキシ基
を表し、また１個の炭素原子上の２個のＹａ’が、該炭素原子と一緒になって、カルボニル基を形成してもよい。］
で示される化合物、薬学的に許容される塩、またはその溶媒和物を極性溶媒で処理することを特徴とする一般式

（式中の記号は、上記と同一の意味を表す。）
で示される化合物、薬学的に許容される塩、またはその溶媒和物の製造方法。
［１８］
極性溶媒が、アルコール溶媒またはスルホキシド溶媒である上記［１７］に記載の製造方法。 [17]
General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A3 '
Represents a nitrogen-containing heteroaryl group optionally substituted by one or more Y _b ;
Y ₁ , Y _a and Y _b are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group);
And two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and 1 Two Y _a on one carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
Or a pharmaceutically acceptable salt thereof, or a solvate thereof, treated with a polar solvent,

(The symbols in the formula have the same meaning as above.)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
[18]
The production method according to the above [17], wherein the polar solvent is an alcohol solvent or a sulfoxide solvent.

［式中、
Ａ_１は、
１個以上のＹ_ａで置換されていてもよい環を表し；
Ｘ₁は、
Ｓ、ＮＨまたはＯを表し；
ｎ１は、
０から４の整数を表し；
Ｙ_１およびＹ_ａは、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子、
3)カルボキシ基、
4)ニトロ基、
5)シアノ基、
6)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基、
7)アリール基、または
8)Ｒ^１−Ｚ_２−Ｚ_１−
（式中、
Ｒ^１は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ_２は、−Ｓ（Ｏ）ｑ−、−Ｏ−、−Ｓ−、−ＮＲ^２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ^２−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ−ＮＨ−、−Ｓ（Ｏ）ｑ−ＮＨ−または−ＮＲ^２−Ｓ（Ｏ）ｑ−（ｑは０〜２の整数を、Ｒ^２は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ_１は結合手またはアルキレン鎖を表す。）を表し
（但し、Ｘ₁がＯのとき、Ｙ_１は水酸基ではない）；
また、隣接する２個のＹ_ａが、これらが結合している２個の原子と一緒になって、１個以上のＹａ’で置換されていてもよい環を形成してもよく、および
１個の炭素原子上の２個のＹ_ａが、該炭素原子と一緒になって、カルボニル基またはチオカルボニル基を形成してもよい；
Ｙａ’は、各出現において、それぞれ独立して、
水酸基、
ハロゲン原子、
カルボキシ基、
ニトロ基、
アルキル基、
シクロアルキル基または
アルコキシ基
を表し、また１個の炭素原子上の２個のＹａ’が、該炭素原子と一緒になって、カルボニル基を形成してもよい。］
で示される化合物、薬学的に許容される塩、またはその溶媒和物と、
一般式

［式中、
Ａ３’は、
Ｙ_ｂで置換されていてもよい、窒素原子を含むヘテロアリール基を表し；
Ｙ_ｂは、
1)水酸基、
2)ハロゲン原子、
3)カルボキシ基、
4)ニトロ基、
5)シアノ基、
6)ハロゲン原子およびアリール基から選択される１個以上の置換基でそれぞれ置換されていてもよい非環状炭化水素基またはシクロアルキル基、
7)アリール基、または
8)Ｒ^１−Ｚ_２−Ｚ_１−
（式中、
Ｒ^１は、水素原子、または１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、
Ｚ_２は、−Ｓ（Ｏ）ｑ−、−Ｏ−、−Ｓ−、−ＮＲ^２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＯ−ＮＨ−、−Ｏ−ＣＯ−ＮＨ−、−ＮＨ−ＣＯ−ＮＨ−、−ＮＲ^２−ＣＯ−、−ＮＨ−Ｓ（Ｏ）ｑ−ＮＨ−、−Ｓ（Ｏ）ｑ−ＮＨ−または−ＮＲ^２−Ｓ（Ｏ）ｑ−（ｑは０〜２の整数を、Ｒ^２は水素原子、アルキル基またはシクロアルキル基を表す。）を表し、
Ｚ_１は結合手またはアルキレン鎖を表す。）を表す。］で示される化合物、薬学的に許容される塩、またはその溶媒和物と
を反応させることを特徴とする
一般式

（式中の記号は、上記と同一の意味を表す。）
で示される化合物、薬学的に許容される塩、またはその溶媒和物の製造方法。 [19]
General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
X ₁ is
Represents S, NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ and Y _a are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group);
And two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and 1 Two Y _a on one carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof,
General formula

[Where:
A3 '
Y represents a heteroaryl group containing a nitrogen atom which may be substituted with _b ;
Y _b is
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. ). And a pharmaceutically acceptable salt thereof, or a solvate thereof.

(The symbols in the formula have the same meaning as above.)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[20]
The production method [21] according to the above [19], wherein X ₁ is O.
The pharmaceutical composition containing the compound in any one of said [3]-[11], and a pharmaceutically acceptable carrier.
[22]
The pharmaceutical composition according to the above [21], which is used for prevention or treatment of a disease involving the activity of a neurotrophic factor.
[23]
Diseases that involve neurotrophic factor activity include stroke, cerebral ischemic disease, multiple cerebral infarction dementia, binswanger leukoencephalopathy, Alzheimer's disease, Down's syndrome, Parkinson's disease, amyotrophic lateral sclerosis, or retinal degenerative disease The pharmaceutical composition according to the above [22].

  In the present specification, a compound represented by the formula (Ia) or (Ib) may be referred to as a compound (I). In the present specification, compound (I), a pharmaceutically acceptable salt of compound (I), or a solvate thereof may be referred to as a compound of the present invention.

  According to the present invention, it is possible to provide a low molecular weight compound effective for treatment or prevention of a disease involving the activity of neurotrophic factor.

  Hereinafter, the present invention will be described in detail.

  The terms used in this specification will be explained below.

  Examples of “halogen (atom)” include fluorine, chlorine, bromine, iodine and the like.

Examples of the “acyclic hydrocarbon group” include an alkyl group, an alkenyl group, an alkynyl group, and an alkenylene group.
Examples of the “alkyl (group)” include alkyl having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. (Group).
Examples of the “alkenyl (group)” include acyclic or cyclic alkenyl having 1 to 6 carbon atoms such as vinyl, 2-propenyl, 3-methyl-2-butenyl, 1,3-butadienyl, and 3-cyclohexenyl. (Group).
Examples of the “alkynyl (group)” include alkynyl (group) having 1 to 6 carbon atoms such as ethynyl, 2-propynyl, and 2-penten-4-ynyl.
Examples of the “alkenylene (group)” include alkenylene (group) having 1 to 6 carbon atoms such as vinylene, propenylene, and 1,3-butadienylene.

“Cycloalkyl (group) includes, for example, cycloalkyl (group) having 3 to 6 carbon atoms such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
Examples of the “alkoxy (group)” include an alkyl (group) bonded through an oxygen atom. As the alkyl (group), the above “alkyl (group)” can be referred to. Examples of such alkoxy (group) include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, and n-hexyloxy groups. It is done.

“Alkyl (group)”, “alkoxy (group)”, “alkenyl (group)”, and “alkynyl (group)” may each be linear or branched.

  Examples of the “alkylene (chain)” include linear alkylene chains having 1 to 3 carbon atoms such as methylene, ethylene, and trimethylene.

Examples of the “carbocycle” include carbocycles having 3 to 10 carbon atoms. The “carbocycle” may be an aromatic carbocycle or a non-aromatic carbocycle.
Examples of the “aromatic cyclic carbocycle” include benzene.
As the “non-aromatic carbocycle”, for example,
A cycloalkane having 3 to 10 carbon atoms (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane),
C3-C10 cycloalkene (e.g., cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene), and C3-C10 cycloalkadiene (e.g., cyclobutadiene, cyclopentadiene, cyclohexene) Hexadiene, cycloheptadiene, cyclooctadiene, cyclononadiene, cyclodecadiene).
As the “heterocycle”, for example, as a ring-constituting atom, a 5- to 6-membered member having 1 to 3 (preferably 1 to 2) heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Heterocycles are mentioned. The “heterocycle” may be an aromatic heterocycle or a non-aromatic heterocycle.
As the “aromatic heterocycle”, for example, 5 to 6 having 1 to 3 (preferably 1 to 2) heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms. Member aromatic heterocycles (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, oxadiazole (eg, 1,2,3-oxadiazole, 1,2,4- Oxadiazole, 1,3,4-oxadiazole), furazane, thiadiazole (eg, 1,2,3-thiadiazole, 1,2,4-thiadiazole. 1.3.4-thiadiazole), triazole (eg, 1,2,3-triazole, 1,2,4-triazole), tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine) It is below.
Examples of the “non-aromatic heterocycle” include 3 to 3 (preferably 1 to 2) heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms. 8-membered (preferably 4-6 membered) non-aromatic heterocycles (eg oxirane, azetidine, oxetane, thietane, pyrrolidine, pyrazolidine, imidazolidine, isoxazolidine, oxazolidine, isothiazolidine, thiazolidine, tetrahydrofuran, thiolane, dioxolane (eg 1,3-dioxolane), tetrahydropyran, dihydropyran, pyran, hexahydropyridine (piperidine), tetrahydropyridine, dihydropyridine, thiane, morpholine, thiomorpholine, piperazine, hexahydropyrimidine, tetrahydropyrimidine, azepan, oxepane Thiepane, oxazepane, thiazepane, azocane, oxocane, thiocane, Okisazokan, Chiazokan, dioxin) and the like. The “non-aromatic heterocycle” may be saturated or partially saturated.

Examples of the “aryl (group)” include aryl (group) having 6 to 14 carbon atoms (eg, phenyl, naphthyl).
As the “heteroaryl (group)”, for example, 5 to 3 (preferably 1 to 2) heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom are used as ring-constituting atoms. 6-membered heteroaryl (group) (eg, thienyl, furyl, pyrrole, imidazolyl, pyrazolyl, triazolyl (eg, 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, furazanyl, thiadiazolyl (eg, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), Pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl) and these are condensed with a benzene ring And the like.
The “nitrogen-containing heteroaryl (group)” includes, for example, 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to one nitrogen atom as a ring-constituting atom. 5 to 6-membered nitrogen-containing heteroaryl (group) (eg, pyrrole, imidazolyl, pyrazolyl, triazolyl (eg, 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, oxazolyl, isoxazolyl, thiazolyl , Isothiazolyl, furazanyl, thiadiazyl (eg, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl) , Pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl).

  Hereinafter, symbols used in the formula (Ia) or (Ib) will be described.

In the above formula (Ia) or (Ib),
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A ₂ is,
Represents an alkylene chain;
A ₃ is,
Represents an aromatic group optionally substituted by one or more Y _b ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
X ₁ is
Represents S, SO, SO ₂ , NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ , Y _a and Y _b are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. );
Also,
Two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and one Two Y _a on a carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group.

Examples of the “ring” of the “ring optionally substituted with one or more Y _a ” represented by A ₁ include a carbocyclic ring and a heterocyclic ring.

The “ring” may be substituted with one or more (preferably 1 to 3) Y _a .
Represented by Y _a "non-cyclic hydrocarbon group" and "cycloalkyl group" is one or more substituents selected from halogen atoms and aryl groups (preferably, 1-3) each optionally substituted with a substituent May be.
^R 1 _-Z 2 -Z ₁ represented by Y _a - "alkyl" represented by ^{R 1} s, one or more (preferably 1 to 3) may be substituted with a halogen atom .

Preferably a Y _a "one or more Y _a ring which may be substituted with" represented by A _1, for example,
1) a hydroxyl group,
2) a halogen atom (preferably fluorine),
3) an acyclic hydrocarbon group (preferably an alkyl group having 1 to 6 carbon atoms, more preferably methyl, ethyl), and
4) R ¹ —Z ₂ —Z ₁ — (R ¹ represents an alkyl group which may be substituted with one or more (preferably 1 to 3) halogen atoms, and Z ₂ represents —O—. Z ₁ represents a bond.) (Preferably, alkyl-O— having 1 to 6 carbon atoms, more preferably methoxy, trifluoromethoxy)
It is.

Also, two adjacent Y _a is, as a "ring" of these forms together with the two atoms bonded "ring which may be substituted with one or more Ya '' is Examples include carbocycle and heterocycle. Among these, preferably, a 5- to 6-membered non-aromatic heterocyclic ring having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom (preferably 1, 3-dioxolane, pyran) and benzene.
It is also preferred that two Y _a on one carbon atom together with the carbon atom form a carbonyl group.

Y _a is preferably Y _c when present on a nitrogen atom.
Y _c is
1) Hydrogen atom
2) a halogen atom,
3) An acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group
4) Aryl group
5) R1'-Z2'-Z1'-
(Where
R1 ′ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z2 ′ is —S (O) q′—, —O—, —S—, —NR2′—, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH. -, -NH-CO-NH-, -NR2'-CO-, -NH-S (O) q'-NH-, -S (O) q'-NH- or -NR2'-S (O) q '-(Q' represents an integer of 0 to 2, R2 'represents a hydrogen atom, an alkyl group or a cycloalkyl group),
Z1 ′ represents an alkylene chain. ), Or
6) R1 "-Z2"-
(Where
R1 ″ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z2 ″ is —CO—, —O—CO—, —NR2 ″ —CO—, —NH—S (O) q ″ —, or —S (O) q ″ — (q ″ is An integer of 0 to 2, R2 ″ represents a hydrogen atom, an alkyl group or a cycloalkyl group. ).

The “acyclic hydrocarbon group” and “cycloalkyl group” represented by Y _c are each substituted with one or more (preferably 1 to 3) substituents selected from a halogen atom and an aryl group. May be.
Represented by Y _c represented by R1'-Z2'-Z1'- of R1 '"alkylgroup", one or more (preferably 1 to 3) may be substituted with a halogen atom .

で示される環である。
Ｘ_２１、Ｘ_２２、Ｘ_２３およびＸ_２４は、それぞれ独立して、ＮまたはＣ−Ｙ_ａを表す。但し、Ｘ_２１、Ｘ_２２、Ｘ_２３およびＸ_２４の２つ以上がＣ−Ｙ_ａである。
また、下記のように、Ｘ_２１上のＹ_ａは、Ａ_４と結合して２価の鎖状基を形成してもよい。
当該環（Ｙ_ａを除く部分）として、好ましくは、ベンゼン環、およびピリジン環、特に好ましくは、ベンゼン環である。
特に当該環において、Ｙ_ａとして好ましくは、例えば、
1)水酸基、
2)ハロゲン原子（好ましくは、フッ素）、
3)非環状炭化水素基（好ましくは、炭素数１〜６のアルキル基、より好ましくは、メチル、エチル）、および
4)Ｒ^１−Ｚ_２−Ｚ_１−（Ｒ^１は、１個以上（好ましくは、１〜３個）のハロゲン原子で置換されていてもよいアルキル基を表し、Ｚ_２は−Ｏ−を表し、Ｚ_１は結合手を表す。）（好ましくは、炭素数１〜６のアルキル−Ｏ−、より好ましくはメトキシ、トリフルオロメトキシ）
である。 The “ring optionally substituted with one or more Y _a ” represented by A ₁ is preferably, for example,
General formula

It is a ring shown by.
X ₂₁ , X ₂₂ , X ₂₃ and X ₂₄ each independently represent N or C—Y _a . However, two or more of X ₂₁ , X ₂₂ , X ₂₃ and X ₂₄ are C-Y _a .
Further, as described below, Y _a on X ₂₁ may be bonded to A ₄ to form a divalent chain group.
As the ring (portion excluding the Y _a), preferably a benzene ring, and pyridine ring, particularly preferably a benzene ring.
Particularly in the ring, Y _a is preferably, for example,
1) a hydroxyl group,
2) a halogen atom (preferably fluorine),
3) an acyclic hydrocarbon group (preferably an alkyl group having 1 to 6 carbon atoms, more preferably methyl, ethyl), and
4) R ¹ —Z ₂ —Z ₁ — (R ¹ represents an alkyl group which may be substituted with one or more (preferably 1 to 3) halogen atoms, and Z ₂ represents —O—. Z ₁ represents a bond.) (Preferably, alkyl-O— having 1 to 6 carbon atoms, more preferably methoxy, trifluoromethoxy)
It is.

当該化合物には、次式（Ｉ１ｂ）で示される互変異性体が存在し、当該互変異性体もまた本発明の範囲内であるが、（Ｉ１ａ）で示される化合物が優勢的に存在する。

In this case, the compound represented by the general formula (Ia) or (Ib) is represented by the following formula.

The compound has a tautomer represented by the following formula (I1b), and the tautomer is also within the scope of the present invention, but the compound represented by (I1a) exists predominantly. .

で示される環である。
Ｘ_３１はＮ−Ｙ_ｃまたはＯを表し；
Ｘ_３２およびＸ_３３は、それぞれ独立して、Ｃ−Ｙ_ａまたはＮを表す（但し、Ｘ_３２およびＸ_３３のうち少なくとも１つは、Ｃ−Ｙ_ａである）。
当該環（Ｙ_ａおよびＹ_ｃを除く部分）として、特に好ましくは、例えば、３−シクロヘキセン−１−オン、１，２，３，４−テトラヒドロピリジン−２−オンおよび３，４−ジヒドロピラン−２−オンである。
特に当該環において、Ｙ_ａとして好ましくは、例えば、非環状炭化水素基（好ましくは、炭素数１〜６のアルキル基、より好ましくは、メチル、エチル）である。
特に当該環において、Ｙ_ｃとして好ましくは、例えば、非環状炭化水素基（好ましくは、炭素数１〜６のアルキル基、より好ましくは、メチル）である。 In addition, the “ring optionally substituted with one or more Y _a ” represented by A ₁ is preferably, for example,
General formula

It is a ring shown by.
X ₃₁ represents N—Y _c or O;
X ₃₂ and X ₃₃ each independently represent C—Y _a or N (provided that at least one of X ₃₂ and X ₃₃ is C—Y _a ).
As the ring ( _a part other than Y _a and Y _c ), particularly preferably, for example, 3-cyclohexen-1-one, 1,2,3,4-tetrahydropyridin-2-one and 3,4-dihydropyran- 2-one.
Particularly in the ring, Y _a is preferably, for example, an acyclic hydrocarbon group (preferably an alkyl group having 1 to 6 carbon atoms, more preferably methyl or ethyl).
Particularly in the ring, _Yc is preferably, for example, an acyclic hydrocarbon group (preferably an alkyl group having 1 to 6 carbon atoms, more preferably methyl).

当該化合物には、次式（Ｉ２ａ）で示される互変異性体が存在し、当該互変異性体もまた本発明の範囲内であるが、（Ｉ２ｂ）で示される化合物が優勢的に存在する。

In this case, the compound represented by the general formula (Ia) or (Ib) is represented by the following formula.

The compound has a tautomer represented by the following formula (I2a), and the tautomer is also within the scope of the present invention, but the compound represented by (I2b) exists predominantly. .

で示される環である。
Ｘ_４１およびＸ_４３は、
それぞれ独立して、ＣＨ_２、ＣＨ−Ｙ_ａ、Ｃ（Ｙ_ａ）_２またはＮ−Ｙ_ｃを表し；
Ｘ_４２は、ＣＨ_２、ＣＨ−Ｙ_ａまたはＣ（Ｙ_ａ）_２を表し；
ｎ２は０〜４の整数を表す。
ｎ２は、特に好ましくは、１である。
当該環（Ｙ_ａを除く部分）として、特に好ましくは、例えば、シクロヘキサノンおよびヘキサヒドロピリミジン−２，４−ジオンである。
特に当該環において、Ｙ_ａとして好ましくは、例えば、非環状炭化水素基（好ましくは、炭素数１〜６のアルキル基、より好ましくは、メチル）である。
特に当該環において、Ｙ_ｃとして好ましくは、例えば、非環状炭化水素基（好ましくは、炭素数１〜６のアルキル基、より好ましくは、メチル）である。 In addition, the “ring optionally substituted with one or more Y _a ” represented by A ₁ is preferably, for example,
General formula

It is a ring shown by.
X ₄₁ and X ₄₃ are
Each _{independently} represents _{CH 2, CH-Y a,} C (Y a) 2 or _{N-Y c;}
X _{42 represents} CH 2, _{CH-Y a} or _{C (Y a) 2;}
n2 represents an integer of 0 to 4.
n2 is particularly preferably 1.
Particularly preferable examples of the ring ( _a portion excluding Ya) include cyclohexanone and hexahydropyrimidine-2,4-dione.
Particularly in the ring, Y _a is preferably, for example, an acyclic hydrocarbon group (preferably an alkyl group having 1 to 6 carbon atoms, more preferably methyl).
Particularly in the ring, _Yc is preferably, for example, an acyclic hydrocarbon group (preferably an alkyl group having 1 to 6 carbon atoms, more preferably methyl).

当該化合物には、次式（Ｉ３ａ）で示される互変異性体が存在し、当該互変異性体もまた本発明の範囲内であるが、（Ｉ３ｂ）で示される化合物が優勢的に存在する。

In this case, the compound represented by the general formula (Ia) or (Ib) is represented by the following formula.

The compound has a tautomer represented by the following formula (I3a), and the tautomer is also within the scope of the present invention, but the compound represented by (I3b) exists predominantly. .

The “alkylene chain” represented by A ₂ is preferably a methylene chain, for example.

As the “aromatic group” of the “aromatic group optionally substituted with one or more Y _b ” represented by A ₃ , for example, an “aryl group” and a “heteroaryl group” are preferable.
Among these, (1) phenyl, and (2) a 5- to 6-membered heteroaryl group having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms. (Preferably pyridyl, more preferably 2-pyridyl).

The “aromatic group” may be substituted with one or more (preferably 1 to 3) Y _b .
The “acyclic hydrocarbon group” and “cycloalkyl group” represented by Y _b are each substituted with one or more (preferably 1 to 3) substituents selected from a halogen atom and an aryl group. May be.
^R 1 _-Z 2 -Z ₁ represented by Y _b - "alkyl" represented by ^{R 1} s, one or more (preferably 1 to 3) may be substituted with a halogen atom .

Y _b is preferably, for example,
1) a hydroxyl group,
2) a halogen atom (preferably fluorine, chlorine),
3) Acyclic hydrocarbon group (preferably an alkyl group having 1 to 6 carbon atoms, more preferably methyl)
and
4) R ¹ —Z ₂ —Z ₁ — (R ¹ represents an alkyl group which may be substituted with one or more (preferably 1 to 3) halogen atoms, and Z ₂ represents —CO—O. -And Z ₁ represents a bond.) (Preferably alkyl-CO-O- having 1 to 6 carbon atoms, more preferably acetyloxy.)
As the “aromatic group optionally substituted with one or more Y _b ” represented by A ₃ , an unsubstituted aromatic group is also preferable.

A ₄ is preferably a hydrogen atom or methyl.
The “divalent chain group” formed by A ₄ bonding to one Y _a is preferably —X ₂ — (CH ₂ ) _m — (X ₂ is a bond, NH, O or S M represents an integer of 0 to 2).
X ₂ is preferably O and m is preferably 1. The divalent chain group is preferably —O—CH ₂ —, for example.
A ₄ is, as the bond to _{Y a, Y a} position represented in the following formula are preferable.

X ₁ is preferably S or O.

  n1 is preferably 0 or 1.

The “acyclic hydrocarbon group” and the “cycloalkyl group” represented by Y ₁ are each substituted with one or more (preferably 1 to 3) substituents selected from a halogen atom and an aryl group. May be.
^R 1 _-Z 2 -Z ₁ represented by Y ₁ - "alkyl" represented by ^{R 1} s, one or more (preferably 1 to 3) may be substituted with a halogen atom .
Y ₁ is preferably, for example,
A halogen atom (preferably chlorine),
An acyclic hydrocarbon group which may be substituted with one or more halogen atoms (preferably an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more halogen atoms, more preferably trifluoro Methyl)
It is.

  As the compound (I), those in which two or more selected from the above preferred examples, more preferred examples, and further preferred examples are used in combination are preferred.

  Preferably as compound (I), the following specific aspects are mentioned, for example.

［式中、
Ｘ_２１、Ｘ_２２、Ｘ_２３およびＸ_２４は、、それぞれ独立して、Ｎ、Ｃ−ＨまたはＣ−Ｙ_ａ（但し、Ｘ_２１、Ｘ_２２、Ｘ_２３およびＸ_２４の２つ以上（好ましくは、３つ）がＣ−ＨまたはＣ−Ｙ_ａである）を表す。
Ａ_２は、
炭素数１〜３の直鎖状のアルキレン鎖（好ましくは、メチレン鎖）を表し；
Ａ_３は、
環構成原子として、窒素原子、酸素原子、および硫黄原子から選択される１〜３個（好ましくは、１個）のへテロ原子を有する５〜６員（好ましくは、６員）のヘテロアリール基（好ましくは、ピリジル、より好ましくは、２−ピリジル）を表し；
Ａ_４は、
水素原子を表すか、あるいは１個のＹ_ａと結合して−Ｘ_２−（ＣＨ_２）_ｍ−（Ｘ_２はＯまたはＳを表し、ｍは０〜２の整数を表す；Ｘ_２は好ましくはＯであり、ｍは、好ましくは１である。）（好ましくは、−Ｏ−ＣＨ_２−）を形成してもよく；
Ｘ₁は、
ＯまたはＳを表し；
ｎ１は、
０を表し；
Ｙ_ａは、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子（好ましくは、フッ素）、
3)炭素数１〜６のアルキル基（好ましくは、メチル）、および
4)Ｒ^１−Ｚ_２−Ｚ_１−（Ｒ^１は、１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、Ｚ_２は−Ｏ−を表し、Ｚ_１は結合手を表す。）（好ましくは、１〜３個のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル−Ｏ−、より好ましくはメトキシ、トリフルオロメトキシ）
を表す。
また、隣接する２個のＹ_ａが、これらが結合している２個の原子と一緒になってオキソ基で置換されていてもよい、環構成原子として、窒素原子、酸素原子、および硫黄原子から選択される１〜３個（好ましくは、１〜２個）のへテロ原子（好ましくは、酸素原子）を有する３〜８員（好ましくは５〜６員）の複素環（例、１，３−ジオキソラン、ピラン）を形成してもよい。
］
で示される化合物、その薬学的に許容される塩、またはその溶媒和物。 [Specific Embodiment 1]
General formula

[Where:
X ₂₁ , X ₂₂ , X ₂₃ and X ₂₄ are each independently N, C—H or C—Y _a (provided that two or more of X ₂₁ , X ₂₂ , X ₂₃ and X ₂₄ (preferably 3) represents C—H or C—Y _a ).
A ₂ is,
Represents a linear alkylene chain having 1 to 3 carbon atoms (preferably a methylene chain);
A ₃ is,
5- to 6-membered (preferably 6-membered) heteroaryl group having 1 to 3 (preferably 1) heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms (Preferably pyridyl, more preferably 2-pyridyl);
A ₄ is,
Represents hydrogen atom, or one of _{Y a} bond to a _{-X 2 - (CH 2) m} - (X 2 represents O or S, m is an integer of 0 to 2; the _{X 2} preferably Is O and m is preferably 1.) (preferably —O—CH ₂ —) may be formed;
X ₁ is
Represents O or S;
n1 is
Represents 0;
Y _a is independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom (preferably fluorine),
3) an alkyl group having 1 to 6 carbon atoms (preferably methyl), and
4) R ¹ —Z ₂ —Z ₁ — (R ¹ represents an alkyl group which may be substituted with one or more halogen atoms, Z ₂ represents —O—, and Z ₁ represents a bond. (Preferably, alkyl having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms, more preferably methoxy, trifluoromethoxy)
Represents.
Further, two adjacent Y _a may be substituted with an oxo group together with two atoms to which they are bonded, and as a ring-constituting atom, a nitrogen atom, an oxygen atom, and a sulfur atom A 3- to 8-membered (preferably 5 to 6-membered) heterocyclic ring having 1 to 3 (preferably 1 to 2) heteroatoms (preferably oxygen atoms) selected from 3-dioxolane, pyran) may be formed.
]
Or a pharmaceutically acceptable salt or solvate thereof.

［式中、
Ｘ_３１はＮ−Ｙ_ｃまたはＯを表し；
Ｘ_３２およびＸ_３３は、それぞれ独立して、Ｃ−ＨまたはＣ−Ｙ_ａを表す。
Ａ_２は、
炭素数１〜３の直鎖状のアルキレン鎖（好ましくは、メチレン鎖）を表し；
Ａ_３は、それぞれ１〜３個（好ましくは１個）のＹ_ｂで置換されていてもよい（１）フェニル、または（２）環構成原子として、窒素原子、酸素原子、および硫黄原子から選択される１〜３個（好ましくは１〜２個）のへテロ原子を有する５〜６員のヘテロアリール基（好ましくは、イミダゾリル、ピリジル；より好ましくは、２−イミダゾリル、２−ピリジル）を表し；
Ａ_４は、
水素原子または炭素数１〜６の直鎖状もしくは分岐鎖状のアルキル基（好ましくは、メチル）を表し；
Ｘ₁は、
ＯまたはＳを表し；
ｎ１は、
０〜２（好ましくは、０〜１）の整数を表し；
Ｙ_１は、各出現において、それぞれ独立して、
ハロゲン原子（好ましくは、塩素）、
１個以上のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル基（好ましくは、トリフルオロメチル）
を表し
（但し、Ｘ₁がＯのとき、Ｙ_１は水酸基ではない）；
Ｙ_ａは、各出現において、それぞれ独立して、
炭素数１〜６のアルキル基（好ましくは、メチル、エチル）、
を表す。
Ｙ_ｃは、各出現において、それぞれ独立して、
炭素数１〜６のアルキル基（好ましくは、メチル）、
を表す。
また、隣接する２個のＹ_ａが、ベンゼン環を形成してもよい。］
で示される化合物、その薬学的に許容される塩、またはその溶媒和物。 [Specific Embodiment 2]
General formula

[Where:
X ₃₁ represents N—Y _c or O;
X ₃₂ and X ₃₃ each independently represent C—H or C—Y _a .
A ₂ is,
Represents a linear alkylene chain having 1 to 3 carbon atoms (preferably a methylene chain);
A ₃ is each selected from (1) phenyl optionally substituted with 1 to 3 (preferably 1) Y _b , or (2) a ring atom, from a nitrogen atom, an oxygen atom, and a sulfur atom Represents a 5- to 6-membered heteroaryl group having 1 to 3 (preferably 1 to 2) heteroatoms (preferably imidazolyl or pyridyl; more preferably 2-imidazolyl or 2-pyridyl) ;
A ₄ is,
Represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms (preferably methyl);
X ₁ is
Represents O or S;
n1 is
Represents an integer of 0 to 2 (preferably 0 to 1);
Y ₁ is independently at each occurrence,
A halogen atom (preferably chlorine),
An alkyl group having 1 to 6 carbon atoms which may be substituted with one or more halogen atoms (preferably trifluoromethyl)
(However, when X ₁ is O, Y ₁ is not a hydroxyl group);
Y _a is independently at each occurrence,
An alkyl group having 1 to 6 carbon atoms (preferably methyl, ethyl),
Represents.
Y _c is independently at each occurrence,
An alkyl group having 1 to 6 carbon atoms (preferably methyl),
Represents.
Also, two adjacent Y _a may form a benzene ring. ]
Or a pharmaceutically acceptable salt or solvate thereof.

［式中、
Ｘ_４１およびＸ_４３は、
それぞれ独立して、ＣＨ_２、またはＮ−Ｙ_ｃを表し；
Ｘ_４２は、
ＣＨ_２、ＣＨ−Ｙ_ａまたはＣ（Ｙ_ａ）_２を表し；
ｎ２は、
１を表し；
Ａ_２は、
炭素数１〜３の直鎖状のアルキレン鎖（好ましくは、メチレン鎖）を表し；
Ａ_３は、
１〜３個（好ましくは、１個）のＹ_ｂで置換されていてもよい、環構成原子として、窒素原子、酸素原子、および硫黄原子から選択される１〜３個（好ましくは１〜２個）のへテロ原子を有する５〜６員（好ましくは、６員）のヘテロアリール基（好ましくは、ピリジル；より好ましくは、２−ピリジル）を表し；
Ａ_４は、
水素原子または炭素数１〜６のアルキル基（好ましくは、メチル）を表し；
Ｘ₁は、
Ｓを表し；
ｎ１は、
０を表し；
Ｙ_ａは、各出現において、それぞれ独立して、
炭素数１〜６のアルキル基（好ましくは、メチル）、
を表す。
Ｙ_ｃは、各出現において、それぞれ独立して、
炭素数１〜６のアルキル基（好ましくは、メチル）、
を表す。
また、１個の炭素原子上の２個のＹ_ａが、該炭素原子と一緒になって、カルボニル基またはチオカルボニル基（好ましくは、カルボニル基）を形成してもよい。］
で示される化合物、その薬学的に許容される塩、またはその溶媒和物。 [Specific embodiment 3]

[Where:
X ₄₁ and X ₄₃ are
Each independently represents CH ₂ or N—Y _c ;
_X42 is
CH _2, represents a _{CH-Y a} or _{C (Y a) 2;}
n2 is
Represents 1;
A ₂ is,
Represents a linear alkylene chain having 1 to 3 carbon atoms (preferably a methylene chain);
A ₃ is,
1-3 (preferably, 1) substituents may be substituted with Y _b of, as a ring-constituting atom, a nitrogen atom, an oxygen atom, and 1 to 3 groups selected from a sulfur atom (preferably 1 to 2 A 5- to 6-membered (preferably 6-membered) heteroaryl group having a hetero atom (preferably pyridyl; more preferably 2-pyridyl);
A ₄ is,
Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (preferably methyl);
X ₁ is
Represents S;
n1 is
Represents 0;
Y _a is independently at each occurrence,
An alkyl group having 1 to 6 carbon atoms (preferably methyl),
Represents.
Y _c is independently at each occurrence,
An alkyl group having 1 to 6 carbon atoms (preferably methyl),
Represents.
Further, two Y _a on one carbon atom may be combined with the carbon atom to form a carbonyl group or a thiocarbonyl group (preferably a carbonyl group). ]
Or a pharmaceutically acceptable salt or solvate thereof.

Examples of the pharmaceutically acceptable salt of compound (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Can be mentioned. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, such as an alkali metal salt (eg, lithium salt, sodium salt, potassium salt), an alkaline earth metal salt (eg, magnesium salt, calcium salt, barium salt, etc.) Inorganic salts, ammonium salts, etc., and when the compound has a basic functional group, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid And salts with organic acids such as acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
Of these, metal salts are preferred.
Compound (I) has a compound represented by the formula (Ia) and a compound represented by the formula (Ib) as tautomers, and any one of the isomers and the mixture is within the scope of the present invention. is there.
In the fused 6-membered ring compound of the present invention, the tautomers of the fused 6-membered ring when A1 is a fused ring and when A1 is not, can take different stable structures. For example, 2,3-dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4 synthesized in Example 2 shown below. Thiazine has an enamine structure by two-dimensional NMR of H-N, and is synthesized in the following examples. 2- (2-Pyridylmethyl) -3- (2-hydroxy-6-fluorophenyl) -2H-benzo It has been confirmed that [1,4] thiazine mainly has an imine structure. Therefore, the compound (I) is preferably an isomer having such a stable structure, but the present invention is not limited to this and does not exclude other isomers.

Further, when Compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., any one of the isomers and a mixture are within the scope of the present invention. Included in the compounds of the present invention. Furthermore, when compound (I) has an optical isomer, the optical isomer resolved from the racemate is also within the scope of the present invention.
Compound (I) may be crystalline or amorphous and both are within the scope of the present invention.
Compound (I) labeled or substituted with an isotope (eg, ² H, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) is also within the scope of the present invention.
Compound (I) may be a solvate (such as a hydrate) or a non-solvate.

Next, specific examples of the compound of the present invention are shown in Tables 1 to 3 below. When _{Y 1} in Tables 1 to 3 is H, n1 is 0. The number of _{Y 1} in Tables 1 to 3 (except H) corresponds to the number of n1.

  Below, the manufacturing method of compound (I) is demonstrated.

  A part of the compound (I) is already known and can be produced by a known method (for example, Tetrahedron (2005), 61 (27), 6642-6651, Magnetc Resonance in Chemistry (2005), 43, 557- 562).

（Ａ３’は、前記と同一の意味を示す。）で示される、含窒素ヘテロアリール基である。

A method for producing Compound (I) and its intermediate will be described. First, the outline is summarized. In the following scheme, only one of the tautomers is shown. In addition, as described below, in production methods 2 to 4 in the scheme, A ₃ is

(A3 ′ represents the same meaning as described above), and is a nitrogen-containing heteroaryl group.

Compound (I) can be produced, for example, according to any method shown below or a method analogous thereto.
Unless otherwise specified, each symbol of the compound in the reaction formula represents the same meaning as described above. In addition, the compound in a formula also includes the case where it forms the salt, As such a salt, the thing similar to the salt of compound (I) is mentioned, for example. In addition, the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and a means known per se, for example, It can be easily purified by separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, distillation, chromatography and the like. Or when the compound in a formula is marketed, a commercial item can also be used as it is.
Unless otherwise specified, room temperature is about 10 ° C. to about 35 ° C. in this specification.

で表される化合物（化合物（ＩＩ））と下記一般式
Ｘａ−Ａ_２−Ａ_３
（式中、Ｘａは脱離基を表す。）
で表される化合物（化合物（ＩＩＩ））とを、反応させて製造することができる。
Ｘａで表される脱離基としては、例えば、
ハロゲン原子；
１個以上（例、１〜３個）のハロゲン原子で置換されていてもよいアルキルスルホニルオキシ基（例、メタンスルホニルオキシ基、エタンスルホニルオキシ基、およびトリフルオロメタンスルホニルオキシ等のハロゲン原子で置換されていてもよいアルキルスルホニルオキシ基）；および
ニトロ基およびアルキル基から選択される１個以上（例、１〜３個、好ましくは１個）の置換基で置換されてもよいアリールスルホニルオキシ基（例、ベンゼンスルホニルオキシ、ｐ−トルエンスルホニルオキシ基、および２−ニトロベンゼンスルホニルオキシ基）等が好ましい。
化合物（ＩＩＩ）の使用量は、化合物（ＩＩ）１モルに対し、通常１〜２モル、好ましくは１〜１．５モルである。
本反応において、反応温度の範囲は、通常−７８度から室温であり、反応時間の範囲は、通常瞬時〜約２４時間である。この反応は塩基の存在下で行うことができる。用いられる塩基としては、n-ブチルリチウム、sec-ブチルリチウム、tert-ブチルリチウム、リチウムジイソプロピルアミド、リチウムビス(トルメチルシリル)アミド等が挙げられる。その使用量は、化合物（ＩＩ）１モルに対して、通常１〜４モルである。所望により、この反応は添加剤の存在下で行ってもよい。用いられる添加剤としては、ヘキサメチルリン酸トリアミド、およびジメチルスルホキシド等が挙げられ、その使用量は、化合物（ＩＩ）１モルに対して、通常４〜２０モルが用いられる。本反応は溶媒中で行わせる事ができる。使用しうる溶媒としては、テトラヒドロフラン、およびジエチルエーテル等のエーテル溶媒等が挙げられる。
製法１で使用される、化合物（ＩＩ）（ただし、１，２−ジヒドロ−３−（２−ヒドロキシ−３，５−ジクロロフェニル）−キノキサリン、
３−（２−ヒドロキシフェニル）−２Ｈ−ベンゾ［１，４］チアジン、
３−（２，５−ジヒドロキシフェニル）−２Ｈ−ベンゾ［１，４］チアジン、および
２，３−ジヒドロ−３−（５−オキソ−２−フェニル−４Ｈ−オキサゾール−４−イリデン）−ベンゾ［１，４］オキサジンを除く。）は、新規化合物であり、本発明は、該化合物もまた提供する。 [Production method 1]
As a production method of production method 1, compound (I) is represented by the following general formula:

And a compound represented by the formula (Compound (II)) and the following general formula Xa-A ₂ -A ₃
(In the formula, Xa represents a leaving group.)
Can be produced by reacting the compound represented by formula (compound (III)).
As the leaving group represented by Xa, for example,
A halogen atom;
Alkylsulfonyloxy group (eg, methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy, etc.) that may be substituted with one or more (eg, 1 to 3) halogen atoms An optionally substituted alkylsulfonyloxy group); and an arylsulfonyloxy group which may be substituted with one or more (eg, 1 to 3, preferably 1) substituents selected from a nitro group and an alkyl group Examples, benzenesulfonyloxy, p-toluenesulfonyloxy group, and 2-nitrobenzenesulfonyloxy group) are preferred.
The amount of compound (III) to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (II).
In this reaction, the reaction temperature is usually from −78 ° C. to room temperature, and the reaction time is usually from instant to about 24 hours. This reaction can be carried out in the presence of a base. Examples of the base used include n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis (tolmethylsilyl) amide and the like. The amount of its use is 1-4 mol normally with respect to 1 mol of compounds (II). If desired, this reaction may be carried out in the presence of additives. Examples of the additive to be used include hexamethylphosphoric triamide, dimethyl sulfoxide and the like, and the amount thereof used is usually 4 to 20 mol per 1 mol of compound (II). This reaction can be carried out in a solvent. Examples of the solvent that can be used include tetrahydrofuran and ether solvents such as diethyl ether.
Compound (II) (however, 1,2-dihydro-3- (2-hydroxy-3,5-dichlorophenyl) -quinoxaline used in Preparation Method 1,
3- (2-hydroxyphenyl) -2H-benzo [1,4] thiazine,
3- (2,5-dihydroxyphenyl) -2H-benzo [1,4] thiazine and 2,3-dihydro-3- (5-oxo-2-phenyl-4H-oxazol-4-ylidene) -benzo [ 1,4] Oxazine is excluded. ) Is a novel compound, and the present invention also provides the compound.

A more preferred embodiment of compound (II) is a compound in which X ₁ in the above formula is S.

Ａ_１は、
それぞれ、１〜６個のＹ_ａで置換されていてもよい、（１）炭素数５〜６（好ましくは６）の炭素環（例、ベンゼン、シクロヘキサン）、または（２）環構成原子として、窒素原子、酸素原子、および硫黄原子から選択される１〜３個（好ましくは１〜２個）のへテロ原子を有する５〜６員（好ましくは６員）の複素環（例、ジヒドロピラン、テトラヒドロピリジン）を表し；
Ａ_４は、
水素原子、または炭素数１〜６の直鎖状もしくは分岐鎖状のアルキル基（好ましくは、メチル）を表すか、あるいは１個のＹ_ａと結合して−Ｘ_２−（ＣＨ_２）_ｍ−（Ｘ_２はＯまたはＳを表し、ｍは０〜２の整数を表す；Ｘ_２は好ましくはＯであり、ｍは、好ましくは１である。）（好ましくは、−Ｏ−ＣＨ_２−）を形成してもよく；
Ｘ₁は、
Ｓ、またはＯを表し；
ｎ１は、
０を表し；
Ｙ_ａは、各出現において、それぞれ独立して、
1)水酸基、
2)ハロゲン原子（好ましくは、フッ素）、
3)炭素数１〜６のアルキル基（好ましくは、メチル）、および
4)Ｒ^１−Ｚ_２−Ｚ_１−（Ｒ^１は、１個以上のハロゲン原子で置換されていてもよいアルキル基を表し、Ｚ_２は−Ｏ−を表し、Ｚ_１は結合手を表す。）（好ましくは、１〜３個のハロゲン原子で置換されていてもよい炭素数１〜６のアルキル−Ｏ−、より好ましくはメトキシ、トリフルオロメトキシ）
を表す。
また、隣接する２個のＹ_ａが、これらが結合している２個の原子と一緒になって、（１）ベンゼン環、または（２）環構成原子として、窒素原子、酸素原子、および硫黄原子から選択される１〜３個（好ましくは、１〜２個）のへテロ原子（好ましくは、酸素原子）を有する３〜８員（好ましくは５〜６員）の複素環（例、１，３−ジオキソラン）を形成してもよく、および
１個の炭素原子上の２個のＹ_ａが、該炭素原子と一緒になって、カルボニル基を形成してもよい。］
で示される化合物、薬学上許容される塩、またはその水和物である。
製法１の中間体として使用する本発明化合物の具体例を以下の表に表す。 Preferred specific embodiments of compound (II) are:
General formula

A ₁ is,
Each optionally substituted with 1-6 _{Y a,} as a carbon ring (e.g., benzene, cyclohexane), or (2) ring members (1) having a carbon number 5-6 (preferably 6), A 5- to 6-membered (preferably 6-membered) heterocycle having 1 to 3 (preferably 1 to 2) heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom (eg, dihydropyran, Tetrahydropyridine);
A ₄ is,
Hydrogen atom, or a linear or (preferably methyl) branched-chain alkyl group having 1 to 6 carbon atoms _-X 2 bonded or represents, or the one _{Y a - (CH 2) m} - (X ₂ represents O or S, m represents an integer of 0 to 2; X ₂ is preferably O, and m is preferably 1.) (Preferably —O—CH ₂ —) May form;
X ₁ is
Represents S or O;
n1 is
Represents 0;
Y _a is independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom (preferably fluorine),
3) an alkyl group having 1 to 6 carbon atoms (preferably methyl), and
4) R ¹ —Z ₂ —Z ₁ — (R ¹ represents an alkyl group which may be substituted with one or more halogen atoms, Z ₂ represents —O—, and Z ₁ represents a bond. (Preferably, alkyl having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms, more preferably methoxy, trifluoromethoxy)
Represents.
In addition, two adjacent Y _a together with the two atoms to which they are bonded have (1) a benzene ring or (2) a ring constituent atom as a nitrogen atom, an oxygen atom, and sulfur. A 3 to 8 membered (preferably 5 to 6 membered) heterocyclic ring having 1 to 3 (preferably 1 to 2) heteroatoms (preferably oxygen atoms) selected from atoms (e.g., 1 , 3-dioxolane) and two Y _a on one carbon atom together with the carbon atom may form a carbonyl group. ]
Or a pharmaceutically acceptable salt or hydrate thereof.
Specific examples of the compound of the present invention used as an intermediate of production method 1 are shown in the following table.

Next, specific examples of compound (II) are shown in Tables 4 to 6 below. When _{Y 1} in the table 4-6 is H, n1 is 0. The number of _{Y 1} in Tables 1 to 3 (except H) corresponds to the number of n1.

１分子内環化反応として、例えば公知の方法（例えばＵＳ６３５０７３３）等に記載の方法に準じて製造可能な下記一般式

で表されるニトロ基を有する化合物（化合物（ＩＶ））を、酸存在下で還元剤によって処理することによって下記一般式

を製造することができる。
本反応において反応温度の範囲は、室温から還流温度であり、反応時間の範囲は、通常瞬時〜約２４時間である。還元剤の使用量は、化合物（ＩＶ）１モルに対し、通常１〜１０モルである。還元剤として鉄粉等が用いられ、酸としては、塩酸水溶液、または酢酸等が用いられる。本反応は溶媒中で行わせる事ができる。溶媒としては、例えば、メタノール、およびエタノール等のといったアルコール溶媒、ならびに酢酸等が挙げられる。 Compound (II) can be produced by an intramolecular cyclization reaction based on the reduction of a nitro group or an intermolecular cyclization reaction as shown below.

As the intramolecular cyclization reaction, for example, the following general formula that can be produced according to a method described in a known method (for example, US Pat.

By treating a compound having a nitro group represented by the formula (compound (IV)) with a reducing agent in the presence of an acid, the following general formula

Can be manufactured.
In this reaction, the reaction temperature range is from room temperature to reflux temperature, and the reaction time range is usually from instantaneous to about 24 hours. The amount of the reducing agent to be used is generally 1 to 10 mol per 1 mol of compound (IV). As the reducing agent, iron powder or the like is used, and as the acid, hydrochloric acid aqueous solution, acetic acid or the like is used. This reaction can be carried out in a solvent. Examples of the solvent include alcohol solvents such as methanol and ethanol, and acetic acid.

（Ｘａは脱離基を表す。）
で表される化合物を市販等で入手可能な下記一般式

（式中の記号は、前記と同一の意味を示す。）
の化合物と反応させて下記一般式

（式中の記号は、前記と同一の意味を示す。）
の化合物を製造することができる。
Ｘａで表される脱離基としては、化合物（ＩＩＩ）において例示したもの前記と同様のものが挙げられる。
Ｘ_１はＳ（硫黄原子）であることが好ましい。
化合物（ＶＩ）の使用量は、化合物（Ｖ）１モルに対し、通常１〜２モル、好ましくは１〜１．５モルである。
本反応において、反応温度の範囲は、通常室温から還流温度であり、反応時間の範囲は、通常瞬時〜約２４時間である。本反応は溶媒中で行わせる事ができる。溶媒としては、例えば、メタノール、およびエタノール等のアルコール溶媒；テトラヒドロフラン、およびジオキサン等のエーテル溶媒；アセトニトリル；ジメチルホルムアミド；ジメチルスルホキシド；ならびにハロゲン化炭化水素類が用いられる。 In the bimolecular cyclization reaction, the following general formula available commercially

(Xa represents a leaving group.)
The following general formula, which is commercially available

(The symbols in the formula have the same meaning as described above.)
The following general formula

(The symbols in the formula have the same meaning as described above.)
Can be produced.
Examples of the leaving group represented by Xa include those exemplified for the compound (III) as described above.
X ₁ is preferably S (sulfur atom).
The amount of compound (VI) to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (V).
In this reaction, the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from instant to about 24 hours. This reaction can be carried out in a solvent. Examples of the solvent include alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; acetonitrile; dimethylformamide; dimethyl sulfoxide; and halogenated hydrocarbons.

(Ａ３’は１個以上のＹｂで置換されていてもよい、窒素原子を含むヘテロアリール基を表す。）
で表される化合物を、市販品にて、または公知の製造方法（例えば特公昭４１−００１４１２に記載の方法）により入手可能な下記一般式

（Ａ３’は上記と同様の意味を表す。）
で表される化合物（化合物（ＶＩＩ））と、市販品等にて入手可能な下記一般式

で表される化合物（化合物（ＶＩＩＩ））とを反応させて製造することができる。
Ｘ_１はＳ（硫黄原子）であることが好ましい。
化合物（ＶＩＩＩ）の使用量は、化合物（ＶＩＩ）１モルに対し、通常１〜３モル、好ましくは１〜１．５モルである。
本反応において、反応温度の範囲は、通常室温から還流温度であり、反応時間の範囲は、通常瞬時〜約２４時間である。この反応は塩基の存在下で行うことができる。用いられる塩基としては、n-ブチルリチウム、sec-ブチルリチウム、tert-ブチルリチウム、リチウムジイソプロピルアミド、およびリチウムビス(トルメチルシリル)アミド等の金属塩、ならびにモルホリン、ピペリジン、ピリジン、トリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン、および４−ジメチルアミノピリジンピリジン等の有機アミン等が挙げられる。その使用量は化合物（ＶＩＩＩ）１モルに対して、通常０．００１〜４モルである。溶媒としては、例えば、メタノール、およびエタノール等のアルコール系溶媒；テトラヒドロフラン、およびジオキサン等のエーテル系溶媒；アセトニトリル；ジメチルホルムアミド；ジメチルスルホキシド；ならびにハロゲン化炭化水素類が用いられる。
本反応に類似する反応として、以下で示すように、3-シンナモイル2-ピロン誘導体（R=2-OMe, 2-OH, 4-OH, 4-NO2, 2,6-diCl, 2-Cl）と2-アミノチオフェノールからベンゾ[１，５]チアゼピン誘導体のような縮合7員環構造が構築されるという報告がある（例えばIndian Journal of Chemistry section B, 1995, 34B, pp. 893-894.）

しかし、例えば、以下に示す実施例２において合成した化合物をＨ−Ｃの２次元ＮＭＲおよびＨ−Ｎの２次元ＮＭＲで詳細に解析したところ、当該化合物は、縮合６員環化合物すなわち、２，３−ジヒドロ−２−(２−ピリジルメチル)−３−（２，４−ジオキソ−６−メチルピラン−３−イリデン）−ベンゾ［１，４］チアジンであることが判明した。また、同一の化合物を製法１の製造法によって得られたことからも、本反応で得られた生成物が、縮合６員環構造であることを確認している。

[Production method 2]
As the production method of production method 2, the following general formula

(A3 ′ represents a heteroaryl group containing a nitrogen atom which may be substituted with one or more Yb.)
The compound represented by the following general formula can be obtained by a commercially available product or by a known production method (for example, the method described in JP-B-41-001412).

(A3 ′ represents the same meaning as described above.)
A compound represented by the formula (compound (VII)) and the following general formula available in a commercial product

It can manufacture by making the compound (compound (VIII)) represented by these react.
X ₁ is preferably S (sulfur atom).
The amount of compound (VIII) to be used is generally 1 to 3 mol, preferably 1 to 1.5 mol, per 1 mol of compound (VII).
In this reaction, the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from instant to about 24 hours. This reaction can be carried out in the presence of a base. Bases used include metal salts such as n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, and lithium bis (tolmethylsilyl) amide, and morpholine, piperidine, pyridine, trimethylamine, triethylamine, And organic amines such as diisopropylethylamine and 4-dimethylaminopyridinepyridine. The amount of its use is 0.001-4 mol normally with respect to 1 mol of compounds (VIII). Examples of the solvent include alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; acetonitrile; dimethylformamide; dimethyl sulfoxide; and halogenated hydrocarbons.
As a reaction similar to this reaction, as shown below, 3-cinnamoyl 2-pyrone derivatives (R = 2-OMe, 2-OH, 4-OH, 4-NO2, 2,6-diCl, 2-Cl) And 2-aminothiophenol have been reported to construct condensed seven-membered ring structures such as benzo [1,5] thiazepine derivatives (see, for example, Indian Journal of Chemistry section B, 1995, 34B, pp. 893-894. )

However, for example, when the compound synthesized in Example 2 shown below is analyzed in detail by two-dimensional NMR of HC and two-dimensional NMR of HN, the compound is a condensed six-membered ring compound, that is, 2, It was found to be 3-dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine. In addition, since the same compound was obtained by the production method of Production Method 1, it was confirmed that the product obtained by this reaction had a condensed 6-membered ring structure.

（Ａ３’は上記と同様の意味を表す。）
で表される縮合６員環化合物を、下記一般式

（Ａ３’は上記と同様の意味を表す。）
にて表される縮合７員環化合物（化合物（ＩＸ））を極性溶媒で処理することにより製造することができる。ここで、極性溶媒で処理するとは、化合物（ＩＸ）を極性溶媒と接触させることを意味し、例えば、化合物（ＩＸ）を極性溶媒に溶解させることで実現できる。
本反応において、反応温度の範囲は、通常室温から還流温度であり、反応時間の範囲は、通常瞬時〜約1月である。極性溶媒としては、例えば、メタノール、およびエタノール等のアルコール溶媒、ならびにジメチルスルホキシド等のスルホキシド溶媒が用いられる。
本反応の原料および得られた生成物を２次元ＮＭＲで詳細に解析することにより、７員環から６員環への環変換が生じることが確認されている。 [Production method 3]
As production method 3, the following general formula

(A3 ′ represents the same meaning as described above.)
A condensed 6-membered ring compound represented by the following general formula

(A3 ′ represents the same meaning as described above.)
It can manufacture by processing the condensed 7-membered ring compound (compound (IX)) represented by these with a polar solvent. Here, treating with a polar solvent means bringing the compound (IX) into contact with a polar solvent, and can be realized, for example, by dissolving the compound (IX) in a polar solvent.
In this reaction, the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from instantaneous to about 1 month. As the polar solvent, for example, alcohol solvents such as methanol and ethanol, and sulfoxide solvents such as dimethyl sulfoxide are used.
It has been confirmed that ring conversion from a 7-membered ring to a 6-membered ring occurs by analyzing the raw material of this reaction and the resulting product in detail by two-dimensional NMR.

（Ａ_１およびＡ３’は上記と同様な意味を表す）
で表される化合物（化合物（ＶＩＩ’））と、市販等で入手可能な下記一般式

（n1、X１、Y１は上記と同様な意味を表す）
で表される市販等で入手可能な化合物（化合物（ＶＩＩＩ））とを反応させて製造することができる。 Compound (IX) is a compound represented by the following general formula, which is commercially available or can be obtained by a method known in the art (for example, JP-B-41-001412)

_{(A 1} and A3 'are as defined the same as the above)
A compound represented by the formula (compound (VII ′)) and the following general formula available commercially

(N1, X1, and Y1 have the same meaning as above)
It can manufacture by making it react with the commercially available compound (compound (VIII)) represented by these.

The amount of compound (VIII) to be used is generally 1 to 3 mol, preferably 1 to 1.5 mol, per 1 mol of compound (VII ′).
In this production method, the reaction temperature ranges from room temperature to reflux temperature, and the reaction time ranges from instantaneous to about 24 hours. This production method is usually carried out in the presence of an acid. Examples of the acid used include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid. 0.001-100 mol is used with respect to 1 mol of compounds (VII). Examples of the solvent include alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; acetonitrile; dimethylformamide; dimethyl sulfoxide; and halogenated hydrocarbons. It may be used as a solvent.

（Ａ３’は上記と同様の意味を表す。）
で表される化合物を、下記一般式

にて表される化合物（化合物（Ｘ））と、下記一般式

（Ａ３’は上記と同様の意味を表す。）
で表される化合物(化合物（ＸＩ）)とを反応させて製造することができる。
本製法のより好ましい様態は、Ｘ₁がＯ（酸素）である製造法である。
化合物（ＸＩ）の使用量は、化合物（Ｘ）１モルに対し、通常１〜２モル、好ましくは１〜１．５モルである。
本反応において、反応温度の範囲は、通常室温から還流温度であり、反応時間の範囲は、通常瞬時〜約２４時間である。この製造方法は塩基の存在下で行われる。用いられる塩基としては、例えば、n-ブチルリチウム、sec-ブチルリチウム、tert-ブチルリチウム、リチウムジイソプロピルアミド、リチウムビス(トルメチルシリル)アミド等といった金属塩や、モルホリン、ピペリジン、ピリジン、トリメチルアミン、トリエチルアミン、ジイソプロピルエチルアミン、４−ジメチルアミノピリジンピリジンのような有機アミン等が挙げられ、その使用量は、化合物（Ｘ）１モルに対して、通常０．００１〜４モルである。溶媒としては、例えば、メタノール、およびエタノール等のアルコール系溶媒；テトラヒドロフラン、およびジオキサン等のエーテル系溶媒；アセトニトリル；ジメチルホルムアミド；ジメチルスルホキシド；ならびにハロゲン化炭化水素類が用いられ、先の記載の有機塩基を溶媒として用いてもよい。 [Production method 4]
As a production method of production method 4, the following general formula

(A3 ′ represents the same meaning as described above.)
A compound represented by the following general formula

A compound represented by the formula (compound (X)) and the following general formula

(A3 ′ represents the same meaning as described above.)
It can manufacture by making the compound (compound (XI)) represented by these react.
A more preferred embodiment of this production method is a production method in which X ₁ is O (oxygen).
The amount of compound (XI) to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (X).
In this reaction, the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from instant to about 24 hours. This production method is carried out in the presence of a base. Examples of the base used include metal salts such as n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis (tolmethylsilyl) amide, morpholine, piperidine, pyridine, trimethylamine, and triethylamine. , Diisopropylethylamine, organic amines such as 4-dimethylaminopyridine pyridine, and the like. The amount of the amine used is usually 0.001 to 4 mol with respect to 1 mol of compound (X). Examples of the solvent include alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; acetonitrile; dimethylformamide; dimethyl sulfoxide; and halogenated hydrocarbons. May be used as a solvent.

If desired, the target compound can be obtained by converting the substituents of the compounds synthesized in the above production methods 1 to 4 by a method commonly used in the art.
Further, the compounds of the present invention have tautomers, but reactions using these as starting compounds or target compounds are also included in the process for producing the compounds of the present invention, The same can be done.

As mentioned above, although the manufacturing method of compound (I) was demonstrated, the compound (I) synthesize | combined according to these manufacturing methods is a solution, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, and column chromatography. From the reaction mixture, it can be separated and purified by a known technique such as.
In addition, when compound (I) is obtained as a free form, it can be converted to the target salt as described above by a method known per se or a method analogous thereto, and conversely, compound (I) When obtained as a salt, it can be converted into a free form or other desired salt by a method known per se or a method analogous thereto.
For example, the purified compound (I) is converted into inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, succinic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, By reacting with an organic acid such as p-toluenesulfonic acid, a pharmaceutically acceptable acid addition salt can be easily obtained.
Further, the purified compound (I) is converted into, for example, lithium hydroxide, lithium methylate, sodium hydride, sodium carbonate, sodium hydroxide, sodium methylate, potassium hydroxide, potassium carbonate, potassium hydroxide, potassium-t- By reacting with an inorganic / organic metal salt such as butyrate, a pharmaceutically acceptable metal salt can be easily obtained.

  The compounds of the invention can be provided in all forms suitable for the intended administration. Suitable forms include pharmaceutically (ie physiologically) acceptable salts and predrug and prodrug forms of the compounds of the invention. These predrug and prodrug forms are also within the scope of the present invention.

The compound of the present invention has an action of enhancing the activity of neurotrophic factor, and in particular, has an action of inducing NXF gene expression that plays an important role in nerve protection.
Therefore, the compound of the present invention can be used as a therapeutic or prophylactic agent for diseases involving neurotrophic factor activity.
In the present specification, a disease is used in the meaning including a disorder and its symptoms.
In the present specification, treatment is used in the meaning including alleviation of symptoms.

Examples of diseases involving the activity of neurotrophic factors include the following neurological and psychiatric diseases and other diseases.
For example, neurological and psychiatric disorders include
Neurodegenerative diseases [eg, vascular dementia (eg, multiple cerebral infarction dementia, binswanger type leukoencephalopathy), Alzheimer's disease (Alzheimer type senile dementia, familial Alzheimer's disease), mild cognitive impairment, memory deficit and attention deficit , Behavioral problems associated with dementia, progressive supranuclear palsy, Pick's disease, Huntington's chorea, Parkinson's disease, epilepsy (eg, refractory epilepsy), seizures, multiple sclerosis, amyotrophic lateral sclerosis, Down's syndrome , Spinocerebellar degeneration, retinal degenerative diseases],
CNS disorders [eg, cerebrovascular disorders (eg, cerebral ischemia, stroke), cerebral ischemic disease), spinal cord injury, traumatic brain injury],
Peripheral neuropathy [eg, diabetic neuropathy, peripheral neuropathy due to cancer chemotherapy, peripheral neuropathy due to carbon monoxide, lead or domoic acid poisoning, numbness due to wounds],
Anxiety, depression, bipolar disorder, schizophrenia,
Convulsions, chronic subdural hematoma, primary brain tumor, metastatic brain tumor, limbic encephalitis, intermittent claudication, migraine, pain, chronic pain (persistent somatoform pain disorder), cerebral metabolic disorder, collagen disease, Raynaud Disease, and myotonic muscular dystrophy.
Examples of diseases other than neurological diseases and mental diseases include, for example,
Diabetes (type I, type II), hyperinsulinemia, obesity, bulimia, impaired glucose tolerance, hyperlipidemia, hypertension, diabetic cardiomyopathy, narcolepsy, cardiovascular disease, asthma, arrhythmia, dry mouth, baldness Disease, cancer, immunosuppression, secretory diarrhea, dysmenorrhea, premature birth, ischemic heart disease, angina, coronary heart disease, cystic fibrosis, chronic obstructive pulmonary disease, rhinorrhea, vasospasm, coronary Arterial spasm, kidney disease, polycystic kidney disease, bladder spasm, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, Sjogren's syndrome, inflammatory bowel disease, and periodontal disease.
Among them, the compound of the present invention is used for the treatment of stroke, cerebral ischemic disease, multiple cerebral infarction dementia, Binswanger type leukoencephalopathy, Alzheimer's disease, Down's syndrome, Parkinson's disease, amyotrophic lateral sclerosis, retinal degenerative disease or Effective for prevention.

  Since the compound of the present invention has low toxicity, it can be used as a composition (eg, pharmaceutical composition) formulated as it is or mixed with a pharmaceutically acceptable carrier or the like for diseases involving neurotrophic factor activity. For prevention or treatment, it can be safely administered orally or parenterally to mammals such as humans. “Parenteral” includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, and the like.

The composition of the present invention contains, for example, one or more compounds of the present invention and a pharmaceutically acceptable carrier, excipient, and / or additive.
Depending on the form of the composition of the present invention, the compound of the present invention and a pharmaceutically acceptable carrier, excipient, and / or additive (eg, pharmaceutical additive, food additive) Agent, cosmetic additive) and the like.
The pharmaceutically acceptable carrier, excipient, and / or additive used in the composition of the present invention can be appropriately selected depending on the specific use of the composition. Moreover, the form of the said composition can also be made into forms, such as various solid and liquid, according to a specific use, for example.
For example, when the pharmaceutical composition of the present invention or the compound of the present invention is used as a pharmaceutical, specific forms such as powders, fine granules, granules, tablets, syrups, capsules, suspending agents Oral preparations such as emulsions, extracts and pills, transdermal absorption agents (skin preparations for external use) such as injections, liquids for external use and ointments, suppositories, and parenteral preparations for topical use. .
Oral preparations are, for example, gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitol, carboxymethylcellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soybean lecithin, sucrose, fatty acid ester, talc, magnesium stearate, Carriers and excipients such as polyethylene glycol, magnesium silicate, and silicic anhydride, binders, disintegrants, surfactants, lubricants, fluidity promoters, diluents, preservatives, colorants, fragrances, stabilization It can be produced according to a usual method using a pharmaceutical additive such as an agent, a humectant, a preservative, and an antioxidant.
The dose varies depending on the age, sex, weight, disease level, type of compound of the present invention, dosage form, etc. of the mammal to be administered. The amount may be about 1 mg to about 2 g, preferably about 5 mg to about 1 g as the active ingredient amount. In addition, the above-mentioned daily dose can be administered once or divided into several times.

Among parenterals, injections are water-soluble solvents such as physiological saline and sterile water Ringer's solution, non-water-soluble solvents such as vegetable oil and fatty acid esters, isotonic agents such as glucose and sodium chloride, solubilizing agents, stable It can be produced according to a usual method using a pharmaceutical additive such as an agent, a preservative, a suspending agent and an emulsifier. External liquid preparations, transdermal absorption agents such as gel ointments, suppositories for rectal administration, and the like can also be produced according to ordinary methods. In order to administer such a parenteral preparation, injection (subcutaneous, intravenous, etc.), transdermal administration, or rectal administration may be used. The topical agent can be produced, for example, by incorporating the compound of the present invention into a sustained release polymer pellet such as an ethylene vinyl acetate polymer. This pellet may be surgically implanted into the tissue to be treated.
The dose varies depending on the age, sex, body weight, degree of disease, the type of the composition of the present invention or the compound of the present invention, the mode of administration, etc. And about 0.1 mg to about 500 mg may be administered as the active ingredient amount. In addition, the above-mentioned daily dose can be administered once or divided into several times.

When the composition of the present invention or the compound of the present invention is used as a cosmetic, examples of specific forms include creams and lotions. The lotion can be produced according to a usual method using cosmetic additives such as a suspending agent, an emulsifier, and a preservative.
The dosage varies depending on the age, sex, body weight, degree of disease, the type of the composition of the present invention or the compound of the present invention, the dosage form, etc. 0.01 mg to about 50 mg may be administered. In addition, the above-mentioned daily dose can be administered once or divided into several times.

When the composition of the present invention or the compound of the present invention is used as a food, specific forms include, for example, powders, tablets, beverages, ingestible gels or mixed liquids with syrup, such as seasonings, General food and drink such as Japanese confectionery, Western confectionery, ice confectionery, beverages, spreads, pastes, pickles, canned bottles, processed meat products, processed fish / fishery products, processed milk / egg products, processed vegetables products, processed fruit products, processed cereal products, etc. There is a possibility of being used as an object or a favorite item. In addition, it may be used as a food additive to feed and feed for domestic animals such as domestic animals, poultry, bees, cormorants and fish.
The dosage varies depending on the age, sex, body weight, degree of disease, the type of the composition of the present invention or the compound of the present invention, the dosage form, etc. What is necessary is just to administer 0.1 mg-about 500 mg. In addition, the above-mentioned daily dose can be administered once or divided into several times.

  Hereinafter, the present invention will be described in more detail with reference to Production Examples, Examples, Formulation Examples, Test Examples, and the like, but the present invention is not limited only to these examples.

Production Example 1: Intermediate described in Example 4 (Production Method 3) below: 3,4-dihydro-2- (2-pyridylmethyl) -4- (2,4-dioxo-6-methylpyran-3-ylidene) -Synthesis of benzo [1,5] thiazepine N-methyl-3- (3- (2-pyridyl) -acrylonyl) -4-hydroxy-6-methylpyridone 71.5 mg, 2-aminothiophenol 39.8 mg, acetic acid 0.3 mL A mixture of 5 mL of ethanol was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated, 100 mL of aqueous hydrochloric acid was added, and the mixture was washed with ethyl acetate. The aqueous phase was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and dried, and then the solvent was distilled off. The obtained crystals were washed with ethanol to obtain 62 mg (yield 62%) of the title compound as pale yellow crystals.
¹ H-NMR (CDCl ₃ ) δ: 2.29 (3H, s), 3.12 (1H, t, J = 12.2 Hz), 3.39 (3H, s), 4.40-4.46 (1H, m), 5.37 (1H, dd , J = 12.2, 4.6 Hz), 5.80 (1H, s), 7.12-7.34 (4H, m), 7.43-7.53 (2H, m), 7.64 (1H, td, J = 7.8, 1.8 Hz), 8.47 ( 1H, d, J = 4.6 Hz), 16.93 (1H, s).

Production Example 2: Production Method 2, Intermediate described in Production Example 1 above: Synthesis of N-methyl-3- (3- (2-pyridyl) -acrylonyl) -4-hydroxy-6-methylpyridone
A mixture of 3.46 g of N-methyl-3-acetyl-4-hydroxy-6-methylpyridone, 2.25 g of 2-pyridinecarbaldehyde, 13.01 g of a 20% sodium ethoxide / ethanol solution and 70 mL of ethanol was heated to reflux for 6 hours. After concentrating the reaction solution, 3.44 g of acetic acid and 100 mL of water were added. The precipitated crystals were washed with water and recrystallized with ethanol to obtain 1.5 g (yield 29%) of the title compound as yellow crystals.
¹ H-NMR (DMSO-D ₆ ) δ: 2.41 (3H, s), 3.40 (3H, s), 6.06 (1H, s), 7.40-7.45 (1H, m), 7.71-7.78 (2H, m) , 7.89 (1H, td, J = 7.8, 1.8 Hz), 8.69 (1H, d, J = 3.2 Hz), 8.81 (1H, d, J = 15.6 Hz), 15.92 (1H, s).

Example 1: Compound of the present invention according to Production Method 1: 2,3-dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] Synthesis of thiazine (compound C-1) 2,3-dihydro-3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine 273 mg in anhydrous tetrahydrofuran (10 mL) The solution was cooled to −78 ° C., 1M diisopropylamine hexane-tetrahydrofuran solution (3 mL) was added dropwise with stirring, and the mixture was stirred at the same temperature for 30 minutes after completion of the dropwise addition, and further stirred at room temperature for 1 hour. Next, the mixture was cooled again to −78 ° C., an HMPA suspension of 2- (bromomethyl) pyridine hydrobromide was added dropwise, stirred at the same temperature for 30 minutes, and then stirred at room temperature for 2 hours. Next, the reaction solution was extracted with chloroform after adding saturated aqueous ammonium chloride solution (30 mL). The extract was dried, the solvent was distilled off, and the remaining crude crystals were purified by column chromatography to give 66 mg (yield 18%) of the title compound.

Example 2: Compound of the present invention according to Production Method 2: 2,3-dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] Synthesis of thiazine (compound C-1) 3- (3- (2-pyridyl) -acrylonyl) -4-hydroxy-6-methylpyrone 200 mg, 2-aminothiophenol 97.3 mg, 1 drop of piperidine, 5 mL of ethanol Was heated to reflux for 1 hour. After cooling to room temperature, the precipitated crystals were filtered, and the obtained crystals were washed with ethanol to give the title compound (138 mg, yield 49%).

Example 3: Compound of the present invention according to Production Method 2: 2,3-dihydro-2- (2-pyridylmethyl) -3- (N-methyl-2,4-dioxo-6-methylpyridone-3-ylidene) -benzo Synthesis of [1,4] thiazine (Compound C-55) N-methyl-3- (3- (2-pyridyl) -acrylonyl) -4-hydroxy-6-methylpyridone obtained in Production Example 2 400 mg A mixture of 97.3 mg of 2-aminothiophenol, 3 drops of piperidine and 10 mL of ethanol was heated to reflux for 1 hour. After cooling to room temperature, the precipitated crystals were filtered, and the obtained crystals were washed with ethanol to give the title compound (382 mg, yield 69%).

Example 4: Compound of the present invention according to Production Method 3: 2,3-dihydro-2- (2-pyridylmethyl) -3- (N-methyl-2,4-dioxo-6-methylpyridone-3-ylidene) -benzo Synthesis of [1,4] thiazine (compound C-55) 3,4-dihydro-2- (2-pyridylmethyl) -4- (N-methyl-2,4-dioxo-6-methylpyridone-3-ylidene ) -Benzo [1,5] thiazepine 10 mg and ethanol 10 mL were stirred at 80 ° C. for 15 hours. After cooling, the crude product was purified by column chromatography to obtain 7 mg (yield 70%) of the title compound.

Example 5: Compound of the present invention prepared by Process 4: 2,3-dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] Synthesis of Oxazine (Compound C-78) 3- (1- (2-hydroxyphenylimino) ethyl) -4-hydroxy-6-methylpyrone 500 mg, 2-pyridinecarbaldehyde 250 mg, triethylamine 1 mL, ethanol 10 mL for 1 hour Heated to reflux. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, then the solvent was distilled off, and the remaining crude crystals were purified by column chromatography to obtain 100 mg (yield 14%) of the title compound.

Example 6: Compound of the present invention used in Production Method 1: 2,3-dihydro-3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine (Compound F-1) Synthesis of 4-hydroxy-6-methylpyrone 296 mg, 2- (2-nitrophenylthio) -acetic acid 500 mg, chloroform 10 mL in a mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 541 mg 4-Dimethylaminopyridine (402 mg) was added and the mixture was stirred at room temperature for 24 hours. The reaction solution was extracted with chloroform after adding 10% hydrochloric acid (10 mL). The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and then with water, dried, and the solvent was distilled off to give 480 mg of 3- (2- (2-nitrophenylthio) -acetyl) -4-hydroxy-6-methylpyrone ( Yield 64%). ¹ H-NMR (CDCl3) δ: 2.32 (3H, s), 4.54 (2H, s), 6.00 (1H, s), 7.26-7.33 (1H, m), 7.53-7.61 (2H, m), 8.20 ( (1H, d, J = 6.9 Hz).
To the obtained mixed solution of 3- (2- (2-nitrophenylthio) -acetyl) -4-hydroxy-6-methylpyrone (321 mg), acetic acid (5 mL) and ethanol (5 ml) was added 168 mg of iron powder, and the mixture was added for 1.5 hours. Heated to reflux. After cooling to room temperature, the reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the suspension was filtered, and the filtrate was extracted with chloroform. The extract was dried, the solvent was distilled off, and the remaining crude crystals were purified by column chromatography to give 202 mg (yield 74%) of the title compound.

Example 7: Compound of the present invention used in Production Method 1: Synthesis of 2,3-dihydro-3- (2,4-dioxocoumarin-3-ylidene) -benzo [1,4] thiazine (Compound F-23) A mixture of 200 mg of 3- (2-bromoacetyl) -4-hydroxycoumarin, 100 mg of 2-aminothiophenol and 2 mL of ethanol was heated to reflux for 1 hour. After cooling to room temperature, the precipitated crystals were filtered to obtain 40 mg (yield 18%) of the title compound.

Example 8: Compound of the present invention: 2,3-dihydro-2- (4-hydroxyphenylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine ( Synthesis of Compound C-22) 2,3-Dihydro-2- (4-acetyloxyphenylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine 35 mg A two-layer solution of 1N aqueous sodium hydroxide solution 0.15 ml and chloroform 2 ml was stirred at room temperature. Methanol was then added until the bilayer solution was one layer. After stirring at room temperature for 5 minutes, 1N hydrochloric acid was added until acidic, and chloroform and methanol were distilled off. Next, the obtained crystals were collected by filtration, washed with water, and dried to obtain 25 mg (yield 79%) of the title compound.

Example 9: Compound of the present invention: hydrochloric acid of 2,3-dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine Synthesis of salt (compound C-16) 2,3-dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine 50 mg Then, 0.36 mL of a 14% hydrogen chloride-dioxane solution was added to a mixture of 5 mL of dioxane, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were filtered and dried under reduced pressure to obtain 40 mg (yield 72%) of the title compound.

Example 10: Compound of the present invention: 2- (2-pyridylmethyl) -3- (4-hydroxy-6-methylpyron-3-yl) -2H-benzo [1,4] thiazine sodium salt and / or 2, Synthesis of sodium salt of 3-dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine (Compound C-14) 2 , 3-Dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine 50 mg, ethanol 1 mL in a mixture of 20% sodium ethoxy 0.05 mL of do-ethanol solution was added and stirred at room temperature for 1 hour. The precipitated crystals were filtered and dried under reduced pressure to obtain 30 mg (yield 54%) of the title compound.

Example 11: Synthesis of 2- (2-pyridylmethyl) -3- (2,4-dihydroxyphenyl) -2H-benzo [1,4] thiazine (Compound A-4)
A solution of 269 mg of 1-hydroxy-6,7-dihydrobenzopyrano [3,4-b] [1,4] benzothiazine (Compound E-1) in anhydrous tetrahydrofuran (10 mL) is cooled to −78 ° C. and stirred. Then, 1M diisopropylamine hexane-tetrahydrofuran solution (3.3 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature for 1 hour. Next, the mixture was cooled again to −78 ° C., a suspension of 2- (bromomethyl) pyridine hydrobromide (304 mg) in HMPA (1 ml) was added dropwise, and the mixture was stirred at the same temperature for 30 min. Stir for hours. Next, the reaction solution was extracted with chloroform after adding saturated aqueous ammonium chloride solution (30 mL). The extract was dried, the solvent was distilled off, and the remaining crude crystals were purified by column chromatography to obtain 20 mg (yield 5.7%) of the title compound.

Example 12: 2,3-Dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-ethylpyran-3-ylidene) -benzo [1,4] thiazine (Compound C-39) Synthesis of 2,3-dihydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine (Compound C-1) 200 mg 1M diisopropylamine hexane-tetrahydrofuran solution (1.2 mL) was added dropwise with stirring, and the mixture was stirred at the same temperature for 30 minutes and stirred at room temperature for 1 hour. did. Next, the mixture was cooled again to −78 ° C., a solution of methyl iodide (117 mg) in HMPA (0.5 ml) was added dropwise, stirred at the same temperature for 30 minutes, and then stirred at room temperature for 2 hours. Next, the reaction solution was extracted with chloroform after adding saturated aqueous ammonium chloride solution (30 mL). The extract was dried, the solvent was distilled off, and the remaining crude crystals were purified by column chromatography to obtain 109 mg (yield 53%) of the title compound.

The structure and physical properties of a series of compounds synthesized according to these production methods are summarized in Table 7, and the synthesis method is summarized in Table 8. In addition, the numbers 1-12 as a synthesis method in the table | surface description means having synthesize | combined according to the method of Examples 1-12, respectively.
The starting material in Table 8 may represent only one of the plurality of starting materials, but those skilled in the art are not shown from the target compound and the starting materials shown and the description herein. The starting material will be easily identified.

Test Example 1: mRNA quantification by RT-PCR (TaqMan)
Primary cultured neurons were prepared from the cerebral hemispheres of rat fetuses on the 18th day of pregnancy using a neuron dispersion (manufactured by Sumitomo Bakelite). Inoculated on a Sumilon Celtite PL plate 24 Well (Sumitomo Bakelite Co., Ltd.) at about 6 × 10 ⁵ cells / well and cultured for 8 days.
Next, DMSO or a compound dissolved in DMSO was added to the cells together with BDNF prepared to a final concentration of 5 ng / ml. One hour after the addition, RNA was prepared using RNeasy Mini Kit (manufactured by QIAGEN), and reverse transcription reaction was performed using Super Script II RNase H ^- Reverse Transriptase (manufactured by Invitrogen). The extracted RNA was stored at −80 ° C. until use.
1 μg of RNA is mixed with oligo dT (12-18) primer (Amersham Biosciences; 15 μg / ml) 1 μl and dNTP Mixture 2.5 mM each 1 μl and ddH ₂ O in a total volume of 12 μl and heated at 65 ° C. for 5 minutes did. Next, the mixture is put in ice, 5 × reverse transcriptase buffer (250 mM Tris-HCl, pH 8.3, 375 mM KCl, 15 mM MgCl ₂ ) 4 μl, RNaseOUT Ribonuclease Inhibitor 40 u / μl (Invitrogen) 1 μl Then, 2 μl of 0.1 M dithiothreitol was mixed, heated at 42 ° C. for 2 minutes, mixed with 1 μl of Super Script IIRT, heated at 42 ° C. for 50 minutes, added at 70 ° C. for 15 minutes, and then cooled to 4 ° C. The cDNA was stored at -20 ° C until use.
For real-time PCR using TaqMan probe, Rat GAPDH primer & probe set (Applied Biosystems) was used as an internal control to standardize the amount of added cDNA. The primer and probe set of NXF was TaqMan Gene expression Assay (product, Rn00596522_m1) from Applied Biosystems. For quantitative PCR reactions the following components were used in a total reaction volume of 25 μl. NXF primer & probe set 2 × TaqMan Universal PCR Master Mix ( Applied Biosystems , _{Inc.) 12.5μl, ddH 2 O 9.25μl,} 20 × primer & probe set 1.25μl and template cDNA 2 [mu] l. GAPDH primer and probe set is 2 × TaqMan Universal PCR Master Mix 12.5 μl, ddH ₂ O 9.75 μl, 20 × primer & probe set 0.75 μl and template cDNA 2 μl. Quantitative PCR was performed on an Optical 96-Well Reaction Plate (Applied Biosystems) using Applied Biosystems ABI PRISM 7900HT. PCR reaction and TaqMan method analysis (automatic analysis using the standard software attached to ABI PRISM 7900HT) was performed: 1) 2 minutes at 50 ° C; 2) 10 minutes at 95 ° C; 3) 15 seconds at 95 ° C 40 cycles of 60 seconds at 60 ° C.
The results (NXF induction / Fold) of compound C-1 are shown in FIG. Thus, it was confirmed that the compound of the present invention induces the NXF gene.

Test Example 2: (Neuron cell protective effect in middle cerebral artery occlusion / reopening model)
Male 8-week-old C57BL / 6J mice are normally bred for 12 days, then the left common neck and external common artery are ligated in advance, and the middle cerebral artery is occluded for 90 minutes and then reopened. A model was created. In the same model, the compound was administered into the tail vein at 10 mg / kg 2 minutes before occlusion, 30 minutes after, 24 hours and 48 hours later. After 3 days of occlusion / reopening, the head was decapitated, the skull was cut from the cerebellum, and the brain was removed. The excised brain was placed in Buan solution (ph 3.5-4.0) and fixed. From the fixed brain, coronal sections were cut out, and after cutting, dehydration and penetration, and embedded in paraffin. Slicing was performed at 4 sites around Bregma 1.95 mm, Bregma 1.0 mm, Bregma -1.40 mm and Bregma -3.8 mm. Sections with a thickness of about 6 μm were prepared and HE-stained. Infarct volume was calculated as follows.
Digital images were captured using a camera (MCD-350, Olympus Corporation) attached to an optical microscope (objective lens x 1). The imported digital image was pasted on a single mount (new layer) in Adobe Photoshop 2.0. Using the image analysis device (Win ROOF V5.6 Mitani Corporation) based on the image pasted on the mount, the infarct area (S, mm ² ), infarct side (left) area (mm ² ) and non-infarct side (right ) Measure the area (MR, mm ² ) and calculate the non-infarct area (ML, mm ² ) [infarct side (left) area (mm ² ) -infarct area (S, mm ² )] on the infarct side (left) did.
The infarct volume (SV, mm ³ ), infarct side (left) non-infarction volume (MLV, mm ³ ) and non-infarction side (right) volume (MRV, mm ³ ) were calculated by the following equations.

Bregma (Bregma) Calculation method around 1.95mm
SV = 1 / 3Σ (S ₁ + S ₂ + S ₁ ^1/2 × S2 ^1/2 )
MLV = 1 / 3Σ (ML ₁ + ML ₂ + ML ₁ ^1/2 × ML ₂ ^1/2 )
MRV = 1 / 3Σ (MR ₁ + MR ₂ + MR ₁ ^1/2 × MR ₂ ^1/2 )

Calculation method around Bregma 1.0mm, Bregma-1.40mm and Bregma-3.8mm
SV = 2 / 3Σ (Sn + Sn + 1 + Sn1 / 2 × Sn + 11/2)
MLV = 2 / 3Σ (MLn + MLn + 1 + MLn1 / 2 × MLn + 11/2)
MRV = 2 / 3Σ (MRn + MRn + 1 + MRn1 / 2 × MRn + 11/2) (n = 2, 3, 4)

The results (infarct volume) of Compound C-16 are shown in FIG. Thus, the reduction of infarct volume was confirmed in the compound administration group.

  The compounds of the present invention can be used for the treatment or prevention of diseases involving the activity of neurotrophic factors.

The graph which shows NXF induction amount. The graph which shows infarct volume.

Claims (23)

General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A ₂ is,
Represents an alkylene chain;
A ₃ is,
Represents an aromatic group optionally substituted by one or more Y _b ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
X ₁ is
Represents S, SO, SO ₂ , NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ , Y _a and Y _b are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. );
Also,
Two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and one Two Y _a on a carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A therapeutic or prophylactic agent for a disease involving the activity of neurotrophic factor, comprising as an active ingredient a compound represented by the formula: Diseases that involve neurotrophic factor activity include stroke, cerebral ischemic disease, multiple cerebral infarction dementia, binswanger leukoencephalopathy, Alzheimer's disease, Down's syndrome, Parkinson's disease, amyotrophic lateral sclerosis, or retinal degenerative disease The agent according to claim 1. General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A ₂ is,
Represents an alkylene chain;
A ₃ is,
Represents an aromatic group optionally substituted by one or more Y _b ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
X ₁ is
Represents S, NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ , Y _a and Y _b are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group);
And two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and 1 Two Y _a on one carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A compound represented by (however,
1,2,3,4-tetrahydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -quinoxaline,
1,2,3-4-tetrahydro-2- (2-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -6,7-dimethyl-quinoxaline,
2,3-dihydro-2- (4-pyridylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine,
2,3-dihydro-2- (2-nitrophenylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine and 2,3-dihydro-2- (4-Nitrophenylmethyl) -3- (2,4-dioxo-6-methylpyran-3-ylidene) -benzo [1,4] thiazine is excluded. )
, A pharmaceutically acceptable salt, or a solvate thereof. The compound represented by the general formula (Ia) or (Ib)
formula

[Where:
X ₂₁ , X ₂₂ , X ₂₃ and X ₂₄ are
Each independently represents N, C—H or C—Y _a where two or more of X ₂₁ , X ₂₂ , X ₂₃ and X ₂₄ are C—H or C—Y _a ;
A ₄ is,
Represent hydrogen atom or an alkyl group, or combine with _{Y a} on _{X 21 -X 2 - (CH 2} ) m - (X 2 represents O or S, m is an integer of 0 to 2) And other symbols represent the same meaning as described above.
]
The compound of Claim 3 which is a compound shown by these. The compound represented by the general formula (Ia) or (Ib)
formula

[Where:
X ₃₁ represents N—Y _c or O;
X ₃₂ and X ₃₃ each independently represent C—H, C—Y _a or N (provided that at least one of X ₃₂ and X ₃₃ is C—H or C—Y _a ). );
Y _c is
1) Hydrogen atom
2) a halogen atom,
3) An acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group
4) Aryl group
5) R1'-Z2'-Z1'-
(Where
R1 ′ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z2 ′ is —S (O) q′—, —O—, —S—, —NR2′—, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH. -, -NH-CO-NH-, -NR2'-CO-, -NH-S (O) q'-NH-, -S (O) q'-NH- or -NR2'-S (O) q '-(Q' represents an integer of 0 to 2, R2 'represents a hydrogen atom, an alkyl group or a cycloalkyl group),
Z1 ′ represents an alkylene chain. ), Or
6) R1 "-Z2"-
(Where
R1 ″ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z2 ″ is —CO—, —O—CO—, —NR2 ″ —CO—, —NH—S (O) q ″ —, or —S (O) q ″ — (q ″ is An integer of 0 to 2, R2 ″ represents a hydrogen atom, an alkyl group or a cycloalkyl group. And other symbols have the same meaning as described above. ]
The compound of Claim 3 which is a compound shown by these. The compound represented by the general formula (Ia) or (Ib) is

[Where:
X ₄₁ and X ₄₃ are
Each _{independently} represents _{CH 2, CH-Y a,} C (Y a) 2 or _{N-Y c;}
X _{42 represents} CH 2, _{CH-Y a} or _{C (Y a) 2;}
n2 represents an integer of 0 to 4,
Y _c is
1) Hydrogen atom
2) a halogen atom,
3) An acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group
4) Aryl group
5) R1'-Z2'-Z1'-
(Where
R1 ′ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z2 ′ is —S (O) q′—, —O—, —S—, —NR2′—, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH. -, -NH-CO-NH-, -NR2'-CO-, -NH-S (O) q'-NH-, -S (O) q'-NH- or -NR2'-S (O) q '-(Q' represents an integer of 0 to 2, R2 'represents a hydrogen atom, an alkyl group or a cycloalkyl group),
Z1 ′ represents an alkylene chain. ), Or
6) R1 "-Z2"-
(Where
R1 ″ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z2 ″ is —CO—, —O—CO—, —NR2 ″ —CO—, —NH—S (O) q ″ —, or —S (O) q ″ — (q ″ is An integer of 0 to 2, R2 ″ represents a hydrogen atom, an alkyl group or a cycloalkyl group. And other symbols have the same meaning as described above. ]
The compound of Claim 3 which is a compound shown by these. A compound according to any one of claims 3 to 6 A ₂ is a methylene chain. A compound according to any one of claims 3 to 7 A ₃ is one or more optionally substituted with Y _b heteroaryl group. A ₃ has the formula

(A3 'is optionally substituted with one or more Y _b may also be) represented by a nitrogen-containing heteroaryl group, the compound according to claim 8. A compound according to any one of claims 3 to 9 A ₄ is a hydrogen atom. A compound according to any one of claims 3 to 10 X ₁ is S. General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
X ₁ is
Represents S, NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ and Y _a are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group);
Also,
Two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and one Two Y _a on a carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof,
Formula _Xa-A 2 -A ₃
[Where:
A ₂ is,
Represents an alkylene chain;
A ₃ is,
Represents an aromatic group optionally substituted by one or more Y _b ;
Y _b is independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. );
Xa is
Represents a leaving group. ]
A compound represented by the formula: pharmaceutically acceptable salt, or a solvate thereof,
General formula

(The symbols in the formula represent the same meaning as described above.) A method for producing a compound, a pharmaceutically acceptable salt or a solvate thereof. General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
X ₁ is
Represents S, NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ and Y _a are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group);
Also,
Two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and one Two Y _a on a carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A compound represented by (however,
1,2-dihydro-3- (2-hydroxy-3,5-dichlorophenyl) -quinoxaline,
3- (2-hydroxyphenyl) -2H-benzo [1,4] thiazine,
3- (2,5-dihydroxyphenyl) -2H-benzo [1,4] thiazine and 2,3-dihydro-3- (5-oxo-2-phenyl-4H-oxazol-4-ylidene) -benzo [ 1,4] oxazine is excluded. )
, A pharmaceutically acceptable salt, or a solvate thereof. 14. A compound according to claim 13, wherein X < ₁ > is S. General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ^{;
A3 '}
Represents a nitrogen-containing heteroaryl group optionally substituted by one or more Y _b ;
A ₄ is,
Represents a hydrogen atom or an alkyl group, or may combine with one Y _a to form _a divalent chain group;
Y _a and Y _b are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. );
Also,
Two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and one Two Y _a on a carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof,
General formula

[Where:
n1 is
Represents an integer from 0 to 4;
X ₁ is
Represents S, NH or O;
Y ₁ is independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group). ]
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(The symbols in the formula have the same meaning as above.)
Or a pharmaceutically acceptable salt or solvate thereof. The method according to claim 12 or 15 X ₁ is S. General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
A3 '
Represents a nitrogen-containing heteroaryl group optionally substituted by one or more Y _b ;
Y ₁ , Y _a and Y _b are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group);
And two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and 1 Two Y _a on one carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
Or a pharmaceutically acceptable salt thereof, or a solvate thereof, treated with a polar solvent,

(The symbols in the formula have the same meaning as above.)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof. The production method according to claim 17, wherein the polar solvent is an alcohol solvent or a sulfoxide solvent. General formula

[Where:
A ₁ is,
Represents _a ring optionally substituted by one or more Y _a ;
X ₁ is
Represents S, NH or O;
n1 is
Represents an integer from 0 to 4;
Y ₁ and Y _a are each independently at each occurrence,
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. (However, when X ₁ is O, Y ₁ is not a hydroxyl group);
And two adjacent Y _a together with the two atoms to which they are attached may form a ring optionally substituted with one or more Ya ′, and 1 Two Y _a on one carbon atom together with the carbon atom may form a carbonyl group or a thiocarbonyl group;
Ya ′ is independently at each occurrence,
Hydroxyl group,
Halogen atoms,
A carboxy group,
Nitro group,
An alkyl group,
It represents a cycloalkyl group or an alkoxy group, and two Ya ′ on one carbon atom may be combined with the carbon atom to form a carbonyl group. ]
A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof,
General formula

[Where:
A3 '
Y represents a heteroaryl group containing a nitrogen atom which may be substituted with _b ;
Y _b is
1) a hydroxyl group,
2) a halogen atom,
3) a carboxy group,
4) Nitro group,
5) a cyano group,
6) an acyclic hydrocarbon group or a cycloalkyl group each optionally substituted by one or more substituents selected from a halogen atom and an aryl group,
7) an aryl group, or
8) R ¹ -Z ₂ -Z _1-
(Where
R ¹ represents a hydrogen atom or an alkyl group which may be substituted with one or more halogen atoms,
Z ₂ represents —S (O) q—, —O—, —S—, —NR ² —, —CO—O—, —O—CO—, —CO—NH—, —O—CO—NH—. ^{, -NH-CO-NH -,} - NR 2 -CO -, - NH-S (O) q-NH -, - S (O) q-NH- or ^{-NR 2 -S (O) q- (} q Represents an integer of 0 to 2, and R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group.
Z ₁ represents a bond or an alkylene chain. ). And a pharmaceutically acceptable salt thereof, or a solvate thereof.

(The symbols in the formula have the same meaning as above.)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof. The manufacturing method according to claim 19, wherein X ₁ is O. A pharmaceutical composition comprising the compound according to any one of claims 3 to 11, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 21, which is used for prevention or treatment of a disease involving neurotrophic factor activity. Diseases that involve neurotrophic factor activity include stroke, cerebral ischemic disease, multiple cerebral infarction dementia, binswanger leukoencephalopathy, Alzheimer's disease, Down's syndrome, Parkinson's disease, amyotrophic lateral sclerosis, or retinal degenerative disease The pharmaceutical composition according to claim 22.

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