WO2020158870A1 - Parkinson's disease therapeutic - Google Patents

Abstract

The purpose in one embodiment of the present invention is to provide a therapeutic for Parkinson's disease, etc. A compound represented by formulas (1), (2), or (8) or a pharmacologically acceptable salt thereof can be used in the treatment of Parkinson's disease, etc. (Each substituent in the formulas is as described in the specification.)

Description

Parkinson's disease drug

The present invention relates to a therapeutic agent for Parkinson's disease and the like. The present invention also relates to novel compounds useful as therapeutic agents for Parkinson's disease and the like.

It is said that more than 100,000 patients with Parkinson's disease exist in Japan, but the current drug therapy is mainly symptomatic therapy represented by dopamine replacement therapy. It is considered that the cause of Parkinson's disease is a lack of dopamine due to a decrease in nerve cells that produce dopamine, but there is no one on the market as a fundamental therapeutic agent. Therefore, it is desired to develop a drug that can be a fundamental therapeutic drug for Parkinson's disease. In addition, such a fundamental therapeutic agent for Parkinson's disease is expected to be utilized in the treatment of Parkinson's syndrome which exhibits the same symptoms as those in Parkinson's disease.
Meloxicam, which is an oxicam non-steroidal anti-inflammatory drug, has been reported to exhibit an MPP ⁺ -induced neuronal cell death inhibitory effect and a motor dysfunction reducing effect in MPTP-administered Parkinson's disease model mice (Non-Patent Documents 1 to 3). .. Therefore, meloxicam is considered to be a candidate drug such as a therapeutic drug for Parkinson's disease, but it also has a problem. For example, meloxicam has a strong COX inhibitory activity and causes side effects such as gastrointestinal disorders, so it is not desirable as a therapeutic agent for Parkinson's disease and the like.

Tasaki et al., Neurosci Lett, 521, 15, 2012 Tasaki et al., EurJPharmacol, 676, 57, 2012 Tasaki et al., BrainRes, 1344, 25, 2010

In one embodiment of the present invention, it is an object to provide a novel therapeutic agent for Parkinson's disease, which can be a fundamental therapeutic agent for Parkinson's disease. Such a therapeutic agent for Parkinson's disease may be useful as a therapeutic agent for Parkinson's syndrome or a pharmaceutical agent for protecting nerve cells.
Moreover, one embodiment of the present invention aims to provide a novel compound useful as a therapeutic agent for Parkinson's disease and the like.

（式中、
　-X-Y-は、-NR³-SO₂-、-CR⁴R⁵-SO₂-、-CR⁴R⁵-SO-、-CR⁴R⁵-S-、-SO₂-CR⁴R⁵-、-SO-CR⁴R⁵-、-CR⁴R⁵-CR⁶R⁷-、又は-NR³-CR⁴R⁵-を表し、
　R³は、水素原子又はアルキル基を表し、
　R⁴、R⁵、R⁶及びR⁷は、それぞれ独立して、水素原子、ハロゲン原子又はアルキル基を表し、
　Zは、O又はSを表し、

であり、
　R⁸は、水素原子、ハロゲン原子、アルキル基、アルコキシ基、OH、NH₂又はCNを表し、
　ｎは、１～４の整数を表し、
　R¹は、以下から選択される基を表し、

　R⁹は、水素原子、ハロゲン原子、アルキル基、アルコキシ基、アルキルカルボニル基、ホルミル基、又は１～３個のハロゲン原子で水素原子が置換されているアルキル基を表し、
　R¹⁰は、水素原子又はアルキル基を表し、
　ｍは、１～５の整数を表し、
　R²は、水素原子、ハロゲン原子又はOHを表す。）
〔２〕式（１）、（２）もしくは（８）で表される化合物又はそれらの薬学的に許容される塩を含む、神経細胞を保護するための医薬組成物。

（式中、
　-X-Y-は、-NR³-SO₂-、-CR⁴R⁵-SO₂-、-CR⁴R⁵-SO-、-CR⁴R⁵-S-、-SO₂-CR⁴R⁵-、-SO-CR⁴R⁵-、-CR⁴R⁵-CR⁶R⁷-、又は-NR³-CR⁴R⁵-を表し、
　R³は、水素原子又はアルキル基を表し、
　R⁴、R⁵、R⁶及びR⁷は、それぞれ独立して、水素原子、ハロゲン原子又はアルキル基を表し、
　Zは、O又はSを表し、

であり、
　R⁸は、水素原子、ハロゲン原子、アルキル基、アルコキシ基、OH、NH₂又はCNを表し、
　ｎは、１～４の整数を表し、
　R¹は、以下から選択される基を表し、

　R⁹は、水素原子、ハロゲン原子、アルキル基、アルコキシ基、アルキルカルボニル基、ホルミル基、又は１～３個のハロゲン原子で水素原子が置換されているアルキル基を表し、
　R¹⁰は、水素原子又はアルキル基を表し、
　ｍは、１～５の整数を表し、
　R²は、水素原子、ハロゲン原子又はOHを表す。）
〔３〕-X-Y-が、-NR³-SO₂-、-CR⁴R⁵-SO₂-、-SO₂-CR⁴R⁵-、又は-CR⁴R⁵-CR⁶R⁷-を表す、前記〔１〕又は〔２〕に記載の医薬組成物。
〔４〕経口投与で用いられる、前記〔１〕～〔３〕のいずれか１項に記載の医薬組成物。
〔５〕以下の構造式から選択される１の化合物。

As a result of intensive studies to solve the above problems, the present inventors have succeeded in finding a useful compound by modifying the chemical structure including the basic skeleton of meloxicam. The present invention has been completed based on such novel findings.
The present invention relates to the following [1] to [5].
[1] A pharmaceutical composition for treating Parkinson's disease or Parkinson's syndrome, which comprises a compound represented by the formula (1), (2) or (8) or a pharmaceutically acceptable salt thereof.

(In the formula,
-XY- _{^{is, -NR 3 -SO 2 -, -}} CR 4 R 5 -SO 2 -, - CR 4 R 5 -SO -, - CR 4 R 5 -S -, - SO 2 -CR 4 R 5 - , -SO-CR ⁴ R ⁵ -, -CR ⁴ R ⁵ -CR ⁶ R ⁷ -, or -NR ³ -CR ⁴ R ⁵ -,
R ³ represents a hydrogen atom or an alkyl group,
R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, a halogen atom or an alkyl group,
Z represents O or S,

And
R ⁸ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, OH, NH ₂ or CN,
n represents an integer of 1 to 4,
R ¹ represents a group selected from the following,

R ⁹ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group, a formyl group, or an alkyl group in which the hydrogen atom is substituted with 1 to 3 halogen atoms,
R ¹⁰ represents a hydrogen atom or an alkyl group,
m represents an integer of 1 to 5,
R ² represents a hydrogen atom, a halogen atom or OH. )
[2] A pharmaceutical composition for protecting nerve cells, comprising a compound represented by the formula (1), (2) or (8) or a pharmaceutically acceptable salt thereof.

(In the formula,
-XY- _{^{is, -NR 3 -SO 2 -, -}} CR 4 R 5 -SO 2 -, - CR 4 R 5 -SO -, - CR 4 R 5 -S -, - SO 2 -CR 4 R 5 - , -SO-CR ⁴ R ⁵ -, -CR ⁴ R ⁵ -CR ⁶ R ⁷ -, or -NR ³ -CR ⁴ R ⁵ -,
R ³ represents a hydrogen atom or an alkyl group,
R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, a halogen atom or an alkyl group,
Z represents O or S,

And
R ⁸ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, OH, NH ₂ or CN,
n represents an integer of 1 to 4,
R ¹ represents a group selected from the following,

R ⁹ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group, a formyl group, or an alkyl group in which the hydrogen atom is substituted with 1 to 3 halogen atoms,
R ¹⁰ represents a hydrogen atom or an alkyl group,
m represents an integer of 1 to 5,
R ² represents a hydrogen atom, a halogen atom or OH. )
[3]-XY- represents -NR ³ -SO ₂ -, -CR ⁴ R ⁵ -SO ₂ -, -SO ₂ -CR ⁴ R ⁵ -, or -CR ⁴ R ⁵ -CR ⁶ R ⁷ -. The pharmaceutical composition according to the above [1] or [2].
[4] The pharmaceutical composition according to any one of [1] to [3], which is used for oral administration.
[5] A compound selected from the following structural formulas.

The compounds of the invention may have neuronal protective effects. In addition, the compound of the present invention may improve symptoms in Parkinson's disease or Parkinson's syndrome, in particular, motor symptoms.
According to one embodiment of the present invention, a pharmaceutical composition for treating Parkinson's disease or Parkinson's syndrome can be provided.
Moreover, according to one embodiment of the present invention, a pharmaceutical composition for protecting nerve cells can be provided.

It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse. Results for the control group, MPTP group, MPTP + meloxicam group are shown. ***: p<0.001 It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse. The results for the control group, MPTP group, and evaluation compound group (10 mg × 2 administration or 20 mg × 2 administration of IY-027) are shown. ***: p<0.001 It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse. The results of the control group, MPTP group, and evaluation compound group (IY-065 administered at 30 mg × 2 or IY-069 administered at 10 mg × 2) are shown. *: p<0.05 It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse. The results for the control group, MPTP group, and evaluation compound group (IY-053 administered at 10 mg × 2 or IY-060 administered at 10 mg × 2 or 30 mg × 2) are shown. ***: p<0.001 It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse. The results of the control group, MPTP group, and evaluation compound group (10 mg × 1 administration or 7.5 mg × 2 administration of IY-053) are shown. ***: p<0.001, **: p<0.01 It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse. The results of the control group, MPTP group, and evaluation compound group (IY-067 administered at 30 mg × 2 or IY-068 administered at 30 mg × 2) are shown. **: p<0.01, *: p<0.05 It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse. The results for the control group, MPTP group, and evaluation compound group (3 mg × 2 administration or 10 mg × 2 administration of IY-093) are shown. ***: p<0.001, **: p<0.01

（式中、
　-X-Y-は、-NR³-SO₂-、-CR⁴R⁵-SO₂-、-CR⁴R⁵-SO-、-CR⁴R⁵-S-、-SO₂-CR⁴R⁵-、-SO-CR⁴R⁵-、-CR⁴R⁵-CR⁶R⁷-、又は-NR³-CR⁴R⁵-を表し、
　R³は、水素原子又はアルキル基を表し、
　R⁴、R⁵、R⁶及びR⁷は、それぞれ独立して、水素原子、ハロゲン原子又はアルキル基を表し、
　Zは、O又はSを表し、

であり、
　R⁸は、水素原子、ハロゲン原子、アルキル基、アルコキシ基、OH、NH₂又はCNを表し、
　ｎは、１～４の整数を表し、
　R¹は、以下から選択される基を表し、

　R⁹は、水素原子、ハロゲン原子、アルキル基、アルコキシ基、アルキルカルボニル基、ホルミル基、又は１～３個のハロゲン原子で水素原子が置換されているアルキル基を表し、
　R¹⁰は、水素原子又はアルキル基を表し、
　ｍは、１～５の整数を表し、
　R²は、水素原子、ハロゲン原子又はOHを表す。） In the present invention, a pharmaceutical composition is a compound represented by the following formula (1), (2) or (8) or a pharmaceutically acceptable salt thereof (herein, these are referred to as “the present invention: Also referred to as a "compound").

(In the formula,
-XY- _{^{is, -NR 3 -SO 2 -, -}} CR 4 R 5 -SO 2 -, - CR 4 R 5 -SO -, - CR 4 R 5 -S -, - SO 2 -CR 4 R 5 - , -SO-CR ⁴ R ⁵ -, -CR ⁴ R ⁵ -CR ⁶ R ⁷ -, or -NR ³ -CR ⁴ R ⁵ -,
R ³ represents a hydrogen atom or an alkyl group,
R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, a halogen atom or an alkyl group,
Z represents O or S,

And
R ⁸ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, OH, NH ₂ or CN,
n represents an integer of 1 to 4,
R ¹ represents a group selected from the following,

R ⁹ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group, a formyl group, or an alkyl group in which the hydrogen atom is substituted with 1 to 3 halogen atoms,
R ¹⁰ represents a hydrogen atom or an alkyl group,
m represents an integer of 1 to 5,
R ² represents a hydrogen atom, a halogen atom or OH. )

When R ^{2 of the} compound represented by the formula (1) and the compound represented by the formula (2) is a hydrogen atom, there is a relationship of a tautomer which can be converted into each other by keto-enol tautomerism. In each compound, a high abundance ratio of either keto type or enol type can often occur, but a tautomeric organism is rarely present in the form of only keto type or enol type. Therefore, in the pharmaceutical composition of the present invention, the keto-type compound and the enol-type compound may exist in a mixed manner.
In the formula (1), (2) or (8), when a plurality of R ⁸ 's are present, each R ^8's may be the same or different.
In the formula (1), (2) or (8), when a plurality of R ⁹ are present, each R ⁹ may be the same or different.

In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
In the present specification, the “alkyl group” means a linear or branched, monovalent saturated hydrocarbon group. As the alkyl group, for example, there may be mentioned C _1-12 alkyl group having 1 to 12 carbon atoms, but is not limited thereto. In the present invention, the alkyl group can be a C _1-3 alkyl group C _1-6 alkyl group, or 1-3 carbon atoms having 1 to 6 carbon atoms. Specific examples thereof include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, and hexyl group. To be
In the present specification, the “alkoxy group” means a group in which the alkyl group is bonded to an oxygen atom. The alkoxy group, for example, there may be mentioned C _1-12 alkoxy group having 1 to 12 carbon atoms, but is not limited thereto. In the present invention, alkoxy groups may be C _1-3 alkoxy group C _1-6 alkoxy group, or 1 to 3 carbon atoms having 1 to 6 carbon atoms. Specifically, a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a neopentyloxy group, or A group such as a hexyloxy group can be mentioned.
In the present specification, the “alkylcarbonyl group” means a group in which the above alkyl group is bonded to a carbonyl group. Alkyl group in the alkyl group is, for example, C _1-12 alkyl group having 1 to 12 carbon atoms, C _1-6 alkyl group having 1 to 6 carbon atoms, or C _1-3 alkyl group having 1 to 3 carbon atoms Can be Examples of the alkylcarbonyl group include groups such as acetyl group, propionyl group, n-butyryl group, isobutyryl group, valeryl group, pivaloyl group, and hexanoyl group.
In the present specification, the “alkyl group in which a hydrogen atom is substituted with 1 to 3 halogen atoms” means a group in which a hydrogen atom in the alkyl group is substituted with 1 to 3 halogen atoms.

In the formula (1) or (2), -XY- is -NR ³ -SO ₂ -, -CR ⁴ R ⁵ -SO ₂ -, -SO ₂ -CR ⁴ R ⁵ -, or -CR ⁴ R ⁵ -CR ⁶ R ⁷ - is preferred. The compound having a structure represented by -XY- may be more useful in terms of neuronal cell protective effect, reduced COX inhibitory activity, and/or intracerebral transferability.
Among them, in the compound in which -XY- represents -NR ³ -SO ₂ -, R ³ is preferably an alkyl group, more preferably a C _1-6 alkyl group, and further preferably a C _1-3 alkyl group. And particularly preferably a methyl group.
In the compound in which -XY- represents -CR ⁴ R ⁵ -SO ₂ -, R ⁴ and R ⁵ are each independently a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom. And particularly preferably all are hydrogen atoms.
In a compound in which -XY- represents -SO ₂ -CR ⁴ R ⁵ -, R ⁴ and R ⁵ are each independently a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom. And particularly preferably all are hydrogen atoms.
In a compound in which -XY- represents -CR ⁴ R ⁵ -CR ⁶ R ⁷ -, R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom or an alkyl group, and more preferably hydrogen. Atom, a halogen atom or a C _1-6 alkyl group, more preferably a hydrogen atom, a halogen atom or a C _1-3 alkyl group, even more preferably a hydrogen atom, a fluorine atom or a methyl group, and particularly preferably Both are fluorine atoms or a combination of a hydrogen atom and a methyl group. Further, in the compound in which -XY- represents -CR ⁴ R ⁵ -CR ⁶ R ⁷ -, R ⁶ and R ⁷ are each independently a hydrogen atom or a halogen atom, more preferably a hydrogen atom or It is a fluorine atom, and particularly preferably both are hydrogen atoms.

（以下、Ar環という。）としては、好ましくは、

である。
　R⁸は、好ましくは水素原子、アルキル基又はアルコキシ基であり、より好ましくは水素原子、C_1-6アルキル基又はC_1-6アルコキシ基であり、更に好ましくは水素原子、C_1-3アルキル基又はC_1-3アルコキシ基であり、特に好ましくは水素原子、メチル基又はメトキシ基であり、ｎは、好ましくは１又は２であり、より好ましくは１である。 In formula (1), (2) or (8), Z preferably represents O.
In formula (1), (2) or (8),

(Hereinafter, referred to as an Ar ring.)

Is.
R ⁸ is preferably a hydrogen atom, an alkyl group or an alkoxy group, more preferably a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, and further preferably a hydrogen atom, C _1-3 alkyl. Group or a C _1-3 alkoxy group, particularly preferably a hydrogen atom, a methyl group or a methoxy group, and n is preferably 1 or 2, and more preferably 1.

である。
　中でも、R⁹は、好ましくは水素原子、ハロゲン原子、アルキル基、アルコキシ基、又は１～３個のハロゲン原子で水素原子が置換されているアルキル基であり、より好ましくは水素原子、ハロゲン原子、C_1-6アルキル基、C_1-6アルコキシ基、又は１～３個のハロゲン原子で水素原子が置換されているC_1-6アルキル基であり、更に好ましくは水素原子、ハロゲン原子、C_1-3アルキル基、C_1-3アルコキシ基、又は１～３個のハロゲン原子で水素原子が置換されているC_1-3アルキル基であり、特に好ましくは水素原子、フッ素原子、塩素原子、メチル基、メトキシ基、又はトリフルオロメチル基であり、ｍは、好ましくは１、２又は３である。
　R¹が

の場合、特に好ましくは、R⁹はメチル基であり、ｍは１である。
　R¹が

の場合、特に好ましくは、R⁹はメチル基であり、ｍは１である。 In formula (1), (2) or (8), R ¹ is preferably

Is.
Among them, R ⁹ is preferably a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, or an alkyl group in which the hydrogen atom is substituted with 1 to 3 halogen atoms, more preferably a hydrogen atom, a halogen atom, C _1-6 alkyl group, a C _1-6 alkyl group a C _1-6 alkoxy group, or one to three hydrogen atoms with a halogen atom is substituted, more preferably a hydrogen atom, a halogen atom, C _{1 -3} alkyl group, a C _1-3 alkoxy group, or one to three C _1-3 alkyl group wherein a hydrogen atom is substituted with a halogen atom, particularly preferably a hydrogen atom, a fluorine atom, a chlorine atom, methyl A group, a methoxy group, or a trifluoromethyl group, and m is preferably 1, 2 or 3.
R ¹ is

In the case of, particularly preferably, R ⁹ is a methyl group and m is 1.
R ¹ is

In the case of, particularly preferably, R ⁹ is a methyl group and m is 1.

であり、R⁸は、好ましくは水素原子であり、R¹は、好ましくは、

であり、R⁹は、好ましくは水素原子、ハロゲン原子、アルキル基、アルコキシ基、又は１～３個のハロゲン原子で水素原子が置換されているアルキル基であり、より好ましくは水素原子、ハロゲン原子、C_1-6アルキル基、C_1-6アルコキシ基、又は１～３個のハロゲン原子で水素原子が置換されているC_1-6アルキル基であり、更に好ましくは水素原子、ハロゲン原子、C_1-3アルキル基、C_1-3アルコキシ基、又は１～３個のハロゲン原子で水素原子が置換されているC_1-3アルキル基であり、特に好ましくは水素原子、フッ素原子、塩素原子、メチル基、メトキシ基、又はトリフルオロメチル基であり、ｍは好ましくは１、２又は３であり、R²は、好ましくは水素原子である。 In formula (1) or (2), R ² is preferably a hydrogen atom, a fluorine atom or OH, and more preferably a hydrogen atom.
In the present invention, any combination of the preferred groups of the respective substituents relating to the compound represented by formula (1), (2) or (8) can be used.
In one embodiment, in the formula (1) or (2), when -XY- represents -NR ³ -SO ₂ -, R ³ is preferably an alkyl group, more preferably a C _1-6 alkyl group. And more preferably a C _1-3 alkyl group, particularly preferably a methyl group, and the Ar ring is preferably

And R ⁸ is preferably a hydrogen atom, and R ¹ is preferably

And R ⁹ is preferably a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, or an alkyl group in which 1 to 3 halogen atoms are substituted for the hydrogen atom, and more preferably a hydrogen atom or a halogen atom. , C _1-6 alkyl group, a C _1-6 alkyl group a C _1-6 alkoxy group, or 1 to a hydrogen atom at three halogen atoms are replaced, more preferably a hydrogen atom, a halogen atom, C _{A 1-3} alkyl group, a C _1-3 alkoxy group, or a C _1-3 alkyl group in which a hydrogen atom is substituted with 1 to 3 halogen atoms, particularly preferably a hydrogen atom, a fluorine atom, a chlorine atom, It is a methyl group, a methoxy group or a trifluoromethyl group, m is preferably 1, 2 or 3, and R ² is preferably a hydrogen atom.

であり、R⁸は、好ましくは水素原子であり、R¹は、好ましくは、

であり、R⁹は、好ましくは水素原子、ハロゲン原子、アルキル基、又はアルコキシ基であり、より好ましくは水素原子、ハロゲン原子、C_1-6アルキル基、又はC_1-6アルコキシ基であり、更に好ましくは水素原子、ハロゲン原子、C_1-3アルキル基、又はC_1-3アルコキシ基であり、特に好ましくは水素原子、フッ素原子、メチル基、又はメトキシ基であり、ｍは好ましくは１、２又は３であり、R²は、好ましくは水素原子である。 As an embodiment, in formula (1) or (2), -XY- is _{^{-CR 4 R 5 -SO 2 -,}} - CR 4 R 5 -SO-, or -CR ⁴ may represent R ⁵ -S- , R ⁴ and R ⁵ are each independently a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, particularly preferably both a hydrogen atom, and an Ar ring is preferably ,

And R ⁸ is preferably a hydrogen atom, and R ¹ is preferably

And R ⁹ is preferably a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group, more preferably a hydrogen atom, a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group, More preferably a hydrogen atom, a halogen atom, a C _1-3 alkyl group or a C _1-3 alkoxy group, particularly preferably a hydrogen atom, a fluorine atom, a methyl group or a methoxy group, and m is preferably 1, 2 or 3, and R ² is preferably a hydrogen atom.

であり、R⁸は、好ましくは水素原子であり、R¹は、好ましくは、

であり、R⁹は、好ましくは水素原子又はハロゲン原子であり、より好ましくは水素原子又はフッ素原子であり、ｍは好ましくは１であり、R²は、好ましくは水素原子である。 As one aspect, in the formula (1) or (2), when -XY- represents -SO ₂ -CR ⁴ R ⁵ -, or -SO-CR ⁴ R ⁵ -, R ⁴ and R ⁵ are respectively Independently, preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, particularly preferably both hydrogen atoms, Ar ring, preferably,

And R ⁸ is preferably a hydrogen atom, and R ¹ is preferably

And R ⁹ is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, m is preferably 1, and R ² is preferably a hydrogen atom.

であり、R⁸は、好ましくは水素原子、アルキル基又はアルコキシ基であり、より好ましくは水素原子、C_1-6アルキル基又はC_1-6アルコキシ基であり、更に好ましくは水素原子、C_1-3アルキル基又はC_1-3アルコキシ基であり、特に好ましくは水素原子、メチル基又はメトキシ基であり、ｎは、好ましくは１又は２であり、より好ましくは１であり、R¹は、好ましくは、

であり、R⁹は、好ましくは水素原子、ハロゲン原子、アルキル基又はアルコキシ基であり、より好ましくは水素原子、ハロゲン原子、C_1-6アルキル基又はC_1-6アルコキシ基であり、更に好ましくは水素原子、ハロゲン原子、C_1-3アルキル基又はC_1-3アルコキシ基であり、特に好ましくは水素原子、フッ素原子、メチル基又はメトキシ基であり、ｍは、好ましくは１又は２であり、R²は、水素原子、ハロゲン原子又はOHであり、好ましくは水素原子、フッ素原子又はOHであり、より好ましくは水素原子である。 In one aspect, in formula (1) or (2), when -XY- represents -CR ⁴ R ⁵ -CR ⁶ R ⁷ -, R ⁴ and R ⁵ are each independently a hydrogen atom. , A halogen atom or an alkyl group, more preferably a hydrogen atom, a halogen atom or a C _1-6 alkyl group, further preferably a hydrogen atom, a halogen atom or a C _1-3 alkyl group, and even more preferably hydrogen. Atom, a fluorine atom or a methyl group, particularly preferably both a fluorine atom or a combination of a hydrogen atom and a methyl group, R ⁶ and R ⁷ are each independently, preferably a hydrogen atom or a halogen. Atom, more preferably a hydrogen atom or a fluorine atom, particularly preferably both are hydrogen atoms, Ar ring is preferably,

And R ⁸ is preferably a hydrogen atom, an alkyl group or an alkoxy group, more preferably a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, further preferably a hydrogen atom, C _{1 -3} alkyl group or C _1-3 alkoxy group, particularly preferably hydrogen atom, methyl group or methoxy group, n is preferably 1 or 2, more preferably 1, and R ¹ is Preferably,

And R ⁹ is preferably a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, more preferably a hydrogen atom, a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, and further preferably Is a hydrogen atom, a halogen atom, a C _1-3 alkyl group or a C _1-3 alkoxy group, particularly preferably a hydrogen atom, a fluorine atom, a methyl group or a methoxy group, and m is preferably 1 or 2. , R ² is a hydrogen atom, a halogen atom or OH, preferably a hydrogen atom, a fluorine atom or OH, and more preferably a hydrogen atom.

（式中、-X-Y-、Ar環、R¹及びR²は、式（１）又は（２）で定義されるものと同じである。）
　上記反応式において、式（３）で表される化合物は、適切な溶媒中、例えば、ｍ－キシレン等の有機溶媒中で、式（４）で表される化合物と反応させることができる。反応時間及び反応温度等の反応条件は、用いる化合物に応じて適宜選択することができ、還流撹拌して反応を行ってもよい。
　式（８）で表される化合物は、下記実施例２５で示されるように、製法１において、式（３）で表される化合物中-X-Y-が-NR³-CR⁴R⁵-（例えばR⁴及びR⁵は水素原子）であるものを用いた場合に、-X-Y-が-NR³-CR⁴R⁵-である式（２）で表される化合物とともに製造することができる。
　なお、ZがSである式（１）、（２）又は（８）で表される化合物は、式（３）で表される化合物に対応するチオエステルを用いることで得ることができる。また、上記反応式ではケト型が示されているが、エノール型においても同様に製造され得る。 The compound represented by formula (1), (2) or (8) can be produced based on the technical common sense of those skilled in the art, and can be produced, for example, according to the following method.
[Production method 1]

(In the formula, -XY-, Ar ring, R ¹ and R ² are the same as those defined in the formula (1) or (2).)
In the above reaction scheme, the compound represented by the formula (3) can be reacted with the compound represented by the formula (4) in a suitable solvent, for example, an organic solvent such as m-xylene. Reaction conditions such as reaction time and reaction temperature can be appropriately selected according to the compound to be used, and the reaction may be carried out with stirring under reflux.
As shown in Example 25 below, the compound represented by the formula (8) is the compound represented by the formula (3) in the production method 1, wherein —XY— is —NR ³ —CR ⁴ R ⁵ — (for example, When R ⁴ and R ⁵ are hydrogen atoms), they can be produced together with the compound represented by the formula (2) in which —XY— is —NR ³ —CR ⁴ R ⁵ —.
The compound represented by the formula (1), (2) or (8) in which Z is S can be obtained by using a thioester corresponding to the compound represented by the formula (3). Further, although the keto type is shown in the above reaction formula, the enol type can be similarly produced.

（式中、-X-Y-、Ar環、R²は、式（１）又は（２）で定義されるものと同じである。）
　式（５）で表される化合物を、炭酸ジメチルやシアノギ酸メチルと反応させることで、式（３）で表される化合物を合成することができる。炭酸ジメチルを用いる場合、例えば、水素化ナトリウム等の塩基を用い得る。シアノギ酸メチルを用いる場合、例えば、炭酸カリウム等の塩基、及びアセトン等の溶媒を用い得る。反応時間及び反応温度等の反応条件は、用いる化合物に応じて適宜選択することができる。 As the compound represented by the formula (3) and the compound represented by the formula (4), a commercially available product or a synthesized product may be used. For example, when synthesizing the compound represented by the formula (3), it may be synthesized as follows.

(In the formula, -XY-, Ar ring, and R ² are the same as those defined in formula (1) or (2).)
The compound represented by formula (3) can be synthesized by reacting the compound represented by formula (5) with dimethyl carbonate or methyl cyanoformate. When using dimethyl carbonate, for example, a base such as sodium hydride can be used. When using methyl cyanoformate, for example, a base such as potassium carbonate and a solvent such as acetone can be used. Reaction conditions such as reaction time and reaction temperature can be appropriately selected depending on the compound used.

（式中、-X-Y-、Ar環及びR¹は、式（１）又は（２）で定義されるものと同じである。）
　上記反応式において、式（６）で表される化合物は、適切な溶媒中、例えば、THFやジメチルホルムアミド等の適切な有機溶媒中で、水素化ナトリウムや炭酸カリウム等の塩基の存在下、式（７）で表される化合物と反応させることができる。また、炭酸カリウム等の塩基を用いる場合には、アセトン等の有機溶媒を用いてもよい。反応時間及び反応温度等の反応条件は、用いる化合物に応じて適宜選択することができ、還流撹拌して反応を行ってもよい。
　なお、ZがSである式（１）又は（２）で表される化合物は、式（７）で表される化合物に対応するチオイソシアナートを用いることで得ることができる。また、上記反応式ではエノール型が示されているが、ケト型においても同様に製造され得る。
　上記製法１や製法２による本発明の化合物の製造において、精製や抽出操作は当業者の技術常識に基づき行うことができる。 [Production method 2]

(In the formula, -XY-, Ar ring and R ¹ are the same as those defined in formula (1) or (2).)
In the above reaction scheme, the compound represented by the formula (6) can be prepared by reacting a compound represented by the formula (6) in the presence of a base such as sodium hydride or potassium carbonate in a suitable solvent, for example, a suitable organic solvent such as THF or dimethylformamide. It can be reacted with the compound represented by (7). When using a base such as potassium carbonate, an organic solvent such as acetone may be used. Reaction conditions such as reaction time and reaction temperature can be appropriately selected according to the compound to be used, and the reaction may be carried out with stirring under reflux.
The compound represented by formula (1) or (2) in which Z is S can be obtained by using a thioisocyanate corresponding to the compound represented by formula (7). Further, although the enol type is shown in the above reaction formula, the keto type can be similarly produced.
In the production of the compound of the present invention by the above Production Method 1 or Production Method 2, purification and extraction operations can be carried out based on the technical common sense of those skilled in the art.

The compound represented by the formula (1), (2) or (8) may be in the form of a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salt include, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, inorganic salt such as phosphate, acetate, propionate, lactate, Organic acid salts such as oxalate, malonate, succinate, fumarate, maleate, malic acid, tartrate, benzoate, salicylate and phthalate, methanesulfonate, benzenesulfonate Examples thereof include salts and organic sulfonates such as p-toluenesulfonate, but are not limited thereto.

　なお、上記構造式中、「Ac」はアセチル基を表し、「Me」はメチル基を表す。 Specific examples of the compound represented by formula (1) or (2) include the following.

In the above structural formula, "Ac" represents an acetyl group and "Me" represents a methyl group.

It has been confirmed that the compound of the present invention has a neuronal cell protective effect and improves the movement disorder of Parkinson's disease model mice. Thus, the compounds of this invention may be useful in treating Parkinson's disease. The compounds of the invention may also be useful in treating Parkinson's syndrome.
One embodiment of the invention relates to a pharmaceutical composition for treating Parkinson's disease or Parkinson's syndrome.
As used herein, “treating” means ameliorating a subject's symptoms or suppressing the progression of a disease in a subject. That is, the pharmaceutical composition for treating Parkinson's disease or Parkinson's syndrome may improve Parkinson's symptom (Parkinsonism), or may suppress the progression of Parkinson's disease or Parkinson's syndrome. Although Parkinson's symptoms (parkinsonism) include motor symptoms and non-motor symptoms, the pharmaceutical composition of the present invention can be particularly useful for improving motor symptoms.

One embodiment of the invention relates to a pharmaceutical composition for protecting nerve cells.
As used herein, “protecting nerve cells” means reducing the number of deaths of nerve cells. For example, “protecting nerve cells” can be suppressing nerve cell death caused by a substance harmful to nerve cells. The nerve cell can be, for example, a nerve cell that produces dopamine, but is not limited thereto.
Specifically, in nerve cells such as dopamine-producing nerve cells, suppressing cell death caused by 1-methyl-4-phenylpyridinium (MPP ⁺ ) is an example of protecting nerve cells. ..

The pharmaceutical composition of the present invention may contain pharmaceutically acceptable additives such as pharmaceutically acceptable carriers, diluents, excipients, stabilizers, disintegrants and binders. As the pharmaceutically acceptable additives such as carriers, diluents, excipients, stabilizers, disintegrants, binders and the like, those well known in the technical field of the present invention can be used. ..
The administration method of the pharmaceutical composition of the present invention is not particularly limited, and the pharmaceutical composition of the present invention can be used for oral administration or parenteral administration such as injection. Specific routes of administration by injection include, but are not limited to, intravenous administration, intraperitoneal administration, subcutaneous administration, intramuscular administration and the like.
Since the compound contained in the pharmaceutical composition of the present invention does not have the oxicam skeleton that meloxicam has, it may have no COX inhibitory activity or have a reduced COX inhibitory activity. Therefore, when the pharmaceutical composition of the present invention is orally administered, the possibility of causing gastrointestinal disorders is lower than when orally administered meloxicam, and in that it is easy to take, the pharmaceutical composition of the present invention has a great advantage. Have.
The administration subject of the pharmaceutical composition of the present invention is not particularly limited, and may be a human or a mammal other than human.
In the pharmaceutical composition of the present invention, the dose and the frequency of administration can be determined based on the condition of the test subject, the degree of disease and the like.

Another aspect of the invention includes a method of treating Parkinson's disease or Parkinson's syndrome. The treatment method comprises an effective amount of the compound represented by formula (1), formula (2) or formula (8) or a pharmaceutically acceptable salt thereof, or an effective amount of formula (1) or formula (2). Or a compound represented by formula (8) or a pharmaceutically acceptable salt thereof, may be administered to a subject in need of treatment for Parkinson's disease or Parkinson's syndrome.
Another aspect of the present invention includes a method of protecting nerve cells or a method of suppressing nerve cell death. Such a method comprises an effective amount of the compound represented by formula (1), formula (2) or formula (8) or a pharmaceutically acceptable salt thereof, or an effective amount of formula (1) or formula ( 2) or a compound represented by formula (8) or a pharmaceutical composition containing a pharmaceutically acceptable salt thereof, which comprises administering to a subject in need of protection of nerve cells or inhibition of nerve cell death. obtain.
Also in the above method, any of the matters described above regarding the compound or the pharmaceutical composition may be applied.
As used herein, an “effective amount” is an amount that is administered to a subject as a single dose or as part of a dose in a series of administration schedules, and has the desired therapeutic effect, neuronal cell protective effect, or neuronal cell effect. By an amount effective to produce a death control effect.

Hereinafter, the present invention will be described in more detail with reference to specific examples, but the scope of the present invention is not limited to these examples.
For the measurement of nuclear magnetic resonance spectrum (NMR), 400 MHz or 500 MHz-NMR manufactured by Agilent was used.

　2-アミノ-5-メチルチアゾール（8.43 g、73.8 mmol、 3.3当量）をm-キシレン（240 mL）に溶解して室温で1分間撹拌し、1-オキソ-1,2,3,4-テトラヒドロナフタレン-2-カルボン酸メチル（4.53 g、22.2 mmol）を加えて160℃で22時間、還流撹拌した。反応液を室温に戻した後、10%塩酸を加えてpHを3とし、析出した沈殿を吸引濾過し、IY-027（ケト:エノール＝63:37、2.62 g、41%）を茶色固体として得た。
ケト体：¹H-NMR (CDCl₃, 400 MHz) δ: 2.40 (s, 3H), 2.45-2.52 (m, 1H), 2.60-2.68 (m, 1H), 3.03-3.07 (m, 1H), 3.15-3.20 (m, 1H), 3.59 (dd, J=5.1 Hz, 10.4 Hz, 1H), 7.10 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.35 (t, J=7.0 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H)
エノール体：¹H-NMR (CDCl₃, 400MHz) δ: 2.43 (s, 3H), 2.62 (t, J=7.4 Hz, 2H), 2.94 (t, J=7.9 Hz, 2H), 7.10 (s, 1H), 7.20 (d, J=7.1 Hz, 1H), 7.33-7.37 (m, 2H), 7.86 (d, J=7.8 Hz, 1H) [Production example]
Example 1; Synthesis of IY-027 (N-(5-methylthiazol-2-yl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxamide)

2-Amino-5-methylthiazole (8.43 g, 73.8 mmol, 3.3 eq) was dissolved in m-xylene (240 mL) and stirred at room temperature for 1 minute to give 1-oxo-1,2,3,4-tetrahydro. Methyl naphthalene-2-carboxylate (4.53 g, 22.2 mmol) was added, and the mixture was stirred under reflux at 160° C. for 22 hours. After returning the reaction solution to room temperature, 10% hydrochloric acid was added to adjust the pH to 3, and the deposited precipitate was suction-filtered to give IY-027 (keto:enol = 63:37, 2.62 g, 41%) as a brown solid. Obtained.
Keto: ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.40 (s, 3H), 2.45-2.52 (m, 1H), 2.60-2.68 (m, 1H), 3.03-3.07 (m, 1H), 3.15-3.20 (m, 1H), 3.59 (dd, J=5.1 Hz, 10.4 Hz, 1H), 7.10 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.35 (t, J=7.0 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H)
Enol form: ¹ H-NMR (CDCl ₃ , 400MHz) δ: 2.43 (s, 3H), 2.62 (t, J=7.4 Hz, 2H), 2.94 (t, J=7.9 Hz, 2H), 7.10 (s, 1H), 7.20 (d, J=7.1 Hz, 1H), 7.33-7.37 (m, 2H), 7.86 (d, J=7.8 Hz, 1H)

　4-ヒドロキシ-2H-チオクロメン-3-カルボン酸メチル-1,1-ジオキシド(1.04 g, 4.10 mmol) と4-フルオロアニリン (2.35 g、21.1 mmol, 5.1当量) をm-キシレン (50 mL) に溶解して150℃で19.5時間、還流撹拌した。反応液を室温に戻した後、析出した沈殿を吸引濾取してIY-066 (ケト:エノール=2:3、887 mg、64.9%) を黄色粉末として得た。
ケト体： ¹H-NMR (500 MHz, CDCl₃) δ: 4.09 (d, J=10.6 Hz, 1H), 4.09 (d, J=6.0 Hz, 1H), 4.46 (dd, J=10.6 Hz, 6.0 Hz, CH, 1H), 7.07-7.12 (m, 2H), 7.54 (dd, J=9.2 Hz, 4.5 Hz, 2H), 7.82 (t, J=7.2 Hz, 1H), 7.91 (t, J=7.2 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H), 8.18 (d, J=7.2 Hz, 1H)
エノール体： ¹H-NMR (500 MHz, CDCl₃) δ: 4.16 (s, 2H), 7.07-7.12 (m, 2H), 7.47 (dd, J=9.0 Hz, 4.6 Hz, 2H), 7.71 (t, J=7.7 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 8.02 (d, J=7.7 Hz, 1H), 8.16 (d, J=7.7Hz, 1H), 9.11 (brs, 1H) Example 2; Synthesis of IY-066 (4-hydroxy-N-(4-fluorophenyl)-2H-thiochromene-3-carboxamide 1,1-dioxide)

Methyl 4-hydroxy-2H-thiochromene-3-carboxylate-1,1-dioxide (1.04 g, 4.10 mmol) and 4-fluoroaniline (2.35 g, 21.1 mmol, 5.1 eq) in m-xylene (50 mL). After dissolution, the mixture was stirred under reflux at 150°C for 19.5 hours. After returning the reaction solution to room temperature, the deposited precipitate was collected by suction filtration to obtain IY-066 (keto:enol=2:3, 887 mg, 64.9%) as a yellow powder.
Keto: ¹ H-NMR (500 MHz, CDCl ₃ )δ: 4.09 (d, J=10.6 Hz, 1H), 4.09 (d, J=6.0 Hz, 1H), 4.46 (dd, J=10.6 Hz, 6.0) Hz, CH, 1H), 7.07-7.12 (m, 2H), 7.54 (dd, J=9.2 Hz, 4.5 Hz, 2H), 7.82 (t, J=7.2 Hz, 1H), 7.91 (t, J=7.2 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H), 8.18 (d, J=7.2 Hz, 1H)
Enol form: ¹ H-NMR (500 MHz, CDCl ₃ )δ: 4.16 (s, 2H), 7.07-7.12 (m, 2H), 7.47 (dd, J=9.0 Hz, 4.6 Hz, 2H), 7.71 (t , J=7.7 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 8.02 (d, J=7.7 Hz, 1H), 8.16 (d, J=7.7Hz, 1H), 9.11 (brs, 1H )

　窒素雰囲気下、市販の4-ヒドロキシ-1-メチル-1H-ベンゾ[c][1,2]チアジン 2,2-ジオキシド (1.42 mmol、300 mg) を無水THF (20 mL) に溶解し、水素化ナトリウム (2.13 mmol、85.4 mg、 1.5当量) を加えて室温で撹拌した。次いで2,5-フルオロフェニルイソシアナート (2.84 mmol、440.7 mg、2.0 当量) を加え80℃で4時間撹拌した。室温に戻した反応液に 2 M HClを加えpHを3とし、酢酸エチルで抽出、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで脱水、溶媒を減圧下に留去して褐色固体（308.3 mg）を得た。酢酸エチルから再結晶してIY-068 (89.2 mg、収率17%) を薄橙色針状結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 3.53 (s, 3H), 6.81-6.85 (m, 1H), 7.00-7.14 (m, 1H), 7.27 (d, J=6.9 Hz, 1H), 7.35 (t, J=7.2 Hz, 1H),7.69 (t, J=7.2 Hz, 1H) 8.10-8.14 (m, 1H), 8.16 (d, J=7.6 Hz, 1H) 9.85 (s, 1H) Example 3; of IY-068 (N-(2,5-difluorophenyl)-4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2-dioxide) Synthesis

Under a nitrogen atmosphere, commercially available 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) was dissolved in anhydrous THF (20 mL), and hydrogen was added. Sodium chloride (2.13 mmol, 85.4 mg, 1.5 equivalents) was added, and the mixture was stirred at room temperature. Next, 2,5-fluorophenyl isocyanate (2.84 mmol, 440.7 mg, 2.0 equivalent) was added, and the mixture was stirred at 80°C for 4 hr. The pH of the reaction mixture returned to room temperature was adjusted to 3 with 2 M HCl, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a brown solid ( 308.3 mg) was obtained. Recrystallization from ethyl acetate gave IY-068 (89.2 mg, yield 17%) as light orange needle crystals.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 3.53 (s, 3H), 6.81-6.85 (m, 1H), 7.00-7.14 (m, 1H), 7.27 (d, J=6.9 Hz, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.69 (t, J=7.2 Hz, 1H) 8.10-8.14 (m, 1H), 8.16 (d, J=7.6 Hz, 1H) 9.85 (s, 1H)

　実施例3と同様の手法で、4-ヒドロキシ-1-メチル-1H-ベンゾ[c][1,2]チアジン 2,2-ジオキシド (2.47 mmol, 500 mg) と2,4-フルオロフェニルイソシアナート (4.26 mmol, 660.4 mg, 1.8当量) を縮合して得られる黄色固体（540.4 mg）を酢酸エチルから再結晶し、IY-069 (285.2 mg、収率33%) を無色針状結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 3.53 (s, 3H), 6.90-6.97 (m, 2H), 7.27 (d, J=5.3 Hz, 1H), 7.35 (t, J=7.4 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 8.14-8.16 (m, 2H), 9.62 (s, 1H) Example 4; of IY-69 (N-(2,4-difluorophenyl)-4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2-dioxide) Synthesis

In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (2.47 mmol, 500 mg) and 2,4-fluorophenyl isocyanate were used. The yellow solid (540.4 mg) obtained by condensing (4.26 mmol, 660.4 mg, 1.8 eq) was recrystallized from ethyl acetate to obtain IY-069 (285.2 mg, yield 33%) as colorless needle crystals. ..
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 3.53 (s, 3H), 6.90-6.97 (m, 2H), 7.27 (d, J=5.3 Hz, 1H), 7.35 (t, J=7.4 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 8.14-8.16 (m, 2H), 9.62 (s, 1H)

　実施例3と同様の手法で、4-ヒドロキシ-1-メチル-1H-ベンゾ[c][1,2]チアジン 2,2-ジオキシド (1.42 mmol、300 mg) とp-トリルイソシアナート (2.84 mmol、379.4 mg、2.0当量) を縮合して得られる黄色固体（642.6 mg）を酢酸エチルから再結晶してIY-075 (323.7 mg、収率66%) を黄色板状結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 2.35 (s, 3H), 3.52 (s, 3H), 7.19 (d, J=8.3 Hz, 2H), 7.25 (d, J=6.8 Hz, 1H), 7.33 (dt, J=1.0, 6.8 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.67 (dt, J=1.0, 7.3 Hz, 1H), 8.14 (dd, J=1.4, 7.3 Hz, 1H), 9.36 (s, 1H) Example 5; Synthesis of IY-075 (4-hydroxy-1-methyl-N-(p-tolyl)-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2-dioxide)

In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) and p-tolyl isocyanate (2.84 mmol) were used. , 379.4 mg, 2.0 eq.) to give a yellow solid (642.6 mg) which was recrystallized from ethyl acetate to give IY-075 (323.7 mg, yield 66%) as yellow plate crystals.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.35 (s, 3H), 3.52 (s, 3H), 7.19 (d, J=8.3 Hz, 2H), 7.25 (d, J=6.8 Hz, 1H) , 7.33 (dt, J=1.0, 6.8 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.67 (dt, J=1.0, 7.3 Hz, 1H), 8.14 (dd, J=1.4, 7.3 Hz, 1H), 9.36 (s, 1H)

　実施例3と同様の手法で、4-ヒドロキシ-1-メチル-1H-ベンゾ[c][1,2]チアジン 2,2-ジオキシド (1.42 mmol, 300 mg) と2,3,4-フルオロフェニルイソシアナート (2.84 mmol、491.3 mg、2.0当量) の縮合により得られる黄色固体（673.1 mg）を酢酸エチルから再結晶し、IY-077 (311.6 mg、収率57%) を無色針状結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 3.54 (s, 3H), 7.00-7.03 (m, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.35 (dt, J=1.0, 7.7 Hz, 1H), 7.90-7.92 (m, 1H), 8.15 (dd, J=1.4, 8.0 Hz, 1H), 9.65 (s, 1H) Example 6; IY-077 (4-hydroxy-1-methyl-N-(2,3,4-trifluorophenyl)-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2- Dioxide) synthesis

In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) and 2,3,4-fluorophenyl were used. The yellow solid (673.1 mg) obtained by condensation of isocyanate (2.84 mmol, 491.3 mg, 2.0 eq) was recrystallized from ethyl acetate to obtain IY-077 (311.6 mg, 57% yield) as colorless needle crystals. It was
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 3.54 (s, 3H), 7.00-7.03 (m, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.35 (dt, J=1.0, 7.7 Hz, 1H), 7.90-7.92 (m, 1H), 8.15 (dd, J=1.4, 8.0 Hz, 1H), 9.65 (s, 1H)

　実施例3と同様の手法で、4-ヒドロキシ-1-メチル-1H-ベンゾ[c][1,2]チアジン 2,2-ジオキシド (1.42 mmol、300 mg) と2,4,6-フルオロフェニルイソシアナート (2.84 mmol、491.3 mg, 2.0当量) を縮合して得られる黄色固体（675.0 mg）を酢酸エチルから再結晶し、IY-078 (68.9 mg、収率13%) を無色針状結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 3.54 (s, 3H), 6.79-6.83 (m, 2H), 7.27 (d, J=6.3 Hz, 1H), 7.35 (dt, J=1.0, 7.8 Hz, 1H), 7.69 (dt, J=1.5, 7.8 Hz, 1H), 8.14 (dd, J=1.5, 8.1 Hz, 1H), 8.86 (s, 1H) Example 7; IY-078 (4-hydroxy-1-methyl-N-(2,4,6-trifluorophenyl)-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2- Dioxide) synthesis

In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) and 2,4,6-fluorophenyl were used. The yellow solid (675.0 mg) obtained by condensing isocyanate (2.84 mmol, 491.3 mg, 2.0 equivalents) was recrystallized from ethyl acetate to give IY-078 (68.9 mg, yield 13%) as colorless needle crystals. Obtained.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 3.54 (s, 3H), 6.79-6.83 (m, 2H), 7.27 (d, J=6.3 Hz, 1H), 7.35 (dt, J=1.0, 7.8 Hz, 1H), 7.69 (dt, J=1.5, 7.8 Hz, 1H), 8.14 (dd, J=1.5, 8.1 Hz, 1H), 8.86 (s, 1H)

　実施例3と同様の手法で、4-ヒドロキシ-1-メチル-1H-ベンゾ[c][1,2]チアジン 2,2-ジオキシド (1.42 mmol、300 mg) を無水THF (20 mL) と3-クロロ-4-メチルフェニルイソシアナート (2.84 mmol、474.3 mg、2.0当量) の縮合により得られる黄色固体（669.8 mg）を酢酸エチルから再結晶し、IY-079 (269.1 mg、収率50%) を無色針状結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 2.36 (s, 3H), 3.51 (s, 3H), 7.23 (t, J=8.3 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.31 (dd, J=1.7, 7.9 Hz, 1H), 7.34 (dt, J=1.2, 7.8 Hz, 1H), 7.67 (dt, J=1.7, 7.9 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 8.14 (dd, J=1.2, 7.8 Hz), 9.39 (s, 1H) Example 8; IY-079 (N-(3-chloro-4-methylphenyl)-4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2-dioxide ) Synthesis

In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) was mixed with anhydrous THF (20 mL) and 3 A yellow solid (669.8 mg) obtained by condensation of -chloro-4-methylphenylisocyanate (2.84 mmol, 474.3 mg, 2.0 eq) was recrystallized from ethyl acetate to give IY-079 (269.1 mg, 50% yield). Was obtained as colorless needle crystals.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.36 (s, 3H), 3.51 (s, 3H), 7.23 (t, J=8.3 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H) , 7.31 (dd, J=1.7, 7.9 Hz, 1H), 7.34 (dt, J=1.2, 7.8 Hz, 1H), 7.67 (dt, J=1.7, 7.9 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 8.14 (dd, J=1.2, 7.8 Hz), 9.39 (s, 1H)

　実施例3と同様の手法で、4-ヒドロキシ-1-メチル-1H-ベンゾ[c][1,2]チアジン 2,2-ジオキシド (1.42 mmol、300 mg) と3-トリフルオロメチル-4-クロロフェニルイソシアナート (2.84 mmol、629.3 mg、2.0当量) の縮合により得られる黄色固体（1.0 g）を酢酸エチルから再結晶して、IY-080 (405.3 mg、収率66%) を無色針状結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 3.53 (s, 3H), 7.27 (d, J=8.8 Hz, 1H), 7.36 (dt, J=1.0, 7.8 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.67 (dt, J=1.5, 7.7 Hz, 1H), 7.80 (dd, J=1.5, 7.8 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 8.16 (dd, J=1.5, 7.7 Hz, 1H), 9.59 (s, 1H) Example 9; IY-080 (N-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine-3-carboxamide 2 ,2-Dioxide)

In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) and 3-trifluoromethyl-4- The yellow solid (1.0 g) obtained by condensation of chlorophenyl isocyanate (2.84 mmol, 629.3 mg, 2.0 eq) was recrystallized from ethyl acetate to give IY-080 (405.3 mg, 66% yield) as colorless needle crystals. Got as.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 3.53 (s, 3H), 7.27 (d, J=8.8 Hz, 1H), 7.36 (dt, J=1.0, 7.8 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.67 (dt, J=1.5, 7.7 Hz, 1H), 7.80 (dd, J=1.5, 7.8 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 8.16 ( dd, J=1.5, 7.7 Hz, 1H), 9.59 (s, 1H)

　実施例3と同様の手法で、4-ヒドロキシ-1-メチル-1H-ベンゾ[c][1,2]チアジン 2,2-ジオキシド (1.42 mmol、300 mg) と3-メチル-4-クロロフェニルイソシアナート (2.84 mmol、474.3 mg、2.0当量) の縮合により得られる黄褐色固体（531.6 mg）から酢酸エチルから再結晶し、IY-081 (285.4 mg、収率53%) を黄色粒状結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 2.40 (s, 3H), 3.52 (s, 3H), 7.26 (t, J=8.3 Hz, 1H), 7.33-7.40 (m, 3H), 7.45 (ds, J=2.2, 1H), 7.68 (dt, J=1.6, 7.8 Hz, 1H), 8.14 (dd, J=1.2, 7.8 Hz, 1H), 9.40 (s, 1H) Example 10; IY-081 (N-(4-chloro-3-methylphenyl)-4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2-dioxide ) Synthesis

In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) and 3-methyl-4-chlorophenylisocyanate were used. Recrystallization from ethyl acetate from tan solid (531.6 mg) obtained by condensation of nato (2.84 mmol, 474.3 mg, 2.0 eq) gave IY-081 (285.4 mg, 53% yield) as yellow granular crystals. ..
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.40 (s, 3H), 3.52 (s, 3H), 7.26 (t, J=8.3 Hz, 1H), 7.33-7.40 (m, 3H), 7.45 ( ds, J=2.2, 1H), 7.68 (dt, J=1.6, 7.8 Hz, 1H), 8.14 (dd, J=1.2, 7.8 Hz, 1H), 9.40 (s, 1H)

　窒素雰囲気下、脱水ヘキサンで洗浄した水素化ナトリウム (315 mg、7.88 mmol、1.4 当量) に無水THF (40 mL) に溶解したイソチオクロマン-4-オン (948 mg、5.77 mmol) を加え、室温で5 分間撹拌した。次いで無水THF (5 mL) に溶解したフェニルイソシアナート (1750 mg、14.7 mmol、2.5当量) を加え、80℃で3時間還流撹拌した。反応液に希塩酸を加えてpHを2とし、酢酸エチルで3回抽出、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、溶媒を減圧下に留去して、黒色固体（2600 mg）を得た。粗生成物に不純物を認めたため、メタノール (20 mL) を加えて析出した黄土色固体を吸引濾取により単離してIY-082 (1280 mg、収率78.2%) を得た。
¹H-NMR (500 MHz、CDCl₃) δ: 3.87 (s, 2H), 7.16-7.21 (m, 2H), 7.36-7.42 (m, 4H) , 7.56 (d,J=7.2 Hz, 2H), 7.90 (dd, J=7.2,1.3 Hz, 1H), 8.17 (brs, 1H) Example 11; Synthesis of IY-082 (4-hydroxy-N-phenyl-1H-isothiochromene-3-carboxamide)

Under a nitrogen atmosphere, isothiochroman-4-one (948 mg, 5.77 mmol) dissolved in anhydrous THF (40 mL) was added to sodium hydride (315 mg, 7.88 mmol, 1.4 equivalents) washed with dehydrated hexane, and the mixture was stirred at room temperature. And stirred for 5 minutes. Then, phenyl isocyanate (1750 mg, 14.7 mmol, 2.5 equivalents) dissolved in anhydrous THF (5 mL) was added, and the mixture was refluxed and stirred at 80° C. for 3 hours. The reaction mixture was adjusted to pH 2 with diluted hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and a black solid (2600 mg) was obtained. Got Since impurities were found in the crude product, methanol (20 mL) was added and the precipitated ocher solid was isolated by suction filtration to obtain IY-082 (1280 mg, yield 78.2%).
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 3.87 (s, 2H), 7.16-7.21 (m, 2H), 7.36-7.42 (m, 4H) ,7.56 (d,J=7.2 Hz, 2H), 7.90 (dd, J=7.2,1.3 Hz, 1H), 8.17 (brs, 1H)

　窒素雰囲気下、脱水ヘキサンで洗浄した水素化ナトリウム (115.2 mg、2.88 mmol、1.6 当量)を脱水THF (6.7 mL)に懸濁させ、4,4-ジフルオロ-3,4-ジヒドロナフタレン-1(2H)-オン (327.7 mg、1.80 mmol)を加え、室温で5分間撹拌した。次いで脱水THF (6.7 mL)に溶解したフェニルイソシアナート(450.2 mg、3.76 mmol、2.1当量)を3回に分けて加えながら、80℃で8.5時間還流撹拌した。反応液に2 M 塩酸を加え、酢酸エチルで3回抽出、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に溶媒を留去して褐色ペースト（715.9 mg）を得た。粗生成物をシリカゲルカラムクロマトグラフィー (n-ヘキサン:酢酸エチル=10：1→酢酸エチル)により精製して得られるIY-072 (287.0 mg)を含む分画をn-ヘキサンと酢酸エチルから再結晶し、IY-072(ケト:エノール=63:37、70.9 mg 、収率13%)を淡橙色針状結晶として得た。
ケト体 :  ¹H-NMR (CDCl₃, 400 MHz) δ: 2.85-3.01 (m, 1H), 3.15-3.26 (m, 1H), 3.91 (ddd, J=1.6, 5.5, 12.3 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.36 (t, J=8.6 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.67 (t, J=7.8 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 8.13 (d, J=8.3 Hz, 1H), 9.38 (s, 1H)
エノール体 : ¹H-NMR (CDCl₃, 400 MHz) δ: 3.19 (t, J=16.4 Hz, 2H), 7.20 (t, J=7.2 Hz, 1H), 7.39 (t, J=7.6 Hz, 2H), 7.53 (dd, J=1.0, 8.4 Hz, 2H), 7.56-7.63 (m, 2H), 7.55 (d, J=6.8 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H) Example 12; Synthesis of IY-72 (4,4-difluoro-1-oxo-N-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxamide)

Sodium hydride (115.2 mg, 2.88 mmol, 1.6 equivalents) washed with dehydrated hexane under a nitrogen atmosphere was suspended in dehydrated THF (6.7 mL), and 4,4-difluoro-3,4-dihydronaphthalene-1 (2H )-One (327.7 mg, 1.80 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then, phenyl isocyanate (450.2 mg, 3.76 mmol, 2.1 equivalents) dissolved in dehydrated THF (6.7 mL) was added in 3 portions, and the mixture was refluxed and stirred at 80° C. for 8.5 hours. 2 M hydrochloric acid was added to the reaction solution, which was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a brown paste (715.9 mg). The fraction containing IY-072 (287.0 mg) obtained by purifying the crude product by silica gel column chromatography (n-hexane:ethyl acetate=10:1→ethyl acetate) was recrystallized from n-hexane and ethyl acetate. Then, IY-072 (keto:enol=63:37, 70.9 mg, yield 13%) was obtained as pale orange needle crystals.
Keto: ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.85-3.01 (m, 1H), 3.15-3.26 (m, 1H), 3.91 (ddd, J=1.6, 5.5, 12.3 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.36 (t, J=8.6 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.67 (t, J=7.8 Hz, 1H), 7.80 ( t, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 8.13 (d, J=8.3 Hz, 1H), 9.38 (s, 1H)
Enol body: ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.19 (t, J=16.4 Hz, 2H), 7.20 (t, J=7.2 Hz, 1H), 7.39 (t, J=7.6 Hz, 2H ), 7.53 (dd, J=1.0, 8.4 Hz, 2H), 7.56-7.63 (m, 2H), 7.55 (d, J=6.8 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H)

　窒素雰囲気下、脱水ヘキサンで洗浄した水素化ナトリウム (214.9 mg、5.37 mmol、1.7当量)を脱水THF (11.5 mL)に懸濁させ、2-フルオロ-3,4-ジヒドロナフタレン-1(2H)-オン (505.9 mg、3.08 mmol)を加え、室温で5分間撹拌した。次いで脱水THF (11.5 mL)に溶解したフェニルイソシアナート(803.5 mg、6.75 mmol、2.2当量)を加え、80℃で4時間還流撹拌した。反応液に2M 塩酸を加え、酢酸エチルで3回抽出、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に溶媒を留去して褐色ペースト1.41 gを得た。粗生成物をシリカゲルカラムクロマトグラフィー (n-ヘキサン:酢酸エチル=5:1)により精製して得られるIY-73 (淡橙色粉末、312.2 mg)をn-ヘキサンと酢酸エチルから再結晶し、IY-73(128.4 mg、収率 15%)を白色板状結晶として得た。
¹H-NMR (CDCl₃, 400MHz) δ: 2.53-2.64 (m, 1H), 2.82-2.93 (m, 1H), 3.16 (dt, J=5.5, 17.0 Hz, 1H), 3.49 (ddd, J=5.5, 9.0, 17.0 Hz, 1H), 7.14 (t, J=7.2 Hz, 1H), 7.30-7.39 (m, 4H), 7.55-7.59 (m, 3H), 8.07 (d, J=7.8 Hz, 1H), 8.19 (s, 1H) Example 13; Synthesis of IY-73 (2-fluoro-1-oxo-N-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxamide)

Sodium hydride (214.9 mg, 5.37 mmol, 1.7 eq) washed with dehydrated hexane under a nitrogen atmosphere was suspended in dehydrated THF (11.5 mL), and 2-fluoro-3,4-dihydronaphthalene-1(2H)- ON (505.9 mg, 3.08 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then, phenyl isocyanate (803.5 mg, 6.75 mmol, 2.2 equivalents) dissolved in dehydrated THF (11.5 mL) was added, and the mixture was refluxed and stirred at 80° C. for 4 hours. 2M hydrochloric acid was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.41 g of a brown paste. IY-73 (pale orange powder, 312.2 mg) obtained by purifying the crude product by silica gel column chromatography (n-hexane:ethyl acetate=5:1) was recrystallized from n-hexane and ethyl acetate to obtain IY-73. -73 (128.4 mg, yield 15%) was obtained as white plate crystals.
¹ H-NMR (CDCl ₃ , 400MHz) δ: 2.53-2.64 (m, 1H), 2.82-2.93 (m, 1H), 3.16 (dt, J=5.5, 17.0 Hz, 1H), 3.49 (ddd, J= 5.5, 9.0, 17.0 Hz, 1H), 7.14 (t, J=7.2 Hz, 1H), 7.30-7.39 (m, 4H), 7.55-7.59 (m, 3H), 8.07 (d, J=7.8 Hz, 1H ), 8.19 (s, 1H)

14-1. 4-ヒドロキシ-1H-イソチオクロメン-3-カルボン酸メチル 2,2-ジオキシドの合成
　イソチオクロマン-4-オン-2,2-ジオキシド (105 mg、0.537 mmol) に、K₂CO₃ (307 mg、2.22 mmol、4.1当量) 、シアノギ酸メチル (358 mg、4.21 mmol、7.8当量) をアセトン (15 mL) に溶解して室温で27時間撹拌した。反応液に精製水を加え、反応液をジクロロメタンで2回洗浄、水層に希塩酸を加えpHを1とした後、ジクロロメタンで2回抽出、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に溶媒を留去して4-ヒドロキシ-1H-イソチオクロメン-3-カルボン酸メチル 2,2-ジオキシド(112 mg、収率82.1%) を橙色固体として得た。
¹H-NMR (500 MHz,CDCl₃) δ: 4.03 (s,3H), 4.47 (s, 2H), 7.33 (dd、J=1.1, 7.7 Hz, 1H), 7.54 (dt, J=1.3, 7.7 Hz, 1H), 7.60 (dt, J=1.1, 7.7 Hz, 1H), 8.08 (dd, J=1.3, 7.7Hz, 1H), 13.8 (brs, 1H) Example 14; Synthesis of IY-084 (N-(4-fluorophenyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide)

14-1.Synthesis of methyl 2,2-dioxide 4-hydroxy-1H-isothiochromene-3-carboxylate Isothiochroman-4-one-2,2-dioxide (105 mg, 0.537 mmol) in K ₂ CO ₃ (307 mg, 2.22 mmol, 4.1 eq) and methyl cyanoformate (358 mg, 4.21 mmol, 7.8 eq) were dissolved in acetone (15 mL) and stirred at room temperature for 27 hours. Purified water was added to the reaction solution, the reaction solution was washed twice with dichloromethane, the aqueous layer was diluted with dilute hydrochloric acid to adjust the pH to 1 and then extracted twice with dichloromethane, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 4-hydroxy-1H-isothiochromene-3-carboxylate 2,2-dioxide (112 mg, yield 82.1%) as an orange solid.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 4.03 (s,3H), 4.47 (s, 2H), 7.33 (dd, J=1.1, 7.7 Hz, 1H), 7.54 (dt, J=1.3, 7.7 Hz, 1H), 7.60 (dt, J=1.1, 7.7 Hz, 1H), 8.08 (dd, J=1.3, 7.7Hz, 1H), 13.8 (brs, 1H)

14-2. Synthesis of IY-084 (N-(4-fluorophenyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide) Methyl 4-hydroxy-1H-isothiochromene-3-carboxylate 2 2,2-Dioxide (65.2 mg, 0.256 mmol) and 4-fluoroaniline (86.5 mg, 0.778 mmol, 3.0 equivalent) were dissolved in m-xylene (10 mL), and the mixture was refluxed and stirred at 150° C. for 2.5 hours. Saturated ammonium chloride aqueous solution was added to the reaction solution and extracted three times with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to remove IY-084 (80.7 mg, yield). 94.6%) was obtained as an ocher solid.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 4.54 (s, 2H), 7.08 (t, J=8.5 Hz, 2H), 7.36 (d, J=7.5 Hz, 1H), 7.51-7.54 (m, 2H), 7.58 (dt, J=1.6, 7.5 Hz, 1H), 7.61 (dt, J=1.6, 7.5, Hz, 1H), 8.13 (d, J=7.5, 1.6 Hz, 1H), 9.68 (brs, 1H)

　イソチオクロマン-4-オン-2-オキシド (448 mg、2.49 mmol) とK₂CO₃ (431 mg、3.12 mmol、1.3当量)とフェニルイソシアナート (618 mg、5.19 mmol、2.1当量) をアセトン (30 mL) に溶解し、室温で22時間撹拌した。原料の残存を認めたためフェニルイソシアナート (599 mg、5.03 mmol、2.0 当量)のアセトン(2 mL)溶液を追加し、さらに3時間撹拌した。反応液に希塩酸を加えてpHを5とし、酢酸エチルで3回抽出して試薬の残渣を除去した。水層に希塩酸を加えてpHを1とし、酢酸エチルで2回抽出、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、溶媒を減圧留去してIY-085 (115 mg、収率15.4%) を黄色固体として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 4.07 (d, J=15.2 Hz, 1H), 4.51 (d, J=15.2 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.39 (t, J=8.1 Hz, 2H), 7.42 (d, J=7.4 Hz, 1H), 7.52-7.58 (m, 4H), 8.11 (dd, J=1.6, 7.4Hz, 1H), 8.62 (brs, 1H) Example 15; Synthesis of IY-085 (4-hydroxy-N-phenyl-1H-isothiochromene-3-carboxamide 2-oxide)

Isothiochroman-4-one-2-oxide (448 mg, 2.49 mmol), K ₂ CO ₃ (431 mg, 3.12 mmol, 1.3 eq) and phenyl isocyanate (618 mg, 5.19 mmol, 2.1 eq) were added to acetone ( It was dissolved in 30 mL) and stirred at room temperature for 22 hours. Since it was confirmed that the raw materials remained, a solution of phenyl isocyanate (599 mg, 5.03 mmol, 2.0 equivalents) in acetone (2 mL) was added, and the mixture was further stirred for 3 hours. The reaction mixture was adjusted to pH 5 with diluted hydrochloric acid and extracted with ethyl acetate three times to remove the residue of the reagent. Dilute hydrochloric acid was added to the aqueous layer to adjust the pH to 1, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to remove IY-085 (115 mg, yield). 15.4%) was obtained as a yellow solid.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 4.07 (d, J=15.2 Hz, 1H), 4.51 (d, J=15.2 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.39 (t, J=8.1 Hz, 2H), 7.42 (d, J=7.4 Hz, 1H), 7.52-7.58 (m, 4H), 8.11 (dd, J=1.6, 7.4Hz, 1H), 8.62 (brs, 1H)

　実施例14と同様の手法で、4-ヒドロキシ-1H-イソチオクロメン-3-カルボン酸メチル 2,2-ジオキシド (79.1 mg、0.311 mmol) とp-トルイジン (77.6 mg、0.724 mmol、2.3当量) をm-キシレン (10 mL) に溶解し、150℃で16時間還流撹拌した。反応液に飽和塩化アンモニウム水溶液を加えて酢酸エチルで3回抽出、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に溶媒を留去してIY-091 (98.4 mg、収率96%) を茶色固体として得た後、酢酸エチルから再結晶した。
¹H-NMR (500 MHz, CDCl₃) δ: 2.35 (s, 3H), 4.54 (s, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.35 (dd, J=7.4, 1.2 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.56 (dt, J=7.4, 1.7 Hz, 1H), 7.60 (dt, J=7.4, 1.2 Hz, 1H), 8.13 (dd, J=7.4, 1.7 Hz, 1H), 9.63 (brs, 1H) Example 16; Synthesis of IY-091 (N-(4-tolyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide)

In the same manner as in Example 14, methyl 4-hydroxy-1H-isothiochromene-3-carboxylate 2,2-dioxide (79.1 mg, 0.311 mmol) and p-toluidine (77.6 mg, 0.724 mmol, 2.3 equivalents) were added to m. -Dissolved in xylene (10 mL), and stirred under reflux at 150°C for 16 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give IY-091 (98.4 mg, yield). 96%) was obtained as a brown solid and then recrystallized from ethyl acetate.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.35 (s, 3H), 4.54 (s, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.35 (dd, J=7.4, 1.2 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.56 (dt, J=7.4, 1.7 Hz, 1H), 7.60 (dt, J=7.4, 1.2 Hz, 1H), 8.13 (dd, J=7.4 , 1.7 Hz, 1H), 9.63 (brs, 1H)

　実施例14と同様の手法で、4-ヒドロキシ-1H-イソチオクロメン-3-カルボン酸メチル 2,2-ジオキシド (200.0mg、0.785 mmol) と2,4-ジフルオロアニリン (308.0 mg、2.39 mmol、2.3当量) をm-キシレン (15 mL) に溶解し、150℃で3時間還流撹拌した。反応液に飽和塩化アンモニウム水溶液を加えて酢酸エチルで3回抽出、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に溶媒を留去してIY-092 (189.0 mg、収率96%) を茶色固体として得た後、酢酸エチルから再結晶して黄土色粒状結晶 (54.5 mg、53.2 %) のIY-092を得た。
¹H-NMR (500 MHz, CDCl₃) δ: 2.35 (s, 3H), 4.54 (s, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.35 (dd, J=7.4 Hz, 1.2 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H), 7.56 (dt, J=7.4, 1.7 Hz, 1H), 7.60 (dt, J=7.4, 1.2 Hz, 1H), 8.13 (dd, J=7.4, 1.7 Hz, 1H), 9.63 (brs, 1H) Example 17; Synthesis of IY-092 (N-(2,4-difluorophenyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide)

In the same manner as in Example 14, methyl 4-hydroxy-1H-isothiochromene-3-carboxylate 2,2-dioxide (200.0 mg, 0.785 mmol) and 2,4-difluoroaniline (308.0 mg, 2.39 mmol, 2.3 equivalents) ) Was dissolved in m-xylene (15 mL), and the mixture was refluxed with stirring at 150° C. for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to remove IY-092 (189.0 mg, yield). 96%) as a brown solid and then recrystallized from ethyl acetate to obtain ocher granular crystals (54.5 mg, 53.2%) of IY-092.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.35 (s, 3H), 4.54 (s, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.35 (dd, J=7.4 Hz, 1.2 Hz , 1H), 7.43 (d, J=8.3 Hz, 2H), 7.56 (dt, J=7.4, 1.7 Hz, 1H), 7.60 (dt, J=7.4, 1.2 Hz, 1H), 8.13 (dd, J= 7.4, 1.7 Hz, 1H), 9.63 (brs, 1H)

　実施例14と同様の手法で、4-ヒドロキシ-1H-イソチオクロメン-3-カルボン酸メチル 2,2-ジオキシド (225.0mg、0.885 mmol) と2,3,4-トリフルオロアニリン (515.0 mg、3.50　mmol、4.0当量) をm-キシレン (20 mL) に溶解し、150℃で3.5時間還流撹拌した。反応液に飽和塩化アンモニウム水溶液を加えて酢酸エチルで3回抽出、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に溶媒を留去してIY-093 (304.0 mg) を桃色固体として得た後、酢酸エチルから再結晶して薄茶色針状結晶 (195.0 mg、59.8 %) のIY-093を得た。
¹H-NMR (500 MHz, CDCl₃) δ: 4.56 (s, 2H), 7.02 (ddd, J=17.2, 9.6, 2.3 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.59 (dt, J=7.6, 1.3 Hz, 1H), 7.63 (dt, J=7.6, 1.5 Hz, 1H), 7.82-7.87 (m, 1H), 8.14 (dd, J=7.6, 1.3 Hz, 1H), 9.92 (brs,1H) Example 18; Synthesis of IY-093 (N-(2,3,4-trifluorophenyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide)

In the same manner as in Example 14, methyl 4-hydroxy-1H-isothiochromene-3-carboxylate 2,2-dioxide (225.0 mg, 0.885 mmol) and 2,3,4-trifluoroaniline (515.0 mg, 3.50 mmol) were used. , 4.0 equivalents) was dissolved in m-xylene (20 mL), and the mixture was stirred under reflux at 150° C. for 3.5 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate.The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and IY-093 (304.0 mg) was pink. After obtained as a solid, it was recrystallized from ethyl acetate to obtain light brown needle crystals (195.0 mg, 59.8%) of IY-093.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 4.56 (s, 2H), 7.02 (ddd, J=17.2, 9.6, 2.3 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.59 ( dt, J=7.6, 1.3 Hz, 1H), 7.63 (dt, J=7.6, 1.5 Hz, 1H), 7.82-7.87 (m, 1H), 8.14 (dd, J=7.6, 1.3 Hz, 1H), 9.92 (brs,1H)

　実施例14と同様の手法で、4-ヒドロキシ-1H-イソチオクロメン-3-カルボン酸メチル 2,2-ジオキシド (220.0 mg、0.866 mmol) と2,-メトキシアニリン (291.0 mg、2.37 mmol、2.7当量) をm-キシレン (10 mL) に溶解し、150℃で3時間還流撹拌した。反応液に飽和塩化アンモニウム水溶液を加えて酢酸エチルで3回抽出、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に溶媒を留去してIY-094 (279.0 mg) を茶色固体として得た後、酢酸エチルから再結晶して褐色粒状結晶 (186.0 mg、収率62%)のIY-094を得た。
¹H-NMR (500 MHz, CDCl₃) δ: 3.83 (s, OCH₃, 3H), 4.55 (s, CH₂, 2H), 6.76 (ddd, J=7.8, 2.4, 0.88 Hz, 1H), 7.09 (d, J=7.7 Hz,1H), 7.22 (t, J=2.4 Hz, 1H), 7.28 (t, J=7.8 Hz,1H), 7.36 (dd, J=7.8 Hz, 0.88 Hz, 1H), 7.57 (dt, J=7.7 Hz, 1.8 Hz, 1H), 7.61 (dt, J=7.7, 1.7 Hz, 1H), 8.14 (dd, J=7.7, 1.8 Hz, 1H), 9.70 (brs, 1H) Example 19; Synthesis of IY-094 (N-(2-methoxyphenyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide)

In the same manner as in Example 14, methyl 4-hydroxy-1H-isothiochromene-3-carboxylate 2,2-dioxide (220.0 mg, 0.866 mmol) and 2,-methoxyaniline (291.0 mg, 2.37 mmol, 2.7 equivalents) Was dissolved in m-xylene (10 mL), and the mixture was refluxed with stirring at 150° C. for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate.The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and IY-094 (279.0 mg) was brown. After being obtained as a solid, it was recrystallized from ethyl acetate to obtain brown granular crystals (186.0 mg, yield 62%) of IY-094.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 3.83 (s, OCH ₃ , 3H), 4.55 (s, CH ₂ , 2H), 6.76 (ddd, J=7.8, 2.4, 0.88 Hz, 1H), 7.09 (d, J=7.7 Hz,1H), 7.22 (t, J=2.4 Hz, 1H), 7.28 (t, J=7.8 Hz,1H), 7.36 (dd, J=7.8 Hz, 0.88 Hz, 1H), 7.57 (dt, J=7.7 Hz, 1.8 Hz, 1H), 7.61 (dt, J=7.7, 1.7 Hz, 1H), 8.14 (dd, J=7.7, 1.8 Hz, 1H), 9.70 (brs, 1H)

　窒素雰囲気下、脱水ヘキサンで洗浄した水素化ナトリウム (304.1 mg、7.61 mmol、1.7 当量) を脱水THF (17 mL) に懸濁し、4-メチル-3,4-ジヒドロナフタレン-1(2H)-オン (707.6 mg、4.42 mmol)を加え、室温で5分間撹拌した。次いで脱水THF (17 mL) に溶解したフェニルイソシアナート (1.15 g、9.70 mmol、2.2当量) を加え、80℃で21時間還流撹拌した。反応液に2 M 塩酸を加え、酢酸エチルで3回抽出、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧下に溶媒を留去して褐色ペースト（1.79 g）を得た。粗生成物をシリカゲルカラムクロマトグラフィー (n-ヘキサン:酢酸エチル=8：1) により精製して黄色油状物質のIY-095 (375.9 mg、収率30%) を得た。¹H-NMRでは互変異性体３種（ケト体ジアステレオマー２種とエノール体）を認めたため、特徴的なピークのみ以下に記す。
¹H-NMR (CDCl₃, 400 MHz) δ: 1.36 (d, J = 6.8 Hz, -CH₃), 1.43 (d, J = 7.0 Hz, -CH₃), 1.50 (d, J = 6.8 Hz, -CH₃), 3.53 (dd, J = 12.9, 4.7 Hz, -COCH-), 3.72 (dd, J = 8.8, 5.3 Hz, -COCH-) Example 20; Synthesis of IY-095 (4-methyl-1-oxo-N-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxamide)

Sodium hydride (304.1 mg, 7.61 mmol, 1.7 equivalents) washed with dehydrated hexane under a nitrogen atmosphere was suspended in dehydrated THF (17 mL), and 4-methyl-3,4-dihydronaphthalene-1(2H)-one was suspended. (707.6 mg, 4.42 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then, phenyl isocyanate (1.15 g, 9.70 mmol, 2.2 equivalents) dissolved in dehydrated THF (17 mL) was added, and the mixture was refluxed and stirred at 80° C. for 21 hours. 2 M hydrochloric acid was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a brown paste (1.79 g). The crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to obtain IY-095 (375.9 mg, yield 30%) as a yellow oily substance. ^{In 1} H-NMR, 3 types of tautomers (2 types of keto diastereomer and enol form) were observed, so only the characteristic peaks are described below.
¹ H-NMR (CDCl ₃ ,400 MHz) δ: 1.36 (d, J = 6.8 Hz, -CH ₃ ), 1.43 (d, J = 7.0 Hz, -CH ₃ ), 1.50 (d, J = 6.8 Hz, -CH ₃ ), 3.53 (dd, J = 12.9, 4.7 Hz, -COCH-), 3.72 (dd, J = 8.8, 5.3 Hz, -COCH-)

　窒素雰囲気下、市販の6,7-ジヒドロベンゾ[b]チオフェン-4(5H)-オン (300.0 mg、1.97 mmol) を無水THF (15 mL) に溶解し、-78℃に冷却してカリウムヘキサメチルジシラジド溶液 (6.0 ｍL, 2.96 mmol、1.5当量) を加え、30分間撹拌した。次いでフェニルイソシアナート (327.0 mg、2.75 mmol、1.5 当量) の無水THF (3 mL) 溶液を15分かけて滴下した後、緩やかに昇温して室温でｓらに8時間攪拌した。反応液に 2 M HClを加えpHを3とし、酢酸エチルで抽出、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで脱水、溶媒を減圧下に留去して褐色油状物質（667.0 mg）を得た。n-ヘキサンと酢酸エチルから再結晶してIY-101 (40.0 mg、収率7%) を無色針状結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 2.65 (ddd, J=6.2, 6.2, 6.2 Hz, 2H), 3.07 (ddd, J=17.2, 6.2, 6.2 Hz, 1H), 3.36 (ddd, J=17.3, 6.2, 6.2 Hz, 1H), 3.50 (t, J=6.2 Hz, 1H), 7.08-7.12 (m, 2H), 7.32 (t, J=7.6 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 7.56 (d, J=7.6, 2.0 Hz, 1H), 8.39 (dd, J=7.7 Hz, 2H), 9.14 (s, 1H) Example 21; Synthesis of IY-101 (4-oxo-N-phenyl-4,5,6,7-tetrahydro[b]thiophene-3-carboxamide)

Under a nitrogen atmosphere, commercially available 6,7-dihydrobenzo[b]thiophen-4(5H)-one (300.0 mg, 1.97 mmol) was dissolved in anhydrous THF (15 mL), cooled to -78 °C, and potassium hexahydrate was added. Methyldisilazide solution (6.0 mL, 2.96 mmol, 1.5 eq) was added and stirred for 30 minutes. Then, a solution of phenyl isocyanate (327.0 mg, 2.75 mmol, 1.5 equivalents) in anhydrous THF (3 mL) was added dropwise over 15 minutes, and then the temperature was slowly raised and the mixture was stirred at room temperature for 8 hours. The reaction mixture was adjusted to pH 3 with 2 M HCl, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a brown oil (667.0 mg). Got Recrystallization from n-hexane and ethyl acetate gave IY-101 (40.0 mg, yield 7%) as colorless needle crystals.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.65 (ddd, J=6.2, 6.2, 6.2 Hz, 2H), 3.07 (ddd, J=17.2, 6.2, 6.2 Hz, 1H), 3.36 (ddd, J =17.3, 6.2, 6.2 Hz, 1H), 3.50 (t, J=6.2 Hz, 1H), 7.08-7.12 (m, 2H), 7.32 (t, J=7.6 Hz, 1H), 7.43 (d, J= 7.5 Hz, 1H), 7.56 (d, J=7.6, 2.0 Hz, 1H), 8.39 (dd, J=7.7 Hz, 2H), 9.14 (s, 1H)

　実施例3と同様の手法で、4-ヒドロキシ-1-メチル-1H-ピリド[2,3-c][1,2]チアジン 2,2-ジオキシド (200.0 mg、0.94 mmol) とフェニルイソシアナート (112 mg、1.88 mmol、2.0当量) の縮合により得られる赤白色固体（272.0 mg）を酢酸エチルから再結晶し、IY-102 (100.0 mg、収率32%) を橙色結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 3.30 (s, 3H), 6.94 (tt, J=7.3, 1.1, ArH, 1H), 7.12 (dd, J=7.6, 4.6, ArH, 1H), 7.26 (m, ArH, 2H), 7.57 (dd, J=8.6, 1.0 Hz, 2H), 8.28 (dd, J=7.6, 2.0 Hz, 1H), 8.39 (dd, J=4.7, 2.0 Hz, 1H), 12.6 (s, 1H) Example 22; Synthesis of IY-102 (N-phenyl-4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide)

In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide (200.0 mg, 0.94 mmol) and phenyl isocyanate ( The red-white solid (272.0 mg) obtained by condensation of 112 mg, 1.88 mmol, 2.0 equivalent) was recrystallized from ethyl acetate to obtain IY-102 (100.0 mg, yield 32%) as orange crystals.
¹ H-NMR (500 MHz, CDCl ₃ )δ: 3.30 (s, 3H), 6.94 (tt, J=7.3, 1.1, ArH, 1H), 7.12 (dd, J=7.6, 4.6, ArH, 1H), 7.26 (m, ArH, 2H), 7.57 (dd, J=8.6, 1.0 Hz, 2H), 8.28 (dd, J=7.6, 2.0 Hz, 1H), 8.39 (dd, J=4.7, 2.0 Hz, 1H) , 12.6 (s, 1H)

　実施例3と同様の手法で、4-ヒドロキシ-1-メチル-1H-ピリド[2,3-c][1,2]チアジン 2,2-ジオキシド (300 mg、1.42 mmol) と2.4-ジフルオロフェニルイソシアナート (395.0 mg、2.55 mmol、1.8当量) の縮合により得られる乳白色固体（609.0 mg）を酢酸エチルから再結晶し、IY-103 (394.0 mg、収率77%) を白色結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 3.68 (s, 3H), 6.90-6.98 (m, 2H), 7.26 (m, 1H), 8.10-8.17 (m, 1H), 8.24 (dd, J=7.8, 1.7 Hz, 1H), 8.64 (dd, J=4,7, 1.8 Hz, 1H), 12.6 (s, 1H) Example 23; IY-103 (N-(2.4-difluorophenyl)-4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ) Synthesis

In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide (300 mg, 1.42 mmol) and 2.4-difluorophenyl were used. A milky white solid (609.0 mg) obtained by condensation of isocyanate (395.0 mg, 2.55 mmol, 1.8 equivalents) was recrystallized from ethyl acetate to obtain IY-103 (394.0 mg, yield 77%) as white crystals.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 3.68 (s, 3H), 6.90-6.98 (m, 2H), 7.26 (m, 1H), 8.10-8.17 (m, 1H), 8.24 (dd, J =7.8, 1.7 Hz, 1H), 8.64 (dd, J=4,7, 1.8 Hz, 1H), 12.6 (s, 1H)

　実施例3と同様の手法で、4-ヒドロキシ-1-メチル-1H-ピリド[2,3-c][1,2]チアジン 2,2-ジオキシド (150.0 mg、0.71 mmol) と4-トリルイソシアナート (186.0 mg、1.40 mmol、2.0当量) の縮合により得られる黄白色固体（337.0 mg）を酢酸エチルから再結晶し、IY-104 (158.0 mg、収率64%) を黄色板状結晶として得た。
¹H-NMR (500 MHz, CDCl₃) δ: 2.36 (s, 3H), 3.68 (s, 3H), 7.19 (d, J=8.2 Hz, 2H), 7.25 (dd, J=7.8, 4.7 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 8.41 (dd, J=7.8, 1.8 Hz, 1H), 8.62 (dd, J=4.7, 2.0 Hz, 1H), 9.38 (s, 1H) Example 24; IY-104 (N-(4-tolyl)-4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide) Synthesis of

In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide (150.0 mg, 0.71 mmol) and 4-tolyl isocyanate were used. The yellowish white solid (337.0 mg) obtained by condensation of nato (186.0 mg, 1.40 mmol, 2.0 eq) was recrystallized from ethyl acetate to obtain IY-104 (158.0 mg, yield 64%) as yellow plate crystals. It was
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 2.36 (s, 3H), 3.68 (s, 3H), 7.19 (d, J=8.2 Hz, 2H), 7.25 (dd, J=7.8, 4.7 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 8.41 (dd, J=7.8, 1.8 Hz, 1H), 8.62 (dd, J=4.7, 2.0 Hz, 1H), 9.38 (s, 1H)

　1-メチル-4-オキソ-1,2,3,4-テトラヒドロキノリン-3-カルボン酸メチル（100.0 mg、0.46 mmol）とp-トルイジン（147.9 mg、1.38 mmol）をm-キシレン（12 mL）に溶解して150℃で25時間、還流撹拌した。反応液を室温に戻した後、精製水と飽和塩化アンモニウム水溶液を加えて反応を停止し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで脱水、溶媒を減圧下に留去して茶色油状物質（190.5 mg）を得た。シリカゲルカラムクロマトグラフィー (n-ヘキサン:ジクロロメタン=1：10) により精製し、IY-114 (21.0 mg)、IY-115 (5.8 mg) をそれぞれ無色油状物質として得た。
IY-114；¹H-NMR (400 MHz, CDCl₃) δ: 2.30 (s, 3H), 3.27 (dd, J=10.0 Hz, 15.8 Hz, 1H), 3.38 (dd, J=6.3,15.8 Hz, 1H), 3.42 (s, 3H), 3.53 (dd, J=6.3, 10.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.07-7.11 (m, 3H), 7.29 (t, J=5.8 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 9.66 (s, 1H)
IY-115；¹H-NMR (400 MHz, CDCl₃) δ:2.34 (s, 3H), 3.85 (s, 3H), 7.18 (d, J=8.2 Hz, 2H), 7.36 (t, J=7.8 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.71 (dt, J=1.5, 8.1 Hz, 1H), 7.81 (dd, J=1.4, 7.8 Hz, 1H), 9.01 (s, 1H), 12.01 (s, 1H) Example 25; IY-114 (1-methyl-4-oxo-N-(4-tolyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide) and IY-115 (1-methyl-4- Synthesis of oxo-N-(4-tolyl)-1,4-dihydroquinoline-3-carboxamide)

Methyl 1-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (100.0 mg, 0.46 mmol) and p-toluidine (147.9 mg, 1.38 mmol) in m-xylene (12 mL) And was stirred under reflux at 150° C. for 25 hours. After returning the reaction solution to room temperature, the reaction was stopped by adding purified water and a saturated ammonium chloride aqueous solution, the organic layer was washed with saturated brine, dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a brown color. An oily substance (190.5 mg) was obtained. Purification by silica gel column chromatography (n-hexane:dichloromethane=1:10) gave IY-114 (21.0 mg) and IY-115 (5.8 mg) as colorless oily substances.
IY-114; ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.30 (s, 3H), 3.27 (dd, J=10.0 Hz, 15.8 Hz, 1H), 3.38 (dd, J=6.3,15.8 Hz, 1H), 3.42 (s, 3H), 3.53 (dd, J=6.3, 10.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.07-7.11 (m, 3H), 7.29 (t, J =5.8 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 9.66 (s, 1H)
IY-115; ¹ H-NMR (400 MHz, CDCl ₃ ) δ:2.34 (s, 3H), 3.85 (s, 3H), 7.18 (d, J=8.2 Hz, 2H), 7.36 (t, J=7.8 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.71 (dt, J=1.5, 8.1 Hz, 1H), 7.81 (dd, J=1.4 , 7.8 Hz, 1H), 9.01 (s, 1H), 12.01 (s, 1H)

The compounds shown in Table 1 below were produced in the same manner as in the methods described in Examples 1 to 25 above. Note that the sample numbers in Table 1 below may be abbreviated as IY-XXX (three-digit number) in this specification. For example, IY-027 in Example 1 means a compound represented by sample number: KO-IY-NA-027 in Table 1 below.
Using the produced compound as an evaluation compound, the cyclooxygenase (COX) inhibition test, the protective effect evaluation against MPP ⁺ induced cultured neuronal cell death, the drug efficacy evaluation using the MPTP-induced Parkinson's disease mouse model, the plasma and brain concentration measurement were performed as follows. I went.

[Test example]
Example 26; Cyclooxygenase (COX) Inhibition Test Using a COX Fluorescent Inhibitor Screening Kit (CAYMAN CHEMICAL), the inhibitory activity of each compound on COX-1 and COX-2 was evaluated.
Tris-HCl buffer (pH 8.0), Heme solution, and a solution (10 μM) of the evaluation compound dissolved in DMSO were added to a 96-well plate. Separately, a well to which DMSO was added instead of the evaluation compound solution was prepared as a control. COX-1 or COX-2 solution was added to each well and incubated at room temperature for 5 minutes. ADHP solution and arachidonic acid solution were added to all wells and incubated at room temperature for 2 minutes. The excitation wavelength was 530 nm and the emission wavelength was 585 nm. As positive controls, SC-560 was used for COX-1 and DuP-697 was used for COX-2. For comparison, meloxicam was used instead of the evaluation compound, and the same evaluation was performed. The results are shown in Table 1 below.
The meloxicam had a very strong COX-2 inhibitory activity, whereas the compounds evaluated had a lower COX-2 inhibitory activity than meloxicam. In particular, IY-067, IY-068, IY-077, IY-091, IY-092, IY-093, IY-094, IY-095, IY-101, IY-102, IY-103 and IY-104 are , COX-2 inhibitory activity is significantly weaker than that of meloxicam, and COX-2 of IY-091, IY-092, IY-093, IY-094, IY-101, IY-102, IY-103 and IY-104 No inhibitory activity was detected. The COX-1 inhibitory activity of most compounds, including meloxicam, was almost zero.

Example 27: Evaluation of protective effect against MPP ⁺ -induced cultured neuronal cell death MPP ⁺ (1-methyl-4-phenylpyridinium) was added to the culture solution of human neurofibroblast SH-SY5Y cells, and the cell survival rate was measured by WST. -8 method. Specifically, the test was conducted as follows.
Human neurofibroblast SH-SY5Y cells in Dulbecco's modified Eagle medium (DMEM) (D5796, SIGMA) containing immobilized fetal bovine serum (10%) and penicillin (100 U/mL) streptomycin (100 μg/mL). Was seeded in a 96-well plate at a concentration of 1.5×10 ⁴ cells/cm ² and cultured in a 37° C., 5% CO ₂ incubator. After 24 hours, rinse twice with serum-free DMEM (D5921, SIGMA), and in MPP ⁺ treatment group, 100 μL of serum-free DMEM containing 5 mM MPP ⁺ was evaluated compound (dissolved in 0.1% DMSO, final concentration 0.1 μM, 0.3 μM, 1 μM, 3 μM, or 30 μM) was added and the medium was exchanged. In the non-treated group, the evaluation compound was added to 100 μL of serum-free DMEM containing no MPP ⁺ , and the medium was replaced. After changing the medium, culture again at 37°C in a 5% CO ₂ incubator, and after 18 hours, add 10 μL of WST-8 test reagent (DOJINDO) to each cell to evaluate the viability of cells, and again at 37°C, After returning to a 5% CO ₂ incubator, color reaction was performed for 2 and a half hours. After two and a half hours, the cell viability was evaluated by measuring the absorbance at 450 nm with a microplate reader (SunriseR, TECAN) (reference wavelength 620 nm). As a reference, meloxicam was used instead of the evaluation compound, and the same evaluation was performed.
From the obtained results, the IC ₅₀ was calculated by statistical software (Prism5, MDF). The results are shown in Table 1 below.
All of the evaluated compounds suppressed the MPP ⁺ -induced cultured neuronal cell death to a different degree. Among the evaluated compounds, many compounds were more active than meloxicam.

Table 1: Neuronal cell protective effect and COX inhibitory activity of compounds

In Table 1, what is shown as "ca.30" in the column of neuronal cell protective effect means that the cell viability was about 50% at 30 µM.
In Table 1, "ca.10" in the column of neuronal cell protective effect means that the cell viability was about 50% at 10 µM.

Example 28: Evaluation of drug efficacy using MPTP-induced Parkinson's disease model mouse MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced Parkinson's disease model for drug efficacy evaluation of many therapeutic drugs for Parkinson's disease The mouse is being used. The model mouse can be used to evaluate the drug efficacy dose and the safety.
In this test, MPTP-induced Parkinson's disease model mice were used to evaluate the improving effect of the evaluated compounds on experimental Parkinsonism by the Pole test method. The mice and samples used are as follows.
・Mice: Male C57BL/6 mice (SLC, 9 weeks old at the start of administration, 11 weeks old at the time of behavior evaluation, 20-25 g)
Acclimatized for 7 days after arrival.
・MPTP (Sigma): 30 mg/kg subcutaneously administered to mice (dissolved in Saline)
-Evaluation compound: Intraperitoneally or orally administered to mice at 3, 7.5, 10, 20 or 30 mg/kg (dissolved in 0.5% CMC)
・Meloxicam (reference example): Intraperitoneally administered to mice at 10 mg/kg (dissolved in Saline)
The administration was performed by grouping as follows.
・Control group: CMC twice daily intraperitoneal administration (morning and evening) for 15 days, Saline once daily subcutaneous administration (daytime) for the first 5 days ・MPTP group: CMC twice daily intraperitoneal administration (morning and evening) 15 days, MPTP 30 mg/kg Subcutaneous administration once a day (daytime) First 5 days MPTP + evaluation compound group: Evaluation compound once or twice daily intraperitoneally or orally (10 mg administration once in the morning, or 3, 7.5, 10 , 20 or 30 mg once a day in the morning and evening) 15 days, MPTP 30 mg/kg once a day subcutaneously (day) For the first 5 days MPTP + meloxicam group: meloxicam once a day intraperitoneally (once day) 10 mg administration) 15 days, MPTP 30 mg/kg once daily subcutaneous administration (daytime) First 5 days

As the evaluation compound, IY-027, IY-053, IY-060, IY-065, IY-067, IY-068, IY-069, and IY-093 are used in consideration of the measurement results of neuronal cell protective effect. did. IY-027 was intraperitoneally administered, and the others were orally administered to mice.
The Pole test was performed as follows. Before the administration on the 15th day, the mouse was grasped upward by the tip of a rod having a diameter of 8 mm and a height of 55 cm, and the time from the beginning of movement until the mouse turned completely downward was defined as T _turn . The longer this time is, the greater the degree of movement disorder is. Each mouse was acclimated once, and the same measurement was performed 5 times per mouse, and the average value was used. The results are shown in FIGS.
Each of the compounds to be evaluated shortened the T _turn lengthened by the administration of MPTP to the same extent as the control group not administered with MPTP. Thus, it was shown that any of the evaluated compounds improved the movement disorder.
In addition, a significant difference was observed between the MPTP group and the MPTP+evaluated compound group (IY-027, IY-053, IY-060, IY-093) at a significance level of 0.1%. A significant difference was observed between the MPTP group and the MPTP+assessed compound group (IY-067) at the 1% significance level. A significant difference was observed between the MPTP group and the MPTP+evaluated compound group (IY-068, IY-069) at the 5% significance level. A significant difference was observed between the MPTP group and the MPTP + meloxicam group of the reference example at a significance level of 0.1%. Regarding IY-065, no significant difference was observed between the MPTP group and IY-065 in the present experiment, which was considered to be due to the large variation in the MPTP group.
No remarkable toxicity was observed in the mice by administration of any of the compounds.

Example 29; Measurement of plasma and brain concentrations The mice and samples used are as follows.
・Mouse: Male C57BL/6 mouse (self breeding, 22-30 g)
Evaluation compound: 10 mg/kg (dissolved in 0.5% CMC)
1, 4 and 8 hours after oral or intraperitoneal administration of the compound to be evaluated, blood was collected from the inferior vena cava using a 26G injection needle + 1 mL syringe anesthetized and heparinized, and the microcooled centrifuge (KUBOTA3780 was cooled to 4°C. ) Was centrifuged at 5000 rpm for 5 minutes, and the supernatant was used as plasma. Next, the whole brain was taken out and the brain weight was measured. Plasma and brain were immediately stored at -80°C.
To the frozen brain, add 3 times the brain weight of ultrapure water, add beads with a diameter of 7 mm, and treat the brain with a bead crusher (bead crusher μT-12) (TAITEC) at 2800 rpm for 40 seconds. Crushed. After removing the beads, the brain homogenate sample was stored again at -80°C.
After cryopreserved samples of plasma and brain homogenate were thawed, 3-fold amount of ethanol (including internal standard substance) was added to each and thoroughly mixed with a vortex mixer. After standing at -20°C for 20 minutes, centrifugation was performed for 10 minutes (4°C, 10,000 g), and the supernatant was used as a sample for analysis.
LC-MS [HPLC: AGILENT 1200, MS: AGILENT 6120, Column: InertSustain C18 (4.6 x 10 mm, 3.0 μm, GL SCIENCES)] was used for the analysis. The molecular ion of each compound was monitored by SIM mode, and it quantified from the peak area of the obtained chromatogram using the relative calibration curve method. Further, as a reference, meloxicam was used instead of the evaluation compound, and the same measurement was performed.
As a result of the measurement, among the evaluated compounds, the compound in which -XY- represents -CR ⁴ R ⁵ -CR ⁶ R ^7- has higher intracerebral transferability (brain/plasma concentration ratio) than meloxicam, but its plasma concentration is It was low and tended to decrease rapidly with time. Further, among the evaluated compounds, the compound in which -XY- represents -CR ⁴ R ⁵ -SO _2- showed a high concentration in the brain, and had higher intracerebral transferability (brain/plasma concentration ratio) than meloxicam. The other evaluated compounds behaved similarly to meloxicam. The results of using IY-027 manufactured in Example 1, using IY-065, and using IY-093 are shown in Table 2 below.

　表中、濃度の値は、平均値±標準偏差である（n=3）。なお、IY-027の場合血漿中濃度の定量下限は0.003 μM、脳内濃度の定量下限は0.012 nmol/gであり、IY-065の場合血漿中濃度の定量下限は0.01 μM、脳内濃度の定量下限は0.04 nmol/gであり、IY-093の場合血漿中濃度の定量下限は0.1 μM、脳内濃度の定量下限は1.0 nmol/gである。

In the table, the concentration values are mean±standard deviation (n=3). In the case of IY-027, the lower limit of quantification of plasma concentration was 0.003 μM, the lower limit of quantification of brain concentration was 0.012 nmol/g, and in the case of IY-065, the lower limit of quantification of plasma concentration was 0.01 μM, The lower limit of quantification is 0.04 nmol/g. For IY-093, the lower limit of quantification of plasma concentration is 0.1 μM, and the lower limit of quantification of brain concentration is 1.0 nmol/g.

In addition, the results of brain concentration measurement of the compound evaluated in Example 28 are shown together with the results obtained in Examples 26 and 27.

INDUSTRIAL APPLICABILITY The compound of the present invention has a neuronal cell protective effect and improves motor disorders in Parkinson's disease model mice, and thus may be useful as a therapeutic agent for Parkinson's disease. It is considered that the compound of the present invention can suppress the progression of Parkinson's disease and stop the progression thereof. In addition, the compound of the present invention is considered to be applicable to the treatment of Parkinson's syndrome which exhibits the same symptoms as those in Parkinson's disease. Since the existing drugs bromocriptine, levodopa, and dopamine itself do not have a protective effect on MPP ⁺ -induced neuronal cell death, the compounds of the present invention have utility over these existing drugs for the treatment of Parkinson's disease and the like. I will get it.
Furthermore, oral administration of the compound of the present invention markedly improves the movement disorder of Parkinson's disease model mice, and no remarkable toxicity is observed in the mice, and therefore, it can be easily taken and can contribute to improvement of QOL of patients.
The compounds of the present invention are less likely to cause gastrointestinal disorders and may be more useful because of their lower COX inhibitory activity compared to meloxicam.

Claims (5)

A pharmaceutical composition for treating Parkinson's disease or Parkinson's syndrome, which comprises a compound represented by formula (1), (2) or (8) or a pharmaceutically acceptable salt thereof.

(In the formula,
-XY- _{^{is, -NR 3 -SO 2 -, -}} CR 4 R 5 -SO 2 -, - CR 4 R 5 -SO -, - CR 4 R 5 -S -, - SO 2 -CR 4 R 5 - , -SO-CR ⁴ R ⁵ -, -CR ⁴ R ⁵ -CR ⁶ R ⁷ -, or -NR ³ -CR ⁴ R ⁵ -,
R ³ represents a hydrogen atom or an alkyl group,
R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, a halogen atom or an alkyl group,
Z represents O or S,

And
R ⁸ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, OH, NH ₂ or CN,
n represents an integer of 1 to 4,
R ¹ represents a group selected from the following,

R ⁹ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group, a formyl group, or an alkyl group in which the hydrogen atom is substituted with 1 to 3 halogen atoms,
R ¹⁰ represents a hydrogen atom or an alkyl group,
m represents an integer of 1 to 5,
R ² represents a hydrogen atom, a halogen atom or OH. ) A pharmaceutical composition for protecting nerve cells, comprising a compound represented by formula (1), (2) or (8) or a pharmaceutically acceptable salt thereof.

(In the formula,
-XY- _{^{is, -NR 3 -SO 2 -, -}} CR 4 R 5 -SO 2 -, - CR 4 R 5 -SO -, - CR 4 R 5 -S -, - SO 2 -CR 4 R 5 - , -SO-CR ⁴ R ⁵ -, -CR ⁴ R ⁵ -CR ⁶ R ⁷ -, or -NR ³ -CR ⁴ R ⁵ -,
R ³ represents a hydrogen atom or an alkyl group,
R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, a halogen atom or an alkyl group,
Z represents O or S,

And
R ⁸ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, OH, NH ₂ or CN,
n represents an integer of 1 to 4,
R ¹ represents a group selected from the following,

R ⁹ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an alkylcarbonyl group, a formyl group, or an alkyl group in which the hydrogen atom is substituted with 1 to 3 halogen atoms,
R ¹⁰ represents a hydrogen atom or an alkyl group,
m represents an integer of 1 to 5,
R ² represents a hydrogen atom, a halogen atom or OH. ) -XY- represents -NR ³ -SO ₂ -, -CR ⁴ R ⁵ -SO ₂ -, -SO ₂ -CR ⁴ R ⁵ -, or -CR ⁴ R ⁵ -CR ⁶ R ⁷ -. The pharmaceutical composition according to 1 or 2. The pharmaceutical composition according to any one of claims 1 to 3, which is used for oral administration. One compound selected from the following structural formulas:

Images