JP2000103793A - Pyridobenzothiazine derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having excellent antagonism against a tachykinin receptor, especially a substance P receptor, and useful as a preventive or treating agent for dysuria or the like. SOLUTION: A compound of formula I [R1 to R3 are each H or a 1-6C alkyl; the ring A is a homocycle or heterocycle capable of having 1-3 substituents (two adjacent substituents may form a ring by bonding to each other); the ring B is benzene capable of having 1-5 substituents (two adjacent substituents may form a ring by bonding to each other); the ring C is benzene capable of having 1-3 substituents (two adjacent substituents may form a ring by bonding to each other)], for example, N-[3,5-bis(trifluoromethyl)benzyl]-2,3-dihydro-N- methyl-5-oxo-7-phenyl-5H-pyrido [1,2,3-de]-1,4-benzothiazine-6-carboxamide. The compound of formula I is preferably obtained, for example, by reacting a compound of formula II (R4 is OH or the like) with a compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel pyridobenzothiazine derivative having a tachykinin receptor antagonistic activity or a pharmacologically acceptable salt thereof, a process for producing the same, and a pyridobenzothiazine derivative. It relates to a pharmaceutical composition.

[0002]

2. Description of the Related Art Tachykinin (substance P, neurokinin A, neurokinin B) is a general term for neuropeptides and their respective receptors (neurokinin 1 (NK ₁ ), neurokinin 2 (NK) ₂ ) It is known that various physiological activities are expressed by binding to neurokinin 3 (NK ₃ )). Among them, substance P acts as a transmitter of central and peripheral primary sensory neurons, and has physiological functions such as a diuretic enhancing action, a nerve cell excitatory action, a vascular permeability enhancing action, a vasodilatory action, a smooth muscle contracting action, and an immune action. It has activity and is considered to be deeply involved in various disease states (frequent urination, urinary incontinence, vomiting, inflammation, allergy, airway disease, pain, central nervous system disease, etc.). Therefore, development of a compound having excellent tachykinin receptor antagonistic activity, particularly a substance P receptor antagonistic activity, as well as excellent safety and long-lasting properties, as preventive and therapeutic agents for the above-mentioned various disease states is expected. It is rare. At present, the following compounds and the like have been disclosed as compounds having a substance P receptor antagonistic action.

(1) Japanese Patent Application Laid-Open No. 1-287095 discloses a formula: (Wherein, R ¹ is hydrogen or an amino protecting group, R ² is hydrogen, an amino protecting group, a carbamoyl (lower) alkyl group, a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, and R ³ is (Lower) alkyl group, -N
An (R ⁴ ) (R ⁵ ) group, wherein R ⁴ and R ⁵ are each hydrogen,
An aryl group or a lower alkyl group which may have a suitable substituent, R ⁴ and R ⁵ are bonded to each other to form a benzene condensed lower alkylene group), or —OR
⁶ groups (wherein R ⁶ represents hydrogen, an aryl group or a lower alkyl group which may have a suitable substituent), wherein A is a single bond or one or two amino acid residues. R ⁴ is not hydrogen when A represents one amino acid residue of D-Trp). ) And salts thereof are disclosed.

(2) Formulas described in EP-A-429366: Are disclosed.

(3) In WO 91/09844, the formula is: Are disclosed.

(4) EP-A-532456 has the formula: Are disclosed.

(5) EP-A-522808 describes the formula: Are disclosed.

(6) In WO 93/01169, the formula is: Are disclosed.

(7) JP-A-8-67678 discloses a formula: (Wherein, A ring and B ring are homo or hetero rings, at least one of which is a hetero ring; C ring is a benzene ring; R is H or a hydrocarbon residue; one of X and Y is -NR ^1- (R ¹ is H or a hydrocarbon residue) or —O—, and the other is —CO— or —C
S-, or one -N =, the other ⁼ CR ² - ^(R 2
Is H, a halogen, a hydrocarbon residue, an amino group or a hydroxyl group); n represents 1 or 2. ) Or a salt thereof is disclosed.

(8) Japanese Patent Application Laid-Open No. 9-104467 describes a formula: (Wherein, X represents a hydrogen atom or an oxygen atom, Y represents a nitrogen atom or an oxygen atom which may be alkylated or acylated, and R ¹ contains a hydrogen atom, a lower alkyl group, a lower alkanoyl group, and a nitrogen atom. Alkyl group, carbamoyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, (4-phenylpiperazine-1
-Yl) methyl group, and R ² represents a hydrogen atom, a lower alkyl group, a lower alkyl group containing a hydroxyl group, a lower alkanoyl group, or a lower alkoxy group. Rings A and B represent a benzene ring which may have a substituent. ) Is disclosed.

(9) JP-A-9-263587 describes the formula: (Wherein the M ring has a partial structure -X = Y <, -N = C
A heterocyclic ring having <, -CO-N <or -CS-N <;
^a and R ^b are linked together to form ring A, or are the same or different and are a hydrogen atom or a substituent on ring M;
Ring and ring B are each an optionally substituted homo- or heterocyclic ring, at least one of which is an optionally substituted heterocyclic ring; ring C may have an optionally substituted substituent; A good homo or heterocyclic ring; a ring Z is an optionally substituted ring; and n is an integer of 1 to 6. ) Is disclosed.

[0012]

At present, as a prophylactic or therapeutic agent for the above-mentioned various pathological conditions, it has an excellent antagonism to tachykinin receptor (particularly a substance P receptor antagonism), and its safety, No compound has been found that can be a sufficiently satisfactory pharmaceutical from the viewpoint of sustainability and the like. An object of the present invention is to provide a pharmaceutical composition having a superior antagonism to tachykinin receptors, particularly a substance P receptor antagonism, a tachykinin receptor antagonist, and urination, which have a different chemical structure from known compounds including the aforementioned compounds. An object of the present invention is to provide an agent for preventing or treating disorders, an agent for preventing or treating digestive organ diseases, and an agent for preventing or treating vomiting.

[0013]

Means for Solving the Problems The present inventors have the following general formula (1): (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). And a salt, hydrate and solvate thereof.

The present inventors have found that ring A is a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted aryl group, a hydroxyl group, an optionally substituted C ₁ -C ₆ alkoxy group, C ₃ -C ₁₀ cycloalkoxy group, optionally substituted C ₁ -C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted An arylmethyloxy group, a C ₃ -C ₁₀ cycloalkanoyloxy group, an optionally substituted C ₁ -C ₆ alkylthio group, an optionally substituted C ₁ -C ₆ alkylsulfinyl group, alkylsulfonyl groups of C ₁ -C ₆ optionally, an amino group, mono- or di-substituted alkyl amino group of C ₁ -C _6, also contain one to three hetero atoms 4-9 membered cyclic amino _group, alkylcarbonylamino group of C 1 ~C _6, C 1 ~C alkoxycarbonylamino group _6, C 1 -C alkylsulfonylamino group _6, optionally substituted arylsulfonyl Amino group, C ₁
-C ₆ alkylcarbonyl group, formyl group, carboxyl group, C ₁ -C ₆ alkoxycarbonyl group, mono- or di-substituted C ₁ -C ₆ alkylcarbamoyl group,
1 to 3 substituents each independently selected from a 4- to 9-membered cyclic carbamoyl group, cyano group or nitro group which may contain three heteroatoms (two adjacent substituents May be bonded to each other to form a ring), the ring B may be a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, C
Cycloalkyl group ₃ -C _10, optionally substituted aryl group, a hydroxyl group, an optionally substituted C
_{1 to} C ₆ alkoxy group, optionally substituted C ₁ to C ₆
C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethyloxy group, C ₃ -C ₁₀ cycloalkoxy group, C ₃
Cycloalkanoyl group having -C _10, optionally substituted _C 1 -C ₆ alkylthio group, a substituted alkylsulfinyl group of _C 1 -C ₆ optionally, an optionally substituted _C 1 -C ₆ alkylsulfonyl group, an amino group, mono- or alkylamino group _C 1 -C ₆ di-substituted, 1-3 cyclic amino group having 4 to 9-membered may contain a hetero _atom, C 1 -C ₆ alkylcarbonylamino _group, an alkoxycarbonylamino group of C 1 -C _6, C
Alkylsulfonylamino group ₁ -C _6, which may be substituted arylsulfonylamino _group, C 1 -C ₆ alkylcarbonyl group, a carboxyl _group, an alkoxycarbonyl group having C 1 -C _6, mono- or di-substituted C alkylcarbamoyl group ₁ -C _6, 1-3 amino cyclic carbamoyl groups 4-9 membered may contain a hetero atom, and are each independently selected from among cyano group or a nitro group 1-3
A benzene ring which may have two substituents (adjacent two substituents may be bonded to each other to form a ring), and the C ring may be substituted with a halogen atom C
Alkyl group of ₁ -C _6, a hydroxyl group, a substituted C ₁ optionally -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ alkanoyloxy group, optionally substituted aryloyl oxy group, an optionally substituted arylmethyl _group, C 3 _-C cycloalkoxy group _10, cycloalkanoyl group of C 3 _{-C 10,} an amino group, an alkyl of _C 1 -C ₆ mono- or di-substituted An amino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, a C _{1 to} C ₆ alkylcarbonylamino group, a C _{1 to} C ₆ alkoxycarbonylamino group,
₁ to ₃ alkylsulfonylamino groups, an optionally substituted arylsulfonylamino group, a cyano group or a nitro group, each independently selected from 1 to 3 substituents (two adjacent substituents) The pyridobenzothiazine derivative according to claim 1, which represents a benzene ring which may have a ring which may be bonded to each other to form a ring. I will provide a.

The present inventors have the following general formula (2)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁴Is a hydroxyl group, C₁~ C ₆An alkoxy group, benzylo
A xy group or a reactive residue, wherein ring A is a halogen atom,
May be C₁~ C₆An alkyl group of which is substituted
Aryl group, hydroxyl group, even if substituted
Good C₁~ C₆An alkoxy group of C₃~ C ₁₀The cyclo
An alkoxy group, an optionally substituted C₁~ C₆Al
Canoyloxy group, optionally substituted aryloylo
Xyl group, optionally substituted arylmethyloxy
Group, C₃~ C₁₀A cycloalkanoyloxy group, substituted
C that may be₁~ C₆Alkylthio group, substituted
C that may be₁~ C₆An alkylsulfinyl group of
Optionally substituted C₁~ C₆Alkylsulfonyl of
Group, amino group, mono- or di-substituted C₁~ C₆The alkyl of
An amino group, optionally containing 1 to 3 heteroatoms 4
A 9-membered cyclic amino group, C₁~ C₆Alkyl carboni
Ruamino group, C₁~ C₆Of the alkoxycarbonylamino
Group, C₁~ C₆Alkylsulfonylamino group, substituted
An optionally substituted arylsulfonylamino group, C₁~ C
₆Alkylcarbonyl group, formyl group, carboxyl
Group, C₁~ C₆An alkoxycarbonyl group, mono or di
Substitution C₁~ C₆Alkylcarbamoyl group of 1 to 3
4 to 9-membered cyclic carba optionally containing a heteroatom
Independent of moyl, cyano or nitro groups
1 to 3 substituents (adjacent two substituents
May be bonded to each other to form a ring)
Optionally a homo- or heterocyclic ring, the C ring is a halogen atom,
C that may be₁~ C₆Alkyl group, hydroxyl
Group, optionally substituted C₁~ C₆An alkoxy group of
Optionally substituted C₁~ C₆Alkanoyloxy
Group, an optionally substituted aryloyloxy group,
An optionally substituted arylmethyloxy group, C₃~ C₁₀
A cycloalkoxy group of C₃~ C₁₀The cycloalkano of
Yloxy group, amino group, mono- or di-substituted C₁~ C₆
Alkylamino groups containing 1 to 3 heteroatoms
A 4- to 9-membered cyclic amino group, C₁~ C₆Archi
Carbonylamino group, C₁~ C₆The alkoxy carb
Nylamino group, C₁~ C₆Of alkylsulfonylamino
Group, optionally substituted arylsulfonylamino
Group, cyano group or nitro group
1 to 3 substituents (adjacent two substituents are
To form a ring).
Benzene ring. ) Represented by pyridobenzothiazi
And derivatives, salts, hydrates and solvates thereof.

The present inventors have the following general formula (3)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁵Is(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
X is a halogen atom or OSO₂R⁶(R⁶Ha
C which may be substituted with a logene₁~ C₆An alkyl group of
An aryl group which may be substituted), and ring C is a halogen atom
Child, optionally substituted C₁~ C₆An alkyl group of
A droxyl group, an optionally substituted C₁~ C₆Al
Coxy group, optionally substituted C₁~ C₆No alkano
Yloxy group, optionally substituted aryloyloxy
Group, an optionally substituted arylmethyloxy group, C
₃~ C₁₀A cycloalkoxy group of C₃~ C₁₀No shiku
Lower alkanoyloxy group, amino group, mono- or di-substituted
C₁~ C₆Alkylamino group, 1-3 heteroatoms
A 4- to 9-membered cyclic amino group optionally containing ₁~ C
₆An alkylcarbonylamino group of C₁~ C₆Arco
Xycarbonylamino group, C₁~ C₆Alkylsulfo
Nylamino group, arylsulfonyl which may be substituted
Each independently from the amino, cyano or nitro groups.
1 to 3 substituents selected vertically (two adjacent substituents
Groups may be bonded to each other to form a ring)
Represents an optionally present benzene ring. )
Provide zothiazine derivatives or their salts, hydrates and solvates
Offer.

The present inventors have the following general formula (4)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁵Is(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
Residue, C ring is a halogen atom, C
₁~ C₆Alkyl group, hydroxyl group, substituted
May be C₁~ C₆An alkoxy group, even if it is substituted
Good C₁~ C ₆Alkanoyloxy group, substituted
An aryloyloxy group, an optionally substituted
Reel methyloxy group, C₃~ C₁₀Cycloalkoxy
Si group, C₃~ C₁₀A cycloalkanoyloxy group,
Amino group, mono- or di-substituted C₁~ C₆The alkylamino
Group, 4 to 9 members optionally containing 1 to 3 heteroatoms
A cyclic amino group of C₁~ C₆Alkylcarbonylamido
No group, C₁~ C₆An alkoxycarbonylamino group of C
₁~ C₆Alkylsulfonylamino group, substituted
An arylsulfonylamino group, a cyano group or a
1 to 3 positions independently selected from toro groups
A substituent (two adjacent substituents are bonded to each other to form a ring
Represents a benzene ring which may have
You. ) Or a pyridobenzothiazine derivative represented by
Provides salts, hydrates and solvates.

The present inventors have the following general formula (2)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁴Is a hydroxyl group, C₁~ C ₆An alkoxy group, benzylo
The xy group or the reactive residue and the ring A are each independently selected.
1 to 3 substituents (two adjacent substituents are
May form a ring together)
An aromatic or heterocyclic ring, the C ring has 1 to 3 substituents (adjacent 2
May be bonded to each other to form a ring)
The benzene ring which may be possessed is shown. )
Dobenzothiazine derivatives or their salts, hydrates and solvates
And the following general formula (5)(Where R¹And R²Are the same or different and represent a hydrogen atom or
C₁~ C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two contacting substituents are bonded to each other to form a ring,
A benzene ring which may have a benzene ring. )
Reaction of the compound or its salt, hydrate and solvate
The compound according to claim 1, or a salt thereof, hydration
And a method for producing a solvate.

The present inventors have made the following general formula (6)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁷Is a hydroxyl group, C₁~ C ₆An alkoxy group, benzylo
A xyl group,(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
X is a halogen atom or OSO₂R⁶(R⁶Ha
C which may be substituted with a logene₁~ C₆An alkyl group of
An aryl group which may be substituted), and ring C has 1 to 3
Substituents (two adjacent substituents are bonded to each other to form a ring
A benzene ring which may have
You. ) Or a pyridobenzothiazine derivative represented by
Salts, hydrates and solvates and the following general formula (7)(Where Y is a halogen atom, OSO₂R⁶(R⁶Is
), B (R⁸)₂(R⁸Is a hydroxyl group, C₁~ C₆of
Alkyl group or C₁~ C₆Represents an alkoxy group. is there
Iha R⁸May combine with each other to form a ring
No. ), MgBr or ZnCl, and the A ring are each independently
1 to 3 substituents selected (adjacent two substituents
Which may combine with each other to form a ring)
Or a homocyclic or heterocyclic ring. )
4. The pyridobenzo according to claim 1, wherein
Production of thiazine derivatives or their salts, hydrates and solvates
Provide a way.

The present inventors have the following general formula (8) (Wherein R ³ is the same or different and is a hydrogen atom or C ₁ -C
An alkyl group of ₆ , R ⁷ is a hydroxyl group, a C ₁ -C ₆ alkoxy group, a benzyloxy group, (R ¹ and R ² may be the same or different and each represent a hydrogen atom or C _1-
The C ₆ alkyl group and the ring B represent a benzene ring which may have 1 to 5 substituents (two adjacent substituents may be bonded to each other to form a ring). ) Or a reactive residue, Z is a hydroxyl group, X (X is a halogen atom or OSO
₂ R ⁶ (R ⁶ is C ₁ -C optionally substituted with halogen)
₆ alkyl groups and optionally substituted aryl groups))
Or ring A (ring A may have 1 to 3 substituents each independently selected (two adjacent substituents may be bonded to each other to form a ring) Homo or heterocyclic), P represents 0 or 1. ) Or a salt, hydrate and solvate thereof represented by the following general formula (9) by oxidation: (Wherein R ³ , R ⁷ and Z are the same as above, and m represents p + 1 or 2) or a method for producing a salt, hydrate or solvate thereof.

The present inventors have proposed a tachykinin receptor antagonist comprising a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition. I will provide a.

The present inventors have proposed a substance P receptor antagonist comprising a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition. Provide the agent.

The inventors of the present invention have frequent urination and urinary incontinence characterized by containing a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. And other agents for preventing or treating dysuria including bladder dysfunction.

The present inventors have proposed a ulcerative colitis comprising as a pharmaceutical composition a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof, Provided is an agent for preventing or treating digestive diseases including Crohn's disease.

The present inventors have made it clear that a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof is contained as a pharmaceutical composition, which is characterized by X-ray irradiation, It is intended to provide a therapeutic agent, an agent for preventing or treating vomiting induced by pregnancy, migraine, postoperative illness, gastrointestinal motility depression, side effects of drug administration, and the like.

The present inventors are concerned with tachykinin, which comprises a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. A therapeutic agent for asthma, cough, pain, migraine, toothache, rheumatoid arthritis and the like is provided.

Here, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. C ₁ -C ₆
The alkyl group is a methyl group, an ethyl group, a propyl group,
It means an isopropyl group, a t-butyl group, a hexyl group and the like. The C ₁ -C ₆ alkoxy group means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a t-butoxy group, a hexyloxy group, or the like. The cycloalkoxy group of C ₃ -C _10, cyclopropyl group, cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group and the like. The C ₃ -C ₁₀ cycloalkanoyloxy group means a cyclopropanoyloxy group, a cyclobutanoyloxy group, a cyclopentanoyloxy group, a cyclohexanoyloxy group, or the like. C
₁ The alkylcarbonyl group -C _6, means acetyl group, a propionyl group, a butyryl group. The C ₁ -C ₆ alkoxycarbonyl group is a methoxycarbonyl group,
Ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group,
It means a hexyloxycarbonyl group or the like. The mono- or di-substituted C _{1 to} C ₆ alkylcarbamoyl group means a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, a t-butylcarbamoyl group, a hexylcarbamoyl group, a dimethylcarbamoyl group, or a diethylcarbamoyl group. , Dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, dihexylcarbamoyl and the like. 4 to which may contain 1 to 3 heteroatoms
The 9-membered cyclic carbamoyl group includes an azetidinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidinylcarbonyl group, a 4-methylpiperidinylcarbonyl group, a morpholinylcarbonyl group, a thiomorpholinylcarbonyl group,
It means piperazinylcarbonyl group, 4-methylpiperazinylcarbonyl group and the like. The C ₁ -C ₆ alkylthio group includes a methylthio group, an ethylthio group, a propylthio group,
It means an isopropylthio group, a t-butylthio group, a hexylthio group or the like. The C ₁ -C ₆ alkylamino group is
Methylamino group, ethylamino group, propylamino group,
It means isopropylamino group, t-butylamino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dihexylamino group and the like. A 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms includes an azetidino group, a pyrrolidino group, a piperidino group,
-Methylpiperidino group, morpholino group, thiomorpholino group, piperazino group, 4-methylpiperazino group and the like. The C ₁ -C ₆ alkylcarbonylamino group means an acetylamino group, a propionylamino group, a butyrylamino group, or the like. The C ₁ -C ₆ alkoxycarbonylamino group means a methoxycarbonylamino group, an ethoxycarbonylamino group, a t-butoxycarbonylamino group, a hexyloxycarbonylamino group, or the like.
The C ₁ -C ₆ alkylsulfonylamino group means a methylsulfonylamino group, an ethylsulfonylamino group and the like. The arylsulfonylamino group means a phenylsulfonylamino group, a 4-methylphenylsulfonylamino group, a naphthylsulfonylamino group, and the like. The homocyclic ring of the ring A means a benzene ring, a naphthalene ring or the like. The heterocyclic ring of the ring A is a group containing 1 to 3 hetero atoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom.
Membered or 6-membered aromatic monocyclic heterocycle, or 9- or 1-membered
It means a 0-membered fused aromatic heterocycle. The optionally substituted C ₁ -C ₆ alkyl group includes a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, a mono- or di-substituted C ₁ -C ₆ alkyl group. _{1 to} C
₆ alkylamino group, 1-3 may contain a hetero atom 4-9 membered cyclic amino group, formylamino _group, alkylcarbonylamino group of _C 1 ~C _6, C 1 ~
1 to 5 selected from a C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and the like.
Means a C ₁ -C ₆ alkyl group which may have one or more substituents. The optionally substituted C ₁ -C ₆ alkoxy group means a halogen atom, a hydroxyl group, a C ₁ -C 6
₆ alkoxy groups, C ₁ -C ₆ alkylthio groups, amino groups, mono- or di-substituted C ₁ -C ₆ alkylamino groups, 4- to 9-membered optionally containing 1 to 3 heteroatoms ₁ to 5 selected from a cyclic amino group, a formylamino group, a C _{1 to} C ₆ alkylcarbonylamino group, a C _{1 to} C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and the like. It means a C ₁ -C ₆ alkoxy group which may have a substituent. The optionally substituted C ₁ -C ₆ alkanoyloxy group means a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, a mono- or di-substituted group. alkylamino groups C ₁ ~C _6, 1~3
4- to 9-membered cyclic amino group, formylamino group, C ₁ -C ₆ alkylcarbonylamino group, C ₁ -C ₆ alkylsulfonylamino group, which may be substituted C which may have 1 to 5 substituents selected from good arylsulfonylamino groups and the like
_{1 to} C ₆ alkanoyloxy group (acetyloxy group,
(Propionyloxy group, isopropionyloxy group, hexanoyloxy group, etc.). The aryloyloxy group which may be substituted is a halogen atom, C ₁ -C
₆ alkyl groups, hydroxyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ alkylthio groups, amino groups, mono- or di-substituted C ₁ -C ₆ alkylamino groups, 1-3 hetero groups A 4- to 9-membered cyclic amino group which may contain an atom, a formylamino group, a C ₁ -C ₆ alkylcarbonylamino group, a C ₁ -C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonyl An aryloyloxy group which may have 1 to 5 substituents selected from an amino group and the like (benzoyloxy group, naphthyloxy group, pyridyloxy group, pyrimidyloxy group, quinolyloxy group, indolyloxy group, etc.) Means The optionally substituted arylmethyloxy group includes a halogen atom, a C ₁ -C ₆ alkyl group, a hydroxyl group,
Alkoxy groups of ₁ -C _6, an alkylthio group of C 1 -C _6, an amino group, an alkylamino group of _C 1 -C ₆ mono- or di-substituted, may contain one to three hetero atoms 4
A 9-membered cyclic amino group, a formylamino group, C ₁ -C ₆
An arylmethyloxy group which may have 1 to 5 substituents selected from an alkylcarbonylamino group, a C _{1 to} C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and the like (Phenylmethyloxy group, naphthylmethyloxy group, pyridylmethyloxy group, quinolylmethyloxy group, indolylmethyloxy group, etc.). The optionally substituted arylsulfonylamino group includes a halogen atom, C ₁ -C ₆
Alkyl group, a hydroxyl _group, an alkoxy group of C 1 -C _6, an alkylthio group of C 1 -C _6, an amino group, an alkylamino group of _C 1 -C ₆ mono- or di-substituted, 1-3 heteroatoms A 4- to 9-membered cyclic amino group, a formylamino group, a C _{1 to} C ₆ alkylcarbonylamino group, a C _{1 to} C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino It means an arylsulfonylamino group optionally having 1 to 5 substituents selected from groups and the like. What is a ring in which two adjacent substituents may be bonded to each other to form And so on.

The aryl group which may be substituted includes a halogen atom, a C ₁ -C ₆ alkyl group, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, mono- or alkylamino group _C 1 -C ₆ di-substituted, 1-3 cyclic amino group having 4 to 9-membered may contain a hetero atom, formylamino _{group, C} 1 ~
An aryl group optionally having 1 to 5 substituents selected from a C ₆ alkylcarbonylamino group, a C _{1 to} C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and the like; (Phenyl group, naphthyl group, etc.). The optionally substituted alkylthio group includes a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, a mono- or di-substituted C ₁ -C ₆ alkyl. Amino group,
A 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, a formylamino group, a C _{1 to} C ₆ alkylcarbonylamino group, a C _{1 to} C ₆ alkylsulfonylamino group, And an alkylthio group which may have 1 to 5 substituents selected from an optionally substituted arylsulfonylamino group and the like. The alkylsulfinyl group which may be substituted includes a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, a mono- or di-substituted C ₁ -C ₆ . Alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, formylamino group, C
_It may have 1 to 5 substituents selected from ₁ to ₆ alkylcarbonylamino groups, ₁ to ₆ alkylsulfonylamino groups, and optionally substituted arylsulfonylamino groups. It means an alkylsulfinyl group (methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, etc.). The optionally substituted alkylsulfonyl group includes a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, a mono- or di-substituted C ₁ -C ₆ . Alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, formylamino group, C ₁ to
Alkylcarbonylamino group C _6, C ₁ -C alkylsulfonylamino group _6, 1-5 substituents may alkylsulfonyl optionally having selected from optionally substituted arylsulfonylamino group Group (methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, etc.). The reactive residue is a halogen atom, 1-
It means an imidazolyl group, a 4-nitrophenoxy group, an imidoyloxy succinate group and the like. The C ₁ -C ₆ alkyl group which may be substituted with a halogen means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl which may be substituted with 1 to 13 fluorine atoms or chlorine atoms. Group, hexyl group and the like. The ring which may be formed by bonding to each other of R ⁸ includes —O (CH ₂ ) ₂ O— and —O
CH (Me) CH (Me) O -, - OC (Me) 2 C (Me) 2
Means O- or -O (CH _{2) 3} O- or the like.

As a preferred compound of the present invention, N-
[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-N-methyl-5-oxo-7-phenyl-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide, N- [3,5-bis ( Trifluoromethyl) benzyl] -2,3-dihydro-7- (3-methoxyphenyl) -N-methyl-5-
Oxo-5H-pyrido [1,2,3-de] -1,4-
Benzothiazine-6-carboxamide, N- [3,5-
Bis (trifluoromethyl) benzyl] -7- (2,4
-Dichlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de]-
1,4-benzothiazine-6-carboxamide, N-
[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-N-methyl-5-oxo-7-phenyl-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide, N- [ 3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-5 -Oxo-7-phenyl-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
-Carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [ 1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide, N
-[3,5-bis (trifluoromethyl) benzyl]-
7- (2,4-dichlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3
-De] -1,4-benzothiazine-6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -7- (2,4-dichlorophenyl) -2,3-dihydro- N-methyl-5-oxo-5
H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide, N-
[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-7- (3-fluorophenyl) -N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide;
N- [3,5-bis (trifluoromethyl) benzyl]
-7- (3-chlorophenyl) -2,3-dihydro-N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide;
N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-N-methyl-7- (3-nitrophenyl) -5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide;
7- (3-aminophenyl) -N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide;
N- [3,5-bis (trifluoromethyl) benzyl]
-7- (3,5-dichlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,
3-de] -1,4-benzothiazine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -7- [3,5-bis (trifluoromethyl) phenyl] -2,3 -Dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl]- 2,3-dihydro-N-methyl-7- (4-methylphenyl) -5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide, N- [3 , 5-Bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzothiazine-6 Rubokisamido, N-[3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-fluorophenyl) -N- methyl-5-
Oxo-5H-pyrido [1,2,3-de] -1,4-
Benzothiazine-6-carboxamide, N- [3,5-
Bis (trifluoromethyl) benzyl] -7- (4-chlorophenyl) -2,3-dihydro-N-methyl-5-
Oxo-5H-pyrido [1,2,3-de] -1,4-
Benzothiazine-6-carboxamide, N- [3,5-
Bis (trifluoromethyl) benzyl] -7- (3-chloro-4-fluorophenyl) -2,3-dihydro-N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide;
N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-N-methyl-7- (4-methyl-
3-nitrophenyl) -5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-
Carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (2-methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3 -De] -1,4-benzothiazine-6
-Carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-
7- (1-Naphthyl) -5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
Carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-formylphenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3 -De] -1,4-benzothiazine-6
-Carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-
5-oxo-5H-pyrido [1,2,3-de] -1,
4-benzothiazine-7- [3- (trifluoromethyl) phenyl] -6-carboxamide, N- [3,5-
Bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (3-methylphenyl) -5
Oxo-5H-pyrido [1,2,3-de] -1,4-
Benzothiazine-6-carboxamide, N- [3,5-
Bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-fluorophenyl) -N-methyl-5
-Oxo-5H-pyrido [1,2,3-de] -1,4
-Benzothiazine-6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H -Pyrido [1, 2, 3
-De] -1,4-benzothiazine-6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-
7- (3-nitrophenyl) -5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
-Carboxamide-1-oxide, 7- (3-aminophenyl) -N- [3,5-bis (trifluoromethyl)
Benzyl] -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide, N-
[3,5-bis (trifluoromethyl) benzyl] -7
-(3,5-dichlorophenyl) -2,3-dihydro-
N-methyl-5-oxo-5H-pyrido [1,2,3-
de] -1,4-Benzothiazine-6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -7- [3,5-bis (trifluoromethyl) phenyl] -2 , 3-Dihydro-N-methyl-
5-oxo-5H-pyrido [1,2,3-de] -1,
4-benzothiazine-6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4-methylphenyl) -5-oxo -5H-pyrido [1, 2, 3
-De] -1,4-benzothiazine-6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-
7- (4-methoxyphenyl) -5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-
6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-fluorophenyl) -N-methyl-5-
Oxo-5H-pyrido [1,2,3-de] -1,4-
Benzothiazine-6-carboxamide-1-oxide,
N- [3,5-bis (trifluoromethyl) benzyl]
-7- (4-Chlorophenyl) -2,3-dihydro-N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide-
1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chloro-4-fluorophenyl) -2,3-dihydro-N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide, N-
[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-N-methyl-7- (4-methyl-3
-Nitrophenyl) -5-oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-
(2-methoxyphenyl) -N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide, N-
[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-N-methyl-7- (1-naphthyl)
-5-oxo-5H-pyrido [1,2,3-de]-
1,4-benzothiazine-6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-formylphenyl) -N-methyl-5 -Oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-5-oxo -5H-pyrido [1,2,3-de]
-1,4-benzothiazine-7- [3- (trifluoromethyl) phenyl] -6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro- N-methyl-7- (3-methylphenyl) -5-oxo-5H-pyrido [1,2,3
-De] -1,4-benzothiazine-6-carboxamide-1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-fluorophenyl) -N -Methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-
6-carboxamide-1,1-dioxide, N- [3,
5-bis (trifluoromethyl) benzyl] -7- (3
-Chlorophenyl) -2,3-dihydro-N-methyl-
5-oxo-5H-pyrido [1,2,3-de] -1,
4-benzothiazine-6-carboxamide-1,1-dioxide, N- [3,5-bis (trifluoromethyl)
Benzyl] -2,3-dihydro-N-methyl-7- (3
-Nitrophenyl) -5-oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide, N- [3,5-bis (trifluoromethyl) benzyl] -7- (3,5-dichlorophenyl) -2 , 3-Dihydro-N-methyl-5
-Oxo-5H-pyrido [1,2,3-de] -1,4
-Benzothiazine-6-carboxamide-1,1-dioxide, N- [3,5-bis (trifluoromethyl) benzyl] -7- [3,5-bis (trifluoromethyl)
Phenyl] -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide, N- [3 , 5-Bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4-methylphenyl) -5-oxo-5H-pyrido [1,2,3
-De] -1,4-benzothiazine-6-carboxamide-1,1-dioxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-
(4-methoxyphenyl) -N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide, N
-[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-7- (4-fluorophenyl) -N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide-
1,1-dioxide, N- [3,5-bis (trifluoromethyl) benzyl] -7- (4-chlorophenyl)-
2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-
6-carboxamide-1,1-dioxide, N- [3,
5-bis (trifluoromethyl) benzyl] -7- (3
-Chloro-4-fluorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3
-De] -1,4-benzothiazine-6-carboxamide-1,1-dioxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4 -Methyl-3-nitrophenyl) -5-
Oxo-5H-pyrido [1,2,3-de] -1,4-
Benzothiazine-6-carboxamide-1,1-dioxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (2-methoxyphenyl) -N-methyl-5-oxo -5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4- (Formylphenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide, N- [3,5-bis ( Trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-5-oxo-7
-[3- (trifluoromethyl) phenyl] -5H-pyrido [1,2,3-de] -1,4-benzothiazine-
6-carboxamide-1,1-dioxide, N- [3,
5-bis (trifluoromethyl) benzyl] -2,3-
Dihydro-N-methyl-7- (3-methylphenyl)-
5-oxo-5H-pyrido [1,2,3-de] -1,
Examples thereof include 4-benzothiazine-6-carboxamide-1-oxide.

When the compound of the present invention forms a salt, hydrochloric acid,
Hydrobromic acid, sulfuric acid, inorganic acids such as nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid,
Examples thereof include pharmacologically acceptable salts with organic acids such as citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid.

The compounds of the present invention or salts thereof include optically active isomers, stereoisomers and rotamers as well as racemic isomers.

The compound of the present invention can be produced by various synthetic methods. Next, typical production steps of the compound of the present invention and a salt thereof will be described.

(First Step) In this step, compound (I) (R
³ and C rings have the same meanings as defined above) with the compound (II) ^{(R 9} are the same or different alkyl group of _C 1 -C _6, by reacting a benzyl group), the compound ^{(III) (R 3, R} 9 and Ring C is the same as described above). This reaction is carried out at 100 to 300 ° C., preferably 150 to 150 equivalents using 1 to 20 equivalents, preferably 1 to 5 equivalents of compound (II) relative to compound (I).
Performed at 250 ° C. When a solvent is used, an inert solvent that does not participate in the reaction, for example, xylene, mesitylene,
Nitrobenzene, diphenyl ether, dautherm (a mixture of diphenyl ether and biphenyl) and the like are used.

(Second Step) This step is carried out by reacting the compound (III)
(R ³ , R ⁹ and the ring C are the same as described above)
Is the same as described above), and compound (IV) (X, R ³ ,
R ⁹ and the C ring are the same as described above). In this step, for example, when X is a chlorine atom, a phosphating agent such as triphenylphosphine, tributylphosphine or triphenoxyphosphine is used as a chlorinating agent, and carbon tetrachloride, N
-Using chlorosuccinimide or chlorine, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride. When a solvent is used, an inert solvent that does not participate in the reaction, for example, N, N-dimethylformamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, pyridine and the like are used. This reaction proceeds smoothly at a temperature from room temperature to the boiling point of the chlorinating agent or, when a solvent is used, the boiling point of the solvent. When X is a bromine atom, the reaction can be carried out in the same manner as in the chlorination using the corresponding brominating agent. When X is OSO ₂ R ⁶ (R ⁶ is the same as described above), the sulfonating reagent used in this reaction includes methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonic acid and trifluoromethanesulfonic acid. Romethanesulfonyl chloride,
N-phenyltrifluoromethanesulfonylimide or the like is used, and the reaction is carried out in a solvent in the presence of a base such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, butyllithium, lithium diisopropylamide, and the like. . As the solvent, an inert solvent which does not participate in the reaction, preferably dichloromethane, tetrahydrofuran or the like is used. The reaction is at -78 ° C to 100 ° C, preferably at -3 ° C.
0 ° C to 80 ° C.

(Third Step) In this step, compound (IV)
(X, R ³ , R ⁹ and the C ring are the same as described above) and the compound (V) (the Y and A rings are the same as described above) by a cross-coupling reaction in the presence of a transition metal catalyst such as a palladium or nickel complex to give the compound (VI) A step of producing (R ³ , R ⁴ and Ring A are the same as described above). This reaction is preferably performed using an inert solvent not involved in the reaction,
For example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, ethanol, water and the like can be exemplified. These solvents are used alone or in a mixture at an arbitrary ratio. Examples of the palladium complex used in this reaction include palladium chloride, palladium acetate, acetylacetonato palladium, and tetrakis (triphenylphosphine) palladium. Examples of the nickel complex used in this reaction include bis (acetylacetonato) nickel, bis (1,5-cyclooctadiene) nickel, and tetrakis (triphenylphosphine) nickel. These palladium or nickel complexes are used in an amount of 0.001 to 1 equivalent, preferably 0.01 equivalent, relative to compound (IV).
It is used in the range of ０．１0.1 equivalent. When a ligand for a palladium or nickel complex is used in this reaction, triphenylphosphine, tri-o-tolylphosphine, tri-2-furylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,1′-bis ( Examples thereof include (diphenylphosphino) ferrocene and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl. These ligands are used in an amount of 0.2 to 5 equivalents, preferably 0.3 to 3 equivalents, based on the palladium or nickel complex.
Used in the range of equivalents. X of compound (IV) is OSO ₂
In the case of R ⁶ , copper iodide or lithium chloride can be used together with the palladium or nickel complex, if necessary. This reaction is preferably performed in the presence of a suitable base, for example, organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, carbonate Examples thereof include inorganic bases such as calcium, cesium carbonate, and tripotassium phosphate. These bases are used in the range of 1 to 20 equivalents, preferably 2 to 10 equivalents, relative to compound (IV). The cross-coupling reaction in this step can be performed at room temperature to 150 ° C, preferably at 50 to 120 ° C. When a compound in which Y of compound (V) is not B (R ⁸ ) ₂ is used as a raw material in the cross-coupling reaction of this step, compound (IV) or compound (V) (where Y is B (R ⁸ ) Not ₂ ) and HB
Compound (IV) (X is B (R ⁸ ) ₂ ) or Compound (V) (Y is B (R ⁸ ) ₂ ) obtained by reacting (R ⁸ ) ₂ or (B (R ⁸ ) ₂ ) ₂ To compound (V) (where Y is not B (R ⁸ ) ₂ ) or compound (IV) to produce compound (VI). The compound (IV) (X is B (R ⁸ )
₂ ) or compound (V) (Y is B (R ⁸ ) ₂ ) and the A ring is the same as described above, and may be subjected to the next step without isolation or purification. It is also possible to provide.

(Fourth Step) In this step, compound (VI) (R
³ , R ⁴ and ring A are the same as described above) and compound (VII) (R
¹ , R ² and B are the same as described above) to produce a compound (VIII) (R ¹ , R ² , R ³ , A ring, B ring and C ring are the same). . As a condensing agent used when R ⁴ is a hydroxyl group in the condensation reaction of this step, dicyclohexylcarbodiimide (DCC),
Examples thereof include ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and dimethylimidazolinium chloride (DMC), which are added in a solid state or as a solution in a suitable solvent. When a base is used in the present condensation reaction, an alkali carbonate such as sodium hydrogen carbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicyclo [5.4.0] -7-undecene, pyridine, Dimethylaminopyridine or 1,8
Examples include tertiary amines such as -bis (dimethylamino) naphthalene. As the solvent used in the present condensation reaction, an inert solvent not involved in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, ethyl acetate, Dichloromethane or the like is used. This condensation reaction is-
It proceeds smoothly at 20 ° C to 80 ° C. In the condensation reaction of this step, R ⁴ is a reactive residue (for example, a halogen atom, 1-
Carboxylic acid halides represented by imidazolyl group, 4-nitrophenoxy group, imidoyloxy succinate group, etc., imidazolides of carboxylic acids, active esters of carboxylic acids, mixed acid anhydrides of carboxylic acids (for example, with ethyl carbonate) Anhydrides, anhydrides with isobutyl carbonate, etc.) or symmetric acid anhydrides, in the presence of organic bases such as triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine, and inorganic bases such as sodium hydrogen carbonate and potassium carbonate. Or in the absence of N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, ethyl acetate, toluene, dichloromethane, etc.
It can be carried out by treating at 80 ° C. for 30 minutes to 48 hours. In the condensation reaction of this step, R ⁴ is C ₁
Alkoxy group -C _6, when the ester residue such as benzyl group, trimethylaluminum or tetraisopropoxytitanium in the presence of such titanium, or p- toluenesulfonic acid or the like acid catalyst, or sodium methoxide, potassium -t- Butoxide, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile in the presence of a base such as sodium hydride,
30 ° C. in a solvent such as tetrahydrofuran, dioxane, toluene, xylene, dichloromethane at room temperature to 150 ° C.
It can be carried out by treating for from 48 minutes to 48 hours.

As shown in the fifth step, compound (IX)
Compound (X) (R ³ , R ³ , Z and m are the same as described above) can be produced by oxidizing (R ³ , R ³ , Z and p are the same as described above). This oxidation reaction is carried out by a known method (for example, “Experimental Chemistry Lecture, 4th edition, Vl, 350-3
72, (1991), Maruzen ").

As shown in the sixth step, compound (XIII)
Can also be produced from compound (XI) and compound (XII). In this step, compound (XII)
Using 1 to 10 equivalents of N, N-dimethylformamide, N, N-dimethylacetamide in the presence of an acid catalyst such as p-toluenesulfonic acid or a base such as sodium methoxide, potassium-t-butoxide and sodium hydride; In a solvent such as dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, etc.
It can be carried out by treating at 150 ° C. for 30 minutes to 48 hours. Compound (VIII) can be produced from compound (XIII) obtained according to the method described above.

As shown in the seventh step, compound (XV) can also be produced from compound (XIV) and compound (XII). In this step, the compound (XII) is used in an amount of 1 to 10 equivalents to the compound (XIV), and an acid catalyst such as p-toluenesulfonic acid or a base such as sodium methoxide, potassium-t-butoxide, or sodium hydride is used. In a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, etc.
It can be carried out by treating at 150 ° C. for 30 minutes to 48 hours. Compound (VIII) can be produced from the obtained compound (XV) according to the method described above.

The compound (1) of the present invention can be isolated and purified by usual separation means (eg, extraction, recrystallization, distillation, chromatography, etc.). When the obtained compound forms a salt, various salts can be produced by an ordinary method or a method analogous thereto (eg, neutralization).

The compound (1) of the present invention or a salt thereof can be used alone or together with one or more pharmaceutically acceptable auxiliaries as a pharmaceutical composition, and a pharmacologically acceptable carrier or excipient ( For example, starch, lactose, calcium phosphate, calcium carbonate, etc.), lubricants (eg, magnesium stearate, calcium stearate talc,
Stearic acid, etc.), binders (eg, starch, crystalline cellulose, carboxymethylcellulose, gum arabic, polyvinylpyrrolidone, alginic acid, etc.), disintegrants (eg, talc, calcium carboxymethylcellulose, etc.), diluents (eg, saline, glucose,
Mannitol, aqueous solution of lactose, etc.)
It can be administered orally or parenterally in the form of tablets, capsules, granules, powders, fine granules, ampoules, injections and the like by usual methods. The dose varies depending on the type of the compound (1) of the present invention or a salt thereof, the administration route, the age of the patient, symptoms, and the like. ~ 3
00 mg / kg / day. The administration is performed, for example, once or several times a day.

[0042]

The compounds of the present invention and salts thereof have excellent tachykinin receptor antagonism, have low toxicity, and are safe as pharmaceuticals. Therefore, the compounds of the present invention and salts thereof are useful as pharmaceutical compositions, tachykinin receptor antagonists, therapeutic agents for dysuria, and the like. The usefulness of the present invention is shown by the following experimental examples and examples, but the present invention is not limited to the experimental examples and examples.

[0043]

[Experimental method] NK1 receptor antagonism The method of Dion et al. (“Life Scie
vol. 41, p. 2269 (1987)). After bruising the guinea pig, blood was removed from the carotid artery and the ileum was removed. The removed ileum is placed in a Magnus tube.
g and suspended. Specimen responses were recorded isotonic. The nutrient solution uses Tyrode solution, O ₂ 95%,
A mixed gas of 5% CO ₂ was passed, and the liquid temperature was 32 ° C. The experiment started after the guinea pig ileum was suspended in a Magnus tube and allowed to equilibrate for 20 minutes. The concentration-response curve of substance P in the absence of the test compound was used as a control. The NK1 receptor antagonism of the test compound was determined from a concentration-response curve of substance P, which was pretreated with at least three concentrations of the test compound for 10 minutes and then applied cumulatively. pA ₂ value Schild method ( "British Journal of Pharmacology (Brit. J. Pharmacol.)" 1
4, p. 48 (1959)), and the results are shown in Table 1. The composition of the Tyrode solution was as follows. NaCl; 136.9, KCl; 2.7, CaCl
_{2 · 2H 2 O; 2.5,} MgCl 2 · 6H 2 O; 1.
_{0, NaH 2 PO 4 · 2H} 2 O; 0.4, NaHC
O ₃ ; 11.9, glucose; 11.1 (mM)

[0044]

【Example】

[Table 1]Example No. pA ₂ value (nM)  10 42.1 11 25.2

Embodiment 1 7-chloro-2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-
6-carboxylic acid ethyl ester (123.9 mg, 0.40 mmol) and tetrakistriphenylphosphine palladium (18.5 m
g, 16.0 μmol, 0.04 eq.) was dissolved in 5 ml of benzene and 1 ml of a 2 M aqueous sodium carbonate solution, and phenylboric acid (146.3 mg, 1.2
mmol) in 1,4-dioxane (2 ml) was added and heated to reflux. On the way, tetrakistriphenylphosphine palladium (18.5 mg, 16.0 μmol, 0.04 eq.) Was added, and the mixture was refluxed for 10 hours. Water and methylene chloride were added to the reaction solution, and the mixture was extracted three times with methylene chloride. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (methylene chloride: ethyl acetate).
20: 1) to give colorless crystalline 2,3-dihydro-5-oxo-7-phenyl-5H-pyrido [1,2,3-d
e] -1,4-Benzothiazine-6-carboxylic acid ethyl ester (116.6 mg, 83%) was obtained. EIMS m / z: 351 (M ⁺ )

Embodiment 2 In the same manner as in Example 1, 7-chloro-2,3-dihydro-5-oxo-5H-pyrido [1,2,3-d
e] 1,3-benzothiazine-6-carboxylic acid ethyl ester (309.8 mg, 1.0 mmol) and 3-methoxyphenyl boric acid (303.9 mg, 2.0 mmol) were converted to yellow oily substance, 2,3-dihydro-7- (3 -Methoxyphenyl) -5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxylic acid ethyl ester (341.9 mg, 90%)
I got EIMS m / z: 381 (M ⁺ )

Embodiment 3 In the same manner as in Example 1, 7-chloro-2,3-dihydro-5-oxo-5H-pyrido [1,2,3-d
e] pale yellow amorphous 7- (2,4-dichlorophenyl) from 1,4-benzothiazine-6-carboxylic acid ethyl ester (309.8 mg, 1.0 mmol) and 2,4-dichlorophenyl boric acid (381.6 mg, 2.0 mmol) -2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de]-
1,4-benzothiazine-6-carboxylic acid ethyl ester (372.5 mg, 89%) was obtained. EIMS m / z: 419 (M ⁺ )

Embodiment 4 In the same manner as in Example 1, 7-chloro-2,3-dihydro-5-oxo-5H-pyrido [1,2,3-d
e] Colorless crystals of 2,4-benzothiazine-6-carboxylic acid ethyl ester-1,1-dioxide (136.7 mg, 0.40 mmol) and phenylboric acid (146.3 mg, 1.2 mmol).
3-dihydro-5-oxo-7-phenyl-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
-Carboxylic acid ethyl ester-1,1-dioxide (10
9.7 mg, 72%). EIMS m / z: 383 (M ⁺ )

Embodiment 5 In the same manner as in Example 1, 7-chloro-2,3-dihydro-5-oxo-5H-pyrido [1,2,3-d
e] Colorless crystalline 2,3-dihydrochloride from 1,4-benzothiazine-6-carboxylic acid ethyl ester-1,1-dioxide (136.7 mg, 0.40 mmol) and 3-methoxyphenyl boric acid (182.4 mg, 1.2 mmol) -7- (3-Methoxyphenyl) -5-oxo-5H-pyrido [1,2,3-de]
-1,4-Benzothiazine-6-carboxylic acid ethyl ester-1,1-dioxide (122.7 mg, 74%) was obtained. EIMS m / z: 413 (M ⁺ )

Embodiment 6 2,3-dihydro-5-oxo-7-phenyl-5H-
Pyrid [1,2,3-de] -1,4-benzothiazine-6-carboxylic acid ethyl ester (110.8 mg, 0.315 mmol)
And potassium hydroxide (88.4 mg, 1.58 mmol, 5 eq.) Were dissolved in ethanol (4.5 ml) -water (0.5 ml) and heated under reflux for 3 hours. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, extracted three times with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off. 0.5 ml of thionyl chloride was added to the obtained residue,
The mixture was stirred at room temperature for 0.5 hours. The residue obtained by distilling thionyl chloride was dissolved in 3 ml of methylene chloride, and 0.5 ml of triethylamine was dissolved.
And N-methyl-3,5-bis (trifluoromethyl)
0.081 ml of benzylamine was added, and the mixture was stirred for 0.5 hour. Water and methylene chloride were added to the reaction solution, and the mixture was extracted three times with methylene chloride. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate 20: 1). The obtained crystals were washed with hexane to give N- colorless crystals.
[3,5-bis (trifluoromethyl) benzyl]-
2,3-Dihydro-N-methyl-5-oxo-7-phenyl-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (135.3 mg, 76%) was obtained. . mp 177-180 ℃ _Anal:. Calculated C 59.78% as _{C 28 H 20 F 6 N 2} O 2 S,
H 3.58%, N 4.98%; found C 59.85%, H 3.50%, N 5.07
% EIMS m / z: 562 (M ⁺ )

Embodiment 7 In the same manner as in Example 6, 2,3-dihydro-7-
(3-methoxyphenyl) -5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
Carboxylic acid ethyl ester (341.9 mg, 0.896 mmol) and N-
From 0.23 ml of methyl-3,5-bis (trifluoromethyl) benzylamine, a light brown amorphous N- [3,5-
Bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-methoxyphenyl) -N-methyl-5
-Oxo-5H-pyrido [1,2,3-de] -1,4
-Benzothiazine-6-carboxamide (466.7 mg, 89%)
I got EIMS m / z: 592 (M ⁺ )

Embodiment 8 According to a method similar to that in Example 6, 7- (2,4-dichlorophenyl) -2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-
6-carboxylic acid ethyl ester (360.0 mg, 0.857 mmol) and
From 0.22 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine, N- [3,5
-Bis (trifluoromethyl) benzyl] -7- (2,
4-dichlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de]-
1,4-benzothiazine-6-carboxamide (477.0 m
g, 88%). EIMS m / z: 630 (M ⁺ )

Embodiment 9 In the same manner as in Example 6, 2,3-dihydro-5-
Oxo-7-phenyl-5H-pyrido [1,2,3-d
e] with 1,4-benzothiazine-6-carboxylic acid ethyl ester-1,1-dioxide (109.7 mg, 0.286 mmol)
From 0.074 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine, colorless crystals of N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-5- Oxo-7-phenyl-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
-Carboxamide-1,1-dioxide (26.3 mg, 15%)
I got EIMS m / z: 594 (M ⁺ )

Embodiment 10 In the same manner as in Example 6, 2,3-dihydro-7-
(3-methoxyphenyl) -5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
Carboxylic acid ethyl ester-1,1-dioxide (122.7
mg, 0.297 mmol) and 0.076 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine.
-[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-7- (3-methoxyphenyl) -N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide-
1,1-dioxide (33.4 mg, 18%) was obtained. EIMS m / z: 624 (M ⁺ )

Embodiment 11 N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-N-methyl-5-oxo-7-phenyl-5H-pyrido [1,2,3-de] -1,4-
Benzothiazine-6-carboxamide (68.4 mg, 0.122 mm
ol) was dissolved in 2 ml of methylene chloride, m-chloroperbenzoic acid (23.1 mg, 0.134 mmol) was added under ice cooling, and the mixture was stirred for 3 hours. m
-Chloroperbenzoic acid (5.0 mg, 0.029 mmol) was added, and the mixture was stirred for 2 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol: acetone 20: 1: 1) to give a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-. Dihydro-N-methyl-5-oxo-7-phenyl-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (70.5 mg, 100%) was obtained. EIMS m / z: 578 (M ⁺ )

Embodiment 12 According to a method similar to that in Example 11, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-methoxyphenyl) -N-methyl-5-oxo-5H- Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (116.5 mg, 0.2 mmol)
To N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3
-Methoxyphenyl) -N-methyl-5-oxo-5H
-Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (118.4 mg, 99%)
I got FABMS m / z: 609 (M + H ⁺ )

Embodiment 13 By a method similar to that in Example 11, N- [3,5-bis (trifluoromethyl) benzyl] -7- (2,4-dichlorophenyl) -2,3-dihydro-N-methyl-5
-Oxo-5H-pyrido [1,2,3-de] -1,4
-Benzothiazine-6-carboxamide (126.3 mg, 0.2 m
mol) to colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -7- (2,4-dichlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [ 1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (112.8
mg, 87%). EIMS m / z: 646 (M ⁺ )

Embodiment 14 N- [3,5-bis (trifluoromethyl) benzyl]
-7- (2,4-dichlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1, 2,
3-de] -1,4-Benzothiazine-6-carboxamide (144.0 mg, 0.228 mmol) was dissolved in 2 ml of methylene chloride, m-chloroperbenzoic acid (86.6 mg, 0.502 mmol) was added under ice cooling, and the mixture was stirred for 3 hours. did. m-chloroperbenzoic acid (43.3 mg,
(0.251 mmol) was added twice and stirred for 6 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate 20: 1) to give a colorless amorphous N- [3,5
-Bis (trifluoromethyl) benzyl] -7- (2,
4-dichlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de]-
1,4-benzothiazine-6-carboxamide-1,1
-Dioxide (70.5 mg, 100%) was obtained. EIMS m / z: 662 (M ⁺ )

Reference Example 1 2,3-dihydro-7-hydroxy-5-oxo-5H
-Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxylic acid ethyl ester (514.7 mg, 1.77 mmol)
Was dissolved in 150 ml of methylene chloride, m-chloroperbenzoic acid (670.7 mg, 3.89 mmol) was added under ice cooling, and the mixture was stirred for 2 hours. m
-Chloroperbenzoic acid (335.4 mg, 1.94 mmol; 134.0 mg, 0.77
6 mmol) was added twice and stirred for 2 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained crystals were washed with ethyl acetate, and colorless crystals of 2,3-dihydro-7-hydroxy-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-Benzothiazine-6-carboxylic acid ethyl ester-1,1-dioxide (580.8 mg, 100%) was obtained.

Reference Example 2 2,3-dihydro-7-hydroxy-5-oxo-5H
-Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxylic acid ethyl ester-1,1-dioxide (574.7 mg, 1.78 mmol) and triphenylphosphine (93
(3.8 mg, 3.56 mmol) was dissolved in acetonitrile (20 ml), carbon tetrachloride (1.06 ml, 10.7 mmol) was added, and the mixture was heated under reflux for 3 hours.
Triphenylphosphine (93.4 mg, 0.356 mmol) and carbon tetrachloride (0.11 ml, 1.10 mmol) were added, and the mixture was refluxed for 2 hours. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (methylene chloride), and the obtained crystals were recrystallized from hexane-ether to give 7-chloro-colorless crystals.
2,3-dihydro-5-oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxylic acid ethyl ester-1,1-dioxide (489.5 mg, 80
%).

Reference Example 3 By the same method as in Reference Example 2, 2,3-dihydro-7-
Hydroxy-5-oxo-5H-pyrido [1,2,3-
de] -1,4-Benzothiazine-6-carboxylic acid ethyl ester (1.17 g, 4.0 mmol) from colorless crystals of 7-chloro-2,3-dihydro-5-oxo-5H-pyrido [1,2,3 -De] -1,4-benzothiazine-6-
The carboxylic acid ethyl ester (1.16 g, 93%) was obtained.

Embodiment 15 N- [3,5-bis (trifluoromethyl) benzyl]
-7-Chloro-2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (200 mg, 0.38 mmol)
And 3-fluorophenylboric acid (161 mg, 1.2 mmol) were dissolved in toluene (12 ml), 1,4-dioxane (4.8 ml) and 2M aqueous sodium carbonate solution (2.3 ml), and tetrakis (triphenylphosphine) palladium was added. (88.7mg, 7
(7 μmol) and heated under reflux at 100 ° C. for 2 hours. Methylene chloride was added to the reaction solution, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride: ethyl acetate 20: 1) to give N- [3,5-
Bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-fluorophenyl) -N-methyl-5
-Oxo-5H-pyrido [1,2,3-de] -1,4
-Benzothiazine-6-carboxamide (203 mg, 91%) was obtained. EIMS m / z: 580 (M +) HRMS (EI): C 28 H 19 F 7 N 2 O 2 S Calculated: 580.1055 Found: 580.1045 Anal: calculated as _{C 28 H 19 F 7 N 2} O 2 S Value C 57.93%, H 3.30%, N 4.83% Measured value C 58.09%, H 3.42%, N 4.73%

Embodiment 16 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 3-chlorophenyl boric acid (180 mg, 1.2 mmol), colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl]
-7- (3-chlorophenyl) -2,3-dihydro-N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide (2
12 mg, 92%). EIMS m / z: 596 (M +) HRMS (EI): C 28 H 19 ClF 6 N 2 O 2 S Calculated: 596.0760 Found: 596.0779 Anal: calculated as _{C 28 H 19 ClF 6 N 2} O 2 S Value C 56.33%, H 3.21%, N 4.69% Actual value C 56.28%, H 3.20%, N 4.51%

Embodiment 17 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 3-nitrophenyl borate (192 mg, 1.2 mmol), colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-N-methyl-7- (3-nitrophenyl) -5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide (2
17 mg, 93%). EIMS m / z: 607 (M +) HRMS (EI): C 28 H 19 F 6 N 3 O 4 S Calculated: 607.1000 Found: 607.0962 Anal: calculated as _{C 28 H 19 F 6 N 3} O 4 S Value C 55.36%, H 3.15%, N 6.92% Actual value C 55.41%, H 3.27%, N 6.68%

Embodiment 18 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 3-aminophenyl boric acid (179 mg, 1.2 mmol), colorless amorphous 7- (3-aminophenyl) -N- [3,5-bis (trifluoromethyl) benzyl] -2 , 3-dihydro-N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide (1
33 mg, 60%). FABMS m / z: 578 (M + H ⁺ )

Embodiment 19 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 3,5-dichlorophenyl boric acid (220 mg, 1.2 mmol), colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -7- (3,5-dichlorophenyl) −2,3-
Dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-
Carboxamide (162 mg, 67%) was obtained. EIMS m / z: 630 (M ⁺ ) HRMS (EI): Calculated as C ₂₈ H ₁₈ Cl ₂ F ₆ N ₂ O ₂ S: 630.0370 Found: 630.0327 Anal: C ₂₈ H ₁₈ Cl ₂ F ₆ N ₂ O ₂ Calculated as S C 53.26%, H 2.87%, N 4.44% Measured C 53.40%, H 2.83%, N 4.29%

Embodiment 20 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
Carboxamide (200 mg, 0.38 mmol) and 3,5-bis (trifluoromethyl) phenylborate (297 mg, 1.2 mmo
From l), colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -7- [3,5-bis (trifluoromethyl) phenyl] -2,3-dihydro-N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide (1
42 mg, 53%). EIMS m / z: 698 (M +) HRMS (EI): C 30 H 18 F 12 N 2 O 2 S Calculated: 698.0897 Found: 698.0863 Anal: calculated as _{C 30 H 18 F 12 N 2} O 2 S Value C 51.58%, H 2.60%, N 4.01% Actual value C 51.54%, H 2.57%, N 4.00%

Embodiment 21 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 4-methylphenylborate (157 mg, 1.2 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-N-methyl-7- (4-methylphenyl) -5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide (2
11 mg, 95%). EIMS m / z: 576 (M ⁺ ) HRMS (EI): Calculated as C ₂₉ H ₂₂ F ₆ N ₂ O ₂ S Calculated: 576.1306 Actual: 576.1266 Anal: Calculated as C ₂₉ H ₂₂ F ₆ N ₂ O ₂ S Value C 60.41%, H 3.85%, N 4.86% Actual value C 60.49%, H 3.79%, N 4.71%

Embodiment 22 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 4-methoxyphenyl boric acid (175 mg, 1.2 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4 -Methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide (185 mg, 81%) was obtained. EIMS m / z: 592 (M +) HRMS (EI): C 29 H 22 F 6 N 2 O 3 S Calculated: 592.1255 Found: 592.1247 Anal: calculated as _{C 29 H 22 F 6 N 2} O 3 S Value C 58.78%, H 3.74%, N 4.73% Actual value C 58.81%, H 3.66%, N 4.63%

Embodiment 23 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 4-fluorophenyl boric acid (161 mg, 1.2 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4 -Fluorophenyl) -N-methyl-5-oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide (190 mg, 85%) was obtained. EIMS m / z: 580 (M +) HRMS (EI): C 28 H 19 F 7 N 2 O 2 S Calculated: 580.1055 Found: 580.1022 Anal: calculated as _{C 28 H 19 F 7 N 2} O 2 S Value C 57.93%, H 3.30%, N 4.83% Actual value C 58.21%, H 3.24%, N 4.79%

Embodiment 24 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 4-chlorophenylborate (180 mg, 1.2 mmol), colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl]
-7- (4-Chlorophenyl) -2,3-dihydro-N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide (2
17 mg, 95%). EIMS m / z: 596 (M +) HRMS (EI): C 28 H 19 ClF 6 N 2 O 2 S Calculated: 596.0760 Found: 596.0756 Anal: calculated as _{C 28 H 19 ClF 6 N 2} O 2 S Value C 56.33%, H 3.21%, N 4.69% Actual value C 56.53%, H 3.14%, N 4.50%

Embodiment 25 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
Carboxamide (200 mg, 0.38 mmol) and 3-chloro-4
-Fluorophenyl boric acid (201 mg, 1.2 mol) was converted to N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chloro-4-fluorophenyl) -2,3-dihydro- N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (226 mg, 96%) was obtained. EIMS m / z: 614 (M ⁺ ) HRMS (EI): Calculated as C ₂₈ H ₁₈ ClF ₇ N ₂ O ₂ S Calculated: 614.0666 Actual: 614.0679 Anal: Calculated as C ₂₈ H ₁₈ ClF ₇ N ₂ O ₂ S Value C 54.69%, H 2.95%, N 4.56% Actual value C 54.93%, H 3.14%, N 4.42%

Embodiment 26 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
Carboxamide (200 mg, 0.38 mmol) and 4-methyl-3
From -nitrophenyl boric acid (208 mg, 1.2 mmol), N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7-colorless amorphous was obtained.
(4-methyl-3-nitrophenyl) -5-oxo-5
H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (220 mg, 92%) was obtained. EIMS m / z: 621 (M +) HRMS (EI): C 29 H 21 F 6 N 3 O 4 S Calculated: 621.1157 Found: 621.1144 Anal: calculated as _{C 29 H 21 F 6 N 3} O 4 S Value C 56.04%, H 3.41%, N 6.76% Actual value C 56.28%, H 3.41%, N 6.59%

Embodiment 27 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 2-methoxyphenyl boric acid (175 mg, 1.2 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (2 -Methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide (219 mg, 96%) was obtained. EIMS m / z: 592 (M +) HRMS (EI): C 29 H 22 F 6 N 2 O 3 S Calculated: 592.1255 Found: 592.1214 Anal: calculated as _{C 29 H 22 F 6 N 2} O 3 S Value C 58.78%, H 3.74%, N 4.73% Actual value C 58.86%, H 3.69%, N 4.61%

Embodiment 28 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 1-naphthyl boric acid (198 mg, 1.2 mmol), a colorless amorphous N-
[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-N-methyl-7- (1-naphthyl)
-5-oxo-5H-pyrido [1,2,3-de]-
1,4-benzothiazine-6-carboxamide (230 mg,
98%). EIMS m / z: 612 (M ⁺ )

Embodiment 29 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 4-formylphenylborate (172 mg, 1.2 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4 -Formylphenyl) -N-methyl-5-oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide (218 mg, 96%) was obtained. EIMS m / z: 590 (M +) HRMS (EI): C 29 H 20 F 6 N 2 O 3 S Calculated: 590.1099 Found: 590.1129 Anal: calculated as _{C 29 H 20 F 6 N 2} O 3 S Value C 58.98%, H 3.41%, N 4.74% Actual value C 59.18%, H 3.43%, N 4.61%

Embodiment 30 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 3- (trifluoromethyl) phenylborate (218 mg, 1.2 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro- N-methyl-5
-Oxo-5H-pyrido [1,2,3-de] -1,4
-Benzothiazine-7- [3- (trifluoromethyl)
Phenyl] -6-carboxamide (220 mg, 91%) was obtained. EIMS m / z: 630 (M +) HRMS (EI): C 29 H 19 F 9 N 2 O 2 S Calculated: 630.1024 Found: 630.0981 Anal: calculated as _{C 29 H 19 F 9 N 2} O 2 S Value C 55.24%, H 3.04%, N 4.44% Actual value C 55.25%, H 2.99%, N 4.37%

Embodiment 31 By a method similar to that in Example 15, N- [3,5-bis (trifluoromethyl) benzyl] -7-chloro-2,
3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6
From carboxamide (200 mg, 0.38 mmol) and 3-methylphenylborate (156 mg, 1.2 mmol), colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-N-methyl-7- (3-methylphenyl) -5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide (2
01 mg, 91%). EIMS m / z: 576 (M +) HRMS (EI): C 29 H 22 F 6 N 2 O 2 S Calculated: 576.1306 Found: 576.1270 Anal: calculated as _{C 29 H 22 F 6 N 2} O 2 S Value C 60.41%, H 3.85%, N 4.86% Actual value C 60.68%, H 4.14%, N 4.70%

Embodiment 32 N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-7- (3-fluorophenyl)-
N-methyl-5-oxo-5H-pyrido [1,2,3-
de] -1,4-Benzothiazine-6-carboxamide
After dissolving (58.1 mg, 0.10 mmol) in methylene chloride (1 ml), 3-chloroperbenzoic acid (19.0 mg, 0.11 mmol) under ice cooling
Was added and stirred for 1 hour. Methylene chloride was added to the reaction solution, which was washed sequentially with water, a 2M aqueous solution of sodium carbonate and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl acetate) to give N- [3,3
5-bis (trifluoromethyl) benzyl] -2,3-
Dihydro-7- (3-fluorophenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3-de]-
1,4-benzothiazine-6-carboxamide-1-oxide (52.5 mg, 88%) was obtained. EIMS m / z: 596 (M +) HRMS (EI): C 28 H 19 F 7 N 2 O 3 S Calculated: 596.1005 _{Found: 596.1023 Anal: C 28 H 19} F 7 N 2 O 3 S 0.2H Calculated as ₂ O C 56.04%, H 3.26%, N 4.67% Measured C 55.77%, H 3.29%, N 4.56%

Embodiment 33 According to a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido From [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -7- ( 3-chlorophenyl)
-2,3-dihydro-N-methyl-5-oxo-5H-
Pyrid [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (50.0 mg, 81%) was obtained. EIMS m / z: 612 (M +) HRMS (EI): C 28 H 19 ClF 6 N 2 O 3 S Calculated: 612.0709 _{Found: 612.0718 Anal: C 28 H 19} ClF 6 N 2 O 3 S 0.2H Calculated as ₂ O C 54.54%, H 3.17%, N 4.54% Measured C 54.49%, H 3.07%, N 4.43%

Embodiment 34 According to a method similar to that of Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (3-nitrophenyl) -5-oxo-5H- From pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 99 μmol), colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3 -Dihydro-N-methyl-7- (3-nitrophenyl) -5-oxo-5H-
Pyrid [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (52.0 mg, 84%) was obtained. EIMS m / z: 623 (M ⁺ ) HRMS (EI): Calculated for C ₂₈ H ₁₉ F ₆ N ₃ O ₅ S: 623.0950 Actual: 623.00928 Anal: C ₂₈ H ₁₉ F ₆ N ₃ O ₅ S 0.5 H Calculated as ₂ O C 53.17%, H 3.19%, N 6.64% Actual value C 53.17%, H 3.10%, N 6.47%

Embodiment 35 According to a method similar to that in Example 32, 7- (3-aminophenyl) -N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-5-oxo-5H- From pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol), colorless amorphous 7- (3-aminophenyl)-
N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-N-methyl-5-oxo-5H-
Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (32.9 mg, 53%) was obtained. EIMS m / z: 593 (M ⁺ ) HRMS (EI): Calculated for C ₂₈ H ₂₁ F ₆ N ₃ O ₃ S: 593.1208 Actual: 593.1164 Anal: C ₂₈ H ₂₁ F ₆ N ₃ O ₃ S 0.5H Calculated as ₂ O C 55.81%, H 3.68%, N 6.97% Actual value C 55.80%, H 3.55%, N 6.85%

Embodiment 36 By a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -7- (3,5-dichlorophenyl) -2,3-dihydro-N-methyl-5
-Oxo-5H-pyrido [1,2,3-de] -1,4
-Benzothiazine-6-carboxamide (50.0 mg, 79 μm
ol) from colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -7- (3,5-dichlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (44.
0 mg, 86%). EIMS m / z: 646 (M ⁺ ) HRMS (EI): Calculated for C ₂₈ H ₁₈ Cl ₂ F ₆ N ₂ O ₃ S Calculated: 646.0319 Found: 646.0353 Anal: C ₂₈ H ₁₈ Cl ₂ F ₆ N ₂ O ₃ S 0.2H ₂ O Calculated value C 51.66%, H 2.85%, N 4.30% Actual value C 51.81%, H 2.87%, N 4.02%

Embodiment 37 By a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -7- [3,5-bis (trifluoromethyl) phenyl] -2,3-dihydro-N-methyl -5-oxo-5H-pyrido [1, 2,
3-de] -1,4-benzothiazine-6-carboxamide (50.0 mg, 72 μmol) from colorless amorphous N-
[3,5-bis (trifluoromethyl) benzyl] -7
-[3,5-bis (trifluoromethyl) phenyl]-
2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-
6-carboxamide-1-oxide (42.5 mg, 83%) was obtained. EIMS m / z: 714 (M +) HRMS (EI): C 30 H 18 F 12 N 2 O 3 S Calculated: 714.0847 _{Found: 714.0853 Anal: C 30 H 18} F 12 N 2 O 3 SH 2 O Calculated as C 49.19%, H 2.75%, N 3.82% Measured C 49.44%, H 2.69%, N 3.59%

Embodiment 38 According to a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4-methylphenyl) -5-oxo-5H- From the pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2, 3-dihydro-N-methyl-7- (4-methylphenyl) -5-oxo-5H-
Pyrid [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (57.7 mg, 94%) was obtained. EIMS m / z: 592 (M +) HRMS (EI): C 29 H 22 F 6 N 2 O 3 S Calculated: 592.1255 _{Found: 592.1240 Anal: C 29 H 22} F 6 N 2 O 3 S 0.25H Calculated as ₂ O C 58.34%, H 3.80%, N 4.69% Measured C 58.07%, H 3.54%, N 4.61%

Embodiment 39 According to a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4-methoxyphenyl) -5-oxo-5H- Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol)
From colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4-methoxyphenyl) -5-oxo-5
H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (55.4 mg, 90
%). EIMS m / z: 608 (M ⁺ ) HRMS (EI): Calculated as C ₂₉ H ₂₂ F ₆ N ₂ O ₄ S: 608.1204 Actual: 608.1184 Anal: C ₂₉ H ₂₂ F ₆ N ₂ O ₄ S 0.5H Calculated as ₂ O C 56.40%, H 3.75%, N 4.54% Measured C 56.46%, H 3.61%, N 4.39%

Embodiment 40 According to a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-fluorophenyl) -N-methyl-5-oxo-5H- Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol)
From colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-
(4-fluorophenyl) -N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (58.8 mg, 9
6%). EIMS m / z: 596 (M ⁺ ) HRMS (EI): Calculated as C ₂₈ H ₁₉ F ₇ N ₂ O ₃ S: 596.1005 Observed: 596.0986 Anal: C ₂₈ H ₁₉ F ₇ N ₂ O ₃ S 0.5 H Calculated as ₂ O C 55.54%, H 3.33%, N 4.63% Measured C 55.38%, H 3.23%, N 4.47%

Embodiment 41 According to a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -7- (4-chlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido From [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -7- ( 4-chlorophenyl)
-2,3-dihydro-N-methyl-5-oxo-5H-
Pyrid [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (57.5 mg, 93%) was obtained. EIMS m / z: 612 (M +) HRMS (EI): C 28 H 19 ClF 6 N 2 O 3 S Calculated: 612.0709 Found: 612.0726 Anal: calculated as _{C 28 H 19 ClF 6 N 2} O 3 S Value C 54.86%, H 3.12%, N 4.57% Actual value C 54.73%, H 3.28%, N 4.35%

Embodiment 42 By a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chloro-4-fluorophenyl) -2,3-dihydro-N-methyl-5- Oxo-5H-pyrido [1,2,3-de]
-1,4-benzothiazine-6-carboxamide (60.0 m
g, 98 μmol) from colorless amorphous N- [3,5-
Bis (trifluoromethyl) benzyl] -7- (3-chloro-4-fluorophenyl) -2,3-dihydro-N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide-
1-oxide (59.0 mg, 96%) was obtained. EIMS m / z: 630 (M ⁺ ) HRMS (EI): Calculated as C ₂₈ H ₁₈ ClF ₇ N ₂ O ₃ S Found: 630.0615 Actual: 630.0624 Anal: Calculated as C ₂₈ H ₁₈ ClF ₇ N ₂ O ₃ S Value C 53.30%, H 2.88%, N 4.44% Actual value C 53.05%, H 3.02%, N 4.20%

Embodiment 43 By a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4-methyl-3-nitrophenyl) -5- Oxo-5H-pyrido [1,2,3-de]
-1,4-benzothiazine-6-carboxamide (60.0 m
g, 97 μmol) from colorless amorphous N- [3,5-
Bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4-methyl-3-nitrophenyl) -5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide-
1-oxide (56.7 mg, 92%) was obtained. EIMS m / z: 637 (M +) HRMS (EI): C 29 H 21 F 6 N 3 O 5 S Calculated: 637.1106 _{Found: 637.1110 Anal: C 29 H 21} F 6 N 3 O 5 S 0.5H Calculated as ₂ O C 53.87%, H 3.43%, N 6.50% Measured C 53.99%, H 3.36%, N 6.27%

Embodiment 44 According to a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (2-methoxyphenyl) -N-methyl-5-oxo-5H- Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol)
From colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-
(2-methoxyphenyl) -N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (57.7 mg, 9
4%). EIMS m / z: 608 (M +) HRMS (EI): C 29 H 22 F 6 N 2 O 4 S Calculated: 608.1204 _{Found: 608.1198 Anal: C 29 H 22} F 6 N 2 O 4 S 0.5H Calculated as ₂ O C 56.40%, H 3.75%, N 4.54% Measured C 56.16%, H 3.96%, N 4.34%

Embodiment 45 By a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (1-naphthyl) -5-oxo-5
From H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 98 μmol), colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2 , 3-Dihydro-N-methyl-7
-(1-Naphthyl) -5-oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (40.3 mg, 65%) was obtained. EIMS m / z: 628 (M +) HRMS (EI): C 32 H 22 F 6 N 2 O 3 S Calculated: 628.1255 _{Found: 628.1226 Anal: C 32 H 22} F 6 N 2 O 3 S 0.5H Calculated as ₂ O C 60.28%, H 3.64%, N 4.39% Measured value C 59.99%, H 3.76%, N 4.11%

Embodiment 46 According to a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-formylphenyl) -N-methyl-5-oxo-5H- Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol)
From colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-
(4-formylphenyl) -N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (27.5 mg, 4
4%). FABMS m / z: 607 (M + H ⁺ ) HRMS (FAB ⁺ ): Calculated as C ₂₉ H ₂₁ F ₆ N ₂ O ₄ S Calculated: 607.1126 Actual: 607.1118 Anal: C ₂₉ H ₂₀ F ₆ N ₂ O ₄ Calculated as S 0.5H ₂ O C 56.59%, H 3.44%, N 4.55% Measured C 56.68%, H 3.43%, N 4.51%

Embodiment 47 According to a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3
-De] -1,4-benzothiazine-7- [3- (trifluoromethyl) phenyl] -6-carboxamide (60.
0 mg, 95 μmol) from colorless amorphous N- [3,5
-Bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,
2,3-de] -1,4-benzothiazine-7- [3-
(Trifluoromethyl) phenyl] -6-carboxamide-1-oxide (58.6 mg, 95%) was obtained. EIMS m / z: 646 (M +) HRMS (EI): C 29 H 19 F 9 N 2 O 3 S Calculated: 646.0973 Found: 646.0974 Anal: calculated as _{C 29 H 19 F 9 N 2} O 3 S Value C 53.87%, H 2.96%, N 4.33% Actual value C 53.82%, H 3.06%, N 4.16%

Embodiment 48 According to a method similar to that in Example 32, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (3-methylphenyl) -5-oxo-5H- From the pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2, 3-dihydro-N-methyl-7- (3-methylphenyl) -5-oxo-5H-
Pyrid [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (61.0 mg, 99%) was obtained. EIMS m / z: 592 (M +) HRMS (EI): C 29 H 22 F 6 N 2 O 3 S Calculated: 592.1255 _{Found: 592.1265 Anal: C 29 H 22} F 6 N 2 O 3 S 0.5H Calculated as ₂ O C 57.90%, H 3.85%, N 4.66% Measured C 58.10%, H 3.94%, N 4.40%

Embodiment 49 N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-7- (3-fluorophenyl)-
N-methyl-5-oxo-5H-pyrido [1,2,3-
de] -1,4-Benzothiazine-6-carboxamide
After dissolving (58.1 mg, 0.10 mmol) in methylene chloride (1 ml), 3-chloroperbenzoic acid (43.2 mg, 0.25 mmol) under ice-cooling
Was added and stirred for 1 hour. Methylene chloride was added to the reaction solution, and the mixture was washed sequentially with water, a 2M aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was washed with diisopropyl ether, and N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-colorless amorphous was obtained.
(3-Fluorophenyl) -N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (47.
2 mg, 77%). EIMS m / z: 612 (M ⁺ ) HRMS (EI): Calculated for C ₂₈ H ₁₉ F ₇ N ₂ O ₄ S Calculated: 612.0954 Found: 612.0969. Anal: As C ₂₈ H ₁₉ F ₇ N ₂ O ₄ S Calculated value C 54.90%, H 3.13%, N 4.57% Measured value C 54.77%, H 3.01%, N 4.56%

Embodiment 50 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido From [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -7- ( 3-chlorophenyl)
-2,3-dihydro-N-methyl-5-oxo-5H-
Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (49.8 mg, 7
8%). EIMS m / z: 628 (M +) HRMS (EI): C 28 H 19 ClF 6 N 2 O 4 S Calculated: 628.0658 Found: 628.0646 Anal: calculated as _{C 28 H 19 ClF 6 N 2} O 4 S Value C 53.47%, H 3.04%, N 4.45% Actual value C 53.53%, H 2.95%, N 4.32%

Embodiment 51 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (3-nitrophenyl) -5-oxo-5H- From pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 99 μmol), colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3 -Dihydro-N-methyl-7- (3-nitrophenyl) -5-oxo-5H-
Pyrid [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (55.6 mg, 8
8%). EIMS m / z: 639 (M ⁺ ) HRMS (EI): Calculated as C ₂₈ H ₁₉ F ₆ N ₃ O ₆ S Calculated: 639.0899 Actual: 639.0872 Anal: Calculated as C ₂₈ H ₁₉ F ₆ N ₃ O ₆ S Value C 52.59%, H 2.99%, N 6.57% Actual value C 52.36%, H 2.89%, N 6.35%

Embodiment 52 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -7- (3,5-dichlorophenyl) -2,3-dihydro-N-methyl-5
-Oxo-5H-pyrido [1,2,3-de] -1,4
-Benzothiazine-6-carboxamide (50.0 mg, 79 μm
ol) from colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -7- (3,5-dichlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (42.1 mg, 80%) was obtained. EIMS m / z: 662 (M ⁺ ) HRMS (EI): Calculated for C ₂₈ H ₁₈ Cl ₂ F ₆ N ₂ O ₄ S: 662.0269 Found: 662.0298 Anal: C ₂₈ H ₁₈ Cl ₂ F ₆ N ₂ O ₄ Calculated value as S C 50.69%, H 2.73%, N 4.22% Measured value C 50.60%, H 2.65%, N 4.11%

Embodiment 53 By a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -7- [3,5-bis (trifluoromethyl) phenyl] -2,3-dihydro-N-methyl -5-oxo-5H-pyrido [1, 2,
3-de] -1,4-benzothiazine-6-carboxamide (50.0 mg, 72 μmol) from colorless amorphous N-
[3,5-bis (trifluoromethyl) benzyl] -7
-[3,5-bis (trifluoromethyl) phenyl]-
2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-
6-carboxamide-1,1-dioxide (35.2 mg, 67
%). EIMS m / z: 730 (M +) HRMS (EI): C 30 H 18 F 12 N 2 O 4 S Calculated: 730.0796 _{Found: 730.0830 Anal: C 30 H 18} F 12 N 2 O 4 S 0.5H Calculated as ₂ O C 48.72%, H 2.59%, N 3.79% Actual value C 48.52%, H 2.44%, N 3.70%

Embodiment 54 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4-methylphenyl) -5-oxo-5H- From the pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2, 3-dihydro-N-methyl-7- (4-methylphenyl) -5-oxo-5H-
Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (47.7 mg, 7
5%). EIMS m / z: 608 (M +) HRMS (EI): C 29 H 22 F 6 N 2 O 4 S Calculated: 608.1204 _{Found: 608.1191 Anal: C 29 H 22} F 6 N 2 O 4 S 0.5H Calculated as ₂ O C 56.40%, H 3.75%, N 4.54% Measured C 56.60%, H 3.62%, N 4.46%

Embodiment 55 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-methoxyphenyl) -N-methyl-5-oxo-5H- Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol)
From colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-
(4-methoxyphenyl) -N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (50.
5 mg, 80%). EIMS m / z: 624 (M +) HRMS (EI): C 29 H 22 F 6 N 2 O 5 S Calculated: 624.1154 Found: 624.1130 Anal: calculated as _{C 29 H 22 F 6 N 2} O 5 S Value C 55.77%, H 3.55%, N 4.49% Actual value C 55.48%, H 3.42%, N 4.40%

Embodiment 56 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-fluorophenyl) -N-methyl-5-oxo-5H- Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol)
From colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-
(4-fluorophenyl) -N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (50.
0 mg, 79%). EIMS m / z: 612 (M +) HRMS (EI): C 28 H 19 F 7 N 2 O 4 S Calculated: 612.0954 Found: 612.0966 Anal: calculated as _{C 28 H 19 F 7 N 2} O 4 S Value C 54.90%, H 3.13%, N 4.57% Actual value C 54.71%, H 3.00%, N 4.48%

Embodiment 57 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -7- (4-chlorophenyl) -2,3-dihydro-N-methyl-5-oxo-5H-pyrido From [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -7- ( 4-chlorophenyl)
-2,3-dihydro-N-methyl-5-oxo-5H-
Pyrid [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (53.9 mg, 8
5%). EIMS m / z: 628 (M +) HRMS (EI): C 28 H 19 ClF 6 N 2 O 4 S Calculated: 628.0658 Found: 628.0652 Anal: calculated as _{C 28 H 19 ClF 6 N 2} O 4 S Value C 53.47%, H 3.04%, N 4.45% Actual value C 53.52%, H 3.14%, N 4.30%

Embodiment 58 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chloro-4-fluorophenyl) -2,3-dihydro-N-methyl-5- Oxo-5H-pyrido [1,2,3-de]
-1,4-benzothiazine-6-carboxamide (60.0 m
g, 98 μmol) from colorless amorphous N- [3,5-
Bis (trifluoromethyl) benzyl] -7- (3-chloro-4-fluorophenyl) -2,3-dihydro-N
-Methyl-5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide-
1,1-dioxide (48.5 mg, 77%) was obtained. EIMS m / z: 646 (M +) HRMS (EI): C 28 H 18 ClF 7 N 2 O 4 S Calculated: 646.0564 Found: 646.0559 Anal: calculated as _{C 28 H 18 ClF 7 N 2} O 4 S Value C 51.98%, H 2.80%, N 4.33% Measured value C 51.78%, H 2.66%, N 4.24%

Embodiment 59 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4-methyl-3-nitrophenyl) -5- Oxo-5H-pyrido [1,2,3-de]
-1,4-benzothiazine-6-carboxamide (60.0 m
g, 97 μmol) from colorless amorphous N- [3,5-
Bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (4-methyl-3-nitrophenyl) -5-oxo-5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide-
1,1-dioxide (49.6 mg, 79%) was obtained. EIMS m / z: 653 (M ⁺ ) HRMS (EI): Calculated as C ₂₉ H ₂₁ F ₆ N ₃ O ₆ S Calculated: 653.1055 Actual: 653.1041 Anal: Calculated as C ₂₉ H ₂₁ F ₆ N ₃ O ₆ S Value C 53.30%, H 3.24%, N 6.43% Measured value C 53.08%, H 3.17%, N 6.33%

Embodiment 60 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (2-methoxyphenyl) -N-methyl-5-oxo-5H- Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol)
From colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-
(2-methoxyphenyl) -N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (37.
1 mg, 59%). EIMS m / z: 624 (M +) HRMS (EI): C 29 H 22 F 6 N 2 O 5 S Calculated: 624.1154 Found: 624.1146 Anal: calculated as _{C 29 H 22 F 6 N 2} O 5 S Value C 55.77%, H 3.55%, N 4.49% Actual value C 55.48%, H 3.42%, N 4.42%

Embodiment 61 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-formylphenyl) -N-methyl-5-oxo-5H- Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol)
From colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-
(4-formylphenyl) -N-methyl-5-oxo-
5H-pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (14.
5 mg, 23%). EIMS m / z: 622 (M +) HRMS (EI): C 29 H 20 F 6 N 2 O 5 S Calculated: 622.0997 Found: 622.0984 Anal: calculated as _{C 29 H 20 F 6 N 2} O 5 S Value C 55.95%, H 3.24%, N 4.50% Actual value C 55.86%, H 3.32%, N 4.41%

Embodiment 62 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-5-oxo-7- [3- (trifluoromethyl) phenyl ] -5H-pyrido [1,2,3-d
e] -1,4-benzothiazine-6-carboxamide (6
0.0mg, 95μmol) from colorless amorphous N- [3,
5-bis (trifluoromethyl) benzyl] -2,3-
Dihydro-N-methyl-5-oxo-7- [3- (trifluoromethyl) phenyl] -5H-pyrido [1,2,
[3-de] -1,4-benzothiazine-6-carboxamide-1,1-dioxide (42.0 mg, 67%) was obtained. EIMS m / z: 662 (M +) HRMS (EI): C 29 H 19 F 9 N 2 O 4 S Calculated: 662.0922 Found: 662.0914 Anal: calculated as _{C 29 H 19 F 9 N 2} O 4 S Value C 52.57%, H 2.89%, N 4.23% Actual value C 52.53%, H 2.77%, N 4.22%

Embodiment 63 According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (3-methylphenyl) -5-oxo-5H- From the pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (60.0 mg, 0.10 mmol), a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2, 3-dihydro-N-methyl-7- (3-methylphenyl) -5-oxo-5H-
Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide-1-oxide (48.0 mg, 76%) was obtained. EIMS m / z: 608 (M ⁺ ) HRMS (EI): Calculated as C ₂₉ H ₂₂ F ₆ N ₂ O ₄ S: 608.1204 Actual: 608.11191 Anal: Calculated as C ₂₉ H ₂₂ F ₆ N ₂ O ₄ S Value C 57.24%, H 3.64%, N 4.60% Measured value C 57.12%, H 3.54%, N 4.62%

Embodiment 64 7-hydroxy-2,3-dihydro-5-oxo-5H
N-methyl-3,5-bis (trifluoromethyl) benzylamine (13.3 g) was added to -pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxylic acid ethyl ester (15.0 g, 52 mmol). , 52 mmol) and pyridine (120 ml) were added and the mixture was refluxed for 5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized by adding diisopropyl ether, and N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7- was obtained as yellow crystals. Hydroxy-N-methyl-5-oxo-5H-pyrido [1, 2,
[3-de] -1,4-benzothiazine-6-carboxamide (18.7 g, 72%) was obtained. EIMS m / z: 502 (M ⁺ )

Embodiment 65 N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-7-hydroxy-N-methyl-5
-Oxo-5H-pyrido [1,2,3-de] -1,4
-Benzothiazine-6-carboxamide (15.0 g, 30 mmo
l) was added to phosphorus oxychloride (50 ml), and the mixture was heated under reflux for 3 hours. The reaction solution was poured into ice, and the resulting crystals were collected by filtration.
Purification by silica gel column chromatography (methylene chloride: ethyl acetate 10: 1) gave N- [3,
5-bis (trifluoromethyl) benzyl] -7-chloro-2,3-dihydro-N-methyl-5-oxo-5H
-Pyrido [1,2,3-de] -1,4-benzothiazine-6-carboxamide (13.5 g, 87%) was obtained. EIMS m / z: 520 (M ⁺ )

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 11/06 A61P 11/06 13/00 13/00 25/04 25/04 29/00 29/00 101 101 43/00 111 43/00 111 (72) Inventor Makoto Ikeda 591-7 Marubayashi, Nogi-machi, Shimotsuga-gun, Tochigi Prefecture 201 Maronie Sanbancho 201

Claims (14)

[Claims] 1. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A benzene ring which may have a pyridobenzothiazine derivative or a salt, hydrate or solvate thereof. 2. A ring may be substituted with a halogen atom.
C₁~ C₆An alkyl group of which may be substituted
A hydroxyl group, an optionally substituted C₁~
C₆An alkoxy group of C₃~ C₁₀Cycloalkoxy
Group, optionally substituted C ₁~ C₆The alkanoylo
An xyl group, an optionally substituted aryloyloxy group,
An optionally substituted arylmethyloxy group, C₃~ C
₁₀Cycloalkanoyloxy group, even when substituted
Good C₁~ C₆Alkylthio group, which may be substituted
C₁~ C₆Alkylsulfinyl group of
May be C₁~ C₆An alkylsulfonyl group, amino
Group, mono- or di-substituted C₁~ C₆An alkylamino group of
4- to 9-membered ring optionally containing 1 to 3 heteroatoms
Amino group, C₁~ C₆The alkylcarbonylamino of
Group, C₁~ C₆An alkoxycarbonylamino group of C₁
~ C₆An alkylsulfonylamino group of
Arylsulfonylamino group, C₁~ C₆Al
Kill carbonyl group, formyl group, carboxyl group, C₁
~ C₆An alkoxycarbonyl group, a mono- or di-substituted C
₁~ C₆Alkylcarbamoyl group, 1-3 hetero groups
4- to 9-membered cyclic carbamoyl optionally containing atoms
Group, cyano group or nitro group
1 to 3 substituents (adjacent two substituents are
To form a ring).
Ring B is a halogen atom, optionally substituted C₁~ C₆
An alkyl group of C₃~ C₁₀Cycloalkyl group, substitution
Optionally substituted aryl, hydroxyl, substituted
C that may be₁~ C₆An alkoxy group, which is substituted
May be C₁~ C₆Alkanoyloxy group, substituted
An aryloyloxy group which may be substituted,
Good arylmethyloxy group, C₃~ C₁₀Cycloa
Lucoxy group, C₃~ C₁₀Cycloalkanoyloxy
Group, optionally substituted C₁~ C₆The alkylthio
Group, optionally substituted C₁~ C₆Alkylsulf
Ynyl group, optionally substituted C₁~ C₆The alkyl of
Sulfonyl group, amino group, mono- or di-substituted C₁~ C₆
Alkylamino groups containing 1 to 3 heteroatoms
A 4- to 9-membered cyclic amino group, C₁~ C₆Archi
Carbonylamino group, C₁~ C₆The alkoxy carb
Nylamino group, C₁~ C₆Of alkylsulfonylamino
Group, optionally substituted arylsulfonylamino
Group, C₁~ C₆Alkylcarbonyl group, carboxyl
Group, C₁~ C₆An alkoxycarbonyl group, mono or di
Substitution C₁~ C₆Alkylcarbamoyl group of 1 to 3
4 to 9-membered cyclic carba optionally containing a heteroatom
Independent of moyl, cyano or nitro groups
1 to 3 substituents (adjacent two substituents
May be bonded to each other to form a ring)
An optionally substituted benzene ring, wherein the C ring is a halogen atom or an optionally substituted C₁~ C₆
Alkyl group, hydroxyl group, which may be substituted
C₁~ C₆An alkoxy group, optionally substituted C₁
~ C₆Alkanoyloxy group, which may be substituted
Aryloyloxy group, aryl group which may be substituted
Tyloxy group, C₃~ C₁₀A cycloalkoxy group of C
₃~ C₁₀A cycloalkanoyloxy group, an amino group,
Mono- or di-substituted C₁~ C₆An alkylamino group of 1 to
A 4- to 9-membered cyclic amine optionally containing three heteroatoms
Mino group, C₁~ C₆An alkylcarbonylamino group of C
₁~ C₆An alkoxycarbonylamino group of C₁~ C₆
Alkylsulfonylamino group, which may be substituted
Arylsulfonylamino, cyano or nitro group
1 to 3 substituents each independently selected from
Two contacting substituents are bonded to each other to form a ring,
A benzene ring which may have a benzene ring.
The pyridobenzothiazine derivative according to the above. 3. The following general formula (2)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁴Is a hydroxyl group, C₁~ C ₆An alkoxy group, benzylo
A xy group or a reactive residue, a ring A having a halogen atom, an optionally substituted C₁~ C₆
An alkyl group, an optionally substituted aryl group,
Roxyl group, optionally substituted C₁~ C₆Arco
Xy group, C₃~ C₁₀A cycloalkoxy group, substituted
May be C ₁~ C₆Alkanoyloxy group, substituted
An aryloyloxy group, which may be substituted
Arylmethyloxy group, C₃~ C₁₀The cyclo
Alkanoyloxy group, optionally substituted C₁~ C
₆An alkylthio group of the formula₁~ C₆
An alkylsulfinyl group of an optionally substituted C₁
~ C₆Alkylsulfonyl group, amino group, mono or di
Substitution C₁~ C₆Alkylamino group, 1 to 3
A 4- to 9-membered cyclic amino group optionally containing
₁~ C₆An alkylcarbonylamino group of C₁~ C₆of
Alkoxycarbonylamino group, C₁~ C₆The alkyl of
Sulfonylamino group, aryls which may be substituted
Rufonylamino group, C₁~ C₆Alkyl carbonyl
Group, formyl group, carboxyl group, C₁~ C₆Arco
Xycarbonyl group, mono- or di-substituted C ₁~ C₆Al
Quilcarbamoyl group, containing 1 to 3 heteroatoms
4 to 9-membered cyclic carbamoyl group, cyano group or
1 to 3 independently selected from nitro groups
Substituents (two adjacent substituents are bonded to each other to form a ring
Allomorphic or complex
Ring, ring C is a halogen atom, optionally substituted C₁~ C₆
Alkyl group, hydroxyl group, which may be substituted
C₁~ C₆An alkoxy group, optionally substituted C₁
~ C₆Alkanoyloxy group, which may be substituted
Aryloyloxy group, aryl group which may be substituted
Tyloxy group, C₃~ C₁₀A cycloalkoxy group of C
₃~ C₁₀A cycloalkanoyloxy group, an amino group,
Mono- or di-substituted C₁~ C₆An alkylamino group of 1 to
A 4- to 9-membered cyclic amine optionally containing three heteroatoms
Mino group, C₁~ C₆An alkylcarbonylamino group of C
₁~ C₆An alkoxycarbonylamino group of C₁~ C₆
Alkylsulfonylamino group, which may be substituted
Arylsulfonylamino, cyano or nitro group
1 to 3 substituents each independently selected from
Two contacting substituents are bonded to each other to form a ring,
A benzene ring which may have a benzene ring. )
Pyridobenzothiazine derivatives or their salts and hydrates
And solvates. 4. The following general formula (3)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁵Is(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
X is a halogen atom or OSO₂R⁶(R⁶Ha
C which may be substituted with a logene₁~ C₆An alkyl group of
An aryl group which may be substituted), and ring C is a halogen atom
Child, optionally substituted C₁~ C₆An alkyl group of
A droxyl group, an optionally substituted C₁~ C₆Al
Coxy group, optionally substituted C₁~ C₆No alkano
Yloxy group, optionally substituted aryloyloxy
Group, an optionally substituted arylmethyloxy group, C
₃~ C₁₀A cycloalkoxy group of C₃~ C₁₀No shiku
Lower alkanoyloxy group, amino group, mono- or di-substituted
C₁~ C₆Alkylamino group, 1-3 heteroatoms
A 4- to 9-membered cyclic amino group optionally containing ₁~ C
₆An alkylcarbonylamino group of C₁~ C₆Arco
Xycarbonylamino group, C₁~ C₆Alkylsulfo
Nylamino group, arylsulfonyl which may be substituted
Each independently from the amino, cyano or nitro groups.
1 to 3 substituents selected vertically (two adjacent substituents
Groups may be bonded to each other to form a ring)
Represents an optionally present benzene ring. )
Zothiazine derivatives or salts, hydrates and solvates thereof. 5. The following general formula (4)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁵Is(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
Residue, C ring is a halogen atom, C
₁~ C₆Alkyl group, hydroxyl group, substituted
May be C₁~ C₆An alkoxy group, even if it is substituted
Good C₁~ C ₆Alkanoyloxy group, substituted
An aryloyloxy group, an optionally substituted
Reel methyloxy group, C₃~ C₁₀Cycloalkoxy
Si group, C₃~ C₁₀A cycloalkanoyloxy group,
Amino group, mono- or di-substituted C₁~ C₆The alkylamino
Group, 4 to 9 members optionally containing 1 to 3 heteroatoms
A cyclic amino group of C₁~ C₆Alkylcarbonylamido
No group, C₁~ C₆An alkoxycarbonylamino group of C
₁~ C₆Alkylsulfonylamino group, substituted
An arylsulfonylamino group, a cyano group or a
1 to 3 positions independently selected from toro groups
A substituent (two adjacent substituents are bonded to each other to form a ring
Represents a benzene ring which may have
You. ) Or a pyridobenzothiazine derivative represented by
Salts, hydrates and solvates. 6. The following general formula (2)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁴Is a hydroxyl group, C₁~ C ₆An alkoxy group, benzylo
The xy group or the reactive residue and the ring A are each independently selected.
1 to 3 substituents (two adjacent substituents are
May form a ring together)
An aromatic or heterocyclic ring, the C ring has 1 to 3 substituents (adjacent 2
May be bonded to each other to form a ring)
The benzene ring which may be possessed is shown. )
Dobenzothiazine derivatives or their salts, hydrates and solvates
And the following general formula (5)(Where R¹And R²Are the same or different and represent a hydrogen atom or
C₁~ C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two contacting substituents are bonded to each other to form a ring,
A benzene ring which may have a benzene ring. )
Reaction of the compound or its salt, hydrate and solvate
The compound according to claim 1, or a salt thereof, hydration
And methods for producing solvates. 7. The following general formula (6)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁷Is a hydroxyl group, C₁~ C ₆An alkoxy group, benzylo
A xyl group,(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
X is a halogen atom or OSO₂R⁶(R⁶Ha
C which may be substituted with a logene₁~ C₆An alkyl group of
An aryl group which may be substituted), and ring C has 1 to 3
Substituents (two adjacent substituents are bonded to each other to form a ring
A benzene ring which may have
You. ) Or a pyridobenzothiazine derivative represented by
Salts, hydrates and solvates and the following general formula (7)(Where Y is a halogen atom, OSO₂R⁶(R⁶Is
), B (R⁸)₂(R⁸Is a hydroxyl group, C₁~ C₆of
Alkyl group or C₁~ C₆Represents an alkoxy group. is there
Iha R⁸May combine with each other to form a ring
No. ), MgBr or ZnCl, and the A ring are each independently
1 to 3 substituents selected (adjacent two substituents
Which may combine with each other to form a ring)
Or a homocyclic or heterocyclic ring. )
4. The pyridobenzo according to claim 1, wherein
Production of thiazine derivatives or their salts, hydrates and solvates
Method. 8. The following general formula (8) (Wherein R ³ is the same or different and is a hydrogen atom or C ₁ -C
An alkyl group of ₆ , R ⁷ is a hydroxyl group, a C ₁ -C ₆ alkoxy group, a benzyloxy group, (R ¹ and R ² may be the same or different and each represent a hydrogen atom or C _1-
The C ₆ alkyl group and the ring B represent a benzene ring which may have 1 to 5 substituents (two adjacent substituents may be bonded to each other to form a ring). ) Or a reactive residue, Z is a hydroxyl group, X (X is a halogen atom or OSO
₂ R ⁶ (R ⁶ is C ₁ -C optionally substituted with halogen)
₆ alkyl groups and optionally substituted aryl groups))
Or ring A (ring A may have 1 to 3 substituents each independently selected (two adjacent substituents may be bonded to each other to form a ring) Homo or heterocyclic), P represents 0 or 1. ) Or a salt, hydrate and solvate thereof represented by the following general formula (9) by oxidation: (Wherein, R ³ , R ⁷ and Z are the same as above, and m represents p + 1 or 2) or a method for producing a salt, hydrate or solvate thereof. 9. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A pyridobenzothiazine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. Tachykinin receptor antagonist. 10. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A pyridobenzothiazine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. Substance P receptor antagonist. 11. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A pyridobenzothiazine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. For preventing or treating dysuria including urinary frequency, urinary incontinence and other bladder dysfunctions. 12. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A pyridobenzothiazine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. For preventing or treating digestive diseases including ulcerative colitis and Crohn's disease. 13. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A pyridobenzothiazine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. X-ray irradiation, chemotherapeutic agents, pregnancy, migraine, postoperative illness, reduced gastrointestinal motility or side effects of drug administration An agent for preventing or treating vomiting. 14. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A pyridobenzothiazine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. For the treatment of asthma, cough, pain, migraine, toothache, rheumatoid arthritis, etc. in which tachykinin is involved.