WO2000006580A1 - Pyridobenzothiazine derivatives and process for producing the same - Google Patents

Abstract

Pyridobenzothiazine derivatives having tachykinin antagonism, in particular, substance P receptor antagonism. Namely, pyridobenzothiazine derivatives represented by general formula (1) and salts thereof and medicinal compositions containing these compounds or pharmaceutically useful salts thereof, wherein R?1, R2 and R3¿ are the same or different and each represents hydrogen or C¿1-6? alkyl; the ring A is a homocycle or a heterocycle optionally having 1 to 3 substituents selected independently (wherein 2 substituents adjacent to each other may be bonded together to form a ring); the ring B is a benzene ring optionally having 1 to 5 substituents (wherein 2 substituents adjacent to each other may be bonded together to form a ring); and the ring C is a benzene ring optionally having 1 to 3 substituents (wherein 2 substituents adjacent to each other may be bonded together to form a ring).

Description

 Satsuki Itoda Pyridobenzothiazine derivative and its production method

 The present invention relates to a novel pyridobenzothiazine derivative or a pharmacologically acceptable salt thereof having an inhibitory activity on evening kinkinin receptor, a method for producing the same, and a pharmaceutical composition containing the pyridobenzothiazine derivative. · Background technology

Yukinkinin (substance P, neurokinin A, neurokinin B) is a general term for neuropeptides and their receptors in the body (neurokinin 1, neurokinin 2 (Ν Κ ₂ ) 'neurokinin). 3 (Ν Κ 3)) is known to express various physiological activities. Among them, substance 、 acts as a transmitter of central and peripheral primary sensory neurons, as well as enhancing diuresis, stimulating nerve cells, enhancing vascular permeability, vasodilating, smooth muscle contracting, and immunizing. It 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, it has excellent kinkinin receptor antagonism, especially substrate Ρ receptor antagonism, as a preventive and therapeutic agent for the above-mentioned various disease states, and has excellent safety and long-lasting properties. It is desired to develop a compound having such a compound.

 At present, the following compounds and the like are disclosed as compounds having a substance II receptor antagonistic action.

(1) In Japanese Patent Application Laid-Open No. 1-28795, the formula is: RtA-D-Trp (R ² ) -Phe-R3

(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; R ³ is an alk (lower) alkyl group, —N (R ⁴ ) (R ⁵ ) group (wherein R ⁴ and R ⁵ are each a hydrogen-aryl group or a lower alkyl 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 group, wherein R ⁶ is hydrogen, aryl group or a suitable substituent. Wherein A represents a single bond or one or two amino acid residues, and A is: D—amino acid of Trp When one residue is meant, R ⁴ is not hydrogen.) The compound represented by) and a salt thereof are disclosed. Have been

 (2) E P—A—No. 4 293 6 6 Formula:

Are disclosed.

(3) W〇 9 1/0 9 8 4 Formula No.4: B

And the like are disclosed.

 (4) Ε Ρ— Α— 5 3 2 4 5 6 Formula

And the like are disclosed.

 (5) Ε Ρ— Α—

(6) WO93 / 011169 discloses a compound represented by the formula

Are disclosed.

 (7) Formula is disclosed in JP-A-8-676768

(Wherein, ring A and ring B are homo- or hetero-rings, at least one of which is a heterocycle; ring C 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 - 0 _, the other one C_〇- or one CS-, or one - N =, the other = CR ² i (1 ² 11, halogen, hydrocarbon A hydrogen residue, an amino group or a hydroxyl group); n represents 1 or 2.) or a salt thereof.

(8) Japanese Patent Application Laid-Open No. 9-104646 describes the formula:

(In the formula, 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 represents a hydrogen atom, a lower alkyl group, a lower alkanol group, or a nitrogen atom. alkyl group, a force Rubamoiru group containing, lower alkylthio group, a lower alkyl sulfide El group, a lower alkylsulfonyl group, a (4 one phenylene Rubiperajin one 1-I) methyl group, R ² represents a hydrogen atom, a lower alkyl group, a hydroxyl group And a lower alkenyl group, a lower alkanol group and a lower alkoxy group, and the ring A and the ring B each represent a benzene ring which may have a substituent.

 (9) In Japanese Patent Application Laid-Open No. 9-2636587, the formula is as follows:

(Wherein, the M ring is a heterocycle having a partial structure of X = Y <, 1 N = C, 1 C 一 1 N <, or 1 CS—N; R ^a and R ^b are A ring or a substituent on the same or different hydrogen atom or ring M; ring A and ring B may each have a substituent A heterocyclic or heterocyclic ring, at least one of which may have a substituent; a ring C is a homo- or heterocyclic ring which may have a substituent; a ring Z is substituted. And n represents an integer of 1 to 6. ) Is disclosed.

 At present, it has an excellent antagonistic activity against tachykinin receptor (particularly, a substance P receptor antagonistic activity) as a preventive or therapeutic agent for the above-mentioned various disease states, and in view of safety, sustainability and the like. However, no compound has been found that can be a sufficiently satisfactory drug. An object of the present invention is to provide a pharmaceutical composition having an excellent antagonism to tachykinin receptor, particularly a substance P receptor antagonism, which has a different chemical structure from known compounds including the above-mentioned compounds, and a quinkinin receptor antagonist Another object of the present invention is to provide a prophylactic or therapeutic agent for dysuria, a prophylactic or therapeutic agent for gastrointestinal disorders and a prophylactic or therapeutic agent for vomiting. Disclosure of the invention

 The present inventors have the following general formula (1)

(Wherein, R ¹ R ² and R ³ are the same or different and are a hydrogen atom or a C ₆ -C ₆ alkyl group, and A ring is each independently selected from 1 to 3 substituents (adjacent 2 May be bonded to each other to form a ring) may have a homo- or heterocyclic ring, and the ring B has 1 to 5 substituents (two adjacent substituents are May combine to form a ring The benzene ring and the C ring may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) Shows a good benzene ring. The present invention provides a pyridobenzothiazine derivative represented by the formula or a salt, hydrate and solvate thereof.

The present inventors have found that ring A is a halogen atom, an optionally substituted to C ₆ alkyl group, an optionally substituted aryl group, a hydroxy group, an optionally substituted C i to C ₆ an alkoxy group, a cycloalkoxy group of C ₃ ~ C i 0, the optionally substituted C i to Al Kanoiruokishi group C _6, optionally substituted § Li Roiruokishi group, which may be substitution § Reel methyloxy group, Cs C!. Cycloalkadienyl Noi Ruo alkoxy group, a substituted alkyl optionally C ~ C ₆ even if Chiomoto, alkylsulfinyl group ~ C ₆ optionally C ₁ substituted - the optionally substituted C i C s Alkylsulfonyl group, amino group, mono- or di-substituted CiCe alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, CiC e, an alkylcarbonylamino group, CiCe, an alkoxycarbonylamino group, C! Alkylsulfonyl § Mi amino group of ~ C _6, substituted § Li one but it may also have Le sulfonyl § amino group, an alkylcarbonyl group of C i to C _6. Formyl group, a carboxyl group, alkoxycarbonyl C ~ C ₆ A mono- or di-substituted C ₆ -C ₆ alkyl group, a 4- to 9-membered cyclic group optionally containing 1 to 3 heteroatoms, a cyano group or a nitro group. A homo- or heterocyclic ring optionally having 1 to 3 substituents (each of which may be bonded to two adjacent substituents to form a ring) Indicates that

B ring is a halogen atom, a substituted optionally alkyl group which may _{C ~ C 6, C 3 ~} C t. A cycloalkyl group, an optionally substituted aryl group, a hydroxy group, an optionally substituted C ₁ -C ₆ alkoxy Shi group, alkanoyloxy Noi Ruo alkoxy groups optionally substituted C i to C _6, substitution which may be § Li Roiruokishi group, an optionally substituted Yoia reel methyl O alkoxy group, C ₃ ~ C i. A cycloalkanoyloxy group of c ₃ to C _{1 Q} , an optionally substituted C i to

Alkylthio groups C _6, alkyl sulfinyl group which may be substituted, an alkylsulfonyl group optionally C i to C ₆ which may be substituted, an amino group, mono- or di-substituted C, in ~ C ₆ alkylamino Group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms. Alkylcarbonylamino group of C i Ce, alkoxycarbonylamino group of CC e, C t C alkylsulfonylamino group of e, arylsulfonylamino group which may be substituted, C! Include Al Kirukarubo alkenyl group ~ C _6, a carboxyl group, alkoxycarbonyl alkylsulfonyl group C i to C _6, alkyl force Rubamoiru group C i to C ₆ mono- or di-substituted, from 1 to 3 heteroatoms 1 to 3 substituents independently selected from a 4- to 9-membered cyclic rubamoyl group, a cyano group or a nitro group (two adjacent substituents may be A benzene ring which may have a benzene ring,

C ring is a halogen atom, an optionally substituted alkyl group of C ~ C ₆ also, human Dorokishiru group, an optionally substituted C i C e alkoxy group, optionally substituted C, of ~ C ₆ Arca Noi Ruo carboxy group, it may also be substituted I § Li Roiruokishi group, it may also be substituted I § Li - Rumechiruokishi group, C ₃ ~ C! . Cycloalkoxy group, cycloalkadienyl Noi Ruo alkoxy group of C ₃ ~ C ₁ 0, amino group, mono- or di-substituted C! Alkylamino amino group of ~ C _6, 1 ~ 3 or may also be 4-9 membered contain heteroatoms of the cyclic § Mi amino group, an alkylcarbonyl amino group of C! C e, alkoxy of C i C e Carbonylamino group, C i Ce alkylsulfonylamino group, optionally substituted arylsulfo 1 to 3 substituents independently selected from a nilamino group, a cyano group, or a nitro group (two adjacent substituents may be bonded to each other to form a ring) 3. The pyridobenzothiazine derivative according to claim 1, which represents a benzene ring which may have a benzene ring. I will provide a.

 The present inventors have the following general formula (2)

(In the formula, R ³ is a hydrogen atom or a C i C alkyl group, R ⁴ is a hydroxyl group, a C i C alkoxy group, a benzyloxy group or a reactive residue, even if the A ring is a halogen atom or is substituted. Good C i -C ₆ alkyl group, optionally substituted aryl group, hydroxy group, optionally substituted C -C ₆ alkoxy group, C ₃ -C i ₀ cycloalkoxy group An optionally substituted C ₁ to C ₆ alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylylmethyloxy group, a C ₃ to C. cycloalkanoyloxy group, optionally substituted (^ - (^ (^ alkylthio group, a substituted alkyl sulfide alkylsulfonyl group may optionally have good C i C e, alkylsulfonyl group - C ₆ which may be substituted, amino amino group, Al of ~ C ₆ mono or di-substituted Ruami amino group, one to three of the may contain heteroatoms 4-9 membered cyclic Amino group, an alkylcarbonyl amino group of _{C ~ C 6, C i C} e alkoxycarbonyl § Mi amino group, Alkylsulfonylamino group of C i Ce, arylsulfo which may be substituted Nilamino group, C i -C ₆ alkylcarbonyl group, formyl group, carbonyl group, C i -C ₆ -alkoxycarbonyl group, mono- or di-substituted C i -C ₆ alkyl carbonyl group, 1 1 to 3 substituents independently selected from a 4- to 9-membered cyclic rubamoyl group, a cyano group or a ditoro group which may contain up to 3 heteroatoms (neighboring Two substituents may be bonded to each other to form a ring), a homo- or heterocyclic ring which may have a halogen atom for the C ring, an optionally substituted C i -C ₆ An alkyl group, a hydroxyl group, an optionally substituted C i C alkoxy group, an optionally substituted C i C ₆ alkanoyloxy group, an optionally substituted aryloyloxy group, Optionally substituted arylmethyloxy group, C ₃ -C ₁₀ Lower alkoxy, C g C i. A cycloalkanoyloxy group-amino group, a mono- or di-substituted CiCe alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, C alkylcarbonyl § amino group ~C _6, C i C e of Arukokishikaru Boniruami Roh groups, C alkylsulfonyl § Mi amino group of ~ C _6, optionally substituted § Li one also be Rusuruhoniruami amino group, Shiano group or It may have from 1 to 3 substituents independently selected from among the nitro groups (two adjacent substituents may combine with each other to form a ring) Shows a benzene ring. )

And a salt, hydrate and solvate thereof.

The present inventors have the following general formula (3)

(Wherein, R ³ is a hydrogen atom or a C i Ce alkyl group, and R ⁵ is

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, X is a halogen atom or 0 S 0 ₂ R ⁶ (where R ⁶ is optionally substituted C) i-C ₆ alkyl group, aryl group which may be substituted), C ring is a halogen atom, and optionally substituted C! -C ₆ alkyl group, hydroxy group, optionally substituted C i Ce alkoxy group, optionally substituted C i -C ₆ alkanoyloxy group, optionally substituted Li Roiruokishi group, optionally substituted § reel methyl O alkoxy group, C ₃ ~ C t. The alkoxy group, C ₃ -C ₃ . Cycloalkadienyl Noi Ruo alkoxy group, amino group, mono- or di-substituted alkylamino amino group of C i~ C _6, 1~ 3 amino 4 may contain a hetero atom 9-membered cyclic § Mi amino group A C i -C ₆ alkylcarbonylamino group, a C t -C ₆ alkoxycarbonyl amino group, a C i -C ₆ alkylsulfonylamino group, a substituted or unsubstituted arylsulfonylamino group. 1 to 3 substituents independently selected from a group, a cyano group or a nitro group (two adjacent groups And the substituents may be bonded to each other to form a ring). The present invention provides a pyridobenzothiazine derivative represented by or a salt, hydrate and solvate thereof.

 The present inventors have the following general formula (4)

(Wherein, R ³ is a hydrogen atom or a C i Ce alkyl group, and R ⁵ is

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, and the ring C is a halogen atom, an optionally substituted C ₆ -C ₆ alkyl group, a hydroxyl group, or a substituted benzene ring. Optionally substituted C i Ce alkoxy group, optionally substituted C i Ce alkanoloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethylo group alkoxy group, C ₃ ~ C i. The alkoxy group of the mouth, C ₃ -C i. A cycloalkanoyloxy group, an amino group, a mono- or di-substituted alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, C i to C ₆ alkylcarbonyl amino group, alkoxycarbonyl amino group of _{C i~ C 6, C! C} fj alkylsulfonyl § Mi amino group of substituted 1 to 3 substituents each independently selected from a arylsulfonylamino group, a cyano group and a nitro group (two adjacent substituents are bonded to each other to form a ring A benzene ring which may have The present invention provides a pyridobenzothiazine derivative represented by or a salt, hydrate and solvate thereof.

 The present inventors have the following general formula (2)

(Wherein, R ³ is a hydrogen atom or a C i Ce alkyl group, R ⁴ is a hydroxyl group, a C alkoxy group, a benzyloxy group or a reactive residue, and each of the A rings is independently selected from 1 to 3 (Optionally, two adjacent substituents may be bonded to each other to form a ring), a homo- or heterocyclic ring, and the C-ring may have 1 to 3 substituents. (The two adjacent substituents may be bonded to each other to form a ring).

And a salt, hydrate and solvate thereof represented by the following general formula (5)

(Wherein: and ¹ and R ² are the same or different and each represents a hydrogen atom or C The group and 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). The present invention provides a method for producing a compound or a salt thereof, a hydrate and a solvate according to claim 1 by reacting the compound represented by the formula or a salt, hydrate and solvate thereof.

 The present inventors have the following general formula (6)

(In the formula, R ³ is a hydrogen atom or an alkyl group of CiCe, R ⁷ is a hydroxyl group, an alkoxy group of C to C ₆ , a benzyloxy group,

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, X is a halogen atom or 〇S 0 ₂ R ⁶ (R ⁶ is a halogen-substituted C i- C ₆ alkyl group, aryl group which may be substituted), and ring C has 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). Represents an optionally substituted benzene ring. ) Or a salt, hydrate or solvate thereof with a pyridobenzothiazine derivative represented by the following general formula (7)

(Wherein Υ is a halogen atom, OS〇 ₂ R ⁶ (R ⁶ is the same as described above), B (R ⁸ ) 2 (R ⁸ is a hydroxyl group, a C i -C ₆ alkyl group or a C i -C ₆ Or an alkoxy group, or R ⁸ may be bonded to each other to form a ring.), MgBr or ZnCl, and the A ring are each independently selected from 1 to 3 substituents (The two or more adjacent substituents may be bonded to each other to form a ring.) A homo- or heterocyclic ring which may have a compound represented by the following formula: 3. A method for producing the pyridobenzothiazine derivative or the salt, hydrate and solvate thereof according to 1 or 3.

 The present inventors have the following general formula (8)

2 〇

(Wherein R ³ is the same or different and is a hydrogen atom or a C ₆ -C ₆ alkyl group, R ⁷ is a hydroxyl group, a C! -C ₆ alkoxy group, a benzyloxy group,

(R ¹ and R ² are the same or different and are each a hydrogen atom or an alkyl of C i Ce And the ring B and the ring B represent a benzene ring which may have 1 to 5 substituents (two adjacent substituents may combine with each other to form a ring). ) Or a reactive residue, Z is hydroxyl, X (X is a halogen atom or an OS 0 ₂ R ⁶ (R ⁶ is Kill group optionally C i C e be halogen-substituted, optionally substituted Ariru Group)) or A ring (where A ring is independently selected from 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) An aryl or heterocyclic ring which may be present), and P represents 0 or 1. ) Or a salt, hydrate or solvate thereof represented by the following general formula (9)

(Wherein, R ³ , R ⁷ and Z are the same as above, and m represents p + 1 or 2.) or a salt, hydrate or solvate thereof.

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

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

The present inventors require that the pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof be contained as a pharmaceutical composition. It is intended to provide a preventive or therapeutic agent for dysuria including bladder dysfunction such as urinary frequency and urinary incontinence characterized by the following. -The present inventors have provided a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition, which is characterized by ulcerative colitis and Crohn's disease. And a prophylactic or therapeutic agent for gastrointestinal diseases comprising:

 The inventors of the present invention provide a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition, which is characterized by X-ray irradiation, chemotherapeutic agent, The present invention provides a preventive or therapeutic agent for vomiting induced by migraine, postoperative illness, gastrointestinal motility depression, side effects of drug administration, and the like.

 The present inventors have ascertained tachykinin-related asthma, cough, and the like, comprising a pyridobenzothiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provide therapeutic agents for pain, migraine, toothache, rheumatoid arthritis, etc.

Here, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The C i -C ₆ alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a hexyl group and the like. The alkoxy group of c ₁ to c ₆ means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a t-butoxy group, a hexoxy group, or the like. The cycloalkoxy group of C ₃ ~ C i 0, cyclo propyl O alkoxy group, cyclobutyl O alkoxy group, means a Shikuropenchiruo alkoxy group, Kishiruokishi group cyclohexylene. c ₃ ~ c _1. The cycloalkanoyloxy group means a cyclopropanoyloxy group, a cyclopentanoyloxy group, a cyclopentanoyloxy group, a cyclohexanoyloxy group and the like. The C i -C ₆ alkylcarbonyl group means an acetyl group, a propionyl group, a butyryl group or the like. C The alkoxycarbonyl group of i to C _6, main butoxycarbonyl group, refers to E-butoxycarbonyl group, a propoxycarbonyl group, it isopropoxy force Lupo sulfonyl group, t one-butoxycarbonyl group, a hexyl O propoxycarbonyl two Le group I do. The alkyl carba model I le group C i to C ₆ mono- or di-substituted, methylcarbamoyl group, E Ji carbamoyl group, propyl force Rubamoiru group, Lee an isopropyl force Rubamoiru group, t Buchiruka Rubamoiru group, the alkoxy carbamoyl group A dimethylcarbamoyl group, a getylcarbamoyl group, a dibutyl pill carbamoyl group, a diisopropyl propyl carbamoyl group, a dibutyl carbamoyl group, and a dihexyl carbamoyl group. A 4- to 9-membered cyclic rubamoyl group which may contain 1 to 3 heteroatoms is defined as azetidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group, 4-methylbiperidyl group ACiCe alkylthio group means a carbonyl group, a morpholinylcarbonyl group, a thiomorpholinylcarbonyl group, a piperazinylcarbonyl group, a 4-methylpiperazinylcarbonyl group, etc. , Ethylthio, propylthio, isopropylthio, t-butylthio, hexylthio and the like. The alkylamino group of CiCe includes a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a t-butylamino group, a hexylamino group, a dimethylamino group, a acetylamino group, and a dipropylamino group. , Diisopropylamino group, dibutylamino group, dihexylamino group and the like. The 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms includes azetidino group, pyrrolidino group, piperidino group, 4-methylbiperidino group, morpholino group and thiomorpholino. Group, piperazino group, 4-methylbiperazino group and the like. The CiCe alkylcarbonylamino group means an acetylamino group, a propionylamino group, a petyrylamino group and the like. C i C s The alkoxycarbonylamino group of the above means a methoxycarbonylamino group, an ethoxycarbonylamino group, a t-butoxycarbonylamino group, a hexyloxycarbonylamino group and the like.

The alkylsulfonylamino group of C e means a methylsulfonylamino group, an ethylsulfonylamino group, and the like. The arylsulfonylamino group means a phenylsulfonylamino group, a 4-methylphenylsulfonylamino group, a naphthylsulfonylamino group, or the like. The homocyclic ring of the ring A means a benzene ring, a naphthylene ring or the like. The ring A is a 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 3 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom, or It means a 9- or 10-membered fused aromatic heterocycle. Optionally be substituted with an alkyl group which may _6, halogen atom, human Doroki sill group, an alkoxy group of C i C e, alkylthio group CC e, amino group, alkylamino of C ~ C ₆ mono or di-substituted amino group from 1 to 3 may also be 4-9 membered contain heteroatoms of the cyclic amino groups, Hol Miruami amino group, an alkylcarbonyl § Mi amino group of C i to C _6, of C ₁ ~ C ₆ alkylsulfonyl amino group, means an alkyl group optionally C ₁ ~ C ₆ optionally having 1 to 5 substituents selected from such optionally substituted Ariru Suruhoniruami cyano group. The optionally substituted C i C alkoxy group means a halogen atom, a hydroxyl group, a d-C ₆ alkoxy group, a C-C ₆ alkylthio group, an amino group, a mono- or di-substituted C i C s of alkylamino amino group from 1 to 3 of the TeroHara child to contain an be 4-9 membered cyclic amino groups, Horumiruami amino group, an alkylcarbonyl amino group of C ₁ ~ C _6, C i A C t C ₆ alkoxy group which may have 1 to 5 substituents selected from an alkylsulfonylamino group of Ce and an optionally substituted arylsulfonylamino group, etc. I do. Keys that may be replaced The Rukanoiruokishi group, a halogen atom, arsenic Dorokishiru group, C ₁ alkoxy group ~ c _6, C alkylthio group i to-C _6, an amino group, an alkylamino group of C ₁ -C ₆ mono- or di-substituted, 1 A 4- to 9-membered cyclic amino group, formylamino group, C i Ce alkylcarbonylamino group, C i Ce alkylsulfonylamino group, which may contain up to 3 heteroatoms; Ci to C ₆ alkanoyloxy group (acetyloxy group, propionyl group) which may have 1 to 5 substituents selected from optionally substituted arylsulfonylamino groups and the like. Oxo group, isopropionyloxy group, hexanoyloxy group, etc.). The optionally substituted aryloxy group includes a halogen atom, a C i C alkyl group, a hydroxy group, a C i C alkoxy group, a C to C ₆ alkylthio group, an amino group, a mono or mono group. Di-substituted CiC alkyl amino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, formyl amino group, CiC alkylcarbonyl amino group Aryloxy which may have 1 to 5 substituent (s) selected from a group, a C to C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, etc. A benzoyloxy group, a naphthyloxy group, a pyridyloxy group, a pyrimidyloxy group, a quinolyloxy group, an indyloxy group, and the like. Substituted and which may § reel methyl O alkoxy group, c androgenic atom, an alkyl group of C i C e, human Dorokishiru group, an alkoxy group of C ^ C s, alkylthio group of C i to C _6, amino group, mono- or alkylamino amino group of C i C s disubstituted from 1 to 3 hetero atoms may be free Ndei to the 4-9 membered cyclic amino group, formylamino group, a C i ~ C ₆ alkylcarbonyl § Mi amino group, C t~ alkylsulfonyl Niruami amino group of C _6, may have a selected 1-5 substituents from such optionally substituted § Li one also be Rusuruhoniruami amino group Ariel Mech Roxy group (phenylmethyloxy group, naphthylmethyloxy group, pyridylmethyloxy group, -quinolylmethyloxy group, indolylmethyloxy group, etc.). The substituents on these § Li one Rusuru Honiruami amino group also, Bruno, mouth Gen atom, an alkyl group of ci~ c _6, human de port hexyl group, C! C e alkoxy group, an alkylthio group, an amino group, alkylamino amino group of C i to C ₆ mono- or di-substituted, 1-3 may contain a hetero atom of 4-9 membered cyclic § Mi amino group, Horumiruami amino group, C i to C ₆ alkylcarbonyl § Mi amino group of, have a C i alkylsulfonyl amino group-C _6, substituted 1 also selected from good § Li one Rusuruhoniruami amino group or the like have to 5 substituents Means an arylsulfonylamino group. 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, an ^-(^ (^ alkyl group, a hydroxyl group, a C i -C ₆ alkoxy group, a C i -C ₆ alkylthio group, an amino group, § Rukiruami amino group of C ~ C ₆ mono or di-substituted, 1-3 may contain a hetero atom of 4-9 membered cyclic amino group, formylamino group, alkyl C i to C ₆ Aryl which may have 1 to 5 substituents selected from a carbonylamino group, an alkylsulfonylamino group of CiCe, an optionally substituted arylsulfonylamino group, etc. A phenyl group, a naphthyl group, etc. The optionally substituted alkylthio group includes a halogen atom, a hydroxyl group, a C alkoxy group, and (^ ~. (; Alkylthio group, amino group, mono- or alkyl Ruami amino group of C i to C ₆ disubstituted from 1 to 3 may contain heteroatoms of 4-9 membered cyclic amino group, Horumiruami Bruno group, C. 1 to alkylcarbonylamino group C _6, C i C e alkylsulfonyl § Mi amino group, an optionally substituted good i § reel sulfonyl § amino group 1-5 amino substitution selected from etc. It means an alkylthio group which may have a group. The substituents on these alkyl sulfide El group, a halogen atom, human Dorokishi group, an alkoxy group of C ~ C _6, C alkylthio group ~ C _6, § Mi amino group, mono- or di-substituted C i to alkylamino group C _6,. 1 to 3 or even be 4-9 membered contain heteroatoms of the cyclic § Mi amino group, formyl Ruami amino group, an alkylcarbonyl § Mi amino group of C i to C _6, An alkylsulfenyl group which may have 1 to 5 substituents selected from a C i C fi alkylsulfonylamino group, a substituted or unsubstituted arylsulfonylamino group (a methylsulfinyl group, Ethylsulfinyl group, propylsulfinyl group, etc.). The optionally substituted alkylsulfonyl group includes a halogen atom, a hydroxy group, a C to C ₆ alkoxy group, a C i to C ₆ alkylthio group, an amino group, a mono- or di-substituted C t to alkylamino amino group of C _6,. 1 to 3 or even be 4-9 membered contain heteroatoms of the cyclic § Mi 'amino group, formyl Ruami amino group, an alkylcarbonyl § Mi amino group of C i to C ₆ , (^ To (^ (^) alkylsulfonylamino group optionally having 1 to 5 substituents selected from an optionally substituted arylsulfonylamino group, etc. (Methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, etc.) The reactive residue is a halogen atom, 111-imidazolyl group, 412-trophenoxy group, imidoylsuccinate group, etc. Means halo The emissions may be substituted C ί~ 0 ₆ alkyl group, 1 to 3 full Tsu atom or chlorine It means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a hexyl group, etc. which may be substituted by an atom. The ring which may be formed by bonding R ⁸ to each other is 10 (CH ₂ ) ₂₀ —, 10 CH (Me) CH (Me) 0 —, — OC (Me) ₂ C (M e) ₂ 0— or _ 0 (CH ₂ ) ₃ means one or more.

Preferred compounds of the present invention include N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro-1-N-methyl-15-oxo-17-phenyl-1-H-pyri. De [1,2,3-de] — 1,4-benzothiazine_6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-7_ (3— 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzothiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) ) Benzyl] 1 7— (2,4-dichloromethyl) 1,2,3-dihydro-1-N-methyl-5-oxo-1 5H-pyrido [1,2,3-de] — 1,4— Benzothiazine-6-carboxamide, Ν— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-methyl 1-5-oxo-1 7-phenyl-5-pyrido [1,2,3-de] — 1,4-benzothiazine-1 6-carboxamide 1,1,1—dioxide, N— [3,5— Bis (trifluoromethyl) benzyl] — 2,3-dihydro-1- 7- (3-methoxyphenyl) 1-N-methyl-1 5-oxo-1 5H-pyrido [1,2,3-de] -1 1,4-benzothiazine-6-carboxamide_1,1-dioxide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-5-oxo 1- 7-phenyl-1 5H-pyrido [1,2,3-de] — 1,4—benzothiazine-1 6-carboxamide 1—oxide, N— [3,5-bis (trifluoromethyl) benzyl ] — 2, 3 — 7- (3-Methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3—de] —1,4-Benzothiazine-6_carboxamido-1—oxoxide , Ν— [3,5—Bis (trifluoromethyl) benzyl] —7— (2,4-dichlorophenyl) -1,2,3-dihydro-1-methyl-5-oxo-5-pyrido [1,2,3-de]-1,4,1-benzothiazine-1 6-carboxamido 1-oxide, Ν- [3,5-bis (trifluoromethyl) benzyl] _7 1 (2,4- Dichlorophenyl) 1,2,3-dihydro-1-methyl—5—oxo-5-pyrido [1,2,3-de] —1,4—benzothiazine-16—carboxamido 1,1— Dioxide, N _ [3,5-bis (trifluoromethyl) benzyl] — 2,3 —dihydro-1 7- (3-fluorophenyl) -1-N-meth Cyl-5-oxo-5H-pyrido [1,2,3—de] —1,4-benzothiazine-16—carboxamide, N— [3,5—bis (trifluoromethyl) benzyl]-7- (3-cyclomouth phenyl) 1,2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine-16—carboxamide, N _ [3,5_bis (trifluoromethyl) benzyl] — 2,3—dihydro-1-N-methyl-7— (3—nitrophenyl) -15—oxo-5H—pyrido [1,2, 3-de]-1, 4-Benzothiazine-6-carboxamide, 7-(3-aminophenyl)-N-[3, 5-bis (trifluoromethyl) benzyl]-2, 3-dihydro-N —Methyl-5-oxo-5H—pyrid [1,2,3-de] _1,4-benzothiazine-16—carboxamide, Ν— [3,5 —Bis (trifluoromethyl) benzyl] -7- (3,5-dichlorophenyl) -1,2,3—dihydro-1-methyl-5—oxo-1-5-pyrido [1,2,3- de]-1,4—Benzothiazine-1 6—carboxamide, Ν— [3,5—bis (tri) Fluoromethyl) benzyl] —7— [3,5-bis (trifluoromethyl) phenyl] —2,3-dihydro-1-N-methyl-1-5-oxo-5H-pyrido [1,2,3-de ] — 1,4-benzothiazine-6-carboxamide, N— [3,5_bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-17- (4-methylphenyl) —5— Oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 1 7— (4-Methoxyphenyl) 1 N-methyl-15-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzothiazine-16-carboxamide, N- [3,5 —Bis (trifluoromethyl) benzyl] — 2,3-dihydro-1- (4-fluorophenyl) -1- N-Methyl-5-oxo-5H-pyrido [1,2,3-de]-1,4-benzothiazine — 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] — 7— (4-chlorophenyl) 1,2,3-dihydro-1-N—methyl-5-oxo-5H—pyrido [1,2,3-de] —1,4-benzothiazine-6-carboxami N, N— [3,5-bis (trifluoromethyl) benzyl] —7— (3-chloro-1-4-fluorophenyl) -1,2,3-dihydro N-methyl-1-5-oxo-5H—pyri De [1,2,3-de] — 1,4-benzothiazine-1 6-carboxamide, Ν— [3,5_bis (trifluoromethyl) benzyl] —2,3-dihydro-1-methyl-1 7 _ (4-methyl-3-nitrophenyl) 1-5-oxo-5-pyrido [1,2,3-de]-1,4, -benzothiazine _6-ca Boxamide, N_ [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-7- (2-methoxyphenyl) -1-N-methyl-1-5-oxo-5H-pyrido [1,2 , 3— de] — 1,4,1-benzothiazine-1-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro N-methyl-1 7- (1-naphthyl) -1 5-oxo-1 5H-pyrido [1,2,3- de] — 1, 4-Benzothiazine-1 6-force lipoxamide, N— [3,5-bis (trifluoromethyl) benzyl] — 2,3-Dihydro-1- 7— (4-formylphenyl) -1-N-methyl — 5-oxo-1H-pyrido [1,2,3-de] —1,4-benzothiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2, 3-dihydro-1-N-methyl-5 1-year-old quinol 5 H-pyrido [1,2,3-de] 1-1,4-benzothiazine 7- [3- (trifluoromethyl) phenyl] — 6— Carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro N-methyl-1- 7— (3-me Tylphenyl) 1-5-oxo-5H-pyrido [1,2,3-de] — 1,4,1-benzothiazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) Benzyl] — 2,3-dihydro-1- 7- (3-fluorophenyl N-methyl-5-oxo-5H-pyrido [1,2,3-de]-1,4, benzothiazine-1 6-carboxami 1-Oxide, N— [3,5-bis (trifluoromethyl) benzyl] —71- (3-chlorophenyl) 1-2,3-dihidro N-methyl-1-5-H —Pyrido [1,2,3-de]-1,4-benzothiane-6-carboxamido 1-oxide, N— [3,5-Bis (trifluoromethyl) benzyl] —2,3-dihydro-one N-methyl-1-7- (3-nitrophenyl) -1-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzothiazine-1-6 —Carboxamido 1 —Oxoxide, 7- (3-aminophenyl) -1-N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl

5-oxo-5H-pyrido [1, 2, 3-de] — 1, 4-benzo Thiazine-1 6-carboxamide 1-oxide, N— [3,5-bis (trifluoromethyl) benzyl] —7— (3,5-dichlorophenyl) 1-2,3-dihydro-1-N-methyl 5-oxo-5H-pyrid [1,2,3-de] — 1,4-benzothiazine-1-6-carboxamide-1-1-oxide, N— [3,5-bis (trifluoromethybenzyl) ] — 7— [3,5-bis (trifluoromethyl) phenyl—2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,, 4-benzothiazine-1 6-carboxamide 1-oxide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-17- (4-methylphenyl) — 5—oxo 5 H—pyrid [1, 2, 3-de] — 1,

4-benzothiazine 6-carboxamide 1-oxide, N— [3

5-bis (trifluoromethyl) benzyl] — 2,3-dihydro-1-N-methyl-1- (4-methoxyphenyl) -1-5-oxo-5H-pyrido [1,2,3-de ] — 1,4-Benzothiazine-1 6 _carboxamide 1 1 —Oxide, Ν— [3,5 _bis (trifluoromethyl) benzyl] —2,3-Dihidro 7 _ (4-Fluorophenyl) ) 1-Methyl-5-oxo-5-pyrido [1,2,3-de] —1,4, -benzothiazine-16-carboxamide-1 1-oxide, 3— [3,5-bis ( Fluoromethyl) benzyl] 1 7— (4—Clo-phenyl) 1,2,3-dihydro-1- (methyl-5-oxo) -5-pyrido [1,2,3-de]-1,4— Benzothiazine

6—Carboxamide 1—Oxide, N— [3,5-Bis (trifluoromethyl) benzyl] -17— (3-Cro-4-4-phenyl) 1-2,3-Dihydro N— Methyl-5-oxo-5H-pyrido [1,2,3-de]-1,4-benzothiazine-16-carboxamido-1-oxide, N- [3,5-bis (trifluoromethyl) Benzyl] — 2,3-Dihydro-1-N-methyl-1- 7- (4-Methyl-3-nitrophenyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1,4 N-zothiazine-1 6-carboxamide 1 1-oxide, N- [3,5-bis (trifluoromethyl) benzyl] _2,3-dihydro-1 7- (2-methoxyphenyl) -1 N-methyl-1 5 — Oxo-5H—pyrido [1,2,3—de] —1,4-Benzothiazine-6-carboxamide—1oxide, N— [3,5-bis (trifluoromethyl) benzyl] 1 2,3-Dihydro_N-methyl-7- (1-naphthyl) -1-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzothiazine-1-6-carboxamide 1-1 Oxide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-7- (4-formylphenyl) ) 1-N-methyl-1-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzothiazine-1 6-carboxamide 1 1-oxide, N— [3,5-bis (Trifluoromethyl) benzyl] — 2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine-1 7— [3— (Trifluoromethyl) phenyl] — 6—force ruboxamide 1 —oxide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihidrogen N—methyl-1 7— (3 -Methylphenyl) 1-5-oxo-5H-pyrido [1,2,3-de]-1,4, -benzothiazine-16-carboxamide 1-oxide, N- [3,5-bis ( Trifluoromethyl) benzyl] -2,3-dihydro-1- 7- (3-fluorophenyl) -1-N-methyl-5-oxo-5H-pyri [1,2,3—de] — 1,4,1-Benzothiazine-16-carboxamide-1,1,1-dioxide, N— [3,5-Bis (trifluoromethyl) benzyl] —7— (3— 2,3-dihydro-1-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 1 7— (3–2 trophenyl) — 5-oxo-1 5 H—pyrid [1,2,3-de] —1,

4-benzothiazine-6-carboxamide 1,1-dioxide, N- [3,5-bis (trifluoromethyl) benzyl] — 7— (3,

5-Dichlorophenyl) 1,2,3-dihydro-1-N-methyl-5-oxo-5 H-pyrido [1,2,3-de] —1,4_benzothiazin-1-6-carboxamide 1 , 1-dioxide, N— [3,5-bis (trifluoromethyl) benzyl] -1-7— [3,5-bis (trifluoromethyl) phenyl] —2,3-dihydro N-methyl-5 —Oxo 1 5 H—pyrido [1,2,3—de] —1,4,1-benzodiazine 6—carboxamide 1,1,1-dioxide, N— [3,5-bis (trifluoromethyl) Benzyl] 1,2,3-dihydro-1-N-methyl-7- (4-methylphenyl) -15-oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine-16-carboxamide 1,1,1-dioxide, N— [3,5_bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (4-Methoxyphenyl) 1 N-methyl-5-oxo-5 H-pyrido [1,2,3-de] -1, 4-benzothiazine-1 6 _carboxamide-1 1,1 —dioxy 、, Ν— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1- 7- (4-fluorophenyl) 1-methyl-1 5-oxo-1 5Η-pyrido [1, 2,3—de] — 1,4-Benzothiazine-1 6-carboxamide 1,1-dioxide, N_ [3,5-bis (trifluoromethyl) benzyl] —7— (4-chlorophenyl) 1-2 , 3-Dihydro-1-N-methyl-5-oxo-5H-pyrid [1,2,3-de1—1,4—benzothiazine-1-6-carbo Oxamide 1, 1-dioxide, Ν-[3,5-bis (trifluoromethyl) benzyl]-7-(3-chloro-1-fluorophenyl)-2, 3-dihydro-1-methyl- 5-oxo-1 5 Η-pyrido [1,2,3-de]-1,4, -benzothiazine-1 6-carboxamide 1,1,1-dioxide, Ν— [3,5-bis (trifluoromethyl) benzyl ] — 2,3-Dihydro-1-methyl-1- (4-methyl-3-nitrotropenyl) -1-5-oxo-5-pyrido [1,2,3-de] —1,4-benzothiazine 6-carboxamide 1,1,1-dioxide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7 _ (2-methoxyphenyl) -1-N—methyl—5 —Oxo 1 5 H—pyrido [1,2,3—de] —1,4-benzothiazine-6—carboxamido 1,1,1 Dioxide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7- (4-formylphenyl) -1-N-methyl-5-oxo-5H—pyrido [1,2 , 3-de] — 1,4-benzothiazine-1 6-carboxamide 1, 1 —dioxide, Ν— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1- —Methyl-1-5-Kiso-1-7— [3- (Trifluoromethyl) phenyl] —5-dipyrido [1,2,3-de] —1,4-Benzothiazine-1-6-carboxamide-1, 1-dioxide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-1 7— (3-methylphenyl) 1-5-oxo-5H— Examples of pyrido [1,2,3-de] -11,4-benzothiazine-16-carboxamide 1-oxide are exemplified.

When the compound of the present invention forms a salt, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, lingoic acid, tartaric acid, citrate, Methanesulfonic acid, p-toluenes Examples thereof include pharmacologically acceptable salts with organic acids such as sulfonic acid, salicylic acid, stearic acid, and palmitic acid.

 The compound of the present invention or a salt thereof includes 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.

 丫 (V)

B three steps

 (First step)

In this step, the compound (I) (R ³ and the ring C are the same as described above) and the compound (II) (R ⁹ is the same or different and a C i -C ₆ alkyl group or a benzyl group) are reacted to obtain a compound (III) (R ³ , R ⁹ and the C ring are the same as described above). In this reaction, the compound (II) is used in an amount of 1 to 20 equivalents, preferably 1 to 5 equivalents, to 100 to 300 ° (preferably 150 to 250 °) relative to the compound (I). When using a solvent, use an inert solvent that does not participate in the reaction, for example, xylene, mesitylene, nitrobenezen, diphenyl ether, dausam (diphenyl alcohol and biphenyl). Mixtures) are used. (Second step)

In this step, the hydroxyl group of compound (III) R ³ , R ⁹ and the C ring are the same as described above) is converted into X (X is the same as above) to obtain compound (IV) (X, R ³ , R ^{The 9} and C rings are the same as described above). In this step, for example, when X is a chlorine atom, the chlorinating agent is a phosphine such as triphenylphosphine, tributylphosphine or triphenyloxyphosphine, and carbon tetrachloride, N-chlorosuccinimide. Alternatively, the reaction is carried out using chlorine, thionyl chloride, oxychloride, 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, if 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 chlorination using a corresponding brominating agent. When X is 〇S 0 ₂ R ⁶ (R ⁶ is the same as above), the sulfonating reagent used in this reaction is methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride Trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, N-phenyltrifluoromethanesulfonyl imide, etc. are used, and the reaction is carried out in a solvent in triethylamine, tributylamine, diethylamine, etc. The reaction is performed in the presence of a base such as isopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, butyllithium, and lithium diisopropylamine. As the solvent, an inert solvent which does not participate in the reaction, preferably dichloromethane, methane, tetrahydrofuran or the like is used. The reaction is carried out at a temperature of -80 ° C to 100 ° C, preferably -30 ° C;

(Third step) In this step, compound (IV) (X, R ³ , R ⁹ and C ring are the same as described above) and compound (V) (Y and A ring are the same as described above) are reacted with a transition metal catalyst such as palladium or nickel complex. This is a process for producing a compound (VI) (R ³ , R ⁴ and the A ring are the same as described above) by the cross-coupling reaction below. This reaction is preferably performed using an inert solvent that does not participate in the reaction. For example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, Trahydrofuran, dioxane, dichloromethane, toluene, ethanol, water and the like can be exemplified. These solvents are used alone or in a mixture at any ratio. Examples of the palladium complex used in this reaction include palladium chloride, palladium acetate, acetylacetonato palladium, and tetrax (triphenylphosphine) palladium. The nickel complex used in this reaction is bis

(Acetyl acetate) Nickel, bis (1,5-cyclohexene) nickel, tetrakis (triphenylphosphine) nickel, etc. can be exemplified. These palladium or nickel complexes are used in the range of 0.01 to 1 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound (IV). In the case where a ligand for a palladium or nickel complex is used in this reaction, triphenylphosphine, tri0-tolylphosphine, tri1-2-furylphosphine, 1,

Examples thereof include 2-bis (diphenylphosphino) ethane, 1,1,1-bis (diphenylphosphino) phenyl, and 2,2,1-bis (diphenylphosphino) -11,1, -binaphthyl. These ligands are used in a range of 0.2 to 5 equivalents, preferably 0.3 to 3 equivalents, based on the palladium or nickel complex. X of compound (IV) is 0

For S_〇 ₂ R ^6, together with the palladium or nickel complex, it can be used copper iodide or lithium chloride Lai de like if necessary. This reaction is preferably performed in the presence of a suitable base, for example, organic compounds such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, and collidine. Inorganic bases such as a base, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate or triphosphate lithium can be exemplified. 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 carried out 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 and (R ⁸⁾ not _2), HB (R ⁸⁾ ₂ or (B (R ⁸⁾ _{2) 2} was reacted to give et compound (IV) (X is B (R ⁸⁾ ₂₎ or Compound (VI) is produced by reacting compound (V) (Y is B (R ⁸ ) ₂ ) with compound (V) (but Y is not B (R ⁸ ) ₂ ) or compound (IV) You can do it. This time is a production intermediate obtained compound (IV) (in 8 (1¾ ⁸⁾ 2) or the compound (V) (Y is _{^{B (R 8) 2),}} A ring same above) is a single It can be subjected to the next step after isolation and purification, or can be continuously applied to the next step without isolation and purification.

 (Fourth step)

In this step, the compound (VII) (R ³ , R ⁴ and the ring A are the same as described above) and the compound (VII) (R ¹ R ² and the ring B are the same as described above) are condensed to obtain the compound (VIII) (RR ² , R ³ , ring A, ring B and ring C are the same as described above). As a condensing agent used when R ⁴ is a hydroxyl group in the condensation reaction of this step, dicyclohexyl carpoimide (DCC), 3-ethyl-1- (3-dimethylaminopropyl) carposimid hydrochloride (EDCI) or Dimethylimidazonium Chloride (DMC) and the like, which are added in solid form or as a solution dissolved in a suitable solvent. When a base is used in this condensation reaction, alkali carbonates such as sodium hydrogencarbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholin, diazabicyclo [5 . 4.0] —7-Pendine, pyridine, 4-dimethylaminopyridine or tertiary amines such as 1,8-bis (dimethylamino) naphthalene. As the solvent used in the present condensation reaction, an inert solvent which does not participate in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, tetrahydrofuran , Dioxan, ethyl ether, dimethoxetane, ethyl acetate, dichloromethane and the like are used. This condensation reaction proceeds smoothly from-20 ° C to 80 ° C. In the condensation reaction of this step, R ⁴ is a carboxylic acid represented by a reactive residue (eg, a halogen atom, 1-imidazolyl group, 412 trophenoxy group, imidyloxy succinate group, etc.) In the case of imidazolide of carboxylic acid, active ester of carboxylic acid, mixed anhydride of carboxylic acid (for example, anhydride with ethyl carbonate, anhydride with isobutyl carbonate, etc.) or symmetric acid anhydride, Organic bases such as triethylamine, diisoprovirethylamine, pyridine and 4-dimethylaminopyridine, in the presence of inorganic bases such as sodium bicarbonate and carbon dioxide, or In the presence of N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, tetrahydrofuran, dioxane, etilue It can be carried out by treating in a solvent such as ether, dimethoxetane, ethyl acetate, toluene, dichloromethane and the like at 120 to 80 ° C. for 30 minutes to 48 hours. In the condensation reaction of this step, when R ⁴ is an ester residue such as an alkoxy group of benzyl, a benzyloxy group, etc. Or in the presence of tetraisopropoxytitanium, or an acid catalyst such as p-toluenesulfonic acid, or sodium methoxide or potassium

— N, N-Dimethylformamide, N, N-Dimethylacetamide, Dimethylsulfoxide, Acetonitrile, Tetrahydrofuran, Dioxane in the presence of bases such as t-butoxide and sodium hydride The treatment can be carried out by treating in a solvent such as toluene, xylene, or dichloromethane at room temperature to 150 ° C. for 30 minutes to 48 hours.

2 0 Z 〇

 ίΊΧ) (X)

As shown in the fifth step, compound (X) (R ³ , R ³ , Z and m is converted to the compound (IX) (R ³ , R ³ , Z and p are the same as described above) by oxidation. The same) can be manufactured. This oxidation reaction can be performed according to a known method (for example, “Experimental Chemistry Lecture, 4th edition, VI, pp. 350-372, (1991), Maruzen”).

R 5

 (iv) (XV) As shown in the sixth step, compound (XIII) can also be produced from compound (XI) and compound (XII). In this step, the compound (XII) is used in an amount of 1 to 10 equivalents with respect to the compound (XI), and an acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium butoxide, hydrogen N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene in the presence of a base such as sodium fluoride It can be carried out by treating in a solvent such as these at 50 to 150 ° C for 30 minutes to 48 hours. Compound (VIII) can be produced from the obtained compound (XIII) 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, p-toluenesulfonic acid is used by using 1 to 10 equivalents of the compound (XII) with respect to the compound (XIV). Acid catalysts such as sodium or bases such as sodium methoxide, potassium-t-butoxide, sodium hydride, etc. in the presence of N, N-dimethylformamide, N, N-dimethylacetamide , Dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, etc. by treating at 50 to 150 ° C for 30 minutes to 48 hours. be able to. 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 a usual method or a method analogous thereto (eg, neutralization).

The compound (1) or a salt thereof of the present invention can be used alone or in combination with one or more pharmaceutically acceptable auxiliaries as a pharmaceutical composition. Excipients (eg, starch, lactose, calcium phosphate, calcium carbonate, etc.), lubricants (eg, magnesium stearate, calcium stearate, talc, stearate, etc.), binders (eg, starch, lactose, Crystalline cellulose, carboxymethylcellulose, gum arabic, polyvinylpyrrolidone, alginic acid, etc., disintegrants (eg, talc, carboxymethylcellulose calcium, etc.), diluents (eg, physiological saline, glucose, mannitol, lactose) Solution, etc.) and tablets, capsules, granules, It can be administered orally or parenterally in the form of powders, fine granules, ampules or injections. 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. For example, the compound of the present invention (1) or a salt thereof may be administered to mammals including humans. 0.0 0.001 to 300 mg / kg / day It is. For example, administration is performed once or several times a day. BEST MODE FOR CARRYING OUT THE INVENTION

 NK1 receptor antagonism

 The method of S. Dion et al. (“Life Sciences, Vol. 41, pp. 2269 (1989))” was partially modified.

After bruising the guinea pig, blood was removed from the carotid artery and the ileum was removed. The removed ileum was suspended in a Magnus tube with a load of 1 g. Specimen responses were recorded isotonic. Nutrient solution, using a T Yrode solution 〇 ₂ 95% was bubbled C 0 ₂ 5% of the mixed gas, liquid temperature and 3 2 ° C. The experiment was started after the guinea pig ileum was suspended in a Magnus tube and allowed to equilibrate for 20 minutes. The concentration response curve of substrate P in the absence of the test compound was used as the 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. p A ₂ value is S chi 1 d of the method ( "Breakfast literals I Tsu Xu journal 'O Breakfast' off Amako Russia Gee (Brit. J. Pharmaco" 1 4 Certificates, 4 page 8 (1 9 5 9 years) ), And the results are shown in Table 1.

 The composition of the Tyrode solution was as follows. N a C l; 1 3 6.

9, KC1; 2.7, CaC122H20; 2.5, MgCl2

_{6 H 2 0; 1. 0,} N aH 2 PO 4, 2 H 2 O; 0. 4, N aH C 0 3; 1 1. 9, glucose; 1 1. 1 (mM)

【table 1】

Example number pA value (nM)

1 0 42. 1 1 1 2 5.2 Example 1

7-chloro-1,2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine-16-carboxylic acid ethyl ester (123.9mg, 0.40mmol) and Tetrataxyl phenylphosphine palladium (18.5 mg, 16.0 zmol, 0.04 eq.) Is dissolved in 5 ml of benzene and 1 ml of a 2M sodium carbonate aqueous solution, and 1,4-diphenyl phenyl borate (146.3 mg, 1.2 mmol) is dissolved. A dioxane (2 ml) solution was added, and the mixture was heated to reflux. In the middle, tetrakistriphenylphosphine palladium (18.5 mg, 16.0 mol, 0.04 eq.) Was added, and the mixture was heated to reflux for 10 hours. Water and methylene chloride were added to the reaction solution, and the mixture was extracted three times with methylene chloride. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel gel chromatography (methylene chloride: ethyl acetate 20: 1) to give colorless crystals. 2,3-dihydro-1-5-oxo-7-phenyl-5H-pyrido [1,2,3-de] — 1,4-benzothiazine-6-potency Ethyl rubonate (116.6mg, 83%) I got

EIMS m / z: 351 (M ⁺ ) Example 2

 According to the same method as in Example 1, 7-chloro-1,2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzothiazine-6 —Ethyl carboxylate (309.8 mg, l.Ommol) and 3 —Methoxyphenylboronic acid (303.9 mg, 2.0 mmo to yellow oily substance 2,3-dihydro-17- (3-methoxyphenyl) 1-5-year-old 1 H-Bide [1,2,3-de] -l, 4-benzothiazine-16-carboxylic acid ethyl ester (341.9 mg, 90%) was obtained.

EIMS m / z: 381 (M ⁺ ) Example 3

According to the same method as in Example 1, 7-chloro-2,3-dihydro-15-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzo- Thiazine-I 6-ethyl ribonate (309.8mg, l.Ommol) and 2,

4—Dichlorophenyl boric acid (381.6 mg, 2.0 mmol) to give pale yellow amorphous 7- (2,4-dichlorophenyl) -1,2,3-dihydro-1

5-Oxo-5H-pyrido [1,2,3-de] 1-1,4-benzothiazine-16-potassium ethyl ester (372.5 mg, 89%) was obtained. EIMS m / z: 419 (M ⁺ ) Example 4

According to a method similar to that of Example 1, 7-clo mouth-2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzothiazine-16 —Ethyl carboxylate 1,1,1—Colorless crystalline 2,3-dihydro-5-oxo-1-7-phenyl-5H from dioxide (136.7 mg, 0.40 mmol) and phenylboric acid (146.3 mg, 1.2 mmol) —Pyrido [1,2,3-de] -1, 4-benzothiazine-1-6-ethyl carboxylate 1,1,1-dioxide (I09.7 mg, 72%) was obtained. EIMS m / z: 383rM ⁺ ) Example 5

 In the same manner as in Example l, 7-chloro-23-dihydro

5-oxo-5H-pyrido [12,3-de -1,4-benzothiazine-6-potassium ethyl ester 11-dioxide (136.7mg, 0.40mmol) and 3-methoxy Phenylboric acid (182.4 mg: 1.2 mmo to colorless crystals of 2,3-dihydro 7_ (3-methoxyphenyl) —5-oxo-5H-pyrido [1,2,3- de] _1,4-Benzothiazine-16-carboxylic acid ethyl ester 1,1,1-dioxide (122.7 mg, 74%) was obtained.

EIMS m / z: 413 (M ⁺ ) Example 6

2,3-Dihydro-5-oxo-1 7-phenyl-1 5 H-pyrido [1 2,3-de] — 1,4-benzothiazine-1 6-ethyl ether Dissolve the ester (110.8 mg, 0.315 mmol) and the hydroxylic rim (88.4 mg, 1.58 ol, 5 eq.) In ethanol (4.5 ml) -water (0.5 ml), Heated 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, and the mixture was stirred at room temperature for 0.5 hour. The residue obtained by distilling off thionyl chloride was dissolved in 3 ml of methylene chloride, and 0.5 ml of triethylamine and 0.081 ml of N-methyl-1,5-bis (trifluoromethyl) benzylamine were added, followed by stirring 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 resulting residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate 20: 1). The obtained crystals are washed with hexane to give colorless crystals of N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1-N-methyl-1-5-oxo-1-7-phenyl-1. 5H-Pyrido [1,2,3-de] -1,4, -benzothiazine-16-carboxamide (135.3mg, 76%) was obtained. mp.177-180 ° C

_{Anal: C 2 8 H 2 o} F 6 N 2 O 2 S and to calculated values C 59.78%, H 3.58%, N 4.98%;

 Found C 59.85%, H 3.50%, N

5.07%

EIMS m / z: 562 (M ⁺ ) Example 7

According to a method similar to that of Example 6, 2,3-dihydro-7- (3-methoxyphenyl) -15-oxo-5H-pyrido [1,2,3-de] -1, 4—Benzothiazin 1-6—Carboxylic acid ethyl ester (341.9 mg, 0.896 mmol) and N-methyl-3,5—bis (trifluomethyl) benzylamine 0.23 ml from light brown amorphous N— [3,5— Bis (trifluoromethyl) benzyl] -1,2,3-dihydro 7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4— Benzothiazine 16-carboxamide (466.7 mg, 89%) was obtained.

EIMS m / z: 592 (M ⁺ ) Example 8

According to the same method as that of Example 6, Ί 一 (2,4-dichlorophenyl) — 2,3-Dihydro-5-oxo-5 H-pyrido [1,2,3-de] — 1,4-benzothia-zin-6-carboxylic acid ethyl ester (360. Omg, 0.857mmol) and N —Methyl-1,3,5-bis (trifluoromethyl) benzylamine from 0.22 ml of colorless amorphous N— [3,5-bis (trifluoromethyl) benzyl] —7— (2,4-dichlorophenyl) one 2,3-Dihydro-1-N-methyl-1-oxo-5H-pyrido [1,2,3-de] — 1,4-benzothiazine-1-6-ruboxamide (477. Omg, 88%) Obtained.

EIMS m / z: 630 (M ⁺ ) Example 9

 By a method similar to that of Example 6, 2,3-dihydro-5-oxo-7-phenylu-5H-pyrido [1,2,3-de] —1,4—benzothiazine-1 —Carboxylic acid ethyl ester 1, 1 —Dioxide (109.7 mg, 0.286 mmol) and N-methyl_3,5—bis (trifluoromethyl) benzylamine 0.074 ml from N- [3,5—bis as colorless crystals (Trifluoromethyl) benzyl] _ 2,3-dihydro-1-N-methyl 5-oxo-7-phenyl-5H-pyrido [1,2,3-de] —1,4-benzothiazine-6- Carboxamido 1,1-dioxide (26.3 mg, 15%) was obtained.

EIMS m / z: 594nVI ⁺ ) Example 10

By a method similar to that of Example 6, 2,3-dihydro-1 7- (3-methoxyphenyl) -15-oxo-5H-pyrido [1,2,3-de] —1, 4 Colorless crystals of N- [3 from 1-benzothiazine-6-carboxylic acid ethyl ester 1,1,1-dioxide (122.7 mg, 0.297 mmol) and N-methyl-1,3,5-bis (trifluoromethyl) benzylamine 0.076 ml , 5—Bis (trifluoromethyl) benzyl] — 2,3-Dihydro 7— (3-Methoxyphenyl) 1-N-methyl-1-5-oxo—5H—pyrido [1,2,3, -de ]-1, 4-Benzothiazine-16-carboxamide-1,1 dioxide (33.4 mg, 18%) was obtained. EIMS m / z: 624 (M ⁺ ) Example 1 1

Ph O

N— [3,5-bis (trifluoromethyl) benzyl] —2,3—dihydro-1-N-methyl-5-oxo-7-phenyi-5H-pyrido [1,2,3-de] Dissolve 1,4-benzothiazine-16-carboxamide (68.4 mg, 0.122 mmol) in 2 ml of methylene chloride, add m-chloroperbenzoic acid (23.1 mg, 0.134 mmol) under ice cooling, and stir for 3 hours. . m-Black perbenzoic acid (5.0 mg, 0.029 mmol) was added 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 residue was purified by silica gel column chromatography (methylene chloride: methanol: aceton 20: 1: 1) to give a colorless amorphous N— [3,5-bis (trifluoromethyl) benzyl] -2 , 3-Dihydro-1-N-methyl-5-oxo—7-Phenyl-5H-pyrido [1,2,3-de] —1,4-Venzothiazine-16—Carboxamide-1 1-year-old oxide (70.5 mg, 100%).

EIMS m / z: 578 (M ⁺ ) Example 1 2

N— [3,5-Bis (trifluoromethyl) benzyl] —2,3 dihydro-17- (3-methoxyphen-2-N-methyl-1-oxo) was prepared in the same manner as in Example 11. One 5H—Pirido [1,2,3 -de]-1, 4_Benzothiazine _ 6 —Carboxamide (116.5 mg, 0.2 mmo to colorless amorphous N— [3,5 _Bis (trifluoromethyl) benzyl)] — 2,3 —Dihydro-7 — (3—Methoxyphenyl) — N-methyl-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzothiazine-6-carboxamide-1-1-oxide ( 118.4 mg, 99%).

FABMS m / z: 609 (M + H ⁺ )

 According to the same method as in Example 11, 1- [3,5_bis (trifluoromethyl) benzyl] _7_ (2,4-dichlorophenyl) -1,2,3-dihydro-1-methyl-methyl Colorless amorphous N— [3,5-bis (to) is obtained from 5-oxo-5-pyrido [1,2,3-de] -1,4-benzothiazine-16-carboxamide (126.3 mg, 0.2 mmol). Trifluoromethyl) benzyl] — 7— (2,4-dichlorophenyl) 1-2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de]-1,, 4-Benzothiazine-1-carboxamide 1-oxide (112.8 mg, 87%) was obtained.

EIMS m / z: 646 (M +) Example 14

 N- [3,5—Bis (trifluoromethyl) benzyl] — 7— (24 dichloromouth phenyl) 1,2,3—dihidr N-methyl-1 5—oxo-1 5H—pyrido [1,2 , 3-de] — 1, 4-benzothiazin-16-carboxamide (144.0 mg, 0.228 mmol) was dissolved in 2 ml of methylene chloride, and under ice-cooling, perfluorobenzoic acid (86.6 mg, 0.502 mmol). ) And stirred for 3 hours. 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), and the 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-16-carboxamido 1,1 —dioxy (70.5 mg, 100%).

EIMS m / z: 662 (M ⁺ ) Reference example 1

2,3-Dihydro-7-hydroxy-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine-16-carboxylic acid ethyl ester (514.7 mg, 1.77 mmol) The residue was dissolved in methylene chloride (150 ml), m-chloroperbenzoic acid (670.7 mg, 3.89 mmol) was added under ice cooling, and the mixture was stirred for 2 hours. m — Mouth perbenzoic acid (335.4 mg, 1.94 mmol; 134. Omg, 0.776 mmol) was added twice and stirred for 2 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained crystals are washed with ethyl acetate, and colorless crystals of 2,3-dihydro-7-hydroxy-5-oxo-5H-pyrido [1,2,3-de] —1,4—benzothiazine 1-Carboxylic acid ethyl ester 1,1-dioxide (580.8 mg, 100%) was obtained. Reference example 2

2, 3 —Hydroxy 7 —Hydroxy 5 _Oxo 1 5 H—Pyrido [1,2,3-de] — 1,4-benzothiazine-16-carboxylic acid ethyl ester 1,1,1 dioxide (574.7 mg, 1.78 mmol) and triphenylphosphine (933.8 mg, 3.56 mmol) in acetone After dissolving in 20 ml of toluene, carbon tetrachloride (1.06 ml, 10.7 mmol) was added, and the mixture was refluxed under heating for 3 hours. Triphenylphosphine (93.4 mg, 0.356 mmol) and carbon tetrachloride (0.11 ml, 110 mmol) were added, and the mixture was refluxed for 2 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride), and the obtained crystals were recrystallized from hexane-ether to give colorless crystals of 7-chloro-1,2-dihydro-1. 5-oxo-5H-pyrido [1,2,3-de] -1,4, -benzothiazine-16-carboxylic acid ethyl ester 1,1,1-dioxide (489.5 mg, 80%) was obtained. Reference example 3

According to the same method as in Reference Example 2, 2,3-dihydro-7-hydroxy-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine From 6-carboxylic acid ethyl ester (1.17 g, 4.0 mmol), colorless crystalline 7-chloro-1,2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] — 1 1,4-Benzothiazine-1-ethyl ruvonic acid ester (ll ⁶ g, 93%) was obtained. Example 15

N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1 1,4-benzothiazine-16-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 sodium carbonate The mixture was dissolved in an aqueous solution of sodium hydroxide (2.3 ml) and dissolved in tetrakis (triphenylphosphine) palladium (88.7 mg, 77 mol). The mixture was heated and refluxed at 100 ° C. for 2 hours. Methylene chloride was added to the reaction solution, which was 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 colorless crystals of N- [3,5-bis (trifluoromethyl). Benzyl] — 2,3-Dihydro-1 7- (3-fluorophenyl) 1-N-methyl-5-oxo-5 H-pyrido [1,2,3-de] —l, 4-benzothiazine-1 6-carboxami (203 mg, 91%).

EIMS m / z: 580 (M ⁺ )

_{HRMS (EI): C 28 H} 19 F 7 N 2 0 2 S and to Calculated: 580.1055

 Found: 580.1045

Anal: C ₂₈ H ₁₉ F ₇ N ₂ 0 ₂ S Calculated as C 57.93%, H 3.30¾, N 4.83% Measured value C 58.09 °, H 3.42¾, N 4.73% Example 1-6

N- [3,5-Bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro N-methyl-15-oxo-5 From H-pyrido [1,2,3-de] —1,4-benzothiazine-6-carboxamide (200mg, 0.38mmol) and 3—clophenylphenylborate (180mg, 1.2mmol), colorless amorphous N- [3,5—Bis (trifluoromethyl) benzyl] —7— (3 chlorophenyl) 1-2,3—dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3 -de] —1,4-benzothiazine-16-carboxamide (212 mg, 92%) was obtained.

_{HRMS (EI): C 28 H} 19 C1F 6 N 2 0 2 S and to Calculated: 596.0760

 Found: 596.0779

Anal: calculated as C ₂₈ H ₁₉ ClF ₆ N ₂ 0 ₂ S C 56.33¾, H 3.21%, N 4.69

Actual value C 56.28%, H 3.20%, N 4.51% Example 1 Ί

According to a method similar to that of Example 15, N— [3,5_bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro N-methyl-15—oxo-5 From H-pyrido [1,2,3-de] —1,4-benzothiazine-16-carboxamide (200mg, 0.38mmol) and 3—nitrophenylborate (192mg, 1.2mmol), colorless amorphous N- [ 3,5—Bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-1 7— (3--2-trophenyl) -1-5-oxo—5H—pyrido [1,2,3-de] — 1, 4-benzothiazine-16-carboxamide (217 mg, 93%) was obtained.

EIMS m / z: 607 (M ⁺ )

_{HRMS (EI): C 28 H} 19 F 6 N 3 0 4 S and to Calculated: 607.1000

 Found: 607.0962

_{Anal: C 28 H 19 F 6} N 3 0 4 S and to calculated values C 55.36%, H 3.15%, N 6.92%

Actual value C 55.41¾, H 3.27%, N 6.68%

In the same manner as in Example 15, N- [3,5_bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro N-methyl-15-oxo-5 H-pyrido [1,2,3-de] — 1,4-benzothiazine-6—carboxamide (200mg, 0.38mmol) and 3-aminophosphorus boric acid (179mg, 1.2mmol) 7- (3—Aminophenyl) -1-N— [3,5—Bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N—methyl-1-5-Hexo—5H—pyrido [1,, [2,3-de] 1-1,4-benzothiazine-16_carboxamide (133 mg, 60%) was obtained.

FABMS m / z: 578 (+ H ⁺ )

_{^{HRMS (FAB +): C 28}} H 22 F 6 N 3 0 2 S and to Calculated: 578.1337

Obtained value: 578.1340 Example 19

According to a method similar to that of Example 15, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro N-methyl-15—oxo-5 From H-pyrido [1,2,3-de] -1, 4-benzothiazine-16-carboxamide (200mg, 0.38mmol) and 3,5-dichlorophenylboric acid (220mg, 1.2mmol), the colorless amorphous N — [3,5—Bis (trifluoromethyl) benzyl] — 7— (3,5—Dichlorophenyl) -1,2,3—dihidro N—Methyl-5—Oxo-1 5H—Pyrido [1,2 , 3-de] — 1,4-benzothiazine-16-carboxamide (162 mg, 675 were obtained.

EIMS m / z: 630 (M ⁺ )

_{HRMS (EI): C 28 H} 18 C1 2 F 6 N 2 0 2 S and to Calculated: 630.0370

 Found: 630.0327

Anal: C ₂₈ H ₁₈ Cl ₂ F ₆ N ₂ 0 ₂ S Calculated value C 53.26% H 2.87%, N 4.44% Actual value C 53.40%, H 2.83%, N 4.29% Example 20

According to a method similar to that of Example 15, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro N-methyl-15—oxo-5 H-pyrido [1,2,3-de] — 1,4-benzothiazine 16-carboxamide (200mg, 0.38mmol) and 3,5-bis (trifluoromethyl) phenylboronic acid (297mg, 1.2mmol) N- [3,5-Bis (trifluoromethyl) benzyl] -1- 7- [3,5-bis (trifluoromethyl) phenyl], colorless and amorphous N-methyl-5-oxo-1 5 H-pyrido [1,2,3-de] -1, 4-benzothiazine-16-carboxamide (142 mg, 53%) was obtained.

EIMS m / z: 698 (M ⁺ )

_{HMS (EI): C 30 H} 18 F 12 N 2 0 2 S Calculated: 698.0897

 Found: 698.0863

Anal: C ₃₀ H ₁₈ F ₁₂ N ₂ 0 ₂ S Calculated as C 51.58%, H 2.60%, N 4.01%

Actual value C 51.54%, H 2.57%, N 4.00%

According to a method similar to that in Example 15, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-2,3-dihydro-1-N-methyl-15-oxo-5H —Pyrido [1,2,3-de] _1,4-benzothiazine—6—Carboxamide (200mg, 0.38mmol) and 4-methylphenylboronic acid (157mg, 1.2mmol) from N- [3, 5—Bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl_7— (4-methylphenyl) -1-5-oxo—5H-pyrido [1,2,3-de] —1 There was obtained 1,4-benzothiazine-16-carboxamide (211 mg, 95%).

EIMS m / z: 576 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 2 S and to Calculated: 576.1306

 Found: 576.1266

Anal: calculated as C ₂₉ H ₂₂ F ₆ N ₂ 0 ₂ S C 60.41%, H 3.85%, N 4.86 °

Measured value C 60.49¾, H 3.79% N 4.71% Example 22

In the same manner as in Example 15, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3—dihydro N-methyl-15—oxo-5H— From the pyrido [1,2,3-de] —1,4-benzothiazine-16-carboxamide (200mg, 0.38mmol) and 4-methoxyphenylboronic acid (175mg, 1.2mmol), a colorless amorphous N— [3, 5 —Bis (trifluoromethyl) benzyl] — 2,3 dihydro 7 — (4-Methoxyphenyl) 1 N—methyl 1 5 —oxo 1 5 H—pyrid [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 0 3 S and to Calculated: 592.1255

 Found: 592.1247

Anal: calculated as C ₂₉ H ₂₂ F ₆ N ₂ 0 ₃ S C 58.78%, H 3.74%, N 4.73%

Measured value C 58.81¾, H 3.66%, N 4.63% Example 23 „

According to a method similar to that of Example 15, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-1,2,3-dihydro N-methyl-15-oxo-5 From H-pyrido [1,2,3-de] —1,4-benzothiazine-6—carboxamide (200mg, 0.38mmol) and 4—fluorophenylboronic acid (161mg, 1.2mmol), colorless amorphous N— [ 3,5—Bis (trifluoromethyl) benzyl] — 2,3 —dihydro-1 7 — (4-fluorophenyl) 1 N—methyl-5 —oxo 1 5 H—pyrido [1,2,3—de ] _ 1,4 Benzothiazine-16-carboxamide (190 mg, 85%) was obtained.

EIMS m / z: 580 ( ⁺ )

_{HRMS (EI): C 28 H} 19 F Y N 2 0 2 S and to Calculated: 580.1055

 Found: 580.1022

Anal: calculated as C ₂₈ H ₁₉ F ₇ N ₂ 0 ₂ S C 57.93%, H 3.30%, N 4.83%

Actual value C 58.21¾, H 3.24%, N 4.79% Example 2 4

N— [3,5—Bis (trifluoromethyl) benzyl] —7—chloro-1,2,3-dihydromethyl N-methyl-1 5—oxo-1 5 by the same method as in Example 15. H-pyrido [1,2,3-de] — 1,4-I-benzothiazine-16-carboxamide (200mg, 0.38mmol) and 4-chlorophenylboronic acid (180mg, 1.2minol) [3,5—Bis (trifluoromethyl) benzyl] _7— (4—Chlorophenyl) 1,2,3—Dihidro N—Methyl-5—Oxo—1 5H—Pyrido [1,2,3—de ] — 1,4-benzothiazine-16-carboxamide (217 mg, 95%) was obtained.

EIMS m / z: 596 (M ⁺ )

_{HRMS (EI): C 28 H} 19 C1F 6 N 2 0 2 S and to Calculated: 596.0760

 Found: 596.0756

Anal: C ₂₈ H ₁₉ ClF ₆ N ₂ 0 ₂ S Calculated as C 56.33%, H 3.21¾, N 4.69%

Actual value C 56.53%, H 3.14%, N 4.50%

In the same manner as in Example 15, N— [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3—dihydro N-methyl-15-oxo-5H-pyrido 1, 2,3 — de] — 1,4-Benzothiazine-16-carboxamide (200 mg, 0.38 mmol) and 3-chloro-1--4-fluorophenylboronic acid (201 mg, 1.2 mol) from colorless N-morphous N— [3,5—Bis (trifluoromethyl) benzyl] — 7— (3-chloro-1-4-fluorophenyl) -1,2,3-dihydro-N-methyl-5-oxo-5H-pyrido [1, 2, 3 — de]-1, 4 -Benzothiazine-16-carboxamide (226 mg, 96%) was obtained. EIMS m / z: 614 (M ⁺ )

_{HRMS (EI): C 28 H} 18 C1F 7 N 2 0 2 S and to Calculated: 614.0666

 Found: 614.0679

Anal: C ₂₈ H ₁₈ ClF ₇ N ₂ 0 ₂ S Calculated as C 54.69% H 2.95¾ _S N 4.56%

Measured value C 54.93¾, H 3.14¾, N 4.42% Example 26

According to the same method as in Example 15, N— [3,5—bis (trifluoromethyl) benzyl] -17—chloro-1,2,3—dihydro N-methyl-15—oxo-5 H-pyrido [1,2,3-de] — 1,4-benzothiazine-6-carboxamide (200mg, 0.38mmol) and 4-methyl_-3-nitrotrophenyl boric acid (208mg, 1.2mmol) Morphas N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N—methyl-1 7— (4-methyl-1-3--2-trophenyl) 1—5—oxo-1 5 H-pyrido [1,2,3-de] -1, 4-benzothiazine-16-carboxamide (220 mg, 92%) was obtained. EIMS m / z: 621 ( ⁺ )

_{HRMS (EI): C 29 H} 21 F 6 N 3 0 4 S and to Calculated: 621.1157

 Found: 621.1144

_{Anal: C 29 H 21 F 6} N 3 calc C 56.04¾ as _{0 4 S, Η 3.41%,} Ν 6.76%

Actual value C 56.28¾, Η 3.41¾, Ν 6.59% Example 2 7

N— [3,5-Bis (trifluoromethyl) benzyl] —7—chloro-1,2,3-dihydro N-methyl-15—oxo-5 From H-pyrido [1,2,3-de] —1,4-benzothiazine_6—carboxamide (200mg, 0.38mmol) and 2-methoxyphenylboronic acid (175mg, 1.2mmol), N of colorless amorphous — [3,5—Bis (trifluoromethyl) benzyl] — 2,3—Dihydro 7— (2—Methoxyphenyl) 1 N—methyl 1 5 —oxo 1 5 H—pyrido [1,, [2,3-de] —1,4-benzothiazine-16-carboxamide (219 mg, 96%) was obtained.

EIMS m / z: 592 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 3 S and to Calculated: 592.1255

 Found: 592.1214

Anal: Calculated as C ₂₉ H ₂₂ F ₆ N ₂ 0 ₃ S C 58.78%, H 3.74¾, N 4.73%

Measured value C 58.86¾, H 3.69%, N 4.61% Example 2 8

In the same manner as in Example 15, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-2,3-dihydro N-methyl-15-oxo-5H-pyrido [1,2,3-De] — 1,4-Benzothiazine 16-carboxamide (200 mg, 0.38 mmol) and 1-naphthyl boric acid (198 mg, 1.2 mmol) were converted to the colorless amorphous N— [35 —bis ( Trifluoromethyl) benzyl] — 2,3 —dihydro N-methyl-1 7— (1 —naphthyl) -1 5 —oxo-5 H-pyrido [1 2,3 — de] —1,4 —benzothiazine 1 6 — Carboxamide (230 mg, 98%) was obtained.

EIMS m / z: 612 (M ⁺ )

_{HMS (EI): C 32 H} 22 F 6 N 2 0 2 S and to Calculated: 612.1306

Obtained value: 612.1290 Example 2 9

According to a method similar to that in Example 15, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-2,3-dihydro N-methyl-15-oxo-5H— From the pyrido [1,2,3-de] —1,4-benzothiazine-6-carboxamide (200mg, 0.38mmol) and 4-formylphenylboronic acid (172mg, 1.2mmol), N- [3,5 —Bis (trifluoromethyl) benzyl] — 2,3 —Dihydro 7 — (4-Formylphenyl) 1 N—methyl-1 5 —oxo 1 5 H—pyrido [1,2,3, -de] —1, 4 Benzothiazine-16-carboxamide (218 mg, 96%) was obtained.

EIMS m / z: 590 (M ⁺ )

_{HRMS (EI): C 29 H} 20 F 6 N 2 0 3 S and to Calculated: 590.1099

 Found: 590.1129

Anal: C ₂₉ H ₂₀ F ₆ N ₂ 0 ₃ S Calculated as C 58.98%, H 3.41¾, N 4.74%

Measured value C 59.18% H 3.43¾, N 4.61% Example 30

According to a method similar to that of Example 15, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-2,3-dihydro N-methyl-15-oxo-5H-pyri [1,2,3-de] — 1,4-Benzothiazine-16-carboxamide (200mg, 0.38mmol) and 3-

(Trifluoromethyl) phenyl boric acid (218 mg, 1.2 mmol) from colorless amorphous N— [3,5-bis (trifluoromethyl) benzyl) -1,2,3—dihydro-1-N-methyl-1-5-oxo-1 There was obtained 5H-pyrido [1,2,3-de] -1, 4-benzothiazine-1 7- [3— (trifluoromethyl) phenyl] -16-carboxamide (220 mg, 91 mg).

EIMS m / z: 630 (M ⁺ )

_{HRMS (EI): C 29 H} 19 F 9 N 2 0 2 S and to Calculated: 630.1024

 Obtained: 630.0981

Anal: calculated as C ₂₉ H ₁₉ F ₉ N ₂ 0 ₂ S C 55.24%, H 3.04¾, N 4.44%

Actual value C 55.25%, H 2.99% N 4.37% Example 3 1

According to a method similar to that of Example 15, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-2,3-dihydro N-methyl-5-oxo-5H-pyri From [1, 2, 3-de] — 1, 4-benzothiazine — 6 — carboxamide (200 mg, 0.38 mmol) and 3 — methylphenylborate (156 mg, 1.2 mmol) from colorless amorphous N— [3, 5, — Bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-1- (3-methylphenyl) -1-5-oxo—5H-pyrido [1,2,3-de] 1-1,4 There was obtained 1-benzothiazine 16-carboxamide (201 mg, 91%).

EIMS m / z: 576 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 2 S and to Calculated: 576.1306

 Found: 576.1270

Anal: C ₂₉ H ₂₂ F ₆ N ₂ 0 ₂ S Calculated value C 60.41%, H 3.85%, N 4.86 °

Measured value C 60.68%, H 4.14¾, N 4.70% Example 3 2

N- [3,5—Bis (trifluoromethyl) benzyl] —2,3 dihidro 7— (3—Fluorophenyl) -1-N—methyl-1-5-oxo-1 5H—pyrido [1,2,3 -de] — 1,4-benzothiazine-6-carboxamide (58.1 mg, 0.1 mmol) was dissolved in methylene chloride (1 ml), and then under ice-cooling, 3-chloroperbenzoic acid (19.Omg, O.llmmol) and stirred for 1 hour. Methylene chloride was added to the reaction solution, which was washed sequentially with water, a 2 M aqueous solution of sodium carbonate and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (ethyl acetate), and N- [3,5-bis (trifluoromethyl) benzyl] _2,3 as colorless crystals was obtained. — Dihydro 7 — (3 — fluorophenyl) mono N — methyl mono 5 — oxo mono 5 H — pyrido [1, 2, 3, 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 0 3 S and to Calculated: 596.1005

 Found: 596.1023

Anal: C ₂₈ H ₁₉ F ₇ N ₂ 0 ₃ S 0.2H ₂ 0 Calculated value C 56.04%, H 3.26¾, N 4.67 Measured value C 55.77%, H 3.29%, N 4.56% Example 3 3

According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —7— (3-chlorophenyl) -1,2,3-dihydro-1-N-methyl-5— Oxo-1 5H-pyrido [1,2,3-de] 1-1,4-benzothiazine-16-carboxamide (60. Omg, O.lOmmol) from the colorless amorphous N- [3,5-bis (Trifluoromethyl) benzyl] — 7— (3-chlorophenyl) 1-2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1 , 4-Benzothiazine-1-6-carboxamide 1-oxide (50.0 mg, 815 was obtained.

EIMS m / z: 612 (M ⁺ )

_{HRMS (EI): C 28 H} 19 C1F 6 N 2 0 3 S and to Calculated: 612.0709

 Found: 612.0718

Anal: C ₂₈ H ₁₉ ClF ₆ N ₂ 0 ₃ S Calculated as 0.2 H ₂ 0 C 54.54%, Η 3.17%, Ν 4.54% Observed C 54.49%, Η 3.07¾, Ν

4.43% Example 3 4

According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl—7— (3-nitrophenyl) -15 _Oxo-1 5H-pyrido [1,2,3-de] 1-1,4 Benzothiazine-16-From carboxamide (60. Omg, 99 / mol), colorless amorphous N— [3,5— Bis (trifluoromethyl) benzyl] —2,3—dihydro-1-N-methyl-7— (3—nitrophenyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1,, 4-benzothiazine-1-6-carboxamide-1-1-oxy (52. Omg, 84%) was obtained.

EIMS m / z: 623 (M ⁺ )

_{HRMS (EI): C 28 H} 19 F 6 N 3 0 5 S and to Calculated: 623.0950

 Found: 623.0928

Anal: C ₂₈ H ₁₉ F ₆ N ₃ 0 ₅ S 0 · 5Η ₂₀ Calculated value C 53.17¾, Η 3.19¾, Ν 6.64% Measured value C 53.17%, Η 3.10¾ _S N 6.47% Example 3 Five

o ',

In the same manner as in Example 32, 7- (3-aminophosphinyl) -N- [3,5_bis (trifluoromethyl) benzyl] -2,3-dihydro-1N-methyl-1-5-oxo-1 From 5H-pyrido [1,2,3-de] _1,4-benzothiazine-16-carboxamide (60. Omg, O.lOmmol), a colorless amorphous 7- (3-aminophenol

N— [3,5—Bis (trifluoromethyl) benzyl] —23-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-ben V There was obtained thiazine-16-carboxamide-1oxide (32.9 mg, 53%).

EIMS m / z: 593 (M ⁺ )

_{HRMS (EI): C 28 H} 21 F 6 N 3 0 3 S and to Calculated: 593.1208

 Found: 593.1164

Anal: C ₂₈ H ₂₁ F ₆ N ₃ 0 ₃ S Calculated as 0.5H ₂ 0 C 55.81%, H 3.68¾, N 6.97% Measured value C 55.80¾, H 3.55% N 6.85% Example 3 6

According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —7— (3,5-dichlorophenyl) -1,2,3-dihydro-1-N-methyl-5- Oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-16-carboxamide (50.Omg, 79 / mol) was converted to colorless amorphous N— [3,5-bis ( Trifluoromethyl) benzyl] — 7 — (3,5-dichlorophenyl) 1, 2,3-dihydro N-methyl-5-oxo-5H-pyrido [1,2,3-de]-1 , 4-Benzothiazine-1 6-carboxamide 1-oxide (44. Omg, 86) was obtained.

EIMS m / z: 646 (M ⁺ )

_{HRMS (EI): C 28 H} 18 C1 2 F 6 N 2 0 3 S and to Calculated: 646.0319

 Observed value: 646.0353

Anal: C ₂₈ H ₁₈ Cl ₂ F ₆ N ₂ 0 ₃ S Calculated as 0.2 H ₂ 0 C 51.66%, Η 2.85% Ν 4.30%

 Measured value C 51.81% Η 2.87%, Ν

4.02¾ Example 3 7

In the same manner as in Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —7— [3,5-bis (trifluoromethyl) phenyl] —2,3-dihydro 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzothiazine-16—carboxamide (50.0mg, 72mol) from colorless amorphous N— [3 , 5 —Bis (trifluoromethyl) benzyl Ί-7-[3, 5

—Bis (trifluoromethyl) phenyl] —23-Dihydro N —methyl-5-oxo-5H-pyrido [1,23-de] 1-1,4-benzothiazine-16 —carboxamido-1oxy (42.5 mg, 83%).

EIMS m / z: 714 (M ⁺ )

_{HRMS (EI): C 30 H} 18 F 12 N 2 0 3 S Calculated: 714.0847

 Observed: 714.0853

Anal: C ₃₀ H ₁₈ F ₁₂ N ₂ 0 ₃ Calculated value as SH ₂₀ C 49.19 ° H 2.75 ° N 3.82% Actual value C 49.44¾, H 2.69%, N 3.59% Example 3 8

According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-1 7— (4-methylphenyl) -1 5 —oxo 1 5 H—pyrido [1, 2,3-de] — 1,4 —benzothiazine-1 6 —carboxamide (60. Orag, O.lOmmol) gives the colorless amorphous N— [3, 5 —Bis (trifluoromethyl) benzyl] — 2,3-dihydro N-methyl-1 7 — (4-methylphenyl) 1 5 —oxo-1 5 H-pyrido [1,2,3-de] — 1 There was obtained 1,4-benzothiazine-1-6-carboxamide-1-1-oxy K (57.7 mg ₅ 94%).

EIMS m / z: 592 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 3 S Calculated: 592.1255

 Found: 592.1240

_{Anal: C 29 H 22 F 6} N 2 0 3 S 0.25H 2 0 and to calculate values C 58.34%, H 3.80¾, N 4.69% actual measured value C 58.07%, H 3.54¾, N

4.61% Example 3 9

According to a method similar to that of Example 32, N— [3,5_bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-7— (4—methoxyphenyl) one 5 —oxo-5H-pyrido [1,2,3—de] —1,4—benzothiazine-16 —carboxamide (60. Omg, O.lOmmol) from colorless amorphous N— [3,5— Bis (trifluoromethyl) benzyl] — 2,3-dihydro-1-N-methyl-17- (4-methoxyphenyl) -1-5-oxo-5H-pyrido [1,2,3-de] — 1 , 4-Benzothiazine-16-carboxamide-11-oxide (55.4 mg, 90%) was obtained.

EIMS m / z: 608 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 4 S and to Calculated: 608.1204

 Observed value: 608.1184

Anal: C ₂₉ H ₂₂ F ₆ N ₂ 0 ₄ S Calculated as 0.5 H ₂ 0 C 56.40%, H 3.75% N 4.54% Actual value C 56.46% H 3.61%, N 4.39% Example 4 0

According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (4-fluorophenyl) -1-N—methyl-1 5 —Hydroxy-5H—pyrido [1,2,3-de] —1,4-Benzothiazine-16—carboxamide (60.0mg, O.lOmmol) from the colorless amorphous N— [3,5—bis (Trifluoromethyl) benzyl] —2,3-dihydro-1- (4-fluorophenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4 -Benzothiazine-1 -carboxamide 1 -oxide (58.8 mg, 96%) was obtained.

EIMS m / z: 596 (M ⁺ )

_{HRMS (EI): C 28 H} 19 F 7 N 2 0 3 S and to Calculated: 596.1005

 Found: 596.0986

Anal: C ₂₈ H ₁₉ F ₇ N ₂ 0 ₃ S Calculated as 0.5H ₂ 0 C 55.54% H 3.33¾, N 4.63% Actual value C 55.38%, H 3.23%, N 4.47% Example 4 1

According to a method similar to that of Example 32, Ν— [3,5-bis (trifluoromethyl) benzyl] —7— (4-chlorophenyl) _2,3-dihydro-1-methyl-methyl 5 —oxo-5-pyrido [1,2,3-de] — 1,4 —benzothiazine _ 6 —carboxamide (60. Omg, O.lOmmol) from the colorless amorphous N— [3,5— Bis (trifluoromethyl) benzyl] _7_ (4-chlorophenyl) 1-2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] ーThere was obtained 1,4-benzothiazine-16-carboxamide-11-oxide (57.5 mg, 93%).

EIMS m / z: 612 (M ⁺ )

_{HRMS (EI): C 28 H} 19 C1F 6 N 2 0 3 S and to Calculated: 612.0709

 Found: 612.0726

Anal: C ₂₈ H ₁₉ ClF ₆ N ₂ 0 ₃ S Calculated as C 54.86% H 3.12%, N 4.57%

Measured value C 54.73¾, H 3.28¾, N 4.35¾ Example 4 2

o "In the same manner as in Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —7— (3-chloro-4-fluorophenyl) 1-2,3-dihydro 1 N-methyl-1 5 —oxo-5 H-pyrido [1,2,3-de] — 1,4,1-benzothiazine-16—carboxamide (60.0 mg, 98 mol) from colorless amorphous N — [3,5—Bis (trifluoromethyl) benzyl] — 7— (3-chloro-1-4-fluorophenyl) -1,2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine-16-carboxamide—1—oxide (59.0 mg, 96%) was obtained.

EIMS m / z: 630 (M ⁺ )

_{HRMS (EI): C 28 H} 18 C1F 7 N 2 0 3 S and to Calculated: 630.0615

 Found: 630.0624

Anal: C ₂₈ H ₁₈ ClF ₇ N ₂ 0 ₃ S Calculated as C 53.30%, H 2.88 °, N 4.44%

Actual value C 53.05%, H 3.02%, N 4.20% Example 4 3

According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-17— (4-methyl-1-3-ni Torophenyl) 1 5 —oxo 1 5 H—pyrido [1,2,3-de]-1,4 benzothiazine-1 6 —carboxamide (60.0 mg, 97 mol) from colorless amorphous N— [3, 5—Bis (trifluoromethyl) benzyl] — 2,3-dihydro-1-N-methyl-7- (4-methyl-1-nitrophenyl) -1 5 —oxo-1 5H—Pyrido [1,2,3 -de] — 1,4-benzothiazine-16-carboxamide-1 — oxide (56.7 mg, 925 was obtained.

EIMS m / z: 637 (M ⁺ )

_{HRMS (EI): C 29 H} 21 F 6 N 3 0 5 S and to Calculated: 637.1106

 Found: 637.1110

Anal: C ₂₉ H ₂₁ F ₆ N ₃ 0 ₅ S 0.5H ₂₀ Calculated value C 53.87%, H 3.43%, 6.50% Actual value C 53.99 °, H 3.36¾, N 6.27% Example 4 4

According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7- (2-methoxyphenyl) -N-methyl-5— Oxo-5H-pyrido [1,2,3-de] — 1,4,1-benzothiazine-16-carboxamide (60. Omg, O.lOmmol) from the colorless amorphous N— [3,5-bis (Trifluoromethyl) benzyl] -2,3-dihydro-1 7- (2-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4 1-benzothiazine 16-carboxamide 1 1-year-old oxide (57.7 mg, 94%) was obtained.

EIMS m / z: 608 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 4 S and to Calculated: 608.1204

 Found: 608.1198

Anal: C ₂₉ H ₂₂ F ₆ N ₂ 0 ₄ S 0.5H ₂ 0 Calculated value C 56.40¾, H 3.75%, N 4.54% Actual value C 56.16%, H 3.96%, N 4.34% Example 4 5

According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-1 7— (1-naphthyl) -15—oxo One 5H-pyrido [1,2,3-de]-1,4—benzothiazine-16-carboxamide (60.0mg, 98zmol) was converted to a colorless amorphous N— [3,5—bis (trifluorome Benzyl] —2,3-dihydro-1-N-methyl-1- (1-naphthyl) -1-5-oxo-5H-pyrido [1,2,3—de] —1,4-benzothiazine 6—Carboxamido 1-oxide (40.3 mg, 65%) was obtained.

EIMS m / z: 628 (M ⁺ )

_{HRMS (EI): C 32 H} 22 F 6 N 2 0 3 S and to Calculated: 628.1255

 Found: 628.1226

Anal: C ₃₂ H ₂₂ F ₆ N ₂ 0 ₃ S 0.5H ₂ 0 Calculated value C 60.28 °, H 3.64¾, N 4.39% Actual value C 59.99%, H 3.76%, N 4.11% Example 4 6

According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (4-formylphenyl) -N-methyl-5-oxo One 5H-pyrido [1,2,3-de] — 1,4,1-benzothiazine-16-carboxamide (60. Omg, O.lOmmol) was converted to the colorless amorphous N— [3,5—bis ( Trifluoromethyl) benzyl] -2,3-dihydro-1-7- (4-formylphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4 Nzothiazine 16-carboxamide 1-oxide (27.5 mg, 44%) was obtained.

FABMS m / z: 607 (M + H ⁺ )

_{^{HRMS (FAB +): C 29}} H 21 F 6 N 2 0 4 S and to Calculated: 607.1126

 Obtained value: 607.1118

_{Anal: C 29 H 20 F 6} N 2 0 4 S 0.5H 2 0 and to calculate values C 56.59%, H 3.44%, N 4.55% Found C 56.68¾, H 3.43%, N 4.51¾ Example 4 7

According to a method similar to that in Example 32, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-15-oxo-5H-pyrido [ 1, 2, 3— de] _ 1, 4 — benzothiazine 7 — [3 — (trifluoromethyl) phenyl] 1 6 — carboxamide (60.0 mg, 95 zmol) from the colorless amorphous N— [3, 5—Bis (trifluoromethyl) benzyl] —2,3-Dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4—Benzothiazine-1— 3- (Trifluoromethyl) phenyl] -6-carboxamide-l-oxide (58.6 mg, 95%) was obtained.

EIMS m / z: 646 (M +)

_{HRMS (EI): C 29 H} 19 F 9 N 2 0 3 S and to Calculated: 646.0973

 Observed value: 646.0974

Anal: C ₂₉ H ₁₉ F ₉ N ₂ 0 ₃ S Calculated as C 53.87%, H 2.96¾ ₅ Ν 4.33%

Actual value C 53.82¾, Η3.06% Ν 4.16% Example 4 8

According to a method similar to that of Example 32, N— [3,5-bis (trifluoromethyl) benzyl] _2,3-dihydro-1-N-methyl-17— (3-methylphenyl) -15— Oxo-5H-pyrido [1,2,3-de] — 1,4—benzothiazine-16-carboxamide (60.0mg, O.lOmmol) was converted from the colorless amorphous N— [3,5-bis ( Trifluoromethyl) benzyl] — 2,3-Dihydro-1-N-methyl-1 7 — (3-Methylphenyl) _5 _oxo-1 5H-pyrido [1,2,3-de] —1,4— Benzothiazine-16-carboxamide 1-oxide (61.0 mg, 99%) was obtained.

EIMS m / z: 592 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 3 S and to Calculated: 592.1255

 Found: 592.1265

Anal: C ₂₉ H ₂₂ F ₆ N ₂ 0 ₃ S Calculated as 0.5H ₂ 0 C 57.90 °, H 3.85%, N 4.66% Actual value C 58.10%, H 3.94%, N

4.40% Example 4 9

N- [3,5—Bis (trifluoromethyl) benzyl] —2,3-Dihydro-7- (3-fluorophenyl) -1-N-methyl_5—oxo-1-5H—pyrido [1,2] , 3-de] — 1,4-benzothiazine-16-carboxamide (58.1 mg, O.lOmmol) dissolved in methylene chloride (1 ml), and then under ice-cooling 3-cyclomouth perbenzoic acid (43.2 mg , 0.25 mmol) and stirred for 1 hour. Methylene chloride was added to the reaction solution, and the mixture was washed sequentially with water, a 2 M aqueous solution of sodium hydrogencarbonate, and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was washed with diisopropyl ether, and the colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-7 was obtained. — (3 —Fluorophenyl) 1 N—methyl 1 5 —oxo 1 5 H—pyrido [1,2,3-de] — 1,4,1benzothiazine 1 6 —carboxamido 1,1, dioxide (47.2 mg, 775.

EIMS m / z: 612 (M ⁺ )

_{HRMS (EI): C 28 H} 19 F 7 N 2 0 4 S and to Calculated: 612.0954

 Found: 612.0969.

Anal: C ₂₈ H ₁₉ F ₇ N ₂ 0 ₄ S Calculated as C 54.90%, H 3.13%, N 4.57%

Measured value C 54.77 ° H 3.01%, N 4.56% Example 5 0_

According to a method similar to that in Example 49, N— [3,5-bis (trifluoromethyl) benzyl] -17— (3-chlorophenyl) 1-2,3-dihydro N-methyl-1-5 —Oxo-1 5H—pyrido [1,2,3-de] —1,4,1-Benzothiazine-16—carboxamide (60. Omg, O.lOmmol) from the colorless amorphous N— [3,5— Bis (trifluoromethyl) benzyl] —7— (3-chlorophenyl) 1-2,3—dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3—de] —1, 4-benzothiazine-16-carboxamide-1,1, dioxide (49.8 mg, 78%) was obtained.

EIMS m 628 (M +)

_{H MS (EI): C 28} H 19 C1F 6 N 2 0 4 S and to Calculated: 628.0658

 Found: 628.0646

Anal: C ₂₈ H ₁₉ ClF ₆ N ₂ 0 ₄ S Calculated as C 53.47%, H 3.04¾, 45 4.45%

Actual value C 53.53%, Η2.95% Ν 4.32% Example 5 1

According to a method similar to that in Example 49, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-1 7— (3-nitrophenyl) -15 —Oxo-5H-pyrido [1,2,3-de] — 1,4-Benzothiazine-16_carboxamide (60. Omg, 99 mol) from colorless amorphous N— [3,5-bis (Trifluoromethyl) benzyl] —2,3-Dihydro-1-N-methyl-1 7— (3-12-Trophenyl) -5-oxo-5H-pyrido [1,2,3-de]-1,4 1-benzothiazine 16-carboxamide_1,1-dioxide (55.6 mg, 88%) was obtained.

EIMS m / z: 639 (M ⁺ )

_{HRMS (EI): C 28 H} 19 F 6 N 3 0 6 S and to Calculated: 639.0899

 Found: 639.0872

_{Anal: C 28 H 19 F 6} N 3 0 6 S and to calculated values C 52.59%, H 2.99%, N 6.57%

Measured value C 52.36¾, H 2.89¾, N 6.35% Example 5 2

According to a method similar to that in Example 49, N— [3,5-bis (trifluoromethyl) benzyl] —7— (3,5-dichlorophenyl) -1,2,3-dihydro-1-N-methyl-1— Oxo-5H-pyrido [1,2,3-de] -1,4-benzothiazine-16-carboxamide (50.0 mg, 79 mol) was converted to colorless amorphous N— [3,5-bis ( Trifluoromethyl) benzyl] — 7 — (3,5-dichlorophenyl) 1, 2,3-dihydro-1N-methyl-1 5 —oxo-5H-pyrido [1,2,3—de] —1,4— Benzothiazine-1-6-carboxamide-1,1-dioxide (42.1 mg, 80%) was obtained.

EIMS m / z: 662 (M ⁺ )

_{HRMS (EI): C 28 H} 18 C1 2 F 6 N 2 0 4 S and to Calculated: 662.0269

 Found: 662.0298

Anal: C ₂₈ H ₁₈ Cl ₂ F ₆ N ₂ 0 ₄ S Calculated as C 50.69%, H 2.73%, N 4.22¾

Measured value C 50.60¾, H 2.65¾, N 4.11% Example 5 3

N— [3,5-bis (trifluoromethyl) benzyl] —7— [3,5—bis (trifluoromethyl) phenyl] —2,3-dihydrido 1 N-methyl-1 5 -oxo-5 H-pyrido [1,2,3-de] — 1,4-benzothiazine-16 — carboxamide (50.0 mg, 72〃mo 1) to colorless amorphous N— [3,5—Bis (trifluoromethyl) benzyl] -1 7— [3,5—Bis (trifluoromethyl) phenyl] —2,3-dihydro-1N—methyl-1-5—oxo-5H—pyrido [1 , 2,3-de] — 1,4 Benzothiazine 16-carboxamide 1-1,1 dioxide (35.2 mg _} 67%) was obtained.

EIMS m / z: 730 (M ⁺ )

_{HRMS (EI): C 3 oH} 18 F 12 N 2 0 4 S Calculated: 730.0796

 Observed value: 730.0830

_{Anal: C 30 H 18 F 12} N 2 0 4 S 0.5H 2 0 and to calculate values C 48.72%, H 2.59%, N 3.79% actual measured value C 48.52%, H 2.44¾, N

3.70% Example 5 4

According to a method similar to that in Example 49, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-7— (4-methylphenyl) -15—oxo-one 5 H—Pyrido [1,2,3-de] — 1,4—Benzothiazine-16—carboxamide (60. Omg, O.lOmmol) is converted to N- [3,5-bis ( Trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-1 7— (4-methylphenyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine One 6-carboxamide 1,1-dioxide (47.7 mg, 75%) was obtained.

EIMS m / z: 608 (M

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 4 S and to Calculated: 608.1204

 Observed value: 608.1191

_{Anal: C 29 H 22 F B} N 2 0 4 S 0.5H 2 0 and to calculate values C 56.40¾, Η 3.75¾, Ν 4.54 % Found C 56.60%, Η 3.62¾, Ν 4.46% Example 5 5

According to a method similar to that in Example 49, N— [3,5_bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (4-methoxyphenyl) -1-N—methyl-1 5— Oxo-5H-pyrido [1,2,3-de] — 1,4-benzothiazine-16-carboxamide (60. Omg, O.lOmmol) was converted to colorless amorphous N— [3,5—bis ( Trifluoromethyl) benzyl Ί — 2,3-dihydro-1- 7- (4-methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4 There was obtained 1-benzothiazine 16-carboxamido 11 1-dioxide (50.5 mg, 80%).

EIMS m / z: 624 ( ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 5 S and to Calculated: 624.1154

 Found: 624.1130

Anal: C ₂₉ H ₂₂ F Calculated C 55.77% as _{6 N 2 0 5 S, H} 3.55¾, N 4.49%

Measured value C 55.48% H 3.42%, N 4.40% Example 5 6

According to a method similar to that in Example 49, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (4-fluorophenyl) -1-N—methyl—5 _Oxo-1 5H-pyrido [1,2,3-de] 11,4,1-benzothiazine-16-carboxamide (60.0mg, O.lOmmol) from the colorless amorphous N- [3,5-bis (Trifluoromethyl) benzyl] — 2,3-dihydro-7- (4-fluorophenyl) -1-N-methyl-5-oxo-5H-pyrido [1,23-de] —1,4 —Benzothiazine-1 6 —carboxamide 11-1 —dioxide (50.0 mg, 795 was obtained.

EIMS m / z: 612 (M ⁺ )

_{HRMS (EI): C 28 H} 19 F 7 N 2 0 4 S and to Calculated: 612.0954

 Obtained: 612.0966

Anal: calculated as C ₂₈ H ₁₉ F ₇ N ₂ 0 ₄ S C 54.90%, H 3.13% N 4.57%

Measured value C 54.71%, H 3.00%, △ 4.48% Example 5 7

According to a method similar to that in Example 49, N— [3,5—bis (trifluoromethyl) benzyl] -17— (4-chlorophenyl) -12,3—dihidro N-methyl-15—oxo One 5H-pyrido [1,2,3-de] —1,4—benzothiazine-16—carboxamide (60. Omg, O.lOmmol) was converted to a colorless amorphous N— [3,5—bis ( Trifluoromethyl) benzyl] — 7— (4-chlorophenyl) 1,2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4 There was obtained 1-benzothiazine 16-carboxamide 1-1,1-dioxide (53.9 mg, 85%).

EIMS m / z: 628 (M ⁺ )

_{HRMS (EI): C 28 H} 19 C1F 6 N 2 0 4 S and to Calculated: 628.0658

 Observed value: 628.0652

Anal: C ₂₈ H ₁₉ ClF ₆ N ₂ 0 ₄ S Calculated as C 53.47%, H 3.04¾, N 4.45%

Actual value C 53.52%, H 3.14%, Ν 4.30% Example 5 8

According to a method similar to that in Example 49, N— [3,5-bis (trifluoromethyl) benzyl] —7— (3-chloro-1-4-fluorophenyl) 1-2,3-dihydro 1-N-methyl-1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine-16—from carboxamide (60.0mg, 98 / mol) to the colorless amorphous N— [3,5-bis (trifluoromethyl) benzyl] -17- (3-chloro-1-4-fluorophenyl) 1-2,3-dihydro N-methyl-5-oxo-5H-pyrido [1 [1,2,3-de] —1,4-benzothiazine-16-carboxamide 1,1,1-dioxide (48.5 mg, 77%) was obtained. EIMS m / z: 646 (M ⁺ )

_{HRMS (EI): C 28 H} 18 C1F T N 2 0 4 S and to Calculated: 646.0564

 Observed value: 646.0559

Anal: C ₂₈ H ₁₈ ClF ₇ N ₂ 0 ₄ S Calculated as C 51.98¾, H 2.80¾, N 4.33%

Actual value C 51.78%, H 2.66¾, N 4.24% Example 5 9

According to a method similar to that in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-1 7— (4—methyl-3-nitrotrope) Nil) 1-5 —oxo 1 5 H-pyrido [1,2,3—de] — l, 4—benzothiazine-1 6 —carboxamide (60.0 mg, 97 mol) from colorless amorphous N— [3 , 5—Bis (trifluoromethyl) benzyl] — 2,3-dihydro-1-N-methyl-1 7- (4-methyl-1-3-nitrophenyl) -1 5 —oxo-1 5H—Pyrido [1,2 , 3-de] 11, 4-Benzothiazine 16-carboxamide-1, 1-dioxide (49.6 mg, 79%) was obtained.

_{HRMS (EI): C 29 H} 21 F 6 N 3 0 6 S and to Calculated: 653.1055

 Found: 653.1041

Anal: C ₂₉ H ₂₁ F ₆ N ₃ 0 ₆ S Calculated value C 53.30%, H 3.24%, N 6.43%

Measured value C 53.08¾, H 3.17% N 6.33% Example 6 0

According to a method similar to that in Example 49, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (2-methoxyphenyl) -N-methyl-5-oxo From 1H-pyrido [1,2,3-de] 1-1,4-benzothiazine-16-carboxamide (60.Omg, O.lOmmol), N- [3,5-bis of colorless amorphous (Trifluoromethyl) benzyl] — 2,3-Dihydro 7- (2-Methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4 1-benzothiazine-16-carboxamide-11-dioxide (37.1 mg, 595 was obtained.

EIMS m / z: 624 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 5 S and to Calculated: 624.1154

 Found: 624.1146

Anal: C ₂₉ H ₂₂ F ₆ N ₂ 0 ₅ S Calculated as C 55.77% H 3.55N, N 4.49¾

Measured value C 55.48%, H 3.42%, N 4.42% Example 6 1

According to a method similar to that in Example 49, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (4-formylphenyl) -1-N-methyl-15— Oxo-5H-pyrido [1,2,3-de] — 1,4-benzothiazine-16-carboxamide (60. Omg, O.lOmmol) was converted to the colorless amorphous N— [3,5—bis ( Trifluoromethyl) benzyl] — 2,3-dihydro-1 7 — (4-formylphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] 1-1,4 —Benzothiazine-16-carboxamide-1,1,1-dioxide (14.5 mg, 23%) was obtained.

EIMS m / z: 622 ( ⁺ )

_{HRMS (EI): C 29 H} 20 F 6 N 2 0 5 S and to Calculated: 622.0997

 Found: 622.0984

_{Anal: C 29 H 20 F 6} N Calculated C 55.95¾ as _{2 0 5 S, H 3.24¾,} N 4.50%

Measured value C 55.86%, H 3.32%, N 4.41% Example 6 2

According to a method similar to that in Example 49, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-5-oxo-1——3— ( Trifluoromethyl) phenyl] — 5 H-pyrido [1,2,3-de] —1,4,1-benzothiazine-1 6 —carboxamide (60.0 mg, 95 mol) 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 16 — Carboxamido 1,1 dioxide (42.0 mg, 67%) was obtained. EIMS m / z: 662 (M ⁺ )

_{HRMS (EI): C 29 H} 19 F 9 N 2 0 4 S and to Calculated: 662.0922

 Observed value: 662.0914

Anal: C ₂₉ H ₁₉ F ₉ N ₂ 0 ₄ S Calculated as C 52.57%, H 2.89%, N 4.23%

Actual value C 52.53%, H 2.77¾, N 4.22% Example 6 3

In the same manner as in Example 49, N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-17- (3-methylphenyl) -15-oxo-5 From H-pyrido [1,2,3-de] 1-1,4-benzothiazine-6-carboxamide (60. Omg, O.lOmmol), the colorless amorphous N- [3,5-bis ( Trifluoromethyl) benzyl] — 2,3-dihydro-1-N-methyl-1- (3-methylphenyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzothiazine One 6-carboxamide 111oxy F (48.0 mg, 76%) was obtained.

EIMS m / z: 608 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 4 S and to Calculated: 608.1204

 Observed value: 608.1191

Anal: C ₂₉ H ₂₂ F ₆ N ₂ 0 ₄ S Calculated value C 57.24%, H 3.64N, N 4.60%

Measured value C 57.12%, H 3.54%, △ 4.62% Example 6 4

7-Hydroxy-1,2,3-dihydroxy 5-Hydroxy-5H-pyrido [1,2,3-de] —1,4-Benzothiazine-16-carboxylic acid ethyl ester (15.0 g, 52 mmol) To the mixture were added N-methyl-1,5-bis (trifluoromethyl) benzylamine (13.3 g, 52 mmol) and pyridine (120 ml), and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized by adding diisopropyl ether. N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3- Dihydro 7-hydroxy-1-N-methyl-5-oxo-5 H-pyrido [1,2,3-de] _1,4-benzothiazine-16_carboxamide (18.7 g, 72%) Was.

EIMS m / z: 502 (M ⁺ ) Example 6 5

N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7-hydroxy N-methyl_5-oxo-1 5H-lide [1,2,3-de] 1-1 , 4-Benzothiazine-16-carboxamide (15.0 g, 30 mmol) 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 and purified by silica gel column chromatography (methylene chloride: ethyl acetate 10: 1) to give pale yellow crystals of N- [ 3,5-bis (trifluoromethyl) benzyl] — 7_chloro-1,2,3-dihydro N-methyl 5-oxo-1 5H-pyrido [1,2,3-de] —1,, 4-Benzothiazine-16-carboxamide (13.5 g, 87%) was obtained.

EIMS m / z: 520 (M ⁺ ) Industrial applicability

 The compounds of the present invention and salts thereof have excellent tachykinin receptor antagonistic activity, 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.

Claims

Scope of word blue

1. The following general formula (1)

(Wherein RR ² and R ³ are the same or different and are a hydrogen atom or a C ₆ -C ₆ alkyl group, and the A ring is independently selected from 1 to 3 substituents (adjacent 2 A substituent may be bonded to each other to form a ring) a homo- or heterocyclic ring, which may have 1 to 5 substituents (two adjacent substituents are bonded to each other) The benzene ring and the C ring which may have a ring may have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring). And a salt, hydrate and solvate of the pyridobenzothiazine derivative represented by the formula:

2. Ring A is a halogen atom, an optionally substituted C i Cs alkyl group, an optionally substituted aryl group, a hydroxyl group, an optionally substituted C ₁ -C ₆ alkoxy group. A C ₃ -C ₁₀ cycloalkoxy group, an optionally substituted c ₁ -c ₆ alkanoyloxy group. An optionally substituted aryloyloxy group, an optionally substituted A methyloxy group, a cycloalkanoyloxy group of c _{3 to} c _{1 ()} , an alkylthio group of c _{1 to} c ₆ which may be substituted, an optionally substituted C! ~ C ₆ alkylsulfinyl group, even if substituted Alkylsulfonyl group optionally C ~ C _6, amino group, mono- or alkylamino group C ₁ -C ₆ di-substituted from 1 to 3 of may 4-9 membered also contain heteroatoms in the cyclic Amino group, CiC alkylcarbonyl amino group, CiCs alkoxycarbonylamino group, CiCe alkylsulfonylamino group, optionally substituted arylsulfonylam amino group, an alkylcarbonyl group of C i to C _6, a formyl group. force Rupokishiru group, an alkoxycarbonyl group having C ~ C _6, alkyl force Rubamoiru group of C ~ C ₆ mono or di-substituted from 1 to 3 of the 1 to 3 substituents independently selected from a 4 to 9-membered cyclic rubamoyl group, a cyano group or a nitro group which may contain a terrorist atom (two adjacent substituents May be bonded to each other to form a ring) Good shows the homocyclic or heterocyclic ring,

B ring is a halogen atom, an optionally substituted C ~ alkyl group _{C 6, C 3 ~ C i} . A cycloalkyl group, an optionally substituted aryl group, a hydroxy group, an optionally substituted C i C alkoxy group, an optionally substituted C ₁ -C ₆ alkanol A alkoxy group, an optionally substituted aryloxy group, an optionally substituted arylmethyloxy group, C ₃ -C 4. Cycloalkoxy group, C ₃ ~ C i. Of the cycloalkanoyloxy group, which may be substituted! -C ₆ alkylthio group, optionally substituted C ₁ -C ₆ alkylsulfinyl group, optionally substituted C i -C ₆ alkylsulfonyl group, amino group, mono- or di-substituted C i A C ₆ alkylamino group; a 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms; an alkylcarbonylamino group of C, an alkoxycarbonylamino group of CiCe, alkylsulfonyl § Mi amino group of C ~ C _6, substitution which may be § reel sulfonyl § Mi amino group, C i to Al kill carbonyl group of C _6, a carboxyl group, an alkoxycarbonyl of C i to C ₆ N-yl group, mono- or di-substituted Ci-C ₆ alkyl group, a 4- to 9-membered cyclic group, which may contain 1 to 3 heteroatoms, cyano group, or 2-port. A benzene ring which may have 1 to 3 substituents independently selected from the groups (two adjacent substituents may be bonded to each other to form a ring) Indicates that

Ring C is a halogen atom, an optionally substituted C i -C ₆ alkyl group, a hydroxyl group, an optionally substituted C i Ce alkoxy group, an optionally substituted C ₁ -C ₆ Alka Noi Ruo alkoxy group, an optionally substituted § Li Roiruokishi group, optionally substituted § Li Rumechiruokishi group, C ₃ ~ C i. Cycloalkoxy group, C ₃ ~ C _1. A cycloalkanoyloxy group, an amino group, a mono- or di-substituted C ₆ -alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, C to C ₆ alkylcarbonyl amino group, C i to alkoxycarbonyl § Mi amino group of C _6, C i C e of § Le kill sulfonyl § Mi amino group, optionally substituted § Li one also be Rusuruho Niruami amino group, Shiano group Or 1 to 3 substituents independently selected from the nitro group (two adjacent substituents may be bonded to each other to form a ring) The pyridobenzothiazine derivative according to claim 1, which exhibits a good benzene ring.

3. The following general formula (2)

Eh. (2) (Wherein, R ³ is a hydrogen atom or a C i C alkyl group, R ⁴ is a hydroxyl group, a C i -C ₆ alkoxy group, a benzyloxy group or a reactive residue,

A ring is a halogen atom, an alkyl group optionally CC e be substituted, may be substituted Ariru group, arsenate Dorokishiru group, optionally substituted (^ - (^ (; alkoxy group, C ₃ ~ C _{1 0} of Shikuroaruko alkoxy group, an optionally substituted good C ~ C ₆ alkanoyloxy Noi Ruo alkoxy group, an optionally substituted § Li Roiruokishi group, optionally substituted § reel methyl O alkoxy group, C ₃ cycloalkanols Noi Ruo alkoxy group -C _{1 (),} an optionally substituted C it to C ₆ alkylthio group, alkylsulfinyl group optionally C ~ C ₆ optionally substituted, may be substituted substituted alkylsulfonyl group of C ~ C _6, an amino group, mono- or di-substituted alkylamino amino group of C ₁ ~C _6, 1~ 3 pieces of annular § also be 4-9 membered contain heteroatoms Mino group, C i -C ₆ alkylcarbonyl amino Group, alkoxycarbonyl § Mi amino group, an alkylsulfonyl amino group of C i to C _6, optionally substituted Arirusu Ruhoniruami amino group, C, alkylcarbonyl ~ C _6, a formyl group, a force Rupokishiru group, C i C e alkoxy force Lupo alkylsulfonyl group, a mono or alkyl force Rubamoiru group C i to C ₆ disubstituted from 1 to 3 cyclic force may 4-9 membered also contain heteroatoms of Rubamoiru 1 to 3 substituents independently selected from a group, a cyano group or a nitro group (two adjacent substituents may be bonded to each other to form a ring) Allo or heterocyclic ring which may have,

C ring is a halogen atom, optionally substituted C ₁ to alkyl groups of C _6, human Dorokishiru group, an optionally substituted C ₁ - alkoxy C _6, optionally C i to C which may be substituted ₆ , alkanoyloxy group, optionally substituted polyaryloxy group, optionally substituted arylmethyloxy group, C 1 -C 4. A cycloalkoxy group, C ₃ -C ₁ . A cycloalkanoyloxy group, an amino group, a mono- or di-substituted C i -C ₆ alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, A C i -C ₆ alkylcarbonylamino group, a C i Cs alkoxycarbonylamino group, a C ^ Cs alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, It has from 1 to 3 substituents independently selected from a cyano group or a nitro group (two adjacent substituents may be bonded to each other to form a ring) Shows a good benzene ring. ) Or a salt, hydrate or solvate thereof.

4. The following general formula (3)

(Wherein, R ³ is a hydrogen atom or a C i Ce alkyl group, and R ⁵ is

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, X is a halogen atom or 〇S 0 ₂ R ⁶ (R ⁶ is optionally substituted with C 1 to C 6) ₆ alkyl groups, substituted Which may be Ariru group), C ring is a halogen atom, an optionally substituted C i to alkyl groups of C _6, human Dorokishiru group, an optionally substituted C i to alkoxy groups of C _6, optionally substituted An optionally substituted alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylmethyloxy group, and C s C 2. The alkoxy group of the mouth, C ₃ -C 丄. Cycloalkadienyl Noi Ruo alkoxy group, amino group, mono- or di-substituted C i to alkylamino group C _6, 1 to 3 amino 4 may contain a hetero atom 9-membered cyclic § Mi amino group A C i -C ₆ alkylcarbonylamino group, a C i -C ₆ alkoxycarbonylamino group, a C i Ce alkylsulfonylamino group, a substituted or unsubstituted arylsulfonylamino group, It has 1 to 3 substituents independently selected from a cyano group or a nitro group (two adjacent substituents may be bonded to each other to form a ring) It may represent a benzene ring. ) A pyridobenzothiazine derivative represented by or a salt, hydrate and solvate thereof.

5. The following general formula (4)

(Wherein, R ³ is a hydrogen atom or an alkyl group of C! Ce, and R ⁵ is

(R ¹ and R ² are the same or different and are a hydrogen atom or a C i C s alkyl group; ring B is 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, the ring C is a halogen atom, an optionally substituted C i -C ₆ alkyl group, or a hydryl xyl group. group, but it may also be substituted alkoxy group of C丄~ C _6, optionally substituted C ₁ -C ₆ of § Rukanoiruokishi group, optionally substituted § Li Roiruokishi group, optionally substituted Yoarylmethyloxy, C ₃ -C 10 cycloalkoxy, C ₃ -C ₃ . Cycloalkadienyl Noi Ruo alkoxy group, amino group, mono- or di-substituted alkylamino amino group of C 1~ C _6, 1~ 3 amino 4 may contain a hetero atom 9-membered cyclic § Mi amino group , C alkylcarbonyl § Mi amino group of ~ C _6, C i~ C alkoxycarbonyl amino group of _6, C. 1 to alkylsulfonyl § Mi amino group of C 6, optionally substituted § Li one also be Rusuruhonirua It has 1 to 3 substituents each independently selected from a mino group, a cyano group or a nitro group (two adjacent substituents may be bonded to each other to form a ring) Represents an optionally substituted benzene ring. ) A pyridobenzothiazine derivative represented by or a salt, hydrate and solvate thereof.

6. The following general formula (2)

(Wherein, R ³ is a hydrogen atom or a C i Ce alkyl group, and R ⁴ is a hydroxyl group. The C i -C ₆ alkoxy group, benzyloxy group or reactive residue, and the ring A are each independently selected from one to three substituents (two adjacent substituents are bonded to each other to form a ring. A homo- or heterocyclic ring, which may have 1 to 3 substituents (adjacent 2 substituents are bonded to each other to form a ring) A benzene ring which may have )

And a salt, hydrate and solvate thereof represented by the following general formula (5)

(Wherein R ¹ and R ² are the same or different and are each a hydrogen atom or a C i C s alkyl group; ring B has 1 to 5 substituents (when two adjacent substituents are bonded to each other, A benzene ring which may have a) or a salt, a hydrate and a solvate thereof. A method for producing a compound or a salt, hydrate and solvate thereof.

7. The following general formula (6)

(Wherein, ³ is a hydrogen atom or an alkyl group of C or C ₆ , R ⁷ is a hydroxyl group. c 丄 to c ₆ alkoxy, benzyloxy,

(R ¹ and R ² are the same or different and each is a hydrogen atom or a C i C s alkyl group; ring B is 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, X is a halogen atom or 0 S 0 ₂ R ⁶ (R ⁶ is a halogen-substituted C i- The C ₆ alkyl group and the aryl group which may be substituted) and the C ring have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). Represents an optionally substituted benzene ring. ) Or a salt, hydrate or solvate thereof with a pyridobenzothiazine derivative represented by the following general formula (7)

(In the formula, Y is a halogen atom, 〇 S_〇 ₂ R ⁶ (R ⁶ is the ^{same), B (R 8) 2} (R 8 is hydroxyl, C i C e alkyl radical or a C ₁ ~ C ₆ of Represents an alkoxy group, or R ⁸ may be mutually bonded to form a ring.), MgBr or ZnCl, and the A ring are each independently selected from 1 to 3 substituents ( And two adjacent substituents may be bonded to each other to form a ring) or a homocyclic or heterocyclic ring which may have a compound represented by the formula: Or the process for producing a pyridobenzothiazine derivative or a salt, hydrate and solvate thereof according to item 3.

8. The following general formula (8) (B)

 (O) pS

(Wherein, R ³ is the same or different and is a hydrogen atom or a C-C ₆ alkyl group, R ⁷ is a hydroxyl group, a C i-C ₆ alkoxy group, a benzyloxy group,

(R ¹ and R ² are the same or different and each is a hydrogen atom or an alkyl group of CCs; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring; Or a reactive residue, Z is a hydroxyl group, X (X is a halogen atom or 〇S 0 ₂ R ⁶ (R ⁶ may be halogen-substituted) Good C i -C ₆ alkyl group, aryl group which may be substituted)) or A ring (A ring is independently selected from one to three substituents (adjacent two The substituents may be bonded to each other to form a ring) or an optionally substituted heterocyclic or heterocyclic ring), and P represents 0 or 1. ) Or a salt, hydrate or solvate thereof represented by the following general formula (9)

(Wherein, R ³ , R ⁷ and Z are the same as above, and m represents p + 1 or 2.) or 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 i -C ₆ alkyl group, and A ring is each independently selected from one to three substituents (adjacent 2 May be bonded to each other to form a ring), may be a homo- or heterocyclic ring, and ring B may have 1 to 5 substituents (when two adjacent substituents A benzene ring, which may have a ring, which may be bonded to each other, and a ring C may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) And a salt, hydrate and solvate of the pyridobenzothiazine derivative represented by the formula (1) as a pharmaceutical composition. Tachykinin receptor antagonist.

1 0. The following general formula (1)

(1)

(Wherein, R ¹ R ² and R ³ are the same or different and are each a hydrogen atom or a C i -C ₆ alkyl group, and A ring is independently selected from one to three substituents (adjacent Two or more substituents may be bonded to each other to form a ring) a homo- or heterocyclic ring which may have 1 to 5 substituents (two adjacent substituents) May be bonded to each other to form a ring.) The benzene ring and the C ring may have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring). A benzene ring which may have the following formula: or a salt, hydrate or solvate of the pyridobenzothiazine derivative represented by the formula: Characteristic substance P receptor antagonist.

1 1. The following general formula (1)

(Wherein, R ¹ R ² and R ³ are the same or different and are a hydrogen atom or a C ₆ -C ₆ alkyl group, and A ring is each independently selected from 1 to 3 substituents (adjacent 2 May be bonded to each other to form a ring) may be a homo- or heterocyclic ring, and ring B is 1 to 5 substituents (when two adjacent substituents are A benzene ring, which may have a ring, may form a ring, and a ring C may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) And a salt, hydrate and solvate of the pyridobenzothiazine derivative represented by the formula (I). A prophylactic or therapeutic agent for dysuria including bladder dysfunction such as urinary frequency and urinary incontinence characterized by containing. -

1 2. 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 i -C ₆ alkyl group, and A ring is independently selected from one to three substituents (adjacent 2 May be bonded to each other to form a ring) or a homocyclic or heterocyclic ring, and ring B may have 1 to 5 substituents (when two adjacent substituents are A benzene ring, which may have a ring, which may be bonded to each other, and C ring, has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring) And a salt, hydrate and solvate of the pyridobenzothiazine derivative represented by the formula (1) as a pharmaceutical composition. For preventing or treating digestive diseases including ulcerative colitis and Crohn's disease.

1 3. The following general formula (1)

(Wherein, R ¹ R ² and R ³ are the same or different and are a hydrogen atom or a C ₆ -C ₆ alkyl group, and A ring is each independently selected from 1 to 3 substituents (adjacent 2 May be bonded to each other to form a ring) may be a homo- or heterocyclic ring, and ring B is 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 and have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring). A benzene ring which may have the formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition. Vomiting induced by X-ray irradiation, chemotherapeutic agents, pregnancy, migraine, postoperative illness, gastrointestinal motility depression or side effects of drug administration Prevention or therapeutic agent.

1 4. The following general formula (1)

(Wherein R !, R ² and R ³ are the same or different and are each a hydrogen atom or C Alkyl C _6, A ring have independently selected 1-3 location substituent (may be bonded two adjacent substituents together form a ring) The allo-heterocyclic or heterocyclic ring, and the ring B may have 1 to 5 substituents (two adjacent substituents may be bonded to each other to form a ring) The ring and the ring C represent a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). ) Or a salt, hydrate or solvate thereof as a pharmaceutical composition, wherein asthma, cough, pain, migraine, toothache associated with evening kinkinin A therapeutic agent for rheumatoid arthritis.