WO2002074771A1 - Tricyclic heterocyclic compound, process for producing the same, and use - Google Patents

Abstract

A compound represented by the formula (I) (wherein ring A represents a substituted pyridine ring; R2 represents hydrogen, halogeno, or optionally halogenated C¿1-6? alkyl; R?3¿ represents hydrogen or C¿1-6? alkyl; R's are the same or different and each represents halogeno, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy, cyano, or hydroxy; m is an integer of 0 to 3; n is 1 or 2; and p is an integer of 0 to 3), a salt of the compound, or a prodrug of either. The compound has an excellent antagonistic effect on a tachykinin receptor, especially on a substance P receptor. (I)

Description

 Specification

 Tricyclic hetero compounds, their production methods and applications

 Technical field

 The present invention relates to a novel tricyclic heterocyclic compound having excellent tachykinin receptor antagonism, a method for producing the same, and a use thereof.

 Background art

 Japanese Patent Application Laid-Open No. 9-2636585 (EP—A—7336632) describes the formula

[Wherein, M is a heterocyclic ring having a partial structure of 1 X 2 Y, 1 N = C, —CO—N or 1 CS—N <; R ^a and R ^b are bonded together A hydrogen atom or a substituent on the M ring which forms the same or different ring A; ring A and ring B are each an optionally substituted homocyclic or complex ring, at least one of which is a substituent; Heterocyclic ring which may have a substituent; ring C is a homo or heterocyclic ring which may have a substituent; ring Z is a nitrogen-containing heterocyclic ring which may be substituted; and n is 1 Or an integer from 6 to 6. It is described that the heterocyclic compound represented by or a salt thereof has a tachykinin receptor antagonistic action, a substance P receptor antagonistic action, and a neurokinin A receptor antagonistic action.

 Disclosure of the invention

An object of the present invention is to provide a tricyclic heterocyclic compound having a stronger action than a conventional compound having a tachykinin receptor antagonistic action, a method for producing the same, a urination disorder improving agent containing the compound, and the like. . The present inventors have conducted intensive studies in view of the above circumstances, and as a result,

 [Wherein the A ring represents a substituted pyridine ring,

R ² represents a hydrogen atom, a halogen atom or an optionally halogenated alkyl group,

R ³ represents a hydrogen atom or an alkyl group,

R is the same or different and represents a halogen atom, an optionally halogenated C ^ 6 alkyl group, an optionally substituted C, _ ₆ alkoxy group, a cyano group or a hydroxy group,

 m is an integer from 0 to 3,

 n represents 1 or 2, and p represents an integer of 0 to 3. The tricyclic heterocyclic compound (hereinafter also referred to as compound (I)) represented by the formula (I) or a salt thereof has an unexpectedly strong tachycun receptor antagonistic activity (in particular, substance P) based on its unique chemical structure. Receptor antagonism), etc., and were found to be sufficiently satisfactory as a medicament, and the present invention was completed based on this finding.

 That is, the present invention

〔1 set

 [Wherein the A ring represents a substituted pyridine ring,

R ² represents a hydrogen atom, a halogen atom or an optionally halogenated alkyl group,

R ³ represents a hydrogen atom or a _ ₆ alkyl group,

R may be the same or different halogen atom, an optionally halogenated C ^ _ ₆ alkyl group, Ji may be halogenated! Alkoxy group, a Shiano group or a hydroxy group,

 m is an integer from 0 to 3,

 n represents 1 or 2, and p represents an integer of 0 to 3. Or a compound represented by the formula (2):

 [Wherein the A 'ring represents a pyridine ring,

R ¹ ′ is (1) an alkyl group optionally having a substituent, (2) an alkoxy group optionally having a substituent, and (3) Ce—i optionally having a substituent. An aryloxy group, (4) a heterocyclic oxy group which may have a substituent, (5) a ₆ alkoxyl group. Karuboyuru group, (6) - substituted may have a group C, - ₆ alkylthio group, (7) may have a substituent group 〇 _6-1. Ariruchio group, (8) substituted heterocyclic ring which may Chiomoto, (9)笸換may have a group C ₆ _ ₁₀ 7 aryl group, Tei has a (10) substituent (11) ₆ -hydroxy group, (12) hydroxy group, (13) nitro group, (14) halogen atom, (15) cyano group, (16) An amino group which may be substituted, (17) an amidino group which may have a substituent, (18) an oxime group, (19) a carboxyl group, and (20) an acyl group which may have a substituent (21) a carpamoyl group which may have a substituent, (22) a thiocarpamoyl group which may have a substituent or (23) a _β- alkylsulfonyl group,

 Other symbols have the same meaning as in [1]. ] The compound according to [1], which is a compound represented by the formula: or a salt thereof. .

[3] R ¹ 'force S (1) may have a substituent group C - e alkyl group, (2) optionally halogenated or Bok ₆ alkoxy group, (3) C alkoxy - carbonyl group, (4) halogenated may CI_ ₆ alkylthio group, (5) C ₆ one] ₀ Ariru group, (6) Ji Ashiruamino group, (7) C Medicine ₆ Ashiruokishi group, (8) hydroxy group, (9 ) Nitro group, (10) halogen atom, (11) cyano group, (12) amino group, (13) mono- or dialkylamino group, (14) other than one nitrogen and carbon atom oxygen atom or a nitrogen atom which may contain 5 or 6-membered cyclic amino group, (15) C, _ ₆ alkyl chromatography sulfonyl § amino group, (16) carboxyl group, (1-7) had ₆ alkyl one group , (18) carbamoyl group, (19) mono or di-C ^ e alkyl carbamoyl group, (20) alkyl Ruhoniru group, (21) mono- mono-, di- one or tree C i-e alkyl ureido group, (22) C, _ ₆ alkoxy one carbonyl § amino group or (23) alkoxy one carbonylation route d alkylamino group And R are the same or different and each is a halogen atom, an alkyl group which may be halogenated, an alkoxy group which may be halogenated, or a cyano group.

[4] Ring A

[R ¹ has the same meaning as R ¹ ′ described in [2]. ] The compound according to item [1], wherein

 (5) Ring A

[R¹は第 〔2〕 項記載の R¹' と同意義を示す。〕 である第 〔1〕 項記載の化合物。

[R ¹ has the same meaning as R ¹ ′ described in [2]. ] The compound according to item [1], wherein

[6] Ring A is (1) a _6- alkyl group which may be substituted with a hydroxy group, a halogen atom or a cyano group, (2) a heterocyclic oxy group, (3) a halogen atom, (4) a cyano group, (5 ) A mono- or di-alkyl _1-6 alkyl group, (6) a 5- or 6-membered cyclic aminocarbonyl group which may contain an oxygen atom, a nitrogen atom or a sulfur atom in addition to one nitrogen atom and carbon atom , (7) C, _ _e alkyl - carbonyl § amino group, (8) a heterocyclic carbonyl § amino group or (9) a compound of the [1], wherein a pyridine ring substituted with a heterocyclic group.

[7] The compound according to [1], wherein R ² is a hydrogen atom or a halogen atom.

[8] The compound according to item [1], wherein R ³ is a C, alkyl group.

[9] The compound according to item (1), wherein R ³ is three-coordinate.

 [10] The compound of [1], wherein R is the same or different and is a halogen atom or an optionally halogenated C-6 alkyl group.

(1 1) Expression

[In the formula, R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group which may be halogenated, ノ, a C! -E alkoxy group which may be Show. ] The compound according to [1], which represents a group represented by the formula:

[12] The compound according to [11], wherein R ⁴ and R ⁵ are the same or different and each is a hydrogen atom or an optionally halogenated s alkyl group.

 (13) Expression

(In)

 [Wherein the A 'ring represents a pyridine ring,

R ¹ ′ is (1) an optionally substituted S group—a 6-alkyl group, (2) an optionally substituted _6- alkoxy group, (3) an optionally substituted group Ce— !. Aryloxy group, (4) heterocyclic oxy group optionally having substituent (s), (5) dioxyalkoxycarbonyl group, (6) C ^ eT alkylthio group optionally having substituent, ( 7) C ₆ _, which may have a substituent. Arylthio group, (8) heterocyclic ring which may have a substituent A thio group, (9) which may have a substituent; Aryl group, (10) heterocyclic group which may have a substituent, (11) acyloxy group, (12) hydroxy group, (13) nitro group, (14) halogen atom, (15) cyano A group, (16) an amino group optionally having a substituent, (17) an amidino group optionally having a substituent, (18) an oxime group, (19) a carboxyl group, and (20) a substituent. An optionally substituted acyl group, (21) an optionally substituted labamoyl group, (22) an optionally substituted thiocarbamoyl group or (23) C ₆ alkyl. A sulfonyl group,

'Is a hydrogen atom, a halogen atom or CI_ ₃ alkyl group,

R ³ 'represents an alkyl group,

R ⁴ 'and R ^5' are the same or different which may be halogenated C, _ ₃ alkyl group. ] The compound according to [1], which is a compound represented by the formula: or a salt thereof.

 〔14〕

である第 〔1 3〕 項記載の化合物。

13. The compound according to item [13], which is

[1 5] R ¹ 'force S (1) hydroxy group, it may be substituted with a halogen atom or Shiano group C, - ₆ alkyl group, (2) heterocyclic Okishi group, (3) halogen atom, (4 ) Cyano group,

(5) Mono- or di-C-B-alkyl rubamoyl group; (6) 5- or 6-membered cyclic aminocarbonyl which may contain oxygen, nitrogen or sulfur atoms in addition to one nitrogen atom and carbon atom The compound according to [13], which is a group, (7) a Ci-e alkyl monocarbonylamino group, (8) a heterocyclic carbonylamino group, or (9) a heterocyclic group.

[16] (a R, 9R) — 7— [3.5-Bis (trifluoromethyl) benzyl] —2-chloro-9-methinole-5-phenyl 8, 8, 9, 10, 11-tetrahydro 1 7H 1 [1, 4] diazocino [2. 1-g] [1, 7] naphthyridine 1 6, 13-dione

(Example 11), (a R, 9R) —7— [3,5-bis (trifluoromethyl) benzyl] —2,9-dimethyl-5-phenyl _ 8, 9, 10, 1 1—tetrahydro-1-H 7 [— 4] diazocino [2, l-g] [1, 7] naphthyridine-1,6,3-dione (Example 12),

(a R, 9R) —7— [3,5-Bis (trifluoromethyl) benzyl] -1-9-methyl-6,13-dioxo-5-phenyl-6,8,9,10,1,1, 13-hexahydro-7H— [1,4] diazosino [2, l—g] [1,7] naphthyridine-12-force liponitrile (Example 13),

 (a R, 9R) —7— [3,5-Bis (trifluoromethyl) benzyl] —2—chloro-5— (4-Funoleolofeninole) 1 9—Methinole 8, 9,10 11-tetrahydro 7H- [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1 6.1 3-dione (Example 25),

 (a R, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] —5— (4-fluorophenyl) -1,2,9-dimethyl-1,8,9,10 1 1—tetrahi Dro 7H— [1,4] diazosino [2,1-g] [1,7] naphthyridine-1,6,13-dione (Example 26),

 (a R, 9 R) —7— [3,5-Bis (trifnorelolomethyl) benzyl] 1- (4-fluorophenyl) 1-9-methyl-1 6,13-dioxo 6, 8, 9, 10, 1 1,1 3 "Kisahydro-1H- [1,4] diazosino [2,1-g] [1,7] naphthyridine-1-2-carbonitrile (Example 27),

 (a R, 9 R) -7- (3,5-dimethylbenzyl) —5- (4-fluorophenyl) —2,9-dimethyl 8, 9, 10, 1 1-tetrahydro-1-H 7 [— 4] diazo sino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione (Example 29),

(a R, 4 R) —2— [3,5-bis (trifnorelomethinole) benzyl] —4.9.1-dimethyl-13-phenyl-1,3,4,5.6-tetrahydro-1H— [ 1, 4] diazocino [1, 2-b] [2, 7] naphthyridine-1.8-dione (Example 32),

(a R, 4R)-2- [3,5-bis (trifluoromethyl) benzyl] — 13 — (4 — fluorophenyl) 1,4,9-dimethyl-1,3,4,5,6-tetrahedral One 2 H— [1.4.] Diazocino [1,2—b] [2,7] naphthyridine-1,8-dione (Example 34),

 (a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] — N, N, 9-Trimethyl-1,6,13-dioxo-5-phenyl-1,6,8,9 10, 11, 1 3 "Kisahi Draw 7H— [1,4] diazosino [2,1-g] —1,7-naphthyridine—2-carboxamide (Example 50),

 (a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] -1-9-methyl-5-phenyl-1-2- (1,3-thiazolidine-1— ^ f-l-carbonyl) -18 , 9,10,1 1-tetrahydro_7H— [1,4] diazosino [2,1—g] —1,7-naphthyridine-1 6,13-dione (Example 63),

 (a R, 9 R) — 7— [3,5-Bis (trifluoromethyl) benzyl] -1-9-methylen-5-pheninole 2- (pyridine-13-inoleoxy) -18,9,10,1 1-Tetrahi Draw 7H— [1,4] diazosino [2,1-g] -1,7-naphthyridine-1,6,13-dione (Example 79),

N— [(a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] 1 9-methyl-6,13-dioxo-5-phenyl-2,8,9,10 1 1,13—hexahydro-7H— [1,4] diazosino [2,1 ”g] —1,7-naphthyridine—2 f1]; cotinamide (Example 85),

 N-[(a R, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] 1 9-methyl-6,13-dioxo-5-phenyl-1 6,8,9,10,1 1,13—HexahiDraw 7H— [1,4] diazosino [2,1-g] -1,7-naphthyridin-1-yl] acetoamide (Example 87)

 (a R, 9 R)-7-[3,5-Bis (trifluoromethyl) benzyl] 1-9-methyl 1-5-Feninole 2- (1H-tetrazo-1-5-inole) 1,8,9 10, 1 1-tetrahidro 7H— [1, 4] diazocino [2, 1-g]-1, 7-naphthyridine — 6, 13-dione (Example 95),

[(a R, 9R) —7— [3,5-bis (trifluoromethyl) benzyl 1—9-me Chinole 6,13-dioxo-5-phenyl-6,8,9,0,1 1,1 3 ^ Kisahydro 7 H— [1,4] diazosino [2,1—g] —: 7-naphthyridine 2-yl] acetonitrile (Example 124),

 (a R, 9 R) 17- [3,5-bis (trifluoromethyl) benzyl] 12- (fluoromethyl) 19-methyl-15-phenyl-8,9,10,11-tetrahi Draw 7H- [1, 4] diazocino [2, 1-g] 1, 7-naphthyridine 1, 6,13-dione (Example 25),

 (a R, 9 R) 1 9-Methyl-7— [3-Methyl-5— (trifluoromethyl) benzinole] — 6,13-Dioxo-5-Feuniru 6, 8, 9, 10, 1 1, 13 — ^ ^ Kisahidro-7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1-2 —carbonitrile (Example 144),

 (R, 9R) — 5— (4-Fluorophenyl) 1 9—Methynole 7— [3-Methyl-5— (trifluoromethyl) benzinole] 1 6,13—Diquino 6,8,9,10,1 1,13—Hexahi Draw 7H— [1,4] diazosino [2,1-g] [l, 7] naphthyridine—2_carbonitrile (Example 175),

 (a R, 9 R) — 2-Chloro-5— (4-fluorophenyl) -1-9-methyl-17— [3-Methyl_5 -— (trifluoromethyl) benzyl] —8, 9, 10, 1 1 —Tetrahydro 7H— [1,4] diazosino [2,1-g] [: 7] Naphthyridine-1 6,3-dione (Example 176)

Or the compound according to [1], which is a salt thereof.

 [17] A prodrug of the compound according to [1].

(18) Expression NH—— (CHjJ (II)

[In the formula, L represents a decondensation group, and the other symbols have the same meanings as described in [1]. [1] The method for producing compound (I) or a salt thereof according to [1], wherein the compound or a salt thereof is subjected to a ring closure reaction.

 [In the formula, A ′ ′ represents a pyridine ring that has been N-oxidized, and the other symbols have the same meanings as described in the item [1]. [1] The method for producing compound (I) or a salt thereof according to [1], wherein the compound or a salt thereof is subjected to a nucleophilic reaction in the presence of an activating agent.

 (20) Expression

 0

〔式中、 R ¹ 'はハロゲン原子を、 その他各記号は第 〔1〕 項記載と同意義を示す〕 で 表される化合物を置換反応あるいは挿入反応に付し、さらに必要に応じて、酸化反応、 転移反応、 加水分解反応、 求核置換反応、 アルキル化反応あるいはァシル化反応を組 み合わせて用いることを特徴とする第 〔1〕 項記載の化合物 （I ) またはその塩の製 造法。

[Wherein, R ¹ ′ represents a halogen atom, and other symbols have the same meanings as described in the item [1].] A method for producing a compound (I) or a salt thereof according to item [1], wherein a combination of a reaction, a transfer reaction, a hydrolysis reaction, a nucleophilic substitution reaction, an alkylation reaction or an acylation reaction is used. .

 (2 1) Formula

[Wherein, R ^lb represents a cyano group, and other symbols have the same meanings as described in item [1]]. Hydrolysis, amidation, acylation, substitution, alkylation A process for producing compound (I) or a salt thereof according to item [1], wherein a reaction, a transfer reaction, an addition reaction, a cyclization reaction and an oxidation reaction are used in combination as necessary.

 [22] A pharmaceutical composition comprising the compound according to [1] or a prodrug thereof and a pharmaceutically acceptable carrier.

 [23] The composition of [22], which is a tachykinin receptor antagonist.

 [24] The composition of [22], which is a substance P receptor antagonist.

 [25] The composition according to [22], which is an agent for preventing or treating substance P-related diseases. [26] The composition according to item [22], which is an agent for improving abnormal urination.

 [27] The composition according to item (22), which is an agent for preventing and treating pollakiuria incontinence.

 [28] Asthma, rheumatoid arthritis, osteoarthritis, pain, cough, pruritus, chronic obstructive pulmonary disease, irritable bowel disease, vomiting, HIV infection, depression, anxiety, neurosis, obsessive-compulsive disorder, depression [22] The composition according to the above [22], which is an agent for preventing or treating sexual disorders, manic dysfunction or schizophrenia.

(29) an effective amount of the compound or a prodrug thereof according to (1), and an agent for treating diabetes, Antidiabetic, antihyperlipidemic, antihypertensive, antiobesity, diuretic, chemotherapeutic, immunotherapeutic, anti-inflammatory, anti-inflammatory, saccharification inhibitor, nerve regeneration promoter Antidepressants, antiepileptics, antiarrhythmic drugs, acetylcholine receptor ligands, endothelin receptor antagonists, phenolamine uptake inhibitors, indolamine uptake inhibitors, narcotic analgesics, GABA receptor agonists, GABA uptake inhibitors, alpha ₂ receptor agonists, topical analgesics, pro Tin kinase C inhibitors, anti-anxiety agents, phosphodiesterase inhibitors, dopamine receptor agonists 'antagonists, serotonin receptor agonists' antagonists, Cerro Tonin uptake inhibitors, sleep inducers, anticholinergics, α receptor blockers, muscle relaxants, potassium channel openers, calcium channel blockers, Alzheimer's disease prevention · Therapeutic agents, prevention of Parkinson's disease · Therapeutic agents, prevention of multiple sclerosis · Therapeutic agents, selected from the group consisting of histamine ^^ receptor inhibitors, proton pump inhibitors, antithrombotics and Ν 2-2 receptor antagonists A medicament comprising an effective amount of one or more drugs.

 [30] A method for preventing and treating pollakiuria and urinary incontinence, comprising administering to a mammal an effective amount of the compound according to [1] or a prodrug thereof.

 [31] asthma, rheumatoid arthritis, osteoarthritis, pain, cough, pruritus, pruritus, chronic obstructive pulmonary disease, hypersensitivity, characterized by administering an effective amount of the compound or prodrug thereof according to item [1]. Prevention and treatment of sexual bowel disease, vomiting, HIV infection, depression, anxiety and neurosis, obsessive-compulsive disorder, panic disorder, depression and schizophrenia.

(32) an effective amount of the compound of (1) or a prodrug thereof according to (1) for a mammal, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, Diuretics, chemotherapeutic agents, immunotherapy agents, cachexia improving agents, anti-inflammatory agents, glycation inhibitors, nerve regeneration promoters, antidepressants, antiepileptics, antiarrhythmic drugs, acetylcholine receptor ligands, endothelin receptor body antagonists, monoamine uptake inhibitors, Indoruamin uptake inhibitors, narcotic analgesics, GAB alpha receptor agonists, GABA uptake inhibitors, alpha ₂ receptor agonists, topical analgesics, Protein kinase C inhibitors, anti anxiolytics, phosphodiesterase inhibitors, dopamine receptor agonists, antagonists, serotonin receptor agonists, antagonists, serotonin preparative interrupt inhibitors, sleep-inducing agents, anticholinergic agents, _{alpha iota} shielding receptor Medicine, muscle relaxants, Kariumuchi Yanner openers, calcium channel blockers, Alzheimer's disease prevention · Therapeutic agents, Nokukinson's disease prevention · Therapeutic agents, Multiple sclerosis prevention · Therapeutic agents, Histamine Hi receptor inhibitors, Proton pump inhibitors, Antithrombotic agents A method for preventing and treating pollakiuria and urinary incontinence, comprising co-administering an effective amount of one or more drugs selected from the group consisting of drugs and NK-2 receptor antagonists.

(33) an effective amount of the compound according to (1) or a prodrug thereof for a mammal, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, Diuretics, chemotherapeutic agents, immunotherapy agents, cachexia improving agents, anti-inflammatory agents, glycation inhibitors, nerve regeneration promoters, antidepressants, antiepileptics, antiarrhythmic drugs, acetylcholine receptor ligands, endothelin receptor body antagonists, monoamine uptake inhibitors, Indoruamin uptake inhibitors, narcotic analgesics, GABA receptor agonists, GABA uptake inhibitors, alpha ₂ receptor agonists, topical analgesics, Protein kina one peptidase C inhibitor, Anxiolytics, phosphodiesterase inhibitors, dopamine receptor agonistsAntagonists, serotonin receptor agonistsAntagonists, serotonin uptake inhibitors, sleep inducers, anticholinergics, _αι receptor blockers Drugs, Muscle relaxants, Potassium channel openers, Calcium channel blockers, Alzheimer's disease prevention 'therapeutic', Parkinson's disease prevention 'therapeutic', Multiple sclerosis prevention · therapeutic, histamine 1 ^ receptor inhibitor, proton Co-administration with an effective amount of one or more drugs selected from the group consisting of pump inhibitors, antithrombotics, drugs for treating HIV infection, drugs for treating chronic obstructive pulmonary disease, and NK-2 receptor antagonists Characterized by asthma, rheumatoid arthritis, osteoarthritis, pain, cough, pruritus, chronic obstructive pulmonary disease, irritable bowel disease, vomiting, depression, anxiety neurosis, obsessive-compulsive disorder, panic disorder, manic depression How to prevent or treat illness or schizophrenia. '

[34] Use of the compound according to [1] or a prodrug thereof for producing an agent for preventing and treating pollakiuria / urinary incontinence.

[35] Asthma, rheumatoid arthritis, osteoarthritis, pain, cough, pruritus, chronic obstructive pulmonary disease, irritable bowel disease, vomiting, HIV infection, depression, anxiety, neurosis, obsessive-compulsive disorder, It is intended to provide use of the compound according to [1] or a prodrug thereof for the manufacture of a preventive or therapeutic agent for panic disorder, manic disorder or schizophrenia. The compound (I) or a salt thereof of the present invention includes stereoisomers such as cis and trans isomers, racemic forms, and optically active forms such as R-form and S-form. Further, depending on the size of the ring, an isomer due to conformation may be formed, and such an isomer is also included in the compound (I) of the present invention or a salt thereof.

 Detailed description of the invention

 Ring A represents a substituted pyridine ring, and the position of the nitrogen atom is not particularly limited.

In ring A, the number of substituents (hereinafter, this substituent is also referred to as R ¹ ) substituting on the pyridine ring is not particularly limited, and one to three substitutions can be considered. No. Is not particularly limited position when the substituent R ¹ of monosubstitution, preferably箧換next to the nitrogen atom of the pyridine ring. More specifically, ring A is, for example,

Or

が好適である。

Is preferred.

Although the type of R ¹ is not particularly limited,

(1) may have a substituent group CI- e alkyl group, (2) an optionally substituted C I ₆ alkoxy group, (3) may have a substituent C ₆ _ _1Q 7-yloxy group, (4) optionally substituted heterocyclic oxy group, (5) alkoxymonocarbonyl group, (6) optionally substituted — 6-alkylthio group, ( 7) may have a substituent group C _e - ₁₀ § Li one thio group, (8) optionally substituted heterocyclic Chio group, may have a (9) substituents . Aryl group, (10) heterocyclic group which may have a substituent, (1 1) C] - _beta Ashiruokishi group, (12) hydroxy group, (13) a nitro group, (14) a halogen atom, (15) Shiano group, (16) an amino group which may have a substituent, (17 Amidino group which may have a substituent, (18) oxime group, (19) carboxyl group, (20) acyl group which may have a substituent, (21) Preferred are (ii) a carbamoyl group which may be substituted, (22) a thiocarbamoyl group which may have a substituent, and (23) an alkylsnorefonyl group.

Specific Examples of R ¹ (1) The number of substituents shown in (23) is not particularly limited as long as it is a number that can be chemically substituted with the group to be substituted. And 4 or more, preferably 1 or 2.

Examples of the ₆ alkyl groups represented by RR ² , R ³ and R include, for example, methinole, ethyl, propynole, isopropyl, butyl, sec-butyl, tert-butynole, pentyl, hexyl and the like. Preferred are alkyl groups such as ethyl, propyl and isopropyl, and particularly preferred is methyl.

The C ^ e alkyl group substituents which may be possessed by represented by R ^1, for example, Nono androgenic atom, Amino, nitro, mono- one or di- one ₆ Arukiruamino, ₆ Al kills one carbonyl O carboxymethyl, Shiano, hydroxy, Bruno, halogenated which may be C alkoxy, Ashiru, Ashiruokishi, Ji alkynyl Honoré sulfonyl, Kanorebo hexyl, C] _ ₆ alkoxy one carbonyl, Kanorebamoiru, mono- or di C i-6 § Norekiru Ichiriki Rubamoiru, sulfamoyl , mono- or di-one C ^ 6 alkyl loose Ruff Amoiru, C ₆ _ ₁₄ 7 reel, like 5 to 14-membered heterocyclic group.

 As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are used, and among them, a fluorine atom is preferable.

The mono- or di-Ji Bok ₆ Arukiruamino, for example, Mechiruamino, Echiru Amino, Jimechiruamino, etc. Jechiruamino are used, in particular Mechiruamino, such as mono- or di-one C i _ ₃ Arukiruamino such dimethyl Chiruamino is preferred.

As C ₆ alkyl-carboxy, for example, methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy and the like are used. Preferred are c-alkyl-carbonyloxy such as rucarponyloxy, ethylcarbonyloxy and propylcarbonyloxy.

The Parogen of which do good C i _ ₆ alkoxy optionally, For instance, main butoxy, ethoxy alkoxy, propoxy, butoxy, Torifuruorome butoxy, 2, 2, 2-Torifuruoroe butoxy are used, Tokunime butoxy, ethoxy and the like Noji, alkoxy, etc. are preferred.

Ji! The Ashiru, for example, (For example, Asechiru, propionyl) formyl and C ₅ alkyl one carbonyl is used, inter alia formyl, Asechiru and C _ ₃ Ashiru such propylene Oniru is preferred.

C The I ₆ Ashiruokishi, for example, Horumiruokishi, Asetokishi, C, such as propionitrile two Ruokishi -! S alkyl one carbonyl O carboxymethyl are used, among others, such as C i _ ₃ Ashiruokishi such Asetokishi are preferred.

The C Bok ₆ alkylsulfonyl, for example, methylsulfonyl, Echirusuruhoni Le, such as professional buildings sulfonyl is used, inter alia methylsulfonyl, etc. alkylsulfonyl such Echirusuruho sulfonyl is preferred.

The alkoxy one carbonyl, for example, main butoxycarbonyl, ethoxycarbonyl, propoxycarbonyl carbo - le, etc. are used, among others main butoxycarbonyl, etc. 〇 I ₃ alkoxy Ichiriki Ruponiru such ethoxycarbonyl are preferable.

Examples of the mono- or di-alkyl carbamoyl include methylcarbamoyl, ethylcarbamoyl, propylcarbamyl, dimethylcarbamoyl, dimethylcarbamoyl, and dicarbylpylbamoyl, and methylcarbamoyl, ethylcarbamoyl, and the like. Ji carbamoyl, dimethylcarbamoyl, mono- if Ku is Gee 〇 such Jefferies Ji carbamoyl, etc. _ ₃ alkyl Ichiriki Rubamoiru are preferred.

Examples of mono- or di-alkyl-sulfamoyl include, for example, methyl sulfamoyl, ethinolesulfamoyl, propyl sulfamoyl, dimethylsnorefamoyl, getyl sulfamoyl, dipropyl sulfamoyl, etc., and methyl sulfamoyl, Ethyl sulfamoyl, dimethyl sulfamoyl, Jethyl sulfam Mono or dialkyl _3- alkyl-sulfamoyl such as amoyl is preferred. The Flip ₆ _ _{1 4} Ariru, for example, phenyl, naphthyl and the like.

 The 5- to 14-membered heterocyclic group includes, for example, 1 to 4, preferably 1 or 2 hetero atoms selected from nitrogen, oxygen, sulfur and the like in addition to carbon atoms. Member (preferably 5 to 9 members, particularly preferably 5 or 6 members) A heterocyclic group is used, among which phenyl (2-phenyl, 3-phenyl), furyl (2-furyl, 3-furyl) , Pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolinyl, 5-quinolyl, 8-quinolyl), isoquinolyl (1- ^ soquinolyl, 3-) Isoquinolyl, 4-isoquinolyl, 5-isoquinolinol), virazinyl, pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl), piralyl (3-pyrrolyl), imidazolyl (2-imidazolino) ), Pyridazininole (3-pyridazinyl), isothiazolyl (3-isothiazolyl), isoxazolyl (3-isoxazolyl), indolyl (1 ^ T-on-drill, 2-^-T-on-drill, 3-indolyl), 2 ^ -n-zothiazolyl, 2-- Aromatic heterocyclic groups such as benzo [b] chenyl, 3-^^ nzo [b] chenyl, 2 ^^ ', nori [b] furanyl, 3-benzo [b] flael, for example, piperidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), imidazo riel (2-imidazolyl, 4-imidazoril), birazolidininole (2-virazolidinyl, 3-virazolidyl, 4-birazolidinyl), piperidino, piperidyl (piperidino) 2-piperidyl, 3-piperidyl, 4-pibelidyl), piperazinyl (1-piperazinyl, 2-biperazinyl), morpho Roh, such as a non-aromatic heterocyclic groups such as thiomorpholino used.

Of these, 2-phenyl, 3-phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3- ^ T-sothiazolyl, 3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-virazolidinyl, 3-virazolidinyl, 4-birazolidinyl, piperidino, 2-piperidyl, 3-piridyl Peridil, one piperidinole, one piperazinyl, two piperazini W

And a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms such as methyl, morpholino and thiomorpholino. ,

The 0 ^ _ ₆ alkoxy group represented by R ^1, for example, methoxy, ethoxy, Provo alkoxy, such as butoxy are used, Tokunime butoxy, ethoxy, preferably such Bok ₃ alkoxy groups such as Buropokishi, especially methoxy are preferred .

Examples of the substituent which the alkoxy group represented by R ¹ may have include, for example, the alkyl group represented by R ¹ and those exemplified as the substituent thereof, and particularly, carboxyl, ethoxycarbonyl , Pyrrolidinyl, pyridyl, halogen and the like are preferred.

The C _{6 1 0} Ariruokishi group represented by R ^1, for example, need use like Fueniruokishi.

C 6 denoted by R ¹ . Examples of the substituent which the aryloxy group may have include, for example, the _6- alkyl group represented by R ¹ and those exemplified as the substituent thereof.Amino which may have a substituent is preferable. .

 Examples of the substituent of the amino which may have a substituent include a -6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl, and methyl snorehoni is preferred.

The heterocyclic oxy group represented by R ¹ includes, for example, a heterocyclic moiety having 1 to 4, preferably 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to a carbon atom. And a pyridyloxy group is preferred.

The heterocyclic Okishi substituent which may be have represented by R ^1, for example, but such as those exemplified as C i _ ₆ alkyl groups and substituents thereof are shown by R ¹ can be mentioned, methylcarbamoyl And an alkyl group such as phenyl.

Examples of the alkoxymonocarbonyl group represented by R ¹ include methoxycarbonyl, ethoxyquinolebonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like, among which methoxycarbonyl, ethoxycarbonyl and the like are used. Carbonyl, C such as propoxycarbonyl, lay like are preferable _ ₃ alkoxy one carbonyl group, including Tokunime butoxycarbonyl is preferred.

As the C— _s alkylthio group represented by R ¹ , for example, methylthio, ethylthio, propylthio, isopropinorethio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, etc. are used, and in particular, methylthio, ethylthio, Alkylthio groups such as propylthio and isopropylthio are preferred, and methylthio is particularly preferred.

C represented by R ^1, - a ₆ have an alkylthio group les, even substituent, for example, those exemplified as Arukinore groups and substituents thereof represented by R ^1, but a halogen and the like, Carpamoyl, mono- or di-alkyl rubamoyl, trifluoromethyl and the like are preferred.

The C ₆ _ _{1 0} § Li one thio group represented by R ^1, for example, phenylene thioether can be found using.

C represented by R ¹ _e - The _{1 0} § Li one thio group substituents which may have, for example, C represented by R ^1, such as those exemplified as _ _beta alkyl groups and substituents Force 5, carboxyl is preferred.

The heterocyclic thio group represented by R ¹ has, for example, a heterocyclic moiety having 1 to 4, preferably 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to a carbon atom Examples include a heterocyclic thio group, and pyridylthio and the like are used.

The heterocyclic Chio substituent group may even have to be represented by R ^1, for example, C represented by R ^1, _ ₆ alkyl and illustrated ones but like as a substituent, carboxyl Is preferred.

Represented by R ^1. As the aryl group, for example, phenyl, naphthyl and the like are used.

The C ₆ _ _{1 0} § Li Ichiru group substituents which may be possessed by represented by R ^1, for example, C represented by R ^1, - such as those exemplified as _e alkyl group and the substituents But optionally halogenated C- ₆ alkyl such as methyl and trifluoromethyl, meth Alkoxy such as xyl is preferred.

Examples of the heterocyclic group represented by R ¹ include a heterocyclic group having 1 to 4, preferably 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to a carbon atom. Although pyridyl, imidazolyl, tetrazolyl, pyrazolyl, triazolyl, thianolyl, oxdiazolyl, tetrahydrotriazinyl, dioxanyl, thiazolyl and the like are used.

The substituent which may be heterocyclic group possessed by R ^1, for example, C represented by R ^1, _ ₆ alkyl and illustrated ones but like as a substituent, methyl, I alkyl such as an isopropyl, phenylmethyl, hydroxycarbonyl, alkoxy one carbonyl such as ethoxycarbonyl, halogenated flicking ₆ alkyl, such as trichloromethyl, pyrrolidinyl, Okiso, Benzuimi Doiruamino _{(C 6 H S C (=} NH) - NH-), hydroxy Is preferred.

The 6 Ashiruokishi group, for example, Horumiruokishi, Aseto alkoxy, propionic - - that represented by by R ¹ Ruokishi etc. - ₅ Ashiruokishi group is used, inter alia formyl Ruokishi, Asetokishi, etc. Ashiruokishi such propionyl Ruo alkoxy is not preferred .

The halogen atom represented by R ^1, a fluorine atom, a chlorine atom, a bromine atom, used is iodine atom is preferable among them a fluorine atom, etc. Shiosaku atom.

Examples of the optionally substituted amino group represented by R ¹ include, for example, an unsubstituted amino group, a monosubstituted amino group, and a disubstituted amino group. Groups are also used.

Examples of the optionally substituted cyclic amino group represented by R ¹ include a 5- or 6-membered cyclic group which may contain an oxygen atom or a nitrogen atom in addition to one nitrogen atom and a carbon atom. An amino group is used, and in particular, pyrrolidino, piperidino, piperazino, morpholino and the like are used, and among them, morpholino is preferable.

Examples of the substituent of an amino group which may have a substituent represented by R ^1, for example, but such as those exemplified as C t ₆ alkyl groups and substituents thereof represented by R ¹ can be mentioned, In particular, CI_ ₆ alkyl, Shiano CI_ ₆ alkyl one carbonyl, c _e _ _{1 0} Arirukarubo sulfonyl, heterocyclic carbonyl, alkoxy one carbonyl, main Toki caulking Chiruka Ci-e alkoxy one such Lupo sulfonyl - _beta alkyl one carbonyl, alkylsulfonyl, C i_ ₆ Ashiru, an amino carbonyl which may have a substituent, good cyclic aminocarbonyl may have a substituent, which may have a substituent amidino, but it may also have a substituent Okisajiazoriru, C -! ₆ alkoxy - carbonyl one CI- e alkyl.

 As the alkyl, methyl, ethyl, propyl, dimethyl, getyl, dipropyl and the like are preferable, and particularly, mono or dialkyl such as methyl, ethyl, dimethyl, dimethyl and propyl is preferable, and methyl and dimethyl are particularly preferable.

 — 6-Alkyl-carbonyl includes methylcarbonyl, ethylcarbonyl and propylcarbonyl.

The C ₆ _ ₁₀ § Li one Honoré carbonyl include phenylalanine carbonyl.

 Examples of the heterocarboxy include pyridylcarbonyl.

— Examples of _6- alkoxymonocarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycanolebonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like. is used, inter alia main butoxycarbonyl, ethoxycarbonyl, propoxy Shikarubo two Honoré, n- butoxycarbonyl two Honoré, sec- butoxide Shikano levo Nino les, C, such as tert- butoxycarbonyl, etc. _ ₄ alkoxy one carbonyl are preferred.

The C ₆ alkylsulfonyl, for example, methylsulfonyl Nino les, E chill sulfo Nino les, CI_ ₅ alkylsulfonyl is used, such as propylsulfonyl, among others Mechirusuru Honiru, C, such as engineering Chirusuruhoniru, preferably _ ₃ alkyl sulfo El.

As the acyl, an acyl such as formyl, acetyl or propionyl is preferable, and an acyl such as forminole, acetyl or propionyl is particularly preferable. Examples of the amino group substituted by an aminocarbonyl which may have a substituent include an ureido group which may have a substituent, and the ureide group includes mono-, di- or tri-C. ₆ alkyl ureido groups are used, N, monomethyl ureide, ', N, Methyl ureide, Ν, Ν ', Ν' — Trimethyl ureide, N'—Ethyl ureide, Ν ', Ν'-Jetyl ureide, Ν, N', N '— Triethyl ureide, N'—Propyl レ イ lay, Ν', Ν '-dipropyl ureide, Ν, Ν', N 'tripropyl ureide, N'-butyl ureide, Ν ', N'-dibutyl ureide, Ν, Ν ', N'-tributyl ureide , Among others, N '—methylureide, N', Ν * dimethyl ureureid, N '—ethyl ureid, Ν', N '—getinoleide, N' propylide, Ν ', Ν * A mono- or di-C ^ s alkyl peridode group such as

 Examples of the substituent of the optionally substituted cyclic aminocarbonyl include acetyl.

 Examples of the substituent of the amidino which may have a 笸 换 group include hydroxy. Examples of the substituent of oxaziazolyl which may have a substituent include methyl and trifluoromethyl.

The alkoxy one carbonylation Lu Ci-e alkyl, main butoxycarbonyl methylation, ethoxycarbonylmethyl, propoxycarbonylmethyl, n- Butokishikaru Bonirumechiru, s _e c- butoxycarbonyl methyl, tert- butoxycarbonyl methyl, pentyl Ruo alkoxycarbonylmethyl , Hexyloxycarbonylmethyl, methoxycanoleponylethenole, ethoxycarbonylethyl, propoxycarbonylethyl, n-butoxycarbonylethyl, sec-butoxycarbonylethylene, tert-butoxycarbonylethyl, pentyloxycarbonyl Ethyl, hexyloxycarbonyl, methoxycarbonylpropyl, ethoxycarbonylpropyl, propoxycarbonylpropyl, p-butoxycarbonylpropyl, sec-butoxy Cycarbonyl propyl, tert-butoxycarbonyl propyl, pentyl oxy carbonyl propyl, hexyl oxy carbonyl propyl, etc. are used, among which methoxy carbonyl methyl, ethoxy carbonyl methyl, propoxy carbonyl methyl, methoxy carbonyl ethyl , Ethoxycarbonylethyl, propoxycarbonylethyl, methoxycarbonylpropyl, ethoxycarbonylpropyl, propoxycarbonylpropyl Alkoxymonocarbonyl-C ^ aalkyl such as mouth pill is preferred.

Examples of the substituent which the amidino group represented by R ¹ may have include, for example, the _6- alkyl group represented by R ¹ and those exemplified as the substituents thereof. Is preferred.

The Okishimu group represented by R ^1, for example, need use the formaldehyde Okishimu.

Examples of the acyl group represented by R ¹ include formyl or Ci-B alkyl-carbonyl group, which may contain an oxygen atom, a nitrogen atom or a sulfur atom in addition to one nitrogen atom and a carbon atom. A 3-membered cyclic aminocarbonyl group is used, and among them, C _1-3 acyl such as formyl, acetyl, propionyl and the like are preferable.

Examples of the substituent that the Ashiru groups have represented by R ^1, for example, C represented by R ^1, - although such as those exemplified as _e alkyl group and the substituent group, such as Metokishika carbonyl Ci-ealkoxy-carbonyl and the like are preferred.

Flip alkyl one carbo - The group, for example, Asechiru, CI_ such propionyl ₅ Arekiru - carbonyl group are used, inter alia Asechiru, such as propionyl

C! _—3 alkyl monocarbonyl group and the like are preferable.

 Examples of the 5- or 6-membered cyclic aminocarbonyl group which may contain an oxygen atom, a nitrogen atom or a sulfur atom in addition to one nitrogen atom and carbon atom include, for example, (pyrrolidine-111) carbonyl, morpholinocarbonyl , (Isothiazolidine-1-yl) carbonyl, thiomorpholinocarbonyl and the like are used.

The cyclic amino group may form a condensed ring with another ring structure. Ring structures that can form a condensed ring together include C ^, such as phenyl. Aryl group. Cyclic Aminokarubo alkenyl group may have a substituent, the substituent For example, although such as those exemplified as C i _ _e alkyl groups and substituents thereof represented by R ¹ is exemplified et al are And alkyl such as methyl, oxo, hydroxy, tert-butoxycarbonyl, and alkoxy-carbonyl such as methoxycarbonyl.

Examples of the group which the carpamoyl group represented by R ¹ may have include, for example, those represented by R ¹ Is the C, _ ₆ alkyl and illustrated but like those as a substituent, in particular, C - 5 alkyl, cyclopentyl, C ₅ _ ₈ cycloalkyl such as cyclohexyl, Jii such main bets alkoxy ₆ Carboxyalkyls such as alkoxy and carboxymethyl, and hydroxyalkyls such as formyl, phenyl, benzyl and hydroxyethyl are preferred.

_{As the 6} alkyl, for example, methyl, ethyl, propyl, isopropyl, tert-butyl, dimethyl, getyl, dibutyl pill, and the like are preferable, and particularly, mono- or dialkyl such as methyl, ethyl, dimethyl, and getyl are preferable. It is.

Examples of the substituent that the Chiokarubamoiru groups have represented by R ^1, for example, but such as those exemplified as Arukinore groups and substituents thereof represented by R ¹ can be mentioned, in particular, methyl, Echiru, isopropyl And the like.

As the —6 alkylsulfonyl group represented by R ¹ , for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like are used, and among them, C ₃ alkylsulfonyl groups such as methylsulfonyl and ethylsulfoyl are preferable.

Examples of the substituent of the amidino group which may have a substituent represented by R ¹ include methoxy, hydroxy, amino which may have a substituent, and 1,3-dihydroxyacetimino. Can be

 Examples of the substituent of the amino which may have a substituent include methyl and tert-butoxycarbonyl.

R ¹ is (1) a C, -6 alkyl group optionally substituted with a hydroxy group, a halogen atom or a cyano group, (2) a heterocyclic oxy group, (3) a halogen atom, (4) a cyano group, ( 5) Mo no or di CI_ ₆ alkyl force Rubamoiru group, (6) one nitrogen atom and carbon atom other than an oxygen atom,窆素atom or a sulfur atom which may contain 5 or 6 membered cyclic aminocarbonyl A group, (7) a Ct-6 alkyl-carbo-amino group, (8) a heterocyclic carbonylamino group or (9) a heterocyclic group.

R ¹ is (1) an alkyl group which may have a substituent, (2) a _6- alkoxy group which may be halogenated, (3) -6-alkoxy-carbonyl group, (4) a halogeno May be down of - 6 alkylthio group, (5) C ₆ _ ₁₀ 7 aryl group, (6) ₆ § Shinoreamino group, (7) Ci-e Ashiruokishi group, (8) hydroxy group, (9) nitro Group, (10) halogen atom, (11) cyano group, (12) amino group, (13) mono or di-- ₆ alkylamino group, (14) one nitrogen atom and carbon atom other than oxygen atom or 5- or 6-membered cyclic amino group which may contain a nitrogen atom, (15) C _1-6 alkyl-sulfoylamino group, 46) carboxyl group, 17) alkyl-carbonyl group, i

8) a formyl group, (19) force Rubamoiru group, (20) mono- or di one C] _ ₆ alkyl force Norebamoiru group, (21) alkylsulfonyl groups, (22) mono- mono-, di- one or tri- one - 6 Arukiruureido group And (23) a C _1-6 alkoxy-carbonylamino group or (24) C, _ ₆ alkoxy-carboxyalkylamino group.

Examples of the halogen atom which the optionally halogenated C- ₆ alkyl group represented by R ² and R may have include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

As the optionally halogenated 〇 ぃ₆ alkyl group represented by R ^{2 and} R, a d-e alkyl group optionally substituted with 1 to 3 halogen atoms is used. Is preferably a _3- alkyl group which may be substituted by 1 to 3 fluorine atoms, such as methyl, ethyl, propyl, tert-butyl, trifluoromethyl and the like.

As the halogen atom represented by R ² and R, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are used, and among them, a fluorine atom and the like are preferable.

As the optionally halogenated d-6 alkoxy group represented by R, a d-e alkoxy group optionally substituted with 1 to 3 halogen atoms is used, and examples thereof include methoxy, ethoxy, and propoxy. , Butoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, and the like, and among them, an optionally halogenated alkoxy group such as methoxy, ethoxy, propoxy, and trinoleolomethoxy is preferable. W

As the halogen atom which the optionally halogenated C ₆ alkoxy group represented by R may have, a fluorine atom, a chlorine atom, a bromine atom and a iodine atom are used.

As R ¹ , the following (A) to (F) are also preferable.

(A) C - _e alkyl group, flicking ₆ alkoxy group, CI- _C6 alkoxy one carbonyl groups, C WINCH ₆ alkylthio groups, C ₆ -,. Aryl, _β- amino, _6- hydroxy, hydroxy, nitro, halogen, cyano, amino, mono- or di- _β- alkylamino, one nitrogen and one carbon atom in addition to the carbon atom or nitrogen atoms contain an be 5 or 6-membered cyclic amino groups, C, _ ₆ alkyl chromatography sulfo - Ruamino groups, C I ₆ alkyl - carbonyl group, a force Rubamoiru group, mono- or di - CI_ ₆ alkyl Scarpa moil ! group, ₆ alkylsulfonyl group, mono-, di- one or tree C alkylureido group, C〗 - ₆ alkoxy - carbonyl § amino group, d_ ₆ alkoxy one carbonylation Lou C alkylamino group. Particularly, an alkyl group and a cyano group.

(B) ₆ alkyl, ₆ alkoxy, Ci- ₆ alkoxy monocarbonyl, C alkylthio, halogen, cyano, amino, mono or dialkylamino, one nitrogen atom and one carbon atom 5- or 6-membered cyclic amino group which may contain an oxygen atom or a nitrogen atom. In particular, C, _ ₆ alkyl group.

(C) — 3 alkyl groups (eg, methyl), C, — ₃ alkoxy groups (eg, methoxy), C, _ ₃ alkoxy monocarbonyl groups (eg, methoxycarbonyl), d_ ₃ alkylthio groups (eg, methylthio), halogen atom (e.g., fluorine atom, chlorine atom), Shiano group, an amino group, model no or di one ₃ alkylamino group (e.g., Mechiruamino, Jimechiruamino), oxygen atom in addition to one nitrogen atom and carbon atoms Or a 5- or 6-membered cyclic amino group that may contain a nitrogen atom (eg, morpholino). In particular, C] _ ₃ alkyl group, Shiano group.

(D) C such as methyl, _ ₃ alkyl group, main butoxy, main butoxycarbonyl, methylthio, halogen atom (especially chlorine atom), Shiano, Jimechiruamino, morpholino. Especially Siano.

(E) Alkyl groups such as methyl, cyano. (F) Methyl, Siano. Especially, Siano.

R ² is preferably a halogen atom such as a hydrogen atom or a fluorine atom, or a C ^ ₃ alkyl group such as methyl, ethyl, propyl, or isopropyl.Among them, a halogen atom such as a hydrogen atom or a fluorine atom, or methyl is preferable. Preferred is a hydrogen atom or a fluorine atom. Further, when R ¹ is methyl, R ² is preferably a fluorine atom, and when R ¹ is cyano, R ² is preferably a hydrogen atom.

As R ^3, a hydrogen atom or a methyl, Echiru, propyl, preferably _ ₃ alkyl groups such as isopropyl, especially 〇 Bok ₃ alkyl group such as methyl preferred.

Further, it is preferred that R ³ is coordinated. In this case, the general formula (I) is

(la)

[Wherein, R ¹ ′ has the same meaning as R ¹ defined above, and each of the other symbols has the same meaning as described above. ] Is represented.

 Ring A 'represents a pyridine ring, and the position of the nitrogen atom is not particularly limited.

The position of R ¹ ′ substituted on the ring A ′ is not particularly limited, but is preferably substituted next to the nitrogen atom on the pyridine ring. More specifically,

などが用いられ、 なかでも

が好適である。 For example,

Etc. are used, especially

Is preferred.

R is preferably a hydrogen atom, a C, _-3 alkyl group which may be substituted by 1 to 3 halogen atoms (particularly, a fluorine atom) such as methyl, ethyl, propyl, trifluoromethyl, etc. Methyl or trifluoromethyl is preferred.

 p represents an integer of 0 to 3, and represents that 0 to 3 Rs may be substituted on the phenyl group. p is preferably 2.

 The substitution position of R is not particularly limited. For example, when p is 2, the 3- and 5-positions of the phenyl group are preferred.

で表される基としては、 More specifically, the expression

As the group represented by

Wherein R ⁴ , R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, Which may C, _ _e alkyl group, an alkoxy group which may be halogenated, showing the Shiano group or arsenate Dorokishi group. And a group represented by the formula:

[Wherein, R ⁴ and R ⁵ are as defined above. A group represented by the formula:

[Wherein, R ⁴ and R ⁵ are as defined above. ] Is preferable. , R ⁴ , R ^s and R ^s — _β- alkyl groups include, for example, methyl, ethanol, propynole, isopropinole, butizole, sec-butyl, tert-butynole, pentynole, hexyl and the like. Among them, C! ₃ alkyl groups such as methyl, engineered, propyl, and isopropyl are preferable, and methyl is particularly preferable.

As the halogen atom which may be possessed by the —6 alkyl group represented by R \ R ⁵ and R ⁵ , a fluorine atom, a clay atom, a bromine atom and an iodine atom are used.

As the optionally halogenated alkynole group represented by R ⁴ , R ^s and R ^e , a _ ₆ alkyl group which may be substituted with 1 to 3 halogen atoms (eg, a fluorine atom) is used. Specifically, an alkyl group which may be substituted with 1 to 3 halogen atoms (eg, a fluorine atom) such as methyl, ethyl, propyl, and trifluoromethyl is preferable, and methyl, trifluoromethyl and the like are particularly preferable. A Ci ₃ alkyl group which may be substituted with a fluorine atom such as is preferred.

As the alkoxy group represented by R ⁴ , R ⁵ and R ⁶ , for example, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, hexyloxy and the like are used. Among them, alkoxy groups such as methoxy, ethoxy, propyloxy and isopropyloxy are preferred, and methoxy is particularly preferred.

The R \ R ⁵ and optionally halogen atom have the C i-s alkoxy group represented by R ^6, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is used.

As the optionally halogenated d ₆ alkoxy group represented by R ⁴ , R ^s and R ⁶ , an alkoxy group optionally substituted by 1 to 3 halogen atoms is used. Is preferably a C, ₃ alkoxy group which may be substituted by 1 to 3 fluorine atoms, such as methoxy, ethoxy, propyloxy, trif-norelomethoxy and the like.

R \ The R ^s and R ^6, a hydrogen atom, 1 to 3 halogen atoms (e.g., knots atom) optionally C, and preferably such _ ₃ alkoxy group optionally substituted with, among others 1 a stone 3 halogen atoms (e.g., fluorine atom) Ji may be substituted by, preferably an alkoxy group, Tokunime butoxy, C physician ₃ alkoxy group optionally substituted with a fluorine atom such as Torifuruorome butoxy are preferred.

 m is preferably 1 or 2, and particularly preferably 1.

 n is preferably 2.

 As the compound (I) of the present invention, specifically, a compound represented by the formula:

(In)

[Wherein, A ′ ring is a pyridine ring, R ¹ ′ is as defined above, R ² ′ is a hydrogen atom, a halogen atom or a d-3 alkyl group, R ³ ′ is an alkyl group, R ⁴ ′ and R ⁵ 'may be halogenated same or different C, shows a _ ₃ alkyl group. ] Compounds and the like are preferred.

Among them, ring A 'is a pyridine ring, R ¹ ' is (1) an alkyl group optionally substituted by a hydroxy group, a halogen atom or a cyano group, (2) a heterodioxy group, (3) A halogen atom, (4) a cyano group, (5) a mono- or dialkylcarbamoyl group, (6) an oxygen atom, a nitrogen atom or a sulfur atom other than one nitrogen atom and a carbon atom 5 or 6-membered cyclic aminocarbonyl group, (7) - ₆ alkyl one carbonyl § amino group, (8) a heterocyclic carbonyl § amino group or (9) a compound showing a heterocyclic group (I ').

Further, the ring A is a pyridine ring, R ¹ ′ alkyl group, (2) ₃ alkoxy group, (3) C ₃ alkoxy monocarbonyl group, (4) alkylthio group, (5) halogen Atom, (6) cyano group, (7) amino group, (8) mono- or di-C ぃ₃ alkylamino group or (9) oxygen atom or nitrogen atom in addition to one nitrogen atom and carbon atom a cyclic amino group which may 5 or 6 membered There, R ² 'is a hydrogen atom, a halogen atom or Ji, the _ ₃ alkyl group, R ^3' and ₃ alkyl groups, the same is R ⁴ 'and R ^5' Alternatively, the compound may be halogenated differently. A compound showing a ₃ alkyl group (1 ′) Power S Preferred.

As the alkyl group represented by R ² ′, R ³ ′, R ⁴ ′, and R ⁵ ′, for example, methyl, ethyl, propyl, and isopropyl are used, and among them, cyano is preferable.

It is a R ⁴ 'and R ^s' are Flip ₃ halogen atom with the alkyl group optionally having the indicated by a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is used.

R ⁴ 'and R ^5' may be halogenated shown in C, and as the _ ₃ alkyl group, 1 to optionally substituted with 1-3 halogen atoms C, - ₃ alkyl group Re et al used Specifically, a Ci- ₃ alkyl group which may be substituted by 1 to 3 fluorine atoms, such as methyl, ethyl, propyl, and small trifluoromethyl, is preferred.

As the halogen atom represented by R ² ′, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are used, and among them, a fluorine atom and the like are preferable.

R ¹ 'is methyl, methoxy, methoxycarbonyl, methylthio, halogen W

Preferred are hydrogen (particularly chlorine atom), cyano, dimethylamino, morpholino, etc., of which methyl, cyano and the like are preferred, and cyan / is particularly preferred.

As R ² ′, a hydrogen atom, a halogen atom such as a fluorine atom, a methyl group, and the like are preferable, and a hydrogen atom and a fluorine atom are particularly preferable. Furthermore, 'if the methyl, R ^2' R ¹ fluorine atom is, 'when it is Shiano, R ^2' R ¹ a hydrogen atom is preferred as.

Preferably, R ³ ′ is coordinate. In this case, the general formula () is

Wherein each symbol is as defined above. ] Is represented.

As R ³ ′, methyl is preferable.

As R ⁴ ′ and R ⁵ ′, an alkyl group which may be substituted by 1 to 3 halogen atoms (eg, a fluorine atom) is preferable, and trifluoromethyl and the like are particularly preferable.

 Specifically, the compound (I) of the present invention includes the compounds of Examples 1 to 199 described below, and among them,

 (a R, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] 1- 2-chloro- 1 9-methyl-5-phenyl 8, 9, 10, 11-tetrahydro 7H — [1, 4] diazocino [2.1-g] [1, 7] naphthyridine-1 6,13-dione (Example 11),

(a R, 9R)-7-[3,5-bis (trifluoromethyl) benzyl] 1,2,9-dimethyl-5-phenyl 8, 9, 10, 11-tetrahydro-1H 7- , 4] diazocino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione (Example 12), (a R, 9 R) -7— [3,5-bis (trifluoromethyl) benzyl] —9-methyl-6,13-dioxo-5-phenyl-6,8,9,10,11,13 — ^ ^ Kisahidro 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1-2-potency reporto-tolyl (Example 13),

 (a R, 9R) — 7— [3,5-Bis (trifluoromethyl) benzyl] —2—chloro 1-5— (4-Funoleolopheninole) 1 9—Methynolee 8, 9, 10, 11-tetrahydro 7H— [1,4] diazosino [2,1—g] [1,7] naphthyridine-16,13 dione (Example 25),

 (a R, 9 R) — 7— [3,5-Bis (trifluoromethyl) benzyl] — 5— (4 —Funoleolopheninole) 1, 2, 9—Dimethinole 8, 9, 10, 1 1-tetrahydro 7H— [1,4] diazosino [2,1-g] [1,7] naphthyridine-1,6,13-dione (Example 26),

 (a R, 9R) -7- [3,5-Bis (trifluoromethyl) benzyl] — (4-phenylenophenyl) -1-9-methinole-6,13-dioxo-1,6,8,9,10 , 1 1,1 3 1 ^> Kisahi Draw 7H— [1,4] diazosino [2,1—g] [1,7] naphthyridine 1-2-carbonitrile (Example 27),

 (a R, 9 R) -7- (3,5-dimethylbenzyl) -1,5- (4-fluorophenyl) -2,9-dimethyl-1,8,10,11-tetrahydro 7H— [1,4 ] Diazo sino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione (Example 29), (aR, 4R) -1-2, [3,5-bis (trifluoromethyl) Benzyl] 1,4,9-dimethyl-13-phenyl 3.4,5,6-tetrahydro-2H— [1,4] diazosino [1,2—b] [2,7] naphthyridine-1 , 8-dione (Example 32),

(a R, 4 R) — 2— [3.5—Bis (trifluoromethyl) benzyl] 1 13— (4—fluorophenyl) 1,4,9-dimethyl-3,4,5,6-tetrahydro 2H—

 [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine-1,8-dione (Example 34),

(a R, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] -N, N, 9-Trimethinole-6,13-Dioxo-5-Phenyl-6,8,9,10,11,1 3 ■ Kisahi Draw 7H— [1, .4] Diazocino [2,1-g]-1,7— Naphthyridine-1-carboxamide (Example 50),

 (a R, 9 R) -7- [3.5-Bis (trifluoromethyl) benzyl] -1-9-methyl-5-phenyl-2- (1,3-thiazolidine-13-ylcarbonyl) -18 , 9,10,1 1-tetrahydro-7H— [1,4] diazino [2,1—g] —1,7-naphthyridine-1,6,13-dione (Example 63),

 (a R, 9R) — 7— [3,5-bis (trifnorolemethinole) benzyl] 1 9-methyl 5-phenyl-1- (pyridine-13-yloxy) 1,8,9,10 , 11-tetrahydro-7H— [1.4.diazino] [2,1 to g] -1,7-naphthyridine-6,13-dione (Example 79),

 N- [(a R, 9R) -7- [3,5-bis (trifluoromethyl) benzyl]-9 -methinole 6,13-dioxo-1-5-phenyl 6,8,9,10,11 , 13—Hexahi draw 7H— [1,4] diazosino [2,1-g] -1, 7-naphthyridin-1-yl] nicotinamide (Example 85),

 N — [(a R, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl] —9—Methinole-6,13-Dioxo-5-Feninole-6,8,9,9 10,1 1,13—Hexahi Draw 7H— [1,4] diazosino [2,1—g] —1,7-naphthyridin-1-yl] acetoamide (Example 87)

 (a R, 9R) —7— [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl-5-phenyl-1- (1H-tetrazo-1-lu-5-yl) 1,8,9 , 10, 1 1—tetrahydro 7H— [1,4] diazosino [2,1-g] -1,7-naphthyridine—6,13-dione (Example 95),

[(a R, 9R) — 7— [3,5-Bis (trifluoromethyl) benzyl] —9-methyl / leic 6, 13-dioxo-1-5-phenyl 6, 8, 9, 10, 11, 13— ^ "Kisahydro-7H— [1,4] diazosino [2,1-g] -1, 7-naphthyridin-2-yl] acetonitrile (Example 124) (a R, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] —2— (phenolomethyl) -19-methyl-5-phenyl 8, 9, 10, 11—tetrahydro-7H — [1, 4] diazocino [2, 1-g] -1, 7-naphthyridine-1,6,13-dione (Example 1 25),

 (a R, 9 R) —9-Methyl-7— [3-Methyl-5— (trifluoromethyl) benzyl) —6,13—Dioxo-5-phenyl-1,6,8,9,10,1,1,13 1 ^^ Kisahidoro-1H- [1,4] diazosino [2,1-g] [1,7] naphthyridine-1-carboditrinole (Example 144),

 (a R, 9 R) 1-5- (4-fluorophenyl) 19-methyl-17- [3-methyl-5- (trifluoromethyl) benzyl] -6,13-dioxo-1,6,8,9 10, 1 1, 13-Hexahi Draw 7H— [1, 4] diazocino [2, 1-g] [l, 7] naphthyridine-12-potassium nitrile (Example 175),

 (a R, 9 R) — 2-Chloro-5— (4-fluorophenyl) -9-methyl-7— [3-Methynole-5- (Triphnorelomethynole) benzyl] —8, 9, 10, 1 1—Tetrahi Dro-1H— [1,4] diazosino [2,1-g] [1,7] naphthyridine-1,6,13-dione (Example 176),

Or a salt thereof is suitable.

Examples of the salt of the compound (I) of the present invention include a metal salt, an ammonium salt, a salt with an organic group, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or amino acid. . Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolanolamine, cyclohexylamine, dicyclohexylamine. Salts with rumamine, N, N'-dibenzylethylenediamine and the like can be mentioned. Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, Examples include salts with acids, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, lingic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, or oleetin, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, etc. Is mentioned.

 Of these, pharmaceutically acceptable salts are preferred. For example, when compound (2) has an acidic functional group, inorganic compounds such as alkali metal spots (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, magnesium salt, barium salt, etc.) Salts, ammonium salts, etc., and when compound (I) has a basic functional group, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid Examples thereof include salts with organic acids such as acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.

 The prodrug of the compound (I) of the present invention or a salt thereof (hereinafter sometimes abbreviated as the compound (I) of the present invention) can be produced by reacting with an enzyme, gastric acid, or the like under physiological conditions in a living body. A compound that converts to the compound (I), that is, a compound that enzymatically oxidizes, reduces, hydrolyzes, etc., and changes to the compound (1) of the present invention; I) is a compound that changes to

As a prodrug of the compound (I) of the present invention, a compound in which the amino group of the compound (I) of the present invention is acylated, alkylated or phosphorylated (for example, the amino group of the compound (I) of the present invention is eicosanoyl) , Araerylation, pentylaminocarbonylation, (5-methyl-1-oxo-1,1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofurolation, pyrrolidylmethylation, Viva A compound in which the hydroxyl group of the compound (I) of the present invention has been acylated, alkylated, phosphorylated, or borated (for example, a compound of the present invention (eg, a compound of the present invention) The hydroxyl group of (I) is acetylated, palmitoylated, propanoylated, bivaloylated, succinylated, fumarylated, alanylated, and dimethylaminomethylcarbonylated. Compound, etc.); compounds (carboxyl group esterification I), amidated compound of the invention (e.g., compounds of the present invention The carboxy group of the product (I) is ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, bivaloyloxymethyl ester, ethoxycarbonyloxystelyl ester, phthalidyl ester, (5-Methylenol 2-oxo-1,1,3-dioxolen-141-yl) Methylesterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, etc.). These compounds can be produced from compound (I) of the present invention by a method known per se.

 The prodrug of the compound (I) of the present invention can be produced under physiological conditions as described in Hirokawa Shoten, 1990, Developing Pharmaceuticals, Vol. 7, Molecular Design, pp. 163-198. May be changed to the compound (I) of the present invention.

 Compound (I) or a salt thereof of the present invention can be produced according to a method known per se, for example, a production method described in JP-A-9-263585 (EP-A-7333362) can do. For example, the compound (I) of the present invention or a salt thereof has the formula

〔式中、 Lは脱離基、 その他の記号は前記と同意義を示す〕 で表される化合物または その塩を環化反応に付し、 閉環させることによって製造することができる （A法)。

Wherein L is a leaving group, and other symbols have the same meanings as described above, or a salt thereof is subjected to a cyclization reaction, followed by ring closure (Method A). .

Examples of the leaving group represented by L include a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.) or a substituted sulfonyloxy group (for example, methanesulfonyloxy, ethanesnolefuroxy, trifluoro) b methanesulfonyl O carboxymethyl optionally substituted C t-6 alkylsulfonyl O alkoxy group such as; benzenesulfonyl O carboxymethyl, p - toluenesulfonyl O carboxymethyl C ₆ _ _{1 4} Arirusuruho such - such Ruokishi group) etc. Is used.

 The compound (II) may be used as a free compound, or may be subjected to the reaction in the form of a salt thereof (eg, an alkali metal salt such as lithium, sodium, potassium and the like). The reaction is usually performed in a solvent inert to the reaction. Examples of the solvent include: hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; ditrinoles such as acetonitrile; ethers such as dimethyloxetane and tetrahydrofuran; dimethylformamide And aprotic polar solvents such as dimethinoresulfoxide and hexamethyl phosphoramide.

 The reaction can advantageously proceed by adding a base. Examples of such bases include inorganic bases (eg, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, sodium carbonate, potassium carbonate, and the like). Alkali metal hydrides such as alkali metal carbonates, sodium hydride, potassium hydride, alkoxides such as sodium amide, sodium methoxide, sodium methoxide, sodium t-butoxide and potassium t-butoxide, and organic bases (trimethyl Amines, triethynoleamines, diamines such as diisopropylethylamine, and cyclic amines such as pyridine are preferred. In the cyclization reaction, instead of using a base, the compound (II) may be converted to a salt with a base (for example, the alkali metal salt, alkaline earth metal salt, or the like) and reacted. The amount of the base varies depending on the compound (II) to be used, the kind of the solvent and other reaction conditions, and is usually about 1 to about 10 mol, preferably about 1 to about 5 mol per 1 mol of compound (II). It is about a mole.

 The reaction temperature is, for example, about -5O to about 200C, preferably about -20 to about 150 ° C, and the reaction time is the kind of the compound (Π) or the kind of the salt thereof. The reaction time varies depending on the reaction temperature and the like, and is, for example, about 1 to about 72 hours, preferably about 1 to about 24 hours.

Further, the compound (I) of the present invention or a salt thereof has the formula

[Wherein the symbols have the same meanings as described above] or a salt thereof is subjected to a nucleophilic reaction in the presence of an activating agent (Method B).

 Compound (II) or a salt thereof can be produced according to a method known per se, for example, a method described in JP-A-10-10989.

 The nucleophilic reaction can be performed by various known methods.For example, a method using various nucleophiles as necessary in the presence of an activator is preferable, but in some cases, the activator itself is nucleophilic. May work as an agent.

 Examples of the activator used include methanesulfonyl chloride, tansulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, benzoyl chloride, acetic anhydride, methyl carbonate, methyl isobutyl carbonate, and dimethylcarbamoyl chloride. For example, lid, dimethylcarbamoyl chloride, phosphorus oxychloride, trimethylsilyl nitrile, dimethyl sulfate, and getyl cyanophosphonate are used.

 As the nucleophile, for example, carbon nucleophiles such as potassium cyanide and Grignard reagent; alkoxides such as sodium methoxide and sodium methoxide are used, and they can be used together with an activating agent if necessary.

Reaction conditions (solvent, temperature, time, etc.) vary depending on the type of activator and nucleophile used. For example, the reaction is usually performed in a solvent inert to the reaction. Examples of the solvent include hydrocarbons such as benzene and acetone, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethyloxetane and tetrahydrofuran. , Alcohols such as methanol and ethanol, dimethylformamide, dimethylsulfoxide, hexamethylphosphorore? Such as Non-protonic polar solvents, water or mixtures thereof.

 The reaction can advantageously proceed by adding a base. Such bases include, for example, inorganic bases (such as sodium hydroxide, alkali metal hydroxides such as hydroxylating hydroxides, alkali metal bicarbonates such as sodium carbonate and potassium hydrogen carbonate, and carbonates). Alkali gold carbonates such as sodium and potassium carbonate, alkoxides such as sodium methoxide and sodium ethoxide, etc., organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, and pyridine-like cyclic Are preferred.

 The amounts of the activator, nucleophile and base vary depending on the type of solvent and other reaction conditions, and are usually about 1 to 10 mol, preferably about 1 to about 10 mol, respectively, per 1 mol of compound (III). It is about 5 mol.

 The reaction temperature ranges, for example, from about 150 to about 200, preferably from about −20 ^ to about 150 ^, and the reaction time varies depending on the type of the compound (ΠΙ) or the salt thereof. It depends on the type, reaction temperature and the like, and is, for example, about 1 to about 72 hours, preferably about 1 to about 24 hours.

 Further, the compound (I) of the present invention or a salt thereof has the formula

[Wherein R ¹ ′ represents a halogen atom, and other symbols have the same meanings as described above]. (Method C)

 Compound (IV) can be produced by Method A, Method B or a method analogous thereto.

As the halogen atom represented by R ¹ ′, a fluorine atom, a chlorine atom, a bromine atom, etc. are used. You can.

 The substitution reaction can be carried out by various known methods. For example, a method using various nucleophiles is preferable, and a transition metal catalyst can be used if necessary.

 Examples of the nucleophilic reagent include potassium cyanide, cyanide, Grignard reagent (eg, methylmagnesium bromide), organic dumbbell reagent, organic boron reagent (eg, methylboronic acid, phenylpoic acid) Carbon nucleophiles such as organotin reagents; optionally substituted alkyl alcohols such as methanol, ethanol, and pyridylmethanol; aromatic alcohols such as phenol and pyridinol; methyl mercaptan and thiophenol Thiols such as mercaptopyridine; alkoxides such as sodium methoxide and sodium methoxide; aromatic alkoxides such as sodium phenoxide; thioalkoxides such as sodium thiomethoxide and sodium thiomethoxide. ; Methylamine, dimethylamine Echiruamin, morpholine, amines such as Ben Jiruamin; imidazo Ichiru, virazole, triazole, 含窆 containing heterocycles such Tetorazo Le is used.

 The amount of the nucleophile to be used varies depending on its type, and is usually 1 mol or more, preferably about 1 to about 5 mol, per 1 mol of compound (IV), but it may be used as a solvent in some cases.

 As the transition metal catalyst, for example, a palladium catalyst such as palladium acetate, palladium chloride, and palladium tetrakis (triphenylphosphine); a nickel catalyst such as nickel chloride; and the like. Organic phosphorus reagents such as, 1'-bis (diphenylphosphino) phenene (dppf) can be used.

 The amount of the catalyst used varies depending on the type of the catalyst, and is usually about 0.001 to about 1 mol, preferably about 0.01 to about 0.5 mol, per 1 mol of compound (IV). The amount of the organic phosphorus reagent is preferably about 0.01 to about 2 mol.

Reaction conditions (solvent, temperature, time, etc.) vary depending on the type of nucleophile and catalyst used. For example, the reaction is usually performed in a solvent inert to the reaction. Examples of solvents For example, hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; nitriles such as acetonitrile; ethers such as dimethoxetane, tetrahydrofuran and dioxane; alcohols such as methanol and ethanol. Aprotic polar solvents such as dimethylhonolemamide, dimethylsulfoxide, and hexamethylphosphoramide; water or a mixture thereof.

 In addition, the reaction can be advantageously promoted by adding a base. Such bases include, for example, inorganic bases (such as sodium hydroxide, alkali metal hydroxides such as hydroxylating limes, sodium bicarbonate, alkali metal hydrogen carbonates such as bicarbonate limes, sodium carbonate, etc.). , Alkali metal carbonates such as potassium carbonate, metal hydrides such as sodium hydride, potassium hydride, etc.), organic bases (amines such as trimethinoleamine, triethylamine, disopropylethylamine, pyridine, etc.) And the like are preferred.

 The amount of the base varies depending on the type of the nucleophile, the catalyst and the solvent, and other reaction conditions, and is usually about 1 to about 100 mol, preferably about 1 to about 1 mol, per 1 mol of compound (IV). It is about 0 mol.

 The reaction temperature is, for example, in the range of about 150 to about 200 ^, preferably about 120 to about 15, and the reaction time is the kind of the compound (IV) or the kind of the salt thereof, The reaction time varies depending on the reaction temperature and the like, and is, for example, about 1 to about 72 hours, preferably about 1 to about 24 hours.

Further, a compound having an alkylsulfonyl group as R ¹ can be produced by oxidizing a compound having an alkylthio group as R ¹ in the compound (I) obtained by the reaction by a method known per se.

Furthermore, among the compounds (I) or a salt thereof of the present invention, compounds wherein R ¹ is a C] _ _e Arukokishikaru Boniru group, a carboxyl group (VI) may be prepared by a method analogous below D method or this I can do it.

[Method D]

 (IV) (VI)

[Wherein, R ⁷ represents an alkynole group or a hydrogen atom, and other symbols have the same meanings as described above].

Examples of the alkyl group represented by R ⁷ include methyl, ethyl, and propyl.

 Compound (IV) to be used as the conjugate in this step can be produced by Method A, Method B or a method analogous thereto.

 This reaction is carried out in a solvent inert to the reaction under a carbon monoxide atmosphere using a transition metal catalyst, dimethyl alcohol, or an alkyl alcohol. If necessary, a reaction reagent can be used. As the transition metal catalyst, for example, a palladium catalyst such as palladium nitrate, palladium chloride, and tetrakis (triphenylphosphine) palladium; a nickel catalyst such as nickel chloride are used. If necessary, triphenylphosphine, 1 , 1 'An organic phosphorus reagent such as bis (diphenylphosphino) phenecene (dppf) can be used. The amount of the catalyst used varies depending on the type of the catalyst, and is usually about 0.001 to about 1 mol, preferably about 0.01 to about 0.5 mol, per 1 mol of compound (IV). Yes, the amount of the organic phosphorus reagent used is preferably about 0.01 to about 2 mol.

C, as the _ ₆ alkyl alcohol, usually an excess amount of methanol or ethanol is used.

Examples of the solvent inert to the reaction include hydrocarbons such as benzene and toluene; nitriles such as acetonitrile; ethers such as dimethoxetane, tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; dimethylform Aprotic poles such as amides, dimethyl sulfoxide, hexamethylphosphoramide Water or a mixture thereof is used.

 The reaction can be advantageously promoted by adding a base or a salt. Such bases include, for example, inorganic bases (such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, sodium carbonate, and potassium carbonate). Alkali metal carbonates) and organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, cyclic amines such as pyridine, etc.) are preferred. Examples of the salt include sodium acetate, lithium chloride, sodium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide and the like. The amount of the base or salt to be used is about 1-about 100 mol, preferably about 1-about 10 mol, per 1 mol of compound (IV). The reaction is usually carried out in a carbon monoxide atmosphere at normal pressure, but can be carried out under pressure (for example, about 3 to about 10 atm) if necessary.

 The reaction temperature ranges, for example, from about 150 to about 200, preferably from about 20 ° to about 150 ^, and the reaction time ranges from compound (IV), metal catalyst, organophosphorus reagent, It depends on the type of base and salt, the reaction temperature, the reaction pressure and the like, and is, for example, about 0.5 to about 72 hours, preferably about 0.5 to about 24 hours.

Further, among the compound (I) of the present invention or a salt thereof, the compound (VIII, IX, XI) in which R ¹ has a C—s alkyl group which may have a substituent, can be prepared by the following method E It can also be manufactured by the method described above or a method analogous thereto.

[Method E]

About 2

Wherein R ⁷ ′ is an alkyl group, R ⁸ is a halogen atom, an optionally substituted oxygen atom, an optionally substituted amino group or a cyano group, and other symbols are as defined above. Is shown).

Examples of the alkyl group represented by R ⁷ ′ include the same ones as described in the description of R ¹ .

Examples of the halogen atom represented by R ⁸ include the same ones as described in the description of R ¹ .

 Examples of the substituent of the oxygen atom include -6 alkyl which may be halogenated (for example, methyl, ethyl, propyl, butyl, trifluoromethyl, 2,2,2-triphnoleroethyl), and acyl (for example, acetyl, Propionyl).

Substituents on an amino group include mono or di-C alkyl (eg, methyl, ethyl, dimethyl, getyl). Compound (VII) used as a starting compound in this step can be produced by Method A, Method C or a method analogous thereto. ,

 (Process 1)

 In this step, after the pyridine ring of the A ring of the compound (VII) is acidified, the obtained N-oxo compound is subjected to a transfer reaction to produce an acyloxy compound (VIII).

 The oxidation reaction of the pyridine ring can be carried out according to a method known per se, for example, a method described in JP-A-10-109989. The transfer reaction of the obtained N-oxide is carried out using a reactive derivative of carboxylic acid, and an inert solvent can be used if necessary.

 Examples of the reactive derivative of a carboxylic acid include an acid anhydride. The amount of the reactive derivative of carboxylic acid to be used is usually 1 equivalent or more per 1 mol of N-oxide, and it can be used as a solvent. Examples of the solvent inert to the reaction include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as dimethoxetane and tetrahydrofuran; dimethylformamide and dimethyl sulfoxide. An aprotic polar solvent, a protic polar solvent such as acetic acid, or a mixture thereof is used. If necessary, a base such as triethylamine or sodium hydrogen carbonate may be used. The reaction temperature ranges, for example, from about 0 to about 200 "C, preferably from about 50 to about 15, and the reaction time is usually about 0.5 to about 72 hours, preferably about 1 to about 72 hours. About 24 hours.

 (Process 2)

 This step is a step of subjecting the acyloxy form (VIII) to a hydrolysis reaction to convert it into the alcohol form (IX). This reaction is usually performed in the presence of an acid or a base, and a solvent that does not adversely influence the reaction can be used, if necessary.

As the acid, mineral acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), carboxylic acids (for example, formic acid, acetic acid, propionic acid, etc.) are used, and among them, hydrochloric acid, sulfuric acid, etc. are preferable. . Examples of the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate; and alkali metals such as calcium hydroxide and potassium hydroxide. Earth metal salts; alkoxides such as sodium methoxide and sodium ethoxide; and among them, potassium hydroxide, sodium hydroxide, sodium methoxide and the like are preferable. The amount of the acid or base to be used is, for example, about 0.01 to about 100 mol, preferably about 0.1 to about 50 mol, per 1 mol of compound (VIII).

 Examples of solvents that do not adversely affect the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, and tert-butanol; and aromatic hydrocarbons such as benzene, toluene, and xylene. Aliphatic hydrocarbons such as hexane and heptane; ethers such as getyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and dimethoxyethane; dimethylformamide, dimethylacetamide and the like Amides; sulfoxides such as dimethyl sulfoxide; and water. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.

 The reaction temperature is usually about 0 ^ to about 150 ^, preferably about 10 to about 100. The reaction time varies depending on the compound (VII1), the type of acid and base, the reaction temperature, and the like, and is, for example, about 0.1 to about 100 hours, and preferably about 0.1 to about 24 hours. (Process 3)

 In this step, the alcohol form (IX) is subjected to an oxidation reaction to produce an aldehyde form (X).

Examples of the oxidizing agent include a manganese compound such as manganese dioxide, a chromic acid compound such as chromium (IV) oxide, and nitric acid. The amount of the oxidizing agent is preferably about 1 to about 3 based on 1 mol of the compound (IX). 0 mole. Reaction conditions (solvent, temperature, time, etc.) vary depending on the type of filtration agent and substrate used. For example, the reaction is usually performed in a solvent that does not interfere with the reaction. Examples of the solvent include acetone, carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, acetic acid, sulfuric acid, pyridine, water, or a mixture thereof. Things. The reaction temperature varies depending on the type of the oxidizing agent and the solvent used, but is usually about 15 to about 150. The reaction time is generally about 1 to about 72 hours, preferably about 1 to about 24 hours.

 Further, if necessary, compound (X) obtained in this step can be subjected to a substitution reaction in the following step 4.

 (Step 4)

 This step is a step of subjecting the hydroxy group of compound (IX) to an alkylation, acylation or substitution reaction by a method known per se to convert it into various substituents. If necessary, a combination of alkylation, acylation or transformation reaction can be used. This step is usually performed in a solvent inert to the reaction, and the reaction can be advantageously performed by adding a base.

 Examples of the alkylating agent include halides of alkanes which may have a substituent (eg, chloride, bromide, iodide, etc.), sulfates or sulfonates (eg, methanesulfonate, p-toluenesulfonate, benzene) Sulfonate and the like). The amount of the alkylating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (IX).

 Examples of the acylating agent include carboxylic acid, sulfonic acid, phosphoric acid, carbonic acid, and reactive derivatives thereof (for example, acid halide, acid anhydride, mixed acid anhydride, active ester, etc.), isocyanate, and isothiocyanate. Esters and the like. The amount of the acylating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (IX).

The substitution reaction can be performed using various reaction reagents. Examples of the reaction reagent include carbon nucleophiles such as potassium cyanide and Grignard reagents; alkoxides such as sodium methoxide and sodium ethoxide; potassium fluoride, tris (dimethylamino) sulfonium difluorotrimethyl silica gel, [bis (2-Methoxyxyl) Amino] -Fluoride such as sulfur trifluoride is used. The amount of the reaction reagent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (IX). Quantity.

 Examples of the base include amines (eg, alkylamines such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] ndecaene-7-ene, etc. , Pyridine, aromatic amines such as N, N-dimethylaniline, etc.), alkali metal salts (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc.) And metal hydrides (eg, potassium hydride, sodium hydride, etc.), alkali metal alkoxides (eg, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, etc.). The amount of the base to be used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (IX).

 Examples of the solvent include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; and ethers such as ethyl acetate. Esters; aromatic amines such as pyridine; amides such as N, N-dimethylformamide; sulfoxides such as dimethylsulfoxide and mixtures thereof.

 The reaction temperature is usually about -50 to about 150, preferably about 110 to about 10OX. The reaction time varies depending on the type of the compound (IX) and the base, the reaction temperature and the like, and is, for example, about 0.5 to about 100 hours, preferably about 0.5 to about 24 hours.

The compounds of the present invention (I) or of a salt thereof, 1¾ ¹ Gazi ₁ _ ₆ § alkoxycarbonyl group, a carboxyl group, which may have an optionally substituted force Rubamoiru groups and substituents Compounds having a good thiocarbamoyl group (VI, XII, XIII) can also be produced by the following steps of Method F or a method analogous thereto.

[Law F] R) P

 Process 6

R) P process 8

 (Via) (XII)

 (XIII)

Wherein, R ^s and R ^{1 Q} are the same or different and may be substituted alkyl groups or C! -B Ashiru group, they may form a heterocyclic ring together. Other symbols are as defined above.

Examples of the ^optionally substituted C ^ ₆ alkyl group represented by R ⁰ and R ¹⁰ include the same ones as described in the description of R ¹ .

The ci-s Ashiru group include the same as those shown in the description of R ^1.

The heterocyclic ring formed by R ⁹ and R ^{1 Q} together includes, for example, a cyclic amino group (for example, a compound containing an oxygen atom or a nitrogen atom in addition to one nitrogen atom and a carbon atom. Or a 6-membered cyclic amino group, in particular, pyrrolidino, piperidino, piperazino, morpholino, etc.).

 Compound (V) used as a starting material compound in this step can be produced according to the above-mentioned Method A, Method B or Method C according to a method analogous thereto.

(Process 5) This reaction is carried out using an alkyl alcohol in the presence of an acid catalyst, and a solvent inert to the reaction can be used if necessary.

Examples of the C ^ _β alkyl alcohol include methanol and ethanol, and can also be used as a solvent.

 Acid catalysts include inorganic acids (for example, hydrochloric acid, sulfuric acid, hydrobromic acid, boron trifluoride, etc.) and organic acids (for example, methanesulfonic acid, benzenesulfonic acid, ρ-toluenesulfonic acid, etc.) Is raised. The amount of the acid catalyst to be used is about 0.001 to about 1 mol, preferably about 0.01 to about 0.5 mol, per 1 mol of compound (V). Examples of the solvent inert to the reaction include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as dimethyloxetane and tetrahydrofuran; dimethylformamide and dimethylsulfoxide. An aprotic polar solvent such as hexamethylphosphoramide or a mixture thereof is used. The reaction temperature is, for example, about 0 to about 20 O, preferably about 50 °: to about 150, and the reaction time varies depending on the type of the compound (V), the reaction temperature, and the like. For example, about 0.5 to about 72 hours, preferably about 1 to about 24 hours.

 (Step 6)

 This step is generally performed in the presence of an acid or a base, and a solvent inert to the reaction may be used as necessary.

 As the acid, mineral acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), carboxylic acids (for example, formic acid, drunk acid, propionic acid, etc.) are used, and among them, hydrochloric acid, sulfuric acid, etc. are used. preferable.

As the base, for example, lithium metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium carbonate and the like; calcium hydroxide, hydroxide Alkaline earth metal salts such as valium; amines such as trimethylamine, triethylamine, ethyldiisopropylamine, N-methylmorpholine and the like, among which potassium hydroxide and sodium hydroxide are preferable. The amount of the acid or base to be used is, for example, about 0.01 to about 100 mol, preferably about 0.1 to about 50 mol, per 1 mol of compound (VI).

 Examples of solvents inert to the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol and tert-butanol; and aromatic hydrocarbons such as benzene, toluene and xylene. Aliphatic hydrocarbons such as xane and heptane; ethers such as getyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and dimethoxetane; dimethylformamide, dimethylacetamide And the like; dimethyl sulfoxide and the like; sulfoxide; water and the like. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.

 The reaction temperature is usually about 0 to about 150, preferably about: I0 ^ to about 100. The reaction time varies depending on the type of compound (VI), the type of acid / base, the reaction temperature and the like, and is, for example, about 0.1 to about 100 hours, preferably about 0.1 to about 24 hours.

 (Step 7)

This step is a step of producing an amide form (XII) by reacting the compound (Via) with a desired amine. This reaction can be carried out usually using a compound (VIa) or its reactive derivative at the carboxyl group and an amine in a solvent inert to the reaction. Examples of the reactive derivative include acid halide, mixed acid anhydride, imidazolide, active ester and the like. Examples of the solvent include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane; esters such as ethyl acetate; An aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide, water, or a mixture thereof is used. The amount of the amine to be used is generally 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of the compound (Via) or its reactive derivative. The reaction can advantageously proceed by adding a base. Such bases include, for example, organic bases (trimethylamine, triethylamine, diisopropyl Alkylamines such as ethylamine, N-methylmorpholine, cyclic amines such as pyridine, aromatic amines such as N, N-dimethylaniline, etc., inorganic bases (alkali metals such as sodium hydrogencarbonate and hydrogencarbonate) Hydrogen carbonate, sodium carbonate, alkali metal carbonates such as carbonated lime, sodium hydroxide, alkali metal hydroxides such as hydroxylated lime, etc.). The amount of the base to be used is, for example, about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of compound (VIa) or a reactive derivative thereof.

 The reaction temperature is usually about 130 to about 150, preferably about 0 to about 10 Ot :. The reaction time varies depending on the type of the compound (Via), the reaction temperature and the like, and is, for example, about 0.5 to about 100 hours, preferably about 0.5 to about 24 hours.

 (Step 8)

 This step is performed in the presence of a sulfurizing agent in a solvent inert to the reaction.

 Examples of the sulfurizing agent include phosphorus pentasulfide, Lowesson reagent and the like. Examples of the solvent inert to the reaction include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane, and mixtures thereof. Used. The amount of the sulfurizing agent to be used is generally about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of compound (XII).

 The reaction temperature is, for example, about 20 ^ to about 15 O ^ C, and the reaction time varies depending on the compound (XI 1), the type of the sulfurizing agent, the reaction temperature, and the like. For example, about 0.5 to about 24 hours It is about.

Among the compound (I) of the present invention or a salt thereof, the compound (XIV) wherein R ¹ has an optionally substituted acyl group can be produced by the following Method G or a method analogous thereto. I can do it.

[G method]

 (XII) (XIV)

[Wherein, R ¹¹ is an alkyl group or. And the other symbols are as defined above.

C represented by R ^11, as the _ ₆ alkyl group include the same as those shown in the description of R ^1.

C ₆ - The ₁₀ Ariru group include the same as those shown in the description of R ^1. Compound (XII) used as a starting compound in this step can be produced by Method F, Step 7, or a method analogous thereto.

 This step is a step of producing an acyl form (XIV) by reacting the amide group of the compound (XII) with a carbon nucleophile, and can be carried out in a solvent inert to the reaction. Examples of the carbon nucleophile include Grignard reagents such as methylmagnesium bromide and phenylmagnesium bromide, and organic lithium reagents such as methyllithium and phenyllithium. Examples of the solvent inert to the reaction include hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane. A non-protonic polar solvent such as hexamethylphosphoramide or a mixture thereof is used. The amount of the carbon nucleophile to be used is generally 1 to 10 molar equivalents, preferably about 1 to 3 molar equivalents, per 1 mol of compound (XII). The reaction temperature is, for example, about -78 to about 150, and preferably about 1 to about 30. The reaction time varies depending on the compound (XII), the type of the carbon nucleophile, the reaction temperature and the like, and is, for example, about 0.1 to about 24 hours.

■ In the compound (I) of the present invention or a salt thereof, R ¹ may have a substituent. Compounds (XV I, XV II) having a thio group can be produced by the following Method H or a method {:

[Method H]

About 1 0

(XVI) (XVI I) [wherein, R] ² and R ¹³ are the same or different and each may have a hydrogen atom, an alkyl group which may have a substituent, or a substituent. An aryl group, an acyl group, an alkylsulfonyl group, an alkoxycarbonyl group, or a sulfamoyl group, and other symbols have the same meanings as described above.

R ^12, R ¹³ which may have a substituent group represented in C, and as the _ ₆ alkyl group include the same as those shown in the description of R ^1.

It may have a substituent. The Ariru groups may be the same as those shown in the description of R ^1.

Examples of the acyl group include the same as those described in the description of R ¹ .

Examples of the alkylsulfonyl group include those described in the description of R ¹ . The same as the alkylsulfonyl group can be mentioned.

The alkoxycarbonyl group include the same C] _ ₆ alkoxy one carboxy group shown in the description of R ^1.

Compound '(VIa) or a salt thereof used as a starting material compound in this step is obtained by the above-mentioned Method D, F It can be produced by method step 6 or a method analogous thereto.

 (Step 9)

 This step is a step of converting the carboxyl group of the compound (VIa) into an isocyanate group. Usually, the compound (VIa) is converted into an acid azide form, and then subjected to a Curtius transfer reaction, whereby the isocyanate form (XV) is converted. Is used. Although various methods are known in the literature, any of these methods can be applied to (Via). For example, by reacting an azidating agent such as diphenylphosphoryl azide with (Via), an acid azide of (Via) can be produced. The amount of the azidating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (Via). This reaction is generally performed in a solvent inert to the reaction. Examples of such a solvent include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethyls such as ethyl ether, dimethoxetane, tetrahydrofuran, and dioxane; ethyl acetate; Esters; ketones such as acetone and 2-butanone; aromatic amines such as pyridine; amides such as N, N-dimethylformamide and mixtures thereof.

 In addition, the reaction may proceed in the presence of a base. Examples of such a base include amines such as trimethylamine, triethylamine, N-methylmorpholine, tetramethylethylenediamine, and 4-dimethylaminopyridine. The amount of the base used is based on the compound (Via). It is preferably 1 to 5 molar equivalents.

 The reaction temperature is usually on the order of about 110 to about 150, preferably about 15 to about 120. The reaction time is usually about 0.5 to about 100 hours, preferably about 0.5 to about 6 hours.

The generated acid azide can be isolated and purified by a step known per se. However, the reaction solution is usually heated as it is without isolation, and is converted to an isocyanate (XV). This conversion reaction is preferably carried out by using the same solvent as that used for the azidation, usually by heating to about 20: to 200 2, preferably to about 30 to 15Οΐ. The reaction time is generally 0.1 to 10 hours, preferably 0.1 to 6 hours. The obtained iso The cyanate compound (XV) can be used for the next step without isolation or isolation without any means known per se.

 (Step 10)

 This step is a step of converting the isocyanate group of the compound (XV) into an amino group to obtain the compound (XVI). This step is usually performed under hydrolysis conditions. This reaction can be performed under acidic or basic conditions, and a solvent can be used if necessary. As such a solvent, for example, phenols such as methanol, ethanol, propanol, and butanol; ethers such as tetrahydrofuran, dioxane, and dimethoxetane; water, and mixtures thereof. As the acid, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid is used. As the base, for example, a hydroxide of an alkali or alkaline earth metal such as sodium hydroxide or barium hydroxide is preferably used. Reaction temperatures are usually on the order of about 0 to about 120, preferably about 15 to about 100. The reaction time is usually about 0.5 to about 36 hours, preferably about 0.5 to about 20 hours.

In this step, the reaction is carried out in the presence of alcohols or amines, if necessary, in a solvent that does not adversely affect the reaction, whereby R ¹² or R ^{13 of} compound (XVII) is converted to an alkoxycarbonyl group. A compound having an amino group or an alkyl ureide group can be produced.

Such alcohols include _6- alkyl alcohols such as methanol, ethanol, and butanol, and amines include primary or secondary C, _6- alkylamino such as methylamine, ethylamine, dimethylamine, and getylamine. And the like. The amount of the alcohol or amine to be used is about 1 molar equivalent or more per 1 mol of compound (XV), and it can be used as a solvent.

Solvents that do not adversely affect the reaction include, for example, hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane; Aprotic polarities such as N, N-dimethylformamide, dimethylsulfoxide Solvents or mixtures thereof are used. The reaction temperature is usually about 0 ° C to about 150X, preferably about 15 ^: to about 10 Ot :. The reaction time is generally about 0.5 to about 48 hours, preferably about 0.5 to about 20 hours. This reaction may be carried out in the presence of a catalytic amount of a base such as N, N-dimethylaminopyridine. Further, if necessary, the compound obtained in the above step can be subjected to the alkylation reaction shown in Step 11.

 (Step 11)

 This step is a step of subjecting the amino group of compound (XVI) to alkylation or acylation by a method known per se to obtain compound (XVII). If necessary, an alkylation reaction and an acylation reaction can be used in combination. This step is usually performed in a solvent inert to the reaction, and the reaction can be advantageously performed by adding a base.

 Examples of the alkylating agent include halides of alkanes which may have a substituent (eg, chloride, bromide, chloride), sulfates or sulfonates (eg, methanesulfonate, p-toluenesulfonate) , Benzenesulfonate, etc.). The amount of the alkylating agent to be used is generally 1-based on compound (XVI).

It is 10 molar equivalents, preferably 1-3 molar equivalents.

 Examples of the acylating agent include carboxylic acid, sulfonic acid, phosphoric acid, carbonic acid and reactive derivatives thereof (for example, acid halide, acid anhydride, mixed acid anhydride, active ester, ester, etc.), isocyanate ester, isothiocyanate Acid esters and the like. The amount of the acylating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (XVI).

Examples of the base include amines (eg, trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] Alkylamines, pyridine, aromatic amines such as N, N-dimethylaniline, etc.), alkali metal salts (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.), metal hydrides (eg, hydrogen Potassium hydride, sodium hydride, etc.), and alkali metal alkoxides (sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, etc.). The amount of the base to be used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (XVI).

 Examples of the solvent include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; and ethers such as ethyl acetate. Esters; aromatic amines such as pyridine; amides such as N, N-dimethylformamide or a mixture thereof.

 The reaction temperature is usually about 150 to about 150 ^, preferably about -10 to about 10. The reaction time varies depending on the type of the compound (XVI) and the base, the reaction temperature and the like, and is, for example, about 0.5 to about 100 hours, preferably about 0.5 to about 24 hours.

Among the compounds (I) or salts thereof of the present invention, compounds (XIX, XX) in which R ¹ has an optionally substituted amidino group or an optionally substituted heterocyclic group It can be produced by each step of the following method I or a method analogous thereto.

 [Method I]

(XX) [In the formula, R ¹⁴ is a C ^ ₆ alkyl group which may have a substituent, a hydroxy group, an amino group which may have a substituent, and R ¹⁵ is hydrogen or a group which has a substituent. also good C, _ ₆ alkyl group, B ring a heterocyclic group, and other symbols are as defined above].

Examples of the alkyl group which may have a substituent represented by R ¹⁴ include the same ones as those described in the description of R ¹ .

The amino group which may have a substituent, similarly to also be mentioned and those indicated in the description of R ^1.

Examples of the optionally substituted _6- alkyl group represented by R ¹⁵ include methyl.

 Examples of the heterocyclic group represented by Ring B include tetrazolyl, pyrazolyl, triazolyl, dihydrotriazolyl, thiazolyl, dihydrothiazolyl, oxadiazolyl, and tetrahydrotriazinyl.

 Compound (V) used as a starting compound in this step can be produced by Method A, Method B, Method C or a method analogous thereto.

 (Process 1 2)

 This step is a step of converting a cyano group of compound (V) to an amidino group. Although various methods are known in the literature, [for example, The Chemistry of the cyano group, Zvi Rappoport (1970), Interscience Publishers (1970) Interscience Publishers)], and any of these methods can be applied to compound (V).

 For example, this reaction can be carried out by using a desired amine or a salt thereof in a solvent inert to the reaction, if necessary, using an acid or a base.

Examples of the acid include Lewis acids such as aluminum chloride, tin chloride, copper chloride, and titanium chloride. Examples of the base include amines (eg, trimethinoleamine, triethylamine, diisopropylethylamine) , N-methylmorpholine, 1,8-diazabicyclo [5.4.0] alkylamines such as 7-diene, pyridine, aromatic amines such as N, N-dimethylaniline, etc. ), Alkali metal salts (eg, hydrogen carbonate Sodium, potassium bicarbonate, sodium carbonate, potassium carbonate, etc., metal peroxides (eg, hydrogen hydride, sodium hydride, etc.), metal alkoxides (eg, sodium methoxide, sodium ethkind, sodium) t-butoxide, potassium t-butoxide, etc.). The amount of the acid or base to be used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (V). Examples of inert solvents include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane. Alcohols such as methanol and ethanol; nitriles such as acetonitrile; non-protonic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide; or mixtures thereof. The reaction temperature is usually about 0 ^ to about 150 ^, preferably about 15 to about 100. The reaction time is generally about 0.5 to about 48 hours, preferably about 0.5 to about 20 hours.

 In this reaction, in some cases, the reaction shown in the following step 13 may proceed at the same time, and the compound (XX) may be directly obtained.

 (Process 13)

 This step is a step of converting the amidino group of compound (XIX) into various heterocyclic groups. Although various methods have been known in the literature (for example, The Chemistry of the cyano group, Zvi Rappoport, ed. Yaz (Interscience Publ ishers)], and any method can be applied to compound (XIX).

For example, this reaction can be carried out in a solvent inert to the reaction, if necessary, by using various reactive derivatives of a carboxylic acid together with an acid or a base. Examples of the reactive derivative of the carboxylic acid include an acid halide, an acid anhydride, a mixed acid anhydride, an active ester, an ester, an orthoester, and the like. The amount of the reactive derivative of the carboxylic acid to be used is generally about 1 molar equivalent or more, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (XIX). Examples of the acid include sulfuric acid and p-toluenesulfonic acid. Any sulfonic acid is used, and as the base, for example, amines (eg, trimethylamine, triethylamine, diisopropyletylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] I-Alkylamines such as 7-ene, pyridine, aromatic amines such as N, N-dimethylaniline), alkali metal salts (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.) ), Metal hydrides (eg, potassium hydride, sodium hydride, etc.), alkali metal alkoxides (eg, sodium methoxide, sodium methoxide, sodium tert-butoxide, potassium t-butoxide, etc.) Used. The amount of the acid or base to be used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (XIX). Solvents inert to the reaction include, for example, hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane; Alcohols such as methanol and ethanol; -tolyls such as acetonitrile; non-protonic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide; water; and mixtures thereof. The reaction temperature is usually about

From about 150 to about 150, preferably from about 15 to about 100. The reaction time is generally about 0.5 to about 48 hours, preferably about 0.5 to about 20 hours.

 (Step 14)

 This step is a step of converting a cyano group of compound (V) to a tetrazole group. Various methods are known in the literature [for example, The Chemistry of the cyano group, Zabi ヲ popo HZvi Rappopor 1970, Interscience Publisher ^ " Interscience Publishers) and any of these methods can be applied to compound (V).

For example, this reaction can be carried out using an azide in a solvent inert to the reaction. Examples of such azides include sodium azide, lithium azide, and trimethylsilyl azide. The amount of azide used is usually about 1 to 1 mole per mole of compound (V). It is about 10 molar equivalents, preferably about 1 to about 5 molar equivalents. Examples of the solvent inert to the reaction include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; and ethers such as ethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane. Ethers; alcohols such as methanol and ethanol; aprotic polar solvents such as, N-dimethylformamide, N-methylpyrrolidone, and dimethinoles phenol; water; and mixtures thereof. Reaction temperatures are usually on the order of about 0 * C to about 150, preferably about 501: to about 120. The reaction time is generally about 0.5 to about 48 hours, preferably about 0.5 to about 20 hours. This reaction may be promoted by adding ammonium chloride, triethylammonium chloride, dibutyltin oxide, zinc chloride, acetic acid or the like.

Compound (XXI I) of compound (I) of the present invention or a salt thereof, wherein R ¹ has an optionally substituted heterocyclic amino group, can be produced by the following method J or a method analogous thereto. You can do it.

 [J method]

 (XlXa) (XXI)

 (XXII)

 [Each symbol in the formula is as defined above].

Compound (Xl Xa) used as a starting compound in this step was prepared according to Method I, Step 12 described above. It can be manufactured.

 (Process 15)

 This step is a step of converting the amidino group of the compound (XIXa) to a cyanamide group, and is a method known per se, for example, subjecting the compound (XIXa) to an acylation reaction and then to a transfer reaction. It can be done by doing.

 (1) The acylation reaction is usually carried out using an acylating agent in a solvent inert to the reaction, and a base can be used if necessary.

 Examples of the acylating agent include carboxylic acid, sulfonic acid, phosphoric acid, carbonic acid and reactive derivatives thereof (eg, acid halide, acid anhydride, mixed acid anhydride, active ester, etc.). The amount of the acylating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (XIXa).

 Examples of the base include amines (eg, alkylamines such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] pendecane-7-ene, etc. Pyridine, aromatic amines such as N, N-dimethylaniline, etc.), and alkali metal salts (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.). The amount of the base to be used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (XIXa).

 Examples of the solvent include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; and esters such as ethyl acetate. Aromatic amines such as pyridine; amides such as N, N-dimethylformamide; water or a mixture thereof.

The reaction temperature is usually about 150 to about 150, preferably about -10 to about 100. The reaction time varies depending on the type of the compound (XlXa) and the base, the reaction temperature and the like, and is, for example, about 0.5 to about 100 hours, preferably about 0.5 to about 24 hours. 2) The transfer reaction is usually performed in the presence of a base in a solvent inert to the reaction.

 Such bases include, for example, amines (eg, trimethylamine, triethylamine, diisopropinoleetamine, di-methyl / ^ remo ^^ holin, 1,8-diazabicyclo [5.4.0] Alkylamines such as pendecar 7-ene, pyridine, aromatic amines such as Ν, Ν-dimethylaniline, etc., metal salts of alkali metal (eg, sodium hydrogen carbonate Vium, potassium hydrogen carbonate, carbonate) Sodium, carbonated lime, sodium hydroxide, potassium hydroxide, etc.). The amount of the base used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of the substrate. Examples of the solvent include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethoxetane, tetrahydrofuran, and dioxane; aromatic amines such as pyridine Amides such as Ν, Ν-dimethylformamide, water or a mixture thereof. The reaction temperature is usually about 150 to about 150, preferably about -10 to about 100. The reaction time varies depending on the type of the substrate, the type of the base, the reaction temperature and the like, and is, for example, about 0.5 to about 100 hours, preferably about 0.5 to about 24 hours.

 The compound (XIX, XX, XXI, XXII) obtained by the above-mentioned Method I or Method J can be subjected to an acylation reaction or an alkylation reaction shown in Step 11 of Method H, if necessary.

When the compound (I) is obtained as a free compound in the above-mentioned method, for example, an inorganic acid (for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), an organic acid (for example, methane snorephonic acid, benzene snorehon) Acids, tonorenensnoleonic acid, oxalic acid, fumarenoleic acid, maleic acid, tartaric acid, etc.), inorganic bases (for example, sodium / potassium etc./recalium metals, alkaline earth metals such as canoleicum, magnesium, aluminum or Or an organic base (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N'-dibenzylethylenediamine, etc.) ) Can also form salts with Can, if I 匕合 compound (I) is obtained in the form of a salt, follow the conventional method It can then be converted into the free compound or other salt.

 The compound (I) or a salt thereof produced by these methods can be separated and purified by using conventional separation and purification means (for example, concentration, solvent extraction, column chromatography, recrystallization, etc.). When the compound (I) is an optically active compound, it can be separated into a d-isomer and a single isomer by a conventional optical resolution method.

 When the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent in each reaction of the target compound and the starting material synthesis, these groups are protected groups such as those commonly used in peptide chemistry and the like. May be protected. In this case, after the reaction, the desired compound can be obtained by removing the protecting group, if necessary. Examples of the protecting group for an amino group include a formyl group and a C i -e alkyl monocarbonyl group.

(Eg, acetyl, propionyl, etc.), fuel carbonyl, C i -e alkyl

- O alkoxycarbonyl group (e.g., main-butoxycarbonyl, ethoxycarbonyl group), § reel O alkoxycarbonyl group (e.g., phenylalanine O alkoxycarbonyl group), c ₇ _ _{1 0} Ararukiru one carbonyl group (e.g., Benjiruo Xycarbonyl group), a trityl group, a phthaloyl group and the like, and these protecting groups may have a substituent. Examples of these substituents include a halogen atom (for example, fluorine, chlorine, bromine, and iodine atom), a C, alkyl-carbonyl group (for example, acetyl, propionyl, butylcarbonyl group, etc.), a nitro group And the number of substituents is about 1 to 3. Examples of the carboxyl-protecting group include an alkyl group (eg, methyl, ethyl, II-propyl, i-propyl, n-butyl, tert-butyl group, etc.), a phenyl group, a trityl group, a silyl group, and the like. These protecting groups may have a substituent. These substituents, for example, a halogen atom (fluorine, chlorine, bromine, iodine), formyl, - ₆ alkyl - group (e.g., Asechiru, pro Pioniru, etc. Buchirukaruponiru group), like nitro groups The number of substituents is about 1 to 3.

Examples of the hydroxyl-protecting group include, for example, an alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl group, etc.) Eniru group, C ₇ - _{1 0} Ararukiru group (e.g., benzyl group), a formyl group, C i - e § Rukirukarubo - Le group (e.g., Asechiru, etc. Puropioyuru group), Ariruokishi carbonyl group (e.g., Fueyuruokishi carbo - such as Le group), c ₇ _ _{1 0} Ararukiru Ichiriki carbonyl group (e.g., benzyl O alkoxycarbonyl group), Villa group, a furanyl group, a silyl group, and these protecting groups substituent May be provided. These location substituent, for example, a halogen atom (fluorine, chlorine, bromine, iodine), C, _ _B alkyl group, phenyl group, C ₇ _ i. Examples include an aralkyl group and a nitro group, and the number of substituents is about 1 to 4.

 The protecting group can be removed by a known or equivalent method, for example, treatment with an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiorubbamate, tetrabutylammonium fluoride, palladium acetate, etc. There is a method available.

 The compound (I) of the present invention produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like. When the compound (I) thus obtained is in a free form, it can be converted into a salt by a known method or a method analogous thereto (for example, neutralization), and conversely, it can be obtained. When compound (I) is obtained in the form of a salt, it can be converted to a free form or another salt by a known method or a method analogous thereto.

 The compound (I) of the present invention or a salt or a prodrug thereof (hereinafter may be abbreviated as the compound of the present invention) has an effect of suppressing the enhancement of tracheal vascular permeability induced by cabsaicin and an excellent tachykinin receptor. It has body antagonism, especially substance P receptor antagonism, and neurocun A receptor antagonism. The compounds of the present invention have low toxicity and are safe.

Therefore, the compounds of the present invention having excellent substance P receptor antagonism, neurokinin A receptor antagonism and the like can be used in mammals (for example, mice, rats, hamsters, rabbits, cats, dogs, dogs, higgies) , Monkeys, humans, etc., against substance P-related diseases, such as inflammatory or allergic diseases (eg, atopy, dermatitis. Psoriasis, asthma, bronchitis, chronic obstructive pulmonary disease, sputum, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis, etc.), pain, migraine, neuralgia, Pruritus, cough, HIV infection, and diseases of the central nervous system [eg, schizophrenia, Parkinson's disease, depression, manic depression, anxiety 'neurosis, obsessive-compulsive disorder, panic disorder, dementia (eg, Alzheimer's) Disease) etc.), digestive disorders [eg, irritable bowel disease, ulcerative colitis, Crohn's disease, urease-positive helical gram-negative bacteria (eg, Helicobacter pylori, etc.) (eg, , Gastritis, gastric ulcer, etc.), vomiting, urinary abnormalities (eg, frequent urination, incontinence, etc.), cardiovascular disorders (eg, angina, high blood pressure, heart failure, thrombosis, etc.) and immunity It can be used as a safe preventive or therapeutic agent for diseases such as normal. In particular, the compounds of the present invention are useful as agents for improving urination abnormalities such as tachycun receptor antagonists, pollakiuria and urinary incontinence, and as therapeutic agents for these urinary abnormalities.

 Further, the compound of the present invention is also useful as an agent for preventing or treating diseases such as depression, anxiety, manic depression, and schizophrenia.

 The pharmaceutical preparation containing the compound of the present invention may be any of solid preparations such as powders, granules, tablets, capsules and suppositories, and liquid preparations such as syrups, syrups, injections and suspensions. ,.

 The pharmaceutical preparation of the present invention can be produced by a conventional method such as mixing, kneading, granulation, tableting, coating, sterilization, emulsification, etc., depending on the form of the preparation. In addition, regarding the production of the drug product, for example, each section of the Japanese Pharmacopoeia Act general rules for drug products can be referred.

 In the pharmaceutical preparation of the present invention, the content of the compound salt of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.01% by weight, based on the whole preparation. It is about 1 to 50% by weight, more preferably about 0.5 to 20% by weight.

'' When the compound of the present invention is used as the above-mentioned pharmaceutical preparation, as it is or as appropriate, a pharmaceutically acceptable carrier, for example, an excipient (eg, starch, lactose, sucrose, calcium carbonate, canolecitrate, etc.) Binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polybutylpyrrolidone, etc.), lubricants (eg, stearic acid, magnesium stearate) , Calcium stearate, etc.), disintegrants (eg, power Ruboxymethylcellulose calcium, talc, etc.), diluents (eg, water for injection, physiological saline, etc.), and additives as necessary (stabilizers, preservatives, coloring agents, fragrances, dissolution aids, emulsifiers, buffers, And is orally or parenterally administered in the form of powders, fine granules, granules, tablets, capsules, etc., or liquid forms such as injections. be able to.

 The dosage varies depending on the type of the compound of the present invention or a pharmaceutically acceptable salt thereof, the administration route, the symptom, the age of the patient, and the like.For example, when administered orally to an adult patient with dysuria About 0.05 to 50 mg, preferably about 0.05 to: 0 mg, and more preferably about 0.2 to 4 mg of the compound of the present invention per kg of body weight per day can be administered in 1 to 3 divided doses.

 The compound of the present invention can be used as appropriate or in combination with other pharmaceutically active ingredients in an appropriate amount or in combination.

 By using the compound of the present invention in combination with other pharmaceutically active ingredients,

 (1) The dose can be reduced as compared with the case where the compound of the present invention or other pharmaceutically active ingredient is administered alone. More specifically, when the compound of the present invention is used in combination with an anticholinergic agent or a NK-2 receptor antagonist, the dose of the compound is reduced as compared with the case where the anticholinergic agent or the NK-2 receptor antagonist is administered alone. Therefore, for example, it is possible to reduce side effects such as roasting.

 (2) The drug used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.)

 (3) The treatment period can be set longer by selecting another pharmaceutically active ingredient having a different mechanism of action from the compound of the present invention.

 (4) by selecting another pharmaceutically active ingredient having a different mechanism of action from the compound of the present invention, it is possible to maintain the therapeutic effect,

 (5) By using the compound of the present invention in combination with other pharmaceutically active ingredients, excellent effects such as synergistic effects can be obtained.

As a drug that can be combined with or used in combination with the compound of the present invention (hereinafter abbreviated as concomitant drug) For example, the following is used.

 (1) Diabetes treatment

 Insulin preparations [eg, animal insulin preparations extracted from the lungs of pigs and pigs; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin insulin clamp; protamine insulin zinc; insulin fragments or Derivatives (eg, INS-1 etc.), insulin sensitive drugs (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP-297, FK_614, CS-011, etc.), α-Darcosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), sulfonyl II Rare agents (eg, tolptamide, glibenclamide, daliclazide, black / Revlopamide, tolazamide, acetatehexamide, glicloviramide, glimepiride, etc.) and other insulin secretagogues (eg, repaglinide, senaglinide, mitiglinide or its calcium hydrate, GLP-1, nateglinide etc.), Dibutidyl peptidase IV inhibitor (eg, NVP-DPP-278, ΡΤ-100, Ρ32-98, etc.), 03 agonist (eg, CL-316243, SR-58611-Α, UL-TG-307, AJ-9677, ΑΖ40140, etc.), amiringagonist (eg, pramlitide, etc.), phosphotyrosine phosphatase inhibitor (eg, panadic acid, etc.), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-1 6) —Phosphatase inhibitors, glucagon antagonists, etc., SGLT (sodium-glucose cotransporter) inhibitors (eg, T-1095, etc.).

 (2) therapeutic agent for diabetic complications

Aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minalrestat (AR I-509), CT-112, etc.), neurotrophic factors (eg, NGF , NT-3, etc.), AGE inhibitors (eg, ALT-945, pimagedin, pyratoxatin, N-phenacyl thiazolidumbumid (ALT-766), EXO-226, etc.), active oxygen scavengers (eg, And cerebral vasodilators (eg, chopride.).

 (3) Antihyperlipidemic agent

 Statin compounds that are cholesterol synthesis inhibitors (eg, bravastatin, simpastatin, oral pastatin, atorvastatin, fuorepastatin, cerivastatin or salts thereof (eg, sodium salt, etc.)), squalene synthase inhibitors or birds Fibrate compounds having a glyceride-lowering effect (eg, bezafibrate, clotofibrate, simfibrate, clinofibrate, etc.) and the like.

 (4) Antihypertensive

 Angiotensin-converting enzyme inhibitors (eg, captobril, enalapril, delapril, etc.), angiotensin II antagonists (eg, oral sultan, candesartan cilexetil, etc.), calcium antagonists (eg, manidibin, nifendipine, amlodipine, efonidipine) , Dicardipine etc.), clonidine etc.

 (5) Anti-obesity agent

 Central antiobesity drugs (eg, dexfenfluamine, fenfluramine, phentermine, sibutramine, ampuebramon, dexoxuefamine, mazindol, phenylpropanolamine, clovenzolex, etc.), lipase inhibitors (eg, , Orlistat, etc.), β3-agonist (eg, CL-316162, SR-586111-A, UL-TG-307, AJ-9677, ΑΖ40140), peptide Anorectic drugs (eg, lebutin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynch tryp, FPL-15849, etc.), etc.

 (6) Diuretics

Xanthine derivatives (eg, sodium theobromine salicylate, calcium thiomide, etc.), thiazide-based preparations (eg, ethiazide, cyclopentiazide, trichlormethiazide, hydroclothiazide, hydroflumethiazide, benzylhydrothiazide, benzothiclotide, thiazide) Polythiazide, methyclothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, Mefluside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, pyretide, butanide, furosemide, etc.

 (7) Chemotherapy ^ j

 Alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexet, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), plant-derived Anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carpoplatin, etopoxide, etc., among others, furtulon or neofurz mouth, which is a 5-fluorouracil derivative.

 (8) Immunotherapy agent

 Microbial or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides with immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by gene transfer techniques (eg, , Interferon, interleukin (IL), etc., colony stimulating factor (eg, granulocyte co-stimulatory factor, erythropoietin, etc.), among others, IL-11, IL-2, IL-12, etc.

 (9) Drugs that have been shown to improve cachexia in animal models and clinically

 Progesterone derivatives (eg, megesterol acetate) 〖Journal of Clinical Oncology, Vol. 12, pp. 213 to 225, 1994], metoclopramide, tetrahydro Cannabinoid drugs (all references are as described above), fat metabolism improvers (eg, eicosapentaenoic acid, etc.) [British Journal of Cancer, Vol. 68, 314-318, 19993], growth hormone, IGF-1, or TNF-a, LIF, IL-16, a factor that induces cachexia, and antibodies to oncostatin M.

 (10) Anti-inflammatory agent

Steroids (eg, dexamethasone, etc.), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, amploxicam, celecoxib, oral fuecoxib, etc.) (1 1) Other

Saccharification inhibitors (eg, ALT-711 etc.), nerve regeneration promoters (eg, Y-128, VX853, prosaptide, etc.), central nervous system drugs (eg, dempramine, amitriptyline, imibramine, floxetine, paroxetine, doxepin Antiepileptic drugs (eg, lamotrigine, carbamazepine), antiarrhythmic drugs (eg, mexiletine), acetylcholine receptor ligands (eg, ABT_594), endothelin receptor antagonists (eg, ABT-627) ), Monoamine uptake inhibitors (eg, tramadol), indolamine uptake inhibitors (eg, floxetine, paroxetine), narcotic analgesics (eg, morphine), GABA receptor agonists (eg, gyabapentin), GABA uptake inhibitors (e.g., tiagabine), alpha ₂ receptor agonists (e.g., click Ronijin), local analgesics (e.g., Kapusaishi ), Protein kinase C inhibitors (eg, L Υ— 33 33 53 1), anxiolytics (eg, benzodiazepines), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptor agonists (eg, , Apomonorefin), dopamine receptor antagonists (eg, haloperidol), serotonin receptor agonists (eg, tandospirone citrate, sumatributane), serotonin receptor antagonists (eg, cyproheptadine hydrochloride, ondansetron) ), Serotonin uptake inhibitors (eg, fluvoxamine maleate, floxetine, paroxetine), sleep-inducing agents (eg, triazolam, zolpidem), anticholinergics, _{α ι} receptor blockers (eg, tamsulosin), muscle relaxants (Eg, baclofen), potassium channel openers (eg, nicorandil), Lucium channel blockers (eg, difedipin), Alzheimer's disease prevention 'treatment (eg, donezil, rivastigmine, galantamine), Parkinson's disease treatment (eg, L-dopa), multiple sclerosis prevention' treatment Drugs (eg, interferon / 3-1a), histamine receptor inhibitors (eg, promethazine hydrochloride), proton pump inhibitors (eg, lansoprazole, omeprazole), antithrombotic drugs (eg, aspirin, cilostazol), Ν Κ—2 receptor antago 2st, drugs for treating HIV infection (saquinavir, zidovudine, lamivudine, nevirabin), drugs for treating chronic closed S † 4 lung disease (salmeterol, ziotropium bromide, cilomilast), etc.

Anticholinergic agents include, for example, atotopin, scopolamine, homatropine, tropi Forcemid, cyclopentolate, butyl scopolamine bromide, propantheline bromide, methyl benactidium bromide, mepenzolate bromide, flavoxait, pyrensebine, ipratopium bromide, trihexyphenidyl, oxyptinin, propiverine, Darifue nacin, tolterodine, temiverine, trospium chloride or a salt thereof (eg, atotopine sulfate, scopolamine hydrobromide, omatopine hydrobromide pin, cyclopentolate hydrochloride, braboxate hydrochloride, pyrensebine hydrochloride, trihexyfe hydrochloride) Nidyl, oxybutynin chloride, tolterodine tartrate, etc.) are used, among which oxybutynin, propiverine, darifenacin, tolterodine, temiverine, trospium chloride or its salts (eg, oxyptinin chloride) , Tolterodine tartrate, etc.) are preferred. Also, acetylcholinesterase inhibitors (eg, distigmine, etc.) can be used.

 Examples of NK-2 receptor antagonists include GR159897, GR149861, SR48968 (saredutant), SR144190, YM35375, Y38336, ZD7944L-1 743986, MDL105212A, ZD6021, MDL105172 A, pyridine derivatives such as SCH 205528, SCH62373, R-1 13281, perhydroisoindole derivatives such as RPR-106145, quinoline derivatives such as SB-414240, pyrrovirimidine derivatives such as ZM-253270, MEN 1 Pseudopeptide derivatives such as 1420 (nepadutant), SCH21 7048, L — 659877, PD-147714 (CAM-2291) MENl 0376, S 16474, etc., GR 100679, DNK 333, GR 94800, UK—224671, MEN 10376, MEN 10627, or salts thereof.

 Pharmaceutical compositions comprising the compound of the present invention and a concomitant drug include or are combined with: (1) a single pharmaceutical composition containing the compound of the present invention and a concomitant drug; (2) the present invention And the concomitant drug are separately formulated. Hereinafter, these are collectively abbreviated as the concomitant drug of the present invention.

The concomitant drug of the present invention comprises the compound of the present invention and the active ingredient of the concomitant drug separately or separately. At the same time, as it is or mixed with a pharmaceutically acceptable carrier, for example, solid preparations such as powders, granules, tablets, capsules, syrups, emulsions, injections (subcutaneous injection, intravenous injection, intramuscular injection) And intravenous administration), or sublingual tablets, buccals, lozenges, sustained-release preparations such as microcapsules, orally disintegrating agents, and suppositories can be administered orally or parenterally.

 As the above-mentioned pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, dissolution aids Formulation, suspending agent, tonicity agent, buffering agent, soothing agent, etc. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.

 Preferable examples of the above-mentioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light gay anhydride, calcium carbonate, calcium phosphate and the like.

 Preferable examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, Tanolek, and colloid silica.

 Preferable examples of the above binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropyl-methylpyrrolidone, polybutyrrolidone, gum arabic, and gelatin.

 Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethinoresel monosaccharide, cross-force noremelose sodium, carboxymethyl starch sodium and the like.

 Preferred examples of the solvent include water for injection, physiological saline, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

Preferable examples of the solubilizer include, for example, polyethylene glycol, propylene glycol, D-mantol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Can be Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium radium sodium sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate. For example, hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methinoresenolose, hydroxymethinoresenorelose, hydroxyxetinoresenorelose, and hydroxypropylcellulose. Is it possible?

 Preferable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like.

 Preferable examples of the moderating agent include, for example, buffers such as phosphate, acetate, carbonate, and citrate.

 Preferable examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the above preservatives include, for example, paraoxybenzoic acid esters, butanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sonolevic acid.

 Preferable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

 Preferable examples of the coloring agent include, for example, a water-soluble edible tar dye, a water-insoluble lake dye, and a natural dye (for example, Ichiroku rotin, chlorophyll, bengalara, and the like).

 Preferable examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

 These preparations can be produced by a method known per se that is generally used in the preparation process.

For example, the compound of the present invention or the concomitant drug may be a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HC060 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, anoreggin Sodium acid, hydroxypropyl methylcellulose, dextrin, etc.), stabilizers (eg, ascorbic acid, pyrosulfite) ■ ', sodium, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solvents (eg, glycerin, ethanol, etc.), buffers (eg, phosphoric acid and its alkali metal salts, citrate and Alkali metal salts, etc.), tonicity agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH regulators (eg, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, Ethyl paraoxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc., solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg, glucose) , Benzyl alcohol, etc.) in aqueous injections, or plant oils such as olive oil, sesame oil, cottonseed oil, corn oil, etc. Oil, dissolved in a solubilizing agent such as propylene glycol, suspending walk will be emulsified into an oily injection, whereby an injection.

 In order to prepare a preparation for oral administration, the compound of the present invention or the concomitant drug is used in a manner known per se, for example, with an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.). Binders (eg, starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 600, etc.) Or the like, and then compression-molded. If necessary, the preparation can be made into an oral administration preparation by coating with a method known per se for the purpose of taste masking, enteric coating or persistence. Examples of the coating agent include hydroxypropyl methylcellulose, ethyl / resenolose, hydroxymethylinoresenolose, hydroxypropinoresenolose, polyoxyethylene glycol, Tween 80, and pull Mouth nick F 68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohme ± ¾, Germany, methacrylic acid / acrylic acid copolymerization) and dyes (eg, Bengala , Titanium dioxide, etc.). The preparation for oral administration may be any of an immediate release preparation and a sustained release preparation.

For example, in order to prepare a suppository, the compound of the present invention or the concomitant drug can be converted into an oily or aqueous solid, semi-solid or liquid suppository according to a method known per se. The above composition The oleaginous bases used include, for example, glycerides of higher fatty acids (eg, cocoa butter, Witepsols (manufactured by Dynamite Nobel, Germany), etc.), and medium fatty acids [eg, miglyols (dynamite Or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers. Examples of the sustained-release preparation include sustained-release micro force capsules.

 A method known per se can be used to prepare a sustained-release microgapsel. For example, it is preferable to administer a sustained-release preparation shown in the following [2] by shaping it.

 The compound of the present invention is preferably formed into a preparation for oral administration such as a solid preparation (eg, powder, granules, tablets, capsules) or a preparation for rectal administration such as a suppository. In particular, preparations for oral administration are preferred.

 The concomitant drug of the present invention can be in the above-mentioned dosage form depending on the type of drug.

 In the following, (1) an injection of the compound of the present invention or the concomitant drug and its preparation, (2) a sustained-release preparation or an immediate-release preparation of the compound or the concomitant drug of the present invention and its preparation, (3) The sublingual tablet, buccal or intraoral quick disintegrating agent of the compound or the concomitant drug and the preparation thereof are specifically described.

 [1] 剤 agent and its preparation

 An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable. The injection may contain benzoate or Z and salicylate.

 The injection can be obtained by dissolving the compound of the present invention or the concomitant drug and, if desired, both benzoate or z and salicylate in water.

 Examples of the salts of benzoic acid and salicylic acid include, but are not limited to, sodium metal salts such as sodium and potassium, metal salts such as potassium and magnesium, ammonium salts, meglumine salts, and organic compounds such as trometamol. Acid salts and the like.

The concentration of the compound of the present invention or the concomitant drug in the injection is about 0.5 to 5 OwZv%, preferably about 3 to 2 OwZv%. The concentration of benzoate and / or salicylate Is 0.5 to 50 w / v ° / _0, preferably 3 to 20 wZ v%.

 The drug also contains additives commonly used in injections, such as stabilizers (ascorbic acid, sodium pyrosulfate, etc.), surfactants (polysorbate 80, macrogol, etc.), Glycerin, ethanol, etc.), buffers (phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), tonicity agents (sodium chloride, potassium chloride, etc.), dispersants (hydroxypropyl methylcellulose) Dextrin), pH regulators (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl ethyl parabenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, medalmine, etc.), solubilizers (propylene glycol, sucrose, etc.) And soothing agents such as glucose, benzyl alcohol, etc. These additives are generally used in injections. It is blended in a proportion of.

 The pH of the injection should be adjusted to pH 2 to 12, preferably 2.5 to 8.0, by adding a pH regulator.

 An injection can be obtained by dissolving the compound of the present invention or the concomitant drug and, if desired, both benzoate or Z and salitate, and if necessary, the above-mentioned additives in water. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.

 The aqueous solution for injection is preferably heated, and can be provided as an injection by, for example, sterilizing by filtration or subjecting to high-pressure heating as in the case of usual injections.

 The aqueous solution for injection is preferably subjected to high-pressure heat sterilization at 100 to 121 ^ for 5 minutes to 30 minutes, for example.

 In addition, the formulation may be provided with antimicrobial properties of the solution so that it can be used as a multiple-dose formulation.

 [2] Sustained-release preparation or immediate-release preparation and its preparation

 A sustained-release preparation comprising a nucleus containing the compound of the present invention or the concomitant drug optionally coated with a film-forming agent such as a water-insoluble substance / swellable polymer is preferred. For example, a once-daily sustained release preparation for oral administration is preferred.

Examples of the water-insoluble substance used in the coating agent include ethyl cellulose and butyl cell. Cellulose ethers such as loin; cellulose esters such as cellulose acetate; cellulose propylate; polyvinyl acetates such as polyvinyl acetate, polyvinyl butyl ether; methacrylic acid acrylate copolymer; methyl methacrylate -Copolymer, ethoxyxyl methacrylate nosinnamoetyl methacrylate aminoamino methacrylate copolymer, polyacrylic acid, polymethacrylic acid, alkyl methacrylate amide copolymer, poly (methyl methacrylate), poly Methacrylate, polymethacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, especially Eudragit RS-100, RL-100, RS-30D, RL-3 OD, RL-PO , RS— PO (A Eudragits (ROHM ') such as ethyl acrylate / methyl methacrylate / trimethyl methacrylate / ammonium dimethyl ester, and Eudragit NE-30D (methyl methacrylate / acrylic / ethyl oleate copolymer) Acrylic acid-based polymers such as Pharma Co., Ltd., hardened oils such as hardened castor oil (eg, Lovely Wax (Freund Corporation), etc.), carnauba wax, fatty acid glycerin esters, paraffins, etc., polyglycerin fatty acid esters, etc. Is mentioned.

 As the swellable polymer, a polymer having an acidic dissociating group and exhibiting pH-dependent swelling is preferable.The swelling is small in an acidic region such as the stomach and large in a neutral region such as the small intestine and the large intestine. Polymers having acidic dissociative groups are preferred.

 Examples of polymers having such a ^ dissociating group and exhibiting pH-dependent swelling include, for example, Carbomer 934 P, 940, 941, 974 P, 980, 1342, etc., polycarbophil, calcium polycarbophil, etc. And Tachibana-type polyacrylic acid polymers such as carcium polycarbophil (all of which are manufactured by BF Goodrich) and Hibis 、 ko 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.). .

 The coating agent used in the sustained-release preparation may further contain a hydrophilic substance. .

Examples of the hydrophilic substance include polysaccharides which may have a sulfate group, such as pullulan, dextrin, and alkali metal alginate; and hydroxypropylcellulose. Polysaccharides having a hydroxyalkyl group or a carboxyalkyl group such as xypropylmethylcellulose and carboxymethylcell mouth-sunatium, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like can be mentioned.

 The content of the water-insoluble substance in the coating agent of the sustained-release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 4 0 to about 75% (w / w), the swellable polymer content is about 3 to about 30% (w / w); preferably about 3 to about 15% (w / w). The coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w). ), More preferably from about 5 to about 35% (w / w). Here, the above% (w / w) indicates the weight% based on the coating composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating composition liquid.

 Sustained-release preparations are prepared by preparing a nucleus containing a drug as exemplified below, and then dissolving the obtained nucleus by heating or dissolving or dispersing a water-insoluble substance, swellable polymer, or the like in a solvent. Manufactured by coating.

 I. Preparation of nuclei containing drugs

 The form of the nucleus containing the drug to be coated with the coating agent (hereinafter sometimes simply referred to as nucleus) is not particularly limited, but is preferably formed into particles such as granules or fine granules.

 When the core is granules or fine particles, the average particle size is preferably about 150 to 2,000 μπι, more preferably about 500 to about 1,400 μπι.

 The nucleus can be prepared by a usual production method. For example, a drug is mixed with appropriate excipients, binders, disintegrants, lubricants, anti-agglomeration agents, lubricants, stabilizers, etc., and prepared by wet extrusion granulation, fluidized bed granulation, etc. .

The drug content of the core is from about 0.5 to about 95% (w / w), preferably from about 5.0 to about 80% (w / w). More preferably, from about 30 to about 70 ° / w. ₀ (w / w).

Examples of excipients contained in the core include sugars such as sucrose, lactose, mannitol, and glucose, starch, crystalline cellulose, calcium phosphate, and corn starch. You. Among them, crystalline cellulose and corn starch are preferred.

 As the binder, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, punorelonic F68, arabic gum, gelatin, starch and the like are used. Disintegrators include, for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), citrus-type polybulpyrrolidone (crospovidone), low-substituted hydroxypropyl cellulose (L-HPC) ) Is used. Among them, hydroxypropylcellulose, polyvinylpyrrolidone and low-conversion hydroxypropylcellulose are preferred. For example, talc, magnesium stearate and its inorganic salts are used as a lubricant and an anti-agglomeration agent, and polyethylene glycol is used as a lubricant. Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as stabilizers.

 The nucleus can be prepared by spraying a binder dissolved in a suitable solvent such as water or lower alcohol (eg, methanol, ethanol, etc.) on inert carrier particles, which are the core of the nucleus, in addition to the above-mentioned production method. It can also be prepared by the tumbling granulation method, pan coating method, fluidized bed coating method or melt granulation method in which a drug or a mixture of this and excipients, lubricants, etc. is added little by little. . As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and the average particle size is about 100 / m to about 1,500 μm. Are preferred.

In order to separate the drug contained in the nucleus from the coating agent, the surface of the nucleus may be coated with a protective agent. As the protective agent, for example, the above-mentioned hydrophilic substances, water-insoluble substances and the like are used. As the protective agent, preferably a polysaccharide having a polyethylenedaricol-hydroxyalkyl group or a carboxyalkyl group is used, and more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose is used. The protective agent may contain, as a stabilizer, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid, and a lubricant such as talc. When a protective agent is used, its coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% based on the core. ° / ₀ (w / w). The protective agent can be coated by a usual coating method. Specifically, the protective agent can be coated by spray coating the nucleus by, for example, a fluidized bed coating method or a pan coating method.

 II- Coating of core with coating agent

 By coating the nucleus obtained in the above I with a coating agent solution in which the water-insoluble substance, the pH-dependent swellable polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. Sustained-release preparations are produced.

 Examples of the method of coating the core with the agent solution include a method of spray coating.

 The composition ratio of the water-insoluble substance, the swellable polymer or the hydrophilic substance in the coating agent solution is appropriately selected so that the content of each component in the coating becomes the above-mentioned content.

 The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), based on the core (not including the protective agent). Preferably it is about 5 to 35% (w / w).

 As the solvent for the coating agent solution, water or an organic solvent can be used alone or in a mixture of both. The mixing ratio of water and organic solvent (water / organic solvent: weight ratio) when using the mixed solution can be changed in the range of 1 to 100%, preferably 1 to about 30%. . The organic solvent is not particularly limited as long as it dissolves a water-insoluble substance. Examples thereof include lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, and π-butyl alcohol, lower alkanones such as acetone, acetonitrile, and chloroform. And methylene chloride are used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred. Water and a mixture of water and an organic solvent are preferably used as a solvent for the coating agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, or maleic acid may be added to the coating agent solution for stabilizing the coating agent solution.

The operation in the case of coating by spray coating can be carried out by a usual coating method. Specifically, the coating agent solution is applied, for example, by a fluidized bed coating method, a pan coating method. It can be carried out by spray coating the nucleus by the wing method or the like. At this time, if necessary, use talc, titanium oxide, magnesium stearate, stearic acid noresicum, light caffeic anhydride, etc. as lubricants, glycerin fatty acid ester, hydrogenated castor oil, triethyl tantalate, cetyl alcohol, stearyl Alcohol or the like may be added as a plasticizer.

 After coating with the coating agent, an antistatic agent such as talc may be mixed as necessary. The immediate release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particle, pill, tablet, etc.). Parenteral preparations such as oral preparations and injections are used, but oral preparations are preferred.

Immediate release preparations usually contain, in addition to the drug as an active ingredient, carriers, additives and excipients (hereinafter sometimes collectively abbreviated as excipients) commonly used in the pharmaceutical field. May be included. The formulation excipient used is not particularly limited as long as it is an excipient commonly used as an excipient in the field of formulation. For example, excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Avicel PH101, etc., manufactured by Asahi Kasei Corporation), powdered sugar, granulated sugar, mannitol, light caffeic anhydride, magnesium carbonate , Calcium carbonate, L-cysteine and the like, and preferably corn starch and mannitol. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w ° / _0, preferably about 20 to about 98.5 w / w%, based on the total amount of the immediate-release preparation, Preferably it is from about 30 to about 97 w / w ° / ₀ .

 The content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95%, preferably about 1 to about 60%, based on the total amount of the immediate release preparation.

When the immediate-release preparation is an oral solid preparation, it usually contains in addition to the above-mentioned components. Examples of such disintegrants include carboxymethylcellulose calcium (ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.), croscarmellose sodium (eg, Axizol, manufactured by Asahi Kasei Corporation), crospovidone (eg, manufactured by BASF) , Corydon CL), low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (pine) Chemical Co.), carboxymethyl starch sodium © beam (Exprotab, manufactured by Kimura Sangyo), partially _α starch (manufactured by Asahi Kasei Corporation, PCS) and the like are used, for example in contact with water and water,膨澗Alternatively, a substance that disintegrates the granules by, for example, forming a channel between the active ingredient constituting the core and the excipient can be used. These disintegrants can be used alone or in combination of two or more. The amount of the disintegrant is appropriately selected depending on the kind and amount of the drug used, the design of the release preparation, and the like. For example, about 0.05 to about 30 w / w based on the total amount of the immediate release preparation %, Preferably from about 0.5 to about 15 w / w%.

 When the immediate-release preparation is an oral solid preparation, in the case of an oral solid preparation, in addition to the above-mentioned composition, if necessary, the solid preparation may further contain a conventional additive. As such an additive, for example, an additive capable of absorbing water, swelling upon contact with water, or disintegrating a granule by forming a channel between the excipient and the excipient that constitute the core can be used. Binders (eg, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropyl cellulose, hydroxypropinolemethinolecellulose, carboxymethylcellulose, polyvinylpyrrolidone, bunolellan, dextrin, etc.) Lubricants (for example, polyethylene glycol, magnesium stearate, talc, light caffeic anhydride (for example, AEROSIL (Nippon AEROSIL))), surfactants (for example, anionic surfactants such as sodium alkyl sulfate, poly) Oxyethylene fatty acid ester and polyoxy Nonionic surfactants such as ethylene sorbitan fatty acid esters and polyoxyethylene castor oil derivatives, etc.), coloring agents (eg, tar dyes, caramel, red bengalah, titanium oxide, riboflavins), if necessary, Hashimi Agents (eg, sweeteners, flavors, etc.), adsorbents, preservatives, wetting agents, antistatic agents, etc. Stabilizers include organic acids such as tartaric acid, citric acid, succinic acid, and fumaric acid. As the above-mentioned binder, hydroxypropylcellulose, polyethylene glycol and polyvinylpyrrolidone are preferably used.

An immediate release preparation can be prepared by mixing the above-mentioned components, kneading and molding as necessary, based on a usual preparation manufacturing technique. The mixing is performed by a commonly used method such as mixing and kneading. Specifically, for example, quick release When the agent is formed into particles, a particle granulator, a universal kneader (manufactured by Hata Iron Works), a fluidized bed granulator FD-5S can be prepared in the same manner as the method for preparing the core of the sustained-release preparation. (Manufactured by Perec Co., Ltd.) and then granulation by wet extrusion granulation or fluidized bed granulation.

 The thus obtained immediate-release preparation and sustained-release preparation can be administered as is or as appropriate, separately and in combination with excipients, etc., in a conventional manner, and then administered simultaneously or in combination at an arbitrary administration interval Alternatively, both preparations may be used alone or as appropriate, together with a pharmaceutical excipient and the like, into a single oral administration preparation (eg, granules, fine granules, tablets, capsules, etc.). Both preparations may be made into granules or fine granules and filled into the same capsule or the like to prepare a preparation for oral administration.

 [3] Sublingual tablet, buccal or oral fast disintegrating agent and its preparation

 When the concomitant drug of the present invention is manufactured as a sublingual tablet, a puccal preparation, or a rapidly disintegrating agent for the oral cavity, it may be a solid preparation such as a tablet or an oral mucosal patch (film). ,.

 As the sublingual tablet, puccal or intraoral quick disintegrant, a preparation containing the compound of the present invention or the concomitant drug and an excipient is preferable. In addition, auxiliary agents such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer may be contained. Further, in order to facilitate absorption and increase bioavailability, β-cyclodextrin or a 3-cyclodextrin derivative (eg, hydroxypropyl-1-j3-cyclodextrin, etc.) may be contained.

Examples of the above-mentioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light caffeic anhydride. Examples of the lubricant include magnesium stearate, canolecidium stearate, talc, colloid silica and the like, and magnesium stearate and colloidal silica are particularly preferable. Examples of the tonicity agent include sodium chloride, dalcose, funolectose, mannitol, sonolebitol, lactose, saccharose, glycerin, urea and the like, with mannitol being particularly preferred. Examples of the hydrophilic carrier include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, citrus polyvinylpyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, and calcium carbonate. Preferred is crystalline cellulose (eg, microcrystalline cellulose). Water-dispersible polymers include gums (eg, tragacanth gum, acacia gum, guar gum), alginate (eg, sodium anoregate), senorellose derivatives (eg, methylcellulose, carboxymethinolese / relulose, hydroxymethylinole) Senorelose, Hydroxypropinoreserenololose, Hydroxypropyl methylcellulose), Gelatin, Water-soluble starch, Polyacrylic acid (eg, Riki-boma), Polymethacrylic acid, Polybutyl alcohol, Polyethylene glycol, Polyvinylpyrroli And polycarbophil, such as hydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, and polyethylene glycol. . Particularly, hydroxypropyl methylcellulose is preferable. Examples of the stabilizer include cysteine, thiosorbitol, tartaric acid, cunic acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite, and the like, and in particular, diascorbic acid citrate is preferable. The sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or the concomitant drug with the above-mentioned excipient by a method known per se. Further, if necessary, the above-mentioned auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, a coloring agent, a sweetening agent and a preservative may be mixed. By mixing the above components simultaneously or with a time lag, and then press-molding, sublingual tablets, puccal tablets or orally rapidly disintegrating tablets can be obtained. In order to obtain an appropriate hardness, it may be produced by humidifying and moistening with a solvent such as water or alcohol as necessary before and after the process of the collapse molding, followed by molding and drying.

When molded into a mucosa-adhered tablet (film), the compound of the present invention or the concomitant drug, the above-mentioned water-dispersible polymer (preferably, hydroxypropylcellulose, hydroxypropylmethylcellulose), an excipient, etc. And then cast the resulting solution into a (cast) film. Further, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a coloring agent, a buffer, and a sweetener may be added. Glycols such as polyethylene glycol and propylene dalicol are included to give the film adequate elasticity, and a bioadhesive film is used to enhance the adhesion of the film to the oral mucosal lining. Remars (eg, polycarbophil, carbopol) may be included. Casting involves pouring the solution onto the non-adhesive surface, spreading it to a uniform thickness (preferably about 100 to 100 microns) with an application tool such as a doctor blade, and then drying the solution to form a film. This is achieved by forming The film thus formed may be dried at room temperature or under heating, and cut into a desired surface area.

 Preferred rapid oral disintegrating agents include solid rapid forms comprising a network of the compound of the present invention or the concomitant drug, and a water-soluble or water-diffusible carrier inactive with the compound of the present invention or the concomitant drug. Diffusion administration agents are included. The network can be obtained by evaporating the solvent from the solid composition comprising a solution of the compound of the present invention or the concomitant drug in a suitable solvent.

 The composition of the oral disintegrating agent preferably contains a matrix forming agent and a secondary component in addition to the compound of the present invention or the concomitant drug.

 Examples of the matrix-forming agent include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat and psyl 1ium seed proteins; gums such as gum arabic, guar gum, agar, and xanthan. Polysaccharides; Alginic acids; Carboxymethylcellulose; Lagenanes; Dextranes; Pectins; Synthetic polymers such as polybierpyrrolidone: Includes substances derived from gelatin-arabia gum complex. It is. Furthermore, saccharides such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inexpensive such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartate Amino acids having 2 to 12 carbon atoms, such as L-glutamic acid, L-hydroxyproline, L-isoleucine, L-mouth isine, and L-phenylalanine.

One or more matrix-forming agents can be introduced into the solution or suspension prior to solidification. Such a matrix forming agent may be present in addition to the surfactant, or may be present without the surfactant. Matric In addition to forming the matrix, the solution-forming agent can help maintain the solution state of the compound of the present invention or the concomitant drug in suspension in solution.

 Secondary ingredients such as preservatives, antioxidants, surfactants, thickeners, coloring agents, pH adjusters, flavors, sweeteners or taste masking agents may be included in the composition. Suitable preservatives include parabens, sorbic acid. Suitable antioxidants include sulfites and ascorbic acid. Suitable surfactants include Polysorbate 80, Macrogol. Suitable thickeners include natural gums and cell mouth derivatives. Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis 'and' Everard. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof. Suitable pH adjusters include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials and microencapsulated compounds.

 Formulations usually contain about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight, of the compound of the present invention or the concomitant drug, and for about 1 minute to about 60 minutes. A formulation capable of dissolving 90% or more of the compound of the present invention or a concomitant drug (in water) preferably for about 1 minute to about 15 minutes, more preferably for about 2 minutes to about 5 minutes Oral disintegrating within 1 to 60 seconds, preferably within 1 to 30 seconds, and more preferably within 1 to 10 seconds after being placed in the oral cavity Fast disintegrants are preferred.

Content relative to the whole preparation of the excipient is from about 1 0 to about 9 9 weight _^0/0, preferably about 3 0 to about 9 0 wt%. The content of the / 3 -cyclodextrin or -cyclodextrin derivative in the whole preparation is 0 to about 30% by weight. The content of the lubricant with respect to the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight. The content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 90% by weight. 70% by weight. The content of the hydrophilic carrier based on the whole preparation is about 0.1 to about 50% by weight / ₀ , preferably about 10 to about 30% by weight / ₀ . The content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. / ₀ . The above preparations may further contain additives such as coloring agents, sweetening agents, preservatives and the like, if necessary.

 The daily dose of the concomitant drug of the present invention depends on the severity of symptoms, age, sex, body weight, susceptibility difference of administration subject, timing of administration, interval, nature of pharmaceutical preparation, preparation, type, type of active ingredient, etc. However, there is no particular limitation. The dose of the compound of the present invention is not particularly limited as long as it does not cause side effects, but is usually about 0.005 to 100 mg, preferably about 0.05 mg / kg body weight of a mammal by oral administration. 5050 mg, more preferably about 0.2-30 mg, which is usually administered once to three times a day.

 Any amount of the compound of the present invention or the concomitant drug can be set as long as side effects do not pose a problem. The daily dose of the compound of the present invention or the concomitant drug may include the degree of symptoms, age, gender, weight, receptivity difference, administration timing, interval, properties of pharmaceutical preparation, preparation, type, and active ingredient of the administration subject. The amount of the active ingredient varies depending on the type and the like, but is not particularly limited.Typically, the amount of the active ingredient is, for example, about 0.001-2 OO mg per kg body weight of a mammal by oral administration, preferably about 0.01-500 mg, more preferably about 0.01-500 mg. 0.1 to: About I0 Omg, which is usually administered in 1 to 4 divided doses per day.

When administering the concomitant drug of the present invention, the compound of the present invention and the concomitant drug may be administered at the same time, but the compound of the present invention may be administered after the concomitant drug is administered first. Alternatively, the compound of the present invention may be administered first, and then the concomitant drug may be administered. When administration is carried out with a time difference, the time difference varies depending on the active ingredient, dosage form and administration method to be administered.For example, when the concomitant drug is administered first, within 1 minute to 3 days after administration of the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the compound of the present invention is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably 15 minutes to 1 hour. A method of administering a concomitant drug within the above is mentioned.

 As a preferred administration method, for example, about 0.01 to 20 OmgZkg of the concomitant drug formed into an oral administration preparation is orally administered, and after about 15 minutes, about 0 to 10 mg of the compound of the present invention formed into an oral administration preparation is obtained. OO 5-10 Omg / kg orally as daily dose.

 In the combination preparation of the present invention, the content of the compound of the present invention in the whole preparation varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 50% by weight, based on the whole preparation. %, More preferably about 0.5 to 20% by weight.

 Example

 Hereinafter, the ability to explain the present invention in more detail based on Reference Examples, Examples, Formulation Examples, and Test Examples The present invention is not limited to Examples and does not depart from the scope of the present invention. It may be changed.

 Elution in column chromatography-I of Reference Examples and Examples, unless otherwise specified,

The observation was performed by TLC (Thin Layer Chromatography). In the TLC observation, 60 F254 manufactured by Merck was used as a TLC plate, and the solvent used as an elution solvent in column chromatography was used as a developing solvent. A UV detector was used for detection. As silica gel for column chromatography, Merck silica gel 60 (70-230 mesh) was used. Room temperature usually means a temperature of about 10 to 35. Further, sodium sulfate or magnesium sulfate was used for drying the extract.

 Abbreviations in Examples and Reference Examples have the following meanings.

 NMR: Nuclear magnetic resonance spectrum

 DMF: dimethylformamide, THF: tetrahydrofuran, DMSO: dimethylsulfoxide, Hz: hertz, J: coupling constant, m: multiblet, q: quartet, t: triplet, d: doublet. S: Singlelet, br: Prode, 1 ike: Approximate.

Reference example 1

(9 S) -7- (3,5-dimethylbenzyl) -19-methyl-15-phenyl 7, 8, 9, 10—tetrahydro [1, 4] diazepino [2, 1-g] [1, 7] naphthyridin-6, 12—dione

 (Process 1)

 8-oxo-15-phenyl-8H-pyrano [3,4-b] pyridine-16-carboxylic acid (4.30) synthesized by the method described in JP-A-9-263585 (EP-A-733632). g) in DMF (9 OmL) solution, 3,5-dimethylbenzylamine (2.39 g), 1-ethyl-3- (3-dimethylaminopropyl) -carposimid hydrochloride (WSC) (6. 17 g) and 1-hydroxyl 1 H-benzotriazole monohydrate (HOBT) (3.26 g) were added at room temperature, and the mixture was stirred for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, a 10% aqueous solution of citric acid and saturated saline, dried, and the solvent was distilled off under reduced pressure to give N- (3,5-dimethylbenzyl) -18-oxo-one. 5-phenyl-8H-pyrano [3,4-b] pyridine-16-carboxamide was obtained as colorless prisms (4.90 g, 92%).

 Melting point: 168-170 ^ (recrystallized from ethyl acetate-disopropyl ether). (Process 2)

To a mixed solution of the compound obtained in Step 1 (2.95 g) in THF (6 OmL) -methanol (20 mL) was added (R) -3-amino-2-methyl-1-propanol (1.44 g) at room temperature. And stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure. To a mixed solution of the obtained residue in toluene (10 OmL) -acetonitrile (2 OmL) was added 1,8-diazabicyclo [5,4,0] -7-indenecene (DBU) (2.2 OmL) at room temperature. And stirred at 130 ^ for 2 hours. The reaction solution was poured into water, and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure to obtain crude (R) -N- (3,5-dimethylbenzyl) -17- (3- 1-hydroxypropyl-2-methyl-5-oxo-5-phenyl-1,8-dihydroxy-1,7-naphthyridine-1 6-cal Boxamide was obtained as an oil (4.30 g). This compound was used for the reaction of Step 3 without purification.

 (Process 3)

 Triethylamine (2.9 OmL) and methanesulfonyl chloride (1.60 mL) were added to a solution of the compound (4.30 g) obtained in step 2 in THF (2 OmL) at 0 ^, and the mixture was added at 0 ° C. Stir for 30 minutes. Further, triethylamine (2.9 OmL) and methanesulfuryl chloride (1.6 OmL) were added to the reaction solution with O :, and the mixture was stirred at 0 for 30 minutes. To the reaction solution was added a 1 N aqueous solution of sodium hydroxide (2 OmL), and the mixture was stirred at room temperature for 1 hour, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried, and then the solvent was distilled off under reduced pressure. Sodium hydride (60% oil, 0.72 g) was added at 0 to the THF (30 OmL) solution of the obtained residue, and the mixture was stirred at 8010 for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol = 9: 0.1) to give the title compound as colorless prisms (1.15 g, 29%).

 Melting point: 1 28-130 ^: (Recrystallized from ethyl ethyl diisopropyl ether). Reference example 2

 (9 S) 1 7—. (3,5-dimethylbenzyl) 1 5— (4-fluorophenyl) 1 9-methyl-7,8,9,10-tetrahydro [1,4] dazepino [2,1—g ] [1, 7] Naphthyridine 1, 6, 12-dione

 (Process 1)

5- (4-Fluorophenyl) -18-oxo-18H-pyrano [3,4-b] pyridin-16-caprolubone synthesized by the method described in JP-A-9-1263585 (EP-A-733632) Using acid (5.0 g) and 3,5-dimethylbenzylamine (2.7 g), the reaction and treatment were carried out in the same manner as in Step 1 of Reference Example 1, and the N- (3,5-dimethylamino) was obtained. Benzinole) 1-5— (4-Funoleolofeninole) _ 8—Okinoh 8 H—Pyrano [3, 4 -b] Pyridine-1-6-carboxamide was obtained as colorless prisms (6.0 g _F 85%). This compound was used for the reaction of Step 2 without purification.

 (Process 2)

 The compound (1.1 g) obtained in Step 1 was reacted and treated in the same manner as in Step 2 of Reference Example 1 to give (R) —N— (3,5-dimethylbenzyl) -1-5- (4 —Fluorophenyl) -7- (3-Hydroxy-2-methylpropyl) -1-8-oxo-7,8-dihydro-1,1-Naphthyridi — 6-carboxamide as a pale yellow foam Was. This compound was used for the reaction in Step 3 without purification.

 (Process 3)

 The compound obtained in Step 2 was reacted and treated in the same manner as in Step 3 of Reference Example 1, and the title compound was obtained as colorless prisms (948 mg, 76%).

 Melting point: 21 3-215 ^ (recrystallized from ethanol diisopropyl ether). Reference example 3

 (a R, 9 R) —7— (3,5-dimethylbenzyl) -1-9-methyl-5-phenyl-1,8,9,10,11-tetrahydro-1H 7H— [1,4] diazosino [2, 1 -g] [1, 7] naphthyridine-1,6,13-dione

 (Process 1)

A mixture of the compound (3.30 g) obtained in Step 1 of Reference Example 1 in THF (61 mL) -methanol (20 mL) was added to a mixed solution of (R) -4-4-amino-12-methyl-11-butanol tetrahydrobila- Then, ether (3.4 Og) was added at room temperature, and the mixture was stirred at room temperature for 14 hours. After pouring the reaction solution into water, the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure. To a mixed solution of the obtained residue in toluene (10 OmL)-acetonitrile (2 OmL) was added DBU (2.56 mL) at room temperature, and the mixture was stirred at 130 for 2 hours. After pouring the reaction solution into water, the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure. To a solution of the obtained residue in methanol (10 OmL) was added p-toluenesulfonic acid monohydrate (3.00 g). Was added at room temperature, and the mixture was stirred at room temperature for 14 hours. After pouring the reaction solution into water, the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure to give (R) -N- (3,5-dimethylbenzyl) -17- (4-hydroxy- 3-Methylbutyl) 1-8-oxo-5-phenyl-1,8-dihydro1,7-naphthyridine-16-carboxamide was obtained as a white powder (4.02 g, 84%).

_{'H-NMR (CDC 1 3} ) δ 0. 902 (3Η, d, J = 6. 6Hz), 1. 60-

2.00 (2H, m), 2.25 (6 H, s), 2.90— 3.10 (1H, br),

3.30-3.60 (4H, m), 3.92-4.06 (2H, m), 4.16 (2H, d, J = 5.2Hz), 6.56 (2H, s ), 6.70—6.80 (1H, br),

6; 88 (1 H, s), 7.35-7.50 (6 H, m), 7.60 (1 H, dd, J = 8.5, 2.OH z), 8.71 (1 H, dd, J = 4.0, 1.4 Hz).

 (Process 2)

 The compound (4.02 g) obtained in Step 1 was reacted and treated in the same manner as in Step 3 of Reference Example 1, and the title compound was obtained as colorless prisms (3.56 g, 81%). . Melting point: 180-182 ^ (recrystallized from ethyl ethyl diisopropyl ether). Reference example 4

 (a R, 9 R) —7— (3,5-dimethylbenzyl) 1-5— (4-fluorophenyl) —9-methyl-8,9,10,11-tetrahydro-1 7H— [1,4] diazosino [2, 1-g] [1, 7] naphthyridine-1. 13-dione

 (Process 1)

The compound (2.2 g) obtained in Step 1 of Reference Example 2 was reacted and treated in the same manner as in Step 1 of Reference Example 3. (R) —N— (3,5-dimethylbenzyl) _5— (4-Fluorophenyl) -7- (4-Hydroxy-3-methylbutyl) -18-oxo-1,8-dihydro 1,7-naphthyridine-1-6-carboxamide is colorless prism (2.4 g, 90% ). This compound was used for the reaction of Step 2 without purification. (Process 2) The compound (2.4 g) obtained in Step 1 was reacted and treated in the same manner as in Step 3 of Reference Example 1, and the title compound was obtained as a pale yellow foam (2.04 g, 88%). Was. _{^{r H-NMR (CDC 1 3}} ) δ 0. 8 7 (3Η, d, J = 7. OH z), 1, 5- 1. 8 (1 H, m), 1. 80-2. 40 (2H , m), 2.25 (6 H, s), 2.90-3.35 (2 H, m), 3.46-3.78 (2 H, m), 5.08 (1 H, dd, J = 1,5,5.8Hz), 5.35 (1H, d, J = 15Hz), 6.47 (2H, s), 6.93 (2H, s), 6. 97 (1H, s), 7.23 (1H, m), 7.42-7.60 (3H, m), 8.91 (1H, dd, J = 4.0, 2. OH z) _D

Reference example 5

 (a R, 4 R) — 2— [3,5-bis (trifluoromethyl) benzyl] 1-4-methylone 13-phenyl-2,4,5,6-tetrahydro 2H— [1, 4] Giazosino

 [1, 2—b] [2, 7] naphthyridine 1, .8—dione

 (Process 1)

A mixture of 4-benzoyl-3-pyridinecarboxylic acid (32.6 g), bromomalonic acid ethyl ester (42.0 g), triethylamine (2.5 OmL) and THF (30 OmL) was heated under reflux for 4 hours. The reaction mixture was poured into dilute ice-hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried, and then the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1). To a solution of the resulting brown oil (37.1 g) in THF (30 OmL) was added 781; (18 mL). After the mixture was heated to room temperature, it was diluted with ethyl acetate. The solution was washed sequentially with water, diluted hydrochloric acid and saturated saline, dried, and then the solvent was distilled off. A mixture of the obtained brown oil, acetic acid (15 OmL) and hydrochloric acid (15 OmL) was heated under reflux for 6 hours. The solvent was distilled off, and dimethyl ether was added to the residue. 1-oxo-14-phenyl-1-H-pyrano [3,4-c] pyridine-13-carboxylic acid was a pale yellow crystal (12 . 78 g, 33%). This compound was used for the reaction of Step 2 without purification. (Process 2) The compound (12.78 g) obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Example 10 to give N- [3,5-bis (trifluoromethyl) benzyl] 1-oxo-l- 4-fluoro-1H-pyrano [3,4-c] pyridine-l-carboxamide was obtained as colorless prisms (14.4 g, 61%).

 Melting point: 115-116 (recrystallized from ethyl ethyl diisopropyl acetate). (Process 3)

 The compound (5.0 g) obtained in Step 2 was reacted and treated in the same manner as in Step 1 of Reference Example 3 to give (R) —N— [3,5-bis (trifnoroleolomethinole). Benzyl]-2- (4-hydroxy-1-3-methylbutyl) 1-loxo-41-phenylenol 1,2, -dihidro 2,7-naphthyridine-13-carboxamide is a colorless prism (5.03 g, 86%).

 Melting point: 167-168 "Ό (recrystallized from ethyl ethyl diisopropyl acetate). (Step 4)

 The compound obtained in Step 3 (4.93 g) was used, and reacted and treated in the same manner as in Step 3 of Reference Example 1. The title compound was obtained as colorless prisms (3.08 g, 64%). Was done. Melting point: 1 94-196 (recrystallized from ethyl isopropyl ether). Reference example 6

 (a R, 4R) —2— [3,5-bis (trifluoromethyl) benzyl] 1 13— (4-phenololenophenyl) 1 4-methyl-1,3,4,5,6-tetrahydro-2H — [1, 4] diazo sino [1, 2_b] [2, 7] naphthyridine-1,8-dione

 (Process 1)

Chemical Pharmaceutical Bultin, 1997, Vol. 45, pp. 162, synthesized from 4- (4-fluorobenzoyl) pyridinepyridine-3-carbonic acid (10.0 g) in THF (80m l) To the solution was added triethylamine (4.27 g) and bromomalonic acid getyl ester (10.1 g) at room temperature, and the mixture was stirred at 80 for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl thiocyanate and THF. The organic layer was washed 1N hydrochloric acid, with water, dried (Mg S0 _4), the solvent was distilled off under reduced pressure. The resulting residue is Separation by Ricagel column chromatography (ethyl acetate: hexane = 1: 2)-Purification gives 2-[[[4- (4-fluorobenzoyl) pyridine-13-yl] carbonyl] carbonyl Getyl malonate was obtained as an oil (12.3 g, 84%).

JH-NMR (CDC) ₃ ) δ 1-26 (6Η, t, J = 7.1Η ζ), 4.24 (2 H, q, J = 7.2 H z), 4.25 (2H, q , J = 7.2Hz), 5.58 (1H, s), 7.09-7.18 (2H, m), 7.31-7.35 (1H, d1ike), 7. 74-7. 81 (2H, m), 8.95 (1H, d, J = 5.2Hz), 9.45 (1H, s).

 (Process 2)

To a solution of the compound obtained in Step 1 (12.1 g) in THF (100 ml) was added DBU (2.04 g) at -78Ό, and the mixture was stirred for 1 hour. The reaction solution was poured into water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer washed with water, dried (Mg S_〇 ₄₎ and the solvent was distilled off reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 2- [1- (4-fluorophenyl) 13-oxo-1,3. —Dihydrofuro [3,4-c] pyridine-111-fur] -12-hydroxyethyl getyl was obtained as an oil (12.3 g, 84%). _{^ -NMR (CDC 1 3) δ} 1. 09 (3Η, t, J = 7. 1 H z), 1. 21 (3H, t, J = 7. 1 Hz), 4. 07 (2H, q, J = 7.1 Hz), 4.10—4.30 (2 H, m), 4.67 (1H, s), 6.99-7.08 (2H, m), 7.73— 7. 81 (2H, m), 8.01—8.04 (1 H, dd 1 ike), 8.88 (1 H, d, J = 5.2 Hz), 9.14 (1H, s).

 (Process 3)

A solution of the compound (7.01 g) obtained in Step 2 in acetic acid (25 ml) -hydrochloric acid (25 ml) was stirred at 115 ° for 4 hours. After the reaction solution was concentrated under reduced pressure, water was added to the residue. The precipitated crystals are collected by filtration and washed with diisopropyl ether to give 4- (4-fluorophenyl) -11-oxo-1H-pyrano [3,4-c] pyridine-13-carbo. The acid was obtained as colorless prisms (3.04 g, 63%).

 Melting point: 272-274: (recrystallized from ethyl acetate-diisopropyl ether). (Process 4)

 Using the compound (5.00 g) obtained in Step 3 and 3,5-bis (trifluoromethyl) benzylamine (4.90 g), the reaction and treatment were carried out in the same manner as in Step 1 of Reference Example 1. At that time, N— [3,5-bis (trif-noleolomethyl) benzyl] -1-4- (4-fluorophenyl) 1-1-oxo-1H-pyrano [3,4-c] pyridine-1-3- Carboxamide was obtained as a colorless powder (7.77 g, 87%).

 Melting point: 189-191.

 (Process 5)

 The compound (0.80 g) obtained in Step 4 was reacted and treated in the same manner as in Step 1 of Reference Example 3 to give (R) —N— [3,5-bis (trifluoromethyl) Benzyl] 1-4- (4-fluorophenyl) 1-2- (4-hydroxy-13-methylbutyl) 1-1-oxo-1,2-dihydro [2.7] naphthyridine-13-carboxamide is a colorless powder ( 0.85 g, 92%).

 Melting point: 160-1621.

 (Step 6)

 The compound (0.81 g) obtained in Step 5 was reacted and treated in the same manner as in Step 3 of Reference Example 1, and the title compound was obtained as a colorless powder (0.43 g, 54%).

 Melting point: 193-195.

Reference Example 7

 N— [3,5-Bis (trifnorelomethyl) benzyl] —7 — [(3R) —4-Hydroxy-1-3-methylbutyl] -1-2-isopropyl-1-8-oxo-5-phenyl-7,7 8-dihydro-1,7-naphthyridine-6-carboxamide

 (Process 1)

Methyl (2Z) —2-amino-4-oxo-1-4-phenyl-2-butenoate (25.1 g) and (1E) —1-methoxy-4-methyl-11-penten-3-one ( Three To a solution of 8.0 g) in acetic acid (10 OmL) was added a solution of methanesulfonic acid (8.2 mL) in acetic acid (35 mL), and the mixture was stirred at room temperature for 1 hour. Further, methanesulfonic acid (8.2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After adding sodium nitrate (42.1 g) to the reaction solution, the reaction mixture was concentrated under reduced pressure. The residue was poured into ethyl acetate, and the organic layer was washed with a 2N aqueous hydrochloric acid solution and saturated saline, dried, and then the solvent was distilled off under reduced pressure. To a solution of the obtained residue in DMS O (4 OmL) was added potassium carbonate (6.0 g) at room temperature, and the mixture was stirred at 85 for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure. The resulting residue was separated by silica gel column chromatography (ethyl acetate: hexane = 1: 5) and purified to give crude methyl 3-benzoyl-6-isopropylpyridine-12-carboxylate as a brown oil (23 1 g, 67%). The obtained compound was used for the next step without further purification.

 (Process 2)

 To a solution of the compound obtained in Step 1 (22.9 g) in THF (18 OmL) was added a 2 N aqueous potassium hydroxide solution (9 OmL), and the mixture was stirred at 60 ° for 2 hours. After neutralizing the reaction solution with a 2N aqueous hydrochloric acid solution, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure. (19.2 g, 88%). The obtained compound was used for the next step without further purification.

 (Process 3)

Potassium hydrogen carbonate (17.1 g) was added to a solution of the compound obtained in step 2 (18.8 g) and 18-crown-6 (22.4 g) in DMF (165 mL) at room temperature. Stirred for hours. After cooling the reaction mixture to 0, getyl bromomalonate (22.9 g) was added, and the mixture was stirred at room temperature for 1.5 hours. Further, potassium carbonate (11.7 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and then the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography. Separation and purification by chromatography (ethyl acetate: hexane == 1: 2) yielded a blue oil. A solution of the obtained brown oil in acetic acid (70 mL) and concentrated hydrochloric acid (l O Orn L) was stirred at 120 for 2 hours. The reaction mixture was poured into water, and the _P organic layer extracted with ethyl acetate was washed with saturated saline, dried, and then the solvent was distilled off under reduced pressure to give 2-isopropyl pill-18-oxo-15-phenyl. 8H-Pyrano [3,4-b] pyridine-6-force Rubonic acid was obtained as colorless prisms (15.5 g, 71%).

Elemental analysis: C _J8 H ₁₅ N0 ₄ · 2.0H ₂ O

 Calculated value (%): C, 62.60; H, 5.55; N, 4.06.

 Measured value (%): C, 62.50; H, 5.33; N, 3.89.

 (Process 4)

 Using the compound (14.9 g) obtained in Step 3 and 3,5-bis (trifluoromethyl) benzylamine (11.8 g), the same procedure as described in Step 1 of Reference Example 1 was repeated. After treatment, N- [3,5-bis (trifluoromethyl) benzyl] -12-isopropyl-18-oxo-15-phenyl-18H-pyrano [3,4-b] pyridine-6 —Carboxamide was obtained as colorless prisms (23.3 g, 90%). Melting point: 172—174 ^ (recrystallized from ethyl isopropyl ether). (Process 5)

 The compound (22.0 g) obtained in Step 4 was reacted and treated in the same manner as described in Step 1 of Reference Example 3 to give the title compound as colorless prisms (17.5 g, 67% ).

 Melting point: 248-250 (recrystallized from ethyl acetate-diisopropyl ether). Reference Example 8

 (a S, 9 S) 1 7— [3,5-bis (trifnorelolomethyl) benzyl] 1 9—methyl 5-5-phenyl 2, 9, 10, 1 1—tetrahydro 7H— [1, 4] diazocino [2, 1—. G] [1, 7] naphthyridine-1, 6, 1 3—dione

 (Process 1)

Synthesized by the method described in JP-A-9-263585 (EP-A-733632) N- [3,5-bis (trifluoromethyl) benzyl] —8-oxo-5-phen-2-u 8H-pyrano [3,4-b] pyridine-6-carboxamide (0.89 g) And (S) -4-amino-2-methyl-1-butanol tetrahydrovinyl ether (0.59 g) were reacted and treated in the same manner as described in Step 1 of Reference Example 3. , N— [3,5-bis (trifluoromethyl) benzyl] —7 — [(3S) -14-hydroxy-1-3-methylbutyl] —8-oxo-15-phenyl-1,7,8-dihydro One 1,7-naphthyridine-16-carboxamide was obtained as colorless prisms (0.84 g, 80%).

_{'HN R (CDC 1 3)} δ 0. 83 (3Η, d, J = 6. 9Hz), 1. 50-1. 85 (4H, m), 2. 97- 3. 01 (1H, m), 3.31 -3. 40 (l H, m), 3.46—3.52 (1 H, ra), 3.60—3.76 (2H, m), 4. 4 3-4.46 ( 2H.m), 7.19-7.40 (5H, m), 7.75 (1H, dd, J = 8.4, 1.5 Hz), 7.60 (2H, s), 7.78 ( 1H, s), 7.97 (1H, m), 8.68 (lH, dd, J = 4.5, 1-8Hz).

 (Process 2)

 The compound (0.82 g) obtained in Step 1 was reacted and treated in the same manner as described in Step 3 of Reference Example 1 to give the title compound as colorless prisms (0.44 g, 54% ).

_{^ -NMR (CDC 1 3) δ} 0. 92 (3 H, d, J = 7. 0Hz), 1. 60- 1. 80 (1 H, m), 2. 00-2. 40 (2H, m ), 2.97 (1 H, d, J = 1

5.4Hz), 3.38--3.59 (2H, m), 3.96 (1H, d.J = 14.

8 Hz), 5.10 (1 H, dd, J = 14.0, 5.2 Hz), 5.43 (1 H.d, J = 1 5.2 Hz), 6.90-6.94 (1 H, m), 7.14—7.23 (1

H, m), 7.32 to 7.58 (7H, m), 7.80 (1H, s), 8.91 (1H, dd, J = 4.2, 2.0Hz).

Reference Example 9

(a R, 9 R) —9-methyl-17- [3-methyl- (5-trifluoromethyl) ben Jill] —5—Feniru 8, 9, 10, 11—Tetrahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione

 (Process 1)

 8-oxo-15-phenyl-8H-pyrano [3,4-b] pyridine-16-carboxylic acid synthesized according to the method described in JP-A-9-1263585 (EP-A-733632) (1. 69 g) and [3-methyl- (5-trifluoromethyl) benzyl] amine (0.90 g) were reacted and treated in the same manner as described in Step 1 of Reference Example 1. — [3-Methyl- (5-trifluoromethyl) benzyl] —8-oxo-5-phenyl-8H-pyrano [3,4-b] viridine-1 6-carboxamide is achromatic prism crystal (2 . 06 g, 74%).

_{'H-NMR (CDC 1 3} ) δ 2. 40 (3H, s), 4. 50 (2H, d, J = 5. 8H z), 7. 25- 7. 38 (6 H, m), 7 50—7.58 (4H, m), 7.62 (1H, dd, J = 8.0, 4.0Hz), 8.96 (1H, dd, J = 4.4, 1.8) H z).

 (Process 2)

 The compound (2.01 g) obtained in Step 1 was reacted and treated in the same manner as described in Step 1 of Reference Example 3 to give 7-[(3R) -4-hydroxyl-3- Methylbutyl] 1-8-oxo-5-phenyl-7,8-dihydro-1-N— [3-methyl- (5-trifluoromethyl) benzyl] -1,1,7-naphthyridine-16-carboxamide The crystals were obtained as crystals (1.99 g, 83%).

_{- NMR (CDC 1 3) δ} 0. 870 (3Η, d, J = 6. 9H 2), 1. 50 - 1. 85 (3Η, m), 2. 37 (3Η, s), 2. 90- 3.00 (1Η, br), 3.34-3.60 (2Η, m), 3.80— 3.90 (2Η, m), 4.29 (2Η, d, J = 6. 3Hz), 7.00 (11, s), 7.09 (1Η, s), 7.15 to 7.25 (1Η, m), 7.30-7.42 (7Η, m) , 7.57 (1 Η, dd, J = 8.1, 1.2 Hz), 8.70 (1 Η, d, J = 3.9, 1.2 Hz).

(Process 3) The compound obtained in Step 2 (1.95 g) was reacted and treated in the same manner as in Step 3 of Reference Example 1 to give the title compound as colorless prisms (1.33 g, 76%). Obtained.

 Melting point: 20-202 (recrystallized from ethyl acetate-diisopropyl ether). Reference Example 10

 (a R. 9 R) —7— (2-Methoxybenzyl) -1-9-methyl-5-phenyl 8, 9, 10, 1 1—Tetrahydro 7H— [1.4.] diazocino [2, 1 -g] [1, 7] naphthyridine-1,6,13-dione

 (Process 1)

 8-oxo-15-phenyl-18H-pyrano [3,4-b] pyridine-16-carboxylic acid (1.41) synthesized by the method described in JP-A-9-1263585 (EP-A-733632). g) and 2-methoxybenzylamine (0.90 g) were reacted and treated in the same manner as described in Step 1 of Reference Example 1 to obtain N- (2-methoxybenzyl) -18- Oxo-15-phenyl-8H-pyrano [3,4-b] pyridine-61-carboxamide was obtained as colorless prisms (1.52 g, 72%).

] _{H- NMR (CDC 1 3) S} 3. 90 (3H, s), 4. 48 (2H, d, J = 6. 0Hz), 6. 86-6. 93 (2H, m), 7. 19 -7. 34 (4H, m), 7.40-7.64 (6 H, m), 8.94 (1 H, dd, J = 4.4, 1.8 Hz).

 (Process 2)

 The compound (1.42 g) obtained in Step 1 was reacted and treated in the same manner as described in Step 1 of Reference Example 3 to give 7-[(3R) -4-hydroxy-3-methylbutynole] -N- (2-Methoxybenzyl) -1-8-oxo-5-phenyl-7,8 dihydro 1,7-naphthyridine-6-carboxamide was obtained as colorless prisms (1.52 g, 90%). Was done.

_{^ H-NMR (CDC 1 3} ) δ 0. 913 (3Η, d, J = 6. 6H z), 1. 60 - 2. 00 (3H, m), 2. 88- 3. 00 (1 H, br), 3.40-3. 70 (2 H, m), 3.75 (3H, s), 4.05-4.14 (2H, m), 4.26 (2 H, d, J = 5.8Hz), 6.30-6.42 (1H, br), 6.74--6.92 (3H, m), 7.20-7.36 (6H , m), 7.45 (1 H, dd, J = 8.0, 4.OHz), 7.63 (1H, dd, J = 8.0, 1.4 Hz), 8.86 ( 1 H, d, J = 4.0, 1.4 Hz).

 (Process 3)

 The compound obtained in Step 2 (1.47 g) was reacted and treated in the same manner as in Step 3 of Reference Example 1 to give the title compound as colorless prisms (1.14 g, 87%). Obtained.

 Melting point: 261-263 (recrystallized from ethyl acetate-disopropyl ether). Reference example 1 1

 (a R, 9 R) — 9-Methyl-1-5-phenyl-1 7— [(3-Trifluoromethyl) benzyl] —8, 9, 10, 1 1—Tetrahydro 7H— [1, 4] Diazocino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione

 (Process 1)

8-oxo-15-phenyl-18H-pyrano [3,4-b] pyridine-16-hydroxycarboxylic acid (1.35) synthesized according to the method described in JP-A-9-1263585 (EP-A-733632). g) and (3-trifluoromethyl) benzylamine (1.15 g) were reacted and treated in the same manner as described in Step 1 of Reference Example 1 to give 8-oxo-5-phenyl-1-amine. N — [(3-trifluoromethyl) benzyl] -1-H—pyrano

 [3,4-b] pyridine-16-carboxamide was obtained as colorless prisms (2.00 g, 93%).

_{'H-NMR (CDC 1 3} ) δ 4. 54 (2Η, d, J = 6. 4H z), 7. 25- 7. 65 (12H, m), 8. 96 (1 H. dd, J = 4. 4, 1.8 Hz).

 (Process 2)

The compound (1.94 g) obtained in Step 1 was reacted and treated in the same manner as in Step 1 of Reference Example 3 to give 7-[(3R) -4-hydroxy-3-methylbutyl] —8 —Oxo-5-phenyl N— [(3-trifluoromethylbenzyl)] —7,8—Dihydro_1,7—Naphthyridine-1 6-Carboxamide is a colorless prism

(2.07 g, 88%).

_{'H-NMR (CDC 1 3} ) δ 0. 848 (3H, d, J = 6. 8Hz), 1. 50- 1. 90 (3H, m), 2. 90- 3. 05 (1 H, br ), 3, 30-- 3.60 (2 H, m), 3.72-3.84 (2H, m), 4.39 (2 H, d, J = 6.2 Hz), 6.98-7 .03 (1 H, m), 7.30-7.64 (1 1 H, m), 8.67-8.70 (1 H, m) ₀

 (Process 3)

 The compound obtained in Step 2 (2.07 g) was reacted and treated in the same manner as described in Step 3 of Reference Example 1. The title compound was colorless amorphous (1.77 g, 88%). ).

Elemental analysis: C ₂₈ H ₂₄ N ₃ 0 ₂ F ₃ · 0.33 H ₂ 0

 Calculated value (%): C, 67.60; H, 5.00; N, 8.45.

 Measured value (%): C, 67.67; H, 5.31; N, δ.

Reference example 1 2

 Ν— [3,5-bis (trifluoromethyl) benzyl] —5— (4-fluorophenylene) 17 — [(3R) —4-hydroxy-1-3-methylbutyl] 1-2-isopropinole 8 —Oxo 7,8—Dihydro 1,7—Naphthyridine 1—6-Lupoxamide

 (Process 1)

 (2Ζ) — 2-Amino 4- (4-fluorophenyl) -14-oxo-12-butenoic acid methyl ester (20.0 g) and (1 E) — 1-Methoxy-14-methyl-1 Using 1-pentene-3-one (28.0 g), the reaction and treatment were carried out in the same manner as in the filtration method described in Step 1 of Reference Example 7, and the crude 3- (4-fluorobenzoyl) was obtained. —Isopropyl-l'-lysine-12-methyl ribonate was obtained as a brown oil (9, 10 g, 37%). The obtained compound was used for the next step without further purification.

 (Process 2)

Using the compound obtained in Step 1 (2.90 g), the method described in Step 2 of Reference Example 7 was used. The same reaction and treatment gave crude 3- (4-fluorobenzoyl) -16-isopropyl-1-pyridine-monocarboxylic acid as a pale yellow oil (1.90 g, 88%). . The obtained compound was used for the next step without further purification.

 (Process 3)

The compound (6.68 g) obtained in Step 2 was reacted and treated in the same manner as in Step 3 of Reference Example 7, and crude 5- (4-fluorophenyl) 1-2-isopropyl was obtained. 8-oxo-18H-pyrano [3,4-b] pyridine-16-carboxylic acid was obtained as colorless prisms (1.74 g, 16%). The obtained compound was used for the next step without further purification.

 (Process 4)

Using the compound (3.36 g) obtained in Step 3 and 3,5-bis (trifluoromethyl) benzylamine (2.50 g), a reaction was carried out in the same manner as in the method described in Step 1 of Reference Example 1. After treatment, N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-fluorophenyl) -1-2-isopropyl-8-quinone-8H-pyrano [3,4-b] Pyridine-16-carboxamide was obtained as colorless prisms (1.75 g, 83%).

 Melting point: 1 99-201 (recrystallized from ethyl ethyl diisopropyl acetate). (Process 5)

The compound (4.52 g) obtained in Step 4 was reacted and treated in the same manner as described in Step 1 of Reference Example 3, and the title compound was converted to colorless prism crystals (1.75 g, 33% ).

 Melting point: 172 ^ 174 (recrystallized from ethyl acetate-diisopropyl ether). Reference Example 13

 N- (3.5-dimethylbenzyl) -5- (4-fluorophenyl) -17-[(3S) —4-hydroxy-3-methylbutyl] _8-oxo-1 2-methyl-17,8-diethyl 1,7-naphthyridine-1 6-carpoxamide

(Process 1) A solution of 2-chloro-6-methylnicotinic acid (22.6 g) in thionyl chloride (22 OmL) was stirred at 85 for 2 hours. The reaction was concentrated under reduced pressure. A solution of the obtained residue in fluorobenzene (5 OmL) was added to a solution of aluminum chloride (35.1 g) in fluorobenzene (6 OmL) under ice cooling, and the mixture was stirred at 100 攪拌 for 1 hour. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The resulting residue is separated by silica gel column chromatography (ethyl acetate: hexane-1: 4) and purified to give 2-chloro-3- (4-fluorobenzoyl) -16-methyl. Pyridine was obtained as a colorless oil (29.1 g, 88%).

_{^ -NMR (CDC 1 3) 6} 2. 6 4 (3H ,. s), 7. 1 0 - 7. 2 2 (2 H, m), 7. 24 (1 Η, d, J = 7. 6 Hz), 7.65 (1H, d, J = 7.6Hz), 7.79-7.89 (2H, m).

 (Process 2)

 To a solution of the compound (8.15 g) obtained in Step 1 in DMF (5 OmL) and methanol (1 O OmL) was added 1,1′-bis (diphenylphosphino) phenoctene (dppf) (0.9%). 1 g), palladium acetate (0.37 g) and triethylamine (11.9 ml) were added, and the mixture was heated at 100 for 18 hours under a carbon monoxide atmosphere of 5 atm. After the reaction mixture was cooled to room temperature, it was neutralized with 2N hydrochloric acid. After pouring the reaction solution into water, the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated tap water, dried, and then the solvent was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (ethyl ethyl hexane: hexane = 1: 2) to give 3- (4-fluorobenzoyl) -16-methyl-pyridine-12- Carbonic acid methyl ester was obtained as colorless prisms (5.55 g, 61%).

_{^ -NMR (CDC 1 3) 5} 2. 7 (3H, s), 3. 78 (3Η, s), 7. 1 3 (2H, t, J = 8. 6 H z), 7. 4 5 ( 1H, d, J = 8.2Hz), 7.70 (1H, d, J = 7.6Hz), 7.78 (2H, dd, J = 9.2, 5.6H z).

(Process 3) To a solution of the compound (7.50 g) obtained in Step 2 in THF (12 OmL) was added a 2N aqueous potassium hydroxide solution (27.6 mL), and the mixture was stirred at 60 ° C for 2 hours. After the reaction mixture was cooled to room temperature, it was neutralized with 2N hydrochloric acid. After pouring the reaction solution into water, the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer is washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and the solvent is distilled off under reduced pressure to give 3- (4-fluorobenzoyl) -16-methyl-pyridine-12-carboxylic acid in colorless form. Obtained as prism crystals (6.29 g, 89%).

_{Ή-NMR (CDC 1 3)} 6 2.72 (3 H, s), 7. 1 1 (2H, t, J = 5.8 Hz), 7.57 (1H, d, J = 5. 2H z), 7.72- 7.78 ( 3H, m). (Process 4)

The compound (1.12 _g ) obtained in Step 3 was reacted and treated in the same manner as described in Steps 3, 4, and 5 of Example 10 to give 5- (4-fluorophenyl) 1-2- Methyl-5-oxo-18H-pyrano [3,4-b] pyridine-16-carboxylic acid was obtained as colorless prisms (0.55 g, 44%).

'H-NMR (D SO- d β) 52.65 (3Η, s), 7.30-7.40 (5H, m), 7.65-7.72 (1H, m).

 (Process 5)

The compound (0.50 g) obtained in Step 4 was reacted and treated in the same manner as described in Step 1 of Reference Example 1 to give N- (3,5-dimethylbenzyl) -1- ( 4-Fluorophenyl) -18-oxo-12-methyl-18H-pyrano [3,4-b] pyridin-16-carboxamide was obtained as colorless prisms (0.55 g, 78%). _{'H-NMR (CDC 1 3} ) δ 2. 34 (6Η, s), 2. 80 (3Η, s), 4. 4 1 (2Η, d, J = 5. 4 Hz), 6. 91 (2H , s), 6.95 (1H, s), 7.20-7.32 (5H, m), 7.38-7.75 (3H, m).

 (Step 6)

Using the compound (1.50 g) obtained in Step 5 and (S) -4-1-amino-2-methynole-1-butanol-tetrahydrovinylamine (0.94 g), The reaction and treatment were carried out in the same manner as in the method described in Step 1, and the title compound was obtained as colorless prisms (1.65 g, 91%).

 Melting point: 107-109 (recrystallized from ethyl acetate-diisopropyl ether). Reference Example 14

 (a R, 9 R) — 9-Methyl-7— (3-Methyl-5-trifluoromethylinobenzyl) —5-Phenyl-1,8,9,10,1 1-Tetrahydro 7H— [1,4] diazono

 [2. 1-g] [1, 7] naphthyridine-1,6,13-dione

 (Process 1)

 5- (4-Fluorophenyl) -18-oxo-18H-pyrano [3,4-b] pyridin-16-carboxylic acid synthesized by the method described in JP-A-9-263585 (EP-A-733632) (1.80 g) and (3-Methylenole-5-trifluoromethylbenzyl) amine (1.20 g) were reacted and treated in the same manner as described in Step 1 of Reference Example 1. — (4-Fluorophenyl) -1-2-isopropyl-1-N— (3-methyl-15-trifluoromethylbenzyl) -18-oxo-8 H-pyrano [3,4-b] pyridine-16-carboxamide is a colorless prism The crystals were obtained as crystals (2.00 g, 69%).

 Melting point: 182-184 · Ό (recrystallized from ethyl ethyl diisopropyl ether acetate). (Process 2)

 The compound (2.01 g) obtained in Step 1 was reacted and treated in the same manner as in Step 1 of Reference Example 3 to obtain 5_ (4-fluorophenyl) -17-[(3R 1) 4-Hydroxy-1 3-methylbutyl]-N- (3-Methyl-5-trifluoromethylbenzyl) -18-Oxo-1 2-Methyl-7,8-dihydro-1,7-Naphthyridine-16-Carboxamide is a colorless prism The crystals were obtained as crystals (1.99 g, 83%). Melting point: 213-215 (recrystallized from ethyl isopropyl ether). (Process 3)

The compound (1.97 g) obtained in Step 2 was reacted and treated in the same manner as described in Step 3 of Reference Example 1 to give the title compound as colorless prisms (1.28 g, 76% ) Was obtained as

 Melting point: 200-202 ^ (recrystallized from ethanol-diisopropyl ether). Reference Example 15

 2-chloro-1--5- (4-fluorophenyl) -17-[(3R) -4-hydroxy-1-3-methylbutyl] -1-N- (3-methyl-15-trifluoromethylbenzyl) -1-8 O-oxo 7,8-dihidro 1,7-naphthyridine-1 6-carpoxamide

 (Process)

 Aluminum chloride (157 g) was added to a mixed solution of 6-chloro-2,3-pyridinedicarboxylic acid (86.3 g) in fluorobenzene (15 OmL) and nitrobenzene (17 OmL), and the mixture was stirred at 9 for 4 hours. After dilution with nitrobenzene (17 OmL), the reaction solution was poured into ice-cold water, and the product was extracted with ethyl acetate. After the organic layer was back-extracted with a 2N aqueous sodium hydroxide solution, the aqueous layer was acidified with a 6N aqueous hydrochloric acid solution, and the product was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure to give crude 6-chloro-3- (4-fluorobenzoyl) -pyridine-12-carboxylic acid light brown crystals. (60.4 g, 46%). The obtained crystals (60.0 g) were reacted and treated in the same manner as described in Steps 3, 4 and 5 of Example 10 to give crude 5- (4-fluorophenyl) -12-hydroxy. Droxy-1-N— (3-methyl-5-trifluoromethylbenzyl) —8-oxo-1 8 H—pyrano [3,4-b] pyridine-16—force Light brown crystals of rubonic acid (36.7 g, 57 %). The obtained compound was used for the next step without further purification.

 (Process 2)

A solution of the compound obtained in Step 1 (6.0.00 g) in phosphorus oxychloride (24.0 g) was stirred at 100 ° C for 1.5 hours. After cooling, the reaction solution was concentrated under reduced pressure. To a solution of the obtained residue in acetonitrile (4 OmL) was added 3-methyl-1- (trifluoromethyl) benzylamine (4.50 g) with, and then triethylamine (12 mL). After stirring at room temperature for 1 hour, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer is washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried. Is distilled off under reduced pressure to give 2-chloro-1- (4-fluorophenyl) -1-N- (3-methyl-15-trifluoromethylbenzyl) -18-oxo-18H-pyrano [3,4 -b] Pyridine-6-carboxamide was obtained as colorless prisms (8.73 g, 89%).

_{JH-NMR (CDC 1 3)} δ 2. 40 (3Η, s), 4. 49 (2 Η, d, J = 5. 7 Hz), 7. 2-7. 4 (8H, m), 7. 48 (1H, d, J = 8.4Hz), 7.62 (1H, d, J = 8.4Hz).

 (Process 3)

 The compound (8.50 g) obtained in Step 2 was reacted and treated in the same manner as in Step 3 of Reference Example 1 to give the title compound as colorless prisms (7.19 g, 72% ).

_{^ -NMR (CDC 1 3) δ} 0. 926 (3Η, d, J = 7. OH z), 1. 50- 1. 80 (1 H, m), 1. 90- 2. 40 (2 H, m), 2.37 (3H, s), 2.99 (1 H, d, J = 15.2 Hz), 3.35—3.55 (2H, m), 3.99 (1 H, d, 5.01 (1 H, dd, J = 13.7, 5.7 Hz), 5.45 (1 H, d, J = 15.0 Hz), 6.82 (1 H dd, J = 7.8, 1.8 Hz), 6.95-7.10 (2H, m). 7.20-- 7.35 (2 H, m), 7.47 (2 H, s) , 7.82 (1H, s), 8.64 (1H, d, J = 5.6Hz), 9.67 (1H,. S).

Reference Example 16

 (a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl 5- (4-Etrophenyl) -1,6,13-dioxo-1,6,8,9 10, 1 1, 13— ^ "Xahydro-1 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1 2-carbonitrile

To a solution of the compound obtained in Example 13 (8.78 g) and concentrated sulfuric acid (19 mL) in nitromethane (65 mL) was added sodium nitrate at −40 °. After the reaction mixture was slowly heated to room temperature, the reaction mixture was treated with sodium hydrogen carbonate (42 g) in water (15 OmL) and vinegar. Ethyl acid (1 O OmL) was poured into the solution. The organic layer was washed with water, dried, and the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (6.88 g, 73%).

 Melting point: 251-253 ^ (recrystallized from ethyl acetate-methanol).

Reference example 17,

 (a R, 9 R) 1 7— [3,5-bis (trifnorelolomethyl) benzyl] 1 N ′ —hydroxy 9-methyl-5- (4-ditrophenyl) -1 6,13-dioxo-1 6, 8, 9, 10, 1, 1, 13 "Kisahydro 7 H— [1,4] diazocino [2,1—g]

 [1,7] naphthyridine-1-carboximidamide

 The compound obtained in Reference Example 16 (0.55 g) was reacted and treated in the same manner as described in Example 103, and the title compound was converted into a pale yellow amorphous (0.55 g, 93%). Obtained.

Elemental analysis: C _3. As _{H 24 N e 0 5 F 6} · 0. 5H 2 0

Calculated value (%): C, 53.66; H, 3.75; N, 12.51.

Measured value (%): C, 53.60; H, 4.11; N, 12.72.

Reference Example 18

 (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] 1 9-methylone 5- (4-nitrotrophyl) 1 2— (1, 2, 4— Oxaziazol 3-yl) — 8, 9, 10, 1 1 — Tetrahydro 7H— [1, 4] diazocino [2, 1— g]

 [1, 7] naphthyridine-1,6,13-dione

 The compound (0.48 g) obtained in Reference Example 17 was reacted and treated in the same manner as described in Example 106, and the title compound was converted into a pale yellow amorphous (0.26 g, 53%). Obtained.

Elemental analysis: C ₃₁ H ₂₂ N ₆ 0 ₅ F _e · 0.5 H ₂ 0

 Calculated value (%): C, 54.63; H, 3.40; N, 12.33.

 Measured value (%): C, 54.78; H, 3.45; N, 12.09.

Reference Example 19 (a R, 9R) -5- (4-Aminophenyl) 17- [3,5-bis (methyl triphenyleol) benzyl] -9-methyl-1,6,13-dioxo-6,8,9,10,1 1 7H— [1,4] diazosino [2,1—g] [1,7] naphthyridine—2-carbonitrile

 A mixture of the compound obtained in Reference Example 16 (2.52 g) and 5% iridium carbon (0.39 g) in methanol (30 mL) and ethyl acetate (30 mL) was placed under a hydrogen atmosphere at 1 atm. Stirred at room temperature until disappeared. The filtrate was concentrated under reduced pressure after filtering off the insolubles, and the title compound was obtained as colorless prisms (1.25 g, 52%).

 m-point: 222-224 (recrystallized from ethyl acetate-disopropyl ether). Reference Example 20

 (a R, 9 R) —5— (4-aminophenyl) 1 7— [3,5-bis (trifluoromethyl) benzinole] —9—methyl-1,6,13—dioxo-1,6,8,9,10,1 1, 13-1 ^ "Kisahydro-7H— [1,4] diazosino [2,1-g] [1,7] Naphthyridine-1-2-carboxamide

 To a solution of the compound obtained in Reference Example 19 (1.26 g) in 85% ethanol (5. OmL) was added iron powder (0.56 g) and calcium chloride (0.12 g). While stirring. After adding ethyl acetate (1 O OmL) to the reaction solution, insolubles were filtered off. The filtrate was washed with water and dried, and the solvent was distilled off under reduced pressure to obtain the title compound as pale yellow prism crystals (0.65 g, 54%).

 Melting point: 279-28 It (recrystallized from ethyl acetate-ethanol).

Reference Example 21

 (a R, 4 R) —2— [3,5-bis (trifluoromethyl) benzyl] 1-4-methyl 13- (4-methylphen ^ nore) 1,3,4,5,6-tetrahydro 2H — [1, 4] diazocino [1, 2— b] [2, 7] naphthyridine-1,8-dione

 (Process 1)

Synthesized by the method described in JP-A-9-1263585 (EP-A-733632) N- [3,5-bis (trif / noleolomethyl) benzyl] —4- (4-methinolephenyl) -11-oxo-1H-pyrano [3,4-c] pyridine-13-carboxamide (20 Og) and (R) — 4-amino-2-methyl-1-butanol tetrahydrovinylamine (8.90 g) were reacted and treated in the same manner as in Step 1 of Reference Example 3. , Crude (R) -N- [3,5-bis (trifluoromethyl) benzyl] -2-(4-hydroxy-3-methylbutyl) 1 -4-1 (4-methylphenyl) 1 -1oxo 1, 2 —Dihydro [2,7] naphthyridine-13-carboxamide was obtained as pale yellow amorphus (23.4 g, 99%). The obtained compound was used for the next step without further purification.

 (Process 2)

 The compound (23.4 g) obtained in Step 1 was reacted and treated in the same manner as described in Step 3 of Reference Example 1, and the title compound was converted to pale yellow amorphous (13.2 g, 58% ).

'H-NMR (CDC) ₃ ) δ 0.96 (3Η, d, J = 7.0 Hz), 1.50—1.80 (1H, m), 1.90—2.40 (2H , m), 2.37 (3H, s),

2.99 (1H, d, J = 15.2Hz), 3.35-3.55 (2H, m), 3.

99 (1 H, d, J = 15.0 Hz), 5.01 (1 H, d d, J = 1 3. 7, 5.

7Hz), 5.45 (1H, d, J = 15.0Hz), 6.82 (1H, d d, J =

7.8, 1.8Hz), 6.95-7.10 (2H, m), 7.20-7.35 (2H, m), 7.47 (2H, s), 7.82 ( l H, s), 8.64 (1 H, d, J

= 5.6 Hz), 9.67 (1 H, s).

Reference Example 22

 (a R, 9 R) —7— (3,5-di-tert-butyl 4-hydroxybenzyl) 1 5— (4-funolelophenyl) 19-methinole 8, 9, 10, 1 1— Tetrahydro-1 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1-6, 13—dione

(Process 1) 5- (4-Fluorophenyl) -18-oxo-18H-pyrano [3,4-b] pyridin-16-caprolubone synthesized by the method described in JP-A-9-1263585 (EP-A-733632) Using the acid (4.60 g) and 4-aminomethyl-1,6-di-tert-butylbutylenol (3.80 g), the reaction was carried out in the same manner as described in Step 1 of Reference Example 1. After treatment, N- (3,5-di-tert-butyl-14-hydroxybenzyl) -1- (4-fluorophenyl) -18-oxo-18H-pyrano [3,4-b] pyridine-6- Carboxamide was obtained as colorless prisms (7.04 g, 87%).

 Melting point: 166-168 ° (recrystallized from ethyl ethyl diisopropyl acetate). (Process 2)

 The compound (6.94 g) obtained in Step 1 was reacted and treated in the same manner as in Step 1 of Reference Example 3 to give N- (3,5-di-tert-butyl-1-4). —Hydroxybenzyl) 1-5— (4-Fluorophenyl) 1 7— [(3 R) —4-Hydroxy-13-methylbutyl] -8-oxo-17,8-Dihydro-1-1,7-naphthyridine One 6-carboxamide was obtained as colorless prisms (7.05 g, 73%). Melting point: 240 (decomposed) (recrystallized from ethyl acetate-diisopropyl ether). (Process 3)

 The compound obtained in Step 2 (6.90 g) was reacted and treated in the same manner as described in Step 3 of Reference Example 1 to give the title compound as a colorless amorphous (3.30 g, 49% ).

_{'H-NMR (CDC 1 3} ) δ 0. 81 (3Η, d, J = 6. 9H z), 1. 40 (1 8 H, s), 1. 50- 1. 70 (1 H, m) , 1.90-2.25 (2H, m), 3.01 (1 H, d, J = 15.3 Hz), 3.23 (1 H, dd, J = 15.0, 10.5 Hz) .3.52 (1H, dd, J = 14.4, 11.1Hz), 4.04 (1H, d, J = 14.4Hz), 4.98 (1H, d, J = 14. 4H z), 5. 04 (1 H, dd, J = 14. 4, 5. 7H Z), 5. 25 (1H, s), 6. 89 (2H, s), 6. 95 (2H, d, J = 5.4Hz), 7.19 (1H, t, J = W 02

8.6Hz), 7.42-7.56 (3H, m), 8.89 (1H, dd, J = 4.

2, 1.8 Hz).

Example 1

 (9 S) -7- [3,5-bis (trifluoromethyl) benzyl] -1-2-methoxy-9-methyl-5-phenyl-1,8,9,10-tetrahydro [1,4] dazepino

 [2, 1-g] [1, 7] naphthyridine-1,6,12-dione

 (Process 1)

(9S) -7- [3,5-bis (trifluoromethyl) benzyl] 191-methyl-5-phenyl synthesized by the method described in JP-A-9-263585 (EP-A-733632). Roux 7, 8, 9, 10—tetrahydro [1, 4] diazepino [2, 11 g] [1, 7] naphthyridine 1,6, 12-dione (1.53 g) in dichloromethane (CH ₂ C ₁₂ ) (2 OmL) solution, 3-chloroperbenzoic acid (1.20 g) was added, and the mixture was stirred at room temperature for 3 hours. After adding an aqueous solution of sodium thiosulfate to the reaction solution, extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure. (9S) —7— [3,5-bis (trifluoromethylinole) benzyl] -9 Methyl-5-phenyl 7,8,9,10-tetrahydro [1,4] diazepino [2,1-g] [1,7] naphthyridine-1,6,1-dione 1-oxide is pale yellow Obtained as a powder (1.12 _g ). This compound was used for the reaction of Step 2 without purification.

 (Process 2)

The compound obtained in step 1, phosphorus oxychloride (5. OmL), was stirred at 100 for 1 hour. After the reaction solution was poured into water (5 OmL), an aqueous solution of potassium carbonate was added to make it alkaline. The product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure. (9S) — 7— [3.5-bis (trifluoromethyl) benzyl] — 2-chloro 9-methyl-5-phenyl 7, 8, 9, 10-tetrahydro [1, 4] diazepino [2, 1-g] [1, 7] naphthyridine 1-6, 12-dione Is a pale yellow foam (0. W

77 g). This compound was used for the reaction of Step 3 without purification. (Process 3)

To a solution of the compound obtained in Step 2 (158 mg) in HF (1 OmL) was added 28% sodium methoxide methanol solution (0.15 mL), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with diacid ether and washed with water and saturated saline. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = ₃ : 1) to give the title compound as colorless crystals (112 mg, 71%).

 Melting point: 129-131 (recrystallized from getyl ether-diisopropyl ether-hexane).

Example 2

 (9 S) -7- [3,5-bis (trifluoromethyl) benzyl] -9-methyl-2-methylsulfanyl-5-phenyl-1,8,9,10-tetrahydro [1,4] dazepino 2, 1-g] [1, 7] naphthyridine-one 6, 12-dione

A 10% aqueous solution of sodium thiomethoxide (0.45 mL) was added to a solution of the compound (12 Omg) obtained in Step 2 of Example 1 in THF (10 mL), and the mixture was heated under reflux for 4 hours. After diluting the reaction solution with ethyl acetate, the organic layer _D washed with water and saturated saline was dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = ₃ : 1) to give the title compound as colorless crystals (106 mg. 87%).

 ¾ point: 21 7— 21 9 ^ (recrystallized from getyl ether diisopropyl ether).

Example 3

 (9 S) 1 7— [3,5-bis (trifluoromethyl) benzyl] —2,9-dimethyl-15-phenyl 7,8,9,10—tetrahydro [1,4] dazepino [2, 1 ', one g] [1, 7] naphthyridine-1,6,12-dione

Compound obtained in Step 2 of Example 1 (365 mg), methyl boric acid (32 Omg) And 1 carbonate force potassium (590 mg), 4-Jiokisan (1 5 mL) was added tetrakis triphenyl phosphine palladium _{(P d (PP h 3)} 4) pressure to give a (300 mg), under argon, at 100 Stir for 4 hours. The reaction mixture was diluted with diacid ether and washed with water and saturated saline.

 The organic layer was dried and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1) to give the title compound as a white powder (197 mg, 56%).

_{^ -NR (CDC 1 3) δ} 1. 05 (3 Η X 2/3, d, J = 6. 6 H z), 1.

21 (3HX 1/3, d, J = 7.4 Hz), 2.40—2.60 (1 H, m), 2.78 (3H, s), 3.05-3.30 (2 H, m), 3.48 (l HX 2/3, dd, J = 14.0, 4.8 Hz), 3.69 (1 H 1/3, dd, J = 15, 5.

2 Hz), 4.06 (1 HX 1/3, d, J = 15.4 Hz), 4.74 (1 HX 2

Z3, d, J = 15.4 Hz), 5.25—5.65 (2H, m), 6.90— 7.

15 (1 H, m), 7.2-7.7 (8H, m), 7.83 (lH, s).

Example 4

 (9 S) -7- [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl-6,12-dioxo-5-pheninole-6,7,8,9,10,12- Hexahydro [1, 4] diazepino [2, 1—g] [1, 7] naphthyridine-12-caprolipetrile The compound (0.50 g) obtained in Step 1 of Example 1 and triethylamine (0 (19 mL) in acetonitrile (2 OmL) solution was added with trimethylsilyl ditrinole (0.31 mL), and the mixture was stirred at 85 * for 3 hours. After pouring the reaction solution into water (5 OmL), the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with 1N hydrochloric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound as pale yellow crystals (0.22 g, 42%).

Melting point: 138-140 (recrystallized from ethyl isopropyl ether acetate). Example 5 (9 S) 1-chloro-7- (3,5-dimethylbenzyl) 1-methyl-5-phenyl 7, 8, 9, 10-tetrahydro [1,4] diazepino [2,1-g ] [1, 7] Naphthyridine 1, 6, 12-dione

 The compound obtained in Reference Example 1 (1.10 g) was reacted and treated in the same manner as in Steps 1 and 2 of Example 1, and the title compound was converted into colorless prisms (0.46 g, 38%). It was obtained as

 Melting point: 174-176¾ (recrystallized from ethyl ethyl diisopropyl acetate). Example 6

 (9 S) —7— (3,5-dimethylbenzyl) -1-2,9-dimethyl -5-phenyl-1,8,9,10-tetrahydro [1,4] diazepino [2,1—g ] [1, 7] naphthyridine-6,12-dione

 The compound (0.35 g) obtained in Example 5 was reacted and treated in the same manner as in Example 3, and as a result, the title compound was obtained as colorless prisms (0.14 g, 43%).

 Melting point: 125-127 (recrystallized from ethyl acetate-disopropyl ether). Example 7

 (9 S) -7- (3,5-dimethylbenzyl) 1-9-methyl-6,12-dioxo-1-5-pheninole-6,7,8,9,10,12- ^ ■ 1,4] dazepino [2,1-g] [1,7] naphthyridine-1-2-carbonitrile

 The compound (0.48 g) obtained in Reference Example 1 was reacted and treated in the same manner as in Step 1 and Example 4 of Example 1, and the title compound was converted to a pale yellow powder (0.18 g, 35 %).

'H-NMR (CDC I ₃ ) δ 0.97 (3ΗΧ 2/3, d.J = 7.OHz), 1.19 (3HX 1/3, d, J = 7.OHz), 2.10- 2.50 (7H, m), 2.96-4.22 (4H, m), 4.80-5.43 (2H, m), 6.67-6.78 (2H, m), 6.95-7.12 (2H, m), 7.35—7.60 (4H, m), 7.77-7.82 (2H, m).

Example 8 (9 S) 1-2-chloro- 1 7-(3,5-dimethylbenzyl) 1-5-(4-fluorophenyl)-1-9-methyl-7, 8, 9, 10-tetrahydro [1, 4] diazepino [ 2, 1— &] [1, 7] naphthyridine-one 6, 12-dione

 The compound (800 mg) obtained in Reference Example 2 was reacted and treated in the same manner as in Steps 1 and 2 of Example 1, and the title compound was obtained as pale brown crystals (376 mg, 44%).

 Melting point: 182-183 (^ recrystallized from acid ethyl diisopropyl ether). Example 9

 (9 S) — 7— (3,5-dimethylbenzyl) -1-5- (4-fluorophenyl) -1,2,9-dimethyl-1,8,9,10-tetrahydro [1,4] dazepino [2, 1 -g]

 [1,7] naphthyridine-1 6,12-dione

 The compound (329 mg) obtained in Example 8 was reacted and treated in the same manner as in Example 3, and as a result, the title compound was obtained as colorless prisms (128 mg, 41%).

 Melting point: 165-167 (recrystallized from ethyl acetate-disopropyl ether). Example 10

 (8 S) -10- [3,5-bis (trifluoromethyl) benzyl] 1 12— (4-fluorophenyl) 1,2,8-dimethyl 7,8,9,10-tetrahydro [ 1, 4] diazepino [1, 2— g] [1, 6] naphthyridine-1, 5, 1 1—dione

 (Process 1)

A solution of 6-methylpyridine-1,2,3-dicarboxylic acid (53.9 g) in acetic anhydride (312 mL) was stirred at 150 for 3 hours. After evaporating the solvent under reduced pressure, 6-methylpyridin-1,2,3-dicarboxylic anhydride was obtained as a brown powder (45.0 g, 94%). ^ -NMR (DMSO-d ₆ ) δ 2.73 (3Η, s), 7.82 (1 H, d, J = 8.0 Hz), 8.401 H, d, J = 8. OH z).

 (Process 2)

In a solution of magnesium (10.1 g) and iodine (0.020 g) in THF (100 mL) at 40-50, add 4-benzene mobenzene (62.8 g) in HF (73 mL). The solution was added dropwise and stirred for 1 hour. The solution thus obtained was slowly added dropwise to a solution of the compound obtained in Step 1 (45.0 g) in THF (30 OmL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was poured into cold water, 2N hydrochloric acid was added to adjust the pH to 2-3. After the product was extracted four times with ethyl acetate, the organic layer was extracted with 2 N sodium hydroxide (20 OmL). The obtained aqueous layer was acidified with 2 N hydrochloric acid (20 OmL), and extracted three times with a mixed solution of ethyl acetate and THF. The organic layer was washed with saturated saline and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: acetic acid = 3: 1: 0.1) to give 2- (4-fluorobenzoyl) -1-6-methylnicotinic acid. Was obtained as white crystals (20.0 g, 28%).

 Melting point: 1 92— 194 ^ (recrystallized from ethyl ethyl isopropyl ether acetate)

 (Process 3)

 To a solution of the compound obtained in Step 2 (20.0 g) and triethylamine (ί4, lmL) in HFHF (20 OmL) was added bromomalonic acid getyl ester (24.1 g), and the mixture was stirred at 80 for 3 hours. Stirred. After addition of bromomalonic acid getyl ester (3.7 g), the mixture was further stirred at 80 for 5 hours. After filtering off the insoluble matter, the mixture was poured into water. After the product was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give crude 2-[[[[2- (4-fluorophenyl) -16-methylpyridine-1 3]. [Tolu] -carbonyl] oxy] getyl malonate (37.3 g) was obtained as an oil. This compound was used for the reaction of Step 4 without purification.

 (Process 4)

To a solution of the compound obtained in Step 3 (37.3 g) in THF (50 OmL) was added DBU (5.8 mL) at 178, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated aqueous ammonium chloride and saturated After washing with brine and drying, the solvent was distilled off under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6).

2- [7- (4-Fluorophenyl) -1-2-methyl-5-oxo-1,5,7-dihydrofuro [3,4-b] pyridine-17-yl] -1-2-hydroxyethyl malonate ( 27.6 g) were obtained as an oil. This compound was used for the reaction of Step 5 without purification.

 (Process 5)

 A solution of the compound (27.6 g) obtained in step 4 in acetic acid (20 OmL) —hydrochloric acid (20 OmL) was stirred at 115 for 6 hours. After the reaction solution was concentrated under reduced pressure, water was added to the residue.

After adjusting the pH to 3-4 with a 2 N aqueous sodium hydroxide solution, the mixture was extracted with ethyl acetate. The organic layer is washed with saturated saline, dried, and the solvent is distilled off under reduced pressure to give 8- (4-fluorophenyl) -12-methyl-15-oxo-1 5H-pyrano [4,3-b] Pyridine-17-carboxylic acid was obtained as pale yellow crystals (7.00 g, 31%).

 Melting point: 234—236: (recrystallized from ethanol / water).

 (Step 6)

 To a solution of the compound obtained in step 5 (0.80 g) in DMF (2 OmL) was added 3,5-bis (trifluoromethyl) benzylamine (0.68 g), WSC (l. 07 g), HOB t (0.64 g) was added at room temperature, and the mixture was stirred for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give N- [3,5-bis (trifluoromethyl) benzinole] -1- (4- Fluorophenyl) -1-methyl-5-oxo-5H-pyrano [4,

3-b] Pyridine-17-carboxamide was obtained as brown crystals (0.44 g, 29%).

Melting point: 178-180 ^ (recrystallized from ethyl ethyl diisopropyl ether). (Step 7) To a mixed solution of the compound (0.80 g) obtained in the stem 6 (0.80 g) in THF (15 mL) —methanol (5 mL) was added (R) —3-amino-1-methyl-1-propanol (0.23 g). ) Was added at room temperature, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a 10 ° / ₀ aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure. To a mixed solution of the obtained residue in toluene (30 mL) -acetonitrile (5 mL) was added DBU (0.48 mL) at room temperature, and the mixture was stirred at 130 for 2 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and HF. The organic layer was washed with a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 1: 1: 0.1) to give (R) -N- [3,5-bis (trifluoromethyl). Benzyl] -8- (4-fluorophenyl) -1-6- (3-hydroxy_2-methylpropyl) -1-methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-17-carboxamide (0.70 g, 76%).

_{'H-NMR (CDC 1 3} ) δ θ. 9 9 6 (3Η, d, J = 7. OH z), 2. 1 0-

2.25 (1 H, m), 2.56 (3H, s), 3.36-3.54 (2H, m),

3.76-3.86 (1 H, m), 4.26 -4. 39 (3H, m), 6.18—6.22 (1 H, m), 6.88 — 6.97 (2H, m), 7.26-7.33 (3H, m), 7, 53 (2H, s), 7.83 (1H, s), 8.5 7 (1 H, d, J = 8.2 H z)

 (Step 8)

To a solution of the compound obtained in Step 7 (0.70 g) in THF (2 OmL) was added triethylamine (0.5 OmL) and methanesulfonyl chloride (0.3 OmL) at 0. Stir for 30 minutes. Further, triethylamine (0.50 mL) and methanesulfonyl chloride (0.3 OmL) were added to the reaction solution at 0, and the mixture was stirred at 0 at 30 minutes. A 1N aqueous sodium hydroxide solution (10 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, and extracted with ethyl acetate. The organic layer is treated with saturated aqueous sodium bicarbonate and saturated aqueous water. After washing and drying, the solvent was distilled off under reduced pressure. To a solution of the obtained residue in THF (3 OmL) was added sodium hydride (60% oil, 0.15 g) with stirring, and the mixture was stirred at 80 for 1 hour. The reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound as colorless prisms (0.28 g, 41%).

 Melting point: 178-180 ^ (recrystallized from methylene diisopropyl ether hexane).

Example 1 1

 (a R, 9 R)-7-[3,5-Bis (trifluoromethyl) benzyl] -2 -chloro 1-9-methinole-5-phenyl-1,8,9,10,11-tetrahydro-7 H_ [1, 4] diazocino [2, 1-g] [1, 7] naphthyridin-6, 13-dione

 (AR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -9-methyl-5- synthesized by the method described in JP-A-9-1263585 (EP-A-733632). Fenuru 8. 9, 10, 1 1—Tetrahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] Naphthyridine 1, 6, 13—dione (0.81 g) The title compound was obtained as colorless prisms (0.36 g, 41%) by reaction and treatment in the same manner as in steps 1 and 2 of Example 1 using the above.

 Melting point: 120-122 (recrystallized from ethyl acetate-disopropyl ether). Example 12

 (aR, 9R) 1 7— [3,5-bis (trifluoromethyl) benzyl] 1 2,9_dimethyl-5-phenyl 8,9,10 '11-tetrahydro 7H— [1,4] Diazocino [2, 1-g] [1, 7] naphthyridine-1.

 The compound (0.34 g) obtained in Example 11 was reacted and treated in the same manner as in Example 3 to give the title compound as colorless prisms (0.11 g. 32%). Melting point: 121-123 (recrystallized from methylene chloride-1'hexane).

Example 13 (a R, 9R) —7— [3,5-Bis (trifluoromethyl) benzyl] —9—Methyl-6, .13—Dioxo-1-5-Feneru 6, 8, 9, 10, 1 1 , 13—Hexahi Draw 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-one 2—force rubonitrile

 (AR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -9-methyl-5- synthesized by the method described in JP-A-9-1263585 (EP-A-733632). Phenyl _ 8, 9, 10, 1 1-tetrahydro-7H— [1,4] diazosino [2,1-g] [1,7] naphthyridine-6,13-dione (0.63 g) The title compound was obtained as colorless prisms (0.20 g, 31%) by reaction and treatment in the same manner as in Step 1 of Example 1 and Example 4.

 Melting point: 170-173 t (recrystallized from ethanol).

_{'HN R (CDC 1 3)} δ 0. 939 (3Η, d, J = 6. 6Hz), 1. 50- 1. 80 (1 H, m), 2. 00- 2. 40 (2H, m) , 3.02 (1 H, d, J = 15.4 Hz), 3.41 (1 H, dd, J = 15.4, 10.2 Hz), 3.56 (1H, dd, J = 14 6, 11.0 Hz), 3.96 (lH, d, J = 14.6 Hz), 5.09 (1 H, dd, J = 14.6, 5.8 Hz), 5.42 (1 H, d, J = 14.6 H z), 6.87- 6.92 (1 H, dlike), 7.15—7.24 (1 H, t 1 ike), 7.35— 7 54 (5H, m), 7.67 (1H, d, J = 8.4Ήz), 7.78 (1H, d. J = 8.4Hz), 7.81 (1H, s ).

Example 14

 (a R, 9 R) —2—Methyl 7— (3,5-Dimethylbenzyl) 1—9—Methyl-5—Phenyl-1-8,9,10,11—Tetrahydro 7 H— [1,4] Diazocino [2,1-g] [1,7] naphthyridine-1,6,13-dione

The compound (1.00 g) obtained in Reference Example 3 was reacted and treated in the same manner as in Steps 1 and 2 of Example 1, and the title compound was converted to colorless prism crystals (0.14 g, 14%). It was obtained as Melting point: 218-220 (recrystallized from ethyl acetate-disopropyl ether). Example 15

 (a R, 9 R) —7— (3,5-dimethylbenzyl) 1,5-phenyl-1,2,9-dimethyl-1,8,10,1 1—tetrahydro-1 7H— [1,4] diazosino [ 2, 1—g] [1, 7] naphthyridine-1,6,13-dione

 The compound (0.32 g) obtained in Example 14 was reacted and treated in the same manner as in Example 3 to give the title compound as colorless prisms (0.081 g, 26%).

 Melting point: 217—219 ”C (recrystallized from ethyl ethyl diisopropyl ether) Example 16

 (a R, 9 R)-7-(3,5-dimethylbenzinole) 1-9-methyl-6,13-dioxo-5-phenyl 2, 8, 9, 10, 1 1, 13- Hexahydro-1-H 7 -— [1, 4] diazocino [2.1-g] [1.7] Naphthyridine-1-2-carbonitrile

 The compound obtained in Reference Example 3 (0.90 g) was reacted and treated in the same manner as in Step 1 and Example 4 of Example 1, and the title compound was converted to colorless prism crystals (0.10 g, 1 6%).

 Melting point: 251-253 ^ (recrystallized from ethyl acetate-diisopropyl ether). Example 17

 (a R, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] —2-chloro-9-methyl-15- (4-methylphenyl) -18,9,10,11— Tetrahydro-7H- [1, 4] diazocino [2, 1 -g] [1, 7] naphthyridine-1,6,1-dione

 (AR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] —9-methyl-15 synthesized by the method described in JP-A-9-263585 (EP-A-733632) — (4-Methylphenyl) -1, 8, 9, 10, 1 1—Tetrahydro-1H 7H—

[1, 4] diazocino [2.1-] [1, 7] naphthyridine 1,6,13-dione (3.91 g) was reacted and treated in the same manner as steps 1 and 2 in Example 1. The title compound was obtained as colorless prisms (822 mg, 20%). Melting point: 296-298 (reconstituted from ethyl acetate-diisopropyl ether). Example 18

 (aR, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] — 2-methoxy 9-methyl-5- (4-methylphenyl) -1,8,9,10,11-tetrahydrido R 7H_ [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1, 13 dione

 The compound (150 mg) obtained in Example 17 was reacted and treated in the same manner as in Step 3 of Example 1 to give the title compound as pale-yellow prism crystals (95 mg, 64%).

 Melting point: 204-205 ^ (recrystallized from ethyl ethyl diisopropyl ether). Example 19

 (a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] -1-methyl-1-5 -— (4-methylphenyl) -12-methylsulfur-lu 8,9,10,11 — Tetrahi Draw 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-6, 13—dione

 The compound (140 mg) obtained in Example 17 was reacted and treated in the same manner as in Example 2, and the title compound was obtained as colorless prisms (109 mg, 76%). Melting point: 244-245X (recrystallized from ethyl acetate-diisopropyl ether). Example 20

 (a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] —2,9-dimethyl-5- (4-methinolephenyl) 1,8,9,10 1 1— Tetrahydro 7H-I [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1, 6, 13-dione The compound (822 mg) obtained in Example 17 was reacted in the same manner as in Example 3, After treatment, the title compound was obtained as pale yellow prism crystals (354 mg, 45%). Melting point: 273-274 (recrystallized from ethyl acetate-disopropyl ether). Example 21

(aR, 9 R) —7— [3,5-bis (trinonorelomethinole) benzyl Ί—9-meth Le-1 5— (4-Methylphenyl) -1,6,13-dioxo-1,8,9,10,1 1,1.3—HexahiDraw 7H— [1,4] Diazocino [2,1-g] [1, 7] Naphthyl lysine-1—carbonitrile

 (AR, 9R) —7— [3,5-bis (trifluoromethyl) benzyl] -191-methinole 5- (4) synthesized by the method described in JP-A-9-1263585 (EP-A-733632). —Methylpheninole) 1, 8, 9, 10, 1 1—Tetrahydro 1 7 H—

 [1,4] diazosino [2,1 -g] [1,7] naphthyridine Using 1,6,13-dione (1.0 g), the reaction was carried out in the same manner as in Step 1 and Example 4 of Example 1. After treatment, the title compound was obtained as yellow prism crystals (107 mg, 10%).

 Melting point: 296-298 "Ό (recrystallized from Etano-Rujechir 一 tel).

Example 22

 (aR, 9R) —7— [3,5-bis (trifluoromethyl) benzyl] 1 2— (dimethinoleamino) 1 9—methyl-1 5— (4-methinolephenyl) 1 8,9,10 1 1 -Tetrahydro-1-H 7- (1, 4) diazocino [2, 1— g] [1, 7] naphthyridine —6, 13-dione

 A 50% aqueous solution of dimethylamine (2 mL) of the compound (0.15 g) obtained in Example 17 was visually stirred at 180 for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and HF. The organic layer was washed with a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (0.13 g, 90%).

 Melting point: 278-280 ^: (recrystallized from ethyl acetate-diisopropyl ether). Example 23

 (a R, 9 R) 1 7— [3,5-Bis (triphnorelomethyl) benzyl] —9-methyl-5— (4-methylphenyl) 1-2-morpholino 8, 9, 10, 1 1 —Tetrahydro-1-H 7—— [1, 4] diazocino [2, 1 -g] [1, 7] naphthyridine-1 6, 1 3 dione

A solution of the compound (0.15 g) obtained in Example 17 in morpholine (2 mL) was added For 14 hours. After the reaction solution was poured into water, it was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 5: 1) to give the title compound as colorless prisms (0.13 g, 83%).

 Melting point: 310-312 (recrystallized from ethyl acetate-diisopropyl ether). Example 24

 (a R, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] —9-methylone-5- (4-methylphenyl) -6,13-dioxo-1,6,8,9 10,11,13 · Kisahi Draw 7H— [1,4] diazosino [2,1—g] [1,7] naphthyridine mono-2-carboxylate

 To a solution of the compound (0.15 g) obtained in Example 21 in ethanol (1 OmL) was added concentrated sulfuric acid (2.5 mL) at room temperature, and the mixture was stirred at 100 "C for 16 hours. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and the solvent was distilled off under reduced pressure.The residue obtained was purified by silica gel column chromatography (ethyl acetate). : Hexane: methanol = 4: 1: 0.5) Separation and purification gave the title compound as colorless prisms (0.12 g, 57%) Melting point: 260-262 (ethyl acetate) —Recrystallized from disopropyl ether) Example 25

 (a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] —2—chloro 1-5— (4-fluorophenol) 1 9—methyl-1,8,9,10,1 1-tetrahydro 7H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridine-1, 6, 1 3 dione

(AR, 9R) —7— [3,5-bis (trifluoromethyl) benzyl] —5 -— (4-fluoro) synthesized by the method described in JP-A-9-1263585 (EP-A-733632) Phenyl) 1 9-methyl-8, 9, 10. 11-tetrahydro 7H — [1, 4] diazocino [2, 1— g] [1, 7] naphthyridine 1, 6, 13-dione (0.94 g) was reacted and treated in the same manner as in Steps 1 and 2 of Example 1 to give the title compound as colorless prisms (0.30 g, 29%).

 Melting point: 231-233 ^ (recrystallized from methylene diisopropyl ether chloride). Example 26

 (a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] —5— (4-fluorophenyl) -1,2,9-dimethyl-1,8,9,10,11-tetrahydro 1 7 H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridine 1, 6, 13-dione

 The compound (0.37 g) obtained in Example 25 was reacted and treated in the same manner as in Example 3, and the title compound was obtained as a pale-yellow powder (0.099 g, 27%).

_{^{J H-NMR (CDC 1 3}} ) δ 0. 910 (3Η, d, J = 7. OHz), 1. 50- 1. 80 (1 H, m), 2. 00- 2. 40 (2H, m ), 2.97 (1 H, d, J = 15.OHz), 2.77 (3H, s), 3.33-3.60 (2H, m), 3.97 (1 H, d, J = 14.6 Hz), 5.08 (1 H, dd, J = 14.6, 5.4 Hz), 5.42 (1 H, d, J = 14.6 Hz), 6.86-6 90 (2H, m), 7.35-7.50 (5H, m), 7.82 (1 H, s).

Example 27

 (a R, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl] —5— (4—Funolorofue-nore) 1—9-methinole 6, 13—Dioxo-1,6,8,9 10, 1 1, 13 1 ^ · Kisahydro 1.7H— [1, 4] diazocino [2. 1-g] [1, 7] naphthyridine 1 2—carbonitrile

(AR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-fluorophene) synthesized by the method described in JP-A-9-263585 (EP-A-733632). -1,9-methyl-1,8,9,10,1 1-tetrahydro7H-1 [1,4] diazosino [2,1 -g] [1,7] naphthyridine-1,6,13-dione (0 33 g) was reacted and treated in the same manner as in Step 1 of Example 1 and Example 4, to give the title compound as colorless prisms (0.080 g, 22%). Melting point: 225-227 (recrystallized from methylene diisopropyl ether chloride). Example 28

 (a R, 9 R) — 2-chloro-7— (3,5-dimethylbenzinole) 1,5- (4-fluorophenyl) 19-methyl-8,9,10,11-tetrahydro-17H— [1, 4] diazocino [2, 1 -g] [1, 7] naphthyridine-1,6,13-dione

 The compound (1.9 g) obtained in Reference Example 4 was reacted and treated in the same manner as in Steps 1 and 2 of Example 1 to give the title compound as colorless prisms (648 mg, 32%). Was done.

 Melting point: 234-236 (recrystallized from ethyl isopropyl ether acetate). Example 29

 (a R, 9 R) -7- (3,5-dimethylbenzyl) -1-5- (4-fluorophenyl)-2,9-dimethyl-1,8,9,10,11-tetrahydro-1-H- [1,4 ] Diazo sino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione

 The compound (147 mg) obtained in Example 28 was reacted and treated in the same manner as in Example 3, and the title compound was obtained as amorphous (45 mg, 32%).

 Melting point: 228-23 O: (recrystallized from ethanol).

_{'H-NMR (CDC 1 3} ) δ 0. 861 (3Η, d, J = 6. 6Hz), 1. 50 -. 1. 80 (1H, m), 1. 90-2 40 (2H, m) , 2.25 (6 H, s), 2.77 (3H, s), 2.86-3.28 (2H, m), 3.56 (1 H, dd, J = 14.2, 1 1 0 Hz), 3.68 (1 H, d, J = 14.2 Hz), 5.06 (1 H. dd, J = 14.6, 5.0 Hz), 5.36 (l H, d, J = 1.6 Hz), 6.48 (2H, s), 6.91-6.99 (3H, m), 7.16-7.28 (1H, m), 7.34 (1H, d. J = 8.4Hz), 7.42 (l H, d, J = 8.4Hz), 7.50-7.60 (1 H, m) ₀

Example 30

(a R, 9 R) -7- (3,5-dimethylbenzyl) -1-5- (4-fluorophenyl) -9-methyl-6,13-dioxo-6,8,9,10,11,13- Kisahidoro -7H- [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1 2-carbo nitrile

 The compound obtained in Reference Example 4 (497 mg) was reacted and treated in the same manner as in Steps 1 and 4 of Example 1 to give the title compound as yellow prism crystals (43 mg, 8.5%). Was done.

_{^{J H-NMR (CDC 1 3}} ) 60. 89 (3 H, d, J = 6 '. 8Hz), 1. 45- 1. 70 (1 H, m)' 1, 90- 2. 40 (2H, m), 2.25 (6H, s), 2.95- 3.25 (2H, m), 3.60 (1 H, dd, J = 14.2, 11.0 Hz), 3.69 (1 H, d, J = 14.2 Hz), 5.06 (1 H, dd, J = 1 4.2, 5.7 Hz), 5.33 (1 H, d, J = 14.4 Hz), 6.45 (2H, s), 6.90- 7.00 (3H, m), 7.18-7.35 (1 H, m), 7.50-7.60 (1H, m), 7.65 (1 H, d, J = 8.6 Hz), 7.78 (1

H, d, J = 8.6 Hz).

Example 31

 (a R, 4R) — 2— [3,5-bis (trifluoromethyl) benzyl] —9-chloro-1--4-methyl-1,3-phenyl-2,4,5,6-tetrahydro-2H— [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine-1,8-dione

 The compound obtained in Reference Example 5 (1.50 g) was reacted and treated in the same manner as in Steps 1 and 2 of Example 1, and the title compound was converted to a red oily substance (0.54 g, 34%). Was obtained.

_{^{J H-NMR (CDC 1 3}} ) δ 0. 94 (3Η, d, J = 6. 9H z), 1. 55-

I. 75 (1 H, m), 1.95-2.35 (2H, m), 3.00 (1 H, d, J = 15.3 Hz), 3.35--3.55 (2H , m), 3.94 (1 H, d, J = l 4.7 Hz), 4.99 (lH.dd, J = 14.4, 5.4 Hz), 5.39 (1 H, d, J = 15.0Hz), 6.90 (2H, m), 7.18 (1 H, t, J = 7.2Hz), 7.30-7.50 (5H, m), 7.81 (1 H, s), 8.33 (1 H, d, J = 5.7 Hz). Example 32

 (a R, 4 R)-2-[3,5-bis (tribnorelomethinole) benzyl] —4,9-dimethyl-1 13-phenyl-2,4,5,6-tetrahydro-1 2H— [ [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine-1,8-dione

 The compound (52 Omg) obtained in Example 31 was reacted and treated in the same manner as in Example 3 to give the title compound as colorless prisms (126 mg, 25%). Melting point: 103-105 (recrystallized from ethanol).

Example 33

 (a R, 4 R)-2-[3,5-Bis (trif-noleolomethyl) benzyl] 1-9-chloro 13- (4-Fluorophenyl) 14-methyl-1 3,4,5, 6-tetrahydro-2H- [1,4] diazosino [1,2—b] [2,7] naphthyridine-1,8-dione

 The compound (0.57 g) obtained in Reference Example 6 was reacted and treated in the same manner as in Steps 1 and 2 of Example 1, and the title compound was converted to colorless prisms (0.27 g, 47%). It was obtained as

 Melting point: 113-115 (recrystallized from diisopropyl ether> xane). Example 34 (1)

 (a R, 4 R) — 2— [3.5-Bis (trifluoromethyl) benzyl] — 13— (4—Fucleophenyl) 1,4,9-dimethyl-1,3,4,5,6-tetrahydro One 2H—

 [1, 4] diazocino [1, 2-b] [2, 7] naphthyridin-1,8-dione The compound (0.22 g) obtained in Example 33 was reacted and treated in the same manner as in Example 3. As a result, the title compound was obtained as a pale yellow powder (0.16 g, 75%).

_{'H-NMR (CDC 1 3} ) δ 0. 943 (3H, d, J = 7. 0Hz), 1. 40- 1. 75 (1 H, m), 2. 00- 2. 40 (2H, m ), 3.00 (1 H, d, J = 15.2 Hz), 3.17 (3 H, s), 3.52-3.98 (2H, m), 3.95 (1 H , d, J = 14.6 Hz), 4.96 (1H, dd, J = 13.6, 5, 8H2), 5.38 (1H, d, J = 14.6Hz), 6.75 (1H, d, J = 6. OH z), 6.87 (2H, d, J = 6.6 Hz), 7.07-7.16 (1H, m), 7.30-7.55 (3H, m), 7. 82 (1H, s), 8.46 (1H, d, J = 6.OHz).

Example 34 (2)

 (a R, 4 R) -2-[3,5-bis (trifluoromethyl) benzyl] 1 13- (4 -fluorophenyl) 1,4,9-dimethyl-1,3,4.5,6-tetrahydro One H—

 [1, 4] diazocino [2, 1 1 b] [2, 7] naphthyridine 1 1,8-dione ρ monotoluenesolephonate

 To a methyl ether (30 mL) of the compound (1.50 g) obtained in Example 34 (1) was added a 1M p-toluenesulfonic acid monohydrate Z methanol solution (2.55 mL), and the mixture was stirred at room temperature for 30 minutes. Stirred. The title compound was obtained as colorless prisms (1.87 g, 96%) by filtering the resulting white precipitate with a jet filter.

 Melting point: 266-268 (recrystallized from ethanol-ethyl ether).

Example 34 (3)

 (a R, 4R) — 2— [3,5-Bis (trifnorololomethyl) benzyl] —13— (4—Funoleolophenyl) 1,4,9-dimethinole 3,4,5,6-tetrahydro 2H —

 [1, 4] diazocino [2, 1-b] [2, 7] naphthyridine- 1, 1,8 ^ dione.hydrobromide

 To a solution of the compound obtained in Example 34 (1) (1.50 g) in getyl ether (3 OmL) was added a 1M solution of hydrobromic acid in methanol (2.55 mL), and the mixture was stirred at room temperature for 30 minutes. . The title compound was obtained as colorless prisms (1.46 g, 85%) by filtering the precipitated white precipitate with getyl ether.

 Melting point: 243-250 (recrystallized from etano-lugetyl ether).

Example 35

(a R, 4 R) — 2— [3,5-bis (trifluoromethyl) benzyl] 1 13— (4-fluorophenyl) 1 4-methyl-1,8-dioxo 1,3,4,5 , 6,8-Hexahydro-2H— [1,4] diazosino [1,2—b] [2,7] naphthyridine One 9—carbonitrile

Pd (PPh ₃ ) ₄ (0.038 g) was added to a solution of the compound (0.10 g) obtained in Example 33 and Zn (CN) ₂ (0.038 g) in DMF (1 OmL) at room temperature. And stirred at 10 for 6 hours under an argon atmosphere. After pouring the reaction solution into water, the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 3: 2) to give the title compound as colorless prisms (0.058 g, 59%).

 Melting point: 133-135 (recrystallized from diisopropyl ether). Example 36

 (a R, 4 R) — 2— [3,5-Bis (trifluoromethyl) benzyl] — 13— (4—Fluoropheninole) 1-4-methyl-1,8-dioxo-1,3,4 5,6,8—Hexahydro-1H— [1,4] diazosino [1,2—b] [2,7] Naphthyridine-19-Methyl ribonate

To a solution of the compound obtained in Example 33 (0.10 g), 1,1,1-diphenyl senylphosphine palladium (dppf) (0.018 g) and triethylamine (0.060 mL) in a methanol (5 OmL) solution Palladium diacetate (Pd (OAc) ₂ ) (0.0073 g) was added at room temperature, and the mixture was stirred for 8 hours at 100 under an atmosphere of carbon monoxide (5 atm). After pouring the reaction solution into water, the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with saturated sodium hydrogen Natoriumu solution and saturated brine, dried, the solvent was distilled off the _D obtained residue was purified by silica gel column chromatography under reduced pressure (acetic acid Echiru: hexane = 2: 1) in the separation 'Purification gave the title compound as colorless prisms (0.054 g, 52%).

 Melting point: 127-129 (recrystallized from ethyl acetate-disopropyl ether). Example 37

(a R, 9 R)-11-[3, 5 _ bis (trifluoromethyl) benzyl] 1 13-(4 fluorophenyl) 1, 2, 9-dimethyl 1, 8, 9, 10, 1 1-亍 Traffic -5H- [1, 4] diazocino [1, 2— g] [1, 6] naphthyridine-1, 5, 12 (7 H) — dione

 (Process 1)

 A mixture of the compound (0.80 g) obtained in Step 6 of Example 10 in THF (15 mL) —methanol (5 mL) was added to a mixed solution of (R) -4-amino-12-methyl: I-butanol tetrahydrodrobilanyl. Ether (0.50 g) was added at room temperature and stirred for 14 hours at room temperature After pouring the reaction solution into water, the product was extracted with a mixed solution of ethyl acetate and THF. After washing with an aqueous solution and saturated saline and drying, the solvent was distilled off under reduced pressure, and DBU (0.48 mL) was added to a toluene (30 mL) -acetonitrile (5 mL) mixed solution of the obtained residue at room temperature. The reaction mixture was poured into water, and the product was extracted with a mixture of ethyl acetate and THF The organic layer was washed with: a 0% aqueous solution of citric acid and saturated saline, After drying, the solvent was distilled off under reduced pressure and p-toluenesulfone was added to a solution of the obtained residue in methanol (2 OmL). Monohydrate (0.63 g) was added at room temperature, and the mixture was stirred at room temperature for 14 hours.The reaction solution was poured into water, and the product was extracted with a mixed solution of ethyl acetate and THF. The extract was washed with an aqueous solution of sodium hydrogen carbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure.The resulting residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1). (R) — N— [3,5-bis (trifluoromethyl) benzyl] -8— (4-fluorophenyl) -16- (4-hydroxy-13-methynolebutyl) -2-methinolay 5-oxo 5,6-Dihydro-1,6-naphthyridine-17-carboxamide was obtained as an oil (0.68 g, 72%).

_{^ -NMR (CDC 1 3) δ} 0. 935 (3H, d, J = 6. 6Hz), 1. 60- 2. 00 (3H, m), 2. 53 (3 H, s). 3. 40 -3.64 (2H, m), 4, 02-4.12 (2 H, m), 4.35 (2H, d, J = 6.OHz), 6.37-6.43 (1 H , br), 6.86—6.95 (2H, m), 7.22-7.34 (3Ή, m), 7.54 (2H, s), 7.83 (1H, s), 8.50 (1H, d, J = 8.0Hz). (Process 2)

 Triethylamine (0.50 mL) and methanesulfonyl chloride (0.30 mL) were added to a solution of the compound (0.68 g) obtained in Step 1 in THF (1 OmL) at 0, and the mixture was stirred at 0 at 30 minutes. did. Further, triethylamine (0.50 mL) and methanesulfonyl chloride (0.30 mL) were added to the reaction solution by Ot: and the mixture was stirred at 0 for 30 minutes. A 1N aqueous sodium hydroxide solution (10 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried, and then the solvent was distilled off under reduced pressure. To a solution of the obtained residue in THF (3 OmL) was added sodium hydride (60% oil, 0.15 g) at 0, and the mixture was stirred at 80 at 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound as colorless prisms (0.30 g, 46%). Melting point: 194-196 (recrystallized from ethyl ethyl diisopropyl ether). Example 38

 (a R, 9R) —7— [3,5-Bis (trifluoromethyl) benzyl] —9—methyl-6,13-dioxo-5-phenyl-1,6,8,9.10,1 1,13-Hexahydro-7H— [1,4] diazocino [2,1-g] [1,7] naphthyridine-1-2-rububonic acid methyl ester

To a methanol solution (10 OmL) of the compound (5.00 g) obtained in Example 11 was added 1,1′-bis (diphenylphosphino) phenoctene (dppf) (0.23 g), acetic acid Palladium (0.095 g) and triethylamine (2.9 mL) were added, and the mixture was stirred under 100 atmospheres of carbon monoxide at 5 atm for 2 hours. The reaction mixture was cooled to room temperature and neutralized with 2N hydrochloric acid. After pouring the reaction solution into water, the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to give the title. The compound was obtained as colorless prisms (3.43 g, 65%).

 Melting point: 240 ^ (decomposition) (recrystallized from THF-ethyl acetate).

Conduct ^ 39

 (a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl-6,13-dioxo-5-phenyl 6, 8, 9, 10, 1 1 , 13—Hexahi Draw 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1 2-force

 Concentrated sulfuric acid (7.5 mL) was added to an ethanol solution (25 mL) of the compound (1.02 g) obtained in Example 13, and the mixture was stirred at 80 for 5 hours. Further, concentrated sulfuric acid (1. OmL) was added, and it was carried at 8 Ot for 1 hour. After pouring the reaction solution into ice-cold water, the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 6: 1) to give the title compound as colorless prisms (0.46 g, 41%).

 Melting point: 261-263 (recrystallized from ethyl ethyl diisopropyl acetate). Example 40

 (a R, 9 R)-7- [3,5-bis (trifluoromethyl) benzyl] — 9-methionone 6, 13-dioxo-5-phenyl 2, 8, 9, 10, 1 1. 13—Hexahydro-7H— [1, 4] diazocino [2, 1—g] [1, 7] Naphthyridine—2-

 A 2 N aqueous solution of potassium hydroxide (KOH) (13 mL) was added to a THF solution (5 OmL) of the compound (3.33 g) obtained in Example 38, and the mixture was stirred at 60 for 2 hours. After the reaction mixture was cooled to room temperature, it was neutralized with 2N hydrochloric acid. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with brine, dried, and the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (2.86 g, 87%).

Melting point: 152-154 (recrystallized from ethyl acetate-disopropyl ether). Example 41

 (a R, 9 R) — 7— [3,5-Bis (trifluoromethyl) benzyl] 1-9-methyl-1,6,13-dioxo-5-phenyl 2,6,9,10,1 1 , 13—Hexahydro-7H— [1, 4] diazocino [2, 1—g] [1, 7] naphthyridine—2-force Lupoxamide

 To a DMF solution (1 OmL) of the compound obtained in Example 40 (0.33 g) was added WSC (0.25 g) and 1-hydroxy-1H-benzotriazole'ammonia complex (0.15 g) at room temperature. The mixture was stirred for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless amorphous (0.29 g, 81%).

_{'H-NMR (CDC 1 3} ) δ 0. 93 (3Η, d, J = 7. OH z), 1. 58- 1. 80 (1 H, m), 2. 00- 2. 40 (2H, m), 3.01 (1 H, d, J = 15.OHz), 3.37-3.70 (2H, m), 3.97 (1 H, d, J = 7.3 Hz) , 5.08 (1 H, dd, J = 14.6, 5.4 Hz), 5.28 (1 H, d, J = 14.2 Hz), 5.69 (1 H, brs), 6.92 (1 H, d, J = 7.6 Hz), 7.16-7.26 (1 H, t 1 ike), 7.36-7.50 (5H, m), 7.69 (1 H, d , J = 8.4 Hz), 7.82 (1 H, s), 8.30 (1 H, brs), 8.37 (1 H, d, J = 8.4 Hz).

Example 42

 (a R, 9R) -7- [3,5-Bis (trifluoromethyl) benzyl] -N-methoxy N, 9-dimethyl-6] 3-dioxo-5-phenyl-1,6,8,9 10, 1 1, 13—Hexahi Draw 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1-2-carboxamide

The compound obtained in Example 40 (0.61 g), N, O-dimethylhydroxyamine hydrochloride (0.15 g), HOBt (0.15 g) and triethylamine (0.20 g) (mL) of DMF (10 mL) was added with WSC (0.29 g) at room temperature and stirred for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless amorphous (0.65 g, 100%).

_{'H-NMR (CDC 1 3} ) δ 0. 9 3 (3Η, d, J = 7. OH z), 1. 50 - 2. 0 0 (1 H, m), 2. 00- 2. 40 ( 2H, m), 3.00 (1 H, d, J = 1 5.OH z), 3.35-3.62 (5H, m), 3.92-4.05 (4 H, m), 5.07 (1H, dd, J = 14.6, 5.6Hz), 5.4.3 (1H, d, J = 1 5.OHz), 6.8 9 -6. 9 8 (1 H, m), 7.15-7.24 (1 H, m), 7.30-7.50 (5H, m), 7.62 (1 H, m) d, J = 8.2 Hz, 7.8 1 (2H, s).

Example 4 3

 (a R. 9 R) — 2—acetyl-1 7— [3,5-bis (trifluoromethyl) benzinole] -1 9—methino I ^ -1 5—phenyl-1 8, 9, 1 0, 1 1— Tetrahydro Draw 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1,6,1-dione

 To a solution of the compound (0.62 g) obtained in Example 42 in THF (2 OmL) was added 1M methylmagnesium bromide ZTHF solution (2. OmL) at 178, and the mixture was stirred for 10 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and then the solvent was distilled off under reduced pressure. The title compound was obtained as colorless prisms (0.17 g, 29%) by separating and purifying the resulting residue by silica gel column chromatography (ethyl ethyl hexane: hexane = 1: 1). Was. Melting point: 234—236 (recrystallized from ethyl ethyl diisopropyl acetate). R f = 0.9 (ethyl acetate: methanol = 5: 1).

Example 44

(a R, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl] —N, 9—dimethyl-1-6,13-dioxo-5-phenyl 6,8,9,10 , 1 1, 1 3— ^ ^ Xahydro-1 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1-2-carboxamide

The residue obtained in Example ⁴ 3 silica gel column chromatography grayed Wo fee (acetate Echiru: hexane = 1: 1) to give the title compound as colorless prisms (0. 043 g, 7%) by separating 'purified Was done.

 Melting point: 145-147 (recrystallized from ethyl ethyl diisopropyl ether). R f = 0.6 (^ acid acid: methanol = 5: 1).

Example 45

 N-[[((aR, 9R) —7— [3,5-bis (trifluoromethyl) benzyl] —9-methyl-1-6,13-dioxo-5-hue-norre-6,8,9 , 10,11,13—Hexahydro-1 7H— [1,4] diazosino [2,1-g] [1,7] naphthyridin-2-yl] carbonyl] glycine

 (Process 1)

 Of the compound (0.61 g) obtained in Example 40, glycine benzyl ester 'p-toluenesulfonate (0.67 g), HOBt (0.15 g) and triethylamine (0.28 mL) WS C (0.29 g) was added to the DMF solution (1 OmL) at room temperature, and the mixture was stirred for 14 hours. The reaction solution was poured into water, and extracted with a mixed solution of ethyl sulphate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give N — [[(aR, 9R) —7— [3.5—bis (trifur O-methyl) benzyl] — 9-methyl-1,6,13-dioxo-5,5-phenylene 6,8,9,10,1,1,13-hexahi draw 7H— [1,4] diazosino [2,1 -g] [1, 7] naphthyridin-12-yl] carbonyl] glycine benzyl ester was obtained as a white powder (0.44 g).

_{^ H-NMR (CDC 1 3} ) δ 0. 93 (3Η, d, J = 6. 9Hz), 1. 60- 1. 80 (1 H, m), 2. 00- 2. 40 (2H, m ), 3.01 (1 H, d, J = 15.0 Hz), 3.44 (1 H, dd, J = 15.6, 9.9 Hz), 3.57 (1 H, dd, J = 14.4 Hz), 3.97 (1 H, d, J = 15.OH z)

4.33 (2H, d, J = 6.3Hz), 5.08 (1H, dd, J = 14.1, 5.4), 5.22 (2H, s), 5.43 (1 H,. D, J = 14.4 Hz), 6.91

(1 H, d, J = 7.2 Hz), 7.20 (1H, t, J = 7.5 Hz), 7.30-7.52 (10 H, m), 7.69 ( 1H, d, J = 8.4Hz), 7.82 (1H, s), 8.35 (1H, d, J = 8.4Hz), 9.03 (1H, t, J = 6. OH z).

 (Process 2)

 To a mixture of the compound obtained in Step 1 (2.95 g) in ethyl acetate (1 OmL) -ethanol (1 OmL), add 10% palladium on carbon (0.025 g), and place in a hydrogen atmosphere at 5 atm. The mixture was stirred at room temperature for 1 hour. After the catalyst was filtered off, the filtrate was evaporated under reduced pressure to give the title compound as a colorless amorphous (0.077 g, 87%).

_{^ -NMR (CDC 1 3) δ} 0. 94 (3Η, d, J = 6. 6Hz), 1. 60- 1. 80 (1H, m), 2. 00-2. 40 (2H, m), 3.01 (1 H, d, J = 1 5.3 Hz), 3.38-3.47 (1H, ddlike), 3.56-3.68 (1H, dd 1 ike), 3.97 (1 H, d, J = 14.7 Hz), 4.35--4.42 (2H, m), 5.06-5.16 (1 H, ddlike), 5.43 (1 H, d, J = 14 1 Hz), 6.91 (1 H, d, J = 7.2 Hz), 7.19 (1 H, t, J = 7.4 Hz), 7.35-7.50 (5H, m), 7.70 (1 H, d, 'J = 8.7 Hz), 7.81 (1 H, s), 8.35 (1 H, d, J = 8.7 Hz), 9.05 -9. 14 (1H, tlike).

 Example 46

 (a R, 9 R) —7— [3.5-bis (trifluoromethyl) benzinole] — N-formyl-1-9-methyl-6,13-dioxo-5-phenyl-1,6,8,9,10 , 1 1, 1 3 · Kisahido Draw 7H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridine-1 2-carboxamide

N, N-dimethylformamide of the compound (0.50 g) obtained in Example 41 The tilacetal (2 OnxL) solution was stirred at 1201 for 10 minutes. After cooling the reaction mixture on ice, the precipitated white powder was collected by filtration. The obtained powder was dissolved in a 70% aqueous acetic acid solution (2 mL) and stirred at room temperature for 1 hour. The title compound was obtained as colorless prisms (0.28 g, 57%) by filtering the precipitated white powder.

 Melting point: 145-147 (recrystallized from ethyl ethyl isopropyl ether). Example 47

 N-[[((aR, 9R) -1 7- [3,5-bis (triphnoleolomethinole) benzinole]]-9-methyl-1,6,13-dioxo-5-huelu 6,8,9 10,1 1,1 3—Hexahydro-1H— [1,4] diazocino [2,1-g] [1,7] naphthyridine —2-inole] carbinole 1—N-formylglycine

 Benzyl bromoacetate (0.31 mL) was added to a solution of the compound obtained in Example 46 (0.50 g) and potassium carbonate (0.13 g) in DMF (5 mL), and the mixture was stirred at room temperature for 38 hours. The reaction solution was poured into a dilute aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to give a white powder (0.26 g, 44%). To a solution of the obtained white powder (0.25 g) in a mixture of ethyl acetate (1 OmL) and ethanol (1 OmL) was added 10% palladium carbon (0.050 g), and the mixture was stirred at room temperature under a hydrogen atmosphere at 5 atm. Stir for 1 hour. After the catalyst was filtered off, the filtrate was evaporated under reduced pressure to give the title compound as colorless prisms (0.23 g, 100%).

 Melting point: 1 51-153 ^ (recrystallized from ethyl ethyl diisopropyl acetate). Example 48

(a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] 1 N—ethyl 9-methinole 6, 13—dioxo 5—pheninole 6, 8, 9, 10, 1 1,1 3 1 ^ «Kisahi Draw _{7 H-} 1 [1, 4] diazocino [2, 1 -g] [1, 7] Naphthyridine 1 2-carboxamide

The compound obtained in Example 40 (0.20 _g ) and etylamine.hydrochloride (0.0 Using 30 g), the reaction was carried out in the same manner as in Example 42, followed by treatment to give the title compound as colorless amorphous (0.048 g, 23%).

Elemental analysis: C ₃₂ H ₂₈ N ₄ 0 ₃ F ₆ · 1.2 H ₂ 0

Calculated value (./.): C, 58.93; H, 4.70; N, 8.59; F, 17.48 _D measured value (%): C, 58.99; H, 4.67 N, 8.45; F, 17.46. _{'H-NMR (CDC 1 3} ) δ 0. 92- 0. 94 (3Η, m), 1. 30 (3 Η, t, J = 6. 8Η ζ), 1. 66- 1. 69 (1 Η , m), 2.00 (3Η, m), 2.10 (1 Η, m), 2.28- 2.32 (1 Η, m), 2.99- 3.03 (1 Η, m ), 3.40-3.47 (1Η, m), 3.52—3.60 (2Η, m), 3.96—4.00 (1Η, m), 6.91 -6. 93 (1 Η, m), 7.18--7.22 (1 Η, m), 7.39-7.47 (5 Η, m), 7.67-- 7.69 (1 Η, m), 7 81 (1Η, s), 8.37-8. 39 (1Η, m), 8.66 (1Η, m). Example 49.

 Ν- [[(a R, 9 R)-7-[3,5-bis (triphnoleolomethinole) benzyl]] 1 9-Methyl-1, 6,13-dioxo-5-phenyl 2,6,9,9 10, 1 1, 13—Hexahydro-7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1-2-yl] carbonyl] —N-ethylglycine

Compound obtained in Example 40 (0.30 g), N-ethylglycinebenzylester-hydrochloride (0.17 g), HOBt (0.11 g) and triethylamine (0.1 OmL) To a DMF solution (5 mL) of was added WSC (0.19 g) at room temperature, and the mixture was stirred for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to give a white powder (0.21 g. 59%). To a mixed solution of the obtained white powder (0.20 g) in ethyl acetate (1 OmL) -ethanol (1 OmL) was added 10% palladium on carbon (0.05 Og), and the mixture was stirred at room temperature under a hydrogen atmosphere at 5 atm. Stir for 1 hour. After filtering off the catalyst, the filtrate was distilled off under reduced pressure to give the title. The compound was obtained as colorless prism crystals (0.174 g, 100%).

 Melting point: 142-144 (recrystallized from ethyl acetate-disopropyl ether). Example 50

 (a R, 9 R) -7- [3,5-bis (trifluoromethyl) benzyl] —N, N, 9-trimethyl-6,13-dioxo-1-5-phenyl 6,8,9, 10, 11, 1 3—Hexahydro-7H— [1.4.] Diazocino [2, 1— g] [1, 7] Naphthyridine-1-2-carboxamide

 Using the compound obtained in Example 40 (0.20 g) and dimethylamine 'hydrochloride (0.030 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to colorless prism crystals (0.2%). llg, 52%).

 Melting point: 210-212 (recrystallized from ethyl acetate diisopropyl ether). Example 51

 (a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] —9—Methyl-6,13—Dioxo N, 5—Diphenyl 6, 8, 9, 10, 1 1,13—Hexahydro-7H— [1,4] Diazocino [2,1-g] [1,7] Naphthyridine-1-2-carboxamide

 The compound (0.20 g) obtained in Example 40 and aniline (0.033 g) were used, and reacted and treated in the same manner as in Example 42. As a result, the title compound was converted to a colorless morphus (0.2%).

(13 g, 59%).

_{^ -NMR (CDC 1 3) δ} 0. 93-0. 94 (3Η, m), 1. 63- 1. 72 (1 Η, m), 2. 04- 2. 12 (1 Η, m), 2.27-2.34 (1 Η, m),

3.00-3.04 (1Η, m), 3.41—3.48 (1 1, m), 3.56—3.

66 (1 Η, m). 3.96—4.00 (1 Η, m), 5.05-5.10 (1 Η, m), 5.40-5.44 (1 Η.m), 6.92- 6.94 (1Η, m), 6.94-7.23 (2Η, m), 7.34—7.50 (7Η, m), 7.73— 7.75

(1Η, m), 7.82 (1Η, s), 7.87-7.92 (2 (, m), 8.47

— 8.49 (1Η, m), 10.61 (1Η, s). Example 52

 (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] — 9-methyl-1-5-phenyl-2- (piperidine-1-ylcarbonyl) 1,8,9,10,1 1-tetrahydro-1-H 7- [1, 4] diazocino [2, 1-g] [1, 7] naphthyridin-6, 13-dione

 Using the compound (0.20 g) obtained in Example 40 and piperidine (0.031 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0.12 g). , 56%).

Elemental analysis: C _3e H ₃₂ N ₄ 0 ₃ F _e · 5 · 5C ₃ H ₇ NO (DMF)

Calculated value (%): C, 61.99; H, 5.06; N, 8 · 91; F, 16.12. Measured value (%): C, 61.98; H, 5.08; N, 8.85; F, 15.80. _{! H- NMR (CDC 1 3)} δ 0. 88- 0. 93 (3Η, m), 1. 65- 1. 71 (7 Η, m), 2. 1 5 (1 Η, m), 2. 25 (1Η, m), 2.98-3.01 (1Η, m), 3.42-3.56 (2Η, m), 3.65--3.73 (4Η, m), 3. 95 ~ 3.99 (1Η, m), 5.04-5.09 (1 (, m), 5.40-5.43 (1Η, m), 6.91-6.93 (1Η , m), 7.17-7.21 (1 Η, m), 7.38-7.44 (5 Η, m), 7.59-7.62 (1 Η, m), 7.81 -7.83 (2Η, m).

Example 53

 (a R, 9 R) — Ν benzyl 7— [3,5-bis (triphnoreolomethyl) benzyl] 9—dimethyl 6,13—dioxo-5-phenyl 2,6,8,9,10 1 1, 1 3—Hexahydro-7H— [1, 4] diazocino [2, 1-g] [1, 7] Naphthyridine 1-2-carboxamide

 Using the compound obtained in Example 40 (0.20 g) and N-methylbenzylamine (0.055 g), the reaction was carried out in the same manner as in Example 42, and the title compound was colorless amorphous (0%). .071 g, 30%).

Elemental analysis: C ₃₈ H ₃₂ N ₄ 0 ₃ F ₆ · 0.4 C ₃ H ₇ NO (DMF) Calculated value (%): C, 63.98; H, 4.77; N, 8.37; F, 15.49. Measured value (%): C, 64.27; H, 4.73; N, 8.29; F, 15.28. _{'H-NMR (CDC 1 3} ) δ 0. 87-0. 93 (3Η, m), 1. 67 (1 Η, m), 2. 08 (1 Η, m), 2. 25-2. 29 (1Η, m), 2.97-3.01 (1Η, m), 3.07-3.23 (3Η, m), 3.46-3.55 (2Η, m), 3. 94 -3.99 (1Η, m), 4.71—5.04 (3Η, m), 5.39—5.43 (1Η, m), 6.89-6.94 (1Η, m) , m), 7.18-7.22 (2 Η, m), 7.28-7.47 (9 Η, m), 7.59-7.64 (1H, m), 7.81 (1 Η, s), 7.88- 7.95 (1 Η, m).

Example 54

 (a R, 9 R) -N, N-dibenzyl-1- 7- [3,5-bis (trifluoromethyl) benzyl] 1-91-methyl-1-6,13-dioxo-5-phenyl _ 6, 8, 9 , 10, 1 1, 13— ^ · Xahydro-1 7 H— [1,4] diazocino [2, l— g] [1,7] Naphthyridine-1-carboxamide

 Using the compound (0.20 g) obtained in Example 40 and dibenzylamine (0.071 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0.16 g, 65%).

Elemental analysis: C ₄₄ H ₃₆ N _{40 3} F ₆ ■ 0.6 C ₃ H ₇ NO (DMF)

Calculated value (./.): C, 66.55; H, 4.90; N, 7.79; F, 13.79. Measured value (%): C, 66.73; H. 4.85; N, 7.95; F, 13.49. _{^{5 HN R (CDC 1 3)}} 50. 87- 0. 91 (3Η, m), 1. 63- 1. 66 (1 H, m), 2. 04-2. 06 (1H, m), 2. 21-- 2.28 (1 H, m), 2.96-3.00 (1 H, m), 3.40-3.54 (2H, m), 3.93-- 3.97 (1 H, m) m), 4.65-4.80 (2 H, m), 4.92 (2 H, s) '5.00-5.05 (1 H, m), 5.38-5.42 (1 H, m), 6.89—6.91 (1 H, m), 7.16—7.45 (16 H, m), 7.57—7.59 (1H, m), 7 80 (1H, m), 7.89-7.91 (1H, m). Example 55

 (a, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] — N, 9-dimethyl-6,13-dioxo-N, 5-diphenyl 6, 8, 9, 10, 1 1, 1 3 · Kisahedro 7 H— [1, 4] diazocino [2, 1— g] [1, 7] Naphthyridine 1 2-carboxamide

 Using the compound (0.20 g) obtained in Example 40 and N-methylaniline (0.039 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amalfas (0. 13 g, 58%).

Elemental analysis: C ₃₇ H _{3. N 4 0 3 F e · 0.} 5 C 3 H 7 NO as (DMF)

Calculated value (%): C, 63.41; H, 4.63; N, 8.64; F, 15.63. Measured value (%): C, 63.63; H, 4.53; N, 8.59; F, 15.47. ^J HN R (CDC 1 ₃ ) δ θ. 88-0.90 (3Η, m), 1.27 (1Η, m), 1, 57 (1 H, m), 2.03 (1 H, m) , 2.22 (3 H, m), 2.94-2.97 (1 H, m), 3.43-3.53 (4H, m), 3.92-3.96 (1

H, m), 4.97 (1 H, m), 536-5.40 (1H, m) 6.88 (H, m), 7.16 (5H, m), 735-7.40 (5H, m) 7.60 (H, m), 7.79 (1 H, s).

Example 56

 (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] —9-methyl-1-5-ferruo 2- (pyrrolidine-1-ylcarbyl) 1,8,9,10 , 1 1-tetrahydro-1-H, [1, 4] diazocino [2, l-g] [1, 7] naphthyridin-1, 6, 13-dione

 The compound (0.20 g) obtained in Example 40 and pyrrolidine (0.026 g) were reacted and treated in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0.3 g, 0.3 g, 63%).

Elemental analysis: as C ₃₄ H ₃₀ N ₄ O ₃ F ₆

Calculated value (%): C, 62.19; H, 4.61; N, 8.53; F, 17.36. Measured value (%): C, 62.04; H, 4.69; N, 8.60; F, 17.20. Example 57

 (a R, 9R) —7— [3,5 _bis (trifluoromethyl) benzyl] 1 N— (2 —hydroxicetinol) 1 9-methyl-6,13-dioxo-1 5—feneru 6, 8, 9, 10, 1 1, 1 3—Hexahydro 7H— [1.4.] Diazocino [2, 1-g]

 [1, 7] naphthyridine-1-2-carboxamide

 The compound (0.21 g) obtained in Example 40 and 2-aminoethanol (0.0

The reaction was carried out in the same manner as in Example 42 using 23 mL), and the title compound was obtained as colorless prisms (0.19 g, 84%).

 Melting point: 232-234 (recrystallized from ethyl isopropyl ether). Example 58

 (a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] —N-isopropyl-1-9-methyl-6,13-dioxo-1-5-phenyl-2,8,9 , 10,1 1,13—Hexahydro-7H— [1,4] diazosino [2,1-g] [1,7] Naphthyridine-12-carboxamide

 The compound obtained in Example 40 (0.40 g) and isopropylamine (0.04

Using 3 g), the reaction was carried out in the same manner as in Example 42, followed by treatment to give the title compound as colorless amorphous (0.28 g, 66%).

Elemental analysis: C ₃₃ H ₃₀ N ₄ O ₃ F ₆ · 0.5 C ₃ H ₇ NO (DF) · 0.5Η ₂₀

 Calculated value (%): C, 60.04; Η, 5.04; Ν, 9.13; F, 16.52. Measured value (%): C, 59.65; H, 4.87; N, 9.06; F, 16.56.

_{'H-NMR (CDC 1 3} ) δ 0. 91-0 93 (3Η, m), 1. 31- 1. 33 (6Η, m) 1 -.. 65- 1. 68 (1 H, m), 2.09 (1 H, m), 2.27-2.30 (1 H, m), 2.98-3.02 (1 H, m), 3.39-3.46 (1 H, m ), 3.53-3.60 (1 H, m). 3.96—3.99 (lH, m), 4.29-4.34 (1H, m), 5.02-5.07 ( 1H, m), 5.40—5.4 3 (1 H, m), 6.91 -6.93 (1 H, m), 7.18-7.20 (1 H, m), 7.37-7.47 (5H, m), 7 67-7. 69 (1H, m), 7.81 (1H, m), 8.37—8.39 (1H, m), 8.47—8.49 (1H, m) . Example 59

 (a R, 9R) — 7— [3,5-Bis (trifluoromethyl) benzyl] -1-N-cyclopentyl 9-methinole 6,13-dioxo-5-phenyl-1 6,8,9,10 11,13—Hexahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1 2-carboxamide

 Using the compound obtained in Example 40 (0.40 g) and cyclopentylamine (0.062 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless compound (0.4%). 31 g, 70%).

Elementary analysis: as the _{C 36 H 32 N 4 0 3} F 6 · 0. 4 C 3 H 7 NO (DMF) · 0. 3Η 2 0

 Calculated value (%): C, 61.65; Η, 5.06; Ν, 8.74; F, 16.16. Measured value (%): C, 61.44; Η, 4.79; Ν, 8.91; F, 16.38.

_{^{L H-NMR (CDC 1 3}} ) δ 0. 91- 0. 93 (3Η, m), 1. 64- 2. 30 (1 1 Η, m), 2. 98-3. 02 (1 Η, ra ), 3.39—3.41 (1 Η, m),

3.53—3.60 (1Η, m), 3.96—3.99 (1Η, m), 4.42 (1

Η, m), 5.03 (1 Η, m), 5.40—5.43 (1 Η, m), 6.91—6.93 (1Η, m), 7.18—7.22 ( 1Η, m), 7.37-7.47 (5Η, m), 7.66- 7.69 (1Η, m), 7.81 (1Η, m), 8.37—8.3

9 (1Η, m), 8.57-8.59 (1Η, m).

Example 60

(a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] -1-N-cyclohexyl 9-methynolate 6.13—Dioxo-5-phenyl-1 6,8,9,10 , 1 1, 13 1 ^ "Kisahydra 7H— [1, 4] diazocino [2, 1— g] [1, 7] Naphthyridine-1 2-carboxamit ' Using the compound obtained in Example 40 (0.40 g) and cyclohexylamine (0.072 mg), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0.40 g). 24 g, 54%).

Source analysis: C ₃₆ H ₃₄ N ₄ O ₃ F ₆ '0.7 as C ₃ H ₇ NO (DMF)

Calculated value (%): C, 62.19; H, 5.33; N, 8.95; F, 15.49. Measured value (%): C, 62.08; H, 5.08; N, 9.15; F, 15.72. _{'H-NMR (CDC 1 3} ) δ 0. 91-0. 92 (3Η, m), 1. 25 (1 Η, m), 1. 38- 1. 40 (4 Η, m), 1. 63 — 1.67 (2Η, m), 1.78 (2Η, m), 2.03 (3Η, m), 2.25 (1Η, m) '2.98-3.02 (1Η, m) m), 3.39-3.42 (11, m), 3.53-3.59 (1Η, m), 3.95-3.99 (2Η, m), 5.01-5. 06 (1Η, m), 5.39-5. 4 3 (1Η, m), 6.90-6.92 (1Η, m), 7.18—7.22 (1 18, m) , 7.37-7.47 (5Η, m), 7.67- 7.69 (1Η, m), 7.81 (1Η, m), 8.37-8.40 (1Η, m) ), 8.50—8.53 (1 mm, m). Example 61

 (a R, 9 R) 1 7— [3,5-bis (trifnorelomethyl) benzyl] —N— (tert-butynole) 1-9-methinole 6,13-dioxo-1 5—Feninole 1 6, 8, 9, 10, 11, 13 1 ^ «Kisahi Draw 7H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridine-1 2-carboxamide

 Using the compound (0.40 g) obtained in Example 40 and tert-butylamine (0.043 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0.28 g). , 66%).

Elemental analysis: C ₃₄ H ₃₂ N _{40 3} F ₆ 0 0.85 Calculated as C ₃ H ₇ NO (DMF) Calculated (%): C, 60.91; H. 5.31; N, 9.43 F, 15.82. Measured value (%): C, 60.79; H, 4.82; N, 9.71; F, 16.05. _{^{! H-NMR (CDC 1 3}} ) δ 0. 90-0. 92 (3Η, m), 1. 52 (9Η, m), 1 · 62- 1. 66 (1 Η, m), 2. 08 ( 1 Η, m), 2. 24- 2.27 (1 H, m), 2.98-3.02 (1H, m), 3.39-3 · 45 (1H, m), 3.52-3.59 (1H, m), 3.96 -3 99 (1 H, m), 4.99—5.0 5 (1 H, m), 5.39—5.43 (1 H, m), 6.91-6.93 (1 H , m), 7.18-7.22 (1 H, m), 7.37-7.47 (5H, m), 7.67-7.69 (1 H, m), 7.81 (1 H, m), 8.36-8.38 (1 H, m), 8.45 (1H, m).

Example 62

 (a R, 9 R) 1 7- [3,5-bis (trifluoromethyl) benzyl] -9-methinole-1 2- (morpholine-1 4-ylcanoleponyl) 15-phenyl-1 8,9,10,1 1 — tetrahydro 7H_ [1, 4] diazocino [2, 1-g] [1, 7] naphthyridin-6, 13-dione

 Using the compound (0.2′0 g) obtained in Example 40 and morpholine (0.032 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0.12 g). , 55%).

Elementary analysis: as _{C 34 H 30 N e O 4} F e · 0 · 2C 6 H 14 0 ( diisopropyl ether) · 0. 9H ₂ 0

Calculated value (%): C, 59.61; H, 4.92; N, 7.90; F, 16.07. Measured value (%): C, 59.76; H, 4.86; N, 7.86; F, 15.90. _{'H-NMR (CDC 1 3} ) δ 0. 92-0. 93 (3Η, m), 1. 65- 1. 69 (1Η, m), 2. 05 (1 H, m), 2. 27- 2.31 (1 H, m), 2.98 -3.02 (1 H, m), 3.42-3.58 (2H, m), 3.76-3.85 (7 H, m) , 3.95- 3.99 (1 H.m), 4.04 (1 H, m), 5.0 -5.09 (1 H, m), 5.40-5.44 (1 H, m) m), 6.91 -6.93 (1 H, m), 7.18-7.21 (1 H, m), 7.39-7.47 (5H _F m), 7.64- 7.66 (1H, m), 7.81 (1H, m), 7.95—7.97 (1H, m). Example 63

(a R, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl] —9-methyl 1-5-phenyl 2- (1,3-thiazolidine-3-ylcarbonyl) -1,8,9,10,11-tetrahydro-7H— [1,4] diazosino [2,1-g] [1,7] Naphthyridine-1,6, -dione

Using the compound (0.20 g) obtained in Example 40 and thiazolidine (0.032 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0.11 g, 61%).

Elemental analysis: as C ₃₃ H _2e N ₄ 0 ₃ SF ₆

 Calculated (%) C, 58.75; H, 4.18; N, 8.30; S, 4.75; F, 16.90.

Measured value (%) C, 58. 64; H, 4. 13; N, 8. 39; S, 4. 82; F, 16. 76 0

Example 64

 (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] 1-2-(1, 3-dihydro-1 H-isoindole-1-2-carbonyl) 1-9 -methyl-5- Yellow 8, 9, 10, 11—Tetrahydro-1H 7H— [1,4] Diazocino [2,1-g] [1,7] Naphthyridine-1,6,13-dione

 Using the compound (0.20 g) obtained in Example 40 and isoindoline (0.043 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0.14 g). , 60%).

Elemental analysis: C _3B H ₃₀ N ₄ O ₃ F ₆ · 0.1H ₂₀

 Calculated value (%): C, 64.60; H, 4.31; N, 7.93; F, 16.14. Measured value (%): C, 64.44; H, 4.36; N, 8.18; F, 16.04. Example 65

 (a R, 9R)-7- [3,5-bis (trifluoromethyl) benzyl] — 2- (2,3-dihydro-1H-indole-1] -ylcarbonyl-1-9-methinole 5-phenyl One 8, 9, 10, 1 1-Tetrahydro Draw 7H— [1, 4] diazocino [2, 1— g]

[1, 7] naphthyridine-1,6,13-dione The compound (0.20 g) obtained in Example 40 and indoline (0.043 g) were reacted and treated in the same manner as in Example 42 to give the title compound as a colorless amorphous (0.15 g, 64 %).

Elementary analysis: as _{C 38 H 30 N 4 O 3} F 6 · 0. 4C 3 H 7 NO (DMF) · 0. 2C 6 H 14 Ο ( diisopropyl ether) · 0. 2Η ₂ 0

Calculated value (%): C, 64.02; Η, 4.79; Ν, 8.13; F. 15.04. Measured value (%): C, 64.05; Η, 4.54; Ν, 8.37; F, 14.82. _{'H-NMR (CDC 1 3} ) δ 0. 93- 0. 94 (3 H, m), 1. 66- 1. 69 (1H, m), 2. 09 (1 H, m), 2. 27 — 2.31 (1H, m), 3.00 —3.0.3 (1H, m), 3.18-3.22 (2H, m), 3.45—3.67 (2H, m) , 3.96-3.99 (1H, m), 4.61—4.66 (1 H, m), 4.73-5.10 (2H, m), 5.41—5.44 (lH , m), 6.94—6.96 (1 H, m), 7.H 7—7.1 1 (1 H, m), 7.19—7.47 (8H, m), 7. 66- 7.68 (1H, m), 7.81 (1H, m), 8.13-8.15 (1H, m), 8.30-8.32 (1H, m).

Example 66

 (a R, 9R) -7- [3,5-bis (trifluoromethyl) benzinole] —9-methyl 2-([4-oxopiperidin-1-yl) carbonyl] —5-phenyl 8, 9, 10, 1 1—tetrahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1, 6, 13—dione

 Using the compound (0.20 g) obtained in Example 40 and 4-piperidone 'hydrochloride monohydrate (0.056 g), the reaction was carried out in the same manner as in Example 42, followed by treatment. The title compound was obtained. Was obtained as a colorless amorphous (0.15 g, 68%).

Elemental analysis: C ₃₅ H ₃₀ N ₄ O _{4 Fe} · 1. As C ₃ H ₇ NO (DMF)

Calculated value (%): C, 59.83; H, 5.10; N, 9.61; F, 14.48. Measured value (%): C, 59.91; H, 4.70; N, 9.98; F, 14.54. _{^ -NMR (CDC 1 3) 50.} 92- 0, 93 (3Η, m), 1. 80 (1H, m), 2.10 (1 H, m), 2.30 (1 H, m), 2.66 (2H, m), 2.72 (1 H. m), 2.80 (1 H, m), 3 43—3.58 (4 H, m), 3.95—4, 18 (4H, m), 5.03 (1 H, m), 5.39—5.43 (1 H, m), 6.92-6.94 (1 H, m), 7.18-7.22 (1 H, m), 7.37-7.47 (5H, m), 7.66-7.68 ( 1H, m), 7.81 (1H, m), 7.9 6-7. 98 (1H, m).

Example 67

 (a R, 9 R) ~ 7-[3,5-bis (trifluoromethyl) benzyl] -1-2-[(4-hydroxypiperidine-11-yl) carbonyl]-9-methyl-1-5-phen 2,8,10,1 1—Tetrahydro 7H— [1,4] diazocino [2,1—g] [1,7] naphthyridine-1,6,13-dione

 Using the compound (0.20 g) obtained in Example 40 and 4-hydroxypiberidine (0.037 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0 16 g, 72%).

Elemental analysis: C 3 _S H ₃₂ N ₄ 0 ₄ F ₆ · 1.1 C ₃ H ₇ NO (DMF)

Calculated value (%): C, 59.97; H, 5.22; N, 9.31; F, 14.86. Measured value (%): C, 60.26; H, 4.90; N, 9.59; F, 15.32. ] _{H- NMR (CDC 1 3) δ} 0. 92-0. 93 (3Η, m), 1. 67- 1. 70 (2H, m), 2. 02 (2H, m), 2. 32 (1 H, m), 2.98-3.02 (4H, m), 3.43-3.57 (4H, m), 3.95-3.99 (2H, m), 4.20- A. 30 (1H, m), 5.03—5.06 (1H, m), 5.39-5.43 (1H, m), 6.91—6.93 (2H, m), 7 1 7-7. 2 1 (1H, m), 7.37-7.46 (5H, m), 7.61—7.63 (1H, m), 7.8 1—7.84 ( 2H, m).

Example 68

4 — [[(aR, 9R) -1-7— [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl-6,13-dioxo-5-phenyl-1,6,8,9,10 1 1, 13— Hexahi Draw 7H— [1,4] diazosino [2,1-g] [1,7] naphthyridine—2-yl] carbonyl] piperazine-one-potency rubonic acid tert-butyl ester Obtained in Example 40 Using the obtained compound (0.220 g) and piperazine-11-carboxylic acid tert-butyl ester (0.068 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous ( 0.15 g, 61%). Elemental analysis: C ₃₉ H ₃₉ N ₅ 0 ₅ F ₆ · 0.2 C ₃ H ₇ NO (DMF)

Calculated value (%): C, 60.48; H, 5.17; N, 9.26; F, 14.49. Measured values (° /.): C, 60.26; H, 5.03; N, 9.41; F, 14.79. _{'H-NMR (CDC 1 3} ) δ 0. 92- 0. 94 (3Η, m), 1. 48 (9 Η, s), 1. 80 (1 Η, m), 2. 05- 2. 27 (2Η, m), 2.98- 3 ・ 02 (1 Η, m), 3.51 -3.58 (6Η, m), 3.78― 3.83 (3Η, m), 3.95- 3.99 (2Η, m), 5.05 (1Η, m), 5.40--5.44 (1Η, m), 6.91-6.93 (1Η, m), 7.18 — 7.22 (1Η, m), 7.3 9-7.47 (5Η, m), 7.64 -7.66 (1Η, m), 7.81 (1Η, m), 7. 90 (1Η, m).

Example 69

 3— [[(a R, 9 R) —7— [3,5-bis (trifnorolelomethinole) benzyl] —9-methyl-6,1 3-dioxo-5-phenyno-6,8,9 , 10, 11, 1, 13—Hexahi Draw 7H_ [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine — 2-yl] carbonyl] 1, 1, 3 — thiazolidine 1 — force Rubonic acid methyl ester In the same manner as in Example 42, the compound (0.20 g) obtained in Example 40 and 1,3-thiazolidine-12-force rubonic acid methyl ester · hydrochloride (0.067 g) were used. After reaction and treatment, the title compound was obtained as a colorless amorphous (0.084 g, 34%).

Elemental analysis: C _3S door I _3. N _{4 5} SF ₆ · 0.2C _e H ₁₄₀ (diisopropyl ether) · As 0.5H ₂₀

Calculated value (%): C, 57.05; H, 4.47; N, 7.35; S, 4.21; F, 15.96 _β

 Measured value (%): C, 57.13; H, 4.50; N, 7.40; S, 4.44; F, 14.82.

_{^{J H-NMR (CDC 1 3}} ) δ 0. 90- 0. 95 (3H, m), 1. 63 (1 H, m), 2. 09 (1 H, m), 2. 27- 2. 29 (1 H, m), 2.99-3. 1 1 (2 H, m), 3.21-- 3.24 (1 H, m), 3.41-- 3-66 (3H, m), 3 78-4.00 (4H, m), 4.10-4.50 (1H, m), 4.60-4.8

5.04-5.09 (1H, m), 5.40-5.44 (1H, m), 6.89-6.93 (1H, m), 7. 18—7.22 (1H, m), 7.37—7, 47 (5H, m), 7.61-7.65 (1H, m), 7.81 (1H, m), 8. 15—8.21 (l H, m). .

Example 70

 (a R. 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] _9-methinol-5-pheninole-1 2- [(thiomonolefolin-1-4-inole) canoleboninole] —8,9 1 0, 11—tetrahydro-7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1, 6, 1 3—dione

 Using the compound obtained in Example 40 (0.20 g) and thiomorpholine (0.037 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0.14 g). , 63%).

One _{NMR (CDC 1 3) δ 0.} 92- 0. 93 (3Η, m), 1. 68 (1 H, m),

2.04 (1 H, m), 2.26 (1 H, m), 2.78— 3.02 (5 H, m),

3.42-3.57 (2H, m), 3.95—4.15 (5H, m), 5.04—5.06 (1H, m), 5.39-5.43 (1H , m), 6.9 users 6.93 (1 H, m), 7.18-7.19 (1 H, m), 7.38-7.46 (5H, m), 7.62 -7.64 (1H, m), 7.81 (lH, m), 7.86-7.89 (1H, m). Example 71

3— [[(aR, 9R)-7-[3,5-bis (trifluoromethyl) benzyl]- 9-Methyl-1-5- (4-methylpheninole) -16,13-dioxo-1,6,8,9,10,1 1,13 ■ Kisahidro-1H 7- (1,4) diazosino [2,1- g] [1,7] Naphthyridin-2-yl] carbonyl] —3-oxopropionic acid methyl ester Carbonyl was added to a solution of the compound (0.31 g) obtained in Example 167 in HF (15 mL) solution. Diimidazole (0.27 g) was added, and the mixture was stirred at 50 for 3 hours. Magnesium chloride (0.072 g) and potassium monomethylmalonate (0.12 g) were added to the reaction solution, and the mixture was stirred at 80 ^ for 14 hours. The reaction solution was poured into water, and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to give the title compound as pale-yellow bristles (0.19 g, 57%).

 Melting point: 167-169: (recrystallized from ethyl ethyl isopropyl ether). Example 72

 (a R, 9R) —7— [3,5-Bis (trifluoromethyl) benzyl] _9-methino 1-2-methinolesulfanyl-5-phenyl-1 8,9,10,1 1-tetrahydro-1H -[1, 4] diazocino [2. 1 -g] [1, 7] naphthyridine-1,6,13-dione

 Example: To a solution of the compound (0.50 g) obtained in I1 in DMF (1 OmL) was added sodium thiomethoxide (0.20 g), and the mixture was stirred at 110C for 1 hour. After the reaction solution was cooled to room temperature, it was poured into water, and the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to give the title compound as colorless prisms (0.25 g, 49%).

 Melting point: 208-21 (recrystallized from ethyl ethyl diisopropyl acetate). Example 73

(a R, 9 R) -7- [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl No 1 2-Methinolesulphoninole 5-Feninole 8, 9, 10, 1 1-Tetrahydro 7 H— [1,4] Diazocino [2, 1-g] [1, 7] Naphthyridine 6, 13—Jeon

To a solution of the compound (0.15 _g ) obtained in Example 72 in THF (5 mL) was added 3-chloroperoxybenzoic acid (0.18 g), and the mixture was stirred at room temperature for 14 hours. After adding an aqueous solution of sodium thiosulfate to the reaction solution, the product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to give the title compound as colorless prisms (0.074 g, 49%).

 Melting point: 148-150 ^ (recrystallized from diethyl isopropyl ether). Example 74

 (a R, 9R) —7— [3,5-Bis (trifluoromethyl) benzyl] —9—Methyl-1-5-phenyl-2 -— (Pyridine-1-ylthio) -18,9,10,1 1-tetrahydro-7H- [1,4] diazino [2,1-g] [1,7] naphthyridine-6,13-dione

 To a solution of the compound obtained in Example 11 (0.23 g) in DMF (2 mL) was added lithium carbonate (0.27 g) and 4-mercaptopyridine (0.11 g). The mixture was stirred for 1 hour and further stirred at 5 O ^ C for 2 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 4: 6: 1) to give the title compound as a tan amorphous (0.12 g. 47%) , Was obtained as

Elemental analysis: as C ₃₀ H ₂₆ N ₄ O ₃ F ₆

 Calculated values (° /.): C, 59.80; H, 4.01; N, 9.30.

 Measured value (%): C, 59.53; H, 4.05; N, 9.33.

Example 75 2- [[(a R, 9R) —7— [3,5-bis (trifluoromethyl) benzyl] 1-9-methyl-1-6,13-dioxo-5-phenyl 6, 8, 9, 10 , 1 1, 1 3—

: Hexahydro-1-H 7- [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 12-yl] thio] benzoic acid

 To a solution of the compound obtained in Example 11 (0.23 g) in DMF (2 mL) was added lithium carbonate (0.24 g) and thiosalicylic acid (0.092 g), and the mixture was stirred at room temperature for 15 hours. Then, the mixture was stirred at 80 ^ for 3 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 4: 6: 1) to give the title compound as a tan amorphous (0.12 g, 47%) Was obtained as

Elemental analysis: as C ₃₆ H ₂₇ N ₄ 0 ₃ F ₆ -2H ₂ 0

 Calculated value (%): C, 57.83; H, 3.91; N, 5.62.

 Measured value (%): C, 57.84; H, 3.75; N, 5.61.

 Example 76

 (a R, 9 R) —2— (2-Aminophenoxy) 1 7— [3,5-bis (triphnoleromethyl) benzyl] 1 9—methyl-15-pheninole 8, 9, 10, 11, 11-tetrahydro One 7H— [1, 4] diabsino [2, 1-g] [1, 7] naphthyridine one 6, 1

3—Zeon

To a solution of the compound (0.23 g) obtained in Example 11 in DMF (2 mL) was added potassium carbonate (0.27 g) and 2-aminophenol (0.10 g), and the mixture was heated to 11 O). The mixture was stirred for 40 minutes. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydroxide solution and saturated saline, dried, and the solvent was distilled off under reduced pressure to obtain the title compound as yellow-brown prism crystals (0.21 g, 79%). Melting point: 258-26 (recrystallized from ethyl acetate-disopropyl ether) _D Example 77

N— [2 — [[(a R, 9R) -7- 9-methyl-1,6,13-dioxo-5-phenyl-2,8,9,10,1 1.13-hexahydro-7H— [1,4] diazosino [2,1-g ] [1, 7] naphthyridine-2-yl] oxy] phenyl] — N— (methylsulfonyl) methanesulfonamide

To a solution of the compound (0.10 _g ) obtained in Example 76 in ethyl acetate (5 mL) was added triethylamine (0.17 g) and methanesulfoyl chloride (0.070 g) under ice-cooling. ^ For 1 hour. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and the solvent was distilled off under reduced pressure to give the title compound as a yellow-brown amorphous (0.090 g, 76%).

Elemental analysis: C ₃₇ H ₃₂ N ₄ 0 ₇ S ₂ F ₆ · 1.00 H ₂ O

 Calculated value (%): C, 52.85; H, 3.96; N, 6.66.

 Measured value (%): C, 52.88; H, 4.36; N, 6.59.

Example 78

 (a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] 1-9-methyl-1-2-phenoxy-1-5-phenyl 2,9,10,11-tetrahydro 7H— [1, 4] diazocino [2, 1 -g] [1, 7] naphthyridine-1,6,13-dione

 To a solution of the compound obtained in Example 11 (0.15 g) in DMF (1 mL) was added lithium carbonate (0.15 g) and phenol (0.056 g), and the mixture was added at 135 "Ό for 2 hours. The reaction solution was poured into water, and the product was extracted with ethyl acetate.The organic layer was washed with an aqueous solution of sodium hydroxide and saturated saline, dried, and the solvent was distilled off under reduced pressure to give the title. The compound was obtained as colorless prisms (0.12 g, 79%).

Elemental analysis: as C _3B H ₂₇ N ₃ 〇 ₃ F ₆

 Calculated value (%): C, 64.51; H. 4.18; N, 6.45.

 Measured value (%): C, 64.37; H, 4.49; N, 6.45.

 Melting point: 258-260 (recrystallized from ethyl ethyl diisopropyl acetate). Example 79

(a R, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl Lu 5-Fe-1 2- (pyridine-1 3- ^ f-roxy) 1,8,9,10,1 1-Tetrahydro 7H— [1,4] Diazocino [2,1—g] [1,, '7] naphthyridine-1,6,1-dione

To a solution of the compound obtained in Example 11 (0.19 _g ) in DMF (1 mL) was added carbonated potassium (0.21 g) and 3-hydroxypyridine (0.095 g). ^ Was stirred for 2 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydroxide solution and saturated saline, dried, and then the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (0.17 g, 80%). Elemental analysis: C ₃₄ H ₂₆ N ₄ 0 ₃ F _s · 0.5 H ₂ 0

 Calculated value (%): C, 61.72; H, 4.03; N, 8.47.

 Measured value (%): C, 61 · 94; H, 4.05; N, 8.53.

 Melting point: 180-182 ^ (recrystallized from ethyl acetate-disopropyl ether). Example 80

 (a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] 1 2- (dimethylamino) 1-methyl-5-phenyl 1,8,9,10,11-tetrahydro 7H- [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione

 A 50% aqueous solution of the compound obtained in Example 11 (0.15 g) in dimethylamine (2 mL) was stirred at 180 for 14 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to give the title compound as colorless prisms (0.13 g, 85%).

 Melting point: 141-143 (recrystallized from ethyl ethyl isopropyl ether). Example 81

(a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] —9—methyl 2— (morpholine 1-41-yl) 1—5-phenyl 2,8,9,10 1 1—Tetrahi Dro-1.7H— [1,4] diazocino [2,1-g] [1,7] naphthyridine-1,6,1-dione

A solution of the compound (0.15 _g ) obtained in Example 11 in morpholine (2. OmL) was stirred at 180 at 14 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to give the title compound as colorless prisms (0.13 g, 85%). Melting point: 252-254: (recrystallized from ethyl acetate-diisopropyl ether)

 (a R, 9R) -7- [3,5-Bis (trifluoromethyl) benzyl] —2— (1 H—Imidazonole 1—Innole) 1 9—Methinole 1 5—Feninole 1 8,9 , 10, 11-tetrahydro- 1 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-6, 13-dione

 To a solution of the compound obtained in Example 11 (0.17 g) in DMF (0.5 mL) was added 60% oily sodium hydride (0.030 g) and imidazole (0.068 g). Stir for hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydroxide solution and saturated saline, dried, and then the solvent was distilled off under reduced pressure to obtain the title compound as a colorless amorphous (0.17 g, 89%).

Elemental analysis: C ₃₂ H ₂₅ N _s 0 ₂ F ₆ · 1.0 H ₂ O

 Calculated value (%): C, 59.72; H, 4.07; N, 10.88.

 Measured value (%): C, 59.92; H, 4.21; N, 10.81.

Example 83

 (a R, 9 R) — 2-Amino-7— [3.5-Bis (trifluoromethyl) benzyl] — 9-Methyl-1-phenyl-1,8,9,10,11-tetrahydro-1 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione

The compound (0.50 g) obtained in Example 40 and triethylamine (0.15m To a solution of L) in toluene (5. OmL) was added dibutenylphosphoryl azide (DPPA) (0.28 g), and the mixture was stirred with 11 O: for 4 days. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated brine, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give the title compound as colorless prisms (0.24 _g , 51%).

 Melting point: 1 66- 168 ^ (recrystallized from ethyl ethyl diisopropyl ether) Example 84

 N- [(a R, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] —9 —methyl-1,6,13-dioxo-1-5-phenyl 6,8,9,10 , 11, 13 ^^> Kisahidro 7H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridine

2-yl] benzoic acid amide

 To a solution of the compound (0.093 g) obtained in Example 83 and triethylamine (0.27 mL) in THF (1 OmL) was added benzoyl chloride (0.2 OmL), and the mixture was stirred at room temperature for 9 hours. . After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give the title compound as colorless prisms (0.1%).

084 g, 76%).

 Melting point: 160-162 ^ (recrystallized from ethyl acetate-diisopropyl ether)

 N-[(aR, 9R) -7- [3,5-bis (trifnorelolomethyl) benzyl] -9-methyl-1,6,1-dioxo-5-phenyl-1,6,8,9,10 , 1 1, 13-Hexahydro 1H-[1, 4] diazocino [2, 1-g] [1, 7] naphthyridin-1-2-yl] nicotinamide

To a solution of the compound (0.23 g) obtained in Example 83 in DMF (0.7 mL) was added 60% oily sodium hydride (0.032 g), and the mixture was stirred at room temperature for 5 minutes. Nico in the reaction solution Methyl formate (0.10 g) was added and stirred at room temperature for 4 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated brine, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 3: 3: 1) to give the title compound as a colorless amorphous (0.11 g, 40%) Was obtained.

Elemental analysis: C ₃₅ H ₂₇ N ₅ 0 ₃ F ₆ · 0 · 5H ₂₀

 Calculated value (%): C, 61.05; H, 4.10; N, 10.17.

 Measured value (%): C, 61.22; H, 4.19; N, 10.20.

Example 86

 (a R, 9R) _7—to [3,5-bis (trifluoromethyl) benzyl] —9-methyl-6,13-dioxo-5-phenyl-1 6,8,9,10,1,1,13 Kisahidro 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1 2— ^ f

 To a solution of the compound (0.23 g) obtained in Example 83 in DMF (1.0 mL) was added 60% oily sodium hydride (0.032 g), and the mixture was stirred at room temperature for 5 minutes. Dityl formate (0.30 g) was added to the reaction solution, and the mixture was stirred under ice cooling for 3 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and the solvent was distilled off under reduced pressure to obtain the title compound as pale yellow amorphous (0.13 g, 54%).

Elemental analysis: as C _{3 S} H ₂₄ N ₄ 0 _{3 Fe}

 Calculated value (%): C, 59.80; H, 4.01; N, 9.30.

 Measured value (%): C, 59.53; H, 4.05; N, 9.33.

Example 87

N— [(a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] 1 9 —methyl-1,6,13-dioxo-5-phenyl-1,6,8,9,10 1 1,13—Hexahydro 7H— [1, 4] diazocino [2, 1—g] [1, 7] Naphthyridine 2—> f] acetamide

To a solution of the compound (0.23 _g ) obtained in Example 83 in DMF (1.0 mL) was added 60% oily sodium hydride (0.032 _g ), and the mixture was stirred at room temperature for 5 minutes. Ethyl acetate (0.12 g) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and evaporated under reduced pressure to give the title compound as a pale yellow amorphous (0.13 g, 55%).

Elemental _{analysis: C 31 H 26 N 4 0} 3 F 6 · 0. 5 C 4 H 8 0 2 ( acetate Echiru) Calculated (%): C, 60. 39 ; H, 4. 25; N, 9 09.

 Measured value (%): C, 60.12; H, 4.26; N, 9.17.

Example 88

 N-[(aR, 9R) 1 7— [3,5-bis (trifluoromethyl) benzyl] —9-methyl-6,13-dioxo-5-phenyl-6,8,9,10,1 1, 13— ^ ^ Xahydrido 7H— [1,] diazocino [2, 1-g] [1, 7] naphthyridin-1-yl] butanamide

 To a solution of the compound obtained in Example 83 (0.23 g) in DMF (1.0 mL) was added 60% oily sodium hydride (0.032 g), and the mixture was stirred at room temperature for 5 minutes. Methyl butyrate (0.10 g) was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and the solvent was distilled off under reduced pressure to obtain the title compound as pale yellow amorphous (0.12 g, 47%).

Elementary analysis: as _{C 33 H 30 N 4 O 3} F e ■ 0. 5H 2 0

 Calculated value (%): C, 60.64; H, 4.78; N, 8.57.

 Measured value (%): C, 60.96; H, 4.66; N, 8.70.

Example 89

N— [(a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] 1 9 —Methyl-1,6,13-Dioxo-1 5—Feniru 6,8,9,9 To 10, 1 1, 13— Kisahi Draw 7H— [1, 4] diazocino [2, 11 g] [1, 7] naphthyridine 1-2-yl] 12-methoxyacetamide

 To a DMF (0.5 mL) solution of the compound (0.20 g) obtained in Example 83 was added 60% oily sodium hydride (0.032 g), and the mixture was stirred at room temperature for 5 minutes. To the reaction solution was added methyl methoxyacetate (0.10 g), and the mixture was stirred at room temperature for 2 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated brine, dried, and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow amorphous (0.16 g, 73%).

Elementary analysis: as _{C 32 H 28 N 4 0 4} F e · 0. 5H 2 0

 Calculated value (%): C, 59.44; H, 4.36; N, 8.67.

 Measured value (%): C, 59.30; H, 4.35; N, 8.57.

Example 90

 N— [(a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] 1 9 —Methyl-6,13-Dioxo-5-Feninole 6, 8,9 10,1 1,13—Hexahydro-7H— [1,4] diazosino [2,1 -g] [1,7] Naphthyridine-one-one-half-fl] bidiridine-one-one-carboxamide

 To a solution of the compound obtained in Example 83 (0.26 g) in DMF (1. OmL) was added 60% oily sodium hydride (0.024 g), and the mixture was stirred at room temperature for 30 minutes. Ethyl 4-piperidinecarboxylate (0.16 g) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow amorphous (0.16 g, 50%).

Elemental analysis: C ₃₅ H ₃₃ N ₅ 0 ₃ F ₆ · 1.5 H ₂ 0

 Calculated value (%): C, 58.98; H, 5.09; N. 9.83.

 Measured value (%): C, 59.23; H, 4.83; N, 9.64.

Example 91

1-Acetyl-N— [(a R, 9R) 1 7— [3,5-bis (trifluoromethyl) Benzyl] 1-9-methyl-6,13-dioxo-1-5-phenyl-1,6,8,9,10,11,13-hexahiDraw 7H— [1,4] diazosino [2,1-g] [1,7 ] Naphthyridine 1-2] piperidine 1-41-carboxamide

 To a solution of the compound (0.17 g) obtained in Example 90 in pyridine (1. OmL) was added anhydrous anhydride (0.5 mL), and the mixture was stirred at 50 to 55 ^ for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel ^ column chromatography (ethyl acetate: hexane: methanol = 3: 3: 1) 'to give the title compound as a colorless amorphous (0.07 g , 43%).

Elementary analysis: as _{C 37 H 35 N 5 0 4} F 6 · 1. 5H 2 0

 Calculated values (./.): C, 58.88; H, 5.07; N, 9.28.

 Fixed value (%): C, 58.99; H, 5.00; N, 9.05.

Example 92

 N- [(a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzinole] 1 9 —Methyl-6,13-Dioxo-1 5—Furou 6, 8, 9, 10 , 11, 13 — ^-Kisahi draw 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridin-1-yl] methanesulfonamide

 To a solution of the compound obtained in Example 1 (0.24 g) in DMF (2.OmL) was added potassium carbonate (0.28 g) and methanesulfonamide (0.095 g) at 145 ° C. 2. Stirred for 5 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 4: 6: 1) to give the title compound as a pale-yellow amorphous (0.10 g, 38%) .

Elementary analysis: as _{C 30 H 26 N 4 0 4} SF 6

 Calculated value (%) C, 54.46; H, 4.11 ;, 8.47.

 Measured value (%) C, 54.17; H, 3.83; N, 8.30.

Example 93 (a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] -1-9-methyl-1,2,5-diphene-lu 8,9,10,11-tetrahydro-7 H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridine-1,6,13-dione

 To a solution of the compound obtained in Example 11 (0.20 g) in 1,4-dioxane (5. OmL) was added phenylpolonic acid (0.077 g), tetrakis (triphenylphosphine) palladium (0.20 g). 042 g) and potassium carbonate (0.084 g) were added, and the mixture was stirred with lO Ot for 14 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound as colorless prisms (0.19 g, 82%).

 Melting point: 253-255 ^ (recrystallized from ethyl ethyl diisopropyl ether). Example 94

 (a R, 9R) 1 7— [3,5-bis (trifluoromethyl) benzyl] 1 9—methyl 5-5-phenyl 2— (pyridine 13-yl) 1,8,9,10 1 1—Tetrahedral 7H— [1.4.] Diazocino [2, 1— g] [1, 7] Naphthyridine-1, 6, 13—dione

 To a solution of the compound (0.24 g) obtained in Example 11 in 1,4-dioxane (5. OmL) was added pyridine-13-boronic acid (0.086 g), tetrakis (tripheninolephosphine) palladium ( 0.042 g) and a 2M aqueous sodium carbonate solution (1.0 mL) were added, and the mixture was stirred at 100 * C for 14 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 4: 10: 1) to give the title compound as a pale-yellow amorphous (0.14 g, 52%). Was.

Elementary analysis: as _{C 34 H 26 N 4 0 3} SF 6 · 0. 5Η 2 Ο · 0. 5C 3 H e O ( acetone) Calculated value (%): C, 63. 20 .; H, 4.48; N, 8.30.

 Measured value (%): C, 63.21; H, 4.52; N, 8.07.

Example 95

 (a R, 9 R)-7-[3,5-Bis (trifluoromethyl) benzyl] 1-9-methyl-5-phenyl 2- (1H-tetrazole-5-yl) 1,8,9 , 10, 11 1 Tetrahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1, 6, 13-dione

 To a solution of the compound obtained in Example 13 (1.0 g) in DMF (26 mL) was added sodium azide (0.14 g) and triethylamine hydrochloride (0.26 g), and the mixture was stirred at 100 ^ for 50 hours. Stirred. The reaction solution was poured into water, and the mixture was added with hydrochloric acid so that the pH became 112. Then, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (0.93 g, 86%).

 Melting point: 160-162 (recrystallized from ethyl acetate-disopropyl ether). Example 96

 (a R, 9 R) -2-(1-Benzyl-1H-tetrazo-1-yl 5-yl) 17- [3,5-bis (trifluoromethyl) benzyl] -9-methyl-5-phenyl 8, 9, 10. 1 1—Tetrahydro 7H— [1,4] diazocino [2, 1-g] [1, 7] naphthyridine-1,6,1-dione

To a DMF (1.0 mL) of the compound (0.20 g) obtained in Example 95 was added 60% oily sodium hydride (0.013 g), and the mixture was stirred at 0 for 1 hour. Benzyl chloride (0.40 g) was added to the reaction solution, and the mixture was stirred at 100 for 14 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by reversed-phase silica gel column chromatography (acetonitrile: water-7: 3) to give the title compound as a colorless amorphous (0.08 lg, 35%). Elementary analysis: as _{C 37 H 28 N 7 0 2} F 6 '1. 5H 2 0 Total value (%): C, 59.67; H, 4.33; N, 13.17; F, 15.31. Measured value (%): C, 59.69; H, 4.20;, 13.14; F, 15.26. Example 97 '

 (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] — 9-methyl 2- (1-methyl-1-H-tetrazole-5- ^ fur) -1-5-phenyl 1, 8, 9, 1 0, 1 1—tetrahydro 1 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1, 6, 1 3—dione

 60% oily sodium hydride (0.013 g) was added to DMF (1. OmL) of the compound (0.20 g) obtained in Example 95, and the mixture was stirred at 01C for 1 hour. Methyl iodide (0.045 g) was added to the reaction solution, and the mixture was stirred at 100 ° for 14 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated brine, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by reversed-phase silica gel column chromatography (acetonitrile: water = 7: 3) to give the title compound as a colorless amorphous (0.12 g, 57%).

Elemental analysis: C ₃ , H _2S N ₇ 0 ₂ F ₆ · 0.5H ₂ 0

 Calculated value (%): C, 57.23; H, 4.03; N, 15.07; F, 17.52. Measured value (%): C, 57.09; H, 4.08; N, 14.84; F, 17.51. Example 98

 (a R, 9 R) -7- [3,5-Bis (trifluoromethyl) benzyl] — 2- (1-isopropyl-1 H-tetrazol-5-yl) -1-9-methyl-1-5-phenyl-1 8, 9, 1 0, 1 1—Tetrahydro 7 H— [1.4] diazocino [2, 1-g] [1, 7] naphthyridine-1 6, 1 3—dione

60% oily sodium hydride (0.013 g) was added to DMF (1. OmL) of the compound (0.20 g) obtained in Example 95, and the mixture was stirred for 1 hour. Isopropyl iodide (0.054 g) was added to the reaction solution, and the mixture was stirred with 10 O: for 14. hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue is reverse-phase silica gel. Separation and purification by column chromatography (acetonitrile: water = 7: 3) yielded the title compound as a colorless amorphous (0.085 _g , 40%). Elemental analysis: C ₃₃ H ₂₉ N ₇ 〇 ₂ F ₆ · 0 · 2 C ₂ H ₃ N (acetonitrile) as 0.7H ₂ o

 Calculated value (%): C, 58.10; H, 4.53; N, 14.61; F, 16.51. Measured value (%): C, 58.34; H, 4.66; N, 14.37; F. 16.30.

-... NMR (CDC 1 3) δ 0. 91-0 96 (3Η, m) 1. 70-1 81 (7 H, m), 2. 00-2 04 (1 H, m), 2. 27-2. 38 (1 H, m), 2.98—3.02 (1 H, m), 3.37-3. 58 (2 H, m), 3.97-4. 0 1 (lH , M), 5.08-5.22 (2H, m), 5.42— 5.45 (1 H, m), 6.95— 6.97 (1 H, m), 7.19— 7.23 (1 H, m), 7.40- 7.50 (5H, m), 7.68— 7.70 (1 H, m), 7.81 (1 H, m), 8.39 — 8.41 (1H, m).

Example 99

 (4 R)-2-[(a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] —9—methinole 6, 13-dioxo-5-phenyl-1 6,8 9,10,1 1, 1 3 1 ^ · Kisahi Draw 7H— [1,4] diazocino [2,1— g] [1,7] naphthyridine 1 2— ^ T 1] — 4,5—dihydro — 1,3-Thiazoyl 4-carboxylate

 To a solution of the compound obtained in Example 13 (0.50 g) and sodium bicarbonate (0.43 g) in ethanol (20 mL) was added L-cysteineethyl ester ′ hydrochloride (0.23 g), and the mixture was added at room temperature. For 14 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound as a pale-yellow amorphous (0.52 g, 83%).

^ -NM (CDC) ₃ ) δ 0.91 (3Η, d, J = 6.9 Hz), 1.33 (3 H, t, J = 6.9H z), 1.50-1.80 (1 H, m), 2. 00-2.40 (2Ή, m), 2.99 (1 H , D, J = 15.3 Hz), 3.42 (1H, dd, J = 15.0, 10.5Hz), 3.54 (1H, dd, J = 1. 4, 11.1 Hz), 3.60—3.72 (2H, m) .3.97 (1H, dd, J = 15.0, 10.5Hz), 4. 2 9 (2Ή, q, J = 7.1 Hz), 5.06 (1H, dd, J = 14.1, 5.1 Hz), 5.35 (1H, t, J = 9.9Hz), 5.4.2 (1H, d, J = 15.0Hz), 6.91 (1H.d, J = 7.5Hz), 7.19 (1 H, t, J = 7.2 Hz), 7.36-7.50 (4 H, m), 7.58 (1 H, d, J = 8.7 Hz), 7.8 1 (1 H, s), 8.23 (lH, d, J = 8.7Hz). Example 100

 2-[(a R, 9)-7-[3,5-bis (trifluoromethyl) benzyl] 1-9-methinole 6,13-dioxo-5-phenyl-1,6,8,9,10, 1 1,1 3—Hexahydro 1H— [1,4] diazosino [2,1—g] [1,7] Naphthyridine-1-2-inole——1,3-Thiazoinone 4-force Echinorestenore

Example 9 Manganese dioxide (0.10 g) was added to a solution of the compound (0.1 O g) obtained in Example 9 in chloroform (5 mL), and the mixture was stirred at 80 at 0.5 hours. After filtering off the insolubles, the filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow amorphous (0.062 _g , 61%).

'H-NMR (CDC) ₃ ) 0.99 (3 H, d, J = 6.9 Hz), 1.43 (3 H, t, J = 7.2 Hz), 1.60 -1.80 (1 H, m), 2.0 0-2.40 (2H, m), 3.00 (1 H, d, J = 15.3 Hz), 3.45 (1 H, dd, J = 1 5.3, 9.9 Hz, 3.56 (1 H, dd, J = 14.4, 11.1 Hz), 3.98 (1 H, d, J = 1.7 Hz), 4.45 (2H, q, J = 7.1 Hz), 5.08 (1H, dd, J = 1.7, 5.7Hz) , 5.43 (l H, d, J = 15.0 Hz), 6.91 (1 H, d, J = 7.5 Hz), 7.2 1 (1 H, t, J = 5.OHz), 7.36-7.54 (5H, m), 7.64 (1H, d, J = 9.0Hz), 7.82 (1H, s) , 8.33 (1 H, s), 8.49 (1 H, d, J = 9. OHz).

Example 101

 (4 R) -2- [(aR, 9R) — 7— [3,5-bis (trifnoroleolomethyl) benzyl] 1 9-methyl-6,13-dioxo-5-phenyl 6, 8, 9 , 10,11,1 3— ^ ■ xahydro-7H— [1,4] diazosino [2,1-g] [1,7] naphthyridine-1Tl] 1,4,5-dihydro-1,3 —Thiazole-4-carboxylic acid To a solution of the compound obtained in Example 13 (0.50 g) in water (1 OmL) and acetonitrile (1 OmL), add L-cysteine (0.17 g), Stirred for hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent was distilled off under ^ ff to give the title compound as a pale yellow amorphous (0.35 g, 59%).

'H-NMR (DMSO-d ₆ ) δ 0.86 (3Η, d, J = 6.OHz), 1.40 — 1.60 (1 H, m), 2.00-2.20 (2H, m), 3.10-3.80 (5H, m), 4.28 (1H, d, J = 14.7Hz), 4.78-4.82 (1H, m), 5.07 ( 1 H, d, J = 13.8H z), 5.17 (1 H, t, J = 10.

2 Hz), 6.92 (2H, s) ike), 7.18--7.22 (1H, m), 7.

30-7. 40 (2H, m), 7.42-7. 50 (1H, m), 7.76 (2H, s), 7.79 (lH, s) 8.1 9—8.23 (lH, m).

Example 102

 (a R, 9 R) -7- [3,5-bis (trifluoromethyl) benzyl] — 2- (4,5-dihydro-1,3-thiazol-2-^^)-1-9-methyl 1,5-feru-8,9,10,1 1-tetrahydro 7H— [1,4] diazosino [2,1—g] [1,7] naphthyridine 1,6,13-dione

Cysteamine (0.063 g) was added to a solution of the compound (0.30 g) obtained in Example 13 in water (6 mL) and acetonitrile (6 mL), and the mixture was stirred at 361 for 23 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (vinegar). The title compound was obtained as colorless prisms (0.16 g, 49%) by separation and purification with ethyl acetate: hexane = 1: 1).

 Melting point: 256-258 (recrystallized from ethyl acetate-disopropyl ether). Example 1 0 3

 (a R, 9R) i 7— [3,5-bis (trifnorelolomethyl) benzyl] — N '—hydroxy-1 9-methinole 6,1 3 -dioquinol 5-fenelu 6,6,8,9 1 0,1 1, 1 3 一 ^ ■ oxahydro-7H— [1,4] diazocino [2,1—g] [1,7] naphthyridine-12-carboxyimidamide

 To a solution of the compound (1.75 g) obtained in Example 13 in methanol (15 mL) was added a solution of xylamine oxalate (0.42 g) and triethylamine (0.51 g). ) And stirred at 70 ^ for 0.5 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless amorphous (1.88 g, 99%).

Elementary analysis: as _{C 30 H 25 N s O 3} F 6 · 0. 5H 2 0

 Calculated value (%): C, 57.51; H. 4.18; N, 11.18.

 Measured value (%): C, 57.34; H, 4.05; N, 1 1.06.

Example 1 04

 (a R, 9 R) -Ν'-acetoxy-1 7— [3,5-bis (trifnoroleolomethinole) benzyl] _ 9-methyl-6,13-dioxo-5-phenyl 6,8,9 , 10,11,1 3-hexahi draw 7Η— [1,4] diazocino [2,1—g] [1,7] naphthyridine-12-carboxyimidamide

 To a solution of the compound (0.25 g) obtained in Example 103 in pyridine (1.5 mL) was added anhydrous acetic acid (1. OmL), and the mixture was stirred at 100 for 1 hour. After concentration under reduced pressure, the residue was poured into water, and the product was extracted with ethyl acetate.The organic layer was washed with water, dried, and the solvent was distilled off under reduced pressure to give the title compound as a colorless amorphous (0.2%). 0 g, 76%).

Elementary analysis: as _{C 32 H 27 N 5 0 4} F 6 771-

Calculated value (%): C, 57.49; H, 4.22 ;, 10.47.

 Measured value (%): C, 57.28; H.4.44; N, 10.34.

Example 105

 (a R, 9 R) -7- [3,5-bis (trifluoromethyl) benzyl] —9-methyl 2- (5-methyl-1,2-, 4-oxadiazo-one-3-yl) 1 5—Feninole —8, 9, 10, 1 1—Tetrahydro 7H— [1, 4] diazocino [2, 1-g]

 [1, 7] naphthyridine-1,6,13-dione

 To a solution of the compound obtained in Example 104 (0.37 g) in trimethyl orthoacetate (2.0 mL) was added p-toluenesulfonic acid monohydrate (0.012 g), and the mixture was stirred at room temperature for 20 hours. did. The precipitated crystals were collected by filtration to give the title compound as colorless prisms (0.30 g, 78%).

 Melting point: 277-279 ^ (recrystallized from ethyl acetate-disopropyl ether). Example 106

 (a R, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl] 1 9—methyl 1 2— (1,2,4-oxadiazo-1-lu 3-yl) 1 5— Hueneru 8, 9, 1 0, 1 1—tetrahydro 7H—. [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1 6, 13-dione

 To a solution of the compound (0.62 g) obtained in Example 103 in trimethyl orthoformate (1 OmL) was added P-toluenesulfonic acid monohydrate (0.019 g), and the mixture was stirred at room temperature for 20 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure to give the title compound as a colorless amorphous (0.40 g, 71%).

Elemental analysis: C ₃₁ H ₂₃ N ₅ 0 ₃ F ₆ '0.5 H ₂ 0

 Calculated value (%): C, 58.49; H, 3.80; N, 11.00.

 Measured value (%): C, 58.68; H, 3.74; N, 10.75.

Example 107

(a R, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl L-5-phenyl-1-2- [5- (trichloromethyl) -1-1,2,4-oxaziazol-1-3-yl] —8, 9, 10, 1 1—tetrahydro-1-H 7 [—1,4] Giazosino

 [2, 1-g] [1, 7] naphthyridine-1,6,13-dione

 To a solution of the compound (1.63 g) obtained in Example 103 in toluene (12 mL) was added trichloroacetic anhydride (1.55 g), and the mixture was stirred at 14 Ot: for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in DMF (2. OmL). A mixture of pyridine (1.0 mL) and water (0.2 mL) was added to the reaction mixture under ice cooling. After stirring at room temperature for 0.5 hour, the product was extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (1.68 g, 86%).

 Melting point: 276-278 (recrystallized from ethyl ethyl diisopropyl ether). Example 108

 (a R, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] 1- 9-methyl-1- 5-phenyl-1- 2— [5-pyrrolidine-1, 2,4-oxoxadiazo-3 —Yl] — 8, 9, 10, 1 1—tetrahydro 7H— [1, 4] diazosino [2, 1-g] [1, 7] naphthyridine-1,6,13—dione

 Pyrrolidine (1.0 mL) was added to a solution of the compound (0.22 g) obtained in Example 107 in methanol (3, OmL), and the mixture was stirred at 501 C for 0.5 hours. The title compound was obtained as colorless prisms (0.19 g, 89%) Melting point: 287-289 * ^ (recrystallized from methanol-diisopropyl ether) Example 109

 N '-[3-[(aR, 9R) -7- [3,5-bis (trifluoromethyl) benzinole]] — 9-methyl-1-6,] · 3-dioxo-5-phenyl-2 , 8, 9, 10, 1 1, 13 ■ ^ ■ ヒ ヒ 7 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1- 2-inole] — 1, 2, 4 —Oxaziazol-5-yl] Benzenecarboximidamide

To a solution of benzamidine 'hydrochloride (0.16 g) in methanol (3. OmL) was added a 28% solution of methanolic methanol (0.19 g) at room temperature. Example 10 The compound (0.23 g) obtained in 7 was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. After the organic layer was washed with water and dried, the soot was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (ethyl hexane: hexane: methanol = 4: 6: 1) to give the title compound as a colorless amorphous (0.061 g, 27%). Was.

Elementary analysis: as the _{C 38 H 2B N 7 O 3} F 6 '0. 5H 2 O' 0. 3C 3 H 6 0 ( Aseton)

 Calculated value (%): C, 60.51; H, 4.15; N, 12.70.

 Measured value (%): C, 60.46; H, 4.15; N, 12.45.

 R f = 0.33 (ethyl acetate: hexane: methanol = 2: 4: 1).

Example 1 10

 (a R, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] —9—methinole-2- (5-oxoquino-4,5-dihydro-1,2,4-oxaziazinole I 3— ^ (Nore) ― 5—Feniru 8, 9, 10, 1 1—Tetrahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] Naphthyridine 1, 6, 1 3—Zeon

 The residue obtained in Example 109 was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol-4: 6: 1) to give the title compound as a colorless amorphous (0.050) g, 26%).

Elementary analysis: as _{C 31 H 23 N 5 0 4} F 6 · 2. 0H 2 O

 Calculated value (%): C, 54.79; H, 4.00; N, 10.31.

 Measured value (%): C, 54.53; H, 3.70; N, 10.11.

 Rf = 0.26 (ethyl acetate: hexane: methanol-2: 4: 1).

Example 1 1 1

(a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl Ν '— [(methylsulfonyl) oxy] —6,13-dioxo-5-phenyl I 6, 8, 9, 10 '1 1, 13 1 ^ ^ xahydro 1 7Η— [1, 4] diazocino [2, 1-] [1, 7] naphthyridine 1 2-dipropoxyimidamide Triethylamine (0.10 g) and methanesulfonyl chloride (0.10 g) were added at room temperature to a solution of the compound obtained in Example 103 (0.40 g) in ethyl sulphate (15 mL). Stirred for hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (0.30 g, 56%).

 Melting point: 1 51-153 ^ (recrystallized from ethyl ethyl isopropyl ether). Example 1 1 2

 (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzinole] 1 9-methylone 6, 13-dioxo-5-phenyl 2, 8, 9, 10, 1 1, 13—Hexahi Draw 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1-2-lucyanamide

 To a solution of the compound obtained in Example 11 (1.39 g) in THF (7. OmL) was added 2N aqueous sodium hydroxide solution (3, OmL) at 0, and the mixture was added at room temperature and stirred for 13 hours. After the reaction solution was poured into a saturated aqueous solution of ammonium chloride, the product was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure to obtain the title compound as pale yellow prism crystals (1.20 g, 99%).

 Melting point: 248-250 (recrystallized from methanol).

Example 1 13

 N- [(a R, 9R) — 7— [3,5-bis (trifluoromethylinole) benzyl] —9 —methyl-6,13-dioxo-5-phenyl-1,6,8,9,10 1 1, 13—Hexahi draw 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine

2-yl] one N ', hydroxyguanidine

A solution of the compound obtained in Example 12 (0.60 g) in methanol (1 OmL) was sufficiently degassed, and triethylamine (0.30 niL) was added thereto. Droxylamine 'hydrochloride (0.14 g) was added, and the mixture was stirred at room temperature for 24 hours.The reaction solution was concentrated under reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. After washing with water and drying, the solvent is distilled off under reduced pressure to give the title compound. W

Rufas (0 · 59 g, 93%).

Elemental analysis: Calculated as _{C 30 H 26 N 6 O 3} F 6 · 0 · 25C 4 H 8 O z ( acetate Echiru) (%): C, 56. 88; H, 4. 31; N, 12. 84.

 Measured value (%): C, 56.70; H, 4.30; N, 12.61.

Example 1 14

 (a R, 9R) —7— [3,5-bis (trifluoromethyl) benzyl] —9-methyl 5-phenyl-1 2-— [[5- (trifluoromethyl) -1,2,4 —Oxazolyl-3-inole] amino Zeon

 Trifluoroacetic anhydride (0.55 mL) was added to a solution of the compound (0.35 g) obtained in Example 13 in toluene (5. OmL), and the mixture was stirred at 10 for 1 hour. Further, methanol (2. OmL) was added, and the mixture was stirred for 0.5 hour. After the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate, the product was extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 6: 4: 1) to give the title compound as colorless prisms (0.1%, 27%). .

 Melting point: 324-326 ^ (recrystallized from chloroform-methanol).

Example 1 15

 N- [(a R, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] 1-9-methinole 6, 13-dioxo-5-pheninolee 6, 8, 9, 10, 1 1, 13—Hexahi Draw 7H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridine —2 T-nore) —N— (5-methyl-1,2,4-oxoxadizole 1-3 Le) acetamide

To a solution of the compound (0.70 g) obtained in Example 13 in acetic anhydride (2.0 mL) was added methanesulfonic acid (0.082 g), and the mixture was stirred at 145 for 3.5 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure to give the title compound as pale yellow prism crystals (0.45 g, 59%). Was obtained.

 Melting point: 310 (decomposed) (recrystallized from ethyl acetate).

Example 1 1 6

 (a R 9 R) — 7— [3,5-Bis (trifluoromethyl) benzyl] — 9-metreu-5—Feninole-6, 8, 9, 10, 11, 13—Hexahydro 1 7 H— [1,4] diazosino [2,1—g] [1,7] naphthyridine-12-carbohydrazone amide THF (6.OmL) and 1.17 g of the compound obtained in Example 13 (1.17 g) Hydrazine hydrate (1. OmL) was added to the methanol (7.5 tnL) solution, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue to give the title compound as a pale-yellow amorphous (1.21 g, 95%).

As Elemental analysis _{■ · C 30 H 2e N 6} O 2 F 6 · H 2 0

 Calculated value (%): C, 56.78; H, 4.45; N, 13.24.

 Measured value (%): C, 56.94; H, 4.33; N, 13.22.

Example 117

 (a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] —9-methyl-1-N '— (1-methylethylidene) -1 6,13-dioxo-5-phenyl-1 6, 8, 9, 1 0, 1 1, 1 3 "Kisahydro 1H_ [1, 4] diazocino [2, 1-g]

 [1, 7] Naphthyridine-1 2-carbohydrazoneamide

A solution of the compound obtained in Example 13 (0.50 g) in THF (3. OmL) and methanol (3. OmL) was added to hydrazine hydrate (0.5 mL) in methanol (5.0 mL). The solution was added with and stirred at room temperature for 24 hours. After concentrating the reaction solution under reduced pressure, ethyl acetate was added to the residue. After the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in acetone (2 OmL), allowed to stand for 30 minutes, and concentrated under reduced pressure to give the title compound as a colorless amorphous (0.48 g, 86%). Elementary analysis: as _{C 33 H 30 N 6 O 2} F e · 0. 5H 2 0

 Calculated value (%): C, 59 · 55; H, 4.69; N, 12.63.

Measured value (%): C, 59.68: H, 4.79; N, 12.58. Conduct ^ 1 1 8

 (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] 1 N, 1 [2-hydroxy-1- 1- (hydroxymethyl) ethylidene] 1 9-methyl-1 6,1 3-dioxo-5-phenyl 6,8,9,10,11,13-hexahydro 7H— [1,4] diazosino [2,1—g] [1,7] naphthyridine 2 _ Carbohydrazone Ami

 ,

 Example 1 To a solution of the compound (0.25 g) obtained in 16 in methanol (2. OmL) was added 1,3-dihydroxyacetone dimer (0.18 g). Stirred for hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure to give the title compound as pale-yellow prism crystals (0.18 g, 65%).

 Melting point: 209—211 (recrystallized from chill).

Example 1 1 9

 (a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] -1-2_ (5,6-dioxo-1,4,5,6-tetrahydro-1,2,4— Triazine-3— ^ f1) 9-methyl-5-phenyl 8,9,10,11-tetrahydro7H— [1,4] diazosino [2,1-g] [1,7] naphthyridine 6, 1 3—Zeon

 Example 11 Dimethyl oxalate (0.17 g) and 28% sodium methoxide were added to a solution of the compound (0.31 £) obtained in 16 (0.1 OmL) and methanol (1 OmL) in a solution. / Methanol solution (0.29 g) was added and stirred at room temperature for 1.5 hours. The reaction solution was adjusted to pH 2 and the precipitated crystals were collected by filtration to give the title compound as pale yellow prisms (0.24 g, 68%).

 Melting point: 2 15—2 17 (ethyl acetate—recrystallized from water).

Example 1 2 0

(a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] — 9-methyl-1-2- (1-methyl-1,5,6-dioxo-1,4,5,6 —Tetrahydr Draw 1,2,4-Triazine-1-3-yl) -1-5-Phenyl-1,8,9,10,11—Tetrahydr Draw 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1,6,1-dione

 To a DMF (0.50 mL) solution of the compound obtained in Example 19 (0.18 g) was added 60% oily sodium hydride (0.080 g), and then methyl iodide (0.30 mL) was added. ) Was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with black-mouthed form. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure to obtain the title compound as pale yellow prism crystals (0.13 g, 73%).

 Melting point: 196-198 ^ (recrystallized from black mouth formaldehyde).

Example 121

 (a R, 9 R) -7- [3,5-Bis (trifluoromethyl) benzyl] -1- (1-, 4-dimethyl-5,6-dioxo-1,4,5,6-tetrahydro 1, 2,4-triazine-1-3-yl) 1-9-methyl-5-phenyl 8, 9, 10, 11-tetrahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] Naphthyridine-1,6,3-dione

 Example 1 To a solution of the compound obtained in Example 19 (0.22 g) in DMF (3. OmL) was added methyl iodide (0.2 OmL) and potassium carbonate (0.28 g) at room temperature for 20 hours. Stirred. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (0.13 g, 58%).

 Melting point: 334-336¾ (recrystallized from ethyl acetate-diisopropyl ether). Example 122

Acetic acid [(a R, 9R) 1 7— [3,5-bis (trifluoromethyl) benzyl] —9 monomethyl-1,6,13-dioxo-5-phenyl-1 6,8,9,10 1 1 , 13— ^ «Xahydrido 7H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridin-1 2-yl] methyl ester

To a solution of the compound obtained in Example 12 (6.24 g) in water (5 OmL) and acetonitrile (10 OmL) was added magnesium monoperoxyphthalate hexahydrate (12.9 g). Was added at room temperature and stirred for 4 days. After adding an aqueous solution of sodium thiosulfate to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline and dried, and then the solvent was distilled off under reduced pressure.

 Acetic anhydride (3 OmL) was added to a solution of the obtained residue in acetic acid (3 OmL), and the mixture was stirred at 100 with 0.5 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate (5 OmL). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (diethyl acetate: hexane = 4: 1) to give the title compound as a pale-yellow amorphous (6.21 g, 91%).

_{LH-NMR (CDC 1 3)} δ 0. 91 (3Η, d, J = 6. 6Hz), 1. 50-2. 40 (3H, m), 2. 97 (1 H, d, J = 1 5 2Hz), 3.35—3.59 (2H, m), 3.96 (1H, d, J = 1.8Hz), 5.09 (1H, dd, J = 14.8, 5.8Hz), 5.43 (1H, d, J = 15.2Hz), 5.44 (2H, s), 6.90 (1H, d, J = 7.6Hz), 7.18 (lH , t, J = 7.6 Hz), 7.30-7.50 (5H, m), 7.54 (2H, s), 7.80 (1H, s).

Example 123

 (a R, 9R) -7- [3,5-Bis (trifluoromethyl) benzyl] 12- (hydroxymethyl) 19-methyl-5-phenyl 8,9,10,11-tetrahydro 1 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1, 6, 13— dione

To a solution of the compound (6.21 g) obtained in Example 122 in methanol (10 OmL) was added a 1M sodium methoxide Z methanol solution (2. OmL) at room temperature, and the mixture was stirred for 1 hour. After a 2 N aqueous hydrochloric acid solution (1.0 mL) was added to the reaction solution, the solvent was distilled off under reduced pressure. After the obtained residue was dissolved in ethyl acetate (5 OmL), the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried, and the solvent was distilled off under reduced pressure. The resulting residue was separated by silica gel column chromatography (ethyl acetate: hexane = 4: 1). The title compound was obtained as pale yellow prism crystals (5.38 g, 92%) by purification.

 Melting point: 137-139 ^ (recrystallized from ethyl acetate-> xane).

Example 124

 [(a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] —9—methyl—6,13—dioxo-5—phenyl 6, 8, 9, 10, 1 1,13—Hexahydro 7H_ [1, 4] diazocino [2, 1-g] [1, 7] naphthyridin-1 2-yl] acetonitrile

 To a solution of the compound (0.20 g) obtained in Example 123 and triethylamine (0.07 mL) in THF (3.0 mL) was added methanesulfonyl chloride (0.040 mL) at 0, and the mixture was stirred for 1 hour. did. Triethylamine (0.071 mL) and methanesulfonyl chloride (0.040 mL) were further added to the reaction solution, and the mixture was stirred at 0 for 1 hour. The reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried, and then the solvent was distilled off under reduced pressure.

 Sodium cyanide (0.098 g) was added to a solution of the obtained residue in DMSO (3. OmL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to give the title compound as pale-yellow prism crystals (0.11 g, 54%).

 Melting point: 131-133: (recrystallized from ethyl acetate-hexane). .

Example 125

 (a R, 9R) 1 7— [3,5-bis (trifluoromethyl) benzyl] —2— (fluoromethyl) 1 9—methyl-15-phenyl 8, 9, 10, 11—tetrahydro One 7 H— [1, 4] diazocino [2, 1— g] [1, 7] Naphthyridine 1, 6, 13-dione

Dissolution of the compound (0.15 g) obtained in Example 123 in dichloromethane (1.5 mL) [Bis (2-Methoxyxyl) amino] -sulfur trifluoride (0.15 mL) was added to the solution at 1: 78, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to give the title compound as colorless amorphous (0.074 g, 49%).

_{^{! H-NMR (CDC 1 3}} ) 50. 91 (3 H, d, J = 6. 6H z), 1. 60- 1. 80 (1 H, m), 2. 00- 2. 40 (2H, m), 2.98 (1 H, d, J = 15.0 Hz), 3.43 (1 H, dd, J-16.0, 1 1.2), 3.54 (1 H, dd, J = 14.6, 11.4), 3.96 (1H, d, J = 1 5.OHz), 5.08 (1H, dd, J = 14.4, 5.2Hz), 5.43 (1 H, d, J = 1 5. OH z), 5.72 (2 H, d, J = 46.6 H z), 6.88—6.95 (1 H, m), 7.19 (1H, t, J = 7.3Hz), 7.34-7.50 (5H, m), 7.61 (1H, d, J = 8.4Hz), 7 81 (1H, s).

Example 1 26

 (a R, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] —2- (methoxymethyl) -1-9-methyl-5-phenyl 8,9,10 1 1—tetrahydro-1 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione

 To a solution of the compound (0.20 g) obtained in Example 123 in 1,4-dioxane (1. OmL) was added dimethyl sulfate (0.2 OmL) and potassium hydroxide (0.020 g), and the mixture was added at room temperature for 24 hours. Stirred for hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 40: 10) to give the title compound as colorless prisms (0.13 g, 64%).

Melting point, 187-189Ό (recrystallized from ethyl ethyl diisopropyl ether). Example 127

 (a R, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl-6,13-dioxo-5-phenyl-6,8,9,10,1,1, 13—Hexahi Draw 7H— [1,4] diazocino [2, 1-g] [1, 7] naphthyridine 1-force ruboaldehyde

 Manganese dioxide (2.5 g) was added to a solution of the compound obtained in Example 123 (1.00 g) in chloroform (50 mL), and the mixture was stirred at 75 for 9 hours. Manganese dioxide (0.50 g) was further added to the reaction solution, and the mixture was stirred at 75 75 for 12 hours. After filtering off insolubles, the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 40: 10: 1) to give the title compound as a pale yellow amorphous (0.69 g, 69%). Obtained.

'HNR (CDC1 ₃ ) 50.94 (3H, d, J = 6.8 Hz), 1.50-1.80 (1 H, m), 2.00-2.40 (2H, m), 3.01 (l H, d, J = 15.4 Hz), 3.37- 3.64 (2H, m), 3.97 (1 H, d, J = 14.6 Hz), 5. 12 (1 H, dd, J = 14.2, 6.2 Hz), 5.42 (1 H, d, J = 14.6 Hz), 6.91 (1 H, d, J = 7.2 Hz) ), 7.19 (1 H, t, J = 7.5 Hz), 7.35-7.50 (5H, m), 7.69 (1 H, dd, J = 8.4, 1.2 Hz) , 7.81 (1H, m), 8.09 (1H, d, J = 8.4 Hz), 10.31 (1H, d, J = 1.2Hz).

Example 1 28

 (a R, 9R) —7— [3,5 _bis (trifluoromethyl) benzyl] — 2— (difluoromethinole) -1-9-methyl-5-phenyl-8,9,10,1 1—tetrahydro — 7H— [1, 4] diazocino [2. 1-g] [1, 7] naphthyridine-1,6,13—dione

To a solution of the compound (0.13 g) obtained in Example 27 in dichloromethane (1.5 mL) was added [bis (2-methoxethyl) amino] -sulfatrifluoride (0.16 mL) with a solution. The mixture was stirred at room temperature for 14 hours. In addition, add bis (2-methodine) to the reaction mixture. Shetyl) amino] -sulfur trifluoride (0.050 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound as pale-yellow amorphus (0.079 g, 51%).

'HNR (CDC 1 ₃ ) δ 0.93 (3Η, d, J = 6.9H z), 1.60— 1.

8 0 (1 H, m), 2.0 0-2.40 (2 H, m), 3.00 (1 H, d, J = 1

5.3Hz), 3.42 (1H, dd, J = 15.6, 10.5Hz), 3.55 (1H, dd, J = 14.4, 1 1 1 H z), 5.10 (1 H, dd, J = 14.4,

5.7H z), 5.42 (1 H, d, J = 1 5.OH z), 6.89 (1 H, t, J

= 54.8 Hz), 6.88-6.94 (1H, d) ike), 7.19 (1H.t1ike), 7.36-7.50 (5H, m), 7.70 (1 H, d, J = 8.

4H z), 7.80-7.84 (2H, m).

Example 1 2 9

 (a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] — 9-methyl-6,13-dioxo-5-phenylen 6,5,9,10,0,1 1,13-hexahydro-7H— [1,4] diazino [2,1-g] [1; 7] naphthyridine-1-2-ruvoaldehyde doxym

 Compound (0.15 g) obtained in Example 127, hydroxyamine.hydrochloride (0.40 g) and sodium acetate (0.40 g) in water (5 mL) and ethanol (10 ml) solution was stirred at 70 for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated by silica gel column chromatography (ethyl acetate: hexane: methanol = 40: 10: 0: 1). The title compound was converted to a colorless amorphous (0.079 g, 51%) by purification. Obtained.

_{^ -NMR (CDC 1 3) δ} 0. 92 (3Η, d, J = 6. 9H z), 1, 6 0- 1. 80 (1H, m), 2.00-2.40 (2H, m), 2.99 (1H, d, J = 15.3Hz), 3.43 (1H, dd, J = 15.3, 11.1Hz), 3.54 (1H, dd, J = 14.4, 11.1Hz), 3.96 (1H, d, J = 14.7Hz), 5.10 (1 H, dd, J = 13.8, 6.3 Hz), 5.43 (l H, d, J = 1 5.OHz), 6.90-6.93 (1 H, dlike), 7. 19 (1H, t, J = 7.5Hz), 7.36-7.48 (5H, m), 7.52 (1H, d, J = 8.7Hz), 7.81 (1H , s), 8.01 (1 H, d, J = 8.7 Hz), 8.53 (1 H, s).

Example 130

 (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] — 2-isopropinole 9-methyl-5-phenyl-1,8,9,10,11-tetrahydro-1H—

 [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione of the ^ i compound (2.39 g) and triethylamine (0.70 mL) obtained in Reference Example 7 Methanesulfonyl chloride (0.36 mL) was added to the THF (5 OmL) solution at 0, and the mixture was stirred for 2 hours. Triethylamine (0.25raL) and methanesulfonyl chloride (0.12rnL) were further added by Ot: and the mixture was stirred for 2 hours. The reaction solution was poured into a 1 N aqueous sodium hydroxide solution, stirred for 1 hour, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of carbonic acid and brine, dried, and the solvent was distilled off under reduced pressure.

 To a solution of the obtained residue in THF (5 OmL) was added 60% oily sodium hydride (0.32 g), and the mixture was stirred at 5 for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound as colorless prisms (1.27 g, 54%).

 Melting point: 220-2221C (recrystallized from ethyl ethyl diisopropyl acetate). Example 131

(a S, 9 S) -7- [3,5-Bis (trifluoromethyl) benzyl] -1-9-methyl 1-6, 13—Dioxo 1—5—Feniru 6, 8, 8, 9, 10, 1 1, 13—Hexahydro 7Η_ [1, 4] Diazono [2, 1-g] [1, 7] Naphthyridine One-two-force rubonitrile

 The compound (0.40 g) obtained in Reference Example 8 was reacted and treated in the same manner as in Steps 1 and 4 of Example 1 to give the title compound as colorless prisms (0.16 g). g, 38%).

Melting point: 164-166 (recrystallized from ethanol-diisopropyl ether). Specific rotation: [a] _D — 186.4 ° (c = 0.50, Me OH).

Example 132

 (a S, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl] -9-methyl-1 6,13-dioxo-5-phenyl-1 6,8,9,10,11 13 · Kisahidro 7H— [1, 4] diazocino [2, l— g] [1, 7] Naphthyridine 1—2-force Rubonito Linole

 The title compound was obtained as a colorless amorphous (0.052 g, 2%) by fractionating the crude product (2.50 g) obtained in Example 13 by HPLC.

HP LC conditions:

Column CH I RALCEL OD 50mm I DX 50 OmmL

Moving bed Hexane: Ethanore = 85: 1 5

Flow rate 60 → 8 OmL / min

Force ram temperature 3 or

Detection wavelength 254 nm

Retention time (a S, 9R) body, 26.6 minutes: (aR, 9R) body, 36.5 minutes Example 133

(a R, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl] 1 9-methyl 2-([2-methyl pyridine 1-3-yl) oxy] 1 5—phenyl 8, 9, 1 0, 1 1—Tetrahydro 7H— [1, 4] diazocino [2, l— g] [1, 7] naphthyridine-1,6,13-dione To a solution of the compound (0.21 g) obtained in Example 11 in DMF (1. OmL) was added lithium carbonate (0.14 g) and 3-hydroxy-2-methylpyridine (0.055 g). Was added at room temperature, added at 105 ^, and stirred for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of carbonic acid and saturated saline, dried, and the solvent was distilled off under reduced pressure to obtain the title compound as colorless prisms (0.20 g, 85%).

 Melting point: 277-279 ^ (recrystallized from ethyl ethyl diisopropyl acetate). Example 1 34

 (a R, 9R) -7- [3,5-Bis (trif-noleolomethyl) benzyl] 19-methyl-1-2-[(6-Methylpyridine-13-yl) oxy] — 5-phenyl— 8, 9, 1 0, 1 1—tetrahydro-7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1,6,1-dione

 Using the compound obtained in Example 11 (0.21 g) and 3-hydroxy-6-methinolevirizine (0.055 g), the reaction and treatment were carried out in the same manner as described in Example 133. However, the title compound was obtained as colorless prisms (0.20 g, 85%). Melting point: 180-182 (recrystallized from ethyl acetate-disopropyl ether). Example 1 35

 (a R, 9R)-7- [3,5-bis (trifluoromethyl) benzyl] — 9-methyl-5-phenyl-2- (1H-pyrazole-1-yl) 1,8,9,10 , 1 1—Tetrahydro-7H— [1, 4] diazocino [2, 1—g] [1, 7,] naphthyridine-1,6,1 3-dione

 To a solution of the compound obtained in Example 11 (0.21 g) and pyrazole (0.034 g) in DMF (0.7 OmL) was added 60% oily sodium hydride (0.020 g). For 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of carbonic acid and brine, dried, and the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (0.17 g, 77%).

Melting point: 210-212 (recrystallized from ethyl acetate and diisopropyl ether). Example 136

 (a R, 9R)-7- [3,5-bis (trifluoromethyl) benzyl] 1-9-methyl-1-5-phenyl-1 2- (2H-1, 2,3-triazole-2--2- ^ ) 1,8,9,10,1 1—tetrahydro-7H— [1,] diazocino [2,1—g] [1,7] naphthyridine-1,6,13—dione

 The compound (0.26) and 1,2,3-triazole (0.041 g) obtained in Example 11 were reacted and treated in the same manner as in Example 135. The obtained residue was separated by silica gel column chromatography (ethyl acetate: hexane: methanol = 10: 10: 1) and purified, whereby the title compound was obtained as colorless prisms (0.15 g, 57%). Was done.

 Melting point: 258-260 * C (recrystallized from ethyl ethyl isopropyl ether).

 Rf = 0.33 (ethyl acetate: hexane: methanol = 3: 3: 1).

Example 137

 (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] — 9-methylen-5-phenylenol 2- (1 H-1, 2,3-triazol-1-yl 1), 9, 9, 10, 11—tetrahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1, 6, 13_dione

 The residue obtained in Example 136 was separated by silica gel column chromatography (ethyl acetate: hexane: methanol-10: 10: 10: 1) and purified to give the title compound as colorless prisms (0.074 g, 28%).

 Melting point: 144-146 ^ (recrystallized from ethyl isopropyl ether).

 R f = 0.61 (ethyl acetate: hexane: methanol = 3: 3: 1).

Example 138

(a R, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl] 1 9-methyl 5-5-phenyl 2— (1H—1.2, 4-triazole—1-yl ) 1,8,9,10,11 1-tetrahydro 7H— [1,4] diazocino [2,1—g] [1,7] naphthyridine-1 6,13-dione To a solution of the compound (0.26) and 1,2,4-triazole (0.041 g) obtained in Example 11 in DMF (0.7 OmL) was added 60% oily sodium hydride (0.02 4 g) was added at room temperature, and the mixture was stirred at 100 for 1 hour. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of carbonic acid and brine, dried, and the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (0.26 g, 92%).

 Melting point: 245-247: (recrystallized from ethyl isopropyl ether acetate). Example 139

 (a R, 9 R) -7- [3,5-bis (trifluoromethyl) benzyl] — 9-methyl-1,6,13-dioxo-5-phenyl 6,8,9,10,11 13—Hexahydro-7H— [1,4] diazosino [2,1-g] [1,7] naphthyridin-2-yl) oxy] ethyl acetate

 (Process 1)

The crude product obtained in Example 13 by silica gel column chromatography by separating 'purified (chloroform: methanol _{= 50 1), (a R} , 9R) - 7-

 [3,5-bis (trifluoromethyl) benzyl] —9-methyl-5-phenylenol 8, • 9,10,11-tetrahydro-1H— [1,4] diazosino [2,1—g] [ 1,7] Naphthyridine-1.2.6,13 (7H) trione was obtained as a pale yellow amorphous.

^-MR (DMSO— d ₆ ) δ 0.95 (3Η, d, J = 6.9 Hz), 1.50 — 1.70 (1H, m), 2.00—2.40 (2 H, m), 2.99 (1 H, d, J = 15.0 Hz), 3.39 (1 H, dd, J = 1 5. 3, 1 0.5 Hz), 3, 57 (1 H, dd, J = 14.1,] 0.8 Hz), 3.96 (1H, d, J = 15.OHz), 4.99 (1 H.dd, J = 1.4, 5.5.4Hz), 5 42 (1 H, d, J = 15.0 Hz), 6.77 (l H, d, J = 9.9 Hz), 6.86-6.90 (1 H, m), 7.18 ( 1H, t, J = 7.5Hz) '7.21 (1H, d, J = 9.9Hz), 7.34-7.50 (5H, m), 7.81 (lH, s), 9. 82 (1 H, s).

 R f = 0.5 (ethyl acetate: methanol = 10: 1).

 (Process 2)

To a solution of the compound obtained in Step 1 (0.69 g), potassium carbonate (0.28 _g ) and sodium iodide (0.15 g) in DMF (4. OmL) was added ethyl bromoacetate (0.29 g). Was added and stirred at room temperature for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of carbonic acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 10: 10: 1) to give the title compound as colorless amorphous (0.44 g, 55%). Was.

Elemental analysis: as C ₃₃ H _2g N ₃ 0 ₅ F ₆

 Calculated value (%): C. 59.91; H, 4.42; N, 6.35.

 Measured value (%): C, 59.78; H, 4, 22; N, 6.36.

Example 140

 (a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] -1-9-methyl-6.13-dioxo-5-phenyl-6,8,9,10,11,13- KIHAHI DRAW 7H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridin-1-yl) oxy] diacid

 To a solution of the compound (0.42 g) obtained in Example 139 in methanol (4. OmL) was added a 1N aqueous sodium hydroxide solution (2. OmL), and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with 1N hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with saturated saline, dried, and the solvent was distilled off under reduced pressure to obtain the title compound as pale yellow amorphous (0.37 g, 94%).

Elementary analysis: as _{C 31 H 25 N 3 0 5} F 6

 Calculated value (%): C, 58.77; H, 3.98; N, 6.63.

 Measured value (%): C, 58.60; H, 3.98; N, 6.67.

Example 141 (a R, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl] —9-methyl-1-2- (2-oxo-1-pyrrolidine-1; I-ylethoxy) 1-5-phenyl Lu 8, 9, 1 0, 1 1—Tetrahydro 7 H— [1,4] diazosino [2,1-g] [1,7] Naphthyridine-1,6,1-dione

 Using the compound (0.13 g) obtained in Example 14 and reacting and treating in the same manner as described in Example 56, the title compound was colorless amorphous (0.080 g, 5 7%).

Elemental analysis: C _{3 S} H ₃₂ N ₄ 0 ₄ F ₆ '0.2 As 2H ₂₀

 Calculated value (%): C, 60.90; H, 4.73; N, 8.12.

 Measured value (%): C, 60.76; H, 4.73; N, 8.10.

Example 14 2

 (a R, 9 R) 1 7— [3,5-bis (triphnorelomethyl) benzyl] 1 9-methyl 1-5-phenyl 2- (biridin-3-ylmethoxy) 1 8,9,1 0, 1 1—Tetrahydro 7H— [1.4] diazocino [2, 1—g] [1, 7,] naphthyridine 1, 6, 1 3—dione

A solution of the compound (0.18 g) obtained in Example 11 and pyridine-13-methanol (0.055 g) in DMF (1.0 mL) was added to a 60% oily sodium hydride (0.0% 16 g) and stirred at room temperature for 6 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of carbonic acid and saturated brine, dried, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless amorphous (0.14 g, 71%). As _{0. 5H 2 0 - C 3 S} H 28 N 4 O 3 F 6: Elemental analysis

 Calculated value (%): C, 57.14; H, 3.87; N, 12.90.

 Measured value (%): C, 57.05; H, 4.03; N, 12.69.

Example 1 4 3

(a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] —9-methyl-2- (5-oxo-1,4,5-dihidro 1 H—1,2,4 —Triazo-one-three-yl) -1-5-phenyl-1,8,9,10,11-tetrahydro 7 7- [1,4] dia Zosino [2, 1-g] [1, 7] naphthyridine-1,6,13-dione

 The compound (0.64 g) obtained in Example 1 16 was dissolved in getyl carbonate (5. OmL) and evaporated to dryness under reduced pressure. The residue was dissolved in getyl carbonate (3. OmL), 60% oily sodium hydride (0.11 g) was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of carbonic acid and brine, dried, and the solvent was distilled off under reduced pressure to give the title compound as a pale yellow amorphous (0.58 g, 90%).

Elemental analysis: as C ₃₁ H _{24 Ne} 0 _{3 Fe}

 Calculated value (%): C. 63.06; H, 4.23; N, 8.40.

 Measured value (%): C, 63.05; H, 4.38; N, 8.43.

Example 144

 (a R. 9R) —9—Methyl-17— [3-Methyl-5— (trifluoromethyl) benzyl] -1,6,13-dioxo-5—Feniru 6,8,9,10,11 13— ^ ^ Kisahi Draw 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1-one-carbonitrile

 The compound (1.28 g) obtained in Reference Example 9 was reacted and treated in the same manner as described in Steps 1 and 4 of Example 1 to give the title compound. 36 g. 27%).

 Melting point: 204-206 ^ (recrystallized from ethyl ethyl isopropyl ether). Example 145

 (4R) -2-[(aR, 9R) -1-9-methyl-7- [3-methyl-15- (trifluoromethyl) benzyl] —6,13-dioxo-5-phenyl 6,8,9,10 1 1, 13 ^ Kisahi Draw 7H— [1, 4] diazocino [2, 1— g] [1, 7] nabutyridine 1 2— ^ f] — 4,5-dihidro 1,3—thiazolone 4 One-stroke rubonic acid

The compound (0.30 g) obtained in Example 144 was reacted and treated in the same manner as in Example 101 to give the title compound as a colorless amorphous (0.26 g, 7 1%).

— Marauder R (DMS O- d _B ) δ 0.8 1 (3Η, d, J = 6.OH z), 1.40-1.60 (1H, m), 2.00-2.20 (2H, m), 2.31 (3H, s), 2.80-2.95 (1H, d1ike), 3, 20--3.70 (4H, m), 4. 1 0 (1 H, d, J = 1 5.OHz), 4.76--4.88 (1H, m), 5, 08 (1H, dd, J = 14.4Hz), 5.18 (1H, t, J = 9.5Hz), 6.84 (1H, s), 7.00-7.10 (1H, m), 7.16-7. 2 1 (1H, t1ike), 7.25 (1H, s). 7.34—7.54 (5H, m), 8.18-8.30 (1H, m).

Example 14 6

 (a R, 9 R) — 2-methyl-1-methyl-1 7- [3-methyl-5- (trifluoromethyl) benzyl] — 6,13-dioxo-5-phenyl-1,8,9,10, 1 1—Tetrahydro 7H— [1,4] diazocino [2,1-g] [1,7] Naphthyridine 1,6,1 3—dione

 The compound (1.00 g) obtained in Reference Example 9 was reacted and treated in the same manner as described in Steps 1 and 2 of Example 1, and the title compound was converted to a colorless amorphous (0.65 g). g, 51%).

_{iH- NMR (CDC 1 3) δ} 0. 8 9 (3Η, d, J = 6 9H z.), 1. 5 0 - 1.

7 0 (1 H, m), 2.00-2.40 (2H, m), 2.32 (3H, s), 2.95 (1 H, d, J = 1 5.OH z) , 3.29 (1 H, dd, J = 14.7, 1 0.

5 Hz), 3.56 (1 H, dd, J = 14.4, 10.8 Hz), 3.82 (1 H, d, J = 1 5.OHz), 5. 0 6 (1 H, dd, J = 1 4. 4, 5.1 Hz), 5.

3 9 (1 H, d. J = 1 4.7 Hz), 6.78 (1 H, s), 6.94 (1 H, d,

J = 7.8Hz). 7.04 (1H, s), 7.24-7.30 (lH, m), 7.34 (1H, s), 7.40-7.54 (5H, m).

Example 1 4 7

(a R, 9 R) — 9-Methyl-7— [3-Methyl-5— (trifluoromethyl) ben W 02

Jill] 1, 6, 13—Dioxo 5—Feniru 6, 8. 9, 10, 11, 13— ^ ^ Kasahi Draw 7H— [1, 4] Diazocino [2, 11 g] [1, 7] Naphthyridine mono-strength / methinoleestenole levonic acid

 The compound (2.40 g) obtained in Example 146 was reacted and treated in the same manner as in Example 38 to give the title compound as colorless prisms (2.10 g, 83%). Obtained.

 Melting point: 206-208: (Ethyl acetate "recrystallized from xane").

Example 148

 (a R, 9 R) 1 9-Methyl-7— [3-Methyl-5— (trifluoromethyl) benzyl] —6,13—Dioxo-5—Feninole 6, 8, 9, 10, 11, 13 —Hexahi draw 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridin-2 —carboxylic acid

 The compound (2.68 g) obtained in Example 147 was reacted and treated in the same manner as in Example 40 to give the title compound as colorless prisms (2.01 g, 77%). Obtained.

 Melting point: 148-150 "C (recrystallized from ethyl ethyl diisopropyl acetate).

 (a R, 9 R) —9-methinole 1 7— [3-methinole 5— (trifnoreolomethinole) benzil] —6,13—dioxo 5—feneru 6, 8, 9, 10, 1 1 , 13—Hexahydro-7H— [1,4] diazosino [2,1-g] [1,7] naphthyridine-1 2 —carboxamide

 The compound (0.20 g) obtained in Example 148 was reacted and treated in the same manner as in Example 41 to give the title compound as colorless prisms (0.16 g, 80%). Obtained.

 Melting point: 151-153 (recrystallized from ethyl ethyl prosodium acetate). Example 150

(a R, 9R) -N- (2-hydroxyethyl) 19-methyl-17- [3-methyl-1 5— (Trifluoromethyl) benzyl] —6,13-dioxo-1-5-phenyl-1,8,8,9,10,11,13 1 ^ "Xahydro-1 7H— [1,4] diazosino [2, 1—R] [1, 7] naphthyridine-1 2-carboxamide

 Using the compound (0.20 g) obtained in Example 48 and 2-aminoethanol (0.028 mL), the reaction was carried out in the same manner as described in Example 42, and the title compound was colorless. Obtained as prism crystals (0.15 g, 71%).

 Melting point: 153-155 (recrystallized from ethyl isopropyl ether). Example 1 5 1

 (a R, 9 R) 1-9-Methyl-1 7- [3-Methyl-1-5- (Trifnorolelomethynole) benzyl] -5-Phenyl-1-2- (1.3-Thiazolidine-1-ylcarbonyl) -1 8,9,10,11—Tetrahydro 7H— [1,4] diazocino [2,1—g] [1,7] Naphthyridine-1,6,13-dione

 Using the compound (0.20 g) obtained in Example 148 and thiazolidine (0.036 g), the reaction was carried out in the same manner as in Example 42, and the title compound was converted to a colorless amorphous (0.2%). 14 g, 63%).

Elemental analysis: calculated as C ₃₃ H ₃₁ N ₄ 0 ₃ SF ₃ · 0.3 C ₃ H ₇ NO (DMF) (%); C, 63.05; H, 5.29; N, 9.59 S, 4.88; F, 8.67.

 Measured value (%): C, 63.24; H, 5.27; N, 9.62; S, 5.16; F, 8.46.

_{^{J H-NMR (CDC 1 3}} ) δ 0. 8 9- 0. 9 1 (3Η, m), 1. 6 1 - 1. 65 (1H, m), 2. 08 (1 H, m), 2 3 3 (4H, m), 2.96—3.16 (2H, m), 3.32—3.38 (l H, m), 3.5 5-3. 6 1 (1H, m ),

3.82-3.86 (1 H, m), 4.07 (1 H, m), 4.45-4.5 1 (1 H, m), 4.82-4.84 (1 H , m), 5.04—5.75 (1 H, m), 5.

1 3-5.22 (1 H, m), 5.37-5.4 1 (1 H, m), 6.79 (1 H, m), 6.96-7.05 (2H, m ), 7.28—7.35 (2H, m), 7.4 6—7.53 (3 H, m), 7.65-7.67 (1 H, m), 8.09-8.13 (1 H, m).

Example 152

 (a R, 9R) -2- (2,2-Dimethyl-1,3-thiazolidine-13-ylcarbonyl) -1-9-methyl-17- [3-methyl-15- (trifluoromethyl) benzyl] -5 —Feuniru 8, 9, 10, 1 1—Tetrahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1, 6, 13-dione

The compound (0.20 g) obtained in Example 148 and 2,2-dimethylthiazolidin (0.036 g) were reacted and treated in the same manner as described in Example 42. The title compound was obtained as a colorless amorphous (0.1 llg, 46%). Elemental analysis: C ₃₅ H ₃₅ N ₄ 〇 ₃ SF ₃ ■ 0.06 C ₃ H ₇ NO (DMF) · 0.27H ₂ o

 Calculated value (%): C, 64.22; H, 5.51; N, 8.64; S, 4.87; F, 8.66.

 Measured value (%): C, 63.92; H, 5.24; N, 8.94; S, 5.19; F, 8.44.

_{^ -. MR (CDC 1 3} ) δ 0. 88-0 90 (3Η, m), 1. 62- 1. 66 (1H, m), 1. 99 (8H, m), 2. 33 (4 H , m), 2.95-3.03 (3H, m), 3.31 -3. 34 (1H, m), 3.54-3.56 (1 H, m), 3.82- 3. 85 (1 H, m), 4.36 -4.37 (1 H, m), 4.53 (1 H, m), 5.02-5.06 (1 H, m), 5.37- 5.40 (1H, m), 6.79 (1H, m), 6.96-7.05 (1H, m), 7.26-7.35 (2H, m), 7. 46—7.52 (3H, m), 7.61-7. 63 (1H, m), 7.95—7 · 97 (lH, m).

Example 153

(a R, 9R) — 7— (2-Methoxybenzyl) 1 9-methyl-1,6,13-dioxo —5-phenyl-1 6,8,9,10,1,1,13—HexahiDraw 7H— [1, 41 Diazocino [2, 1-g] [1, 7] naphthyridine-1 2-carbo-tolyl

 The compound (0.50 g) obtained in Reference Example 10 was reacted and treated in the same manner as in Steps 1 and 4 of Example 1, and the title compound was converted to colorless prism crystals.

(0.033 g, 6%).

 Melting point: 288-290 ^ (recrystallized from ethanol-diisopropyl ether). Example 154

 (a R, 9R) — 9-methyl-6,13-diquino-5-phenyl 7-[(3-trifluoromethyl) benzyl] —6,8,9,10,11,13-hexahydro 7 H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridine-1 2-carbonitrile

 The compound (0.50 g) obtained in Reference Example 11 was reacted and treated in the same manner as in Steps 1 and 4 of Example 1, and the title compound was converted to colorless prism crystals (0. 13 g, 25%).

 Melting point: 207-209 \ (recrystallized from ethyl isopropyl ether). Example 155

 (a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] —5 -— (4-fluorophenyl) -1-2-isopropyl-1-9-methyl-8,9,10,1 1— Tetrahydridone 7H_ [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1 6, 13-dione

 The compound obtained in Reference Example 12 (1.83 g) was reacted and treated in the same manner as described in Example 130 to give the title compound as colorless prisms (0.36 g, 20%). Obtained.

 Melting point: 126-128 (recrystallized from ethyl acetate-diisopropyl ether). Example 156

(a R, 9 R)-7-(3,5-Dimethylbenzyl) 1 9-Methyl-1 5 -Feninole-1 2-(Trifluoromethyl) 1 8, 9, 10, 1 1 -Tetrahydro 7 H— [1, 4] diazocino [2.1. G] [1, 7] naphthyridine-1 6,13-dione To a solution of the compound obtained in Example 14 (0.90 g) and copper iodide U) (0.39 g) in DMF (1 OmL) was added fluorosulfoninole (difluoro) methyl acetate (2.0 mL). Was added and stirred at 1101 for 14 hours. After pouring the reaction solution into water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound as colorless prisms (0.015 g, 2%). .

 Melting point: 210-212 ^ (recrystallized from ethyl ethyl diisopropyl acetate). Example 157

 (a R, 9R)-7- (3,5-dimethylbenzyl) 1-2- (2,2-dimethinole-1,3-dioxane-5-yl) -1 5— (4-fluorophenyl) -1 9— Methyl-1,8,10,11-tetrahydro-17H— [1,4] diazino [2,1-g] [1,7] naphthyridine-1,6,13-dione

 To a solution of the compound (0.19 g) obtained in Example 165 in 2,2-dimethoxypropane (7. OmL) and dichloromethane (2. OmL) was added methanesulfonic acid (0.20 mL), and the mixture was added at room temperature. The mixture was stirred for 0.5 hours. The reaction solution was poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 8: 8: 1) to give the title compound as a colorless amorphous (0.15 g, 72%). Was.

Elemental analysis: C ₃₅ H ₃₈ N ₄ 0 ₃ F · 0.5 H ₂ 0

 Calculated value (%): C, 63.54; H, 4.72; N, 8.47.

Measured value _{^{(0/0): C,}} 63. 82; H, 4. 74; N, 8. 37.

Example 1 58

(a S, 9 S) -7- (3,5-dimethylbenzyl) _ 5— (4-fluorophenyl) —2,9-dimethyl-8,9,10,11-tetrahydro 7H_ [1,4] Diazo sino [2. 1-g] [1, 7] naphthyridine-1 6, 13-dione The compound (1.30 g) obtained in Reference Example 13 was reacted and treated in the same manner as in Step 3 of Reference Example 1, and the title compound was converted to colorless prism crystals (0.32 g, 30 %).

Melting point: 226-228 (recrystallized from ethanol-diisopropyl ether). Specific rotation: [a] _D -1 4.5 ° (c = 0.50, Me OH).

Example 159

 (a R, 9R) -7- (3,5-dimethylbenzyl) -1-5- (4-fluorophenyl) -12- (hydroxymethyl) -1-9-methyl-1,8,9,10 1 1-tetrahydro-1 7 H— [1, 4] diazocino [2.1.-g] [1.7] naphthyridine-6, 13-dione

 The compound (0.30 g) obtained in Example 29 was reacted and treated in the same manner as described in Examples 122 and 123 to give the title compound as a colorless amorphous (0.22 g, 63% ).

_{Ή-NMR (CDC 1 3)} 50. 88 (3Η, d, J = 6. 9 H z), 1. 50-1. 80 (1 H, m), 2. 00- 2. 40 (8H, m ), 2.99 (1H, d, J = 1

5.0 Hz), 3.19 (1 H _P dd, J = 14.7, 9.3 Hz), 3.54--3.

72 (2H, m), 4.00-4.20 (1H, br), 4.95 (2H, s), 5.

05 (1 H, d d, J = 14.7, 6.3 Hz), 5.35 (1 H, d, J = 14.

4Hz), 6.47 (2H, s), 6.90-7.00 (3H, m), 7.20-7.28 (1H, dtlike), 7.47-7.58 (3 H, m ).

Example 160

 (a R, 9 R) -7- (3,5-dimethylbenzyl) -1-5- (4-fluorophenyl) —9-methyl-2-[[1- (morpholine-4-ylmethyl) bier] 1 8, 9, 10 , 1 1-tetrahydro-7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1 6, 13-dione

To a solution of the compound (0.39 g) obtained in Example 29 in 80% ethanol (4. OmL) was added morpholine (0.35 g), 37% formalin (0.33 g) and acetic acid (0.3%). 45 g) was added and stirred at 10 for 27 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 2: 4: 1) to give the title compound as a pale yellow amorphous (0.1%). 0 g, 21%).

Elemental analysis: as C _3e H ₃₉ N ₄ 0 ₃ F · 0.5H ₂ 0

 Calculated value (%): C, 71.62; H, 6.68; N, 9.28.

 Measured value (%): C, 71 · 61; H, 6.92; N, 9.33.

 Rf = 0.23 (ethyl acetate: hexane: methanol = 2: 4: 1).

Example 16 1

 (a R, 9 R)-7-(3,5-dimethylbenzyl) — 5— (4-fluorophenyl)-9-methinole-1- (2-morpholine-1 4-frutyl) 1, 8, 9, 10 , 1 1—Tetrahydro 7H— [1,4] diazosino [2,1—g] [1,7] Naphthyridine 1,6,13—dione

 The residue obtained in Example 160 was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 2: 4: 1) to give the title compound as a pale yellow amorphous (0.11). g, 22%).

Elemental analysis: C ₃₅ H _{3 B} N ₄ 0 ₃ F · H ₂ 0

 Calculated value (%), 69.98; H, 6.88; N, 9.33.

 Measured value (%): C, 70.21; H, 7.02; N, 9.29.

 Rf = 0.11 (ethyl acetate: hexane: methanol-2: 4: 1).

Example 1 6 2

Butyric acid 2- [[(a R, 9 R) -7- (3,5-dimethylbenzyl) -1-5- (4-funoleo-phenyl) -1-9-methyl-6,13-dioxo-6,8,9.10 , 1 1, 1 3—Hexahydro-1 7 H— [1,4] diazosino [2,1—g] [1,7] Naphthyridine—2-inole

To a solution of the compound (2.42 g) obtained in Example 29 in ethanol (4. O mL) was added 37% formalin (0.8 1 g) and 4- (dimethylamino) pyridine (0.12 g). ) And stirred in a sealed tube at 155 "C for 19 hours. After concentrating the reaction mixture under reduced pressure, pyridin (3. OmL) and butyric anhydride (2. OmL) were added to the residue, and the mixture was stirred at room temperature for 0.5 hour. Further, methanol (0.5 OmL) was added, and the mixture was stirred for 0.5 hour.The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, the organic layer was washed with water, dried, and the solvent was removed. The resulting residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 8: 8: 1) to give the title compound as a pale yellow monorefase (0%). 33 g, 1 1%).

Elemental analysis: C ₃₅ H ₃₈ N ₄ O ₃ F '0.5 H ₂₀

 Calculated value (%): C, 70.93; H, 6.63; N, 7.09.

 Measured value (%): C, 70.99; H, 6 · 49; N, 7.02.

 f = 0.48 (ethyl acetate: hexane: methanol = 6: 6: 1).

Example 163

 (a R, 9 R) -3- [7- (3,5-dimethylbenzyl) 1-5- (4-fluorophenyl) 1-methyl-6,13-dioxo 6,8,9,10,11,13 "Xahydro-7H— [1,4] diazosino [2,1—g] [1,7] naphthyridine-1-yl] pentanedicarboxylic acid dipropyl ester

 The residue obtained in Example 162 was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 8: 8: 1) to give the title compound as a pale-yellow amolefase (0.74 g). , 21%).

Elementary analysis: as _{C 40 H 46 N 3 O 6} F '0. 5H 2 0

 Calculated (° /.): C, 69.34; H, 6.84; N, 6.07.

 Measured value (%): C, 69.16; H, 6.95; N, 6.02.

 R f = 0.65 (Ethyl acetate: Hexane: Methanol = 6: 6: 1).

Example 164

(a R, 9 R) — 7— (3,5-dimethylbenzyl) -1-5- (4-fluorophenyl) —2- (2-hydroxyxethyl) 9-methyl-8,9,10,11—tetrahydro-1 7H— [1, 4] diazocino [2, 1 -g] [1, 7] naphthyridine 6, 13— Zeon

 To a solution of the compound (0.18 g) obtained in Example 162 in methanol (3. OmL) was added 1N aqueous sodium hydroxide solution (0.3 OmL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured on ice and extracted with ethyl acetate. After washing and drying the organic layer, the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow amorphous (0.16 g, 93%).

Elementary analysis: as _{C 31 H 32 N 3 0 3} F · 1. 5H 2 0

 Calculated value (./.): C, 68 · 87; Η, 6.53; Ν, 7.77.

 Measured value (%): C, 68.71; Η, 6.30; Ν, 7.53.

Example 165

 (a R, 9 R)-7-(3,5-dimethylbenzyl) _ 5— (4-fluorophenyl) — 2— [2-hydroxy 1— (hydroxymethyl) ethyl] —9—methyl-8,9 10, 1 1—tetrahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1, 6, 13—dione

 To a solution of the compound (0.73 g) obtained in Example 63 in methanol (6. OmL) was added a 1N aqueous sodium hydroxide solution (3. OmL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. After the organic layer was washed and dried, the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow amorphous (0.57 g, 96%).

Elementary analysis: as _{C 32 H 34 N 3 0 4} F · 0. 5H 2 0

 Calculated value (%): C, 69.55; H, 6.38; N, 7.60.

 Measured value (%): C, 69.54; H, 6.41;

Example 166

(a R, 9R) — 7— [3.5—Bis (trifluoromethyl) benzyl] -1-9-methyl-5— (4-methinorefenyl) -1,6,13—Diokin 6.8,9,10 , 1 1,13-1 ^ ■ oxathi Draw 7H— [1,4] diazocino [2, 1— g] [1, 7] naphthyridine mono-2-carboxylic acid methyl ester 202624

The compound (1.50 _g ) obtained in Example 17 was reacted and treated in the same manner as in Example 38 to give the title compound as colorless prisms (1.44 g, 92). %).

 Melting point: 150-152 (recrystallized from ethanol diisopropyl ether). Example 1 6 7

 (a R, 9 R) 1 7— [3,5-bis (triphnorelomethyl) besidyl] 1-9-methyl-1 5— (4-methinolephenyl) 1,6,13-dioxo 6,8,9,9 1 0,11,13- ^ · Xahydro-7H— [1,4] diazosino [2,1-g] [1,7] Naphthyridine-1-2-carboxylic acid

Using the compound (1.17 g) obtained in Example 16 and reacting and treating in the same manner as described in Example 40, the title compound was converted into colorless prisms (1.14 _g , 9 9%).

 Melting point: 150-152 (recrystallized from ethyl isopropyl ether). Example 1 6 8

 (a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] 1 N-methoxy-1-N, 9-dimethyl 5- (4-methylphenyl) 1,6,13-dioxo 1,6,8,9,10,11,13—Hexahydro-7H— [1,4] diazosino [2,1-g] [1,7] Naphthyridine-12-carboxamide

 The compound (0.60 g) obtained in Example 1 67 was reacted and treated in the same manner as in Example 42 to give the title compound as a pale yellow amorphous (0.64 g, 9 8%).

_{^{J HN R (CDC 1 3)}} δ 0. 9 2 (3Η, d, J = 6. 9H z), 1. 50- 1. 8 0 (1 H, m), 2. 00- 2. 4 0 ( 2 H, m), 2.37 (3 H, s), 2.99 (1 H, d, J = 15.3 Hz), 3.30—3.60 (5 H, m) , 3.95 — 4.08 (4 H, m), 5.06 (1 H, dd, J = 1.4, 6.3 Hz), 5.46 (1 H, d, J = 14.4Hz), 6.82 (1H, dd, J = 7.8, 1.5, Hz), 7.05 (1H, d, J = 8.1Hz) , 7.25-7.3.5 (2H, m), 2/02624

7.47 (2H, s), 7.67 (1 H, d, J = 8.4 Hz), 7.75-7.85 (2H, m) ₀

Example 169

 (a R, 9 R) 1-Acetyl-7- [3,5-bis (trifluoromethyl) benzinole] -9-Methyl-5- (4-methinolephenyl) 1,8,9,10 1 1-Tetrahydride R 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-1 6, 13 dione

 The compound (0.60 g) obtained in Example 168 was reacted and treated in the same manner as in Example 43 to give the title compound as colorless prisms (0.18 g, 32%). Obtained.

 Melting point: 240-242 (recrystallized from ethyl acetate-disopropyl ether).

 R f = 0.7 (ethyl acetate: hexane: methanol = 50: 10: 1).

Example 170

 (a R, 9 R) —7— [3,5-bis (trifluoromethyl) benzyl] — N, 9—dimethyl-5— (4-methylphenyl) -1,6,13-dioxo-1,6,8,9 1 0,11,13—Hexahydro-1 7H— [1,4] diazino [2,1-g] [1,7] Naphthyridine-1 2-carboxamide

 The residue obtained in Example 169 was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound as colorless prisms (0.047 g, 8%). Was done.

 Melting point: 148-150 "C (recrystallized from ethyl acetate-diisopropyl ether).

 R f = 0.3 (ethyl acetate: hexane: methanol = 50: 10: 1).

Example 171

(a R, 9 R) 1 7— [3.5-bis (trifluoromethyl) benzyl] 1-9-methyl 5--1 (4-methylphenyl) 1 6.1 3—Dioxo 6,8,9,10 1 1,13—Hexahydro-1 7H— [1, 4] diazocino [2, 1-g] [1, 7] Naphthyridine 1—2-carboxamide Using the compound (0.20 g) obtained in Example 167 and treating in the same manner as described in Example 41, the title compound was converted to colorless prisms (0.16 g, 80%). Obtained.

 Melting point: 160-162 (recrystallized from ethyl ethyl diisopropyl ether). Example 1 72

 (a R, 9 R)-7-[3,5-Bis (triphnoleolomethyl) benzyl] -9-methyl 5- (4-methylphenyl) 1,6,13-dioxo 6,8,9,10, 1 1, 13 1 ^ · Xahydrid 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine— 2-carbothioamide

 Example 17 The compound obtained in Example 71 (0.85 g) and 2,4-bis (4-methoxyphenyl) -1, 3-dithia-1,2,4-phosphethane-1 2,4-disulfide (0.27 g) ) In toluene (1 OmL) was stirred at 110 for 1 hour. After concentrating the reaction mixture under reduced pressure, the residue was separated and purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give the title compound as a pale yellow amorphous (0.64 g, 73%). Obtained.

_{^ -NMR (CDC 1 3) δ} θ.93 (3Η, d, J = 6.9Hz), 1.60- 1. 80 (1H, m), 2.00- 2.40 (2H, m), 2. 38 (3H, s ), 3.00 (1 H, d, J = 1 5.3 Hz), 3.45 (1 H, dd, J = 15.3, 11.1 Hz),

3.57 (1 H, dd, J = 14.4, 11.1 Hz), 4.00 (1 H.d, .J = 15.3 Hz), 5.06 (1 H, dd, J = 14.4, 5.1 Hz) , 5.46 (1 H, d,

J = 15.OHz), 6.82 (1H, dd, J = 7.5, 1.5Hz), 7.05 (1H, d, J = 7.8Hz), 7.28-7.38 (2H, m), 7.47 (2H , s),

7.66 (1H, d, J = 8.7Hz), 7.83 (2H, s), 8.87 (1H, d, J = 9.0Hz), 9.90-10.00 (1H, m).

Example 173

(a R, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl] 1 9-methyl 2- (4-methyl-1-1,3-thiazol-2-yl) 1-5— (4 —Methylphene 1) 8, 9, 10, 1 1—tetrahydro 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1, 6, 13—dione

 To a solution of the compound (0.60 g) obtained in Example 172 in DMF (3. OmL) was added bromoacetone (0.21 g), and the mixture was stirred at room temperature for 4 days. The reaction solution was poured into water and extracted with ethyl acetate. After washing and drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (form: methanol = 50: 1) to give the title compound as colorless prisms (0.39 g, 61%).

 Melting point: '258-26 Ot (decomposition) (recrystallized from ethyl acetate-disopropyl ether).

Example 174

 (a R. 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] 1-9-methyl 5- (4-methylpheninole) 1,6,13-dioxo 6,8,9 10, 1 1, 13 1 ^ ^ Xahydro 1 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1-2-ylcarboxylic acid tert-butyl ester

 To a solution of the compound (0.15 g) obtained in Example 167 and triethylamine (0.03 OmL) in 2-methyl-2-propanol (2.0 mL) was added DPPA (0.03 mL). And stirred at 100 for 3 hours. Further, DPPA (0.05 OmL) was added, and the mixture was stirred at 100 for 2 hours. The reaction solution was poured into water, and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound as a pale-yellow amorphous (0.075 g, 44%).

_{'H-NMR (CDC 1 3} ) δ 0. 90 (3Η, d. J = 6. 8H z), 1. 20- 1. 80 (10 H, m), 2. 00- 2. 40 (2 H , m), 2.37 (3H, s), 2.96 (1H, d, J = 15.OHz), 3.38-3.60 (2H, m). 3.99 (1H , d, J = 15.OHz), 5.05 (1H, dd, J = 15.0, 7.OH z), 5.46 (1 H, d, J = 15.0 Hz), 6.80-6.83 (1 H, ddlike), 7.01-7.08 (lH, m), 7.23- 738 (2H, m), 7.47 (2H, s), 7.52 (1 H, d, J = 8.8 Hz), 7.78--7.82 (2H, m), 8. 15 (1H, d, J = 8.8Hz).

Example 1 75

 (a R, 9 R) -5- (4-Fluorophenyl) -19-methynole-1 7- [3-Methyl-15- (trifluoromethyl) benzyl] -6,13-dioxo-1,6,8,9 , 1 0, 1 1, 13— ^ "Kisahi Draw 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1-2-carbonitrile

 To a solution of the compound (0.55 g) obtained in Reference Example 14 in THF (15 mL) was added 3-chloroperbenzoic acid (0.78 g) at room temperature, and the mixture was stirred for 14 hours. Further, 3-benzo-perbenzoic acid (2.1 g) was added and the mixture was stirred for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline and dried, and then the solvent was distilled off under reduced pressure. To a solution of the obtained residue and triethylamine (0.22 mL) in acetonitrile (1 OmL) was added trimethylsilyl cyanide (0.43 mL), and the mixture was stirred at 90 for 2 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to give the title compound as a colorless amorphous (0.039 g. 7%).

 Melting point: 133-135 ^ (recrystallized from ethyl acetate-disopropyl ether). Example 1 76

 (a R, 9R) -2-chloro-5- (4-fluorophenyl) 19-methyl-17- [3-methyl-15- (trifluoromethyl) benzyl] -1,8,9,10,11-tetrahydro One 7H— [1, 4] diazocino [2.1.-g] [1.7.] Naphthyridine-1,6,13-dione

Reference Example 15 To a solution of the compound obtained in Step 5 (7.1 g) in pyridine (40 mL) at 0 Silk mouth ride (4.0 g) was added and stirred at room temperature for 4 hours. The reaction solution was poured into ethyl acetate, and the organic layer was washed with a 2N aqueous hydrochloric acid solution and saturated saline, dried, and the solvent was distilled off under reduced pressure. To a solution of the obtained residue in DMSO (4 OmL) was added lithium carbonate (6.0 g) at room temperature, and the mixture was stirred at 851C for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl succinate: hexane = 2: 3) to give the title compound as colorless prisms (1.44 g, 21%).

 Melting point: 122-12 (recrystallized from ethyl ethyl diisopropyl acetate). Example 177

 (a R, 9R) —5— (4-Fluorophenyl) 19-methyl-17- [3-Methyl-5- (trifluoromethyl) benzyl] -1,8,9,10 1 1—Tetrahydro 2- (Trifluoromethyl) 1 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1 6, 13-dione

 The compound (0.90 g) obtained in Example 176 was reacted and treated in the same manner as described in Example 156, and the title compound was converted into colorless prisms (0.015 g, 2%). Was obtained as

 Melting point: 210-212 (recrystallized from ethyl acetate-diisopropyl ether). Example 178

 (a R, 4 R)-2-[3,5-bis (trifluoromethyl) benzyl] 1 13-(4 -fluorofurnyl) -4-monomethyl-1,8-dioxo-1,3 4, 5, 6, 8—hexahydro-2H— [1, 4] diazocino [1, 2— b] [2, 7] naphthyridine-9—potassolenoic acid

A mixed solution of the compound (103 g) obtained in Example 36 in concentrated hydrochloric acid (6. OmL) -acetic acid (6.0 m) was stirred at 100 at 1.5 hours. After concentrating the reaction solution under reduced pressure, the obtained residue is poured into ethyl acetate, washed with water and saturated saline, dried, and the solvent is distilled off under reduced pressure to give the title compound as a brown-brown amorphous compound (1. (00 g, 99%) Obtained.

'H-NMR (CD C 1 3) δ 0. 9 4 (3H, d, J = 7. 0 H z), 1. 5 0 - 1. 8 0 (1 H, m), 2. 0 0 - 2.40 (2H, m), 3.02 (1H, d, J = 14.6Hz), 3.33-3.59 (2H, m), 3.9 6 (1 H, d, J = 5.6 Hz), 4.98 (1 H, dd, J = 1 4.0, 5.8 Hz), 5.39 (1 H, d, J = 14.6 Hz), 6.87 (2 H, d, J = 6.6 Hz), 7.02 (1 H, d, J = 5.4 Hz), 7. 0 8-7.17 (1 H, m), 7.38-7.50 (3 H, m), 7.83 (1 H, s), 8.66 (1 H, d , J = 5.4 Hz).

Example 1 7 9

 (a R, 4 R) — 2— [3, 5—bis (trifluoromethyl) benzyl] 1 13— (4—fluorophenyl) 1 4-methyl-1 1,8—dioxo 1,3,4 , 5, 6, 8—Hexahi Draw 2 H— [1,4] diazocino [1, 2, —b] [2, 7] naphthyridine—9—carboxamide

 The compound (0.29 g) obtained in Example 17 was reacted and treated in the same manner as in Example 41, and the title compound was converted to colorless prism crystals (0.089 g). g, 30%).

 g $ point: 16 0-16 2 結晶 (recrystallized from ethyl acetate diisopropyl acetate). Example 1 8 0

 (a R, 4 R)-2-[3,5-bis (trifluoromethylinole) benzyl] — 1 3— (4—fluorophenyl) 1 4-methinole 1 9—phenyl 2,4,5 , 6—Tetrahydro-1H 2 [—1,4] Diazono [1,2—b] [2,7] Naphthyridine 1 1,8—Dione

 The compound (0.20 °) obtained in Example 33 was reacted and treated in the same manner as described in Example 93, and the title compound was converted to colorless prisms (0.16 g, 7 3%).

Melting point: 288-29 O (recrystallized from ethyl acetate-disopropyl ether). Example 18 1 (a R, 4R) -2- [3,5-bis (trifnoroleolomethinole) benzyl] -9- (dimethylamino) 13- (4-funolelophenyl) 1-4-methyl-1, 3 , 5, 6—tetrahydro 2H— [1, 4] diazocino [1, 2— b] [2, 7] naphthyridine-1 1,8—dione

 The compound (0.15 g) obtained in Example 33 was reacted and treated in the same manner as in Example 22, and the title compound was converted to colorless prisms (0.10 g, 67%). Obtained.

 Melting point: 222-224 (recrystallized from ethyl acetate-hexane).

Example 182

 (a R, 4R) -2- [3,5-Bis (triphneololomethyl) benzyl] -13- (4-fluorophenyl) -19-methoxy-4-methyl-1,3,4,5,6- Tetrahydro-2H- [1, 4] diazocino [1, 2_b] [2, 7] naphthyridine-1,8-dione

 The compound (0.15 g) obtained in Example 33 was reacted and treated in the same manner as described in Step 3 of Example 1 to give the title compound as a colorless amorphous (0.075 g, 51% ).

_{^ -NMR (CDC 1 3) δ} 0. 91 (3Η, d, J = 6. 6 Η ζ), 1. 50- 1. 80 (1 Η, m), 2. 00-2. 30 (2Η, m), 2.98 (1Η, d, J = 15.3Η ζ), 3.35-3.47 (1Η, d, J = 15.OHOH), 4.16 (3Η, s), 4.98 (1 Η, dd, J = 14.7, 5.4 Hz), 5.38 (l Η, d, J = 1.4 Η), 6.46 (1 Η, d, J = 5.4 Η ζ), 6.80—6.92 (2Η, m), 7.08—7.14 (1Η, m), 7.36 -7.46 (3Η, m), 7 82 (1Η, s), 8.14 (1H, d, J = 5.4Η).

Example 183

(a R, 4R) — 2— [3,5-bis (trifluoromethyl) benzyl] — 13— (4 monofluorophenyl) 1-4-methyl-19-1 (methylsulfanyl) 1,3,4,5, 6—Tetrahydro-2H— [1,4] diazosino [1,2—b] [2,7] naphthyridi Nichi 1,8—Zeon

 The compound obtained in Example 33 (0.20 g) was reacted and treated in the same manner as in Example 2, and the title compound was colorless amorphous (0'11 g, 53%). Was obtained as

_{'H-NMR (CDC 1 3} ) δ 0. 93 (3Η, d, J = 6. 6 H z), 1. 50- 1. 80 (1H, m), 1. 95-2. 40 (2H, m), 2.55 (3H, s), 2.98 (1 H, d, J = 15.0), 3.33-3.52 (2H, m), 3.94 (1 H, d, J = 15.2 Hz), 4.99 (1H, dd, J = 1.6, 6.2Hz), 5.38 (1H, d, J = 15.0Hz), 6.53 (1 H, d, J = 6.0 Hz), 6.86 (2 H, d, 6.6 Hz), 7.06—7.18 (1 H.m), 7.36—7.50 (3H, m), 7.82 (1H, s), 8.41 (1H, d, J = 5.4Hz).

Example 184

 (a R, 4 R) —2— [3,5-bis (trifluoromethyl) benzyl] —13— (4-fluorophenyl) -14-methinole-1-91 (methylsulfonyl) -1,3,4,5 , 6—tetrahydro 2H— [1, 4] diazocino [1.2. B] [2, 7] naphthyridine-1, 8—dione

The compound (0.15 g) obtained in Example 183 was reacted and treated in the same manner as in the filtration method described in Example 73, and the title compound was converted to pale yellow amorphus (0.041 _g , 26%). Obtained.

_{'H-NMR (CDC 1 3} ) δ 0. 94 (3Η, d, J = 6. 9Hz), 1. 60-1. 80 (1 H, m), 2. 00-2. 40 (2H, m ), 3.02 (1 H, d, J = 15.6 Hz), 3.37 (1H, dd, J = 15.0, 10.2 Hz), 3.46-3.60 (1 H, m ), 3.52 (3H, s), 3.94 (1 H, d, J = 14.7 Hz), 5.08 (1 H, dd, J = 14.7, 5.7 Hz), 5. 38 (1 H, d, J = 14.4 Hz), 6.86-6.92 (2H, m), 7.10-- 7.18 (2H, m), 7.36-7.50 (3H , m), 7.83 (1 H, s), 8.54 (l H, d, J = 5.4 Hz).

Example 185

 (a R, R) -2- [3,5-bis (trifluoromethyl) benzyl] — 13— (4-fluorophenyl) 1 N, N, 4 trimethinole 1,8-dioxo 1,3, 4,5,6.8-1 ^ ^ Kisahydro 1 2H— [1,4] diazosino [1,2—b] [2,7] Naphthyridine-19_carboxamide

 After a solution of the compound (0.15 g) obtained in Example 178 in thionyl chloride (2. OmL) was stirred at 80 for 1.5 hours, the reaction solution was concentrated under reduced pressure. A solution of the obtained residue in THF (2. OmL) was poured into a 50% dimethylamine (5. OmL) -THF (5. OmL) mixed solution with Ot, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, the obtained residue was poured into ethyl acetate, washed with water and saturated brine, dried, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 8: 1) to give the title compound as colorless prisms (0.11 g, 83%).

 Melting point: 154-156 (recrystallized from ethyl thiocyanate xane).

Example 186

 (a R, 4 R)-2- [3,5-Bis (trifnorelolomethyl) benzyl] -1 13-(4 -Funolelophenyl) -1 4-Methinole 9-(Monolefolin-4f Lecanolebonyl) -1 3,4,5,6-tetrahydro-2H— [1,4] diazosino [1,2-b] [2,7] naphthyridine-1,8-dione

 The compound (0.15 g) obtained in Example 178 and morpholine (0.042 g) were reacted and treated in the same manner as in Example 42 to give the title compound as a colorless amorphous (0.055 g, 33%).

] _{H- NMR (CDC 1 3) δ} 0. 85- 1. 00 (3Η, m), 1. 50-1. 80 (ΙΗ. Πι), 2. 00- 2. 40 (2Η, m), 2 95-4. 04 (12H, m), 4.90-5.10 (1H, m), 5.30—5.46 (1H, m), 6.85-6.98 (3H, m ), 7.07-7.17 (1 H, m), 7.38—7.50 (3H, m), 7.83 (1H, s), 8.58-8.64 (1H, m).

Example 187

Acetic acid [(a R, 4 R) —2— [3,5-bis (trifluoromethyl) benzyl] —1 3— (4-fluorophenyl) -1,8-dioxo-1-4-methyl-1,3 , 4, 5, 6, 8—Hexahi Draw 2H— [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine-1-91] methyl ester

 To a solution of the compound (0.20 g) obtained in Example 34 in THF (1 OmL) was added 3-chloroperoxybenzoic acid (0.25 g) at 0, and the mixture was stirred at room temperature for 14 hours. After adding an aqueous solution of sodium thiosulfate to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried, and then the solvent was distilled off under reduced pressure. A mixed solution of the obtained residue in acetic anhydride (2.5 mL) -acetic acid (2.5 mL) was stirred at 100 for 1 hour. After the reaction solution was concentrated under reduced pressure, the obtained residue was poured into ethyl acetate, washed with water and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound as a colorless amorphous (0.19 g, 87%).

_{^{X H-NMR (CDC 1 3}} ) δ 0. 94 (3Η, d, J = 6. 9H z), 1. 50- 1. 70 (1H, m), 2. 00-2. 40 (2H, m ), 2.26 (3H, s), 3.00 (1H, d, J = 15.3Hz), 3.36--3.51 (2H, m), 3.94 (1H, d, J = 14.7Hz), 4.95 (1H, dd, J = 14.4, 6.OHz), 5.64 (1H, d, J = 14.7Hz), 5.87 (1H, d, J = 16.2Hz), 6.03 (1H, d, J = 16.2Hz), 6.80—6.85 (2H, m), 7.07-7.14 (1 H, m), 7.36-- 7.42 (1 H, m) .7.42 (2H, s), 7.81 (1 H, s), 8.54 (1 H, d, J = 5.4 Hz). Example 188

(a R, 4R) -2- [3,5-bis (trifluoromethyl) benzyl] -13- (4-fluorophenyl) -19- (hydroxymethyl) -14-methyl-1,4,5 6— Tetrahydro-1H— [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine — 1, 8—Zeon

The compound (0.15 g) obtained in Example 187 was reacted and treated in the same manner as described in Example 123 to give the title compound as a colorless amorphous (0.071 _g , 42%) Was obtained as

_{^ H-NMR (CDC 1 3} ) δ 0. 95 (3 H, d, J = 7. 2Hz), 1. 50- 1. 70 (1 H, m), 2. 00-2. 40 (2H, m), 3.01 (1 H, d, J = 15.3 Hz), 3.41 (1 H, dd, J = 14.4, 9.6 Hz), 3.48 (1 H, dd, J = 14.4, 10.8Hz), 3.95 (1H, d, J = 15.OHz), 4.97 (1H, dd, J = 14.7, 5.7Hz), 5.26 -5. 40 (4 H, m), 6.85-6.88 (3H, m), 7.09-7.16 (1 H, m), 7.3 6-7. 42 (1 H, m) m), 7.42 (2H, s), 7.82 (1H, s), 8.54 (1H, d, J = 5.7Hz).

Example 189

 (a R, 4 R) — 2— [3,5-bis (trifluoromethylinole) benzyl] —13— (4 monofluorophenyl) 1,8-dioxo-1 4-methyl-1,3,4 , 5, 6, 8—Hexahydro-1H— [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine —9—carbaldehyde

 The compound (0.50 g) obtained in Example 188 was reacted and treated in the same manner as in Example 127, and the title compound was converted to pale yellow prism crystals (0.28 g, 66 %).

 Melting point: 202-204t: (recrystallized from ethyl ethyl diisopropyl acetate). Example 190

 (a R, 4 R) 1 2— [3,5 _bis (trifluoromethyl) benzyl] —9—chloro 1 4 1 methyl 1 13— (4-methylphenyl) 1 3,4,5 6-tetrahydro 2 H- [1, 4] diazocino [1.2. B] [2, 7] naphthyridine-1, 8-dione

Described in Steps 1 and 2 of Example 1 using the compound (12.9 g) obtained in Reference Example 21 The title compound was obtained as a pale yellow amorphous (5.84 g. 42%).

_{'H-NMR (CDC 1 3} ) δ 0. 934 (3Η, d, J = 7. OH z). 1, 50- 1. 80 (1 H, m), 1 · 90-2. 40 (2H, m), 2.36 (3 H, s), 2.99 (1 H, d, J = 15.0 Hz), 3.35-3.55 (2H, m), 3.97 (1H, d, J = 14.6 Hz), 4.98 (1 H.dd, J = 14.0, 6.0 Hz), 5.41 (1 H, d, J = 14.6 Hz), 6.79 ( 1 H, d, J = 7.8 Hz), 6.90 (1 H.d, J = 5.6 Hz), 7.04 (1 H, d, J = 7.8 Hz). (2H. S 1 ike), 7.44 (2H, s), 7.81 (1 H, s), 8.31 (1 H, d, J = 5.6 Hz).

Example 191

 (a R, 4 R) 1 2— [3,5-bis (trifluoromethyl) benzyl] —4,9-dimethyl-13- (4-methylphenyl) 1,3,4.5,6-tetrahydro-1 2H—

 [1.4] diazocino [1,2-b] [2,7] naphthyridine-1,8-dione Using the compound (0.20 g) obtained in Example 190, the method described in Example 3 The same reaction and treatment gave the title compound as a pale yellow amorphous (0.10 g, 53%).

_{'H-NMR (CDC 1 3} ) δ 0. 924 (3H, d, J = 6. 6 H z), 1. 45- 1. 70 (1 H, m), 1. 90- 2. 40 (2H , m), 2.36 (3 H, s), 2.97 (1 H, d, J = 15.4 Hz), 3.17 (3H, s), 3.35-3.55 (2H, m), 3.98 (l'H, d, J = 15.OHz), 4.96 (1H, dd, J = 14.8, 6.OHz), 5.43 (1H, d , J = 1 5.OH z), 6.75-6.85 (2H, m), 7.03 (1H, d, J = 7.0Hz), 7.20-7.35 (2H, m ), 7.45 (2 H, s), 7.81 (1 H, s), 8.44 (1 H, d, J = 5.6Hi).

Example 192

(a R, 4R) 1 2— [3.5-bis (trifluoromethyl) benzyl] —9 Methylamino) 1 4-methino! ^ 1 13— (4-Methylphenyl) 1,3,4,5.6 , 8—Zeon

 The compound (0.20 g) obtained in Example 190 was reacted and treated in the same manner as described in Example 22, and the title compound was pale yellow amorphous (0.071 g, 35%). Was obtained as

_{- NMR (CDC 1 3) δ} 0. 886 (. 3Η, d, J = 7 OH z), 1. 40- 1. 70 (1 H, m), 1. 90- 2. 40 (. 2H m) , 2.35 (3H, s), 2.98 (1H, d, J = 15.4 Hz), 3.13 (6H, s), 3.30-3.60 (2H, m), 3.98 (1 H, d, J = 14.4 Hz), 4.88 (1 H, dd, J = 14.2, 6.6 Hz), 5.41 (1 H, d, J = 14.4 Hz) ), 6.20 (1H, d, J = 5.6 Hz), 6.82 (1 H, d, J = 7.8 Hz), 6.99 (1 H, d, J = 7.8 Hz) , 7.23 (2H, s 1 ike), 7.48 (2

H, s), 7.82 (1 H, s), 8.05 (1H, d, J = 5.4 Hz).

Example 193

 (a R, 4R) -2- [3,5-Bis (trifluoromethyl) benzyl] -4-methyl-1-13- (4-methylphenyl) -19- (morpholine-1-41) -1,3,4 , 5, 6—tetrahydro-1H— [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine—1,8—dione

 The compound obtained in Example 190 (0.20 g) was reacted and treated in the same manner as described in Example 23, and the title compound was converted to pale yellow amorphous (0.1 lg, 52%). Obtained.

_{^{J H-NMR (CDC 1 3}} ) δ 0. 889 (3Η, d, J = 6. 6Hz), 1. 40-

I. 70 (1 H, m). 1.90-2.40 (2H, m), 2.35 (3H, sj, 2.98 (1H, d, J = 15.4 Hz), 3.35- 3.70 (6H, m), 3.

80-4.10 (5H, m), 4.90 (1H, dd, J = 14.0, 6.4Hz), 5.40 (1H, d, J = 15.4Hz), 6.35 ( 1 H, d, J = 5.4 Hz), 6.81 (1H, d, J = 8. OHz), 6.99 (1H, d, J = 8.OHz),

7.23 (2H, slike), 7.47 (2H, s), 7.82 (1H, s), 8.11 (1H, d, J = 5.4 Hz).

Example 194

 (a R, 9 R) — 2-chloro-1- 7- (3,5-di-tert-butyl-1-hydroxyhydroxybenzole) 5 -— (4-phnoleolophenyl) 19-methyl-8,9 10, 1 1—tetrahydro-1 7 H— [1,] diazocino [2, 1-g] [1, 7] naphthyridine-6, 13-dione

 To a solution of the compound (2.18 g) obtained in Reference Example 22 in water (25 mL) -acetonitrile (5 OmL) was added magnesium monoperoxyphthalate hexahydrate (4.45 g) at room temperature. The mixture was stirred for 14 hours. After adding an aqueous solution of sodium thiosulfate to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was reacted and treated in the same manner as in the method described in Step 2 of Example 1 to give the title compound as colorless prisms (0.98 g, 42%).

 Melting point: 160-162TC (recrystallized from ethyl acetate-diisopropyl ether). Example 195

 (a R, 9 R)-7-(3,5-di-tert-butyl-1-hydroxyhydroxybenzole)-5-(4-fluorophenyl) 19-methylinole 6, 13-dioxo-6, 8,9,10,1 1.13—Hexahi draw 7H— [1,4] diazosino [2,1—g] [1.7] Naphthyridine-1-2-ruthenic acid methyl ester

 The compound obtained in Example 194 (0.90 g) was reacted and treated in the same manner as in Example 36 to give the title compound as colorless prisms (0.73 g, 78%). Obtained.

 Melting point: 156-158 (recrystallized from ethyl acetate-disopropyl ether). Example 1 96

(a R, 9 R) —7— (3,5-di-tert-butyl-4-hydroxybenzyl) —5— (4-Fluorophenyl) 1-9-methinole 6,13-dioxo-1,6,8,9,10,11,13—hexahidraw 7H— [1,4] diazosino [2,1 -g] [ [1, 7] naphthyridine-l-butyric acid

The compound (0.66 g) obtained in Example 195 was reacted and treated in the same manner as in Example 40 to give the title compound as colorless prisms (0.58 _g , 90%). Obtained.

 Melting point: 167-169 (recrystallized from ethyl ethyl diisopropyl acetate). Example 197

 (a R, 9R)-(3,5-di-tert-butynole-1-hydroxybenzyl) 1- (4-fluorophenyl) -1-9-methynole-1- (pyrrolidine-1-ylcarbonyl) — 8, 9, 10, 1 1—tetrahydro 7H— [1, 4] diazocino [2, 1— g]

 [1, 7] naphthyridine-1,6,13-dione

 The compound (0.14 g) obtained in Example 196 was reacted and treated in the same manner as in Example 56 to give the title compound as colorless prisms (0.085 g, 55% ). .) Melting point: 166-168 (recrystallized from ethyl ethyl dipropyl acetate). Example 198

 (a R, 9R) — (3,5-di-tert-butyl-1-hydroxybenzyl) 1 5 1 (4-fluorophenyl)-9-methyl-2--(morpholine 4-1 ^ <carbonyl) — 8, 9 , 10, 1 1—tetrahydro-1-H, [1, 4] diazocino [2, 1-g] '', 7] naphthyridine-1, 6, 13-dione

 The compound (0.14 g) obtained in Example 96 was reacted and treated in the same manner as in Example 62, and the title compound was converted to colorless prisms (0.12 g, 74%). Was obtained as

 Melting point: 190-192 (recrystallized from ethyl ethyl diisopropyl acetate). Example 199

(a R, 9R) 1 (3.5-di-tert-butyl-1-hydroxybenzyl) 15 -(4-funolelophenyl) 19-methyl-1--2- (1,3-thiazolidine-3-ylcarbonyl) 1,8,9,10,11-tetrahydro 7 H— [1,4] diazosino [2, 1-] [1, 7] naphthyridine-1,6,13-dione

 The compound (0.14 g) obtained in Example 196 was reacted and treated in the same manner as described in Example 63, and the title compound was obtained as colorless prisms (0.12 g, 75%).

Melting point: 209-211 ^ (recrystallized from ethyl acetate-diisopropyl ether).

実施例 n A R² R 融点 番号 (。c)

Example n AR ² R melting point number (.c)

1 H 3,5- (CF ₃ ) ₂ 129-131

 MeS,

2 a H 3,5- (CF _{3) 2} 217-219

Me ヽ

3 H 3,5- (CF ₃ ) ₂ amorphous

5 1 ^Clヽ ex H 3,5-Me ₂ 174-176

6 H 3,5-Me ₂ 125-127

7 H 3,5-Me ₂ amorphous

8 1. 'ヽ oc F 3,5-Me ₂ 182-183

Me, \ no

9 oc F 3,5-Me ₂ 165-167

10 F 3,5- (CF ₃ ) ₂ 178-180

 226

Replacement paper (¾ 26) Table 2

実施例 A R 融点

Example AR melting point

 (° C)

12 2 XX H 3,5- (CF ₃ ) ₂ 121-123

227 Difference paper (Rule 2δ)

実施例 n A R² R 融点 番号 (°c)

Example n AR ² R Melting point number (° c)

 Me ヽ

29 2 F 3,5-Me ₂ 228-230

30 2 F 3,5-Me ₂ amorphous

05 15

実施例 n A R² R 融点 赏"⁷ (°c) 228 Replacement form (Rule 26)

Example n AR ² R Melting point 赏 " ⁷ (° c)

34 (1) 2 F _3, 5- (CF ₃ ) ₂ amorphous

34 (2) 2 TsOH F 3,5- (CF ₃ ) ₂ 266-268

34 (3) 2 F 3,5- (CF ₃ ) ₂ 243-250

 Then N

35 2 F 3,5- (CF ₃ ) ₂ 133-135

36 2 F 3,5- (CF ₃ ) ₂ 127-129

37 2 F 3,5- (CF ₃ ) ₂ 194-196

Me0 ₂ O ^

38 2, H 3,5- (CF ₃ ) ₂ 240 (dec.)

39 2 H 3,5- (CF ₃ ) ₂ 261-263

H0 ₂ C ^ ^

40 2 H 3,5- (CF ₃ ) ₂ 152-154

229 Replacement paper (Kaikai IJ26)

実施例 n A R² R 融点 番号 (°c)

Example n AR ² R Melting point number (° c)

52 2 H 3,5- (CF ₃ ) ₂ amorphous

53 2 H 3,5- (CF ₃ ) ₂ amorphous

230 Replacement paper C¾ iJ26)

ωェ

ω

 IZ

 Example

s AR ² R Melting point 县 n

. c)

56 2 H 3,5- (CF ₃ ) ₂ amorphous

58 2 H 3,5- (CF ₃ ) ₂ amorphous

59 2 H 3,5- (CF ₃ ) ₂ amorphous

60 2 H 3,5- (CF ₃ ) ₂ amorphous

61 2 H 3,5- (CF ₃ ) ₂ amorphous

62 2 H 3,5- (CF ₃ ) ₂ amorphous

0

63 2 H 3,5- (CF ₃ ) ₂ amorphous

64 2 H 3,5- (CF ₃ ) ₂ amorphous

231 Replacement sheet (Rule 26)

 Example

县 n AR ² R melting point

 (.C)

70 2 H 3,5- (CF ₃ ) ₂ amorphous

72 2 H 3,5- (CF ₃ ) ₂ 208-210

 o, p

73 2 H 3,5- (CF ₃ ) ₂ 148-150

74 2 H 3,5- (CF ₃ ) ₂ amorphous

75 2 H 3,5- (CF ₃ ) ₂ amorphous

 232

Replacement form (Rule 26)

実施例 n A R² R 融点 番号 (。c)

Example n AR ² R melting point number (.c)

76 2 H 3,5- (CF ₃ ) ₂ 258-260

78 2 H 3,5- (CF ₃ ) ₂ 258-260

79 2 H 3,5- (CF ₃ ) ₂ 180-182

Me

80 2 H 3,5- (CF ₃ ) ₂ 141-143

81 2 XX H 3,5- (CF ₃ ) ₂ 252-254

83 2 H 3,5- (CF ₃ ) ₂ 166-168

84 2 ¾¾ H 3,5- (CF ₃ ) ₂ 160-162

85 2 H 3,5- (CF ₃ ) ₂ amorphous

86 2 H 3,5- (CF ₃ ) ₂ amorphous

233 Replacement sheet (Rule 26) Table 9

 HN

 Example n A R Melting point number (° C)

87 2 Me

Ύ H 3,5- (CF ₃ ) ₂ amorphous o

 H

 88 2 Me

H 3,5- (CF _{3) 2} 7 Amorphous

0

実施例 n A R² R 融点 234 Replacement Form (Rule 26)

Example n AR ² R melting point

 (.C)

98 2 H 3,5- (CF ₃ ) ₂ amorphous

100 2 H 3,5- (CF ₃ ) ₂ amorphous

101 2 H 3,5- (CF ₃ ) ₂ amorphous

102 2 H 3'5- (CF ₃ ) ₂ 256-258

103 2 H 3,5- (CF ₃ ) ₂ amorphous

実施例 n A R² R 融点 番号 (°c) 235 Replacement form (Rule 26)

Example n AR ² R Melting point number (° c)

112 2 ^NC ¾ H 3,5- (CF ₃ ) ₂ 248-250

H ₂ N ^ OH

113 2 HN H 3,5- (CF ₃ ) ₂ amorphous

236 Replacement sheet (Rule 26)

実施例 n A R² R 融点 番号 (。c)

Example n AR ² R melting point number (.c)

123 2 ^H0 H 3,5- (CF ₃ ) ₂ 137-139

124 2 H 3,5- (CF ₃ ) ₂ 131-133

125 2 H 3,5- (CF ₃ ) ₂ amorphous

237 Replacement Form (Rule 26)

実施例 n A R² R 融点 货 (°c)

Example n AR ² R Melting point 货 (° c)

 NC ^

131 2 H 3,5- (CF ₃ ) ₂ 164-166 aS, 9R)

134 2 H 3,5- (CF ₃ ) ₂ 180-182

 Me person N

135 2 H 3,5- (CF ₃ ) ₂ 210-212

136 2 H 3,5- (CF ₃ ) ₂ 258-260

137 2 H 3,5- (CF ₃ ) ₂ 144-146

138 2 H 3,5- (CF ₃ ) ₂ 245-247

238 Replacement sheet (Rule 26)

 Example Melting point

n AR ² R (° c)

142 2 k H 3,5- (CF ₃ ) ₂ amorphous

144 2 XX H 3-Me-5- (CF ₃ ) 204-206

147 2 H 3-Me-5- (CF ₃ ) 206-208

148 2 H 3-Me-5- (CF ₃ ) 148-150

149 2 ¾c H 3-Me-5- (CF ₃ ) 151-153

 239

実施例 Replacement Paper (Kaikai (126)

Example

¾¾. N AR ² R melting point

 (.C)

NC

153 2 H 2- (CH ₃₀ ) 288-290

NC ^ N

154 2 H 3-CF ₃ 207-209

156 2 H 3,5-Me ₂ 210-212

159 2 HO F 3,5-Me ₂ amorphous

160 2 F 3,5-Me ₂ amorphous

161 2 F 3,5-Me ₂ amorphous

162 2 F 3,5-Me ₂ amorphous

PrC0 _2,

163 2 F 3,5-Me ₂ amorphous

240 Replacement Paper (Rule 26)

Example n AR ² R Melting point w (° c)

164 2 F 3,5-Me ₂ 7 morphus

166 2 Me 3,5- (CF ₃ ) ₂ 150-152

173 2 Me 3,5- (CF ₃ ) ₂ 258-260

 241

Replacement form (Rule 26)

実施例 n A R² R 融点

Example n AR ² R melting point

 (° C)

175 2 ^NC x F 3- e-5- (CF ₃ ) 133-135

176 2 F 3-Me-5- (CF ₃ ) 122-124

177 2 ^F3 ¾ F 3-Me-5- (CF ₃ ) 210-212

242 Replacement sheet (Rule 26)

実施例 A R 融点 o (。C)

Example AR Melting Point o (.C)

193 2 ■ I Me 3,5- (CF ₃ ) ₂ amorphous

194 2 3,5- ( ₂ ~ 4-0 ^ 1 160-162

Me0 ₂ C ^ N,

195 2 3,5- ( ^f Bu) ₂ -4-OH 156-158

196 3,5- ( ^f Bu) ₂ -4-OH 167-169

 243

Replacement form (Rule 26) Table 19

実施例 n A R² R 融 番号 (。c)

Example n AR ² R fusion number (.c)

197 2 F 3,5- ( ^f Bu) ₂ -4-OH 166-168

 ^ o ^ one

198 2 F 3,5- ( ^f Bu) ₂ --OH 190-192

In Tables 1-19,

Me is methyl, Et is ethyl, Pr is propyl, ^f Bu is tert-butyl, Boc is tert-butoxycarbonyl, Ms is mesyl, Ac is acetyl, Ph is phenyl.

Formulation Example 1 '

(1) 10 _mg of the compound of Example 1

 (2) Lactose 6 Omg

 (3) Corn starch 35mg

 (4) Hydroxypropyl methylcellulose 3mg

 (5) Magnesium stearate 2mg

Granulated with a mixture of a compound 1 Omg lactose 6 Omg and corn starch 35mg obtained in Example 1 ', (3m g as human Dorokishibu port Pirumechino cellulose) 10 weight _^0/0 hydroxypropylmethylcellulose water ¾¾0.03mL After drying, dry with 40 and sieve. The granules obtained are mixed with 2 mg of magnesium stearate and compressed. The uncoated tablets obtained are coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and acacia. Coating strength The coated tablets are extracted with beeswax to obtain coated tablets.

 In addition, coated tablets are obtained in the same manner except that any of the compounds of Examples 2 to 36 is used in place of the compound of Example 1.

Formulation Example 2

 (1) 1 Omg of the compound of Example 1

 (2) Lactose 7 Omg

 (3) Corn starch 5 Omg

 (4) Soluble starch 7mg

 (5) Magnesium stearate 3mg

 1 Omg of the compound obtained in Example 1 and 3 mg of magnesium stearate are granulated with 0.07 mL of an aqueous solution of soluble starch (7 mg as soluble starch), dried, and mixed with 7 Omg of lactose and 5 Omg of corn starch. . The mixture is compressed to give tablets. In addition, a pharmaceutical preparation is obtained in the same manner except that any of the compounds of Examples 2 to 36 is used instead of the compound of Example 1.

Reference formulation example 1 (1) Oral fuecoxib 5.Omg

 (2) Salt 20.Omg

 (3) Total volume of distilled water is 2mL

 Dissolve 5.Omg of oral fuecoxib and 20.Omg of salt in distilled water, and add water to bring the total volume to 2.OmL. Filter the solution and fill into 2 mL ampoules under aseptic conditions. After sterilizing the ampoule, seal it to obtain a solution for injection.

Reference formulation example 2

 (1) Oral fuecoxib 5 Omg

 (2) Lactose 34mg

 (3) Maize 10.6 mg

 (4) Corn powder (paste) 5mg

 (5) Magnesium stearate 0.4mg

 (6) Canoleboxy methinolate cellulose calcium 2 Omg

 Total 1 20 mg

 According to a conventional method, the above (1) to (6) were mixed and tableted with a tableting machine to obtain tablets.

Formulation Example 4

 Combine the formulation manufactured in Formulation Example 1 or 2 with the formulation manufactured in Reference Formulation Example 1 or 2.

Test Example 1 Radioligand receptor binding inhibitory activity (binding inhibitory activity using receptor from human lymphoblastoid cells (IM-9))

MA Cascieri (Molecular Pharmacology, Vol. 42, p. 458 (published in 1999)) and the like were modified and used. Receptors were prepared from human lymphoblast cells (IM-9). After inoculation of IM-9 cells (2 XI 0 ^s cells / mL), the cells were cultured (1 liter) for 3 days, and then centrifuged at 500 XG for 5 minutes to obtain a cell pellet. The obtained pellet was washed once with a phosphate buffer (Flow Laboratories, CAT. No. 28-103-05), and then 3 OmL of 12 OmM sodium chloride, 5 mM potassium chloride, 2 μg No mL chymostatin, 40 μ 5 OmM Tris containing 5 mL of bacitracin, 5 μg / mL phosphoramidone, 0.5 mM fenii / remethinoresnorelefonyl fluoride, and lmM ethylenediaminetetraacetic acid.Polytron 'homogenizer in hydrochloric acid buffer (pH 7.4). The mixture was disrupted using Kineraatika (Germany, Germany) and centrifuged at 40,000 XG for 20 minutes. The separated product was washed twice with 3 OmL of the above buffer solution, and then stored frozen (180) as a recipient.

This sample was treated with a reaction buffer [5 OmM Tris' hydrochloric acid buffer (ρΗ7.4), 0.02% bovine serum albumin, lmM phenylmethylsulfonyl fluoride, to a protein concentration of 0.5 mg / mL. 2 μg ZmL chymostatin, 40 μg ZmL bacitracin, 3 mM manganese chloride], and used 100 μl volume for the reaction. The sample, ¹²⁵ I-BHSP (G. 46 KB q) was added, and the mixture was reacted in 0.2 mL of a buffer solution at 25 ^ for 30 minutes. Nonspecific binding amount is添Ka卩substance P to be 2 X 10- ⁶ M are determined meta.

 After the reaction, using a cell harvester [290 PHD, Cambridge Technology, Inc., USA, USA], a glass filter (GF / B, manufactured by Whatman, USA) Stop the reaction by rapid filtration on the top and wash three times with 250/21 of 50 mM Tris' hydrochloric acid buffer (pH 7.4) containing 0.02% bovine serum albumin to remove radioactivity remaining on the filter. Before use, the filter was immersed in 0.1% polyethyleneimine for 24 hours and air-dried before use.

Then, the antagonistic activity of the compound obtained in Example, respectively, were determined as the drug concentration required to show 50% inhibition under the conditions described above (IC _5. Values) to obtain results shown in Table 20 .

Table 20

ラジオ ' リガンドとは、 〔¹²⁵1] でラベルされたサブスタンス Pを示す。

Radio 'ligand refers to substance P labeled with [ ¹²⁵¹ ].

 Table 20 shows that the compounds of the present invention have excellent substance P receptor antagonism.

Test Example 2 Inhibitory activity of NK1 agonist GR 73632 on hyperlocomotion induced by intracerebroventricular injection of guinea pig

 The experiment was performed with reference to the method of Rupniak et al. (Neuropharmacology, 39, 1413-1421, 2000). The head of a white male Hartley guinea pig anesthetized with ether

(David Kopf, U.S.A.), drill a small hole at the bregma position of the skull with a dental drill with a midline incision in the scalp, so that the tip reaches the 第 ^ ί chamber (7. (5 to 8 mm below) A 27 G needle was inserted, and GR 73632 (Bachem, Switzerland) dissolved in physiological saline for 0.1 nmo 1 was injected at a volume of 5 / χ1 for 1 minute. After administration, the incision was sutured, and the locomotor activity was measured immediately after the animal awakened from anesthesia.

(AI EX AUTO MK_110, Muromachi Kikai, Japan) for 30 minutes. Medicine Was suspended in a 0.5% methylcellulose solution and orally administered at a volume of 2 mL / kg 45 minutes before GR 73632 administration. The control group was orally administered the same volume of a 0.5% methylcellulose solution. In addition, there was also a sham treatment group in which physiological saline was administered to the ventricle 內 instead of the GR 73632 solution. Each treatment group consisted of at least 4 patients. The drug was evaluated by calculating the inhibition rate according to the following formula. In addition, if necessary, ID _5. The values were calculated using the inhibition rate (Table 21).

 (I) Spontaneous locomotor activity of the subject administration group S—Spontaneous locomotor activity of the sham treatment group

 X 100

 '' Spontaneous momentum of control group-spontaneous treatment Spontaneous momentum of group a Table 2

表 21より、本発明の化合物が優れた NK 1ァゴニスト GR 73632のモノレモット 脳室内 により^ざれる自発運動亢進に^ fる抑制活性を有することが分かった。

From Table 21, it was found that the compound of the present invention has an excellent inhibitory activity on the motility of NK1 agonist GR 73632 in the monoremot of the ventricle.

 Industrial applicability

 The compound (I) of the present invention or a salt or a prodrug thereof has a tachykinin receptor antagonistic activity, particularly a substance P receptor antagonistic activity, is low in toxicity, and is safe as a drug. Therefore, the compound (I) of the present invention or a salt or a prodrug thereof is useful as a pharmaceutical composition, for example, a tachycun receptor antagonist, dysuria, etc. This application is based on a patent application No. 2001-78567 filed in Japan, the contents of which are incorporated in full herein.

Claims

 The scope of the claims  Expression

 [Wherein the ring A is a substituted pyridine ring, R ² represents a hydrogen atom, a halogen atom or a C _β alkyl group which may be halogenated, R ³ represents a hydrogen atom or an alkyl group,  R is the same or different and represents a halogen atom, an optionally halogenated alkyl group, an optionally halogenated de alkoxy group, a cyano group or a hydroxy group,  m is an integer from 0 to 3,  n represents 1 or 2, and p represents an integer of 0 to 3. Or a compound represented by the formula 2. Expression

 [Wherein the A 'ring represents a pyridine ring, R ¹ ′ is (1) an optionally substituted C ^ -e alkyl group, and (2) an optionally substituted C ^ -e alkyl group. An optional Ci-e alkoxy group, (3) optionally having a substituent. § Li one Ruo alkoxy group, (4) an optionally substituted heterocyclic ring Okishi group, (5) - ₆ alkoxy one carboxy group, (6) alkylthio group which may have a substituent, (7) It may have a substituent. Ariruchio group, (8) heterocyclic Chiomoto may have a substituent, (9) may have a substituent group 〇 ₆ _ ₁₀ Ariru group, which may have a (10) substituent Good heterocyclic group, (1 1) Ci-e acyloxy group, (12) hydroxy group, (13) nitro group, (14) halogen atom, (15) cyano group, (16) (17) an amidino group optionally having a substituent, (18) an oxime group, (19) a carboxyl group, (20) an acyl group optionally having an S-substituent, ) A carpamoyl group optionally having a substituent, (22) a thiocarbamoyl group optionally having a substituent or (23) a Ci-e alkylsulfonyl group,  Other symbols have the same meaning as in claim 1. 2. The compound according to claim 1, which is a compound represented by the formula: or a salt thereof. 3. R ¹ 'force; (1) alkyl group which may have a substituent; (2) _β- alkoxy group which may be halogenated; (3) -6-alkoxycarbonyl group , (4) optionally halogenated alkylthio group, (5) C ₆ - ₁₀ Ariru group, (6) Ci one ₆ Ashiruamino group, (7) - 6 Ashiruokishi group, (8) hydroxy group, (9) Nitro group, (10) halogen atom, (11) cyano group, (12) amino group, (13) mono or dialkylamino group, (14) one nitrogen atom other than carbon atom A 5- or 6-membered cyclic amino group which may contain an oxygen atom or a nitrogen atom, (15) ₆ alkyl - sulfonyl ^^ amino group, (16) carboxyl group, (1-7) - 6 alkyl one carbonyl group, (18) Honoremiru group, (1-9) forces Rubamoiru group, (20) mono- or di C _{1- 6} alkyl force Rubamoiru group, (21) ^ - ₆ alkylsulfonyl group, (22) mono-, di- or tree 〇 I ₆ alkylureido group, (23) C -e alkoxy Ichiriki Ruboniruamino group or (24) alkoxy - carbonylation R _{6 is an} alkylamino group wherein R is the same or different and is a halogen atom, an optionally halogenated- ₆ alkyl group, an optionally halogenated alkoxy group or a cyano group 3. The compound according to claim 2, wherein 4. Ring A

[R ¹ has the same meaning as R ¹ 'in Claim 2. 2. The compound according to claim 1, wherein 5. Ring A

[R ¹ has the same meaning as R ¹ 'in Claim 2. 2. The compound according to claim 1, wherein 6. Ring A is (1) an _s- alkyl group which may be substituted with a hydroxy group, a halogen atom or a cyano group, (2) a heterocyclic oxy group, (3) a halogen atom, (4) a cyano group, ( 5) Mono- or di-Ci-s-alkyl rubamoyl group, (6) 5- or 6-membered cyclic aminocarbonyl which may contain an oxygen, nitrogen or sulfur atom in addition to one nitrogen atom and carbon atom Group, (7) old. 2. The compound according to claim 1, wherein the compound is a pyridine ring substituted with (8) a heterocyclic carbonylyl group or (9) a heterocyclic group. 7. The compound according to claim 1, wherein R ² is a hydrogen atom or a halogen atom. 8. The compound according to claim 1, wherein R ³ is an alkyl group. 9. The compound according to claim 1, wherein R ³ is 3-coordinate. 10. R is the same or different compounds according to claim 1, wherein a halogen atom or an optionally halogenated or _ _e alkyl group. 1 1. Expression

[In the formula, R ⁴ and R ⁵ are the same or different and are each a hydrogen atom, a halogen atom, a C ₆ alkyl group which may be halogenated, a C! -E alkoxy group which may be Represents a group. 2. The compound according to claim 1, which represents a group represented by the formula: 12. The compound according to claim 11, wherein R ⁴ and R ⁵ are the same or different and are a hydrogen atom or an alkynole group which may be halogenated.  1 3. Expression (In)

 [Wherein the A 'ring represents a pyridine ring, R ¹ ′ is (ί) an alkyl group optionally having a substituent, (2) an Ci- _β alkoxy group optionally having a substituent, and (3) an optionally substituted substituent. Aryloxy group, (4) optionally substituted heterocyclic oxy group, (5) alkoxy-carbonyl group, (6) optionally substituted — 6-alkylthio group, (7) substituted Ji may have a group _6. Arylthio group, (8) optionally substituted heterocycle A thio group, (9) Ci which may have a substituent. Aryl group, (10) heterocyclic group which may have a substituent, (11) acyloxy group, (12) hydroxy group, (13) nitro group, (14) halogen atom, ( 15) a cyano group, (16) an amino group which may have a substituent, (17) an amidino group which may have a substituent, (18) an oxime group, (19) a carboxyl group, (20 ) An optionally substituted acyl group, (21) an optionally substituted rubamoyl group, (22) an optionally substituted thiocarpamoyl group or (23) alkylsulfonyl Group R ² ′ represents a hydrogen atom, a halogen atom or an alkyl group, R ³ 'is — 3 alkyl group, R ⁴ ′ and R ⁵ ′ represent the same or different and may be halogenated alkyl groups. 2. The compound according to claim 1, which is a compound represented by the formula: or a salt thereof. 14.

14. The compound according to claim 13, which is: 15. R ¹ 'force s (1) _6- alkyl group which may be substituted with a hydroxy group, halogen atom or cyano group, (2) heterocyclic oxy group, (3) halogen atom, (4) cyano group, (5) mono- or di-alkyl rubamoyl group, (6) 5- or 6-membered cyclic aminocarbonyl group which may contain an oxygen atom, a nitrogen atom or a sulfur atom in addition to one nitrogen atom and carbon atom, (7 14. The compound according to claim 13, which is an alkyl-carboamino group, (8) a heterocyclic carbonylamino group, or (9) a heterocyclic group. 16. (a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] 1 2 —chloro-9-methinolee 5—phenyl 8,9,10,1 1—tetrahydro 7H— [1, 4] diazocino [2, 1— g] [l, 7] naphthyridine-1,6,13-dione, (a R, 9R) -1 7— [3,5-bis (trifluoromethyl) benzyl) 2, 9 Dimethinole-5-phenyl8,9,10,1 1-tetrahydro7H— [1,4] diazosino [2,1-g] [1,7] naphthyridine-1,6,1-dione,  (a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] —9—methyl-6,1 3-dioxo-5-phenyl-1,6,8,9,10 1,1 13—Hexahi Draw 7H— [1, 4] diazocino [2, 1— g] [l, 7] naphthyridine-one 2—force  (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] -2-chloro-5- (4-fluorophenyl) -1-9-methyl-8,9,10,1 1- 7H— [1,4] diazino [2,1-g] [1,7] naphthyridine-1,6—dione,  (a R, 9 R)-7— [3,5-bis (trifluoromethyl) benzyl] —5— (4-fluorophenyl) -1,2,9-dimethyl-1,8,9,10,1 1— Tetrahydro-1-H 7 [—1.4] diazocino [2, 1-g] [1, 7] naphthyridine-1-6.13-dione,  (a R, 9 R) — 7— [3,5-Bis (trifluoromethyl) benzyl] 1- (4-F / L-Fe2Z) 1 9-Methinole 6,13-Dioxo-1 6, 8, 9, 10, 1 1, 1 3—Hexahi Draw 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1—force / repo-tolyl,  (a R, 9 R) —7— (3,5-dimethylbenzyl) mono 5 -— (4-phenolelophenyl) -2,9 monodimethyl 8, 9, 10, 1 1—tetrahydro 7H— [1 , 4] diazo sino [2, 1 -g] [1.7.] Naphthyridine-1,6,13-dione,  (a R, 4R) —2— [3,5-Bis (trifluoromethyl) benzyl] -1,4,9-dimethyl-1-13-phenyl-1,3,4,5,6-tetrahydro-1H— [1 , 4] diazocino [1, 2—b] [2.7] naphthyridine-1,8-dione,  (aR, 4R) — 2— [3,5-bis (trifluoromethyl) benzyl] —1 3— (4—fluoropheninole) 1,4,9-dimethyl-3,4,5,6-tetrahydro 2 H— [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine-1,8-dione, (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] — N, N, 9-trimethyl-6,1 3-dioxo-1-5-phenyl 2,6,9 1 0, 1 1, 1 3—Hexahi Draw 7H— [1,4] diazosino [2.1-g] —1,7-naphthyridine-1-2-canoleboxamide,  (a R, 9 R)-7-[3,5-bis (trifluoromethyl) benzyl] — 9-methyl-5-phenyl 2- (1,3-thiazolidine-3-ylcanolebonyl) 1,8,9 , 1 0,1 1—Tetrahydro 7H— [1,4] diazosino [2,1-g]-1,7_naphthyridine-6,1 3—dione,  (a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] — 9-methyl A 5-feru-2-u (pyridine-13-inoleoxy) 1,8,9,10 , 1 1—Tetrahydridone 7H— [1, 4] diazocino [2, 1-g]-1,7—Naphthyridine-1,6,1 3—dione,  N-[(a R, 9 R) — 7— [3,5-bis (trifluoromethyl) benzyl] 1 9—methyl-1,6,13-dioxo-5-pheninolee 6,8,9,10 , 1 1,1 3—Hexahydro-7H— [1,4] diazosino [2,1-g]-1,7—Naphthyridine-1-yl] nicotinamide,  N-[(a R, 9 R) 1 7— [3,5-bis (trifluoromethyl) benzyl]-9—Methinole-6,13-Dioxo_ 5—Feninole-6,8,9 , 1 0,1 1, 1 3—Hexahi Draw 7H— [1,4] diazosino [2,1—g] —: I, 7—Naphthyridin-1-yl] acetamide  (a R, 9 R) ~ 7- [3,5-bis (trifluoromethyl) benzyl] _ 9-methyl 5- 5-phenyl 2- (1H-tetrazo-l-uyl) 1-8, 9, 1 0, 1 1—tetrahydro 7H— [1, 4] diazosino [2, 1-g] -1,7-naphthyridine—6,13-dione, [(a R, 9R) — 7— [3,5-bis (trifluoromethyl) benzyl] — 9-methyl-6,13-dioxo-5-pheninole 6,8,9,10,11, 1 3— ^ «Kisahi draw 7H— [1.4.] Diazocino [2, 1-g]-1, 7—Naphthyridine 1 2— Yl] acetonitrile,  (a R, 9 R) —7— [3,5-Bis (trifluoromethyl) benzyl] -1-2- (phenylolemethyl) -19-methyl-5-phenyl 8, 9, 10, 1 1-tetrahi Draw 7H— [1,4] diazocino [2,1-g]-1,7—naphthyridine-1,6,13—dione,  (a R, 9 R) — 9-Methyl-1 7— [3-Methyl-1 5 _ (trifluoromethyl) benzyl] 1,6,13-Dioxo-1 5—Feninole 6,8,9,10, 1 1, 1 3—Hexahi draw 7H— [1, 4] diazocino [2, 1— g] [1, 7] naphthyridine 1 2  (a R, 9 R) 1-5- (4-fluorophenyl) 1-9-methyl-7- [3-methyl-1-5- (trifluoromethyl) benzyl] — 6,13-dioxo-1,6,8,9 1 0, 1 1, 1 3 1 ^ · Kisahhi Draw 7 H— [1, 4] diazocino [2. 1 -g] [l, 7] naphthyridine 1-2-carbonitrile,  (a R, 9 R) — 2-chloro-1--5- (4-fluorophenyl) -19-methyl -7- [3-Methynole-5- (Trifluoromethynole) benzyl] -18,9,10, 1 1—tetrahydro 7H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine 1-6, 13-dione Or the compound according to claim 1, which is a salt thereof. 1 7. A prodrug of the compound of claim 1. 1 8. Expression

[Wherein, L represents a leaving group, and other symbols have the same meanings as in claim 1.] 2. The compound according to claim 1, wherein the compound or a salt thereof is subjected to a ring closure reaction. A method for producing (I) or a salt thereof.  1 9 Expression

 [In the formula, A and 'represent an N-hydroxylated pyridine ring, and the other symbols have the same meanings as in Claim 1. 2. The method for producing a compound (I) or a salt thereof according to claim 1, wherein the compound or a salt thereof is subjected to a nucleophilic reaction in the presence of an activating agent.  2 0. Expression

Wherein R ¹ ′ is a halogen atom, and other symbols have the same meanings as in claim 1.Substituted or substituted with a compound represented by the formula 2. The method for producing the compound (I) or a salt thereof according to claim 1, wherein a combination of a reaction, a transfer reaction, a hydrolysis reaction, a nucleophilic substitution reaction, an alkylation reaction or an acylation reaction is used. 2 1.

[Wherein, R ^lb represents a cyano group, and other symbols have the same meanings as in claim 1.] Hydrolysis, amidation, acylation, substitution, alkylation 2. The method for producing the compound (I) or a salt thereof according to claim 1, wherein a compounding reaction, a transfer reaction, an addition reaction, a cyclization reaction, and an oxidation reaction are used in combination as necessary.  22. A pharmaceutical composition comprising the compound according to claim 1 or a prodrug thereof and a pharmaceutically acceptable carrier.  23. The composition according to claim 22, which is a tachykinin receptor antagonist.  24. The composition according to claim 22, which is a substance P receptor antagonist. 25. The composition according to claim 22, which is an agent for preventing or treating substance P-related diseases. 26. The composition according to claim 22, which is an agent for improving abnormal urination. 27. The composition according to claim 22, which is an agent for preventing or treating urinary frequency incontinence. 2 8. Asthma, rheumatoid arthritis, osteoarthritis, pain, cough, pruritus, chronic obstructive pulmonary disease, irritable bowel disease, vomiting, HIV infection, depression, anxiety 'neurosis, obsessive-compulsive disorder, panic The composition according to claim 22, which is an agent for preventing and treating disorders, manic disorders and schizophrenia. 29.An effective amount of the compound according to claim 1 or a prodrug thereof, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, Immunotherapeutic agents, cachexia improving agents, anti-inflammatory agents, saccharification inhibitors, nerve regeneration promoters, antidepressants, antiepileptic drugs, antiarrhythmic drugs, acetylcholine receptor ligands, endocerin receptor antagonists, monoamine uptake inhibitors, Indoruamin uptake inhibitors, narcotic analgesics, GABA receptor agonists, GABA uptake inhibitors, alpha ₂ receptor agonists, topical analgesics, pro Tin kinase C inhibitors, anti-anxiety agents, phosphodiesterase inhibitors, Dopamine receptor Body agonistsAntagonists, serotonin receptor agonistsAntagonists, serotonin uptake inhibitors, sleep _inducers , anticholinergics, _Λι receptor blockers, muscle relaxants, potassium channel openers, calcium channel blockers, Alzheimer's disease prevention 'therapeutic agent, Parkinson's disease prevention' therapeutic agent, multiple sclerosis prevention 'therapeutic agent, histamine 1 "^ receptor inhibitor, protonpump inhibitor, antithrombotic agent and NK-2 receptor antagonist A medicament comprising a combination with an effective amount of one or more drugs selected from the group consisting of:  30. A method for preventing and treating pollakiuria and urinary incontinence, comprising administering to a mammal an effective amount of the compound according to claim 1 or a prodrug thereof.  31. Asthma, rheumatoid arthritis, osteoarthritis, pain, cough, pruritus, chronic obstructive pulmonary disease, irritable bowel, characterized by administering an effective amount of the compound according to claim 1 or a prodrug thereof. Prevention of disease, vomiting, HIV infection, depression, anxiety, neurosis, obsessive-compulsive disorder, panic disorder, manic sickness or schizophrenia. 32. An effective amount of the compound according to claim 1 or a prodrug thereof for a mammal, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic for a mammal. , Chemotherapeutic agent, immunotherapy agent, cachexia improving agent, anti-inflammatory agent, glycation inhibitor, nerve regeneration promoter, antidepressant, antiepileptic, antiarrhythmic, acetylcholine receptor ligand, endothelin receptor antagonist drugs, monoamine uptake inhibitors, Indoruamin uptake inhibitors, narcotic properties analgesic agents, GABA receptor agonists, GABA uptake inhibitors, alpha ₂ receptor agonists, topical analgesics, Protein kinase C inhibitors, anxiolytics , phosphodiesterase inhibitors, dopamine receptor agonists, antagonists, serotonin receptor agonists, antagonists, serotonin preparative interrupt inhibitors, sleep-inducing agents, anticholinergic agents, _{alpha iota} receptor blocking , Muscle relaxant, Potassium channel opener, Calcium channel blocker, Alzheimer's disease prevention 'therapeutic', No, 'Kinson's disease prevention'. Urinary frequency and urinary incontinence characterized by co-administration with an effective amount of one or more drugs selected from the group consisting of a proton pump inhibitor, an antithrombotic drug and a ΝII-2 receptor antagonist Prevention and treatment methods. 33. Effective amount of the compound according to claim 1 or a prodrug thereof for a mammal And antidiabetic, antihyperlipidemic, antihypertensive, antiobesity, diuretic, chemotherapeutic, immunotherapeutic, cachexia improving, anti-inflammatory, glycation inhibitor , Nerve regeneration promoter, antidepressant, antiepileptic, antiarrhythmic, acetylcholine receptor ligand, endothelin receptor antagonist, monoamine uptake inhibitor, indolamine uptake inhibitor, narcotic analgesic, GABA receptor agonist drugs, GABA uptake inhibitors, alpha ₂ receptor agonists, topical analgesics, protein kinase C inhibitors, anti-anxiety agents, phosphodiesterase inhibitors, de one dopamine receptor agonist-antagonists, serotonin receptor agonists, antagonists drugs, serotonin preparative interrupt inhibitors, sleep-inducing agents, anticholinergic agents, _{tt l} receptor blockers, muscle relaxants, Kariumuchi Yan'neru openers, calcium channel blockers, Artz Prevention of Hymer's disease 'Therapeutic agent, prevention of Parkinson's disease' remedy, Multiple sclerosis prevention and remedy, Histamine Hi receptor inhibitor, Proton pump inhibitor, Antithrombotic, HIV infection remedy, Chronic obstruction Asthma, rheumatoid arthritis, osteoarthritis, pain, characterized by co-administration with an effective amount of one or more drugs selected from the group consisting of drugs for treating pulmonary diseases and NK-2 receptor antagonists How to prevent and treat cough, pruritus, chronic obstructive pulmonary disease, irritable bowel disease, vomiting, depression, anxiety-neurosis, obsessive-compulsive disorder, panic disorder, mania or schizophrenia.  34. Use of the compound according to claim 1 or a prodrug thereof for producing a prophylactic or therapeutic agent for pollakiuria / urinary incontinence.  3 5. Asthma, rheumatoid arthritis, osteoarthritis, pain, cough, pruritus, chronic obstructive pulmonary disease, irritable illness, vomiting, HIV infection, depression, anxiety neurosis, obsessive-compulsive disorder, panic disorder Use of the compound according to claim 1 or a prodrug thereof for producing an agent for preventing or treating harm, mania, or schizophrenia.