WO2002022574A1 - Tricyclic heterocyclic compound, process for producing the same, and use thereof - Google Patents

Abstract

A compound represented by the formula, a salt thereof, or a prodrug thereof: (I) wherein R1 represents hydrogen, optionally substituted alkyl, aryl, acyl, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl, or alkylsulfonyl; R2 represents hydrogen, halogeno, or optionally halogenated alkyl; R3 represents hydrogen or alkyl; R represents hydrogen, halogeno, optionally halogenated alkyl, or optionally halogenated alkoxy; m is an integer of 0 to 3; n is 1 or 2; and p is an integer of 0 to 3, provided that when R?1 and R2¿ are methyl, R3 is hydrogen, the group represented by formula (A) is the group represented by formula (B), and m is 1, then n is 1. The compound has an antagonistic effect on tachykinin receptors, especially on a substance P receptor, and is useful as a medicine such as a urination anomaly ameliorant.

Description

 Specification

 Tricyclic heterocyclic compound, its production method and its use

 Technical field

 The present invention relates to a novel 3 璟 -heterocyclic compound having an excellent kinkinin receptor antagonistic activity, 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 the M ring has a partial structure

Heterocyclic ring having 112 C, one CO—N or one CS—X as X; R ^a and R ^b are bonded together to form a ring A, or the same or different hydrogen atom; Or a substituent in the M ring; A ring and B ring are each an optionally substituted homo- or heterocyclic ring, at least one of which may have a substituted heterocyclic ring; The ring is a homo- or heterocyclic ring which may have a substituent; the Z-ring is a nitrogen-containing heterocyclic ring which may be substituted; and n is an integer of 1 to 6. It has been described that the heterocyclic compound represented by the formula (1) or a salt thereof has an inhibitory action on a quinkinin receptor, an antagonistic action on a substance P receptor, and an antagonistic action on a eurokinin A receptor.

 Disclosure of the invention

 An object of the present invention is to provide a tricyclic heterocyclic compound having an action stronger than that of a conventional compound having an inhibitory action on evening kikinin receptor, a method for producing the same, and an agent for improving abnormal urination including the compound. And

The present inventors have conducted intensive studies in view of the above circumstances, and as a result,

Wherein, R ¹ represents (1) hydrogen atom, (2) a halogen atom, Shiano, hydroxy, _ ₆ alkoxy ₍₆ Ashiru, C ₆ alkylsulfonyl, carboxyl, CI- _C6 alkoxy - carbonyl, force Rubamoiru, mono- or di - C _i-6 alkyl - force Rubamoiru, sulfamoyl, mono- or di-one CI- e alkyl - Surufamoi Le, C ₆ - ₁₄ Ariru and 5 to have a substituent group selected from the group consisting of 14-membered heterocyclic group C i-6 alkyl group, (3) 〇 ₆ _ ₁₄ aryl group, (4) Ci-e acyl group, (5) C i-6 alkoxymonocarbonyl group, (6) carbamoyl group, (7 ) mono- or di - 6 alkyl Ichiriki Rubamoiru group or (8) - 6 alkyl sulfonyl group, R ² represents a hydrogen atom, a halogen atom or a halogenated may CI- ₆ alkyl group, R ³ is hydrogen Child or CI- ₆ alkyl radical, R is different was the same or a hydrogen atom, a halogen atom, an optionally halogenated C [Bok have ₆ Al kill group or halogenated which may be C i_ ₆ alkoxy group , M is 0 or

で表される基が式 An integer of 3, n represents 1 or 2, and p represents an integer of 0 to 3. Where R ¹ is a methyl group, R ² is a methyl group, R ³ is a hydrogen atom, and the formula

Is a group represented by the formula

で表される基、 mが 1のとき、 nは 1を示す。〕で表される 3璟性複素環化合物ま たはその塩が、 その特異な化学構造に基づいて予想外にも強いタキキニン受容体 拮抗作用 （特に、 サブスタンス P受容体拮抗作用） 等を有し、 医薬として十分に 満足できるものであることを見出し、これらの知見に基づいて本発明を完成した。 すなわち、 本発明は、

When m is 1, n represents 1. The 3 璟 -heterocyclic compound or salt thereof has unexpectedly strong tachykinin receptor antagonism (particularly substance P receptor antagonism) based on its unique chemical structure. The present inventors have found that the present invention is sufficiently satisfactory as a medicine and completed the present invention based on these findings. That is, the present invention

 〔1 set

で表される基が式 Wherein, R ¹ represents (1) hydrogen atom, (2) a halogen atom, Shiano, hydroxy, _ ₆ alkoxy Ashiru, C ^ 6 alkylsulfonyl, carboxyl, - ₆ alkoxy - carbonyl, force Rubamoiru, mono- or di - C i ₆ alkyl - force Rubamoiru, sulfamoyl which may have a substituent selected from the group consisting of mono- or di-one Ci e alkyl one Surufamoi Le, C ₆ _ ₁₄ Ariru and 5 to 14-membered heterocyclic group - ! ₆ alkyl group, (3) C _{6 14} Ariru group, (4) C _ ₆ Ashiru group, (5) C Bok ₆ alkoxy - carbonyl group, (6) force Rubamoiru group, (7) mono- or di one - 6 alkyl Ichiriki Rubamoiru group or (8) Ci ₆ alkyl sulfonyl group, R ² is a hydrogen atom, a halogen atom or a halogenated which may be C ^ 6 alkyl group,: R ³ is a hydrogen atom or a C i-6 The alkyl group, R represents the same or are different and each represents a hydrogen atom, a halogen atom, an optionally halogenated C [Al Kill group or halogenated which may be C I ₆ alkoxy group, m is 0 to 3 An integer, n represents 1 or 2, and p represents an integer of 0 to 3. Where R ¹ is a methyl group, R ² is a methyl group, R ³ is a hydrogen atom, and the formula

Is a group represented by the formula

When m is 1, n represents 1. (Hereinafter also referred to as compound (I)) or a salt thereof,

(2) The compound according to (1), wherein R ² is a hydrogen atom or a halogen atom, (3) the compound according to (1), wherein R ³ is a Ci ₆ alkyl group,

(4) the compound according to (1), wherein R ³ is in the /? Configuration,

で表される基が式 (5) Expression

Is a group represented by the formula

[Wherein, R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom, or a halogenated group (showing a ₆ alkyl group or a C ^ -e alkoxy group).] [1] The compound described in the item,

(6) Expression

(In the formula, R ¹ ′ is an alkyl group or a acyl group, R ² ′ is a hydrogen atom or a halogen atom, R ³ ′ is an alkyl group, and R ⁴ ′ and R ⁵ ′ are the same or different. a C Bok ₃ alkyl group optionally, n represents 1 or 2. The compound according to (1), which is a compound or a salt thereof represented by

[7] R ¹ 'is (Bok ₃ Compound of the [6], wherein a Ashiru group,

 [8] (4 S) — 2 -— [3,5-bis (trifluoromethyl) benzyl] — 12— (4-fluorophenyl) -14,9-dimethyl-1,2,3,4,5,8 9,10,11-octyhydro [1,4] dazepino [1,2, b] [2,7] naphthyridine—1,7-dione (Example 4) or a salt thereof,

 (4S) -9-Acetyl-1-2- [3,5-bis (trifluoromethyl) benzyl] — 12— (4-Fluorophenyl) -14-methyl-2,3,4,5,8,9, 1 0, 11 1-octane hydro [1,4] diazepino [1,2—b] [2,7] naphthyridine-1 1,7-dione (Example 7),

 (aR, 4 R) — 2— [3,5-bis (trifluoromethyl) benzyl] — 13- (4-fluorophenyl) 1,4,10-dimethyl-3,4,5,6,9,10,10 1 1,12-octyhydro-1H- [1,4] diazosino [1,2-b] [2,7] naphthyridin-1,8-dione (Example 12) or a salt thereof,

 (aR, 4 R) — 10-acetyl-2— [3,5-bis (trifluoromethyl) benzyl] -1-13- (4-fluorophenyl) -1-4-methyl-3,4,5,6,9,10 , 1 1, 12-octane hydro-1H— [1,4] diazosino [1,2—b] [2,7] naphthyridine-1,8-dione (Example 15),

(aR, 4 R) —2— [3,5-bis (trifluoromethyl) benzyl] — 13 — (4-Monofluorophenyl) 1,4-methyl-10-propionyl 3,4,5,6,9,10,11,12—Hydrogen hydro-2H— [1,4] diazosino [ 1,2-b] [2,7] naphthyridine-1, 8-dione (Example 16),

 (aR, 4 R) -2-(3,5-dimethylbenzyl) 1 13-(4-fluorophenyl) 1,4,10-dimethyl 1,3,4,5,6,9,10,11 , 1 2-octane hydro-2 H-[1,4] diazocino [1,2-b] [2,7] naphthyridine-1, 8-dione (Example 20) or a salt thereof, or

 (aR, 4 R) 1 10—acetyl-2— (3,5-dimethylbenzyl) 1 13—

(4-Monofluorophenyl) 1,4-methyl-3,4,5,6,9,10,11,12-octanohydro-2H— [1,4] diazino [1,2—b] [2 [7] naphthyridine-1 1,8-dione (Example 25);

(9) a prodrug of the compound according to (1),

 (10) (a)

[Wherein the symbols have the same meanings as described in [1]. To a reduction reaction of the compound represented by the formula

[Wherein the symbols have the same meanings as described in [1]. Or a compound represented by the formula Obtaining a salt, or

 Equation (b)

 [Wherein the symbols have the same meanings as described in [1]. Or a salt thereof represented by the formula

 R ^ -L '(IV)

Wherein, L 'is a leaving group, R ¹ a is as defined for R ¹ of the [1], wherein. Where R

¹ a is not a hydrogen atom. ] Or a salt thereof,

(D-2

 Wherein each symbol is as defined above. Or a salt thereof, or

 Equation (c)

〔式中、 各記号は第〔1〕項記載と同意義を示す。〕で表される化合物またはその 塩を、 式

[Wherein the symbols have the same meanings as described in [1]. A compound represented by the formula:

 R ^ -L '(IV)

Wherein, L 'is a leaving group, R ¹ a is as defined for R ¹ of the [1], wherein. Where R

¹ a is not a hydrogen atom. ] Or a salt thereof to form a quaternary salt.

 Wherein each symbol is as defined above. Or a salt thereof to obtain a compound represented by the formula:

[Wherein the symbols have the same meanings as described in [1]. ] Or a salt thereof.

(11) Expression (R) P

 (CH) m (I)

Wherein, R ¹ represents (1) hydrogen atom, (2) a halogen atom, Shiano, hydroxy, _ ₆ alkoxy Ashiru, C alkylsulfonyl, carboxyl, ₍₆ alkoxy one carbonyl, force Rubamoiru, mono- or di - C i - _e alkyl - force Rubamoiru, sulfamoyl which may have a substituent selected from the group consisting of mono- or di C ₆ alkyl one Surufamoi Le, C ₆ _ ₁₄ Ariru and 5 to 14-membered heterocyclic group C i- 6 alkyl group, (3) C ₆ -! ₁₄ Ariru group, (4) C _ ₆ Ashiru group, (5) C ₆ alkoxy one carbonyl group, (6) force Rubamoiru group, (7) mono- or di one - 6 alkyl Ichiriki Rubamoiru group or (8) - 6 alkyl sulfonyl grave, R ² is a hydrogen atom, a halogen atom or an optionally halogenated C [Bok ₆ alkyl group, R ³ is a hydrogen atom or a Ci-e The alkyl radical, R is different from a hydrogen atom was the same or a halogen atom, an optionally halogenated C [i_ ₆ Al Kill group or halogenated which may be C I ₆ alkoxy group, m is 0 to N is 1 or 2, p is an integer of 0 to 3, provided that R ¹ is a methyl group, R ² is a methyl group, R ³ is a hydrogen atom,

で表される基が式 R) P

Is a group represented by the formula

で表される基、 mが 1のとき、 nは 1を示す。〕で表される化合物もしくはその塩 またはそのプロドラッグ、 および薬理学的に許容される担体を含有する医薬組成 物、

When m is 1, n represents 1. Or a salt thereof or a prodrug thereof, and a pharmacologically acceptable carrier.

 (1 2) The composition according to (11), which is an evening kikinin receptor antagonist,

 (13) The composition according to (11), which is a substance P receptor antagonist,

(14) The composition according to (11), which is an agent for improving urinary abnormality,

 (15) The composition according to (11), which is a preventive and therapeutic agent for pollakiuria and urinary incontinence,

[16] Asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel disease, vomiting,

The composition according to (11), which is an agent for preventing or treating HIV infection, chronic obstructive pulmonary disease, depression, anxiety, manic depression or schizophrenia,

 [17] Formula for mammals

[Wherein the symbols have the same meanings as described in [1]. Or a salt thereof or a prodrug thereof is administered in an effective amount.

 [18] Formula for mammals

〔式中、 各記号は第〔 1〕項記載と同意義を示す。〕で表される化合物もしくはそ の塩またはそのプロドラッグを有効量投与することを特徴とする喘息、 リューマ チ関節炎、 変形関節炎、 疼痛、 咳、 過敏性腸疾患、 嘔吐、 H I V感染症、 慢性閉 塞性肺疾患、 うつ病、 不安症、 躁鬱病または精神分裂病の予防または治療方法。 〔1 9〕頻尿 '尿失禁の予防 ·治療剤を製造するための式

[Wherein the symbols have the same meanings as described in [1]. Characterized by administering an effective amount of a compound represented by the formula (I) or a salt thereof or a prodrug thereof, characterized by asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel disease, vomiting, HIV infection, chronic closure. A method for preventing or treating obstructive pulmonary disease, depression, anxiety, manic depression or schizophrenia. [1 9] Frequent urination 式 Formula for manufacturing a preventive and therapeutic agent for urinary incontinence

[Wherein the symbols have the same meanings as described in [1]. Or a salt thereof or a prodrug thereof.

 [20] Prevention and treatment of asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel disease, vomiting, HIV infection, chronic obstructive pulmonary disease, depression, anxiety, manic depression or schizophrenia Formula for producing

[Wherein the symbols have the same meanings as described in [1]. ] The use of the compound represented by the formula (I) or a salt thereof or a prodrug thereof is provided.

The compound (I) of the present invention or a salt thereof includes stereoisomers such as cis- and trans-isomers, racemic forms, and optically active forms such as R-form and S-form. Depending on the size of the ring, conformational isomers may be formed. Such isomers are also included in the compound (I) of the present invention or a salt thereof.

In the above formula, the (^ _ ₆ alkyl group represented by RR ² R ³ and R, if example embodiment, using methyl, Echiru, propyl, isopropyl, heptyl, sec- butyl, tert- butyl, pentyl, hexyl is to Among them, (^ alkyl groups such as methyl, ethyl, propyl, and isopropyl are preferable, and methyl is particularly preferable.

As the halogen atom which the C—e alkyl group represented by R ¹ may have, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used, and among them, a fluorine atom is preferable.

A good C i _ ₆ alkoxy optionally C alkyl group optionally having represented by R ^1, for example, main butoxy, ethoxy, Purobokishi, and butoxy are used, in particular methoxy, C alkoxy, such as ethoxy are preferred.

The C ₆ optionally C ₆ Ashiru the alkyl group has represented by R ^1, if example embodiment, formyl, C - 5 alkyl - carbonyl (e.g., Asechiru, propionyl, etc.) is used, inter alia formyl, Asechiru, such as propionyl - ₃ etc. § Shi Le is preferred.

The C i may have is _ ₆ alkyl C ₆ alkyl sulfonyl Le represented by R ^1, for example, methylsulfonyl, Echirusuruhoniru and propylsulfonyl two Le is used, inter alia methylsulfonyl, C alkylsulfonyl such as ethylsulfonyl is preferred.

As C i-e alkoxy-carbonyl which the C alkyl group represented by R ¹ may have, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like are used, among which methoxycarbonyl, ethoxycarbonyl and the like are used. such as C I ₃ alkoxy one carbonyl such carbonylation le are preferred.

Examples of the mono- or di-C alkyl monofunctional rubamoyl which the C i-6 alkyl group represented by R ¹ may have include, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, getylcarbamoyl, dipropyl Carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, dimethylcarbamoyl, etc. Alkyl-alkavamoyl and the like are preferred.

The C i-6 alkyl group has optionally may mono- or di-be C Bok ₆ alkylene loose sulfamoyl represented by R ^1, for example, methylsulfamoyl, Echirusu Rufamoiru, propyl sulfamoyl, dimethylsulfamoyl And dimethylsulfamoyl, dimethylsulfamoyl, dimethylsulfamoyl, dimethylsulfamoyl and the like, and mono- or dialkylsulfamoyl and the like.

C alkyl group may also have 〇 ₆ represented by R ¹ - Examples _{1 4} Ariru, for example, Fuweniru, naphthyl and the like.

Examples of the 5- to 14-membered heterocyclic group which may be possessed by the —6 alkyl group represented by R ¹ include a heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. 5 to 14 members, preferably 4 or 1 or 2

(Preferably 5 to 9 members, particularly preferably 5 or 6 members) Heterocyclic groups are used, and among them, phenyl (2-phenyl, 3-phenyl), furyl (2-furyl, 3-furyl) , Pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), quinolyl

(2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolinyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), pyrazinyl, pyrimidinyl (2-pyrimidinyl, 4 —Pyrimidinyl), pyrrolyl (3-pyrrolyl), imidazolyl (2-imidazolyl), pyridazinyl (3-pyridazinyl), isothiazolyl (3-isothiazolyl), isooxazolyl (3-isoxazolyl), indolyl (1-indolyl, 2-— Aromatic complex such as indolyl, 3 ^^-ondolyl), 2-benzothiazolyl, 2-benzo [b] chenyl, 3-benzo [b] chenyl, 2_benzo [b] furanyl, 3-benzo [b] furanyl Ring groups, eg pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl , Imidazolidinyl (2-imidazolinyl, 4-imidazolinyl), birazolidinyl (2-birazolidinyl, 3-birazolidinyl, 4-birazolidinyl), piperidino, piperidyl (2-piperidyl, 3-piperidyl, 4-piperidyl), Non-aromatic heterocyclic groups such as piperazinyl (1-piperazinyl, 2-piperazinyl), morpholino, and thiomorpholino are used. Of these, 2-phenyl, 3-phenyl, 3-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-pipiridinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-virazolidinyl, 3-birazolidinyl, 4-birazolidinyl, piperidino, 2-piperidyl, 4-piperidyl, 4-piperidyl 5- or 6-membered containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, in addition to carbon such as piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino and thiomorpholino A heterocyclic group is preferred.

It is a C i _ ₆ halogen atom may have an alkyl group represented by R ² and R, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is used.

As the optionally halogenated C alkyl group represented by R ² and R, is used a C alkyl group which may be substituted by 1 to 3 halogen atoms, specifically, methyl, Echiru, propyl, triflumizole Ruo b such 1 to 3 substituents C Bok ₃ alkyl group optionally substituted with fluorine atoms, such as methyl is not preferable.

The C ₆ _ _{1 4} Ariru group represented by R ^1, for example, phenyl, naphthyl and used, in particular C ₆ _ _{1 0} Ariru group such as phenyl is preferred.

The C i _ ₆ Ashiru group represented by R ^1, for example, a formyl group, (^ alkyl - carbonyl group (e.g., Asechiru, propionyl, etc.) is used, inter alia formyl, Asechiru, C i, such as propionyl - A gacyl group is preferred.

The C bets ₆ alkoxy one carbonyl group represented by R ^1, for example, main Tokishika carbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc. tert one butoxycarbonyl is used, inter alia main butoxycarbonyl, C, such as ethoxycarbonyl i _ ₃ alkoxy - carbonyl group.

Examples of the mono- or di-C i-e alkyl mono-rubamoyl group represented by R ¹ include methylcarbamoyl, ethylcarbamoyl, propyl-rubamoyl, dimethyl-carbamoyl, getylcarbamoyl, di-propyl-carbamoyl and the like. , Especially methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoy Or a mono- or di-C-alkyl-carbamoyl group such as benzyl or getylcarbamoyl.

The C i_ ₆ alkylsulfonyl group represented by R ^1, for example, Mechirusuruhoni Le, Echirusuruhoniru and propylsulfonyl are used, inter alia methylstyrene Ruhoniru, such as C i_ ₃ alkylsulfonyl group such Echirusuruhoniru are preferred.

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 C ^ alkoxy group represented by R, for example, methoxy, ethoxy, propyloxy, butoxy and the like are used, and among them, C alkoxy groups such as methoxy, ethoxy and propoxy are preferable.

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

The R ^1, - 3 alkyl group (e.g., methyl, Echiru, propyl, isopropyl, etc.), 〇 ₆ _ ₁₄ Ariru group (e.g., such as phenyl), Ci-g Ashiru group (e.g., formyl, Asechiru, propionyl etc.), C Bok ₃ alkoxy one carbonyl group (e.g., main bets alkoxycarbonyl, such as ethoxycarbonyl), mono- or di- (^ alkyl Ichiriki Rubamoiru group (e.g., methylcarbamoyl, E Ji carbamoyl, dimethyl Cal Bamoiru, GETS Ji carbamoyl etc.), C ₃ alkylsulfonyl group (e.g., methylcarbamoyl Rusuruhoniru, etc. Echirusuruhoniru) Shiano alkyl group (e.g., Shianome chill etc.) are preferred, such as, among others (^ _ ₃ alkyl group, a formyl group, (^^ Alkyl-carbonyl groups and the like are preferred, and methyl and acetyl are particularly preferred.

The R ^2, a hydrogen atom, a halogen atom, such as full Uz atom, methyl, Echiru, propyl, are preferred, such as (^ _ ₃ alkyl groups such as isopropyl, inter alia a hydrogen atom, a halogen atom such as fluorine atom, methyl Preference is given, particularly preferred is a fluorine atom.

R ³ is preferably a hydrogen atom or a Ci- ₃ alkyl group such as methyl, ethyl, propyl, and isopropyl, and particularly preferably a Ci- ₃ alkyl group such as methyl. Further, it is preferable that R ³ is in the /? Configuration. In this case, the general formula (I) is

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

 R may be substituted with 1 to 3 halogen atoms (particularly, fluorine atom) such as hydrogen atom, methyl, ethyl, propyl, trifluoromethyl, etc. C! —3 alkyl group and the like are preferable, and methyl and trifluoromethyl are particularly preferable.

 p represents an integer of 0 to 3, and represents that 0 to 3 of the phenyl groups may have 0 to 3 substituents. p is preferably 2.

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

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

As the group represented by

[In the formula, R ⁴ , R ⁵ and R ⁶ are the same or different and each represent a hydrogen atom, an optionally halogenated C alkyl group or a C alkoxy group. The group represented by the formula is used.

[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.

Examples of the alkyl group represented by R ⁴ , R ⁵ and are, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., among which methyl, ethyl, propyl And a C i ₃ alkyl group such as isopropyl is preferable, and methyl is particularly preferable.

The R ^4, R ⁵ and C i_ ₆ halogen atom may have an alkyl group represented by R ^6, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is used.

The R ^4, R ⁵ and optionally halogenated C [Bok ₆ alkyl group represented by R ^6, which may be substituted with 1 to 3 halogen atoms (e.g., full Uz atom) C ₆ alkyl group is used, specifically, methyl, Echiru, propyl, one to three full Uz may be substituted by atom C _ ₃ alkyl group, such as preparative Rifuruoromechiru is preferred.

(As the alkoxy group represented by R ⁴ , R ⁵ and R ⁶ , for example, methoxy, ethoxy, propoxy, butoxy and the like are used, and among them, C alkoxy group such as methoxy, ethoxy and propoxy is preferable.

R \ R ⁵ and R ⁶ are preferably a hydrogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms (eg, a fluorine atom) or a C alkoxy group, and among them, 1 to 3 Alkyl groups which may be substituted with two halogen atoms (eg, fluorine atoms) are preferred, and in particular, methyl, trifluoro A C 3 alkyl group which may be substituted by a fluorine atom such as methyl is preferred. m is preferably 1 or 2, and particularly preferably 1.

 n is preferably 2.

However, from compound (I) of the present invention, R ¹ is a methyl group, R ² is a methyl group, R ³ is a hydrogen atom,

Is a group represented by the formula

And the compounds represented by the formula, wherein m is 1 and n is 2 are excluded.

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

[Wherein, R ¹ ′ is — 3 alkyl group or acyl group, R ² ′ is hydrogen atom or halogen atom, R ³ ′ is Ci-a alkyl group, and R ⁴ ′ and: ⁵ ′ are the same or different. one and a halogenated C Bok ₃ optionally alkyl radical, n is 1 or 2. And the like.

In the above formula,! ^ ¹ ', R ^3', as the CI- s alkyl group represented by R ⁴ 'and R ^5', for example, methyl, Echiru, propyl, isopropyl are used, these, methyl is preferred. As the halogen atom which the C-3 alkyl group represented by R ⁴ ′ and R ⁵ ′ may have, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used.

And the R ⁴ 'and R ^5' optionally halogenated and C ₃ alkyl group represented by the 1 to 3 substituents C Bok ₃ alkyl group optionally substituted by a halogen atom is used, specifically For example, a Ci-g alkyl group which may be substituted by 1 to 3 fluorine atoms, such as methyl, ethyl, propyl, and trifluoromethyl, is preferred.

As the acetyl group represented by R ¹ ′, a formyl group or a Ci ₂ alkyl-carbonyl group (eg, acetyl, propionyl) is used, and among them, acetyl is preferable.

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 preferably methyl or acetyl.

As R ² ′, a hydrogen atom, a fluorine atom and the like are preferable, and a fluorine atom is particularly preferable.

R ³ 'is preferably in the /? Configuration. In this case, the general formula (Γ) is

(Ia,)

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

As R ³ ′, methyl is preferable.

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

Further, in the compound (Γ), R ¹ ′ is a C ^ ₂ alkyl monocarbonyl group (eg, Compounds in which R ⁴ ′ and R ⁵ ′ are C ₃ alkyl groups (eg, methyl) are also preferable.

 Specifically, as the compound (I) of the present invention,

 (4 S) -2-[3,5-bis (trifluoromethyl) benzyl] 1 12- (4 -fluorophenyl) 1,4,9-dimethyl 2,3,4,5,8,9,10 1

1-octane hydro [1, 4] diazepino [1, 2— b] [2, 7] naphthyridine

1. 7-dione (Example 4) or a salt thereof,

 (4S) —9-acetyl-1-2- [3,5-bis (trifluoromethyl) benzyl] -12- (4-fluorophenyl) -1-methyl-2,3,4,5,8,9 1 0,11 1-octane hydro [1,4] dazepino [1,2—b] [2,7] naphthyridin-1,1,7-dione (Example 7),

 (aR, 4 R) —2— [3,5-bis (trifluoromethyl) benzyl] — 13- (4-fluorophenyl) 1,4,10—dimethyl-1,4,5,6,9,10 , 11, 12-year-old hydro-1H- [1,4] diazosino [1,2-b] [2,7] naphthyridin-1,8-dione (Example 12) or a salt thereof,

 (aR, 4 R) -10-Acetyl-2- [3,5-bis (trifluoromethyl) benzyl] -1-13- (4-fluorophenyl) -1-4-methyl-1,3,4,5,6,9, 10, 11, 12-octane hydro-1H— [1,4] diazosino [1,2-b] [2,7] naphthyridine-1,8-dione (Example 15),

 (aR, 4 R)-2-[3, 5-bis (trifluoromethyl) benzyl]-13-(4-fluorophenyl) 1-4-methyl-10-propionyl 1, 3, 4, 5, 6, 9, 10,11,12—Hydrohydrogen 2H_ [1, 4] diazocino [1,

2-b] [2,7] naphthyridine—1,8-dione (Example 16),

 (aR, 4 R) —2— (3,5-dimethylbenzyl) -13- (4-fluorophenyl) — 4,10-dimethyl-3,4,5,6,9,10,11,12-octane Evening hydro 2H— [1,4] diazosino [1,2—b] [2,7] naphthyridine

1.8-dione (Example 20) or a salt thereof,

(aR, 4 R) — 10—Acetyl-1-2- (3,5-dimethylbenzyl) —13— (4 _fluorophenyl) -1-4-methyl-1,3,4,5,6,9,10,11,1 2-oxohydro-2H- [1,4] diazosino [1,2-b] [2,7] naphthyridine-1,8-dione (Example 25) is preferred, and in particular

 (4 S) -9-acetyl-2— [3,5-bis (trifluoromethyl) benzyl] -1-12- (4-fluorophenyl) -1-4-methyl-1,2,3,4,5,8,9 1 0,11-octyhydro [1,4] dazepino [1,2-b] [2,7] naphthyridine 1,7-dione (Example 7),

 (aR, 4 R)-2-(3,5-dimethylbenzyl) _13— (4-fluorophenyl) 1,4,10—dimethyl-1,3,4,5,6,9,10,11,12-octane Even hydro-2H— [1,4] diazosino [1,2-b] [2,7] naphthyridin-1,8-dione (Example 20) or a salt thereof is preferred.

 Examples of the salt of compound (I) of the present invention include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Can be 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 salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, tolylamine, cyclohexylamine, Salts with dicyclohexylamine, N, N'-dibenzylethylenediamin and the like can be mentioned. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid And salts with 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, orditin, and the like. Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid And the like.

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

 The prodrug of the compound (I) of the present invention or a salt thereof (hereinafter, may be abbreviated as the compound (I) of the present invention) can be obtained by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body. A compound that converts into the compound (I) of the present invention, that is, a compound that changes into the compound (I) of the present invention by enzymatic oxidation, reduction, hydrolysis, or the like; A compound that changes to (I). Examples of the prodrug of the compound (I) of the present invention include a compound in which the amino group of the compound (I) of the present invention is acylated, alkylated or phosphorylated (for example, a compound of the present invention)

The amino group of (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-12-oxo-1,3-dioxolen-14-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated A compound in which the hydroxyl group of the compound (I) of the present invention is acylated, alkylated, phosphorylated or borated (for example, the compound of the present invention). Compound

A compound in which the hydroxyl group of (I) is acetylated, palmitoylated, propanoylated, bivaloylated, succinylated, fumalylated, alanylated, dimethylaminomethylcarbonylated, etc.); Compounds in which the carboxy group is esterified or amidated (for example, the compound (I) of the present invention is obtained by converting the carboxy group into ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, or vivaloyl) Oxymethyl esterification, ethoxycarbonyloxysethyl esterification, fluoridyl esterification, (5-methyl-21-oxo-1,3-dioxolen-1-yl) methyl esterification, cyclohexyloxy Carbonylethyl esterified, methylamidated compounds, 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 may be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, Molecular Design, pp. 163 to 198. May be changed to the compound (I) of the present invention. The compound (I) or a salt thereof of the present invention can be produced according to a method known per se, for example, the production method described in JP-A-9-136585 (EP-A-7333362) can do. For example, the compound (I) of the present invention or a salt thereof has the formula

[Wherein, L is a leaving group, and other symbols are as defined above. Or a salt thereof, by subjecting it to a cyclization reaction to close the ring.

Examples of the leaving group represented by L include a halogen atom (eg, a chlorine atom, a bromine atom, an iodine atom, etc.) and a substituted sulfonyloxy group (eg, C i such as methanesulfonyloxy, phenylsulfonyloxy, etc.) _ ₆ alkylsulfonyl O dimethylvinylsiloxy groups; benzenesulfonyl O C ₆ _ i ₄ § Li one Le sulfonyl O alkoxy group such as alkoxy; and C sheet _{1 6} Arukiruari one Le sulfonyl O alkoxy group such as p- toluenesulfonyl O carboxymethyl) 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, or potassium).

 The reaction is usually performed in a solvent inert to the reaction. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and hexane. An aprotic polar solvent such as methylphosphoramide is preferably used.

The reaction can advantageously proceed by adding a base. Examples of such a base include inorganic bases (eg, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate). Alkali metal carbonates such as sodium carbonate and lium carbonate; Alkali metal hydrides such as sodium hydride and hydrogen hydride; sodium amide; Alkoxides such as sodium methoxide and sodium ethoxide ) And organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, and the like; cyclic amines such as pyridine, etc.) are preferred.

 In the cyclization reaction, instead of using a base, compound (II) is converted to a salt with a base.

(For example, the above-mentioned alkali metal salts and alkaline earth metal salts). The amount of the base varies depending on the compound (II) to be used, the type of the solvent, and other reaction conditions, and is usually about 1 to 10 mol, preferably about 1 to 5 mol, per 1 mol of the compound (II). It is.

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

Further, in the compound (I) of the present invention or a salt thereof, a compound represented by the formula wherein R ¹ is a hydrogen atom

 Wherein each symbol is as defined above. ] Or a salt thereof represented by the formula:

〔式中、各記号は前記と同意義を示す。〕で表わされる化合物またはその塩を還元 反応に付すことにより製造することもできる。

Wherein each symbol is as defined above. ] Or a salt thereof is subjected to a reduction reaction.

 This reduction reaction can be performed by various methods. For example, a method of reducing in the presence of a metal catalyst for catalytic reduction is preferable. Examples of the catalyst used in the catalytic reduction method include a platinum catalyst such as platinum black, platinum oxide, and platinum carbon; a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, and palladium carbon; reduced nickel; Nickel catalysts such as nickel, Raney nickel and Urushibara nickel are examples. The amount of the catalyst used varies depending on the type of the catalyst, and is usually about 0.1 to 10% (w / w) based on the compound (I) or a salt thereof.

 The reduction reaction is usually performed in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol and isopropanol; ethers such as tetrahydrofuran and dioxane; and esters such as ethyl acetate. The reaction temperature is, for example, about 0 ° C to 200 ° C, preferably about 20 ° C to 110 ° C, and the reaction time is usually about 0.5 to 48 hours, preferably about 1 to 16 hours. . Usually, the reaction is usually carried out under normal pressure. However, if necessary, the reaction is carried out under pressure (for example, about 3 to 10 atm).

 Such a reduction reaction can also be applied to a method of converting another aromatic heterocycle into a non-aromatic heterocycle.

Further, in the compound (I) of the present invention or a salt thereof, R ¹ is a group other than a hydrogen atom,

[Wherein I ^ a has the same meaning as R ¹ above. However, H ¹ a is not a hydrogen atom. Other symbols are as defined above. Or a salt thereof], a compound of (III) or a salt thereof, - OH wherein, R ¹ a is as defined above. 〕 so It can also be produced by reacting with a reactive derivative of the compound or a salt thereof to form a quaternary salt, and then subjecting the resulting quaternary salt to a reduction reaction. Examples of the reactive derivative of the compound represented by 1 ^ & -011 or a salt thereof include, for example, a compound represented by the formula

R ^x a - 'in (IV) [wherein, L' L is a leaving group, R ¹ a is as defined above. Or a salt thereof, or the like.

 Specifically, the compound (ΙΠ) or a salt thereof is reacted with the compound (IV) or a salt thereof to obtain a compound represented by the formula

 Wherein each symbol is as defined above. And then subjecting the resulting compound (V) to a reduction reaction to obtain compound (1) -2 or a salt thereof.

 As the leaving group represented by L ′, those similar to the leaving group represented by L are used.

R ¹ a- L used for conversion to a quaternary salt, as is specifically pay de of R ¹ a (for example, chloride, bromide, etc. ® one iodide), sulfate ester or sulfo phosphate ester ( For example, methanesulfonate, P-toluenesulfonate, benzenesulfonate and the like are used, and halides are particularly preferably used. The amount of compound (IV) or a salt thereof to be used is, for example, about 1 to 100 equivalents, preferably about 1 to 30 equivalents, per 1 mol of substrate. '

The reaction with compound (IV) or a salt thereof is usually performed in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, and isopropanol; ethers such as tetrahydrofuran and dioxane; esters such as ethyl acetate; dichloromethane; and 1,2-dichloromethane. Halogenated hydrocarbons such as butane may be used, and compound (IV) itself may be used as a solvent. The reaction temperature is, for example, 10 ° C to 200 ° C, preferably 20 ° C! ~ 110 ° C, The reaction time is generally about 0.5 to 24 hours, preferably about 1 to 16 hours. The reduction reaction of the generated quaternary salt to the tetrahydropyridine ring can be performed in an inert solvent in the presence of a reducing agent such as a metal hydride. Examples of the metal hydride as the reducing agent include sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, lithium cyanoborohydride, lithium aluminum hydride and the like. Preferred metal hydrides include sodium borohydride and the like. The amount of the reducing agent used is, for example, 1 to 10 equivalents to the quaternary salt, preferably:! ~ 2 equivalents. Examples of the reaction solvent include lower alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; and hydrocarbons such as benzene and toluene. These solvents may be used alone. Or mixed and used. The reaction temperature is usually about —100 ° C. to 40 ° C .; preferably about −80 ° C. to 25 ° C., and the reaction time is usually 5 minutes to 10 hours. Preferably, it is about 10 minutes to 5 hours.

 In the reduction reaction of the quaternary salt, a compound having a dihydropyridine ring may be produced depending on the kind of the compound. This dihydropyridine ring can be converted to a further reduced tetrahydropyridine ring by, for example, the above-described catalytic reduction method.

When the nitrogen atom of the tetrahydropyridine ring has a hydrogen atom, a compound having an R ¹ group introduced into the nitrogen atom can be obtained by subjecting the nitrogen atom to an alkylation or acylation reaction.

 For more information, see Expression

Wherein each symbol is as defined above. A compound represented by the formula: OH wherein R ^ a is as defined above, ; ] Or a reactive derivative of a salt thereof represented by the formula:

 Wherein each symbol is as defined above. Or a salt thereof.

As the reactive derivative of the compound represented by R ¹ a- 0 H indicates, for example, in R ^ -L ⁵ [wherein, L, is a leaving group, R ¹ a is as defined above . Or a salt thereof.

 The alkylation reaction can be performed by reacting an alkylating agent in a solvent in the presence of a base. Examples of the solvent include alcohols such as methanol, ethanol, and propanol; ethers such as dimethoxyethane, dioxane, and tetrahydrofuran; ketones such as acetone; and amides such as N, N-dimethylformamide. . Bases include, for example, organic bases such as trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N, N-dimethylaniline, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide. Bases are included. Examples of the alkylating agent include, for example, halides of alkanes which may have a substituent (eg, chloride, bromide, chloride, etc.), sulfates, or sulfonates (eg, methanesulfonate, p-toluene) Sulfonate, benzenesulfonate, etc.) are used, and halides are particularly preferably used.

 The amount of the alkylating agent to be used is, for example, about 1 to 5 equivalents, preferably about 1 to 3 equivalents, per 1 mol of the substrate. The reaction temperature is usually -10 ° (~ 200 ° C, preferably about 0 ° C-110 ° C), and the reaction time is usually 0.5-48 hours, preferably 0.5 hours. ~ 16 hours.

Ashiru reaction is desired I ^ a- OH wherein, R ¹ a is C i-6 Ashiru group, Ci-e alkoxy one carbonyl group, the force Rubamoiru group, mono- or di - CI- e alkyl It represents a one-piece rubamoyl group or a C i-e alkylsulfonyl group. ] Or a reactive derivative of the salt thereof. This reaction varies depending on the type of acylating agent and the type of substrate, but is usually performed in a solvent, and a convenient base may be added to promote the reaction. Examples of the solvent include hydrocarbons such as benzene and toluene, ethers such as ethyl ether, dioxane, and tetrahydrofuran; esters such as ethyl acetate; halogenated hydrocarbons such as chloroform and dichloromethan; Examples include amides such as N-dimethylformamide and aromatic amines such as pyridine. Examples of the base include, for example, bicarbonates such as sodium bicarbonate and potassium bicarbonate, carbonates such as sodium carbonate and potassium carbonate, acetates such as sodium acetate, tertiary amines such as triethylamine, and pyridine. And aromatic amines.

During R ¹ a- OH [Formula as Ashiru agent, R ¹ a is C i-e Ashiru group, (Bok ₆ alkoxy one carbonyl group, the force Rubamoiru group, a mono- or di-one C alkyl Ichiriki Rubamoiru group or a C i.sub.- ₆ alkylsulfonyl group.] Examples of the reactive derivative of the compound or a salt thereof include acid anhydrides, mixed acid anhydrides, and acid halides (eg, chloride, promide). Can be used.

 The amount of these acylating agents to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the substrate. The reaction temperature is usually from 10 ° C to 150 ° C, preferably from about 0 ° C to 10 ° C. C, and the reaction time is usually about 15 minutes to 24 hours, preferably about 30 minutes to 16 hours.

Compound (I) or a salt thereof can also be produced by reacting a compound having a hydrogen atom at the nitrogen atom of the tetrahydropyridine ring with an aldehyde in the presence of a reducing agent such as a metal hydride. . Metal hydrides as reducing agents include, for example, sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, aluminum hydride Lithium and the like are included. Preferred metal hydrides include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. The amount of the reducing agent to be used is, for example, about 1 to 50 equivalents, preferably about 1 to 10 equivalents, per 1 mol of the substrate. As the aldehyde, for example, formalin, C i _ ₅ alkyl one aldehyde (§ acetaldehyde, etc.) is used, the amount used, for example from 1 to 100 equivalents relative to 1 mol of the substrate, preferably 1 to 20 equivalents It is. Examples of the reaction solvent include lower alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and hydrocarbons such as benzene and toluene.These solvents may be used alone or as a mixture. Can be used. The reaction temperature is usually about -80 ° C to 40 ° C, preferably about -50 ° C to 25 ° C, and the reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. It is about.

Further, compound (I) or a salt thereof can also be produced by reacting a compound having a hydrogen atom at the nitrogen atom of the tetrahydropyridine ring with a C60 aryl metal reagent in the presence of a metal salt. I can do it. 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, nitriles such as acetonitrile, ethers such as dimethoxyene and tetrahydrofuran, and dimethylformamide. An aprotic polar solvent such as dimethylsulfoxide and hexamethylphosphoramide is preferably used. C ₆ _ ₁₀ § Li Ichiru metal reagent as triarylbismuth di § Sete Ichito, such as triaryl bismuth ditolyl full O lower cell Tate is preferably used as the metal salt is copper acetate (11), pivalic copper ( Copper salts such as II) are preferably used. The amount of c ₆ _ ₁₀ Ariru metal reagent, if example embodiment, 1 to 10 equivalents relative to 1 mol of the substrate, preferably 1 to 5 equivalents, the amount of gold Shokushio, for example, to 1 mole of the substrate On the other hand, it is 0.01 to 1 equivalent, preferably 0.1 to 0.5 equivalent. The reaction temperature is usually about -10 ° C to 150 ° C, preferably about 0 ° C; to about 100 ° C, and the reaction time is usually 5 minutes to 48 hours, preferably 30 minutes. Minutes to 24 hours.

When the compound (I) is obtained as a free compound in the above method, for example, an inorganic acid (for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), an organic acid (for example, methanesulfonic acid, benzene Sulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum Or an organic base (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N'-dibenzylethylenediamine) When compound (I) is obtained in the form of a salt, it can be converted into a free compound or another salt according to a conventional method.

 The compound (I) or a salt thereof produced by these methods can be separated and purified by using a conventional separation and purification means (for example, concentration, solvent extraction, column chromatography, recrystallization, etc.). When the compound (I) is an optically active form, it can be separated into d-form and 1-form 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 may be protected groups such as those commonly used in peptide chemistry and the like. May be protected. In this case, the target compound can be obtained by removing the protecting group, if necessary, after the reaction.

Examples of the protecting group for an amino group include a formyl group, a C ₆ alkyl-carbonyl group (for example, acetyl and propionyl groups), a phenylcarbonyl group, and a C ₆ alkyl-oxycarbonyl group (for example, methoxycarbonyl, Etokishikaru etc. Boniru group), § reel O alkoxycarbonyl group (e.g., phenylalanine O carboxymethyl carbonylation Le group), C ₇ _ _{1 0} Ararukiru - carbonyl group (e.g., benzyl O propoxycarbonyl group), trityl group, And a fluoroyl group. These protecting groups may have a substituent. Examples of these substituents include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom), an alkylcarbonyl group (for example, acetyl, propionyl, and butylcarbonyl group), and a nitro group. And the number of substituents is about 1 to 3.

Examples of the carboxyl-protecting group include a C-e alkyl group (for example, methyl, ethyl, propyl, isopropyl, 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 include, for example, halogen atom (fluorine atom, chlorine Atom, a bromine atom, an iodine atom), formyl groups, C WINCH ₆ alkyl - if carbonyl group (eg, Asechiru, propionyl, butyl group), a nitro group and the like, the number of the substituents is one to three or so It is.

Examples of the hydroxyl-protecting group include (^ alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl group, etc.), phenyl group, aralkyl group (eg, benzyl group, etc.), formyl Group, C i- ₆ alkyl-carbonyl group (eg, acetyl, propionyl group, etc.), aryloxycarbonyl group (eg, phenyloxycarbonyl group, etc.), C ₇ _ _{1 (3} aralkyl monocarbonyl group (eg, benzyl group) Oxycarbonyl group), a vinyl group, a furanyl group, a silyl group, etc., and these protecting groups may have a substituent. fluorine atom, chlorine atom, bromine atom, iodine atom), C _i-6 alkyl group, phenyl group, C ^ -. i Araruki Group, two such Toro group and the like, the number of substituents is 1 to about 4.

 For the removal of the protecting group, known methods or modifications thereof, for example, acids, bases, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiolrubamate, tetrabutylammonium fluoride, palladium acetate, etc. A method of processing is 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 a free compound, it can be converted to a salt by a known method or a method analogous thereto (eg, neutralization, etc.), and conversely 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 sometimes abbreviated as the compound of the present invention) has an excellent effect of suppressing the increase in tracheal vascular permeability induced by cabsaicin, It has an inhibitory action on evening kinkinin receptor, especially a substance P receptor antagonism and a neurokinin 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, etc. can be used in mammals (for example, mice, rats, hamus yuichi, egrets, cats, dogs, dogs, Inflammation or allergic diseases (eg atopic, monkey, human) such as atopy, dermatitis, herpes, psoriasis, asthma, bronchitis, sputum, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, polymorphism (Sclerosis, conjunctivitis, cystitis, etc.), pain, migraine, neuralgia, pruritus, cough, HIV infection, chronic obstructive pulmonary disease, and diseases of the central nervous system (e.g., schizophrenia, Parkinson's disease) , Psychosomatic disease, dementia (eg, Alzheimer's disease, etc.), gastrointestinal diseases [eg, irritable bowel disease, ulcerative colitis, Crohn's disease, urease-positive Abnormalities (eg, gastritis, gastric ulcers, etc.) caused by spiral gram-negative bacteria (eg, Helicopak Yuichi's pylori), vomiting, urination abnormalities (eg, pollakiuria, urinary incontinence, etc.), circulation It is useful as a safe prophylactic / therapeutic agent for diseases such as organ diseases (eg, angina, hypertension, heart failure, thrombosis, etc.) and immune disorders. In particular, the compound of the present invention is useful as a dyskinetic receptor antagonist, an agent for improving dysuria such as pollakiuria and urinary incontinence, and a therapeutic agent for these dysuria.

 Further, the compound of the present invention is also useful as an agent for preventing and 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, emulsions, injections and suspensions.

 The pharmaceutical preparation of the present invention can be produced by a conventional method such as mixing, kneading, granulation, tableting, coating, sterilizing treatment, 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 to.

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. The content is about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight. When the compound of the present invention is used as the above-mentioned pharmaceutical preparation, it may be used as such or as a suitable pharmacologically acceptable carrier, for example, an excipient (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), a binder (Eg, starch, arabic Rubber, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone, etc., lubricants (eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.), disintegrants (eg, carboxymethylcellulose calcium) , Talc, etc.), diluents (eg, water for injection, physiological saline, etc.), and additives (stabilizers, preservatives, coloring agents, fragrances, dissolution aids, emulsifiers, buffers, isotonic agents, if necessary) ) Can be administered orally or parenterally in the form of solid preparations such as powders, fine granules, granules, tablets, capsules and the like, or liquid preparations such as injections.

 The dose varies depending on the type of the compound of the present invention or a pharmaceutically acceptable salt thereof, the administration route, symptoms, age of the patient, and the like.For example, when administered orally to an adult patient with dysuria, About 0.05 to 5 Omg, preferably about 0.05 to: L Omg, 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 by being appropriately compounded with other pharmaceutically active ingredients in an appropriate amount. For example, the following are used as such active ingredients. (1) Antidiabetic agent

Insulin preparations [eg, animal insulin preparations extracted from the tongue of P. and Bush; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; prominin insulin zinc; insulin Fragments or derivatives (eg, INS-1 etc.)), insulin sensitizers (eg, pioglicusone hydrochloride, troglisuzone, mouth diglyuzone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP_297, FK-614, CS-011, etc., Hi-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, Metformin, buformin, etc.), sulfonylurea agents (eg, tolptamide, glibenclamide, gliclazide, chlorpropamide) , Trazamide, acetohexamide, glicloviramide, glimepiride, and other insulin secretagogues (eg, repaglinide, senaglinide, mitiglinide or its calcium salt hydrate, GLP-1, nateglinide, etc.), dipeptidyl Peptidase IV inhibitors (eg, NVP — DPP—278, PT—100, P32 / 98, etc., 3 agonists (eg, CL—316243, SR-58611—A, UL—TG—307, AJ-9677, AZ 40140, etc.), amylinagonist ( E.g., pramlintide), phosphotyrosine phosphatase inhibitor (e.g., vanadic acid), gluconeogenesis inhibitor (e.g., glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, etc.) , SGLT (sodium-glucose cotransporter) inhibitors (eg, T-1095 etc.) and the like.

 (2) Agent for treating diabetic complications

 Aldose reductase inhibitors (eg, Torres evening, Epalles evening, Zenares evening, Zobolles evening, Fidalest evening (SNK-860), Minareth evening (AR I_509), CT — 112, etc.), neurotrophic factor (eg, NGF, NT—3, etc.), AGE inhibitor (eg, ALT—945, pimagedin, pyratoxatin, N—phenacylthiazolium promide (ALT—766), EXO — 226, etc.), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (eg, thiopride, etc.), etc. (3) Antihyperlipidemic agent

 A cholesterol synthesis inhibitor, such as a suvatin-tin compound (eg, pravasu-tin, roba-sutin, atorba-sutin, full-basin-sutin, seribas-sutin, or a salt thereof (eg, sodium salt)) ), Fibrates based on squalene synthase inhibitors or triglycerides (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.). (4) Antihypertensive

 Angiotensin converting enzyme inhibitors (eg, captopril, enalapril, derapril, etc.), angiotensin Π antagonists (eg, oral sultan, candesartan cilexetil, etc.), calcium antagonists (eg, manidipine, diflupine, amlodipine, etc.) Ejonidipi, n, dicardipine etc.), clonidine etc.

 (5) Anti-obesity agent

Central anti-obesity drugs (eg, dexfenfluamine, fenfluramine, fuentermin, cyptramine, ampuepramone, dexfenfemin, mazindol, phenylpropanolamine, clovenzolex, etc.), Teng lipase inhibitor (eg, Orlistat, etc.), ^ 3agonist (eg, CL-316243, SR-5861 1-A, UL-TG-307, AJ-9677, AZ40140, etc.), peptide anorectic (eg, lebutin, CNTF (hairy) Somatic neurotrophic factor), etc.), cholecystokinin agonist (eg, lynch tribute, FPL-15849, etc.).

 (6) Diuretic

 Xanthine derivatives (eg, sodium theopromine salicylate, calcium thiophene salicylate, etc.), thiazide-based preparations (eg, ethiazide, cyclopentiazide, trichlormethiazide, hydrochloride thiazide, hydroflumethiazide, benzyl hydrochlorothiazide, penflutide, polythiazide, polythiazide) Methiclothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetone zolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapami) Etc.), azosemide, isosorbide, phosphoric acid, pyreinide, bumeinide, furosemide, etc.

 (7) Chemotherapeutic agent

 Alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), plant-derived anticancer agents (eg, mitomycin, adriamycin) For example, vincristine, bindesin, taxol, etc.), cis-bratin, carboblatin, etopoxide, etc., among others, 5-fluorouracil derivatives such as fluperon or neofluronone c

(8) Immunotherapy agent

 Microbial or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides with immuno-enhancing activity (eg, lentinan, schizophyllan, krestin, etc.), and site-specific proteins obtained by genetic engineering techniques ( Examples include interferon, inulin-leukin (IL), colony-stimulating factors (eg, granulocyte colony-stimulating factor, erythropoietin, etc.), among which IL-1, IL-2, IL-12, etc.

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

Cyclooxygenase inhibitors (eg, indomethacin, etc.) (Cancer. Reseach, Vol. 49, pp. 5935-5939, 1989), progesterone derivatives (eg, megestrol acetate) [Journal 'ob' clinical · Oncology (Journal of Clinical Oncology), Vol. 12, Vol. 21, pp. 23-225, 1990), carbohydrate steroids (eg, dexamethasone, etc.), metoclobramide drugs, tetrahydrocannabinol drugs Drugs (all references are the same as above), Fat metabolism improvers (eg, eicosapenic acid, etc.) [British Journal of Cancer, Vol. 68, 3 Pp. 14-318, 1993], growth hormone, IGF-1, or TNF, which is a factor that induces cachexia, LIF, IL-6, and antibodies to Oncoscintin M.

 (10) Other

 Saccharification inhibitors (eg, ALT-711 etc.), nerve regeneration promoters (eg, Y-128, VX853, prosaptide, etc.), central nervous system drugs (eg, antidepressants such as desibramine, amitriptyline, imipramine), anti- Epilepsy drugs (eg, lamotrigine), antiarrhythmic drugs (eg, mexiletine), acetylcholine receptor ligands (eg, ABT-594), endothelin receptor antagonists (eg, ABT-627), monoamine uptake inhibitors (eg, Tramadol), narcotic analgesics (eg, morphine), GABA receptor agonists (eg, gearbapentin), spermatid-2 receptor agonists (eg, clonidine), topical analgesics (eg, capsaicin), protein kinase C Inhibitors (eg, LY-333531), anxiolytics (eg, benzothiazepine), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptor agonists (eg, apomorphine), Cholinergic drugs (eg, oxiptinin), i-receptor blockers (eg, musk mouth sin), muscle relaxants (eg, baclofen, etc.), force channel openers (eg, nicorandil), calcium Channel blockers (eg, diphdipine), Alzheimer's disease prevention 'treatments (eg, donezil, rivastigmine, galan-yumin), Parkinson's disease drugs (eg, L-dopa), antithrombotics (eg, aspirin) , Shirosuzozoru), drugs for treating HIV infection (saquinavir, zidovudine, lamivudine, nevirapine), drugs for treating chronic obstructive pulmonary disease (sarmeteril, tiotropium bromide, cilomilast) and the like.

 Example

 Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples. However, the present invention is not limited to the Examples, and may be changed without departing from the scope of the present invention. .

Elution in column chromatography in Reference Examples and Examples is not particularly mentioned As far as possible, it was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, using Merck (Merck) manufactured by 60F ₂₅₄ as TLC plate, was used as a developing solvent, the solvent used as an elution solvent medium by column chromatography. A UV detector was used for detection. Silica gel 60 (70-230 mesh) manufactured by Merck was used as silica gel for column chromatography. Room temperature usually means a temperature of about 10 ° C to 35 ° C. 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: N, N-dimethylformamide, THF: tetrahydrofuran, DM S 0: dimethyl sulfoxide, CD C 1 _3: Black port Holm, Mg S 0 _4: sulfuric mug Neshiumu, Hz: Herudzu, J: a coupling constant, m: Maruchipuredzuto , Q: quartet, t: triplet, d: doublet, s: singlet, br *: broad, like: approximation.

2- (3,5-dimethoxybenzyl) -12- (4-monofluorophenyl) -2,3,4,5-tetrahydro [1,4] diazepino [1,2—b] [2,7] naphthyridine 1, merge on

 (Process 1)

Chemical Pharmaceutical Bulletin, 1997, vol. 45, p. 1642, 4- (4-fluorobenzoyl) pyridine-3-3 ribonucleic acid (lO.Og) in THF (80 ml) )) Triethylamine (4.27 g) and bromomalonic acid getyl ester (10 lg) were added to the solution at room temperature, and the mixture was stirred at 80 ° C for 14 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. The organic layer was washed with 1N hydrochloric acid, with water, dried (MgSO _4), 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 2-[[[[4-[(4-fluorophenyl) carbonyl] -13-pyridinyl]. Carbonyl] oxy] propanedicarboxylic acid di The ethyl ester was obtained as an oil (12.3 g, 84%).

One _{NMR (CD C 1 3) δ} 1. 26 (6 Η, t, J = 7. 1 Hz), 4. 2

4 (2H, q, J = 7.2 Hz), 4.25 (2H, q, J = 7.2 Hz), 5.

58 (1 H, s), 7.09-7.18 (2 H, m), 7.3 1-7.35 (1 H, dlike), 7.74-7.81 (2H, m), 8.95 (1 H, d, J = 5.2 Hz), 9.45 (1 H, s) ₀

 (Process 2)

To a solution of the compound (12.1) obtained in Step 1 in THF (100 ml) was added 1,8-diazabicyclo [5.4.0] -17-indene (DBU) (2.04 g) at 178 ° C. Stirred for 1 hour. The reaction solution was poured into water, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layer washed with water, dried (MgSO _4), 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 getyl 2- [5- (4-fluorophenyl) -17-oxo-1-5,7-. Dihydrofuro [3,4-b] pyridin-5-yl] -2-hydroxymalonate was obtained as an oil (12.3 g, 84%).

! H-NMR (CD C 1 3) δ 1. 0 9 (3 Η, t, J = 7. 1 Hz), 1. 2 1 (3 H, t, J = 7. 1 Hz), 4. 07 (2 H, q, J = 7.1 Hz), 4.10 -4.30 (2 H, m), 4.67 (1 H, s), 6.99-7.08 (2 H, m), 7.73 -7.81 (2H, m), 8.01-8.04 (1H, ddli ke), 8.88 (1H, d, J = 5.2Hz), 9. 14 (1 H, 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 ° C. 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) 1-1-oxo-1H-pyrano [3,4-c] pyridin-3-carboxylic acid. Obtained as prism crystals (3.04 g, 63%). Melting point: 272-274 ° C (recrystallized from ethyl isopropyl ether acetate). (Step 4), To a solution of the compound obtained in step 3 (1.50 g) in DMF (20 ml) was added 3,5-dimethoxybenzylamine (1.01 g) and N- (3-dimethylaminopropyl) -N'-e Tilcarbodiimide hydrochloride (2.01 g) and 1-hydroxy-1H-benzotriazole monohydrate (1.21 g) were added at room temperature, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. The organic layer saturated aqueous sodium bicarbonate solution, washed with 10% Kuen acid solution and water, dried (M gS0 _4), the solvent was distilled off under reduced pressure. The precipitated crystals are collected by filtration and washed with diisopropyl ether monoethyl acetate (10: 1) to give N- (3,5-dimethoxybenzyl) -14- (4-fluorophenyl) -11-oxo. 1H-Virano [3,4-c] pyridine-'3-carboxamide was obtained as a colorless powder (1.93 g, 84%).

Melting point: 171-171 ° C.

 (Process 5)

To a mixed solution of the compound (0.57 g) obtained in Step 4 in THF (15 ml) -methanol (5 ml) was added 3-amino-1-propanol (0.172 g) at room temperature, and the mixture was stirred at room temperature for 14 hours. did. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. The organic layer washed with 10% Kuen acid solution and water, dried (MgSO _4), 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 (0.33 g) at room temperature, and the mixture was stirred at 130 ° C for 2 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. Organic layer washed with 10% Kuen acid solution and water, dried (MgSO ₄₎ after the solvent was distilled off reduced pressure N-(3, 5-dimethoxybenzyl) Single 4- (4-off Ruorofeniru) 1-2- (3-Hydroxypropyl) -11-oxo-1,2,3-dihydro [2,7] naphthyridine-3-carboxamide was obtained as a colorless oil (0.64 g, 99%).

! H-NM (CDC1 ₃ ) 5- 2.00-2.18 (2H, m), 3.30—3.42 (1H, br), 3.56-3.68 (2H, m), 3.77 (6H, s), 4.12-4.28 (4H, m), 6.09 (2H, d, J = 2.2 Hz), 6.26-6.38 (2H, m) , 6.98—7.25 (4H, m), 7.24 to 7.32 (2 H, m), 8.63 (1H, d, J = 5.6 Hz), 9.59 (1 H, s).

 (Step 6)

To a solution of the compound (0.61 g) obtained in Step 5 in THF (50 ml) was added triethylamine (1.70 g) and methanesulfonyl chloride (2.000 g) at 0 ° C. The mixture was stirred at C for 3 hours. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, and then extracted with a mixture of ethyl acetate and THF. Organic layer washed with 10% Kuen acid solution and water, dried (MgSO _4), and the solvent was distilled off reduced pressure. To a solution of the obtained residue in THF (40 ml) was added sodium hydride (60% oil, 0.10 g) at 0 ° C, and the mixture was stirred at 80 ° C for 1 hour. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. The organic layer washed with 10% Kuen acid aqueous solution and water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 40: 10: 1) to give the title compound as a colorless prism (0.39 g, 66% ).

Melting point: 186-188 ° C (recrystallized from ethyl acetate-diisopropyl ether). Reference example 2

 (4 S) -2- (3,5-Dimethoxybenzyl) -1-12- (4-fluorophenyl) -1-methyl-2,3,4,5-tetrahydro [1,4] diazepino [1,2-b ] [2,7] naphthyridine-1,7-dione

 (Process 1)

 Using the compound (0.50 g) obtained in Step 4 of Reference Example 1 and (R) -3-amino-2-methyl-1-propanol (0.174 g), reacted in the same manner as in Step 5 of Reference Example 1. After treatment, (R) -N- (3,5-dimethoxybenzyl) 1-4

(4-Monofluorophenyl) 1-1- (3-hydroxy-2-methylpropyl) 1-1-oxo-1,2,3-dihydro [2,7] naphthyridine-1-carboxamide is a colorless powder (0.42 g, 72% ).

Melting point: 172-174 ° C.

 (Process 2)

Using the compound (0.50 g) obtained in Step 1, reverse reaction was performed in the same manner as in Step 6 of Reference Example 1. The title compound was obtained as a colorless powder (0.30 g, 74%).

_{- NMR (CD C 1 3)} δ 0. 96 (3ΗΧ 2/3, d, J = 6. 6 Hz), 1. 1 6 (3 Hx 1/3, d, J = 6. 6 Hz), 2 20— 3.90 (10 H, m) 4.25 -4. 46, 4. 6 8-4.76 and 5.13-5.38 (2 H, m), 6.24-6. 46 (2 H, m), 6.98-7.54 (6 H ₅ m), 8.69 (1 Hx 1/3, d, J = 5.6 Hz), 8.70 (1 Hx 2 / 3, d, J = 5.6 Hz), 9.69 (1 H, s) _Q

Reference example 3

 (4 S) — 2 -— [3,5-bis (trifluoromethyl) benzyl] -1-12- (4-fluorophenyl) -1-methyl-2,3,4,5-tetrahydro [1,4] dazepino [1 , 2—b] [2, 7] naphthyridine-1, 7—dione

 (Process 1)

 Using the compound (5.00 g) obtained in Step 3 of Reference Example 1 and 3,5-bis (trifluoromethyl) pendylamine (4.90 g), the reaction was carried out in the same manner as in Step 4 of Reference Example 1, and treated. N- [3,5-bis (trifluoromethyl) benzyl] —4- (4-fluorofuranyl) -1-1-oxo _ 1 H-pyrano [3,4-c] pyridin-13-carboxamide Was obtained as a colorless powder (7 g, 87 g, 87%). Melting point: 189-191 ° C.

 (Process 2)

 Using the compound (4.00 g) obtained in Step 1 and (R) -3-amino-2-methyl-1-propanol (1.22 g), the reaction was carried out in the same manner as in Step 5 of Reference Example 1, and the treatment was carried out. As a result, (R) -N- [3,5-bis (trifluoromethyl) benzyl] -1- (4-fluorophenyl) -2- (3-hydroxy-l-methylpropyl) -l-oxo-l 2,3-Dihydro [2,7] naphthyridine-13-carboxamide was obtained as an oil (3.27 g, 70%).

_{- NMR (CD C 1 3)} δ 0. 98 (3 Η, d, J = 7. O Hz), 2. 2 0- 2. 40 (l H, m), 3. 30 - 3. 43 (l H, m), 3.5 1—3.58 (1 H, m), 3.80-3.89 (1 H, m), 4.07-4.20 (1 H, m m), 4.36 (2 H, d, J = 5.8 Hz), 6.92-7.00 (4H, m), 7.18-7.26 (2 H, m), 7 _{. 56 (2 H 3 s)} , 7. 84 (1 H, s), 8. 58 (1 H, d, J = 5. 8Hz), 9. 49 (1 H, s).

 (Process 3)

 The compound (1.56 g) obtained in Step 2 was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was converted to colorless prism crystals (0.86 g, 65%). Was obtained.

Melting point: 185-187 ° C (recrystallized from methylene diisopropyl ether-hexane).

Reference example 4

 (4 R) -2- (3,5-dimethylbenzyl) -12- (4-fluorophenyl) —4-methyl-2,3,4,5-tetrahydro [1,4] diazepino [1,2—b] [2,7] naphthyridine-1,7-dione

 (Process 1)

 Using the compound (1.50 g) obtained in Step 3 of Reference Example 1 and 3,5-dimethyldimethylamine (0.82 g), reacted and treated in the same manner as in Step 4 of Reference Example 1. , N— (3,5-dimethylbenzyl) _4_ (4-fluorophenyl) 11-oxo-1 H-pyrano [3,4-1c] pyridine-13-carboxamide is a colorless powder (1.71 g ヽ) 80%).

Melting point: 130-1 32 ° C.

 (Process 2)

 Using the compound (0.80 g) obtained in Step 1 and (R) —3-amino-2-methyl-1-propanol (0.32 g), the reaction was carried out in the same manner as in Step 5 of Reference Example 1, and the treatment was carried out. Then, (R) — N— (3,5-dimethylbenzyl) -4- (4-fluorophenyl) -12- (3-hydroxy-2-methylpropyl) 1-1-oxo-1 2,3-dihydro [2 , 7] Naphthyridine-3-carboxamide was obtained as a colorless powder (0.776 g, 80%).

Melting point: 186-188 ° C.

(Process 3) The compound obtained in Step 2 (0.74 g) was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was converted to a non-powder (0.33 g, 46%). Obtained.

Melting point: 160-162 ° C! .

Reference example 5

 2— [3,5-bis (trifluoromethyl) benzyl] —12— (4-methylphenyl) -1,2,3,4,5-tetrahydro [1,4] diazepino [1,2—b]

[2, 7] naphthyridine-1, 7-dione

 (Process 1)

 N- [3,5-bis (trifluoromethyl) benzyl] -4-1- (4-methylphenyl) 1-1-1 synthesized by the method described in JP-A-9-263585 (EP-A-733632) Step 5 of Reference Example 1 was carried out using oxo- 1 H-pyrano [3,4-c] pyridine- 13-force lipoxamide (0.30 g) and 3-amino-1-propanol (0.10 g). After reacting and treating similarly, N- [3,5-bis

(Trifluoromethyl) benzyl] -2- (3-hydroxypropyl) -1- (4-methylphenyl) -11-oxo-1,2,3-dihydro [2,7] naphthyridine-13-carboxamide is pale yellow oil Was obtained as This compound was used for the reaction of Step 2 without purification.

 (Process 2)

 The compound obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was obtained as colorless crystals (0.095 g, 30%).

Melting point: 108-110 ° C (recrystallized from ethyl isopropyl ether). Reference example 6

 (4 S) —2— [3,5-bis (trifluoromethyl) benzyl] —4-methyl-12- (4-methylphenyl) -1,2,3,4,5-tetrahydro [1,4] dazepino [1,2—b] [2,7] naphthyridine-1,7-dione

 (Process 1)

N— [3,5-bis (trifluoromethyl) benzyl] synthesized by the method described in JP-A-9-1263585 (EP-A-733632) —4 -— (4— Methylphenyl) _1-oxo-1H-pyrano [3,4-c] pyridine-13-force lipoxamide (0.55 g) and (R) —3-amino-1-2-methyl-11-propanol ( 0.30 g), and reacted and treated in the same manner as in Step 5 of Reference Example 1.

(R) -N- [3,5-bis (trifluoromethyl) benzyl] —2— (3-hydroxy-1-2-methylpropyl) 1-4- (4-methylphenyl) 1-1-oxo-1,2,3- Dihydro [2,7] naphthyridine-13-carboxamide was obtained as an oil. This compound was used for the reaction of Step 2 without purification.

 (Process 2)

 The compound obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Reference Example 1, whereby the title compound (0.25 g, 42%) was obtained as colorless crystals.

Melting point: 183-185 ° C (recrystallized from ethyl acetate-diisopropyl ether). Reference Example 7

 (aR, 4 R) —2— (3,5-dimethoxybenzyl) -1-13- (4-fluorophenyl) 1,4-methyl-1,4,5,6-tetrahydro-1H— [1,4] diazono [1, 2—b] [2, 7] naphthyridine-1,8-dione

 (Process 1)

To a solution of the compound obtained in Step 4 of Reference Example 1 (0.80 g) in a mixed solution of THF (15 ml) and methanol (5 ml), was added (R) -4-amino-2-methyl-1-butyl-1-butanol. One tetrahydroviranyl (THP) ether (0.52 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 mixture of ethyl acetate and THF. The organic layer washed with 10% Kuen acid solution and water, dried (MgSO _4), followed by distilling off the solvent medium under reduced pressure. The resulting residue in toluene (30 ml) —acetonitrile

(5 ml) To the mixed solution was added DBU (0.45 g) at room temperature, and the mixture was stirred at 130 ° C for 2 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. Organic layer

Washed with 10% Kuen acid solution and water, dried (MgSO _4), the solvent was distilled off under reduced pressure. To a solution of the obtained residue in methanol (30 ml) was added p-toluenesulfonic acid monohydrate (0.50 g), 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 saturated sodium hydrogen Natoriumu aqueous solution and water, dried (MgSO _4), the solvent was distilled off under reduced pressure. Deposited The crystals are collected by filtration to give (R) -N- (3,5-dimethoxybenzyl) -14- (4-fluorophenyl) 1-2- (4-hydroxy-13-methylbutyl) 1-1_oxo- 1,2,3 —Dihydro [2,7] naphthyridine-13-carboxamide was obtained as a colorless powder (0.89 g, 92%).

Melting point: 158-160 ° C.

 (Process 2)

 The compound (0.85 g) obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was obtained as a colorless powder (0.68 g, 83%). Melting point: 186-188 ° C.

Reference Example 8

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

 (Process 1)

 Using the compound (0.80 g) obtained in Step 1 of Reference Example 3 and (R) _4-amino_2-methyl-1-butanol THP ether (0.44 g), When the reaction and treatment were carried out in the same manner as in Step 1, (R) -N- [3,5-bis (trifluoromethyl) pentyl] -4- (4-fluorophenyl) -2- (4-hydroxy-3-) Methylbutyl) 1-oxo-1, 2,3-dihydro [2,7] naphthyridin-3-carboxamide was obtained as a colorless powder (0.85 g, 92%). Melting point: 160-162 ° C.

 (Process 2)

 The compound (0.81 g) obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was obtained as a colorless powder (0.43 g, 54%). Melting point: 193-195 ° C.

Reference Example 9

(aR, 4 R) —2— (3,5-dimethylbenzyl) -1-13— (4-fluorophenyl) -14-methyl-3,4,5,6-tetrahydro-1-H— [1,4] dia Zosino [1,2—b] [2,7] naphthyridine 1, 8—dione

 (Process 1)

 Using the compound (0.80 g) obtained in Step 1 of Reference Example 4 and (R) —4-amino-2-methyl-1-butanol THP ether (0.65 g), By reacting and treating in the same manner as in step 1, (R) -N- (3,5-dimethylbenzyl) -14- (4-fluorophenyl) 1-2- (4-hydroxy-13-methylbutyl) 111-oxo-1,2,3-dihydro [2,7] naphthyridine-3-carboxamide was obtained as a colorless powder (0.92 g, 90%).

Melting point: 162-164 ° C.

 (Process 2)

 The title compound was obtained as a colorless powder (0.59 g, 66%) by reacting and treating the compound (0.92 g) obtained in Step 1 in the same manner as in Step 6 of Reference Example 1. .

Melting point: 171-173 ° C.

Reference Example 10

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

(Process 1)

N— [3,5-bis (trifluoromethyl) benzyl] —41- (4-methylphenyl) -11 synthesized by the method described in JP-A-9-1263585 (EP-A-733632) —Oxo-1 H—pyrano [3,4—c] pyridine-13-force lipoxamide (0.55 g) and (R) — 4-amino-2-methyl-1-butanol THP ether (0. Using 35 g), the reaction and treatment were carried out in the same manner as in Step 1 of Reference Example 7. (R) -N- [3,5-bis (trifluoromethyl) benzyl] -2- (4-hydroxy-3 —Methylbutyl) -1- (4-methylphenyl) -1-oxo-1,2,3-dihydro [2,7] naphthyridine-13-carboxamide was obtained as a pale yellow oil. This compound was used for the reaction of Step 2 without purification. (Process 2)

 The compound obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was obtained as a pale-yellow oil (0.38 g, 66%).

_{iH- NMR (CD C 1 3)} δ 0. 92 (3H, J = 6. 6 Hz), 1. 69 (1 H, m), 1. 9 - 2. 5 (2 H, m), 2. 37 (3 H, s), 2.99 (1 H, d, J = 15 Hz), 3.4--3.6 (2 H, m), 3.99 (1 H, d, J = 1 5Hz), 5. 0 1 (1 H, dd, J = 1 5 3 5. 8 Hz), 5. 45 (1 H, d, J = 1 5 H z), 6. 82 (1 H , D, J = 8.0 Hz), 7.00 (1H, d, J = 8.0Hz), 7.01 (lH, m), 7.30 (2H, m), 7 . 47 (2 H, s), 7.82 (1 H, s), 8.64 (1 H, d, J = 5.8 Hz), 9.68 (1 H, s).

Example 1

 2- (3,5-Dimethoxybenzyl) 1-12- (4-Fluorophenyl) -19-methyl-2,3,4,5,8,9,10,11,1-Hydrohydro [1, 4] Jazepino [1,2—b] [2,7] Naphthyridine-1,1,7-dione

To a solution of the compound (0.61 g) obtained in Reference Example 1 (0.61 g) in ethyl acetate (10 ml) -THF (5 ml) was added methyl iodide (5 ml), and the mixture was stirred at 80 ° C for 2 hours. did. After the solvent was distilled off under reduced pressure, the precipitated crystals were collected by filtration. To a solution of the obtained crystals in methanol (30 ml), sodium borohydride (0.29 g) was added at 0 ° C, and the mixture was stirred at 0 ° C for 1 hour. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried (M gS0 _4), the solvent was distilled off under reduced pressure. To a solution of the obtained residue in methanol (100 ml) was added 10% palladium on carbon (containing 50% water, 0.15 g), and the mixture was stirred at room temperature under a hydrogen atmosphere of 1 atm for 3 hours. After filtering off the catalyst, the filtrate was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methyl alcohol = 60: 10: 1) to give the title compound as a colorless prism (0.222 g, 74%).

Melting point: 187-189 ° C (recrystallized from methylene chloride-diisopropyl ether-hexane). Example 2

 (4 S) —2— (3,5-dimethoxybenzyl) -1-12— (4-fluorophenyl) -1,4,9-dimethyl-1,2,3,4,5,8,9,10,11 Evening hydro

[1, 4] diazepino [1, 2—b] [2, 7] naphthyridine-1,1, 7-dione Same as Example 1 using the compound (0.28 g) obtained in Step 2 of Reference Example 2. The title compound was obtained as colorless prisms (0.16 g, 55%).

Melting point: 92-94 ° C (recrystallized from ethyl isopropyl ether acetate).

Example 3

 (4 S)-2-[3,5-bis (trifluoromethyl) benzyl] 1 12-(4 -fluorophenyl) 1-4-methyl-1,2,3,4,5,8,9,10,1 1-octane hydro [1,4] diazepino [1,2-b] [2,7] naphthyridine 1, 7

—Dione monohydrochloride

 A solution of the compound (0.66 g) obtained in Step 3 of Reference Example 3 and 10% palladium on carbon (50% water content, 0.33 g) in acetic acid (30 ml) was heated at 60 ° C under a hydrogen atmosphere at 5 atm. For 3 hours. After filtering off the catalyst, the filtrate was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol-40: 10: 1) to give (4S) -2- [3,5-bis (trifluoro Oromethyl) benzyl] -12- (4-fluorophenyl) —4-methyl-1,2,3,4,5,8,9,10,11-octahydro [1,4] diazepino [1,2, b] [2,7] naphthyridine-1,7, -dione was obtained as a pale yellow foam (0.60 g, 90%). This was treated with a 4 N hydrochloric acid-ethyl acetate solution to give the title compound as colorless prisms.

Melting point: 263-265 ° C (recrystallized from ethanol-diisopropyl ether). Example 4

(4 S)-2-[3,5-bis (trifluoromethyl) benzyl] 1 12- (4 -fluorophenyl) 1,4,9-dimethyl 2,3,4,5,8,9,10 1 1-octane hydro [1, 4] diazepino [1, 2, b] [2, 7] naphthyridine-1, 1, 7-dione The compound (0.42 g) obtained in Step 3 of Reference Example 3 was reacted and treated in the same manner as in Example 1 to give the title compound as colorless prisms (0.24 g, 69%). Was.

Melting point: 175-177 ° C (recrystallized from diisopropyl ether-hexane). Example 5

 (4 S) 1 2— [3,5-bis (trifluoromethyl) benzyl] 1 9 1-ethyl — 12— (4-fluorophenyl) 1 4-methyl-1 2, 3, 4, 5, 8, 9 , 10,11 1-octane hydro [1,4] diazepino [1,2—b] [2,7] naphthyridine-1,1,7-dione

To a solution of the compound obtained in Example 3 (0.10 g) and acetoaldehyde (0.016 g) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (NaBH (OAc)). ₃ ) (0.15 g) was added at 0 ° C, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 60: 10: 1) to give the title compound as a pale-yellow powder (0.025 g). Was.

Melting point: 88-90 ° C.

Example 6 '

 (4 S)-2-[3,5-bis (trifluoromethyl) benzyl]-12- (4-fluorophenyl)-4-methyl-9-phenyl- 1,2,3,4,5,8,9,10 , 11-octyhydro [1,4] dazepino [1,2-b] [2,7] naphthyridine-1 1,7-dione.

Triphenyl bismuth diacetate was added to a solution of the compound (0.10 g) obtained in Example 3 and copper (II) pivalate (Cu (Piνθ) ₂ ) (0.016 g) in methylene chloride (5 ml). (Ph ₃ B i (OAc) ₂ ) (0.12 g) was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate). Hexane = 2: 1) The title compound was obtained as pale yellow powder (0.058 g, 51%).

Melting point: 150-152 ° C.

Example 7

 (4 S) -9-acetyl-2— [3,5-bis (trifluoromethyl) benzyl] -1-12- (4-fluorophenyl) -1-4-methyl-2,3,4,5,8,9,1 0,11-octyhydro [1,4] dazepino [1,2—b] [2,7] naphthyridine 1,1,7-dione

 Acetyl chloride (0.028 g) was added to a solution of the compound obtained in Example 3 (0.10 g) and triethylamine (0.036 g) in THF (5 ml) at 0 ° C, and the mixture was added at room temperature.

Stir for 14 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. Wash the organic layer with 1 N hydrochloric acid and water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 40: 10: 1) to give the title compound as a colorless powder (0.086 g, 80%). Obtained.

Melting point: 240-242 ° C.

Example 8

 (4S) -1- (3-, 5-dimethylbenzyl) -12- (4-fluorophenyl) -4,9-dimethyl-1,2,3,4,5,8,9,10,11 1, 4] diazepino [1, 2— b] [2, 7] naphthyridine-1,7 dione

 The compound (0.20 g) obtained in Step 3 of Reference Example 4 was reacted and treated in the same manner as in Example 1, and the title compound was converted to colorless prism crystals (0.13 g, 60% ).

Melting point: 146-148 ° C (recrystallized from methylene chloride-diisopropyl ether-hexane).

Example 9

2- [3,5-bis (trifluoromethyl) benzyl] -9-methyl-12- (4-methylphenyl) -1,2,3,4,5,8,9,10,11 [1,4] diazepino [1, 2—b] [2, 7] naphthyridine-1,7-dione The compound (0.063 g) obtained in Step 2 of Reference Example 5 was reacted and treated in the same manner as in Example 1, and the title compound was obtained as pale yellow crystals (0.065 g, 100%). Was.

Melting point: 218-221 ° C (recrystallized from ethyl isopropyl ether). Example 10

 (4 S) — 2— [3,5_bis (trifluoromethyl) benzyl] 1,4,9-dimethyl-12— (4-methylphenyl) 1,2,3,4,5,8,9,10, 11 —Okyu hydro [1,4] dazepino [1,2—b] [2,7] naphthyridine-1,1,7-dione

 The compound (0.16 g) obtained in Step 2 of Reference Example 6 was reacted and treated in the same manner as in Example 1, and the title compound was obtained as pale yellow crystals (0.16 g, 99%). .

Melting point: 183-185 ° C (recrystallized from ethyl acetate-diisopropyl ether). Example 11

 (aR, 4 R) —2— (3,5-dimethoxybenzyl) -1 13— (4-fluorophenyl) -1,4,10-dimethyl 3,4,5,6,9,10,11,12 Kuhu hydro-2H— [1, 4] diazocino [1, 2— b] [2, 7] naphthyridine-1, 8-dione

 The compound (0.25 g) obtained in Step 2 of Reference Example 7 was reacted and treated in the same manner as in Example 1, and the title compound was obtained as colorless prisms (0.14 g, 55%).

Melting point: 139-141 ° C (recrystallized from methylene diisopropyl ether-hexane).

Example 12

 (aR, 4) —2— [3,5_bis (trifluoromethyl) benzyl] 1 13 1 (4-fluorophenyl) 1,4,10-dimethyl-3,4,5,6,9,10,11 , 12-year-old hydro-2H— [1,4] diazosino [1,2—b] [2,7] naphthyridine-1, 8—dione

The compound (0.29 g) obtained in Step 2 of Reference Example 8 was reacted in the same manner as in Example 1, After treatment, the title compound was obtained as colorless prisms (0.22 g, 74%).

Melting point: 183-185 ° C (Methylene diisopropyl ether-hexane

Example 13

 (aR, 4 R)-2-[3,5-bis (trifluoromethyl) benzyl]-13- (4-fluorophenyl) 1-4-methyl- 1,4,5,6,9,10,1 1,12 One year old Kutahydro _ 2 H— [1,4] diazosino [1,2—b] [2,7] naphthyridine—1,8-dione monohydrochloride

 The compound (2.01 g) obtained in Step 2 of Reference Example 8 was reacted and treated in the same manner as in Example 3 to give (aR, 4R) — 2 -— [3,5-bis (trifluoromethyl) benzoate. Ndyl] — 13— (4-Fluorophenyl) 1,4-methyl-1,3,4,5,6,9,10,11,12-octahydro-2H— [1,4] diazino [1,2—b]

[2,7] Naphthyridine-11,8-dione was obtained as a pale yellow foam (1.96 g, 96%). This was treated with a 4 N hydrochloric acid-ethyl acetate solution to obtain the title compound as a pale yellow powder.

_{iH- NMR (CD C 1 3)} δ 0. 922 (3 Η, J = 6. 6 Hz), 1. 40 - 1. 70 (1H, m), 1. 90 - 2. 25 (4H, m) , 2.89-2.99 (3H, m), 3.28-3.47 (2H, m), 3.80-3.98 (3H, m), 4.90 (1H, dd, J = 14.2, 5.2 Hz), 5.37 (1H, d, J = 14.2Hz), 6.76-6.82 (2H, m), 7.00-7.10 (1H, m), 7.26-7.36 (lH, m), 7.40 (2H, s), 7.81 (1H, Example 14

 (aR, 4 R) -2-[3,5-bis (trifluoromethyl) benzyl] 1-113- (4-fluorophenyl) _10-formyl-4-methyl-1-3,4,5,6,9 , 10,11,12-Hydrohydro-2H— [1,4] diazosino [1,2-b] [2,7] Naphthyridin-1,8-dione

A mixed solution of formic acid (0.55 g) and acetic anhydride (0.90 g) was stirred at 60 ° C for 2 hours. After stirring, this was added to a solution of the compound (0.20 g) obtained in Example 13 in formic acid (3 ml) at room temperature and stirred for 14 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in a mixed solution of ethyl acetate and THF. The solution 1 N aqueous sodium hydroxide, washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The obtained residue was separated by silica gel column chromatography (ethyl acetate: hexane: methanol = 60: 10: 1). Purification gave the title compound as colorless crystals (0.115 g, 54%). Was done.

Melting point: 279-281 ° C (recrystallized from ethyl acetate diisopropyl ether). Example 15

 (aR, 4 R) — 10-acetyl-1 2— [3,5-bis (trifluoromethyl) benzyl] — 13— (4-fluorophenyl) 1-4-methyl-1 3,4,5,6,9, 10, 11, 12-octyhydro-2H— [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine-1 1, 8-dione

 The compound (0.20 g) obtained in Example 13 was reacted and treated in the same manner as in Example 7, to give the title compound as colorless crystals (0.18 g, 85%). Melting point: 237-239 ° C (recrystallized from ethyl isopropyl ether). Example 16

 (aR, 4 R) — 2 -— [3,5-bis (trifluoromethyl) benzyl] —13- (4-fluorophenyl) —4-methyl-1-10-propionyl-1 3,4,5,6,9 , 10,11,12-octahydro-1 2H_ [1,4] diazocino [1,2-b] [2,7] naphthyridin-1 1,8-dione

To a solution of the compound obtained in Example 13 (0.20 g) and triethylamine (0.070 g) in THF (10 ml) was added propionyl chloride (0.064 g) at 0 ° C. Stirred for hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. Wash the organic layer with 1 N hydrochloric acid and water, dried (MgSO _4), and the solvent was distilled off reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 40: 10: 1) to give the title compound as colorless crystals (0.15 g, 70%). Was.

Melting point: 187-1 & 9 ° C (recrystallized from methylene diisopropyl ether chloride). Example 17

 (aR, 4 R) -2-[3,5 _bis (trifluoromethyl) benzyl] 1 13-(4-fluorophenyl) 1 -4-methyl -10 -methylsulfonyl-3,4,5,6, 9, 10, 11, 12-octane hydro-1 2 H_ [1, 4] diazocino [1, 2-b] [2, 7] naphthyridine 1, 8-dione

To a solution of the compound obtained in Example 13 (0.20 g) and triethylamine (0.070 g) in THF (10 ml) was added methanesulfonyl chloride (0.064 g) at 0 ° C. For 14 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. Wash the organic layer with 1 N hydrochloric acid and water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography.

Separation and purification by (ethyl acetate: hexane: methanol = 40: 10: 0) gave the title compound as colorless crystals (0.17 g 77%).

Melting point: 223-225 ° C (recrystallized from methylene chloride-diisopropyl ether). Example 18

 (aR, 4 R) 1 2— [3,5-bis (trifluoromethyl) benzyl] —13- (4-fluorophenyl) —10-methoxycarboxy 4-methyl-3,4,5,6, 9, 10, 11, 12-octane hydro-1H, [1, 4] diazocino [1, 2-b] [2, 7] naphthyridine-1, 8-dione

To a solution of the compound obtained in Example 13 (0.20 g) and triethylamine (0.070 g) in THF (10 ml) was added methyl methyl carbonate (0.055 g) at 0 ° C. In addition, the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. Wash the organic layer with 1 N hydrochloric acid and water, dried (MgSO _4), and the solvent was distilled off reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 40: 10: 1) to give the title compound as colorless crystals (0.17 g, 77%) Was obtained as

Melting point: 194-196 ° C (recrystallized from ethyl acetate-diisopropyl ether). Example 19

(aR, 4 R)-2-[3,5-bis (trifluoromethyl) benzyl] — 10 1 (N, N-dimethylcarbamoyl) 1 13 — (4 monofluorophenyl) 14 — Methyl-1,4,5,6,9,10,11,12-octyhydro-1H— [1,4] diazosino [1,2-b] [2,7] naphthyridine-1,8— Zeon

To a solution of the compound obtained in Example 13 (0.20 g) and triethylamine (0.070 g) in THF (10 ml) was added N, N-dimethylcarbamoyl chloride (0.075 g) at 0 ° C. The mixture was stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. Wash the organic layer with 1N hydrochloric acid and water, dried (Mg S0 _4), the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane: methanol = 40: 10: 1) to give the title compound as colorless crystals (0.17 g, 76%). Was.

Melting point: 193-195 ° C (recrystallized from ethyl isopropyl ether). Example 20

 (aR, 4 R) one 2- (3,5-dimethylbenzyl) -13- (4-fluorophenyl) one 4,10-dimethyl-3,4,5,6,9,10,11,12- Hisayu Hydro-1H— [1,4] Diazocino [1,2—b] [2,7] Naphthyridine-1,8-dione

 The compound (0.20 g) obtained in Step 2 of Reference Example 9 was reacted and treated in the same manner as in Example 1 to give the title compound as colorless prisms (0.18 g, 87%) .

Melting point: 215-217 ° C (recrystallized from ethyl acetate-diisopropyl ether). Example 21

 (aR, 4 R) — 2— [3,5-Bis (trifluoromethyl) benzyl]-13 — (4-Methylphenyl) 1,4,10—Dimethyl-1,3,4,5,6,9,10 11,12-year-old hydro-2H— [1,4] diazocino [1,2—b] [2,7] naphthyridine-1,8-dione

 The compound (0.26 g) obtained in Step 2 of Reference Example 10 was reacted and treated in the same manner as in Example 1, and the title compound was obtained as pale yellow crystals (0.12 g, 46%).

Melting point: 191-193 ° C (recrystallized from ethyl isopropyl acetate). Example 22

 [(aR, 4 R) —2— [3,5-bis (trifluoromethyl) benzyl] —1 3— (4-fluorophenyl) 1-4-methyl-1,8-dioxo 1,3,4,5 , 6,9,11,12-year-old hydro [1,4] diazosino [1,2—b] [2,7] naphthyridine _ 10 (8 H) -yl] acetonitrile

To a solution of the compound obtained in Example 13 (0.20 g) and triethylamine (0.104 g) in DMF (4 ml) was added bromoacetonitrile (0.144 g) at room temperature, and the mixture was stirred at 80 ° C for 2 hours. did. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. Wash the organic layer with 1N hydrochloric acid and water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and separated and purified with ethyl acetate-hexane-methanol (50: 10: 1) to give the title compound as colorless prisms (0.171 g, 80%). Obtained. 233-235 ° C (recrystallized from ethyl isopropyl ether acetate). Example 23

 (aR, 4 R) 1 2- (3,5-dimethylbenzyl) 1 13- (4-fluorophenyl) 1-4-methyl-1,4,5,6,9,10,11,12-octyl Hydro-2H- [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine 1,8

—Dione monohydrochloride

 The compound (5.30 g) obtained in Step 2 of Reference Example 9 was reacted and treated in the same manner as in Example 3 to obtain (aR, 4R) —2- (3,5-dimethylbenzyl) —13— (4-Monofluorophenyl) 1,4-methyl-1,3,4,5,6,9,10,11,12-octane hydro-2H— [1,4] diazino [1,2—b] [2,7] Naphthyridine-1, 8-dione (4.80 g, 90%) was obtained as a colorless powder. The compound thus obtained (0.43 g) was treated with a 4 N hydrochloric acid / ethyl acetate (0.3 ml) solution and recrystallized from getyl ether to give the title compound (0.43 g) as colorless. Obtained as prism crystals. Melting point: 280 ° C (decomposition) (recrystallized from dimethyl ether).

Example 24 (aR, 4 R) -2- (3,5-dimethylbenzyl) -1 10-ethyl- 13- (4-fluorophenyl) 1-4-methyl-3,4,5,6,9,10,11,12- Hydroxyl hydro 2H— [1, 4] diazocino [1, 2— b] [2, 7] naphthyridine 1, 1, 8-dione

To a solution of the compound (0.20 g) obtained in Example 23 in ethyl acetate (1 Oml) was added iodinated tyl (5 ml), and the mixture was stirred at 85 ° C for 2 hours. After the solvent was distilled off under reduced pressure, the precipitated crystals were collected by filtration. Sodium borohydride (0.20 g) was added to a solution of the obtained crystals in methanol (1 Oml) at 0 ° C, and the mixture was stirred at 0 ° C for 1 hour. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF. The organic layer was washed with saturated sodium hydrogen carbonate solution and water, dried (MgSO _4), the solvent was distilled off under reduced pressure. To a solution of the obtained residue in methanol (20 ml) was added 10% palladium on carbon (containing 50% water, 0.10 g), and the mixture was stirred at room temperature under a hydrogen atmosphere of 1 atm for 3 hours. After filtering off the catalyst, the filtrate was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and purified by separation with ethyl acetate-hexane (4: 1) to give the title compound (0.087 g, 40%) as a colorless prism. Obtained as crystals. Melting point 170-172 ° C (recrystallized from ethyl acetate-diisopropyl ether).

Example 25

 (aR, 4 R) —2— (3,5-dimethylbenzyl) 1-10-acetyl-13— (4-fluorophenyl) 1-4-methyl-3,4,5,6,9,10,11,1

2-octane hydro-2H— [1, 4] diazocino [1, 2—b] [2, 7] naphthyridine—1, 8-dione

 When the compound (0.20 g) obtained in Example 23 was reacted and treated in the same manner as in Example 7, the title compound (0.18 g, 81%) was obtained as colorless prism crystals. Melting point 180-182 ° C (recrystallized from ethyl isopropyl ether).

Example 26

(aR, 4 R)-2-(3,5-dimethylbenzyl) 1 13-(4 1-Methyl-10-propionyl 3,4,5,6,9,10,11,12-Hydrohydro-2H— [1,4] diazosino [1,2—b] [2 , 7] naphthyridine 1, 8—dione

When the compound (0.20 g) obtained in Example 23 was reacted and treated in the same manner as in Example 16, the title compound (0.096 g, 42%) was obtained as colorless prism crystals. Melting point 140-142 ° C (from methylene diisopropyl ether).

実施例

Example

 xa. R '

 畨 FT R

19 Me ₂ NCO F Me CF ₃ CF ₃ 193--195 20 Me F Me Me Me 215-217 21 Me Me Me CF ₃ CF ₃ 191-193 22 NCCH ₂ F Me CF ₃ CF ₃ 233-235 23 HF Me Me Me ND 23 2 HF Me Me Me HCI salt 280 (decomposed) 24 2 Et F Me Me Me 170-172 25 2 Ac F Me Me Me 180-182

Fetch (26 2 EtCO F Me Me Me 140—142

Formulation Example 1

 (1) 1 Omg of the compound of Example 1

 (2) Lactose 6 Omg

 (3) Corn starch 35 mg

 (4) Hydroxypropyl methylcellulose 3mg

 (5) Magnesium stearate 2mg

 A mixture of 1 Omg of the compound obtained in Example 1, 6 Omg of lactose and 35 mg of corn starch was granulated using 0.03 ml of a 10% by weight aqueous solution of hydroxypropylmethylcellulose (3 mg as hydroxypropylmethylcellulose), and then granulated. Dry at ° C and sieve. The granules obtained are mixed with 2 mg of magnesium stearate and compressed. The resulting uncoated tablets are coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and acacia. The coated tablets are lustered with a wax to obtain coated tablets.

 Also, coated tablets are obtained in the same manner except that any of the compounds of Examples 2 to 26 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

 Granulate 10 mg of the compound obtained in Example 1 and 3 mg of magnesium stearate in an aqueous solution of soluble starch (0.07 ml, 7 mg as soluble starch), dry, mix with lactose 7 Omg and corn starch 5 Omg . Compress the mixture to obtain tablets.

 Also, tablets are obtained in the same manner except that the compound of Example 1 is replaced with any of the compounds of Examples 2 to 26.

Test Example 1 Radioligand receptor binding activity (receptor binding activity using receptor from human lymphoblastoid cells (IM-9)) A modified version of the method described in MA Cascieri [Molecular Pharmacology, Vol. 42, p. 458 (issued in 1992)] was used. Receptors were prepared from human lymphoblast cells (IM-9). After inoculation of IM-9 cells (2 × 10 ⁵ cells / ml), the cells were cultured for 3 days (1 liter), and then centrifuged at 500 × G 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 30 ml of 12 OmM sodium chloride, 5 mM potassium chloride, 2 μg Zml chymosin In 5 OmM Tris' hydrochloric acid buffer (pH 7.4) containing 40 μg / ml bacitracin, 5 μg Zml phosphoramidone, 0.5 mM phenylmethylsulfonyl fluoride, 1 mM ethylenediaminetetraacetic acid Using a Polytron homogenizer (Kinematika, Germany) and centrifuged at 40,000 XG for 20 minutes. The separated product was washed twice with 30 ml of the above buffer solution, and then stored frozen (180 ° C) as a receptor product.

 This sample was treated with a reaction buffer [50 mM Tris' hydrochloric acid buffer (pH 7.4), 0.02% bovine serum albumin, ImM phenylmethylsulfonylfluoride so as to have a protein concentration of 0.5 mg / ml. De, Kimos Yu Chin, 0

1 bacitracin, 3 mM manganese chloride], and 1 volume of 10 〃 was used for the reaction. The sample, ¹²⁵ I-BHSP (0.46 KBq), was also added, and the mixture was reacted in 0.2 ml of a reaction buffer at 25 ° C for 30 minutes. The amount of non-specific binding was determined by adding substance P so as to be 2 × 10 ⁶ M.

 After the reaction, you can use a glass-filled Yuichi [GF / B, Whatman, Inc.] using Cell Harvest Yuichi [290 PHD ヽ Cambridge 'Technology' Inc. (Cambridge Technology, Inc.), USA]. The reaction was stopped by rapid filtration over the filter and washed three times with 250 1 of 5 OmM Tris-HCl buffer (PH7.4) containing 0.02% bovine serum albumin. The remaining radioactivity was measured at Gamma'County. Before the use, the film was immersed in 0.1% polyethyleneimine for one day and then air-dried before use.

The antagonistic activity of the compounds obtained in Examples was determined as the drug concentration (IC50 value) required to exhibit ₅₀ % inhibition under the above conditions. I got

 Table 3

Example No. C ₅₀ value (nM)

 3 0489

 4 0597

 7 0164

 12 0569

 13 0332

 14 0417

 15 0269

 o ooooooooo.

 16 0432

 19 0377

25 0762 Radio 'ligand refers to substance P labeled with [ ¹²⁵ 1]. Table 3 shows that the compounds of the present invention have excellent substance P receptor antagonism.

Test Example 2 Inhibitory activity of NK1 (neurokinin 1) 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). A Hartley white male guinea pig anesthetized with ether was fixed to the head with a stereotaxic apparatus (David Kopf, USA). Insert a 27G injection needle so that the tip reaches the third ventricle (7.5 to 8 mm below bregma), and GR73632 (Bachem, Switzerland) dissolved in saline for injection 0.1 nmol in a volume of 51 Injected over 1 minute. After the administration, the incision was sutured, and the locomotor activity was measured for 30 minutes using a locomotor activity analyzer (ANIMEX AUTO MK-110, Muromachi Kikai, Japan) immediately after the animal awakened from anesthesia. The test drug was suspended in a 0.5% methylcellulose solution and orally administered at a volume of 2 mL / kg 45 minutes before administration of GR73632. 0.5% ethylcelliilose solution for control group The same volume was orally administered. A sham treatment group in which physiological saline was administered into the ventricle instead of the GR73632 solution was also provided. Each treatment group consisted of 4 or more patients. The evaluation of the drug was evaluated by calculating the inhibition rate according to the following formula. In addition, if necessary, ID _5. The value was calculated using the suppression rate (Table 4).

Spontaneous locomotor activity in the test group vs. spontaneous locomotion in the sham treatment group j

 X 100 Spontaneous locomotor activity in the control group-Spontaneous locomotor activity in the sham treatment group Table 4 Test compound dose (po)

 (Example No.) _ Mg / kg

 7 1.0 84.1

 15 1.0 92.2

 16 1.0 78. 7

 20 1.0 66.4 From Table 4, it was found that the compound of the present invention had excellent inhibitory activity on hyperlocomotion induced by intracerebroventricular injection of NK1 agonist GR 73632 in guinea pigs.

 Industrial applicability

 The compound (I) of the present invention or a salt thereof or a prodrug thereof has a high kinkinin receptor antagonism, particularly a substance P receptor antagonism, is low in toxicity, and is safe as a drug. Therefore, the compound (I) or a salt thereof or a prodrug thereof of the present invention is useful as a pharmaceutical composition, for example, a quinkinin receptor antagonist, a dysuria improving agent and the like. This application is based on a patent application No. 2000-280154 filed in Japan, the contents of which are incorporated in full herein.

Claims

 The scope of the claims  Expression

[Wherein, R ¹ represents (1) a hydrogen atom, (2) a halogen atom, cyano, hydroxy, _ ₆ alkoxy, acyl, C alkylsulfonyl, carboxyl, ( ₆ alkoxy-monocarbonyl, di-rubamoyl, mono- or di-C _ ₆ alkyl Ichiriki Rubamoiru, sulfamoyl, mono- or di - C i _ ₆ alkylene loose Alpha Moi le may have a substituent selected from the group consisting of 〇 ₆ _ ₁₄ Ariru and 5 to 14-membered heterocyclic group C Bok ₆ alkyl group, (3) C ₆ -! ₁₄ Ariru group, (4) C _ ₆ Ashiru group, (5) C Bok ₆ alkoxy - carbonyl group, (6) force Rubamoiru group, (7) mono- or di C _i-6 alkyl Ichiriki Rubamoiru group or (8) - 6 alkyl sulfonyl group, R ² represents a hydrogen atom, a halogen atom or an optionally halogenated and C ^ - _e-alkyl group, R ³ is a hydrogen atom or An alkyl radical, R is different from a hydrogen atom was the same or a halogen atom, an optionally halogenated C [Al Kill group or halogenated which may be C i _ ₆ alkoxy group, m is 0 to 3 N is 1 or 2, and p is an integer of 0 to 3, provided that R ¹ is a methyl group, R ² is a methyl group, R ³ is a hydrogen atom,

Is a group represented by the formula

When m is 1, n represents 1. ] Or a salt thereof _c 2. The compound according to claim 1, wherein R ² is a hydrogen atom or a halogen atom. 3. The compound according to claim 1, wherein 3 R ³ is a C i — ₆ alkyl group. 2. The compound according to claim 1, wherein 4 R ³ is in the /? Configuration. 5 formulas

Is a group represented by the formula

[In the formula, R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom, a halogenated C ₆ alkyl group or C i — ₆ alkoxy group. The compound according to claim 1, which represents a group represented by the formula: 6. Expression

[Wherein R ¹ ′ is an alkyl group or —3 acyl group, and R ² ′ is a hydrogen atom or A halogen atom, R ³ ′ is a C ^ -3 alkyl group, R ⁴ ′ and R ^5> are the same or different and optionally halogenated C ₃ alkyl groups, n is 1 or 2 Show. The compound according to claim 1, which is a compound represented by the formula: or a salt thereof. 7. The compound of claim 6 wherein the R bur C i _ ₃ Ashiru group. 8. (4 S) - 2 - [3 ₃ 5-bis (triflate Ruo ii) benzyl] - 12 one (4-fluorophenyl) one 4, 9 Jimechiru one 2, 3, 4, 5, 8, 9, 1 0, 1 1-year-old hydro [1,4] diazepino [1,2-b] [2,7] naphthyridine-1,7-dione or its salt,  (4S) -9-Acetyl-1-2- [3,5-bis (trifluoromethyl) benzyl] -12- (4-fluorophenyl) -14-methyl-1,2,3,4,5,8,9 , 1 0,1 1-year-old hydro [1,4] diazepino [1,2-b] [2,7] naphthyridine 1, 7-dione,  (aR, 4 R) _ 2— [3,5-bis (trifluoromethyl) benzyl] — 13 — (4-fluorophenyl) 1, 4,10-dimethyl-3,4,5,6,9,10,1 1,12-octane hydro-1H— [1,] diazosino [1,2—b] [2,7] naphthyridine-1,8-dione or a salt thereof,  (aR, 4 R) _ 10-Acetyl-1-2- [3,5-bis (trifluoromethyl) benzyl] — 13- (4-Fluorophenyl) -14-methyl-1,3,4,5,6,9 , 10,11,12-octanohydro-2H— [1,4] diazosino [1,2-b] [2,7] naphthyridine-1,8-dione,  (aR, 4 R) — 2— [3,5-bis (trifluoromethyl) benzyl] — 13- (4-fluorophenyl) 1-4-methyl-10 _propionyl _ 3,4,5,6,9 10,11,12-octane hydro-1H- [1,2] diazosino [1,2-b] [2,7] naphthyridine-1,8-dione,  (aR, 4 R)-2-(3,5-dimethylbenzyl) 1 13- (4-fluorophenyl) _4,10-dimethyl-3,4,5,6,9,10,11,12-octane Even hydro-2H— [1,4] diazino [1,2—b] [2,7] naphthyridine-1,8-dione or a salt thereof, or (aR, 4 R) — 10—acetyl-1 2— (3,5-dimethylbenzyl) 1 13— (4-Monofluorophenyl)-4-methyl-1,3,4,5,6,9,10,11,12-octanehydro-1H- [1,4] diazosino [1,2-b] [2 , 7] Naphthyridine-l 1,8-dione.  9. A prodrug of the compound of claim 1.  10.Formula (a)

[Wherein each symbol has the same meaning as described in claim 1.] To a reduction reaction of the compound represented by the formula

 [Wherein each symbol has the same meaning as described in claim 1.] A step of obtaining a compound represented by the formula  Equation (b) One one

[Wherein each symbol has the same meaning as described in claim 1.] ] Or a salt thereof represented by the formula  R ^ -L '(IV) [Wherein L ′ represents a leaving group, and I ^ a has the same meaning as R ^{1 in} claim 1. However, R ¹ a is not a hydrogen atom. ] Or a salt thereof,

 Wherein each symbol is as defined above. Or a salt thereof, or  Equation (c)

[Wherein each symbol has the same meaning as described in claim 1.] A compound represented by the formula:  R ^ -L '(IV) [Wherein L ′ represents a leaving group, and I ^ a has the same meaning as R ^{1 in} claim 1. However, R ¹ a is not a hydrogen atom. And a salt thereof to form a quaternary salt.

 Wherein each symbol is as defined above. Or a salt thereof to obtain a compound represented by the formula:

[Wherein each symbol has the same meaning as described in claim 1.] ] Or a salt thereof.  11. Expression

Wherein, R ¹ represents (1) hydrogen atom, (2) a halogen atom, Shiano, hydroxy, (丄_ ₆ alkoxy, d ₆ Ashiru, C i ₆ alkylsulfonyl, carboxyl, ₆ alkoxy one carbonyl, force Rubamoiru, mono or di-one d ₆ alkyl Ichiriki Rubamoiru, sulfamoyl, mono- or di-C i_ ₆ alkyl one Surufamoi Le, C ₆ _ ₁₄ to Ariru and 5 which may have a substituent selected from the group consisting of 14-membered heterocyclic group - 6 alkyl group, (3) C ₆ - ₁₄ Ariru group, (4) C! _ _6- acyl group, (5) C ぃ₆ alkoxy-carbonyl group, (6) carbamoyl group, (7) mono- or di-C ぃ_6- alkyl lbamoyl group or (8) ( ₆ alkylsulfonyl group, ² is a hydrogen atom, halogen atom or halogenated (化₆ alkyl group; R ³ is a hydrogen atom or (^ alkyl group, R is the same or different hydrogen atom, halogen atom, halogen Optionally substituted C i — e alkyl group or optionally halogenated — 6 alkoxy group, m is an integer of 0 to 3, n is 1 or 2, p is an integer of 0 to 3 Where R ¹ is a methyl group, R ² is a methyl group, R ³ is a hydrogen atom, formula ) P

Is a group represented by the formula

When m is 1, n represents 1. Or a salt thereof or a prodrug thereof, and a pharmacologically acceptable carrier.  12. The composition according to claim 11, which is an evening kikinin receptor antagonist.  13. The composition according to claim 11, which is a substance P receptor antagonist.  14. The composition according to claim 11, which is an agent for improving abnormal urination.  15. The composition according to claim 11, which is an agent for preventing and treating urinary frequency and urinary incontinence.  16. Prevention and treatment of asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel disease, vomiting, HIV infection, chronic obstructive pulmonary disease, depression, anxiety, manic depression or schizophrenia 12. The composition of claim 11, wherein the composition is 17. Formula for mammals (R) P  (CH) m (I) [Wherein 1 ^ is (1) a hydrogen atom, (2) a halogen atom, cyano, hydroxy, d- ₆ alkoxy, acyl, C- ₆ alkylsulfonyl, carboxyl, ₆ alkoxy-carbonyl, carbamoyl, mono or di C i-e alkyl Ichiriki Rubamoiru, sulfamoyl, mono- or di - have a C i_ ₆ alkyl one Surufamoi Le, C ₆ one ₁₄ Ariru and 5 to substituents selected from the group consisting of 14-membered heterocyclic group a C Bok ₆ alkyl group, (3) C ₆ -! ₁₄ Ariru group, (4) C _ ₆ Ashiru group, (5) C ₆ alkoxy one carbonyl group, (6) force Rubamoiru group, (7) mono- or di one C _i-6 alkyl Ichiriki Rubamoiru group or (8) - 6 alkyl sulfonyl group, R ² represents a hydrogen atom, a halogen atom or a halogenated may CI- ₆ alkyl group, R ³ is also hydrogen (^ Alkyl radical, R is different from a hydrogen atom was the same or a halogen atom, an optionally halogenated to (^ _-6 al Kill group or halogenated which may be C alkoxy group, m is 0 And n is 1 or 2, and p is an integer of 0 to 3, provided that H ¹ is a methyl group, R ² is a methyl group, R ³ is a hydrogen atom,

Is a group represented by the formula

When m is 1, n represents 1. ] The method for preventing or treating pollakiuria and urinary incontinence, comprising administering an effective amount of the compound represented by the formula (I) or a salt thereof or a prodrug thereof.  18. Formula for mammals

Wherein 1 ^ is (1) hydrogen atom, (2) a halogen atom, Shiano, hydroxy - ₆ alkoxy, Ci-e Ashiru, C i_ ₆ alkylsulfonyl, carboxyl, C ^ - ₆ alkoxy one carbonyl, force Rubamoiru Having a substituent selected from the group consisting of mono- or di-C ₆ alkyl-sulfamoyl, mono- or di-C i- _e alkyl-sulfamoyl, _4- aryl and 5- to 14-membered heterocyclic groups. which may C ₆ alkyl group, (3) C ₆ -! ₁₄ Ariru group, (4) C _ ₆ Ashiru group, (5) C i-6 alkoxy one carbonyl group, (6) force Rubamoiru group, (7) mono Or di-C i-6 alkyl monovalent rubamoyl group or (8) C- ₆ alkyl sulfonyl group, R ² is a hydrogen atom, a halogen atom or an alkyl group which may be halogenated, and R ³ is a hydrogen atom or a The alkyl radical, R is different from a hydrogen atom was the same or a halogen atom, an optionally halogenated C [Bok ₆ Al Kill group or halogenated which may be C Bok ₆ alkoxy group, m is 0 to An integer of 3, n represents 1 or 2, and p represents an integer of 0 to 3. Where R ¹ is a methyl group, R ² is a methyl group, R ³ is a hydrogen atom, and the formula

Is a group represented by the formula

When m is 1, n represents 1. Asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel disease, vomiting, HIV infection, chronic obstructive pulmonary disease, including administering an effective amount of a compound represented by How to prevent or treat depression, anxiety, manic depression or schizophrenia. 19. Frequent urination · Prevention of urinary incontinence · Formulas for manufacturing therapeutic agents

Wherein,;! R ¹ is (1) hydrogen atom, (2) a halogen atom, Shiano, hydroxy, _ ₆ alkoxy, C i_ ₆ Ashiru, C WINCH ₆ alkylsulfonyl, carboxyl, C _ ₆ alkoxy one carbonyl, a force a Surufamoi Le, a C _{6 14} Ariru and 5 to substituents selected from the group consisting of 14-membered heterocyclic group - Rubamoiru, mono- or di - C ₆ alkyl - force Rubamoiru, sulfamoyl, mono- or di-one C i_ ₆ alkyl ! good C ₆ alkyl group optionally, (3) C _{6 14} Ariru group, (4) C _ ₆ Ashiru group, (5) CL- 6 alkoxy - carbonyl group, (6) force Rubamoiru group, (7) mono or di - C-alkyl Ichiriki Rubamoiru group or (8) Ci ₆ alkyl sulfonyl group, R ² is a hydrogen atom, a halogen atom or an optionally halogenated alkyl group, R ³ is a hydrogen atom or a Ci ₆ alkyl R is the same or different and represents a hydrogen atom, a halogen atom, an optionally halogenated alkyl group or an optionally halogenated C alkoxy group, m is an integer of 0 to 3, and n is 1 or 2, and p represents an integer of 0 to 3. Where R ¹ is Methyl group, R ² is methyl group, R ³ is hydrogen atom, formula

Is a group represented by the formula

When m is 1, n represents 1. Or a salt thereof or a prodrug thereof.  20. Prevention and treatment of asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel disease, vomiting, HIV infection, chronic obstructive pulmonary disease, depression, anxiety, manic depression or schizophrenia Formula for manufacturing

Wherein, R ¹ represents (1) hydrogen atom, (2) a halogen atom, Shiano, hydroxy, _ ₆ alkoxy, C Ashiru, C ₆ alkylsulfonyl, carboxyl, C! _ ₆ alkoxy one carbonyl, force Rubamoiru, mono- or di one C i_ ₆ alkyl - force Rubamoiru, sulfamoyl, optionally having mono- or di-C ₆ alkyl loose Alpha Moi Le, substituent C ₆ _ ₁₄ to Ariru and 5 are selected from the group consisting of 14-membered heterocyclic group good C i-6 alkyl group, (3) C ₆ - ₁₄ Ariru group, (4) CI_ ₆ Ashiru group, (5) C ₆ alkoxy one carbonyl group, (6) force Rubamoiru group, (7) mono- or di one — 6-alkyl-rubamoyl group or (8) Ci— e-alkyl A sulfonyl group, represents a hydrogen atom, a halogen atom or an alkyl group which may be halogenated, R ³ represents a hydrogen atom or ( ₆ alkyl group, and R represents the same or different hydrogen atom, halogen atom, halogenated An optionally substituted C i-6 alkyl group or an optionally halogenated C ₆ alkoxy group, m is an integer of 0 to 3, n is 1 or 2, and p is an integer of 0 to 3. Where R ¹ is a methyl group, R ² is a methyl group, R ³ is a hydrogen atom,

Is a group represented by the formula

When m is 1, n represents 1. Or a salt thereof or a prodrug thereof.