WO1998016519A1

WO1998016519A1 - [φ-(2,3-DIHYDRO-1-BENZOXEPIN-4-YL)ALKYL]AMINE DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF, AND MEDICINAL COMPOSITIONS CONTAINING THE SAME

Info

Publication number: WO1998016519A1
Application number: PCT/JP1997/003672
Authority: WO
Inventors: Toshiya Morie; Aki Kanehira; Naoki Kai; Katsuhiko Hino; Katsuyoshi Kawashima; Isao Shimizu; Kazuhisa Akiyama
Original assignee: Dainippon Pharmaceutical Co., Ltd.
Priority date: 1996-10-16
Filing date: 1997-10-14
Publication date: 1998-04-23
Also published as: AU4571697A

Abstract

[φ-(2,3-Dihydro-1-benzoxepin-4-yl)alkyl]amine derivatives represented by general formula (I), and salts and N-oxide derivatives thereof; a process for the preparation of them; and medicinal compositions containing the same as formula (I) (wherein R?1 and R2¿ are each hydrogen, halogeno, alkyl, alkoxy or the like, or alternatively R?1 and R2¿ may be united to form ethyleneoxy, trimethylene or the like; R3 is hydrogen, alkyl or the like; R4 is hydrogen, alkyl, acyl or the like, and R5 is cycloalkyl, or alternatively R?4 and R5¿ may form together with the adjacent nitrogen atom a cyclic amino group; and p is an integer of 2 to 6). The compounds exhibit a potent inhibitory activity against micturition reflex, being useful as remedies for pollakiuria and urinary incontinence.

Description

Details

[Ω- (2,3-Dihidrone 1-benzoxepin-141-yl) alkyl] amine derivative, process for producing the same, and pharmaceutical composition containing the same

The present invention relates to a novel [ω- (2,3-dihydro-1-benzoxepin-14-yl) alkyl] amine derivative having an effect of suppressing urinary reflex, a method for producing the derivative, and a compound containing the compound. The present invention relates to a pharmaceutical composition comprising: Background art

JP-A-61-130286 [Chem. Abstr., 106, 18390u (1987)] discloses a 2,3-dihydro-1-benzoxepin derivative represented by the following formula and a pharmacologically acceptable derivative thereof. It is described that salts are effective in improving and treating symptoms based on organic and mental disorders in the brain.

[In the formula, A represents a halogen atom or a lower alkoxy group, R represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, Y represents a piperidyl group, a group -NR ^! R ² (where R ¹ and R ² represents the same or different alkyl groups having 1 to 3 carbon atoms) or a group

(Where R ³ represents an alkyl group having 1 to 3 carbon atoms). However, when A is a halogen atom, Y is a group other than 1-piperazyl group. With the advent of an aging society in recent years, the number of patients suffering from frequent urination and urinary incontinence has been increasing year by year, and the emergence of superior therapeutic agents is desired. The present inventors have conducted intensive studies and as a result, [ω— (2,3—dihydro-11-benzoxepin-14-yl) alkyl] amine derivative represented by the following formula (I) Have a strong urinary reflex suppression effect, and completed the present invention. Disclosure of the invention

The present invention provides a compound represented by the general formula (I):

[Wherein, R ¹ and R ² are the same or different and are each a hydrogen atom, a halogen atom, a hydroxy group, a C! Cs alkyl group, a CiCs alkoxy group: a hydroxymethyl group, a formyl group, a carboxy group; Or C! Cs alkoxycarbonyl, or R ¹ and R ² are adjacent When bound to that carbon atom, they are together a connexion methylene Nji Okishi group, ethylene Nokishi group _{_{(- CH 2 CH 2 0-)}} , to form an ethylene Njiokishi group, Application Benefits methylene down group or Te Toramechire emissions group You can,

R ³ represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a C 1 -C _δ alkyl group, a C i -C ₃ alkoxy group or a phenyl group, and R ⁴ represents a hydrogen atom, ~ Ji alkyl group, Ashiru group, C, -C ₅ al alkylsulfonyl group, or an unsubstituted young properly refers to substituents off Wenirusuruhoniru group,

R ⁵ represents a C ₃ to C _s cycloalkyl group, or R ⁴ and R ⁵ may form a cyclic amino group represented by the following formula (A) together with an adjacent nitrogen atom;

(A)

(In the formula, R ^s , R ⁷ and q are as defined below.)

R ⁶ represents a hydrogen atom, a halogen atom, a hydroxy group, a C ^ Cs alkyl group or a (C, to C ₂ alkoxy) methyl group;

R ⁷ is a hydrogen atom, a halogen atom, a C! Cs alkyl group,

~ C ₂ alkoxy) methyl group, a benzyl group or either meaning taste phenethyl, or when R ⁶ and R ⁷ are bonded to a carbon atom other than a carbon atom adjacent to the nitrogen atom, they are together a connexion Okiso May form a group,

p represents an integer of 2 to 6, and q represents an integer of 3 to 7. [Ω- (2,3-Dihydro-1 1-benzoxepin-1 4-yl) alkyl] amine derivative represented by the formula: and its physiologically acceptable acids It is intended to provide an addition salt, an N-oxide derivative, a method for producing them, and a pharmaceutical composition containing these compounds.

The physiologically acceptable acid addition salts of the compound represented by the formula (I) include inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate. Salts and oxalates, malonates, succinates, maleates, fumarates, lactates, lingates, citrates, tartrates, benzoates, methansulfonates , P — Organic salts such as toluenesulfonate. Since the compounds of the formula (I) and their salts and N-hydroxy derivatives may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention. Included. An N-year-old oxide derivative of the compound of the formula (I) means that in the formula (I), R ⁴ is C! A C ₅ alkyl group, or an N-substituted oxide derivative of a compound in which R ⁴ and R ⁵ form a cyclic amino group together with an adjacent nitrogen atom.

The compounds of formula (I) optionally have one or more asymmetric carbon atoms and may give rise to geometric isomerism. Thus, the compounds of formula (I) may optionally exist as several stereoisomers. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention.

The terms used in this specification are described below.

The alkyl group and the alkyl moiety may be linear or branched. “Halogen atom” means fluorine, chlorine, bromine, or iodine, but fluorine and chlorine are preferred, and fluorine is particularly preferred. The term "acyl group" means a saturated aliphatic carboxylic acid residue or an aromatic carboxylic acid residue, and examples thereof include formyl, acetyl, propionyl, butyryl, isoptyryl, and benzoyl. The "unsubstituted young properly is substituted off Enirusuruhoniru group", Nono androgenic, ~C ₅ alkyl,

To C ₃ alkoxy or phenyl optionally substituted with nitrogen It means a sulfonyl group and includes, for example, phenylsulfonyl, p-chlorophenylsulfonyl, p-methylphenylsulfonyl, p-methoxyphenylsulfonyl, and p-methoxyphenylsulfonyl.

Specific examples of the “alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isosulfone pyrsulfonyl, butylsulfonyl, and isobutylsulfonyl.

Preferred examples of R ¹ and R ² include a hydrogen atom, a halogen atom (especially a fluorine atom), a hydroxy group, a methyl group, an ethyl group, a propyl group, a methoxy group and an ethoxy group. , A hydroxydimethyl group, a carboxy group, a methoxycarbonyl group or an ethoxycarbonyl group. Further, when R ¹ and R ² are bonded to adjacent carbon atoms, they together form a methylenedioxy, ethylenoxy, ethylendioxy, trimethylen or tetramethylen group. I like it. More preferred specific examples of R ¹ and R ² include a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group or a hydroxymethyl group, which are in the 7-position or 7-position. Particularly preferred is a bond at positions 7 and 8 or at positions 7 and 9. Further, 7- and 8-position R ¹ and R ² together such connexion ethylene Nokishi group attached to the carbon atom of the _{_{(8 - CH 2 CH 2 0-}} 7) or even preferred to the case of forming the Application Benefits methylene down group Particularly, it is preferable to form a trimethylene group. It is also more preferred that R ¹ is a hydrogen atom or a halogen atom (especially a fluorine atom), and that R ² is a halogen atom (especially a fluorine atom), such as 7,8-dihalogen or 91 halogen. Is particularly preferred. Preferred examples of R ³ and R ⁴ include a hydrogen atom. Is a preferred embodiment of R ^5, consequent opening pentyl, Ru include heptyl hexyl or cycloheteroalkyl but cyclopentyl group is particularly preferred arbitrariness. Furthermore, when R ⁴ and R ⁵ form a cyclic amino group represented by the above formula (A) together with an adjacent nitrogen atom, q is particularly preferably 4, 5, or 6. . R ⁶ preferred Specific examples include a hydrogen atom, a halogen atom (particularly, a fluorine atom), a hydridyl group or a methyl group, and a hydrogen atom or a methyl group is more preferable. Preferred specific examples of R ⁷ include a hydrogen atom and a methyl group. It is also preferred that R ⁶ and R ⁷ together form an oxo group. As ρ, an integer of 2 to 5, particularly 2, 3, or 4, is preferred, and 2 is most preferred.

Among the compounds of the present invention, preferred are those in which R ¹ and R ² in formula (I) are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a C 1 -C ₃ alkyl group, a methoxy group, An ethoxy group, a hydroxymethyl group, a carboxy group, a methoxycarbonyl group or an ethoxycarbonyl group, or R ¹ and R ² bonded to adjacent carbon atoms are linked to form a methylenedioxy group, an ethylenoxy group; , An ethylenedioxy group, a trimethylene group or a tetramethylene group, wherein R ³ is a hydrogen atom and R ⁴ , R ⁵ and p are the same as those described above, and the physiologically acceptable compounds thereof. Acid addition salts and N-oxide derivatives. Further preferred compounds are those wherein R rod ² and 1¾ ³ is Re of the respective it In the formula (I), heptyl by R ⁴ is a hydrogen atom, R ⁵ is consequent Ropenchiru group, the consequent b hexyl group or a cycloalkyl Or R ⁴ and

Together with the nitrogen atom to which R ⁵ is adjacent 1 - Azechijiniru group, 1 one pyro Li Jiniru group, 2 - methyl one 1 one pyro Li Jiniru group, 2, 5 - dimethyl -

1 — A compound which forms a pyrrolidinyl group, a piperidino group or a hexahydryl 1 H —azepine-11-yl group and p is an integer of 2 to 4, and physiologically acceptable acid addition salts thereof It is.

Particularly preferred compounds are those represented by the following formula (la) and physiologically acceptable acid addition salts thereof.

(Wherein, R ^1a represents a C! -C ₃ alkyl group,

R ^2a and R ^3a represent a hydrogen atom or a C, to C ₃ alkyl group, or R ^1a and R ^2a may be taken together to form a tritylene group,

R "is a hydrogen atom, R ^{5 a} is or R means a consequent opening pentyl" Kisahi draw 1 and R ^{5 a} 1 one pyro Li isoxazolidinyl group together with the adjacent nitrogen atom, to Piperi Gino group or An H-azepine-1-yl group may be formed. However, at least one of R ^2a and R ^3Λ represents a hydrogen atom. )

Specific examples of particularly preferred compounds include the following compounds and their physiologically acceptable acid addition salts, with the former three being the most preferred.

1— [2— (2,3—dihidro 7,9—dimethyl-11-benzoxepin—4—yl) ethyl] hexahydro—1H-azepine (compound of Example 2),

1— [2— (2,3-Dihydro-1,7,9-1-dimethyl-1—benzoxepin-4-yl) ethyl] piperidine (compound of Example 1).

1— [2— (2,3—Dihydro-1,7,8-dimethyl-1—benzoxepin-14—yl) ethyl] pyrrolidine (compound of Example 19).

1 1 [2 — (2, 3 — dihydro 7, 8 — dimethyl 1 — benzoxepin 1 4 — yl) ethyl] piperidine (compound of Example 20)- 1— [2— (2,3-Dihydro-7—Propyl-1 1—Benzoxepin—4—yl) ethyl] piperidine (compound of Example 11),

1— [2— (2,3—dihydro-7-methyl-1—benzoxepin-1-4-ethyl) hexahydro-1H-azepine (compound of Example 7),

1 1 [2 — (2, 3, 8, 9 — tetrahydro □ 1 7H-cyclopentene [h] benzoxepin-4-yl) ethyl] piperidine (compound of Example 29), and

Hexahydr-1-1-1 [2— (2,3,8,9—Tetrahydr-7-H-cyclopentene [h] Benzoxepin-14-yl) ethyl] -11H-azepine (Example 30) Compound).

Specific examples of the compounds included in the present invention include the compounds shown in Tables 1 and 2 as well as the physiologically acceptable acid addition salts and N-oxide derivatives thereof in addition to the compounds of Examples described later. . In the table, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, iPr represents an isopropyl group, and Bu represents a butyl group. table 1

Come 13d 2S9U86 OAV

i

o

e

Two

R ¹ R ² R ⁶ R ⁷ PQ

7 One F H H H 2 6

H 9-F H H 2 5

7 — M e H H H 3 5

7 — MeH2 One MeH2 5

7 One M iVi p u Π VI IVI c 9 L J c;

7 One E t H H H 3 6

7 One E t 8-E t H H 25

7 1Et 9 1EtH H2 6

7-P r H H H 3 7

7 Pr H 2 1 Me H 2 5

7 One PrH 2 One Me 5 One Me 2 5

H 9 — 0 M e H H 4 6

7 -M e 8 -M e H H 4 5

7 — M e 8 -M e H H 2 7

7 — Me 8 — Me H H 3 5

7 — M e 9 -M e H H 3 5

7 -M e 9 — Me 2 1 Me 5 1 Me 2 5

7 -M e 9 -M e H H 2 7

7-(CH ₂ ) A '― 8 HH 3 5

7-0 (CH 2) 2 18 HH 25 The compound of the present invention can be produced, for example, by the following method. You.

Production method (a):

In the formula (I), R ⁴ is a hydrogen atom or a C, to C ₅ alkyl group, or R ⁴ and R ⁵ together with an adjacent nitrogen atom form a cyclic amino group represented by the formula (A). The compound represented by the following formula (E) can be produced by dehydrating the compound represented by the following formula (E).

[Wherein, R ¹ , R ² , R ³ , R ⁵ and p mean the same as described above, and R ⁴ ′ means a hydrogen atom or a C! To C ₅ alkyl group, or R ⁴ ′ and R ⁵ may form a cyclic amino group represented by the formula (A) together with an adjacent nitrogen atom. ]

This dehydration reaction can be performed under conditions applicable to the dehydration reaction from alcohol to olefin. For example, the reaction is carried out by reacting the compound of the formula (H) with a dehydrating agent without a solvent or in an appropriate solvent. Specific examples of dehydrating agents include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, and boric acid; organic acids such as oxalic acid, formic acid, and trifluoroacetic acid; and p-toluene sulfone. Aromatic sulfonic acids such as acids. Organic acid anhydrides such as acetic anhydride, 0-sulfobenzoic anhydride, anhydrous inorganic salts such as potassium hydrogen sulfate, and inorganic salts such as thionyl chloride and phosphorus oxychloride. Acid chlorides, organic acid chlorides such as acetyl chloride, p-sulfones such as p-toluenesulfonyl chloride, methanesulfonyl chloride Acid chlorides, boron trifluoride 'getyl ether complex, Lewis acid such as zinc chloride, iodine, alumina, silica gel. The solvent used should be appropriately selected according to the type of dehydrating agent, etc.-For example, aromatic hydrocarbons such as benzene, toluene, xylene, getyl ether, tetrahydrofuran, dioxane Alcohols such as ethers such as ketones such as acetone and ethyl methyl ketone, acetate nitrolene, methanol, ethanol and isopropyl alcohol. Organic solvents such as ethylene glycol, formic acid, acetic acid, and propionic acid, pyridine, dimethyl sulfoxide, and water. These solvents can be used alone or as a mixture of two or more. . The reaction temperature varies depending on the type of the dehydrating agent and the like, but is usually about -20 ° C to about 200 ° C. The compound of the formula (H) used in the present dehydration reaction may be in the form of a complex with a boron-containing reducing agent such as borane or a decomposition product thereof, such as an inorganic acid or an organic acid. By using an acidic dehydrating agent, the compound of the formula (I) can be obtained.

The starting compound (H) can be produced, for example, by a method shown in the following reaction scheme.

Process 1

JS vat process 2

(VI)

(In the formula, R ¹ , RR ³ , R ⁴ ′, R ⁶ and p have the same meanings as described above, and R ¹ ′ and R ² ′ have a formyl group and a carboxy group respectively protected. Same as R ¹ and R ² except that it is replaced with a formyl group and a protected carboxy group.) In the above reaction scheme, represented by R ^] ′ or R ² ′ Examples of the protected formyl group include acexyls such as dimethoxymethyl, ethoxymethyl, and ethylenoxymethyl, and oximes such as hydroxyiminomethyl, and the protected carboxy group. Examples include lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxydicarbonyl, and alcohols such as benzyloxycarbonyl. And a carbonyloxy group.

Each step in the above reaction process diagram will be described in detail below.

(Process 1)

This step is carried out by reacting a compound of the formula (V) or a reactive derivative thereof with a compound of the formula (IV) under ordinary amidation reaction conditions.

Examples of the reactive derivative of the compound of the formula (V) include lower alkyl esters (especially methyl esters), active esters, acid anhydrides, and acid halides (especially acid chlorides). Specific examples of active esters include p-ditrophenyl ester, 2,45-trichlorophenyl ester, and N-hydroxycarboxylic acid imido ester. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include alkyl chlorocarbonate such as ethyl chlorocarbonate and isobutyl chlorocarbonate. Mixed anhydrides with aralkyl esters of chlorocarbonate, such as benzyl carbonate, mixed acid anhydrides with alkaryl esters of chlorocarbonate, such as phenyl carboxylate, isovaleric acid, bivari And mixed acid anhydrides with alkanoic acids such as acid.

When the compound of the formula (V) itself is used, NN 'dicyclohexylcarpoimide, 1-ethyl-3- (3-dimethylaminopropyl pill) carposimid hydrochloride, NN' monocarbonyldiimidazole , NN'—Caprolidonic acid imid, 1-ethoxycarbonyl-2—Ethoxy 1 12—Dihydroquinoline, diphenylphosphorinoleazide, propanephosphonic anhydride, benzotria The reaction can be performed in the presence of a condensing agent such as zirro-tris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent).

A compound of the formula (V) or a reactive derivative thereof with a compound of the formula (IV) The reaction is carried out in a solvent or without solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound, etc., for example, aromatic hydrocarbons such as benzene, toluene, xylene, getyl ether, tetrahydrofuran, Ethers such as dioxane, halogenated hydrocarbons such as dichloromethane and chloroform, alcohols such as ethanol, isopropyl alcohol, ethyl acetate, acetate, and acetate. Examples include tolyl, dimethylformamide, 1,3-dimethyl-2, imidazolidinone, dimethylsulfoxide, ethylene glycol, and water. These solvents may be used alone or in combination of two or more. Used as a mixture. This reaction is carried out in the presence of a base, if necessary. Specific examples of the base include sodium hydroxide, alkali hydroxide such as potassium hydroxide, and sodium carbonate. Alkali carbonates such as calcium carbonate, sodium bicarbonate, alkali bicarbonates such as potassium bicarbonate, or triethylamine, triptylamine, disopropyrethylamine Organic bases such as N, N-methylmorpholine, but can also serve as an excess of the compound of formula (IV). The reaction temperature varies depending on the type of the starting compound used and the like, but is usually about 130 ° C to about 200 ° C, preferably about -10 ° C to about 150 ° C.

The starting compound (V) in this step is prepared by a method known per se starting from 3,4 dihydro-'1 1-benzoxepin-5 (2H) 1-ones, for example, the method described in Reference Example 8 below, or It can be manufactured according to a method according to this.

On the other hand, 3,4-dihydro-1 1-benzoxepin-15 (2H) ones, which are the starting materials of the compound (V), are obtained by a method known in the art or known in the art, for example, see Reference Examples 1 to It can be produced according to the method described in 7 or a method analogous thereto.

The other starting compound (IV) in this step is commercially available, or a method known per se, for example, the method described in Syn lett, 1995, 55, Alternatively, it can be produced according to a method according to this.

(Step 2):

In this step, the compound of formula (VI) is reduced in a suitable solvent to reduce the carbonyl group of ketone to an alcoholic hydroxy group and the carbonyl group of amide to a methylene group. This is done by treating with a suitable reducing agent. Specific examples of the reducing agent include aluminum aluminum hydride, diisobutylaluminum hydride, bis (2-methoxetoxy) aluminum sodium, aluminum such as aluminum hydride. Hydride or hydrogen complex compound, sodium borohydride, or Lewis acid such as anhydrous aluminum chloride, cobalt chloride (H), boron trifluoride 'getyl ether complex, etc. In combination with sodium hydrogenated acetooxyborohydride, hydrogen hydride complex compounds such as sodium trifluoroacetoxyborohydride, borane compounds such as diborane, triethylsilan chloride Zinc. The solvent to be used should be appropriately selected according to the type of reducing agent and the like. For example, ethers such as getyl ether, tetrahydrofuran, dimethoxetane, dioxane, diglyme, benzene, Examples include aromatic hydrocarbons such as toluene, halogenated hydrocarbons such as dichloromethane and chloroform, alcohols such as methanol and ethanol, acetic acid, and pyridine. These solvents are used alone or in combination of two or more. The reaction temperature varies depending on the type of the reducing agent used, etc., but is usually about -10 ° C to about 130 ° C. This reduction step is performed in an inert atmosphere, if necessary, for example, in nitrogen or argon. In the case of compounds in which R ¹ ′ and Z or R ² ′ in formula (VI) are a protected formyl group and Z or a protected carboxidi group, the protecting group in the reaction product after reduction is removed. The compound of formula (I) can be obtained by elimination according to a conventional method. The compound of the formula (mutual) formed in this step can be used for the dehydration reaction without isolation and purification. Can be. When a boron-containing reducing agent such as a borane is used as the reducing agent, the compound of the formula (H) can be obtained in the form of a complex with the boron-containing reducing agent or a decomposition product thereof. Can be used for dehydration reactions.

Production method (b):

In the formula (I), R ⁴ is a hydrogen atom or a C, to C ₅ alkyl group, or R ⁴ and R ⁵ are adjacent to a nitrogen atom together with the cyclic amine represented by the formula (A). The compound which forms a thio group is also represented by the following formula (IE)

(Wherein, R ¹ , R ² , R ³ and p have the same meanings as described above, X and Y are the same or different and represent a reactive ester residue of an alcohol, and Z is a hydrogen atom. Or Y or Z may together form a bond.)

And a compound represented by the following formula (IV)

(In the formula, R ⁴ ′ and R ⁵ mean the same as described above.)

Can also be produced by reacting with the compound represented by Wear.

The reactive ester residue of the alcohol represented by X and Y in the formula (IE) includes, for example, halogen atoms such as chlorine, bromine and iodine, and methyl sulfonyloxy and ethane sulfonylodoxy. And lower alkylsulfonyloxy groups, benzenesulfonyloxy, ρ-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy, and arylsulfonyloxy groups.

The reaction between the compound of the formula (ΠΠ) and the compound of the formula (IV) is usually carried out in the presence of a base in a suitable solvent. Specific examples of the base include sodium carbonate and potassium carbonate Alkali carbonates such as sodium, triethylamine, tributylamine, diisopropylethylamine, organic bases such as N-methylmorpholine, sodium methoxide, sodium ethoxy Alkali metal alkoxides such as sodium hydroxide, sodium hydride, hydrogen hydride Al metal hydrides such as rims and the like. The compound of formula (IV) may also serve as an excess amount. The solvent to be used should be appropriately selected according to the type of the starting compound, the type of base, etc. Examples thereof include aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, dioxane, and jig. Ethers such as dimethyl ether, dichloromethane, halogenated hydrocarbons such as black mouth form, ketones such as acetate and ethyl methyl ketone, acetonitril, Alcohols such as methanol, ethanol, and isopropyl alcohol, dimethylformamide, and 1,3-dimethyl-2-imidazolidinone are listed. These solvents are each used alone. The reaction temperature may vary depending on the type of the starting compound used, etc., usually about 20 ° C to about 150 ° C, preferably about 80 ° C to about 120 ° C. The starting compound (1) can be produced according to a method known per se, for example, the methods described in Reference Examples 11 to 14 below, or a method analogous thereto. When a compound in which R ¹ and / or R ² in formula (I) is a C! To C ₃ alkoxylponyl group can be obtained by the above-mentioned production method (a) or production method (b), the compound is subjected to a conventional method. A compound in which R ¹ and / or R ² is a formyl group or a hydroxydimethyl group by reduction, and a compound in which R ¹ and Z or R ² is a carboxy group by hydrolysis according to a conventional method Can be led to When a compound of the formula (I) in which R ⁴ is a hydrogen atom is obtained, alkylation, acylation, alkylsulfonylation or unsubstituted or substituted phenylsulfonyl is carried out using a corresponding reagent according to a conventional method. of child R ⁴ is C] by a ~ C ₅ alkyl group, Ashiru group, C, is ~ C ₅ alkylsulfonyl group or an unsubstituted young properly can and this leading to the compound is a substituted Funini Le sulfonyl group.

The compound of the formula (I) produced by each of the above production methods can be isolated and purified according to a conventional method such as chromatography, recrystallization, and reprecipitation. The compound of the formula (I) can be obtained in the form of a free base or an acid addition salt depending on the selection of the starting compounds, the reaction and the treatment conditions, and the like. The acid addition salt can be converted to the free base by a conventional method, for example, by treating with a base such as an alkali carbonate or an hydroxide hydroxide. On the other hand, the free base can be converted into an acid addition salt by treating it with various acids according to a conventional method.

Further, in the formula (I), a compound in which R ⁴ is a C, to C ₅ alkyl group or a compound in which R ⁴ and R ⁵ form a cyclic amino group together with an adjacent nitrogen atom is Oxidation under normal N-oxidation conditions can lead to N-amine derivatives of the amide moiety. This N-oxidation reaction is carried out by reacting the compound of the formula (I) with an oxidizing agent in a suitable solvent. Specific examples of the oxidizing agent include hydrogen peroxide and organic peracids such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, and monoperphthalic acid. The amount of the oxidizing agent used is expressed by the formula (I) Usually about 0.9 to about 2 equivalents to compound. The solvent to be used should be appropriately selected according to the type of the oxidizing agent and the like. Examples thereof include water, acetic acid, alcohols such as methanol and ethanol, and acetone. Ketones, ethers such as getyl ether and dioxane, and halogenated hydrocarbons such as dichloromethane and chloro-form. The reaction temperature varies depending on the type of the oxidizing agent and the like, but is usually about 130 ° C to about 100 ° C, preferably about -20 ° C to about 30 ° C.

Hereinafter, the results of pharmacological tests for representative compounds of the present invention are shown. Test Example 1 Inhibitory effect of rhythmic bladder contraction (micturition reflex)

This test was performed according to the method of Maggi, C.A. and Meli, A. (J. Pharmacol.

Methods, 10, 79 (1983)). It is understood that regular rhythmic bladder contractions triggered by saline infusion in this study are triggered via the same micturition reflex pathway as spontaneous voiding.

Three to four Std-Wistar female rats weighing 160 to 190 g were used in each group. Urethane (1 gZkg, subcutaneous administration) After anesthesia, a midline incision was made in the lower abdomen, and the ureters on both sides were ligated and cut at the kidney side. A force unit connected to a syringe and a pressure transducer was inserted into the bladder from the external urethral opening, and the proximal urethra was ligated. After standing for about 30 minutes after the operation, a syringe was used to slowly inject warm physiological saline (0.4 to 1.0 ml) into the bladder until rhythmic contraction was induced. Changes were recorded on the recorder via a pressure transducer. After the rhythmic contraction of the bladder stabilized, the test compound dissolved or suspended in a 0.5% aqueous tragacanth solution was administered via a pre-attached duodenal force nucleus, and the number of contractions every 15 minutes ( Frequency) was observed up to 2 hours after administration. The effect on contractile force was also examined up to 2 hours after administration.

Table 3 shows the contraction frequency suppression rate (2 hours) and the presence or absence of a contraction force suppression effect at a predetermined dose of the test compound. The contraction frequency suppression rate (2 hours) was calculated as 15% after the administration, assuming that the number of contractions for 15 minutes before the administration of the test compound was 100%. The inhibition rate per minute was obtained up to 2 hours, and the average value was shown.

Table 3 Rhythmic bladder contraction inhibitory effect test Test frequency inhibitory effect Contractile force inhibitory effect Compound dosage .; Inhibition rate (%) m; Effect * / fe HM 1

m 1 ¹ J 丄 0 mg / kg, 27%, 20 mg / kg; O10 /

8 丄 0 10 mg / kg; + lol iiirt L 0 mg / k; 40%, 20 mg / kg; 0 o 5 mg / kg; +

^ iit. I \ Q

Lost fm 'J o 丄 υ mg / kg; 32%, 30 mg / kg; 0 /

DO / 30 mg / kg;

Φ IM A

Husband JM F'J 4 1

丄 A υ mg / kg; 20%, 30 rag / kg; 0 丄 / () 30 mg / kg; Keio iJiftlr, i F'J 0 ο υ mg / kg; 54% 30 rag / kg; + Treasure iTj

Young manure 1, \ \ 夫 0 U mg / kg; 75% 30 mg / kg; Takao JtEb M F'J 71 丄 1 η υ mg / kg; 55%, 30 rag / kg; O QQ 0 /

ϋ / 0 10 mg / kg; + Keio ijiith ^ 1 gly ly 丄 10 υ mg / kg; 39%, 30 mg / kg; 30 mg / kg; + Keiya JitbE MU 1 丄 1 丄丄 υ mg / kg; 50%, 30 mg / kg; fi Un U /% () 30 mg / kg; + Keio fih ^ 1 me l l 1 Q.丄 1 Π υ mg / kg; 34% 10 mg / kg;

Takao Εb M 1 / 'J 1 丄 ^ A 1 丄 A υ mg / kg; 30% 10 mg / kg; Husband 1 ^{1 1} J 丄 01 A mg / kg; 34% 10 mg / kg; 审

¾ / J & L 1

5 丄 0 丄 π υ mg / kg; 10%, 30 mg / kg; UJ κ () 10 mg / kg; + Takao i DvVlt 1 1 l ¹ Jl 1 Q 丄 1 A mg / kg; 77%, 30 rag / kg; 70 l% 10 mg / kg; + Example 20 10 mg / g, 400 / Q1 / 84% ϋ U mg / kg; + Example 21 10 mg / kg; 47%, 30 mg / kg; 80% 10 mg / kg; + Example 26 10 rag / kg; 35% 10 mg / kg; Example 27 10 mg / kg; 39% 10 rag / k; + Example 28 20 mg / kg; 21 % 20 mg / kg; + Example 29 10 mg / kg; 34%, 20 mg / kg; 52% 20 mg / kg; Ten Examples 30 10 mg / kg; 35%, 20 mg / kg; 50% 20 mg / kg; + +: Inhibitory effect, no inhibitory effect. Table 3 (continued)

Trial

Test substance Frequency-suppressing action Contractile force-suppressing action Dose; Inhibition rate (ίί) No effect Example 32 10 mg / kg; 37% 10 mg / k; Example 36 10 mg / kg; 32% 10 mg / kg;

Example 37 10 mg / kg; 43% 10 mg / kg; Example 38 10 mg / kg; 32% 10 mg / kg; Example 40 20 mg / kg; 35% 20 rag / kg; + Example 41 20 mg / kg; 32% 20 rag / kg; + Example 42 20 mg / kg; 14% 20 rag / kg; +

As is clear from Table 3, all of the tested compounds of the present invention showed a strong inhibitory effect on rhythmic bladder contraction at doses of 5 to 30 mg / kg. Furthermore, more than half of the compounds also exhibited a contractile force-suppressing action.

Test Example 2 Acute toxicity

5 to 15 ddY male mice weighing 18 to 25 g were used in each group. The compound of Example 20 suspended in a 0.5% aqueous tragacanth solution was orally administered, and thereafter, death was observed for 7 days. LD ₅ . The value (50% death dose) was calculated by the Litchfield-Wilcoxon method C J. Pharmacol. Exp. Ther., 96, 99 (1949), and as a result, it was 516 mg / kg.

As is evident from the above test results, the compound represented by the formula (I) and its physiologically acceptable acid addition salts and N-oxide derivatives (hereinafter sometimes referred to as “the compound of the present invention”) Has a strong urinary reflex inhibitory activity and low toxicity, and as a therapeutic agent for pollakiuria and urinary incontinence, is a disease caused by a decrease in the urinary bladder storage function caused by various causes in mammals including humans (Eg, unstable bladder, neuropathic bladder, chronic cystitis, chronic prostatitis, neurotic pollakiuria). The administration route of the compound of the present invention may be oral administration, parenteral administration or rectal administration, but oral administration is preferred. The dosage of the compound of the present invention may vary depending on the type of the compound, the method of administration, the patient's symptoms, such as "age," usually 0.1 to 20 mg / kg / day, preferably 0.4 to 10 mg. / kg / day and can be administered once or in several divided doses.

The compounds of the present invention are usually administered in the form of a pharmaceutical composition prepared by mixing with a pharmaceutical carrier. As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, lactose, inositol, glucose, mannitol, dextran, starch, partially alpha-starched starch, sucrose, magnesium metasilicate alginate, synthetic gay acid Aluminum, crystalline cellulose, carboxymethylcellulose sodium, hydroxypropyl starch, carboxymethylcellulose calcium, ion-exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropyl cellulose, low-substituted hydroxypropyl Pilcellulose, hydroxypropylmethylcellulose, polyvinylpyridone, polyvinyl alcohol, alginic acid, sodium alginate, light silicic anhydride, magnesium stearate, talc, carboxyvinyl polymer , Acid Titanium chloride, sorbitan fatty acid ester, sodium rauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerin gelatin, polysorbate, mac Logol, vegetable oil, roux, liquid paraffin, white petrolatum, nonionic surfactant, propylene glycol, and water.

Specific examples of the pharmaceutical composition include tablets, capsules, granules, powders, syrups, suspensions, suppositories, patches and injections. These pharmaceutical compositions are prepared according to a conventional method. When used, liquid preparations may be dissolved or suspended in water or other suitable medium. Tablets and granules can be coated by well-known methods. Good.

These pharmaceutical compositions can usually contain the compound of the present invention as an active ingredient in an amount of 0.1% or more, preferably 1 to 70%. These preparations may also contain other therapeutically active ingredients ₍ the best mode for carrying out the invention).

EXAMPLES The present invention will be described more specifically with reference to the following Examples and Reference Examples. However, the present invention is not limited to these Examples. The compounds were identified by elemental analysis, mass spectrum, IR spectrum, NMR spectrum, and the like.

In the following Examples and Reference Examples, the following abbreviations may be used for simplification of the description.

M e: methyl group

E t: ethyl group

P r: propyl group

iPr: Isopropyl group

B υ: butyl group

P h: phenyl group

F U: fumaric acid

0 X: oxalic acid

A: Ethanol

A C Aceton

A N Acetonitrile

D E Jethyl ether

E M Ethyl methyl ketone

Example 1

1— [2— (2,3—dihydro o—7,9—dimethylbenzoxepin-1-ethyl) ethyl] Preparation of piperidine: 2,3,4,5—Tetrahydro7,9—Dimethyl-4—C 2-(piperidino) ethyl) manufactured in Reference Example 10 below, 1 1 1 Benzoxepin-5—All 21.4 g It was dissolved in a 30% hydrogen chloride ethanol solution and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was made alkaline by adding a 1N aqueous solution of sodium hydroxide, and then extracted three times with α-form. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (10: 1) .The fractions containing the desired product were collected and concentrated under reduced pressure to give 16.1 g of the desired product as an oil. I got it as a thing.

After dissolving the above free base in 150 ml of a 30% hydrogen chloride ethanol solution, about half of the ethanol was distilled off under reduced pressure, and getyl ether was added. The precipitated crystals were collected by filtration and recrystallized from ethanol to obtain the desired hydrochloride. Melting point 2 19 to 22 1 ° C

! H—NMR spectrum (200 MHz, (CD ₃ ) ₂ S0, 5 ppm): 1.24-1,51 (m,

1H), 1.60-1.80 (m, 5H), 2.12 (s, 3H), 2.19 (s, 3H), 2.54-2.70 (m, 4H), 2.74-3.00 (m, 2H), 3.18-3.24 (m, 2H, 3.38-3.54 (m, 2H), 4.13 (t, 2H, 6.18 (s, 1H), 6.80 (s, 2H, 10.38 (br s, 1H).

Example 2

1 — [2 — (2, 3 —dihydro-1,7,9—dimethyl-1-benzoxepin—4-yl) ethyl] hexahi draw 1 H-azepine Production:

2,3,4,5—Tetrahydro-7,91-Dimethyl-4— [2— (HexahiDraw 1 H—azepin-1 1-yl) ethyl] manufactured in Reference Example 14 below 6.8 g of p-toluenesulfonic acid 'monohydrate and 100 ml of toluene were added to 9.4 g of —benzoxepin-l-5—ol, and the mixture was refluxed for 2 hours. After cooling, the precipitated crystals were collected by filtration and washed with toluene. 26

Then, it was dissolved in dilute sodium hydroxide aqueous solution and extracted with dichloromethane. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 7.8 g of the desired product as an oil.

The above free base was dissolved in 60 ml of ethanol, 20 ml of a 30% solution of hydrogen chloride in ethanol was added, and about half the amount of ethanol was distilled off under reduced pressure, followed by cooling with ice. The precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 4.4 g of the desired hydrochloride. Melting point 2 17 ~ 220 ° C

^! H—NMR spectrum (200 MHz, (CD ₃ ) ₂ SO, 5 ppm): 1.48-1.92 (m, 8H), 2.12 (s, 3H), 2.20 (s, 3H), 2.54-2.71 (m, 4H ), 3.00-3.30 (m, 4H), 3.30-3.48 (m, 2H), 4.14 (t, 2H), 6.20 (s, 1H), 6.82 (s, 2H), 10.46 Cbr s, 1H).

Examples 3 to 3 1

Reaction and treatment in the same manner as in Example 1 using the corresponding 2, 3, 4, 5 — tetrahydro 4- 1 [2 — (1 — cyclic amino) ethyl] — 1 — benzoxepin — 5 — ols Thus, the compounds shown in Table 4 were obtained. In addition, 2, 3, 4, 5 — tetrahydroquinone 4 1 [2 — (1 — ring amino) ethyl] 1 1 1 benzoxepin — 5 — all correspond to 3, 4 —Dihydro— 1 Benzoxepin 1-5 (2H) —ones were reacted and treated in the same manner as in Reference Example 8 below to give 2,3,4,5 —Tetrahydro-5—oxo—1 1-Benzoxepin-4-acetic acid was obtained, and then the product and the corresponding cyclic amine were reacted and treated according to the method of Reference Example 9. Subsequently, the product was subjected to the method of Reference Example 10. It was produced by reducing according to the following. Table 4

Perform R ¹ R ² R ³ q Q melting point recrystallization Example 1

3 H H H 5 HC1 240-242 A

4 7-OMe H H 5 HC1 190-192 A

5 7-Me H H 4 HC1 184-186 A

6 7-Me H H 5 HC1 208-213 A

7 7-Me H H 6 HC1 198-201 A

8 7-Et H H 40 X 155 158 A

9 7-Et H H 5 HCl 188-189 A

10 7-Et H H 6 HC1 208-212 A

11 7 Pi.H H5 HCl 159-162 A

12 7 Pr H H 6 HCl 194-199 A

13 7 Bu H H 5 HCl 178-180 A N

14 H 8-Me H 5 HCl 240-244 A-A N

15 H 8-Et H 5 HCl 244-250 A

16 H H 9 OMe 5 HCl 236 240 A

17 6 Me 8-Me H 5 HCl 242-246 A-D E

18 7-OMe 8-OMe H 5 HCl 215-217 A Table 4 (continued) Implementation R ¹ R ² R ³ q Q point, recrystallization

(° r

\ '6

19 7 Me 8 Me H 4 HC1 215.-219 A

20 7- Me 8-Me H 5 HCl 257 -260 A

21 7 Me 8-Me H 6 HC1 236.-240 A

22 7-Et 8-Et H 5 HCl 225- -229 A

23 7- (CH _; 8 H 4 HCl 212- 215 A

24 7 (Cl 8 H 5 HCl 260- -265 A

25 7- (CI ";), -8 H 6 HCl 238- -245 A

26 7 iPr 8 Me H5 HCl 234- -237 AN

28 7-CCH, -8 H 4 F U 179- -181 E M

29 7- (CI 8 H5 HCl 255- 260 A

30 T- (CH _: 8 H 6 HCl 215 -228 A-AN

31 6-Me 8-Me 9 Me 5 HCl 234- ■ -237 A-A C Example 3 2 3 9

The corresponding 2,3 4 5 —tetrahydro-1-41 [2— (1—cyclic amino) ethyl] —1 1 prepared in the same manner as described in Example 3 31 Using benzoxepin-1-ols, the reaction and treatment were carried out in the same manner as in Example 1, and the resulting hydrochloride was recrystallized from ethanol to obtain the compounds shown in Table 5. Table 5

Example R 'R ² R (i R melting point (° C)

32 Ryo-Me 8 Me 2, Me II 222-226

33 7-Me 8-Me 3 'Me H 232-235

34 7-Me 8-Me 4 '-Me H 268-272

35 7 Me 8 Me 2 '-Et H 193-195

36 7 Me 8 Me 3 '-Me 5' Me 264-267

37 7 ™ Me 8 Me 2 '-Me 6' -Me 258 265

38 7-Me 8-Me 4 '-CH ₂ Ph H 209-214

39 H H 3 'Me 3' -Me 227-230 Example 40

N-cyclopentyl [2— (2,3,8,9—tetrahydro 7H—1—cyclopen] [h] benzoxe pin 1-4 4-yl) ethyl :

2,3,4,5,8,9 1-hexahydrid □ 1-41 (2 — methanesulfonyloxexetil) 1 7H— 1-cyclopentene prepared in Reference Example 12 below [H] Benzoxepin-1-5-inomethane sulfonate was dissolved in 50 ml of acetonitrile, 3.5 g of cyclopentylamine was added, and the mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure to give a residue. After adding chloroform, the mixture was washed with water, an aqueous sodium hydroxide solution, water, and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with a chromatographic form-methanol (20: 1), and the fractions containing the desired compound were collected. Concentration gave 1.0 g of the desired product as an oil.

To 1.0 g of the above free base was added a 30% solution of hydrogen chloride in ethanol, and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain the desired hydrochloride. Melting point 2 62 to 2 65 ° C

NMR spectrum (200 band z, (CD ₃ ) ₂ S0, δ ppm): 1.43-1.80 (m, 6H), 1.86-2.10 (m, 4H), 2.46-2.64 (m, 4H), 2.70-2.86 ( m, 4H), 3.03 (br s, 2H), 3.30 (s, 1H, 3.49 (br s, 1H, 4.10 (t, 2H), 6.20 (s, 1H,), 6.72 (s, 1H), 7.02 ( s, 1H), 8.81 (br s, 1H).

The corresponding cycloalkylamine was reacted and treated in the same manner as in Example 40, and the product was recrystallized from ethanol to obtain the compounds shown in Table 6.

Table 6

Example R ⁵ Q Melting point

4 1 Sk Mouth opening HC1 1 / 4Η ₂ 0

4 2 Cyclopeptin HC1 1 / 10Η ₂₀

The starting compounds used in the above examples were produced as follows.

Reference example 1

4 — (4 — Methoxypoxy) Production of butanoic acid:

13.6 g of metal sodium was added little by little to 270 ml of ethanol while stirring, and after the addition was completed, 70 g of 4-methoxyphenol and y-butyrolactone 49. 1 g was added and then the reaction mixture was heated at reflux for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water, and acidified with concentrated hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 29.9 g of the desired product.

Reference example 2

7 — Methoxy-1,4 dihydro 1 1 Benzoxepin 1 5 (2H) — Production of

4 — (4-Methoxyphenoxy) 29.9 g of butanoic acid was dissolved in 150 ml of dichloromethane, and 22 ml of trifluoracetic anhydride and 3 ml of boron trifluoride / ethyl ether complex were dissolved with stirring. In addition, the mixture was stirred at 25 ° C for 4 hours. The reaction solution was poured into ice water, and the aqueous layer was made alkaline with potassium carbonate. The organic layer was separated, washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a black form, the fraction containing the desired product was collected, and concentrated under reduced pressure to obtain 28.0 g of the desired product as an oil. Was.

Reference example 3

Production of 4— (2,4-dimethylphenoxy) butanoic acid:

2,4-Dimethylphenol 100 g, 4 Ethyl monobromobutanoate

176 g and 1 g of potassium iodide were suspended in 1,000 ml of acetate and heated under reflux overnight. After cooling, insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in getyl ether, and 1N aqueous sodium hydroxide solution, water, After washing with a saturated saline solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.

The residue was dissolved in 100 ml of ethanol, 500 ml of an aqueous solution of 72 g of sodium hydroxide was added, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled on ice, acidified with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration to obtain 127 g of the desired product.

Reference example 4

3,4-Dihydro 7-, 9-Dimethyl 1-Benzoxepin-5 (2H) Production of 1-year-old:

4 Dissolve 127 g of mono (2,4-dimethylphenoxy) butanoic acid in 500 ml of dichloromethane, and agitate with stirring 141 g of trifluoroacetic anhydride and boron trifluoride. 12 ml of getyl ether complex was added, and the mixture was stirred at 25 ° C for 4 hours. The reaction solution was poured into ice water, and the aqueous layer was made alkaline with potassium carbonate. The organic layer was separated, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by distillation under reduced pressure to obtain 36 g of the desired product as an oil. Boiling point about 120 V / 3 mmHg

The corresponding phenols were substituted for 2,4-dimethylphenol in Reference Example 3 and reacted and treated in the same manner as in Reference Examples 3 and 4 to obtain compounds shown in Table 7.

Table 7

R ¹ R ² R ³ R ¹ R ² R ³

7 Me H H 7- Me H 9- Me

7-Et H H 6- Me 8-Me H

7-Pr H H 6- Me 8-Me 9- Me

7-Bu H H 7-Et 8-Et H

H 8-Et H 7-iPr 8 Me H

H 8-Me H 7- (CH ₂ ) 8 H

7-OMe 8-OMe H 7- (CH ₂ ) Factory 8 H

7 Me 8-Me H Reference example 5

2 — [3 (ethoxycarbonyl) propoxy] 3 Methoxy Ethyl benzoate Production:

(1) To a solution of 50.0 g of 2-hydroxy-3-hydroxybenzoic acid in 800 ml of ethanol was added 7 ml of concentrated sulfuric acid, and the mixture was heated under reflux for two nights. After cooling, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with a black form.The fractions containing 2 hydroxydiethyl 3 methoxyethyl benzoate were collected and concentrated under reduced pressure. Thus, 46.3 g of the ethyl benzoate was obtained as an oil. ^! H- NMR-spectrum le _{(200MHz, CDC1 3, δ ppm} ): 1.41 (t, 3H, 3.90 (s, 3H), 4.41 (q, 2H), 6.82 (t, 1H), 7.40 (dd, 1H) , 7.45 (dd, 1H), 11.10 (s, 1H).

(2) Suspend 34.7 g of the above ethyl benzoate, 38.0 g of tetrabutyl α-mobutanoate, 27. Og of potassium carbonate and 1 g of potassium iodide in 500 ml of acetate, and heat overnight. Refluxed. After cooling, insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in diethyl ether, washed with a cold 1N aqueous sodium hydroxide solution and water three times, and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. . The residue was subjected to silica gel column chromatography, eluted with hexane-toluene (1: 1), the fractions containing the desired product were collected, and concentrated under reduced pressure to give 31.Og of the desired product as an oil. I got it as a thing.

'Η—NMR spectrum (200 MHz, CDCh, δ ppm): 1.26 (t, 3H), 1.38 (t, 3H), 2.02-2.17 (m, 2H), 2.60 (t, 2H), 3.85 (s, 3H ), 4.06 (t, 2H), 4.15 (t, 2H), 4.36 (t, 2H), 6.99-7.33 (m, 3H). Reference Example 6

2,3,4,5—Tetrahydric 1—9—Methoxy 1—5—Okifour 1 Benzoxepin—4 Manufacture of ethyl ethyl rubonate:

Suspension of tert-butoxide 28.lg is suspended in 300 ml of toluene, stirred with a Dean-Stark device, stirred and heated under reflux, and 2- [3- (ethoxycarbonyl) propoxy] — 3 — methoxy After a solution of 25.9 g of ethyl benzoate in 300 ml of toluene was added dropwise, the mixture was further heated under reflux for 1 hour. After cooling, the reaction solution was acidified with diluted hydrochloric acid, and the organic layer was separated. The organic layer was washed twice with water and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 24.5 g of the desired product as an oil.

Reference Example 7

3, 4-Draw 9-Methoxy 1-Benzoxepin 5 (2H) Production: 2, 3, 4, 5 — Tetrahydric mouth 9 — Methoxy 1 5 — oxobenzoxepin — 4 14.5 g of ethyl ethyl ruvonate in 150 ml of acetic acid, 50 ml of concentrated hydrochloric acid, 25 ml of water and 50 ml of ethanol It was dissolved in the mixed solution and heated under reflux for 7 hours. After cooling, water was added to the reaction solution, and the mixture was extracted three times with black hole form. The extract was washed three times with a 1N aqueous solution of sodium hydroxide, three times with water, and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform to collect the fractions containing the desired product, and concentrated under reduced pressure to obtain 13.8 g of the desired product as an oil. ,

-NMR spectrum (200 z, CDC1 δ ppm: 2.16-2.31 (m, 2

H), 2.91 (t, 2H), 3.90 (s, 3H, 4.32 (t, 2H), 7.02 7.06 (m,

2H), 7.29-7.38 (m, 1H).

The same reaction as in Reference Examples 5 to 7 was carried out using 2-hydroxy-benzoic acid instead of 2-hydroxy-3-methoxybenzoic acid in Reference Example 5. 1-Benzoxepin-1- (5%)-one was obtained as an oil.

Reference Example 8

2,3,4,5—Tetrahydro7,9—Dimethyl-5—oxo-1- 1—Benzoxepin-1-monoacetic acid

A mixture of 37.1 g of CO 37% formalin and 37.3 g of dimethylamine hydrochloride was stirred at 25 ° C for 30 minutes, then at 70 ° C for 30 minutes, and then the reaction temperature was raised to 80 ° C and stirred for 1 hour. Thereafter, 3,4-dihydro-7,9-dimethyl-1-benzoxepin-5 (2H) -one (72.5 g) was added, and the mixture was heated to 90 ° C and stirred for 6 hours. The solvent was distilled off under reduced pressure, and acetate was added to the residue. The precipitated crystals are collected by filtration, washed with acetone, and washed with 4-acetylaminomethyl-3,4-dihydro7,9-1-dimethyl-1—benzoxepin-5 (2H) -one hydrochloride 95.4 g I got

(2) Dissolve 60.0 g of the Mannich base / hydrochloride in ice water WO 98/16519 _nr . PCT / JP97 / 03672

36

After being rendered alkaline with nia water, it was extracted with dichloromethane. The dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The residue was dissolved in acetone, and 37.8 ml of methyl iodide was added dropwise with stirring under ice-cooling. After stirring for 30 minutes under ice-cooling, the temperature was raised to 25 ° C, and stirring was continued for 2 hours. The crystals are collected by filtration, washed with acetonitrile (2,3,4,5—tetrahydro-n—N, N, N, 7,9-pentamethyl-1-5—oxo-1 1-benzoxepin 14-yl) 142 g of methamine amine were obtained.

(3) 142 g of the above quaternary salt was dissolved in 500 ml of methanol, a solution of 31.6 g of potassium cyanide in 150 mi of water was added, and the mixture was stirred at 25 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure (2,3,4,5—tetrahydro7,9—dimethyltin-5). —Oxo 1 1 —Benzoxepin 1 4 —Il) 67.6 g of acetonitrile was obtained.

(4) 67.6 g of the above acetonitrile was dissolved in a mixed solution of 200 ml of concentrated hydrochloric acid and 200 ml of glacial acetic acid, and the mixture was heated under reflux for 6 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with water to obtain 54.1 g of the desired product.

Reference Example 9

1 — [(2,3,4,5—Tetrahydro7,9—Dimethyl-5—Okitwo 1 Benzoxepin 1-4—yl) acetyl] Manufacture of piperidin:

2,3,4,5 —Tetrahydro-1,7,9-dimethyl-5-oxo-1 —benzoxepin-4 monoacetic acid 24.3 g, piperidin 12.5 g and benzotriazole-1-yloxytris (dimethylamido) No.) To a solution of 47.6 g of phosphonium hexafluorophosphate in 250 ml of dichloromethane, 10.9 g of triethylamine was added dropwise with a 25 bar, followed by stirring for 3 hours. The solvent was distilled off under reduced pressure, and water and toluene were added to the residue. The solution was removed by filtration. The toluene layer was separated, washed with a 1N aqueous solution of sodium hydroxide, water, and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was applied to silica gel column chromatography, and eluted with hexane monoacetate (4: 1). Fractions containing the target compound were collected and concentrated under reduced pressure. 26.2 g of the desired product were obtained as crystals. Reference example 10

2,3,4,5—Tetrahydro-1,7,9—Dimethyl-1— (2— (Piperidino) ethyl) 1—1 Benzoxepin—5—All:

1 _ [(2,3,4,5—Tetrahydro-1,7,9—Dimethyl-15-oxo-1—Benzoxepin—4—yl) acetyl] Piperidin 26.2 g of toluene in 200 ml of toluene and ice While stirring under cooling, 71.8 g of a 70% toluene solution of hydrogenated bis (2-methoxyethoxy) aluminum sodium was added dropwise, and stirring was continued for 1 hour under ice-cooling and then at 25 ° C for 3 hours. Was. The reaction mixture was ice-cooled, 70 ml of an aqueous solution of saturated sodium potassium tartrate was added dropwise, and the mixture was stirred for 30 minutes under ice-cooling to decompose excess reducing agent. The organic layer was separated, washed with water and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with toluene-ethyl acetate (10: 1), the fractions containing the desired product were collected, and concentrated under reduced pressure to give 21.4 g of the desired product as an oil. I got it.

Reference example 1 1

2,3,4,5,8,9 1-hexahydro-5-oxo-7H-1-cyclopentene [h] Benzoxepin-4—Production of acetic acid:

(1) 2,3,4,5,8,9 1-hexahydro-5-oxo-7H

— 1 — Cycopene [h] To a solution of 10.0 g of benzoxepin in 200 ml of tetrahydrofuran, with stirring — At 78 ° C, add 33 ml of 2 M lithium diisopir, amide, and stir for 15 minutes. After continuing, at the same temperature 9.1 g of ethyl acetate was added dropwise. The reaction temperature was gradually raised to 25 ° C. and stirred for 6 hours. The reaction solution was poured into water and extracted with getyl ether three times. The organic layers were combined, washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with hexane-ethyl acetate (9: 1), and 2,3,4,5,8,9,9-hexahydro-5-oxo-17. H—1—cyclopentyl [h] Fractions containing benzoxepin-4-ethyl acetate were collected and concentrated under reduced pressure to obtain 10.2 g of the desired product as an oil.

(2 To a 200 ml ethanol solution of 10.2 g of the above ethyl ester compound was added 20 g of an aqueous solution of 4.2 g of sodium hydroxide), and the mixture was heated under reflux for 3 hours. After cooling, ethanol was distilled off under reduced pressure. The aqueous layer was acidified with concentrated hydrochloric acid, extracted three times with a cross-hole form, combined with an organic layer, washed with water, dried over anhydrous magnesium sulfate, and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.6 g of the desired product as crystals.

'H-NMR spectrum (200 band z, CDCh, δ ppm): 1.65-1.86 (m, 1H), 1.97-2.20 Cm, 2H), 2.40-2.62 (m, 2H, 2.76-3.14 (m, 5H ), 3.46-3.66 (m, 1H), 3.72-3.92 Cm, 1H, 4.48-4.62 (m, 1H), 6.91 (s, 1H), 7.69 (s, 1H).

Reference example 1 2

2,3,4,5,8,9 —Hexahydro 1 4-1 (2—Methanesulfonyloxyschityl) 1 7 7—1 —Cyclopene [h] Benzoxepin—5—Illmeta Manufacture of sulfonenet:

(1) 2,3,4,5,8,9 —Hexahi Draw 5 —Okifu 7 H-1 —Cyclopene [h] Benzoxepin—4 —Acetic acid 12.2 g is dissolved in 150 ml of toluene and cooled on ice. While stirring, 39 ml of a 70% toluene solution of bis (2-methoxyethoxy) aluminum sodium hydride was added dropwise. After raising the reaction temperature to 25 ° C and stirring for 5 hours, saturated tartaric acid About 40 ml of an aqueous solution of sodium calcium was added dropwise, and stirring was continued for 30 minutes. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform, and 2,3,4,5,8,9-hexahydro 4-(2-hydroxyxetil) 1 7H-1-cyclopen Evening [h] The fraction containing benzoxepin-5-ol was collected and concentrated under reduced pressure to obtain 5.1 g of the diol as an oil.

] H- NMR-spectrum le _{(200MHz, CDC1 3, δ ppm} ): 1.45-1.82 (m, 3H), 1.98-2.36 (m, 5H), 2.74-2.94 (m, 5H, 3.68-3.84 (m, 2H , 3.94 -4. 11 Cm, 2H '), 4.60 (d, 1H), 6.83 (s' 1H), 7.14 (s, 1H).

(2) To a solution of 2.0 g of the above diol compound in 40 ml of dichloromethane-dimethane was added dropwise 2.4 g of triethylamine under ice-cooling, and the mixture was stirred for 15 minutes, and 2.2 g of sulfonyl chloride was added dropwise. The mixture was further stirred for 2 hours. The solvent was distilled off under reduced pressure to obtain the desired product as an oil.

Reference Example 1 3

HexahiDraw 1 — [(2,3,4,5—Tetrahydro-1,7,9—Dimethyl-5—Oxo 1 1 Benzoxepin 1 4-yl) acetyl] 1 1H—azepine :

Hexahydro-1H-T-zepin was used in place of piperidin in Reference Example 9, and the reaction was carried out in the same manner as in Reference Example 9. After completion of the reaction, the solvent was distilled off under reduced pressure, water and toluene were added to the residue, and the insoluble matter was removed by filtration. The toluene layer was separated, washed with a 1N aqueous solution of sodium hydroxide, water, and a saturated saline solution in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with getyl ether to obtain the desired product. Reference example 1 4

2,3,4,5—Tetrahydric 7,9—Dimethyl-1-41 [2— (HexahiDraw 1 H—azepine-1—yl) ethyl] 1 1—Benzoxepin 1—All Manufacturing of : Reference Example 10 1 — [(2,3,4,5—Tetrahydro 7: 91-Dimethyl 5-5-Oxo-1 1-Benzoxepin-1 4-—yl) acetyl] Instead of peridine Hexahydr — 1 — ((2,3,4: 5 — tetrahydro-1,7,9 —dimethyl-5 —oxo-1 —benzoxepin —41) acetyl) 1 1 Η —azepine The reaction and treatment were carried out in the same manner as in Reference Example 10 to give the desired product as an oil.

Example 4 3

Preparation of tablets:

1— [2— (2,3—dihydro-1,7,9—dimethyl-1—benzoxepin-1-yl) ethyl] hexahi draw 1Η—azepine hydrochloride (compound of Example 2) 30 g corn Starch… g 5 25 g lactose · ■ ■ 8 58 g Crystallized cell mouth '30 g hydroxypropylcellulose--· · · · · · · · · 5 g Light anhydrous Caic acid. . 1 g Magnesium stearate '-1 g According to a conventional method, the above components are mixed, granulated, and compression-molded. One tablet, 150 mg, and a tablet core of 1,000 tablets are prepared. Then, using hydroxypropyl methylcellulose, macrogo-one, titanium oxide, talc, and light anhydrous anhydrous citric acid, apply the coating in the usual manner to give a film-coated tablet.

Example 4 4

Preparation of powder:

1- (2- (2,3-Dihydro7,9-dimethyl-11-benzoxepin-1-yl) ethyl) piperidine hydrochloride (Compound of Example 1) 30 g

D — mannitol 9 25 g Hydroxypropylcellulose 30 g Magnesium stearate 10 g Light gay anhydride 5 g The above components are mixed and granulated according to a conventional method to prepare a 2% powder. Industrial applicability

As described above, [ω- (2,3-dihydr-1-onebenzoxepin-4-yl) alkyl] amine derivative represented by the formula (I) and physiologically acceptable acid addition salts thereof And Ν-oxide derivatives have a strong anti-micturition reflex activity and low toxicity, and are produced as a remedy for pollakiuria and urinary incontinence due to various causes in mammals including humans It can be used to improve the symptoms of diseases caused by decreased urinary storage function of the bladder.

Claims

Scope of request

1. General formula (I)

Wherein, R ¹ and R ² are the same or different, a hydrogen atom, a halogen atom, arsenic Dorokishi group, Ji, ~ ₍₅ alkyl group, C i C s alkoxy groups, human Dorokijimechiru group, formyl group , carboxy or C, or means a ~ C ₃ § Rukokishikarubo two group, or when R ¹ and R ² bonded to the carbon atom you adjacent, they together such connexion methylene Nji Okishi group, ethylene Nokishi based on (_CH _₂ CH ₂ 0-), ethylene Njiokishi group, rather it may also be forming a door re-methylene down group or Te tiger methylene down group,

R ³ represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a di-C ₅ alkyl group, a C! -C ₃ alkoxy group or a phenyl group;

R ⁴ is a hydrogen atom, C! C s alkyl group, Ashiru group, C, ~ C ₅ Al alkylsulfonyl group or a non-a substituted or is substituted off We sulfonyl sulfonyl group,

R ⁵ represents a C ₃ -C ₈ cycloalkyl group, or R ⁴ and R ⁵ may form a cyclic amino group represented by the following formula (A) together with an adjacent nitrogen atom,

(In the formula, R ⁶ , R ⁷ and q are as defined below.)

R ⁶ is a hydrogen atom, a halogen atom, a hydroxy group, ~ Ji ₃ Al kills group or means (C, ~ Ji ₂ Arukokiji) methyl group,

R ⁷ is a hydrogen atom, a halogen atom, C, -C ₃ alkyl group, (C, ~ C 2 alkoxy) methyl group, or means a benzyl group or Fuwenechiru group, or adjacent R ^s and R ⁷ to the nitrogen atom When bonded to a carbon atom other than the carbon atom to be bonded, they may be taken together to form an oxo group,

P represents an integer of 2 to 6, and q represents an integer of 3 to R. Or a physiologically acceptable acid addition salt or N-oxide derivative thereof.

2. R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1 to C ₃ alkyl group, a methoxy group, an ethoxy group, a hydroxymethyl group, a carboxy group, a methoxycarbonyl group. Or R ¹ and R ² , which are ethoxycarbonyl groups or are bonded to adjacent carbon atoms, become a methylenedioxy group, an ethylenoxy group, an ethylenedioxy group, a trimethylene group or a tetramethylene group; 2. The compound according to claim 1, wherein R ³ is a hydrogen atom, or a physiologically acceptable acid addition salt or N-oxide derivative thereof.

3. R ⁴ is hydrogen and R ⁵ is cyclopentyl, cyclohexyl or cycloheptyl, or R ⁴ and R ⁵ are adjacent 1 azetidinyl group, 1 1 pyrrolidinyl group, 2 — methyl 1 1 1 pyrrolidinyl group, 2, 5 — dimethyl 1 1 1 pyrrolidinyl group, piperidino group or hexahydro 1 H — 3. The compound or a physiologically acceptable acid addition salt thereof according to claim 2, wherein the compound forms a azepine-11-yl group and P is an integer of 2 to 4.

4. General formula (l a)

(Wherein, R ^{1 a} denotes a C t~C 3 alkyl group,

R ^{2 a} and R ^{3 a} is a hydrogen atom or a C, -C ₃ or refers to an alkyl group, or, R ^{1 a} and R ^{2 beta} rather it may also be formed a connexion Application Benefits methylene down groups together,

R ⁴ a is a hydrogen atom, R ^{5 beta} is Kisahi draw 1 or R ^{4 a} and R ^{5 a} means cyclopentyl 1 one pyro Li isoxazolidinyl group together with the adjacent nitrogen atom, to Piperi Gino group or It may form an H—azepine-11-yl group. However, one also least for the R ^{2 a} and R ^{3 a} is a hydrogen atom. )

Or a physiologically acceptable acid addition salt thereof.

5. The compound is 1- [2- (2,3-Dihydro-7,8-Dimethyl-1-Benzoxepin-1-ethyl) ethyl] piperidine, 1-1 [2— (2,3— Dihydro 1 7 —propyl 1 —benzoxepin — 4-yl) ethyl] piperidine, 1 1 [2— (2,3—dihydro — 7 — Methyl-1 1-benzoxepin-1 4 —yl) ethyl] Hexahydro 1 H-azepine, 1 — [2 — (2,3,8,9—Tetrahydro 7H—cyclopentene h] Benzoxepin-l-ethyl) piperidine and hexahydro-l-l- [2- (2,3,8,9-tetrahydro-l- 7H-cyclopentyl [h] benzoxepin Claim 1 which is a compound selected from 1-1H-azepine, or the compound according to claim 4 or a physiologically acceptable acid addition salt thereof,

6. 1— [2— (2,3—dihydro-1,7,9—dimethyl-1—benzoxepin—41) ethyl] hexahydr-1H-azepine or its physiologically acceptable Acid addition salts.

7.1— [2— (2,3—dihydro-1,7,9-dimethyl-1—benzoxepin—4—yl) ethyl] piperidine or a physiologically acceptable acid addition salt thereof.

8. 1— [2— (2,3-Dihidro 7,8-Dimethyl-1-benzoxepin-4-yl) ethyl] Pyrrolidine or a physiologically acceptable acid addition salt thereof.

9. General formula (I)

(In the formula, R ¹ , RR ³ , R ⁴ , R ⁵ and p are the same as defined in claim 1.)

Or a physiologically acceptable acid addition salt or N thereof A method for producing an oxide derivative, comprising:

0) General formula (I)

(Wherein, R ¹ , R ² , R ^s , R ⁵ and p are the same as defined in claim 1, and R ⁴ ′ represents a hydrogen atom or a C, to C ₅ alkyl group Alternatively, R ⁴ ′ and R ⁵ may form a cyclic amino group represented by the above formula (A) together with an adjacent nitrogen atom.) , Or

(b) General formula (M)

(Wherein, R ¹ , R ² , R ³ and p are the same as defined in claim 1, and X and Y are the same or different and represent an alcohol reactive ester residue. , Z means a hydrogen atom, or Y and Z may be joined together to form a bond.)

And a compound represented by the general formula (IV)

(In the formula, R ⁴ ′ and R ⁵ mean the same as described above.)

When a compound having R ¹ and Z or R ² is a C, C 3 alkoxycarbonyl group is formed, the product may be reduced or hydrolyzed as required. the a result, each of R ¹ and Z or R ² is formate group, converted to compound a human Dorokishimechiru group or force Rubokishi group, when a compound R ^'1 is a hydrogen atom is produced may, if desired alkylating the product, Ashiru reduction, alkylsulfonyl or non substituted young properly by the child substituted phenylalanine sulfonylation, R ⁴ is C! ~ C ₅ alkyl group, Ashiru group, C! -C ₅ alkyl sulfonyl Conversion to a compound which is a substituted or unsubstituted or substituted phenylsulfonyl group, and / or, if desired, the conversion of the product to a physiologically acceptable acid addition salt or N-hydroxyoxide derivative. Characteristic manufacturing method.

10. The product according to claim 2, wherein the product is the compound according to any one of claims 2 to 8, or a physiologically acceptable acid addition salt or N-oxide derivative thereof. 9. The production method according to item 9.

11. The compound according to any one of claims 1 to 8 or a physiologically acceptable acid addition salt or N-oxide derivative thereof as an active ingredient, and a pharmaceutical carrier. A pharmaceutical composition which is contained together.

12. Treatment of pollakiuria and urinary incontinence using the compound according to any one of claims 1 to 8 or a physiologically acceptable acid addition salt or N-oxide derivative thereof as an active ingredient. medicine.