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WO1998016519A1 - DERIVES DE [φ-(2,3-DIHYDRO-1-BENZOXEPIN-4-YL)ALKYL]AMINE, PROCEDE DE PREPARATION DE CES DERNIERS ET COMPOSITIONS MEDICAMENTEUSES CONTENANT CEUX-CI - Google Patents

DERIVES DE [φ-(2,3-DIHYDRO-1-BENZOXEPIN-4-YL)ALKYL]AMINE, PROCEDE DE PREPARATION DE CES DERNIERS ET COMPOSITIONS MEDICAMENTEUSES CONTENANT CEUX-CI Download PDF

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Publication number
WO1998016519A1
WO1998016519A1 PCT/JP1997/003672 JP9703672W WO9816519A1 WO 1998016519 A1 WO1998016519 A1 WO 1998016519A1 JP 9703672 W JP9703672 W JP 9703672W WO 9816519 A1 WO9816519 A1 WO 9816519A1
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Prior art keywords
group
compound
benzoxepin
hydrogen atom
physiologically acceptable
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PCT/JP1997/003672
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English (en)
Japanese (ja)
Inventor
Toshiya Morie
Aki Kanehira
Naoki Kai
Katsuhiko Hino
Katsuyoshi Kawashima
Isao Shimizu
Kazuhisa Akiyama
Original Assignee
Dainippon Pharmaceutical Co., Ltd.
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Application filed by Dainippon Pharmaceutical Co., Ltd. filed Critical Dainippon Pharmaceutical Co., Ltd.
Priority to AU45716/97A priority Critical patent/AU4571697A/en
Publication of WO1998016519A1 publication Critical patent/WO1998016519A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to a novel [ ⁇ - (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.
  • 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
  • R 3 represents an alkyl group having 1 to 3 carbon atoms.
  • A is a halogen atom
  • Y is a group other than 1-piperazyl group.
  • the present invention provides a compound represented by the general formula (I):
  • 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 ⁇ alkyl group, a C i -C 3 alkoxy group or a phenyl group
  • 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;
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • alkylsulfonyl group examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isosulfone pyrsulfonyl, butylsulfonyl, and isobutylsulfonyl.
  • 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.
  • 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.
  • 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.
  • R 3 and R 4 include a hydrogen atom.
  • R 5 consequent opening pentyl
  • Ru include heptyl hexyl or cycloheteroalkyl but cyclopentyl group is particularly preferred arbitrariness.
  • 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 ⁇ , an integer of 2 to 5, particularly 2, 3, or 4, is preferred, and 2 is most preferred.
  • 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.
  • Particularly preferred compounds are those represented by the following formula (la) and physiologically acceptable acid addition salts thereof.
  • 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,
  • particularly preferred compounds include the following compounds and their physiologically acceptable acid addition salts, with the former three being the most preferred.
  • the compound of the present invention can be produced, for example, by the following method. You.
  • 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).
  • 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.
  • 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.
  • 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. .
  • 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,
  • 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.
  • a boron-containing reducing agent such as borane
  • a decomposition product thereof such as an inorganic acid or an organic acid.
  • the starting compound (H) can be produced, for example, by a method shown in the following reaction scheme.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a suitable 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.
  • 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.
  • ethers such as getyl ether, tetrahydrofuran, dimethoxetane, dioxane, diglyme, benzene
  • aromatic hydrocarbons such as toluene, halogenated hydrocarbons such as dichloromethane and chloroform, alcohols such as methanol and ethanol, acetic acid, and pyridine.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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.
  • 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, ⁇ -toluenesulfonyloxy, m-nitrobenzenesulfonyloxy, and arylsulfonyloxy groups.
  • the reaction between the compound of the formula ( ⁇ ) and the compound of the formula (IV) is usually carried out in the presence of a base in a suitable solvent.
  • a 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.
  • 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.
  • 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.
  • the free base can be converted into an acid addition salt by treating it with various acids according to a conventional method.
  • 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.
  • 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.
  • Test Example 1 Inhibitory effect of rhythmic bladder contraction (micturition reflex)
  • 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.
  • 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; +
  • 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.
  • 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.
  • a 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.
  • compositions 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • ⁇ -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.

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Abstract

La présente invention concerne des dérivés de [φ-(2,3-dihydro-1-benzoxepin-4-yl)alkyl]amine représentés par la formule générale (I), ainsi que les sels et dérivés N-oxydes de ces derniers, un procédé de préparation de ceux-ci et des compositions médicamenteuses contenant ceux-ci. Dans cette formule R1 et R2, sont chacun un hydrogène, halogéno, alkyle, alkoxy ou analogue ou, selon une variante, R1 et R2 peuvent être liés pour former de l'éthylène-oxy, du triméthylène ou analogue; R3 est un hydrogène, un alkyle ou analogue; R4 est un hydrogène, un alkyle, acyle ou analogue et R5 est un cycloalkyle, ou, selon une variante, R4 et R5 peuvent former avec l'atome d'azote adjacent un groupe amino cyclique; et p est un entier de 2 à 6. Les composés de la présente invention sont dotés d'une puissante activité inhibitrice du réflexe de la miction, et sont par conséquent utilisés comme remèdes contre la pollakiurie et l'incontinence urinaire.
PCT/JP1997/003672 1996-10-16 1997-10-14 DERIVES DE [φ-(2,3-DIHYDRO-1-BENZOXEPIN-4-YL)ALKYL]AMINE, PROCEDE DE PREPARATION DE CES DERNIERS ET COMPOSITIONS MEDICAMENTEUSES CONTENANT CEUX-CI WO1998016519A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
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JPS61130286A (ja) * 1984-11-28 1986-06-18 Suntory Ltd ２，３−ジヒドロ−１−ベンズオキセピン誘導体

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* Cited by examiner, † Cited by third party
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JPS61130286A (ja) * 1984-11-28 1986-06-18 Suntory Ltd ２，３−ジヒドロ−１−ベンズオキセピン誘導体

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