JPH10120632A - N-cycloalkyl-(omega-(3,4-dihydro-2naphthalenyl) alkyl)amine derivative and medicine containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as a medicine composition for treating pollakiuria and urinary incontinentia, having strongly inhibitory action on micturition reflex. SOLUTION: This compound is shown by formula I (R<1> and R<2> are each a halogen, a 1-5C alkyl, etc.; R<3> is H, a halogen, a 1-5C alkyl, etc.; R<4> is H, a 1-5C alkyl, etc.; R<5> is a 3-8C cycloalkyl; (p) is 2-6) such as 1,2,3,4- tetraphydro-6,7-dimethyl-1-oxo-2-naphthaleneacetic acid. The compound of formula I is produced, for example, by dehydrating a compound of formula II when R<4> is H or a 1-5C alkyl of the compound of formula I. The dehydration reaction is carried out by using a dehydrating agent such as HC1 generally at about -20 deg.C to about 200 deg.C through the reaction temperature is different depending upon the kind of the dehydrating agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a novel N-cycloalkyl- [ω- (3,4)
-Dihydro-2-naphthalenyl) alkyl] amine derivatives and pharmaceutical compositions containing said compounds.

[0002]

2. Description of the Related Art U.S. Pat. No. 4,022,791 describes that a compound represented by the following formula (3) is useful as an analgesic and a tranquilizer.
ed. Chem., 21 , 257 (1978).

[0003]

Embedded image (Wherein X and Y are independently H, F, Cl, Br, carbon number 4)
Means up to alkyl or alkoxy having up to 4 carbon atoms, and Z means a secondary or tertiary amino group. Where X
And Y are both H. )

[0004]

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 excellent therapeutic agents is desired. The present inventors have conducted intensive studies and found that the formula (I)
It has been found that an N-cycloalkyl- [ω- (3,4-dihydro-2-naphthalenyl) alkyl] amine derivative represented by the formula (1) has a strong urinary reflex suppressing action, and thus completed the present invention.

[0005]

According to the present invention, an N-cycloalkyl- [ω- (3,4) represented by the following formula (I):
-Dihydro-2-naphthalenyl) alkyl] amine derivatives and physiologically acceptable acid addition salts thereof, and pharmaceutical compositions containing these compounds.

[0006]

Embedded image [Wherein R ¹ and R ² are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a C ₁ -C ₅ alkyl group, a C ₁ -C ₃ alkoxy group, a hydroxymethyl group, a formyl group, a carboxy group Or a C ₁ -C ₃ alkoxycarbonyl group, or when R ¹ and R ² are bonded to adjacent carbon atoms, they are taken together to form a methylenedioxy group, an ethyleneoxy group (—CH ₂ CH ₂ O-), ethylenedioxy group, may form a trimethylene group or a tetramethylene group, R ³ is a hydrogen atom, a halogen atom, a trifluoromethyl group, C ₁ -C ₅ alkyl group, C ₁ -C
₃ means an alkoxy group or a phenyl group, R ⁴ is a hydrogen atom, C ₁ -C ₅ alkyl group, acyl group, C ₁ -C ₅ alkylsulfonyl group or an unsubstituted or substituted phenylsulfonyl group, R ⁵ is means C ₃ -C ₈ cycloalkyl group, p is an integer of 2-6. ]

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. Salt and oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfone Organic acid salts such as acid salts. Since the compounds of formula (I) and salts thereof may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The terms used in the present specification will be 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. "Acyl group" means a saturated aliphatic carboxylic acid residue or an aromatic carboxylic acid residue, and examples include formyl, acetyl, propionyl, butyryl, isobutyryl, and benzoyl. The “unsubstituted or substituted phenylsulfonyl group” means a phenylsulfonyl group optionally substituted with halogen, lower alkyl, lower alkoxy or nitro, for example, phenylsulfonyl, p-chlorophenylsulfonyl, p-methylphenylsulfonyl, p-methoxyphenylsulfonyl and p-nitrophenylsulfonyl. Specific examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, and isobutylsulfonyl.

Preferred examples of R ¹ and R ² include a hydrogen atom, a halogen atom (particularly a fluorine atom), a hydroxy group, a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group, a hydroxymethyl group, a carboxy group. Group, methoxycarbonyl group or ethoxycarbonyl group. Further, R ¹ and R ² are bonded to adjacent carbon atoms,
It is also preferred that they together form a methylenedioxy, ethyleneoxy, ethylenedioxy, trimethylene or tetramethylene group. R ¹ and R ²
More preferred specific examples include a methyl group, an ethyl group, a methoxy group, an ethoxy group or a hydroxymethyl group, and the case where they are bonded to the carbon atoms at the 6-position and the 7-position is particularly preferable. Further, R ¹ and R ² bonded to the carbon atoms at the 7th and 6th positions together form an ethyleneoxy group (6-C
H ₂ CH ₂ O-7) or the case of forming a trimethylene group are also particularly preferred. It is still more preferred that R ¹ is a hydrogen atom or a halogen atom (especially a fluorine atom), and R ² is a halogen atom (especially a fluorine atom), and 6,7-dihalogen or 5-halogen is particularly preferred. Preferred specific examples of R ³ and R ⁴ include a hydrogen atom. Preferable specific examples of R ⁵ include a cyclopentyl group, a cyclohexyl group and a cycloheptyl group, and a cyclopentyl group is particularly preferable. p is an integer of 2 to 5, particularly preferably 2, 3 or 4, and most preferably 2.

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 hydrogen, halogen, hydroxy, methyl, ethyl, propyl or methoxy. , 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 together form a methylenedioxy group, an ethyleneoxy group, an ethylene group. Forming a dioxy, trimethylene or tetramethylene group, R ³ and R ⁴
Is a hydrogen atom, R ⁵ is a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, and p is an integer of 2 to 6 and physiologically acceptable acid addition salts thereof.

Further preferred compounds are those of the formula (I)
¹ and R ² are each bonded to the carbon atom at the 7-position and the 6-position and are both hydrogen atoms, or are the same or different and are a methyl group, an ethyl group, a methoxy group, an ethoxy group or a hydroxymethyl group; R ¹ and R ² together form an ethyleneoxy group (6-CH ₂ CH ₂ O-7) or a trimethylene group, R ³ and R ⁴ are hydrogen atoms,
R ⁵ is a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, and p is an integer of 2 to 5 and a physiologically acceptable acid addition salt thereof.

Another group of more preferred compounds are compounds of formula (I)
In the above, R ¹ is a hydrogen atom and R ² is a halogen atom at position 5 (especially a fluorine atom), or R ¹ and R ² are a halogen atom bonded at positions 7 and 6 (especially a fluorine atom). , R ³ and R ⁴ are hydrogen atoms, R ⁵ is a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, and p is an integer of 2 to 5, and physiologically acceptable acid addition salts thereof. .

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

Embedded image [Wherein R ^1a and R ^2a both represent a hydrogen atom,
Or the same or different, meaning a methyl or ethyl group, or R ^1a and R ^2a together forming an ethyleneoxy group (6-CH ₂ CH ₂ O-7) or a trimethylene group. ]

The most preferred compounds include, for example, the following compounds and their physiologically acceptable acid addition salts.

N-cyclopentyl- [2- (3,4-dihydro-2-naphthalenyl) ethyl] amine;
Cyclopentyl- [2- (3,4,7,8-tetrahydro-6H-cyclopenta [g] naphthalen-2-yl)
Ethyl] amine [compound in which R ^1a and R ^2a together form a trimethylene group in formula (Ia)].

As specific examples of the compounds included in the present invention,
In addition to the compounds of Examples described later, the compounds of Tables 1 and 2 represented by Chemical Formula 6 and physiologically acceptable acid addition salts thereof can be mentioned. In the table, Me represents a methyl group, Et represents an ethyl group, and Pr represents a propyl group.

[0018]

Embedded image

[0019]

[Table 1] ^{━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ R 1 R 2 R 4 p} q ━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 7-Cl H H 2 4 H H Ac 2 4 H H MeSO 2 2 4HHH34HHH44H5-FH25H5-FH34H5-FH44H5-ClH247-F6-FH257- F5-FH24-F5-FH24-F5-FH24-EtHH24} ━━━━━━━━━━━━━━━━━

[0020]

[Table 2] Continued from Table 1 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ R ¹ R ² R ⁴ p q ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 6-Pr H H 24 7-Et 6-Et H 2 4 7-OMe 6- Me H 2 4 7-OMe 6-OMe H 2 4 7-Me 6-CH 2 OH H 2 4 7-CH 2 OH 6-Me H 2 4 7- (CH 2) 3 _{-6 Ac 2 4 7- (CH 2} ) 3 -6 MeSO 2 2 4 7- (CH 2) 4 -6 H 2 4 7- (CH 2) 4 -6 H 3 4 7- (CH 2) 3 - _{6 H 4 4 8- (CH 2} ) 3 -7 H 2 4 6- (CH 2) 3 -5 H 2 4 7-OCH 2 O-6 H 2 4 7-O (CH 2) 2 -6 H 2 _{5 7-O (CH 2)} 2 O-6 H 2 4 ━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━━

The compound of the present invention can be produced, for example, by the following method.

Production method (a) :-In the formula (I), the compound wherein R ⁴ is a hydrogen atom or a C ₁ -C ₅ alkyl group can be produced by dehydrating the compound represented by the formula (II). it can.

Embedded image (In the formula, R ¹ , R ² , R ³ , R ⁵ and p have the same meanings as described above, and R ⁴ ′ has a hydrogen atom or a C ₁ -C ₅ alkyl group.)

This dehydration reaction can be performed under conditions applicable to the dehydration reaction of alcohol to olefin.
For example, the reaction is carried out by reacting the compound of the formula (II) with a dehydrating agent without a solvent or in a suitable solvent. Specific examples of the dehydrating agent 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-toluenesulfonic acid. Aromatic sulfonic acid, organic acid anhydride such as acetic anhydride, o-sulfobenzoic anhydride, anhydrous inorganic salt such as potassium hydrogen sulfate, inorganic acid chloride such as thionyl chloride, phosphorus oxychloride, acetyl chloride Organic acid chlorides, such as
Sulfonate such as p-toluenesulfonyl chloride and methanesulfonyl chloride; boron trifluoride / diethyl ether complex; Lewis acid such as zinc chloride; iodine; alumina; The solvent to be used should be appropriately selected according to the type of the dehydrating agent and the like. For example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, acetone and ethyl Ketones such as methyl ketone, alcohols such as acetonitrile, methanol, ethanol, and isopropyl alcohol; organic acids such as ethylene glycol, formic acid, acetic acid, and propionic acid; pyridine, dimethyl sulfoxide, and water. Are each alone or 2
Used as a mixture of more than one species. 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 (II) 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, and may be an acidic compound such as an inorganic acid or an organic acid. The use of a dehydrating agent can lead to compounds of formula (I).

The starting compound (II) can be produced, for example, by the method shown in the following Chemical formula 8.

[0025]

Embedded image

(Wherein, R ¹ , R ² , R ³ , R ⁴ ′, R ⁵ and p have the same meanings as described above, and R ¹ ′ and R ² ′ are formyl and carboxy groups respectively protected) The same as R ¹ and R ² above, except that the substituted formyl group and the protected carboxy group are replaced.)

In the above formula 8, the protected formyl groups represented by R ¹ ′ and R ² ′ include, for example, acetals such as dimethoxymethyl, diethoxymethyl and ethylenedioxymethyl, and oximes such as hydroxyiminomethyl. Examples of the protected carboxy group include a lower alkoxycarbonyl group such as methoxycarbonyl and ethoxycarbonyl, and an aralkyloxycarbonyl group such as benzyloxycarbonyl.

Each step of the above formula 8 will be described in detail below.

(Step 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 the active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, and N-hydroxysuccinimide ester. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include a mixed acid anhydride with an alkyl chlorocarbonate such as ethyl chlorocarbonate and isobutyl chlorocarbonate, and chlorinated acid anhydride. Mixed anhydrides with aralkyl chlorocarbonates such as benzyl carbonate, mixed anhydrides with aryl chlorocarbonates such as phenyl chlorocarbonate, mixed anhydrides with alkanoic acids such as isovaleric acid and pivalic acid Is mentioned.

When using the compound of formula (V) itself,
N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-carbonyldiimidazole, N,
N'-carbonyldisuccinimide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphorylazide, propanephosphonic anhydride, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluoro The reaction can be carried out in the presence of a condensing agent such as a phosphate.

The reaction of the compound of the formula (V) or a reactive derivative thereof with the compound of the formula (IV) is carried out in a solvent or without a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compounds and the like. For example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, dichloromethane, chloroform , Alcohols such as ethanol and isopropyl alcohol, ethyl acetate, acetone, acetonitrile, dimethylformamide, 1,3-dimethyl-2.
-Imidazolidinone, dimethylsulfoxide, ethylene glycol and water. These solvents are used alone or in combination of two or more. This reaction is carried out in the presence of a base, if necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, and sodium bicarbonate. , Potassium bicarbonate, or an organic base such as triethylamine, tributylamine, diisopropylethylamine, or N-methylmorpholine, but can also serve as an excess of the compound of the formula (IV). The reaction temperature varies depending on the type of the starting compound used, etc.
200 ° C, preferably from about -10 ° C to about 150 ° C.

The starting compound (V) in this step is
Starting from 4-dihydro-1 (2H) -naphthalenones, a method known per se, for example, J. Med. Chem., 17 , 273.
(1974); JP-A-54-24861 [Chem. Abstr., 91 , 5
6702b (1979)]; Pharmazie, 41 , 835 (1986);
110 , 561 and 922 (1990); Heterocycles, 34 , 1303 (19
92); Tetrahedron, 48 , 4027 (1992) or Reference Example 1 below
To 3, or a method analogous thereto.

On the other hand, 3,3 which is the starting material of compound (V)
4-Dihydro-1 (2H) -naphthalenones are commercially available or known per se, for example, J. Chem. S
oc., 1961 , 4425; J. Org. Chem., 26 , 1109 (1961);
Heterocycl. Chem., 10 , 31 (1973); U.S. Pat.
2,791; Chem. Pharm. Bull., 25 , 632 (197
7); ibid, 31 , 2006 (1983); J. Med.Chem., 17 , 273 (19
74); ibid., 50 , 4933 (1985); JP-A-6-87746;
Synth. Commun., 21 , 981 (1991); Tetrahedron Lett.,
33 , 5499 (1992) or a method analogous thereto.

In this step, the other starting compound (I
V) is commercially available or can be produced according to a method known per se.

(Step 2) —This step is suitable for reducing the compound of formula (VI) in a suitable solvent to reduce the carbonyl group of the ketone to an alcoholic hydroxy group and the carbonyl group of the amide to a methylene group. This is performed by treating with a reducing agent. Specific examples of the reducing agent include lithium aluminum hydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride,
Aluminum hydride or hydrogen complex compound such as aluminum hydride, sodium borohydride, or the compound and anhydrous aluminum chloride, cobalt chloride (I
I), a combination with a Lewis acid such as boron trifluoride / diethyl ether complex, sodium acetoxyborohydride,
Hydrogen complex compounds of boron such as sodium trifluoroacetoxyborohydride, borane compounds such as diborane,
Triethylsilane-zinc chloride. The solvent to be used should be appropriately selected according to the type of the reducing agent and the like. For example, diethyl ether, tetrahydrofuran,
Ethers such as dimethoxyethane, dioxane and diglyme; aromatic hydrocarbons such as benzene and 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 and the like, but is usually about-
10 ° C to about 130 ° C. This reduction step is performed in an inert atmosphere, for example, in nitrogen or argon if necessary. In addition,
In the case of the compound of the formula (VI) wherein R ¹ ′ and / or R ² ′ is a protected formyl group and / or a protected carboxy group, after the reduction, the protecting group in the reaction product is removed by an ordinary method. Upon separation, the compound of formula (II) can be obtained. The compound of the formula (II) produced in this step can be used for the dehydration reaction without isolation and purification. When a boron-containing reducing agent such as borane is used as the reducing agent, the compound of the formula (II) can be obtained in the form of a complex with the boron-containing reducing agent or a decomposition product thereof. can do.

Process (b) : The compound of the formula (I) wherein R ⁴ is a hydrogen atom or a C ₁ -C ₅ alkyl group is also
Formula (III) below

Embedded image

Wherein R ¹ , R ² , R ³ and p are the same as described above, X and Y are the same or different and each represents a reactive ester residue of an alcohol, and Z is hydrogen. Or a compound represented by the following formula (IV):

Embedded image

(Wherein, R ⁴ ′ and R ⁵ have the same meanings as described above).

The reactive ester residue of the alcohol represented by X and Y in the formula (III) includes, for example, halogen atoms such as chlorine, bromine and iodine, and lower alkylsulfonyl such as methanesulfonyloxy and ethanesulfonyloxy. And an arylsulfonyloxy group such as an oxy group, benzenesulfonyloxy, p-toluenesulfonyloxy, and m-nitrobenzenesulfonyloxy.

The reaction of the compound of the formula (III) with the compound of the formula (IV) is usually carried out in a suitable solvent in the presence of a base.
Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate; organic bases such as triethylamine, tributylamine, diisopropylethylamine and N-methylmorpholine; alkali metal alkoxides such as sodium methoxide and sodium ethoxide;
Examples thereof include alkali metal hydrides such as sodium hydride and potassium hydride, but they can also serve as an excess amount of the compound of the formula (IV). The solvent used is the starting compound,
It should be appropriately selected according to the type of base, etc., for example, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, dioxane and diglyme, halogenated hydrocarbons such as dichloromethane and chloroform, Ketones such as acetone and ethyl methyl ketone; acetonitrile; alcohols such as methanol, ethanol and isopropyl alcohol; dimethylformamide; and 1,3-dimethyl-2-imidazolidinone. ,
Alternatively, two or more kinds are used in combination. The reaction temperature varies depending on the type of the starting compound used, etc.
150 ° C, preferably from about 80 ° C to about 120 ° C.

The starting compound (III) can be produced according to a method known per se, for example, the method described in Reference Examples 6 and 7 below, or a method analogous thereto.

When a compound in which R ¹ and / or R ² is a C ₁ -C ₃ alkoxycarbonyl group in the formula (I) is obtained by the above-mentioned production method (a) or (b), the compound is prepared according to a conventional method. To a compound in which R ¹ and / or R ² is a formyl group or a hydroxymethyl group, and to a compound in which R ¹ and / or R ² is a carboxy group by hydrolysis according to a conventional method. it can. When a compound in which R ⁴ is a hydrogen atom in the formula (I) is obtained, R ⁴ can be obtained by alkylation, acylation, alkylsulfonylation or unsubstituted or substituted phenylsulfonylation using a corresponding reagent according to a conventional method. It can be led to compounds wherein ⁴ is a C ₁ -C ₅ alkyl group, an acyl group, a C ₁ -C ₅ alkylsulfonyl group or an unsubstituted or substituted phenylsulfonyl group. Example 13 below illustrates the conversion to a methyl group by the reductive methylation method.

The compound of the formula (I) produced by each of the above-mentioned 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, reaction and treatment conditions, and the like. Acid addition salts can be prepared by a conventional method,
For example, treatment with a base such as an alkali carbonate or an alkali hydroxide can convert it to a free base. On the other hand, the free base can be converted to an acid addition salt by treating it with various acids according to a conventional method.

The results of pharmacological tests on representative compounds of the present invention are shown below.

Test Example 1 Rhythmic bladder contraction (micturition reflex)
Inhibitory effect-This test was performed using the method of Maggi, CA and Meli ,, A. [J.
rmacol. Methods, 10 , 79 (1983)]. It is understood that the regular rhythmic bladder contractions triggered by saline infusion in this study are triggered via the same voiding reflex pathway as spontaneous voiding.

Three to four Std-Wistar female rats weighing 160 to 190 g were used in each group. A midline incision was made in the lower abdomen under urethane (1 g / kg, subcutaneous administration) anesthesia, and the ureters on both sides were ligated and cut at the kidney side. A cannula to which a syringe and a pressure transducer were connected was inserted into the bladder from the external urethral opening, and the urethral neck was ligated. After standing for about 30 minutes after the operation, a warm saline solution (0.4 to 1.0 ml) is slowly injected into the bladder using a syringe until a rhythmic contraction is induced in the bladder. And recorded on the recorder. After the rhythmic contraction of the bladder stabilizes, a test compound dissolved or suspended in a 0.5% tragacanth aqueous solution is administered via a pre-mounted duodenal cannula, and the effect on the number of contractions (frequency) every 15 minutes is administered. Observed for up to 2 hours. 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 rate of suppression of contraction frequency (2 hours) was determined by setting the number of contractions 15 minutes before the administration of the test compound to 100% and calculating the inhibition rate every 15 minutes after administration up to 2 hours, and expressed as the average value.

[0049]

[Table 3] Rhythmic bladder contraction inhibitory effect 抑制 Test frequency inhibitory effect Compound that suppresses contractile force Dose; Inhibition rate (%) Dose; Effect ^*) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━ Example 1 10 mg / kg; 43% 10 mg / kg;-Example 4 10 mg / kg; 33% 10 mg / kg; + Example 5 10 mg / kg; 66% 10 mg / kg -Example 10 20 mg / kg; 49% 20 mg / kg; + Example 11 10 mg / kg; 18%, 20 mg / kg; 57% 10 mg / kg; + ━━━━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━ *) +: Suppressive action, −: No suppressive action

As is evident from Table 3, all the tested compounds of the present invention showed a strong inhibitory effect on rhythmic bladder contractions at doses of 10 to 20 mg / kg. Further, the compounds of Examples 4, 10 and 11 suppressed not only the frequency but also the magnitude of the contraction.

As is evident from the above test results, the compound represented by the formula (I) and the physiologically acceptable acid addition salts thereof (hereinafter sometimes referred to as "the compound of the present invention") have strong potency. It has a urinary reflex suppression effect,
Diseases caused by reduced urinary bladder function caused by various causes as urinary incontinence drugs (eg, unstable bladder, neurogenic bladder, chronic cystitis, chronic prostatitis, frequent urinary frequency)
Can be used to improve the symptoms.

The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, but oral administration is preferred. The dose of the compound of the present invention is:
Although it depends on the type of compound, administration method, patient's symptoms and age, etc., it is usually 0.1-20 mg / kg / day, preferably 0.4-10 mg / kg.
/ 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 pregelatinized starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxymethylcellulose calcium , Ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylalcohol, alginic acid,
Sodium alginate, light silicic anhydride, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, Examples include 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. In the case of liquid preparations,
It may be in the form of a solution or suspension in water or other suitable medium. Tablets and granules may be coated by a known method.

These pharmaceutical compositions usually contain the compound of the present invention as an active ingredient in an amount of 0.1% or more, preferably 1 to 70%.
At a ratio of These pharmaceutical compositions may also contain other therapeutically effective ingredients.

[0056]

EXAMPLES The present invention will be described more specifically with reference examples and examples, but the present invention is not limited to these examples. The compounds were identified by elemental analysis values, mass spectra, IR spectra, NMR spectra, and the like.

In the following Reference Examples and Examples, the following abbreviations may be used for simplification of the description. Me: methyl group, A: ethanol, AC: acetone, DE: diethyl ether, EM: ethyl methyl ketone.

Reference Example 1 1,2,3,4-tetrahydro-6,7-dimethyl-1
-Preparation of oxo-2-naphthaleneacetic acid:-

(1) A mixture of 18 g of 37% formalin and 18 g of dimethylamine hydrochloride was stirred at 25 ° C. for 30 minutes, then at 70 ° C. for 30 minutes, the reaction temperature was raised to 80 ° C., and 80 ml of acetic anhydride was added dropwise. After stirring the reaction mixture at 80 ° C. for 1 hour, 3,4-
26 g of dihydro-6,7-dimethyl-1 (2H) -naphthalenone was added, and the mixture was heated to 90 ° C and stirred for 6 hours. The solvent was distilled off under reduced pressure, and acetone was added to the residue. The precipitated crystals are collected by filtration, washed with acetone, and washed with 2-dimethylaminomethyl-3,4-dihydro-6,7-dimethyl-1 (2H)-.
39 g of naphthalenone hydrochloride were obtained.

(2) 39 g of the above Mannich base / hydrochloride was dissolved in ice water, made alkaline with aqueous ammonia, and extracted with dichloromethane. The dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off at 40 ° C. or lower. The residue was dissolved in acetone, and 10.8 ml of methyl iodide was added dropwise with stirring under ice cooling. After stirring for further 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 acetone and washed with 1,2,3,4-tetrahydro-N, N, N, 6,7-pentamethyl-1-oxo-
46 g of 2-naphthalenemethanaminium iodide was obtained.

(3) 46 g of the above quaternary salt was dissolved in 300 ml of methanol, and a solution of 9.6 g of potassium cyanide in 80 ml of water was added.
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 to remove 1,2,3,4-tetrahydro-6,7.
-Dimethyl-1-oxo-2-naphthaleneacetonitrile 22 g was obtained as crystals.

(4) 22 g of the acetonitrile was dissolved in a mixture 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, washed with water and recrystallized from ethyl methyl ketone to obtain 16.5 g of the desired product
I got Melting point 193-194 ° C

IR spectrum (KBr, cm ^-1 ): 1707, 167
6.1 ¹ H-NMR spectrum (200 MHz, CDCl ₃ , δ ppm): 1.81-
2.24 (m, 2H), 2.27 (s, 3H), 2.29 (s, 3H), 2.38-2.56
(m, 1H), 2.89-3.15 (m, 4H), 7.02 (s, 1H), 7.80
(s, 1H), 10.50 (br s, 1H).

Reference Example 2 Production of 1,2,3,4-tetrahydro-1-oxo-2-naphthalenepropanoic acid:

(1) To a solution of 16 ml of diisopropylamine in 350 ml of tetrahydrofuran was added dropwise 71 ml of a 1.6 M butyllithium hexane solution under cooling at -78 ° C, and the mixture was stirred for 30 minutes. The reaction mixture was cooled at −78 ° C. with 3,4-dihydro-
1 (2H) -naphthalenone 16.5 g of tetrahydrofuran
A 60 ml solution was added dropwise over about 20 minutes, and the mixture was stirred for 30 minutes. Then, a solution of 20.5 g of ethyl 3-bromopropanoate in 60 ml of tetrahydrofuran was added dropwise over about 20 minutes, and further stirred for 30 minutes. The reaction mixture was stirred at 20 ° C. overnight, diluted with diethyl ether, water, 5% aqueous sodium bicarbonate, 5%
After washing in the order of hydrochloric acid, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give ethyl 1,2,3,4-tetrahydro-1-oxo-2-naphthalenepropanoate.
0.1 g was obtained as an oil.

(2) Dissolve 10.1 g of the above ethyl ester in 200 ml of ethanol, and add 2N aqueous sodium hydroxide solution
After adding ml, the mixture was heated under reflux for 3 hours. After the ethanol was distilled off under reduced pressure, the aqueous layer was made acidic by adding concentrated hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was 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. The fractions containing the desired product were collected and concentrated under reduced pressure to obtain 6.3 g of the desired product as an oil.

Reference Example 3 Production of 1,2,3,4-tetrahydro-1-oxo-2-naphthalenebutanoic acid:

(1) 200 g of diethyl carbonate and 800 ml of toluene
After adding 27.4 g of 60% sodium hydride to the solution and stirring at 50 ° C. for 30 minutes, a solution of 3,4-dihydro-1 (2H) -naphthalenone (50 g) in toluene (200 ml) was added dropwise, followed by heating under reflux for 1 hour. The reaction solution was poured into ice water and neutralized with acetic acid. The toluene layer was separated, washed sequentially with an aqueous solution of potassium carbonate and water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue is purified by distillation under reduced pressure,
47 g of ethyl 4-tetrahydro-1-oxo-2-naphthalenecarboxylate was obtained as an oil. Boiling point 135-14
5 ℃ / 2mmHg

(2) 32 g of the above-mentioned ethyl carboxylate was tert-
Dissolve in 120 ml of butanol and add potassium tert-butoxide
25 g was added, and the mixture was heated under reflux for 30 minutes. After cooling to 25 ° C,
34 g of ethyl bromobutanoate was added, and the mixture was heated under reflux overnight.
The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with diethyl ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 50 g of ethyl 2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-oxo-2-naphthalenebutanoate as an oil. As obtained.

(3) The above-mentioned ethyl butanoate is converted to ethanol 50
The solution was dissolved in 0 ml, and 300 ml of a 30% aqueous potassium hydroxide solution was added thereto, followed by heating under reflux overnight. After ethanol was distilled off under reduced pressure, the mixture was acidified with concentrated hydrochloric acid and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 23 g of the desired product as an oil.

Reference Example 4 N-cyclopentyl- (5-fluoro-1,2,3,4
Preparation of -tetrahydro-1-oxo-2-naphthalenyl) acetamide:-

3.0 g of 5-fluoro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid, 1.3 g of cyclopentylamine and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) 1.6 g of triethylamine was added dropwise to a solution of 6.3 g of dichloromethane in 60 ml at 25 ° C., and the mixture was stirred for 5 hours. The reaction solution was diluted with water, 1N hydrochloric acid,
After washing in order with a 1N aqueous solution of sodium hydroxide, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform. Fractions containing the desired product were collected and concentrated under reduced pressure to obtain 3.0 g of the desired product as an oil.

The corresponding 1,2,3,4-tetrahydro-
Using 1-oxo-2-naphthaleneacetic acid, the reaction and treatment were carried out in the same manner as in Reference Example 4 to obtain a compound of Table 4 represented by Chemical Formula 11 as an oil.

[0074]

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[0075]

[Table 4] ━━━━━━━━━━━━━━━━━━━━━━━━━━━ R ¹ R ² q ━━━━━━━━━━━━━━ {7-F H4 7-F 6-F4 7-Me 6-Me4} ━━━━━━━━━

Reference Example 5 5-fluoro-1,2,3,4-tetrahydro-2-
Production of [2- (cyclopentylamino) ethyl] -1-naphthalenol:-

N-cyclopentyl- (5-fluoro-
1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl) acetamide 3.0 g of tetrahydrofuran 30
While stirring under ice-cooling, 42 ml of a 1M tetrahydrofuran solution of a borane-tetrahydrofuran complex was added dropwise to the ml solution, followed by stirring at 20 ° C. for 16 hours. After the excess reducing agent was decomposed by adding 70 ml of methanol dropwise to the reaction solution under ice cooling, the solvent was distilled off under reduced pressure to obtain the desired product in the form of a complex with borane.

Reference Example 6 Production of 3,4-dihydro-2-naphthaleneethyl methanesulfonate:-

(1) A mixture of 50 g of 3,4-dihydro-2 (1H) -naphthalenone, 8.3 g of benzoic acid, 143 g of ethyl triphenylphosphoranylidene acetate and 200 ml of toluene was heated under reflux for 15 hours. The solvent was distilled off under reduced pressure, and after cooling the residue, diethyl ether was added. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (10: 1). The fraction containing ethyl 3,4-dihydro-2-naphthaleneacetate was collected, and concentrated under reduced pressure to give 58 g of the ester. Was obtained as an oil.

¹ H-NMR spectrum (60 MHz, CDCl ₃ , δ
ppm): 1.30 (t, 3H), 2.35 (t, 2H), 2.85 (t, 2H), 3.2
2 (s, 2H), 4.19 (q, 2H), 6.35 (br s, 1H), 6.95-7.3
0 (m, 4H).

(2) 45 g of the above ester compound was dissolved in 450 ml of anhydrous tetrahydrofuran, and stirred at 1.5 M under ice-cooling.
500 ml of toluene solution of diisobutylaluminum hydride
After dropwise addition, stirring was continued for another hour. A saturated aqueous solution of sodium potassium tartrate was added dropwise to the reaction solution to decompose excess reducing agent, and insolubles were removed by filtration and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform, and the fraction containing 3,4-dihydro-2-naphthaleneethanol was collected. After concentration under reduced pressure, 28 g of the ethanol compound was obtained as an oil.

¹ H-NMR spectrum (60 MHz, CDCl ₃ , δ
ppm): 1.70 (br s, 1H), 2.07-2.65 (4H, m), 2.97 (t,
2H), 3.85 (t, 2H), 6.35 (br s, 1H), 7.05-7.55 (m,
4H).

(3) 28 g of the above ethanol compound and 24.4 g of triethylamine were dissolved in 280 ml of dichloromethane, and 25 g of methanesulfonyl chloride was added dropwise with stirring under ice cooling.
Stirring was continued for another hour. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product as an oil.

Reference Example 7 Production of 1,2,3,4,7,8-hexahydro-2- (2-methanesulfonyloxyethyl) -6H-cyclopenta [g] naphthalen-1-yl methanesulfonate:

(1) 3,4,7,8-tetrahydro-6H
-Cyclopenta [g] naphthalen-1 (2H) -one 30
g was dissolved in 300 ml of tetrahydrofuran.
98 ml of a tetrahydrofuran solution of lithium diisopropylamide was added dropwise. After stirring for 30 minutes, 29.7 g of ethyl bromoacetate was added dropwise at -70 ° C, and the mixture was stirred at the same temperature for 2 hours and further at 20 ° C overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, 10% hydrochloric acid, and 10% aqueous sodium bicarbonate in that order, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain 43 g of ethyl 1,2,3,4,7,8-hexahydro-1-oxo-6H-cyclopenta [g] naphthalene-2-acetate as an oil.

(2) 20 g of the above ester compound was added to 200 ml of toluene.
Under ice-cooling, 85 g of a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride was added, and the mixture was stirred at 25 ° C for 6 hours. A saturated solution of sodium potassium tartrate was added to the reaction mixture under ice cooling, and the mixture was stirred for 1 hour. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (20:
The fraction containing 1,2,3,4,7,8-hexahydro-2- (2-hydroxyethyl) -6H-cyclopenta [g] naphthalen-1-ol was collected and concentrated under reduced pressure. Thus, 8.0 g of the diol was obtained as an oil.

¹ H-NMR spectrum (200 MHz, CDCl ₃ , δ
(ppm): 1.45-2.65 (m, 9H), 2.70-3.11 (m, 6H), 3.69-3.
95 (m, 2H), 4.47 (d, 1H), 6.95 (s, 1H), 7.40 (s, 1
H).

(3) 4.0 g of the above diol and 5.2 g of triethylamine were dissolved in 80 ml of dichloromethane, and 4.9 g of methanesulfonyl chloride was added dropwise under ice cooling, followed by stirring for 1 hour. The solvent was distilled off under reduced pressure to obtain the desired product as an oil.

Using 3,4,6,7-tetrahydro-furo [3,2-g] naphthalen-2 (1H) one, the reaction and treatment were carried out in the same manner as in Reference Example 7 to give 1,2,3,4 , 6,
7-hexahydro-2- (2-methanesulfonyloxyethyl) -furo [3,2-g] naphthalen-1-yl
Methanesulfonate was obtained as an oil.

Example 1 N-cyclopentyl- [2- (5-fluoro-3,4-
Preparation of dihydro-2-naphthalenyl) ethyl] amine:
−

The borane-5-fluoro-1,2,3,4-tetrahydro-2- [2- (cyclopentylamino) ethyl] -1-naphthalenol complex prepared in Reference Example 5 was added to p-toluenesulfonic acid / 1 Hydrate 4.0 g and toluene 80
Then, the mixture was heated and refluxed for 4 hours. After cooling, the reaction solution was washed with a 10% aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. A 35% ethanol solution of hydrogen chloride was added to the residue, and the solvent was distilled off under reduced pressure. The obtained crystals were recrystallized from ethyl methyl ketone to obtain the desired hydrochloride. 205-207 ° C

¹ H-NMR spectrum (60 MHz, CDCl ₃ , δ
ppm): 1.30-2.59 (m, 10H), 2.60-4.05 (m, 8H), 6.35
(br s, 1H), 6.62-7.75 (m, 3H), 10.20 (br s, 1H).

Examples 2 to 4 The corresponding borane-1,2,3,4-tetrahydro-2- [2- (cycloalkylamino) ethyl] obtained by reaction and treatment in the same manner as in Reference Example 5. Using -1-naphthalenol complexes, the reaction and treatment were carried out in the same manner as in Example 1 to obtain the compounds of Table 5 represented by Chemical Formula 12.

[0094]

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[0095]

[Table 5] Example R ¹ R ² q Melting point Recrystallization (℃) Solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 27-F H4 200-203 A3 7-F 6-F 4 235-238 A 47-Me 6-Me 4 234-236 EM ━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━

Example 5 N-cyclopentyl- [2- (3,4-dihydro-2-
Preparation of naphthalenyl) ethyl] amine:-

The 3,4-dihydro- produced in Reference Example 6
280 ml of acetonitrile and 72 g of cyclopentylamine were added to 2-naphthaleneethyl methanesulfonate, and the mixture was refluxed for 15 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform. The fractions containing the desired product were collected and concentrated under reduced pressure to obtain the desired product as an oil.

The free base was treated with a 35% ethanol solution of hydrogen chloride to form a hydrochloride in the same manner as in Example 1, and recrystallized from ethyl methyl ketone to obtain 28 g of the desired hydrochloride. 184-185 ° C

¹ H-NMR spectrum (60 MHz, CDCl ₃ , δ
ppm): 1.30-2.59 (m, 10H), 2.60-3.95 (m, 8H), 6.31
(br s, 1H), 6.72-7.80 (m, 4H), 10.41 (br s, 1H).

Examples 6 to 12 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 5 to obtain the compounds of Table 6 represented by Chemical Formula 13.

[0101]

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[0102]

[Table 6] 実 施 Implementation R ¹ R ² q Q Melting point Recrystallization example (℃) solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 6 H H 2 HCl · 0.1H 2 ^{O 148-152 DE *) 7 H H} 3 HCl 164-168 A-AC 8 H H 5 HCl 235-236 A 9 H H 6 HCl 207-210 A 10 7-O (CH 2) 2 -6 4 HCl 227 _{-229 EM 11 7- (CH 2)} 3 -6 4 HCl 215-217 EM 12 7- (CH 2) 3 -6 5 HCl 254-255 EM ━━━━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━━━ *) Crystallizing solvent

Example 13 Preparation of N-cyclopentyl-N-methyl- [2- (3,4-dihydro-2-naphthalenyl) ethyl] amine:-

(1) N-cyclopentyl- [2- (3,4
-Dihydro-2-naphthalenyl) ethyl] amine 1.0 g
0.15 g of paraformaldehyde in 10 ml of methanol
Was added thereto, and 0.68 g of sodium borohydride was added with stirring under ice cooling. The temperature was gradually raised to 25 ° C., and stirring was continued overnight. After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform, washed with water, a 1N aqueous sodium hydroxide solution and water in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and chloroform-methanol (10: 1)
The fractions containing the desired product were collected and concentrated under reduced pressure to obtain 0.67 g of the desired product as an oil.

¹ H-NMR spectrum (200 MHz, CDCl ₃ , δ
ppm): 1.30-1.95 (m, 8H), 2.30 (s, 3H), 2.20-2.45
(m, 4H), 2.56-2.86 (m, 5H), 6.21 (s, 1H), 6.90-7.1
6 (m, 4H).

(2) The above free base is dissolved in ethanol,
A 30% solution of hydrogen chloride in ethanol was added. Ethanol was distilled off under reduced pressure, and the obtained crystals were washed with diethyl ether to obtain the desired hydrochloride. 144-146 ° C

¹ H-NMR spectrum (200 MHz, (CD ₃ ) ₂ S
O, δppm): 1.42-1.80 (m, 6H), 1.80-2.12 (m, 2H),
2.24 (t, 2H), 2.66-2.85 (m, 6H), 3.28 (s, 1H), 3.0
2-3.38 (m, 2H), 3.50-3.75 (m, 1H), 6.36 (s, 1H), 6.
86-7.20 (m, 4H), 10.66 (br s, 1H).

Example 14 Preparation of Tablet:

N-cyclopentyl- [2- (3,4-dihydro-2-naphthalenyl) ethyl] amine hydrochloride (compound of Example 5) (15 g), corn starch (30 g), lactose (68 g) crystalline cellulose ( 30
g), hydroxypropylcellulose (5 g), light anhydrous silicic acid (1 g), and magnesium stearate (1 g).
g).

According to a conventional method, the above-mentioned components are mixed, granulated, and compression-molded to prepare 1,000 tablets of 150 mg each. Then, hydroxypropyl methylcellulose,
Using macrogol, titanium oxide, talc, and light anhydrous silicic acid, the skin is applied according to a conventional method to give a film-coated tablet.

Example 15 Preparation of powder:

N-cyclopentyl- [2- (3,4,
7,8-tetrahydro-6H-cyclopenta [g] naphthalen-2-yl) ethyl] amine hydrochloride (the compound of Example 11) (20 g), D-mannitol (935 g),
Hydroxypropyl cellulose (30 g), magnesium stearate (10 g), and light anhydrous silicic acid (5 g)
g).

According to a conventional method, the above components are mixed and granulated to prepare a 2% powder.

[0114]

As described above, N- represented by the formula (I)
Cycloalkyl- [ω- (3,4-dihydro-2-naphthalenyl) alkyl] amine derivatives and their physiologically acceptable acid addition salts have a strong anti-micturition reflex action, and are therefore used for treatment of pollakiuria and urinary incontinence. As a drug, it can be used for ameliorating symptoms of diseases caused by reduced urinary storage function of the bladder caused by various causes.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 307/92 C07D 307/92 317/58 317/58 319/18 319/18

Claims (12)

[Claims] 1. A compound represented by the following formula (I) or a physiologically acceptable acid addition salt thereof. Embedded image [Wherein R ¹ and R ² are the same or different and are a hydrogen atom, a halogen atom, a hydroxy group, a C ₁ -C ₅ alkyl group, a C ₁ -C ₃ alkoxy group, a hydroxymethyl group, a formyl group, a carboxy group Or a C ₁ -C ₃ alkoxycarbonyl group, or when R ¹ and R ² are bonded to adjacent carbon atoms, they are taken together to form a methylenedioxy group, an ethyleneoxy group (—CH ₂ CH ₂ O-), ethylenedioxy group, may form a trimethylene group or a tetramethylene group, R ³ is a hydrogen atom, a halogen atom, a trifluoromethyl group, C ₁ -C ₅ alkyl group, C ₁ -C
₃ means an alkoxy group or a phenyl group, R ⁴ is a hydrogen atom, C ₁ -C ₅ alkyl group, acyl group, C ₁ -C ₅ alkylsulfonyl group or an unsubstituted or substituted phenylsulfonyl group, R ⁵ is means C ₃ -C ₈ cycloalkyl group, p is an integer of 2-6. ] 2. R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a methyl group, an ethyl group, a propyl 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 together form a methylenedioxy, ethyleneoxy, ethylenedioxy, trimethylene or tetramethylene group; ^2. The compound according to claim 1, wherein ³ is a hydrogen atom, or a physiologically acceptable acid addition salt thereof. 3. The compound according to claim 2, wherein R ⁴ is a hydrogen atom and R ⁵ is a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, or a physiologically acceptable acid addition salt thereof. 4. R ¹ and R ² are bonded to the 7-position and 6-position, respectively, and are both hydrogen atoms or are the same or different and are a methyl group, an ethyl group, a methoxy group, an ethoxy group or a hydroxymethyl group. Or the compound according to claim 3, wherein R ¹ and R ² together form an ethyleneoxy group (6-CH ₂ CH ₂ O-7) or a trimethylene group, and p is an integer of 2 to 5. Its physiologically acceptable acid addition salts. 5. The compound according to claim 4, wherein p is 2, 3 or 4, or a physiologically acceptable acid addition salt thereof. 6. R ¹ is a hydrogen atom and R ² is a halogen atom at the 5-position, or R ¹ and R ² are a halogen atom bonded to the 7-position and 6-position, respectively, and R ³ and R ⁴ Is a hydrogen atom, and p is an integer of 2-5, or its physiologically acceptable acid addition salt. 7. The compound according to claim 6, wherein the halogen atom is a fluorine atom and p is 2, 3 or 4, or a physiologically acceptable acid addition salt thereof. 8. A compound represented by the following formula (Ia) or a physiologically acceptable acid addition salt thereof. Embedded image [Wherein R ^1a and R ^2a both represent a hydrogen atom,
Or the same or different, meaning a methyl or ethyl group, or R ^1a and R ^2a together forming an ethyleneoxy group (6-CH ₂ CH ₂ O-7) or a trimethylene group. ] 9. The compound according to claim 8, wherein R ^1a and R ^2a are both hydrogen atoms, or a physiologically acceptable acid addition salt thereof. 10. The compound according to claim 8, wherein R ^1a and R ^2a together form a trimethylene group, or a physiologically acceptable acid addition salt thereof. 11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a physiologically acceptable acid addition salt thereof as an active ingredient. 12. A therapeutic agent for pollakiuria and urinary incontinence, comprising the compound according to any one of claims 1 to 10 or a physiologically acceptable acid addition salt thereof as an active ingredient.