JP2003327534A - Therapeutic or preventive agent for pollakiuria or anischuria - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new therapeutic or preventive agent for pollakiuria or anischuria reduced in adverse effects. <P>SOLUTION: The therapeutic or preventive agent for pollakiuria or anischuria contains a quinolinoisoquinoline derivative such as 2-phenethyl-4aα-(3- hydroxyphenyl)-1,2,3,4,4a,5,12,12aβ-octahydro-quinolino[2,3-g]isoquinoline or the like or its pharmaceutically permissible acid-addition salt as an effective ingredient. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an agent for treating or preventing urinary frequency or urinary incontinence, which comprises a quinolinoisoquinoline derivative or a pharmaceutically acceptable acid addition salt thereof.

[0002]

2. Description of the Related Art In recent years, with the advent of an aging society, the number of patients suffering from frequent urination or urinary incontinence has been increasing year by year. Currently, propiverine hydrochloride, oxybutynin hydrochloride, and flavoxate hydrochloride, which have anticholinergic action and smooth muscle direct relaxing action, are mainly used as drug therapeutic agents for urinary frequency or urinary incontinence diseases.

However, these existing drugs are used for digestive symptoms such as dry mouth and constipation, cardiovascular symptoms such as orthostatic hypotension, urinary retention,
Urination disorders such as residual urine often occur as a side effect.

Cerebrovascular disorders and dementia are considered to be the largest causes of dysuria in the elderly. In recent years, by applying an existing drug having an anticholinergic effect to the treatment of urinary frequency or urinary incontinence associated with these brain diseases, the action of acetylcholine in the brain is suppressed, and there is concern that the brain disease itself may progress. ing.

The side effects of these existing drugs are unsatisfactory in the quality of life (QOL) of patients, and development of therapeutic or preventive agents for frequent urination or urinary incontinence without side effects is strongly desired.

On the other hand, as prior art of quinolinoisoquinoline derivatives, there are International Publication No. 9301186 and International Publication No. 9902157, including Japanese Patent Laid-Open No. 4-275288. These patents describe immunosuppressants, analgesics, antitussives, etc., but do not disclose therapeutic or preventive agents for urinary frequency or urinary incontinence.

[0007]

An object of the present invention is to provide a novel therapeutic or prophylactic agent for frequent urination or urinary incontinence with reduced side effects.

[0008]

As a result of earnest research, the inventors of the present application have found that a specific quinolinoisoquinoline derivative is effective for treating or preventing urinary frequency or urinary incontinence, and has few side effects. Completed the invention.

That is, the present invention has the general formula (I)

[0010]

[Chemical 2]

[Wherein R ¹ is hydrogen, alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 5 to 7 carbons, aralkyl having 7 to 14 carbons, carbon number 4-5 transalkenyl, allyl, furanyl-2-ylalkyl, thienyl-2-ylalkyl, alkanoyl having 1 to 5 carbon atoms, benzoyl,
Represents vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or arylalkanoyl having 8 to 14 carbon atoms, R ² is hydrogen or OR
⁶ (wherein R ⁶ represents hydrogen, alkyl having 1 to 5 carbons, or alkanoyl having 1 to 5 carbons), R ³ , R ^3
' Is independently alkyl having 1 to 5 carbons, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, alkoxycarbonyl having 1 to 3 carbons, alkylcarbonylamino having 1 to 3 carbons, Represents alkoxy having 1 to 5 carbons, nitro, amino, or alkylamino having 1 to 3 carbons, R ⁴ is hydrogen, hydroxy, alkoxy having 1 to 3 carbons, benzyl, or alkanoyl having 1 to 5 carbons; Represents halogen, X represents nitrogen or carbon, R ⁵ is present only when X is carbon, and has 1 to 5 carbon atoms.
Alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, alkoxycarbonyl having 1 to 3 carbon atoms, alkylcarbonylamino having 1 to 3 carbon atoms, alkoxy having 1 to 5 carbon atoms, nitro, Amino or alkylamino having 1 to 3 carbon atoms] or a quinolinoisoquinoline derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient. provide.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION A preferred embodiment of the therapeutic or prophylactic agent for urinary frequency or urinary incontinence comprising the isoquinoline derivative represented by the general formula (I) or a pharmaceutically acceptable acid addition salt thereof of the present invention. The form is as follows.

R ¹ is hydrogen, alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, 5 carbons
~ 7 cycloalkenylalkyl, aralkyl having 7 to 14 carbons, transalkenyl having 4 to 5 carbons, allyl, furanyl-2-ylalkyl, thienyl-2-ylalkyl, alkanoyl having 1 to 5 carbons, benzoyl,
Vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or arylalkanoyl having 8 to 14 carbon atoms is preferable, and hydrogen, methyl,
Ethyl, cyclopropylmethyl, allyl, phenethyl,
Furan-2-ylethyl and thiophen-2-ylethyl are preferred.

R ² is hydrogen or OR ⁶ (wherein R ⁶
Is hydrogen, alkyl having 1 to 5 carbons, or 1 to 5 carbons
Of alkanoyl) is preferable, and hydrogen, hydroxy, methoxy and ethoxy are particularly preferable.

R ³ and R ^{3 '} each independently have 1 to 1 carbon atoms.
5 alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, carbon number 1-3
Alkoxycarbonyl, C1-C3 alkylcarbonylamino, C1-C5 alkoxy, nitro, amino, or C1-C3 alkylamino are preferred, and especially methyl, hydrogen, chlorine, fluorine, bromine, iodine. ,
Hydroxy, methoxy, nitro, amino and dimethylamino are preferred.

R ⁴ is hydrogen, hydroxy or 1 carbon atom
Alkoxy, benzyl or alkanoyl having 1 to 5 carbon atoms and halogen are preferable, and hydrogen, hydroxy and methoxy are particularly preferable.

X represents nitrogen or carbon, R ⁵ is present only when X is carbon, and is alkyl having 1 to 5 carbon atoms,
Hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, alkoxycarbonyl having 1 to 3 carbon atoms, alkylcarbonylamino having 1 to 3 carbon atoms,
Alkoxy having 1 to 5 carbon atoms, nitro, amino, or alkylamino having 1 to 3 carbon atoms is preferable, and especially methyl,
Hydrogen, chlorine, fluorine, bromine, iodine, hydroxy, methoxy, nitro, amino and dimethylamino are preferred. Of course, the present invention is not limited to these.

The pharmacologically preferable acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide and phosphate, acetate, lactate and citrate. Acid, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate and other organic carboxylates, methanesulfonate, ethane Sulfonate, benzene sulfonate,
Organic sulfonates such as p-toluene sulfonate and camphor sulfonate are listed, and among them, hydrochloride, hydrobromide, phosphate, tartrate, methane sulfonate and the like are preferably used. However, this is also not limited to these.

The compounds represented by the present invention also include novel compounds represented by the following general formula (II).

[0020]

[Chemical 3]

[(A) In the formula, R ¹ is hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, or 7-1 to carbon atoms.
Aralkyl of 4, transalkenyl having 4 to 5 carbon atoms,
Allyl, furanyl-2-ylalkyl, thienyl-2-
Ylalkyl, alkanoyl having 1 to 5 carbon atoms, benzoyl, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or 8 to 14 carbon atoms
Of aryl alkanoyl, R ² is hydrogen or OR ⁶
(Wherein R ⁶ represents hydrogen, alkyl having 1 to 5 carbons, or alkanoyl having 1 to 5 carbons), and R ³ and R ^3
' Is independently alkyl having 1 to 5 carbon atoms, chlorine, fluorine,
Bromine, iodine, trifluoromethyl, cyano, hydroxy, C1-C3 alkoxycarbonyl, C1-C1
3 alkylcarbonylamino, a C1-5 alkoxy, represents nitro, amino, or alkylamino of 1 to 3 carbon atoms, R ⁴ represents hydrogen or alkyl of 1 to 3 carbon atoms, R ⁵ is the number of carbon atoms 1 to 5 alkyl, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, alkoxycarbonyl having 1 to 3 carbon atoms, alkylcarbonylamino having 1 to 3 carbon atoms, alkoxy having 1 to 5 carbon atoms, nitro , Amino, or alkylamino having 1 to 3 carbon atoms. Alternatively, in the formula (B), R ¹ is hydrogen,
Represents thienyl-2-ylalkyl, alkanoyl having 1 to 5 carbon atoms, benzoyl, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or arylalkanoyl having 8 to 14 carbon atoms, R ² is hydrogen or OR ⁶ (wherein OR ⁶ represents hydrogen, alkyl having 1 to 5 carbons, or alkanoyl having 1 to 5 carbons)
The stands, R ^3, R ^{3 'are} each independently alkyl of 1 to 5 carbon atoms, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, alkoxycarbonyl having 1 to 3 carbon atoms, carbon atoms 1 to 3 represents alkylcarbonylamino, alkoxy having 1 to 5 carbons, nitro, amino, or alkylamino having 1 to 3 carbons, R ⁴ represents hydrogen or alkyl having 1 to 3 carbons, and R ⁵ is Carbon number 1
~ 5 alkyl, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, alkoxycarbonyl having 1 to 3 carbon atoms, alkylcarbonylamino having 1 to 3 carbon atoms, alkoxy having 1 to 5 carbon atoms, nitro, It represents amino or alkylamino having 1 to 3 carbon atoms. ]

Further, the compound of the general formula (I) of the present invention is, for example, JP-A-4-275288 or International Patent Publication 99021.
57, the O-aminobenzaldehyde derivative (IVa) or the O-aminoacetophenone derivative (IVb) or the O-aminobenzonitrile (in the solvent, starting from the ketone body (III) in the presence of an acid catalyst. It can be obtained by condensation with IVc), and an optically active compound can be obtained by using an optically active substance as a raw material (Scheme 1).

[0023]

[Chemical 4] Scheme 1

The fact that the quinolinoisoquinoline derivative represented by the general formula (I) is effective in treating or preventing urinary frequency or urinary incontinence means that rhythmic bladder contraction motion is suppressed or urinary reflex is prolonged in animals. It can be confirmed by showing. The effect of suppressing rhythmic bladder contraction movement or the effect of prolonging the micturition reflex in animals has already been reported [Brain. Res., Vol. 297, 191 (1
984) or J. Pharmcol. Exp. Ther., Vol. 240, 978 (1
987)], but is not necessarily limited thereto.

The compound of the present invention can be used as a medicament useful for treating or preventing urinary frequency or urinary incontinence. In particular, neuropathy, neurogenic bladder disorders, nocturia,
It can be used for treating or preventing urinary disorders such as urinary frequency or urinary incontinence caused by overactive bladder, unstable bladder, nocturnal enuresis, bladder spasm, chronic cystitis, chronic prostatitis, prostatic hypertrophy, prostate cancer and the like. The neuropathic bladder disorder referred to here is a condition in which the nerves that control the lower urinary tract, which is the bladder, urethra, and external urethral sphincter, are impaired, resulting in abnormal urinary storage and voiding functions. Say. Diseases that damage nerves include cerebrovascular accidents, brain tumors, brain trauma, encephalitis, brain tumors, normal pressure hydrocephalus, dementia, Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy,
Olive / pons / cerebellar atrophy, Shy-Drager syndrome, spinal cord injury, spinal vascular disorder, spinal cord tumor, myelitis, cervical spinal cord compression disease, syringomyelia, multiple sclerosis, spina bifida, spinal meningocele, Tethered cord Syndrome, myelopathy, psychogenic urinary frequency, etc. Moreover, the same abnormality may occur due to aging. However, the use of the compound of the present invention is not limited to only these disease examples.

When the therapeutic or prophylactic agent for urinary frequency or urinary incontinence according to the present invention is clinically used as a medicine, the medicine may be a free base or its salt itself, and an excipient, a stabilizer, a preservative, Buffer, solubilizer, emulsifier, diluent,
Additives such as a tonicity agent may be appropriately mixed. As a dosage form, either parenteral administration or oral administration can be used. Examples of dosage forms include injections, tablets, solutions, capsules, granules and powders, and these dosage forms can be produced by known formulation techniques. The dose is appropriately selected according to the patient's symptoms, age, weight, administration method, etc., but the amount of the active ingredient for an adult is 0.0001 m / day.
g to 10 g, preferably 0.001 mg to 1 g,
Each can be administered once or divided into several times.

[0027]

EXAMPLES The present invention will be specifically described below with reference to Reference Examples and Examples. Reference Example 1 (4aS, 12aS) -2-Methyl-4a- (3-hydroxyphenyl) -1,2,3,4,4a, 5,12,
12a- octahydro - quinoline [2,3-g] isoquinoline 1 methanesulfonate This compound Hei 4-
It was synthesized by the method described in No. 275288.

Reference Example 2 2-Cyclopropylmethyl-4aα- (3-hydroxyphenyl) -1,2,3,4,4a, 5,12,12a
β- octahydro - quinolino [2,3-g] isoquinoline 2 methanesulfonate This compound Hei 4-27
It was synthesized by the method described in No. 5288.

Reference Example 3 2-Methyl-4aα- (3-methoxyphenyl) -11
-Amino-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline
3- Methanesulfonate 2-methyl-4aα- (3-methoxyphenyl) -6-
Oxo-1,2,3,4,4a, 5,6,7,8,8a
β-octahydroisoquinoline 150 mg (0.55 m
mol) and 130 mg of O-aminobenzonitrile (1.
10 mmol) was added to 5 mL of acetic acid, and the mixture was heated under reflux for 44 hours. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with a chloroform: methanol (4: 1) mixed solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was separated and purified by amine-coated silica gel column chromatography (chloroform: methanol = 50: 1) to obtain 83 mg of the title compound (yield 41%).

Reference Example 4 2-Methyl-4aα- (3-hydroxyphenyl) -1
1-amino-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline 4- methanesulfonate 2-methyl-4aα- (3-methoxyphenyl) -11-amino-1,2,3,4,4 obtained in Reference Example 3 4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline 83 mg (0.22 mmol), n
-Propanethiol 0.10 mL (1.060 mmo
l) was dissolved in 7 mL of DMF solvent under an argon atmosphere,
106 mg of potassium-t-butoxide (0.95 mmo
1) was added, and the mixture was heated with stirring at 120 ° C. for 20 hours. The mixture was acidified with 1N hydrochloric acid (4 mL) under ice-cooling, saturated aqueous sodium hydrogen carbonate solution was added to make the mixture alkaline again, and the mixture was extracted with a chloroform: methanol (4: 1) mixture. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was recrystallized from a dichloromethane-methanol mixture to give 35 mg of the title compound (yield 44
%). This was suspended in methanol, methanesulfonic acid was added for salification, the mixture was concentrated, ether was added, and the solid was filtered to obtain 40 mg of the methanesulfonate of the title compound.

Reference Example 5 2-phenethyl-4aα- (3-hydroxyphenyl)
-1,2,3,4,4a, 5,12,12aβ- octahydro - quinolino [2,3-g] isoquinoline 5 methanesulfonate 2- phenethyl -4aα- (3- hydroxyphenyl)
-6-oxo-1,2,3,4,4a, 5,6,7,
92 mg of 8,8aβ-octahydroisoquinoline (0.
26 mmol) and O-aminobenzaldehyde 95 mg
(0.78 mmol) and methanesulfonic acid 74 mg
(0.77 mmol) was added to 3 mL of ethanol, and the mixture was heated under reflux for 3 hours. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with a chloroform: methanol (3: 1) mixed solution. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was recrystallized from a mixed solution of dichloroethane: methanol to obtain 84 mg of the title compound (yield 74%). This is suspended in methanol, methanesulfonic acid is added to salify, and after concentration,
Ethyl acetate was added and the solid was filtered to obtain 90 mg of the methanesulfonate of the title compound.

The structural formulas of compounds 3 , 4 , and 5 described in Reference Examples, acid addition salts, and various spectral data are shown in the following list.

[0033]

[Table 1]

[0034]

[Table 2]

Example Effects on Rat Rhythmic Bladder Contraction Movement SD female rats were anesthetized by intraperitoneal administration of urethane (1.0 g / kg). After inserting a polyethylene tube into the bladder through the urethral opening of the animal and ligating and fixing it, physiological saline is appropriately injected from the tube (injection rate: about 0.2 ml / min, maximum about 1.5 ml / animal) to rhythmically contract the bladder. Was expressed. The rhythmic contractile movement of the bladder was monitored by measuring the intravesical pressure via a polyethylene tube inserted into the bladder. After confirming that stable rhythmic contraction movements were observed at least 10 times,
It was administered intravenously at a dose of l / kg. Bladder pressure within 10 minutes after administration of the test compound was 50% of that immediately after administration
In the following cases, it was determined that there was bladder contraction, and the time until the bladder pressure of 50% or more was again shown was defined as the rhythmic bladder contraction suppression time. Test compound 1 , 5 as a solvent for administration of the test compound
A physiological saline solution was used as the test compound, and 5% xylitol solution was used as the test compounds 2 and 4 . The 5% xylitol solution was also examined at a dose of 1 ml / kg. The results are shown in Table 3. In all compounds, the rhythmic bladder contraction inhibitory effect was observed as compared with the solvent used alone.

[0036]

[Table 3]

[0037]

The therapeutic or preventive agent for urinary frequency or urinary incontinence of the present invention has an excellent therapeutic or preventive effect for urinary frequency or urinary incontinence, and has few side effects.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 487/04 147 C07D 487/04 147 (72) Inventor Kuniaki Kawamura 1111 Tehiro, Kamakura-shi, Kanagawa Toray Co., Ltd. Corporate Research Laboratory, Pharmaceutical Research Laboratory (72) Inventor, Yasushi Miyauchi, 1111 Tehiro, Kamakura City, Kanagawa Toray Industries, Inc.F-Term (Reference) 4C050 AA01 AA07 AA08 BB07 BB08 CC07 EE02 EE03 FF02 FF03 FF05 GG02 GG02 GG04 HH01 4C065 AA05 BB09 BB12 CC09 DD02 DD03 EE02 HH02 HH04 HH09 JJ03 JJ05 KK08 LL02 LL05 4C086 AA01 AA02 BC27 CB09 NA06 NA14 ZA81

Claims (2)

[Claims] 1. A compound represented by the general formula (I): [Wherein R ¹ is hydrogen, alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 5 to 7 carbons, aralkyl having 7 to 14 carbons,
C4-C5 transalkenyl, allyl, furanyl-2-ylalkyl, thienyl-2-ylalkyl, C1-C5 alkanoyl, benzoyl, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or C8. To aryl alkanoyl, R ² represents hydrogen or OR ⁶ (wherein R ⁶ represents hydrogen, alkyl having 1 to 5 carbons, or alkanoyl having 1 to 5 carbons), R ³ , R ^{3 '} Is independently alkyl having 1 to 5 carbons, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, alkoxycarbonyl having 1 to 3 carbons, alkylcarbonylamino having 1 to 3 carbons, Represents alkoxy having 1 to 5 carbon atoms, nitro, amino, or alkylamino having 1 to 3 carbon atoms, R ⁴ is hydrogen, Hydroxy, alkoxy having 1 to 3 carbons, benzyl, or alkanoyl having 1 to 5 carbons, halogen, X represents nitrogen or carbon, R ⁵ is present only when X is carbon, and has 1 to 5 carbons. Alkyl, hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, cyano, hydroxy, alkoxycarbonyl having 1 to 3 carbon atoms, alkylcarbonylamino having 1 to 3 carbon atoms,
Represents an alkoxy, nitro, amino having 1 to 5 carbon atoms, or alkylamino having 1 to 3 carbon atoms] or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. A therapeutic or preventive agent for urine or urinary incontinence. 2. In the general formula (I), R ¹ is hydrogen, methyl, ethyl, cyclopropylmethyl, allyl, phenethyl, furan-2-ylethyl or thiophen-2-ylethyl, and R ² is hydrogen, hydroxy, Methoxy or ethoxy, R ³ , R ^{3 '} is independently methyl, hydrogen, chlorine, fluorine, bromine, iodine, hydroxy, methoxy, nitro, amino or dimethylamino, R ⁴
Is hydrogen, hydroxy or methoxy, X is carbon and R ⁵ is methyl, hydrogen, chlorine, fluorine, bromine, iodine, hydroxy, methoxy, nitro, amino or dimethylamino. Treatment or prevention agent for urinary incontinence.