JP3000713B2 - Inner ear microcirculation improver containing dihydropyridine compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel agent for improving microcirculation of the inner ear.

[0002]

An object of the present invention is to provide an inner ear microcirculation improving agent containing a dihydropyridine compound or a pharmaceutically acceptable salt thereof.

[0003]

DETAILED DESCRIPTION OF THE INVENTION Wherein R ¹ is nitrophenyl, R ² , R ³ and R ⁴
Each represents a lower alkyl], or a pharmaceutically acceptable salt thereof.

[0004] Suitable pharmaceutically acceptable salts of compound (I) include, for example, inorganic bases such as alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), ammonium and the like. Salts with organic bases such as organic amines (eg, toluethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine); Conventional non-toxic salts.

[0005]

The dihydropyridine compounds (I) used in the present invention are known and are described, for example, in British Patent 2,033.
No. 6,722 and the like. Further, the pharmacological action of the dihydropyridine compound (I) has a vasodilatory action based on Ca ²⁺ antagonism, and is used as a therapeutic agent for angina pectoris or a hypotensive agent, or as a cerebral circulation improving agent or an anti-atherosclerotic agent. It is known to be useful as

[0006]

[Means for Solving the Problems] As a result of intensive studies, the present inventors have found that the dihydropyridine compound (I) or a pharmaceutically acceptable salt thereof can improve the microcirculation of the inner ear in addition to the above-mentioned actions. It has been found that the present invention also has an effect, and the present invention has been completed.

[0007] The effect of dihydropyridine compound (I) or a pharmaceutically acceptable salt thereof on the improvement of the inner ear microcirculation is a novel pharmacological action based on inhibition of microthrombus formation and prevention of spasm, which is considered to be the main cause of microcirculation disorder of the inner ear. It is considered that the above-mentioned effects are pharmacologically different. Therefore, an object of the present invention is to provide a novel inner ear microcirculation improving agent containing dihydropyridine compound (I) or a pharmaceutically acceptable salt thereof for improving and preventing inner ear microcirculation disorder. Diseases caused by inner ear microcirculation disorder include hearing loss, dizziness, and the like.

With respect to the dihydropyridine compound (I),
The definitions of R ¹ , R ² , R ³ and R ⁴ and preferred examples thereof will be described in detail below.

Preferable examples of "nitrophenyl" represented by R ¹ include 2-nitrophenyl, 3-nitrophenyl, and 4-nitrophenyl, and preferable examples thereof include 3-nitrophenyl.

Preferred examples of the "lower alkyl" represented by R ² , R ³ and R ⁴ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, pentyl, isopentyl, neopentyl, Or alkyl having 1 to 6 carbon atoms such as 2-methylbutyl, hexyl, etc., of which preferred examples are C ₁ -C ₄ alkyl, most preferred examples of R ² are isopropyl, R ³ and The most preferred example of each of R ⁴ is methyl.

The agent for improving microcirculation of the inner ear of the present invention can be administered to mammals including humans in capsules, microcapsules, tablets, granules, powders, troches, pills, ointments, suppositories,
It can be administered orally or parenterally in the form of conventional pharmaceutical preparations such as injections, syrups and the like.

The agent for improving microcirculation of the inner ear of the present invention includes excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.
Methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, binders such as starch, for example, starch, carboxymethylcellulose, hydroxypropyl starch, sodium hydrogen carbonate, calcium phosphate, disintegrants such as calcium citrate, for example Lubricants such as magnesium stearate, aerosil, talc, sodium lauryl sulfate and the like, for example, flavoring agents such as citric acid, menthol, glycine, orange powder and the like, preservatives such as sodium benzoate, sodium bisulfite, methylparaben, propylparaben, For example, stabilizers such as citric acid, sodium citrate, and acetic acid; for example, suspending agents such as methylcellulose, polyvinylpyrrolidone, and aluminum stearate; Dispersing agents such as Russia carboxymethyl cellulose, such as diluents such as water, for example cocoa butter,
It can be produced by a conventional method using various organic or inorganic carriers commonly used for formulation such as a base wax such as white petrolatum or polyethylene glycol.

The dose of the active ingredient compound (I) varies depending on various factors such as the weight and / or age of the patient and / or the degree of the disease and the route of administration. 0.5-100 per day
0 mg, preferably 1-500 mg, is administered. Effective single doses range from 0.01 to 20 per kg of patient weight.
mg, preferably in the range of 0.05 to 2 mg.

[0014]

In order to show the usefulness of the dihydropyridine compound (I) or a pharmaceutically acceptable salt thereof used in the inner ear microcirculation improving agent of the present invention, pharmacological test data of this compound are shown below.

Test 1: Test Method Male Wistar rats (body weight 240-260 g) were used, and after pentobarbital anesthesia, a rose bengal (RB) solution (saline dissolution 10 mg / ml) was introduced into the femoral vein at 24 μmoles. / Kg / hr
Inject at a speed of After starting continuous injection of Rose Bengal,
The left middle ear is opened, and electrodes are inserted by a round window lead method for recording an electrocochleogram. After incising the skin and muscles of the neck, the middle ear cavity is opened with a mini drill, and a silver ball electrode is inserted into a round window to make an active electrode. The indifferent and ground electrodes are inserted into the neck muscle near the active electrode. Thirty minutes after the start of the injection of the Rose Bengal aqueous solution, green light (540 nm) is guided from the light source to the outer wall of the cochlea using an optical fiber, and irradiated.
(L-3306-01A, manufactured by Hamamatsu Photonics). At this time, the tip of the fiber is fixed with a manipulator at a position about 5 mm away from the outer wall of the cochlea. Thereafter, the action potential (AP) is recorded every other minute. The recording of the electrocochleogram
Nihon Kohden's Neuropack II
II) using 8kHz click sound with 100dBSP
L is added 128 times. A solvent [mixture of polyethylene glycol 400 and water (volume ratio 1: 1)] or a test compound (dissolved in the same solvent) is injected intravenously 10 minutes before light irradiation.

Test compound 6-cyano-5-methoxycarbonyl-2-methyl-4
Isopropyl ester of-(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (hereinafter referred to as dihydropyridine compound A)

[0017]

Histologically, one hour after the light irradiation, the stria vascularis on the outer wall was damaged, and the hair cells were lost 24 hours after the irradiation. Robert Kimura (Robert Kimura)
[Annals of Otology, Rh.
innovation and Laryngology, 6
7 , pp6-24 (1958)]. Morphological ischemic changes were also observed, and the pre-administration of heparin (5 minutes before light irradiation) prolonged the AP elimination time. It is thought that the microcirculation of the stomach was disrupted.

Test 2: Test Method Under pentobarbital anesthesia, rats maintained at 37 ° C. with a heating pad are continuously infused with a rose bengal aqueous solution through the femoral vein. Open the middle ear and remove the eardrum, kinuta bone, and thigh bone so as not to damage the inner ear.
The green light is 540 nm light, which is guided by a fiber from a xenon lamp manufactured by Hamamatsu Photonics and irradiates the oval window. From the tip of the fiber to the outer wall, fix it at about 3 mm with a manipulator. Light irradiation is started 20 minutes after the start of the injection of rose bengal, and the test compound is dissolved in a mixture of polyethylene glycol 400 and water (volume ratio 1: 1) and administered intravenously at the start of the light irradiation. After the 40 spectral irradiations, the light irradiation and the continuous infusion of Rose Bengal are terminated, the wound is closed, and the patient is allowed to wait for the anesthesia to wake up. Twenty-four hours after the termination, the presence of nystagmus and a swimming test are performed to evaluate the imbalance.

Test compound Dihydropyridine compound A

[0021]

From the above results, the dihydropyridine compound A improves the microcirculation disorder of the inner ear, prolongs the disappearance time of the action potential (AP), suppresses the occurrence of nystagmus and impaired balance (vertigo), It is understood that it is useful as a microcirculation improving agent.

[0023]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below with reference to embodiments.

Example 1 Dihydropyridine compound A 100 g Hydroxypropyl methylcellulose 500 g Dihydropyridine compound A is dissolved in anhydrous ethanol (5 L), and hydroxypropylmethylcellulose is added to this solution to prepare a suspension. Next, the organic solvent is removed under reduced pressure to obtain a solid dispersion composition.

Example 2 Dihydropyridine compound A 100 g Hydroxypropyl methylcellulose 500 g Sucrose 9.4 kg Sucrose is added to a suspension of dihydropyridine compound A and hydroxypropylmethylcellulose in absolute ethanol (5 L) and the resulting mixture is stirred. Next, the organic solvent is removed under reduced pressure to obtain a solid dispersion composition. This composition is made into fine granules by a conventional method.

Example 3 Dihydropyridine compound A 100 g Hydroxypropyl methylcellulose 500 g Lactose 6.87 k
g Lower-substituted hydroxypropylcellulose 1.5 kg Magnesium stearate 30 g To a suspension of dihydropyridine compound A and hydroxypropylmethylcellulose in absolute ethanol (5 L), lactose and lower-substituted hydroxypropylcellulose were added, and the resulting mixture was stirred. Then, the organic solvent is removed under reduced pressure to obtain a solid dispersion composition. After granulating this composition by a conventional method, magnesium stearate is added to form a tablet by a conventional method. This tablet contains 2 mg of dihydropyridine compound A per tablet.

Example 4 Each tablet obtained in Example 3 was mixed with hydroxypropylmethylcellulose (5.1 mg) and titanium dioxide (1.6 m).
g), polyethylene glycol 6000 (0.8 m
g), talc (0.4 mg), yellow iron oxide (0.1 m
g), and 2 mg of dihydropyridine compound A per tablet.
To obtain a film-coated tablet.

Example 5 5-carboxy-2-cyano-6-methyl-4- (3-
After refluxing a solution of racemic (nitrophenyl) -1,4-dihydropyridine-3-carboxylate (16.7 g) and cinchonidine (14.4 g) in methanol (100 ml) for 15 minutes, the reaction solution is left at room temperature. . The resulting precipitate is collected by filtration, washed with methanol and air-dried,
(-)-5-carboxy-2-cyano-6-methyl-4
Cinchonidine salt of methyl- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate (11.74
g). The solvent of the mother liquor is distilled off under reduced pressure. The crystalline residue is washed with a mixture of ethyl acetate and diisopropyl ether, and 2N hydrochloric acid (40 ml) is added, followed by extraction with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 5-carboxy-.
2-cyano-6-methyl-4- (3-nitrophenyl)
Mixture of (+)-form and (-)-form of methyl-1,4-dihydropyridine-3-carboxylate (11.15 g)
Get. This mixture (11.15 g) and cinchonine (9.54 g) are dissolved in ethyl acetate under heating, and the solution is left at room temperature. The resulting precipitate is collected by filtration, washed with ethyl acetate, recrystallized from ethanol, and treated with (+)-
5-carboxy-2-cyano-6-methyl-4- (3-
A cinchonine salt of methyl (nitrophenyl) -1,4-dihydropyridine-3-carboxylate (7.62 g) is obtained.

Example 6 (+)-5-Carboxy-2-cyano-6-methyl-4
Cinchonine salt of methyl-(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate (7.41 g)
To a suspension of ethyl acetate (50 ml) in 2N hydrochloric acid (20 m
l) is added under stirring and then the aqueous layer is removed. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give (+)-5-carboxy-2-cyano-6-methyl-4- (3-nitrophenyl)-. 1,4
-Methyl dihydropyridine-3-carboxylate (3.67
g). _{NMR (DMSO-d 6, δ} ): 2.34 (3H,
s), 3.71 (3H, s), 5.13 (1H, s),
7.56-7.82 (2H, m), 7.91-8.25
(2H, m), 10.25 (1H, broad s)

Example 7 Phosphorus pentachloride (2.46 g) was converted to (+)-5-carboxy-2
-Cyano-6-methyl-4- (3-nitrophenyl)-
To a suspension of methyl 1,4-dihydropyridine-3-carboxylate (3.12 g) in methylene chloride (30 ml) is added under ice-cooling, and the mixture is stirred for 30 minutes. Then, methylene chloride (10 m) of isopropyl alcohol (1.4 g) was added thereto.
l) The solution is added dropwise over 10 minutes. After stirring for 20 minutes,
A 5% aqueous sodium carbonate solution (30 ml) is added to the reaction solution, and the mixture is stirred at room temperature for 1 hour. Separate the organic layer and extract the aqueous layer with methylene chloride. The combined organic layers are washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (75 g), eluting with a mixture of benzene and ethyl acetate (10: 1). The solvent of the eluate was distilled off under reduced pressure, and the residue was crystallized from diisopropyl ether to give (+)-2-cyano-6-methyl-4- (3-
(Nitrophenyl) -1,4-dihydropyridine-3,5
-5-isopropyl 3-methyl dicarboxylate (3.34
g).

Example 8 (-)-5-Carboxy-2-cyano-6-methyl-4- (3-nitrophenyl) -1,4 obtained in Example 5
Recrystallize the cinchonidine salt of methyl-dihydropyridine-3-carboxylate (11.74 g) from methanol to obtain a purified product (9.36 g). To a suspension of this product (9.05 g) in ethyl acetate (50 ml) is added 2N hydrochloric acid (20 ml) with stirring, then the aqueous layer is removed. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give (-)-5.
-Methyl carboxy-2-cyano-6-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridine-3-carboxylate (5.11 g) is obtained.

Example 9 In the same manner as in Example 7, (-)-5-carboxy-2-
Cyano-6-methyl-4- (3-nitrophenyl)-
Methyl 1,4-dihydropyridine-3-carboxylate (4.47 g) was reacted with phosphorus pentachloride (3.62 g) and isopropyl alcohol (2.5 g) to give (-)-
2-cyano-6-methyl-4- (3-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid 5
-Isopropyl 3-methyl (4.9 g) is obtained.

Claims (2)

(57) [Claims] 1. The formula: Wherein R ¹ is nitrophenyl, R ² , R ³ and R ⁴
Each represents a lower alkyl], or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1, wherein the dihydropyridine compound is 6-cyano-5-methoxycarbonyl-2-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid isopropyl ester. The agent for improving microcirculation of the inner ear according to the above.