JPH03251531A - Peripheral circulatory improver containing dihydropyridine compound - Google Patents

Abstract

PURPOSE:To obtain a peripheral circulatory improver containing a specific dihydropyridine compound or salt thereof. CONSTITUTION:The aimed improver contains a compound expressed by the formula (R<1> is nitrophenyl; R<2> to R<4> are lower alkyl) or pharmaceutically acceptable salt thereof such as isopropyl 6-cyano-5-methoxycarbonyl-2-methyl-4-(3- mitrophenyl)-1,4-dihydropyridine-3-carboxylate as an active ingredient. The compound has action capable of improving deformation of erythrocyte and is useful in treatment and prevention of peripheral circulatory deficiency and used in the range of normally 0.5-1000mg, preferably 1-500mg per day according to oral administration.

Description

[Detailed description of the invention] "Industrial application field" The present invention relates to a novel peripheral circulation improving agent.

More particularly, the invention relates to compounds of the formula: [wherein R1 is nitrophenyl, R2, R3 and R4
each represents lower alkyl] or a pharmaceutically acceptable salt thereof.

2) The dihydropyridine compound is 6-diaz-5-me,
Toxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid isopropyl ester [wherein R is nitrophenyl, R2, R3 and R4 are each The present invention relates to a novel peripheral circulation improving agent containing a dihydropyridine compound represented by [meaning lower alkyl] or a pharmaceutically acceptable salt thereof.

Suitable pharmaceutically acceptable salts of compound (I) include conventional non-toxic salts, such as alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., calcium, magnesium, etc.), ammonium salts, etc. salts with inorganic bases such as organic amines (e.g. toluethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N
-N'-dibenzylethylenediamine, etc.);

"Prior Art" The dihydropyridine compound (I) used in the present invention is known and is described, for example, in British Patent No. 2.036.722. In addition, dihydropyridine compounds (
As for the pharmacological action of I), it has a vasodilatory action based on Ca2+1 anti-action, and is useful as an angina treatment agent or antihypertensive agent, or as a cerebral circulation improving agent or an anti-arteriosclerotic agent. Are known.

[Means for Solving the Problems] As a result of intensive research, the inventors of the present invention found that dihydropyridine compound (1) or a pharmaceutically acceptable salt thereof is
In addition to the above-mentioned effects, it has an effect of improving red blood cell deformability,
Therefore, they found that it is useful as a peripheral circulation improving agent and completed this invention.

The peripheral circulation improving effect of dihydropyridine compound (I) or a pharmaceutically acceptable salt thereof is a new pharmacological effect, and can be said to be pharmacologically different from the above-mentioned effects.

Therefore, an object of the present invention is to provide a novel peripheral circulation improving agent containing dihydropyridine compound (I) or a pharmaceutically acceptable salt thereof for the treatment and prevention of peripheral circulation failure.

Regarding the dihydropyridine compound (I), the definitions of R13 RR and R4 and preferred examples thereof will be explained in detail as follows.

Preferred examples of "nitrophenyl" represented by R1 include 2-nitrophenyl, 3-nitrophenyl, and 4-nitrophenyl, and a preferred example thereof is 3-nitrophenyl.

3 Suitable examples of "lower alkyl" represented by RR and R4 include methyl, ethyl, propyl, isopropyl,
Alkyl having 1 to 6 carbon atoms such as butyl, isobutyl, sec-butyl, pentyl, impentyl, neopentyl, 1- or 2-methylbutyl, hexyl, etc., and preferred examples thereof include C1-04 alkyl. However, the most preferred example of R2 is isopropyl;
The most preferred example of each of 3 and R4 is methyl.

The peripheral circulation improving agent of this invention can be applied to mammals including humans,
It can be administered orally or parenterally in the form of conventional pharmaceutical preparations such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, ointments, tablets, injections, syrups, etc. .

The peripheral circulation improving agent of the present invention includes excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, and calcium carbonate, such as cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, and gelatin. , gum arabic, polyethylene glycol, sucrose, binders such as starch, carboxymethyl cellulose, hydroxypropyl starch,
Disintegrants such as sodium bicarbonate, calcium phosphate, calcium citrate, e.g. magnesium stearate,
Lubricants such as Aerosil, talc, sodium lauryl sulfate, flavoring agents such as citric acid, menthol, glycine, orange powder, etc., preservatives such as sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc., such as citric acid, Stabilizing agents such as sodium citrate, acetic acid, suspending agents such as methylcellulose, polyvinyl and lolidon, aluminum stearate, dispersing agents such as hydroxypropyl methylcellulose, diluents such as water, such as cocoa butter, white petrolatum, etc. It can be produced by conventional methods using various organic or inorganic carriers commonly used in formulations, such as base waxes such as polyethylene glycol and the like.

The dosage of the active ingredient compound (I) is determined depending on the patient's weight and/or
Although it varies depending on various factors such as age and/or severity of disease and the route of administration, it is usually administered orally in an amount of 0.5 to 1000 mg, preferably 1 to 500 mg per day. An effective single dose is
ranging from 0.01 to 20 mg/kg of patient body weight,
It is preferably selected within the range of 0.05 to 2 mg.

"Effect of the invention" As is well known, normal red blood cells have a diameter of 7.5-8.0 μm.
It is approximately 2.2 μm thick and has a disk shape with concave central portions at both ends. On the other hand, the capillary bed forming the microcirculation has a diameter of about 2-3 μm and a length of 14 μm or more, and red blood cells pass through this narrow channel with a pressure of 0.2-3 mm of water column. During passage through such capillaries, red blood cells must change their shape, and their ability to deform, or red cell deformability,
It is known that the quality of y) has important meaning for microcirculation at the capillary level. In particular, the significance of the quality of red blood cell deformability is important in peripheral arterial occlusive diseases where peripheral blood flow is severely insufficient.For example, Raynaud syndrome, arteriosclerosis obliterans (A
It has also been revealed that the deformability of red blood cells in peripheral arterial occlusive diseases such as SO) and Buerger's disease is significantly lower than that in a healthy control group.

Diseases induced by peripheral circulation failure include Raynaud's syndrome, arteriosclerosis obliterans, and thrombovasculitis obliterans (T
AO) or Bersher's disease, and diabetic microangiopathy (DM) or diabetic scarring (DG).

The deformability of red blood cells is thought to be mainly determined by the following three factors.

(1) Properties of red blood cell membrane (viscoelasticity) (2) Geometric shape of red blood cell (surface area/volume ratio, S/■
(ratio) (3) Internal viscosity (internal state such as hemoglobin concentration) However, in vivo, these factors are not independent but often influence each other.

Methods for measuring deformability can be roughly divided into the following three types depending on the principle of measurement.

(1) To observe changes in viscosity and morphology when a suspended liquid is made to flow. (2) To observe deformation by fixing a part of red blood cells and applying stress. (3) To observe the degree of passage through a certain pore. The inventors of the present invention have proposed the above measurement principle (1) as a measurement method.
), the deformability of red blood cells was measured using a method based on the above method, and the usefulness of the peripheral circulation improving agent of the present invention was confirmed, thereby completing the present invention.

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

Test method: An experiment was conducted using four rabbits (3.5 kg in weight).

Rabbits in each group were fed a standard diet containing 1% cholesterol (manufactured by Oriental Yeast) and water ad libitum for 2 weeks. The test compound was dissolved in a mixed solvent of ethyl alcohol and polyethylene glycol 400 (volume ratio 1:1) and administered subcutaneously once a day. To the control group, only the same amount of mixed solvent was administered in the same manner.

Heparinized blood was collected from the ear artery before and after administration. Red blood cell counts were counted using a mixing pipette and Thoma's counting plate.

Deformability measurement is a life science (Life, Sci,
) 45, p. 1089, helium-neon laser (helit+m-neon 1a
ser) and a laser diffraction method using a flat cell.

10 red blood cells were placed in a phosphate buffer (pH 7,4290mOs) containing 15% dextran (average molecular weight 40,000).
m) Float in 10ml, flat cell (0,20X
7 x 25 mm3) using a syringe pump. Helium-neon perpendicular to this flat cell
1aser was transmitted and a diffraction image was obtained on a screen. Photodiodes are placed on the X and Y axes on the screen.
(1,0 x 370m) and calculate the light intensity (light + intensity) of each
The deformability index (DI=L−W/L+W) was determined using a computer as W. The data are expressed as 100% of the DI at the maximum shear stress of the control (%DI).

The results are expressed as the standard deviation above the mean, and the significance test was performed using 5ch.
The method of effe was used.

Koshi1''i1so6-dia2-5-methoxycarbonyl-2-methyl-4
-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid isopropyl ester (hereinafter referred to as dihydropyridine compound A) Test results Red blood cell deformability (%DI) As is clear from this result, dihydropyridine compound A Under physiological shear stress (3 dyne/cm2) or higher, it significantly suppresses the decline in blood red cell deformability caused by cholesterol diet and is useful for improving peripheral circulation.

"Example" The present invention will be explained below according to examples.

Cold nose ■ Dihydropyridine Compound A 100g Hydroxypropyl methylcellulose 500g Dihydropyridine Compound A is dissolved in absolute ethanol (5 liters), and hydroxypropylmethylcellulose is added to this solution to prepare a suspension. Then, the organic solvent is removed under reduced pressure to obtain a solid dispersion composition.

Dihydropyridine Compound A 100 g Hydroxypropyl methylcellulose 500 g Sucrose 9.4 kg Dihydropyridine Compound A and hydroxypropyl methylcellulose are suspended in absolute ethanol (5 kts) by adding sucrose and stirring the resulting mixture. Then, 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.

Kansan ■ Nidihydropyridine Compound A 100g Hydroxypropyl methylcellulose 500g Lactose 6.87kg Lower substituted hydroxypropylcellulose 1.5kg Magnesium stearate 30g Dihydropyridine compound @ A and human dihydropyridine compound A in absolute ethanol (5 liters) as a cloudy solution , lactose and lower substituted hydroxypropyl cellulose are added, the resulting mixture is stirred, and the organic solvent is then removed under reduced pressure to obtain a solid dispersion composition. This composition is made into granules by a conventional method, and then magnesium stearate is added thereto to form tablets by a conventional method. This tablet contains 2 mg of dihydropyridine compound A per tablet.

"Cold Nose ■" Each tablet obtained in Example 3 was mixed with hydroxypropyl methylcellulose (5.1 mg) and titanium dioxide (1.6 mg).
mg), polyethylene glycol 6000 (0,8
mg), talc (0.4 mg), yellow iron oxide (0.4 mg), yellow iron oxide (0.4 mg), talc (0.4 mg),
A film-coated tablet containing 2 mg of dihydropyridine compound A per tablet is obtained by film-coating with a coating layer consisting of 1 mg) using a conventional method.

Example 5 A dextrorotatory dihydropyridine compound A was used in place of the dihydropyridine compound A, and the same procedure as in Example 3 was used to obtain 1.
Tablets containing 2 mg of crude drug in the tablet are manufactured.

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Claims (1)

[Scope of Claims] 1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is nitrophenyl, and R^2, R^3 and R^4 each mean lower alkyl. ] A peripheral circulation improving agent containing a dihydropyridine compound or a pharmaceutically acceptable salt thereof. 2) Claim 1) wherein the dihydropyridine compound is isopropyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid. Peripheral circulation improving agent as described in section.