JPH0138088B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula wherein R ₃ and R ₄ are independently alkoxy of 1 to 6 carbon atoms.

The above compounds are known, for example, from European Patent Application No. 78100165.6 and are said to be effective in the treatment of coronary insufficiency and hypertension.

This time, the compound of the formula is, surprisingly,
It was found to have other particularly valuable pharmacological activities.

The compound of formula increases cerebral blood flow, which was determined by the microsphere method to 30-50μ in anesthetized cats.
g/Kgi.v. or 50-150 μg/Kgi.d.

Additionally, about 0.4 to about 1.0 μ during carotid cannulation
g/min, these compounds significantly improve post-ischemic recovery in isolated rat heads ( Reference W. Wiernsperger, P. Gygax, O. Hunziker, A.
Schweizer, J. Pharmacol (Paris), 1979, 10,
4bis, 495).

Accordingly, compounds of the formula are effective in the treatment of cerebrovascular insufficiencies, such as cerebrovascular accidents, cerebrovascular spasms, and acute cerebrovascular insufficiencies, such as stroke.

Accordingly, the present invention provides a method of treatment for cerebrovascular insufficiency comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula. For the aforementioned uses, the dosage will, of course, depend on the compound used, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained with a daily dose of 0.01 to 10 mg/Kg animal body weight, conveniently a daily dose of 2 to 4 mg per day.
Administered in divided or delayed doses. For large mammals, the total daily dose ranges from about 5 to 100 mg, and dosage forms suitable for oral administration range from about 1.25 mg to about 1.25 mg mixed with a solid or liquid pharmaceutical carrier or diluent. Consists of approximately 50 mg of compound.

Furthermore, these compounds have calcium antagonistic activity, which can be determined by standard tests, e.g.
Godraind and Kaba, Brit.J.Pharm. 36 , 549−
560, 1969 by the inhibition of calcium-induced contraction of isolated canine coronary arteries suspended in depolarized solutions at concentrations of the compound from 10 ⁻¹⁰ to 10 ⁻⁸ molar. Therefore, these compounds are
As an antispasmodic agent, it is effective in treating smooth muscle spasms, such as cholic.

In another aspect, the invention provides a method for the treatment of spastic conditions comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula. For the aforementioned uses, the dosage will, of course, vary depending on the compound used, the method of administration and the treatment desired. However, in general,
A satisfactory result is 0.01-10 mg/Kg of animal body weight.
The daily dose is conveniently obtained in divided doses 2 to 4 times a day or in delayed form. For animals of large body weight, the total daily dose ranges from about 5 to 100 mg, and dosage forms suitable for oral administration include about 1.25 mg, mixed with a solid or liquid pharmaceutical carrier or diluent. ~50 mg of compound.

A preferred compound of the formula is 4-(2,1,3-
benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester.

A compound of formula can be administered per se or in the form of a pharmaceutical composition.

Tablets, capsules, hard gelatin capsules, dragees, powders, suspensions, syrups and elixirs can be used for oral administration. Injectable solutions or suspensions can be used for parenteral administration. Preferably, compounds of formula are administered orally, especially lingually or intravenously.

In addition to the compound of the formula, the pharmaceutical composition contains pharmaceutically inert organic or inorganic auxiliaries, optionally granulating agents, binders, lubricants, dispersants, wetting agents and preservatives. can contain. Additionally, the pharmaceutical compositions can contain coloring agents, flavoring agents, sweetening agents, and the like. Aids for the manufacture of tablets can include calcium carbonate, lactose, microcrystalline cellulose, mannitol or talc. Starch and alginic acid or microcrystalline cellulose as granulating and disintegrating agents, starch, polyvinylpyrrolidone and gelatin as binders, and magnesium stearate, stearic acid, colloidal silicon dioxide and talc as lubricants, respectively. Can be used. The tablet formulation may be double coated or uncoated, the coating may be applied by methods known per se and has the purpose of delaying disintegration and absorption in the gastrointestinal tract; This provides extended effects over a long period of time. Suspending agents suitable for the preparation of liquid dosage forms are, in particular, methylcellulose, tragacanth and sodium alginate. , suitable wetting agents are, for example, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate. Additionally, preservatives such as p-hydroxy-benzoic acid alkyl esters can be used. Capsule formulations can contain a compound of the formula by itself or together with inert diluents such as calcium phosphate, starch, lactose, mannitol, polyvinylpyrrolidone, colloidal silicon dioxide and microcrystalline cellulose.

Solid formulations are preferred, especially hard gelatin capsules and tablets, since they are easy to manufacture and convenient for administration.

The invention also provides a package containing a pharmaceutical composition containing a compound of formula, together with instructions for use in the methods of the invention.

Pharmaceutical compositions may consist of a plurality of unit dosage forms conveniently arranged to facilitate a particular daily dose or regimen.

A unit dose pharmaceutical composition can be in solid form, for example, a blister pack made of metal or plastic foil.

The following examples illustrate compositions for use in the present invention.

Example 1 Hard Gelatin Capsules for Oral Administration Hard gelatin capsules containing the ingredients listed below can be manufactured by conventional techniques and include:
It is effective in the treatment of cerebrovascular attacks or as an antispasmodic agent when administered as one or two capsules four times a day, or one capsule two to four times a day. Ingredient Weight 4-(2,1,3-Benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester
10.0mg Polyvinylpyrrolidone 30.0mg Lactose 208.5mg Magnesium Stearate 1.5mg 250.0mg Example 2 Hard Gelatin Capsules for Oral Administration Hard gelatin capsules containing the ingredients listed below can be manufactured by conventional techniques. I can do it,
It is effective in the treatment of cerebrovascular attacks or as an antispasmodic agent when administered as one or two capsules four times a day, or one capsule two to four times a day. Ingredient Weight 4-(2,1,3-Benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester
25.0mg Polyvinylpyrrolidone 19.0mg Lactose 241.0mg Emkalyx-Pluronic F68 10.0mg Polyethylene Glycol 6000 10.0mg 305.0mg Toxicity Acute toxicity of compounds can be determined by conventional methods.

4-(2,1,3-benzoxadiazole-4-
yl)-2,6-dimethyl-1,4-dihydro-
Pyridine-3,5-dicarboxylic acid diethyl ester has the following LD ₅₀ value for a 24 hour acute study.

LD ₅₀ (mg/Kg) po mice > 3000 LD ₅₀ (mg/Kg) iv mice 6.34 LD ₅₀ (mg/Kg) po rats > 3000 LD ₅₀ (mg/Kg) iv rats 6.31 Other compounds are equally well tolerated. Ru.

The aforementioned test for reduced cerebral blood flow (second test) investigated the onset of post-ischemic recovery for the specific compounds described above. Post-ischemic EEG recovery was shown to be sped up by a factor of 2-3 compared to controls (animals treated with saline solution were used as controls).

In the aforementioned calcium antagonism test, the compound
It has a pA ₂ of 10.5.

Comparison Test In the comparison test, DARODIPINE
(PY107−068) and NICAROPINE, the following two dihydropyridine dicarboxylic acid esters were compared, respectively.This invention Comparative example (JP-A-50-84576) The results are shown in Figures 1 and 2.

FIG. 1 is a dose-response curve for DARODIPINE, PY108-068 (invention).
Injury size measured 24 hours after MCAO (MRI
The drug efficacy in terms of brain wet weight (measured in 2000) and brain wet weight is described in relative values (±SEM, N=6-10, see below for calculations). Here, vehicle-injected MCA
(middle cerebral artery) occluded rats (control) and normal non-occluded rats have relative values of 1 and 0, respectively. Drugs were injected subcutaneously immediately after MCAO at the various doses indicated. The presence of edema in rats with MCA occlusion results in increased brain wet weight in the relevant hemisphere of the brain.

FIG. 2 is a similar dose-response curve for NICARDIPINE (comparative example).

Calculation of infarct size (IS) in the dose-response curve
infract size) and brain wet weight (BW)
Relative values for wstweight) were calculated as follows: Relative IS = IS[drug]/IS[control] Relative BW = (BW[left, drug] - BW[right, drug])/BW[left, control] -BW [right, control]) As is clear from Figures 1 and 2, in the rat model of embolic stroke (unilateral permanent occlusion [MCAO] of a midbrain artery),
DARODIPINE (PY108−068) of the present invention is an MRI
Measurements by magnetic resonance imaging (magnetic resonance imaging) and histology show that it reduces cerebral infarction size and has excellent cytoprotective effects. That is, the present invention
For DARODIPINE (PY108−068), for example, 10
A better effect in infarct size was obtained with a 20-30% improvement in mg/Kg. On the other hand, with NICARDIPINE as a comparative example, only a smaller effect was obtained, with a maximum improvement of 10% at 5 to 10 mg/Kg. As is clear from FIGS. 1 and 2, it can be concluded that DARODIPINE of the present invention is significantly different from NICARDIPINE of the comparative example in both efficacy and efficacy.

[Brief explanation of drawings]

FIGS. 1 and 2 are dose-response curves showing the drug efficacy on cerebral infarct size and wet brain weight in rats.

Claims (1)

[Claims] 1 formula A composition for the treatment of cerebrovascular insufficiency, comprising as an active ingredient a compound of the formula: wherein R ₃ and R ₄ are independently alkoxy of 1 to 6 carbon atoms. 2 The compound is 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-
The composition according to claim 1, which is dihydropyridine-3,5-dicarboxylic acid diethyl ester. 3. The composition according to claim 1 or 2 in unit dosage form containing 1.25 to 50 mg of active ingredient. 4 formula Claim 1, which is a composition for the treatment of cerebrovascular accidents, containing as an active ingredient a compound of the following formula: wherein R ₃ and R ₄ are independently alkoxy of 1 to 6 carbon atoms. Compositions as described. 5 The compound is 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-
The composition according to claim 4, which is dihydropyridine-3,5-dicarboxylic acid diethyl ester. 6. A composition according to claim 4 or 5 in unit dosage form containing 1.25 to 50 mg of active ingredient.