JPH0784384B2 - Treatment for ischemic brain damage - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD The present invention relates to a therapeutic agent for ischemic brain damage, which contains a 1,2-benzisoxazole derivative as an active ingredient.

Background Art Unlike other organs, the brain exists in a special environment immersed in cerebrospinal fluid within rigid bodies such as the skull and cerebral infarction, and is one of the organs with the most active energy metabolism, with the highest oxygen consumption rate of all organs. Most of the energy required by brain neurons is supported by oxygen and glucose, and these energy sources are hardly stored in the brain and are constantly supplied from the blood.
Therefore, in order to provide a stable energy source for brain tissue and maintain a constant external environment for brain neurons, the cerebral blood vessels themselves have a well-developed mechanism for regulating cerebral blood flow. When the brain's homeostatic mechanism is disrupted by physical pressure from hematomas, tumors, or brain trauma, cerebral ischemia occurs, and brain neurons are exposed to a hypoxic state, preventing them from functioning normally. When brain neurons are in a state of oxygen deficiency (hereinafter referred to as "cerebral hypoxia"),
This causes changes in the permeability of brain nerve cell membranes,
Edema is caused by the infiltration of extracellular fluid. When cerebral edema increases beyond a certain level, intracranial pressure increases, causing cerebral circulatory disorders. This in turn increases cerebral hypoxia, glucose deficiency, and the accumulation of its metabolites, further promoting cerebral edema.
Cerebral edema and increased intracranial pressure become even more severe, causing pressure on the brainstem and obstruction of cerebrospinal fluid flow, which in turn creates a vicious cycle of increased cerebral hypoxia, accelerated cerebral edema, and increased intracranial pressure.As a result, the lesion expands, and even healthy brain tissue develops cerebral hypoxia, leading to cerebral circulatory failure and severe damage.
Cerebral hypoxia is the common denominator of most diseases based on cerebral circulatory disorders [Eur. Neurol., 17 (Supple. 1), 113-120 (197
8)] is why it is called

With the advent of an aging society, senile dementia is becoming a major social problem, and the overwhelming majority of cases of senile dementia are cerebrovascular dementia, Alzheimer's dementia, and a mixture of the two. Cerebrovascular dementia appears as a sequela of cerebrovascular disease, and one of the causes is thought to be brain neuron damage caused by cerebral ischemia during an attack. Therefore, drugs that have a preventive effect against brain neuron damage that occurs after transient cerebral ischemia, i.e., a cytoprotective effect, are expected to be useful in the prevention and treatment of senile dementia.

It is known that 3-sulfamoylmethyl-1,2-benzisoxazole and its alkali metal salts are useful as antiepileptic agents [see, for example, Arzheim.-Forsc
h./Drug Res., 30 (I), 477-483 (1980) and U.S. Pat. No. 4,172,896. Meanwhile, it has been reported that typical antiepileptic drugs, phenytoin and carbamazepine, are effective against cerebral hypoxia [Arch. in
t.Pharmacodyn., 286 , 282-298 (1987)].

Currently, hypnotic anesthetics such as phenobarbital and thiobarbital are used to treat ischemic brain damage. Hypnotic anesthetics suppress neural activity in the brain, reducing the energy demand of nerve cells themselves and exerting a protective effect on nerve cell function. In other words, hypnotic anesthetics forcibly suppress nerve cell function to a level below normal,
Therefore, in order to expect the desired effect, it is necessary to administer an amount of medication that can exert a suppressive effect on the central nervous system as a whole, which results in adverse side effects such as adverse effects on the respiratory and circulatory systems due to suppression of the respiratory and blood pressure control centers.

The present inventors have found that 3-sulfamoylmethyl-1,2-benzisoxazole or its alkali metal salt exhibits a strong protective effect against cerebral hypoxia without the side effects seen in hypnotic anesthetics, and further that, while phenytoin and carbamazepine only exhibit a relatively weak protective effect against neuronal damage in the hippocampus, an important region of the brain that controls emotions, memory, etc., 3-sulfamoylmethyl-
It has been found that 1,2-benzisoxazole or its alkali metal salts exhibit extremely strong protective effects.

DISCLOSURE OF THE INVENTION The present invention provides a therapeutic agent for ischemic brain damage, which comprises 3-sulfamoylmethyl-1,2-benzisoxazole or an alkali metal salt thereof as an active ingredient.

Specific examples of alkali metal salts of 3-sulfamoylmethyl-1,2-benzisoxazole include sodium salts, potassium salts and lithium salts.

3-sulfamoylmethyl-1,2-benzisoxazole (hereinafter sometimes referred to as "the active compound of the present invention")
and its alkali metal salts are known compounds as mentioned above, and can be prepared, for example, according to the method described in U.S. Patent No. 4,172,896. The active compound of the present invention is represented by the following chemical structural formula:

As is evident from the results of the following pharmacological tests, the active compound and its alkali metal salt of the present invention exhibit excellent pharmacological activity, supporting their usefulness as therapeutic agents for ischemic brain damage. Specifically, the active compound and its alkali metal salt exhibit potent protective effects against cerebral hypoxia at extremely low doses. Furthermore, the active compound and its alkali metal salt exhibit extremely potent protective effects against cellular damage in the hippocampus, an important region of the brain responsible for emotion, memory, and other functions. Furthermore, unlike the hypnotic anesthetics conventionally used to treat ischemic brain damage, they do not exert protective effects on neuronal function by suppressing neuronal activity in the brain, and therefore do not cause side effects such as respiratory depression or circulatory failure due to general suppression of the central nervous system. Furthermore, while hypnotic anesthetics are limited to acute administration, the active compound and its alkali metal salt of the present invention do not exhibit hypnotic anesthetic activity, and therefore can be administered not only in the acute phase but also in the chronic phase and for the purpose of preventing recurrence of attacks. The active compound and its alkali metal salt of the present invention also have low toxicity and are therefore highly safe.

Test Example 1 Anti-cerebral hypoxia effect (1) Effect of extending the mouth opening movement time due to complete ischemia This test was conducted in accordance with the method described in Arch. int. Pharmacodyn., 233 , 136-144 (197
8) was carried out in accordance with the method described above.

Five STD-ddY male mice (weight 22-26 g) were used in each group. The required amount of test compound was suspended in 0.5% tragacanth solution and orally administered at a rate of 0.1 ml per 10 g of mouse body weight. Two or one hour (in the case of carbamazepine) after administration, the neck of each mouse was cut with decapitation scissors, and the duration until the jaw opening movement exhibited by the isolated head disappeared was measured. The control group received the same volume of 0.5% tragacanth solution. The dose of test compound required to extend the duration of jaw opening movement by 15% compared to the control group ( _PD15 ) was calculated using the dose-response relationship. The results are shown in Table 1.

(2) Survival-prolonging effect on mice induced by normobaric hypoxia. This study was conducted at Naunyn-Schmiedeberg's Arch. Pharmacol.,
334 , 282-289 (1986).

Five STD-ddY male mice (weight 22-25 g) were used in each group. The required dose of test compound was suspended in 0.5% tragacanth solution and orally administered at a rate of 0.1 ml per 10 g of mouse body weight. Two or one hour (in the case of carbamazepine) after administration, each mouse was placed in a 2.5-volume plastic container, which was aerated with a mixture of 4% oxygen and 96% nitrogen at a rate of 4/min. The time until death (cessation of breathing) was measured. The control group received the same volume of 0.5% tragacanth solution orally. The dose of test compound required to prolong the time until respiratory cessation by 30% compared to the control group ( _PD30 ) was calculated using the dose-response relationship. The results are shown in Table 1.

As is clear from Table 1, the active compounds of the present invention exhibited anti-cerebral hypoxia activity almost equivalent to that of phenobarbital, phenytoin and carbamazepine.

Test Example 2 Protective Effect Against Delayed Neuronal Necrosis in the Hippocampal CA1 Region This test was carried out according to the method described in Prairie Res., 239 , 57-69 (1982).

Groups of five or six male gerbils (65-85 g body weight) were used. The required dose of test compound was suspended in 0.5% tragacanth solution and orally administered at a rate of 0.2 ml per 100 g of gerbil body weight. The control group received the same volume of 0.5% tragacanth solution. One hour after administration, the gerbils' necks were anesthetized with ether, and a midline incision was made. The left and right common carotid arteries were exposed, and blood flow in both common carotid arteries was blocked with Zen clips. Blood flow was blocked for 5 minutes, and then the clips were released to allow blood flow to resume. A sham-operated group was also anesthetized, but without the blood flow blocking or recanalization procedures. Four days later, the gerbils were anesthetized with pentobarbital, and a fixative [2.5% glutaraldehyde and 2% formaldehyde in 0.1 M phosphate buffer (pH 7.0)] was injected into the left atrium.
4)] were perfusion-fixed at a perfusion pressure of 120 cm _H2O , and the brains were removed. After leaving the brains in fixative for 1 day, tissue sections containing the dorsal hippocampus were dehydrated, cleared, and embedded in paraffin. 4-μm-thick sections, corresponding to 0.5–1.0 mm from the apical end of the hippocampus or 1.4–1.9 mm posterior to the sagittal suture, were prepared from the paraffin blocks and stained with hematoxylin and eosin. The number of remaining pyramidal neurons in the hippocampal CA1 region of the tissue specimens was counted at 200x magnification using an image processor (Imaging Research, Canada, Model MCID), and the remaining neuronal density per ^mm2 of the pyramidal cell layer in the left and right hippocampi was calculated. The results are shown in Table 2. The values in the table represent the average of the left and right remaining neuronal counts for each individual. Statistical tests were performed using the Student's t-test.

As is clear from Table 2, the active compound of the present invention was administered at 30 mg/kg.
At a dose of 100 mg/kg, phenytoin and carbamazepine showed a very strong protective effect against delayed neuronal necrosis in the hippocampal CA1 region, and at 100 mg/kg, they almost completely prevented delayed neuronal necrosis. In contrast, phenytoin and carbamazepine showed relatively weak protective effects even at a dose of 100 mg/kg.

Test Example 3 Hypnotic Anesthetic Action This test was carried out according to the method described in Japan. J. Pharmacol., 13 , 259-273 (1963).

5-10 STD-ddY male mice (weight 22-26g) per group
The required amount of test compound was suspended in 0.5% tragacanth solution and orally administered to mice at a rate of 0.1 ml per 10 g of body weight. After administration, the mice were monitored over time for loss of righting reflex. If the loss of righting reflex persisted for 60 minutes or more, it was considered to be an anesthetic effect, and the dose that produced the effect in 50% of the animals (HD ₅₀ ) was calculated using the probit method. The results are shown in Table 3.

Test Example 4 Acute Toxicity: 1 group: 5 to 10 STD-ddY male mice (weight: 22 to 26 g)
The required amount of test compound was suspended in 0.5% tragacanth solution and orally administered to mice at a rate of 0.2 ml per 10 g of body weight. After administration, the animals were observed for survival for 7 days, and the dose of test compound at which 50% of the animals died (LD ₅₀ ) was determined.
was calculated using the probit method. The results are shown in Table 3.

As is clear from Table 3, the hypnotic and anesthetic action of the active compound of the present invention was about 1/10 as strong as that of phenobarbital.
Moreover, its toxicity was also low.

The active compound of the present invention and its alkali metal salts exhibit a strong anti-cerebral hypoxia effect that is well separated from the hypnotic anesthetic effect, and also exhibit a very strong cytoprotective effect, and their toxicity is low, so they can be used for the prevention and treatment of intracranial diseases in mammals (including humans) caused by cerebral ischemia or various accompanying symptoms.Specific examples of intracranial diseases include cerebral infarction (cerebral thrombosis, cerebral embolism), intracerebral hemorrhage, subarachnoid hemorrhage, head trauma, brain tumor, encephalomeningitis, and cerebral edema, and specific examples of symptoms associated with intracranial diseases include impaired consciousness, neurological disorders, dementia, subjective symptoms (dizziness, headache, migraine, nausea,
These include increased intracranial pressure during or after brain surgery (e.g., vomiting), and increased intracranial pressure during or after brain surgery. The route of administration may be oral, parenteral, or rectal. The dosage of the active compound of the present invention or its alkali metal salt varies depending on the route of administration, the type of disease, the severity of symptoms, the age of the patient, etc., but is usually 1 to 50 mg/kg/day, and can be administered in a single dose or in divided doses.

The active compound of the present invention or its alkali metal salt can be used as a therapeutic agent for ischemic brain damage either directly or in the form of a pharmaceutical composition prepared by mixing with a pharmaceutical carrier, such as tablets, capsules, granules, fine granules, powders, syrups, injections, suppositories, etc.
These pharmaceutical compositions are prepared according to conventional methods.

As the pharmaceutical carrier, a substance commonly used in the pharmaceutical field and which does not react with the active compound of the present invention or its alkali metal salt is used. Specific examples of pharmaceutical carriers used in the manufacture of tablets, capsules, granules, fine granules, and powders include excipients such as lactose, corn starch, sucrose, mannitol, calcium sulfate, and crystalline cellulose;
Examples of the disintegrating agents include sodium carboxymethylcellulose, modified starch, and calcium carboxymethylcellulose; binders include methylcellulose, gelatin, gum arabic, ethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone; and lubricants include light anhydrous silicic acid, magnesium stearate, talc, and hydrogenated oil. Tablets are coated with coating agents such as carnauba wax, hydroxypropylmethylcellulose, macrogol, hydroxypropylmethylphthalate, cellulose acetate phthalate, sucrose, titanium oxide, sorbitan fatty acid ester, and calcium phosphate.
Coating may be carried out by known methods.

Specific examples of carriers used in the production of syrups include sweeteners such as sucrose, glucose, fructose, and sorbitol, gum arabic, tragacanth, sodium carboxymethylcellulose, methylcellulose, sodium alginate,
Examples of suitable syrups include suspending agents such as crystalline cellulose and Veegum, and dispersing agents such as sorbitan fatty acid esters, sodium lauryl sulfate, and polysorbate 80. When producing syrups, flavoring agents, fragrances, preservatives, etc. can be added as needed. Alternatively, the syrup may be in the form of a dry syrup that is dissolved or suspended just before use.

Specific examples of suppository bases include cacao butter, saturated fatty acid glycerin esters, glycerogelatin, macrogol, etc. When producing suppositories, surfactants, preservatives, etc. can be added as needed.

Injectable preparations are usually prepared by dissolving an alkali metal salt of the active compound of the present invention in distilled water for injection, and solubilizers, buffers, pH adjusters, isotonicity agents, soothing agents, preservatives, etc. can be added as needed. Furthermore, the active compound of the present invention itself may be suspended in distilled water for injection or vegetable oil in the form of a suspension injection, in which case, a base, suspending agent, viscosity modifier, etc. can be added as needed. Furthermore, the active compound of the present invention may be in the form of a powder or lyophilized product that is dissolved just before use, in which case, excipients, etc. can be added as needed.

These pharmaceutical compositions usually contain the active compound of the present invention or its alkali metal salt as the active ingredient in an amount of 0.5% or more, preferably 10 to 70%. These pharmaceutical compositions may also contain other therapeutically effective substances as described below.

The therapeutic agent for ischemic brain damage of the present invention contains Glyceol (trademark;
Glycerin and fructose combination), intracranial pressure lowering agents such as mannitol, antioxidants such as vitamin E, vitamin C, and vitamin K, indomethacin, ibuprofen, sulindac,
It can also be used in combination with other medications such as nonsteroidal anti-inflammatory drugs such as tolmetin, calcium antagonists such as nicardipine, nimodipine and flunarizine, thromboxane antagonists, 5-lipoxygenase inhibitors, and prostaglandin derivatives as disclosed in U.S. Pat. No. 4,499,085.

BEST MODE FOR CARRYING OUT THE INVENTION In order to explain the present invention more specifically, examples are given below, but the present invention is not limited to these examples.

Example 1 Tablets: 3-sulfamoylmethyl-1,2-benzisoxazole 100g, lactose 35g, corn starch 17g, crystalline cellulose 40g, hydroxypropyl cellulose 6g, light anhydrous silicic acid 1g, magnesium stearate 1g. Of the above ingredients, 3-sulfamoylmethyl-1,2-benzisoxazole, lactose, corn starch, and crystalline cellulose were mixed, and hydroxypropyl cellulose dissolved in water was added. The mixture was then kneaded and dried to form granules. Magnesium stearate and light anhydrous silicic acid were added, and the mixture was compressed to prepare 1,000 core tablets, each 200mg. Next, the tablets were coated with hydroxypropylmethylcellulose, macrogol, titanium oxide, talc, and light anhydrous silicic acid according to the usual method to form film-coated tablets.

Example 2 20% Powder 3-sulfamoylmethyl-1,2-benzisoxazole 200 g Lactose 719 g Hydroxypropyl cellulose 20 g Light anhydrous silicic acid 1 g The above ingredients were mixed using a high-speed agitating granulator, and then 200 g of an ethanol solution containing 40 g of ethyl cellulose and 20 g of hydroxypropyl cellulose was sprayed onto the mixture to granulate.
Dry and granulate to make a 20% powder.

Example 3 Injection: 3-sulfamoylmethyl-1,2-benzisoxazole sodium salt: 276 g, glycine: 10 g, 1N sodium hydroxide: appropriate amount , distilled water for injection: appropriate amount. 5. Of the above ingredients, 3-sulfamoylmethyl-1,2-benzisoxazole sodium salt and glycine are dissolved in a portion of the distilled water for injection with stirring, and 1N sodium hydroxide is slowly added while stirring to adjust the pH to 11.5. The remaining distilled water for injection is added, and the resulting solution is filtered through a membrane filter (0.22 μm), then filled into ampoules in 5 ml portions, purged with nitrogen, fused, and sterilized by high-pressure steam at 121°C for 20 minutes to produce 1,000 injections.

Example 4 Injection 3-sulfamoylmethyl-1,2-benzisoxazole 500 g Sodium carbonate 20 g 1N Sodium hydroxide appropriate amount Propylene glycol 4 g Ethanol 1 g Distilled water for injection appropriate amount 10 g Of the above ingredients, 3-sulfamoylmethyl-1,2-benzisoxazole, sodium carbonate, propylene glycol, and ethanol were suspended in a portion of the distilled water for injection,
Slowly add 1N sodium hydroxide under stirring until a clear solution of pH 11.0 is obtained. Add the remaining water for injection and filter the resulting solution through a membrane filter (0.22
After filtering with a 10-μm filter, 10 ml of each was filled into ampoules, and the air was replaced with nitrogen.
After fusion sealing, it is sterilized by high-pressure steam at 121℃ for 20 minutes and then used as an injection 1000ml.
Manufacture books.

INDUSTRIAL APPLICABILITY As described above, 3-sulfamoylmethyl-1,2-benzisoxazole and its alkali metal salts are useful as therapeutic agents for ischemic brain disorders in the prevention and treatment of intracranial diseases caused by cerebral ischemia in mammals (including humans) or various associated symptoms.

──────────────────────────────────────────────────── Continued from the front page (56) References: JP 53-77057 (JP, A)

Claims (1)

[Claims] 1. A therapeutic agent for ischemic brain damage, comprising 3-sulfamoylmethyl-1,2-benzisoxazole or an alkali metal salt thereof as an active ingredient.