JPS6159288B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 3-sulfamoylmethyl-1.2
- An antiepileptic agent containing benzisoxazole or an alkali metal salt thereof as a main ingredient. The compound of the present invention is a new compound and has the formula () It is expressed as Compounds of the invention may be of the formula () (In the formula, X means a halogen atom.) It can be obtained by reacting the compound represented by the following with ammonia according to a conventional method. The compound can be converted into an alkali metal salt (eg, sodium salt, potassium salt) according to a conventional method. The raw material compound represented by formula () can be produced, for example, by the following method. (In the formula, X means the same as above, and Hal means a halogen atom.) The compound of the present invention and its alkali metal salt are:
It not only has a strong anticonvulsant effect, but also has a long duration of action, and has weak sedative or ataxia-inducing effects, making it useful as an antiepileptic agent. Below, the results of pharmacological experiments on the compound of the present invention and commercially available drugs will be shown, and the pharmacological action of the compound of the present invention will be explained. ED ₅₀ is Litchfield−
It was calculated using the Wilcoxon method. In addition,
The compounds used in the experiment are as follows. (Compound of the present invention) A: 3-sulfamoylmethyl-1,2-benzisoxazole (control compound) 1: Diphenylhydantoin (commercially available antiepileptic drug) 2: Carbamazepine (commercially available antiepileptic drug) ( 1) Anticonvulsant action (a) Antimaximal electric shock convulsive action (hereinafter referred to as anti-MES)
dd male mice (weight 20 g, 10 mice per group),
Wistar male rats (weight 100g, 1 group)
10 rabbits), male albino rabbits (weight 3-4
Kg, 4 dogs per group) and female beagle dogs (body weight 4-6 kg, 4 dogs per group) were used. The test compound was orally administered at 0.5, 1, 2,
After 4, 6, 8, 10, 24, and 48 hours, mice (25 mA, 60 Hz, 0.2 sec) were injected into the cornea via corneal electrodes, and rats (50 mA, 60 Hz,
0.2sec), rabbit (200mA, 200Hz, 0.8m
sec, 3sec) and dog (200mA, 200Hz,
(0.8 msec, 3 sec), electrical stimulation was applied to both ear wings through alligator clips, and the effect was judged by the presence or absence of the induced convulsive symptoms [tonic extension of the hind limbs (hereinafter referred to as TE)]. Table 1 shows the TE suppressing effect of each compound at the peak time.

[Table] As shown in Table 1, the efficacy of the compound of the present invention was almost the same as that of carbamazepine. It was also weaker in mice than diphenylhydantoin, but more potent in rats, rabbits, and dogs. Furthermore, the anti-MES effect of the compound of the present invention lasted for a long time, with the peak effect lasting from 2 to 10 hours after administration in rats, and weakening somewhat after 24 hours. This duration of action was longer than that of carbamazepine and diphenylhydantoin. (b) Effect on pentetrazole-induced convulsions (hereinafter referred to as anti-PTZ effect) 10 DD male mice per group (weight 20 g)
was used. The test compounds were administered orally, and at the peak of the anti-MES effect of each compound, 170 mg/Kg of pentetrazole was administered intraperitoneally, and the efficacy was determined based on the presence or absence of induced convulsive symptoms (TE). Table 2 shows the experimental results.
Shown below.

[Table] As shown in Table 2, the compound of the present invention significantly suppressed TE like diphenylhydantoin and carbamazepine. (2) Effects on Cooperative Movement A group of 10 male DD mice (weight 20 kg) trained to sustain cooperative movement for 100 seconds or more on a rotating rod (11 rpm) were used. The test compound was orally administered and the effects were examined hourly for 6 hours to calculate the dose (NTD ₅₀ ) at which the coordination ability of 50% of the animals was suppressed. Table 3 shows the NTD ₅₀ and therapeutic index [NTD ₅₀ / ED ₅₀ (anti-MES effect)] of each compound at the peak time.
Shown below.

[Table] Numbers in brackets indicate peak hours in hours.
Indicated by
As shown in Table 3, the ataxia-inducing effect of the compounds of the present invention was weak, about 1/4 of diphenylhydantoin and about 1/2 of carbamazepine. Furthermore, the therapeutic index of the compound of the present invention is 1.6 times and 1.4 times that of diphenylhydantoin and carbamazepine, respectively, and the compound of the present invention has a wider safety margin than diphenylhydantoin and carbamazepine. (3) Sleep enhancing effect 10 male DD mice (weight 20 g) were used in each group. The test compound was administered orally, and at the peak, hexobarbital sodium 40 mg/Kg was administered intraperitoneally. Administration of hexobarbital alone did not abolish the righting reflex, but pretreatment with the drug enhanced its effect, and the righting reflex disappeared. The test is considered positive if the righting reflex has disappeared for more than 60 minutes.
The dose at which an effect occurs in 50% of the animals (PD ₅₀ ) was calculated. The experimental results are shown in Table 4.

[Table] As shown in Table 4, the sleep enhancing effect (sedative effect) of the compound of the present invention was weak, being 1/14 as strong as diphenylhydantoin and about 1/11 as strong as carbamazepine. (4) Acute toxicity DD male mice (body weight 20 g) and Wistar male rats (body weight 200 g) were used in groups of 10 mice. The test compound was suspended in 0.5% tragacanth solution, and for mice, it was administered per 10 g of body weight.
For rats, 0.4 to 1.0 ml was administered per 100 g of body weight. For intravenous administration experiments, the sodium salt was dissolved in physiological saline and used. 7 after medication
The animals were observed whether they were alive or dead over a period of days, and the dose of drug at which 50% of the animals died (LD ₅₀ ) was calculated by the probit method. The experimental results are shown in Table 5.

[Table] As shown in Table 5, the acute toxicity of the compounds of the present invention was weaker than that of diphenylhydantoin and carbamazepine. As is clear from the above experimental results, the compounds of the present invention and their alkali metal salts not only have strong anticonvulsant effects comparable to the efficacy of commercially available antiepileptic drugs, but also have long-lasting effects and side effects (sedation). It is superior to commercially available antiepileptic drugs in terms of its action and ataxia-inducing effect, and it is also less toxic. Therefore, the compounds of the present invention or their alkali metal salts can be used as antiepileptic agents.
The administration mode may be oral, parenteral or rectal administration. The dosage of the compound of the present invention or its alkali metal salt varies depending on the administration method, symptoms, age, etc., but is usually 2 to 20
mg/Kg/day, and can be administered once or in several divided doses. The compound of the present invention or its alkali metal salt is
It is usually applied in the form of a preparation prepared by mixing it with a pharmaceutical carrier. Specific examples of formulations include tablets, capsules, granules, fine granules, powders, syrups,
Examples include injections and suppositories. These formulations are prepared according to conventional methods. As a pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the 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, and fine granules include lactose, starch, sucrose, mannitrate, calcium sulfate, excipients such as crystalline cellulose, sodium carboxymethyl cellulose, and modified starch. , disintegrants such as calcium carboxymethylcellulose, methylcellulose, gelatin, gum arabic, ethylcellulose, hydroxypropylcellulose, binders such as polyvinylpyrrolidone, lubricants such as light silicic anhydride, magnesium stearate, talc, hydrogenated oils. etc. The tablets may be coated by known methods using coating agents such as calcium phosphate, carnauba wax, hydroxypropyl methyl cellulose, macrogol, hydroxypropyl methyl phthalate, cellulose acetate phthalate, titanium oxide, sorbitan fatty acid ester. Specific examples of carriers used in syrup production include white sugar, glucose, fructose, sweeteners such as sorbitate, gum arabic, tragacanth, sodium carboxymethylcellulose, methylcellulose, sodium alginate, crystalline cellulose,
Examples include suspending agents such as Veegum, dispersing agents such as sorbitan fatty acid ester, sodium lauryl sulfate, and polysorbate 80. When producing syrup, flavoring agents, aromatics, preservatives, etc. may be added as necessary. It may also be in the form of a dry syrup to be dissolved or suspended before use. Specific examples of suppository bases include cacao butter, saturated fatty acid glycerin ester, glycerogelatin,
Examples include macrogol. When producing suppositories, surfactants, preservatives, etc. may be added as necessary. Injections are usually prepared by dissolving the alkali metal salt of the compound of the present invention in distilled water for injection, and if necessary, a solubilizing agent, a buffering agent, a PH adjusting agent, an isotonic agent, and an analgesic agent are added. , preservatives, etc. can be added. Alternatively, it may be in a form that is dissolved before use. These preparations can usually contain the compound of the present invention or its alkali metal salt as an active ingredient in a proportion of 0.5% or more, preferably 10 to 70%. These formulations may also contain other therapeutically effective compounds. The present invention will be explained in more detail with reference to Reference Examples and Examples below, but the present invention is not limited to these Examples. Reference example 1 1,2-benzisoxazole-3-methanesulfonic acid chloride Dissolve 8.0 g of 3-bromomethyl-1,2-benzisoxazole (melting point 64-66°C) in 130 ml of methanol, and dissolve 8.1 g of sodium sulfite. Add a solution of dissolved in 130ml of water. The above mixture was heated and stirred at 50° C. for 4 hours, concentrated under reduced pressure, and 250 ml of methanol was added to the remaining crystals and dissolved by heating. After removing unnecessary impurities from methanol, the methanol was distilled off under reduced pressure, and the residue was crystallized and washed with ether to yield crude 1,2-benzisoxazole.
10.5 g of sodium salt of 3-methanesulfonic acid are obtained. 10.5g of the above sodium salt to 100% phosphorus oxychloride
ml and heated under reflux for 3 hours. Excess phosphorus oxychloride is distilled off under reduced pressure and dried. The residue is dissolved in 200 ml of ethyl acetate, and insoluble materials are removed to obtain a solution of the target product in ethyl acetate. Reference Example 2 3-Sulfamoylmethyl-1,2-benzisoxazole 200 ml of an ethyl acetate solution of 1,2-benzisoxazole-3-methanesulfonic acid chloride (the solution obtained in Reference Example 1) was placed on ice. Cool and saturate with ammonia gas. After standing at room temperature for 1 hour, substances insoluble in ethyl acetate were removed, and then ethyl acetate was distilled off. The residue was washed with a small amount of ethyl acetate and then recrystallized from ethyl acetate to obtain 5.2 g of the desired product. Melting point 160-163℃ Reference example 3 3-sulfamoylmethyl-1,2-benzisoxazole sodium salt Dissolve 7.0 g of 3-sulfamoylmethyl-1,2-benzisoxazole in 300 ml of ethanol, Add a solution of 0.76 g of sodium dissolved in 40 ml of ethanol. After standing for a while, ethanol is distilled off under reduced pressure, and the precipitated crystals are washed with ethanol and dried to obtain 6.5 g of the desired product.
Melting point 225-230℃ (decomposed) Example 1 Tablet 3-Sulfamoylmethyl-1,2-benzisoxazole...100g Lactose...35g Corn starch...17g Crystalline cellulose...40g Polyvinylpyrrolidone... 6g Light anhydrous silicic acid...1g Magnesium stearate...1g According to a conventional method, the above ingredients are mixed, made into granules, and compressed to prepare 1000 tablets each weighing 200mg. Example 2 20% fine granules 3-sulfamoylmethyl-1,2-benzisoxazole...200g Lactose...779g Hydroxypropyl cellulose...20g Light silicic anhydride...1g The above components were mixed together. , prepare 20% fine granules according to a conventional method.

Claims (1)

[Claims] 1. An antiepileptic agent containing 3-sulfamoylmethyl-1,2-benzisoxazole or an alkali metal salt thereof as a main component.