FR4456M - Pharmaceutical compositions used as anti-convulsants. - Google Patents

Description

French Republic

MINISTRY OF INDUSTRY

SERVICE of INDUSTRIAL PROPERTY

SPECIAL PATENT OF MEDICINE

P.Y. No. 22.001 International Classification:

N 4.456 M A 61 k // C 07 c

Pharmaceutical compositions used as anti-convulsants.

Company known as: IMPERIAL CHEMICAL INDUSTRIES LIMITED residing in England.

Requested on June 23, 1965, at 16 "35m, at 16"? Eigendom

Issued by decree of 26 September 1966. 1 JULY 1957

{Official Bulletin of Industrial Property [5.S.M.], No. 44 of November 2, 1966.)

The present invention relates to novel drugs which are fluorinated derivatives of benzene and which have anticonvulsant properties while inhibiting carbonic anhydrase.

The new drugs in question are ia 2, 3, 5, 6-tetrafluorosulfanilamide and 4-methoxy-2,3,5,6-tetrafluorobenzenesulfonamide. 2,3,5,6-Tetrafluorosulfanilamide (mp 202-203 ° C, after crystallization from methanol) can be obtained by reaction of pentafluorobenzene sulfonamide with ammonia in ethanol at 95 ° C. (Journal of the Royal Institute of Chemistry 1960, 14). 4-Methoxy-2,3,5,6-tetrafluorobenzenesulfonamide (mp 126 ° C after crystallization from water) can be obtained by reaction of pentafluorobenzenesulfonamide with sodium methoxide in methanol (Journal of the Royal Institute of Chemistry 1960, 14).

As indicated above, the novel drugs of the invention possess anticonvulsant properties and inhibit carbonic anhydrase. Thus they are effective in protecting rats and mice against disorders caused by chemical compositions and by electrical effects, and they are of interest for the treatment of epilepsy, especially of the great disease, of the small disease. of psychomotor epilepsy, in humans.

The pharmacological properties and the therapeutic activity of the new drugs of the invention are given below:

Anti-convulsive activity in mice.

at. Electroshock process

The anti-convulsive activity of the drugs according to the invention was tested in mice by the following electroshock method. The drug was orally administered to groups of 10 male mice. Two hours later, the mice were electroshocked at 20 mA for 0.3 seconds, the current being generated by a DC source and applied by electrodes attached to the ears. The mice were stunned by electric shock and presented with a clonic convulsion, followed by a tonic extension. Mice administered an effective dose of an anticonvulsant did not show the tonic extension and are considered to be protected. The percentages of the protected animals were noted and the average effective doses (ED50) calculated according to the known methods. The average effective oral doses (ED50) of the medicaments of the invention, determined by this electroshock method on mice, are as follows:

2, 3, 5, 6-tetrafluorosulfanilamide 13.2 mg / kg. 4 - methoxy - 2,3,5,6 - tetrafluorobenzenesulfonamide 33 mg / kg.

b. Disorders caused by Metrazol.

When administering to mice by intraperitoneal injection of "metrazol" at a dose of 160 mg / kg of the weight of the mouse, it presents clonic convulsions after a few minutes after the injection. These convulsions are quickly followed by major tonic convulsions and tonic spasms from which the animal may or may not recover. Most mice that are unprotected succumb after 30 minutes after injection. The anti-convulsive effects of the novel drugs of the invention are determined by their ability to avoid spasms and their ability to postpone death after thirty minutes according to the following method.

Groups of 10 mice orally were given the drug to be tested and 2 hours after intraperitoneal injection of "Metrazol" at a dose of 160 mg / kg. The percentage of mice that do not have a tonic extension and the percentage of mice that do not succumb after 30 minutes are noted and the mean effective dose (ED50) is calculated according to known methods.

The oral DE50 dose of the drugs of the invention determined by this method is shown in Table I below.

Anti-convulsive activity in rats, electroshock method.

7 210266 7

Price of the booklet: 2 francs

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The anticonvulsant activities of the novel drugs of the invention were determined in rats by the low current electroshock method described hereinafter.

Disorders are caused by passing an alternating current of 7.5 mA, 50 cycles by means of electrodes fixed on the ears. A timer is incorporated in the circuit and adjusted so that the maximum shock time does not exceed ten seconds. Within two to seven seconds, a normal rat has the tonic extension feature of the hind limbs. When this result is obtained, the electric current is cut off and the time is recorded. The initial threshold, expressed as energy required to cause the tonic extension associated with disorders caused by an electrical means is determined for each animal, which then serves as a control. Only rats that exhibit the tonic extension characteristic after a shock intensity of 23-30 mA per second or 600-800 mW dry. (duration of the shock 3-4 sec.) are chosen for the anticonvulsant test. The day after the initial threshold is determined, the rats are orally administered the drug to be tested and the percentage of rats that do not exhibit tonic extension spasms of the hind limbs is noted at intervals of one, three, six and twenty-four hours after administration. The average effective dose (ED50) is calculated according to known methods. The ED50 of the new drugs of the invention is determined by this method and is shown in Table I below.

Acute toxicity in mice.

Acute oral toxicity to mice of the new drugs is expressed as mean lethal doses, ie the dose that suppresses 50% of the animals tested as shown in Table I.

Table I

Drug

Test of <on

Protection against tonic extension DE ,,

Metrazol »

mouse

Protection against death after 30 minutes DEfi0

Electroshock procedure on rats

Deso

Acute toxicity in DLsd mice

2,3,5,6-tétrafluorosulfanilamide

4-methoxy-2,3,5,6-tétrafluorobenzènesulfonamide

mg / kg

16 25

mg / kg greater than 100 50

mg / kg

16 17.5

mg / kg

2,825 2,300

Duration of the action.

The duration of the anti-convulsive activity of the new drugs was determined by administering the drugs orally to groups of 10 to 20 mice at a dose double that previously calculated for ED 50. The percentage of animals protected against electrically induced disorders at different time intervals after administration was determined and the results are shown in Table II.

Table II

Percentage of protected animals

for the following durations after administration

Drug

Oral dose

(<

11:00)

1/2

1

2

4

8

16

24

mg / kg

2,3,5,6-tétrafluorosulfanilamide

26.4

80

90

100

50

0

0

0

4-methoxy-2,3,5,6-tétrafluorobenzènesulfonamide

66

100

100

70

60

10

20

10

Acute toxicity of 2,3,5,6-tetrafluorosulfanilamide in the rat, dog, monkey and rabbit. The cats.

An adult cat weighing 3.1 kg was administered an oral dose of 2,3,5,6-tetrafluorosulfanilamide at a dose of 200 mg / kg, administered as a powdery compound contained in a capsule of hard gelatin. Medication

causes mild sedation but does not cause any other symptoms. The next day the cat is completely recovered.

A cat weighing 3 kg was administered intravenously with the drug at 50 mg / kg. Apart from a slight loss of appetite and slight sedation, no other symptoms are observed and the animal is completely recovered after twenty-four hours.

Dogs.

A male dog weighing 4 kg was administered orally with a dose of 200 mg / kg of 2,3,5,6-tetrafluorosulfanilamide. Shortly after administration, the dog vomits and shows some signs of mild ataxia, particularly in the area of the hind limbs. The next day the dog is fully recovered and is given a second oral dose of the drug at 200 mg / kg. On this occasion, there is no evidence of vomiting but the dog seems to be struck by mild ataxia and mild sedation. The next day the dog is fully recovered.

A male dog weighing 3.9 kg was administered intravenously at a dose of 40 mg / kg. Shortly after administration, vomiting is observed and the dog shows signs of ataxia. The next day, he is completely recovered. Two days later the same dog is given a second intravenous dose of the drug at 40 mg / kg. The dog seems to be slightly affected by ataxia but on this occasion there is no sign of vomiting. The day after the dog is fully recovered and seems to be perfectly normal.

Monkeys.

A monkey weighing 2.4 kg was given a single oral dose of the drug at a dose of 200 mg / kg. There are no untoward symptoms and when examined on the day of administration and the next day, the monkey seems to be perfectly normal.

A guenon weighing 2.4 kg was given an intravenous dose of the drug at a dose of 40 mg / kg. No symptoms are observed and the animal remains normal.

Rabbits.

A rabbit weighing 2.1 kg was given an oral dose of the drug at a dose of 200 mg / kg. The compound was administered as a dispersion. There are no symptoms of toxicity after administration of the drug and the animal appears to be completely normal.

A rabbit weighing 2.1 kg intravenously administered the drug at 200 mg / kg. The compound was administered as a solution of the sodium salt. There are no symptoms of drug toxicity after intravenous injection and the animal appears to be completely normal.

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Acute toxicity of 2,3,5,6-tetrafluorosulfanilamide in rats.

The toxicity of the drug was determined on rats by oral administration to groups of 5 rats of a unit oral dose of the drug. The animals are observed for 7 days, and the number of animals that have died has been noted. The results are as follows:

Dose

Proportion of animals that have died

4/4

3.15 g

3/5

2.5 g

0/5

2 g

0/5

1 g

0/5

The symptoms of toxicity noted during this test are ataxia and hypnosis at high doses. The animals that survived the test continue to behave normally.

Subacute toxicity of 2,3,5,6-tetrafluorosulfanilamide in rats.

The subacute toxicity of 2,3,5,6-tetrafluorosul-fanilamide was determined in rats by oral administration to groups of 6 rats (3 males and 3 females) for a period of 7 days. On the seventh day, the surviving rats are sacrificed, examined and tissue removed for histopathological examination. The results obtained were as follows:

Group I. Daily dose of 500 mg / kg (33 times the amount of anti-convulsive DE50 in rats).

Both male and female rats do not gain weight. 5 out of 6 survive and post-mortem examination of survivors shows some changes in the kidneys of male rats, which are related to the diuretic action of the compound. There are average variations in the liver, which can be associated with the detoxification of the compound. A slight contraction effect is indicated by a reduction of lymphocities in the spleen and lymphatic centers.

Group II. Daily doses at 250 mg / kg (16 times the anti-convulsive ED50 in rats).

Male and female rats continue to gain weight but at a lower rate than the control animals. All animals survive treatment and post mortem examination, two male rats had hydronephrosis, which is probably not associated with the action of the drug. There are slight changes in the kidneys, liver and spleen that are qualitatively similar to those seen in group I but to a lesser extent.

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Inhibition of carbonic anhydrase.

The new drugs of the invention are inhibitors of the carbonic anhydrase enzyme. • The anticonvulsant properties of drugs may be considered to be due to the high degree of inhibition of carbonic anhydrase, which has been demonstrated. The in vitro inhibition of carbonic anhydrase by the new drugs of the invention was determined by the method of pH change as follows:

A constant stream of carbon dioxide is passed through 0.4 ml of a solution of red phenol in a solution of 0.0026 M sodium bicarbonate at 0 ° C. The enzyme and the drug to be tested are added to the mixture and the total volume is brought to 0.7 ml. 0.1 ml of a buffer solution containing 0.3 M sodium carbonate and 0.0206 M sodium bicarbonate are added and the time is started. The end point is taken as the time when the indicator changes color from red to yellow. The duration of the reaction in the absence of the enzyme and the drug to be tested and the duration in the absence of the drug alone are also noted. The activity of the enzyme is expressed in units such that in the presence of one unit of enzyme the activity expressed in the duration of the reaction is half that of the uncatalyzed reaction. The 50% inhibitory concentration (I50) is the molar concentration of the drug to be tested which, when present with 2 units of enzyme activity, gives the same reaction time as that which one would have with one unit. enzyme in the absence of an inhibitor and under the same conditions.

The inhibitory activities of carbonic anhydrase determined in vitro for the new drugs of the invention are as follows:

pharmaceuticals

1.0

2,3,5,6 tetrafluorosulfanilamide

4-methoxy-2,3,5,6-fluorobeiizènesulfo-

0.125 x 10 "6 M 0.21 x 10-e m

It will be seen from these results that the drugs of the invention are inhibitors of carbonic anhydrase.

The novel drugs of the invention may be administered in the form of pharmaceutical compositions comprising the drug and a pharmaceutically acceptable diluent or excipient.

The pharmaceutical compositions may, for example, be in the form of an appropriate oral dose, for example in the form of tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions,

hard capsules or moles, or syrups or elixirs.

Compositions suitable for oral administration may be prepared by any method known for the manufacture of orally administrable pharmaceutical compositions, and such compositions may contain one or more agents selected from sweetening agents, fragrances, dyes and agents. of conservation to give a preparation having good aspect and pleasant to the taste.

The tablets of the invention contain the active ingredient in admixture with non-toxic excipients known to be suitable in the manufacture of tablets. The pharmaceutically acceptable excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example corn starch. alginic acid, binding agents such as, for example, starch, gelatin or acacia gum and lubricating agents such as, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disaggregation and absorption in the gastrointestinal tract of the drug and thereby cause a delayed action extending over time.

The aqueous suspensions of the invention contain the active ingredient in admixture with one or more excipients known to be suitable in the manufacture of aqueous suspensions. Suitable excipients include, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum. Suitable dispersing agents and wetting agents are naturally occurring phosphatides, such as, for example, lecithin, or the condensation products of ethylene oxide with fatty acids such as polyoxyethylene. ethylene stearate, or the condensation products of ethylene oxide with long-chain aliphatic alcohols, such as, for example, heptadecaethyleneoxyketanol, or condensation products of ethylene oxide, with esters derivatives of fatty acids and a hexitol, such as polyoxyethylene sorbitol mono-oleate, or ethylene oxide condensation products with partial esters derived from fatty acids and anhydrides. hexitol, such as polyoxyethylene sorbitan mono-oleate. Aqueous suspensions may also contain one or more preservatives, such as

ethyl or n-propyl p-hydroxybenzoate or one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose, saccharin or sodium cyclamate.

Oily suspensions can be obtained by suspending the active ingredient in a vegetable oil such as, for example, peanut oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin, and the oily suspensions in question may contain a thickening agent such as, for example, tallow, hard paraffin or ethyl alcohol. Sweetening agents, such as icing sugar, sodium saccharin or sodium cyclamate, and flavoring agents, such as caramel, may be added to provide an orally administrable and palatable preparation. These compositions may also contain an antioxidant, such as for example propyl gallate or ascorbic acid.

Dispersible powders and granules suitable for the extraporate preparation of an aqueous suspension by the addition of water contain the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing agents or wetting agents as well as suspending agents are those mentioned above for the case of aqueous suspensions. Other excipients that may be mentioned include, for example, one or more sweetening, flavoring and / or coloring agents which may optionally be present.

The pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as for example olive oil or peanut oil, or a mineral oil such as liquid paraffin, or mixtures of these oils. Suitable emulsifying agents are natural gums such as, for example, acacia gum or tragacanth gum, natural phosphatides such as, for example, soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as, for example, sorbitan mono-oleate, and condensation products of these partial esters with condensation of these partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan mono-oleate. The emulsions may optionally contain one or more sweetening and / or flavoring agents.

The orally administrable formulations may be in the form of hard gelatin capsules containing the active ingredient alone or containing the active ingredient in admixture with a

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an inert solid diluent, such as, for example, calcium carbonate, calcium phosphate or kaolin, or they may be in the form of soft gelatin capsules in which the active ingredient is mixed with an oily medium, such as by example of peanut oil, liquid paraffin or olive oil.

The syrups and elixirs may be prepared with sweetening agents, for example glycerol, sorbitol or sucrose. These formulas may also contain an emollient, a preservative and coloring flavoring agents.

The pharmaceutical compositions may alternatively be in the form of aqueous or nonaqueous solutions or suspensions suitable for administration of the active ingredient by inhalation.

The pharmaceutical compositions may also be in the form of a sterile injectable preparation, such as, for example, a sterile injectable aqueous suspension. This suspension can be prepared according to the known methods using those of suitable dispersing or wetting agents as well as the appropriate suspending agents which have been mentioned above.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol.

The pharmaceutical compositions may also be in the form of suppositories suitable for rectally administering the active ingredient. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at rectal temperatures and therefore melt in the rectum to release the active ingredient. Suitable excipients are cocoa butter and polyethylene glycols.

Preferred pharmaceutical compositions are tablets or capsules containing 20 to 1000 mg of the active ingredient. When using any of the new drugs for the treatment of epilepsy, especially grand mal, petit mal and psychomotor epilepsy in humans, it is recommended that the total daily dose per oral route is between 60 mg and 3 g. For the treatment of conditions in which the inhibition of carbonic anhydrase is beneficial, in particular glaucoma and edema in humans, one of the medicaments of the invention can be used in the form of tablets containing from 50 to 500 mg of the active ingredient.

The invention is illustrated in no way

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by the following examples in which the parts are by weight.

EXAMPLE 1 250 parts of 2,3,5,6-tetrafluorosulfanilamide and 30 parts of calcium phosphate are mixed and mixed with a 10% solution of gelatin and the granulation is then carried out by passing through a sieve with a mesh size of 1 mm. The granules are dried at a temperature not exceeding 66 ° C. The granules are then passed through a 0.775 mm mesh screen. The granules are then intimately mixed with a mixture of 7.5 parts of corn starch powder and 1 part of magnesium stearate which has previously been passed through a 0.25 mm mesh screen. The resulting mixture is compressed into tablets by conventional means, thereby obtaining tablets which can be used orally for the treatment of epilepsy and for the treatment of conditions in which the inhibition of carbonic anhydrase is beneficial.

EXAMPLE 2 7 parts of 2, 3, 5, 6-tetrafluorosulfanilamide, 0.05 parts of vanillin and 20 parts of powdered sucrose are mixed together and a solution of 0.04 part of the condensation product is added to this mixture. of cetyl alcohol with 17 molecular proportions in 2 parts of water. A solution of 0.15 part of methyl p-hydroxybenzoate, 0.015 part of propyl p-hydroxybenzoate and 1.6 part of sodium carboxymethylcellulose in 70 parts of water is mixed with a quantity of sufficient water to have a volume of 100 parts per volume. After thorough mixing, an aqueous suspension is obtained which is suitable for oral administration, for the treatment of epilepsy and for the treatment of conditions in which the inhibition of carbonic anhydrase is beneficial.

EXAMPLE 3 250 parts of 4-methoxy-2,3,5,6-tetrafluorobenzenesulfonamide and 30 parts of calcium phosphate are mixed with a 10% gelatin solution and granulated by passing through a sieve. with 1 mm mesh. The granules are dried at a temperature not exceeding 66 ° C and then passed through a sieve of 0.775 mm mesh. The granules are then intimately mixed with a mixture of 7.5 parts of corn starch powder and a portion of magnesium stearate which has previously been passed through a 0.25 mm mesh screen. The resulting mixture is compressed into tablets by conventional methods; thereby obtaining tablets which can be used orally for the treatment of epilepsy or for the treatment of conditions in which the inhibition of carbonic anhydrase is beneficial.

EXAMPLE 4 7 parts of 4-methoxy-2,3,5,6-tetrafluorobenzenesulfonamide, 0.05 parts of vanillin and 20 parts of powdered sucrose are mixed and to this mixture a solution of 0.04 part of the mixture is added. cetyl alcohol condensation product with 17 molecular proportions of ethylene oxide in 2 parts of water. A solution of 0.15 parts of methyl p-hydroxybenzoate, 0.015 parts of propyl p-hydroxybenzoate and 1.6 parts of sodium carboxymethylcellulose in 70 parts of water is mixed with a sufficient amount of water. water so that the volume volume is 100 parts by volume. After mixing, an aqueous suspension is obtained which is suitable for oral administration for the treatment of epilepsy and for the treatment of conditions in which inhibition of carbonic anhydrase is beneficial.

resume

As new drugs:

1 ° 2, 3, 5, 6 - tetrafluorosulfanilamide and 4 - methoxy - 2, 3, 5, 6 - tetrafluorobenzenesulfonamide.

2. The above drugs that can be administered in the form of pharmaceutical compositions comprising the drug and a pharmaceutically acceptable diluent or carrier.

3 ° Pharmaceutical compositions which may be in the form of tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, aqueous or oily suspensions sterile injectables or suppositories.

4. The preferred pharmaceutical compositions are tablets or capsules containing from 20 to 1000 mg of drug.

5 ° For the treatment of epilepsy, in particular of great illness, small illness and psychomotor epilepsy in men, it is recommended that the total daily dose administered orally be 60 mg to 3 g.

6. For the treatment of conditions in which the inhibition of carbonic anhydrase is beneficial, in particular glaucoma and edema in man, the new drugs may be used in the form of tablets containing 50 to 500 mg of medicament .

Society says:

IMPERIAL CHEMICAL INDUSTRIES LIMITED By proxy:

SlMONNOT & RlNUY