WO1999023056A1 - New anticonvulsant drugs - Google Patents

Abstract

The present invention relates to a high-efficiency anti-epileptic preparation that comprises one of several new derivatives of alicyclic carboxylic acid. In a same aspect, this invention also relates to the alkaline metal salts or alkaline-earth metal salts of bicyclo-[2,2,2]octan-carboxylic acid, wherein said salts have an anticonvulsant activity. These compounds are not toxic, have no adverse effect and can be used in mammals for treating or preventing epileptic conditions due to their selective activity against convulsive reactions. The most efficient salt among the above-mentioned ones is a Na-salt of said acid named sacricin. This preparation is preferably administered by the nose into the body. This invention also relates to pharmaceutical compositions containing the above-mentioned salts, as well as to the use thereof in the production of drugs for treating or preventing and even controlling convulsive conditions in mammals, including human beings.

Description

NOW

The invention concerns the treatment of new medicinal substances with anticonvulsant properties

5 actions. In particular, it relates to new derivatives of alicyclic carboxylic acid, namely, to alkaline and alkaline earth salts of bicyclo- [2, 2, 2] octane-2-carboxylic acid, pharmaceutical compositions containing these salts, for example

10 their use for the production of a drug suitable for the treatment or prevention of epilepsy, as well as a method of stopping other convulsive reactions.

Technique level

15

Anticonvulsant action can be exerted by various substances that weaken excitation processes or enhance relaxation processes in the central nervous system. Of particular importance are

20 Anticonvulsants, effective in epilepsy and used for the prevention or termination of epilepsy: seizures or their equivalents.

One of the best known anticonvulsant 25 drugs is tenobarbital. Diphenin, hexamidine, diazepam, clonazepam, ethosuximide, etc. are also used to treat or prevent epilepsy. derivatives of various nitrogen-containing heterocycles, as well as: chlorachone, mydocalm, methinedionine and a number of

30 others. Later drugs should include valproic acid (2-propylvaleric) and its sodium salt (convulex, convulsofin, etc. analogues).

35 Η ₃ C - CΗ ₂ - CΗ ₂ ^ 0

- СΗ - С Η ₃ С - СΗ? - SΗ _? ^ΟΗ (or ΟΝа) - 2 - which, unlike other known anticonvulsants, is a nitrogen-free compound, which is comparable to the claimed compounds. However, all of the listed drugs

5 greater or lesser degrees have a number of disadvantages, to which the side effects they cause can be attributed: general depression or excitation of the nervous system, sedative, tranquilizing or allergic effects, disturbance of coordination

10 movements, toxic reactions, etc. Valproic acid salts are also not free of side effects, as they affect blood luminosity, irritate the gastrointestinal tract, sometimes cause hair loss, etc. (B.M.I.Mooogy et al.).

15 Αηгϊеρϋеρ-Ys ϋgidz, 2ηά еά., Ν.ϋ ^~ .Κаνеη Ρезз, 1982, ρ.879; ϋ.Зсηтιάг. - Αάνерзе егезг. ο£ Αηg.ιеρι1еρг-ϊс Bgidz, Κаνеη Ρезз, 4, 1982. Τ.Τakadι eg. aϊ., Νeigozsι Κez. , 1990, Ν' 11. S.Μеѷιег, 0 ^~ .Сагкааζ ег аϊ., Τηеριе, 1963, ν.118 ρρ .435-440; Ό.ЗΙΙΙУП,

20 _^ Ι.Κ.Ρеηу, Ερϋеρзιа, 1975, ν.ϊb, ρρ.459-573; Μ.Βaintoub - Peculiarities of side effects of judicial medicine, Sov.med., Ν' 8, pp. 102-104, 1982). In addition, many known epilepsy drugs are insufficient

25 are soluble in water, which makes their introduction into the body difficult.

As for the bicyclo [2, 2, 2] octane-2-carboxylic acid itself and its salts, ^there is no information in the literature about their possible application in

30 medical purposes. These acids are patented, which have a vascular effect (patent SPΑ 2942026, 1960), as well as amino-substituted esters similar to the bicyclic acid [2, 2, 2] about-5-ene-2-kabonovy acid (SP patent 2668021), 1954;

35 patent USH 2797227, 1957) and bicyclo [2, 2, 2] οκτ-5-en-2, 3-dicabonic acid (patent 244929, - 3 - 1966), possessing ganglionic blocking, diuretic and hypotensive action. However, the Pharmacopoeia of SPIA and Velikobritanie do not contain information about any medicinal preparations produced on the basis of the above-mentioned urethanes or amino-substituted esters.

The mechanism of action of anticonvulsants obviously varies among drugs of different structural types. Their inhibitory effect on the transmission of excitation to synaptic contacts of certain areas of the brain and the reduction of impulses leading to the occurrence of seizures plays a significant role.

Taking into account the above about the known PSP and the duration of treatment of epilepsy, it becomes obvious that there is a need to create a drug, the use of which will eliminate or reduce the severity of side effects.

Statement of the essence of the invention

0 The present invention established that derivatives of bicyclo[2, 2, 2]octane-2-carboxylic acid, in particular its alkali and alkaline earth metal salts, have antivascular activity in the absence of any side effects and may be useful for the prevention and treatment of epilepsy as a result of their effective and selective effect on the convulsive response in mammals, regardless of the sex of the animal.

Thus, the present invention relates to the new bicyclic derivative [2, 2, 2] tan-2-cabonova acids of molecule I.

where M represents Y, Na, Sa, Md - 4 - Compounds of φοορmu I are obtained in the usual way from the well-known bicyclo [2, 2, 2] οκτtan-2-kabonovic acid κκορο II (K.Zeka, Ο.Τgatροzsη, Sηet.Βreg., 1942, b.75, 3.1379).

0

0

and a suitable base (alkalis, bicarbonates, carbonates, metal alcohols) in an aqueous or aqueous-alcohol environment. The obtained salts are 5 non-toxic compounds, well soluble in water and moderately soluble in ethanol, stable in solid state and in solutions. They are not hygroscopic, do not form stable crystal hydrates, aqueous solutions have a neutral reaction. The structure and composition of the obtained 0 salts are confirmed by elemental analysis data, as well as by IR and NMR spectroscopy methods.

The invention also includes methods of practical application of the claimed compounds by administering to the recipient compounds of formula I in 5 dosed form, calculated for one dose or for multiple uses. The methods cover both therapeutic and prophylactic use.

Therefore, another subject of the invention is a pharmaceutical composition containing

30 effective amount of bicyclic [2, 2, 2] octane-2-carboxylic acid salt in admixture with pharmaceutically acceptable carriers or diluents in solid, semi-solid or liquid state.

35 The present invention also proposes the use of the said salts of this acid for the production of medicines useful for the treatment or - 5 - warnings of epilepsy, as well as a method of stopping convulsions in mammals, including humans.

The term "effective amount" means that amount of the compound required to control the convulsive condition or any symptom thereof, which can be treated with a pharmaceutical composition containing the compound of formula I.

Τemin "buying a seizure condition"

10 is used in its generally accepted meaning which includes warning, containment, alleviation of the severity of a disease or symptom or its consequences.

Pharmaceutical compositions preferably exist in the form of dosage units calculated to obtain the desired therapeutic effect. They can be administered orally in the form of tablets, capsules or powders, parenterally in the form of subcutaneous, intramuscular or intravenous injections and intranasally, which is the most effective and preferable.

Pharmaceutical compositions in the form of tablets or capsules containing from 50 to 100 mg of the active ingredient are prepared according to standard methods widely used in pharmaceutical chemistry and including standard stages of mixing, granulation and pressing.

For parenteral injections, the declared salts are converted into appropriate solutions using pharmaceutically acceptable solvents or diluents.

Such pharmaceutical compositions, having the necessary purity, stability and adaptability for patient administration, are obtained by dissolution

35 active ingredient in an amount of 70 to 100 mg in water or saline. - 6 - This invention proposes a method for treating a medical condition that allows for administration to animals an effective amount of bicyclo salt [2, 2, 2] katan-2-kabonovic 5 acid. The effective amount is usually determined by the attending physician in each individual case and depends on the degree of the disease, age, weight of the patient and the method of administration of the drug.

In those cases where the drug exists in the form of a 10 unit dose, i.e. contains a predetermined amount of active ingredient, it is prescribed in the form of a single or multiple daily dose, calculated to create a therapeutic effect and administration, for example, in 2-4 15 doses.

The present invention is illustrated by examples of production and data on the pharmacological activity of the claimed compounds.

20 Example 1

Preparation of sodium salt bicyclo [2, 2, 2] otan-2-kabonovic acid

%: С 61.34 Η 7.43 61.29 7.51 - 7 - Пρименение в синτезе чисτыχ κислοτы и οснοвания даеτ сοль 98-99%-οй сτеπени чисτοτы и исκлючаеτ неοбχοдимοсτь дοποлниτельнοй οчисτκи на κοнечнοй сτадии синτеза . Пοлнοτу высушивания κοнτροлиρуюτ πο οτсуτсτвию ποлοсы πρи 3430 см^~1 в ИΚ сπеκτρе сοли. Χаρаκτеρисτиκами чисτοτы являеτся: οτсуτсτвие ποлοс в οбласτи 3040 см^~1 в ИΚ сπеκτρа и сигналοв в οбласτи 6.5-7.0 м.д. сπеκτρа προτοннοгο магниτнοгο ρезοнанса. Сτρуκτуρнο-χаρаκτеρисτичными являюτся 0 ποлοсы валенτныχ κοлебаний κаρбοκсильнοгο аниοна- дублеτы πρи 1570-1554 и 1420-1411 см^~1 в ИΚ сπеκτρе (вазелинοвοе маслο) ; мульτиπлеτ πρи 2.42 м.д., οτнοсящийся κ α-προτοну, в сπеκτρе προτοннοгο магниτнοгο ρезοнанса (200.13 мГц, ϋ^Ο) ; девяτь 5 сигналοв πρи 21.72, 23.71 (С₄), 24.75, 24.96, 26.03, 27.71 (Сχ), 29.03, 44.22 и 185.65 (СΟΟ-) м.д. в сπеκτρе углеροднοгο магниτнοгο ρезοнанса (50.31 мГц, ϋ^Ο) . Пοлученная данным сποсοбοм наτρиевая сοль οπτичесκοй аκτивнοсτью не οбладае . 0To a paste of 0.18 mol NaAΟΗ or NaΗСοz or 0.9 mol 25 in water it is added with 0.2 mol bicycloοκτtan [2, 2, 2] Kabonova -2 acids with τ. πl . 84-86°С, stir for 1 hour at room temperature, excess acid is filtered or extracted with organic paste, aqueous paste 30 is packed in a vacuum to dryness at 120-140°C, sodium salt is obtained, yield 93, mp. 440-450°C with decomposition, white scaly crystals with a weak "sour" smell, moderately soluble in alcohol, soluble in water, slightly hygroscopic, stable 35 crystal hydrates do not form, aqueous solutions have a neutral reaction. Found %: C 61.23 H 7.69. Calculated for

%: C 61.34 Η 7.43 61.29 7.51 - 7 - The use of pure acid and base in the synthesis gives a salt of 98-99% purity and eliminates the need for additional purification at the final stage of synthesis. The completeness of drying is checked by the absence of a band at 3430 cm ^~ 1 in the IR spectrum of the salt. The purity characteristics are: the absence of bands in the region of 3040 cm ^~ 1 in the IR spectrum and signals in the region of 6.5-7.0 ppm. spectrum of the carbon magnetic resonance. The structural-characteristic bands are 0 of the stretching vibrations of the carboxyl anion - doublets at 1570-1554 and 1420-1411 cm ^~ 1 in the IR spectrum (vaseline oil); multiplet 2.42 ppm, related to α-ππροτο, in the spectrum of magnetic magnetic resonance (200.13 MHz, ϋ^Ο) ; nine 5 signals πρ 21.72, 23.71 (С ₄ ), 24.75, 24.96, 26.03, 27.71 (Сχ), 29.03, 44.22 and 185.65 (СΟΟ-) ppm. in the spectrum of carbon magnetic resonance (50.31 MHz, ϋ^Ο). The sodium salt obtained in this way does not have optical activity. 0

Example 2

Obtaining magnesium salt of bicyclo[2, 2, 2]octan-

2-catabonovic acid

5 Dissolve 0.05 g of activated magnesium in 50 ml of dry methanol in an inert gas atmosphere while heating. The resulting solution is gradually mixed with a solution of 0.1 mol bicyclooctane [2, 2, 2] carbonic-2 acid in 50 ml of methanol, stirred for 1 hour at room temperature, the precipitate that forms is separated, dried in a vacuum, and magnesium salt is obtained. yield about 99%. White plates, t . p . 432-436 ° C with decomposition. Found %: C 64.97 H 8.26. Calculated for C]_8 ^H 26 ^M 9°4% ^{: C} 65.37 H 7.92. The product obtained in this way

35 In this way, salt is relatively inactive.

- 8 - Pharmacology

For the claimed compounds, an assessment was made of anticonvulsant activity, acute and chronic toxicity, anaphylactogenic properties, embryotoxicity and tetatogenicity, and the pharmacokinetics and effect on animal behavior were studied. The study of general and specific activity was carried out in accordance with the general requirements for new

10 drugs and in comparison with the most well-known anticonvulsant drugs - fenobarbital, diphenin, convulex.

Various salts of formula I have been tested. All of them, to a greater or lesser extent, possess

15 anticonvulsant activity, but the sodium salt of bicyclo [2, 2, 2] octane-2-carboxylic acid, conventionally called "Sacricin", according to its specific properties turned out to be more active than others and surpassed many of those used in medical practice Anticonvulsants. The test results are presented in Tables 1-6.

Example 3 Study of anticonvulsant properties 5

The study of the anticonvulsant properties of the drug was conducted:

1. According to the coral model on white nonlinear mice, males and females, weighing 25-30 g at

30 injection (subcutaneous or intramuscular). Corazole (pentylene-tetazole) - a test agent - is one of the most widespread seizure-causing convulsants.

2. According to the corazol model on white nonlinear 35 rats, male and female, weighing 200-300 g with injection (subcutaneous and intramuscular), oral and intranasal (nasal drops) administration. - 9 -

3. According to the audiogenic model on white rats, males and females, weighing 200-300 g of the Kurshinsky line

Молодкина (КМ), brought out for increased sensitivity to sound impact and giving

5 pronounced judicial type on the bell (L. B. Kushinsky - “Mining knowledge in science and pathology”, Moscow, Moscow State University, 1960).

The test drug was administered to the animals 15-25 minutes before testing at a dose of 200 mg/kg, and

10 intranasally at a dose of 100 mg/kg. Kasazol was administered to the animals at a dose of 50 mg/g, and the body was exposed to a sound of 80 dB. In all cases, in parallel, we carried out the analysis of the physiological effect together with the physiological one. Judicial therapy in the same volume

15 and with the same time interval. All animals were strictly tested by a forensic agent. The adverse effect of phenytopathate was assessed on a 4-point scale with a severity of seizures ranging from 1 to 4:

20 1 - motor excitation in response to the action of a convulsive agent, not progressing to an epileptic seizure;

2 - motor excitement ending in a stuporous state, sometimes with a fall on the abdomen;

25 3 motor excitation ending with the animal falling on its side with clonic convulsions; 4 - motor excitation ending with the animal falling on its side with ^severe tension of all muscles and cessation of breathing for several

30 seconds.

The latent period before the onset of motor excitation and all subsequent stages, the strength and duration of motor reactions and the actual convulsive phases were recorded.

35 Results obtained on mice and rats

(gas model of seizure disorder) and kysa

(audiogenic seizure model) - 10 - indicate the effective and selective effect of the drug on the convulsive reaction and do not depend on the sex of the animal; 70% of animals showed a weakened reaction of 2-3 degrees. In all models

5 there is a significant prolongation of the latent period, both before the onset of motor excitations and the convulsive phases themselves. In this case, both the general motor and convulsive reactions were greatly weakened and short-lived.

10 The appearance of a second wave of excitation is also observed, indicating an extension of the toxic process. In some cases, convulsive reactions were generally absent. This was especially clearly revealed with intranasal administration of the drug.

15 coral reef model (Tables 1, 2), clearly illustrated in Table 1.

Since the claimed compounds differ from all known medicinal agents obtained The results are compiled in

20 frames of the same methods with known standards from different classes of anticonvulsant drugs: phenobarbital, diphenylamine and convulex (Tables 3, 4). Phenobarbital in doses of 15-30 mg/kg, weakening the convulsive attack, causes depression of general motor activity, ataxia, drowsiness, i.e. generalized depression. Diphenin at a dose of 20 mg/kg slightly weakens the severity of the attack without a pronounced drowsiness ^effect and slightly prolongs the latent periods without removing

30 convulsive attacks of 3-4 degrees. Convulex in a dose

200 mg/kg exhibits an anticonvulsant effect with an extension of the latent period before the onset of motor excitation, however, the duration of the actual convulsive phases does not practically differ from the control ones. Only 22% of animals show grade 2 reactions, the rest show grade 3 and 4 reactions. - 11 - Thus, in comparison with the above-mentioned reference drugs, Sacricin is a more effective anticonvulsant drug. 5

Let's get 4 rating of the sharpness and toxicity

To assess the declared toxicity

10 compounds were studied in male mice, male rats and dogs, both by subcutaneous and intragastric administration. The following doses of the drug were tested by subcutaneous administration: in mice - 10% solution of the substance from 500 to

15 2250 mg/kg; for rats - 9.0 solution from 400 to 2000 mg/kg; for dogs - 10% solution of the substance from 90 to 180 mg/kg. Survival was monitored for a month. The acute toxicity when administered into the stomach in the above-mentioned animals was determined as 10%

20 solution of the substance in 1% starch gel. On average, with subcutaneous administration Ъϋ50 ⁼ 1500 mg/kg, with intragastric administration up to 1000 mg/kg.

Studies on the study of the chromatic and subchromatic toxicity of compounds on rats and

25 chronological toxicity studies in dogs with both types of administration showed that the drug is well tolerated by animals even when administered in total doses significantly exceeding lethal ones, which indicates the absence of cumulative properties of the drug and his

30 rapid elimination from the body. This property allows easy management of safe concentration in the body during therapy (Table 5).

As a result, the value of bΕ>50 ^For laboratory animals for the classification of BΒΟ3 drugs

35 can be classified as low-oxygen medicinal drugs of the 4th group. .

- 12 -

Example 5

Study of anaphylactogenic properties

Evaluation of the anaphylactogenic properties of the declared

5 compounds were administered to guinea pigs weighing 250-

280 g for all animals. Pevaya received patina at a dose of 29 mg/kg, votaya - 200 mg/kg and teta - 600 mg/kg, each dose was administered liquid.

The intensity of the anaphylactic reaction was assessed

10 on a 4-point scale. No anaphylactic reactions were observed in animals sensitized with doses of 20x3 mg/kg and 200x3 mg/kg.

(Table 6). Sensitized by the maximum dose

600x3 mg/kg animals showed the development of individual

15 manifestations of anaphylactic shock such as scratching, chewing, which allows us to estimate the intensity of the reaction from 0.5 to 1 point. However, the maximum dose turned out to be significantly higher than the toxic dose, which indicates the absence of the declared compounds

20 sensitizing activity.

Example 6 Study of embryotoxic, teratogenic and mutagenic properties 25

Conducted studies on the determination of embryotoxicity and tetogenicity on rats showed that the claimed compounds and, in particular, Sacricin do not possess either of these

30 action and can be used during pregnancy.

Similar results were obtained when studying the effect of the drug on mutagenicity in a bacterial test system (Ames test) and by the method of accounting for dominant lethal mutations in mouse embryonic 35 cells. It was revealed that Sakopicin does not have mutagenic activity against strains ΤΑ 98 and ΤΑ 100 Zatoka gupρηιtigιit as in .

- 13 - conditions with and without metabolic activity, and does not exhibit mutagenic properties in relation to mouse reproductive cells.

Example 7

Study of pharmacokinetics

The pharmacokinetics of the claimed compounds were studied using various routes of administration to dogs: intravenous, subcutaneous and oral. Regardless of the route of administration, the dose was 600 mg/kg. It was found that the claimed compounds are distributed fairly quickly throughout the body's organs and tissues. The corresponding distribution period for 5-Sacrificin (A-H) is only 0.087 h. When the drug is administered extravascularly, its absorption occurs fairly quickly with a mean absorption time (MAT) of approximately 0.9 h and is virtually independent of the route of administration. The rate of elimination from the body is determined by the method of its administration and is greatest with oral administration, then subcutaneous administration and only then with internal administration.

Thus, as studies have shown for all 5 toxicity tests, the claimed compounds do not have cumulative properties, do not affect the basic mechanisms of cellular and humoral immunity, do not have embryotoxic and mutagenic properties, do not cause local tissue reactions 0

Example 8

Study of the influence on behavior and memory processes

5 The study of the influence of the declared compounds on the behavior of animals and memory processes was carried out on the basis of the assessment of motor and orientation - 14 - research activity and the method of conditioned reflex of active (URAI) and passive (URPI) avoidance on white parasitic rats.

As studies have shown, the declared salts

5 bicyclo [2 , 2 , 2 ] okotan-2-kabonovic acid and especially

Saccharin did not have a noticeable effect on the behavior of animals and on conditioned reflex activity, i.e. on memory processes (Fig. 1).

10 Example 9

0 mechanism of action

To clarify the electrophysiological mechanisms of action of the claimed compounds, studies were carried out

15 experiments on the neuron of the grape snail Hepix ycocortis Tariqsa ryug in the preparation of an isolated ganglion. The obtained data allow us to assume the ability of substances to stimulate cholinergic transmission in the nervous system by reducing

20 sensitivity of polylinic peptides of synaptic neutrophil.

CONCLUSION

25 Thus, the obtained results of the experimental study of safety, general pharmacological and specific activity of salts of bicyclo [2, 2, 2] octane-2-carboxylic ^acid allowed us to draw a conclusion about the emergence of a new class chemical

30 compounds that have a more effective and less toxic anticonvulsant effect on the body than previously known drugs.

At the same time, the salt of the said acid - Sacricin - turned out to be more preferable for use in

35 as a vascular drug, in comparison with such well-known drugs as phenobabital, diphenine and Convulex. - 15 -

Table 1

Latent periods (LP) of motor excitations (MA) (sec) and the degree of decline (points) according to data from sample experiments

(5 rats each), corazol model, (Intranasal administration)

Control

N' Latent period of seizures, sec of experience, severity of seizures, points (degree)

1 2 3 4

1 820 964 1140

2 330 520 1655

3 595 750 1325 1360

4 70 610 1265 2012

5 310 380 1425

6 390 855 1155 2385 average 419 2+258 .54 685 .8+227.25 1327.5+192.66 1919.0 those 360 680.0 1295.0 2012.0

Experience

Ν< Latent period of seizures, sec of experience, severity of seizures, points (degree)

1 2110

2 970 975

3 1205

4 845 925

5 820 1120

6 755 1810 average 1117.5+511.59 1207.5+410.09 those 907&5 1535.0 -16 -

Table 2 Latent periods (LP) of motor excitations (MA) according to data from 4 random experiments (ten mice in each) corazol model (subcutaneous administration)

Ν' Sakoptsin Κοnοποοοοποοοποποποποππππππκκικικικικαικικικαικικικικαικικικαικικικαιικικικικακικικαικκικικακια sec sec

1 151 339.4 77.5 200.6

2 89 130 60 93

3 83.5 223.1 70 130.5

4 112.5 288.9 67 101.5 average 109 245 68.6 131.4

Table 3

Latent periods (LP) of motor arousal (MA) and seizure severity in mice, corazol model

(subcutaneous administration)

Pepapat Dose of medicinal product before the onset of LP phase-fall - Degree mg/g la Dosage, sec, sec of phase-fall

(points)

Saksin 200 55-120 130-290 0.1.2

400 65-245 100-675 0.1

Phenobabital 15 40-87 45-205 2.3

30 85-170 65-220 2

Kontol 50-75 36-110 48-180 2,3,4 Table 4 Comparative data on average values in KM-ykh rats (subcutaneous administration)

Sak- 200 0 ^I 8 2.25+0.16*** 5.38+0.7 17.25+4.4 14.0 - 8.38+0.8* 5.0 - 12.5 ρищш 200 ? 8 2.25+0.13*** 9.87+3.7 23.75+4.7** 30.00+10.4 - 6.88+0.7* 7.0+2.1 - 25.0

200 ρ+σ* 16 2.25+0.10*** 7.63+1.9* 20.50±3.0*** 23.60±6.9 - 7.63+0.5*** 6.20+1.2* - 18.8

Konwu- 150- 0* 8 3.12±0.39 3.86+0.9 9.71 + 1.9 10.20+0.6 15.5±0.8 5.85+1.0 3.40±0.4 8.7+0.5 0 lex 200 ? 8 3.50+0.16 3.31+0.6 20.75+6.5 23.13±6.5 24.9±5.4 5.63±1.3 2.38±0.5 8.14+1.3 37.5

200 ο+ ø* 9 3.16±0.26* 3.78+0.7 21.11+5.5* 25.43±6.9* 26.7+5.9 6.83+1.0 3.14+0.4 8.83+1.2 33.3

Diphenin 12- σ* 6 Z.δZ±Ο.P 2.67±0.6 7.33+0.8 I.ΟΟ±Ο.b 16.7±0.6 4.67+0.2 3.67+0.3 9.33±0.8 0

20 ? 7 3.21±0.24* 2.86±0.5 8.57+1.2 12.67±2.2 16.2±2.1 5.71+0.8 4.33+0.9 9.75±1.8 0

20 £+0* 6 3.25±0.31 3.67±0.7 9.83±1.2 14.40±2.2 16.7±0.7 6.17±0.6 4.60+0.9 8.33+0.8 0

Κοнι- 1 ml σ* 8 3.67+0.13 3.13+0.8 8.00+1.6 11.00±1.9 16.79+2.3 4.87±0.9 3.00+0.6 8.79+0.9 0 ροol φ/ρ ? 8 3.87+0.08 3.13+1.0 7.25±1.1 10.38±1.4 15.13±1.5 4.12±0.4 3.12+0.5 7.87+0.9 0 ο_+σ* 16 3.78+0.08 Z.ΙЗ±Ο.b 7.62+0.9 yu.bδ±ι.ι 15.90+1.3 4.50+0.4 3.06+0.4 8.30+0.6 0

The presence of indicators of experienced state tests is available: * - πρρ<0.05; ** - πρand ρ<0.01; *** - πρand ρ<0.001

18

Table 5

Acute toxicity of Sacrycin to mice after subcutaneous administration

Dose Quantity in Quantity Quantity Time of death (mg/kg) in a group of victims (days of experiment)

500 12 0 0 -

750 12 0 0 -

10 1000 12 1 8 4

1250 12 3 25 1 ; 1 ; 3

1500 12 7 58 1 ; 1 ; 2 ; 2 ; 3 ; 4 ; 4

2000 12 8 66 1 ; 1 ; 1 ; 2 ; 4 ; 4 ; 5 ; 5

2250 12 12 100 all fell during

15 48 hours

ЛДϊ б=И 32 мг/κг ЛД₈ =203 б мг/κг 20 ЛД5=938 ( 875- 98 6 ) мг/κг

LDϊ b=I 32 mg/κg LD ₈ =203 b mg/κg 20 LD5=938 (875-98 6) mg/κg

Table 6

Study of anaphylactogenic properties in guinea pigs

Sensitization- Resolution, Quantity Quantity Average mg/kg mg/kg animals (+) -r-tion anafilac.

(Sacricin) index ύ

20 χ 3 200 9 0 0

200 χ 3 200 9 0 0

600 χ 3 200 5 3 0.4

200 i/v 200 3 0 0 υθ Κοнτροol 200 3 0 -

Claims

- 19 - ΦΟΡΜULΑ IZΟBΡΕΤΕΗIYA 1. Derivatives of bicyclo[2,2,2]octane-2-carboxylic acid of formula I

where Μ represents Oa, S, Od, Sa. 10 2. Hattium salt bicyclo [2, 2, 2] okatan-2-kabonovic acid - Sakopicin, which has anti-convulsant activity. 3. A pharmaceutical composition for the treatment or prevention of epilepsy, which contains as an active The 15th ingredient contains an effective amount of bicyclic derivative [2 2, 2] okotan-2-cabonova acids φορmules πο π. 1 together with a pharmaceutically acceptable carrier or diluent. 4. Pharmaceutical composition. 3, containing as an active ingredient the sodium salt of bicyclo [2, 2, 2] okotan-2-kabonovic acid. 5. A method of relieving a convulsive condition in a mammal, including a human, comprising administering to the mammal an effective amount 25 bicyclic derivatives [2 , 2, 2] about tan-2-kabonovic acid πο π . 1. 6. Method πο π . 5, where as a derivative of bicyclic acid [2, 2, 2] okotan-2-kabonovic acid is used its sodium salt - Saksin. 30 7. Use of derivatives of bicyclo[2, 2, 2]octane-2-carboxylic acid according to paragraph 1 for the production of a drug intended for the relief of convulsions in a mammal, including humans. 35 8. Application of πο π. 7, where as a derivative of bicyclic acid [2, 2, 2] okotan-2-kabonovic acid is used its sodium salt - Saksin.