Sulfamate pseudofractures and pharmaceutical composition based on them

 

(57) Abstract:

Sulfamate pseudofractures formula I, where R1-R4-H, C1-6-alkyl; X is carbon or sulfur, provided that when X is carbon, R5and R6- H1-6-alkyl, whereas, if X is sulfur, one of R5and R6- oxygen and the other represents a pair of electrons, or both, are oxygen, or their pharmaceutically acceptable salt, hydrate, anomer, diastereoisomer or enantiomer, possess anticonvulsant activity. 2 C. and 8 C.p. f-crystals.

There are publications relating to sulfamates different patterns, including derived from monosaccharides (J. Med.Chem., 1987, 30, 880 and U.S. Patent N 4075351). Some of these sulfamate used as pharmaceuticals. Later information sulfamate, with a variety of pharmaceutical activity against epilepsy, glaucoma, peptic ulcers and male infertility, is contained in U.S. Patents NN 4513006, 4459601 and 4792569. It was found that one described in U.S. Patent N 4513006 compounds, topiramate, shows not only a significant anticonvulsant activity in relation to animals, but is also useful for the treatment of epilepsy in humans (Drugs of the Future,1989, 14, 342).

The substitution of oxygen in the ring of cyclic monosaccharides methylene group leads to an interesting class of compounds that have been designated as "pseudosuchia". Such compounds cyclica may have increased biological activity in comparison with the original monosaccharides.

In accordance with the foregoing, an object of the present invention are new sulphamate derivatives pseudo-d - fructopyranose that relate to topiramate, with potential anticonvulsant activity.

It is shown that some derivatives of sulpham corresponding to the General formula 1

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where R1, R2, R3, R4, R5and R6and X will be defined below,

possess anticonvulsant activity. Accordingly, the compounds and pharmaceutical compositions containing the compounds of the present invention, are useful for the treatment of seizures, such as epileptic seizures. More specifically, the present invention relates to compounds described by the following formula 1

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where R1and R2Cloacina, allyl or benzyl. Preferably, R1and R2they were both represented by hydrogens.

R3and R4can accept the same or different values and are selected from hydrogen or lower alkyl.

X may be selected from carbon (C) or sulfur (S); provided that when X is carbon, R5and R6may be the same or different and are selected from hydrogen or lower alkyl, and when X is sulfur, one of R5and R6represents oxygen and the other of them represents one pair of electrons, or both, are oxygens.

In the context of the present description, the term "alkyl" includes straight or branched chain. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and t-butyl.

The most preferred compounds of formula 1 are:

(1R, 2R, 3S, 4S)-(1,2:3,4-di-O-metiletilketoksim - 1,2,3,4-tetraol-4-yl)methyl sulpham, i.e., in the formula 1 R1and R2denote hydrogen, R3, R4, R5and R6are metelli, and X represents the carbon.

(1R, 2S, 3S, 4S)-(3,4-0-methylethylidene-1,2-0-sulphonylchloride - 1,2,3,4-tetraol-4-yl)methyl sulpham, i.e., in the formula 1 R1

(1R, 2S, 3S, 4S)-(3,4-0-methylethylidene-1,2-0-sulphonylchloride - 1,2,3,4-tetraol-4-yl)methyl sulpham, i.e., in the formula 1 R1and R2denote hydrogen, R3and R4denote methyl, both R5and R6represents oxygen, and X is sulfur.

In the scope of the present invention include various individual anomers, the diastereomers and enantiomers, and mixtures thereof. All such compounds are defined by formula 1. In addition, the compounds of the present invention include pharmaceutically acceptable salts, for example alkali metal salts, such as sodium or potassium, ammonium salts, dialkylammonium salt, dialkylammonium salt, tetraalkylammonium salt and tromethamine salts. In the scope of the present invention also includes a hydrate and a solvate of the compounds of formula 1.

The compounds of formula 1 can be obtained in accordance with the following schema.

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More specifically, the alcohol 11 in which R5and R6denote methyl (obtained by the method of Shing T. K and Targ Y. Tetrahedron,1990, 46, 6575-6584), is treated with a mixture of penishealthinformation and pyridine, and a catalytic amount of 4-dimethylaminopyridine in an appropriate solvent, such SUB>=Me). The resulting carbonate restore tributyltinhydride in conditions conducive to the formation of free radicals using peroxide tert - butyl toluene boiling under reflux for 2 hours to obtain ester IV (R5=R6=Me).

Diol Y (R5=R6=Me) is produced by interaction of the ether IV (R5=R6=Me) with oxide trimethylamine, pyridine, water and osmium tetroxide in t-butanol boiling under reflux for 2 hours. Specified diol is treated with 2-methoxypropene and acid catalyst, such as camphorsulfonic acid, in a suitable solvent, such as methylene chloride, at room temperature for 2-6 hours to obtain bis-acetonide VI (R3, R4, R5, R6=Me).

Recovery VI (R3, R4, R5, R6=Me) hydride diisobutylaluminum at a temperature of from -20oC to room temperature in a suitable solvent, such as tetrahydrofuran, gives the alcohol VII (R3, R4, R5, R6=Me). Sulpham VIII (R1= R2=H; R3,R4, R5, R6=Me) receive processing VII (R3, R4, R5, R6=Me) sulfhemoglobin and tritium">

Getting diol IX (R1=R2=H; R3=R4=Me) can be carried out by hydrolysis (see J. Med. chem. 1987, 30, 880) VIII (R1=R2=H; R3, R4, R5, R6=Me) in the presence of an acid catalyst, such as HCl, in a suitable solvent, such as THF or ethanol, at temperatures from room temperature up to the boiling temperature under reflux for 2-6 hours. Processing IX (R1=R2=H; R3= R4= Me) sulfurylchloride in the presence of pyridine or triethylamine at a temperature from -78oC to 25oC in a suitable solvent, such as methylene chloride or toluene (see U.S. Patent N 5242942), gives bis-chlorosulphate X (R1=R2= H; R3= R4= Me). The interaction of X with a weak base, such as NAHCO3or pyridine, in an alcohol solvent such as ethanol, at temperatures from -40oC to 25oC gives the cyclic sulfate XI (R1=R2=H; R3=R4=Me).

Cyclic sulfite XII (R1=R2=H; R3=R4=Me) can be obtained (see U.S. Patent N 5242942) interaction IX (R1=R2=H; R3=R4=Me) with thionyl chloride in the presence or absence of a weak base, such as pyridine, in a suitable solvent, such coolfit XII (R1=R2=H; R3=R4=Me) can be oxidized to the cyclic sulfate XI (R1=R2=H; R3=R4=Me) using a suitable oxidant, such as ruthenium tetroxide, in a suitable solvent, such as methylene chloride or benzene.

Pharmaceutically acceptable salts of the compounds of formula 1 can be obtained by the reaction of sulpham formula (1) with an appropriate base, followed by separation of salt.

The compounds of formula 1 is most useful for use as anticonvulsants in mammals, including humans. Anticonvulsant activity of the described compounds is determined using the standard test on the maximum electroshock" [MES (MES)]. In this test the activity specifies the blocking tonic extensor convulsions caused by the use of electric shock in mice via corneal electrodes, as described by Swinyard et al.,J. Pharmacol. Expt. Ther, 1952, 106, 319, and is estimated as the percent blocking. More recent data on screening currently used anticonvulsants are also given in the work Swinyard, Epilepsia, 1978, 19, 409.

In this test using male albino mice CRS-CDI weighing 18 to 25 g (and corneal electrodes receive from Wahjquist Jnstrument Company, Salt Lake City, Utah.

Maximal electroshock seizures cause the influence of the current at 60 Hz, the power of 50 milliamps (mA) per mouse via corneal electrodes for 0.2 seconds, as was first described by Swinyard 1952. The intensity corresponds to about 4-6 times the current value, resulting in 100% tonic extensor seizures. When assessing the MES test, the duration of the various components of convulsions following the impact of maximal electroshock, is measured as follows: tonic flexion of the hind legs is measured in the time period from exposure to the stimulus before straightening tonic hind legs (i.e., until the rear legs away from the body at an angle greater than 90oC), toniceski extension of the hind legs is measured in the time period from the moment of the first extensor impulse prior to the overall muscle contractions and final muscle contraction measured in the period of time from beginning to end bilateral rhythmic clonic convulsions. Also committed deaths. The duration of each component of the seizures is consistent with the values given earlier in Tedeschi et al., J. Pharmacol. Expt. Ther., 1955, 116, 107. Corneal electrodes have a concave shape, taxpercent must always be less than 40% of the control mice. Thus, under the action of electric shock with a frequency of 60 Hz, amperage of 50 mA and a duration of 0.2 seconds constituent order convulsive reaction and the percentage of control animals exhibiting corresponding to these components behavior are as follows: tonic flexion (100%), tonic straightening (100%) and muscle contraction (100%), it is noted a mortality rate below 40%.

For test compounds, the elimination of the component of the tonic extension is an endpoint of the reaction. Animals administered orally or dose media, or the compounds, and at a certain time give the maximum electric shock through corneal electrodes soaked in saline solution (as described above). In each group use a minimum of 10 animals and note the percentage of animals which have not been recorded straightening tonic hind limb. Determine the dose ED50(i.e. the dose that inhibits 50% of straightening tonic convulsions). For example, the anticonvulsant activity of the compounds of formula 1 in which R1and R2denote hydrogen, R3, R4, R5and R6denote methyl and X denotes carbon, corresponds to the value ED5016 mg/cojet to be used daily in a dosage of about 10 to 2000 mg, usually take an average adult 1-4 reception. Unit dose contains from about 5 to 500 mg of active ingredient. This corresponds to a dose of from about 0.1 to 30 mg/kg/day.

In General, the compounds of formula 1 can be used to treat epilepsy in a manner analogous to that practised in respect of phenytoin, i.e., by oral administration twice a day solid forms of the drug. Medical aspects of epilepsy treatment is described in more detail in the work of L. S. Goodman et al. "The Pharmacological Basis of Treurapeutics", 5 th Ed., Macmillan, 1975, 201-206.

The compounds of formula 1 is administered preferably in the form of pharmaceutical compositions. To prepare the pharmaceutical compositions of the present invention one or more of the sulphamate compounds of formula 1 is mixed until smooth with a pharmaceutical carrier according to conventional pharmaceutical methods, these media can be used in different types, depending on the method of administration of the drug: oral, use of suppositories, or parenterally. In the manufacture of the compositions in oral dosage form may be any of the usual pharmaceutical media. So, for example, to obtain a liquid pericoli, oils, alcohols, flavoring agents, preservatives, dyes and other ; for solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricating agents, binders, loosening agents and others In connection with the ease of the introduction of tablets and capsules represent the most convenient oral dosage form, in this case are, of course, a solid pharmaceutical carriers. If necessary, the tablets may be using standard techniques covered with sugar or intersolubility shell. Can also be prepared suppositories, in this case, as the carrier used cocoa butter. Used for parenteral administration, the carrier includes sterile water, can be included and other ingredients, to provide, for example, solubility or for preservation purposes. Can also be made suspension for injection using suitable liquid carriers, suspendida agents etc.

Mainly to prepare the above pharmaceutical composition in unit dosage form, as indicated in exce of the present description and claims refers to physically discrete units, suitable for use as a single dose, despite the fact that each unit contains a predetermined quantity of active ingredient that can lead to the desired therapeutic effect, in combination with the required pharmaceutical carrier.

The described pharmaceutical compositions contain the correct dosage for a certain preparative form, i.e., per pill, powder, injectable portion, teaspoonful, suppository, etc. of the Composition administered in the dosages indicated previously calculated in relation to the amount of the active ingredient and the severity of the condition. The dosages, however, may vary depending on the needs of the patient, the severity of the condition and nature of the applied compounds. Determination of the optimal dosage for each specific situation available to every specialist with the average level of knowledge in this field.

In the following examples, and throughout the description, the following terms and abbreviations: g (grams), ml (milliliters), min (minute), h (hours), mol (moles), mmol (mmol), M (molar) volume/volume (volume to volume), TCS (thin layer chromatography), HPLC (high performance liquid chromatography), C, H, N, and th rotation, measured at a temperature of 25oC in the light, the length of 589 nanometers), C (concentration in grams per 100 ml)1H NMR (spectrum nuclear magnetic resonance), reduction NMR: s=singlet, d=doublet, so=triplet, m=multiplet, W.=advanced DD. = doublet of doublets; Cl-MS (mass spectrum chemical ionization), TPL(the melting point). All the melting points are corrected.

Example 1: (1R, 2R, 3S, 4S)-[1,2:3,4-di-0-(1-methyl - ethylidene)cyclohexane-1,2,3,4-tetraol-4-yl]methyl sulpham [VIII (R1=R2=H; R3, R4, R5, R6=Me)]

(1R, 2R, 3S)-2,3-0-(1-methylethylidene)-5-methoxycarbonyl-4 - cyclohexene-1,2,3-triol (1.56 g, 6.8 mmole; obtained by the method of Shing T. k. and Tang Y. Tetrahedron, 1990, 46, 6575-6584), pyridine (2.16 g, 27 mmole) and a catalytic amount of 4-dimethylaminopyridine dissolved in methylene chloride (35 ml) and slowly in an argon atmosphere at a temperature of 23oC add fenilalaninemia (1.77 g, 10.2 mmole). After 2 hours the reaction mixture was poured into saturated ammonium chloride (200 ml) and dilute the mixture with methylene chloride. Separate the organic layer, wash it with saline, dried (MgSO4) and evaporated under vacuum to obtain a yellow oil, which is further cleaned using the preparative VAA/2 - propanol gives analytically pure white solid thionocarbonate III (R5=R6= Me):

TPL123 -125oC; CI-MS (CH4) MH+= 365;

1H NMR 1.42 (SD,CH3), 1.45 (SD,CH3), 2.77 (m,1H, H6a), 3.0 (DD., 7= 16.5, 5.5 Hz, H6e), 3.80 (S., OCH3), 4.67 (sm., J=3.4 Hz, H3), 4.85 (BL.,1H, H2), 5.60 (DDD., J=10.1, 5.5, 2.3 Hz, H1), 6.81 (m, 1,OH,H4), 7.13 (DD, J= 7.4, 1.2 Hz, ortho arene.), 7.31 (DD., 1H, J=7.3, 7.4 Hz, a pair of arene.), 7.43 (DD.,2H, J=7.4, 8.0 Hz, meta arene.);

[]2D0-6,07 (c=0,692, CH3HE);

Analytical data for C18H20O6S:

Calculated,%: C - 59,33; H - Of 5.53.

Found, %: C - 59,22; H - 5,48.

Thionocarbonate III (R5= R6= Me; 1,53 g, 4.2 mmole), tributyltin hydride (1,83 g, 6.3 mmole) and peroxide tert-butyl (123 mg, from 0.84 mmole) was placed in toluene (80 ml) and refluxed for 1.5 hours. After cooling, the reaction mixture is evaporated under vacuum to obtain a clear oil, which was dissolved in diethyl ether (100 ml). The ether solution is washed once with 1M NaOH (100 ml), water (50 ml), brine (50 ml), dried (MgSO4) and evaporated under vacuum to obtain the crude product. It further purified using preparative HPLC (ethyl acetate/hexane, 1:8) to obtain the complex ester IV (R5=R6=Me) as prozrachnoj), 2.05 (m, 1H, H5a), 2.25-2.45 (m, 2H, H5e/H6e), 3.76 (S., OCH3), 4.35 (DDD., J=3.0, 5.4, 5.4 Hz, H1), 4,59 (m, H2), 6.78 (CL., 0,95 H, H3).

Ester IV (R5= R6= Me; 0.66 g, 3.1 mmole) was placed with the dihydrate of trimethylamine oxide (0,49 g, and 4.40 mmole), pyridine (1.50 g, 18,8 mmole) and water (0,30 g, a 16.8 mmole) in tert-butanol (30 ml) and added dropwise at a temperature of 23oC osmium tetroxide (30 mg, 0.12 mmole). The reaction mixture is refluxed for 2 hours, cooled, diluted with 20% NaHSO3(15 ml) and stirred for 30 minutes at a temperature of 23oC. the Solution is evaporated under vacuum to obtain a residue, which was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (MgSO4) and evaporated under vacuum to obtain a light yellow oil, diol V (R5=R6=Me):

CI-MS (CH4) MH+= 247;

1H NMR 1.39 (C., CH3), 1.55 (C., CH3), 1.65 (M,1H, H6a), 2.0-2.2 (m, 3H, H6e/H5a/H5e), 2.28 (D., J=7.2 Hz, HE), 3.28 (SD, OH), 3.88 (DD., J=7.3, 7.5 Hz, H3), 3.98 (DD, J=5.1, 7.7 Hz, H2), 4.45 (m,1H, H1).

2-Methoxypropene (0.26 g, 3.5 mmole) are added to dealu V (R5=R6=Me; of 0.44 g, 1.8 mmole) in methylene chloride (10 ml) in an atmosphere of ar is in the equivalent 2-methoxypropene (0,13 g, 1.8 mmole) and continue stirring for 1 hour. Add saturated NaHCO3(5 ml), the organic phase is separated, washed with brine, dried (MgSO4) and evaporated under vacuum to obtain the crude bis-acetonide VI (R3, R4, R5, R6=Me) in the form of oil:

CI-MS (CH4) CI-MS MH+=287;

1H NMR 1.34 (C., CH3), 1.35 (C., CH3), 1.47 (SD, CH3), 1.48 (SD, CH3), 1.60-1.90 (m , 3H, H5e/H6e/H6a), 2.00 (DDD., J=5.3, 15,0, 15.0 Hz, H5a), 3.80 (S. , OCH3), 4.43 (m H1), 4.50 (DD., J=2.2, 7.6 Hz, H2), 4.71 (D., J= 2.2 Hz, H3).

Bis-acetonide VI (R3, R4, R5, R6=Me; 390 mg of 1.36 mmole) in tetrahydrofuran (7.0 ml) is cooled to a temperature of -20oC (ice/methanol bath) and within 15 minutes add the hydride diisobutylaluminum (DIBAL-H 2,75 ml, 1M in THF), and then the reaction temperature was raised to 23oC. After 30 minutes the reaction mixture is cooled to a temperature of -10oC and add another portion of DIBAL-H (2,75 ml). Upon completion of the reaction (monitoring by TLC) to chilled on ice mixture is added saturated ammonium chloride (10 ml) and the resulting mixture was stirred for 10 minutes. Next, the mixture is evaporated under vacuum and the residue is shaken out three times with PI the PTO to obtain a clear oil. The oil obtained is subjected to further cleaning using preparative TLC (ethyl acetate/hexane, 1:2) to give the alcohol VII (R3, R4, R5, R6=Me) as a pure viscous oil:

CI-MS (CH4) MH+=259;

1H NMR 1.34 (C., CH3), 1.40 (C., CH3), 1.46 (SD, CH3), 1.47 (SD, CH3), 1.60-1.95 (m, 2 aliphatic gr.), 2.08 (DD., J=5.7, 7.2 Hz, HE), 3.55 (m , 2H, CH2Oh), 4.27 (D., J=2.7 Hz, H3), 4.44 (m, 1H, H1), 4.54 (DD., J=2.7, 7.5 Hz, H2).

Alcohol VII (R3, R4, R5, R6=Me; 0.24 g, of 0.93 mmole) and triethylamine (0.20 g, 2 mmole) is mixed in dimethylformamide (6 ml) and cooled to a temperature of 0oC in argon atmosphere. After that add sulfhemoglobin and stirred the reaction mixture for 2 hours at a temperature of ABOUToC, then add a couple of triethylamine (0.20 g, 2 mmole) and sulfhemoglobin (0,215 g, 1.86 mmole); the stirring is continued for 1 hour at a temperature of ABOUToC. the Reaction mixture was distributed between methylene chloride and dilute NaHCO3, after which the organic phase is separated and washed three times with water, once with brine, dried (MgSO4) and evaporated under vacuum to obtain a viscous oil. The product is cleaned by using preparative, 5, R6=Me):

CI-MS (NH3) MH+=338

1H-NMR 1.34 (C., CH3), 1.44 (SD, CH3), 1.45 (SD, CH3), 1.47 (SD, CH3), 1.60-1.90 (m, 4 aliphatic gr.), 4.16 (D., J=11.1 Hz, CHaOSO2), 4.21 (D. , J= 2.6 Hz, H3), 4.29 (D., J=11.1 Hz, CHbOSO2), 4.44 (sm., J=7.5 Hz, H1), 4.53 (DD., J=2.6, 7.5 Hz, H2), 4.95 (CL., NH2);

[]2D5D25+1,20 (C=O,5, CH3OH).

Analytical data for C13H23NO7S

Calculated,%: C-46,28; H-6,87; N-4,15.

Found,%: C-46,08; H-6,89; N-4,19.

Example 2: (1R, 2R, 3S, 4S)-[1,2:3,4-di-O-(1-methyl - ethylidene)cyclohexane-1,2,3,4-tetraol-4-yl] methyl dimethylsulfate [VIII (R1, R2, R3, R4, R5, R6= Me)]

Alcohol VII, obtained by the method of example 1, (R3, R4, R5, R6=Me; 0.24 g, of 0.93 mmole) and triethylamine (0.20 g, 2 mmole) was placed in dimethylformamide (6 ml) and cool the resulting solution to ABOUToC in argon atmosphere, adding dimethylsulphamoyl (0,275 g of 1.86 mmole). After incubation for 3 hours at a temperature of 0oC, the reaction mixture was distributed between methylene chloride and NaHCO3. The organic solution is separated and washed three times with water, once with brine, vysushivaya TLC (ethyl acetate/hexane), getting in the sulpham VIII (R1, R2, R3, R4, R5, R6=Me).

Example 3: (1R, 2S, 3S, 4S)-[3,4-0-(1-methylethylidene)-1,2-0 - sulphonylchloride-1,2,3,4-tetraol-4-yl)methyl sulpham [XI (R1, R2=H; R3, R4=Me)]

Sulpham VIII (R1=R2=H; R3<R, R5, R6=Me; of 0.38 g, 1.0 mmole) in THF (5 ml) and 3N HCl (5 ml) is stirred at a temperature of 45oC for 4 hours. The solution is cooled to room temperature, adjusted the pH to 7.0 using Na2CO3and spend three times extraction with THF. Next, the organic solution is dried (MgSO4) and evaporated under vacuum to obtain an oily IX (R1, R2=H, R3, R4=Me). This diol is dissolved in ethyl acetate (10 ml) and pyridine (3 ml), cooled to a temperature of 60oC, treated with sulfurylchloride (0,30 g of 2.24 mmole) and the resulting mixture was stirred at room temperature for 3 hours. Filter the white solid, and the filtrate is washed once with 1N HCl, once with saturated NaHCO3once brine, dried (MgSO4) and evaporated under vacuum to obtain bis-chlorosulphate X (R1, R2=H; R3, R4=Me). This bis - chlorosulphate in meta is actionnow the mixture is filtered and evaporated under vacuum. The residue is dissolved in ethyl acetate, washed with brine, dried (MgSO4) and evaporated under vacuum to obtain the cyclic sulfate XI (R1, R2=H; R3, R4=Me).

Example 4: (1R, 2S, 3S, 4S)-[3,4-0-(1-methylethylidene)-1,2-0 - sulphonylchloride-1,2,3,4-tetraol-4-yl)methyl sulpham [XII (R1, R2=H; R3, R4=Me)]

Diol XI (R1, R2= H; R3, R4=Me) (0,30 g, 1.0 mmole) in dioxane (5 ml) is refluxed immediately after the addition of thionyl chloride (1.5 ml, 20 mmole). After 15 minutes the reaction mixture is cooled and evaporated under vacuum. The residue is dissolved in ethyl acetate and washed twice with saturated NaHCO3twice with saline, dried (MgSO4) and evaporated under vacuum to obtain the cyclic sulfite XII (R1, R2=H; R3, R4=Me).

1. Sulfamate pseudofractures formula I

< / BR>
where R1and R2the same or different, is hydrogen or C1- C6-alkyl;

R3and R4the same or different, is hydrogen or C1- C6-alkyl;

X - carbon (s) or sulfur (S), provided that when X is carbon, R5and R6may be the same or different and selected from the waters of the free pair of electrons, or are both oxygen,

or their pharmaceutically acceptable salt, hydrate, anomer, diastereoisomer or enantiomer.

2. Connection on p. 1, in which each of R1and R2- hydrogen.

3. Connection on p. 1, in which X is carbon.

4. Connection on p. 1, in which X is sulfur.

5. Connection on p. 4, in which each of R5and R6the oxygen.

6. Connection on p. 4, in which R5and R6- free pair of electrons, and oxygen.

7. Connection on p. 1, which is selected from:

(1R, 2S, 3S, 4S)-(1,2:3,4-di-O-matricellular-1,2,3,4-tetraol-4-yl)methylsulfonate, i.e., in the formula I R1and R2each is hydrogen, R3- R6each is methyl, and X is carbon;

(1R, 2S, 3S, 4S)-(3,4-O-methylethylidene-1,2-O-sulphonylchloride-1,2,3,4-tetraol-4-yl)methylsulfonate, i.e., in the formula I R1and R2each is hydrogen, R3- R4each is methyl, R5is oxygen, R6electronic pair, and X is sulfur;

(1R, 2S, 3S, 4S)-(3,4-O-methylidene-1,2-O-sulphonylchloride-1,2,3,4-tetraol-4-yl)methylsulfonate, i.e., in the formula I R1and R2each is hydrogen, R3and R4each is methyl, R5and R6both oxygen and X is sulfur.

8. Pharmaceutical companies the compound is present in a therapeutically effective amount for the treatment of seizures.

9. Connection on p. 1, used to treat spasms.

10. Connection under item 1 for use in the manufacture of a medicinal product for the treatment of seizures.

Priority by all indications from 23.12.93.

Priority by all indications from 10.11.94.

 

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