NO771773L - PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE COMPOUNDS - Google Patents

Description

The present invention relates to a new method for the production of therapeutically active compounds with the formula:

and pharmaceutically acceptable salts thereof. The invention further relates to new intermediates which can be used in the preparation of the compound with the formula stated above.

The purpose of the invention is to provide a new and technically advantageous process for the preparation of compounds of formula I.

The end product N,N~dimethyl-3-(4-bromophenyl)-3~(3-pyridyl)-allylamine is previously known from Swedish patent 361 663" and it is believed to be useful as a therapeutic agent, especially as an antidepressant or anxiolytic agent.

Said patent shows a method for producing said product, comprising dehydration of a compound with the formula:

with a dehydrating agent such as concentrated sulfuric acid. While this method is stated to work and to give an acceptable yield

on a laboratory scale, it does not work well on a scale that is desirable for commercial production* Thus, on such a scale, a total yield of isomer-pure product of more than 20% has not been achieved. Depending on this and other circumstances, the production of the compound according to the known method is far too expensive.

J. Am. Chem.Soc, 77»4^36 (1955) describes a reaction according to the reaction scheme:

where -R^ is or -R-^ is or -R^ and R£ are both

In these systems, the formation of an active intermediate is promoted according to the formula:

by the reaction of the electron-donating groups and Rg.

In a corresponding system where a compound with the formula:

is used, however, the formation of a similar active intermediate is not likely due to the absence of such electron-donating groups.

Attempts have, however, been made to carry out an amine methylation reaction with said compound under the conditions suggested in the reference. This was not successful, although several variations of these conditions were tried.

According to the present invention, however, it has surprisingly been found that under certain conditions a reaction according to the scheme can:

carried out with great advantages. This method enables an improved yield and greatly improved production economy compared to the previously proposed method for producing the same compound. The improved production economy, besides being due to the improved yield, is partly dependent on the fact that cheap starting materials can be used and that unconverted starting material can be easily collected for recycling.

To be able to carry out the reaction, the reaction conditions must be carefully controlled. Thus, it has been found that an excess of amine in relation to formaldehyde must be used. Appropriately, the molar ratio between said reactants is around 2:1.

The relative amounts of 1-(4-bromophenyl)-1-(3-pyridyl)-ethylene and formaldehyde should give a significant excess of formaldehyde. Preferably, the molar ratio should be around 1:2, however, the ratio can vary up to 1:6, while maintaining a good turnover.

The reaction is suitably carried out in solution. A preferred solvent is acetic acid. Other possible solvents are e.g. the lower alcohols. It has been found desirable to use a relatively high concentration of the reactants in the solvent. When acetic acid is used, the molar ratio of l-(4-bromophenyl)-l-(3-pyridyl)-ethene to solvent should be about 1:4 to about 1:8, preferably about 1:5-

The reaction temperature is suitably around 110-120°C, i.e. close to the boiling point of the preferred solvent. Lower temperatures can be used, although this reduces the reaction rate* Appropriately, the reaction is allowed to proceed for about 4~7 hours. With such a reaction time, maximum yield is achieved and the formation of pollutants and by-products is largely avoided.

The reaction is catalyzed by acids. A preferred catalyst is HCl. The acid catalyst effect can be provided in a simple way by using the reacted amine in the form of its acid addition salt and thus dimethylamine hydrochloride is the most preferred amine reactant.

The turnover can be further improved by adding molecular sieves, preferably with a fineness of jk.

A method that has been found to achieve improved conversion is the distillation of part of the solvent followed by replacement with an equal amount of new solvent. This method can be carried out one or more times during the course of the reaction. The favorable effect achieved in terms of the yield is believed to be due to the elimination of water formed during the reaction. After the reaction has stopped and the solvent has been removed, a crude oil containing the desired end product and certain amounts of the starting material is usually obtained. The starting material can be obtained as the hydrochloride by extraction with a solvent such as methylene chloride having a pH between 1 and 4. The recovered 1-(4-bromophenyl)-1-(3-pyridyl)-ethylene hydrochloride can be recovered either directly or after conversion to 1-(4-bromophenyl)-1(3-pyridyl)-ethene. Purification of the recovered starting material is generally not necessary.

From the resulting mixture, the final product can be obtained by crystallization, optionally after decolorization with an absorbent such as carbon or silicon dioxide gel.

The final product exists in different stereoisomeric forms, i.e. in a Z-form and an E-form according to the IUPAC nomenclature (J.Org.Chem. 35, 2849-2867, Sept. 1970), which can be isolated. Preferably, the Z-isomer which is therapeutically active as an antidepressant is isolated. According to the present method, a ratio between the Z-isomer and the E-isomer of around 2.5:1* is achieved

Isolation of the end product as a base or as a salt of an acid, preferably a therapeutically acceptable acid, is within the scope of the invention and this also applies to isolation in various hydrated crystallized forms.

The starting material used in the process described above constitutes a further aspect of the present invention; Said starting material can be prepared from known compounds according to the following reaction core:

A Grignaré compound prepared from dibromobenzene is reacted with 3-acetylpyridine in an ether solution to form 1-r(4-bromophenyl)-1-(3-pyridyl)-ethanol. This intermediate product constitutes a further feature of the invention.

The intermediate is then dehydrated to form 1-(4-bromophenyl)-1-(3-pyridyl)-ethene. This can be carried out by heating in acetic anhydride. The intermediate product, which is an ethanol derivative, does not necessarily have to be isolated during the process.

According to a modification of the present method, the final product of formula I is prepared from 1-(4-bromophenyl)-1-(3-pyridyl)-ethanol without isolation of the corresponding substituted ethene that is formed. In this case, the substituted ethanol is dehydrated in a dehydrating agent such as acetic anhydride, optionally with the addition of a small amount of sulfuric acid. Excess dehydrating agent is then broken down with a suitable amount of water. After defecation, formaldehyde and dimethylamine are added and the procedure continues essentially as stated above.

In clinical use, the prepared compounds are normally administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic acid addition salt, e.g. such as hydrochloride, hydrobromide, lactate, acetate, sulfate or <g>ulfamate in association with a pharmaceutical carrier. Accordingly, what is stated regarding the new compounds is generically or specifically intended to include both the free amine base and the acid addition salts of the free base unless the context in which such terms are used, e.g. the specific examples do not correspond to the broad term. The carrier may be a solid, semi-solid or liquid diluent, or a capsule. Generally, the active substance constitutes 0.1 to 95% by weight of the preparation, more particularly 0.5 to 20% by weight for the preparation intended for injection and 2-5% by weight for preparations suitable for oral administration.

In order to prepare pharmaceutical preparations containing a compound according to the invention in the form of dosage units for oral use, the selected compound can be mixed with a solid powdered carrier, such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives -water or gelatin, and a lubricant such as magnesium stearate, calcium stearate or polyethylene glycol wax, and then compressed to form tablets. If coated tablets are necessary, the cores prepared as stated above can be given a coating of concentrated sugar solution which may contain e.g. gum arabic, gelatin, talc or titanium dioxide. Alternatively, the tablets can be covered with a varnish dissolved in a volatile organic solvent or a mixture of organic solvents. The dyes can be added to these coatings to distinguish between tablets containing different active substances or different amounts of the active compound.

For the production of soft gelatin capsules (bead-shaped closed capsules) consisting of gelatin and e.g. glycerol or similar closed capsules, the active substance can be mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active substance together with solid powdered carriers such as lactose, sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal use can be produced in the form of suppositories comprising the active substance in a mixture with a neutral fat base or rectal gelatin capsules comprising the active substance in a mixture with vegetable oil or paraffin oil.

Liquid preparations for oral use can be in the form of syrups or suspensions, e.g. sugar solutions containing from approximately 0.2% by weight to approximately 20% by weight of the indicated active substance, whereby the remainder is made up of sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain dyes, flavoring substances, saccharin and carboxymethyl cellulose as a thickening agent.

Solutions for parenteral use by injection may be prepared from an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration of from about 0.5% by weight to about 10% by weight. These solutions may contain stabilizing agents and/or buffering agents and can conveniently be stored in ampoules with different dosage divisions.

Suitable daily doses for the compounds produced in therapeutic treatment are 25-250 mg by oral administration, preferably 50-150 mg, 5-50 mg by parenteral administration, preferably 10-30 mg. A preparation in the form of dosage units for oral administration may contain 10-50 mg, preferably 10-25 mg of active compound per dosage unit.

The preparation for oral use such as tablets or granules conveniently contains the active ingredient in the form of its dihydrochloride monohydrate.

The invention is further illustrated by the following examples.

Manufacturing; a<y>the starting material0%intermediates for the starting material.

Example 1

1-( 4- Bromophenyl)- 1-( 3- Pvridyl)- ethanol:

48.8 g (0.206 mol) of 1,4-dibromobenzene was dissolved in

200 ml ether petroleum ether (40-60°)-toluene = 7:2:1 and placed in a dropping funnel. 4.88 g (0.20 mol) of magnesium was covered by 15 ml of the above solution. To initiate the Grignard reaction, an iodine crystal and 3 drops of methyl iodide were added and this mixture was stirred under argon. After initiation, the remaining dibromobenzene solution was added at a rate that produced rapid reflux. This method took 15 minutes, the reaction temperature was 36-38°C. After completion of the addition, the reaction mixture was stirred for a further 60 min.

at room temperature and cooled to l8-20°C. 18 g (0.15 ml) of 3-acetylpyridine in 80 ml of ether was added at such a rate that the reaction temperature did not exceed 25-27°C. The reaction was then allowed to proceed for one hour at room temperature, and was cooled to 15°C. 25 ml, 25% ammonium chloride was added dropwise, and the clear reaction solution was separated from the precipitate. This precipitate was washed with 200 ml of hot MIBK containing

10 ml of 25% ammonium chloride, filtered and washed with another 50 ml of MIBK. The combined organic phases were extracted four times

times with 100 ml of 1-N hydrochloric acid. The aqueous phases were neutralized with 30% sodium hydroxide and extracted four times with 100 ml of methylene chloride. The organic layers were evaporated. 42 g of crude product was dissolved in 60 ml of ethanol and 20 ml of concentrated hydrochloric acid added dropwise. After the addition of approx. 40~5° ml of ether gave crystallized 1-(4-bromophenyl)-1-(3-pyridyl)-ethanol hydrochloride. The product was collected by filtration and dried. Yield 25.4 g (54%), m.p. 191-194°C. After further crystallization of a small sample from ethanol, the melting point was 199~200°C.

The free base was obtained in 90~95$ after extraction with carbonate methylene chloride and crystallization from toluene-petroleumether. Temp. 104-105°C.

The above procedure was repeated using other amounts of 3-acetylpyridine with equivalent amounts of solvent and reactants. Said amounts and the percentage yield of 1-(4-bromophenyl)-1-(3-pyridyl)-ethanol hydrochloride are as follows: 74 - 53#> 9 6 - 57%.

18 g - 47% and 18 g in a repeated attempt 59%.

Example 2

1-(4-bromophenyl)-1-(pyridyl)-ethene

101 g (0.32 mol) of 1-(4-bromophenyl)-1-(3-pyridyl)-ethanol hydrochloride in 280 ml of acetic anhydride was heated at 130°C under reflux and argon in a closed system. This solution was allowed to cool to <$ Q°G and 4 ml of 6N hydrochloric acid

was added dropwise. The reaction solution was allowed to cool to room temperature and 400 ml of ether was added with stirring to

complete the felling. This precipitate was filtered and washed with ether and dried. 85 g (89%) of 1-(4-bromophenyl)-1-(3-pyridyl-ethylene hydrochloride, m.p. 230-233°C) was obtained. The free base was obtained after carbonate-methylene chloride extraction as an oil , bp 115-120°C/0.1 torr After crystallization the melting point of the free base was 44»5-46»5°C

Example 3

1-(4-bromophenyl)-1-(3-pyridyl)-ethanol.

187 ml of thionyl chloride was added to 50 g (0.406 mol) of nicotinic acid in an ice bath in such a way that the reaction temperature was maintained at 40°C. This mixture was heated for half an hour at 40°C, one hour at 50°C and one and a half hours at <r>fO°G bath temperature.

The excess of thionyl chloride was distilled off under reduced pressure and the suspension was allowed to cool. 100 ml of ether was added and the crystals collected by filtration. 68 g of nicotinic acid chloride hydrochloride were obtained. Dividend 94$-

14.24 g (0.08 mol) of nicotinic acid chloride hydrochloride was dissolved in 70.65 g (0.45 mol) of bromobenzene. With careful stirring, 26.7 g (0.2 mol) of aluminum trichloride was added in such a way that the reaction temperature did not rise above 35°C. At the end of the addition, the temperature was allowed to drop to approx. 30°G. The mixture was then heated for 45 minutes at 80°C bath temperature. raw ride. Evolution of hydrogen chloride gas began at 70°C and the color changed from dark yellow to dark red-brown. The solution was stirred for 17 hours at 80°C bath temperature.

The hot mixture was poured over 600 g of crushed ice containing 16 ml of concentrated hydrochloric acid. The organic layer was separated and the acidic aqueous layer was extracted three times with ether. The aqueous phase was basified with 50% sodium hydroxide solution and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and evaporated.

17 g of crude product was obtained.

The crude product contained 4-bromophenyl and 2-bromophenyl-3-pyridyl ketone. The 4-bromophenyl compound was crystallized from toluene-hexane. 10.5 g crystals m.p. 120-125°C. Dividend 50%.

10.8 g (4-1.2 mmol) of 4-b**omphenylketone was added with stirring to 60 ml of ether solution containing 60 mmol of methylmagnesium bromide in such a way that the reaction temperature was kept at 5°C. The reaction mixture was stirred for one hour at room temperature. After addition of 20 ml of THF, the reaction mixture was heated to 40-45°C for four and a half hours. By this time, almost all of the ketone had reacted.

The reaction mixture was poured onto ice and the organic layer was separated. The aqueous solution was extracted with methylene chloride. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue, 12 g, crystallized from toluene/petroleum ether. 1-(4-Bromophenyl)-1-(3-pyridyl)ethanol was obtained as white crystals.

Temp. 104-106°C. Yield 91%.

Production of the final product

Example 4

Z- N, N- dimethyl- 3-( 4- bromophenyl)- 3-( 3- pyridyl) allylamine

2.6 g (10 mmol) 1-(4-bromophenyl)-1-(3-pyridyl)-ethene, 2.6 g (31.9 mmol) dimethylamine hydrochloride, 0.6 g (20 mmol) paraformaldehyde and 4 >5ml of acetic acid, was heated to 115°C under argon. When the solution was clarified, the acetic acid was distilled off under reduced pressure. After a reaction time of two hours, a further 1.3 g (15>95 mmol) of dimethylamine hydrochloride and 0.4 g (13>2 mmol) of paraformaldehyde were added. After a total reaction time of 5 hours, as much acetic acid as possible was removed, and the reaction solution was cooled to 80°C. 20 ml of water and 5 ml of 2N hydrochloric acid were added and the solution was allowed to cool.

This aqueous solution was extracted three times with 20 ml of chloroform. The chloroform layer was washed with bicarbonate, dried over magnesium sulfate and evaporated. The residue was dried at 40°/100 torr. 1.15 g of unreacted 1-(4-bromophenyl)-1-(3-pyridyl)-ethene (4>45 mmol), (44>5%) was recovered. The above aqueous phase was basified with 30% sodium hydroxide and extracted 3 times with 25ml methylene chloride. The organic layers were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The dark brown residue was dried at 40°C/100 torr and filtered over 2.5 g of activated carbon with hot ethanol. The ethanol was evaporated and 1.65 g of crude product was obtained. This crude oil was dissolved in 15 ml of ethanol-ether (1:1) solution and 1 ml of concentrated hydrochloric acid was added dropwise. Ether (approx. 3~5ml) was added dropwise with continuous stirring to the point where the solution just started to become cloudy. Crystallization took place quickly and the suspension was allowed to stand for 2-3 hours at room temperature. Filtration and drying of the colorless crystals gave 1.15 g of Z-N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride. Temp. l85-l87°C, 50.5% calculated on converted starting material. Recrystallization from ethanol gave 1.02 g of the compound (44.7%), m.p. 193-196°C.

Example 5

80.0 g (0.308 mol) 1-(4-bromophenyl)-1-(3-pyridyl)-ethylene, 22.6 g (0.745 mol) paraformaldehyde, 123.0 g (1.51 mol) dimethylamine hydrochloride, 50 rog hydroquinone and 8.0 g of molecular sieves 3Å in 123 ml of acetic acid were heated to 115°C under argon. 35 ml

acetic acid was removed after 2 hours. The reaction was allowed to continue for a total of 6 hours. After total distillation of the acetic acid, 400 ml of 0>5N hydrochloric acid was added. Extraction with chloroform (5 times 200 ml) gave 49.5 g of 62% starting material. The water solution was neutralized with 30% sodium hydroxide, extracted with methylene chloride (5 times with 200 ml) to give 34 g of crude product. This brown oil was filtered over 60 g of activated carbon

with hot ethanol. The ethanol was removed at approx. 150 ml, 150 ml of ether added and 14 ml of concentrated hydrochloric acid were added dropwise. Crystallization gave 19.8 g of Z-N,N-dimethyl~3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride, m.p. 187-181°C.

Example 6

18.0 g (60.7 mmol) 1-(4-bromophenyl)~1-(3-pyridyl)-ethylene hydrochloride, 7.2 g (240 mmol) formaldehyde, 49.0 g (490 mmol) dimethylamine- hydrochloride and 19 ml of acetic acids were heated to 115°C under argon. 2.4 g (30 mmol) of sodium acetate were added

set and the reaction was allowed to continue for 7 hours. As much acetic acid as possible was removed (approx. 8 ml) and 40 ml of 2N hydrochloric acid was added when the temperature of the reaction solution had fallen to 80°C. This suspension was allowed to cool and stand overnight. Filtration gave 7.55 g ($42) of unreacted starting material. The filtrate was precipitated with a further 30 ml of water and extracted three times with 70 µl of chloroform. The chloroform solution was washed with bicarbonate, dried and evaporated and an additional 1.65 g (10.4$) of unreacted starting material, in the form of the free base, was recovered. The above acidic brown aqueous solution was basified with 30% sodium hydroxide and extracted with 4 x 50 ml methylene chloride. The combined organic layers were dried and evaporated and 9>6 g of crude product was collected. The crude product was dissolved in ethanol and filtered while hot over 8 g of activated carbon. Ethanol was removed so that 50 ml of solution was obtained, 70 ml of ether and 4.6 ral of concentrated hydrochloric acid were added. 6.0 g of precipitate was filtered off and dried, m.p. 185-187°C. Recrystallization from ethanol gave 5.15 g of Z-N,N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride, mp 195-198°C.

Example 7

50.0 g (0.1685 mol) 1-(4-bromophenyl)-1-(3-pyridyl)-ethylene hydrochloride, 10.5 g (0.349 mol) paraformaldehyde, 57>° g (0.349 mol) dimethylamine- hydrochloride and 60 ml of acetic acid were heated under argon and gentle stirring to 115°C. 12.0 g (0.147 mol) of sodium urea acetate was added in 2 g portions at 5 minute intervals. After 3 hours, 25 ml of acetic acid was removed under reduced pressure. After 4 hours, an additional 4.0 g (0.133 mol) of paraformaldehyde and 25 ml of fresh acetic acid were added. After four and a half hours, all the acetic acid was removed. The reaction was terminated after a total of 6 hours of reaction time. The mixture was allowed to cool to 80°C and 80 ml of water and 10 ml

6N hydrochloric acid was added. The cooled reaction solution was prepared as in Example 6.

Filtration gave 17>6 g of unreacted starting material (35>2$). Chloroform extraction gave 5>4g of unreacted starting material as free base ($12.3). Crystallization gave 14.9 g, m.p. 184-187°C Z-N,N-dimethyl-3-(3-pyridyl)-allylamine dihydrochloride.

Example 8

11.12 g (40 mmol) of 1-(4-bromophenyl)-1-(3-pyridyl)-ethanol was heated at 130°C in 20 ml of acetic anhydride containing 12.65 ml of concentrated sulfuric acid under argon for one hour.

(The sulfuric acid had previously been added in 0°C acetic anhydride). The reaction solution was cooled to 65°C and 2.95 g of water was added dropwise, at such a rate that. the reaction temperature was maintained at approx. 80-90°C, to decompose unreacted acetic anhydride. During cooling, 1304 g (160 mmol) of dimethylamine hydrochloride and 2.4 g (80 mmol) of paraformaldehyde were added. This suspension was heated to 115°C and all acetic acid was removed. After 3 hours, 1.0 g (33.mmol) of paraformaldehyde and 25 ml of acetic acid were added. After three and a half hours, the acetic acid was again removed. The reaction was terminated after a total reaction time of 5 hours. 18 ml of water was added and some 6N hydrochloric acid to lower the pH value to 1. The work-up was carried out as in Example 6. Filtration gave 1.4 g (12$) of 1-(4-bromophenyl)-1-(3- pyridyl)-ethylene hydrochloride and chloroform extraction gave 1.345 g (13$) of somewhat impure 1-(4-bromophenyl)-1-(3-pyridyl)-ethene which was converted to 1.1 g (72$) of its hydrochloride. A total of 2.5 g ($21.5) of this salt was recovered.

8.74 g of crude product was dissolved in ethanol and. filtered

in hot condition over 20 g of activated carbon. This purified crude product was dissolved in 60 ml of ethanol-ether (1:1), treated with 1.2 g of hydrochloric acid (gas) and dissolved in 10 ml of ethanol. A first crystallization gave 4»85 g»m.p. 184-187°C. A second crystallization gave 4»55g>smP*193~196°C.

Example 9

In the same way as in Example 8, 5>56 g of 1-(4-bromophenyl)-1-(3-pyridyl)-ethanol were reacted. 2.22 g (42.7$) of unreacted 1-(4-bromophenyl) -1-(3-pyridyl)-ethene was recovered. 3>°15 g crude product gave 1.7<8>5 g (49$) Z-N,N-dimethyl-3-(4-<b>romphenyl)-3 -(3-pyridyl)-allylamine dihydrochloride, mp 189-194°C.

Claims (14)

1. Method for the preparation of a therapeutically active compound with the formula: or a salt thereof, characterized by a compound with the formula: or a salt thereof, is reacted with an excess of formaldehyde, and dimethylamine, or a salt thereof, in excess in relation to the amount of formaldehyde under acid catalysis in an organic solvent, whereby the product formed, if desired, is converted into or isolated as one of its geometric isomers. 2. Process according to claim 1, characterized in that the product formed is converted to or isolated as the Z-isomer. 3. Method according to claim 1 or 2, characterized in that the solvent is acetic acid. 4. Method according to claim any one of the preceding claims, characterized in that the amount of starting material according to formula II is more than one mole per four moles of solvent. 5* Method according to any one of the preceding claims, characterized in that the molar amount of dimethylamine is about twice the molar amount of formaldehyde. 6. Method according to any one of the preceding claims, characterized in that the molar amount of formaldehyde is about twice the molar amount of starting material according to formula II. 7. Method according to any one of the preceding claims, characterized in that the acid catalysis is achieved by using HC1. 8. Method according to claim 7> characterized in that dimethylamine is added in the form of its hydrochloride, whereby the acid catalysis is achieved. 9. Method according to any one of the preceding claims, characterized in that the reaction is carried out at a temperature close to the boiling point of the solvent. 10. Method according to any one of the preceding claims, characterized in that a significant amount of solvent is distilled off during the course of the reaction. 11. Method according to any one of the preceding claims, characterized in that unreacted starting material according to formula II is recovered for reuse. . 12. Method according to any one of the preceding claims, characterized in that the obtained product according to formula II is introduced into a pharmaceutical preparation. 13. Compound, characterized in that it has the formula: or a salt thereof. 14. Compound, characterized in that it has the formula: or a salt thereof.