CS208157B2 - Method of making the new amino-derivatives of the glycaroles - Google Patents

Description

The present invention relates to a process for the preparation of novel amine derivatives of glycerols with anti-glare effect.

Viral infections that attack mammals, including humans, are contagious and can cause major health problems and economic losses. Unfortunately, the discovery of pro-active compounds is far more complex and difficult than that of antibacterial and antifungal compounds. Probably, the obstacle to research is the close structural affinity of viruses and some essential cell components, such as ribonucleic acid and deoxyribonucleic acid. However, a number of non-viral anti-viral agents have been discovered, i.e., compounds that prevent or treat viral infections, or are materials that substantially increase antibody production, improve antibody efficacy, increase non-specific resistance, accelerate recovery or reduce symptoms. [Herriman et al., Why. Soc. Exptl. Biol. Med., 103, 625 (1960)]. Anti-viral agents include, for example, interferon and synthetic materials such as amantadine hydrochloride, pyrimidines, trguanides, guanidine, pteiridines, and methisazone. Since each of these agents can be treated with several of these viral infections, it is necessary to find new synthetic antiviral agents to better prevent and treat viral infections.

Mammalian cells produce a substance in a viral infection that allows the cell to inhibit the reproduction of the virus. These compounds are called inteferferons. Interferons are glyico-proteins, which may differ in their physical-chemical properties, but have the same trologic properties, by inhibiting a wide range of mutually non-adherent viruses. These compounds do not have toxic or other adverse effects on the cells and are specific within one species. (Lockart, Froners of Biology, vol. 2, "interferons", published by Fiinter, W. B. Saunders Co., Philadelphia, 1966, pp. 19-20).

To date, no economical and practicable method has been proposed for the production of exogenous interferon for current chemical use. Efforts have therefore been made in a different direction to be able to administer to the animals or human being to be protected against infection a non-viral substance which promotes or induces the generation of iinterference in cells. The interferon obtained by this method is called endogenous interferon.

U.S. Patent No. 2,738,351 discloses compounds of the general formula

R 1 - X - CH ₂ 1 I

CH — Z — ALK — B,

AND

R 2 - Y - CH 2 where denote

R 1 and R 2 alkyl, arylalkyl, aryl, cycloalkyl, aryl substituted with nitro or halogen, optionally alkyl or alkoxy,

X, Y and Z are oxygen, sulfur or sulfonyl,

Straight chained or branched chain alkylene of 1 to 6 carbon atoms; and

B is the lowest alkylamino group, piperidine group, morpholino group, pyrrolidino group, (lower) alkylpyrrolidine group, N‘ -alkylpyridazino group, or pipecoline group, are local anesthetics. In explaining the various routes for producing these compounds, for example in column 1 on page 11, lines 57-70 of the aforementioned patent, the intermediates of the above formula are mentioned, wherein B is amino or lower alkylamino. However, none of these compounds contains a higher alkyl group than n-pentyl in the meaning of R1 or R2. Furthermore, in neither of these compounds, R1 and R2 are both alkyl and X and Y are both oxygen.

Japanese Patent No. J7-6O42-177 discloses insecticidal and miticidal compounds of the general formula:

R 1 - CH 2

CH- (CH2) _q -A,

Rz — CH2 where they are

R 1 and R 2 include, but are not limited to, lower alkylthio, q 0 to 5, and

And, among others, a 1-piperidine group or a di (lower alkyl) amino group.

It has now been found that some novel amine derivatives of di-O- (n-higher alkyl and alkenyl) glyceirols are substances that can serve to combat viral infections in mammals.

The novel amine derivatives of glycerols having a pirotiviral activity of the general formula I,

CH 2 —Q 1 • CH 2 Q 2 • CH 2 OR 2, (I) as well as pharmaceutically acceptable acid addition salts of these compounds, wherein one of the symbols

Q 1 and Q 2 represent —O — Y — NHR3 and the other —OR 1,

R1 and R2 are straight chain alkyl of 12 to 20 carbon atoms,

Y represents alkylene of 2 to 4 carbon atoms, the valences of which are on different carbon atoms and

R 3 is hydrogen or C 2 -C 4 alkyl are produced by the process of the invention, which comprises

a) reacting a compound of formula II in the reaction,

CHz — Qs • CH — Qe

CHz — OR2, (Π) where one of the symbols

Qs and Qe are R10- and the other is —O — Y‘ — CHO,

Y ‘represents alkylene of 1 to 3 atoms

whose left bonds are linked to oxygen atoms, to a compound of the formula NH21R3 under reducing conditions, and

b) optionally converting the compound of formula I thus obtained into a pharmaceutically acceptable acid salt thereof.

The compounds produced by the method of the invention have a direct antiviral effect on a variety of viruses in vivo in mammals and in vitro in tissue cultures of mammalian cells. A substantial part of this effect is believed to be that the compounds of the invention induce the generation of interferon in cells, i.e., endogenous interferon.

The term "pharmaceutically acceptable" acid addition salts refers to salts that are nontoxic at the dosages used. These are water-soluble and insoluble salts such as hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, octains, hexafluorophosphates, citrons, gluconates, beinzoates, propionates, butyrates, sulfosalieylates, maleates, laurates, malate, fumarates, fumarates , amsonates (4,4'-diaminosilbene-2,2'-disulfonates), pamoates (1,1'-methylene-bis-2-hydroxy-3-naphthoates), stearates, 3-hydroxy-2-naphthoates, p-toluenesulfonates, methanesulfoinates, lactates and salts with suramine.

Preferred groups of compounds of formula I are:

hydrochlorides of the following compounds:

substances in which R1 and R2 are straight chain alkyl of 14 to 18 carbon atoms;

compounds wherein R 1 and R 2 are straight chain alkyl of 14 to 18 carbon atoms, both groups being identical; compounds wherein R1 and R2 are n-hexadecyl;

substances in which R3 represents a hydrogen atom and Y represents a straight chain alkylene of 2 to 4 carbon atoms.

Of particular interest are the following compounds and their pharmaceutically acceptable acid addition salts:

1,3-di-O- (n-hexadecyl) -2-O- (3-aminopropyl) glycerol,

1,2-di-O- (n-ihexadecyl) -3-O- (3-aminopropyl) glycerol,

1,3-di-O- (n-hexadeicyl) -2-O- (meta-aimimomethylbenzylenglycylol),

1,2-di-O- (n-hexadecyl) -3-O- (meta-aminomethylbenzyl) glycerol,

1,2-di-O- (n-fetradecyl) -3-O- (imeta-aminomethylbenzyl) glycerol,

1,3-di-O- (in-hexadecyl) -2-O- (meta-aminomethylphenyl) glyceirol,

1,3-di-O- (n-1-hexadecyl) -2-O- (para-aminomethylphenyl) glycerol,

1,2-di-O- (n-hexadecyl) -3-O- (para-aminomethylphenyl) glyceirol.

Acid addition salts of the compounds of formula (I) may be prepared by conventional means, for example by mixing an amine derivative in a suitable solvent with the desired acid and isolating the salt ¹ by evaporation or precipitation after addition of a solvent in which the salt is present. does not dissolve. Hydrochlorides can be readily prepared by passing hydrogen chloride through a solution of the amine derivative in an organic solvent. Obviously, many of the hydrochlorides or dihydrochlorides of the compounds of formula I contain some water after isolation. It is not known whether it is crystal water or the formation of true hydrates, but these salts can also be formulated and administered without prior dehydration.

The starting 1,2-di-O- (n-higher alkyl) glycerols can be obtained according to the method of Kaites et al., Biochemistry, 2, 394 (1963). The glycerols can be obtained according to the method of Daimico R. et al., J. Lipid Res., 8, 63 (1967) The starting 1,2- and 1,3-di-O- (n-higher alkenyl) glycerols can be obtained by according to Baumain WJ and Magold HK, J. Org.Cihem., 31, 498 (1966J).

The antiviral activity of the compounds of formula (I) was determined by two basic independent procedures. In the first procedure, the test substance is administered to mice intraperitoneally 18 to 24 hours prior to the administration of a lethal dose of encephalomyocarditis virus (EMC). Ten days thereafter, the number of surviving mice is examined and compared to the number of surviving mice without treatment. The procedure is carried out by administering the test compound far from the site where the virus is administered, so that it is possible to eliminate the interactions between the active substance and the virus and to detect only substances which actually increase the resistance to the virus.

In the second procedure, simple layers of human nasal polyp cells are grown on small plates. These cells ¹ are then treated with the investigated slouičeninalmi approximately 18 · hour before -než added to the cells lethal dose of virus vasikuláirní stomiatitidy (VSV). The test substance is washed out of the tissue culture prior to virus application. The fluid that is extracted from the plates after infection is titrated to detect the virus content of L-929 mouse fibroblast cultures. The values determined are compared to those from tissue cultures not contacted with the compounds of the invention. ·

In addition, a number of compounds produced by the process of the invention have been investigated for their ability to increase the known antiviral activity of poly / carrier and polycytidylic acid. In addition, some compounds were investigated for their ability to induce interferon formation in mice following parenteral administration as described by Hoffman, W. W., et al., Antimicrobial Agents and Gheimotherapy, 3, 498-501 (1973).

Parenteral, topical or intranasal administration of the above-mentioned amines to mammals prior to virus infection rapidly results in virus resistance. Preferably, administration of the active ingredient should occur at least 2 days or the day before infection, although this value varies somewhat according to the type of virus and the species of animal to which the compound is administered.

The compounds of formula I are most readily and most conveniently administered in dispersed form together with a suitable carrier. With respect to the term dispersed forms, it is meant that the particles are kept individually in a volatile solution, in a suitable solvent, in a suitable solvent, furthermore they can be colloidal particles which optionally form a suspension or an emulsion. They may also be particles dispersed in the solid carrier to form a powder. The mixtures thus prepared are suitable for use as spirals, in the form of solutions, suspensions or emulsions of the active compounds according to the invention.

For parenteral, i.e. subcutaneous, intramuscular or intraperitoneal administration of the compounds of formula I, doses of 1 to 250 mg / kg body weight, preferably 5 to 100 mg / kg body weight, especially 5 to 50 mg / kg body weight, are used. Of course, the dose depends on the species of the mammal, the amine, and is determined by the result obtained on the first administration. Usually, small doses are administered initially, which are gradually increased until an optimum effect is obtained.

As regards carriers for parenteral administration, these may be aqueous liquids such as water, isotonic sodium chloride solution or dextrose, Ringer's solution, or they are non-aqueous liquids, for example, live or vegetable oils such as flaxseed oil. However, any solvent which does not interfere with the activity of the compounds of formula (I) and is not toxic may be used. They are, for example, glycerol, ethanol, propylene glycol or scrbitol. Thus, liquid formulations containing the compounds of the present invention may also contain various liquid diluents such as propylene glycol, diethyl carbonate, glycerol or sorbitol.

For intrapasal administration of the compounds of formula (I), any method can be used to contact the anti-inflammatory compound with the mammalian respiratory system. Effective methods are, for example, administration of nolsm drops or administration of drops directly into the noisopharynx, inhalation and nebulization in the form of an aerosol. These routes are particularly important because they are easy, safe and effective routes of administration. For imtranasal administration, a compound of formula (I) is usually used together with a carrier at a concentration of 1 to 100 mg / ml of carrier. A concentration of 30 to 50 (mg / ml) is generally best.

For topical administration, the compounds of formula I are also preferably used together with a suitable carrier, in particular to ensure perfect absorption. In this case, a concentration of 1 to 250 mg / ml is used. Usually, in the above-mentioned two administration route Celik 1 '250 ¹ mg / kg of a compound of vzoiree I, preferably 5-50 mg / kg.

The compounds produced by the process of the invention can be used as such or in admixture with one or more excipients or other drugs such as analgesics, anesthetics, anti-sepsis, anti-vascular agents, antibiotics, vaccines, buffers and inorganic salts. In addition, these compounds may be administered in admixture with hyailuiromidase to avoid or reduce irritation as much as possible and to increase the rate of absorption of the compound of the invention. Said enzyme is used at a dose of at least 150 units, although in exceptional cases lower or higher doses may be used.

Compounds of formula I that are insoluble in water, or those whose water solubility is low, are preferably administered in suspensions or emulsions that allow the formation of particles less than 20 microns in size. This is because the particle size influences the biological activity of the compounds according to the invention, which is probably based on a better absorption of the active substance. Various surfactants and protective colloids may also be used in the formulations containing these substances. Suitable surfactants are, for example, partial esters of conventional aliphatic acids such as lauric, oleic or istearic acid with sorbitol-derived hexitolic anhydrides, and polyoxyethylene derivatives of these esters. These compounds are commonly marketed under the trade names "Spanis" and "Tweens" and are available from ICI United States Inc., Wilmngtoin, Del. Cellulose ethers, especially cellulose methyl ether (methocel, Dow Chemical Co., Midland, Mich.), Are highly effective as protective colloids for use in emulsions containing the compounds of the invention.

If the compounds of the formula I are water-soluble, it is most advantageous to administer them in the form of aqueous solutions, in particular in physiological saline containing phosphorus pulses. The water-insoluble compounds are preferably administered in formulations of the above type. A suitable solvent for water-insoluble compounds is, for example, dimethylsulfoxide. Such a preparation contains, for example, 25 to 100 mg of the selected active ingredient in the form of an emulsion in admixture with an equal amount of Polysorbate 80 in a mixture with glycerine, to which the water at 80 ° C is added under vigorous stirring. Sodium chloride to a final concentration of 0.14 M and sodium phosphate at pH 7 to a final concentration of 0.01 M are added to the concentrated solution.

active substance mg / ml 50.0 Polysorbate 80 50.0 glycerine 50.0 mioinohydrogeinformate, hydrated 1.4 sodium chloride 7.9 water 842.0

1001.3

In those cases where the active substance particles are agglomerated, ultrasound can be used to obtain a homogeneous system.

The invention will be illustrated by the following examples.

Example 1

1,2-Di-O- (n-hexadeeyl) -3-O- (2-isopropyllaiminoethyl) glycerol hydrochloride

A. 1,2-di-O- (n-hexadecyl) -3-O-allylglycerol

1.78 g (37 mimoles) of sodium hydride in the form of 50 o / _o dipperpaste in mineral oil is added at 60 ° C to a solution of 10 g (18.5 mimoles) of 1,2-di-O- (n). -hexa-decyl jglycerol in 100 ml of N, Nd ^; methylfoirimamide and the resulting solution was stirred at 60 ° C for 20 minutes, then 4.47 g (37 imimoles) of allyl chloride were added dropwise and the resulting mixture was stirred at 90 ° C for 3 hours. ° C, then cooled, carefully diluted with 200 ml of water to quench the reaction and then extracted three times with 150 ml of ether. The ether extracts are combined, piromized with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo to an oil. The residue was purified by chromatography on silica gel eluting with benzene to give 10 g of an oily title compound in a yield of 93%.

NMR (CDCl3) δ:

5.66 to 6.16 (m, 1, -OCH 2 CH = CH 2),

5.25 (d doublets, 2, -OCH 2 CH = CH 2) and 4.03 (d, 2, -OCH 2 CH = CH 2).

B. 1,2-Di-O- (n-hexadecyl) -3-O-formylmethylglycerol mg (0.354 mmol) of osmium tetroxide is added to a solution of 6.5 g (7.75 mmol)

1,2-di-O- (n-hexaidyl) -3-O-allylglycerol in 120 ml of a 3: 1 mixture of tetrahydrofuran and water was stirred for 5 minutes at room temperature. Then 9 g (4'2 mimoles) of sodium iodine is added and the reaction solution is stirred for 16 hours at room temperature under a nitrogen atmosphere. The reaction solution was diluted with 150 mL of water and extracted twice with 150 mL of ether. The ether extracts were combined, washed with 150 ml of water, and dried over magnesium sulfate. and evaporated in vacuo to an oil which was purified by chromatography on a silica gel column eluting with a mixture of benzene and ethyl acetate to give 2.6 g of a waxy solid in 57% yield.

The infrared spectrum in chloroform has a maximum at 1735 om ^-1 .

NMR (CDCl3) δ:

9.38 (t, J = 1 Hz, 1, -OCH 2 CHO) and 4.07 (d, J = 1 Hz, 2, -OCH 2 CHO).

C. Resulting substance

0.1 g (1.6 mimoles) of sodium cyanoborohydride is added to solution 1: 5 g (2.6 mmol)

1,2-di-O- (n-hexadeicyl) -3-O-formylmethylglycerol and 0.89 g (15 mmol) of isopropylaimide in 1: 1 methanol / tetrahydrofuran (50 ml) and stirred at room temperature for 2 hours. The pH is adjusted to 6 by adding 5N methanolic hydrochloric acid solution, 1.1 g (1.6 mmol) of sodium cyanoborohydride are added and the mixture is stirred for a further 60 hours at room temperature, then filtered, 10 ml is added. 3N aqueous sodium hydroxide solution and 200 ml of saturated aqueous sodium chloride solution are then extracted with 2 times 150 ml of ether. The ether extracts were combined, dried (MgSO4), filtered and evaporated in vacuo to an oily solid which was purified by silica gel column chromatography eluting with benzene / ethanol to dissolve the resulting material in Meitlhainol. The solution is mixed with gaseous. HCl and evaporated in vacuo to a solid which was recrystallized from ethyl acetate. In this way 400 mg of a solid are obtained in a yield of 23%, m.p. 71-72 ° C. This material contains 1/4 mole of water per mole of product.

NMR (CDCl3) δ:

1.42 [d, J = 6 Hz, 6, -NHCH (CH 3) 2). Elemental analysis: calculated:

72.02 o / _o C, 12.76% H, 2.10 Q / o N, found ·

% C, 71.89;% H, 12.34; N. 2.09%. Example 2

Efficacy of 1,3-di-O- (n-hexadecyl) -2-O- (3-amino-propyl) glycerol hydrochloride against EMC virus in vivo

The emulsion formulation was prepared by melting and mixing equal parts of the active ingredient, polysoirate 80 and glycerin followed by dispersion of the mixture in hot water with vigorous stirring. The concentration of the mixture was then adjusted to 0.14 M sodium chloride with addition; 0.01 M sodium phosphate pH 7. Further dilution was performed with a buffer consisting of a mixture of 0.14 M sodium chloride and 0.01 M sodium phosphate pH 7.

Three groups of 20-25 g white female mice were given 1.5, 5 and 15 mg of active ingredient per kg as a 0.5 ml intraperitoneal injection. A fourth control group of 10 mice was left untreated. 18 to 24 hours after injection, all four groups of 0.2 ml were injected subcutaneously with an amount equal to 20-fold LD 50, i.e., the dose causing 50 o / ₀ mice to die within 10 days for injection. use encephalomyocairditis virus (EMC). The number of surviving mice was recorded over 10 days and the average survival time (S _r ) was recorded.

Dose of active substance S _r (average of 7 times) 15 img / lkg 61 5 mg.kg 45 1.5 mg / kg 24

The antiviral activity is expressed as the relative survival time (S _r ) in the experimental groups compared to the 10th dine control groups after virus injection. This value is defined as follows:

s, i, = 1sl10 č = 1 & Z.10

Ο'ΐ,

100 +100 x 100 (Li, i * 1 * i10 where it means

S _r relative survival time,

With _x percent survival after 10 days in the ipolkusin group,

Xi the number of surviving mice on day "i" in the experimental group and ej the number of surviving mice on day "i" in the control group.

He did

Reduction of virus yield from human pollype cells in vitro * using 1,3-di-O- (n-hexadecyl) -2-O- (3-amimopropyl) glyicerol hydrotchloride

Growth medium was prepared by adding 100 ml of Eagle's base medium to 2 ml of 100 times concentrated material solution to determine efficacy with antimycotic antibiotic activity, 1 ml (200 mmol of glutamine solution, 1 ml 100 times concentrated non-essential amino acid solution, 1 ml 100 microlitres of sodium pyrobarbose * and 10% heat-inactivated fetal calf serum using 96-well micirotitration plates, each containing 50,000 cells of the human nasal polyp as a suspension in 0.2 ml of growth Plates were then incubated for 8-10 days at 37 ° C in an atmosphere of 5% carbon dioxide to form continuous single cell layers.

_; At the end of the 8 to 10 days of growth, the cell shells thus obtained were washed four times with saline containing phosphate buffer, and 0.2 ml of maintenance medium containing 10, 5.0, 1.0 was added to each well. , 0.5, 0.1 and 0 µg / ml of active ingredient. The maintenance environment had the same composition as the growth medium, with the difference that it contained only 2% fetal calf serum. Plates were incubated for an additional 18 hours at 37 ^° C, after which the cell layers were washed again four times with phosphate buffered saline to remove the drug, and a dose equivalent to 1000 times TCID 50, a dose of which cause 50% infection in unprotected ikultuir. Veisicular stomatitis virus (VCV) was used, which was kept in the cultures for 2 hours at 37 ° C, then the cultures were washed four times with saline containing phosphate buffer to remove unadsorbed virus particles and to each well was plated. * 0.2 ml of maintenance medium was added again. Plates were then incubated for 7 hours at 37 ° C, after which liquid was removed from each plate, stored in frozen state in tubes and titrated for infectious virus amount using higher fibroiblaists L-929. These mouse cell cultures were analyzed after 3-4 days, and the following table shows the decreases in virus yields compared to the control, determined for the five concentrations of the active compound used.

Reduction of virus yield * in% Concentration of active substance in (jug / ml)

5.0 1.0 0.5 0.1% 90% 84% 75% <68%

He attaches

By the method of Example 3, the reduction in virus yields from human * polyp cells in vitro was determined for the compound shown in the following table:

208137

Example Compound produced number ·, according to example number% reduction of virus yield ³ concentration (^ g / ml)

5.0 1.0 0.5 0.1

11 (a) + ξ> 68o / _o reduction, + = ~ 68% reduction, + + - ND ND —- = <68% reduction, ND ξ was not performed.

Example 5

The ability of 1,3-di-O- (n-hexadecyl) -2-0- (3-amimopropyl) glyceirol hydrochloride to induce the formation of interpheniron which can be demonstrated in the circulation

Simes equal parts by weight of the active ingredient, polysorbate 80 and glyceirol are melted and then homogenized in hot 0.14 M sodium chloride solution containing 0.01 M sodium phosphate · ipH 7 (PBS). The resulting oil-in-water emulsion is further diluted with PBS prior to administration.

Swiss female mice weighing 20-25 g are administered by intraperitoneal injection of 0.5 ml amount of the diluted emulsion containing the active ingredient at a dose of 25 mg / kg body weight. 8, 12, 16, and 20 hours post-injection were collected (pilazima samples from four mice were pooled. Serial dilution in L-15 (Leibovitz medium) containing 5% fetal calf serum was incubated on microtitration plates. overnight at 37 [deg.] C. for continuous individual layers of L-929 Fibroblaista Mice Fibers, the layers were then washed with a shiny protein environment and then contacted at a dose equivalent to 10 times TCID 50, a dose that causes 50% infection in unprotected cultures. The infection was using vesicular stomatitis virus (VSV), which had been contacted by the β culture for 1 hour at 37 ° C, the unadsorbed virus was washed out and the cells were re-contacted with L-15 containing 5 o / _o fetal calf serum. and then were re-incubated for 48 hours at 37 ^Q C. the cultures of L-929 were then microscopically examined for Cytopathological changes caused by a virus which was · ( an indirect relationship between plasma interferon levels and fibroblaist damage can be demonstrated. At the same time, a plasma dilution has been determined which can guarantee 50% protection of simple layers of L-929 cells.

Second (experiment was performed in a similar manner, except that 10 mg of active ingredient / kg was injected into the toy, and then peritoneal fluid samples from four mice were collected and decanted. The samples were again taken 6, 9, 12 , 15 and 18 hours after injection Samples were taken to say that after opening the abdominal cavity, 1 ml of Hank's balanced solution containing 100 units of penicillin / ml and 100 µg sltrepitomycin / ml was injected, then the abdomen was massaged briefly, then removed from the abdomen. peritoneal cavity liquid.

The results obtained from both experiments are shown in the following table:

Source of interferon 6

Interferon source Interferon levels and levels (units / ml) after injection at (h)

9. 18 plasma - 34 peritoneal fluid 16 - - 67 -

768 320 448 40

208137

Claims (4)

1. A process for the preparation of novel amine derivatives of glycerols having antiviral activity, General Wes I, CH2 — Qi CH — Qž I CH 2 OR 2, (I) Whereas, even from a pharmaceutical standpoint, the acid addition salts of these compounds, where one of the symbols Q 1 and Q 2 represent —O — Y — NH.R3 and the other —OR 1, R1 and R2 are straight-chain alkyl groups having 12 to 20 carbon atoms, Y represents alkylene of 2 to 4 carbon atoms, the valences of which are found on different carbon atoms and R3 represents a hydrogen atom or a C2-C4 alkyl group, characterized in that a compound of general formula II is mentioned in the reaction; CH2 — Qs CH — Qe CH 2 —OR 2, (II) wherein one of the symbols Q5 and Q6 represent a group R10-, wherein R1 is as defined above, and a second group -O-Y‘-CHO, VYNALEZU Y 'represents alkylene of 1 to 3 atoms, the left bonds of which are bonded to oxygen atoms, with the compound of the formula NH 2 R 3, where R 3 is as defined above, under reducing conditions and optionally converting the compound of formula I to its pharmaceutically acceptable salt with acid, 2. The method of claim 1, wherein the starting material of general formula II, wherein R1 and R2 are alkyl, is a straight chain of 14 to 18 carbon atoms. 3. A process according to claim 2, wherein the starting material of formula (II) is one in which R1 and R2 are n-hexadecyl. 4. The process of claim 1, wherein the starting material of formula (II) wherein R1 and R2 are n-hexadecyl, Y &apos; is methyl, is a compound wherein the group is -O-Y —CHO in position 2.