FI76088C - Process for the preparation of antiviral purine derivatives - Google Patents

Description

1 76088

Method for the preparation of antiviral purine derivatives

This invention relates to a process for the preparation of antiviral purine derivatives containing an acyclic chain at the 9-position.

GB Patent Publication No. 1,523,865 describes a wide range of 10 purine derivatives containing an acyclic side chain at the 9-position. These purine derivatives have been found to have antiviral activity against various groups of DNA viruses, especially herpesviruses such as Herpes simpelx.

Of these derivatives, 9- (2-hydroxyethoxymethyl) -guanine (also known as acyclovir) has been found to be particularly effective against herpesviruses such as Herpes simplex. But although acyclovir has been found to be very effective when administered topically or parenterally, it is only moderately absorbed when administered orally at similar drug concentrations in the blood fluid. It is fully understood that in the treatment of an internal disorder by oral administration of a drug, it is obviously desirable for the drug to be well absorbed from the gastrotestinal region, resulting in high blood fluid concentrations.

We have now made the surprising finding that purine derivatives, which are characterized by having a hydrogen atom in the 6-position of the purine nucleus, are readily modified in vivo by molybro-flavo protein-type enzymes (especially xanthine oxidase / dehydrogenase or aldehyde oxidase). -hydroxypurine derivatives having antiviral activity. Furthermore, in experiments on rats, we have found that oral administration of such 6-hydrogen derivatives results in efficient absorption from the gastrointestinal tract and high concentrations of the corresponding 6-hydroxy compound formed in the blood fluid as a result of enzymatic conversion of the 6-hydrogen compound.

The group of such 6-hydrogenpurine derivatives includes compounds of general formula (I) wherein X is an oxygen or sulfur atom and physiologically acceptable salts of such compounds of formula (I) and their esters, with the exception of the compound of formula I. , wherein X is oxygen and its benzoate ester and physiologically acceptable salts. The invention relates to a process for the preparation of these compounds, characterized in that a) deprotection of a compound of formula (II) xx> 25 CH2XCH2CH2r4 wherein X is as defined above, R * represents an amino group or a protected amino group and R * represents a hydroxy group , provided that at least one of the symbols R * and R * represents a protected group; or b) hydrogenating a compound of formula (III)

II

3,76088 rVx I X (III) ch2xch2ch2oh wherein X is as defined above and M is a halogen atom, or a salt or ester thereof; and optionally performing one or more of the following reactions in any desired order: i) when the obtained product is a base, converting this base to a physiologically acceptable acid addition salt, ii) when the obtained product is an acid addition salt, converting this salt to the corresponding base, iii) when the obtained product is a compound of formula (I), converting this compound into a physiologically acceptable barrier; and / or iv) when the product obtained is an ester of a compound of formula (I), this ester is converted into the corresponding compound of formula (I).

In process a) it is understood that the protecting groups may be selected, for example, from acyl groups such as C 1-6 alkanoyl groups, e.g. acetyl or pivaloyl, or from aroyl groups, e.g. benzoyl; arylmethyl groups, e.g. benzyl; 25 or tri-C 1-4 alkylsilyl groups, e.g. trimethylsilyl. Arylmethyl protecting groups can be removed, for example, by hydrogenolysis, e.g., by hydrogenation in the presence of Raney nickel or palladium catalyst, or by the use of sodium in liquid ammonia. The acyl protecting groups can be removed, for example, by hydrolysis using, for example, an amine such as methylamine or triethylamine, preferably in an aqueous medium. The trialkylsilyl protecting groups can be removed, for example, by solvolysis, e.g. with alcoholic or aqueous ammonia or alcohol.

4,76088

The conversion of a compound of formula (III) into a compound of formula (I) by method b) can be carried out by conventional methods. These are described in Fused Pyrimidines, Part II, Purines, ed. D.J.

5 Brown (1971), Wiley-Interscience.

The coupled starting materials in the methods described above can be prepared in a conventional manner, e.g., by the methods described in the aforementioned GB Patent Publication No. 1,523,865.

Salts of the compounds of formula (I) which may conveniently be used in therapy include physiologically acceptable salts of organic acids such as lactic, acetic, maleic or p-toluenesulfonic acid and physiologically acceptable salts of mineral acids such as hydrochloric or sulfuric acid. salts.

Esters of compounds of formula (I) which may conveniently be used in therapy include compounds containing a formyloxy or C 1-6 (e.g. C 1-6) alkanoyloxy ester group (e.g. acetoxy or propionio-20-yloxy group), optionally substituted aralkanoyl. an oxy (e.g. phenyl-C 1-4 alkanoyloxy such as phenylacetoxy) or optionally substituted aroyloxy (e.g. benzoyloxy or naphthyloxy) group at the 9-position side chain end position of the compounds of formula (I).

The above-mentioned aralkanoyloxy and aroyloxyester groups may be substituted, for example, by one or more halogen atoms (e.g. chlorine or bromine) or an amino, cyano or sulfamido group, the aryl part of the group preferably containing 6 to 10 carbon atoms.

2-Amino-9- (2-benzoyloxyethoxymethyl) purine (i.e.

benzoate ester of a compound of formula (I) wherein X is an oxygen atom) is described in U.S. Patent 4,199,547 and does not claim to prepare this compound. However, there is no mention or indication in said U.S. Patent Publication that the compound can be converted to the corresponding 6-hydroxy analog in vivo.

5,76088

The finding that the above 6-hydrogen purines are readily convertible to the corresponding 6-hydroxy analogs is surprising because previous studies using cow's milk xanthine oxidase (H. Lettre et al. (1967) Biochem. Pharmacol. 16, 1747-1755; TA Krenitsky et al (1972) Arch. Biophys., 150, 585-599) showed that the 9 substitution greatly inhibits or reduces the rate at which various purines are oxidized. In light of these findings, it was surprising to find that this enzyme oxidized, for example, 6-deoxyacyclovir, a 9-substituted derivative of 2-aminopurine, at a higher rate than 9-unsubstituted purine, as we have found in enzyme studies.

The high level of absorption of the compounds of formula (I) from the gastrointestinal tract makes the compounds particularly useful when the compounds are to be administered orally, e.g. in the treatment of diseases caused by various DNA viruses such as herpes infections, e.g. Herpes simplex. Varicella or Zoster, cytomegalovirus, and diseases caused by hepatitis B 20 or Epstein-Barr virus. The compounds of formula (I) may also be used for the treatment or prophylaxis of papillomavirus infections. In addition to being useful in human drug therapy, the compounds of formula (I) may be administered to other animal species for the treatment or prevention of viral diseases, e.g. other mammals.

The compounds of formula (I) and their physiologically acceptable salts and esters (hereinafter collectively referred to as active ingredients) may be administered by any route suitable for the condition being treated, including oral, rectal, nasal, topical (including buccal or sublingual) administration. ), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, dermal, membrane, and epidural). It will be appreciated that the recommended route of administration may vary depending on, for example, the condition of the recipient.

6 76088

In all of the above uses and indications, the amount of active ingredient required (as defined above) will depend on a number of factors, including the severity of the condition being treated and the characteristics of the recipient, and will be at the discretion of the attending physician or veterinarian. However, in general, for all of these uses and indications, a suitable, effective dose is in the range of 0.1 mg to 250 mg per kilogram of patient body per day, preferably in the range of 1 to 100 mg per kilogram of body weight per day for 10 days, and most preferably in the range of 5 to 20 mg per kilogram of body weight. a day; the optimal dose is about 10 mg per kilogram of body weight per day. (Unless otherwise stated, all amounts of active ingredient are calculated as the corresponding compound of formula (I): for the salts and esters of the compound, the numerical values would be relatively higher).

The desired dose is preferably administered in two, three, four or more sub-doses at appropriate intervals throughout the day. These sub-doses are administered in unit dosage forms containing, for example, 10-1000 mg, preferably 20-20,500 mg and most preferably 100-400 mg of active ingredient per unit dosage form.

Although it is possible to administer the active ingredients alone, it is preferable to administer them in the form of pharmaceutical preparations. Formulations of this invention for use in both veterinary medicine and medicine contain at least one active ingredient as defined above in association with one or more carriers, and optionally other therapeutic ingredients. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Formulations include those suitable for oral, rectal, nasal, topical (including buccal or sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, dermal, membrane, and epidural) administration. Formulations are inexpensive! unit dosage forms and those

II

7,76088 can be prepared by any of the methods well known in the pharmaceutical art. These methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and effectively bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or anhydrous liquid; or as a liquid oil-in-water emulsion or a liquid water-in-oil emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

The tablet may be made by compression or molding and optionally contains one or more excipients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, glidant, inert diluent, preservative, surfactant or dispersant. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

For infections of the eye or other external tissues, e.g. the mouth or skin, the formulations are preferably used as an external ointment or cream containing, for example, 0.075-20% by weight, preferably 0.2-15% by weight and most preferably 0.5-% by weight of the active ingredient. 10% by weight.

ΤΓΖ.

8 76088

When formulated in an ointment, the active ingredients may be incorporated. used in conjunction with a paraffinic or water-miscible ointment base. Alternatively, the active ingredients may be formulated in an ointment with an ointment base of type 5 in oil-in-water form.

The aqueous phase of the ointment base may, if desired, contain, for example, at least 30% by weight of polyhydroxy alcohol, i.e. an alcohol having two or more hydroxy groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. Formulations for topical use may preferably contain a compound which enhances the absorption or penetration of the active ingredient through the skin or other infected areas. Examples of such compounds that promote penetration into the skin include dimethyl sulfoxide and its analogs.

The oil phase of the emulsions of this invention may be formulated from known ingredients in a known manner. Although this phase may consist only of an emulsifying agent (also known as an emulsifier), it preferably comprises at least one emulsifier in admixture with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is used in combination with a lipophilic emulsifier which acts as a stabilizing agent.

It is also preferred to use both oil and fat. The emulsifier (s) together with or without the stabilizer or stabilizers form a so-called emulsifying wax and the wax together with the oil and / or fat form a so-called emulsifying cream base which forms an oily dispersed phase in the ointment formulations.

Suitable emulsifiers and stabilizers for use in the formulations of this invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alkanol, glyceryl monostearate, and sodium lauryl sulfate.

The choice of suitable oils and β 76088 fats for use in the formulations is based on the achievement of the desired cosmetic properties, as the solubility of the active compound in most oils most likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with a suitable consistency to avoid leakage from tubes or other containers. Unbranched or branched mono- or dibasic alkyl esters such as diisoadipate, isoethyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, carbonylate ethanate, decyl oleate, isopropyl palmitate, isopropyl palmitate, butyvlistea can be used. CAP, the latter three being preferred esters. These can be used alone or in mixtures depending on the desired properties. Alternatively, high melting lipids such as white soft paraffin and / or liquid para-20in or other mineral oils may be used.

Formulations for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for dissolving the active ingredient. In such formulations, the content of active ingredient is from 0.5 to 20% by weight, preferably from 0.5 to 10% by weight, in particular about 1.5% by weight.

Topical formulations for oral administration include pills containing the active ingredient in a flavored base material, usually cane sugar and gum arabic or tragacanth; lozenges containing the active ingredient in an inert base such as gelatin and glycerin or cane sugar and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

___ .. HZ.- 10 76088

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations for nasal administration, in which the carrier is a solid, naturally comprise a powder having, for example, a particle size in the range of 20 to 500 microns and used in the same manner as snus, i.e. by rapid inhalation through the nasal passage from a powder container held close to the nose. Suitable formulations in which the carrier is a liquid and which are administered, for example, as nasal sprays or nasal drops are aqueous or oily solutions of the active ingredient.

Formulations for vaginal use may be presented as pessaries, tampons, creams, troches, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Formulations for parenteral use include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the subject to be treated; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit dose containers or in multi-dose containers, for example, sealed ampoules and vials, and may be stored lyophilized, requiring only the addition of a sterile liquid carrier, e.g. water for injections, just prior to use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing an active ingredient in a daily dose or as a portion of a daily dose, as previously described, or an appropriate fraction thereof.

It will be appreciated that in addition to the ingredients expressly mentioned above, the formulations of this invention may contain other substances conventional in the art for the particular formulation in question, for example formulations suitable for oral administration may contain flavoring agents.

The compounds 10 of this invention may be used, further in veterinary compositions, in association with a veterinary carrier.

Carriers used in veterinary medicine are substances which are useful for the administration of the composition and may be solid, liquid or gaseous substances which are otherwise inert or approved in veterinary medicine and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

Compositions for oral administration may be in the form of tablets, granules, medicated drink, paste, sachets, capsules or feed additive. The granules can be prepared by well-known techniques of wet granulation, pre-compression or granulation. They may be administered to the animals in an inert liquid vehicle to form a medicated beverage or in suspension with an aqueous or oily vehicle. Preferably other additives such as a dispersant are added. These formulations preferably contain 15-85% of the active ingredient.

The paste can be prepared by suspending the active ingredient in a liquid diluent. The stiffening or thickening agent of the paste may be used in combination with a wetting agent or a wetting agent if the liquid solvent is water. If an emulsion paste is required, it is recommended that one or more surfactants be used. 25-80% by weight of these paste formulations may be the active ingredient.

As feed additives, the active ingredient is generally present in large amounts corresponding to the additives and the excipients can be added directly or intermittently after mixing or dilution. Examples of additives used in such formulations include solid, edible carriers such as corn flour, soybean meal, coarse wheat flour, soybean meal, edible plant materials, and fermentation residues. The active ingredient is usually added to one or more additional ingredients and dispersed efficiently and uniformly by grinding, drum treatment or mixing with conventional equipment. Formulations containing from 1 to 90% by weight of active ingredient are suitable for addition to feedingstuffs.

For the treatment of equine herpes infections, an oral or parenteral dose of 0.1 to 250 mg per kilogram of body weight per day, preferably 2 to 100 mg / kg per day, may be required. The dose can be divided into separate units of 20 to 20 at regular intervals throughout the day and repeated daily for up to 14 days or until the infection has disappeared. In the treatment of viral infections in other animals, the dose may vary depending on the size and metabolism of the animal. The compositions may be administered in unit dosage form such as tablets a few times a day in amounts of 10 to 100 mg / unit dose.

The following examples illustrate this invention.

Example 1 2-Amino-9- (2-hydroxyethylthiomethyl) -9H-purine In a 30 L round bottom flask equipped with a magnetic stirrer and a CaCl 2 drying tube, 5.0 g (29.50 mmol) of 2-amino-6- chloropurine, 6.8 g (29.50 mmol) of 2- (chloromethylthio) ethyl benzoate, 4.07 g (29.50 mmol) of potassium carbonate and 750 ml of anhydrous dimethyl-35-formoform. The reaction mixture was stirred at room temperature for 16 hours, then an additional 2.0 g (8.7 mmol) of li 13 76088 2- (chloromethylthio) ethyl benzoate and 1.2 g (8.7 nunol) of potassium carbonate were added and stirring was continued for another 24 hours at room temperature. The reaction mixture was then filtered through a pad of Celite in a sintered glass funnel and evaporated in vacuo on a rotary evaporator to a viscous yellow oil.

the oil was adsorbed onto 20.0 g of silica gel Merck silica gel 60 (70-230 mesh) and this pre-adsorbed phase was applied to the top of 10 columns packed with Merck silica gel 60 (230-400 mesh). Elution of the column with ethyl acetate / benzene 6: 4 gave 2-amino-9- (2-benzoyloxyethylthiomethyl) -6-chloro-9H-purine as an off-white solid which was one compound by thin layer chromatography using silica gel. and 8: 2 ethyl-15 acetate / hexane. Δ NMR, CDCl 3: 8.0-8.15, 6H, multiplet; 5.1 4H, broad singlet; 4.5: 2H: triplet; 2.985, 2H, triplet.

The latter product (0.98 g, 2.70 mmol) was placed in a 500 mL Parr hydrogenation flask while measuring 2.5 g of 20 Pd (OH) 2 catalyst, 50 mL of triethylamine, and 200 mL of methanol. This mixture was shaken on a Parr hydrogenator under 3.4 atm of hydrogen for 16 hours at room temperature. Thin layer chromatography of the hydrogenolysis product on silica gel using 8% methanol / ethyl acetate showed only partial reaction. The catalyst was removed by filtration through a pad of Celite in a glass sinter funnel, 2.0 g of new Pd (OH) 2 catalyst and 7.0 mL of triethylamine were added and the reaction mixture was shaken again under 3.4 atm of hydrogen for 20 hours. At this time, thin layer chromatography indicated the reaction was complete, the catalyst was removed as above, and the methanol was removed on a rotary evaporator in vacuo to give a clear glass which was taken up in 100 mL of a 1: 1 methanol-water mixture containing 20% methylamine. The resulting solution was stirred at room temperature for 4 hours and evaporated on a rotary evaporator in vacuo to give an amorphous solid. The solid was adsorbed onto 10.0 g of 70-230 mesh Merck silica gel 60 and this pre-adsorbed phase was applied to the top of a column packed with 230-400 mesh Merck silica gel 60. Elution of the column with 10% methanol-ethyl acetate gave a solid which crystallized from ethyl acetate-hexane to give the title compound as needles, m.p. 122-124 ° C, thin layer chromatography: 1 spot on silica gel with 15% methanol / ethyl acetate; Δ NMR dmso-66 8.59, 1H, singlet; 8.15, 10 1H, singlet; 6.56, 2H, broad singlet; 5.24, 2H, singlet; 4.83, 1H, triplet; 3.49, 2H, multiplet; 2.69, 2H, multiplet.

Analysis, theoretical C 42.65, H 4.92, N 31.09

Found: C 42.70, H 4.94, N 31.04.

Example 2 9- (2-acetoxyethoxymethyl) -2-amino-9H-purine

A mixture of 0.82 g (2.92 mmol) of 9- (2-hydroxyethoxymethyl) -2-amino-9H-purine, 48 mg (0.392 mmol) of 4-dimethylaminopyridine and 0.75 mL (7.84 mmol) of 20 acetic anhydride in 18 ml of dimethylformamide, stirred at room temperature for two days.

The reaction mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate and absorbed onto silica gel. The solvent was removed by flash evaporation and the remaining powder was added to a column prepared for flash chromatography. Elution with 5% methanol in dichloromethane gave 1.0 g of a semi-crystalline oil which, recrystallized from benzene-hexane, gave analytically pure 9- (2-acetoxyethoxymethyl) -2-amino-9H-30 purine, m.p. 115-118 ° C.

Example 3 9- (2-Acetoxyethylthiomethyl) -2-amino-9H-purine To a 100 mL flask equipped with a magnetic stirrer and a CaCl 2 drying tube was charged 1.0 g (4.4 to 35 mmol) of 2-amino 9- (2-hydroxyethylthiomethyl) -9H-purine, 0.045 g (0.44 mmol) of 4-dimethylaminopyridine, 0.9 ml (8.8, 76088 mmol) of acetic anhydride and 20 ml of dry DMF. The solution was stirred for 24 hours at room temperature and 5 mL of MeOH was added. The solution was evaporated in vacuo (bath temperature 40 ° C) and the resulting brown oil was chromatographed using the 5 flash method. Elution of the column with 1.5% methanol in ethyl acetate gave a yellow oil which crystallized on standing. The pale yellow crystals were dissolved in 2% MeOH in toluene and treated with 0.05 g of Darco G-60. The methanol was evaporated from toluene to give pale yellow crystals.

The product was dried for 16 hours at 78 ° C to give the title compound, m.p. 119-120.5 ° C.

Analysis: Calculated for C 10 H 13 N 2 O 2 S: C 44.93, H 4.9, N 26.20 Found: C 44.97, H 4.96, N 26.17.

1 H NMR in DMSO 9 8.59 (1H, s) 8.15 (1H, s), 6.52 (2H broad, s), 5.26 (2H, s) 4.15 (2H t J = 6, 36 Hz), 2.89 (2H t J = 6, 36 Hz), 1.99 (3H, s).

Example 4 2-Amino-9- (2-bentosyloxyethylthiomethyl) -9H-purine A 5-liter three-necked flask was equipped with an air stirrer motor, a glass stirring rod with a Teflon paddock, and equipment for vacuuming and feeding either N2 or H2 gas. The flask was then charged with 7.0 g (0.019 mol) of 2-amino-9- (2-benzoylthiomethyl) -6-chloro-9H-purine, 14.0 g of palladium hydroxide on carbon, 12.0 ml (0.163 mol) of triethyl amine, 75.0 ml of water and 3.0 liters of methanol. The 30 bottles were then sealed and evacuated with a water-jet pump, purged with N 2 gas, evacuated and continued for three full cycles. The flask was evacuated, purged with H2 gas, evacuated and refilled with H2 gas. The stirring engine was started and the reaction mixture was stirred in H 2 for 4 days at room temperature.

76088 BC

The solution was filtered through sintered glass and the catalyst was washed with 800 ml of methanol. The methanol solution was evaporated in vacuo to give 6.0 g of a pale yellow solid. The solid was absorbed into 18.0 g of 70-230 5 mesh silica gel 60 and this pre-absorbed phase was applied to the top of a column packed with 230-400 mesh silica gel 60. Elution of the column by flash using 5% methanol in ethyl acetate gave a white solid which was recrystallized from ethyl acetate / hexane-10 and dried at 78 ° C under a vacuum of 1.0 mmHg to give white flakes, m.p. 120-121 ° C, 1 H NMR at d 6mo dg 8.60 (1H, s), 8.19 (1H, s), 8.0, 7.5 (5H, m), 6.55 (2H, s ); 5.32 (2H, s), 4.52 (2H, t), 3.06 (2H, t).

Analysis theoretical: C 54.69, H 4.59, N 21.26 Found: C 54.68, H 4.64, N 21.24.

2-Amino-9- (2-hydroxyethylthiomethyl) -9H-purine was obtained by continuing the elution on the above column.

Claims (5)

17 76088 5 A process for the preparation of therapeutically active compounds of general formula (I) xx> h2n CH2XCH2CH2OH wherein X is an oxygen or sulfur atom, and for the preparation of their physiologically acceptable esters and salts, with the exception of the compound of formula (I) wherein X is oxygen and its benzoate ester and physiologically acceptable salts, characterized in that a) deprotecting is the formula (II) 20 * 1 Il \> (II) Rixk. Jk. Yan CH0XCH0CH „R4 2 2 2 a wherein X is as defined above, R * 25 represents an amino group or a protected amino group and 4 R represents a hydroxy group or a protected hydroxy group, provided that at least one of the symbols R cl ^ d 4 R means a protected group; or b) hydrogenating a compound of formula (III) CH 2 X CH 2 CH 2 OH ie 76088 wherein X is as defined above and M is a halogen atom, or a salt or ester thereof? and optionally performing one or more of the following reactions in any desired order: i) when the obtained product is a base, converting this base to a physiologically acceptable acid addition salt, ii) when the obtained product is an acid addition salt, converting this salt to the corresponding base, (iii) when the obtained product is a compound of formula (I), converting this compound into a physiologically acceptable ester; and / or iv) when the product obtained is an ester of a compound of formula (I), this ester is converted into the corresponding compound of formula (I). 2) Process according to Claim 1a), characterized in that any acyl-protecting group is removed by hydrolysis. Process according to Claim Ib), characterized in that the hydrogenation is carried out in the presence of a palladium-on-catalyst. il 19 n ^ 76088 1. A formulation for therapeutic use of an active ingredient with all the formulas (I) 5, .xx> CH9XCH9CH90H 10 of color X is not a substance or a physiological formulation, and a physiological formulation of the formulation is preferred. with Formula I color X is a mixture of benzoatesther and physiologically active substances, having a value of 15 times, as shown in (a) of the first group of compounds of formula (II) - iOC> CH2XCH2CH2Ra color X is somewhat defined, R * or an amino group and an R 1 moiety in the hydroxy group, or a hydroxy moiety having the same amino acid symbol and a hydroxyl group; or b) hydrer in the formulation of formula (III) 30 M is ^ l111 'h2n 35 ch2xch2ch2oh