CS262696B2 - Process for preparing new racemic and optical active derivatives of interfuranylenprostacycline - Google Patents

Abstract

Method of producing new racemic and optically interfuranylenepostacycline derivatives of formula I wherein R * 1 is hydrogen or C 1 -C 4 alkyl or protonated inorganic form cation, R2 is hydrogen, Cl-C1alkanoyl or tetrahydropyranyl R3 is C1-C6 alkyl or a C 5 -C 6 cycloalkyl group, A represents a group —CH — CH— or And C represents a chemical bond or the group —CH2 — is that it is a compound of formula III in which R 1, R 2, R 3, A and B are as defined above, is reacted with a compound of the general formula of formula Ε-X, wherein E is halogen, an acid amide residue or an imide residue the acid and X are halogen, and are then substituted the resulting compound of formula IIIa, wherein R 1, R 2, R 3, A, B and X are as defined above meaning, acts as a principle and, where appropriate the hydroxyl protecting groups are removed and / or the resulting compound is optionally converted in your salt. Compounds of formula I produced have therapeutically advantageous biological activity and are prostacyclin analogs; ve however, comparisons with him are much more stable than natural prostacyclin.

Description

A process for producing the novel racemic and optically active derivatives interfuranylenprostacyklinu formula I wherein ^{R 1} is hydrogen or C, -C4 alkyl group or the protonated form of an inorganic cation, R ² represents hydrogen, C Cíalkanoylovou or tetrahydropyranyl group, R ³ is C A C 6 alkyl group or a C 5 -C 6 cycloalkyl group, A represents a group -CH-CH- or -CsC- and B represents a chemical bond or a group -CH 2 -, characterized in that the compound of formula III in which R ¹ , ^{R2, R3,} a and B have the abovementioned meanings, is reacted with a compound of formula Ε -X wherein E is halogen, the residue amidu kyseliny or the radical imidu kyseliny and X is halogen, then to the resulting compound of formula IIa wherein R ¹ , R ² , R ³ , A, B and X are as defined above, act with a base and optionally remove the hydroxyl protecting groups and / or the compound optionally converts to its salt.

The compounds of formula I produced have therapeutically advantageous biological activity and are prostacyclin analogs; however, they are much more stable than natural prostacyclin.

262896

The present invention relates to a process for the preparation of novel racemic and optically active interfuranylenepostacycline derivatives having a therapeutically advantageous biological activity of the formula I

(I) in which

R ¹ represents hydrogen or a C 1 -C 4 alkyl group in a straight or branched chain or a protonated form of an inorganic cation,

R ² represents hydrogen, alkanoyl having 1-4 carbon atoms or tetrahydropyranyl group,

R ³ represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 5 or 6 carbon atoms,

A represents —CH = CH— or or —C = C—, and

B represents a chemical bond or a group --CH 2 - as well as pharmaceutical compositions containing these compounds.

The process according to the invention consists in the compound of the formula III

in which

R ¹ , R ² , R ³ , A and B are as defined above, reacted with a compound of formula

E — X in which

E represents halogen, an acid amide residue or an acid imide residue, and

X is halogen, whereupon the resulting compound of formula IIa is formed

in which

R ¹ , R ² , R ³ , A, B and X are as defined above, act with a base and optionally remove the hydroxyl and / or carboxyl protecting groups and / or optionally convert the resulting compound into a salt thereof.

The compounds of formula (I) produced by the process of the present invention can be considered as analogs of prostacyclin (PGI 2), a physiologically important natural substance that is stable and exhibits a selective pharmacological effect.

Prostacyclin (PGI2), a widely used metabolite of arachic acid, was discovered in 1976. It has a number of therapeutically valuable effects: for example, it inhibits platelet aggregation, lowers blood pressure, expands the airways and reduces gastric secretion . In addition, prostacyclin has a cytoprotective effect in various organs, such as the stomach, liver, heart and kidney. This means that the destructive effects of various organ damages can be prevented or eliminated by the action of prostacyclin.

To date, a large number of papers on the above-mentioned beneficial pharmacological effects of prostacyclin have been published [see, for example, Flohé et al., Arzneimittelforschung 33, 1240 (1983), S. Moncada and J. R. Vane: J. Med. Chem. 23, p. 591 (1980), W. Bartman et al., Angewandte Chemie, Int. Ed. Engl. 21, p. 751 (1982), R. F. Newton et al., Synthesla 1984, p. 449).

Now, the beneficial pharmacological effects of prostacyclin have already been used in clinical treatment. Sodium salt was marketed by Wellcome under the designation Flolan and Upjohn in 1983 under the designation Cycloprostin [Drugs of Today, 19, p. 605 (1983)], with cardiopulmonary bypasses, perfusion during hepatic insufficiency and haemolysis.

However, there are serious problems with the use of prostacyclin due to its extreme instability [A. J. Kresge et al., J. Chem. Soc. Chem. Comm. 1979, p. 129]). The most sensitive part of the cyclin-free molecule of 2669696 is the ethanol ether function. The main principles of chemical and biological stabilization of the prostacyclin molecule are set forth in the above-cited articles.

The interfuranylene analogs of prostacyclin of formula (I), the method of manufacture of which is the subject of the present invention, are much more stable compounds than natural prostacyclin. The compounds of the invention are stabilized in a manner not previously described in the literature. The reason for their stability is their new chemical structure. The combustion ring of the compounds of the invention contains six members instead of five, thereby distinguishing them from the structure of natural prostacyclin. This ring, which is stabilized by an aromatic ring built into the burning chain, is characterized by an unusual endocyclic enol ether teat. This aromatic ring exerts its effect by delocalizing the electron system.

Surprisingly, the compounds of formula (I) stabilized by this novel process exhibit a spectrum of activity characteristic of natural prostacyclin (PGI 2), in addition to a considerably higher stability and selective mode of action.

According to the invention, the starting compound of formula (III) is reacted with a halogenating agent of formula (E-X) at a temperature in the range of -20 to +100 ° C, preferably at room temperature. This reaction is carried out in an organic solvent such as an ether type solvent such as ethyl ether, tetrahydrofuran, dioxane, or in halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride or the like, or in polar aprotic solvents such as acetonitrile and the like, or in alcohols such as methanol, ethanol and the like in the presence or absence of an inorganic base, preferably in the presence of an alkali metal carbonate such as sodium or potassium carbonate, or in the presence of an alkali metal bicarbonate such as sodium bicarbonate.

A preferred embodiment of this process involves the use of N-succinimide as the reagent of formula (E-X), dichloromethane as solvent, and the reaction at room temperature in the absence of a base.

Thereafter, the resulting compounds of formula (IIa) are converted to the interfuranyleneprostacycline derivatives of formula (I) by cleavage of the hydrogen halide molecule H-X, where X is halogen, using an organic or inorganic base, optionally in a solvent. This hydrogen halide cleavage reaction is carried out at a temperature in the range of 0 ° C to 200 ° C, preferably at 80 to 120 ° C. As organic bases, amidine-type bases such as diazabicycloundecene or diazabicyclononene and the like, or a tertiary amine such as triethylamine, or aromatic bases such as pyridine, or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, tert-butoxide are preferably used. Inorganic bases such as sodium or potassium hydroxides may also be advantageously used. As solvents, inorganic liquids such as water, organic solvents such as alcohols, for example preferably methanol or ethanol and the like, or aromatic solvents such as benzene and toluene, or polar aprotic solvents such as dimethylsulfoxide and the like can be used. Reactions to cleave hydrogen halide it is very preferably carried out in benzene or toluene using diazabicyclononene or diazabicycloundecene as the base at a temperature in the range of 80 to 120 ° C.

The PGF2 analogue of formula (III) used as the starting material in the process of the invention can be prepared by literature procedures (see, for example, P.L. Caton: Tetrahedron, 35, 2705 81979 and references therein).

The protecting groups R @ ¹ and R @ ² can optionally be cleaved from the compounds of the formula I prepared by methods known from the literature. Optionally, salts of the compounds of formula I may also be prepared.

The stability of the compounds of formula (I) produced by the process of the invention was compared with that of the prostacyclin PGI 2 sodium salt. The latter compound is quite unstable with a half-life of 3-4 minutes at pH 7.4. The free acid (prostacyclin-2 PGI2) cannot even be prepared due to its even greater volatility [RA Johnson et al.]. Am. Chem. Soc., 100, p. 7690 (1978)]. The stability of the compounds of formula I prepared by the process of the invention is significantly greater. One of these, namely 2 ', 5'-interfuranylen-2,3,4-trinor-5,9a-epoxy-9-deoxy-5,6-didehydro-PGF _and can be kept as a free acid at pH 7 , 4, without any apparent decomposition for 12 hours. The compound may be stored at -20 ° C with less than 10% decomposition for at least one month. The half-life of 2 ', 5'4-nituranylene-2,3,4-trinor-5,9 _and -didehydro-16,17,18,19,20-pentanor-15-cyclopentyl-PGF 1 _K is approximately 3 hours at pH 3.

One of the pharmacologically most potent agents of the compounds of the invention is 2 ', 5'-interfuranyl-2,3,4-trinor-5,9a-epoxy-9-desoxy-5,6-didehydro-PGFi _and whose activity is characterized by these data :

1)

Inhibition of platelet aggregation induced by 2.0 moles of adenosine diphosphate in platelet-enriched plasma:

(ID5q = 20 ng.ml ^-1 (human plasma));

ID50 = 350 ng. ml ^-1 (rabbit plasma).

Other compounds of the invention inhibit platelet aggregation induced by adenosine diphosphate in human platelet-enriched plasma with the following ID50 values:

2 ', 5'-Interfanylene-2,3,4-trinor-5,9a-epoxy-9-desoxy-5,6-didehydro-16,17,18,19,20-pentanor-15-cyclopentyl- PGF _and 35 ng. ml ¹ ;

2 ', 5'-inte: rfuranylen-2,3,4-trinor-5,9a-epoxy-9-deoxy-5,6,13,14-tetrahydro-20-methyl-PGF _and 40 ng. ml ¹ .

2)

Hypotensive effect induced in anesthetized cat by intravenous administration of kaolin; ED 50 = 14 μξ. kg ^-1 body weight.

Both the platelet aggregation inhibitory effect and the hypotensive properties exhibit at a concentration one order of magnitude higher than the respective effects of the reference PGL · (prostacyclin-2).

In addition, the compounds of the invention exhibit a broad spectrum of cytoprotective efficacy, both on the myocardium and on the gastrointestinal tract, as well as in liver diseases. The compounds of the invention have other pharmacodynamic effects, namely a guinea pig trachea relaxing effect and a tumor metastasis inhibitory effect induced in rats.

In view of the pharmacological effects described above, the compounds of the invention can be used effectively alone or in combination with heparin to inhibit platelet aggregation without any loss in extracorporeal circulation (such as haemodialysis, extracorporeal heart-lung circulation, etc.). The compounds of the invention may also be used for the prevention or treatment of peripheral vascular diseases (etherosclerosis obliterans, Burrger's disease, diabetic angiopathy, Raynaud's disease).

The dimensions of the areas affected by myocardial infarction as well as mortality are reduced by the use of the compounds of the invention. The number and severity of seizures of angina pectoris decrease in several types of angina pectoris. Due to their bronchial dilatation effect, the compounds of the invention can be advantageously used to reduce the number (frequency) of asthma attacks. Furthermore, these compounds can be advantageously used for the treatment of ulcer diseases due to their gastrointestinal cytoprotective effect. In addition, the use of the compounds of the invention can prevent the spread of tumors (after surgery).

An advantage in treatment with the compounds of the invention is that they can be administered by the gastrointestinal route, for example orally, in addition to intravenous, subcutaneous and intramuscular administration. A preferred dose of the compounds of the invention is from 1 ng. kg ^-1 body weight up to 10 ng. kg ¹ body weight. The appropriate dose depends on the type and severity of the disease, the rate at which the drug reaches the site of action, as well as the individual sensitivity of the patient or organ in need of treatment and the response of the patient. Appropriate dosages and the most appropriate route of administration will be readily appreciated by those skilled in the art.

Commonly used fillers, diluents, flavoring agents, formulation aids, pH adjusting and osmotic pressure agents, and stabilizing and absorption enhancing agents can be used to prepare the pharmaceutical compositions. These pharmaceutical compositions may be solid (e.g. tablets, capsules, dragees, pills, etc.), liquid (e.g. drops, syrups, etc.) or semi-solid (creams, ointments, balms, suppositories, and so on).

The compounds of the invention may be used in the pharmaceutical compositions as the sole active ingredients or in combination with other active ingredients.

The invention is illustrated by the following examples.

He did

Preparation of 2 ', 5'-Interfanylene-2,3,4-trinor-5, ga-epoxy-S-desoxy-S-didehydro-PGF 1, (compound of formula I wherein R ¹ = hydrogen, R ² = H, R ³ = -. (CH2) 4CH3, and - a - trans -CH = CH- and B = valence bond)

To a solution containing 400 mg (1.02 millimoles) of 2 ', 5'-interfuranylene-2,3,4-trinor-5,9a-epoxy-9-desoxy-5,6-didehydro-PGFi methyl ester _and (compound of formula Where R ¹ = methyl, R ² = hydrogen, R ³ = = - (CH 2) 4 CH 3, A = trans-CH = CH- and B equals the valence bond) in 10 ml of methanol is added 5 ml (5 mmol) of aqueous sodium hydroxide solution and the mixture was stirred at room temperature for 3 hours. The methanol was then removed without heating under reduced pressure and the residue was extracted with solvents cooled to 5 ° C. First 25 ml of ether and 30 ml of water are added and the ether phase is separated. The aqueous phase is washed several times with 20 ml of ether, then acidified to pH 3-4 with about 8 ml of aqueous sodium hydrogen sulphate solution. The aqueous layer is extracted several times with 25 ml of ether each time, the organic phases are combined and washed twice with 10 ml of saturated sodium chloride solution each time and dried over anhydrous magnesium sulfate. This gave 292 mg of pure title compound as yellowish-white crystals after evaporation, m.p. 108-110 ° C.

R _t = 0.30 (benzene-dioxane-acetic acid 20; 10; 1);

UV (C2H5OH):

Λ _max - 295 nm, log ε = 4.16 a

Ainax = 235 nm, log ε = 3.93.

Example 2

Preparation of 2 ‘, 5‘-interfuranylene262696 methyl ester

-Z 2 -triiior-5-a-epoxy-g-desoxy-e-iodo-PGF ^f (compound of formula (IIa) wherein R ¹ == methyl, R ² = hydrogen, R ³ = - (GH 2) ) 4CH3, A - trans —CH2CH—, B equals valency bond and X = iodine)

To a solution containing 528 mg (1.40 millimoles) of 2 ', 5'-interfuranylene-2,3,4-trinor-PGF 2 methyl ester _and (a compound of formula III wherein R ¹ -methyl, R ² -hydrogen, K' (-, (CH 2) 4 CH 3, A - trans - CH = - (Cl - 1 - and B - valence bond)) in 20 ml of dichloromethane is added 10 ml of saturated solution, sodium bicarbonate and stirred in portions at 0 ° C with vigorous stirring 310 mg (1.22 mmol) of iodine are added. After 1 hour, 10 mL of sodium thiosulfate solution was added to the reaction mixture, the mixture was stirred for an additional 15 minutes, then 100 mL of ethyl acetate was added. The organic layer was successively extracted with 10 [mu] l of sodium thiosulfate solution, 10 ml of water and 10 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The reaction mixture was purified by short column chromatography (50 g silica gel G, eluting with hexane / acetone 2: 1 to hexane / acetone 4: 3) to give 280 mg of the title compound as a yellow oil.

Rf = 0.64 (acetone / hexane 2: 1);

UV (C2H5OH):

A ', _a; - 256 mn, log ε - 4.25.

Example 3

Preparation of 2 ', 5'-interfuranylene-2,3,4-trifluoro-5,9a-epoxy-9-desoxy-5,6-didehydro-PGF ¹ , methyl ester (compound of formula I wherein R ¹ -methyl , R ² = hydrogen, R ³ = = - (CH 2) 4 CH 3, A - trans - CH = CH - and B valence bond)

To a solution containing 823 mg (1.63 mmol) of 2 ', 5'iuterfuranylen-2,3,4-trinor-5,9a-epoxy-9-deoxy-6-judo-PGF _(r (compound IIa, wherein R ^l - methyl, R ² --- hydrogen, R ³ · - ~ (CH2) 4CH3, and - a valence bond and X - iodine) in 10 ml toluene was added 3 mL diazabicycloundecene, and the sines stirred for 3 hours The mixture is diluted with 100 ml of cold ethyl acetate, extracted twice with 10 ml of cold sodium hydrogen sulphate solution each, then with 10 ml of water and 10 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. in the presence of triethylamine. Purification by short column chromatography (100 g of silica gel G, eluting with ethyl acetate containing 1% triethylamine) gave 362 mg of the title compound:

mp 86-88 ° C,

Rf ₌ 0.45 (ethyl acetate),

UV (C2H5OH):

Amax - 260 nm, log ε = 4,210.

Example 4

Preparation of 2 ', 5'-interfuranylen-2,3,4-trinor-5,9a-epoxy-9-deoxy-5,6-didehydro-PGF _ff (formula I wherein R ¹ - is hydrogen, R ² = hydrogen, R ³ = - (CH 2) 4 CH 3, A - trans —CH = CH— and B = valence bond)

A solution containing 105 mg (0.22 mmol) of methyl 1 _l> L5-diacetyl-2 ', 5'-interferon-! Ranyιlen-2,3,4-trinor-5,9α-epoxy-9-deoxy-5,6- didehydro-PGFJ. _(β (compound of formula I wherein R ¹ = methyl, R ² = acetyl, R ³ = - (CH 2) 4 CH 3, A - trans —CH = CH— and B = valence bond) and 1 ml (1 mmol) of aqueous 1M sodium hydroxide solution in 5 ml of methanol are left at room temperature for 2 days, then the methanol is removed at room temperature under reduced pressure and 20 ml of ether and 20 ml of water are added. to pH 3-4 by addition of approximately 1.2 millimoles of sodium bisulfate solution, the aqueous layer was extracted twice with 25 ml of ether each time, the ether phases were combined and washed twice with 5 ml of saturated sodium chloride solution each time and dried over anhydrous magnesium sulfate. The physical properties of this compound are identical to those of the compound described in the Example

1.

Example 5

Preparation of 2 ', 5'-inte: furanylene-2,3,4-trinor-5,9a-epoxy-9-desoxy-5,6-dihydro-PGFia methyl ester (compound of formula I wherein R ¹ = methyl, R ² = hydrogen R ³ = = - (CH 2) 4 CH 3, A - trans - CH = CH - and B - valence bond)

Solution containing 94 mg (0.20 mmol) of 1,1,15-diacetyl-2 ', 5'-interfuranylene-2,3,4-dinoror-5,9a-epoxy-9-desoxy-5,6-didehydro-PGF1 methyl ester _and (a compound of formula I in which R ¹ = methyl, R ² = acetyl, R ³ = = - (Cl 2) 4 CH 3, A = trans —CH — CH— and B —- valence bond) and 1 ml (1 mmol) of a methanolic 1M solution of sodium methoxide in 3 ml of methanol are stirred at room temperature for 3 hours, after addition of 50 ml of ether, the mixture is washed with 8 ml of cold water and twice with 8 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. A short chromium column (10 g silica gel and hexane / acetone 2: 1) gave 63 mg of the title compound, mp 114-117 ° C.

Rf ₌ 0.62 (hexane / acetone 1: 1); UV (C2H5OH):

AND

Λ _max = 326 nm, log ε = 3.93 and 301 nm, log ε = 4.14.

Example 6

Preparation of 2 ', 5'-interfuranylen-2,3,4-trinor-5,9a-epoxy-9-deoxy-6-bromo-PGF _TT (formula IIa, wherein R ¹ - methyl, R ² = hydrogen, R ³ = = - (CH 2) 4 CH 3, A - trans - CH = CH -, B equals the war bond and X - bromo)

To a solution containing 87 mg (0.2 mmol) of methyl 2 ', 5'-interfuranylene-2,3,4-trinor-PGF ² - (a compound of formula III wherein R ¹ = methyl, R ² - hydrogen, R ³ = - (CH 2) 4 CH 3, A = trans-C 1 = CH- and B - valence bond) in 3 ml of dichloromethane was added 60 mg (0.33 mmol) of N-bromosuccinimide and the mixture was stirred at room temperature for 3 hours. The reaction mixture was chromatographed on a short column (20 g of silica gel, eluting with dichloromethane / acetone 1: 1) to give 50 mg of the title compound.

Rf ₌ 0.23 (1: 1 hexane: acetone); UV (C2H5OH):

A-, '_a; = 258 nm, log ε = 4.18.

Example 7

Preparation of 2 ', 5'-interfuranylene-2,3,4-trinor-5, -9a-epoxy-9-desoxy-5,6-didehydro-16,17,18,19,20-pentanone 15-cyclopentyl-PGFi _ff (a compound of formula I wherein R ¹ - hydrogen, R ² - = hydrogen, R ³ - cyclopentyl, A - = trans -CH C 1 - and B = valence bond)

A mixture of a solution containing 250 mg (0.64 millimoles) of 2 ', 5'-interfuranylene-2,3,4-trinor-5,9a-epoxy-9-desoxy-5,6-didehydro-16,17,18 methyl ester, 19,20-pentanor-15-cyclopentyl-PGFi _a (compound of formula I wherein R ¹ = methyl, R ² = hydrogen, R ³ = cyclopentyl, A-trans —CH — CH— and B = valence bond) with 5 ml (5 mmol) of aqueous 1 M sodium hydroxide solution is left at room temperature for 3 hours, then evaporated to approximately half its volume and purified with cooled solvents as described below. It is diluted with 25 ml of water and 25 ml of ether and the aqueous phase is acidified to pH 3-4 by addition of 1M sodium bisulfate solution. The white precipitate formed is dissolved in 50 ml of ethyl acetate and the two phases are separated. The aqueous phase is washed again with 20 ml of ethyl acetate, the ethyl acetate phases are combined, washed twice with 10 ml of saturated sodium chloride solution each time and dried over anhydrous magnesium sulfate. Evaporation gave 199 mg of the title product as white crystals, m.p. 157-160 ° C.

R; = 0.28 (benzene / dioxane / acetic acid = 20: 10: 1).

Example 8

Preparation of 2 ', 5'-Etherfuranylene-2,3,4-trino; η 5,9α-epoxy-9-desoxy-5,6-didehydro-16,17,18.19,20-pentanor-15-cyclopentyl calcium salt PGF _(compound of formula I in which R ¹ = Ca / _2j R ² - H, R ³ = cyclopentyl, a - trans -CH = CH- and B = valence bond)

A mixture of a solution containing 176 mg (0.45 mmol) of 2 ', 5'-interfuranylene-2,3,4-trinor-5,9s-epoxy-9-desoxy-5,6-didehydro-16,17,18 methyl ester , 19,20-pentanor-15-cyclopentyl-PGF _rz with 5 ml of iN sodium hydroxide in 10 ml methanol was stirred for 90 minutes at room temperature, then the methanol was distilled off under reduced pressure. After addition of 10 ml of water to the residue, the resulting solution is washed with 25 ml of ether, the aqueous phase is acidified to pH 4 by addition of approximately 5 ml of 1M sodium hydrogen sulphate solution and extracted three times with cold 30 ml of ethyl acetate each time. The combined ethyl acetate solutions were washed with 10 mL of saturated sodium chloride solution. After evaporation, the residue is dissolved in 10 ml of tetrahydrofuran and, after addition of 3 ml of water, 30 mg (0.53 mmol) of calcium oxide are added. The resulting cloudy solution was stirred overnight, then filtered, the filtrate was evaporated to dryness and p.) Adding benzene to the residue was again evaporated to dryness. The evaporation residue is stirred for 29 minutes with 20 ml of ethanol and then filtered. Evaporation of the filtrate gave the title compound as a white solid, m.p. 150-155 ° C (dec.).

Rf ₌ 0.28 (benzene / dioxane / acetic acid = 20: 10: 1).

The calcium content of the compound can be determined by titration using acid. In this particular case, the calcium content is 0.785 mg in a sample of 15 mg.

Claims (3)

Subject A process for the preparation of novel racemic and optically active interuranylene propacycline derivatives of the general formula I OF THE INVENTION in which R ¹ , R ² , R ³ , A and B are as defined above, reacted with a compound of formula E — X in which E represents halogen, an acid amide residue or an acid imide residue, and X is halogen, whereupon the resulting compound of formula IIa in which R ¹ represents hydrogen or a C 1 -C 4 alkyl group in a straight or branched chain or a protonated form of an inorganic cation, R ² represents hydrogen, alkanoyl having 1-4 carbon atoms or tetrahydropyranyl group, R ³ represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 5 or 6 carbon atoms, A is C11 CH- or —C = O—, and B represents a chemical bond or a group -CH 2 - characterized in that the compound of the general formula (III) in which R ¹ , R ² , R ³ , A, B and X are as defined above with a base, optionally removing the hydroxyl protecting groups and / or optionally converting the resulting compound into a salt thereof. 2. A process according to claim 1, wherein the halogenating agent of the general formula (E-X) is halogen, N-halogenated acid amide, preferably elemental iodine or N-bromosuccinimide. 3. A process according to claim 1, wherein the base used to treat the compound of formula IIIa is an amidine-type base, preferably diazabicycloundecene.