WO1994025478A1

WO1994025478A1 - 16α,17α-ACETAL GLUCOCORTICOSTEROIDAL DERIVATIVES

Info

Publication number: WO1994025478A1
Application number: PCT/PL1994/000009
Authority: WO
Inventors: Teresa Uszycka-Horawa; Barbara Trzpil; Grzegorz Grynkiewicz
Original assignee: Infarm Sp Zoo; Instytut Farmaceutiyczny
Current assignee: Infarm Sp Zoo; Instytut Farmaceutiyczny
Priority date: 1993-04-29
Filing date: 1994-04-28
Publication date: 1994-11-10
Anticipated expiration: 1995-10-29

Abstract

New 16α,17α-acetal glucocorticosteroid derivatives of general formula (I), wherein dotted line in the 1,2-position represents optional bond, R represents hydrogen atom or acetyl group and R1 and R2 represent independently hydrogen atom or fluorine atom, and their solvates with organic solvents, with antiinflammatory, antiallergic and immunosuppressive activities, the process for their preparation and pharmaceutical compositions containing them.

Description

16α.17 -Acetal glucocorticosteroidal derivatives

Field of the invention

The present invention relates to new, I6α. I7α-acetal glucocorticosteroidal derivatives, to a process for their preparation and to pharmaceutical composition containing them with antiinflammatory, antiallergic and immunosuppres- sive properties. Background art

Natural glucocorticosteroids, such as hydrocortisone and cortisone, possessing potent antiinflammatory, immunosu¬ ppressive and anti-shock properties and widely used in medi- cal practice, exhibit various, severe adverse effects, par- ticulary after systemic administration.

The investigations on chemical modifications of the na¬ tural glucocorticosteroids allowed to obtain many new syn¬ thetic drugs, characterized by higher activity and milder adverse effects. One of the most important drug of this class is prednisolone, that is llβ, 17α.21-trihydroxypreg- na-1,4-diene-3,20-dione and compounds obtained by modi¬ fication of prednisolone. An introduction of a 16α-hydroxyl group is one of the methods for modification,- it leads to the synthesis of triamcinolone and fluocinolone.

16α, 17α-Acetal derivatives of 16α-hydroxyprednisolone are much more active, for example: triamcinolone acetonide and budesonide (16αl7α-butylidenedioxy-llβ, 21-dihydroxy- pregna-l,4-diene-3,20-dione) . These derivatives are charac- terized by strong topical antiinflamma ory action and redu¬ ced hormonal systemic effects, so they may be widely used, especially in the treatment of bronchial asthma (aerosols, inhalations) and in the treatment of skin diseases of va- rious origin (creams, ointments) . Budesonide has been ap¬ plied in drug production both as a 1:1 mixture of 22R and 22S diastereoisomers, and as the 22R diastereoisomer, which is 2 times more potent than the 22S diastereoisomer.. Bude¬ sonide and budesonide 22R have been disclosed, among others, in German patent description No 2323216 and in European pa¬ tent description No 164636. New 21-esters of 16α, 17α-acetal derivatives of 16α-prednisolone possessing antiinflammatory and immunosuppressive properties, a process for the prepara¬ tion of these derivatives and pharmaceutical compositions containing them have been disclosed in a Great Britain pa¬ tent application No 2247680. The disclosed compounds are characterized by a substituent R at 22-position, wherein R represents 2-propyl, 1-butyl, 2-butyl, cyclohexyl, pheriyl or benzyl group. In the international patent applications W092/13873 and WO 92/138774 there are disclosed 16α, 17α-acetal steroidal derivatives, having double or saturated bond between carbon atoms at the 1,2-positions, substituted at 22-position by an alkyl group or a hydrogen atom, and at 6 and/or 9-p .3ition by a halogen atom. It has been stated that these comoounds exhibit topical antiinflammatory, antiallergic and immuno¬ suppressive properties.

The aim of the present invention is to provide new, 16,17-acetal glucocorticosteroidal derivatives characterized by potent antiinflammatory, immunosuppressive and antialler¬ gic properties with the minimum adverse effects, which might be applied as active components of drugs. Disclosure of the invention

The compounds according to the present invention are characterized by the general formula I,

wherein the dotted line at 1,2-position represents optional bond, R represents hydrogen atom or acetyl group, and su- bstituents R, and R~ represent independently hydrogen atom or fluorine atom, and their solvates with organic solvents. These compounds have not been yet described in the literatu¬ re.

The dotted line at the 1,2-position of a compound means that the invention comprises compounds having a single bond at 1,2-position, as well as compounds having a double bond at 1,2-position.

Due to the presence of asymmetry centre at the acetal 22-carbon atom, the compounds according to the present in¬ vention may occur in a form of two diastereoisomers of dif- ferent configuration at the acetal 22-carbon atom (namely, the 22R and 22S diastereoiso ers) , as well as in the form of an equimolar mixture of these diastereoisomers and in the form of mixtures wherein the ratio of the diastereoisomers is not equimolar.

Therefore, the present invention relates to the new, 16α, lTα-acetal glucocorticosteroidal derivatives of the ge¬ neral formula I as defined hereinbefore, in the form of the diastereoisomer 22R as well as in the form of the diastereo- isomer 22S and in the form of equimolar or non-equimolar mixtures of these diastereoisomers.

A preferred compound according to the present invention is the compound of formula I, having a double bond at

1,2-position, wherein R represents acetyl, and substituents i and R₂ both represent hydrogen atoms, especially in the form of the diastereoisomer 22R.

In another aspect the present invention provides also a process for the preparation of the novel, 16α, 17α-acetal glucocorticosteroidal derivatives of the general formula I,

wherein the dotted line at the 1,2-position represents an optional bond, R represents hydrogen atom or acetyl, and the substituents R, and R₂ represent independently hydrogen atom or fluorine atom, characterized in that compound of general formula II,

II wherein the dotted line at the 1,2-position represents an optional bond, R represents hydrogen atom or acetyl, and su¬ bstituents R, and R₂ represent independently hydrogen atom or fluorine atom, is condensed with 2-furaldehyde in the presence of an acidic catalyst.

Reaction is carried out at room temperature, in aprotic organic solvent, such as, for example, chlorinated hydrocar¬ bons, such as, for example, methylene chloride and chloro¬ form, ethyl acetate, ethers, such as for example dioxane or tetrahydrofurane.

Depending on the type of an acidic catalyst, the resul¬ ting product demonstrates either a higher content of the 22R diastereoisomer, if the reaction is performed under the pre¬ sence of a strong mineral acid, such as perchloric acid, or a higher content of the 22S diastereoisomer, if reaction is conducted under the presence of a strong organic acid, such as for example trifluoroacetic acid, or para-toluenesulfonic acid. The reaction may be also performed under the presence of a mixture of acids, depending on a desired ratio of the diastereoisomers. The reaction time depends on a strength of the acid employed, it is longer when the acid used is wea¬ ker.

Diastereoisomers of the compound according to the pre- sent invention may be separated by known methods, for exam¬ ple by preparative HPLC or by fractional crystallization in appropriate solvents.

Alternatively, the process for preparation of glucocor- ticoidal derivatives of general formula I, as defined here- inbefore, is characterized in that a compound of general formula III,

III wherein the dotted line at the 1,2-position represents an optional bond, R represents hydrogen atom or acetyl, and su- bstituents R_χ and ₂ represent independently hydrogen atom or fluorine atom, is condensed with 2-fury1 aldehyde in the presence of acidic catalyst.

In further aspect the present invention provides also a pharmaceutical composition containing as an active Lngre- dient novel glucocorticosteroidal derivatives of general formula I as defined hereinbefore or their solvates with an organic solvent.

Preferably the pharmaceutical composition according to the present invention contains as an active ingredient a compound of general formula I, wherein there is a double bond at 1,2-position, R represents acetyl, and substituents -_j^ and R₂ both represent hydrogen atoms, more preferably in a form of a mixture of diastereoisomers 22R and 22S in a ra¬ tio from about 80:20 to about 100:0, especially from about 90:10 to about 100:0.

The pharmaceutical composition according to the present invention contains also - depending on a desired dosage form of a medicament - carriers, vehicles and/or auxilliary su¬ bstances known to the persons skilled in the art. The pharmaceutical composition, containing the compound according to the present invention as an active ingredient, may be formulated in various dosage forms, depending on rou¬ tes of administration appropriate for certain diseases.

It may be formulated in the dosage forms suitable for topical administration in dermatological disorders (for example: ointment, cream, gel, spray-type aerosol for exter¬ nal use, foam aerosols and the like) , as well as in tie do¬ sage forms suitable for inhalation (aerosol, solution for nebulization, powder for inhalation) . It may be also formu- lated in the form suitable for parenteral administration, for example: subcutaneous and intramuscular injections and intravenous infusions, and in the form of suppositories for rectal administration. The composition according to the present invention may be also formulated in the form suitable for oral administra¬ tion, such as, for example, tablets, capsules, coated tab¬ lets - especially with coating, which protects the tablet from gastric juice or coating, which delays a release of an active component, syrups and solutions, as well as dry pow¬ ders which are solubilized before use, e.g. effervescent powders.

In order to obtain the dermatological preparations such as ointments and creams, the compound according to the pre- sent invention, preferably in a micronized form - especially in a case of ophtalmic ointments, is associated with a pro¬ per ointment vehicle. As carriers, there may be applied hyd¬ rocarbon gels, such as, for example vaseline, ceresine, pa¬ raffin, lipoidal gels, such as, for example animal lipideε, vegetable oils, stearic acid, waxes, lanoline. There may be also applied emulsion carriers containing emulsifiers which, with water, give water-in-oil emulsions, such as lanoline, cholesterol, steroidal alcohols obtained from lanoline, as well as emulsion carriers containing emulsifiers, which give oil-in-water emulsions as creams, e.g. sodium lauryl sulfa- te, cetostearyl alcohol and the like. There may be also ap¬ plied fat-free carriers, like hydrogels consisting of col¬ loids, such as starch and its derivatives, polivinyl pyr- rolidone, alginates, silicones and polyethylene glycols such as Carbowax, Macrogol.

The composition according to the present invention may be formulated in the form of aerosols containing a mixture of compressed gas (propellant) with a solution of an active component in alcohols, glycols, natural and synthetic oils (for example isopropyl myristate, sorbitan trioleate) as well as the emulsion or suspension of the active component in a liquefied propellant. As propellants, there are usually used fluorinated hydrocarbons, liquefied saturated hydrocar- bons such as propane and butane, liquefied carbon dioxide or a mixture of these compounds. Particles of active compounds of aerosols administered via the respiratory tract most com¬ monly range from 0,01 μ to 5 μ in diameter, and aerosols for application on skin (spray-type aerosols) - from 250 μm to 1000 μm.

Foam aerosols, containing an active component dissolved in an emulsion base, may be also applied on skin.

The composition according to this invention may be also used in the form of an aqueous solution for inhalation (ne- bulization) , usually containing propylene glycol in addi¬ tion, or in the form of a powder for inhalation, which most commonly consist of a mixture of a micronized active compo¬ nent and a solid carrier, e.g. lactose.

Preparations for parenteral administration are usually formulated in the form of an aqueous suspension of a micro¬ nized active component with addition of auxilliary substan¬ ces emulsifying and stabilizing the suspension, substances maintaining isotonicity of a solution and preservatives. The dosage form of dry, liophilized powders to be solubilize be- fore use, also may be formulated.

A content of the compound according to the present invention in a single dose of the pharmaceutical composition according to the present invention - relating to therapeu- tical aerosols - ranges from 10 μg to 1000 μg, preferably from 50 μg to 250 μg, and in tablets or similar oral dosage forms - from 0,01 mg to 5 mg, preferably from 0,1 mg to 2 mg. The concentration of the active ingredient applied in dosage forms formulated for topical use, as ointments and creams, ranges from 0,01% by weight to 1% by weight, prefe¬ rably from 0,01% by weight to 0,5% by weight.

As it has been demonstrated by pharmacological investi¬ gations, antiinflammatory and immunosuppressive properties of the compounds according to this invention are comparable with those of budesonide R. Thus, they may be of value in the treatment of inflammatory states, allergic diseases, es¬ pecially bronchial asthma, in the treatment of diseases of autoimmunological origin, such as systemic lupus erythemato- sus and nephrotic syndrome, and in transplantology for pre- vention of resistence of grafts.

Therefore the present invention relates also to the use of the novel glucocorticosteroidal derivatives of the gene¬ ral formula I, as defined hereinbefore, and their solvates with organic solvents, for the preparation of antiinflamma- tory, antiallergic and immunosuppressive medicaments.

A daily dosage of the compound according to the present invention usually ranges from 250 μg to 2500 μg, preferably from 500 μg to 2000 μg pertaining to therapeutical aerosols. In a case of oral administration, the daily dosage ranges from 0,lmg to 5mg, preferably from 0,5 to 2mg. However, the daily dosage is always individually determined in each case, depending upon a type and course of a disease, age and con¬ dition of a patient and other factors.

Pharmacological tests.

Pharmacological activity of the compounds according to the invention was proved by pharmacological tests, the re¬ sults of which are presented below. i) . Evaluation of immunosupressive properties Methods

Investigations were carried out using male rats, out- bred Ipf:RIZ, weighing 95-120 g. The tested preparations we¬ re given to the rats intragastrically as a suspension in a 5% solution of arabic gum, in a volume of lml/lOOg, every day at the same time for 14 days. The following doses were applied: 0,11, 0,22, 0,55, 1,1 and 2,2 mg/kg of body weight. Control group animals were given 5% solution of arabic gum (lml/lOOg of body weight) . After 14 days the animals were sacrificed by Vetbutal injection and then, thymus and spleen were removed and weighed (measuring accuracy = 0.1 mg) . The results were statistically analysed by Student's t-distri- bution (paired data, level of significancy p < 0,05).

The tested preparation A consists of a mixture of the diastereoisomers (22R) and (22S) (llβ.16α) -16, 17- (furfuryli- denedioxy) -21-acetoxy-ll-hydroxy-l,4-pregnadiene-3,20-dione

(the compound of the formula I, wherein there is a double bond at 1,2-position, R represents acetyl group, and

R =R₂=H) in a ratio of 94:4, and the tested preparation B is the mixture of the diastereoisomers (22R) and (22S) (llβ- 16α)-16, 17-(furfurylidenedioxy) -21-acetoxy-ll-hydroxy- 1,4-pregnandiene-3,20-dione in a ratio of 8:92. The results A) The influence on weight of thymus

A reduction in weight of thymus after administration of the tested preparations was proportional to dosing. The pre¬ paration A was more potent than budesonide (by 14-15% - de¬ pending on the applied doses) . Differences between the ef- fects exerted by the preparation A and budesonide R were statistically significant. The preparation B was less potent than budesonide R (Table 1) . B) The influence on weight of spleen

The preparation A caused a statistically significant reduction in weight of spleen proportionally to dosing. The preparation A was more potent than budesonide. Differences between the effects exerted by the preparation A and budeso¬ nide were statistically significant after administration of higher doses ( 0,55-2,2 mg/kg ) . The preparation B caused a statistically significant reduction in weight of spleen only after administration of 1,1 mg/kg. (Table 1) .

Table 1: The influence of budesonide R and the compounds according to the invention on weight of thymus and spleen in rats.

*

- p < 0,05 with reference to a control group

- p < 0,01 with reference to a control group p < 0,05 with reference to budesonide p < 0,01 with reference to budesonide 2) Evaluation of antiinflammatory effect

A) A model of an acute inflammatory state (carrageenin test) Methods

The investigations were carried out on starved, female rats (outbred Ipf:RIZ), weighing 140-160 g. The acute in- flammatory state was induced by an injection of 0,1 ml of 1% carrageenin solution in a hind paw of a rat according to a method by Winter (Winter C. A. et al. , Proc. Soc. Exp. Biol. Med. Ill, 1962, 544) and Lence (Lence P., Arch. Ziter. Phar- mac. Ther. 136, 1962, 237) . The tested preparations were gi¬ ven to the rats intragastrically as a suspension in 5% solu¬ tion of arabic gum, in a volume of 1 ml/100 g of body weight, 1 hour before the injection of carrageenin. The con¬ trol group animals were given 5% solution of arabic gum (iml/100 g of body weight) . Measurements of rat paws were done three times: before and in 2 and 4 hours after the car¬ rageenin injection. A degree of edema inhibition (%) was calculated according to the formula: k - d

100 k wherein k represents an average increase of a rat paw edema in the control group during a given period, and d represents an average increase of a rat paw edema in the control group during a given period.

The results were statistically analysed by the paired student's t-distribution, level of significance p< 0,05. The results are presented in Table 2.

Table 2 : The influence of the preparation A and budesonide R on a rat paw edema induced by carrageenin.

p < 0,05 with reference to the control group p < 0, 01 B) A model of a subacute inflammatory state (cotton test) Methods

The investigations were carried out on female rats (outbred Ipf:RIZ), weighing 160-200 g, which had an access to the food. The subacute inflammatory state was induced in rats under a slight Vetbutal narcosis by subcutaneous im¬ plantation of cotton-wool pellets impregnated in 1% carrage¬ enin solution according to a method by Pusch (Bush E. et al. , Acta Endocr. 33, 1960, 268) and Meier (Meier H. et al. , Experimentia 6, 1950, 469) . The investigated preparations were given to the rats intragastrically as a suspension in 5% arabic gum solution, in a volume of 1 ml/100 g of body weight daily for 8 days. The animals of the control group were given 5% solution of arabic gum (lml/100 g of body weight) . The rats were sacrificed after 8 days; granulomas were removed and dried at 100°C until they reached constant weight.

The antiinflammatory effect was evaluated considering a difference in weight of granuloma tissues between the con¬ trol and the tested group. The results were statistically analysed by the paired student's t-distribution, significan¬ ce level p< 0, 05 ) .

Table 3 : The influence of preparation A and budesonide R on granuloma growth in rats.

** p < 0,001, p < 0,01 with reference to the control group 3) Evaluation of acute toxicity of the preparation A.

The acute toxicity of the preparation A of the compound according to the invention was compared with the toxicity of budesonide R. Investigations were conducted on male mice, (outbred Ipf:RIZ), weighing 20,0-24,0 g, in groups of ten for each dose. The compared preparations were given intragastrically in a form of 10% suspension in 0,5% tylose collodion at do¬ ses up to 4 g/kg of body weight. The animals were observed within 4 hours after the administration and, after that, every day twice daily for 14 days. During the experiment the animals were on diet, which consisted of "Murigran" mixture and received water ad libitum.

It was determined that administration of budesonide and the preparation A according to the invention, which consists of the mixture of the diastereoisomers 22R and 22S in a ra¬ tio of 96:4, did not induce toxic effects at doses up to 4 g/kg of body weight. The acute toxicity of the preparation A (compared to budesonide) of the agent according to the in- vention is within the same range as that of budesonide.

The compound according to the invention demonstrated immunosuppressive properties after multiple administration (14 days) in rats. The immunosuppressive action, expressed as a reduction in thymus and spleen weight after administra- tion of the preparation A of the compound according to the invention, was stronger than that of budesonide.

Examples presented below illustrate the present inven¬ tion, nevertheless they do not limit its scope. Example 1

Preparation of the diastereoisomer (22R) (llβ, 16α)-16, 17- (furfurylidenedioxy)-21-acetoxy-ll-hydroxy-l,4-pregnadiene- 3,20-dione (a double bond at the 1,2-position in the formula 1, R represents acetyl group, R₁=R₂=H)

21-acetate of 16α-hydroxyprednisolone (3g, 7mκiθl) is suspended in 150 ml ethylene dichloride at room temperature, 2-furaldehyde is added (3ml, 366mmol ) and, while stirring, lml 70% perchloric acid solution. Stirring is continued for 6 hours. During the reaction, the suspension is dissolved and the solution darkens. In 6 hours, when a control by thin-layer chromatography (plates of Kieselgel Merck GF 254, developing system toluene:acetone:ethanol 10:1:1) demonstra¬ tes lack of the substrate, the reactant mixture is neutrali¬ zed by 10% solution of potassium carbonate. The layers are separated, an aqueous layer is extracted by ethylene dichlo¬ ride, combined organic layers are washed with water and et¬ hylene dichloride is evaporated on a vacuum evaporator. Dry residue is crystallized from a mixture of ethanol wit-h ethyl acetate 1:1. 1 g of (llβ, 16α)-16, 17-(furfurylidenedioxy)-21- acetoxy-ll-hydroxy-l,4-pregnadiene-3,20-dione is obtained as a solvate with ethanol, in the form of white, crystalline solid. Yield: 29%.

The product was analysed by a method of HPLC (column 250 x 4 mm, packing Lichosorb RP 18, 10μ, elution system methanol-water 2:1, UV detection at λ=242 nm) . Retention ti¬ mes for the diastereoisomers 22R and 22S in this system were equal to about 19 min. and about 23 min respectively. It was determined, that a ratio of the 22R diastereoisomer to the 22S diastereoisomer in the product was 96,1:3,9. An absolute configuration of the product was determined by rentgenogra- phy.

Physico-chemical characteristics of the product: t.t. 265-8°C; [α]^D = +64,1 (c 1%, CHCI3); UV (CH₃OH) :

219 nm, a^1% _lcm = 335; 242 nm, a^1% _lcm = 302;

IR (tablet KBr), μ (cm^-1): 3370, 2930, 1750, 1720, 1650,

1610, 1600, 1430, 1400, 1380, 1220.

Example 2_.

Preparation of the diastereoisomer (22S) (llβ, I60 -I6, 17-

(furf rylidenedioxy)-21-acetoxy-ll-hydroxy-l,4-pregnadiene-3

,20-dione (a double bond at the 1,2-position, R₁=R₂=H ), in a form of a solvate with ethanol

21-Acetate of 16α-hydroxyprednisolone (3g, 7mmol) is suspended in 90ml of dioxane at room temperature, 2-fural- dehyde is added (3ml, 36mmol) and, while stirring, 0,5ml of trifluoroacetic acid. Stirring is continued. The suspension is dissolved during the reaction, and the solution darkens. After 24 hours, when a control by thin-layer chromatography (conditions as in example 1) demonstrates lack of the su¬ bstrate, the reactant mixture in neutralized by pyridine and dioxane is distilled off on a vacuum evaporator. Dry residue is dissolved in chloroform, inorganic substances are washed out, chloroform is distilled off, and the residue is crys¬ tallized from ethanol. 1 g of (llβ, 16α)-16, 17-(furfurylide¬ nedioxy)-21-acetoxy-ll-hydroxy-l,4-pregnadiene-3,20- dione is obtained as a solvate with ethanol, in the form of white, crystalline solid. Yield: 28%.

Using a HPLC method in the system such as presented in example 1, it was determined that a ratio of the diastereoi¬ somer 22R to 22S in the product is 4:96. Physico-chemical characteristics of the product: t.t. 183-5°C; [α]^D = +82,2 (c 1%, CHCI3); UV (CH3OH) : 224 nm, a^1% _lcm = 251; 241 nm, a^1% _lcιn = 263; IR (tablet KBr), μ (cm^-1): 3400, 2930, 1750, 1720, 1650, 1610, 1600, 1430, 1380, 1220. Example 3.

Preparation of the diastereoisomer (22R) (llβ, 16α)-16, 17- (furfurylidenedioxy)-21-acetoxy-ll-hydroxy-l,4-pregnadiene- 3,20-dione (a double bond at the 1,2-position, R=acetyl, <⁼Ro⁼H ) .

16α-Hydroxy-2l-acetoxyprednisolone 16,17-acetonide (0,5g, 0,113mmol ) is suspended at room temperature in 30 ml of ethylene chloride, 2-furaldehyde is added (0,15 ml, 0,117 mmol) and, while stirring, 0,5 ml of 72% perchloric acid. Stirring is continued at room temperature for 4 hours. As soon as a lack of the substrate is determined by thin-layer chromatography (the system as in example 1) the reaction is interrupted by adding 10% aqueous solution of potassium car¬ bonate. Subsequently the aqueous and the organic layers are separated and the aqueous phase is extracted by ethylene chloride, and the organic phase is washed with water. The organic phases are combined and solvent is distilled off on a vacuum evaporator, which leads to obtaining an amorphous residue. After a double crystallization from ethanol, 110 mg of the product (properties as in example 1) is obtained (yield: 19% ) . Example 4.

(llβ, 16α)-16, 17-(furfurylidenedioxy)-ll,21-dihydroxy-9_'χ- fluoro-1,4-pregnadiene-3,20-dione (a double bond at 1,2-position, R=R₂=H, R^F)

Triamcinolone acetonide (300mg, 0,7mmol) (6α-fluoro- llβ, 16α, 17α, 21-tetrahydroxypregna-l,4-diene-3,20-dione ace¬ tonide) is suspended in 30 ml ethylene chloride, 0,3 ml of 2-furaldehyde is added and, while stirring, 0,1 ml of 70% perchloric acid is added dropwise in at room temperature. After 24 hours perchloric acid is neutralized by 10% potas¬ sium carbonate, the layers are separated and the organic la¬ yer is washed with water. After distilling off the solvent and crystallizing from ethanol, 60 mg (yield: 18%) of the pure diastereoisomer 22R of the titled compound, possessing the following characteristics is obtained : [α] +92,9 (0,2, CHCI₃)

^al%lcm ³³⁰ P^r2^ ^λmax ^{220 nm} ^al%lcm ³⁰⁰ P^rz^ ^λmax ²³⁵ ∞" Example 5_.

(llβ, 16α)-16, 17-(Furfurylidenedioxy)-ll,21-dihydroxy-6tt, 9α- difluoro-l,4-pregnadiene-3,20-dione (a double bond at 1,2-position, R=H, R₁=R₂=F)

Fluocinolone acetonide (300mg, 0,67mmol) (6α, 9α~diflu- oro-llβ, 16α, 17α, 21-tetrahydroxypregna-l,4-diene-3, 20-dione acetonide) is suspended in 30 ml ethylene chloride, 0,3 ml of 2-furaldehyde is added and, while stirring, 0,1 ml of 70% perchloric acid is added dropwise in at room temperature. After 24 hours, perchloric acid is neutralized by 10% solu¬ tion of potassium carbonate, the layers are separated and and the organic layer is washed with water. After distilling off the solvent and crystallizing from ethanol, 80 mg (yield: 25%) of the pure diastereoisomer of the titled com¬ pound, possessing the following characteristics is obtained: [_α] +59,65 (c=0,5, CHC1₃) ^al%lcm ³³⁷ P^rz^ ^λmax ²²° ^nτn ^al%lcm ³⁰⁴ P^rzy ^λmax ^{234 nm} Example 6_.

The pressurized aerosol for administration via the respira- tory tract

Composition of the aerosol:

Glucocorticosteroidal derivative 32 g

Span 85 32 g

Freon 11 5,2 1 The active component in the form of the mixture of the diastereoisomers 22R and 22S in a ratio of 96:4, micronized so that the size of particles is 5μ, is stirred with Span 85 (sorbitan trioleate) and Freon 11 untill a homogenous sus¬ pension is obtained, subsequently proportionizing into aero- sol blocks is done, the blocks are closed with proportioni- zing valves and filled up with freon so that a single dose of 150 μg active substance is obtained. Example __ The ointment Micronized glucocorticosteroidal derivative 0,1 g Lanoline 10 g

White petrolatum up to 100 g Example 8_

The oil-in-water cream

Micronized glucocorticosteroid 0,1 g

White petrolatum 15,0 g

Cetyl alcohol 7,0 g

Glycerine monostearate 4,0 g

Propylene glycol 25,0 g

Citric acid 0,1 g

Sodium citrate 0,2 g

Water up to 100 g

Example 9_.

The suspension for injections

Micronized glucocorticosteroid 0, 01-5 mg

Sodium salt of carboxymethylcellulose 6 mg Polisorbat 80 0, 5 mg

Benzyl alcohol 7 mg

Sodium chloride 10 mg

Water for injection up to 1 ml

Example 10 The lotion for external use

Glucocorticosteroid 0, 01-0, 025 mg

Isopropyl alcohol 50 ml

Karbopol 0,6 g

NaOH as much as needed Water up to 100 g

Claims

1. New 16α,I7α-acetal glucocorticosteroid derivatives of the general formula I,

wherein dotted line in the 1,2-position represents optional bond, R represents hydrogen atom or acetyl group and R-, and R₂ represent independently hydrogen atom or fluorine atom, and their solvates with organic solvents.

2. New I6α, I7α-acetal glucocorticosteroid derivatives ac¬ cording to claim 1, in the form of diastereoisomer 22R or 22S.

3. Novel 16α, 17α-acetal glucocorticosteroid derivatives according to claim 1 or 2, having a double bond in the 1,2-position, wherein R represents acetyl group, and R, and R₂ both represent hydrogen atoms, especially in the form of diasteroisomer 22R.

4. A process for the preparation of the novel 16α, 17α-ace- tal glucocorticosteroid derivatives of the general formula I as defined in any of the claims 1-3, characterized in that a compound of the general formula II, 25

II wherein dotted line in the 1,2-position represents optional bond, R represents hydrogen atom or acetyl group and R and R₂ represent independently hydrogen atom or fluorine atom, is condensed with 2-furaldehyde in the presence of acidic catalyst.

5. A process for the preparation of the novel 16α,17α- acetal glucocorticosteroid derivatives of the general formu¬ la I as defined in any of the claims 1-3, characterized in that a compound of the general formula III,

III wherein dotted line in the 1,2-position represents optional bond, R represents hydrogen atom or acetyl group and R-^ and R₂ represent independently hydrogen atom or fluorine atom, is condensed with 2-furaldehyde in the presence of ϊcidic catalyst.

6. A pharmaceutical composition, coprising as an active ingredient novel, 16α,17α-acetal glucocorticosteroid deriva¬ tive of the general formula I as defined in any of the claims 1-3, or solvate thereof, together with pharmaceuti¬ cally acceptable carriers, vehicles and/or auxilliary su¬ bstances.

7. A pharmaceutical composition according to claim 6, com¬ prising as an active ingredient new 16α,17α-acetal gluco¬ corticosteroid derivative of the general formula I, wherein there is a double bond in 1,2-position, R represents acetyl group and R, and R₂ both represent hydrogen atom, preferably in the form of the mixture of diastereoisomers 22R and 22S in the ratio from about 80:20 to about 100:0, especially from about 90:10 to about 100:0.

8. A use of the new 16α,17α-acetal glucocorticosteroid de¬ rivative of the general formula I as defined in any of the claims 1-3 and their solvates with organic solvents for the preparation of antiinflammatory, antiallergic and im uno- suppresive medicaments.