SI9210064A - Novel antiinflamatory and antialergic active compounds, glucocorticosteroids and processes for their preparation - Google Patents

Abstract

A compound of the general formula 1 * 2 or a stereoisomeric component thereof into which the formula is 1.2 or saturated with double bond, Ri is hydrogen or branched or unbranched hydrocarbon which has a chain of 1-4 carbon atoms, R2 is an acyl having branched or unbranched, saturated or unsaturated hydrocarbon chain with 1 -20 carbon atoms, Χ1 is is hydrogen or halogen, Χ2 is hydrogen or halogen and is determined that Ri and R2 are not hydrogen at one time, Χ1 and Χ2 they are not hydrogen at one time when they are double at the 1.2 position bond, Ri and R2 are not simultaneously methyl groups when on 1,2 position of the double bond, R 1 is a hydrogen atom and R 2 branched or unbranched hydrocarbon having a chain with 1-10 carbon atoms; R3 is an acyl having 11-20 carbon atoms, processes for their preparation, pharmaceutical the compositions they contain and the use of the compounds in the treatment of inflammatory and allergic conditions.

Description

NEW ANTI-INFLAMMATORY AND ANTI-ALLERGY ACTIVE COMPOUNDS GLUCOCORTICOSTEROIDS AND PROCEDURES FOR THEIR PREPARATION

FIELD OF THE INVENTION

The present invention relates to novel anti-inflammatory and anti-allergic active compounds and to methods for their preparation. The invention also relates to pharmaceutical compositions containing the compounds and methods for the pharmacological use of the compositions.

It is an object of the invention to provide an anti-inflammatory, immunosuppressive and anti-allergic glucocorticosteroid or a high-activity pharmaceutical composition thereof at the site of application, e.g. in the respiratory tract, on the skin, in the intestinal tract, in the joints or in the eye, by directing the drug to a restricted target area, thus inducing low glucocorticoid systemic effects.

It is a further object of the invention to provide a pharmaceutical composition comprising liposomes containing the pharmacologically active fatty acid steroid ester of the invention in order to improve drug delivery and minimize side effects of therapy.

Scientific basis

Glucocorticosteroids (GCS) are the most valuable medicines for the relief of asthma and rhinitis. It is generally accepted that GCSs show their therapeutic efficacy through anti-inflammatory and anti-anaphylactic activity within airways and lung tissue. Long-term oral administration of GCS is very difficult with strong side effects outside the lung region. Thus, at present, only a small proportion of patients with asthma or rhinitis undergo GCS therapy. Greater safety can be achieved by delivering GCS by inhalation. However, predominantly inhaled GCSs, which are currently in widespread clinical use (beclomethasone 17a, 21-dipropionate and budesonide), have a fairly low safety margin, both of which have been reported to perform undesirably within the general circulation at the highest recommended inhaled doses.

Liposomes are membrane-like vesicles consisting of a series of concentric lipid bilayers with alternating hydrophilic compartments.

Liposomes have been used as carriers for various types of pharmaceutically active compounds in order to improve drug delivery and minimize side effects of therapy.

Glucocorticosteroids are only involved in liposomes at low concentrations and are poorly retained in the vesicles. GCS esterification at 21 positions with fatty acids increases the rate of incorporation and retention of steroids in the bladder. The fatty acid chain has been shown to act as a hydrophobic anchor that holds the steroid core in groups of hydrated phospholipid polar heads, thus enhancing the interaction between glucocorticosteroid and liposome.

Glucocorticosteroids encapsulated in liposomes have been described (M. De Silva et al., Lancet 8130 (1979), 1320), U.S. Pat. No. 4 693 999 describes liposomal formulations of glucocorticosteroids for inhalation.

Discovery of the invention

One object of the present invention is to provide novel GCS compounds. The novel compounds are characterized by anti-inflammatory, immunosuppressive and anti-anaphylactic potency at the application site and, in particular, have a markedly improved relationship between this potency and the ability to induce GCS activity outside the treated regions. The most desirable form of administration of new compounds is by inhalation when the application site is within the airways.

Another object of the invention is to provide an anti-inflammatory and anti-allergic pharmaceutical composition comprising liposomes with steroidal esters for topical administration primarily to the respiratory tract. Such a composition improves the therapeutic properties of steroid esters by extending local airway retention and by targeting the drug to specific target cells.

The compounds of the invention are designated by Formula 1

CH3COOH

C2H5COOH

C3H7COOH

C4H9COOH

C ₅ HjjCOOH

C ₆ H ₁₃ COOH

C ₇ Hj ₅ COOH

C ₈ H ₁₇ COOH or a stereoisomeric component thereof in which the formula 1,2 is saturated or has a double bond there,

Rj is hydrogen or branched or unbranched hydrocarbon having 1-4 carbon atoms, R2 is hydrogen or branched or unbranched hydrocarbon having 1-10 carbon atoms,

R3 is an acyl having a branched or unbranched, saturated or unsaturated hydrocarbon chain having 1-20 carbon atoms,

Χ-j is hydrogen or halogen

Χ2 is hydrogen or halogen and it is specified that

1) Rj and R2 are not hydrogen at one time,

2) Xj and Χ2 are not hydrogen at one time,

3) when there is a double bond at the 1,2 position, R j and R2 are not at one time methyl groups,

4) when at the 1,2 position there is a double bond, R j is a hydrogen atom and R2 is a branched or unbranched hydrocarbon having 1-10 carbon atoms, R3 is acyl having 1120 carbon atoms.

Acyl is derived from:

acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid,

CgH-jgCOOH

CioH- | gCOOH

C-j and H23COOH

C-12H25COOH

C-13H27COOH

C-14H29COOH

C ₁₅ H ₃₁ COOH c ₁₆ h ₃₃ cooh c ₁₇ h ₃₅ cooh

Ci 7H33COOH

C ₁₇ H ₃₁ COOH

C17H29COOH

C18H37COOH

C19H39COOH Decanoic acids, capric acids, lauric acids, tridecanoic acids, myristic acids, pentadecanoic acids, palmitic acids, heptadecanoic acids, stearic acids, oleic acids, linoleic acids, linolenic acids, nonadecanoic acids.

C13H27COOH

C ₁₅ H ₃₁ COOH

C ₁₇ H ₃₅ COOH

C-J7H33COOH

C-17H31COOH

C17H29COOH

Desired acyl groups are derived from:

C11H23COOH Lauric acids, myristic acids, palmitic acids, stearic acids, oleic acids, linoleic acids, linoleic acids, and in particular palmitic acid.

A branched or unbranched hydrocarbon chain having 1-4 carbon atoms is preferably an alkyl group having 1-4 carbon atoms, especially a methyl group.

A branched or unbranched hydrocarbon chain having 1-10 carbon atoms is preferably an alkyl group having 1-10 carbon atoms, more preferably 1-4 carbon atoms, especially a methyl or propyl group.

Halogen is fluorine, chlorine or bromine in this specification. The desired halogen is fluorine.

The preferred compounds of the invention are those wherein, in formula 1, the site 1,2 is saturated,

R- | is hydrogen or a branched or unbranched hydrocarbon chain having 1-4 carbon atoms,

R2 is hydrogen or a branched or unbranched hydrocarbon chain having 1-10 carbon atoms,

R3 is an acyl having a branched or unbranched, saturated or unsaturated hydrocarbon chain having 1-20 carbon atoms,

Xj is hydrogen or halogen,

Xp is hydrogen or halogen, it is specified that:

1) R-j and R2 are not hydrogen at one time,

2) Xj and Χ2 are not hydrogen at one time.

Particularly desirable compounds of the invention are those wherein, in formula 1, the site 1,2 is saturated,

Rj is hydrogen,

R2 is a propyl group,

R3 is an acyl having 11-20 carbon atoms,

Xj is fluorine,

X2 is fluorine.

A further desirable compound of the invention is that of Formula I, where applicable

1,2 double bond,

Rj is hydrogen,

R2 is a propyl group,

R3 is a palmitoyl group,

Xj is fluorine,

Χ2 is fluorine.

The most preferred compound of the invention has the formula

CH ₂ OC (CH ₂ ) ₁₄ CH ₃

C = O

CH.

H '

CH.

F

A preferred embodiment of the invention is a composition comprising the desired compound of the invention in combination with liposomes.

In cases where the object of the invention is to provide a pharmaceutical composition containing liposomes, the active compound of the composition should be a compound of formula 1 wherein R3 is acyl having 11-20 carbon atoms.

In cases where the object of the invention is to provide a liposome-free pharmaceutical composition, the active compound should be a compound of formula I wherein R3 is acyl having 1-10 carbon atoms, preferably 5-10 carbon atoms.

The individual stereoisomeric components present in the mixture of the steroid having the above formula (1) can be explained as follows because of the chirality on the carbon atom at position 22 and with respect to the R2 substituent:

f ^H 2 ^OR 3

Oh

(22S epimer)

The desired stereoisomeric components have a 22R configuration.

PREPARATION METHODS

The steroid does not ester

Oh

St-OCR. 4 where St

and Xj, Χ2, R- ,, R2 have the meaning given above, R4 is a branched or unbranched, saturated or unsaturated alkyl group having 1-19 carbon atoms and the site 1,2 is saturated or has a double bond there, prepared by any of the alternative methods that follow.

A. The reaction of a compound of formula

St-OH, where St is defined above, with a compound of formula

Oh

R.COH where R4 is as defined above.

The esterification of the 21-hydroxy compound may be effective in a known manner, i.e. by reacting the parent 21-hydroxy steroid with a suitable carboxylic acid, preferably in the presence of trifluoroacetic acid anhydride, and preferably in the presence of an acid catalyst, i.e. p-toluensultonic acid.

The reaction is preferably carried out in an organic solvent such as benzene or methylene chloride; the reaction is ready to be carried out at a temperature of 20 to 100 ° C.

B. Reaction of a compound of formula

St-OH wherein St is defined above with a compound of formula

Oh

R.CX where R4 is defined above, X is halogen such as chlorine, bromine, iodine and fluorine; or with a group

Oh

-O-C-R wherein R4 is as defined above.

The parent 21-hydroxy compound may be treated with a suitable carboxylic acid halide or anhydride, preferably in a solvent such as a halogenated hydrocarbon, e.g. methylene chloride or ethers, e.g. dioxane in the presence of a base such as triethylamine or pyridine, preferably at low temperature, i.e. -5 ° C to + 30 ° C.

C. The reaction of a compound of formula

St-Y wherein St is defined above and Y is selected from halogens, i.e. Cl, Br and iodine or from mesylate or p-toluenesulfonate, with a compound of the formula

Oh

R.CO A ⁺ where R4 is defined above and A + is a cation.

Salt of a suitable carboxylic acid with an alkali metal, e.g. The lithium, sodium or potassium or triethylammonium or tributylammonium salt may be reacted with a suitable alkylating agent of the formula St-Y. The reaction is preferably carried out in a polar solvent such as acetone, methylethyl ketone, dimethylormamide or dimethylsulfoxide, suitably at a temperature in the range of 25-100 ° C.

If a pure epimer is desired, a final reaction step may be required for each method A through C to disassemble the epimeric mixture into its components.

PHARMACEUTICAL INGREDIENTS

The compounds of the invention can be used for various topical administration routes depending on the site of inflammation, i.e. percutaneously, parenterally or for topical administration to the respiratory tract by inhalation. In formulating the formulation, the important goal is to achieve optimal bioavailability of the active steroid ingredient. For percutaneous formulations, this is preferably achieved if the steroid is dissolved with high thermodynamic activity in the carrier. This is accomplished by using a suitable system or solvents containing suitable glycols, such as propylene glycol or 1,3butanediol per se, or in combination with water.

The steroid ester can also be completely or partially dissolved in the lipophilic phase by the addition of surfactant as a dissolving agent. Percutaneous compositions may be ointment, oil-in-water cream, water-in-oil cream or lotion. A system containing a dissolved active component may form a dispersion phase in the emulsion carriers as well as a continuous phase. In the above compositions, the steroid may also exist as a micronized solid.

Aerosols for pressure steroids are for oral or nasal inhalation. The aerosol system is designed in such a way that each delivered dose contains 10-1000 pg, preferably 20-250 pg of active steroid. The most active steroids are administered in the lower portion of the dose frame. A micronized steroid consists of particles substantially less than 5 pm, which are suspended by a dispersing agent (such as sorbitan trioleate, oleic acid, lecithin, or sodium salt of dioctylsulfosuccinic acid) into the propellant mixture.

The steroid can also be administered using a dry powder inhaler.

One option is to mix a micronized steroid with a carrier substance such as lactose or glucose. The powder mixture is divided into hard gelatin capsules, each containing the desired dose of steroid. The capsule is then placed in a powder inhaler and the patient is inhaled into their airways.

Alternatively, the micronized powder can be placed into spheres that break during the dosing process. This micronized powder is fed into drug tanks into a multidose inhaler, i.e. Turbuhaler. The dosage unit measures the desired dose, which is then inhaled by the patient. In this way, the steroid is delivered to the patient without or with a carrier substance.

The steroid can also be included in formulations that are intended to treat inflammatory bowel diseases, both by oral route or rectally.

Oral route formulations must be designed to deliver the steroid to the inflamed parts of the intestine. This can be achieved through various combinations of intestinal and / or gradual or controlled release principles. An enema formulation is suitable for the rectal route.

PREPARATION OF LIPOSOMIC COMPOSITIONS

The lecithins used in the present invention have different lengths of fatty acid chains and thus have different phase transition temperatures. Examples of lecithins used were those obtained from eggs and soybeans and synthetic lecithins such as dimiristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC) and distearoyl phosphatidylcholine (DSPC). Lecithin stable carriers with different biodegradation properties could be prepared by manipulating the structure. This would allow prolonged release of the captured steroid ester.

The extent of the interaction of the steroid ester with bubbles, e.g. dipalmitoyl phosphatidylcholine (DPPC), is dependent on the length of the ester chain and increases with the length of the chain.

The incorporation of cholesterol or cholesterol derivatives into liposome compositions has become very common because of its properties to increase liposome stability.

For the initial stages of liposome preparation according to the present invention, it may be convenient to follow the procedures described in the literature, i.e. the components are dissolved in a solvent (eg ethanol or chloroform) which is then evaporated. The resulting lipid layer is then dispersed into the selected aqueous medium, after which the solution is stirred or sonicated. The liposomes of the present invention preferably have a diameter between 0.1 and 10 pm.

To modify the structure of the liposome membrane, other lipids (eg, cholesterol or cholesterol stearate) can be added to the major liposome-forming lipids (usually cholesterol or cholesterol stearate), in an amount of 0-40 weight percent (w / w) of total lipids. In optimizing liposome uptake, a third component may be included that provides a negative charge (e.g. dipalmitoyl f osf atidyl glycerol) or a positive charge (e.g. stearylamine acetate or cetylpyridine chloride).

During the formation, depending on the conditions and the lipid used, a broad framework of spheroid ester to lipid ratios can be used. Liposome drying (freeze drying or spray drying) in the presence of lactose can be used, with a lactose content in the range of 0 to 95% of the final composition.

The particularly preferred composition of the invention comprises liposomes and (22R) -16a, 17a-butylidenedioxy-6a., 9a-difluoro-11B-hydroxy-21-palmitoyloxypropene-4-ene-3,20-dione. The routes of administration include powder aerosols, instillation, dispersion and pressurized aerosols.

WORKING EXAMPLES

The invention will be further illustrated by the following non-limiting examples. In the cases, a preparative chromatographic series was used with a flow rate of 2.5 ml / cmn χ h ¹ . Molecular masses were in all cases determined by chemical ionization mass spectrometry (CH4 as reagent gas) and the melting points were determined using a Leitz VVetzlar microscope with a heating table. HPLC analyzes (High Performance Liquid Chromatography) were performed on a pBondapak C-) g column (300 x 3.9 mm id) at a flow rate of 1.0 ml / min and with ethanol and water in a ratio of 40:60 to 60:40 as a mobile phase, unless otherwise specified.

EXAMPLE 1 (22R) -16a..17a-Butylidenedioxy-6a.9a-difluoro-11 B-hydroxy-21-palmitoyloxypropane-4-ene-3.20-dione

A solution of palmitoyl chloride (1.2 g) in 10 ml of dioxane was added dropwise to a solution of (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B, 21dihydroxypropene-4-ene-3,20-dione (200 mg) in 5 ml of pyridine. The reaction mixture was stirred for 16 hours at room temperature. Methylene chloride (150 ml) was added and the solution was washed with 1M hydrochloric acid, 5% aqueous potassium carbonate and water and dried. The crude product after evaporation was purified by chromatography on a Sephadex LH-20 column (87 x 2.5 cm) and chloroform was used as the mobile phase. Fractions between 210 and 255 ml were collected and evaporated, yielding 203 mg (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B-hydroxy-21 palmitoyl-oxypregn-4-ene-3,20- diona. Tal. 87-90 ° C; mol. mass 706 (calc. 707.0). Purity: 96% (HPLC analysis).

EXAMPLE 2 (22R) -16α, 17a-Butylidenedioxy-6a.9a-difluoro-11 B-hydroxy-21-palmitoyloxypropene-4-en-3.20-dione

To a solution of (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-113,21 dihydroxypropene-4-ene-3,20-dione (50 mg) and palmitoyl chloride (35 mg) in 10 ml of methylene chloride was dropwise a solution of triethylamine (13 mg) in 2 ml of methylene chloride was added. The reaction mixture was stirred for 2 hours at room temperature. Another 50 ml of methylene chloride was added and the reaction mixture was treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (87 x

2.5 cm) and used chloroform as the mobile phase. Fractions between 210 and 255 ml were collected and evaporated, yielding 34 mg (22R) -16a, 17a-butylidenedioxy-6a, 9adifluoro-11B-hydroxy-21-palmitoyl-oxypregn-4-ene-3,20-dione . Mol. mass 706 (calc. 707.0). Purity: 95% (HPLC analysis).

EXAMPLE 1 (22S) -16a.17a-Butylidenedioxy-6a.9a-difluoro-11 B-hydroxy-21-palmitoyloxypropene-4-ene-3.20-dione

A solution of palmitoyl chloride (0.4 ml) in 10 ml of dioxane was added dropwise to a solution of (22S) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-113,21 dihydroxypropene-4-ene-3,20-dione (70 mg) in 25 ml of pyridine. The reaction mixture was stirred for 16 hours at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (87 x

2.5 cm) and used chloroform as the mobile phase. Fractions between 225 and 265 ml were collected and evaporated, yielding 92 mg (22S) -16a, 17a-butylidenedioxy-6a, 9adifluoro-11B-hydroxy-21-palmitoyl-oxypregn-4-ene-3,20-dione in the form of oil. Mol. mass 706 (calc. 707.0). Purity: 97% (HPLC analysis).

EXAMPLE 4 (22R) -16q, 17a-Butylidenedioxy-6a.9a-difluoro-11 B-hydroxy-21 myristyloxypropane-4-en-3.20-dione

Myristoyl chloride was synthesized by three-hour refluxing of myristic acid (7.0 g) and thionyl chloride (9 ml) in trichloroethylene (100 ml). The solvent was then evaporated.

To a solution of (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B, 21 dihydroxypropene-4-ene-3,20-dione (51 mg) in 10 ml of methylene chloride was added myristoyl chloride (32 mg). this was followed by triethylamine (13 mg) dissolved in 5 ml of methylene chloride. The reaction mixture was stirred for 4 hours at room temperature. Further methyl chloride was added and the mixture was washed sequentially with 0.1 M hydrochloric acid and water (3 x 50 ml). After drying and evaporation, the residue was purified by chromatography on Merck Kieselgel 60 and used heptane-acetone, 6: 4 as the mobile phase, yielding 27 mg (22R) -16a, 17abutylidenedioxy-6a, 9a, -difluoro-11B-hydroxy -21-myristyloxypropene-4-en-3,20dione. Mol. mass 678 (calc. 678.9). Purity: 96.8% (HPLC analysis).

EXAMPLE 5 (22R) -16a, 17a-Butylidenedioxy-6oi.9 (x-difluoro-11B-hydroxy-21-lauroyloxypropane4-en-3.2Q-dione

To a solution of (22R) -16a, 17a-butylidenedioxy-6a, 9oc-difluoro-113,21 dihydroxypropene-4-ene-3,20-dione (51 mg) in 5 ml of methylene chloride was added lauroyl chloride (28 mg). this was followed by triethylamine (13 mg) dissolved in 2 ml of methylene chloride. The reaction mixture was stirred for 3 hours at room temperature, further methylene chloride was added and the organic phase was washed successively with 0.1 M hydrochloric acid and water (3 x 30 ml). After drying and evaporation, the residue was purified by chromatography on Merck Kieselgel 60 and used heptane-acetone, 6: 4 as the mobile phase. The resulting product was further purified in the second chromatographic step using petroleum ether: ethyl acetate, 3: 2 as the mobile phase, yielding 33 mg (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B-hydroxy- 21-lauroyloxypropene-4-en-3,20-dione. Mol. mass 650 (calc. 650.8). Purity: 96.9% (HPLC analysis).

EXAMPLE 6 (22R) -16a.17a-Butylidenedioxy-6a.9a-difluoro-11B-hydroxy-21-palmitoyloxypropane-1.4-diene-3.20-dione

A solution of palmitoyl chloride (2.3 ml) in 15 ml of dioxane was added dropwise to a solution of (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B, 21dihydroxypropene-1,4-diene-3,20-dione (700 mg) in 30 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first case. The crude product was purified by chromatography on a Sephadex LH-20 column (76 x 6.3 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 1020 and 1350 ml were collected and evaporated, yielding 752 mg (22R) -16a, 17ct-butylidenedioxy-6a, 9a-difluoro-11B-hydroxy-21 palmitoyloxypropene-1,4-diene-3,20- diona. Tal. 141-145 ° C; [α] _D ²⁵ = + 71.6 ° (c = 0.204; CH 2 Cl 2); mol. mass 704 (calc. 704.9). Purity: 97.7% (HPLC analysis).

EXAMPLE 7 (22S) -16a.17a-Butylidenedioxy-6a.9a-difluoro-11 B-hydroxy-21-palmitoyloxypropene-1.4-diene-3.20-dione

A solution of palmitoyl chloride (0.5 ml) in 5 ml of dioxane was added dropwise to a solution of (22S) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B, 21dihydroxypropene-1,4-diene-3,20-dione (150 mg) in 10 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first case. The crude product was purified by chromatography on a Sephadex LH-20 column (89 x 2.5 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 215 and 315 ml were collected and evaporated, yielding 132 mg (22S) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B-hydroxy-21 palmitoyloxypropene-1,4-diene-3,20- diona. Tal. 176-180 ° C; [α] _D ²⁵ = + 47.5 ° (c = 0.198; CH 2 Cl 2); mol. mass 704 (calc. 704.9). Purity: 99% (HPLC analysis).

EXAMPLE 8 (22R) -21-Acetoxy-16a.17a-butylidenedioxy-6a.9a-difluoro-11 B-hydroxy-pregn-4-ene-3,20-dione

A solution of acetyl chloride (38 mg) in 5 ml of dioxane was added dropwise to a solution of (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B, 21 dihydroxypropene-4-ene-3,20-dione (75 mg) in 5 ml of pyridine. The reaction mixture was stirred for 16 hours at room temperature. After evaporation, methylene chloride (75 ml) was added and the solution was washed with cold 5% aqueous potassium carbonate and saturated sodium chloride solution. After evaporation, the crude product was purified by chromatography on a Sephadex LH-20 column (85 x 2.5 cm) and chloroform was used as the mobile phase. Fractions between 365 and 420 ml were collected and evaporated, yielding 57 mg of (22R) -21-acetoxy-16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B-hydroxy-pregn-4-ene-3,20 -diona. Tal. 182-189 ° C; [α] _D 25 ₌ + 112.0 ° (c = 0.225; CH ₂ Cl ₂ ); mol. mass 510 (calc. 510.6). Purity: 99.0% (HPLC analysis).

EXAMPLE 9 (22R) -iea.17a-Butylidenedioxy-6a.9a-difluoro-11 B-hydroxy-21-valeroyloxypropene-4-ene-3.20-dione

A solution of valeroyl chloride (60 mg) in 5 ml of dioxane was added dropwise to a solution of (22R) -16a, 17a-butylidenedioxy-6a., 9a.-difluoro-11B, 21dihydroxypropene-4-ene-3,20-dione (75 mg) in 5 ml of pyridine. The reaction mixture was stirred for 16 hours at room temperature and treated as in the first example. After evaporation, methylene chloride (75 ml) was added and the solution was washed with cold 5% aqueous potassium carbonate and saturated sodium chloride solution. After evaporation, the crude product was purified by chromatography on a Sephadex LH20 column (85 x 2.5 cm) and chloroform was used as the mobile phase. Fractions between 265 and 325 ml were collected and evaporated, yielding 50 mg of (22R) -16a, 17abutylidenedioxy-6a, 9a-difluoro-1LB-hydroxy-21-valeroyloxypropene-4-ene-3,20dione. Tal. 181-185 ° C; [α] _D ²⁵ = + 109.4 ° (c = 0.212; CH ₂ Cl ₂ ); mol. mass 552 (calc. 552.7). Purity; 99.8% (HPLC analysis).

EXAMPLE 10 (22R) -16a.17a-Butylidenedioxy-6a.9a-difluoro-11 B-hydroxy-21-capryloxypropene - 1.4-diene-3.20-dione

A solution of decanoyl chloride (0.2 ml) in 3 ml of dioxane was added dropwise to a solution of (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B, 21dihydroxypropene-1,4-diene-3,20-dione (100 mg) in 6 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. After evaporation, the crude product was purified by chromatography on a Sephadex LH-20 column (71 x 6.3 cm) and chloroform was used as the mobile phase. Fractions between 1470-1725 were collected and evaporated, yielding 113 mg (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11B-hydroxy-21-capryloxypropene-1,4-diene3,20-dione . Tal. 182-184 ° C; [α] _D ²⁵ = + 71.5 ° (c = 0.186; CH ₂ Cl ₂ ); mol. mass 620 (calc. 620.9). Purity: 97.7% (HPLC analysis).

EXAMPLE 11

6a.9a-Difluoro-116.21-dihydroxy-16a, 17a-f (1-methylethylidene) bis (oxy) lpreqn-4-en-3.20-dione

A suspension of 0.9 g of tris (triphenylphosphine) rhodium chloride in 250 deaerated toluene was hydrogenated for 45 min at room temperature and atmospheric pressure. A solution of 1.0 g of fluocinolone 16α, 17α-acetonide in 100 ml of absolute ethanol was added and the hydrogenation continued for another 40 hours. The reaction product was evaporated and the residue was purified by flash chromatography on silica gel using acetone-petroleum ether as the mobile phase to remove the main catalyst. The eluate was evaporated on a Sephadex LH-20 column (72.5 x 6.3 cm) and chloroform was used as the mobile phase. Fractions between 3555-4125 were collected and evaporated, yielding 0.61 g of 6a, 9a-difluoro-110,21 dihydroxy-16α, 17a - [(1-methylethylidene) bis (oxy)] pregn-4-en-3,20- diona. Tal. 146151 ° C; [α] _{D =} + 124.5 ° (c = 0.220; CH 2 Cl 2); mol. mass 454 (calc. 454.6). Purity: 98.5% (HPLC analysis).

EXAMPLE 12

6a, .9oc-difluoro-110-hydroxy-16a.17a - [(1-methylethylidene) bis (oxy) 1-21-palmitoyloxioreqn-4-en-3.20-dione

A solution of palmitoyl chloride (2.1 ml) in 15 ml of dioxane was added dropwise to a solution of 6a, 9a-difluoro-110,21-dihydroxy-16a, 17a - [(1methylethylidene) bis (oxy)] pregn-4-en-3. 20-dione (310 mg) in 30 ml pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (76 x 6.3 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 1035-1260 were collected and evaporated, yielding 158 mg of 6a, 9a-difluoro-110-hydroxy-16a, 17a - [(1-methylethylidene) bis (oxy)] - 21palmitoyloxypropene-4-ene-3,20 -diona. Tal. 82-86 ° C; [α] _D ²⁵ = + 85.3 ° (c = 0.232; CH 2 Cl 2); mol. mass 692 (calc. 692.9). Purity: 98.6% (HPLC analysis).

EXAMPLE 13 (22R) - and (22S) -21-acetoxy-16α, 17a-butylidenedioxy-6 (x-fluoro-11B-hydroxypropene-4-ene-3.20-dione (22R, S) -16a, 17a-butylidenedioxy- 6a-fluoro-11B-hydroxypropene-4-ene-3,20dione (68 mg) was dissolved in 1 ml of pyridine, acetic anhydride (1 ml) was added and the reaction mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with 3 x 25 ml of methylene chloride The extract was dried and evaporated The remaining 22R, the mixture was separated by chromatography on a Sephadex LH-20 column (89 x 2.5 cm) and heptane: chloroform: ethanol used, 20: 20: 1 fractions between 380-400 (A) and 420-440 (B) were collected and evaporated.

After precipitation from methylene chloride-petroleum ether, fraction A yielded 14 mg (22S) of 21-acetoxy-16a, 17a-butylidenedioxy-6a-fluoro-11 B-hydroxypropene-4-ene-3,20 dione. Tal. 179-186 ° C; [α] _D ²⁵ = + 86.2 ° (c = 0.188; CH ₂ Cl ₂ ); mol. mass 492 (calc. 492.6). Purity: 97.5% (HPLC analysis).

After precipitation from methylene chloride-petroleum ether, a fraction of B 20 mg (22R) of 21-acetoxy-16a, 17oc-butylidenedioxy-6a-fluoro-11 B-hydroxypreg-4-ene-3,20 dione was obtained. Tal. 169-172 ° C; [α] _D ²⁵ = + 139.0 ° (c = 0.200; CH ₂ Cl ₂ ); mol. mass 492 (calc. 492.6). Purity: 97.9% (HPLC analysis).

EXAMPLE (22R.S) -16a.17a-Butylidenedioxy-6-fluoro-11B-hydroxy-21-palmitoyloxypropene-4-ene-3.20-dione

To a suspension of 1.4 g of tris (triphenylphosphine) rhodium chloride in 300 deaerated toluene was added a solution of 1170 mg of 6a-fluoro-11B, 16a, 17cc, 21-tetrahydroxypropane 1,4,4-diene-3,20-dione in 250 ml of absolute ethanol. The mixture was hydrogenated for 22 hours at room temperature and atmospheric pressure and evaporated. The residue was precipitated from acetone-chloroform, yielding 661 mg of 6a-fluoro-11B, 16a, 17a, 21tetrahydroxypropene-4-ene-3,20-dione. Mol. mass 396 (calc. 396.5). Purity: 96.6% (HPLC analysis).

6a-fluoro-11 B, 16α, 17a, 21-tetrahydroxypropene-4-ene-3,20-dione (308 mg) was added in portions to a solution of butanal (115 mg) and 70% perchloric acid (0.2 ml) in 50% ml of dioxane. The reaction mixture was stirred at room temperature for 6 hours. Methylene chloride (200 ml) was added and the solution was washed with 10% aqueous potassium carbonate and water and dried. The evaporation residue was purified on a Sephadex LH-20 column (87 x 2.5 cm) and chloroform was used as the mobile phase. Fractions between 420-500 ml were collected and evaporated, yielding 248 mg (22R, S) -16a, 17a-butylidenedioxy-6a-fluoro-11β, 21-dihydroxypropene-4-en3,20-dione. Tal. 85-96 ° C; [ct] _D ²⁵ = + 119.8 ° (c = 0.192; CH ₂ Cl ₂ ); mol. mass 450 (calc. 450.6). Purity: 96.1% (HPLC analysis). The ratio of the 22R- and 22-S epimers was 59/41 (HPLC analysis).

A solution of palmitoyl chloride (0.21 ml) in 3 ml of dioxane was added dropwise to a solution of (22R, S) -16a, 17a-butylidenedioxy-6a-fluoro-116,21dihydroxypropene-4-ene-3,20-dione (50 mg) in 6 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (89 x

2.5 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 185-230 were collected and evaporated, yielding 42 mg of (22R, S) -16a, 17abutylidenedioxy-6a-fluoro-116-hydroxy-21-palmitoyloxypropene-4-ene-3,20-dione as an oil. Mol. mass 688 (calc. 688.97). Purity: 99% (HPLC analysis). The ratio of the 22R- and 22-S epimers was 15/85 (HPLC analysis).

EXAMPLE 15 (22R) -16a.17a-Butylidenedioxy-6a-fluoro-116-hydroxy-21-palmitoyloxypropene-4-ene-3.20-dione (22R, S) -16a, 17a-butylidenedioxy-6a-fluoro-116.21 -dihydroxypregn-4-ene-3,20dione (225 mg) was separated by preparative HPLC in portions on a μBondapak Cjg column (150 x 19 mm) using an ethanohydrate 40:60 as the mobile phase. Fractions centered at 265 ml (A) and 310 ml (B) were collected and evaporated. After precipitation from methylene chloride-petroleum ether, fraction A gave 68 mg (22R) -16a, 17abutylidenedioxy-6a-fluoro-116,21-dihydroxypropene-4-ene-3,20-dione. Tal. 180192 ° C; [α] _D ²⁵ = + 138.9 ° (c = 0.144; CH ₂ Cl ₂ ); mol. mass 450 (calc. 450.6). Purity: 99.4% (HPLC analysis).

After precipitation from methylene chloride-petroleum ether, a fraction of B was 62 mg (22S) of 16a, 17a-butylidenedioxy-6a-fluoro-116,21-dihydroxypropene-4-ene-3,20-dione. Mp 168-175 ° C; [α] _D ²⁵ = + 103.7 ° (c = 0.216; CH ₂ Cl ₂ ); mol. mass 450 (calc. 450.6). Purity: 99.5% (HPLC analysis).

A solution of palmitoyl chloride (0.22 ml) in 5 ml of dioxane was added dropwise to a solution of (22R) -16a, 17a-butylidenedioxy-6a-fluoro-11B, 21dihydroxypropene-4-ene-3,20-dione (32 mg) in 10 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (87 x

2.5 cm) and used chloroform as the mobile phase. Fractions between 215-250 were collected and evaporated, yielding 38 mg of (22R) -16a, 17a-butylidenedioxy-6a-fluoro11B-hydroxy-21-palmitoyloxypropene-4-ene-3,20-dione as an oil. Mol. mass 688 (calc. 688.97). Purity: 96.0% (HPLC analysis).

EXAMPLE 16 (22S) -16a, 17a-Butylidenedioxy-6a-fluoro-11 B-hydroxy-21-palmitoyloxypropene-4-ene-3.20-dione (22R, S) -16a, 17a-butylidenedioxy-6a-fluoro-11B. 21-dihydroxypropene-4-ene-3,20dione (68 mg) was dissolved in 1 ml of pyridine. Acetic anhydride was added and the reaction mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with 3 x 25 ml of methylene chloride. The extract was dried and evaporated. The remaining 22R, S epimer mixture was separated by chromatography on a Sephadex LH20 column (89 x 2.5 cm) and used heptane: chloroform-ethanol, 20: 20: 1 as the mobile phase. Fractions between 380-400 (A) and 420-440 (B) were collected and evaporated.

After precipitation from methylene chloride-petroleum ether, fraction A gave 14 mg (22S) of 21-acetoxy-16a, 17a-butylidenedioxy-6a-fluoro-11B-hydroxypregn-4-ene-3,20 dione. Tal. 179-186 ° C; [α] _D ²⁵ = + 86.2 ° (c = 0.188; CH ₂ Ci ₂ ); mol. mass 492 (calc. 492.6). Purity: 97.5% (HPLC analysis).

After precipitation from methylene chloride-petroleum ether, a fraction of B 20 mg (22 R) of 21-acetoxy-16a, 17cc-butylidenedioxy-6a-fluoro-11 B-hydroxypropene-4-ene-3,20 dione was obtained. Tal. 169-172 ° C; [<x] _D ²⁵ = + 139.0 ° (c = 0.200; CH ₂ Cl ₂ ); mol. mass 492 (calc. 492.6). Purity: 97.9% (HPLC analysis).

To a solution of 14 mg (22S) -21-acetoxy-16a, 17a-butylidenedioxy-6a-fluoro11B-hydroxypropene-4-ene-3,20-dione in 2 ml ethanol was added 2 ml 2M hydrochloric acid. After stirring for 5 hours at 60 ° C, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with 3 x 25 ml of methylene chloride. The combined extracts were washed with water, dried and evaporated. The residue was purified by chromatography on a Sephadex LH-20 column (87 χ 2.5 cm) and used chloroform as the mobile phase. Fractions between 455510 were collected and evaporated, yielding 7 mg (22S) -16a, 17a-butylidenedioxy-6a -fluoro-11B-21-dihydroxypropene-4-ene-3,20-dione. Mol. mass 450 (calc. 450.6). Purity: 96.6% (HPLC analysis).

A solution of palmitoyl chloride (195 mg) in 5 ml of dioxane was added dropwise to a solution of (22S) -16a, 17a-butylidenedioxy-6a-fluoro-11B, 21dihydroxypropene-4-ene-3,20-dione (32 mg) in 10 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (89 x

2.5 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 205-245 ml were collected and evaporated, yielding 38 mg (22S) -16Ot, 17abutylidenedioxy-6a-fluoro-11B-hydroxy-21-palmitoyloxypropene-4-ene-3,20-dione as an oil. Mol. mass 688 (calc. 688.97). Purity: 96.4% (HPLC analysis).

EXAMPLE 17 (22RS) -16oc.17a-Butylidenedioxy-6a-fluoro-11 B-hydroxy-21-lauroyloxypropene-4-ene-3,20-dione

To a solution of (22RS) -16a, 17a-butylidenedioxy-6a-fluoro-11B, 21dihydroxypropene-4-ene-3,20-dione (50 mg) in 6 ml of pyridine was added dropwise a solution of lauroyl chloride (0.4 ml) in 3 ml of dioxane. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (89 x 2.5 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 215-255 ml were collected and evaporated, yielding 15 mg (22S) -16a, 17abutylidenedioxy-6cc-fluoro-11 B-hydroxy-21-lauroyloxypropene-4-ene-3,20-dione. Tal. 125-143 ° C; [ot] _D ²⁵ = + 92.8 ° (c = 0.208; CH ₂ Cl ₂ ); mol. mass 632 (calc. 632.9). Purity: 96.2% (HPLC analysis). The ratio of the 22R- and 22-S epimers was 58/42 (HPLC analysis).

EXAMPLE 18 (22R) -16α. · 17tx-Butylidenedioxy-6a-fluoro-11 B-hydroxy-21-palmitoyloxypropene-1.4-diene-3.20-dione

6a-fluoro-11 B, 16a, 17a, 21-tetrahydroxypropene-1,4-diene-3,20-dione (400 mg) was added in portions to a solution of butanal (0.18 ml) and 70% perchloric acid (0.2 ml) in portions. in 50 ml of dioxane. The reaction mixture was stirred at room temperature for 16 hours. Methylene chloride (200 ml) was added and the solution was washed with 10% aqueous potassium carbonate and water and dried. The evaporation residue was purified on a Sephadex LH-20 column (75 x 6.3 cm) and chloroform was used as the mobile phase. Fractions between 2880-3300 ml were collected and evaporated, yielding 1209 mg of (22R, S) -16a, 17a-butylidenedioxy-6a-fluoro-11B, 21-dihydroxypropane 1,4,4-diene-3,20-dione. Mol. mass 448 (calc. 448.5). Purity: 95.7% (HPLC analysis). The ratio of the 22R- and 22-S epimers was 55/45 (HPLC analysis).

(22R, S) -16a, 17a-butylidenedioxy-6a-fluoro-113,21-dihydroxypropene-1,4diene-3,20-dione (36 mg) was chromatographed on a Sephadex LH-20 column (89 x

2.5 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 1720-1800 ml (A) and 1960-2025 (B) were collected and evaporated. Two products were precipitated from methylene chloride-petroleum ether. Product from fraction A (12 mg) was determined for (22S) -16a, 17a-butylidenedioxy-6afluoro-113,21-dihydroxypropene-1,4-diene-3,20-dione by ¹ H-NMR and mass spectroscopy from fraction B (10 mg) to 22R-epimer.

The epimers had the following properties. Epimer 22S: m.p. 172-180 ° C; [ot] _D 25 _ ₊ G2.3 ^O (c = 0.132; CH2Cl2); mol. mass 448 (calc. 448.5). Epimer 22R m.p. 95-106 ° C; [α] D ²⁵ = + 105.9 ° (c = 0.152; CH ₂ Cl ₂ ); mol. mass 448 (calc. 448.5). The purity of the epimers was determined by HPLC analysis and was 98.9% for 22Sin and 97.7% for the 22R- epimer.

A solution of palmitoyl chloride (172 mg) in 5 ml of dioxane was added dropwise to a solution of (22R) -16a, 17a-butylidenedioxy-6a-fluoro-113,21 dihydroxypropene-1,4-diene-3,20-dione (56 mg) in 10 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (89 x 2.5 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 225-285 ml were collected and evaporated, yielding 31 mg of (22R) -16a, 17a-butylidenedioxy-6a-fluoro-11 B-hydroxy-21-palmitoyloxypropene 1,4,4-diene-3,20-dione. Tal. 95-100 ° C; [ot] _D ²⁵ = + 68.0 ° (c = 0.200; CH ₂ Cl ₂ ); mol. mass 686 (calc. 686.95). Purity: 97.7% (HPLC analysis).

EXAMPLE 19 (22S) -16a.17a-Butylidenedioxy-6a-fluoro-11B-hydroxy-21-palmitoyloxypropane-1,4-diene-3.20-dione

A solution of palmitoyl chloride (110 mg) in 5 ml of dioxane was added dropwise to a solution of (22S) -16a, 17a-butylidenedioxy-6a-fluoro-113,21 dihydroxypropene-1,4-diene-3,20-dione (46 mg ) in 10 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (89 x 2.5 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 185-225 ml were collected and evaporated, yielding 37 mg (22S) -16a, 17a-butylidenedioxy-6a-fluoro-11B-hydroxy-21-palmitoyloxypropene 1,4,4-diene-3,20-dione. Tal. 65-68 ° C; [α] _D ²⁵ = + 53.0 ° (c = 0.200; CH ₂ Cl ₂ ); mol. mass 686 (calc. 686.95). Purity: 95.9% (HPLC analysis).

EXAMPLE 20

6a-fluoro-11B.21-dihydroxy-16a., 17a.-i (1-methylethylidene) bis (oxy) prepreg-4-en-3.20-dione

A suspension of 2.1 g of tris (triphenylphosphine) rhodium chloride in 500 toluene was hydrogenated for 45 min at room temperature and atmospheric pressure when the catalyst was in solution. A solution of 6a-fluoro-11B, 21-dihydroxy-16a, 17 a - [(1-methylethylidene) bis (oxy)] pregna-1,4-diene-3,20-dione in 1000 ml of absolute ethanol was added and the hydrogenation continued for another 65 hours. The reaction mixture was evaporated and the residue purified on a Sephadex LH-20 column (71 x 6.3 cm) and chloroform was used as the mobile phase. Fractions between 2010-2445 ml were collected and evaporated, yielding 1.51 g of 6a-fluoro-11B, 21-dihydroxy-16a, 17a - [(1methylethylidene) bis (oxy)] pregn-4-en-3,20-dione . Tal. 209-219 ° C; [a] _D ² θ = + 133.5 ° (c = 0.230; CH ₂ CI ₂ ); mol. mass 436 (calc. 436.5). Purity: 99.6% (HPLC analysis).

EXAMPLE 21

6a-fluoro-11 B-hydroxy-16a, 17a [(1-methylethylidene) bis (oxy) T21-palmitoyloxypropene-4-en-3.20-dione

A solution of palmitoyl chloride (0.21 ml) in 3 ml of dioxane was added dropwise to a solution of 6a-fluoro-11B, 21-dihydroxy-16a, 17a - [(1methylethylidene) bis (oxy)] pregn-4-en-3,20- of dione in 6 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (76 x

6.3 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 1035-1230 ml were collected and evaporated, yielding 63 mg of 6a-fluoro-11Bhydroxy-16a, 17a - [(1-methylethylidene) bis (oxy)] - 21-palmitoyloxypropene-4-ene-3,20 dione. Tal. 99-101 ° C; [<x] _D ²⁵ = + 89.8 ° (c = 0.206; CH ₂ Cl ₂ ); mol. mass 674 (calc. 674.94). Purity: 97.9% (HPLC analysis).

EXAMPLE 22

9g-fluoro-113,21-dihydroxy-16g, 1 7g - [(1-methylethylidene) bis (oxy)] pregn-4-en-3,20-dione

A suspension of 675 mg of tris (triphenylphostine) rhodium chloride in 250 toluene was hydrogenated for 45 min at room temperature and pressure. A solution of 1 g of triamcinolone 16g, 17g-acetonide in 100 ml of absolute ethanol was added and the hydrogenation continued for another 40 hours. The reaction mixture was evaporated and the main catalyst was removed by flash chromatography with acetone.petrol ether (40-60 ° C), 40:60 as the mobile phase. The crude product was further purified on a Sephadex LH-20 column (72.5 x 6.3 cm) and used chloroform as the mobile phase. Fractions between 2746-3195 ml were collected and evaporated, yielding 404 mg of 9a-fluoro-113,21-dihydroxy-16a, 17a - [(1-methylethylidene) bis (oxy)] pregn-4en-3,20-dione . Tal. 238-241 ° C; [g] _D ²⁵ = + 145.2 ° (c = 0.288; CH ₂ Cl ₂ ); mol. mass 436 (calc. 436.5). Purity: 99% (HPLC analysis).

EXAMPLE 23

9g-fluoro-11 B-hydroxy-16g, 17g-f (1-methylethylidene) bis (oxy)] - 21 -palmitoyloxypropene-4-ene-3.20-dione

A solution of palmitoyl chloride (0.69 ml) in 10 ml of dioxane was added dropwise to a solution of 9g-fluoro-113,21-dihydroxy-16g, 17g - [(1methylethylidene) bis (oxy)] pregn-4-en-3,20- of dione in 20 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (89 x

2.5 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 240-305 ml were collected and evaporated, yielding 102 mg of 9g-fluoro-11325 hydroxy-16g, 17g - [(1-methylethylidene) bis (oxy)] - 21-patmitoyloxypropene-4-ene-3,20dione in the form of oil. Mol. mass 674 (calc. 674.94). Purity: 98% (HPLC analysis).

EXAMPLE 24 (22RS) -16g.17g-Butylidenedioxy-9g-fluoro-11 B-hydroxy-21-palmitoyloxypropene-4-ene-3.20-dione

9g-fluoro-11β, 16a, 17a, 21-tetrahydroxypropene-4-ene-3,20-dione (340 mg) was added in portions over 20 minutes while stirring in freshly distilled butanal solution (100 mg) and 70% perchlorine acid (0.2 ml) in 50 ml of purified and dried dioxane. The reaction mixture was stirred at room temperature for a further 5 hours. Methylene chloride (200 ml) was added and the solution was washed with aqueous potassium carbonate and water and dried with anhydrous magnesium sulfate. After evaporation, the crude product obtained was purified on a Sephadex LH-20 column (72.5 x 6.3 cm) and chloroform was used as the mobile phase. Fractions between 2760-3195 ml were collected and evaporated, yielding 215 mg (22R, S) -16g, 17g-butylidenedioxy-9g-fluoro-11B-21-dihydroxypropene-4-ene-3,20dione. mass 450 (calc. 450.6). Purity: 97.4% (HPLC analysis).

A solution of palmitoyl chloride (0.13 ml) in 2.5 ml of dioxane was added dropwise to a solution of (22R, S) -16g, 17g-butylidenedioxy-9g-fluoro-11B, 21dihydroxypropene-4-ene-3,20-dione (40 mg) in 5 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (87 x

2.5 cm) and used chloroform as the mobile phase. Fractions between 220-300 ml were collected and evaporated, yielding 42 mg (22R, S) -16g, 17g-butylidenedioxy-9gfluoro-11B-hydroxy-21-palmitoyloxypropene-4-ene-3,20-dione as a oils. Mol. mass 688 (calc. 688.97). Purity: 99% (HPLC analysis). The ratio of the 22R- and 22-S epimers was 61/39 (HPLC analysis).

EXAMPLE 25 (22R) -16g, 17g-Butylidenedioxy-9g-fluoro-11B-hydroxy-21-palmitoyloxypropene-4-ene-3.20-dione (22R, S) -16g, 17g-butylidenedioxy-9g-fluoro-11B- 21-dihydroxypropene-4-en3,20-dione (200 mg) was separated by chromatography on a Sephadex LH-20 column (76 x

6.3 cm) and used the heptane: chloroform: ethanol mixture, 20: 20: 1 as the mobile phase.

Fractions between 7560-8835 ml (A) and 8836-9360 (B) were collected and evaporated. The product from fraction A (128 mg) was by ¹ H-NMR and mass spectroscopy to determine the (22S) -16a, 17a-butylidenedioxy-9a-fluoro-11B, 21-dihydroxypregn-4-ene-3,20dion, the product of the fraction B (50 mg) for 22R-epimer.

The epimers had the following properties. Epimer 22S: m.p. 180-190 ° C; [α] _D ²⁵ = + 105.6 ° (c = 0.214; CH 2 Cl 2); mol. mass 450 (calc. 450.6). Epimer 22R m.p. 147-151 ° C; [α] _D ²⁵ = + 133.7 ° (c = 0.196; CH 2 Cl 2); mol. mass 450 (calc. 450.6). The purity of the epimers was determined by HPLC analysis and was 95.6% for 22Sin and 98.2% for 22R- epimer.

A solution of palmitoyl chloride (0.34 ml) in 5 ml of dioxane was added dropwise to a solution of (22R) -16ot, 17a-butylidenedioxy-9a-fluoro-11B, 21dihydroxypropene-4-ene-3,20-dione (50 mg) in 10 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (89 x

2.5 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 180-205 ml were collected and evaporated, yielding 36 mg (22R) -16a, 17abutylidenedioxy-9a-fluoro-11 B-hydroxy-21-palmitoyloxypropene-4-ene-3,20-dione as an oil. Mol. mass 688 (calc. 688.97). Purity: 97.7% (HPLC analysis).

EXAMPLE 26 (22S) -16a.17a-Butylidenedioxy-9g-fluoro-11 B-hydroxy-21-palmitoyloxypropene-4-ene-3,20-dione

A solution of palmitoyl chloride (0.14 ml) in 15 ml of dioxane was added dropwise to a solution of (22S) -16a, 17a-butylidenedioxy-9a-fluoro-11B, 21dihydroxypropene-4-ene-3,20-dione (41 mg) in 3 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (89 x

2.5 cm) and used heptane: chloroform: ethanol, 20: 20: 1 as the mobile phase. Fractions between 215-260 ml were collected and evaporated to give 26 mg (22S) -16a, 17abutylidenedioxy-9a-fluoro-11 B-hydroxy-21-palmitoyloxypropene-4-ene-3,20-dione as an oil. Mol. mass 688 (calc. 688.97). Purity: 91.4% (HPLC analysis).

EXAMPLE 27 (22R) -16α, 17a-Butylidenedioxy-9a-fluoro-113-hydroxy-21-palmitoyloxypropene-1.4-diene-3.20-dione

A solution of palmitoyl chloride (75 mg) in 2.5 ml of dioxane was added dropwise to a solution of (22R) -16a, 17a-butylidenedioxy-9a-fluoro-11B, 21dihydroxypropene-1,4-diene-3,20-dione (25 mg) in 5 ml of pyridine. The reaction mixture was stirred overnight at room temperature and treated as in the first example. The crude product was purified by chromatography on a Sephadex LH-20 column (85 x

2.5 cm) and used chloroform as the mobile phase. Fractions between 235-285 ml were collected and evaporated, yielding 27 mg (22R) -16a, 17a-butylidenedioxy-9a-fluoro11B-hydroxy-21-palmitoyloxypropene-1,4-diene-3,20-dione. Tal. 116-121 ° C; [[alpha]] _D &lt; 25 &gt; +67.40 ( _{c =} 0.172; CH2Cl2); mol. mass 686 (calc. 687.0). Purity 96.5% (HPLC analysis).

EXAMPLE 28

PHARMACEUTICALS

The non-limiting examples that follow illustrate formulations that are intended for various targeted administration forms. The amounts of active steroid in the percutaneous formulations are usually 0.001-0.2% (w / w), preferably 0.01-0.1% (w / w)

Formulation 1, ointment [g]

Steroid, micronized 0.025

Liquid paraffin 10.0

White soft paraffin up to 100.0

Formulation 2, Ointment [gj

Steroid 0.025

Propylene glycol 5.0

Sorbitan sesquioleate 5.0

Liquid paraffin 10.0

White soft paraffin up to 100.0

Formulation 3, oil-in-water cream [g]

A steroid 0.025 Cetanol 5.0 Glyceryl monostearate 5.0 Liquid paraffin 10.0 Cetomacrogol 1000 2.0 Citric acid 0.1 Sodium citrate 0.2 Propylene glycol 35.0 Water to 100.0

Formulation 4, cream oil in water [gj

A steroid, micronized 0.025 White soft paraffin 15.0 Liquid paraffin 5.0 Cetanol 5.0 Sorbimacrogol strearate 2.0 Sorbitan monostearate 0.5 Sorbic acid 0.2 Citric acid 0.1 Sodium citrate 0.2 Water to 100.0

Formulation 5, water-in-oil cream [g]

A steroid 0.025 White soft paraffin 35.0 Liquid paraffin 5.0 Sorbitan sesquioleate 5.0 Sorbic acid 0.2 Citric acid 0.1 Sodium citrate 0.2 Water to 100.0

Formulation 6, Lotion [mg]

Steroid 0.25

Isopropanol 0.5

Carboxyvinylpolymer 3

NaOH until supplemented

Water up to 1.0

Formulation 7, suspension for injections

Steroid, micronized 0.05-10 mg

Sodium carboxymethyl cellulose 7 mg

NaCl 7 mg

Polyoxyethylene (20) sorbitan monooleate 0.5 mg

Phenyl carbinol 8 mg

Water, sterile up to 1.0 ml

Formulation 8, aerosol for oral and nasal inhalation [% w / w]

A steroid, micronized 0.1 Sorbitan trioleate 0.7 Trichlorofluoromethane 24.8 Dichlorotetrafluoromethane 24.8 Dichlorodifluoromethane 49.6

Formulation 9, atomization solution

A steroid 7.0 mg Propylene glycol 5.0 g Water to 10.0 g

Formulation 10, inhalation powder_

Gelatin capsule filled with micronized steroid 0.1 mg

Lactose 20 mg

The powder is inhaled using an inhalation device.

Formulation 11, powder for inhalation

Powder in the form of beads, stuffed into a multi-dose powder inhaler. Each dose contains a micronized steroid. 0.1 mg

Formulation 12, powder for inhalation

Powder in the form of beads, stuffed into a multi-dose powder inhaler. Each dose contains a micronized steroid. 0.1 mg Lactose, micronized 1 mg

Formulation 13, capsules for the treatment of the small intestine [mg]

Steroid 1.0

Sugar beads 321

Aquacoat EC D 30 6.6

Acetyltributyl citrate 0.5

Polysorbate 80 0.1

Eudragit L100-55 17.5

Triethyl citrate 1.8

Talc 8.8

Foaming agent MMS 0.01

Formulation 14, capsules for the treatment of colon [mg]

Steroid 2.0

Sugar beads 305

Aquacoat ECD 30 5.0

Acetyltributyl citrate 0.4

Polysorbate 80 0.14

Eudragit N E30 D 12.6

Eudragit S100 12.6

Talc 12.6

Formulation 15. rectal enema

A steroid

Sodium carboxymethyl cellulose Disodium acetate Methyl parahydroxybenzoate Propyl parahydroxybenzoate Sodium chloride Citric acid anhydride Polysorbate 80 Water, purified to

0.02 mg 25 mg 0.5 mg 0.8 mg 0.2 mg 7.0 mg 1.8 mg 0.01 mg 1.0 ml

Formulation 16, a formulation containing a steroid bound to liposomes

A. Preparation of the formulation for burial

Synthetic dipalmitoylphosphatidylcholine (45 mg), dimiristoylphosphatidylcholine (7 mg), dipalmitoylphostatidylglycerol (1 mg) and (22R) -16a, 17a-butylidenedioxy-6a, 9adifluoro-11B-hydroxy-21-3-pyriminoxy (5 mg) was mixed in a glass tube. All components were dissolved in chloroform. Most of the solvent was evaporated using N2 and then under reduced pressure, which formed a thin film of lipid components on the surface of the glass tube. An aqueous solution of 0.9% NaCl was added to the lipids. Liposome formation was performed at a temperature above the lipid phase transition temperature. Liposomes were formed by shaking or sonication with a sonifier probe. The resulting suspension contained liposomes ranging in size from very small bubbles to 2 pm.

B. Preparation of formulation for inhalation

Liposome preparation was performed as in Example A, where the aqueous solution contained 10% lactose. The ratio of lactose to lipid was 7: 3.

The liposome suspension was frozen on dry ice and lyophilized. The dry product was micronized, yielding particles with a mean mass aerodynamic cross section (MMAD) of about 2 pm.

PHARMACOLOGY

The selectivity for local anti-inflammatory activity can be illustrated by the following path model.

A significant portion of inhaled GCS is deposited in the pharynx and subsequently swallowed and ends in the intestine. This part contributes to the unwanted side effects of the steroid because it works outside of the area we intend to treat (the lungs). Thus, the use of GCS with high local anti-inflammatory activity but with low GCS-induced effects after oral administration is preferred. Thus, studies were conducted to determine the GCS-induced effects after topical administration to the lungs as well as after oral administration and differences between glucocorticosteroid activity in and outside the treated lung region, which was tested as follows.

TEST MODELS

A) Test model for desirable lacrimal anti-inflammatory action on mucosal airways (left lung)

Sprague Dawley rats (250 g) were given a slight anesthesia with Ephrane and injected exactly into the left lung lobe a glucocorticosteroid test preparation (in liposomes suspended in brine), volume 0.5ml / kg. Two hours later, a suspension of Sephadex (5 mg / kg in a volume of 1 ml / kg) was injected into the trachea sufficiently above the cleft to allow the suspension to reach both the left and right lung lobes. Twenty hours later, the rats were killed, the left lung lobes were dissected and weighed. Control groups were given a vehicle instead of glucocorticosteroids, and brine instead of Sephadex suspension to measure normal lung weight and non-drug treated Sephadex edema.

B) A test model for the undesirable systemic effects of orally absorbed glucocorticosteroids

Sprague Dawley rats (250 g) were given a slight anesthesia with Ephrane and given an oral glucocorticosteroid test preparation, volume 1.0 ml / kg. Two hours later, a suspension of Sephadex (5 mg / kg in a volume of 1 ml / kg) was injected into the trachea sufficiently above the cleft to allow the suspension to reach both the left and right lung lobes. Twenty hours later, the rats were killed, the lung lobes were dissected and weighed. Control groups were given a vehicle instead of glucocorticosteroids, and brine instead of Sephadex suspension to measure normal lung weight and non-drug treated Sephadex edema.

The results of the comparative study are given in Table 1. The pharmacological profile of the compounds of the invention was compared with the profiles of budesonide-21-palmitate and flumetazone-21-palmitate in liposomes. All the steroids of the invention showed greater local anti-inflammatory potency in the lung after topical administration than budesonide21-palmitate in liposomes. Moreover, the results also show higher pulmonary selectivity of the tested compounds of the invention compared to the previously known compounds, since the dose of the above-mentioned compounds required to inhibit pulmonary edema (Εϋςθ) by oral administration 158 (Example 3), 247 ( case 7) and 559 (case 1) times higher and budesonide-21-palmitate 66 times higher and flumetazone-21-palmitate 8 times higher than the dose required to inhibit pulmonary edema with topical administration of drugs to the lungs.

Thus, it can be found that the compounds of the invention are well adapted for topical treatment of inflammatory disorders in the skin and in various body cavities (i.e., lungs, nose, intestines, and joints).

Effects of tested glucocorticosteroids in liposomes on a Sephadex-induced rat model of pulmonary edema. The results are given according to the appropriate control group given Sephadex.

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Claims (15)

PATENT APPLICATIONS 1) R-j and R2 are not hydrogen at one time, 1) R-, and R2 are not hydrogen at one time, A compound characterized in that it has the general formula 1 or a stereoisomeric component thereof in which the formula 1,2 is saturated or has a double bond therein, R-j is hydrogen or branched or unbranched hydrocarbon having a chain of 1-4 carbon atoms, R2 is hydrogen or branched or unbranched hydrocarbon having a chain of 1-10 carbon atoms, R3 is an acyl having a branched or unbranched, saturated or unsaturated hydrocarbon chain of 1-20 carbon atoms, X- | is hydrogen or halogen Χ2 is hydrogen or halogen and it is specified that 2) X- | and Χ2 are not hydrogen at one time. A compound according to the first claim, characterized in that, in general formula 1, the site 1,2 is saturated, R-l is hydrogen or a branched or unbranched hydrocarbon chain having 1-4 carbon atoms, R2 is hydrogen or a branched or unbranched hydrocarbon chain having 1-10 carbon atoms, R3 is an acyl having a branched or unbranched, saturated or unsaturated hydrocarbon chain having 1-20 carbon atoms, X- | is hydrogen or halogen, Χ2 is hydrogen or halogen, it is specified that: 2) Χ-j and Χ2 are not hydrogen at one time, A compound according to any one of claims 1-2, characterized in that R 3 is acyl having 11-20 carbon atoms. 3) when there is a double bond at the 1,2 position, R- | and R2 are not at one time methyl groups, A compound according to any one of claims 1-2, wherein R 3 is acyl having 1-10 carbon atoms. 4) when there is a double bond at the 1,2 position, R- | hydrogen atom and R2 is a branched or unbranched hydrocarbon having a chain of 1-10 carbon atoms, R3 is acyl having 11-20 carbon atoms. A compound according to the third claim, characterized in that the site 1,2 is saturated, R 2 is hydrogen, R 2 is a propyl group, X- | is fluorine and Χ2 is fluorine. A compound according to the first claim, characterized in that at the site 1,2 is a double bond, R 1 is hydrogen, R 2 is a propyl group, R 3 is a palmitoyl group, X- | is fluorine, Χ2 is fluorine. A compound according to the first claim, characterized in that the formula f f ^H 2 ^{OC (CH} 2> 14 ^CH 3 A process for the preparation of a compound of general formula 1, as defined in the first claim, which is designated stem to comprise a) reacting a compound of formula wherein R1, R2, Χ1 and Χ2 are defined as in the first claim, with a compound of formula R4COOH wherein R4 is a branched or unbranched, saturated or unsaturated alkyl group having 1-19 carbon atoms, or b) reacting a compound of formula wherein R 1, R ₂ , X 1 and X ₂ are as defined in the first claim, with a compound of formula R _{4 is} COX where R 4 is as defined above and X is a halogen or aliphatic moiety -OOCR4, or c) reacting a compound of formula O · where R1, Rp, Xj and X ₂ are as defined in the first claim and Y is halogen, mesylate or p-toluenesulfonate with a compound of formula R4COO-A + where R4 is defined above and A ⁺ is a cation, then, if the compound thus obtained is an epimeric mixture and a pure epimer is desired, the epimeric mixture is separated into its stereoisomeric components. The process according to claim 8, wherein the compound of any one of claims 2-7 is prepared. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1-7. Pharmaceutical composition according to claim 10, characterized in that it contains liposomes containing a pharmacologically active compound according to claim 3. Pharmaceutical preparation according to claims 10-11, characterized in that it is in the form of a dosage unit. A pharmaceutical composition according to claims 10-12, characterized in that it contains an active ingredient coupled to a pharmaceutically acceptable carrier. A compound according to any one of claims 1-7, 'characterized in that it is useful as a therapeutically active substance. Use of a compound according to any one of claims 1-7 for the preparation of medicaments having anti-inflammatory and anti-allergic activity.