Steroid esters or their stereoisomers, the method of production thereof, and pharmaceutical composition

 

(57) Abstract:

Usage: as anti-allergic and anti-inflammatory drug. Steroid esters of the formula I listed in the description, or their stereoisomers, in position 1, 2 may be a double bond, R1-H, C1-C4-alkyl, R2-H, C1-C6-alkyl, R3-C4-C20-acyl, one of X1and X2-F, and the second is H or F, provided that R1and R2simultaneously H, or when 1, 2 - double bond is present, then R1- H, and R2- C1-C6-alkyl, and R3- C11-C20-acyl. 1 is produced by interaction of the 21-hydroxy 1 with the compound of the formula R4COX, where R4- C3-C19-alkyl, X is halogen or the group-R4followed if necessary by separation of the stereoisomers. 1 is used in a dose of from 10 to 1000 mg as the active principle in farbkomposition, and as the carrier liposome. 3 S. and 18 C.p. f-crystals, 1 table.

The invention relates to new anti-inflammatory and antiallergic active compounds and methods for their preparation. The invention also relates to pharmaceutical compositions containing this compound, and to methods farmacologicas is, immunosuppressive and anti-allergic steroids or pharmaceutical compounds with high activity at the application site, for example, in the respiratory tract, skin, gastrointestinal tract, joints and eyes; drug action aimed at unrestricted area targets due to weak induction systemic glucocorticosteroid effects.

The more distant the aim of the present invention is to provide pharmaceutical compositions containing liposomes, which include pharmacologically active esters of steroids and fatty acids of the present invention. In order to improve the delivery of medicines and reduce side effects of such treatment.

Prior art

Glucocorticosteroids (GCS) are valuable drugs in asthma and rhinitis. It is generally accepted that GCS exert their therapeutic effect by manifestations of anti-inflammatory and anaphylactic properties within the respiratory tract and lung tissue. Long-term use of corticosteroids by mouth largely contraindicated because of severe side effects outside the lung area. Accordingly, only a minor part of the patient is ignoti by delivery of corticosteroids by inhalation. However, potent inhaled corticosteroids, which are currently widely used in the clinic, - beclomethasone-17 , 21-dipropionate and budesonide - also have a pretty tight border security and

The invention

One of the purposes of the present invention is to provide new compounds SCS. New connections are different anti-inflammatory, immunosuppressive and anaphylactic activity at the application site and, in particular, they have a much improved relationship between their performance and ability to cause action GKS outside the treated area. The preferred method of appointment of the new compounds are inhalation, if the application site is located within the respiratory tract.

Another objective of the present invention is the provision of anti-inflammatory and antiallergic compounds containing liposomes with prisoners in them steroid esters, for local purposes, for example, the introduction into the respiratory tract. These formulations designed to improve therapeutic properties of the steroid ether by extending local retention in the respiratory tract and direction drugs to specific cell targets.

Soumerai. In the formula 1,2-th position is saturated or represent a double bond;

R1is hydrogen or straight or branched hydrocarbon chain having 1-4 carbon atoms;

R2is hydrogen or straight or branched hydrocarbon chain having 1-10 carbon atoms;

R3- acyl, having a straight or branched, saturated or unsaturated hydrocarbon chain of 4 to 20 carbon atoms;

at least one of X2and X2is fluorine and the other is hydrogen, provided that 1) R1and R2at the same time are not hydrogen, 2) if 1,2-th position presents a double bond, R1and R2at the same time are not a methyl group, 3) if 1,2-th position presents a double bond, R1is hydrogen and R2is a straight or branched hydrocarbon chain having 1-10 carbon atoms, R3- acyl having 11-20 carbon atoms.

Acyl may occur from:

C3H7COOH: butyric acid,

C4H9COOH: valerianic acid,

C5H11COOH: Caproic acid,

C6H13COOH: enanthic acid,

C7H15COOH: octanoic acid,

C8H17
C11H23COOH:lauric acid,

C12H25COOH: tridecanoic acid,

C13H27COOH: myristic acid,

C14H29COOH: pentadecanoic acid,

C15H31COOH: palmitic acid,

C16H33COOH: heptadecanoic acid,

WITH17H35COOH: stearic acid,

C17H33COOH: oleic acid,

WITH17H31COOH linoleic acid,

C17H29COOH: linolenic acid,

C18H37COOH: nonadecanoic acid,

WITH19H39COOH: Casanovas acid,

Preferred acyl groups come from

C11H23COOH: lauric acid,

C13H27COOH: myristic acid,

C15H31COOH: palmitic acid,

C17H35COOH: stearic acid,

C17H33COOH: oleic acid,

C17H31COOH linoleic acid,

C17H29COOH: linolenic acid,

and, in particular, palmitic acid.

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

Preferred compounds of the present invention are compounds in which in formula I, 1,2-th position is saturated.

The most preferred compound of the present invention are those compounds in which in formula I, 1,3-th position is saturated,

R1is hydrogen,

R2- propyl group,

R3- acyl having 11-20 carbon atoms,

X1- fluorine,

X2- fluorine,

The following preferred compound of the present invention is a compound in which in formula I, 1,2-th position is a double bond,

R1is hydrogen,

R2- propyl group,

R3- palmitoleate group,

X1- fluorine,

X2- fluoride.

The most preferred compound of the present invention has the formula:

< / BR>
The preferred embodiment of the present invention is a composition containing the preferred compound of the present invention in combination with liposomes.

In cases where the aim of the invention avlaia to be the compound according to formula I, where R3acyl having 11-20 carbon atoms,

In cases where the aim of the invention is the provision of pharmaceutical compounds without liposomes, the active compound of these compositions should be the compound according to formula I. where R3- acyl having 1-10 carbon atoms, preferably: 5-10 carbon atoms.

Individuality stereoisomeric components present in a mixture of steroids having the above formula I can be set as follows on the chirality of the carbon atom in position 22 and the substituent R2:

< / BR>
Preferred stereoisomeric compound has the configuration 22 R.

Methods for the preparation of

Steroidy ether

< / BR>
where

is

< / BR>
and X1X2, R1, R2have the meanings given above, R4is a straight or branched, saturated or unsaturated alkyl group with 3-19 carbon atoms and 1,2-th position is saturated or is a double bond, are prepared by any of the following alternative methods.

A. the Reaction of the compound with the formula , where is the definition given above, with the compound according to the formula

< / BR>
where

R4has definition, Denmark source 21-hydroxy-steroid with a suitable carboxylic acid, better in the presence of triperoxonane anhydride, preferably in the presence of an acid catalyst, e.g. p-toluensulfonate acid.

The reaction is best conducted in an organic solvent such as benzene or methylene chloride; typically the reaction is carried out at a temperature of 20-100oC.

B. the Reaction of the compound with the formula , where is the definition given above, with the compound according to the formula

< / BR>
where

R4has the definition given above,

X is halogen, such as chlorine, bromine, iodine and fluorine, or a group

,

where

R4has the definition given above.

The original 21-hydroxy compound can be treated with a suitable halide compound carboxylic acid or anhydride, preferably in solvents such as halogen-substituted hydrocarbon, for example methylene chloride, or an ether, such as dioxane, in the presence of alkali, such as triethylamine or pyridine, preferably at a low temperature, for example, from -5 to +30oC.

C. the Reaction of the compound with the formula , where is the definition given above, and Y is selected from halogen atoms, for example, Cl, Br and I or nelfinavir and p-toluensulfonate, with the compound according to the formula

,
oC.

When using any of methods A-C, if it is desirable to obtain a pure epimer, might need the final phase for the separation of mixtures of epimeres on its components.

Pharmaceutical

Compounds of the present invention can be used for a variety of ways for local purposes, depending on the location of inflammation, for example, subcutaneous, parenteral or local destination in the respiratory tract by inhalation. The main purpose of the recipe purpose is to achieve optimal biological suitability active steroid ingredient. In subcutaneous recipes this can advantageously be achieved if the steroid is dissolved in the carrier with a high thermodynamic activity. This can be used a suitable solvent system, including suitable glycols, such as propylene-glycol is roida, either fully or partially, in the lipophilic phase with the surface of the substance as a solvent. Skin compositions can be ointments, oil solutions creams are oil-based or lotions. When using emulsion carrier system comprising the dissolved active ingredient may be dispersed phase or the continuous phase. Steroid may also be present in the above compositions in the form of very finely ground solids.

Steroid aerosols under high pressure are intended for oral or nasal inhalation. The aerosol system is designed so that the dose at one time contained 10 to 1000 μg, preferably from 20 to 250 micrograms of the active steroid. The most active steroids are prescribed in doses of from the lower part of the dose range. Very crushed steroids consist of particles, mostly smaller than 5 microns, which are suspended in dispergating mixture using dispersant, such as sarbatorile, oleic acid, lecithin or sodium salt dioctylsulfosuccinate acid.

The steroid can also be assigned by inhalation of a dry powder.

One possibility is mixing is distributed in hard gelatin capsules, each of which contains the desired dose of the steroid. The capsules are then placed in the inhaler for powdered, and medication dose by inhalation gets into the respiratory tract of the patient.

Another possibility is the formation of very finely ground powder in the balls, which are destroyed in the process of using doses. These balls of powder is filled in a medicinal capacity pump designed for a lot of doses, for example, Turbuhaler. A measuring device measures the desired dose at one time, which is then inhaled by the patient. In this system, a steroid with a substance carrier, or without it is delivered to the patient.

The steroid can also be included in the prescriptions intended for the treatment of intestinal inflammatory diseases, either through the mouth or through the rectum. Recipes for insertion through the mouth should be drawn up in such a way that the steroid was delivered to inflamed areas of the intestine. This can be achieved through different combinations of the principles of control over the release of the active substance in the intestine and/or delayed release of the active substance. For drug administration through the rectum is appropriate assignment in the form of an enema.

Preparation liposome vetelino, have different phase transition temperature. Examples used lecithins are those that are derived from eggs and soybeans, as well as synthetic lecithins, such as dimyristoyl-phosphatidylcholine (DMPG), dipalmitoyl-phosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC). By manipulating the structure of lecithins can form a stable media with different possibilities of biological destruction. This gives the possibility to extend the prisoner's release (in liposomes) steroid ether.

The length of interaction of the steroid ether, for example, bubbles dipalmitoylphosphatidylcholine (DPPC) depends on the length of the ether chain, and found that the interaction increases with the elongation of the chain.

The inclusion of cholesterol or derivatives of cholesterol recipes liposomes has become very common because of their ability to increase the stability of liposomes.

In the initial stages of preparation of liposomes in accordance with the present invention it is possible to follow the traditional methods described in the literature, namely; the components are dissolved in a solvent, for example, the standard or chloroform, which is then evaporated. After that is provide with the help of ultrasound. Liposomes of the present invention preferably have a diameter between 0.1 and 10 microns.

In addition to the main liposome-forming the lipid (s), which is typically a phospholipid, other lipids (e.g. cholesterol or cholesterol-stearate) in an amount of 0-40% V/V from the total number of lipids can be included to change the structure of liposomal membranes. To optimize the absorption capacity of liposom can be turned on and the third component, which provides a negative charge (for example, dipalmitoyl-phosphatidyl-glycerol) or a positive charge (for example, stearylamine-acetate or chloride of cetylpyridinium).

Can be used with a wide range of ratios of steroid ether lipids depending on what conditions and lipids are used. Can be used for drying (drying from the frozen state or drying by spraying) litecom in the presence of lactose, the content of which is in the range from 0 to 95% of the final composition.

Compositions in accordance with the present invention, which are particularly preferred contain liposomes with (22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11 - hydroxy-21-palmitoylation-4-ene-3,20-dione.rosali under high pressure.

Working examples

The present invention will be further illustrated by the following non-limiting examples. In these examples to work with preparative chromatography, was used with a flow rate of 2.5 ml/cm2h-1. Molecular weight in all examples was determined using mass spectrometry with chemical ionization (CH4as the gas-reagent), the melting point was determined on the microscope Latta-Wetzlar with a hot table. The HPLC analyses (highly effective liquid chromatography ) was performed on a column (Bondapak C18(30o3.9 mm C. D.) with a volumetric flow rate of 1.0 ml/cm2min-1and with a mixture of ethanol/water in the ratio between 40:60 and 60:40 as the mobile phase, if not stated another way.

Example 1

(22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-palmitoylation-4-ene-3,20-dione

A solution of Palmitoyl-chloride (1.2 g) in 10 ml of dioxane was added drop by drop to a solution of (22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11 , 21-dihydroxypregna-4-ene-3,20-dione (200 mg) in 25 ml of pyridine. The reaction mixture was stirred for 16 h at room temperature. Then was added methylene chloride (150 ml), the solution was washed Melanie was purified by chromatography on a column of Sephadex LH-20 (787,5 cm), using chloroform as mobile phase. Faction 210 - 255 ml was collected and evaporated to education 203 mg (22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-Palmitoyl-oxepin-4-ene-3,20-dione. The melting point of 87 - 90oC. Molecular weight 706 (RASSC. 707,0).

The purity of 96% (HPLC analysis).

Example 2

(22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-palmitoylation-4-ene-3,20-dione

To a solution of (22 R)- 16,17-butylidenedioxy - 6,9-debtor 11 , 21-dihydroxypregna-4-ene-3,20-dione (50 mg) and palmitoylated (35 mg) in 10 ml of methylene chloride was added drop by drop a solution of triethylamine (13 mg) in 2 ml of methylene chloride. The reaction mixture was stirred for 2 h at room temperature. Then add another 50 ml of methylene chloride. Next, the reaction mixture was processed as in example 1. The crude product was purified on a column of Sephadex LH-20 (85% to 2.5 cm) using chloroform as mobile phase. Faction 210-250 ml was collected and evaporated with the formation of 34 mg (22 R) -16,17 - butylidenedioxy - 6,9-debtor - 11-hydroxy-21-palmitoylation-4-ene-3,20 dione. Molecular weight 706 (RASSC. 707.0).

Purity 95% (HPLC analysis).

Example 3

(22 S)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-palmitoylated S)- 16,17-butylidenedioxy - 6,9-debtor - 11 , 21-dihydroxypregna-4-ene-3,20 dione (70 mg) in 25 ml of pyridine. The reaction mixture was stirred for 16 h at room temperature and further processed as in example 1. The crude product was purified on a column of Sephadex LH-20 (and 872.5 cm) using chloroform as mobile phase. Faction 225-265 ml was collected and evaporated with the formation of 92 mg (22 S)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-palmitoylation-4-ene-3,20-dione in the form of oil. Molecular weight 706 (RASSC. 707.0). Purity 97% (HPLC analysis).

Example 4

(22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-myristoylation-4-ene-3,20-dione

Myristoyl-chloride was synthesized by heating under reflux myristic acid (7.0 g) and thionyl-chloride (9 ml) trichloroethylene (100 ml) for 3 h Then the solvent was evaporated.

To a solution of (22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11 , 21-dihydroxypregna-4-ene-3,20-dione (51 mg) in 10 ml of methylene chloride was added myristoyl-chloride (32 mg), accompanied by triethylamine (13 mg), dissolved in methylene chloride (5 ml). The reaction mixture was stirred for 4 hours at room temperature. Next was added methylene chloride and the mixture is successively washed with 0.1 M hydrochloric acid and water (3 50 ml). is ceton in the ratio 6:4 as the mobile phase, with the formation of 27 mg (22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-myristoylation-4-ene-3,20-dione. Molecular weight 678 (RASSC. 678,9). The purity of 96.8 per cent (HPLC analysis).

Example 5

(22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-euroelixir-4-ene-3,20-dione

To a solution of (22 R)- 16,17-butylidenedioxy - 6,9-debtor -11, , 21-dihydroxypregna-4-ene-3,20-dione (51 mg) in 5 ml of methylene chloride was added lauroyl-chloride (28 mg), followed by triethylamine (13 mg) dissolved in 2 ml of methylene chloride. The reaction mixture was stirred at room temperature for 3 h, then was added methylene chloride and the organic phase was washed sequentially with 0.1 M hydrochloric acid and water (3 30 ml). After drying and evaporation the residue was purified by chromatography on Kieselgel-60 (Merck) using a mixture of hexane : acetone in the ratio 6:4 as the mobile phase. The resulting product was further purified on a second chromatographic step using a mixture of petroleum ether : ethyl acetate in a ratio of 3:2 as the mobile phase, with the formation of 33 mg (22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-droloxifene-4-ene-3,20-dione. Molecular weight of 650 (RASSC. 650,8). The purity of 96.9 percent (HPLC analysis).

Example 6

(22 R)- 16-17-butyl) in 15 ml of dioxane was added drop by drop to a solution of (22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11 , 21-dihydroxypregna-1,4-diene-3,20-dione (700 mg) in 30 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (76 6.3 cm) using a mixture of heptane:chloroform:ethanol in a ratio of 20:20:1 as mobile phase. Faction 1020-1350 ml was collected and evaporated with the formation of 752 mg (22 R) - 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-palmitoylation. -1,4-diene-3,20-dione. The melting point 141-145oC; []2D5= +71,6o(c = 0,204; CH2Cl2). Molecular weight of 704 (RASSC. 704,9). The purity of 97.7% (HPLC analysis).

Example 7

(22 S)- 16,17-butylidenedioxy - 6,9-debtor - 11 hydroxy-21-palmitoylation-1,4-diene-3,20 dione

A solution of Palmitoyl-chloride (0.5 ml) in 5 ml of dioxane was added drop by drop to a solution of (22 S)- 16,17-butylidenedioxy - 6,9-debtor - 11 , 21-dihydroxypregna-1,4-diene-2,20-dione (150) in 10 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified in a column with Sephadex LH-20 (89 2.5 cm) using a mixture of heptane:chloroform:ethanol in a ratio of 20:20:1 as mobile phase. Faction 215-315 ml were collected and privateco melting point of 176 180oC; []2D5= +47,5o(c = 0,198; CH2Cl2). Molecular weight of 704 (RASSC. 704,9). Purity 99% (HPLC analysis).

Example 8

(22 R)-21-acetoxy - 16,17-butylidenedioxy - 6,9-debtor - 11 hydroxypregn-4-ene-3,20 dione

A solution of acetyl chloride (38 ml) in 5 ml of dioxane was added drop by drop to a solution of (22 S)- 16,17-butylidenedioxy - 6,9-debtor - 11 , 21-dihydroxypregna-4-ene-3,20-dione (75 mg) in 5 ml of pyridine. The reaction mixture was stirred for 16 h at room temperature. After evaporation was added methylene chloride (75 ml), and then the solution was washed with cold 5% aqueous potassium carbonate solution and saturated sodium chloride solution. After evaporation the crude product was purified by chromatography on a column of Sephadex LH-20 (85 2.5 cm) using chloroform as mobile phase. Faction 365 - 420 ml was collected and evaporated to education 57 mg (22 R)-21-acetoxy - 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxypregn-4-ene-3,20 dione. The melting point 182 - 189oC; []2D5= +112,0o(c = 0,225; CH2Cl2). Molecular weight of 510 (RASSC. 510.6). The purity rate of 99.0% (HPLC analysis).

Example 9

(22 R)-16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21 - valerolactone-4-ene-3,20-dione

the solution Wal-dihydroxypregna-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 was added methylene chloride (75 ml), then the solution was washed with cold aqueous 5% potassium carbonate solution and saturated sodium chloride solution. After evaporation the crude product was purified by chromatography on a column of Sephadex LH-20 (85 2.5 cm) using chloroform as mobile phase. Faction 265 - 325 ml was collected and evaporated to education 50 mg (22 R)-21-acetoxy - 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-valerolactone-4-ene-3,20 dione. The melting point 181 - 185oC; []2D5= +109,4o(c = 0,212; CH2Cl2). Molecular weight 552 (RASSC. 552,7). Purity 99.8% (HPLC analysis).

Example 10

(22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-ciproxifan-1,4-diene-3,20-dione

The solution decanoyl-chloride (0.2 ml) in 3 ml of dioxane was added drop by drop to a solution of (22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11-21-dihydroxypregna-1,4-diene-3,20-dione (100 mg) in 6 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (71 6.3 cm) using chloroform as mobile phase the 21-ciproxifan-1,4-diene-3,20-dione. The melting point 182 - 184oC. []2D5= +71,5o(c = 0,186; CH2Cl2). Molecular weight of 620 (RASSC. 620,9). The purity of 97.7% (HPLC analysis).

Example 11

6,9-Debtor - 11, , 21-dihydroxy - 16,17 [/1-methylethylidene/bis/oxy/]pregn-4-ene-3,20-dione

A suspension of 0.9 g of chloride Tris/triphenylphosphine/rhodium in 250 ml of degassed toluene was hydrogenosomal for 45 min at room temperature and atmospheric pressure. Then the solution was added 1.0 g portinale - 16,17-acetonide in 100 ml of absolute ethanol and hydrogenation continued for another 40 hours the reaction Product was evaporated, the residue was purified by thin-layer chromatography on silica gel using a mixture of acetone/petroleum ether as mobile phase to remove the main part of the catalyst. The eluate was evaporated, the residue was further purified by chromatography on a column of Sephadex LH-20 (72,5 6.3 cm) using chloroform as mobile phase. Faction 3555 - 4125 ml was collected and evaporated to education and 0.61 g 6,9-debtor - 11 , 24-dihydroxy - 16,17 -[/1-methylethylidene/bis/oxy/] pregn-4-ene-3,20-dione. The melting point of 146 to 151oC. []2D5= +124,5o(c = 0,220; CH2Cl2). Molecularly weight 454 (RASSC. 454.6). The purity of 98.5% (HPLC analysis).

Example 12
2D5[/I-methylethylidene/bis/oxy/]-21-palmitoylation-4-ene-3,20 dione. The melting point of 82 - 86oC. 16,17 = +85,3oC (c = 0,232; CH2Cl2). Molecular weight 692 (RASSC.692,9). Purity 98,6% (HPLC analysis).

Example 13

(22 R)- and (22 S)-21-acetoxy - 6-butylidenedioxy - 11-fluoro - 16,17-hydroxypregn-4-ene-3,20-dione

(22 RS)- 6-butylidenedioxy - 11-fluoro - 16-21-dihydroxypregna-4-ene-3,20-dione (68 mg) was dissolved in 1 ml of pyridine. Was added acetic anhydride (1 ml) and the reaction mixture was stirred at room temperature for 1 h Then was poured into ice water and was extracted with 3 times 25 ml of methylene chloride. The extract was dried and evaporated. The remaining mixture 22 RS were separated by chromatography on a column of Sephadex LH-20 (89 2.5 cm) using a mixture of heptane: chloroform: this is

After deposition of a mixture of methylene chloride (petroleum ether fraction formed A 14 mg (22 S)-21-acetoxy - 17 , 6-butylidenedioxy - 11-fluoro- []2D5-hydroxypregn-4-ene-3,20-dione. The melting point of 179 - 186oC. 16,17 = +86,2o(c = 0,188; CH2Cl2). Molecular weight of 492 (RASSC.492,6). The purity of 97.5% (HPLC analysis).

Fraction B is formed after deposition of 20 mg (22 R)-21-acetoxy - 6-butylidenedioxy - 11-fluoro- []2D5-hydroxypregn-4-ene-3,20-dione. The melting point of 169 - 172oC. 16,17 = +139,0o(c=0,200; CH2Cl2). Molecular weight of 492 (RASSC. 492,6).The purity of 97.9% (HPLC analysis).

Example 14

(22 RS)- 6-butylidenedioxy - 11-fluoro - 6-hydroxy-21-palmitoylation-4-ene-3,20-dione

To a suspension of 1.4 g of chloride, Tris(triphenylphosphine)rhodium in 300 ml of toluene was added to the solution 1170 mg 11,16,17, -fluoro - 6-21-tetrahydroxypregna-1,4-diene-3,20-dione in 250 ml of absolute ethanol. The mixture was hydrogenosomal 22 h at room temperature and atmospheric pressure and evaporated. The residue was besieged from a mixture of acetone with chloroform education 661 mg 11,16,17-fluoro - 6, 21-tetrahydroxypregna-4-one-3,20-dione. Molecular weight of 396 (RASSC. 396,5). Purity 96:6% (HPLC analysis).

11,16,17-fluoro - 16,17 , 21-tetrahydroxypregna-4-ene-3,20-dione (308 mg) add the Wali at room temperature for 6 hours Then was added methylene chloride (200 ml), the solution washed with 10% aqueous potassium carbonate solution, water and dried. The residue after evaporation was purified on a column of Sephadex LH-20 (and 872.5 cm) using chloroform as mobile phase. Faction 420 - 500 ml was collected and evaporated education 248 mg (22 RS)- 6-butylidenedioxy - 11-fluoro- []2D5, 21-dihydroxypregna-4-ene-3,20-dione. The melting point of 85 - 96o16,17 = +119,8o(c = 0,192; CH2Cl2). Molecular weight of 450 (RASSC.450,6). The purity of 96.1 per cent (HPLC analysis). The distribution between 22 R and 22 S-epimerase was 59/41 (HPLC analysis).

A solution of Palmitoyl-chloride (0,21 ml) in 3 ml of dioxane was added drop by drop to a solution of (22RS)- 6-butylidenedioxy - 11-fluoro - 16,17 , 21-dihydroxypregna-4-ene-3,20-dione (50 mg) in 6 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (89 2.5 cm) using a mixture of heptane : chloroform : ethanol in a ratio of 20: 20: 1 as mobile phase. Faction 185 - 230 ml was collected and evaporated to education 42 mg (22 RS)- 6-butylidenedioxy - 11-fluoro - 16,17-hydroxy-21-palmitoylation-4-ene-3,20-dione in the form of oil. Molecular weight 688 (RASSC. -utilisations - 11-fluoro - 16,17-hydroxy-21-palmitoylation-4-ene-3,2-dione

(22 RS)- 6-butylidenedioxy - 11-fluoro- , 21-dihydroxypregna-4-ene-3,20-dione (225 mg) was divided into portions preparative HPLC on a column 16,17 Bondapak C18(15019 mm) using a mixture of ethanol: water in a ratio of 40:60 as the mobile phase. Fractions concentrated to about 265 ml (A) and 310 ml (B) were collected and one stripped off. After deposition of a mixture of methylene chloride/petroleum ether fraction formed A 68 mg of (22R)- 6-butylidenedioxy - 11-fluoro- []2D5, 21-dihydroxypregna-4-ene-3,20-dione. The melting point of 188 - 192oC. 16,17 = +138,9o(c = 0,144; CH2Cl2). Molecular weight of 450 (RASSC. 450,6). The purity of 99.4% (HPLC analysis).

Fraction B is formed after deposition of 62 mg (22 S)- 6-butylidenedioxy - 11-fluoro- []2D5, 21-dihydroxypregna-4-ene-3,20-dione. The melting point of 168 - 175oC. 16,17 -103,7o(C = 0,216; CH2Cl2). Molecular weight of 450 (RASSC. 450,6). Purity of 99.5% (HPLC analysis).

A solution of Palmitoyl-chloride (0,22 ml) in 5 ml of dioxane was added drop by drop to a solution of (22 R)-6-butylidenedioxy - 11-fluoro - 16,17 , 21-dihydroxypregna-4-ene-3,20-dione (32 mg) in 10 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column with ivali with the formation of 38 mg (22 R)- 6 - butylidenedioxy - 11-fluoro - 16a,17-hydroxy-21-palmitoylation-4 - ene-3,20-dione in the form of oil. Molecular weight 688,97). Purity 96,0% (HPLC analysis).

Example 16

(22 S)- 6-butylidenedioxy - 11-fluoro - 16,17, -hydroxy-21-palmitoylation-4-ene-3,20-dione

(22 RS)- 6-butylidenedioxy - 11-fluoro - 16,17 , 21-dihydroxypregna-4-ene-3,20-dione (68 mg) was dissolved in 1 ml of pyridine. Was added acetic anhydride (1 ml) and the reaction mixture was stirred at room temperature for 1 h, then was poured into ice water and was extracted with 3 times 25 ml of methylene chloride. The extract was dried and evaporated. The remaining mixture ephemeron 22 RS were separated by chromatography on a column of Sephadex LH-20 (892,5 cm) using a mixture of heptane: chloroform: ethanol in a ratio of 20: 20: 1 as mobile phase. Faction 380-400 ml (A) and 420-440 ml (B) was collected and evaporated.

After deposition of a mixture of methylene chloride /petroleum ether fraction F formed 14 mg (22 S)-21-acetoxy - 6-butylidenedioxy - 11-fluoro- []2D5-hydroxypregn-4-ene-3,20 dione. The melting point of 179 - 186oC. 16,17 = +86,2o(c = 0,188; CH2Cl2). Molecular weight of 492 (RASSC.492,6). The purity of 97.5% (HPLC analysis).

Fraction B after deposition formed 20 mg (22 R)-21-acetoxy - 6-butylidenedioxy - 11-fluoro- []2D5-hydroxypregn-4 - ene-3,20-dione. Point Plavinas).

To a solution of 14 mg (22 S)-21-acetoxy - 6-butylidenedioxy - 11-fluoro - 16,17-hydroxypregn-4-ene-3,20-dione in 2 ml of ethanol was added 2 ml of 2M hydrochloric acid. After stirring at 60oC for 5 h, the reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and was extracted with 3 times 25 ml of methylene chloride. The combined extracts were washed with water, dried and evaporated. The residue was purified on a column of Sephadex LH-20 (87 2.5 cm) using chloroform as mobile phase, fraction 455-510 ml was collected and evaporated with the formation of 7 kg (22 S)- 6-butylidenedioxy - 11-fluoro - 16,17, 21-dihydroxypregna-4-ene-3,20-dione. Molecular weight of 450 (RASSC. 450,6). The purity of 96.6 percent.

A solution of Palmitoyl-chloride (195 mg) in 5 ml of dioxane was added drop by drop to a solution of (22 S)- 6-butylidenedioxy - 11-fluoro - 16,17 , 21-dihydroxypregna-4-ene-3,20-dione (32 mg) in 10 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (89 2.5 cm) using a mixture of heptane: chloroform: ethanol in a ratio of 20: 20: 1 as mobile phase. Faction 205 - 245 ml was collected and evaporated to education 37 mg (22 S)- 6-butylidenedioxy - 11-fluoro - 16,1 is HPLC).

Example 17

(22 RS)- 6-butylidenedioxy - 11-fluoro - 16,17-hydroxy-21-lauracomedian-4-ene-3,20-dione

The solution lauroyl-chloride (0.4 ml) in 3 ml of dioxane was added drop by drop to a solution of (22 RS)- 6-butylidenedioxy - 11-fluoro - 16,17 , 21-dihydroxypregna-4-ene-3,20-dione (50 ml) in 6 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (89 2.5 cm) using a mixture of heptane: chloroform: ethanol in a ratio of 20: 10: 1 as the mobile phase, fraction 215-250 ml was collected and evaporated education 15 mg (22 RS)- 6-butylidenedioxy - 11 - fluoro- []2D5-hydroxy-21-euroluxe-pregn-4-one-3,20-dione. The melting point 125 - 143oC. 16,17 = +92,8o(c=0,208; CH2Cl2). Molecular weight 632 (RASSC. 632,9). The purity of 96.2% (HPLC analysis). The distribution between 22 R - 22 S-epimerase was 58/42 (HPLC analysis).

Example 18

(22 R)- 6-butylidenedioxy - 11-hydroxy-21-palmitoylation-1,4-diene-3,20 dione

6-fluoro - 11,16,17 , 21-tetrahydroxypregna-1,4-diene-3,20-dione (400 mg) portions was added to a solution of butanal (of 0.18 ml) and 70% perchloric acid (0.2 ml) in 50 ml of dioxane. The reaction mixture was stirred at room temperature for 16 hours Dobutton after evaporation was purified on a column of Sephadex LH-20 (75 6.3 cm) using chloroform as mobile phase. Faction 2880-3300 ml was collected and evaporated to education 1209 mg (22 R)- 16,17-butylidenedioxy- -fluoro - 11 , 21-dihydroxypregna-1,4-diene-3,20-dione. Molecular weight 448 (RASSC. 448,5). Purity was 95.7 per cent. The distribution between 22 R and 22 S - epimerase was 55/45 (HPLC analysis).

(22 RS)- 16,17-butylidenedioxy - 6-fluoro - 11 , 21-dihydroxy-pregn-1,4-3,20-dione (36 mg) was chromatographically on a column of Sephadex LH-20 (89 2.5 cm) using a mixture of heptane: chloroform: ethanol in a ratio of 20: 20:1 as mobile phase. Faction 1720-1800 ml (A) and 1960-20258 ml (B) was collected and evaporated. Two product besieged from a mixture of methylene chloride /petroleum ether. The product of the fraction And (12 mg) methods 1H NMR and mass spectrometry was identified (22 S)- 16,17-butylidenedioxy - 6-fluoro - 11 , 21-dihydroxypregna-1,4-diene-3,20-dione and the product of the fraction In (10 mg) with its 22 R - epimer.

Epimere have the following properties. Epimere 22 S : the melting point of 172 - 180oC; []2D5= +62,3oC (=0,132; CH2Cl2); molecular weight 448 (RASSC. 448,5). Epimere 22 R: melting point 95 - 106oC; []2D5= +105,9o(C=0,152; CH2Cl2). Molecular weight 448 (RASSC. 448,5). The purity of jemerov was determined by HPLC analysis and 98.9% for 22 S-epimer and 97.7% for the (22 R)- 16,17-butylidenedioxy - 6-fluoro - 11 , 21-dihydroxypregna-1,4-diene-3.20-dione (56 mg) in 10 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (89 2.5 cm) using a mixture of heptane: chloroform: ethanol in a ratio of 20: 20: 1 as mobile phase. Faction 225-285 ml was collected and evaporated to education 31 mg (22 R)- 16,17-butylidenedioxy - 6-fluoro - 11-hydroxy-21-palmitoylation-1,4-diene-3,20-dione. The melting point of 95 - 100oC. []2D5= +68,0oC (=0,200; CH2Cl2). Molecular weight 686 (RASSC. 686,95). The purity of 97.7% (HPLC analysis).

Example 19

(22 S)- 16,17-butylidenedioxy - 6-fluoro-11-hydroxy-21-palmitoylation-1,4-3,20-dione

A solution of Palmitoyl-chloride (110 mg) in 5 ml of dioxane was added drop by drop to a solution of (22 S)- 16,17-butylidenedioxy - 6-fluoro - 11 , 21-dihydroxypregna-1,4-diene-3,20-dione (46 mg) in 10 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (89 2.5 cm) using a mixture of heptane:chloroform in a ratio of 20:20:1 as mobile phase. Faction 185-225 ml was collected and evaporated to education 3P>oC. []2D5=+53,0 (=0,200; CH2Cl2). Molecular weight 686 (RASSC. 686,95). Purity 95,5% (HPLC analysis).

Example 20

6-fluoro - 11 , 21-dihydroxy - 16,17 [/1-methyl-ethylidene/bis/oxy/] pregn-4-ene-3,20-dione

A suspension of 2.1 g of chloride Tris/triphenylphosphine/rhodium 500 ml of toluene was hydrogenosomal at room temperature and atmospheric pressure for 45 min in the presence of catalyst in solution. Then the solution was added 2.0 g of 6-fluoro - 11 , 21-dihydroxy - 16,17 - [/1-methylethylidene/bis/oxy/] pregn-1,4-diene-3,20-dione in 1000 ml of absolute ethanol and hydrogenation continued for a further 65 hours, the Reaction mixture was evaporated, the residue was purified on a column of Sephadex LH-20 (71 6.3 cm) using chloroform as mobile phase, faction 2010-2445 ml was collected and evaporated with the formation of 1.51 g of 6-fluoro 11 21-dihydroxy - 16,17 -[/1-methylethylidene/bis/oxy/] pregn-4-ene-3,20-dione. The melting point 209-219oC []2D5= +133,5o(C= 0,230; CH2Cl2). Molecular weight of 436 (RASSC. 436,5). Purity 99,6% (HPLC analysis).

Example 21

6-fluoro - 11-hydroxy - 16,17 - [/1-methylethylidene/bis/oxy/]-21-palmitoylation-4-ene-3,20-dione

A solution of Palmitoyl-chloride (0,21 ml) in 3 ml of dioxane was added drop by drop to rastvorosmesiteli at room temperature overnight and treated as in example 1. The crude product on a column of Sephadex LH-20 (766,3 cm) using a mixture of heptane: chloroform: ethanol in a ratio of 20:20:1 as mobile phase. Faction 1035 - 1230 ml was collected and evaporated to education 63 mg of 6-fluoro - 11-hydroxy - 16,17 [/1-methylethylidene/bis/oxy/]-21-palmitoylation-4-ene-3,20-dione. The melting point of 99 - 101oC. []2D5= +89,8o(c=0,206; CH2Cl2). Molecular weight 674 (RASSC. 674,94). The purity of 97.9% (HPLC analysis).

Example 22

9-fluoro - 11 , 21-dietoksi - 16,17 [/1-methylethylidene/bis/oxy/] pregn-4-ene-3,20-dione

A solution of 675 mg of chloride Tris/triphenylphosphine/rhodium in 250 ml of toluene was hydrogenosomal at room temperature and atmospheric pressure for 45 minutes was Added a solution of 1 g triamcinolone - 16,17-acetonide in 100 ml of absolute ethanol and hydrogenation continued for a further 40 hours, the Reaction mixture was evaporated, the bulk catalyst was removed by thin-layer chromatography using a mixture of acetone/ petroleum ether (so Kip. 40 - 60oC) in a ratio of 40:60 as the mobile phase. The crude product was further purified on a column of Sephadex LH-20 (72,5 6.3 cm) using chloroform as mobile phase. Faction 2746 - 3195 ml was collected and evaporated with images is SUP>C []2D5= +145, 2mmoC (c=288; CH2Cl2). Molecular weight of 436 (RASSC. 436,5).

Purity 99% (HPLC analysis).

Example 23

9-fluoro - 11-hydroxy - 16,17 -[/1-methylethylidene/bis/oxy/] -21 - palmitoylation-4-ene-3,20-dione

A solution of Palmitoyl-chloride (0,69 ml) in 10 ml of dioxane was added drop by drop to a solution of 9-fluoro - 11 , 21-dihydroxy - 16,17 -[/1-methylethylidene/bis/oxy/] pregn-4-ene-3,20-dione in 20 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (892,5 cm) using a mixture of heptane: chloroform: ethanol in a ratio of 20:20:1 as mobile phase. Faction 240 - 305 ml was collected and evaporated to education 102 mg of 6-fluoro - 11-hydroxy - 16,17 -[/1-methylethylidene/bis/oxy/] -21 - palmitoylation-4-ene-3,20-dione in the form of oil. Molecular weight 674 (RASSC. 674,94). Purity 98% (HPLC analysis).

Example 24

(22 RS)- 16,17-butylidenedioxy - 9-fluoro - 11-hydroxy-21 - palmitoylation-4-ene-3,20-dione

To a solution of freshly distilled butanol (100 mg) and 0.2 ml of perchloric acid (70%) in 50 ml of purified dried dioxane was added 9-fluoro - 11,16,17 , 21-tetrahydroxypregna-4-one-3,20-dione (340 mg) small Porti 5 o'clock Added methylene chloride (200 ml), the solution was washed with an aqueous solution of potassium carbonate, water and dried over anhydrous magnesium sulfate. The crude product obtained product obtained after evaporation was purified on a column of Sephadex LH-20 (72,56,3 cm) using chloroform as mobile phase. Faction 2760 - 3195 ml was collected and evaporated to education 215 mg (22 RS)- 16,17-butylidenedioxy - 9-fluoro - 11-21-dihydroxypregna-4-ene-3,20-dione. Molecular weight of 450 (RASSC. 450,6). The purity of 97.4% (HPLC analysis).

A solution of Palmitoyl-chloride (0,13 ml) in 2.5 ml of dioxane was added drop by drop to a solution of (RS 22)- 16,17-butylidenedioxy - 9-fluoro - 11 , 21-dihydroxypregna-4-ene-3,20-dione (40 mg) in 5 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (87 2.5 cm) using chloroform as mobile phase. Faction 220 - 300 ml was collected and evaporated to education 42 mg (22 RS)- 16,17-butylidenedioxy - 9-fluoro - 11-hydroxy-21-palmitoylation-4-ene-3,20-dione in the form of oil. The molecular weight. 688 (RASSC. 688,97). The distribution between 22 R - 22 S-epimerase was 61/39 (HPLC analysis).

Example 25

(22 R)- 16,17-butylidenedioxy - 9-is n-4-ene-3,20-dione (200 mg) was separated by chromatography on a column of Sephadex LH-20 (766,3 cm) using a mixture of heptane: chloroform: ethanol in a ratio of 20:20:1 as mobile phase. Faction 7560 - 8835 ml (A) and 8836 - 9360 ml (B) was collected, evaporated. The product from fraction A (128 mg) was identified methods IH NMR and mass spectrometry (22 S)- 16,17-butylidenedioxy - 9-fluoro - 11-21-dihydroxypregna-4-ene-3,20-dione and the product of the fraction B (50 mg) with its 22 R-epimer.

Epimer had the following properties. Epimere 22 S melting point 180 - 190oC: []2D5= +105,6o(c = 0,214; CH2Cl2); the molecular weight of 450 (RASSC. 450,6). Epimere 22 R; melting point 147 - 151oC: []2D5=133,7o(c = 0,196; CH2Cl2); the molecular weight of 450 (RASSC. 450,6). The purity of epimeres was determined by HPLC analysis and stood at 95.6% for 22 S - epimer and 98.2% for 22 R - epimer.

A solution of Palmitoyl-chloride (0,34 ml) in 5 ml of dioxane was added drop by drop to a solution of (22 R)- 16,17-butylidenedioxy - 9-fluoro - 11 , 21-dihydroxypregna-4-ene-3,20-dione (50 mg) and 10 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (89 2.5 cm) using a mixture of heptane: chloroform ethanol in a ratio of 20:20:1 as mobile phase. Faction 180 - 205 ml was collected and evaporated to education 36 mg (22 R)- 16,17-butylidenedioxy - 9-FPO is SSC. 688,97).

Example 26

(22S S)- 16,17-butylidenedioxy - 9-fluoro - 11 - hydroxy-21-palmitoylation-4-ene-3,20-dione

The solution Palmitoyl-chloride (0,14 ml) in 15 ml of dioxane was added drop by drop to a solution of (22 S)- 16,17-butylidenedioxy - 9 - fluoro - 11 , 21-dihydroxypregna-4-ene-3,20-dione (41 mg) in 3 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column of Sephadex LH-20 (89 2.5 cm) using a mixture of heptane: chloroform: ethanol and a ratio of 20:20:1 as mobile phase. Faction 215 - 260 ml was collected and evaporated to education 26 mg (22 S)- 16,17-butylidenedioxy - 9-fluoro - 11-hydroxy-21-palmitoylation-4-ene-3,20-dione in the form of oil. Purity 91,4 (HPLC analysis). Molecular weight 688 (RASSC.688.97).

Example 27

(22 R)- 16,17-butylidenedioxy - 9-fluoro - 11-hydroxy-21-palmitoleic-1,4-diene-3,20-dione

A solution of Palmitoyl-chloride (75 mg) in 2.5 ml of dioxane was added drop by drop to a solution of (22 R)- 16,17-butylidenedioxy - 9 - fluoro - 11 , 21-dihydroxypregna-1,4-diene-3,20-dione (25 mg) in 5 ml of pyridine. The reaction mixture was stirred at room temperature overnight and treated as in example 1. The crude product was purified on a column with Sefa and education 27 mg (22 R)- 16,17-butylidenedioxy - 9-fluoro - 11 - hydroxy-21-palmitoylation-1,4-diene-3,20-dione. The melting point of 116 - 121oC. []2D5= +67,4o(C=0,172; CH2Cl2). Molecular weight 686 (RASSC. 687,0). The purity of 96.5% (HPLC analysis).

Example 28

Pharmaceutical

The following examples, non-limiting of the invention, illustrate the recipes, designed for different topically-active forms of assignment. The number of active steroid in skin recipes usually 0.001 to 0.2% (weight/weight), preferably between 0.01 and 0.1% (weight/weight).

Recipe 1. Ointment

Steroid, very finely chopped - 0,025 g

Liquid paraffin 10.0 g

Soft white paraffin to 100.0 g

Recipe 2. Ointment

Steroid - 0,025 g

Propylene glycol 5.0 g

Sorbitan-sesquioleate - 5.0 g

Liquid paraffin is 10.1 g

Soft white paraffin to 100.0 g

Recipe 3. The oil solution in cream, water-based

Steroid - 0,025 g

Cetanol - 5.0 g

Glycerol-monostearate - 5.0 g

Liquid paraffin 10.0 g

Cetomacrogol 1000 - 2.0 grams

Citric acid 0.1 g

Sodium citrate 0.2 g

Propylene-glycol - 35,0 g

Water up to 100.0 g

Recipe 4. The oil solution in cream, water-based

Steroid, very finely chopped - 0,025 g<2.0 g

Sorbitan-monostearate - 0.5 g

Sorbic acid 0.2 g

Citric acid 0.1 g

Sodium citrate 0.2 g

Water up to 100.0 g

Recipe 5. Aqueous solution in the cream is oil-based

Steroid - 0,025 g

White soft paraffin - 35,0 g

Liquid paraffin - 5.0 g

Sorbitan-sesquioleate - 5.0 g

Sorbic acid 0.2 g

Citric acid 0.1 g

Sodium citrate 0.2 g

Water up to 100.0 g

Recipe 6. Lotion

Steroid - 0.25 mg

Isopropyl alcohol and 0.5 ml

Carboxyquinolone 3 mg

NaOH - C. N.

Water is 1.0 g

Recipe 7. Suspension for injection

Steroid, very finely chopped 0.05 to 10 mg

Sodium-carboxymethylcellulose - 7 mg

NaCl - 7 mg

Polyoxyethylene (20)servicemanual 0.5 mg

Phenyl-carbinol 8 mg

Sterile water to 1.0 ml

Recipe 8. Aerosol for inhalation through the mouth and through the nose

Steroid, very finely chopped - 0.1% in/in

Sorbitan-trioleate - 0.7% in/in

Trichloromethane

24.8% in/in

Dichlorotetrafluoroethane - 24.8% in/in

DICHLORODIFLUOROMETHANE - 49,6% in/in

Recipe 9. The solution for spray

Steroid - 7,0 mg

Propylene glycol 5.0 mg

Water - to 10.0 mg

Recipe 10. Powder for inhalation

Desire is Udra inhaled by using the apparatus for inhalation

Recipe 11. Powder for inhalation

Powder, formed into balls, is reusable nebulizer for powder. Each dose contains

Steroid, very finely chopped - 0.1 mg

Recipe 12. Powder for inhalation

Powder, formed into balls, filled reusable nebulizer for powder. Each dose contains

Steroid, very finely chopped - 0.1 mg

Lactose, very finely chopped 1 mg

Recipe 13. Capsules for the treatment of small intestine

Steroid - 1.0 mg

Sugar balls - 321 mg

Aquacoat EOD 30 - 6.6 mg

Acetyltributyl-citrate - 0.5 mg

Polysorbate 80 - 0.1 mg

Eudragit L100-55 - 17,5 mg

Triethylcitrate - 1.8 mg

Talc was 8.8 mg

Antifoam MMS 0.01 mg

Recipe 14. Capsules for the treatment of colon cancer

Steroid - 2.0 mg

Sugar balls - 305 mg

Aquacoat ECD 30 - 5,0 mg

Acetyltributyl - 0.4 mg

Polysorbate 80 - 0.14 mg

Eudragit NE30D - 12.6 mg

Eudragit S100 - 12.6 mg

Talc - 12.6 mg

Recipe 15. Enema through the rectum

Steroid - 0.02 mg

Sodium-carboxymethylcellulose - 25 mg

Disodium salt of ethylenediaminetetraacetic acid 0.5 mg

Methyl-parahydroxybenzoate 0.8 mg

Propyl-parahydroxybenzoate - Naya water to 1.0 ml

The recipe contains a steroid associated with liposomes

A. Preparation of dipalmitoylphosphatidylcholine (45 mg), dimyristoylphosphatidylcholine (7 mg), dipalmitoylphosphatidylcholine (1 mg) and (22 R)- 16,17-butylidenedioxy - 6,9-debtor - 11-hydroxy-21-palmitoylation-4-ene-3,20-dione (5 mg) is mixed in a glass test tube. All components are dissolved in chloroform. A large part of the solvent is evaporated with the use of N2and then under reduced pressure, resulting in a thin film lipid compounds on the surface of the glass tube. To lipids add an aqueous solution of NaCl (0.9 per cent). The formation of liposomes is carried out at a temperature higher than the phase transition temperature of the lipids. Liposomes formed by shaking or sound solution with the selection of the sounding conditions on the ultrasonic device. The resulting suspension contains liposomes, the size of which ranges from very small bubbles to 2 μm.

B. Preparation of recipes for inhalation

Preparation of liposomes is performed in accordance with example A, and an aqueous solution containing 10% lactose. The relationship between lactose and lipids is 7: 3. The suspension of liposomes is frozen on the su is Uchenie aerodynamic diameter (SAD) is 2 μm.

Pharmacology

The selectivity of the local anti-inflammatory action can be demonstrated on the following models of the respiratory tract.

A significant portion of inhaled corticosteroids is deposited in the throat, and later when ingested is in the gut. This part contributes to the unwanted side effects of steroid, because it operates outside the area intended for treatment (light). Therefore, it is advantageous to use GCS with high local anti-inflammatory activity in the lungs, but that they caused a weak action of GCS after administration by mouth. Therefore, studies were designed to determine the effect caused by GCS after local application in the lungs, and after the appointment through the mouth; the difference between the effect of glucocorticosteroid in the treated lung area and outside this area was tested as follows.

The model to test

A. the Model to verify that the desired local anti-inflammatory action on the mucous membranes of the respiratory tract (left lobe of the lungs)

Rats Spraque Dawley (250 g) was slightly anestesiologi using afrana, and trial glucocorticosteroid drug in suspension Sephadex (5 mg/kg in a volume of 1 ml/kg) was poured into the puncture of the trachea, made above the bifurcation, so that the suspension has reached both the right and left lobes of the lungs. After 20 h, the rats were scored, the left lobes of the lungs were excised and weighed. The control group received the media instead of the drug of glucocorticosteroid and a salt solution instead of suspension Cephadex in order to determine the weight swelling from Sephadex, raw medicine, and the weight of a normal lung.

B. Model validation unwanted systemic effects of glucocorticosteroid taken by mouth

Rats Spraque Dawley (250 g) was slightly anestesiologi using afrana and they were given (by mouth) trial GKS-the drug in a volume of 1.0 ml/kg After 2 h the suspension Sephadex (5 mg/kg in a volume of 1 ml/kg) was poured into the puncture of the trachea above the bifurcation, so that the suspension has reached both the left and right lobes of the lungs. After twenty hours the rats were killed and weighed lobes of the lungs. The control group received the media instead of the drug of glucocorticosteroid and a salt solution instead of suspension Cephadex in order to determine the weight swelling from Sephadex, raw medicine, and normal weight.

Results of the comparative study are shown in table. Pharmacological profile of tested compounds of the present is installed) steroids of the present invention showed higher anti-inflammatory effect in the lungs after topical application compared with budesonide-21-palmitate in the liposomes. Moreover, the results also demonstrate higher selectivity in respect of the lungs checked compounds of the present invention in comparison with selected compounds of the prior art, since the dose required to suppress edema [ED50] when assigning through the mouth of the aforementioned compounds in 158 times (example 3), 247 times (example 7) and 559 times (example 1) above, and the dose of budesonide-21-palmitate in 66 times higher dose flumetazon-21-palmitate 8 times higher than the dose neobhodimye to suppress edema in the local application in light of these medicines.

Thus, it can be concluded that the compounds of the present invention are well suited for the topical treatment of inflammatory skin lesions and various body cavities (e.g., lungs, nose, intestines and joints).

1. Steroid esters of the General formula I

< / BR>
or stereoisomer, and 1.2-m position there is a single or double carbon-carbon bond;

R1is hydrogen, straight or branched C1- C4-alkyl;

R2is hydrogen or straight or branched C1- C6-alkyl;

R3- C4- C20-acyl, having a straight or branched, saturated or rendered or fluorine, provided what R1and R2at the same time are not hydrogen; or when 1,2-th position is a double bond, R1and R2at the same time are not methyl groups, or, when 1,2-th position is a double bond, R1is hydrogen, and R2- C1- C6-alkyl and R3- acyl C11- C20.

2. Connection on p. 1, characterized in that the 1,2-position is single bond.

3. Connection under item 1 or 2, wherein R3- C11- C20-acyl.

4. The compound according to any one of paragraphs.1 to 3, wherein R3- Palmitoyl.

5. Connection on p. 3, wherein R3- C1- C10-acyl.

6. The compound according to any one of paragraphs.1 to 5, characterized in that X1is hydrogen or fluorine, X2- fluoride.

7. The compound according to any one of paragraphs.1 - 6, characterized in that X1and X2- fluoride.

8. The compound according to any one of paragraphs.1 to 7, characterized in that R1- hydrogen.

9. Connection on p. 3, characterized in that the 1,2-positions is a single bond, R1is hydrogen, R2- through group, X1is fluorine and X2- fluoride.

10. Connection on p. 1, characterized in that the 1.2-m position is z, X1and X2- fluoride.

11. Connection on p. 1, characterized in that it is a 16,17-butylidenedioxy-6,9-debtor-11-hydroxy-21-palmitoylation-4-ene-3,20-dione.

12. Connection on p. 1, characterized in that it is (22S)-16,17-butylidenedioxy-6,9-debtor-11-hydroxy-21-palmitoylation-4-ene-3,20-dione,(22R)-16-butylidenedioxy-6,9-debtor-11-hydroxy-21-myristoylation-4-ene-3,20-dione, (22R)-16,17-butylidenedioxy-6,9-debtor-11-hydroxy-21-euroelixir-4-ene-3,20-dione,(22R)-16-butylidenedioxy-6,9-,debtor-11-hydroxy-21-palmitoylation-1,4-diene-3,20-dione, (22S)-16,17-butylidenedioxy-6,9-debtor-11-hydroxy-21-palmitoylation-1,4-diene-3,20-dione,(22R)-16-butylidenedioxy-6,9-debtor-11-hydroxy-21-valerolactone-4-ene-3,20-dione, (22R)-16,17-butylidenedioxy-6,9-debtor-11-hydroxy-21-ciproxina-1,4-diene-3,20-dione, 6,9-debtor-11-hydroxy-16,17-[(1-methylethylidene) bis(oxy)]-21-palmitoylation-4-ene-3,20-dione, (22RS)-16,17-butylidenedioxy-6-fluoro-11-hydroxy-21-palmitoylation-4-ene-3,20-dione,(22R)-16-butylidenedioxy-6-fluoro-11-hydroxy-21-palmitoylation-4-ene-3,20-dione,(22S)-16-butylidenedioxy-6-fluoro-11-hydroxy-21-palmitoylation-4-ene-3,20-dione,(22RS)-16-butylidenedioxy-6-fluoro-11-hydroxy-21-euroelixir-4-ene-3,20-dione, (22R)-16,17-butylidenedioxy-6-fluoro-11-guide-diene-3,20-dione,6-hydroxy-16,17-[(1-methylethylidene) bis(oxy)]-21-palmitoylation-4-ene-3,20-dione, 9-fluoro-11-hydroxy-16,17-[(1-methylethylidene) bis(oxy)] -21-palmitoylation-4-ene-3,20-dione,(22RS)-16,17-butylidenedioxy-9-fluoro-11-hydroxy-21-palmitoylation-4-ene-3,20-dione, (22R)-16,17-butylidenedioxy-9-fluoro-11-hydroxy-21-palmitoylation-4-ene-3,20-dione,(22S)-16-butylidenedioxy-9-fluoro-11-hydroxy-21-palmitoylation-4-ene-3,20-Dionisi(22R)-16-butylidenedioxy-9-fluoro-11-hydroxy-21-palmitoylation-1,4-diene-3,20-dione.

13. Connection on p. 1, characterized in that it has formula

< / BR>
14. The method of obtaining compounds on p. 1, characterized in that the compound of General formula

< / BR>
where R1, R2X1and X2matter under item 1, is subjected to the interaction with the compound of General formula

R4COX,

where R4- straight or branched, saturated or unsaturated C3- C19- alkyl;

X is halogen or fragment-OOCR4,

and then, if necessary, the mixture of epimeres divided into its constituent stereoisomers.

15. The method according to p. 14, characterized in that the compound according to any one of paragraphs.2 - 12.

16. Pharmaceutical composition having anti-inflammatory activity, containing steroid esters as the active start and farmacevticheskomu of PP.1 - 13, in the amount of 10 to 1000 μg.

17. The composition according to p. 16, characterized in that the active agent connection on p. 3.

18. The composition according to p. 7, characterized in that it is a form of a single dose.

19. The composition according to p. 16, characterized in that it contains 20 to 250 micrograms of the active principle.

20. The compound according to any one of paragraphs.1 - 13, have therapeutic properties.

21. The compound according to any one of paragraphs.1 - 13, which has anti-inflammatory and anti-allergic properties.

 

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17th-butylidenedioxy - 11, 21-dihydroxypregna-1,4-diene-3,20-dione" target="_blank">

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< / BR>
where

if OR3is set tothen

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< / BR>
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