Derivative of prednisolone, the way they are received and drug

 

(57) Abstract:

Derivative of prednisolone General formula I, Ia and IB effective treatment for the prevention of skin diseases, diseases of the upper respiratory tract. The compounds of formula 1 is produced by interaction of the 16-hydroxyprednisolone with cyclohexanoltramadol. 4 C. and 5 C.p. f-crystals, 1 PL.

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The scope of the invention.

The invention relates to new derivatives of prednisolone, which are used in the pharmaceutical industry for the manufacture of medicines.

The prior art.

In lined with the description of unaccepted application for patent in Germany 4129535 reveal pregna-1,4-diene-3,20-dione-16,17-acetal-21-esters, which are cyclic acetaldol ring residue butyl, isopropyl, sec.-butyl, cyclohexyl or phenyl and C-21-hydroxyl group which allerban the rest of the acetyl or isobutyryl.

Description of the invention.

Now found that the following compounds according to the invention, which differ from the compounds of the patent application Germany 4129535 missing acyl residue at the C-21-hydroxyl group, have unexpected and advantageous properties.

is Oseni components of the mixture.

Epimere the compounds of formula I can be described by formulas Ia and 1B.

Another object of the invention is a method for producing compounds according to the invention. The method differs in that 16-hydroxyprednisolone interacts with cyclohexanoltramadol.

Interaction by prominent professional way in suitable solvents, such as ethers, for example dioxane, simple diisopropyl ether, esters, such as complex ethyl ester acetic acid, halogenated hydrocarbons such as methylene chloride, chloroform, nitride hydrocarbons such as nitromethane, or without solvents, with the addition of catalytic or very large quantities of acid, such as mineral acids, for example perchloric acid, hydrochloric acid, tetraberlinia acid, or sulfonic acids, such as methanesulfonate, at temperatures mainly from 0 to 60oC.

Mainly the interaction to a mixture of epimeres (formula I) is carried out in dioxane or ethyl ether complex of acetic acid and 70% perchloric acid or 85% terraforming acid at a temperature of from 0oC to room temperature.

the rich a corresponding change in the reaction conditions can be adjusted turning so that is formed mainly of a specific epimer.

Expressing a preference for obtaining R-epimer (formula Ia) are preferred, for example, the following conditions: halogenated hydrocarbons or nitromethane turn with methansulfonate at a temperature of from room temperature to 40oC, or 35-70% perchloric acid at a temperature of from 0oC to room temperature.

Another possibility for preferential obtain R-epimer is in the handling of a mixture of epimeres (formula I) 70% perchloric acid in a suitable solvent, such as methylene chloride, at 0oC (epimerization).

The predominant S-epimer (formula IB) is achieved by using gaseous hydrogen chloride in a solvent such as dioxane, at temperatures from 0oC to room.

Since it is desirable getting epimer in a purer form, as this is achieved on the basis of the reaction conditions, can be optionally connected to the interaction stage separation and purification, such as preparative thin layer chromatography (HPLC).

The following examples serve for a more detailed explanation of the invention.

Examples.

1. 500 mg (1.3 mmol) of 16-CL (1.6 mmol) of cyclohexanediamine.

After 4.5 hours of stirring at room temperature (the ratio of epimeres in the reaction mixture R/S = 55/45, preparative thin layer chromatography HPLC - content 95%), the reaction mixture is mixed with sodium bicarbonate solution, the precipitate is sucked off, washed with water and nitromethane and dried at 50oC in high vacuum.

Yield: 440 mg (70%), the ratio of epimeres R/S = 57/43 (definition by the method of preparative thin-layer chromatography, the stationary phase ODS hypersil, the mobile phase of water/ethanol = 60/40).

2. 2,0 (5.3 mmol) of 16-hydroxyprednisolone suspended in 20 ml of nitromethane and mixed with 0,88 ml (10.2 mmol) of 70% perchloric acid and 0.78 ml (6.4 mmol) of cyclohexanediamine.

After 4.5 hours of stirring at room temperature (the ratio of epimeres in the reaction mixture R/S = 73/27, preparative thin layer chromatography HPLC - content 95%) are working as in example 1.

Output: 1,96 g (78%), the ratio of epimeres R/S = 76/24.

3. 2.0 g (5.3 mmol) of 16-hydroxyprednisolone suspended in 10 ml of nitromethane and 1.5 ml of a (17.4 mmol) of 70% perchloric acid and then buried 0.8 ml (6.6 mmol) of cyclohexanediamine. Stirred for 2 hours at room temperature (the ratio of epimeres in the reaction mixture R/S = 92/8, >4. 2.0 g (5.3 mmol) of 16-hydroxyprednisolone suspended in 20 ml of nitromethane and mixed with 3,52 ml (4 mmol) of 70% perchloric acid and 0.78 ml (6.4 mmol) of cyclohexanediamine. After 1 hour stirring at room temperature served on a sodium bicarbonate solution, extracted with methylene chloride, the organic phase is dried using sodium sulfate and concentrated in vacuum.

The remainder chromatographic on silica gel with methylene chloride/complex ethyl ester acetic acid = 1/1 (Rf=0,5).

Yield: 1.0 g (40%), the ratio of epimeres R/S = 89/11.

5. 20 g (53 mmol) of 16-hydroxyprednisolone suspended in 300 ml of chloroform, mixed with 8.0 ml (66 mmol) of cyclohexanediamine and cooled in an ice bath buried by 17.6 ml (205 mmol) of 70% perchloric acid.

After 2.5 hours stirring at room temperature the reaction mixture is poured on soda solution, the organic phase is extracted with water, dried using sodium sulfate and concentrated in vacuum (the ratio of epimeres in the crude product R/S = 85/15). The residue is dissolved in warm methanol, mix until the turbidity of water, cooled in an ice bath and the precipitate is sucked off and dried.

Yield: 20.2 g (81%), the ratio of epimeres R/S = 85/15.

6. 5.0 g (Noi acid and buried 2,1 ml (17.3 mmol) of cyclohexanediamine.

After 1.25 hours the reaction mixture is poured on soda solution, the organic phase is washed with water, dried with magnesium sulfate and concentrated in vacuum.

Crude yield: quantitative HPLC - content of 96%, the ratio of epimeres R/S = 89/11.

7. 300 g (797 mmol 16-hydroxyprednisolone suspended in 3.0 l of complex ethyl ester acetic acid, mixed with 120 ml (991 mmol) cyclohexanediamine and within 20 minutes buried 150 ml (1,75 mmol) of 70% perchloric acid.

After 1 hour of stirring the solution is mixed with 250 g of sodium carbonate and stirred with 1.5 l of water. The aqueous phase is extracted with complex ethyl ester acetic acid, the collected organic phases are extracted with a saturated solution of sodium chloride. After drying the organic phase with sodium sulfate slowly thicken it in a vacuum, sucked off the formed solid substance, optionally washed with a simple diethyl ether and dried.

Output: 282 g (75%), the ratio of epimeres R/S = 58/42.

8. 10.0 g (to 26.6 mmol) of 16-hydroxyprednisolone when cooling is suspended in an ice bath, 100 ml of dioxane, mixed with 8.8 ml (102,4 mmol) of 70% perchloric acid and within 45 minutes buried with 3.7 ml (30,5 mmol) cyclohexanediamine.

Total yield: 11 g (88%).

9. 0.5 g (1.3 mmol) of 16-hydroxyprednisolone suspended at room temperature in 20 ml simple diisopropyl ether and mixed with 120 μl (1.56 mmol) of cyclohexanediamine and 440 ml (5.1 mmol) of 70% perchloric acid.

After 45 minutes the reaction mixture is stirred with a complex ethyl ester, acetic acid and extracted with sodium bicarbonate solution and water. The organic phase is dried using magnesium sulfate and concentrated in vacuum.

Crude yield: quantitative; HPLC - content of 95%, the ratio of epimeres R/S = 57/43.

10. 2.0 g (5.3 mmol) of 16-hydroxyprednisolone suspended at room temperature in 20 ml of nitromethane and mixed with 1.4 ml (21.5 mmol) of methanesulfonate and 0.78 ml (6.4 mmol) of cyclohexanediamine.

The solution is stirred for 3 hours at 40oC and diluted after ohla the second phase is dried using sodium sulfate and concentrated in vacuum. The residue is subjected to chromatography as in example 4.

Yield: 1.7 g (68%), the ratio of epimeres R/S = 85/15.

11. 5.0 g (13.3 mmol) of 16-hydroxyprednisolone suspended in 50 ml of methylene chloride, mixed with cooling in an ice bath from 3.45 ml (53,1 mmol) methansulfonate and within 10 minutes buried 1,95 ml (16, 1 mmol) cyclohexanediamine. Leave to obtain room temperature and then stirred for 3 hours at 40oC. the Solution is extracted with water, dried using sodium sulfate and concentrated in vacuum.

Crude yield: quantitative HPLC - content of 96%, the ratio of epimeres R/S = 85/15.

12. 10.0 g (to 26.6 mmol) of 16-hydroxyprednisolone while cooling in an ice bath suspended in 60 ml of 70% perchloric acid and within 10 minutes mix from 3.7 ml (30,5 mmol) cyclohexanediamine.

After 30 minutes of stirring while cooling with ice served chilled on ice sodium bicarbonate solution and extracted with complex ethyl ester of acetic acid. The organic phase is washed with sodium bicarbonate solution and water, dried with sodium sulfate and concentrated in vacuum (the ratio of epimeres in the crude product R/S = 93/7).

The residue is purified as in example 8. 1st fraction: is Pimenov: R/S = 91,5/8,5.

Total yield: 9,95 g (79.5%).

At the proper interaction of the products of allocating 50% or 35% perchloric acid in the crude product get the ratio epimeres R/S = 95/5 or 81/19.

13. 5.0 g (13.3 mmol) of 16-hydroxyprednisolone while cooling in an ice bath is suspended in 80 ml of dioxane, mixed with 2.5 ml of 85% terraforming acid in a simple diethyl ether and added dropwise within 10 minutes of 1.95 ml (16,1 mmol) cyclohexanediamine.

Stirred for 1 hour at room temperature, then poured into sodium bicarbonate solution and extracted with complex ethyl ester of acetic acid. The organic phase is extracted with water, dried using sodium sulfate and concentrated in vacuum. The remainder chromatographic as in example 4.

Yield: 4.0 g (64%), the ratio of epimeres R/S = 47/53.

14. 100 mg (0.27 mmol) of 16-hydroxyprednisolone suspended in 5 ml of nitromethane mixed with 50 ál of 85% terraforming acid in a simple diethyl ether and 35 μl (0.29 mmol) of cyclohexanediamine and stirred for 15 hours at room temperature. The ratio of epimeres reaction mixture R/S = 80/20, HPLC - content of 96%. Ratio control of epimeres can be achieved by heating the reaction mixture for 3 which when cooled in a water bath with 760 ml (6.3 mmol) of cyclohexanediamine and within 20 minutes buried 15 ml of 14.8%-aqueous solution of hydrochloric gas/dioxane.

After 2 hours stirring at 0oC and 2 hours at room temperature, add sodium bicarbonate solution and extracted with complex ethyl ester of acetic acid. The organic phase is washed with water, dried using sodium sulfate and concentrated in vacuum. The remainder chromatographic as in example 4.

Output: 620 mg (25%), the ratio of epimeres R/S = 25/75.

16. 12.0 g (25.5 mmol) of 16-17-cyclohexylmethoxy-11-21-dihydroxy-pregna-1,4-diene-3,20-dione (compound 1, the ratio of epimeres R/S = 60/40) is dissolved at 0oC in 240 ml of methylene chloride, mixed with 8.7 ml (101,1 mmol) of 70% perchloric acid and after 40 minutes of stirring to the sodium bicarbonate solution. Extracted the aqueous phase with methylene chloride, the collected organic phases with water and dried with magnesium sulfate. After concentration of solvent in vacuo Recuperat quantitatively connection 1 ratio epimeres R/S = 90/10 (HPLC - content 98%).

17. Division of epimeres (based on any mix of epimeres) can be done using preparative thin-layer chromatography HPLC as follows:

Devices: HP V liquid chromatograph, HP 79850BLC terminal and a UV detector; the column material: hypersil samples: 220 mg in 600 μl of dimethyl-sulfoxide + 3800 μl of ethanol; boot volume: 200 ál = 10 mg of a mixture of epimeres; flow: 10 ml/min; oven temperature: 40oC; achieved purity: R-epimer 99,6%, S-epimer of 99.4%.

Compounds according to the invention have valuable pharmacological properties, which provide the ability to apply them in industry. Usually the compounds according to the invention is used for the treatment of painful conditions that can be treated with steroid anti-inflammatory drugs. This includes, first of all, diseases of the skin and respiratory tract, as well as inflammatory bowel disease and allergic rhinitis/conjunctivitis.

In the field of skin compounds according to the invention on the basis of their anti-inflammatory, antiproliferative, immunosuppressive, anisogamy and vasoconstrictive properties suitable for (especially local) treatment of dermatoses of various origins. For example, we can mention: allergic contact eczema, atopic eczema, seborrheic eczema, simple herpes, psoriasis (psoriasis), sunburn, itching in the genital area, alopecia areata, hypertrophic scars and discoid lupus erythematosus.

In the field of respiratory compounds according to the invention almost suppress linzirowanii, migration and activation of inflammatory cells and the formation of prostaglandins, leukotrienes and PAF.

Due to this connection according to the invention reduce bronchial Hyper-reactivity, reduce mucus formation, improve mucus clearance and increase (partly due to the increased expression of adrenergic receptors) action-sympathomimetic funds.

On the basis of these properties, the compounds according to the invention, first and foremost, is used (in the form of local inhalers) for long-term treatment of bronchial asthma.

Compounds according to the invention are characterized by low toxicity, mainly topical efficiency, a large therapeutic range, long action and lack of significant side effects. The effectiveness of the compounds according to the invention makes possible their use in human and veterinary medicine.

Therefore, another object of the invention is a method of treating mammals, including humans, suffering from one of these diseases. The method differs in that the afflicted mammal prescribed therapeutically effective and pharmacologically tolerated amount of one or neskolko the invention for use in the treatment and/or prevention of these diseases.

The invention relates also to the use of compounds according to the invention for the manufacture of medicines used for the treatment and/or prevention of these diseases.

Further, the subject invention are medicines for the treatment and/or prophylaxis of the aforementioned diseases, which contain one or more compounds according to the invention.

For the treatment of dermatoses compounds according to the invention is used especially in the form of such medicines, suitable for topical application. For the manufacture of pharmaceuticals compounds according to the invention (= activedata substance) is mixed mainly with suitable pharmaceutical excipients and processed in the appropriate dosage forms.

Suitable dosage forms should be called, for example, powders, emulsions, suspensions, aerosols, oils, ointments, fatty ointments, creams, pastes, gels or solutions.

What auxiliary substances for the desired dosage forms suitable specialist known on the basis of his special knowledge. Along with solvents, geleobrazovanie, the basics of ointments and the preservatives, agents of dissolution or permeation promoters.

For the treatment of respiratory diseases, the compounds according to the invention is used primarily as inhalers. To do this, they appoint directly or as powders (preferably in micronized form) or spray solutions or suspensions that contain them. Regarding dosage forms and forms introduction refer to, for example, on explanations in the European patent 163965.

Medicinal product according to the invention are produced by known methods. The dosage of the active substances is common for highly efficient glucocorticoids order of magnitude. Thus, topical application (such as ointment) for the treatment of dermatoses contain the active substance in a concentration of, for example, 0.1 to 1%.

Dose for use in inhalation is usually between 0.2 and 2 mg per day. Regular (maintenance) dose systemic therapy is about 10 mg per day, and in the case of severe asthma attacks, and especially when an asthmatic condition and can also be used higher doses (e.g., 250-500 mg intravenously).

Pharmacological data.

Conduct experiments to determine the local and ncacii in rats (using a cotton pellet):

Sprague-Dawley-rats male (respectively 8-16 animals per dose; the weight of each animal: 180-230 g) implanted under isoflurane-anesthesia and sterile conditions in the shoulder on both sides for 1 cotton ball (manufacturer: company Hartmann/Heidenheim; cotton ball size 2,N4865/2) 13,00,5 mg, subcutaneously.

Before the beginning of the experience provided for implantation in the left side of the body cotton balls drop accordingly alcohol solution (0.05 ml/bead; 96% alcohol) of the test compounds. At the time of implantation of the beads are dry, i.e., substances deposited on the threads of wool. Balls right side of the body implanted without treatment.

Within 7 days due to irritation foreign body formed granulomas. The last - on the 8th day care, i.e when sparing connective tissue capsule, completely removed from dead animals, dried (15 hours at 120oC and weighed. Subtracting the weights of cotton balls get the number of newly formed granulation tissue.

The criterion for the antiproliferative activity of a compound is reduced as a percentage of the average weight of granuloma in a dry condition treated group compared with the checkpoints for important locations the tx2">

To register systematic actions corticoids also defined the wet weight of the thymus gland and adrenal gland.

1. Derivative of prednisolone General formula I

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chemical name 16, 17-(22R, S)-cyclohexylmethoxy-11, 21-dihydroxypregna-1,4-diene-3,20-dione.

2. Derivative of prednisolone General formula Ia under item 1,

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chemical name 16, 17 - (22R)-cyclohexylmethoxy-11, 21-dihydroxypregna-1,4-diene-3,20-dione.

3. Derivative of prednisolone General formula Ib under item 1

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chemical name 16, 17-(22S)-cyclohexylmethoxy-11, 21-dihydroxypregna-1,4-diene-3,20-dione.

4. Derivative of prednisolone General formula I, which is a mixture of epimeres the compounds of formula Ia and compounds of formula Ib.

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and having any relation of these epimeres in the mixture.

5. Derivative of prednisolone General formula I on PP.1 to 4, with antiproliferative properties.

6. The method of obtaining derivatives of prednisolone General formula I on PP.1 to 4, characterized in that 16-hydroxyprednisolone enter into interaction with cyclohexanoltramadol.

7. Drug for the treatment or prevention of diseases to the existing substances it contains a compound of General formula I on PP. 1 to 4 in the form of a mixture of epimeres compounds of formulas Ia and Ib in any ratio epimeres in the mixture in an effective amount.

8. Drug under item 7, characterized in that as activitiesthese substances it contains a compound of formula Ia.

9. Drug under item 7, characterized in that as activitiesthese substances it contains a compound of formula Ib.

 

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