Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1995-09-29
1998-03-31
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
540 63, C07J 7100, A61K 31705
Patent
active
057339015
DESCRIPTION:
BRIEF SUMMARY
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel prednisolone derivatives which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
DE-OS 41 29 535 discloses pregna-1,4-diene-3,20-dione-16,17-acetal-21-esters which carry a butyl, iso-propyl, sec-butyl, cyclohexyl or phenyl radical on the cyclic acetal ring, and whose C-21 hydroxyl group is acylated by an acetyl or isobutyryl radical.
DESCRIPTION OF THE INVENTION
It has now been found that the following compounds according to the invention, which differ from the compounds of DE-OS 41 29 535 by the missing acyl radical on the C-21 hydroxyl group, have surprising and advantageous properties.
DESCRIPTION OF DRAWINGS
The invention relates to the epimers of the compound of the formula I (see accompanying formula sheet) in pure form, and to mixtures of these epimers 1, 1a and 1b in any desired mixture ratio.
The epimers of the compound of the formula I can be characterized by the formulae Ia and Ib (see accompanying formula sheets).
The invention further relates to a process for the preparation of the compounds according to the invention. The process comprises reacting 16-hydroxyprednisol-one with cyclohexanecarboxaldehyde.
The reaction is carried out in a manner known per se to the person skilled in the art in suitable solvents such as ethers, e.g. dioxane, diisopropyl ether; esters, e.g. ethyl acetate; halogenated hydrocarbons, e.g. methylene chloride, chloroform; nitrated hydrocarbons, e.g. nitromethane, or without solvents, with addition of catalytic or even larger amounts of acid, such as mineral acids, e.g. perchloric acid, hydrochloric acid, tetrafluoroboric acid, or sulfonic acids, e.g. methane-sulfonic acid, at temperatures of, preferably, 0.degree. to 600.degree. C. Preferably, the reaction to give the epimer mixture (formula I) in dioxane or ethyl acetate is carried out using 70% strength perchloric acid or 85% strength tetrafluoroboric acid at 0.degree. C. to room temperature.
The reaction of 16-hydroxyprednisolone with cyclohexanecarboxaldehyde as a rule yields an epimer mixture, it being possible by means of suitable variation of the reaction conditions to control the reaction in such a way that a specific epimer mainly results.
To prepare mainly the R epimer (formula Ia), the following conditions, for example, are preferred: halogenated hydrocarbons or nitromethane with methane-sulfonic acid at room temperature to 40.degree. C., or 35-70% strength perchloric acid at 0.degree. C. to room temperature. A further possibility of preparing mainly the R epimer consists in the treatment of the epimer mixture (formula I) with 70% strength perchloric acid in a suitable solvent, e.g. methylene chloride, at 0.degree. C. (epimerization).
Preparation mainly of the S epimer (formula Ib) is achieved with the aid of hydrogen chloride gas in a solvent such as dioxane, at 0.degree. C. to room temperature.
If an epimer is desired in purer form than is achievable on the basis of the reaction conditions, suitable separation and purification steps, for example preparative HPLC can be added after the reaction.
The following examples serve to illustrate the invention in greater detail:
EXAMPLES
1. 500 mg (1.3 mmol) of 16-hydroxyprednisolone are suspended in 5 ml of nitromethane and treated with 33 .mu.l (0.38 mmol) of 70% strength perchloric acid and 195 .mu.l (1.6 mmol) of cyclohexanecarboxaldehyde. After stirring at room temperature for 4.5 h (epimer ratio in the reaction mixture R/S=55:45, HPLC content 95%), the reaction mixture is treated with sodium hydrogen carbonate solution, and the precipitate is filtered off with suction, washed with water and nitromethane and dried at 50.degree. C. in a high vacuum. Yield: 440 mg (70%), epimer ratio R:S=57:43 (determined by means of HPLC, stationary phase ODS Hypersil, mobile phase water/ethanol=60:40).
2. 2.0 g (5.3 mmol) of 16-hydroxyprednisolone are suspended in 20 ml of nitromethane and treated with 0.88 ml (10.2 mmol) of 70% strength perchlor
REFERENCES:
patent: 3856954 (1974-12-01), Jackson
patent: 4695625 (1987-09-01), MacDonald
ByK Gulden Lomberg Chemische Fabrik GmbH
Shah Mukund J.
Sripada Pavanaram K.
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