Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1993-08-31
1997-10-07
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
540 70, C07J 7100
Patent
active
056748612
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
The present invention relates to novel anti-inflammatory and anti-allergic active compounds and to processes for their preparation. The invention also relates to pharmaceutical compositions containing the compounds and to methods of the pharmacological use of the compounds.
The object of the invention is to provide an anti-inflammatory, immunosupressive and anti-allergic glucocorticosteroid or a pharmaceutical composition thereof with high activity at the application place, e.g. in the respiratory tract, on the skin, in the intestinal tract, in the joints or in the eye directing the drug to a delimited target area, thereby inducing low glucocorticoid systemic effects.
BACKGROUND ART
It is known that glucocorticosteroids (GCS) can be used for local therapy of inflammatory, allergic or immunologic diseases in respiratory airways (e.g. asthma, rhinitis), in skin (eczema, psoriasis) or in bowel (ulcerative colitis, Morbus Crohn). With local glucocorticosteroid therapy, clinical advantages over general therapy (with e.g. glucocorticosteroid tablets) are obtained, especially regarding reduction of the unwanted glucocorticoid effects outside the diseased area due to reduction of the necessary dose. To reach even higher clinical advantages, in e.g. severe respiratory airway disease, GCS must have a suitable pharmacological profile. They should have high intrinsic glucocorticoid activity at the application site but also a rapid inactivation before or after uptake into the general circulation.
DISCLOSURE OF THE INVENTION
One object of the invention is to describe new GCS compounds. They are characterized by high anti-inflammatory, immunosupressive and anti-anaphylactic potency at the application site and particularly they have a markedly improved relationship between that potency and the activity to provoke GCS actions outside the treated region.
The compounds of the invention are a 22R or 22S epimer of a compound of the general formula ##STR2## wherein X.sub.1 and X.sub.2 are the same or different and each represents a hydrogen atom or a fluorine atom, provided that X.sub.1 and X.sub.2 are not simultaneously a hydrogen atom.
The individual 22R and 22S epimers of the formula (I) can be elucidated in the following way due to the chirality at the carbon atom in 22-position: ##STR3## wherein X.sub.1 and X.sub.2 are as defined above.
An epimer 22R and 22S, respectively, of formula I above is by definiton a compound containing not more than 2 per cent by weight, preferably not more than 1 per cent by weight of the other epimer.
The preferred compounds of the invention are the 22R and 22S epimers of the structure ##STR4##
The preferred steroid has the R configuration at the 22 carbon atom.
Methods of Preparation
The 16.alpha.,17.alpha.-acetals of the formula I are prepared by reaction of a compound with the formula ##STR5## wherein X.sub.1 and X.sub.2 have the above given definition, with an aldehyde of the formula ##STR6##
The reaction is carried out by adding the steroid to a solution of the aldehyde together with an acid catalyst, e.g. perchloric acid, p-toluenesulfonic acid, hydrochloric acid in an ether, preferably dioxane or in acetonitril.
The compounds of the formula I, are also prepared by transacetalisation of the corresponding 16.alpha.,17.alpha.-acetonides ##STR7## wherein X.sub.1 and X.sub.2 have the above given definition, with an aldehyde of the formula ##STR8##
The reaction is carried out by adding the steroid to a solution of the aldehyde together with an acid catalyst, e.g. perchloric acid, p-toluenesulfonic acid, hydrochloric acid in an ether, preferably dioxane, or in acetonitril.
The reaction can also be performed in a reaction medium which is a hydrocarbon, preferably isooctane, wherein the solubility of the pregnane derivative (the 16,17-acetonide or the 16,17-diol) is less than 1 mg/l, or in a halogenated hydrocarbon, preferably methylene chloride or chloroform.
The reaction is catalysed by a hydrohalogen acid or an organic sulphonic acid such as p-toluenesulfonic acid.
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Abstract of JP 58-176485 (1985).
Andersson Paul
Axelsson Bengt
Brattsand Ralph
Thalen Arne
Astra Aktiebolag
Berch Mark L.
Kifle Bruck
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