Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1996-01-18
1998-04-21
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514178, 514181, A61K 3156
Patent
active
057417873
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to the use of antiglucocorticoid steroids for the manufacture of a pharmaceutical composition for the treatment of anxiety disorders.
BACKGROUND OF THE INVENTION
Antiglucocorticoid steroids are a well known group of steroids which exhibits affinity for the glucocorticoid receptor (GR) and reduce completely or to a considerable extent the action of cortisol. For example, 11.beta.-substituted steroids having antiglucocorticoid activity are disclosed in EP-A-190759 and EP-A-57115. Other steroids having antiglucocorticoid activity are 10.beta.-substituted steroids as disclosed in EP-A-188396.
SUMMARY OF THE INVENTION
It has now been found that antiglucocorticoid steroids also exert anxiolytic effects, which make these steroids useful for the treatment of anxiety disorders. Anxiety disorder is a rather broad concept including for instance general anxiety, panic disorder, and various kinds of withdrawal symptoms (see: Diagnostic and Statistical Manual of Mental Disorders, 3 RD ED DSM-III, Washington, American Psychiatric Ass., p. 225-239, 1980).
The aim of this invention is to provide a pharmaceutical composition which can be used for the treatment or prevention of anxiety disorders.
Steroids that can be used for the treatment of anxiety disorders are known from WO 9303732. These steroids, however, have no hormonal effects and have no affinity to the glucocorticoid receptor: they activate the GABA receptor/chloride ionophore complex instead. No hint or suggestion towards the use of antiglucocorticoid steroids for the treatment or prevention of anxiety disorders is made in said publication. Antidepressant activity was suggested by De Kloet et al. (Neuroendocrinology, 47 (1988), 109-115) and by Veldhuis et al. (Eur. J. Pharmacol., 115 (1985)211-217). However, since there is no relation between antidepressant and anxiolytic effects, no activity of antiglucocorticoid steroids for treating of preventing anxiety was suggested.
Benzodiazepines, such as librium and valium, are the most commonly used drugs for the treatment of anxiety disorders. However, these compounds are no steroids.
DETAILED DESCRIPTION OF THE INVENTION
In a preferred embodiment of the invention the antiglucocorticoid steroids according to the invention are 11.beta.- or 10.beta.-sustituted steroids having the general formula: ##STR1## wherein: R.sub.1 is H, CH.sub.3, unsubstituted or OH or halogen substituted CH.sub.2 .dbd.CH--CH.sub.2 or CH.tbd.C--CH.sub.2, or an aryl, arylthio or arylmethyl group, the aryl moieties of which may optionally be substituted with (C1-C6) alkyl, (C1-C6) alkoxy, OH, halogen or CF.sub.3, or R.sub.1 together with R.sub.7 is a bond; group selected from (C1-C6) acyl, (C1-C6) alkoxy, (C1-C6) thioalkoxy, --O--(CH.sub.2).sub.n --O--, n being 1 or 2, and ##STR2## X and Y each being independently H or a group selected from (C1-C6) alkyl and (C1-C6) acyl, or R.sub.2 together with R.sub.7 is a bond; (C1-C6) alkyl, (C1-C6) alkenyl and (C1-C6) alkynyl, each of which group may be substituted with hydroxy, oxo, halogen, azido or cyano, or --C.tbd.C-phenyl, the phenyl group of which may optionally be substituted with --S(O)m--(C1-C6) alkyl, m being 1 or 2, or with ##STR3## X and Y each being independently H or a group selected from (C1-C6) alkyl and (C1-C6) acyl, or X and Y together with the nitrogen to which they are bonded form a ring; (C1-C6) acyl, each of which group may optionally be substituted with hydroxy, (C1-C6) alkoxy, (C1-C6) acyloxy or halogen; or form a 5- or 6-membered ring system; alkoxy;
In a more preferred embodiment the steroids have above-mentioned formula wherein R.sub.1 together with R.sub.7 is a bond, R.sub.2 represents a phenyl group which is substituted in the para position with an amino group ##STR4## R.sub.3 is methyl or ethyl, R.sub.4 is prop-1-ynyl, R.sub.5 is hydroxy and R.sub.6 is H, hydroxymethyl or methoxymethyl.
In particular 11.beta.B-(4-dimethylaminophenyl)-17.beta.-hydroxy-17.alpha.-(prop-1-ynyl) -estra-4,9-dien-3-one (RU38486) is a preferred ster
REFERENCES:
patent: 5232917 (1993-08-01), Bolger et al.
D.F. Papolos, Brain Research, 615 (1993) 304-309.
S.M. Korte et al., Hormones and Behavior, 27:167-183 (1993).
H.D. Veldhuis et al., European Journal of Pharmacology, 115(1985) 211-217.
E.R. De Kloet et al., Neuroendocrinology, 47:109-115 (1988).
Akzo Nobel N.V.
Blackstone William M.
Gormley Mary E.
Reamer James H.
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