Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-03-23
2001-10-16
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06303591
ABSTRACT:
The present invention relates to the use of pure antiglucocorticoids for the treatment or profilaxis of diseases associated to an excess of glucocorticoids. In particular, the invention relates to the use of 21-hydroy-6,19-oxidoprogesterone (21OH-6OP) for treating Cushing's syndrome or depression.
Cushing's syndrome or pituitary basophilism is a disorder resulting from increased adrenocortical secretion of cortisol. Hyperfunction of the adrenal cortex may be ACTH-dependent or it may be independent of ACTH regulation, eg, production of cortisol by an adrenocortical adenoma or carcinoma. The administration of supraphysiologic quantities of exogenous cortisol or related synthetic analogs suppresses adrenocortical function and mimics ACTH-independent hyperfunction. ACTH-dependent hyperfunction of the adrenal cortex may be due to hypersecretion of ACTH by the pituitary, secretion of ACTH by a nonpituitary tumor such as small cell carcinoma of the lung (the ectopic ACTH syndrome), or administration of exogenous ACTH. While the term Cushing's syndrome has been applied to the clinical picture resulting from cortisol excess regardless of the cause, hyperfunction of the adrenal cortex resulting from pituitary ACTH excess has frequently been referred to as Cushing's disease, implying a particular physiologic abnormality. Patients with Cushing's disease may have a basophilic adenoma of the pituitary or a chromophobe adenoma. Microadenomas can usually be visualized by CT or, preferably, MRI scan, using a high-resolution technique augmented by gadolinium. Some microadenomas are difficult to visualize even with these modalities. In some cases, no histologic abnormality is found in the pituitary despite clear evidence of ACTH overproduction.
Reference to Cushing's syndrome is herein intended to mean the clinical picture resulting from cortisol excess regardless of the cause, which may be also iatrogenic, both by the injection of ACTH or by the direct administration of cortisol or synthetic analogs such as prednisone, prednisolone, dexamethasone or others that are widely used in various types of diseases including allergic, asthmatic, inflammatory or immunologic. Cushing's syndrome includes in addition adrenal tumours secreting corticoids, ectopic ACTH production and Cushing's disease.
Clinical manifestations include rounded “moon” facies with a plethoric appearance. There is truncal obesity with prominent supraclavicular and dorsal cervical fat pads (“buffalo hump”); the distal extremities and fingers are usually quite slender. Muscle wasting and weakness are present. The skin is thin and atrophic, with poor wound healing and easy bruising. Purple striae may appear on the abdomen. Hypertension, renal calculi, osteoporosis, glucose intolerance, reduced resistance to infection, and psychiatric disturbances are common. Cessation of linear growth is characteristic in children. Females usually have menstrual irregularities. An increased production of androgens, in addition to cortisol, may lead to hypertichosis, temporal balding, and other signs of virilism in the female.
To-date, the only therapeutical application for antiglucocorticoids (e.g. Mifepristone) that has been attempted in a clinical setting is to treat inoperable cases of nonpituitary Cushing's syndrome. In the case of Mifepristone (both an anti-progesterone ad an anti-glucocorticoid), a very high dose (20-800 mg per day) is needed for the effectiveness in this indication.
The glucocorticoid receptor (GR), cloned in 1985 (1), is member of a protein super family of closely related intracellular receptors which function as ligand-activated transcription factors (2). Steroid ligands which are able to activate GRs and trigger a biological response exhibit a slightly torsioned steroid nucleus at the A/B-ring junction for optimal glucocorticoid (GC) activity (3,4). On the other hand, mineralocorticoid (MC) agonists require an overall flat conformation to acquire sodium-retaining activity (5). The mineralocorticoid receptor (MR), cloned by Arriza et al. (6) in 1987, showed to be highly homologus with GR. Due to that considerable homology, it was not too surprising that natural and even synthetic steroids exhibited cross-reaction between GR and MR. The progesterone receptor (PR) is the third member of a subfamily of these highly related steroid receptors. Its natural ligand, progesterone, exhibits cross-reaction with both MR and GR
Employing a systematic application of strategies to increase activity and decrease crossreactivity and undesirable side effects, impressive progress has been reported in the development of new antihormonal agents with greater potency and selectivity, especially in the antiestrogen and antiandrogen fields.
The development of selective anti-corticoids is more restricted. Reference can be made to steroids of the spironolactone family which are used in therapeutics. Those inhibitors seem to belong to the class of rapidly dissociating anti-MCs (7). Another synthetic steroid described as an anti-MC, ZK91587, shows specific binding properties for kidney (8) and hippocampus type I MR (9), but not for type II GR. It may therefore be conveniently useful as a tool in the investigation of MR function in tissues containing both receptor systems.
A long-lasting search for the GC antagonist finally succeeded with the development of the 11&bgr;-aminophenyl-substituted 19-norsteroid RU38486, later shortened to RU486, in the early 80's (10). It soon became apparent, however, that this compound also possessed strong antiprogestin activity, which led to its applications as a contraceptivelcontragestive agent (11). Avoiding cross-reactions between GR and PR is still an unachieved goal for phannacologists.
We have now found that the synthetic steroid, 21-hydroxy-6,19-oxidoprogesterone (21 OH-6OP, I),
is a selective antiglucocorticoid which is unable to cross-react with uterus-PR or kidney-MR. The new structure has been developed as a result of systematic studies on MC potencies on a series of 21-deoxysteroids, among which the highly bent -6,19-oxidoprogesterone (6OP—
FIG. 1
) exhibited practically no Na
+
retaining properties (5).
Preliminary studies also showed lack of GC properties for this steroid. The 21-hydroxy introduced group into its structure conferred anti-GC properties to the 6,19-oxidopregnane skeleton.
The pure antiglucocorticoid of the present invention is, therefore, used in the treatment of diseases associated to an excess of glucocorticoids, where an antiglucocorticoid virtually lacking mineralocorticoid or glucocorticoid properties as well as affinity for MR or PR is highly desirable. In particular, the antiglucocorticoid of the present invention is used for the treatment of Cushing syndrome and depression, which are associated with an excess of glucocorticoids in the body.
The present invention, thus, provides 21-hydroxy-6,19-oxidoprogesterone of Formula I for use as a medicament.
It is a further object of the present invention the use of 21-hydroxy-6,19-oxidoprogesterone of Formula I in the manufacture of a medicament for the treatment or prophylaxis of diseases associated to an excess of glucocorticoids.
Preferably, the compound of Formula I is used in the manufacture of a medicament for the treatment of Cushing's syndrome, iatrogenic hypercortisolism or depression.
The compound of Formula I may be formulated in accordance with usual steroid formulations with one or more suitable carriers thereof.
REFERENCES:
patent: 6150349 (2000-11-01), Schatzberg et al.
patent: 0763541A1 (1997-03-01), None
patent: 0763541 (1997-03-01), None
“RU-26988—A New Tool for the Study of Mineralcorticoid Receptor”; Gomez-Sanchez, et al.;Endocrinology; vol. 113, No. 3 pp. 1004-1009.
“Glucocorticoid Receptors”; Funder;J. Steroid Biochem. Molec. Biol.; vol. 43, No. 5, pp. 389-394.
“Ligand Properties of 11,19-Oxido Progesterone. A Preliminary Report”; Galigniana, et al.;An. Assoc. Quim. Argent; 81:333-340 (1993).
“Renal Mineralocorticoid Receptors and Hippocampal Corticosterone-B
Burton Gerardo
Lantos Carlos Pedro
Applied Research Systems ARS Holding NV
Ostrolenk Faber Gerb & Soffen, LLP
Reamer James H.
LandOfFree
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