Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-03-27
2004-07-06
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S169000, C514S170000, C514S172000, C514S173000, C514S175000, C514S176000, C514S179000, C514S180000, C514S182000
Reexamination Certificate
active
06759399
ABSTRACT:
Use of compounds having an antimineralocorticoid activity for the preparation of medicaments intended for the prevention or treatment of symptoms linked to drug dependence or to the spontaneous or induced withdrawal syndrome, caused by narcotics and the compositions containing them.
The products having an antimineralocorticoid activity are known as being able to be used as medicaments. They are, in particular, antagonists of aldosterone and they increase salt and water diuresis with conservation of organic potassium; moreover they have, for some, the advantage of being devoid of hormonal side-effects, in particular anti-androgen and anti-estrogen effects. They can therefore be used to combat, in particular, arterial hypertension and cardiac insufficiencies.
There are two major types of glucocorticoid receptor at the level of the central nervous system, the type I receptor and the type II receptor (R. Ahima et al. J. Comp. Neurol. 313 (1991) 522-528; Neuroscience 39 (1990) 579-604).
The type I receptor, at the level of the brain, is identical to the standard mineralocorticoid receptor found at the level of the kidney, and it has a high affinity and a low bonding capacity for the endogenous glucocorticoids. In others terms, an antimineralocorticoid behaves at the level the central nervous system as a type I antiglucocorticoid.
The Applicant has demonstrated the new and unexpected use of these products, mentioned above.
It has previously been shown that the glucocorticoids (dexamethasone type) antagonize the analgesic activity of morphine while an antagonist of the glucocorticoids, of 17&bgr;-hydroxy 11&bgr;-(4-dimethylaminophenyl) 17&agr;-(prop-1-ynyl) estra 4,9-diene-3-one type, or a suprarenalectomy, potentializes this activity (Capasso et al. Life Science 51 139 (1992), Ratka et al. Neuroendocrinology 49 439 (1988) Pieretti et al. Gen. Pharmacol. 22 929 (1991)).
However, to the knowledge of the Applicant, nobody has demonstrated the activity of an antimineralocorticoid vis-à-vis the undesirable effects of opiates and in particular of the induction of a physical or psychological dependent state and the withdrawal syndrome associated with this state. These dependence and withdrawal phenomena involve complex central mechanisms, multiple and different from those which are observed in the analgesic activity of opiates.
On the other hand, recent data has been reported on the important role that the endogenous glucocorticoids could play in the symptoms of narcotic withdrawal, as well as in the dependence phenomena induced by opiates or cocaine. Thus, hypercortisolism has been observed in man over the course of clinical trials, during withdrawal spontaneous or induced by naloxone consecutive with taking heroin or morphine (Cami et al. Br. J. Addict 87 1145 (1992), Higgins et al. Drug Alcohol Depend. 30 13 (1992). Other elements reported in animals show an activation of the hypothalamo-surrenal axis by cocaine (Borowsky and Kuhn, J. Pharmacol. Exp. Ther. (1991) 256, 204) administered in an acute or repeated treatment with an increase in plasmatic levels of corticosterone and ACTH (Moldow and Fischman, Peptides 8 819 (1987), Yang et al. Pharmacol. Biochem Behau. 41 643 (1992); Saphier et al. Neuroendocrinology 57 54 (1993)) consecutive with a mediation of monoaminergic origin (dopamine for example). For example the involvement of the dopaminergic system appears confirmed by the fact that haloperidol and metoclopramide (dopaminergic antagonists) oppose respectively the increase in corticosterone levels induced by cocaine and the phenomenon of morphinic withdrawal (Ramaswamy and Bapna, Life Science 40 807 (1987)).
This data appears to show that the endogenous glucocorticoids could intervene in the phenomena of withdrawal and dependence, in the same way as dopaminergic mechanisms but at a stage further upstream than the latter.
These different elements have justified the study of antagonists of mineralocorticoids in particular vis-à-vis the phenomena of physical and psychological dependence or morphinic withdrawal syndrome induced by naloxone in animals since no data is currently available on the activity of this therapeutic class in this axis.
In fact, while an increase in endogenous glucocorticoid levels has been reported in opiate withdrawal phenomena, it has not been demonstrated that this increase could have a physiopathological repercussion and that in particular the blocking of these endogenous glucocorticoids at the level of their receptors by an antimineralocorticoid would be translated into a beneficial effect on physical and psychological dependence and on the symptoms of the withdrawal syndrome.
Thus, the Applicant has demonstrated a new and unexpected use of antimineralocorticoids.
Therefore a subject of the present invention is the use of compounds having an antimineralocorticoid activity for the preparation of medicaments intended for the prevention or treatment of symptoms linked to drug dependence or to the spontaneous or induced withdrawal syndrome, caused by narcotics or mixtures of narcotics.
By compounds having an antimineralocorticoid activity is meant,
either compounds which are antagonists of the aldosterone receptor, which compounds are competitive inhibitors of the steroid bond to its receptor, thus preventing the natural hormone from carrying out its activity, or compounds which inhibit the biosynthesis of aldosterone, by inhibiting in particular 18-hydroxylase. In fact, the oxidation in position 18 constitutes the last stage of the biosynthesis of aldosterone and a selective inhibition of this stage allows, in principle, the inhibition of biosynthesis of other essential steroid hormones such as cortisol or androstanedione to be avoided. These compounds are essentially represented by the compounds of Figure (I
j
) described below in which R
4j
is an alkenyl or alkynyl group and R
5j
is either a hydroxyl radical, or a hydrogen atom.
By narcotics is meant all drugs entailing a psychological and physical dependence phenomenon and the spontaneous or induced stopping of which leads to a withdrawal syndrome. There can be mentioned:
1) natural morphinomimetics such as:
a) the opium alkaloids, for example morphine,
b) the alkaloid derivatives of morphine, for example heroin or codeine,
2) synthetic morphinomimetics such as:
a) piperidine derivatives, for example pethidine or
b) methadone and its derivatives, for example dextromoramide,
3) cocaine,
as well as all combinations containing two or more of these narcotic products.
A more particular subject of the present invention is the use of compounds having an antimineralocorticoid activity for the preparation of medicaments intended for the prevention or treatment of symptoms linked to dependence or spontaneous or precipitated withdrawal syndrome caused by morphinomimetic narcotics chosen from heroin, morphine and methadone.
A more particular subject of the present invention is the use of compounds having an antimineralocorticoid activity for the preparation of medicaments intended for the prevention or treatment of symptoms linked to dependence or spontaneous or precipitated withdrawal syndrome caused by cocaine.
A more particular subject of the present invention is the use as defined previously, characterized in that compounds having an antimineralocorticoid activity correspond to general formula (I):
in which rings A, B and C have one of the following structures:
and in which:
either X and Y represent the groups:
Alk
1
representing an alkyl group containing at most 8 carbon atoms,
or X represents a hydroxyl, acetyloxy, propionyloxy, methoxy or ethoxy radical and Y represents a CH
2
CH
2
CO
2
M, CH
2
CH
2
SO
2
M or CH
2
CH
2
CH
2
OH radical, M being a hydrogen atom, an alkali metal atom or an ammonium radical,
or X represents a COCH
2
Z radical, in which Z represents a hydrogen atom, a hydroxyl radical or an acyloxy radical containing 1 to 18 carbon atoms, and Y represents a hydrogen atom,
or X represents a
radical, S being an alkyl radical containing at most 8 carbon atoms, or a hydrogen atom and Y represents
Goeders Nick
Petit Francis
Philibert Daniel
Aventis Pharma S.A.
Muserlian Lucas and Mercanti
Qazi Sabiha
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