U.S. patent application number 10/858320 was filed with the patent office on 2004-12-02 for new use of antimineralocorticoid compounds against narcotic withdrawal syndrome.
This patent application is currently assigned to Aventis Pharma S.A.. Invention is credited to Goeders, Nick, Petit, Francis, Philibert, Daniel.
Application Number | 20040242552 10/858320 |
Document ID | / |
Family ID | 9482793 |
Filed Date | 2004-12-02 |
United States Patent
Application |
20040242552 |
Kind Code |
A1 |
Petit, Francis ; et
al. |
December 2, 2004 |
New use of antimineralocorticoid compounds against narcotic
withdrawal syndrome
Abstract
A method of treating narcotic withdrawal symptoms in
warm-blooded animals comprising administering to warm-blooded
animals in need thereof an amount of a compound having
anti-mineralocorticoid activity sufficient to treat narcotic
withdrawal sypmtoms.
Inventors: |
Petit, Francis; (Colombes,
FR) ; Philibert, Daniel; (La-Varenne-Saint-Hilaire,
FR) ; Goeders, Nick; (Shreveport, LA) |
Correspondence
Address: |
Charles A. Muserlian
c/o Muserlian, Lucas and Mercanti
475 Park Avenue South
New York
NY
10016
US
|
Assignee: |
Aventis Pharma S.A.
|
Family ID: |
9482793 |
Appl. No.: |
10/858320 |
Filed: |
June 1, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10858320 |
Jun 1, 2004 |
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09535711 |
Mar 27, 2000 |
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6759399 |
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09535711 |
Mar 27, 2000 |
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09043382 |
Mar 16, 1998 |
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6147066 |
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09043382 |
Mar 16, 1998 |
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PCT/FR96/01459 |
Sep 19, 1996 |
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Current U.S.
Class: |
514/179 |
Current CPC
Class: |
A61K 31/585 20130101;
A61P 25/36 20180101; A61P 25/30 20180101; A61K 31/58 20130101 |
Class at
Publication: |
514/179 |
International
Class: |
A61K 031/56 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 21, 1995 |
FR |
95/11086 |
Claims
1) 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
mixtures of narcotics.
2) Use according to claim 1, characterized in that the narcotic is
a morphinomimetic chosen from heroin, morphine and methadone.
3) Use according to claim 1, characterized in that the narcotic is
cocaine.
4) Use according to any one of claims 1 to 3, characterized in that
the compounds having an antimineralocorticoid activity correspond
to general formula (I): 22in which rings A, B and C have one of the
following structures: 23and in which: either X and Y represent the
groups: 24Alk.sub.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.sub.2CH.sub.2CO.sub.2M, CH.sub.2CH.sub.2SO.sub.2M or
CH.sub.2CH.sub.2CH.sub.2OH radical, M being a hydrogen atom, an
alkali metal atom or an ammonium radical, or X represents a
COCH.sub.2Z 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
25radical, S being an alkyl radical containing at most 8 carbon
atoms, or a hydrogen atom and Y represents a hydrogen atom, A and B
are hydrogen atoms or together form a methylenic bridge in position
15.alpha.,16.alpha. or 15.beta., 16.beta., A' and B' are hydrogen
atoms, alkyl radicals containing 1 to 4 carbon atoms, or form with
the carbon which carries them a cyclopropyl radical, R.sub.1
represents a methyl radical or a CC--W group, in which W represents
either a hydrogen atom, or an alkyl radical containing at most 8
carbon atoms optionally substituted by a hydroxyl, free, esterified
or salified carboxy, amino, tritylamino, chloroacetylamino,
trifluoroacetylamino, halogen, monoalkylamino, dialkylamino
radical, each alkyl radical containing at most 8 carbon atoms, or
an aryl or aralkyl radical containing at most 14 carbon atoms,
optionally substituted by a hydroxyl, free esterified or salified
carboxy, amino, monoalkylamino, dialkylamino, alkyl, alkoxy or
alkylthio radical, each alkyl radical containing at most 8 carbon
atoms, or a halogen atom, or a trialkylsilyl radical, each alkyl
radical containing at most 8 carbon atoms, R.sub.2 and R.sub.3 are
such that either R.sub.2 and R.sub.3 form together a methylenic
bridge in position 6.alpha., 7.alpha. or 6.beta., 7.beta., or
R.sub.2 and R.sub.3 are hydrogen atoms, or R.sub.3 is a hydrogen
atom and R.sub.2 represents a SCOCH.sub.3, CO.sub.2Alk group, Alk
being an alkyl radical containing at most 8 carbon atoms, alkyl,
alkenyl or alkynyl radicals containing at most 8 carbon atoms and
optionally substituted by a hydroxyl, free, esterified or salified
carboxy, halogen, amino, monoalkylamino, dialkylamino radical, each
alkyl radical containing at most 8 carbon atoms, R.sub.4 represents
an alkyl, alkenyl or alkynyl radical containing at most 8 carbon
atoms, R.sub.5 represents either an allenyl radical, or a hydroxyl
radical, or a hydrogen atom, the dotted lines represent a possible
second bond, the wavy lines indicate that the substituents are in
position .alpha. or .beta., as well as the salts of the products of
formula (I) with pharmaceutically acceptable acids and bases.
5) Use according to claim 4, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.a): 26in which: either X.sub.a and Y.sub.a represent
the groups 27Alk.sub.1 being as defined in claim 4, or X.sub.a
represents a hydroxyl, acetyloxy, propionyloxy, methoxy or ethoxy
radical and Y.sub.a represents a CH.sub.2CH.sub.2CO.sub.2M,
CH.sub.2CH.sub.2SO.sub.2M or CH.sub.2CH.sub.2CH.sub.2OH radical, M
being as defined in claim 4, R.sub.2a, R.sub.3a and W.sub.a
respectively have the same values as R.sub.2, R.sub.3 and W as
defined previously and the dotted or wavy lines have the meaning
indicated in claim 4.
6) Use according to claims 4 or 5, characterized in that the
compounds corresponding to general formulae (I) and (I.sub.a) are
chosen from the following list: .gamma.-lactone of 10.beta.-ethynyl
17.beta.-hydroxy
3-oxo-19-nor-17.alpha.-pregna-4,9(11)-diene-21-carboxylic acid,
.gamma.-lactone of 17.beta.-hydroxy
3-oxo-10.beta.-(1-propynyl)-19-nor-17-
.alpha.-pregna-4,9(11)-diene-21-carboxylic acid, .gamma.-lactone of
17.beta.-hydroxy
3-oxo-10.beta.-(1-propynyl)-19-nor-17.alpha.-pregn-4-ene-
-21-carboxylic acid, .gamma.-lactone of 10.beta.-ethynyl
17.beta.-hydroxy 3-oxo-19-nor-17.alpha.-pregn-4-ene-21-carboxylic
acid.
7) Use according to claim 4, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.b): 28in which: either X.sub.b and Y.sub.b represent
the groups 29or X.sub.b represents a hydroxyl radical and Y.sub.b
represents a CH.sub.2CH.sub.2CO.sub.2M radical, M being as defined
in claim 4, R.sub.2b and R.sub.3b are such that either R.sub.2b
represents an alkyl, alkenyl or alkynyl radical optionally
substituted as defined previously and R.sub.3b is a hydrogen atom,
or R.sub.2b and R.sub.3b together form a methylenic bridge in
position 6.alpha.,7.alpha. or in position 6.beta.,7.beta..
8) Use according to one of claims 4 or 7, characterized in that the
compounds corresponding to general formulae (I) or (I.sub.b) are
chosen from the following list:
(17R)-6.beta.,7.beta.-methylene-2'-oxydospiro-(a-
ndrost-4-ene-17,5'-(1',2')-oxathiolane)-3-one
(17R)-6.alpha.,7.alpha.-meth-
ylene-2'-oxydospiro-(androst-4-ene-17,5'-(1',2')-oxathiolane)-3-one
(17R)-7.alpha.-methyl-2'-oxydospiro-(androst-4-ene-17,5'-(1',2')-oxathiol-
ane)-3-one
(17R)-7.alpha.-n-propyl-2'-oxydospiro-(androst-4-ene-17,5'-(1',-
2')-oxathiolane)-3-one .gamma.-lactone of
17.beta.-hydroxy-3-oxo-7.alpha.--
propyl-17.alpha.-pregna-1,4-diene-21-carboxylic acid, potassium
17.beta.-hydroxy-3-oxo-7.alpha.-propyl-17.alpha.-pregna-1,4-diene-21-carb-
oxylate, .gamma.-lactone of
17.beta.-hydroxy-3-oxo-7.alpha.-propyl-(17.alp-
ha.)-pregn-4-ene-21-carboxylic acid, potassium
17.beta.-hydroxy-3-oxo-7.al-
pha.-propyl-(17.alpha.)-pregn-4-ene-21-carboxylate.
9) Use according to claim 4, characterized in that the compounds
having an antimineralocorticoid activity, corresponding to general
formula (I.sub.c): 30in which either X.sub.c and Y.sub.c represent
a group 31or X.sub.c represents a hydroxyl radical and Y.sub.c
represents a CH.sub.2CH.sub.2CO.sub.2M or CH.sub.2CH.sub.2SO.sub.2M
group, M being as defined in claim 4, or X.sub.c represents a
COCH.sub.2Z radical in which Z is as defined in claim 4 and Y.sub.c
is a hydrogen atom, A'.sub.c and B'.sub.c respectively have the
same values as A' and B' as defined in claim 4, R.sub.4c is a
methyl or ethyl radical, R.sub.5c is either a hydrogen atom, or an
allenyl radical, it being understood that when R.sub.5c is an
allenyl radical, A'.sub.c and B'.sub.c are hydrogen atoms, R.sub.4c
is a methyl radical, X.sub.c and Y.sub.c together form a 32group,
the dotted lines in position 9-10 form a second bond, and those in
position 11-12 do not form a second bond.
10) Use according to any one of claims 4 or 9, characterized in
that the compounds corresponding to general formulae (I) or
(I.sub.c) chosen from the following list: 2,2-dimethyl 19-nor
pregn-4-ene-3,20-dione, 21-acetoxy 2,2-dimethyl 19-nor-pregn-4-ene
3,20-dione, 2,2-dimethyl 21-hydroxy 19-nor-pregn-4-ene 3,20-dione,
2,2-dimethyl 19-nor-pregna-4,9-diene 3,20-dione, 21-acetoxy
2,2-dimethyl 19-nor-pregna-4,9-diene 3,20-dione, 2,2-dimethyl
21-hydroxy 19-nor-pregna-4,9-diene 3,20-dione, 2,2-dimethyl
19-nor-pregna-4,9,11-tri- ene 3,20-dione, 21-acetoxy 2,2-dimethyl
19-nor-pregna-4,9,11-triene 3,20-dione, 2,2-dimethyl 21-hydroxy
19-nor-pregna-4,9,11-triene 3,20-dione, (17R)
2'-oxydospiro-(estra-4,9-diene-17,5'-(1',2')-oxathiolan- e) 3-one,
(17R) 2'-oxydospiro-(estra-4,9,11-triene-17,5'-(1',2')-oxathiola-
ne) 3-one, (17R) 11.beta.-hydroxy
2'-oxydospiro-(estra-4,9-diene-17,5'-(1'- ,2')-oxathiolane) 3-one,
2,2-dimethyl-13-ethyl-21-hydroxy-18,19-dinor-preg- n-4-ene
3,20-dione, .gamma.-lactone of 11.beta.-allenyl-17.beta.-hydroxy-3-
-oxo-19-nor-17.alpha.-pregna-4,9-diene-21-carboxylic acid.
11) Use according to claim 4, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.d): 33in which: either X.sub.d and Y.sub.d represent
the group 34or X.sub.d represents a hydroxyl radical and Y.sub.d
represents a CH.sub.2CH.sub.2CO.sub.2M radical, M being as defined
in claim 4, A.sub.d and B.sub.d respectively have the same values
as A and B as defined in claim 4, R.sub.2d represents either a
thioacetyl radical, or a CO.sub.2Alk radical, Alk being an alkyl
radical containing at most 8 carbon atoms and the dotted line in
position 1-2 represents an optional double bond.
12) Use according to one of claims 4 or 11, characterized in that
the compounds corresponding to general formula (I) or (I.sub.d) are
chosen from the following list: .gamma.-lactone of
7.alpha.-acetylthio-17.beta.--
hydroxy-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregna-1,4-diene-21-ca-
rboxylic acid, .gamma.-lactone of
17.beta.-hydroxy-7.alpha.-methoxycarbony-
l-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic
acid, .gamma.-lactone of
7.alpha.-acetylthio-17.beta.-hydroxy-3-oxo-17.al-
pha.-pregn-4-ene-21-carboxylic acid, .gamma.-lactone of
17.beta.-hydroxy-7.alpha.-methoxycarbonyl-3-oxo-17.alpha.-pregn-4-ene-21--
carboxylic acid, the potassium salt of
17.beta.-hydroxy-7.alpha.-methoxyca-
rbonyl-3-oxo-pregn-4-ene-21-carboxylic acid.
13) Use according to claim 4, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.e): 35in which: either X.sub.e and Y.sub.e represent
the group 36or X.sub.e represents a hydroxyl radical and Y.sub.e
represents a CH.sub.2CH.sub.2CO.sub.2M radical, M being as defined
previously, R.sub.2e or R.sub.3e are such that: either R.sub.2e and
R.sub.3e together form a methylenic bridge in position
6.alpha.,7.alpha. or 6.beta.,7.beta., or R.sub.2e and R.sub.3e are
hydrogen atoms, A.sub.e and B.sub.e respectively have the same
values as A and B as defined in claim 4, the dotted or wavy lines
keeping the same meaning as in claim 4.
14) Use according to one of claims 4 or 11, characterized in that
the compounds corresponding to general formula (I) or (I.sub.e),
are chosen from the following list: .gamma.-lactone of
17.beta.-hydroxy-6.beta.,7.be-
ta.,15.beta.,16.beta.-dimethylene-3-oxo-17.alpha.-pregna-1,4-diene-21-carb-
oxylic acid, .gamma.-lactone of
17.beta.-hydroxy-6.beta.,7.beta.,15.beta.,-
16.beta.-dimethylene-3-oxo-17.alpha.-pregna-4-ene-21-carboxylic
acid, .gamma.-lactone of
17.beta.-hydroxy-3-oxo-17.alpha.-pregna-4,6-diene-21-c- arboxylic
acid, the potassium salt of 17.beta.-hydroxy-3-oxo-17.alpha.-pre-
gna-4,6-diene-21-carboxylic acid .gamma.-lactone of
17.beta.-hydroxy-3-oxo-17.alpha.-pregna-4,6,11-triene-21-carboxylic
acid, .gamma.-lactone of
17.beta.-hydroxy-6.beta.,7.beta.-methylene-3-oxo-17.al-
pha.-pregn-4-ene-21-carboxylic acid, potassium salt of
17.beta.-hydroxy-6.beta.,7.beta.-methylene-3-oxo-17.alpha.-pregn-4-ene-21-
-carboxylic acid.
15) Use according to claim 4, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.f): 37in which S represents an alkyl radical
containing 1 to 8 carbon atoms, or a hydrogen atom.
16) Use according to claim 4, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.g): 38in which A.sub.g and B.sub.g respectively have
the same values as A and B as defined in claim 4.
17) Use according to claim 4, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.h): 39in which A.sub.h, B.sub.h and R.sub.2h
respectively have the same values as A, B and R.sub.2 as defined in
claim 4.
18) Use according to claim 4, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.i): 40in which A.sub.i, B.sub.i, R.sub.2i and
R.sub.3i respectively have the same values A, B, R.sub.2 and
R.sub.3 as defined in claim 4.
19) Use according to claim 4, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.j): 41in which R.sub.4j is an alkenyl or alkynyl
group containing 1 to 8 carbon atoms and R.sub.5j is a hydroxyl
radical or a hydrogen atom.
20) The pharmaceutical compositions, containing as active
ingredient at least one medicament as defined in claim 1, 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.
21) The pharmaceutical compositions according to claim 20,
containing as active ingredient at least one medicament as defined
in any one of claims 2 or 3, 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.
22) The pharmaceutical compositions according to claim 20,
containing as active ingredient at least one medicament as defined
in claim 4, 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.
23) The pharmaceutical compositions according to claim 20,
containing as active ingredient at least one medicament as defined
in any one of claims 5, 7, 9, 11, 13, 15, 16, 17, 18 or 19,
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.
24) The pharmaceutical compositions according to claim 20,
containing as active ingredient at least one medicament as defined
in claim 4, 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,
chosen form the following list: .gamma.-lactone of
10.beta.-ethynyl, 17.beta.-hydroxy
3-oxo-19-nor-17.alpha.-pregna-4,9(11)-- diene-21-carboxylic acid,
potassium 17.beta.-hydroxy-3-oxo-7.alpha.-propyl-
-17.alpha.-pregn-4-ene-21-carboxylate, .gamma.-lactone of
11.beta.-allenyl-17.beta.-hydroxy-3-oxo-19-nor-17.alpha.-pregna-4,9(11)-d-
iene-21-carboxylic acid, .gamma.-lactone of
17.beta.-hydroxy-7.alpha.-meth-
oxycarbonyl-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregn-4-ene-21-car-
boxylic acid, .gamma.-lactone of
7.alpha.-acetylthio-17.beta.-hydroxy-3-ox-
o-17.alpha.-pregn-4-ene-21-carboxylic acid, .gamma.-lactone of
17.beta.-hydroxy-7.alpha.-methoxycarbonyl-3-oxo-17.alpha.-pregn-4-ene-21--
carboxylic acid, .gamma.-lactone of
17.beta.-hydroxy-3-oxo-17.alpha.-pregn- a-4,6-diene-21-carboxylic
acid 13.beta.-(propen-2-yl)-18-nor-pregn-4-ene-3- ,20-dione.
Description
[0001] 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.
[0002] 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.
[0003] 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).
[0004] 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.
[0005] The Applicant has demonstrated the new and unexpected use of
these products, mentioned above.
[0006] It has previously been shown that the glucocorticoids
(dexamethasone type) antagonize the analgesic activity of morphine
while an antagonist of the glucocorticoids, of 17.beta.-hydroxy
11.beta.-(4-dimethylaminophenyl) 17.alpha.-(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)).
[0007] However, to the knowledge of the Applicant, nobody has
demonstrated the activity of an antimineralocorticoid vis--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.
[0008] 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)).
[0009] 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.
[0010] These different elements have justified the study of
antagonists of mineralocorticoids in particular vis--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.
[0011] 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.
[0012] Thus, the Applicant has demonstrated a new and unexpected
use of antimineralocorticoids.
[0013] 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.
[0014] By compounds having an antimineralocorticoid activity is
meant,
[0015] 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,
[0016] 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.sub.j) described below in which R.sub.4j is an alkenyl or
alkynyl group and R.sub.5j is either a hydroxyl radical, or a
hydrogen atom.
[0017] 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:
[0018] 1) natural morphinomimetics such as:
[0019] a) the opium alkaloids, for example morphine,
[0020] b) the alkaloid derivatives of morphine, for example heroin
or codeine,
[0021] 2) synthetic morphinomimetics such as:
[0022] a) piperidine derivatives, for example pethidine or
[0023] b) methadone and its derivatives, for example
dextromoramide,
[0024] 3) cocaine,
[0025] as well as all combinations containing two or more of these
narcotic products.
[0026] 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.
[0027] 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.
[0028] 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): 1
[0029] in which rings A, B and C have one of the following
structures: 2
[0030] and in which:
[0031] either X and Y represent the groups: 3
[0032] Alk.sub.1 representing an alkyl group containing at most 8
carbon atoms,
[0033] or X represents a hydroxyl, acetyloxy, propionyloxy, methoxy
or ethoxy radical and Y represents a CH.sub.2CH.sub.2CO.sub.2M,
CH.sub.2CH.sub.2SO.sub.2M or CH.sub.2CH.sub.2CH.sub.2OH radical, M
being a hydrogen atom, an alkali metal atom or an ammonium
radical,
[0034] or X represents a COCH.sub.2Z 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,
[0035] or X represents a 4
[0036] radical, S being an alkyl radical containing at most 8
carbon atoms, or a hydrogen atom and Y represents a hydrogen atom,
A and B are hydrogen atoms or together form a methylenic bridge in
position 15.alpha.,16.alpha. or 15.beta.,16.beta., A' and B' are
hydrogen atoms, alkyl radicals containing 1 to 4 carbon atoms, or
form with the carbon which carries them a cyclopropyl radical,
R.sub.1 represents a methyl radical or a CC--W group, in which W
represents
[0037] either a hydrogen atom,
[0038] or an alkyl radical containing at most 8 carbon atoms
optionally substituted by a hydroxyl, free, esterified or salified
carboxy, amino, tritylamino, chloroacetylamino,
trifluoroacetylamino, halogen, monoalkylamino, dialkylamino
radical, each alkyl radical containing at most 8 carbon atoms,
[0039] or an aryl or aralkyl radical containing at most 14 carbon
atoms, optionally substituted by a hydroxyl, free esterified or
salified carboxy, amino, monoalkylamino, dialkylamino, alkyl,
alkoxy or alkylthio radical, each alkyl radical containing at most
8 carbon atoms,
[0040] or a halogen atom,
[0041] or a trialkylsilyl radical, each alkyl radical containing at
most 8 carbon atoms,
[0042] R.sub.2 and R.sub.3 are such that
[0043] either R.sub.2 and R.sub.3 form together a methylenic bridge
in position 6.alpha.,7.alpha. or 6.beta.,7.beta.,
[0044] or R.sub.2 and R.sub.3 are hydrogen atoms,
[0045] or R.sub.3 is a hydrogen atom and R.sub.2 represents a
SCOCH3, CO2Alk group, Alk being an alkyl radical containing at most
8 carbon atoms, alkyl, alkenyl or alkynyl radicals containing at
most 8 carbon atoms and optionally substituted by a hydroxyl, free,
esterified or salified carboxy, halogen, amino, monoalkylamino,
dialkylamino radical, each alkyl radical containing at most 8
carbon atoms, R.sub.4 represents an alkyl, alkenyl or alkynyl
radical containing at most 8 carbon atoms, R.sub.5 represents
either an allenyl radical, or a hydroxyl radical, or a hydrogen
atom, the dotted lines represent a possible second bond, the wavy
lines indicate that the substituents are in position .alpha. or
.beta., as well as the salts of the products of formula (I) with
pharmaceutically acceptable acids and bases.
[0046] By alkyl group containing at most 8 carbon atoms, is meant
linear or branched alkyl radicals such as methyl, ethyl, n-propyl,
iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, isohexyl,
sec-hexyl, tert-hexyl, heptyl or octyl.
[0047] Alkyl radicals having at most 4 carbon atoms are preferred
and in particular methyl, ethyl, propyl and isopropyl radicals.
[0048] When R.sub.4 is an alkyl group, it is quite particularly the
methyl radical.
[0049] The alkali metal atom which can be represented by M is
preferably sodium, potassium or lithium.
[0050] By acyloxy radical is meant in particular formyloxy,
acetoxy, propionyloxy, butyryloxy or benzoyloxy radicals.
[0051] As preferred values of W, there can be mentioned the
hydrogen atom and alkyl radicals containing 1 to 8 carbon atoms
optionally substituted by the radicals as described previously, and
quite particularly the methyl radical.
[0052] As the preferred value of Rl, there can be mentioned the
C.ident.C--H and C.ident.C--Me group.
[0053] The term optionally esterified carboxy designates
alkyloxycarbonyl radicals containing at most 9 carbon atoms, such
as for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
n-butyloxycarbonyl, tert-butyloxycarbonyl or also benzyloxycarbonyl
radicals.
[0054] The terms monoalkylamino and dialkylamino designate the
amino radical substituted by one or two alkyl radicals as defined
above. In particular it is the methylamino and dimethylamino
radicals.
[0055] By halogen atom, is meant quite particularly chlorine and
bromine atoms.
[0056] The aryl and aralkyl radicals which can be represented by W
are preferably a phenyl, benzyl or phenethyl radical.
[0057] The term alkoxy designates alkoxy radicals containing 1 to 8
carbon atoms such as for example methoxy or ethoxy.
[0058] The term alkylthio designates alkylthio radicals containing
1 to 8 carbon atoms such as for example methylthio or
ethylthio.
[0059] The term alkenyl designates a linear or branched alkenyl
radical such as for example vinyl, allyl, 1-propenyl, butenyl,
pentenyl or hexenyl radicals.
[0060] Among the alkenyl radicals, there are preferred those with 4
carbon atoms such as allyl, propenyl or butenyl radicals.
[0061] The term alkynyl designates a linear or branched alkynyl
radical, having at most 12 carbon atoms such as ethynyl, propargyl,
butynyl, pentynyl or hexynyl radicals.
[0062] Among the alkynyl radicals, there are preferred those with 4
carbon atoms such as the propargyl radical.
[0063] When R.sub.4 is an alkenyl or alkynyl group, it is quite
particularly a CH.sub.2--C.ident.CH or CH.sub.2--CH.dbd.CH.sub.2
radical.
[0064] When R.sub.3 is a hydrogen atom and when the dotted line
does not represent a double bond, R.sub.2 is preferably found in
position .alpha..
[0065] When the products of formula (I) contain a carboxy function,
this can be salified. Among the possible salts, there can be
mentioned for example the salts of sodium, potassium, lithium,
calcium, magnesium or ammonium. There can be mentioned, for the
organic bases, methylamine, propylamine, trimethylamine,
diethylamine, triethylamine, N,N-dimethylethanolamine,
tri-(hydroxymethyl) amino methane, ethanolamine, pyridine,
picoline, dicyclohexylamine, morpholine, benzylamine, procaine,
lysine, arginine, histidine, N-methylglucamine.
[0066] When the products of formula (I) contain a function which
can be salified with an acid and in particular an amino function,
addition salts are obtained with acids.
[0067] The invention naturally extends to the addition salts with
acids of the compounds of formula (I), which can be salified, such
as for example salts formed with the following acids: hydrochloric,
hydrobromic, nitric, sulphuric, phosphoric, acetic, formic,
propionic, benzoic, maleic, fumaric, succinic, tartaric, citric,
oxalic, glyoxylic, aspartic, alkane sulphonics such as methane or
ethane sulphonics, arylsulphonics, such as benzene or paratoluene
sulphonics and arylcarboxylics.
[0068] The products of formula (I) are known or are prepared
according to methods known to a person skilled in the art.
[0069] A more precise subject of the present invention is the use
as defined previously, characterized in that the compounds having
an antimineralocorticoid activity corresponding to general formula
(I.sub.a): 5
[0070] in which:
[0071] either X.sub.a and Y.sub.a represent the groups 6
[0072] Alk.sub.1 being as defined previously,
[0073] or Xa represents a hydroxyl, acetyloxy, propionyloxy,
methoxy or ethoxy radical and Y.sub.a represents a
CH.sub.2CH.sub.2CO.sub.2M, CH.sub.2CH.sub.2SO.sub.2M or
CH.sub.2CH.sub.2CH.sub.2OH radical, M being as defined
previously,
[0074] R.sub.2a, R.sub.3a and W.sub.a respectively have the same
values as R.sub.2, R.sub.3 and W as defined previously and the
dotted or wavy lines retain the same meaning as previously.
[0075] A quite particular subject of the present invention is the
use as defined previously of the products corresponding to general
formula (I.sub.a) chosen from the following list:
[0076] .gamma.-lactone of 10.beta.-ethynyl 17.beta.-hydroxy
3-oxo-19-nor-17.alpha.-pregna-4,9 (11)-diene-21-carboxylic
acid,
[0077] .gamma.-lactone of 17.beta.-hydroxy
3-oxo-10.beta.-(1-propynyl)-19-- nor-17.alpha.-pregna-4,9
(11)-diene-21-carboxylic acid,
[0078] .gamma.-lactone of 17.beta.-hydroxy
3-oxo-10.beta.-(1-propynyl)-19--
nor-17.alpha.-pregn-4-ene-21-carboxylic acid,
[0079] .gamma.-lactone of 10.beta.-ethynyl 17.beta.-hydroxy
3-oxo-19-nor-17.alpha.-pregn-4-ene-21-carboxylic acid.
[0080] The products of general formula (I.sub.a) are described and
prepared in the Patent Applications EP 0176399-A1 and EP 0237397-A1
and by methods known to a person skilled in the art.
[0081] A more precise subject of the present invention is the use
as defined previously, characterized in that the compounds having
an antimineralocorticoid activity correspond to general formula
(I.sub.b): 7
[0082] in which:
[0083] either X.sub.b and Y.sub.b represent the groups 8
[0084] or X.sub.b represents a hydroxyl radical and Y.sub.b
represents a CH.sub.2CH.sub.2CO.sub.2M radical, M being as defined
previously,
[0085] R.sub.2b and R.sub.3b are such that
[0086] either R.sub.2b represents an alkyl, alkenyl or alkynyl
radical optionally substituted as defined previously and R.sub.3b
is a hydrogen atom,
[0087] or R.sub.2b and R.sub.3b together form a methylenic bridge
in position 6.alpha.,7.alpha. or in position 6.beta.,7.beta..
[0088] When R.sub.2b is an alkyl group, it will be quite
particularly the propyl radical in position .alpha..
[0089] A quite particular subject of the present invention is the
use as defined previously, of the products corresponding to general
formula (I.sub.b) chosen from the following list:
[0090]
(17R)-6.beta.,7.beta.-methylene-2'-oxydospiro-(androst-4-ene-17,5'--
(1',2')-oxathiolane)-3-one
[0091]
(17R)-6.alpha.,7.alpha.-methylene-2'-oxydospiro-(androst-4-ene-17,5-
'-(1',2')-oxathiolane)-3-one
[0092]
(17R)-7.alpha.-methyl-2'-oxydospiro-(androst-4-ene-17,5'-(1',2')-ox-
athiolane)-3-one
[0093]
(17R)-7.alpha.-n-propyl-2'-oxydospiro-(androst-4-ene-17,5'-(1',2')--
oxathiolane)-3-one
[0094] .gamma.-lactone of
17.beta.-hydroxy-3-oxo-7.alpha.-propyl-17.alpha.-
-pregna-1,4-diene-21-carboxylic acid,
[0095] potassium
17.beta.-hydroxy-3-oxo-7.alpha.-propyl-17.alpha.-pregna-1-
,4-diene-21-carboxylate,
[0096] .gamma.-lactone of
17.beta.-hydroxy-3-oxo-7.alpha.-propyl-(17.alpha-
.)-pregn-4-ene-21-carboxylic acid,
[0097] potassium
17.beta.-hydroxy-3-oxo-7.alpha.-propyl-(17.alpha.)-pregn--
4-ene-21-carboxylate
[0098] The products of formula (Ib) are prepared in the Patent
Applications EP 0018245A, EP 0055170A, FR 2344286, FR 2421913, FR
2465749, and by methods known to a person skilled in the art.
[0099] A more precise subject of the present invention is the use
as defined previously, characterized in that the compounds having
an antimineralocorticoid activity, corresponding to general formula
(I.sub.c): 9
[0100] in which
[0101] either X.sub.c and Y.sub.c represent a group 10
[0102] or X.sub.c represents a hydroxyl radical and Y.sub.c
represents a CH.sub.2CH.sub.2CO.sub.2M or CH.sub.2CH.sub.2SO.sub.2M
group, M being as defined previously,
[0103] or X.sub.c represents a COCH.sub.2Z radical in which Z is as
defined previously and Y.sub.c is a hydrogen atom,
[0104] A'.sub.c and B'.sub.c respectively have the same values as
A' and B' as defined previously,
[0105] R.sub.4c is a methyl or ethyl radical, R.sub.5c is either a
hydrogen atom, or an allenyl radical, it being understood that when
R.sub.5c is an allenyl radical, A'.sub.c and B'.sub.c are hydrogen
atoms, R.sub.4c is a methyl radical, X.sub.c and Y.sub.c together
form a 11
[0106] group, the dotted lines in position 9-10 form a second bond,
and those in position 11-12 do not form a second bond.
[0107] A quite particular subject of the present invention is the
use as defined previously of the products corresponding to general
formula (I.sub.c) chosen from the following list:
[0108] 2,2-dimethyl 19-nor pregn-4-ene-3,20-dione,
[0109] 21-acetoxy 2,2-dimethyl 19-nor-pregn-4-ene 3,20-dione,
[0110] 2,2-dimethyl 21-hydroxy 19-nor-pregn-4-ene 3,20-dione,
[0111] 2,2-dimethyl 19-nor-pregna-4,9-diene 3,20-dione,
[0112] 21-acetoxy 2,2-dimethyl 19-nor-pregna-4,9-dien
3,20-dione,
[0113] 2,2-dimethyl 21-hydroxy 19-nor-pregna-4,9-dien
3,20-dione,
[0114] 2,2-dimethyl 19-nor-pregna-4,9,11-triene 3,20-dione,
[0115] 21-acetoxy 2,2-dimethyl 19-nor-pregna-4,9,11-triene
3,20-dione,
[0116] 2,2-dimethyl 21-hydroxy 19-nor-pregna-4,9,11-triene
3,20-dione,
[0117] (17R)
2'-oxydospiro-(estra-4,9-diene-17,5'-(1',2')-oxathiolane)
3-one,
[0118] (17R)
2'-oxydospiro-(estra-4,9,11-triene-17,5'-(1',2')-oxathiolane)
3-one,
[0119] (17R) 11.beta.-hydroxy
2'-oxydospiro-(estra-4,9-diene-17,5'-(1',2')- -oxathiolane)
3-one,
[0120] 2,2-dimethyl-13-ethyl-21-hydroxy-18,19-dinor-pregn-4-ene
3,20-dione,
[0121] .gamma.-lactone of
11.beta.-allenyl-17.beta.-hydroxy-3-oxo-19-nor-1-
7-pregna-4,9-diene-21-carboxylic acid.
[0122] The products of general formula (I.sub.c) are described and
prepared in Patent Applications FR 2364655, FR 2374037, EP 0012641,
in the following publication: G. AUZOU et al. J. Med. Chem. (1993)
36 2404-2407, and by methods known to a person skilled in the
art.
[0123] A more precise subject of the present invention is the use
as defined previously characterized in that the compounds having an
antimineralocorticoid activity corresponding to general formula
(I.sub.d): 12
[0124] in which:
[0125] either X.sub.d and Y.sub.d represent the group 13
[0126] or X.sub.d represents a hydroxyl radical and Y.sub.d
represents a CH.sub.2CH.sub.2CO.sub.2M radical, M being as defined
previously,
[0127] A.sub.d and B.sub.d respectively have the same values as A
and B as defined previously,
[0128] R.sub.2d represents either a thioacetyl radical, or a
CO.sub.2Alk radical, Alk being an alkyl radical containing at most
8 carbon atoms. It is preferably a methyl, ethyl and isopropyl
radical, and the dotted or wavy lines keep the same meaning as
previously.
[0129] A quite particular subject of the present invention is the
use as defined previously of the products corresponding to general
formula (I.sub.d) chosen from the following list:
[0130] .gamma.-lactone of
7.alpha.-acetylthio-17.beta.-hydroxy-15.beta.,16-
.beta.-methylene-3-oxo-17.alpha.-pregna-1,4-diene-21-carboxylic
acid (Mespirenone),
[0131] .gamma.-lactone of
17.beta.-hydroxy-7.alpha.-methoxycarbonyl-15.bet-
a.,16.beta.-methylene-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic
acid (ZK91587),
[0132] .gamma.-lactone of
7.alpha.-acetylthio-17.beta.-hydroxy-3-oxo-17.al-
pha.-pregn-4-ene-21-carboxylic acid (Spironolactone),
[0133] .gamma.-lactone of
17.beta.-hydroxy-7.alpha.-methoxycarbonyl-3-oxo--
17.alpha.-pregn-4-ene-21-carboxylic acid (Mexrenone),
[0134] the potassium salt of
17.beta.-hydroxy-7.alpha.-methoxycarbonyl-3-o-
xo-pregn-4-ene-21-carboxylic acid.
[0135] The products of formula (I.sub.d) are commercial products or
are prepared or described in the following Patent Applications or
publications:
[0136] Mespirenone: Drug of the Future Vol. 12 No. 1 (1987) 27,
[0137] Mexrenone: G. B. Cutler et al. J. Pharmacol. and Exp. Ther.
(1979) 209 144,
[0138] ZK 91587: H. J. Grill et al. J. Ster. Biochem, 23 (Suppl.)
Abst. 19 (1985),
[0139] Spironolactone: J. A. Cella and C. M. Kawaga J. Am. Chem.
Soc. (1957) 79 4808,
[0140] K. Mexrenoate: L. M. Hoffmann et al. The Journal of
Pharmacol. and Exp. Ther. (1977) 102 (3) 762, or according to
methods known to a person skilled in the art.
[0141] A more precise subject of the present invention is the use
as defined previously, characterized in that the compounds having
an antimineralocorticoid activity correspond general formula
(I.sub.e): 14
[0142] in which:
[0143] either X.sub.e and Y.sub.e represent the group 15
[0144] or X.sub.e represents a hydroxyl radical and Y.sub.e
represents a CH.sub.2CH.sub.2CO.sub.2M radical, M being as defined
previously,
[0145] R.sub.2e or R.sub.3e are such that:
[0146] either R.sub.2e and R.sub.3e together form a methylenic
bridge in position 6.alpha.,7.alpha. or 6.beta.,7.beta.,
[0147] or R.sub.2e and R.sub.3e are hydrogen atoms,
[0148] A.sub.e and B.sub.e respectively have the same values as A
and B as defined previously, the dotted or wavy lines keeping their
previous meaning. A quite particular subject of the present
invention is the use as defined previously of the products
corresponding to general formula (I.sub.e), chosen from the
following list:
[0149] .gamma.-lactone of
17.beta.-hydroxy-6.beta.,7.beta.,15.beta.,16.bet-
a.-dimethylene-3-oxo-17.alpha.-pregna-1,4-diene-21-carboxylic acid
(Spirorenone),
[0150] .gamma.-lactone of
17.beta.-hydroxy-6.beta.,7.beta.,15.beta.,16.bet-
a.-dimethylene-3-oxo-17.alpha.-pregna-4-ene-21-carboxylic acid
(dihydrospirorenone),
[0151] .gamma.-lactone of
17.beta.-hydroxy-3-oxo-17.alpha.-pregna-4,6,11-t-
riene-21-carboxylic acid,
[0152] .gamma.-lactone of
17.beta.-hydroxy-3-oxo-17.alpha.-pregna-4,6-dien- e-21-carboxylic
acid (Canrenone),
[0153] the potassium salt of
17.beta.-hydroxy-3-oxo-17.alpha.-pregna-4,6-d- iene-21-carboxylic
acid (potassium Canrenoate),
[0154] .gamma.-lactone of
17.beta.-hydroxy-6.beta.,7.beta.-methylene-3-oxo-
-17.alpha.-pregn-4-ene-21-carboxylic acid (Prorenone),
[0155] potassium salt of
17.beta.-hydroxy-6.beta.,7.beta.-methylene-3-oxo--
17.alpha.-pregn-4-en-21-carboxylic acid (potassium protenoate).
[0156] The products of formula (I.sub.e) are commercial products or
are prepared or described in the following Patent Applications or
publications:
[0157] Spirorenone: W. Losert et al. Arzneim-Forsch/Drug. Res.
(1986) 36 1583,
[0158] Dihydrospirorenone: DE 2652761-A,
[0159] K canrenoate: L. E. Ramsay et al. Adrenal Steroid
Antagonism. Ed. M. K. Agarwal Berlin, N.Y. 1984,
[0160] Prorenone, K prorenoate: J. Casals-Stenzel et al. Arch.
Pharmacol. Suppl. 316 (1981) R49,
[0161] .gamma.-lactone of
17.beta.-hydroxy-3-oxo-17.alpha.-pregna-4,6,11-t-
riene-21-carboxylic acid, Anu. Drug. Data Rep. (1985) 7 (2) 94.
[0162] A quite particular subject of the present invention is the
use as defined previously, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.f): 16
[0163] in which S represents an alkyl radical containing 1 to 8
carbon atoms, or a hydrogen atom.
[0164] The products of general formula (I.sub.f) are described in
Patent Application EP 402857-A.
[0165] A more particular subject of the present invention is the
use as defined previously, characterized in that the compounds
having an antimineralocorticoid activity correspond to general
formula (I.sub.g): 17
[0166] in which A.sub.g and B.sub.g respectively have the same
values as A and B as defined previously, the dotted or wavy lines
keeping the same meaning as previously.
[0167] The products of general formula (I.sub.g) are described in
Anu. Drug. Data Rep. (1986) 8 (9) 824.
[0168] A more particular subject of the present invention is the
use as defined previously, characterized in that the compounds
having an antimineralocorticoid activity corresponding to general
formula (I.sub.h): 18
[0169] in which A.sub.h, B.sub.h and R.sub.2h respectively have the
same values as A, B and R.sub.2 as defined previously.
[0170] The products of general formula (I.sub.h) are described in
Anu. Drug. Data Rep. (1985) 7(5) 295, (1986) 8(2) 152.
[0171] A more particular subject of the present invention is the
use as defined previously, characterized in that the compounds
having an antimineralocorticoid activity correspond general formula
(I.sub.i): 19
[0172] in which A.sub.i, B.sub.i, R.sub.2i and R.sub.3i
respectively have the same values as A, B, R.sub.2 and R.sub.3 as
defined previously.
[0173] The products of general formula products (I.sub.i) are
described in Anu. Drug. Data Rep. (1985) 7(5) 295, (1986) 8(9)
824.
[0174] A more precise subject of the present invention is the use
as defined previously, characterized in that the compounds having
an antimineralocorticoid activity correspond to general formula
(I.sub.j): 20
[0175] in which R.sub.4j is an alkenyl or alkynyl group containing
1 to 8 carbon atoms and R.sub.5j is a hydroxyl radical or a
hydrogen atom.
[0176] A quite particular subject of the present invention is the
use as defined previously, of the products corresponding to general
formula (I.sub.j) in which
[0177] either R.sub.4j is a CH.sub.2--CH.dbd.CH.sub.2,
CH.dbd.CH.sub.2, CH.sub.2--C.ident.CH radical and R.sub.5j is a
hydrogen,
[0178] or R.sub.4j is a --CH.sub.2--C.ident.CH radical and R.sub.5j
is an OH radical.
[0179] The products of formula (I.sub.j) are inhibitors of the
biosynthesis of aldosterone. They are described in the following
publications:
[0180] A. Viger et al., Tetrahedron (1988) 44 1127, J. Steroid
Biochem. (1988) 30 469,
[0181] B. W. Metcalf et al., Tet. Lett. (1985) 26 1137-1140.
[0182] The invention extends to the pharmaceutical compositions
containing at least one medicament as defined above as active
ingredient, 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.
[0183] The compounds of the invention are used by digestive,
parenteral or local route, for example by percutaneous route. They
can be prescribed in the form of plain or sugar-coated tablets,
capsules, granules, suppositories, pessaries, injectable
preparations, ointments, creams, gels, microspheres, implants,
patches, which are prepared according to the usual methods.
[0184] The active ingredient or ingredients can be incorporated
with excipients usually employed in these pharmaceutical
compositions, such as talc, gum arabic, lactose, starch, magnesium
stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty
substances of animal or vegetable origin, paraffin derivatives,
glycols, various wetting, dispersing or emulsifying agents,
preservatives.
[0185] In particular, the invention extends to the pharmaceutical
compositions containing as active principle at least one medicament
as defined above, corresponding to any one of general formulae (I),
(I.sub.a), (I.sub.b), (I.sub.c), (I.sub.d), (I.sub.e), (I.sub.f),
(I.sub.g), (I.sub.h), (I.sub.i) or (I.sub.j), as defined
previously. More particularly the invention extends to the
pharmaceutical compositions containing as active principle at least
one medicament as defined above, chosen from the following
list:
[0186] .gamma.-lactone of 10.beta.-ethynyl,17.beta.-hydroxy
3-oxo-19-nor-17.alpha.-pregna-4,9(11)-diene-21-carboxylic acid,
[0187] potassium
17.beta.-hydroxy-3-oxo-7.alpha.-propyl-17.alpha.-pregn-4--
ene-21-carboxylate,
[0188] .gamma.-lactone of
11.beta.-allenyl-17.beta.-hydroxy-3-oxo-19-nor-1-
7.alpha.-pregna-4,9(11)-diene-21-carboxylic acid,
[0189] .gamma.-lactone of
17.beta.-hydroxy-7.alpha.-methoxycarbonyl-15.bet-
a.,16.beta.-methylene-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic
acid,
[0190] .gamma.-lactone of
7.alpha.-acetylthio-17.beta.-hydroxy-3-oxo-17.al-
pha.-pregn-4-ene-21-carboxylic acid,
[0191] .gamma.-lactone of
17.beta.-hydroxy-7.alpha.-methoxycarbonyl-3-oxo--
17.alpha.-pregn-4-ene-21-carboxylic acid,
[0192] .gamma.-lactone of
17.beta.-hydroxy-3-oxo-17.alpha.-pregn-4,6-diene- -21-carboxylic
acid
[0193] 13.beta.-(propen-2-yl)-18-nor-pregn-4-ene-3,20-dione.
[0194] The useful dose varies as a function of the type of
withdrawal or dependence to be prevented or treated and the
administration route. It can vary from 1 to 1000 mg per day for an
adult by oral route.
PHARMACOLOGICAL STUDY
[0195] A) Evaluation of the Withdrawal Syndrome Induced by Naloxone
in Mice.
[0196] 1--Equipment and Method.
[0197] 1.1 Animals.
[0198] The experiments were carried out with male Swiss mice
(Charles River, France) of a body weight comprised between 20 and
25 g. During the tests, the animals had free access to food and
drinking water. The number of animals per group is 10 to 13
mice.
[0199] 1.2 Products.
[0200] The following antimineralocorticoids (AM):
[0201] AM1 Spironolactone,
[0202] AM2 potassium 17.beta.-hydroxy 3-oxo
7.alpha.-propyl-(17.alpha.)-pr- egn-4-ene-21-carboxylate.
[0203] were suspended in 0.5% methyl cellulose and administered by
oral route (p.o). The morphine was put into solution in
physiological serum and administered by sub-cutaneous (s.c) route.
Finally, the naloxone hydrochloride was solubilized in distilled
water and injected by intra-peritoneal route.
[0204] All the products were administered to the animal under a
volume of 25 ml/kg.
[0205] 1.3 Treatment Methods and Doses Administered.
[0206] 1.3.1 Treatment with Morphine: Induction of Morphinic
Dependent State.
[0207] The first day (D1), the animals received 5 sub-cutaneous
injections with increasing doses of morphine spread through the
morning and at the beginning of the afternoon, at one hour
intervals. On the following 3 days (D2, D3, D4), these same animals
were treated in the morning with two administrations of the maximum
dose used on day 1.
1 Morphine-Doses (mg/kg, s.c.) Cumulative D1 D2 D3 D4 dose(mg/kg) 8
100 100 100 799 16 100 100 100 25 50 100
[0208] 1.3.2 Repeated Treatment with the Studied Products.
[0209] The antimineralocorticoids AM1 and AM2 were administered by
oral route in the form of a daily treatment 2 hours before
administration of the morphine and this took place for 4 days.
21
[0210] 1.4 Operating Method
[0211] The technique used is inspired by that described by Way et
al. J. Pharmacol. Exp. Ther. (1969), 167: 1-8 and Huidobro and
Maggiolo Acta Physiol. Pharmacol. Latinoam. (1961), 11: 201-9.
Thus, the repeated administration of a morphinic induces a
phenomenon of physical dependence which can be easily demonstrated
by the induction of a withdrawal syndrome using an opiate
antagonist such as naloxone. This syndrome manifests itself, in
mice in the form of stereotyped behaviour characterized by the
appearance of repetitive jumps the number of which is related to
the duration and intensity of the treatment by the morphinic.
[0212] The animals' withdrawal was carried out on the fourth day;
three hours after the last treatment, using naloxone hydrochloride
injected by intraperitoneal route at a dose of 100 mg/kg.
Immediately after this injection, the animals were placed
individually in Plexiglas cylinders (height 40 cm, diameter=20 cm).
The number of consecutive jumps as a result of withdrawal and
carried out by each animal was counted over a period of 10
minutes.
[0213] The results shown in tables represent the averages of thr
individual values together with the standard error of the mean
(m.+-.sem).
[0214] 2. Results
[0215] 2.1 Withdrawal Induced by Naloxone in Normal Mice Treated
with Morphine.
2 Number of jumps/10 minutes Doses (mg/kg (m .+-. sem) % protection
Controls 0 7 .+-. 5 Morphine 799 s.c. 76 .+-. 15 (cumulative over 4
days) AM1 4 .times. 10 p.o. 3 .+-. 2 Morphine + AM1 799 s.c. + 4
.times. 10 p.o. 51 .+-. 7 -33 Controls 0 0 Morphine 799 s.c. 114
.+-. 8 (cumulative over 4 days) AM1 4 .times. 20 p.o. 11 .+-. 4
Morphine + AM1 799 s.c. + 4 .times. 20 p.o. 77 .+-. 8** -32 n = 10
mice/group; **p. < 0.01 according to the Dunnett test relative
to the morphine group.
[0216]
3 Number of jumps/10 minutes Doses (mg/kg (m .+-. sem) % protection
Controls 0 0 Morphine 799 s.c. 99 .+-. 13 (cumulative over 4 days)
AM2 4 .times. 20 p.o. 4 .+-. 4 Morphine + AM2 799 s.c. + 4 .times.
20 p.o. 51 .+-. 8 -48 Controls 0 7 .+-. 3 Morphine 799 s.c. 102
.+-. 10 (cumulative over 4 days) AM2 4 .times. 10 p.o. 2 .+-. 2 AM2
4 .times. 50 p.o. 3 .+-. 2 Morphine + AM2 799 s.c. + 4 .times. 10
p.o. 76 .+-. 16 -25 Morphine + AM2 799 s.c. + 4 .times. 50 p.o. 61
.+-. 8** -40 n = 10 mice/group; **p. < 0.01 according to the
Dunnett test relative to the morphine group.
Discussion--Conclusion
[0217] Co-administered for four days with morphine, the compound
AM2 (4.times.20 mg/kg, p.o) significantly inhibits (-48%) the
withdrawal syndrome induced by naloxone in mice dependent on
morphine.
[0218] In conclusion, these results confirm the participation of
endogenous glucocorticoids in the morphinic withdrawal syndrome,
such as demonstrates itself in mice by stereotyped behaviour of
jumping, since the latter is inhibited by
antimineralocorticoids.
[0219] The antimineralocorticoid activity, through the results
obtained with compounds AM1 and AM2 shows that an antagonist of the
mineralocorticoids can have a beneficial effect in human clinical
medicine in the prevention and treatment of narcotic withdrawal
syndrome.
[0220] B) Evaluation of Dependence Induced by Cocaine
[0221] 1--Method.
[0222] The anti-mineralocorticoid product AM2 was tested on 5 rats
which were trained in the self-administration of cocaine during
daily periods of one hour.
[0223] These rats were pre-treated 1 hour before the start of the
self-administration sessions.
[0224] The product AM2 dissolved in a saline solution was
administered by intra-peritoneal route. The doses range from 10 to
100 mg/kg.
[0225] 2--Result.
[0226] The pre-treatment with 10 or 20 mg/kg of product AM2 has
little or no effect on the self-administration of cocaine.
[0227] However, pre-treatment with 50 or 75 mg/kg of product AM2
leads to a significant reduction in the self-administration of
cocaine.
[0228] 3--Conclusion.
[0229] On the one hand these results suggest that the
mineralocorticoid receptors are involved in the strengthening
behaviour to cocaine.
[0230] On the other hand the antimineralocorticoid activity,
through the results obtained with compound AM2 shows that an
antagonist of the mineralocorticoids can have a beneficial effect
in human clinical medicine in the treatment of dependence on
narcotics and in particular cocaine.
* * * * *