U.S. patent application number 10/935250 was filed with the patent office on 2005-02-03 for use of central cannabinoid receptor antagonists for the preparation of drugs.
Invention is credited to Maruani, Jeanne, Soubrie, Philippe.
Application Number | 20050026986 10/935250 |
Document ID | / |
Family ID | 9503028 |
Filed Date | 2005-02-03 |
United States Patent
Application |
20050026986 |
Kind Code |
A1 |
Maruani, Jeanne ; et
al. |
February 3, 2005 |
Use of central cannabinoid receptor antagonists for the preparation
of drugs
Abstract
The invention relates to the use of a central cannabinoid
receptor antagonist, by itself or in association with a compound
for regulating metabolic disorders, especially a
.beta..sub.3-adrenergic receptor agonist, for the preparation of
drugs useful in the treatment of appetency disorders.
Inventors: |
Maruani, Jeanne;
(Vailhauques, FR) ; Soubrie, Philippe; (Saint
Mathieu De Treviers, FR) |
Correspondence
Address: |
SANOFI-SYNTHELABO INC.
9 GREAT VALLEY PARKWAY
P.O. BOX 3026
MALVERN
PA
19355
US
|
Family ID: |
9503028 |
Appl. No.: |
10/935250 |
Filed: |
September 7, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10935250 |
Sep 7, 2004 |
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10044531 |
Jan 11, 2002 |
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10044531 |
Jan 11, 2002 |
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09341764 |
Aug 19, 1999 |
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6344474 |
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09341764 |
Aug 19, 1999 |
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PCT/FR98/00154 |
Jan 28, 1998 |
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Current U.S.
Class: |
514/406 |
Current CPC
Class: |
A61P 3/00 20180101; A61P
25/32 20180101; A61P 43/00 20180101; A61P 25/00 20180101; A61P 3/04
20180101; A61K 31/00 20130101; A61K 31/454 20130101; A61K 31/415
20130101; A61K 45/06 20130101; A61K 31/445 20130101; A61P 25/30
20180101; A61K 31/415 20130101; A61K 2300/00 20130101; A61K 31/445
20130101; A61K 2300/00 20130101; A61K 31/454 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/406 |
International
Class: |
A61K 031/415 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 28, 1997 |
FR |
97/00870 |
Claims
1-18. (cancelled)
19. A pharmaceutical composition containing a CB.sub.1 receptor
antagonist and a regulator of metabolic functions together with a
pharmaceutical excipient.
20. A pharmaceutical composition according to claim 19, wherein
said regulator of metabolic functions is a
.beta..sub.3-agonist.
21. A pharmaceutical composition according to claim 20, wherein the
CB.sub.1 receptor antagonist is a compound of the formula 6in
which: R.sub.1 is hydrogen, a fluorine, a hydroxyl, a
(C.sub.1-C.sub.5)alkoxy, a (C.sub.1-C.sub.5)alkylthio, a
hydroxy(C.sub.1-C.sub.5) alkoxy, a group --NR.sub.10R.sub.11, a
cyano, a (C.sub.1-C.sub.5)alkylsulfonyl or a
(C.sub.1-C.sub.5)alkylsulfinyl; R.sub.2 and R.sub.3 are a
(C.sub.1-C.sub.4)alkyl or, together with the nitrogen atom to which
they are bonded, form a saturated or unsaturated 5- to 10-membered
heterocyclic radical which is unsubstituted or monosubstituted or
polysubstituted by a (C.sub.1-C.sub.3)alkyl or by a
(C.sub.1-C.sub.3)alkoxy; R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8 and R.sub.9 are each independently hydrogen, a halogen or a
trifluoromethyl, and if R.sub.1 is a fluorine, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.8 and/or R.sub.9 can also be a
fluoromethyl, with the proviso that at least one of the
substituents R.sub.4 or R.sub.7 is other than hydrogen; R.sub.10
and R.sub.11 are each independently hydrogen or a
(C.sub.1-C.sub.5)alkyl, or R.sub.10 and R.sub.11, together with the
nitrogen atom to which they are bonded, form a heterocyclic radical
selected from pyrrolidin-1-yl, piperidin-1-yl, morpholin4-yl and
piperazin-1-yl, which is unsubstituted or substituted by a
(C.sub.1-C.sub.4)alkyl, one of its salts or one of their
solvates.
22. A pharmaceutical composition according to claim 21, wherein the
CB.sub.1 receptor antagonist is
N-piperidino-5-(4-chlorophenyl)-1-(2,4-di-
chlorophenyl)4-methylpyrazole-3-carboxamide, one of its
pharmaceutically acceptable salts or one of their solvates.
23. A pharmaceutical composition according to claim 21 wherein the
.beta..sub.3-agonist is a compound of the formula 7in which: X is
hydrogen, a halogen, a trifluoromethyl or a (C.sub.1-C.sub.4)alkyl;
R is hydrogen or a methyl which is unsubstituted or substituted by
a carboxyl or an alkoxycarbonyl in which the alkoxy is
(C.sub.1-C.sub.6), or one of its pharmaceutically acceptable
salts.
24. A pharmaceutical composition according to any one of claims 20
to 22, characterized in that claim 21 wherein the
.beta..sub.3-agonist is a compound of the formula 8in which: n is
1, 2 or 3; A is a benzofuran-2-yl or a phenyl which is
unsubstituted or substituted by one or two halogen atoms or by a
(C.sub.1-C.sub.4)alkyl or a trifluoromethyl; R' is: hydrogen; a
(C.sub.1-C.sub.6)alkyl; a functional group selected from the
following groups: hydroxyl; (C.sub.1-C.sub.6)alkoxy;
(C.sub.2-C.sub.6) alkenyloxy; (C2-C.sub.6)alkynyloxy;
(C.sub.3-C.sub.8)cycloalkoxy;
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6- )alkoxy; benzyloxy;
phenoxy; mercapto; (C.sub.1-C.sub.6)alkylthio;
(C.sub.2-C.sub.6)alkenylthio; (C.sub.2-C.sub.6)alkynylthio;
(C.sub.3-C.sub.8)cycloalkylthio;
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.su- b.6)alkylthio;
benzylthio; phenylthio; (C.sub.1-C.sub.6) alkylsulfinyl;
(C.sub.2-C.sub.6)alkenylsulfinyl; (C.sub.2-C.sub.6)alkynylsulfinyl;
(C.sub.3-C.sub.8)cycloalkylsulfinyl;
(C.sub.3-C.sub.8)cycloalkyl(Cl-C.sub- .6)alkylsulfinyl;
benzylsulfinyl; phenylsulfinyl; (C.sub.1-C.sub.6)alkylsu- lfonyl;
(C.sub.2-C.sub.6)alkenylsulfonyl; (C.sub.2-C.sub.6)alkynylsulfonyl-
; (C.sub.3-C.sub.8)cycloalkylsulfonyl;
(C.sub.3-C.sub.8)-cycloalkyl(C.sub.- 1-C.sub.6) alkylsulfonyl;
benzylsulfonyl; phenylsulfonyl; cyano; nitro; amino which is
unsubstituted or substituted by one or two identical or different
radicals selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6) alkyl, benzyl and
phenyl groups; carboxyl; alkoxycarbonyl in which the alkoxy is
(C.sub.1-C.sub.6); (C.sub.2-C.sub.6)alkenyloxycarbonyl;
(C.sub.2-C.sub.6)alkynyloxycarbonyl;
(C.sub.3-C.sub.8)cycloalkoxycarbonyl- ; (C.sub.3-C.sub.8)
cycloalkyl(C.sub.1-C.sub.6)alkoxycarbonyl; benzyloxycarbonyl;
phenoxycarbonyl; and carbamoyl which is unsubstituted or
substituted on the amino group by one or two identical or different
radicals selected from (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)
cycloalkyl(C.sub.1-C.sub.6)alkyl, benzyl and phenyl groups; a group
R'" selected from the following groups: (C.sub.1-C.sub.6)alkyl
substituted by a functional group; (C.sub.2-C.sub.6)alkenyl
substituted by a functional group; (C.sub.2-C.sub.6)alkynyl
substituted by a functional group; phenyl(C.sub.1-C.sub.6)alkyl
substituted on the phenyl by a (C.sub.1-C.sub.6)alkyl or by a
functional group; phenyl(C.sub.2-C.sub.6)a- lkenyl substituted on
the phenyl by a (C.sub.1-C.sub.6)alkyl or by a functional group;
phenyl(C.sub.2-C.sub.6)alkynyl substituted on the phenyl by a
(C.sub.1-C.sub.6)alkyl or by a functional group; benzyl substituted
on the phenyl by a (C.sub.1-C.sub.6)alkyl or by a functional group;
and phenyl which is unsubstituted or substituted by a
(C.sub.1-C.sub.6)alkyl or by a functional group, the functional
group being as defined above; a group O--R'", S--R'", SO--R'" or
SO.sub.2--R'", in which R'" is as defined above; a group
NR'"R.degree., in which R'" is as defined above and R.degree. is
hydrogen or is as defined above for R'", or R'" and R.degree.,
together with the nitrogen to which they are bonded, form a group
selected from pyrrolidino, piperidino and morpholino groups; a
group COOR'" or a group CO--SR'", in which R'" is as defined above;
a group CONR'"R.degree., in which R'" is as defined above and
R.degree. is hydrogen or is as defined above for R'", or R'" and
R.degree., together with the nitrogen to which they are bonded,
form a group selected from pyrrolidino, piperidino and morpholino
groups; a group SO.sub.2NR'"R.degree., in which R'" is as defined
above and R.degree. is hydrogen or is as defined above for R'", or
R'" and R.degree., together with the nitrogen to which they are
bonded, form a group selected from pyrrolidino, piperidino and
morpholino groups; R" is hydrogen; a halogen; a
(C.sub.1-C.sub.6)alkyl; a functional group as defined above; a
group OR'", R'" being as defined above; a group COOR'", R'" being
as defined above; or a group CONR'"R.degree., in which R'" is as
defmed above and R.degree. is hydrogen or is as defined above for
R'", or R'" and R.degree., together with the nitrogen to which they
are bonded, form a group selected from pyrrolidino, piperidino and
morpholino groups; W is a direct bond or an oxygen atom; X' is
hydrogen, a (C.sub.1-C.sub.6)alkyl or a
(C.sub.1-C.sub.6)alkylcarbonyl; Y is hydrogen or a group
A'--CH(OH)--CH.sub.2--, A' being identical to A but other than
benzofuran-2-yl; or X' and Y, taken together, form a methylene
group optionally substituted by an alkoxycarbonyl in which the
alkoxy is (C.sub.1-C.sub.6); an ethylene group optionally
substituted by an oxo group; or a 1,3-propylene group; Z is
hydrogen or a (C.sub.1-C.sub.6)alkyl, or one of its
pharmaceutically acceptable salts.
25. A pharmaceutical composition according to wherein the
.beta..sub.3-agonist is a compound of the formula 9in which: E is
hydrogen, a (C.sub.1-C.sub.4)alkyl, a (C.sub.1-C.sub.4)alkoxy, a
phenyl, a nitro, a halogen atom or a trifluoromethyl; L is
hydrogen, a (C.sub.1-C.sub.4)alkyl, a (C.sub.1-C.sub.4)alkoxy, a
phenyl, a nitro or a halogen atom; or E and L together are a group
--CH.dbd.CH--CH.dbd.CH-- or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--; and G is hydrogen, a
chlorine atom, a hydroxyl or a group OG', in which G' is a
(C.sub.1-C.sub.4)alkyl which is unsubstituted or substituted by a
hydroxyl, (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkoxycarbonyl,
carboxyl or (C.sub.3-C.sub.7)cycloalkyl; a
(C.sub.3-C.sub.7)cycloalkyl; or a (C.sub.2-C.sub.4)alkanoyl, or one
of its pharmaceutically acceptable salts.
26. A pharmaceutical composition according to claim 23, wherein the
.beta..sub.3 agonist is
N-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydr-
onaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamine or one of
its pharmaceutically acceptable salts.
27. A pharmaceutical composition according to claim 23 containing
from 0.5 to 600 mg of CB.sub.1 receptor antagonist and from 0.5 to
600 mg of .beta..sub.3-agonist.
28. A pharmaceutical composition according to claim 27 containing
from 1 to 400 mg of CB.sub.1 receptor antagonist and from 2 to 400
mg of .beta..sub.3-agonist.
29. A pharmaceutical composition according to claim 28 containing
from 2 to 200 mg of CB.sub.1 receptor antagonist and from 10 to 250
mg of .beta..sub.3-agonist.
30. A kit for the treatment of appetency disorders, which contains:
a CB.sub.1 receptor antagonist, and a regulator of metabolic
disorders, said active principles being in separate compartments
and being intended to be administered simultaneously, sequentially
or over a period of time.
31. A kit according to claim 30 in which said regulator of
metabolic disorders is a .beta..sub.3-agonist.
32. A kit according to claim 31 in which said CB.sub.1 receptor
antagonist is
N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)4-methylpyrazole-
-3-car-boxanide, one of its pharmaceutically acceptable salts or
one of their solvates and said .beta..sub.3-agonist is
N-[(2S)-7-ethoxycarbonylm-
ethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyeth-
anamine or one of its pharmaceutically acceptable salts.
33. A kit according to claim 30 in which said active principles are
in different packagings.
34-38. (cancelled)
39. A pharmaceutical composition according to claim 26 wherein the
CB.sub.1 antagonist is
N-piperidino-5-(4-chlorophenyl)4-methylpyrazole-3-- carboxamide or
one of its pharmaceutically acceptable solts or one of their
solvates.
Description
[0001] The present invention relates to a novel use of antagonists
of the central cannabinoid receptors or so-called CB.sub.1
receptors.
[0002] More particularly, the invention relates to the use of
CB.sub.1 receptor antagonists for the preparation of drugs useful
in the treatment of appetency disorders. The purpose of drugs
useful in the treatment of appetency disorders is to regulate
consumption desires, particularly desires to consume sugars,
carbohydrates, alcohol or drugs and more generally to consume
appetizing ingredients.
[0003] In the present description and in the claims, appetency
disorders are understood as meaning:
[0004] disorders associated with a substance and especially abuse
of a substance and/or dependency on a substance,
[0005] disorders of food behaviors, especially those liable to
cause excess weight, irrespective of its origin, for example:
bulimia, appetency for sugars, non-insulin-dependent diabetes.
[0006] Substances are understood as meaning appetizing ingredients
such as sugars, carbohydrates, alcohols or drugs.
[0007] The present invention therefore further relates to the use
of a CB.sub.1 receptor antagonist for the preparation of drugs
useful in the treatment of bulimia and obesity, including obesity
associated with type II diabetes (non-insulin-dependent diabetes),
or more generally any disease resulting in the patient becoming
overweight, and in the treatment of drug abuse or drug
dependency.
[0008] Delta-9-tetrahydrocannabinol, or .DELTA..sup.9-THC, is the
main active constituent extracted from Cannabis sativa (Tuner,
1985; in Marijuana, 84, Ed. Harvey, D Y, IRL Press, Oxford).
[0009] The effects of cannabinoids are due to an interaction with
high affinity specific receptors coupled to G proteins. Two types
of receptors are currently described: the CB.sub.1 receptors, which
are present predominantly in the central nervous system (Devane et
al., Molecular Pharmacology, 1988, 34, 605-613), and the CB.sub.2
receptors, which are present in the immune system (Nye et al., The
Journal of Pharmacology and Experimental Therapeutics, 1985, 234,
784-791; Kaminski et al., 1992, Molecular Pharmacology, 42,
736-742; Munro et al., Nature, 1993, 365, 61-65). Characterization
of these receptors has been made possible by the development of
synthetic ligands such as CP 55,940 (J. Pharmacol. Exp. Ther.,
1988, 247, 1046-1051) and WIN 55212-2 (J. Pharmacol. Exp. Ther.,
1993, 264, 1352-1363) and, more recently, by the discovery of the
selective CB.sub.1 receptor antagonist SR 141716 A (M.
Rinaldi-Carmona et al., FEBS Lett., 1994, 350, 240-244).
[0010] Families of compounds having an affinity for the cannabinoid
receptors have been described in several patents or patent
applications, especially European patent application EP-576 357,
which describes pyrazole derivatives, and patent application WO
96/02248, which describes especially benzofuran derivatives.
[0011] More particularly, N-piperidino-5-(4-chlorophenyl)-
1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, also called
SR 141716, of the formula 1
[0012] its pharmaceutically acceptable salts and their solvates are
described in European patent application EP-656 354 as CB.sub.1
central receptor antagonists.
[0013] SR 141716 A is the hydrochloride of SR 141716.
[0014] It is known that delta-9-tetrahydrocannabinol, whose
international non-proprietary name is Dronabinol, is used in the
treatment of anorexia, especially in patients suffering from AIDS
(J. Pain Symptom Manage., 1995, 10 (2), 89-97) or cancer (J.
Palliat. Care, 1994, 10 (1), 14-18).
[0015] It is further described that SR 141716 and its salts, which
are central cannabinoid receptor antagonists, can be used in the
treatment of appetite disorders, especially as anorexigenic agents,
and in the treatment of disorders associated with the use of
psychotropic substances.
[0016] Conventional anorexigenic agents cause an appetite reduction
which is generally independent of the foods to be consumed.
[0017] Surprisingly, it has now been found that CB.sub.1 receptor
antagonists have a specific property by acting electively on
consumption behavior disorders pertaining to appetizing
substances.
[0018] Thus the administration of a CB.sub.1 receptor antagonist
makes it possible to regulate the desire to consume non-essential
food items such as excess sugars, excess carbohydrates, alcohol or
drugs.
[0019] In fact, after having conducted tests in animals, a novel
behavior of the animal has been noted: animal tests have revealed a
novel behavior: the animal no longer shows spontaneous appetency
for the ingredient, for example sugar or alcohol, which usually
brings pleasure to it. This lack of appetency also manifests itself
when the animal has been pretreated with a neuropeptide known to
increase the appetite, for example neuropeptide Y (NPY).
[0020] According to one of its aspects, the present invention
relates to the use of a CB.sub.1 receptor antagonist for the
preparation of drugs useful in the treatment of appetency
disorders.
[0021] The CB.sub.1 receptor antagonists appropriate for the
purposes of the invention are particularly the compounds of the
formula 2
[0022] in which:
[0023] R.sub.1 is hydrogen, a fluorine, a hydroxyl, a
(C.sub.1-C.sub.5)alkoxy, a (C.sub.1-C.sub.5)alkylthio, a
hydroxy(C.sub.1-C.sub.5)alkoxy, a group --NR.sub.10R.sub.11, a
cyano, a (C.sub.1-C.sub.5)alkylsulfonyl or a
(C.sub.1-C.sub.5)alkylsulfinyl;
[0024] R.sub.2 and R.sub.3 are a (C.sub.1-C.sub.4)alkyl or,
together with the nitrogen atom to which they are bonded, form a
saturated or unsaturated 5- to 10-membered heterocyclic radical
which is unsubstituted or monosubstituted or polysubstituted by a
(C.sub.1-C.sub.3)alkyl or by a (C.sub.1-C.sub.3)alkoxy;
[0025] R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are
each independently hydrogen, a halogen or a trifluoromethyl, and if
R.sub.1 is a fluorine, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8
and/or R.sub.9 can also be a fluoromethyl, with the proviso that at
least one of the substituents R.sub.4 or R.sub.7 is other than
hydrogen; and
[0026] R.sub.10 and R.sub.11 are each independently hydrogen or a
(C.sub.1-C.sub.5)alkyl, or R.sub.10, and R.sub.11, together with
the nitrogen atom to which they are bonded, form a heterocyclic
radical selected from pyrrolidin-1-yl, piperidin-1-yl,
morpholin-4-yl and piperazin-1-yl, which is unsubstituted or
substituted by a (C.sub.1-C.sub.4)alkyl, and their salts and their
solvates.
[0027] More particularly, the present invention relates to the use
of
N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-
-carboxamide, its pharmaceutically acceptable salts and their
solvates for the preparation of drugs useful in the treatment of
appetency disorders.
[0028] According to the present invention, the CB, receptor
antagonists can also be used in association with another active
principle for the preparation of drugs useftul in the treatment of
appetency disorders, especially in the treatment of disorders of
food behaviors; it is possible to use a pharmaceutical composition
comprising a CB.sub.1 receptor antagonist in association with a
compound for regulating metabolic disorders, especially a
.beta..sub.3-adrenergic receptor agonist, hereafter called a
.beta..sub.3-agonist.
[0029] Thus the present invention further relates to pharmaceutical
compositions containing a CB.sub.1 receptor antagonist and a
regulator of metabolic disorders, for example a hypolipemic,
hypolydemic or lipolytic. More particularly, the present invention
relates to pharmaceutical compositions containing a CB.sub.1
receptor antagonist and a .beta..sub.3-agonist.
[0030] .beta..sub.3-agonists which can be used according to the
present invention are the compounds of the formula 3
[0031] in which:
[0032] X is hydrogen, a halogen, a trifluoromethyl or a
(C.sub.1-C.sub.4)alkyl;
[0033] R is hydrogen or a methyl which is unsubstituted or
substituted by a carboxyl or an alkoxycarbonyl in which the alkoxy
is (C.sub.1-C.sub.6),
[0034] and their pharmaceutically acceptable salts, indicated in EP
0 211 721 and EP 0 303 546 as intestinal spasmolytics.
[0035] Among the compounds of formula (III), the following
compounds:
[0036]
2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol;
[0037]
2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chloropheny-
l)-ethanol;
[0038]
2-[(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1--
(3-chlorophenyl)ethanol;
[0039]
2-[(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1--
phenylethanol;
[0040]
(1R,2'RS)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phen-
yl-ethanol;
[0041]
(1S,2'RS)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phen-
yl-ethanol;
[0042]
(+)-(1R)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-pheny-
l-ethanol;
[0043]
(+)-(1S)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-pheny-
l-ethanol;
[0044]
(-)-(1R)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-pheny-
l-ethanol;
[0045] (-)-(1S)-2-[(7-hydroxy-
1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phen- yl-ethanol;
[0046]
N-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-
-2-(3-chlorophenyl)-2-hydroxyethanamine; and
[0047]
N-[(2R)-7-methoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R-
)-2-(3-chlorophenyl)-2-hydroxyethanamine, and their
pharmaceutically acceptable salts, are particularly
advantageous.
[0048]
N-[(2S)-7-Ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-
-2-(3-chlorophenyl)-2-hydroxyethanamine (SR 58611) and its
pharmaceutically acceptable salts are very particularly
advantageous, especially its salt with hydrochloric acid, SR 58611
A.
[0049] Other .beta..sub.3-agonists which can be used according to
the present invention are the compounds of the formula 4
[0050] in which:
[0051] n is 1, 2 or 3;
[0052] A is a benzofuran-2-yl or a phenyl which is unsubstituted or
substituted by one or two halogen atoms or by a
(C.sub.1-C.sub.4)alkyl or a trifluoromethyl;
[0053] R' is:
[0054] hydrogen;
[0055] a (C.sub.1-C.sub.6)alkyl;
[0056] a functional group selected from the following groups:
hydroxyl; (C.sub.1-C.sub.6)-alkoxy; (C.sub.2-C.sub.6)alkenyloxy;
(C.sub.2-C.sub.6)alkynyloxy; (C.sub.3-C.sub.8)cycloalkoxy;
(C.sub.3-C.sub.8) cycloalkyl(C.sub.1-C.sub.6)alkoxy; benzyloxy;
phenoxy; mercapto; (C.sub.1-C.sub.6)alkylthio;
(C.sub.2-C.sub.6)alkenylthio; (C.sub.2-C.sub.6)alkynylthio;
(C.sub.3-C.sub.8)cycloalkylthio;
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkylthio; benzylthio;
phenylthio; (C.sub.1-C.sub.6) alkylsulfinyl;
(C.sub.2-C.sub.6)alkenylsulf- inyl;
(C.sub.2-C.sub.6)alkynylsulfinyl; (C.sub.3-C.sub.8)
cycloalkylsulfinyl;
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkylsulf- inyl;
benzylsulfinyl; phenylsulfinyl; (C.sub.1-C.sub.6)alkylsulfonyl;
(C.sub.2-C.sub.6)alkenylsulfonyl; (C.sub.2-C.sub.6)
alkynylsulfonyl; (C.sub.3-C.sub.8)cycloalkylsulfonyl;
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-- C.sub.6) alkylsulfonyl;
benzylsulfonyl; phenylsulfonyl; cyano; nitro; amino which is
unsubstituted or substituted by one or two identical or different
radicals selected from (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.8) cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl, benzyl and
phenyl groups; carboxyl; alkoxycarbonyl in which the alkoxy is
(C.sub.1-C.sub.6); (C.sub.2-C.sub.6)-alkenyloxycarbonyl;
(C.sub.2-C.sub.6)alkynyloxycarbonyl; (C.sub.3-C.sub.8)
cycloalkoxycarbonyl;
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkoxyca- rbonyl;
benzyloxycarbonyl; phenoxycarbonyl; or carbamoyl which is
unsubstituted or substituted on the amino group by one or two
identical or different radicals selected from
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.8)-cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6- )alkyl, benzyl and
phenyl groups;
[0057] a group R'" selected from the following groups:
(C.sub.1-C.sub.6)alkyl substituted by a functional group;
(C.sub.2-C.sub.6)alkenyl substituted by a functional group;
(C.sub.2-C.sub.6)-alkynyl substituted by a functional group;
phenyl(C.sub.1-C.sub.6)alkyl substituted on the phenyl by a
(C.sub.1-C.sub.6)alkyl or by a functional group;
phenyl(C.sub.2-C.sub.6)a- lkenyl substituted on the phenyl by a
(C.sub.1-C.sub.6)alkyl or by a functional group;
phenyl(C.sub.2-C.sub.6) alkynyl substituted on the phenyl by a
(C.sub.1-C.sub.6)alkyl or by a functional group; benzyl substituted
on the phenyl by a (C.sub.1-C.sub.6)alkyl or by a functional group;
and phenyl which is unsubstituted or substituted by a
(C.sub.1-C.sub.6)alkyl or by a functional group, the functional
group being as defined above;
[0058] a group O--R'", S--R'", SO--R'" or SO.sub.2--R'", in which
R'" is as defined above;
[0059] a group NR'"R.degree., in which R'" is as defined above and
R' is hydrogen or is as defined above for R'", or R'" and
R.degree., together with the nitrogen to which they are bonded,
form a group selected from pyrrolidino, piperidino and morpholino
groups;
[0060] a group COOR'" or a group CO--SR'", in which R'" is as
defined above;
[0061] a group CONR'"R.degree., in which R'" is as defined above
and R.degree. is hydrogen or is as defined above for R'", or R'"
and R.degree., together with the nitrogen to which they are bonded,
form a group selected from pyrrolidino, piperidino and morpholino
groups;
[0062] a group SO.sub.2NR'"R.degree., in which R'" is as defined
above and R.degree. is hydrogen or is as defined above for R'", or
R'" and R.degree., together with the nitrogen to which they are
bonded, form a group selected from pyrrolidino, piperidino and
morpholino groups;
[0063] R" is hydrogen; a halogen; a (C.sub.1-C.sub.6)alkyl; a
functional group as defined above; a group OR'", R'" being as
defined above; a group COOR'", R'" being as defined above; or a
group CONR'"R.degree., in which R'" is as defined above and
R.degree. is hydrogen or is as defined above for R'", or R'" and
R.degree., together with the nitrogen to which they are bonded,
form a group selected from pyrrolidino, piperidino and morpholino
groups;
[0064] W is a direct bond or an oxygen atom;
[0065] X' is hydrogen, a (C.sub.1-C.sub.6)alkyl or a
(C.sub.1-C.sub.6)alkylcarbonyl;
[0066] Y is hydrogen or a group A'--CH(OH)--CH.sub.2--, A' being
identical to A but other than benzofuran-2-yl; or
[0067] X' and Y, taken together, form a methylene group optionally
substituted by an alkoxycarbonyl in which the alkoxy is
(C.sub.1-C.sub.6); an ethylene group optionally substituted by an
oxo group; or a 1,3-propylene group;
[0068] Z is hydrogen or a (C.sub.1-C.sub.6)alkyl,
[0069] and their pharmaceutically acceptable salts, indicated in EP
0 255 415 as intestinal spasmolytics.
[0070] Other .beta..sub.3-agonists which can also be used according
to the present invention are the compounds of the formula 5
[0071] in which:
[0072] E is hydrogen, a (C.sub.1-C.sub.4)alkyl, a
(C.sub.1-C.sub.4)alkoxy, a phenyl, a nitro, a halogen atom or a
trifluoromethyl;
[0073] L is hydrogen, a (C.sub.1-C.sub.4)alkyl, a
(C.sub.1-C.sub.4)alkoxy, a phenyl, a nitro or a halogen atom; or E
and L together are a group --CH.dbd.CH--CH.dbd.CH-- or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--; and
[0074] G is hydrogen, a chlorine atom, a hydroxyl or a group OG',
in which G' is a (C.sub.1-C.sub.4) alkyl which is unsubstituted or
substituted by a hydroxyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4) alkoxycarbonyl, carboxyl or
(C.sub.3-C.sub.7)cycloalkyl; a (C.sub.3-C.sub.7)cycloalkyl; or a
(C.sub.2-C.sub.4) alkanoyl,
[0075] and their pharmaceutically acceptable salts, indicated in EP
0 436 435 as intestinal spasmolytics.
[0076] Among the compounds of formula (V),
N-[(2R)-(6-hydroxy-1,2,3,4-tetr-
ahydronaphth-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine
(SR 59104),
N-[(2R)-(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)methyl]-(2R)-2-h-
ydroxy-2-(3-chlorophenyl)ethanamine (SR 59119) and their
pharmaceutically acceptable salts are particularly advantageous
compounds.
[0077] Other advantageous .beta..sub.3-agonists according to the
present invention are the compound BRL 35135 described in EP 23385;
the compound CL 316243 described in U.S. Pat. No. 5,061,727; the
compound AZ 002 described in EP 218440; the compound BMS 187257
described in U.S. Pat. No. 5,321,036; the compound ZD 7114
described in EP 473 285; the compound RO 40-2148 described in Am.
J. Clin. Nutr., 1992, 55 (1, Suppl.), 249S -251S; and the products
described in the following patents/patent applications: WO
96/35671, WO 96/35670, WO 96/ 16038, WO 96/04233, WO 95/33724, WO
95/29159, EP 659737, WO 95/04047, EP 516349, EP 473285, EP 23385,
EP 21636, EP 7205, JP 08198866, JP 08165276, JP 08157470, WO
96/16938, EP 714883, WO 96/04234, US 5 488 064, U.S. Pat. No.
5,482,971, U.S. Pat. No. 5,491,134, WO 95/29159, WO 95/33724, ZA
9409874, WO 95/29903, U.S. Pat. No. 5,461,163, WO 95/25104, EP
659737, JP 07112958, WO 95/8527, WO 95/07284, JP 07025756, WO
95/03289, WO 95/04047, WO 95/01170, WO 94/29290, U.S. Pat. No.
5,373,020, JP 06293664, WO 94/12166 and U.S. Pat. No.
5,451,677.
[0078] For its use as a drug, a CB.sub.1 receptor antagonist
compound, by itself or in association with a .beta..sub.3-agonist,
must be formulated as a pharmaceutical composition.
[0079] In the pharmaceutical compositions of the present invention
for oral, sublingual, subcutaneous, intramuscular, intravenous,
transdermal, local or rectal administration, the active principle,
by itself or in association with another active principle, can be
administered to animals and humans in unit forms of administration
mixed with conventional pharmaceutical carriers. The appropriate
unit forms of administration include oral forms such as tablets,
gelatin capsules, powders, granules and solutions or suspensions to
be taken orally, sublingual and buccal forms of administration,
aerosols, implants, subcutaneous, intramuscular, intravenous,
intranasal or intraocular forms of administration and rectal forms
of administration.
[0080] In the pharmaceutical compositions of the present invention,
the active principle or active principles are generally formulated
in dosage units. The dosage unit contains from 0.5 to 1000 mg,
advantageously from 1 to 500 mg and preferably from 2 to 200 mg of
CB.sub.1 receptor antagonist per dosage unit for daily
administration.
[0081] In cases where 2 active principles are associated, the
dosage unit contains from 0.5 to 600 mg, advantageously from 1 to
400 mg and preferably from 2 to 200 mg of CB, receptor antagonist
compound and from 0.5 to 600 mg, advantageously from 2 to 400 mg
and preferably from 10 to 250 mg of the other active principle,
especially a .beta..sub.3-agonist.
[0082] When a solid composition is prepared in the form of tablets,
a wetting agent such as sodium laurylsulfate can be added to the
micronized or non-micronized active principle(s) and the whole is
mixed with a pharmaceutical vehicle such as silica, starch,
lactose, magnesium stearate, talcum or the like. The tablets can be
coated with sucrose, a variety of polymers or other appropriate
substances, or else they can be treated so as to have a sustained
or delayed activity and so as to release a predetermined amount of
active principle continuously.
[0083] A preparation in the form of gelatin capsules is obtained by
mixing the active principle or active principles with a diluent,
such as a glycol or a glycerol ester, and incorporating the
resulting mixture into soft or hard gelatin capsules.
[0084] A preparation in the form of a syrup or elixir can contain
the active principle or active principles together with a
sweetener, which is preferably calorie-free, methylparaben and
propylparaben as antiseptics, a flavoring and an appropriate
color.
[0085] The water-dispersible powders or granules can contain the
active principle or active principles mixed with dispersants or
wetting agents or with suspending agents such as
polyvinylpyrrolidone or polyvidone, as well as with sweeteners or
taste correctors.
[0086] Rectal administration is effected using suppositories, which
are prepared with binders melting at the rectal temperature, for
example cocoa butter or polyethylene glycols.
[0087] Parenteral administration is effected using aqueous
suspensions, isotonic saline solutions or injectable sterile
solutions containing pharmacologically compatible dispersants
and/or solubilizing agents, for example propylene glycol or
butylene glycol.
[0088] Thus, to prepare an aqueous solution for intravenous
injection, it is possible to use a cosolvent, for example an
alcohol such as ethanol or a glycol such as polyethylene glycol or
propylene glycol, and a hydrophilic surfactant such as Tween.RTM.
80. To prepare an oily solution for intramuscular injection, the
active principle can be solubilized with a triglyceride or a
glycerol ester.
[0089] Transdermal administration can be effected using patches in
multilaminar form or with a reservoir in which the active principle
is in alcoholic solution.
[0090] The active principle or active principles can also be
formulated as microcapsules or microspheres, optionally with one or
more carriers or additives.
[0091] The active principle or active principles can also be
presented in the form of complexes with a cyclodextrin, for example
.alpha.-, .beta.- or .gamma.-cyclodextrin,
2-hydroxy-propyl-.beta.-cyclodextrin or
methyl-.beta.-cyclodextrin.
[0092] Among the sustained release forms useful in the case of
chronic treatments, it is possible to use implants. These can be
prepared in the form of an oily suspension or in the form of a
suspension of microspheres in an isotonic medium.
[0093] According to another aspect of the invention, the CB.sub.1
receptor antagonist and the regulator of metabolic disorders,
especially the .beta..sub.3-agonist, can be administered
simultaneously, sequentially or over a period of time in the
treatment of appetency disorders, especially in the treatment of
disorders of food behaviors.
[0094] The invention therefore further relates to a kit for the
treatment of appetency disorders by the administration,
simultaneously, sequentially or over a period of time, of a
CB.sub.1 receptor antagonist and a regulator of metabolic
disorders, especially a .beta..sub.3-agonist, in which kit said
CB.sub.1 receptor antagonist and said regulator of metabolic
disorders, especially said .beta..sub.3-agonist, are in separate
compartments and optionally in different packagings.
[0095] More particularly, said kit contains
N-piperidino-5-(4-chlorophenyl- )-
1-(2,4-dichlorophenyl)4-methylpyrazole-3-carboxamide, one of its
pharmaceutically acceptable salts or one of their solvates, and
N-[(2S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3--
chlorophenyl)-2-hydroxyethanamine or one of its pharmaceutically
acceptable salts.
[0096] According to another of its aspects, the invention further
relates to a method of treating appetency disorders, especially a
method of treating disorders of food behaviors, which consists in
administering, to a subject in need thereof, a (therapeutically)
effective amount of a CB.sub.1 receptor antagonist as defined
above. Said CB.sub.1 receptor antagonist can advantageously be used
in association with a regulator of metabolic disorders, especially
a P, agonist, as defined above. In particular, the CB.sub.1
receptor antagonist and the regulator of metabolic disorders can be
administered simultaneously, sequentially or over a period of
time.
[0097] TEST No. 1: Effect of SR 141716 A on the intake of a sucrose
solution in rats
[0098] The experiment is performed according to W. C. Lynch et al.,
Physiol. Behav., 1993, 54, 877-880.
[0099] Male Sprague-Dawley rats weighing 190 to 210 g are under a
normal light cycle (from 7 am to 7 pm) and receive water and food
ad libitum.
[0100] For 6 days, between 11 am and 3 pm, the food and the water
bottles are withdrawn and the rats are given a 5% sucrose solution
to drink.
[0101] Rats drinking less than 3 g of sucrose solution are
eliminated.
[0102] On the seventh day the test is carried out according to the
following procedure:
[0103] 9 am: withdrawal of food, 10 am: oral administration of SR
141716 A,
[0104] 11 am=T0: introduction of bottles containing a weighed
sucrose solution, T0+1 hour, T0+2 hours, T0+3 hours, T0+4 hours:
measurement of the sucrose consumption by weighing of the
bottles.
1 TABLE 1 Number Consumption of sucrose solution in g Treatment po
of rats 1 hour 2 hours 3 hours 4 hours Vehicle 8 11.33 .+-. 2.50
17.74 .+-. 4.00 22.50 .+-. 4.83 28.34 .+-. 5.01 2 ml/kg SR 141716 A
6 5.18 .+-. 1.61 9.18 .+-. 2.12 12.49 .+-. 4.47 16.10 .+-. 3.95 0.3
mg/kg SR 141716 A 6 3.27* .+-. 1.40 3.61** .+-. 1.40 5.65* .+-.
2.23 7.43** .+-. 2.81 1 mg/kg SR 141716 A 6 2.95* .+-. 1.20 5.41*
.+-. 1.33 6.96* .+-. 2.15 8.58** .+-. 2.92 3 mg/kg *p < 0.05;
**p < 0.01, Dunnett test
[0105] It is seen from the results reported in TABLE 1 that the
administration of SR 141716 A very considerably reduces the
consumption of aqueous sugar solution at or above a dose of 0.3
mg/kg.
[0106] TEST No. 2: Effect of SR 141716 A on the consumption of an
alcohol solution in mice
[0107] Male C 57 BL 6 mice (Iffa-Credo) are isolated on the day of
their arrival in an animal housing under a reverse cycle (night
from 10 am to 10 pm) with 2 bottles filled with water. After 1
week, one of the bottles of water is replaced with a bottle filled
with a 10% alcohol solution for 6 hours of the test. Each day, 30
minutes before the bottle of alcohol is introduced, the mice are
treated subcutaneously with SR 141716 A. The amounts of alcohol and
water consumed are measured after 6 hours. The test is repeated for
4 days.
2TABLE 2 Treatment mg/kg/sc Number Amount of alcohol Amount of
water SR 141716 A of mice consumed in g on D4 consumed in g Vehicle
20 1.9 .+-. 0.1 1.1 .+-. 0.1 0.1 10 1.4 .+-. 0.2 1.1 .+-. 0.3 0.3
10 1.3 .+-. 0.2 1.1 .+-. 0.3 1 10 1.1 .+-. 0.2** 1.3 .+-. 0.1 3 10
1.0 .+-. 0.2** 1.6 .+-. 0.3 **p < 0.01, Dunnett test
[0108] The results show that the alcohol consumption decreases very
substantially for the treated animals: from 1.9.+-.0.1 g for an
untreated animal to 1.0.+-.0.2 g for an animal receiving 3 mg/kg of
SR 141716 A; the water consumption increased in parallel: from
1.1.+-.0.1 to 1.6.+-.0.3 g.
EXAMPLE 1
Gelatin Capsule Containing a 1 mg Dose of CB.sub.1 Receptor
Antagonist
[0109]
3 Micronized SR 141716 1.00 mg Corn starch 51.00 mg Lactose
monohydrate 103.33 mg Polyvidone 4.30 mg Sodium laurylsulfate 0.17
mg Crosslinked sodium carboxymethyl cellulose 8.50 mg Purified
water: QS for wet granulation Magnesium stearate 1.70 mg
[0110] For a no. 3 opaque white gelatin capsule filled to 170
mg
EXAMPLE 2
Gelatin Capsule Containing a 10 mg Dose of CB.sub.1 Receptor
Antagonist
[0111]
4 Micronized SR 141716 A 10.00 mg Corn starch 51.00 mg Lactose
monohydrate 94.33 mg Polyvidone 4.30 mg Sodium laurylsulfate 0.17
mg Crosslinked sodium carboxymethyl cellulose 8.50 mg Purified
water: QS for wet granulation Magnesium stearate 1.70 mg
[0112] For a no. 3 opaque white gelatin capsule filled to 170
mg
EXAMPLE 3
Gelatin Capsule Containing a 30 mg Dose of CB.sub.1 Receptor
Antagonist
[0113]
5 Micronized SR 141716 30.00 mg Corn starch 51.00 mg Lactose
monohydrate 74.33 mg Polyvidone 4.30 mg Sodium laurylsulfate 0.17
mg Crosslinked sodium carboxymethyl cellulose 8.50 mg Purified
water: QS for wet granulation Magnesium stearate 1.70 mg
[0114] For a no. 3 opaque white gelatin capsule filled to 170
mg
EXAMPLE 4
Tablet Containing a 30 mg Dose of CB.sub.1 Receptor Antagonist
[0115]
6 Micronized SR 141716 30.00 mg Lactose monohydrate QS Corn starch
40.00 mg Hydroxypropyl methyl cellulose 6 cP 5.00 mg Purified
water: QS for wet granulation Crosslinked sodium carboxymethyl
cellulose 10.00 mg Magnesium stearate 2.00 mg
[0116] For a finished tablet of 200 mg
EXAMPLE 5
Tablet containing 30 mg of CB.sub.1 Receptor Antagonist and 200 mg
of .beta..sub.3-Agonist
[0117]
7 Micronized SR 141716 30.00 mg SR 58611 A expressed as the base
200.00 mg Lactose monohydrate QS Polyvidone 15.00 mg Purified
water: QS for wet granulation Crosslinked sodium carboxymethyl
cellulose 10.00 mg Magnesium stearate 5.00 mg
[0118] For a finished tablet of 500 mg
EXAMPLE 6
Tablet Containing 10 mg of CB.sub.1 Receptor Antagonist and 100 mg
of .beta..sub.3-agonist
[0119]
8 Micronized SR 141716 10.00 mg SR 58611 A expressed as the base
100.00 mg Corn starch 30 mg Lactose monohydrate QS Hydroxypropyl
methyl cellulose 6 cP 5.00 mg Purified water: QS for wet
granulation Sodium carboxymethyl starch 6.00 mg Magnesium stearate
3.00 mg
[0120] For a finished tablet of 300 mg
* * * * *