Note: Descriptions are shown in the official language in which they were submitted.
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Novel medical uses of compounds showing C8,-antagonistic activity and
combination treatment involving said compounds
The present invention relates to novel therapeutic and/or prophylactic uses of
compounds showing CB,-antagonistic activity and to pharmaceutical
compositions containing one or more of these compounds as an active
component for the novel uses. The compounds addressed in this invention show
Cannabis-1 (CB,) receptor antagonistic activity and may provide outstanding
utility for the novel medical uses provided by the present invention.
Furthermore,
according to an embodiment of the present invention said compounds with CB,-
antagonistic activity may be used in combination with a further active
principle,
and to pharmaceutical compositions containing at least one of these CB,-
antagonistic compounds in combination with said further active principle for
the
treatment and/or prophylaxis of obesity. The combination provided by the
present
invention of said compounds having Cannabis-1 (CB,) receptor antagonistic
activity with said further active principle are of particular utility for
treating of
obesity.
Cannabinoids are present in the Indian hemp Cannabis Sativa L. and have been
used as medicinal agents for centuries (Mechoulam, R.; Feigenbaum, J.J. Prog.
Med. Chem. 1987, 24, 159). However, only within the past ten years the
research
in the cannabinoid area has revealed pivotal information on cannabinoid
receptors and their (endogenous) agonists and antagonists. The discovery and
the subsequent cloning of two different subtypes of Cannabinoid receptors (CB,
and CB2) stimulated the search for novel cannabinoid receptor antagonists
(Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61. Matsuda, L.A.;
Bonner, T.I. Cannabinoid Receptors, Pertwee, R.G. Ed. 1995, 117, Academic
Press, London). In addition, pharmaceutical companies became interested in the
development of cannabinoid drugs for the treatment of diseases connected with
disorders of the cannabinoid system. The wide distribution of CB, receptors in
the
brain, in combination with the strictly peripheral localization of the CB2
receptor,
makes the CB, receptor a very interesting molecular target for CNS-directed
drug
discovery in several areas of medical indications, e.g. psychiatric and
neurological disorders are described in the state of the art as being of
interest
(Consroe, P. Neurobiology of Disease 1998, 5, 534. Pop, E. Curr. Opin. In CPNS
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2
Investigational Drugs 1999, 1, 587. Greenberg, D.A. Drug News Perspect.
1999, 12, 458).
From the international patent applications WO 03/026647, WO 03/027076, WO
03/078413, WO 03/078413, and the recently filed international patent
application
which is going to be published in March/April 2004 and which is based on the
European priority application EP 02078966.5 with priority date 19.09.2002,
compounds are known, with utility for the treatment of diseases connected with
disorders of the cannabinoid system. Thus, these compounds exhibit activity on
the cannabis CB,-receptor showing e.g. CB, antagonistic activity, and they
have
the formulas (I) , (II), (III), (IV) or (V) as defined below in this
specification.
Inparticular said compounds with cannabis CB,-receptor activity have been
suggested for use in the treatment of psychiatric disorders such as psychosis,
anxiety, depression, attention deficits, memory disorders, cognitive
disorders,
appetite disorders, obesity, addiction, appetence, drug dependence and
neurological disorders such as neurodegenerative disorders, dementia,
dystonia,
muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain
injury,
stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's
disease,
Tourette's syndrome, cerebral ischemia, cerebral apoplexy, craniocerebral
trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque
sclerosis,
viral encephalitis, demyelinisation related disorders, as well as for the
treatment
of pain disorders, including neuropathic pain disorders, and other diseases
involving cannabinoid neurotransmission, including the treatment of septic
shock,
glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases,
gastrointestinal disorders, gastric ulcers, diarrhea and cardiovascular
disorders.
The international patent application WO 03/026647 describes a group of novel
compounds which are 4,5-dihydro-1 H-pyrazole derivatives and have the formula
(I) defined below. These 4,5-dihydro-1 H-pyrazole derivatives are potent
cannabinoid (CB,) receptor antagonists with utility for the treatment of
diseases
connected with disorders of the cannabinoid system. The compounds have the
general formula (I) wherein the symbols have the meanings given below in the
specification, and show in particular potent CB, antagonistic activity.
The international patent application WO 03/027076 describes a group of novel
compounds which are 1 H-imidazole derivatives and have the formula (II)
defined
below. These 1H-imidazole derivatives are potent cannabinoid (CB,) receptor
agonists, partial agonists or antagonists, useful for the treatment of
psychiatric
and neurological disorders, as well as and other diseases involving
cannabinoid
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3
neurotransmission. The compounds have the general formula (II) wherein the
symbols have the meanings given below in the specification.
The international patent application WO 03/026648 describes a group of novel
compounds which are also 4,5-dihydro-1 H-pyrazole derivatives and have one of
the formulas (I I I) defined below. These 4,5-dihydro-1 H-pyrazole derivatives
again
are potent cannabinoid (CB1) receptor antagonists with utility for the
treatment of
diseases connected with disorders of the cannabinoid system. In particular,
the
compounds have the general formula (Ills) or (Illb) wherein the symbols have
the
meanings given in the specification below.
The international patent application WO 03/078413 describes a group of novel
compounds which are thiazole derivatives and have of the formula (IV) defined
below. These thiazole derivatives are potent antagonists, agonists or partial
agonists of the cannabinoid CB1-receptor, with utility for the treatment of
diseases connected with disorders of the cannabinoid system. The compounds
have the general formula (IV) wherein the symbols have the meanings given in
the specification below.
The recently filed international patent application, which is going to be
published
in March/April 2004 and which is based on the European priority application EP
02078966.5 with priority date 19.09.2002, describes a group of novel compounds
which are 1,5-diaryl-1H-1,2,4-triazole-3-carboxamide derivatives and have of
the
formula (V) defined below. These 1,5-diaryl-1H-1,2,4-triazole-3-carboxamide
derivatives are potent antagonists, agonists, inverse agonists or partial
agonists
of the cannabinoid CBS receptor, with utility for the treatment of diseases
connected with disorders of the cannabinoid system. The compounds have the
general formula (V) wherein the symbols have the meanings given in the
specification below.
It is an objective of the invention to provide improved methods of treatment
and/or prophylaxis which are particularly suitable in patient groups with
enhanced
need of safety and tolerability, e.g. in the treatment of obesity patients, in
particular such as juvenile obesity patients and/or patients subject to long
term
treatment, e.g. in drug induced obesity in juvenile or adolescent patients. A
further objective is to provide particular beneficial combination treatments
and
medicaments therefore for the treatment and/or prophylaxis of obesity in
patients
of any age, e.g. in adolescent as well as in juvenile patients, wherein the
compounds with CB, antagonistic activity used according to the present
invention
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4
are combined with a further active principle for the treatment of obesity.
It has now surprisingly been found that due to the outstanding unique
pharmacological profile of selective CB,-antagonistic compounds which includes
particularly high safety and tolerability the compounds particularly suitable
for
treatments and/or prophylaxis of diseases connected with disorders of the
cannabinoid system, in particular in patient groups with enhanced need of
safety
and tolerability, in particular such as juvenile patients and/or patients
subject to
long term treatment, e.g. in drug induced obesity.
Therefore, the invention pertains to a combination of a compound with CB,-
receptor activity having one of the formulas (I), (II), (III), (IV) or (V) as
subsequently defined, or a prodrug, tautomer or salt thereof, preferably of a
CB,
receptor antagonistic compound or a prodrug, tautomer or salt thereof, with at
least one lipase inhibiting compound. In a variant of the invention, the
compound
with CBS-receptor activity having one of the formulas (I), (II), (III), (IV)
or (V) as
subsequenzly defined, or a prodrug, tautomer or salt thereof, preferably the
CB,
receptor antagonistic compound or a prodrug, tautomer or salt thereof, is in
combination with at least one lipase inhibiting compound selected from the
group
of lipase inhibiting polymers, oriistat, panclicins, ATL_-962 and lipstatin.
In particular, it has surprisingly been found that the CB,-antagonists of
formulas
(I), (II), (III), (IV) and/or (V), prodrugs thereof, tautomers thereof and
salts thereof,
show a unique pharmacological profile and therefore are particularly suited
for
the use in the manufacture of a medicaments for the treatment and/or
prophylaxis of obesity patients, in particular of obesity in juvenile patients
and/or
drug induced obesity in juvenil~, as well as adolescent, patients. In this
regard
the CB,-antagonistic compounds of formulas (I), (II), (III), (IV) and/or (V),
prodrugs
thereof, tautomers thereof and salts thereof, are highly valuable in providing
medicaments for pediatric use on the one hand, and for the general use in drug
induced obesity.
Due to their activity on the cannabis CB,-receptor the compounds used
according
to the invention are suitable also for use in pediatric treatment and/or
prophylaxis
of other disorders than juvenile obesity and drug induced obesity in juvenile
patients. The other disorders include those known from the literature for the
concerned compounds with activity on the cannabis CB,-receptor, and e.g. the
pediatric treatment and/or prophylaxis may also pertain to psychiatric
disorders
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such as psychosis, anxiety, depression, attention deficits, memory disorders,
cognitive disorders, obesity, dis orders, addiction, appetence, drug
dependence
and neurological disorders such as neurodegenerative disorders, dementia,
dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic
brain
5 injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy,
Huntington's
disease, Tourette's syndrome, cerebral ischemia, cerebral apoplexy,
craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory
disorders,
plaque sclerosis, viral encephalitis, demyelinisation related disorders, as
well as
for the pediatric treatment of pain disorders, including neuropathic pain
disorders,
and other diseases involving cannabinoid neurotransmission, including the
pediatric treatment of septic shock, glaucoma, cancer, diabetes, emesis,
nausea,
asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers,
diarrhoea
and cardiovascular disorders, in young patients.
The whole content of the literature mentioned in the description of the
present
invention is incorporated by reference into the present application.
The CB, antagonistic compounds used in the present the invention can be
obtained according to known methods. Suitable ways of synthesis for the
compounds used according to the present invention are described in the state
of
the art, e.g. in the documents cited in the present application and
incorporated by
reference.
Furthermore, it has surprisingly been found that CB, antagonistic compounds
(CB, antagonists), of the formulas (I), (II), (III), (IV) and/or (V), as well
as
prodrugs, tautomers and salts thereof, due to their unique pharmacological
profile
are particularly suited in combination with at least one lipase inhibiting
compound
(lipase inhibitor) for the use in the manufacture of a medicaments for the
treatment and/or prophylaxis of obesity, including in particular the treatment
and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity
in
juvenile as well as adolescent patients. In this regard combinations of at
least one
CB, antagonistic compound as defined herein with at least one lipase
inhibiting
compound are highly valuable in providing medicaments for the treatment and/or
prophylaxis of obesity in general, e.g. in adolescent patients of any age, and
particularly also in pediatric or juvenile obesity, and also in drug induced
obesity
in adolescent and juvenile patients.
In particular the present invention is based on the surprising finding that
the CB,
antagonistic compounds of the formulas (I) being 4,5-dihydro-1 H-pyrazole
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6
derivatives, (I I) being 1 H-Imidazole derivatives , (III) being also 4,5-
dihydro-1 H-
pyrazole derivatives, (IV) being thiazole derivatives or (V) being 1 H-1,2,4-
triazole-
3-carboxamide derivatives, which are antagonists of the cannabis CBS-receptor,
prodrugs thereof, tautomers thereof and salts thereof, due to their unique
pharmacological profile are particularly suited in combination with at least
one
lipase inhibiting compound for the use in the manufacture of a medicament for
the treatment and/or prophylaxis of obesity in general, e.g. of obesity in
adolescent patients of any age, and particularly also for the treatment and/or
prophylaxis of obesity in juvenile patients and/or drug induced obesity in
juvenile
as well as adolescent patients. In this regard combinations each of the
compounds with the formulas (I), (II), III), IV or (V), together with lipase
inhibiting
compounds are highly valuable in providing medicaments for the treatment
and/or prophylaxis of obesity in general, e.g. of obesity in adolescent
patients of
any age, and particularly also in pediatric or juvenile obesity, and in drug
induced
obesity.
The compounds of the formulas (I), (II), III), (IV) or (V) used in the present
the
invention can be obtained according to known methods. A suitable synthesis for
the compounds of the formulas (I), (II), III), (IV) used according to the
present
invention is described in the international patent applications WO 03/026647,
WO 03/027076, WO 03/078413 or WO 03/078413, which are incorporated by
reference into this specification. Compounds of formula (V) can be prepared
according to a recently filed international patent application, which is going
to be
published in March/April 2004 and is based on the European priority
application
EP 02078966.5 with priority date 19.09.2002, which is also incorporated by
reference into the present specification. Preparation of compounds of formula
(V)
is also described at the end of this specification.
In the following the embodiments of the invention are described in more detail
with reference to the compounds with the formulas (I), (II), III), IV or (V),
exemplary in particular in the context of obesity.
Compounds of formula (I)
In a first embodiment the present invention is based on the surprising finding
that
the 4,5-dihydro-1 H-pyrazole derivatives of the formula (I) which are potent
and
selective antagonists of the cannabis CB,-receptor, prodrugs thereof,
tautomers
thereof and salts thereof:
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7
R R~
N/ ~~Rz
~N /Rs
~N (I)
N / ~a
I
O=S=O
I
R5
wherein
- R and R, independently represent phenyl, thienyl or pyridyl which groups may
be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or
different, from the group C,_3-alkyl or alkoxy, hydroxy, halogen,
trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or
dialkyl (C,_2)-amino, mono- or dialkyl (C,_2)-amido, (C,_3)-alkyl sulfonyl,
dimethylsulfamido, C,_3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl,
cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R, represent naphtyl,
- R2 represents hydrogen, hydroxy, C,_3-alkoxy, acetyloxy or propionyloxy,
- R3 represents a hydrogen atom or a branched or unbranched C,_$ alkyl group
or a C~~ cycloalkyl group which alkyl group or cycloalkyl group may be
substituted with a hydroxy group,
- R4 represents a Cz_,o branched or unbranched heteroalkyl group, C~$ non-
aromatic heterocycloalkyl group or Cø,o non -aromatic heterocycloalkyl-alkyl
group which groups contain one or more heteroatoms from the group (O, N,
S) or a -S02- group, which C2_,o branched or unbranched heteroalkyl group,
C~8 non-aromatic heterocycloalkyl group or Cø,o non-aromatic
heterocycloalkyl-alkyl group may be substituted with a keto group,
trifluoromethyl group, C,_3 alkyl group, hydroxy, amino, monoalkylamino, or
dialkylamino group or a fluoro atom, or R4 represents an amino, hydroxy,
phenoxy or benzyloxy group, or R4 represents a C,_8 alkoxy, C~8 alkenyl, C~8
cycloalkenyl or C&9 cycloalkenylalkyl group which groups may contain a
sulphur, nitrogen or oxygen atom, a keto group or -S02- group, which alkoxy,
alkenyl and cycloalkenyl groups may be substituted with a hydroxy group, a
trifluoromethyl group, an amino group, a monoalkylamino group or
dialkylamino group or a fluoro atom, or R4 represents a C2_5 alkyl group which
alkyl group contains a fluoro atom, or R4 represents an imidazolylalkyl group,
benzyl, pyridylmethyl, phenethyl or thienyl group, or R4 represents a
substituted phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl group
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8
wherein the aromatic rings are substituted with 1, 2 or 3 of the substituents
Y,
wherein Y has the meaning as indicated above,
or when R3 is H or methyl, R4 may represent a group NRgR~ wherein
- R6 and R~ are the same or different and represent C2~ alkyl , C2~
trifluoroalkyl
or Rg represents a methyl group with the proviso that R~ represents a C2~
alkyl group, or Rg and R~ - together with the nitrogen atom to which they are
bonded - form a saturated or unsaturated heterocyclic moiety having 4 to 8
ring atoms which heterocyclic moiety may contain an oxygen or sulphur atom
or a keto group or -S02- group or an additional nitrogen atom, which
saturated or unsaturated heterocyclic moiety may be substituted with a C,~
alkyl group, or
- R3 and R4 together with the nitrogen atom to which they are bonded form a
saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4
to 10 ring atoms, which heterocyclic moiety may contain one or more atoms
from the group (O, N, S) or a keto group or -S02- group, which moiety may
be substituted with a C~~ alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl,
amino,
monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino,
aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1H-azepinyl
group,
- RS represents benzyl, phenyl, thienyl or pyridyl which may be substituted
with
1, 2, 3 or 4 substituents Y, wherein Y has the meaning as indicated above,
which can be the same or different, or R5 represents C,_$ branched or
unbranched alkyl, C~8 alkenyl, C~,o cycloalkyl, C~,o bicycloalkyl, C~.,o
tricycloalkyl or C~$ cycloalkenyl or R5 represents naphtyl,
due to their unique pharmacological profile are particularly suited in
combination
with at least one lipase inhibiting compound for the use in the manufacture of
a
medicament for the treatment and/or prophylaxis of obesity in general, e.g. of
obesity in adolescent patients of any age, and particularly also for the
treatment
and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity
in
juvenile as well as adolescent patients. In this regard combinations of the
compounds of formula (I) together with lipase inhibiting compounds are highly
valuable in providing medicaments for the treatment and/or prophylaxis of
obesity
in general, e.g. of obesity in adolescent patients of any age, and
particularly also
in pediatric or juvenile obesity, and in drug induced obesity.
At least one centre of chirality is present (at the C4 position of the 4,5-
dihydro-1 H-
pyrazole moiety) in the compounds of the formula (I). The invention relates
both
to racemates, mixtures of diastereomers and the individual stereoisomers of
the
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9
compounds having formula (I). Particular compounds of interest of formula (I)
have the absolute stereoconfiguration at the C4 position of the 4,5-dihydro-1
H-
pyrazole moiety as represented by formula (1 a).
R R~
N~ ~.~~~RZ
N /Rs
~N~ (la)
N Ra
I
O=S=O
I
Rs
The invention also relates both to the E isomer, Z isomer and E2 mixtures of
compounds having formula (I).
Compounds of formula (II)
In a second embodiment the present invention is based on the surprising
finding
that the 1 H-imidazole derivatives with CB, antagonistic activity of the
formula (II),
prodrugs thereof and salts thereof, which are potent antagonists on
cannabinoid
CB, receptors:
O ~ R2
N
\R3 (II)
R' N Ra
R
wherein
- R represents phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,
pyrimidinyl,
pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted with 1,
2, 3
or 4 substituents Y, which can be the same or different, from the group C,_3-
alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio,
trifluoromethoxy, vitro, amino, mono- or dialkyl (C,_2)-amino, mono- or
dialkyl
(C,_2)-amido, (C,_3)-alkoxycarbonyl, carbonyl, cyano, carbamoyl and acetyl, or
R represents naphtyl, with the proviso that when R is 4-pyridinyl, R4
represents a halogen atom or a cyano, carbamoyl, formyl, acetyl,
trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl,
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methylsulfanyl or branched or unbranched C» alkyl group, which C,~ alkyl
group may be substituted with 1-3 fluoro atoms or with a bromo, chloro, iodo,
cyano or hydroxy group,
- R, represents phenyl or pyridinyl, which groups may be substituted with 1-4
5 substituents Y, which can be the same or different, wherein Y has the above
mentioned meaning, or R, represents pyrimidinyl, pyrazinyl, pyridazinyl or
triazinyl, which groups may be substituted with 1-2 substituents Y, which can
be the same or different or R, represents a five-membered aromatic
heterocyclic ring having one or two heteroatoms from the group (N, O, S),
10 which heteroatoms can be the same or different, which five-membered
aromatic heterocyclic ring may be substituted with 1-2 substituents Y, which
can be the same or different or R, represents naphtyl,
- R2 represents H, branched or unbranched C~_8 alkyl, C~8 cycloalkyl, C~a
alkenyl, C~8 cycloalkenyl which groups may contain a sulfur, oxygen or
nitrogen atom,
- R3 represents branched or unbranched C2~ alkyl, C,_8 alkoxy, C~8
cycloalkyloxy, C~$ cycloalkyl, C~,o bicycloalkyl, C~,o tricycloalkyl, C~8
alkenyl,
C~8 cycloalkenyl, which groups may optionally contain one or more
heteroatoms from the group (O, N, S) and which groups may be substituted
with a hydroxy group or 1-2 C,_3 alkyl groups or 1-3 fluoro atoms, or R3
represents a benzyl or phenethyl group which aromatic rings may be
substituted with 1-5 substituents Z, which can be the same or different, from
the group C,_3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,
trifluoromethylthio, trifluoromethoxy, vitro, amino, mono- or dialkyl (C,_2)-
amino, mono- or dialkyl (C,_2)-amido, (C,_3)-alkylsulfonyl, dimethyl-
sulfamido,
C,_3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl,
sulfamoyl and acetyl, or R3 represents a phenyl or pyridinyl group, which
groups are substituted with 1-4 substituents Z, wherein Z has the meaning as
indicated above,
or R3 represents a pyridinyl group, or R3 represents a phenyl group, with the
proviso that R4 represents a halogen atom or a cyano, carbamoyl, formyl,
acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl,
methylsulfanyl or C,.~ alkyl group, which C,~ alkyl group may be substituted
with 1-3 fluoro atoms or with a bromo, chloro, iodo, cyano or hydroxy group,
or R3 represents a group NR5R6 with the proviso that R2 represents a
hydrogen atom or a methyl group, wherein
- R5 and Rs are the same or different and represent branched or unbranched
C,~ alkyl, or R5 and Rs - together with the nitrogen atom to which they are
bonded - form a saturated or unsaturated, monocyclic or bicyclic heterocyclic
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11
group having 4 to 10 ring atoms which heterocyclic group contains one or two
heteroatoms from the group (N, O, S), which heteroatoms can be the same or
different, which heterocyclic group may be substituted with a C,_3 alkyl group
or a hydroxy group, or R2 and R3 - together with the nitrogen atom to which
they are bonded - form a saturated or unsaturated heterocyclic group having
4 to 10 ring atoms which heterocyclic group contains one or two heteroatoms
from the group (N, O, S), which heteroatoms can be the same or different,
which heterocyclic group may be substituted with a C,_3 alkyl group or a
hydroxy group,
- R4 represents a hydrogen or halogen atom or a cyano, carbamoyl, formyl,
acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl,
methylsulfanyl or branched or unbranched C,~ alkyl group, which C,~ alkyl
group may be substituted with 1-3 fluoro atoms or with a bromo, chloro, iodo,
cyano or a hydroxy group,
due to their unique pharmacological profile are particularly suited in
combination
with at least one lipase inhibiting compound for the use in the manufacture of
a
medicament for the treatment and/or prophylaxis of obesity in general, e.g. of
obesity in adolescent patients of any age, and particularly also for the
treatment
and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity
in
juvenile as well as adolescent patients. In this regard combinations of the
compounds of formula (II) together with lipase inhibiting compounds are highly
valuable in providing medicaments for the treatment and/or prophylaxis of
obesity
in general, e.g. of obesity in adolescent patients of any age, and
particularly also
in pediatric or juvenile obesity, and in drug induced obesity.
Compounds of formula (III)
In a third embodiment the present invention is based on the surprising finding
that potent and selective antagonism of cannabinoid-CB, receptors is present
in
the 4,5-dihydro-1 H-pyrazole derivatives of the formula (Illa) or (Illb),
prodrugs
thereof, tautomers thereof and salts thereof:
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12
R R~ R R~
N/ ~\R2 N/ ~\R2
-N s ~-S
N / ~Ra N /
O=S=O O=S=O
Rs N\Rg R~N\Rs
(Illa) (Illb)
wherein
- R and R, independently represent phenyl, thienyl or pyridyl which groups may
be substituted with 1, 2 or 3 substituents Y, which can be the same or
different, from the group C~_3-alkyl or alkoxy, hydroxy, halogen,
trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or
dialkyl (C,_2)-amino, mono- or dialkyl (C,_2)-amido, (C,_3)-alkyl sulfonyl,
dimethylsulfamido, C,_3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl,
cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R, represent naphtyl,
- R2 represents hydrogen, hydroxy, C,_3-alkoxy, acetyloxy or propionyloxy,
- R3 represents a hydrogen atom or a branched or unbranched C,_8 alkyl group
or a C~~ cycloalkyl group which alkyl group or cycloalkyl group may be
substituted with a hydroxy group,
- R4 represents a hydrogen atom or a branched or unbranched C,_$alkyl,
C~8 cycloalkyl, C2_,o heteroalkyl, C~8 nonaromatic heterocycloalkyl or Cø,o
nonaromatic heterocycloalkyl-alkyl moiety which moieties may contain one or
more heteroatoms from the group (O, N, S), which moieties may be
substituted with a keto group, trifluoromethyl group, C,_3 alkyl group,
hydroxy,
amino, monoalkylamino, or dialkylamino group or a fluoro atom, or R4
represents an amino, hydroxy, phenoxy or benzyloxy group or R4 represents
a branched or unbranched C,_8 alkoxy, C~8 alkenyl, C~8 cycloalkenyl or C~.9
cycloalkenylalkyl group which groups may contain a sulphur, nitrogen or
oxygen atom, a keto group or -S02- group which C,_8 alkoxy, C~8 alkenyl, C~8
cycloalkenyl or C~9 cycloalkenylalkyl groups may be substituted with a
hydroxy group, a trifluoromethyl group, an amino group, a monoalkylamino
group or dialkylamino group or a fluoro atom, or R4 represents a phenyl,
benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl group wherein the
aromatic
rings may be substituted with 1, 2 or 3 of the substituents Y, wherein Y has
the meaning as indicated above, or
R4 represents a group NR8R9 with the proviso that R3 represents a hydrogen
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13
atom or a methyl group and wherein R$ and R9 are the same or different and
represent C,~ alkyl or C2~ trifluoroalkyl or R8 and R9 - together with the
nitrogen atom to which they are bonded -form a saturated or un-saturated
heterocyclic moiety having 4 to 8 ring atoms which heterocyclic moiety may
contain an oxygen or sulphur atom or a keto group or -S02- group or an
additional nitrogen atom, which saturated or unsaturated heterocyclic moiety
may be substituted with a C~~ alkyl group or
R3 and R4 - together with the nitrogen atom to which they are bonded - form a
saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4
to 10 ring atoms, which heterocyclic moiety may contain one or more atoms
from the group (O, N, S) or a keto group or -S02- grou p, which moiety may
be substituted with a C,~ alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl,
amino,
monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino,
aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1 H-azepinyl
group,
- R5 and Rg independently of each other represent a hydrogen atom or a
branched or unbranched C,_8 alkyl or alkenyl group which groups may contain
one or more heteroatoms from the group (O, N, S), a keto group or a -S02-
group and which groups may be substituted with a hydroxy or amino group, or
R5 and Rs independently of each other represent a C~.B cycloalkyl group or C~$
cycloalkenyl group which may contain one or more ring heteroatoms from the
group (O, N, S) or the -S02- group and which groups may be substituted with
a hydroxy group, alkyl (C~_3), the -S02- group, the keto group, amino group,
monoalkylamino group (C,_3) or dialkylamino group (C,_3), or
R5 represents a naphtyl group or a phenyl group which phenyl group may be
substituted with 1, 2 or 3 substituents Y wherein Y has the meaning as
described hereinabove, with the proviso that Rg represents a hydrogen atom,
or a branched or unbranched alkyl group (C,_5) which alkyl group may contain
one or more heteroatoms from the group (O, N, S) or the -S02- group and
which alkyl group may be substituted with a hydroxy, keto or amino group, or
R5 and R6 - together with the nitrogen atom to which they are bonded - form a
monocyclic, bicyclic or tricyclic alkyl or alkenyl group which may contain
ring
heteroatoms from the group (O, N, S), the keto or the S02 group and which
monocyclic, bicyclic or tricyclic alkyl or alkenyl group may be substituted
with
a hydroxy group, alkyl (C,_3) group, SOZ group, keto group, amino group,
monoalkylamino group (C~_3), dialkylamino group
(C,_3), pyrrolidinyl group or piperidinyl group, which monocyclic, bicyclic or
tricyclic alkyl or alkenyl group may contain an annelated phenyl group which
annelated phenyl group may be substituted with 1 or 2 substituents Y,
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14
wherein Y has the meaning as described herein above,
- R, represents branched or unbranched C,_3 alkyl,
due to their unique pharmacological profile are particularly suited in
combination
with at least one lipase inhibiting compound for the use in the manufacture of
a
medicament for the treatment and/or prophylaxis of obesity in general, e.g. of
obesity in adolescent patients of any age, and particularly also for the
treatment
and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity
in
juvenile as well as adolescent patients. In this regard combinations of the
compounds of formula (Illa) and/ or (Illb) together with lipase inhibiting
compounds are highly valuable in providing medicaments for the treatment
and/or prophylaxis of obesity in general, e.g. of obesity in adolescent
patients of
any age, and particularly also in pediatric or juvenile obesity, and in drug
induced
obesity.
At least one centre of chirality is present (at the C4 position of the 4,5-
dihydro-1 H-
pyrazole moiety) in the compounds of the formula (Illa) and (Illb). The
invention
relates both to racemates, mixtures of diastereomers and the individual
stereoisomers of the compounds having formula (Ills) or (Illb). Particular
compounds of interest of formula (Illa) or (Illb) have the absolute
stereoconfiguration at the C4 position of the 4,5-dihydro-1 H-pyrazole moiety
as
represented by the formulas (Ills*) and (Illb*):
R ~ R R~
N/N~...'Rz N/N/....Rz
~N s / S/- -7
N ~< N
O=S=O O=S=O
R/NWRs R5 NWRs
5
(Illa*) (Illb*)
The invention also relates both to the E isomer, Z isomer and E/Z mixtures of
compounds having formula (Illa) or (Illb).
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Compounds of formula (IV)
In a fourth embodiment the present invention is based on the surprising
finding
that the 4,5-diarylthiazole derivatives with CBS antagonistic activity of the
formula
(IV), pro-drugs thereof and salts thereof
5
R O NiRs
~ N=~ ~R4 (IV)
~ S
R,
Rz
wherein
- R represents a hydrogen atom or a substituent X from the group branched or
10 unbranched C~_3-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl,
trifluoromethylthio, trifluoromethoxy, vitro, amino, mono- or dialkyl (C,_2)-
amino, mono- or dialkyl (C,_2)-amido, branched or unbranched (C,_3)-
alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, branched or unbranched
alkyl(C,_3)sulfonyl, carboxyl, cyano, carbamoyl, branched or unbranched
15 dialkyl(C,_3) aminosulfonyl, branched or unbranched monoalkyl(C,_3)-
aminosulfonyl and acetyl,
- R, is a hydrogen atom or represents 1-4 substituents X, wherein X has the
abovementioned meaning,
- R2 represents a phenyl, thienyl, pyridyl or pyrimidinyl group, which groups
may be substituted with 1-4 substituents X, wherein X has the
abovementioned meaning or R2 represents naphtyl,
- R3 represents a hydrogen atom or a branched or unbranched C,_,o alkyl or
cycloalkyl-alkyl group or a phenyl, benzyl or phenethyl group which aromatic
rings may be substituted with 1-5 substituents Z, which can be the same or
different, from the group branched or unbranched C,_3-alkyl or alkoxy,
hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy,
vitro,
amino, mono- or dialkyl (C,_2)-amino, mono- or dialkyl (C,_2)-amido, branched
or unbranched (C,_3)-alkylsulfonyl, dimethylsulfamido, branched or
unbranched C,_3-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano,
carbamoyl, sulfamoyl and acetyl, or R3 represents a pyridyl or thienyl group,
- R4 represents branched or unbranched C,_,o alkyl or cycloalkyl-alkyl group,
branched or unbranched C,_1o alkoxy, C~$ cycloalkyl, C~,o bicycloalkyl, C~,o
tricycloalkyl, branched or unbranched C~,o alkenyl, C~8 cycloalkenyl, which
groups may contain one or more heteroatoms from the group (O, N, S) and
which groups may be substituted with a hydroxy group, 1-3 methyl groups, an
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16
ethyl group or 1-3 fluoro atoms, or R4 represents a phenyl, benzyl or
phenethyl group which aromatic rings may be substituted with 1-5
substituents Z, wherein Z has the abovementioned meaning, or R4 represents
a pyridyl or thienyl group, or R4 represents a group NR5R6 wherein
R5 and R6 together with the nitrogen atom to which they are attached form a
saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having 4
to 10 ring atoms, which heterocyclic group contains one or more heteroatoms
from the group (O, N, S) and which heterocyclic group may be substituted
with a branched or unbranched C,_3 alkyl, hydroxy or trifluoromethyl group or
a fluoro atom, or
- R3 and R4 - together with the nitrogen atom to which they are attached -
form
a saturated or unsaturated, monocyclic or bicyclic, heterocyclic group having
4 to 10 ring atoms, which heterocyclic group contains one or more
heteroatoms from the group (O, N, S) and which heterocyclic group may be
substituted with a branched or unbranched C,_3 alkyl, hydroxy or
trifluoromethyl group or a fluoro atom,
due to their unique pharmacological profile are particularly suited in
combination
with at least one lipase inhibiting compound for the use in the manufacture of
a
medicament for the treatment and/or prophylaxis of obesity in general, e.g. of
obesity in adolescent patients of any age, and particularly also for the
treatment
and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity
in
juvenile as well as adolescent patients. In this regard combinations of the
compounds of formula (IV) together with lipase inhibiting compounds are highly
valuable in providing medicaments for the treatment and/or prophylaxis of
obesity
in general, e.g. of obesity in adolescent patients of any age, and
particularly also
in pediatric or juvenile obesity, and in drug induced obesity.
Compounds of formula (V)
In a fifth embodiment the present invention is based on the surprising finding
that
1,5-diaryl-1H-1,2,4-triazole-3-carboxamide derivatives with CB, antagonistic
activity of the formula (V), as well as prodrugs, salts, and stereo-isomers
thereof,
are potent antagonists, agonists, inverse agonists or partial agonists of the
cannabinoid CB, receptor:
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17
R R~
N
N~ N
O
N
R2 R3
wherein
- R and R~ independently represent a phenyl, naphtyl, thienyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl or triazinyl group, which groups may be
substituted with 1-4 substituents X, which can be the same or different,
from the group branched or unbranched (C~_3)-alkyl or alkoxy, hydroxy,
halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino,
mono- or dialkyl (C,_2)-amino, mono- or dialkyl (C,_Z)-amido,
(C,_3)-alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl, (C,_3)-alkylsul-
fonyl, carboxyl, cyano, carbamoyl, (C,_3)-dialkylaminosulfonyl, (C~_3)-
monoalkylamino-sulfonyl and acetyl,
- R2 represents a hydrogen atom or a branched or unbranched C~_$ alkyl or
C1_8 cycloalkyl-alkyl group or a phenyl, benzyl or phenethyl group which
aromatic rings may be substituted with 1-4 substituents X, wherein X has
the meaning as indicated above, or R2 represents a pyridyl or thienyl
group,
- R3 represents branched or unbranched C,_$ alkyl, C,_8 alkoxy, C~8
cycloalkyl, C~~o bicycloalkyl, C~,o tricycloalkyl, C~8 alkenyl, C~.B
cycloalkenyl, which groups may optionally contain one or more
heteroatoms from the group (O, N, S), which groups may be substituted
with a hydroxy group, an ethynyl group or 1-3 fluoro atoms, or R3
represents a phenyl, benzyl or phenethyl group which aromatic rings may
be substituted with 1~ substituents X, wherein X has the meaning as
indicated above, or R3 represents a pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, triazinyl or thienyl group which heteroaromatic rings may be
substituted with 1-2 substituents X, wherein X has the meaning as
indicated above, or R3 represents a group NR4R5 wherein
R4 and R5, together with the nitrogen atom to which they are bonded, form
a saturated or unsaturated, monocyclic or bicyclic, heterocyclic moiety
having 4 to 10 ring atoms, which heterocyclic group contains one or two
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18
heteroatoms from the group N, O or S, which heteroatoms can be the
same or different, which heterocyclic moiety may be substituted with a
branched or unbranched C,_3 alkyl, hydroxy or trifluoromethyl group or a
fluoro atom, or
- R2 and R3, together with the nitrogen atom to which they are bonded, form
a saturated or unsaturated, monocyclic or bicyclic, heterocyclic moiety
having 4 to 10 ring atoms, which heterocyclic group contains one or two
heteroatoms from the group N, O or S, which heteroatoms can be the
same or different, which heterocyclic moiety may be substituted with a
branched or unbranched C,_3 alkyl, hydroxy, piperidinyl or trifluoromethyl
group or a fluoro atom,
due to their unique pharmacological profile are particularly suited in
combination
with at least one lipase inhibiting compound for the use in the manufacture of
a
medicament for the treatment and/or prophylaxis of obesity in general, e.g. of
obesity in adolescent patients of any age, and particularly also for the
treatment
and/or prophylaxis of obesity in juvenile patients and/or drug induced obesity
in
juvenile as well as adolescent patients. In this regard combinations of the
compounds of formula (V) together with lipase inhibiting compounds are highly
valuable in providing medicaments for the treatment and/or prophylaxis of
obesity
in general, e.g. of obesity in adolescent patients of any age, and
particularly also
in pediatric or juvenile obesity, and in drug induced obesity.
In the following the embodiments of the invention are described in more detail
with reference to the medical and pharmaceutical utility of the compounds with
the formulas (I), (II), III), IV or (V).
Medical and pharmaceutical utility
Due to their beneficial activity on the cannabis CB,-receptor the compounds of
formulas (I), (II), (III), (IV) and/or (V) used according to the invention are
suitable
also for general use in pediatric treatment and/or prophylaxis of other
disorders
than juvenile obesity and drug induced obesity in juvenile patients. The other
disorders include those known from the literature for the concerned compounds
with activity on the cannabis CB,-receptor, and e.g. the pediatric treatment
and/or
prophylaxis may also pertain to psychiatric disorders such as psychosis,
anxiety,
depression, attention deficits, memory disorders, cognitive disorders,
appetite
disorders, obesity, addiction, appetence, drug dependence and neurological
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disorders such as neurodegenerative disorders, dementia, dystonia, muscle
spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury,
stroke,
Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease,
Tourette's syndrome, cerebral ischemia, cerebral apoplexy, craniocerebral
trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque
sclerosis,
viral encephalitis, demyelinisation related disorders, as well as for the
pediatric
treatment of pain disorders, including neuropathic pain disorders, and other
diseases involving cannabinoid neurotransmission, including the pediatric
treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma,
respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhoea
and
cardiovascular disorders, in young patients.
The affinity of the compounds of the formulas {I), (II), III), (IV) or (V) for
cannabinoid CB, receptors can be determined as described in the WO
03/026647, WO 03/027076, WO 03/026648 or WO 03/078413, e.g. it can be
determined using membrane preparations of Chinese hamster ovary (CHO) cells
in which the human cannabis CBS receptor is stably transfected in conjunction
with [3H]CP-55,940 as radioligand. After incubation of a freshly prepared cell
membrane preparation with the [3H]-ligand, with or without addition of
compounds of the invention, separation of bound and free ligand was performed
by filtration over glass fibre filters. Radioactivity on the filter was
measured by
liquid scintillation counting.
The cannabinoid CB, antagonistic activity of compounds of the formulas (I),
(II),
III), (IV) or (V) is also described in the WO 03/026647, WO 03/027076, WO
03/026648 or WO 03/078413, and was determined by functional studies using
CHO cells in which human cannabinoid CB, receptors are stably expressed.
Adenylyl cyclase was stimulated using forskolin and measured by quantifying
the
amount of accumulated cyclic AMP. Concomitant activation of CB, receptors by
CB, receptor agonists {e.g. CP-55,940 or (R)-WIN-55,212-2) can attenuate the
forskolin-induced accumulation of CAMP in a concentration-dependent manner.
This CB, receptor -mediated response can be antagonized by CB, receptor
antagonists such as the compounds used in the present invention.
The cannabinoid CB, receptor antagonistic, agonistic or partial agonistic
activity
of compounds e.g. formula (V) of the invention can be also determined by
functional studies using the human CBS receptor cloned in Chinese hamster
ovary (CHO) cells according to the following protocol. CHO cells were grown in
a
DMEM culture medium, supplemented with 10% heat-inactivated fetal calf serum.
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Medium was aspirated and replaced by DMEM, without fetal calf serum, but
containing [3H]-Arachidonic acid and incubated overnight in a cell culture
stove
(5% C02/95% air; 37 °C; water-saturated atmosphere). During this period
[3H]-
Arachidonic acid was incorporated in membrane phospholipids. On the test day,
5 medium was aspirated and cells were washed three times using 0.5 ml
phosphate-buffered saline, containing 0.2% bovine serum albumin. Stimulation
of
the CBS receptor by WIN 55,212-2 led to activation of PLAZ followed by release
of
[3H]-Arachidonic acid into the medium. This WIN 55,212-2-induced release was
concentration-dependently antagonized by CB, receptor antagonists.
Cannabinoid receptor agonistic or partial agonistic activity of compounds of
the
invention can be determined according to published methods, such as
assessment of in vivo cannabimimetic effects (Wiley, J. L. Jefferson et al.,
J.
Pharmacol. Exp. Ther. 2001, 296, 1013).
Cannabinoid receptor antagonists may behave as inverse agonists (Landsman,
R. S. et al., Eur. J. PharmacoL 1997, 334, R1-R2).
The whole content of the international patent applications WO 03/026647, WO
03/027076, WO 03/026648 and WO 03/078413 is incorporated by reference into
the present application regarding the disclosure of the CB, antagonistic
compounds of the formulas (I), (II), III), (IV) or (V) used according to the
present
invention in combination with lipase inhibitors.
The outstanding unique pharmacological profile of compounds with CB,-receptor
activity and the formulas (I), (II), III), (IV) or (V) which are antagonists
of the
cannabis CB,-receptor, as well as prodrugs, tautomers and salts thereof,
includes
particularly high safety and tolerability also in combination with other
drugs, in
particular in combination with lipase inhibiting compounds according to the
present invention. Thus the CB, antagonistic compounds of the formulas (I),
(II),
III), (IV) or (V) in combination with lipase inhibiting compounds are
particularly
suitable also in patient groups with enhanced need of safety and tolerability,
in
particular such as juvenile patients and/or patients subject to long term
treatment,
e.g. in drug induced obesity.
This safety and tolerability of CB, antagonistic compounds of the formulas
(I), (II),
III), (IV) or (V) in combination with lipase inhibiting compounds is
advantageous in
the treatment and/or prophylaxis of obesity in those patient populations where
a
single treatment is not sufficiently effective and a combination treatment
and/or
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21
prophylaxis involving different medical or metabolic mechanisms is desired or
required for achieving and stabilizing a defined degree of weight loss.
Hence, combination of CB, antagonistic compounds of the formulas (I), (II),
III),
(IV) or (V) in combination with lipase . inhibiting compounds according to the
present invention is expected to be very is advantageous in the treatment
and/or
prophylaxis of obesity in general, e.g. of obesity in adolescent patients of
any
age, and particularly also in pediatric or juvenile obesity, and in drug
induced
obesity.
The CB, receptor modulating activity of the compounds of the formulas (I),
(II),
III), (IV) or (V) of the invention makes them particularly useful in the
treatment of
obesity, juvenile obesity and drug induced obesity, when used in combination
with lipase inhibitors. Specific examples of lipase inhibiting compounds which
can
be used in such combination preparations are (but not restricted to) the
synthetic
lipase inhibitor orlistat, panclicins, lipase inhibitors isolated from micro
organisms
such as lipstatin (from Streptomyces toxytricini~, ebelactone B (from
Streptomyces aburaviensis), synthetic derivatives of these compounds, 2-oxy-4H-
3,1-benzoxazin-4-one derivatives like ATL-962 and structurally related
compounds, 2-amino-4H-3,1-benzoxazin-4-one derivatives, as well as extracts of
plants known to possess lipase inhibitory activity, for instance extracts of
Alpinia
officinarum Hance or compounds isolated from such extracts like 3
methylethergalangin (from A. officinarum). The lipase inhibiting compound may
also be a lipase inhibiting polymer. These lipase inhibiting compounds and
their
manufacture are well known in the state of the art.
Lipase inhibiting compounds used in the combinations according to the present
invention may be any lipase inhibiting compound suitable for pharmaceutical
use,
e.g. in particular inhibitors of pancreatic lipases. Lipases are key enzymes
in the
digestive system which break down tri- and diglycerides, which are too large
to be
absorbed by the small intestine into fatty acids which can be absorbed. Since
lipases are responsible for the hydrolysis of fat, a consequence of their
inhibition
is a reduction in fat hydrolysis and absorption. Therefore, inhibition of
lipases
results in a reduction in the absorption of fat. The lipase inhibiting
compound is
preferably the synthetic lipase inhibitor orlistat and structurally related
compounds, 2-oxy-4H-3,1-benzoxazin-4-one derivatives like ATL-962 and
structurally related compounds, 2-amino-4H-3,1-benzoxazin-4-one derivatives,
lipase inhibitors isolated from micro organisms such as lipstatin, ebelactone
B, or
synthetic derivatives of these compounds, however may also be a lipase
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22
inhibiting polymer. Most preferred are orlistat, panclicins, ATL-962 and
lipstatin.
Oriistat (tetrahydrolipstatin) and lipstatin are described in the US-patent US
4,598,089 and its European equivalent EP 0 129 748 B1 in more detail. The
compounds are 2-hexyl-3-hydroxy-hexadecanoic acid lactone derivatives with the
chemical names (2S,3S,5S,7Z,10Z)-5-((S)-2-formamido-4-methylvaleryloxy)-2-
hexyl-3-hydroxy-7,10-hexadecadienoic acid lactone (lipstatin) and (2S,3S,5S)-5-
((S)-2-4-methylvaleryloxy)-2-heyl-3-hydroxy-hexadecanoic acid lactone (tetra-
hydrolipstatin). The compounds are known to be inhibitors of pancreas lipase
which can be used for the prevention of treatment of obesity and
hyperiipaemia,
for which purpose they can be formulated as medicaments or incorporated into
industrially prepared foodstuffs. Inhibition of pancreas lipase prevents the
hydrolysis of dietary fats to give absorbable free fatty acids and
monoglycerides,
so that the fats are excreted unchanged. IC50's for lipstatin and
tetrahydrolipstatin for inhibition of hydrolysis of triolein by porcine
pancrease
lipase are 0.07 and 0.18 mcg/ml, respectively.
Furthermore, there are suitable lipase inhibitors which are structurally
related to
oriistat and/or lipstatin and which are known as panclicins. These panclicines
are
derived from orlistat and contain a 4-ring lactone (Mutoh M; Nakada N;
Matsukima S; Ohshima S; Yoshinari K; Watanabe J Location: Kanagawa, Japan
Issue Date: 19-JAN-1995 Journal: J.Antibiot., 47, No. 12, 1369-75, 1994). The
biological data of these panclicins may be summarized as follows: Panclicins
A,
B, C, D and E, structural analogs of tetrahydrolipstatin (THL), dose-
dependently
inhibited hydrolysis of triolein of fatty acids by porcine pancreatic lipase,
with IC50
values of 2.9, 2.6, 0.62, 0.66 and 0.89 microM, respectively. The inhibitory
activity
of panclicins A and B (alanine moiety in place of leucine in THL) was 2-3-fold
weaker than that of THL; in contrast, the inhibitory activity of panclicins C,
D and
E (glycine moiety in place of leucine in THL) was 2-fold stronger than that of
THL.
Panclicins A, B, C, D and E also potently inhibited plasma lipases with IC50
values of 1.0, 1.2, 0.29, 0.25 and 0,15 microM, respectively. Panclicins A and
B
inhibited plasma lipases with the same potency as THL, while panclicins C, D
and
E had a 3-6-fold greater inhibitory activity than THL. Panclicins A, B, C, D
and E
inhibited bacterial and fungal lipases with profiles similar to those for
porcine
pancreatic lipase. Panclicins inhibited pancreatic lipase irreversibly, but
less
irreversibly than THL. Panclicins A, B, C, D and E irreversibly inhibit
pancreatic
lipase.
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Ebelactone B is described in the US -patent US 4,358,602 and its German
equivalent DE 3 109 335 C1. Ebelactone A and ebelactone B belong to a group
of compounds that exhibit activity to enhance the cell mediated immune
response
in living animals and they also inhibit inflammations in living animals. Thus
they
may be used in the immunological treatment of tumours and for enhancing anti-
tumour agents such as bleomycins. The compounds have anti-esterase activity
and anti-formylmethionine aminopeptidase activity. Admininistration to mice of
these compounds at a dosage of 0.781-50 mg/kg (i.p.) or 0.5 mg/kg (per os)
enhances the development of DTH response and the compounds show a
potentiating effect on cell-mediated immunity. Ebelactone B reduces
carragheenin-induced swelling in mice.
In the context of the present invention the lipase inhibitors administered in
combination with the CB, antagonistic compounds to a patient for treating
obesity
may be also a polymer that has been substituted with or comprises one or more
groups which can inhibit a lipase. Such lipase inhibiting polymers are
described in
the US patents US 6572850, US 6558657, US 6352692, US 6267952 and in the
international patent application WO 99/34786. In one embodiment, the lipase
inhibiting group can be a "suicide substrate" which inhibits the activity of
the
lipase by forming a covalent bond with the enzyme either at the active site or
elsewhere. In another embodiment, the lipase inhibiting group is an isosteric
inhibitor of the enzyme.
In a first aspect of the present invention when using lipase inhibiting
polymers in
addition to the CBS antagonistic compounds, the lipase inhibiting group
inactivates a lipase such as gastric, pancreatic and lingual lipases.
Inactivation
can result by forming a covalent bond such that the enzyme is inactive. The
covalent bond can be formed with an amino acid residue at or near the active
site
of the enzyme, or at a residue which is distant from the active site provided
that
the formation of the covalent bond results in inhibition of the enzyme
activity.
Lipases contain a catalytic triad which is responsible for the hydrolysis of
lipids
into fatty acids. The catalytic triad consists of a serine, aspartate and
histidine
amino acid residues. This triad is also responsible for the hydrolysis of
amide
bonds in serine proteases, and it is expected that compounds that are serine
protease inhibitors will also inhibit lipases. Therefore, serine protease
inhibitors
that can be covalently linked to a polymer are preferred lipase inhibiting
groups.
For example, a covalent bond can be formed between the lipase inhibiting group
and a hydroxyl at or the catalytic site of the enzyme. For instance, a
covalent
bond can be formed with serine. Inactivation can also result from a lipase
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WO 2005/039550 PCT/EP2004/052639
24
inhibiting group forming a covalent bond with an amino acid, for example
cysteine, which is at some distance from the active site. In a second aspect
of the
present invention when using lipase inhibiting polymers in addition to the CB,
antagonistic compounds, non-covalent interaction between the lipase inhibiting
group and the enzyme can also result in inactivation of the enzyme. For
example,
the lipase inhibiting group can be an isostere of a fatty acid, which can
interact
non-covalently with the catalytic site of the lipase. In addition, the lipase
inhibiting
group can compete for lipase hydrolysis with natural triglycerides.
A variety of polymers can be employed in the invention described herein. The
polymers can be aliphatic, alicyclic or aromatic or synthetic or naturally
occurring.
However, aliphatic and alicyclic synthetic polymers are preferred.
Furthermore,
the polymer can be hydrophobic, hydrophilic or copolymers of hydrophobic
and/or
hydrophilic monomers. The polymer can be non-ionic (e.g., neutral), anionic or
cationic, in whole or in part. Furthermore, the polymers can be manufactured
from olefinic or ethylenic monomers (such as vinylalcohol) or condensation
polymers. For example, the polymers can be a polyvinylalcohol, polyvinylamine,
poly-N-alkylvinylamine, polyallylamine, poly-N-alkylallylamine,
polyalkylenimine,
polyethylene, polypropylene, polyether, polyethylene oxide, polyamide,
polyacrylic acid, polyalkylacrylate, polyacrylamide, polymethacrylic acid,
polyalkylmethacrylate, polymethacrylamide, poly-N-alkylacrylamide, poly-N-
alkylmethacrylamide, polystyrene, vinylnaphthalene, ethylvinylbenzene,
aminostyrene, vinyl biphenyl, vinylanisole, vinylimidazolyl, vinylpyridinyl,
dimethylaminomethylstyrene, trimethylammoniumethylmethacrylate,
trimethylammoniumethylacrylate, carbohydrate, protein and substituted
derivatives of the above (e.g., fluorinated monomers thereof) and copolymers
thereof. Preferred polymers include polyethers, such as polyalkylene glycols.
The polymers employed in the methods described herein as well as intermediates
and methods for preparing the polymers are described in detail in the US
patents
US 6572850, US 6558657, US 6352692, US 6267952 and in the international
patent application WO 99/34786, which are all incorporated by reference into
the
present invention.
Recently, in the international patent application WO 03/072555 new 5-
hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones of formula (A) are described to
be pancreatic lipase inhibitors useful for treating metabolic diseases,
cardiovascular diseases or especially obesity.
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WO 2005/039550 PCT/EP2004/052639
R4
R1 ( )
5 R3 N~N~~ A
~O
O
Such oxadiazolones of formula (A) and their salts and acid addition salts are
also
10 suitable for combinations with the CB, antagonistic compounds used
according to
the present invention. In formula (A) the substituents may be as follows:
R1 may be 7-22C alkyl; 2-4C alkyl substituted by 4-20C alkoxy, 6-10C aryl, 6-
10C
aryloxy or (4-12C) alkoxy-(2-4C) alkoxy (where aryl can be substituted by one
or more of halogen, 1-4C alkyl, 1~C alkoxy, N02 or CF3); 7-20C alkenyl; or
15 phenyl substituted by 6-12C alkyl or by phenoxy; and
R2 to R5 each may be H, halogen, N02, 1-4C alkyl, 1-4C alkoxy, CF3 or OCF3;
or (6-10C) aryl-(1-4C) alkoxy, 6-10C aryloxy, 6-10C aryl, 3-8C cycloalkyl or 3-
8C cycloalkoxy (optionally substituted by halogen, CF3, 1-4C alkoxy or 1-4C
alkyl).
These 5-hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones are described to have
pharmacological properties as anorectic, antidiabetic, hypotensive or
cardiant,
with mechanism of action as pancreatic lipase inhibitors. For example 5-
dodecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one had IC50
0.03 microM for inhibition of porcine pancreatic lipase. Hence, these 5-
hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones may be used as medicaments,
especially for the treatment of obesity. As pancreatic lipase inhibtors, the 5-
hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones inhibit the resorption of the
fat
content of foods and thus reduce fat uptake and body weight (or prevent
increase in body weight). Furthermore, the 5-hydrocarbyloxy-3-phenyl-1,3,4-
oxadiazol-2-ones are reported to also have a beneficial effect in the
treatment of
metabolic disorders (e.g. diabetes) or cardiovascular disorders (e.g.
hypertension
and cardiac infarction). The lipase inhibiting compounds of formula (A) are
described in more detail. in the WO 03/072555 and can be obtained according to
known methods. A suitable synthesis for the lipase inhibiting compounds of
formula (A) is described also in the international patent application
WO 03/072555. The whole content of the international patent application
R5
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26
WO 03/072555 is incorporated by reference into the present application
regarding the disclosure of lipase inhibitors of formula (A).
In addition, in the international patent application WO 03/072098 further 5-
hydrocarbyloxy-3-phenyl-1,3,4-oxadiazol-2-ones of formula (A) are described to
be pancreatic lipase inhibitors useful for treating of obesity or diabetes
mellitus
type 1 and 2. Such oxadiazolones of formula (A) as described in WO 03/072098
and their salts and acid addition salts are also suitable for combinations
with the
CB, antagonistic compounds used according to the present invention. In formula
(A) the substituents may be as follows:
R1 may be 1-6C alkyl; 3-9C-cycloalkyl, both groups optionally may be
substituted
by phenyl, 1-4C alkoxy, S-1-4C alkyl, N(1-4C-alkyl)2; and phenyl optionally
may be also substituted by halogen, 1-4C alky, 1-4C-alkyloxy, vitro or CF3;
and
R2 to R5 each may be independently H, halogen, N02, 1-4C alkyl, 1-9C alkoxy
which is substituted by F, 6-10C-aryl, amino or1-4C alkyl amino;
6-10C-aryl-1~C-alkyloxy, 6-10C-aryloxy, 6-10C-aryl, 6-10C-aryloxy-1-4C-
alkyl, 3-8C cycloalkyl or O(3-8 cycloalky), which may optionally be
substituted
by halogen, CF3, 1-4 alkyloxy or 1-4C alkyl;
S02-NH-(1-6C alkyl), optionally substituted by N(1-6C alkyl)2, S02-NH-
(2,2,6,6-tetramethylpiperidin-4-yl), S02-NH-(3-8C cycloalkyl), optionally
substituted by 1-4C alkyl, S02-N(1-6Calkyl)2 or COX;
2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7
with the proviso that R2, R3, R4 and R5 are not H at the same time when
X is O(1-6C alkyl), NH(1-6C alkyl), NH(3-8C cycloalkyl or N(1-6C alkyl)2 and
N(1-6C alkyl)2 may be also pyrrolidino, piperidino, morpholino,
thiomorpholino or piperazino, which optionally substituted by 1-4C alkyl,
benzyl, 6-10C aryl, CO-(1-4 alkyl), CO-(6-10 aryl), CO-O-(1-4C alkyl),
S02-(1-4C alkyl) or S02-(6-10C aryl);
R6 is H, 1-4C alkyl or 6-10C-aryl-1-4C-alkyl, wherein aryl may be substitutet
by halogen, CF3, 1-8C alkyloxy or 1-4C alkyl;
A is a single bond, COn, SOn or CONH;
n is 1 oder2:
R7 is H; 1-18C alkyl or 2-18C alkenyl, which may up to three times substituted
by 1-4C alkyl, halogen, CF3, 1-4C alkyloxy, N(1-4C alkyl)2, -COOH, 1-4C
alkyloxycarbonyl, 6-12C aryl, 6-12C aryloxy, 6-12C arylcarbonyl, 6-10-aryl-
1-4C-alkyloxy or oxo, wherein aryl itself may be optionally substituted by
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27
halogen, 1-4C alkyl, aminosulfonyl or methylmercapto;
6-10C-aryl-1-4C-alkyl, 5-8C-cycloalkyl-1-4C-alkyl, 5-8C cycloalkyl, 6-10-
aryl-2-6C-alkenyl, 6-10C aryl, biphenylyl, Biphenyl-(1-4 alkyl), indanyl,
which may be optionally substituted by 1-18C alkyl, 1-18C alkyloxy,,3-8C
cycloalkyl, COOH, hydroxy, 1-4C alkylcarbonyl, 6-10C-aryl-1-4C alkyl, 6-
10C-aryl-1-4C-alkyloxy, 6-10C aryloxy, vitro, cyano, 6-10C aryl,
fluorsulfonyl, 1-6C alkyloxycarbonyl, 6-10 arylsulfonyloxy, pyridyl, NHS02-
(6-10 aryl), halogen, CF3 or OCF3, wherein alkyl may be additionally
substituted by 1-4C alkyloxycarbonyl, CF3 or carboxy and aryl by halogen,
CF3 or 1-4C alkyloxy;
or the group Het-(CH2)r- with r = 0, 1, 2 or 3 and Het = saturated or
unsaturated 5-7-membered heterocyclus, which may be optionally benzo
anellated and substituted by 1-4C alkyl, 6-1 OC aryl, halogen, 1-4C
alkyloxy, 1~4C alkyloxycarbonyl, 6-10C-aryl-1-4Calkyl, 6-10C-aryl-1-4C-
alkylmercapto or vitro, wherein benzo anellated aryl may be substituted by
halogen, 1-4C alkyloxy or CF3 and alkyl in arylalkyl may be substituted by
methoxy and CF3.
The lipase inhibiting compounds of formula (A) are described in more detail in
the
WO 03/072098 and can be obtained according to known methods. A suitable
synthesis for the lipase inhibiting compounds of formula (A) is described also
in
the international patent application WO 03/072098. The whole content of the
international patent application WO 03/072098 is incorporated by reference
into
the present application regarding the disclosure of lipase inhibitors of
formula (A).
In addition, in the US patent US 6,624,161 and its corresponding international
patent application WO 00/040569 and WO 00/40247 further lipase inhibiting
compounds are described which are also suitable in the context of the present
invention for combination with CB1 antagonistic compounds described herein.
These patent documents US 6,624,161 and WO 00/040569 describe a series of
compounds which are 2-oxy-4H-3,1-benzoxazin-4-one derivatives, including ATL-
962, and their use in obesity and obesity-related disorders, including type 2
diabetes. The 2-oxy-4H-3,1-benzoxazin-4-one derivatives have the formula (B)
or
are or a pharmaceutically acceptable salt, ester, amide or prodrug thereof:
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28
Rsa
R9a
-O
~ / ~ /R1a (g)
R~oa ~ ~N O
R~~a
wherein:
R1a is
(i) a C10-30 branched or unbranched alkyl , optionally substituted by one or
more independently of C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl,
heteroaryl, reduced heteroaryl, -C(O)R13, -C02R13, -SOR13, -
S02R13, -NR13R14, -OR13,
-SR13, -C(O)NR13R14, -NR14C(O)R13, halogen, cyano, and vitro
and/or optionally interrupted by one or more oxygen atoms with the
proviso that any hetero atom in R1a must be separated from the
exocyclic oxygen atom (or from any other heteroatom) by at least two
carbon atoms;
(ii) C2-25 alkenyl, C2-25 alkynyl, C3-6 cycloalkenyl, aryl-C2-25 alkenyl,
heteroaryl-C2-25 alkenyl, reduced heteroaryl, reduced heteroaryl-C1-25
alkyl or a substituted derivative of any of the foregoing groups wherein
the substituents are one or more independently of C1-6 alkyl,
halosubstituted C1-6 alkyl, aryl, aryl-C1-6 alkyl, heteroaryl, reduced
heteroaryl, reduced heteroaryl-C1-6 alkyl, C1-6 alkoxy, aryl-C1-6 alkoxy, -
-C(O)R13, -C02R13, -SOR13, -S02R13, -NR13R14, -OR13, -SR13,
-C(O)NR13R14, -NR14C(O)R13, halogen, cyano, and vitro, with the
proviso that any hetero atom in R1a must be separated from the
exocyclic oxygen atom (or from any other heteroatom) by at least two
carbon atoms;
(iii) a C2-9 alkyl group interrupted by one or more oxygen atoms and
optionally substituted by one or more independently of C3-6 cycloalkyl,
C3-6 cycloalkenyl, aryl, heteroaryl, reduced heteroaryl, -C(O)R13, -
C02R13, -SOR13, -S02R13, NR13R14, OR13, SR13, -C(O)NR13R14,
-NR14C(O)R13, halogen, cyano and vitro with the proviso that any
hetero atom in R1a must be separated from the exocyclic oxygen atom
(or from any other heteroatom) by at least two carbon atoms; or
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29
(iv) a C1-9 alkyl group substituted by a group selected from -C(O)R13, -
C02R13, SOR13, S02R13, NR13R14, OR13, SR13, C(O)NR13R14,
NR14C(O)R13; tetrahydronaphthyl, pyridyl, pyrrolyl, piperidinyl, halogen,
cyano, vitro, bicyclic aryl, bicyclic heteroaryl, monocyclic or bicyclic
reduced heteroaryl, monocyclic heteroaryl other than imidazolyl;
(v) a phenyl group substituted by a group selected from OR17, -COR13, -
C02R13, SOR13, S02R13, CONR13R14, NR14C(O)R13 ;
halosubstituted C1-6 alkyl, aryl, aryIC1-6 alkyl, heteroaryl and
heteroarylC1-6 alkyl; or
(vi) a bicyclic aryl, bicyclic heteroaryl, monocyclic or bicyclic reduced
heteroaryl, or monocyclic heteroaryl group other than imidazolyl,
optionally substituted by a group selected from OR17, -COR13, -
C02R13, SOR13, S02R13, CONR13R14,
NR14 C(O)R13; halosubstituted C1-6 alkyl, aryl, arylC1-6 alkyl, heteroaryl
and heteroarylC1-6 alkyl;
where R13 and R14 each independently represents hydrogen, C1-10
alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-6 cycloalkyl, C3-6
cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl,
reduced heteroaryl or reduced heteroaryl,
C1-10 alkyl, and R17 represents hydrogen or C2-10 alkenyl, C2-10
alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, arylC1-10 alkyl,
heteroaryl, heteroarylC1-10 alkyl, reduced heteroaryl or reduced
heteroarylC1-10 alkyl
and RBa, R9a, R10a and R11a
are each independently hydrogen, halo, hydroxy, amino, vitro, cyano, thiol, C1-
10
alkyl,
C1-10 alkoxy, C1-10 cycloalkyl, C1-10 cycloalkoxy, C(O)R15, C(O)NR15R16,
S(O)R15 or haloC1-10 alkyl;
where R15 and R16 each independently represent hydrogen or C1-10 alkyl with
the proviso that when RBa, R9a, R10a, and R11a are H, R1a is not CH2CH2CI or
C3 alkenyl.
Furthermore in the international patent application WO 00/40247 related 2-
amino-4H-3,1-benzoxazin-4-one derivatives are described as lipase inhibiting
compounds for the treatment of obesity. In formula (B) then the -OR1a
substituent is replaced by a -NR1 R2 group with the definitions for R1 and R2
as
given in the WO 00/40247.
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The above group of structurally related compounds include ATL-962, an oral non-
absorbed synthetic lipase inhibitor derived from Alizyme's pancreatic lipase
inhibitor research program, is under development for the potential treatment
of
obesity and the potential management of type 2 diabetes. ATL-962 has the
5 chemical name 2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one. Preclinical
studies showed that ATL-962 had similar efficacy to orlistat and no toxicity
was
observed. Clinical data for these compounds is also available in the public
domain, e.g. resulting from clinical studies with ATL-962 in obesity.
10 Thus, the results from a phase Ib program with ATL-962 were presented at
the
International Congress of Obesity in Sao Paulo, Brazil. The three phase Ib
trials
involved a total of 99 healthy male volunteers in groups of seven or nine,
given
one of several doses of ATL-962 (66 subjects) or placebo (24 subjects), tid
(three
times in day) with food for 5 days. In one group the nine subjects were given
15 orlistat (qv) 120 mg tid. Overall, ATL-962 was safe and well tolerated and
showed
evidence of efficacy as indicated by an increase in excretion of fat from the
diet.
Subjects given doses between 50 mg and 300 mg ATL-962 bid with meals
excreted fat at an average of between 4.9 (+/~.3) and 11.2 (+/-6.9) g/day
compared to 1.4 (+/-1.0) g/day on placebo and 5.6 (+/-3.8) g/day on orlistat.
20 Compared to placebo, 55% of subjects who received ATL-962 (50 mg to 300 mg)
demonstrated a 3-fold or greater increase in fat excretion and 27% of subjects
demonstrated a 7-fold or greater increase. There was evidence of dose
dependency. Adverse events and their frequency were similar between ATL-962
and placebo and were mainly gastrointestinal, with the predominant event being
25 oily stool.
The results of a multicenter, randomized, double-blind, parallel-group trial
(phase
Ilb study), involving 370 clinically obese patients, was being performed in
specialist clinics in 5 European countries, and in September 2003 preliminary
30 results were reported. All dose levels of ATL-962 (60, 120 and 240 mg)
demonstrated a significant reduction in weight, compared to placebo, for all
treatment groups. There was no difference in the extent of weight loss between
treatment groups. LDL-cholesterol decreased in the treatment groups, but not
for
placebo. There was no difference in HDL-cholesterol levels in the treatment
groups, whilst it increased in placebo-treated patients. Total cholesterol
decreased in the treatment groups, whilst placebo showed an increase. ATL-962
was safe and generally well tolerated.
The lipase inhibiting compounds of formula (B) like ATL-962 and structurally
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31
related compounds are described in more detail in the US patent US 6,624,161
and its corresponding international patent application WO 00/040569, and can
be
obtained according to known methods. A suitable synthesis for the lipase
inhibiting compounds of formula (B) is described also in the US 6,624,161 and
international patent application WO 00/040569. The whole content of the US
6,624,161 and international patent application WO 00/040569 is incorporated by
reference into the present application regarding the disclosure of lipase
inhibitors
of formula (B). The whole content of the international patent application WO
00/040247 is also incorporated by reference into the present application
regarding the disclosure of lipase inhibitors described therein, with related
2-
amino-4H-3,1-benzoxazin-4-one compound structure.
Pharmaceutically acceptable salts, hydrates and solvates, and prodrugs of all
the
above described lipase inhibiting compounds may also be used in the context of
the present invention.
The CB, antagonistic compound of the formulas (I), (II), III), (IV) or (V), or
a
prodrug, tautomer or salt thereof, and the lipase inhibiting compound used
according to the invention can be brought into forms suitable for pediatric
treatment and/or prophylaxis of the diseases indicated above, and in
particular of
obesity, e.g. for adolescent or pediatric administration, as well as for the
administration in treating drug induced obesity by means of usual processes
using pharmaceutical excipients, auxiliary substances and/or liquid or solid
carrier
materials. As therapeutic agents, the CB, antagonistic compound and/or the
lipase inhibiting compounds may be contained together with (conventional)
pharmaceutical excipients, adjuvants and/or auxiliaries in pharmaceutical
preparations such as tablets, capsules, suppositories or solutions. These
pharmaceutical preparations may be prepared according to known methods,
using conventional solid or liquid vehicles such as lactose, starch or talc,
or liquid
paraffins and/or using (conventional) pharmaceutical excipients, adjuvants
and/or
auxiliaries, such as tablet disintegrating agents, solubilisers or
preservatives.
Hence, in a further aspect the invention also pertains to a pharmaceutical
composition containing at least one compound with CB,-receptor activity of the
formulas (I), (II), III), (IV) or (V), or a prodrug, tautomer or salt thereof,
in
combination with at least one lipase inhibiting compound. A preferred
pharmaceutical composition contains at least one compound of the formulas (I),
(II), III), (IV) or (V) as defined above in combination with at least one
lipase
inhibiting compound as combined active components. A further pharmaceutical
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32
composition according to the invention contains as active components at least
one compound with CBS-receptor activity having the formula (I), (II), III),
(IV) or (V)
as defined above, preferably the CB1 antagonistic compound , or a prodrug,
tautomer or salt thereof, and at least one lipase inhibiting compound for the
treatment and/or prophylaxis of obesity in adolescent or in juvenile patients
and/or for the treatment and/or prophylaxis of drug induced obesity in
juvenile as
well as adolescent patients. Particular pharmaceutical compositions according
to
the invention, are characterized in that the at least one compound with CB,-
receptor activity hav ing the formula (I), (II), III), (IV) or (V) as defined
above,
preferably the CBS antagonist, or the prodrug, tautomer or salt thereof, and
the at
least one lipase inhibiting compound each are present in an amount effectively
suited for the treatment and/or prophylaxis of obesity in a juvenile patient
in need
of such treating. In a further embodiment of the invention the CB,
antagonistic
compound, in particular the CB, antagonistic compound of the formulas (I),
(II),
III), (IV) or (V), and the lipase inhibiting compound are each present in the
pharmaceutical composition in an amount effectively suited for the treatment
and/or prophylaxis of drug induced obesity in juvenile as well as adolescent
patients in need of such treating. In the pharmaceutical compositions
according
to the invention the CB, antagonistic compound, preferably the CB,
antagonistic
having the formula (I), (II), III), (IV) or (V), or the prodrug, tautomer or
salt thereof,
is used preferably in combination with at least one lipase inhibiting compound
selected from the group of lipase inhibiting polymers, orlistat, panclicins,
ATL-962
and lipstatin.
The invention also pertains to a pharmaceutical product containing as a
medicament a CB, antagonistic compound, preferably the CBS antagonistic
compound having one of the formulas (I), (II), III), (IV) or (V) as defined
above, or
a prodrug, tautomer or salt thereof, and a leaflet indicating that said CB,
antagonistic compound may be administered in combination with a lipase
inhibiting
compound for simultaneous, separate or step-wise administration in the
treatment
and/or prophylaxis of obesity.
Finally the invention also includes a method of treatment and/or prophylaxis
of
obesity, e.g. in adolescent or in juvenile patients and/or for the treatment
and/or
prophylaxis of drug induced obesity in juvenile as well as adolescent
patients,
characterized in that a CB, antagonistic compound, in particular a compound of
the formula (I), (II), III), (IV) or (V), which is an antagonist of the
cannabis CB,-
receptor, or a prodrug, tautomer or salt thereof, is administered in
combination
with at least one lipase inhibiting compound to a patient in need of such
treating.
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33
In a preferred method of treatment and/or prophylaxis of obesity according to
the
invention a CB, antagonistic compound which is a compound of one of the
formulas (I), (II), III), (IV) or (V)as defined above, or a prodrug, tautomer
or salt
thereof, is administered in combination with at least one lipase inhibiting
compound. The method of treatment and/or prophylaxis of obesity according to
the present invention may be directed to obesity in adolescent or in juvenile
patients and/or to drug induced obesity in juvenile as well as adolescent
patients.
In a variant of the invention the method of treatment and/or prophylaxis is
characterized in that the treating is directed to obesity in juvenile
patients. In a
further variant of the invention the method of treatment and/or prophylaxis is
characterized in that the treating is directed to drug induced obesity in
juvenile or
adolescent patients. In the method of treatment and/or prophylaxis according
to
the invention the CB, antagonistic compound, preferably the CB, antagonistic
compound having one of the formulas (I), (II), III), (IV) or (V) as defined
above, or
a prodrug, tautomer or salt thereof, is administered preferably in combination
with
at least one lipase inhibiting compound selected from the group of lipase
inhibiting polymers, orlistat, panclicins, ATL-962 and lipstatin.
According to the invention the CB, antagonistic compound, preferably the CB1
antagonistic compound having one of the formulas (I), (II), III), (IV) or (V)
as
defined above, or a prodrug, tautomer or salt thereof, is administered in
combination with the lipase inhibiting compound by simultaneous, separate or
step-
wise administration route.
The compounds used in the combinations or compositions according to the
present invention each are preferably administered to a patient in need
thereof
and in a quantity sufficient to prevent and/or treat the symptoms of the
condition,
disorder or disease, e.g. obesity. For all aspects of the invention,
particularly
medical ones, the administration of a compound or composition has a dosage
regime which v~iill ultimately be determined by the attending physician and
will
take into consideration such factors such as the compound being used, animal
type, age, weight, severity of symptoms, method of administration, adverse
reactions and/or other contraindications. Specific defined dosage ranges can
be
determined by standard design clinical trials with patient progress and
recovery
being fully monitored. Such trials may use an escalating dose design using a
low
percentage of the maximum tolerated dose in animals as the starting dose in
man.
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34
The physiologically acceptable compounds used in the combinations or
compositions according to the present invention each are will normally be
administered in a daily dosage regimen (for an adult patient) of, for example,
an
oral dose of between 1 mg and 2000 mg, preferably between 30 mg and 1000
mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or
intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg
and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a
physiologically acceptable salt thereof calculated as the free base, the
compound
being administered 1 to 4 times per day. Suitably the compounds will be
administered for a period of continuous therapy, for example for a week or
more.
For a juvenile patient usually a part of the oral dose for an adult patient is
administered, e.g. 1 fifth to 1 half of the oral dose described before for an
adult
patient.
Preferably, in one embodiment of the invention the method of treatment and/or
prophylaxis is directed to the treating of obesity in juvenile patients. In
another
preferred embodiment of the invention the method of treatment and/or
prophylaxis is directed to the treating of drug induced obesity in juvenile or
adolescent patients. This drug induced obesity may be in particular caused by
drugs like atypical antipsychotics.
In one embodiment of the invention the method of treatment and/or prophylaxis
is
directed to the treating of obesity in juvenile patients. Thus, it is
advantageous
that Cannabinoid antagonists in combination with lipase inhibitors are
particularly
suitable for the treatment of Childhood Obesity and related Comorbidities as
for
example Type 2 Diabetes. There is a clear medical need for improved therapy as
obesity has become an increasingly important medical problem not only in the
adult population but increasingly in children and (young and older)
adolescents.
In national surveys from the 1960s to the 1990s in the United States, the
prevalence of overweight in children grew from 5% to 11% (Sorof and Daniels
2002). In Canada as another example childhood obesity has tripled in the past
20
years (Spurgeon 2002). Obesity in childhood causes a wide range of serious
complications, and increases the risk of premature illness and death later in
life,
raising public-health concerns (Ebbeling, Pawlak et al. 2002). Over the last
decades a tremendous increase of cases of type 2 diabetes was observed,
especially also in children. This epidemic trend is clearly reflecting the
increasing
rates of obesity. Type-2-diabetes was in the past considered a disease of
adults
and older individuals, not a pediatric condition (Arslanian 2002). One of the
main
risk factor of pediatric type 2 diabetes is obesity.
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Type 2 diabetes in children (as is in adults) is part of the insulin
resistance
syndrome (Rosenbloom 2002) that includes hypertension, dyslipidemia and other
atherosclerosis risk factors, and hyperandrogenism seen as premature
5 adrenarche and polycystic ovary syndrome. Other outcomes related to
childhood
obesity include left ventricular hypertrophy, nonalcoholic steatohepatitis,
obstructive sleep apnea, orthopedic problems, and severe psychosocial
problems.
10 In addition primary hypertension has become increasingly common in children
again associated obesity as a major independent risk factor. Obese children
are
at approximately a 3-fold higher risk for hypertension than non-obese children
(Sorof and Daniels 2002). The benefits of weight loss for blood pressure
reduction in children have been demonstrated in both observational and
15 interventional studies.
Public concerns are rising because of a rapid development of the childhood
obesity epidemic in genetically stable populations. Driving factors are
assumed to
be mainly adverse environmental factors for which straightforward
20 recommendations of life style modifications exists. Obesity and it's
related co-
morbidities are very serious medical conditions and state of the art measures
and
treatment of obesity and especially childhood obesity remain largely
ineffective at
the time being (Ebbeling, Pawlak et al. 2002). The management of type 2
diabetes in is also especially difficult in children and the adolescent age
group
25 (Silink 2002). Craving for and over consumption of palatable food is one of
the
important factors of life-style related obesity in humans and especially also
in
children and adolescents. Treatment of type 2 diabetes and other co-morbid
conditions by the degree of metabolic derangement and symptoms: The only
data on the use of oral hypoglycemic agents in children with type 2 diabetes
has
30 been with metformin (Rosenbloom 2002).
Thus, CB, antagonists used according to the present invention in combination
with lipase inhibitors offer a unique opportunity for the treatment of obesity
by
interacting with these "driving forces°. They are superior to current
medical
35 treatments and especially suited for adolescent as well as pediatric
treatment
because of their outstanding safety profile and/or tolerability and
surprisingly
beneficial combination effects. Besides efficacy, the treatment of obesity,
especially the treatment of childhood obesity, dictated by safety.
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Obesity in childhood is a medical condition that is likely to require long-
term
management. The safety profile of CB, antagonists used according to the
present invention in combination with lipase inhibitors are suggested to be
superior to current standard medications, and these CB, antagonists in
combination with lipase inhibitors will be especially suited for the.treatment
and
prevention of obesity in adolescents and in childhood obesity and related co-
morbidities.
Literature:
Arslanian, S. (2002). "Type 2 diabetes in children: clinical aspects and risk
factors." Horm Res 57 Suppl 1: 19-28.
Ebbeling, C. B., D. B. Pawlak, et al. (2002). "Childhood obesity: public-
health
crisis, common sense cure." Lancet 360(9331 ): 473-82.
Rosenbloom, A. L. (2002). "Increasing incidence of type 2 diabetes in children
and adolescents: treatment considerations." Paediatr Druas 4(4): 209-21.
Silink, M. (2002). "Childhood diabetes: a global perspective." Horm Res 57
Suppl
1: 1-5.
Sorof, J. and S. Daniels (2002). "Obesity hypertension in children: a problem
of
epidemic proportions." Hypertension 40(4): 441-7.
Spurgeon, D. (2002). "Childhood obesity in Canada has tripled in past 20
years."
324(7351 ): 1416.
In another embodiment of the invention the method of treatment and/or
prophylaxis is directed to the treating of drug induced obesity in juvenile or
adolescent patients. Drug induced weight gain is also of major concern and
subject to high medical need of improved treatments. Again, in this context
the
CB, antagonists in combination with lipase inhibitors according to the present
invention are suggested to be superior to current standard medications, and
these CB, antagonists in combination with lipase inhibitors will be especially
suited for the treatment and prevention of drug induced obesity in juvenile as
well
as in adolescent patients.
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Regarding drug induced weight gain, it is reported by Zimmermann, U., T.
Kraus,
et al. (2003, "Epidemiology, implications and mechanisms underlying drug-
induced weight gain in psychiatric patients." J Psychiatr Res 37(3): 193-220)
that
body weight gain frequently occurs during drug treatment of psychiatric
disorders
and is often accompanied by increased appetite or food craving. While
occurrence and time course of this side effect are difficult to predict, it
ultimately
results in obesity and the morbidity associated therewith in a substantial
part of
patients, often causing them to discontinue treatment even if it is effective.
Weight gain appears to be most prominent in patients treated with some of the
second generation antipsychotic drugs and with some mood stabilizers. Marked
weight gain also frequently occurs during treatment with most tricyclic
antidepressants.
Very large weight gains are associated with drugs like for example the
atypical
antipsychotics clozapine and olanzapine. Some atypical antipsychotics,
however,
tend to cause significant weight gain, which may lead to poor compliance and
other adverse health effects (Nasrallah, H. (2003). "A review of the effect of
atypical antipsychotics on weight." Psychoneuroendocrinology 28 Suppl 1: 83-
96.). The mechanisms involved in antipsychotic drug-related weight gain are as
yet uncertain, although serotoninergic, histaminic, and adrenergic affinities
have
been implicated along with other metabolic mechanisms. The atypical
antipsychotics vary in their propensity to cause weight change with long-term
treatment. Follow-up studies show that the largest weight gains are associated
with clozapine and olanzapine, and the smallest with quetiapine and
ziprasidone.
Risperidone is associated with modest weight changes that are not dose
related.
Given the equivalent efficacy of atypical antipsychotics, weight-gain profile
is a
legitimate factor to consider when constructing an algorithm for treatment due
to
the serious medical consequences of obesity. In this regard co-administration
of
a CB, antagonist in combination with lipase inhibitors according to the
invention is
suggested to work beneficially.
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Experimental protocol for study of
CB, antagonistic compound plus lipase inhibitor effects on obesity
The beneficial pharmacological effects of the combination of a CB, antagonist
with a lipase inhibitor according to the invention can be shown by standard
experimental animal models by measuring the influence of the administered
combination of a CB, antagonist with a lipase inhibitor on the driving and
characteristic parameters associated with obesity.
For investigation of the influence of the combination of a CB, antagonist with
a
lipase inhibitor on obesity the body weight gain in rats may be measured as a
pharmacological indicator. Here fore, the following experimental protocol for
rats
may be applied:
The rats will have unlimited access to feed for two 2.5h periods per day,
during
the dark phase of a reversed 12h/12h light cycle, e.g. lights are put on at
21.15h
and put off at 09.15h. The rats will be offered a high fat, high sucrose diet
(Western diet). The lipase inhibitor will be dosed immediately before the rats
are
fed. The CB, antagonist will be dosed 1 h before the lipase inhibitor is
administered.
As an example, the following daily dosing schedule is applicable for a given
period of e.g. days, weeks or months:
The CB, antagonist, in particular the CB, antagonisic compound of formula (I)
as
defined above, or a vehicle dose is administered (po) in the morning at ca.
07.45
to 08.00 h. The lipase inhibitor, e.g. in particular orlistat, or a vehicle
dose is
administered (po) ca. 08.45 to 09.00 h. After medication the rats are set to
ad
libitum feed from 09.15 to 11.45h, followed by feed removal from about 11.45
to
14.45 h. Another dose of lipase inhibitor, e.g. in particular orlistat, or
vehicle
(Labrasol) dose is administered (po) in the afternoon at about 14.15 to
14.30h,
followed by ad-libitum feed from 14.45 to 17.15 h. Thereafter, the rats are
set to
feed deprivation from 17.15 - 09.15 h.
The experimental protocol results will compare daily food intake and body
weight
gain as indicators for the effects of the combination treatment on obesity
during
the experimental phase. In addition to the before given parameters it may be
desired to also collect faeces and to estimate fat digestibility. Eventually
it may be
also desired to perform a carcass analysis.
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Furthermore, after finishing the experimental feeding and administering phase,
biochemical parameters may be measured at slaughter of the rats.
For investigating the effects the total number of rats subject to the
experimental
protocol is divided into the following groups with approximately the same
number
of rats in each group:
1 ) Control group: The rats receive only vehicle according to the protocol to
simulate administration (placebo group).
2) CBS group: The rats receive a CB, antagonist in a vehicle.
3) LI group: The rats receive as lipase inhibitor ("LI") e.g. the compound
orlistat in a vehicle.
4) CB,+LI group (combination group): The rats receive a CB, antagonist in a
vehicle and as lipase inhibitor (°LI") e.g. the compound orlistat in a
vehicle.
The results of this protocol and the respective investigations show the
beneficial
suitability of the combination of a CBS antagonist and a lipase inhibitor in
the
treatment and / or prophylaxis of obesity.
Preparation of compounds of formula N)
The 1H-1,2,4-triazole-carboxamide derivatives of formula (V), which are potent
cannabinoid-CB, receptor agonists, partial agonists, inverse agonists or
antagonists, useful for the treatment of psychiatric and neurological
disorders, as
well as other diseases involving cannabinoid-CBS neurotransmission, are
defined
above in the specification.
1,5-Diaryl-1H-1,2,4-triazole-3-carboxamide derivatives have been described in
EP 0346620 and GB 2120665 as herbicides. Recently 1,2,4-triazoles were
described as potential agonists and antagonists of cannabinoid-CB, and -CB2
receptors (Jagerovic, N. et al., Drugs Fut. 2002, 27(Suppl. A): XVllth Int.
Symp.
on Medicinal Chemistry, P284)
A group of four 1,5-diaryl-1H-1,2,4-triazole-3-carboxamide derivatives in
which
the amide N-atom is part of an unsubstituted piperidinyl or morpholinyl group
is
described by D. Clerin and J.P. Fleury in Bull. Soc. Chim. Fr., 1974, 1-2,
Pt.2,
211-217.
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1-(4-Methylphenyl)-5-phenyl-N-(2-pyridyl)-1 H-1,2,4-triazole-3-carboxamide is
described by M. H. Elnagdi et al. in Heteroatom Chem., 1995, 6, 589-592.
A group of four 1,5-diaryl-N-(2-pyridyl)-1H-1,2,4-triazole-3-carboxamides is
5 described by A. H. Harhash et al. in Indian J. Chem., 1976, 14B, 268-272.
Suitable synthetic routes for the compounds of formula (V) used in the
invention
are the following:
Synthetic route A
Step 1: Ester hydrolysis of a compound having formula (S-II) wherein R6
represents a branched or unbranched (C,.~)-alkyl group or a benzyl group,
R~
N
N ~ N (S-II)
O
RB O
yields a compound having formula (S-III)
R~
N
N ~ N (S-III)
O
H-O
wherein R and R, have the meanings as described above.
The compounds of the invention having formula (S-II), wherein Rg represents a
branched or unbranched alkyl group (C,~) or benzyl group can be obtained
according to methods known, for example:
a) Sawdey, G.W. J. Am. Chem. Soc. 1957, 79, 1955
b) Czollner, l_. et al., Aroh. Pharm. (Weinheim) 1990, 323, 225
c) Eicher, T. and Hauptmann, S. The Chemistry of Heterocycles, Thieme Verlag,
Stuttgart, 1995 (ISBN 313 100511 4), p. 208-212.
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41
Step 2: Reaction of a compound having formula (S-III) with a compound having
formula R2R3NH wherein R2 and R3 have the meanings as described above via
activating and coupling methods such as formation of an active ester, or in
the
presence of a coupling reagent such as DCC, HBTU, BOP, CIP (2-chloro-1,3-
dimethylimidazolinium hexafluorophosphate) or PyAOP (7-azabenzotriazol-1-
yloxytris(pyrrolidino)phosphonium hexafluorophosphate). Activating and
coupling
methods of this type are described in
a) M. Bodanszky and A. Bodanszky: The Practice of Peptide Synthesis,
Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7;
b) K. Akaji et al., Tetrahedron Lett. (1994), 35, 3315-3318);
c) F. Albericio et al., Tetrahedron Lett. (1997), 38, 4853-4856).
This reaction gives a 1H-1,2,4-triazole derivative having formula (V).
Synthetic route B
A compound having formula (S-III) is reacted with a halogenating agent such as
thionyl chloride (SOCI2) or oxalyl chloride. This reaction yields the
corresponding
carbonyl chloride (acid chloride) (S-IV).
R~
N
N ~ N (S-IV)
O
CI
Reaction of a compound having formula (S-IV) with a compound having formula
R2R3NH wherein wherein R2 and R3 have the meanings as described above gives
a 1 H-1,2,4-triazole derivative having formula (V).
Synthetic route C
A compound having formula (S-II) is reacted in an amidation reaction with a
compound having formula R2R3NH wherein R2 and R3 have the meanings as
described hereinabove to give a 1H-1,2,4-triazole derivative having formula
(V).
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Such amidation reactions can be promoted by the use of trimethylaluminum
AI(CH3)3 (For more information on aluminum-mediated conversion of esters to
amides, see: J. I. Levin, E. Turns, S. M. Weinreb, Synth Commun. (1982), 92,
989-993. )
Example I
Part A: To a stirred solution of dimethyl aminomalonate hydrochloride (25
gram,
0.136 mol) in dichloromethane (200 mL) triethylamine (41.4 mL, 2.2 molar
equivalent) is added at 0 °C. 4-Chlorobenzoyl chloride (23.8 gram,
0.136 mol) is
slowly added and the resulting solution is allowed to stand at room
temperature
overnight. Water is added and the organic layer is separated. The water layer
is
extracted twice with dichloromethane. The collected organic layers are washed
with water, dried over MgS04, filtered and concentrated in vacuo. The residue
is
recrystallised from methanol (400 mL) to give dimethyl 2-(4-
chlorobenzoylamino)malonate (30.5 gram, 79 % yield). Melting point: 146-148
°C.
'H-NMR (200 MHz, CDCI3): , 3.86 {s, 6H), 5.38 (d, J = 6 Hz, 1H), 7.15 (br d, J
6Hz, 1H),7.43(d,J=8Hz,2H),7.79(d,J=8Hz,2H).
Part B: To a stirred suspension of 2,4-dichloroaniline (19.44 gram, 0.12 mol)
in
concentrated HCI (25 mL) and acetic acid ( 75 mL) at 0 °C is added a
solution of
NaN02 (9.0 gram, 0.13 mol) in water (50 mL) and the resulting solution is
stirred
for 15 minutes. A solution of dimethyl 2-(4-chlorobenzoylamino)-malonate
(28.55
gram, 0.10 mol) in acetone (200 mL) is slowly added while keeping the
temperature below 0 °C. A solution of K2C03 (120 gram) in water (200
mL) is
slowly added and the resulting black mixture is stirred for 30 minutes at 0
°C. The
mixture is extracted three times with EtOAc. The collected organics are washed
with water, aqueous NaHC03 and water, respectively, dried over MgS04, filtered
and concentrated in vacuo. The residue is dissolved in methanol (500 mL) and a
solution of sodium (1 gram) in methanol (75 mL) is added. The resulting
stirred
mixture is allowed to stand overnight at room temperature and cooled in a
refrigerator. The formed precipitate is collected by filtration and washed
with
methanol to give methyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-1,2,4-
triazole-3-carboxylate (11.4 gram, 30 % yield). Melting point: 153-154
°C.'H-NMR
(200 MHz, CDCI3): , 4.07 {s, 3H), 7.287.60 (m, 7H).
Part C: To a stirred suspension of methyl 5-(4-chlorophenyl)-1-(2,4
dichlorophenyl)-1 H-1,2,4-triazole-3-carboxylate (11.3 gram, 0.0295 mol) in
methanol (100 mL) is added KOH (45 % aqueous solution, 7.5 mL) and the
resulting mixture is heated at reflux temperature for 4 hours. The mixture is
concentrated in vacuo and water (150 mL) and concentrated HCI are added. The
yellow precipitate is collected by filtration, washed with water and dried in
vacuo
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to give 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-
carboxylic
acid (10.0 gram, 92 % yield). Melting point: 141-144 °C
(decomposition).
Part D: To a stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1 H
1,2,4-triazole-3-carboxylic acid (1.48 gram, 4.0 mmol) in acetonitrile (20 mL)
is
successively added diisopropylethylamine (DIPEA) (1.5 mL, 2.1 molar
equivalent), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophos-
phate (HBTU) (1.66 gram, 1.1 molar equivalent) and 1-aminopiperidine (0.44
gram, 1.1 molar equivalent). After stirring overnight an aqueous NaHC03
solution
is added. The resulting mixture is three times extracted with dichloromethane.
The combined organic layers are washed with water, dried over Na2S04, filtered
and concentrated in vacuo to give a crude oil (3.6 gram). This oil is further
purified by flash chromatography (silica gel; EtOAc / petroleum ether (40-60
°C) _
7/3 (v/v)). The purified material is treated with ethanolic HCI (1 M solution)
to give
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1 H-1,2,4-
triazote-3-
carboxamide hydrochloride (1.50 gram, 77 % yield). Melting point: 238-240
°C
(decomposition). 'H-NMR (400 MHz, DMSO-ds): , 1.46-1.54 (m, 2H), 1.78-1.85
(m, 4H), 3.22-3.28 (m, 4H), 7.50 (s, 4H), 7.70 (dd, J = 8 and 2 Hz, 1 H), 7.85-
7.87
(m, 1 H), 7.91 (d, J = 8 Hz, 1 H), (NH not visible).
Analogously were prepared the examples 2-18:
2. 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-(pyrrolidin-1-yl)-1 H-1,2,4-
triazole-3-carboxamide hydrochloride. Melting point: 248-255 °C
(decomposition).
3. 5-(4-Chlorophenyl)-N-cyclohexyl-1-(2,4-dichlorophenyl)-1 H-1,2,4-triazole-
3-carboxamide. Melting point: 186-188 °C.
4. N-t-Butoxy-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-
carboxamide. Melting point: 150-152 °C.
5. 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-(n-pentyl)-1H-1,2,4-triazole-3-
carboxamide. 'H-NMR (400 MHz, CDCI3): , 0.92 (t, J = 7 Hz, 3H), 1.35-
1.44 (m, 4H), 1.62-1.70 (m, 2H), 3.48-3.56 (m, 2H), 7.20-7.25 (m, 1 H),
7.34 (dt, J = 8 and 2 Hz, 2H), 7.42-7.50 (m, 4H), 7.54 (d, J = 2 Hz, 1 H).
6. 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-(morpholin~-yl)-1 H-1,2,4-
triazole-3-carboxamide. Melting point: 184-186 °C.
7. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1 H-1,2,4-
triazole-3-carboxamide hydrochloride. Melting point: 234-237 °C
(decomposition).
8. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(pyrrolidin-1-yl)-1 H-1,2,4-
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triazole-3-carboxamide hydrochloride. Melting point: 234-236 °C
(decomposition).
9. 1-(4-Chlorophenyl)-N-cyclohexyl-5-(2,4-dichlorophenyl)-1 H-1,2,4-triazole-
3-carboxamide. 'H-NMR (400 MHz, CDCI3): 1.14 -1.81 (m, 8H), 2.02
2.10 (m, 2H), 4.00-4.11 (m, 1 H), 7.08 (br d, J ~ 7 Hz, 1 H), 7.26 (br d, J ~
8
Hz, 2H), 7.34 (br d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1 H), 7.44-7.48
(m, 2H).
10. N-t-Butoxy-1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-
carboxamide. 'H-NMR (400 MHz, CDCI3): 1.38 (s, 9H), 7.25 (br d, J ~ 8
Hz, 2H), 7.35 (br d, J ~ 8 Hz, 2H), 7.41 (dd, J = 8 and 2 Hz, 1 H), 7.44-7.48
(m, 2H), 9.18, br s, 1 H).
11. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(n-pentyl)-1 H-1,2,4-triazole-
3-
carboxamide. 'H-NMR (400 MHz, CDCI3): , 0.91 (t, J = 7 Hz, 3H), 1.35-
1.41 (m, 4H), 1.60-1.70 (m, 2H), 3.48-3.56 (m, 2H), 7.21 (br t, J ~ 7 Hz,
1 H), 7.26 (br d, J - 8 Hz, 2H), 7.34 (br d, J ~ 8 Hz, 2H), 7.40 (dd, J = 8
and 2 Hz, 1 H), 7.44-7.48 (m, 2H).
12. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(morpholin-4-yl)-1 H-1,2,4
triazole-3-carboxamide hydrochloride. Melting point: 224-226 °C.
13. 1-(2,4-Dichlorophenyl)-5-(pyridin-2-yl)-N-(piperidin-1-yl)-1 H-1,2,4-
triazole-
3-carboxamide. Melting point: 191-193 °C.
14. 5-(2,4-Dichlorophenyl)-N-(piperidin-1-yl)-1-(4-(trifluoromethyl)phenyl)-1
H-
1,2,4-triazole-3-carboxamide. Melting point: 159-161 °C.
15. 1'-[5-(2,4-dichlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1 H-1,2,4-triazol-
3-
yl)carbonyl]piperidine. Melting point: 155-156 °C.
16. 1-(2,4-Dichlorophenyl)-N-(piperidin-1-yl)-5-(pyridin-3-yl)-1 H-1,2,4-
triazole-
3-carboxamide. Melting point: 219 °C.
17. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(5,5,5-trifluoropenty1)-1 H-
1,2,4-triazole-3-carboxamide. 'H-NMR (400 MHz, CDCI3): , 1.681.80 (m,
4H), 2.06-2.22 (m, 2H), 3.54 (q, J ~ 7 Hz, 2H), 7.26 (m, 3H), 7.34 (br d, J
~ 8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1 H), 7.44-7.48 (m, 2H).
18. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(5-fluoropentyl)-1 H-1,2,4-
triazole-3-carboxamide. 'H-NMR (400 MHz, CDCI3): , 1.631.80 (m, 4H),
2.06-2.22 (m, 2H), 3.54 (q, J ~ 7 Hz, 2H), 7.22-7.28 (m, 3H), 7.34 (br d, J
8 Hz, 2H), 7.40 (dd, J = 8 and 2 Hz, 1 H), 7.44-7.48 {m, 2H).
Example 19
Part A: 1-{Chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-carboxylic
acid was prepared analogously to the procedure as described in Example 1, Part
A-C by using dimethyl aminomalonate hydrochloride, 2,4-dichlorobenzoyl
chloride
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and 4-chloroaniline as starting materials, respectively. Melting point: 102-
104 °C.
'H-NMR (400 MHz, DMSO-dg):, 7.36 (br d, J ~ 8 Hz, 2H), 7.50 (br d, J ~ 8 Hz,
2H), 7.59 (dd, J = 8 and 2 Hz, 1 H), 7.70 (d, J = 2 Hz, 1 H), 7.75 (d, J = 8
Hz, 1 H),
OH proton is part of water peak at 3.4.
5 Analogously was 1-(chlorophenyl)-5-(2,5-dichlorophenyl)-1H-1,2,4-triazole-3
carboxylic acid prepared by using dimethyl aminomalonate hydrochloride, 2,5
dichlorobenzoyl chloride and 4-chloroaniline as starting materials,
respectively.
Melting point: 183-188 °C. 'H-NMR (400 MHz, DMSO-ds):, 7.41 (br d, J
~ 8 Hz,
2H), 7.52 (br d, J ~ 8 Hz, 2H), 7.56 (d, J = 8 Hz, 1 H), 7.65 (dd, J = 8 and 2
Hz,
10 1 H), 7.88 (d, J = 2 Hz, 1 H), OH proton is part of water peak at 3.5.
Part B: To a stirred solution of 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-
1,2,4
triazole-3-carboxylic acid (0.37 g, 1.00 mmol) in dichloromethane (10 mL) is
added oxalyl chloride (0.254 g, 2.00 mmol). The resulting mixture is
concentrated
in vacuo to give crude 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1,2,4-
triazole
15 3-carbonyl chloride.
Part C: The crude 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-
carbonyl chloride is dissolved in tetrahydrofuran (THF) (10 mL). 2,3-Dihydro-1
H-
inden-2-ylamine (0.40 g, 3.00 mmol) is added and the resulting solution is
stirred
for 42 hours at 25 °C. The mixture is concentrated in vacuo and the
residue is
20 purified by preparative liquid chromatography to give pure 1-(4-
chlorophenyl)-5-
(2,4-dichlorophenyl)-N-(2,3-dihydro-1 H-inden-2-yl)-1 H-1,2,4-triazole-3-
carboxamide (393 mg, 81 % yield). MS (ESI+) 485.6. 'H-NMR (400 MHz, DMSO-
ds): 3.06 (dd, J = 16 and 8 Hz, 2H), 3.21 (dd, J = 16 and 8 Hz, 2H), 4.71-4.82
(m,
1 H), 7.12-7.16 (m, 2H), 7.19-7.24 (m. 2H), 7.39 (br d, J ~ 8 Hz, 2H), 7.52
(br d, J
25 ~ 8 Hz, 2H), 7.60 (dd, J = 8 and 2 Hz, 1H), 7.71 (d, J = 2 Hz, 1H), 7.79
(d, J = 8
Hz, 1 H), 8.93-8.97 (m, 1 H, NH).
Analogously were prepared the examples 203:
30 20. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(1-ethynylcyclohexyl)-1H-
1,2,4-triazole-3-carboxamide. MS (ESI+) 473.3.
21. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(2-methylcyclohexyl)-1 H-
1,2,4-triazole-3-carboxamide. MS (ESI+) 465.5.
22. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(4-methylcyclohexyl)-1 H-
35 1,2,4-triazole-3-carboxamide. MS (ESI+) 465.5.
23. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-cyclooctyl-1 H-1,2,4-triazole-
3-
carboxamide. MS (ESI+) 477.3.
24. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(azepan-1-yl)-1 H-1,2,4-
triazole-3-carboxamide. MS (ESI+) 466.4.
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25. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-cycloheptyl-1 H-1,2,4-triazole-
3-carboxamide. MS (ESI+) 465.5.
26. N-t-Butyl-1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-
carboxamide. MS (ESI+) 425.4.
27. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(1,1-diethylprop-2-yn-1-yl)-
1H-1,2,4-triazole-3-carboxamide. MS (ESI+) 461.5.
28. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(2,2,2-trifluoroethyl)-1 H-
1,2,4-
triazole-3-carboxamide. MS (ESI+) 451.3.
29. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(exo-bicyclo[2.2.1 ]hept-2-yl)-
1H-1,2,4-triazole-3-carboxamide. MS (ESI+) 461.5.
30. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(4-(2-propyl)piperazin-1-yl)-
1H-1,2,4-triazole-3-carboxamide. MS (ESI+) 480.3. 'H-NMR (400 MHz,
DMSO-ds): 1.00 (d, J = 7 Hz, 6H), 2.46-2.56 (m, 4H), 2.72 (septet, J = 7
Hz, 1 H), 3.66-3.74 (m, 4H), 7.36 (br d, J = 8 Hz, 2H), 7.51 (br d, J = 8 Hz,
2H), 7.59 (dd, J = 8 and 2 Hz, 1H), 7.72 (d, J = 2 Hz, 1H), 7.75 (d, J = 8
Hz, 1 H).
31. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-
(hexahydrocyclopenta[c]pyrrol-2(1 H)-yl)-1 H-1,2,4-triazole-3-carboxamide.
MS (ESI+) 476.4.
32. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-pentyl-1H-1,2,4-triazole-3-
carboxamide. MS (ESI+) 435.5.
33. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(2,2-dimethylpropyl)-1 H-
1,2,4-triazole-3-carboxamide. MS (ESI+) 439.6.
34. 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-N-(3-(trifluoromethyl)phenyl)-
1H-1,2,4-triazole-3-carboxamide. MS (ESI+) 511.7.
35. 1'-[1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-1 H-1,2,4-triazol-3-
yl)carbonyl]-1,4'-bipiperidine. MS (ESI+) 520.5.
36. 1-(4-Chlorophenyl)-N-(4-chlorophenyl)-5-(2,5-dichlorophenyl)-N-methyl-
1H-1,2,4-triazole-3-carboxamide. MS (ESI+) 491.4.
37. 1-(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-(1-ethynylcyclohexyl)-1H-
1,2,4-triazole-3-carboxamide. MS (ESI+) 473.4.
38. 1-(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-(2-methylcyclohexyl)-1 H-
1,2,4-triazole-3-carboxamide. MS (ESI+) 465.5.
39. 1-(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-(4-methylcyclohexyl)-1 H-
1,2,4-triazole-3-carboxamide. MS (ESI+) 465.6.
40. 1-(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-cyclooctyl-1 H-1,2,4-triazole-
3-
carboxamide. MS (ESI+) 477.3.
41. 1-(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-cycloheptyl-1 H-1,2,4-triazole-
3-carboxamide. MS (ESI+) 465.6.
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42. 1-(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-cyclopentyl-1 H-1,2,4-triazole-
3-carboxamide. MS (ESI+) 435.5.
43. 1-(4-Chlorophenyl)-5-(2,5-dichlorophenyl)-N-(2,2-dimethylpropyl)-1 H-
1,2,4-triazole-3-carboxamide. MS (ESI+) 439.6.
Pharmacological test results of a subset of the compounds of the invention,
obtained with the assays described above, are given in the table below:
Human cannabinoid-CB,
rece tors
In vitro affini In vitro anta onism
Exam 1e K, value AZ value
Example 2 6.6 7.2
Example 3 6.9 8.7
Example 5 6.9
Example 9 7.4 8.2
Example 11 6.3
