Note: Descriptions are shown in the official language in which they were submitted.
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SULPHUR CONTAINING PYRAZOLE DERIVATIVES AS SELECTIVE CANNABINOID CB1
RECEPTOR ANTAGONISTS
INDEX page
Title of the invention 1
Index 1
Summary: technical field of the invention 1
Background of the invention 2
Detailed description of the invention 3
Definitions of chemical and other terms 7
Examples 10
Example 1: Analytical methods 10
Example 2: General aspects of syntheses 11
Example 3: Syntheses of compounds of the invention 14
Example 4: Pharmacological methods 19
Example 5: Pharmacological test results 20
Example 6: Pharmaceutical preparations 21
References, cited patents and patent applications 23
Claims 25
Abstract 29
SUMMARY: TECHNICAL FIELD OF THE INVENTION
The present invention relates to sulphur containing pyrazole derivatives, and
their S-oxidized
active metabolites, as selective cannabinoid CB1 receptor antagonists having a
high CB1/CB2
receptor subtype selectivity, to methods for the preparation of these
compounds, to novel
intermediates useful for the synthesis of said pyrazole derivatives, to
pharmaceutical
compositions comprising one or more of these pyrazole derivatives as active
ingredients, as
well as to the use of these pharmaceutical compositions for the treatment of
psychiatric and
neurological disorders. The compounds have the general formula (I)
0
ci
N- H-N
R1 N / x-Y
/
(I)
RZ
wherein the symbols have the meanings given in the specification.
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BACKGROUND OF THE INVENTION
Pyrazole derivatives having CB receptor affinity are known from several patent
applications,
(including WO 98/43636, WO 98/43635, WO 2005/000820, W02006/030124, WO 2004/
099157, EP 0876350 and US 2006/0100208), and other publications (Lan, 1999;
Francisco,
2002; Katoch -Rouse, 2003; Meschler, 2000; Matthews, 1999). CB1 receptor
antagonists, in
particular SR141716A, now known as rimonabant, and their potential therapeutic
applications,
have been the subject of several reviews (Boyd, 2005; Sorbera, 2005; Carai,
2005; Lange,
2004, 2005; Hertzog, 2004; Smith, 2005; Thakur, 2005; Padgett, 2005; Muccioli,
2005, 2006;
Reggio, 2003; Adam, 2006). The abovementioned patent applications and articles
disclose a
number of CB1/CB2 receptor subtype selective receptor antagonists. Cannabinoid
(CB)
receptors are part of the endocannabinoid system which is involved in
neurological-, psychiatric-
cardiovascular-, gastrointestinal-, reproductive- and eating disorders as well
as in and cancer
(De Petrocellis, 2004; Di Marzo, 2004; Lambert, 2005; Vandevoorde, 2005;
Centonze, 2007).
CB1 receptor modulators have several potential therapeutic applications such
as
medicaments for treating psychosis, anxiety, depression, attention deficits,
memory disorders,
cognitive disorders, appetite disorders, obesity, addiction, appetence, drug
dependence,
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 ischaemia, 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, septic shock, glaucoma,
diabetes, cancer,
emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhoea, sexual
disorders, impulse
control disorders and cardiovascular disorders.
CB2 receptors occur predominantly in the immune system (spleen, tonsils,
immune cells)
as well as in microglial cells and astrocytes and have recently also been
found in the central
nervous system brainstem and cerebellum) (Van Sickle, 2005; Ashton, 2006).
Potent CB1 receptor modulators having low CB2 receptor affinity (i.e.
compounds having
a high CB1/CB2 receptor subtype selectivity) are advantageous compounds as
compared to
non-selective or less selective cannabinoid receptor modulators as they will
be devoid of
undesired CB2 receptor mediated side-effects, such as immunologic side-effects
or
inflammatory related side- effects or effects on neuropathic pain perception.
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DETAILED DESCRIPTION OF THE INVENTION
The goal of the present invention was to develop further orally active CB 1
receptor antagonists
with a high CB1/CB2 receptor subtype selectivity.
Certain pyrazole derivatives of formula (I), in which X (see below) represents
a CH2
group, are known to be CB1 receptor antagonists. Surprisingly, it was found
that replacement of
this CH2 group by a sulphur atom results in compounds that not only are
CB1/CB2 receptor
subtype selective CB1 receptor antagonists, but that are more potent than
their non-sulphur
containing analogs when tested orally in an in vivo CB 1 receptor mediated
pharmacological
assay. Compounds of the general formula (I) wherein X represents a S=O or a
SO2 group can
be considered as metabolites of the compounds of the general formula (I)
wherein X represent a
sulphur atom. Such compounds of the general formula (I) wherein X represents a
S=O
(sulfoxide) or a SO2 (sulfone) group were surprisingly found to elicit also
significant CB1 receptor
affinities and as a result can be considered as active S-oxidized metabolites
of the compounds
of the general formula (I) wherein X represents a sulphur atom. The formation
of active
metabolites is known in general to enhance the potency of therapeutics in
vivo. Active
metabolites of the general formula (I) wherein X represents a S=O or a SO2
group are part of
the present invention. Cytochrome P450 is an important endogenous enzyme which
is involved
in such metabolic oxidations of alkyl sulfides into corresponding sulfoxides
and sulfones
(Denisov, 2005; Nnane, 2001).
The present invention relates to compounds of the general formula (I):
0
CI
N H-N
R1
X-Y In
(I)
R2
wherein:
- R, represents H, Cl or Br,
- R2 represents Cl or Br,
- X represents a sulphur atom, a sulfoxide (S=0) or a sulfone (SO2) moiety,
- Y represents a methyl or an ethyl group,
- n can have the value 1, 2 or 3,
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and tautomers, stereoisomers, prodrugs and N-oxides thereof, and isotopically-
labelled
compounds of formula (I), as well as pharmacologically acceptable salts,
hydrates and solvates
of said compounds of formula (I) and its tautomers, stereoisomers, prodrugs, N-
oxides or
isotopical ly-labelled analogs.
All sulfoxides within this invention contain a centre of chirality. The
invention relates to
racemates, mixtures of diastereomers as well as the individual stereoisomers
of the compounds
having formula (I). The invention also relates to the E isomer, Z isomer and
E/Z mixtures of
compounds having formula (I).
The invention particularly relates to compounds of the general formula (I) in
which R, and R2
represent Cl, Y represents a methyl group and X has t he meanings as given
above, n
represents 1 or 2.
Even more in particular the invention relates to the compounds represented by
the formulae:
0 0
cl cl
N H-No H-N3
CI _ N ~ S-CH3 CI / _ \ N S-CH3
/ I / I
CI CI
Due to the potent CB1 antagonistic or inverse agonist activity the compounds
according to the
invention are suitable for use in the treatment of psychiatric disorders such
as psychosis,
anxiety, depression, attention deficits, memory disorders, cognitive
disorders, appetite
disorders, obesity, in particular juvenile obesity and drug induced 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 ischaemia, cerebral apoplexy, cranio-cerebral 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, diarrhoea, sexual disorders,
impulse control disorders
and cardiovascular disorders.
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The cannabinoid receptor modulating activity of the compounds of the invention
makes
them particularly useful in the treatment of obesity, juvenile obesity and
drug induced obesity,
especially when used in combination with lipase inhibitors. Specific examples
of compounds
which can be used in such combination preparations are (but not restricted to)
the synthetic
lipase inhibitor orlistat, lipase inhibitors isolated from micro organisms
such as lipstatin (from
Streptomyces toxytricini), ebelactone B (from Streptomyces aburaviensis),
synthetic derivatives
of these compounds, as well as extracts of plants known to possess lipase
inhibitory activity, for
instance extracts of Alpinia officinarum or compounds isolated from such
extracts like 3-
methylethergalangin (from A. officinarum).
The invention also embraces:
a pharmaceutical composition for treating, for example, a disorder or
condition treatable
by blocking cannabinoid-CB, receptors, the composition comprising a compound
of formula (I)
or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier;
a method of treating a disorder or condition treatable by blocking cannabinoid-
CB,
receptors, the method comprising administering to a mammal in need of such
treating a
compound of formula (I) or a pharmaceutically acceptable salt thereof;
a pharmaceutical composition for treating, for example, a disorder or
condition selected
from the group consisting of the disorders listed herein;
a method of treating a disorder or condition selected from the group
consisting of the
disorders listed herein, the method comprising administering to a mammal in
need of such
treating a compound of formula (I) or a pharmaceutically acceptable salt
thereof;
a pharmaceutical composition for treating the disorders listed herein, the
composition
comprising a compound of formula (I) or a pharmaceutically acceptable salt
thereof, and a
pharmaceutically acceptable carrier;
a method for treating the disorders listed herein, the method comprising
administering to
a patient in need of such treating a compound of formula (I) or a
pharmaceutically acceptable
salt thereof.
a method of antagonizing a cannabinoid-CB, receptor that comprises
administering to a
subject in need thereof, an effective amount of a compound of formula (I);
The invention also provides the use of a compound or salt according to formula
(I) for
the manufacture of a medicament.
The invention further relates to combination therapies wherein a compound of
the
invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition or
formulation comprising a compound of the invention, is administered
concurrently or
sequentially or as a combined preparation with another therapeutic agent or
agents, for treating
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one or more of the conditions listed. Such other therapeutic agent(s) may be
administered prior
to, simultaneously with, or following the administration of the compounds of
the invention.
The invention also provides compounds, pharmaceutical compositions, kits and
methods
for treating the disorders listed herein, the methods comprising administering
to a patient in
need of such treating a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
The compounds of the invention possess cannabinoid-CB, antagonistic act ivity.
The
antagonizing activities of the compounds of the invention is readily
demonstrated, for example,
using one or more of the assays described herein or known in the art.
The invention also provides methods of preparing the compounds of the
invention and
the intermediates used in those methods.
The compounds of the present invention may contain one or more asymmetric
centers
and can thus occur as racemates and racemic mixtures, single enantiomers,
diastereomeric
mixtures and individual diastereomers.
Depending on the nature of the various substituents, the molecule can have
additional
asymmetric centers. Each such asymmetric center will independently produce two
optical
isomers. All of the possible optical isomers and diastereomers, in mixtures
and as pure or
partially purified compounds, belong to this invention. The present invention
comprehends all
such isomeric forms of these compounds. Formula (I) shows the structure of the
class of
compounds without preferred stereochemistry. The independent syntheses of
these
diastereomers, or their chromatographic separations, may be achieved as known
in the art by
appropriate modification of the methodology disclosed therein. Their absolute
stereochemistry
may be determined by the x-ray crystallography of crystalline products or
crystalline
intermediates, which are derivatized, if necessary, with a reagent containing
an asymmetric
center of known absolute configuration. Racemic mixtures of the compounds can
be separated
into the individual enantiomers by methods well-known in the art, such as the
coupling of a
racemic mixture of compounds to an enantiomerically pure compound to form a
diastereomeric
mixture, followed by separation of the individual diastereomers by standard
methods, such as
fractional crystallization or chromatography. The coupling often consists of
the formation of salts
using an enantiomerically pure acid or base, for example (-)-di-p-toluoyl-D-
tartaric acid and/or
(+)-di-p-toluoyl-L-tartaric acid. The diasteromeric derivatives may then be
converted to the pure
enantiomers by cleavage of the added chiral residue. The racemic mixture of
the compounds
can also be separated directly by chromatographic methods utilizing chiral
stationary phases:
Methods well-known in the art. Alternatively, any enantiomer of a compound may
be obtained
by stereoselective synthesis using optically pure starting materials or
reagents of known
configuration by methods well-known in the art.
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Cis and trans isomers of the compound of formula (I), or a pharmaceutically
acceptable
salt thereof, also belong to the invention, and this also applies to tautomers
of the compounds of
formula (I) or a pharmaceutically acceptable salt thereof.
Some of the crystalline forms for the compounds may exist as polymorphs: as
such
intended to belong to the invention. In addition, some of the compounds may
form solvates with
water (i.e. hydrates), or common organic solvents. Such solvates also fall
within the scope of
this invention.
Isotopically-labeled compound of formula (I) or pharmaceutically acceptable
salts
thereof, including compounds of formula (I) isotopically -labeled to be
detectable by PET or
SPECT, also fall within the scope of the invention. The same applies to
compounds of formula
(I) labeled with [13C]-, [14C]_ [3H]_ [18 F]_ [125I]- or other isotopically
enriched atoms, suitable for
receptor binding or metabolism studies.
DEFINITIONS OF CHEMICAL AND OTHER TERMS
The term `alkyl' refers to straight or branched saturated hydrocarbon
radicals. `AIkyI(C1_3)' for
example, means methyl, ethyl, n-propyl or isopropyl, and `alkyl(C1_4)' means
`methyl, ethyl, n-
propyl, isopropyl, n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyl'. The term
`aryl' embraces
monocyclic or fused bicyclic aromatic or hetero-aromatic groups, including but
not limited to
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, imidazo[2,1-
b][1,3]thiazolyl, pyrazolyl,
isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-
triazinyl, phenyl,
indazolyl, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, 1,2,3,4-
tetrahydro-naphtyl, 1,2,3,4-
tetrahydroisoquinolinyl, indanyl, indenyl, benzo[b]thienyl, 2,3-dihydro-1,4-
benzodioxin-5-yl,
benzimidazolyl, benzothiazolyl, benzo[1,2,5]thia-diazolyl, purinyl,
quinolinyl, isoquinolinyl,
phtalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, naphthyl,
pteridinyl or azulenyl. `Halo'
or `Halogen' means chloro, fluoro, bromo or iodo; `hetero' as in `heteroalkyl,
heteroaromatic'
etc. means containing one or more N, 0 or S atoms. `heteroalkyl' includes
alkyl groups with
heteroatoms in any position, thus including N-bound 0-bound or S-bound alkyl
groups. The
terms "oxy", "thio" and "carbo" as used herein as part of another group
respectively refer to
an oxygen atom, a sulphur atom and a carbonyl (C=0) group, serving as linker
between two
groups, such as for instance hydroxyl, oxyalkyl, thioalkyl, carboxyalkyl, etc.
The term "amino"
as used herein alone, or as part of another group, refers to a nitrogen atom
that may be either
terminal, or a linker between two other groups, wherein the group may be a
primary, secondary
or tertiary (two hydrogen atoms bonded to the nitrogen atom, one hydrogen atom
bonded to the
nitrogen atom and no hydrogen atoms bonded to the nitrogen atom, respectively)
amine. The
terms "sulfinyl" and "sulfonyl" as used herein as part of another group
respectively refer to an
-SO- or an - SO2- group.
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As used herein, unless otherwise noted, the term "leaving group" shall mean a
charged
or uncharged atom or group that departs during a substitution or displacement
reaction. Suitable
examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and
the like.
N-oxides of the compounds mentioned above belong to the invention. Tertiary
amines may or
may not give rise to N-oxide metabolites. The extent to what N-oxidation takes
place varies from
trace amounts to a near quantitative conversion. N-oxides may be more active
than their
corresponding tertiary amines, or less active. Whilst N-oxides can easily be
reduced to their
corresponding tertiary amines by chemical means, in the human body this
happens to varying
degrees. Some N-oxides undergo nearly quantitative reductive conversion to the
corresponding
tertiary amines, in other cases conversion is a mere trace reaction, or even
completely absent
(Bickel, 1969).
To provide a more concise description, some of the quantitative expressions
given herein are
not qualified with the term "about". It is understood that whether the term
"about" is used
explicitly or not, every quantity given herein is meant to refer to the actual
given value, and it is
also meant to refer to the approximation to such given value that would
reasonably be inferred
based on the ordinary skill in the art, including approximations due to the
experimental and/or
measurement conditions for such given value. Throughout the description and
the claims of this
specification the word "comprise" and variations of the word, such as
"comprising" and
"comprises" is not intended to exclude other additives, components, integers
or steps.
Any compound metabolized in vivo to provide the bioactive agent (i.e., the
compound of formula
(I)) is a prodrug within the scope and spirit of the application. Prodrugs are
therapeutic agents,
inactive per se but transformed into one or more active metabolites. Thus, in
the methods of
treatment of the present invention, the term "administering" shall encompass
treating the
various disorders described with the compound specifically disclosed, or with
a compound that
not specifically disclosed, but that converts to the specified compound in
vivo after
administration to the patient. Prodrugs are bioreversible derivatives of drug
molecules used to
overcome some barriers to the utility of the parent drug molecule. These
barriers include, but
are not limited to, solubility, permeability, stability, presystemic
metabolism and targeting
limitations (Bundgaard, 1985; King, 1994; Stella, 2004; Ettmayer, 2004 ;
J5rvinen, 2005).
Prodrugs, i.e. compounds that when administered to humans by any known route,
are
metabolised to compounds having formula (I), belong to the invention. In
particular this relates
to compounds with primary or secondary amino or hydroxy groups. Such compounds
can be
reacted with organic acids to yield compounds having formula (I) wherein an
additional group is
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present that is easily removed after administration, for instance, but not
limited to amidine,
enamine, a Mannich base, a hydroxyl-methylene derivative, an O-
(acyloxymethylene
carbamate) derivative, carbamate, ester, amide or enaminone.
The term "composition" as used herein encompasses a product comprising
specified
ingredients in predetermined amounts or proportions, as well as any product
that results,
directly or indirectly, from combining specified ingredients in specified
amounts. In relation to
pharmaceutical compositions, this term encompasses a product comprising one or
more active
ingredients, and an optional carrier comprising inert ingredients, as well as
any product that
results, directly or indirectly, from combination, complexation or aggregation
of any two or more
of the ingredients, or from dissociation of one or more of the ingredients, or
from other types of
reactions or interactions of one or more of the ingredients. In general,
pharmaceutical
compositions are prepared by uniformly and intimately bringing the active
ingredient into
association with a liquid carrier or a finely divided solid carrier or both,
and then, if necessary,
shaping the product into the desired formulation. The pharmaceutical
composition includes
enough of the active object compound to produce the desired effect upon the
progress or
condition of diseases. Accordingly, the pharmaceutical compositions of the
present invention
encompass any composition made by admixing a compound of the present invention
and a
pharmaceutically acceptable carrier.
Within the context of this application, the term `combination preparation'
comprises
both true combinations, meaning compounds of the invention and other
medicaments physically
combined in one preparation such as a tablet or injection fluid, as well as
`kit-of-parts',
comprising compounds of the invention and a lipase inhibitor in separate
dosage forms,
together with instructions for use, optionally with further means for
facilitating compliance with
the administration of the component compounds, e.g. label or drawings. With
true combinations,
the pharmacotherapy by definition is simultaneous. The contents of `kit-of-
parts', can be
administered either simultaneously or at different time intervals. Therapy
being either
concomitant or sequential will be dependant on the characteristics of the
other medicaments
used, characteristics like onset and duration of action, plasma levels,
clearance, etc., as well as
on the disease, its stage, and characteristics of the individual patient.
By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient
must be
compatible with the other ingredients of the formulation and not deleterious
to the recipient
thereof.
The affinity of the compounds of the invention for cannabinoid receptors was
determined
as described below. From the binding affinity measured for a given compound of
formula (I),
one can estimate a theoretical lowest effective dose. At a concentration of
the compound equal
to twice the measured K;-value, nearly 100% of the cannabinoid-CB, receptors
likely will be
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occupied by the compound. Converting that concentration to mg of compound per
kg of patient
yields a theoretical lowest effective dose, assuming ideal bioavailability.
Pharmacokinetic,
pharmacodynamic, and other considerations may alter the dose actually
administered to a
higher or lower value. The dosage expediently administered is 0.001 - 1000
mg/kg, preferably
0.1-100 mg/kg of patient's bodyweight.
The term "therapeutically effective amount" as used herein refers to an amount
of a
therapeutic agent to treat or prevent a condition treatable by administrating
a composition of the
invention. That amount is the amount sufficient to exhibit a detectable
therapeutic, preventative
or ameliorative response in a tissue system, animal or human. The effect may
include, for
example, treating or preventing the conditions listed herein. The precise
effective amount for a
subject will depend upon the subject's size and health, the nature and extent
of the condition
being treated, recommendations of the treating physician (researcher,
veterinarian, medical
doctor or other clinician), and the therapeutics, or combination of
therapeutics, selected for
administration. Thus, it is not useful to specify an exact effective amount in
advance.
The term "pharmaceutically acceptable salt" refers to those salts that are,
within the
scope of sound medical judgment, suitable for use in contact with the tissues
of humans and
lower animals without undue toxicity, irritation, allergic response, and the
like, and are
commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable
salts are well-
known in the art. They can be prepared in situ when finally isolating and
purifying the
compounds of the invention, or separately by reacting them with
pharmaceutically acceptable
non-toxic bases or acids, including inorganic or organic bases and inorganic
or organic acids.
The term "treatment" as used herein refers to any treatment of a mammalian,
preferably
human condition or disease, and includes: (1) preventing the disease or
condition from
occurring in a subject predisposed to the disease, but not yet diagnosed as
having it, (2)
inhibiting the disease or condition, i.e., arresting its development, (3)
relieving the disease or
condition, i.e., causing the condition to regress, or (4) stopping the
symptoms of the disease.
As used herein, the term "medical therapy" intendeds to include prophylactic,
diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans
or other
mammals. The term "subject" as used herein, refers to an animal, preferably a
mammal, most
preferably a human, who has been the object of treatment, observation or
experiment.
EXAMPLES
EXAMPLE 1: ANALYTICAL METHODS
'H NMR spectra were recorded on a Bruker 400 MHz or a 300 MHz instrument using
CDC13 as
solvent with tetramethylsilane as an internal standard. 13C NMR spectra were
recorded on a
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Bruker instrument (100 MHz) using CDC13 as solvent. Chemical shifts are given
in ppm (b scale)
downfield from tetramethylsilane. Coupling constants (J) are expressed in Hz.
Flash
chromatography was performed using silica gel 60 (0.040-0.063 mm, Merck).
Column
chromatography was performed using silica gel 60 (0.063-0.200 mm, Merck).
Melting points
were recorded on a Buchi B-545 melting point apparatus.
EXAMPLE 2: GENERAL ASPECTS OF SYNTHESES
The synthesis of compounds having formula (I) is outlined in Scheme 1. The
synthesis of the
intermediates having formula (II) proceeds analogously to published procedures
(Lan, 1999;
Francisco, 2002; Katoch-Rouse 2003). The carboxylic acid of general formula
(II) wherein R,
and R2 have the abovementioned meaning can be brominated to the corresponding
4-bromo
derivative (III) using a brominating agent such as bromine in an inert organic
solvent such as
dichloromethane. This bromo derivative (III) wherein R, and R2 have the
abovementioned
meaning can be treated with a strong base such as n-butyllitium in an inert
anhydrous organic
solvent such as tetrahydrofuran and subsequently reacted with a sulphur-
derived electrophile
YSSY wherein Y represents a methyl or ethyl group to afford a compound of
general formula
(IV) wherein R,, R2 and Y have the abovementioned meaning, R4 is a hydrogen
atom and X
represents a sulphur atom. This compound of general formula (IV) can be
converted to the
corresponding ester of general formula (V) wherein R,, R2 and Y have the
abovementioned
meaning, R3 represents a linear C,_3 alkyl group (methyl, ethyl or n-propyl)
and X represents a
sulphur atom. This ester of general formula (V) can be oxidised with one molar
equivalent of an
oxidizing reagent such as meta-chloroperbenzoic acid to give the corresponding
sulfinyl
analogue. Alternatively, reaction of a compound of general formula (V) with
two or more molar
equivalents of meta-chloroperbenzoic acid can convert the sulfanyl moiety to
the corresponding
sulfonyl moiety. The ester of general formula (V) wherein R,, R2 and Y have
the
abovementioned meaning and X represents a sulfoxide or sulfone moiety can be
hydrolysed -
preferably under acidic conditions - to give the corresponding carboxylic acid
(VI). The resulting
compound of general formula (VI) can be coupled with an amine in the presence
of an activating
or coupling reagent to give a compound of general formula (I), wherein R,, R2,
Y and n have the
abovementioned meaning and X represents a sulfoxide (S=O) moiety or a sulfone
(SO2) moiety.
Alternatively, a compound of general formula (IV) wherein R,, R2 and Y have
the
abovementioned meaning and X represents a sulphur atom can be coupled with an
amine in the
presence of an activating or coupling reagent to give a compound of general
formula (I),
wherein R,, R2, Y and n have the abovementioned meaning and X represents a
sulphur atom.
Alternatively, an ester derivative having formula (V) can be reacted in a so-
called Weinreb
amidation reaction with an amine to give a compound of general formula (I),
wherein R,, R2, Y
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and n have the abovementioned meaning and X represents a sulphur atom or a
sulfoxide (S=O)
moiety or a sulfone (SO2) moiety. Such Weinreb amidation reactions can be
promoted by the
use of trimethylaluminum AI(CH3)3 (Levin, 1982). Activating and coupling
methods of amines to
carboxylic acids are well documented (Bodanszky, 1994; Akaji, 1994; Albericio,
1997;
Montalbetti, 2005).
Scheme 1 a
o 0 0
o ci ci ci
ci ~ OH - OH - N- N-Nq Jn
N- OH b,c
i a R N R, N Rl- N
R~ N Br S Y d = S Y
H
y
Rz Rz Rz
(III) (IV) wherein Ra is H
O
ci ci ci
N
N- OR N-N
OH
e R N h ~~ N d R N XHY
q
(IV) X-Y R N X Y
vI I I~ vI
(V)
R2 Rz R2
f[- s=s(o) (VI) wherein X is a sulfinyl or sulfonyl moiety (I) wherein X is a
sulfinyl or sulfonyl moiety
x=s
9 x=S(oz)
a Reagents and conditions: (a) Br2, CHzCl2; (b) n-BuLi, THF;
(c) YSSY; (d) amine derivative, coupling reagent, dichloromethane, rt;
(e) R3 OH, acid catalyst or thionylchloride; (f) 1 equivalent m-CPBA, CHzCl21
rt;
(g) 2 or more equivalents m-CPBA, CHzCl21 rt; (h) aqueous base; (i) amine, Al
(CH3)3
An alternative synthesis of compounds having formula (I) is outlined in Scheme
2. The
bromoacetophenone derivative of general formula (VII) wherein R2 has the
abovementioned
meaning can be reacted with a compound of general formula NaS-Y to the
corresponding 1-
aryl-2-(alkylsulfanyl)ethanone derivative (VIII) in an inert organic solvent
such as methanol. This
1-aryl-2-(alkylsulfanyl)ethanone derivative (VIII) wherein R2 has the
abovementioned meaning
can be reacted with a oxalic ester derivative of general formula (IX) in the
presence of a base
such as sodium alkanoate in an inert anhydrous organic solvent, followed by a
reaction with an
arylhydrazine (X) or a salt thereof, wherein R, has the abovementioned meaning
to give an
ester of general formula (V) wherein R,, R2 and Y have the abovementioned
meaning, R3
represents a linear C,_3 alkyl group (methyl, ethyl or n-propyl) and X
represents a sulphur atom.
This ester of general formula (V) can be hydrolyzed under basic conditions for
example with
lithium hydroxide to give the corresponding carboxylic acid of general formula
(IV) or its alkali-
element (such as lithium, sodium or potassium) salt. This carboxylic acid or
carboxylic acid
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WO 2007/138050 PCT/EP2007/055192
alkali-element salt of general formula (IV) wherein R,, R2 and Y have the
abovementioned
meaning and X represents a sulphur atom can be coupled with an amine in the
presence of an
activating or coupling reagent in an inert organic solvent such as
dimethylformamide to give a
compound of general formula (I), wherein R,, R2, Y and n have the
abovementioned meaning
and X represents a sulphur atom. This compound of general formula (I), wherein
R,, R2, Y and n
have the abovementioned meaning and X represents a sulphur atom can be
oxidised with one
molar equivalent of meta-chloroperbenzoic acid to give the corresponding
sulfinyl analogue (X
represents a S=O group). Alternatively, reaction of a compound of general
formula (I) wherein X
represents a sulphur atom with two or more molar equivalents of meta-
chloroperbenzoic acid
can convert the sulfanyl moiety in (I) to the corresponding sulfonyl moiety.
Scheme 2a
O OR3 CI 0 O
ORs CI N-N
Br O S -Y 1) , base N H
1
O O OR3 R ~~ N S-Y R ~\
- X-Y in
NaS-Y (IX) a) ' N
I I \ 2) CI NH (V) \ ~ \ I
Rz z
zR ~ ~ N R2
(VII) (VIII) H Rz
(X) (I) wherein X represents S
O 0 O
G CI CI
N_ OR3 N- ORa e N_ H-N~
~ b) R ~ n1 ) R, ~ ~ N J
R' N S-Y - S-Y - X-Y
d ~ X = S(O)
\ I \ I \
(V) (IV) e ~ X=S
R X=S(oz)
R2 R2 z
(I) wherein X represents S
a Reagents and conditions: (a) amine, AI(CH3)3; (b) aqueous base;
(c) amine derivative, coupling reagent, rt; (d) 1 equivalent m-CPBA, CH2CI2,
rt;
(e) 2 or more equivalents m-CPBA, CH2CI2, rt.
The selection of the particular synthetic procedures depends on factors known
to those skilled in
the art such as the compatibility of functional groups with the reagents used,
the possibility to
use protecting groups, catalysts, activating and coupling reagents and the
ultimate structural
features present in the final compound being prepared.
Pharmaceutically acceptable salts may be obtained using standard procedures
well
known in the art, for example by mixing a compound of the present invention
with a suitable
acid, for instance an inorganic acid such as hydrochloric acid, or with an
organic acid. Hydrates
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WO 2007/138050 PCT/EP2007/055192
can be obtained using standard procedures well known in the art, for example
by crystallization
or evaporation from a water-containing (non-anhydrous) organic solvent.
EXAMPLE 3: SYNTHESES OF SPECIFIC COMPOUNDS
Compound 1
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazole-3-carboxylic acid.
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (m.p.
185-187 C) was
obtained from methyl 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazole-3-
carboxylate via
ester hydrolysis under basic conditions (methanol, aqueous KOH).
4-Bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1 H-pyrazole-3-carboxylic
acid.
To a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-1H-pyrazole-3-
carboxylic acid (20.0 g, 54.5 mmol) in dichloromethane (400 ml) was slowly
added bromine
(5.62 ml, 109 mmol) and the resulting mixture was reacted for 16 hours at room
temperature.
Diethyl ether (400 ml) and excess aqueous saturated NaHCO3 solution were
successively
added. The organic layer was separated, twice washed with aqueous saturated
NaHCO3
solution and subsequently washed with brine, dried over MgSO4, filtered and
concentrated to
give 4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-
carboxylic acid (19.77
gram, 81 % yield). Melting point: 222-224 C.
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1 H-pyrazole-3-
carboxylic acid
To a magnetically stirred solution of 4-bromo-5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-1H-
pyrazole-3-carboxylic acid (5.00 g, 11.2 mmol) in anhydrous tetrahydrofuran
(THF) (250 ml) was
added n-butyllithium (15.75 ml, 1.6 M solution, 25.2 mmol) and the resulting
solution was stirred
for 15 minutes under N2 at -78 C. A solution of dimethyl disulfide (CH3S)2
(3.16 g, 33.6 mmol) in
anhydrous THF (20 ml) was added by syringe an d the resulting solution was
stirred at -78 C
overnight. The reaction mixture was quenched with excess water and the
resulting solution was
extracted with diethyl ether. The diethyl ether layer was washed with water,
dried over MgSO4,
filtered and concentrated to give crude 5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-4-
methylsulfanyl-1 H-pyrazole-3-carboxylic acid which was further purified using
flash
chromatography (eluant: dichloromethane/methanol = 95/5 (v/v)) followed by
another flash
chromatographic purification (eluant: dichloromethane/ethanol = 95/5 (v/v)) to
give 5-(4-
chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-lH-pyrazole-3-carboxylic
acid (2.75 g)
which was immediately converted in the next reaction step.
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WO 2007/138050 PCT/EP2007/055192
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yI)-
1 H-
pyrazole-3-carboxamide.
0
CI
N- H-No
S-CH3
CI compound 1
To a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-4-methylsulfanyl-
1 H-pyrazole-3-carboxylic acid (4.69 g, 11.3 mmol) in dichloromethane (100 ml)
was
successively added 7-aza-l-hydroxybenzotriazole (HOAt) (2.2 g, 16.0 mmol), (1-
(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (3.1 g, 16.1
mmol) and 1-
aminopiperidine (1.6 gram, 16.0 mmol). After stirring for 16 h, the resulting
mixture was
successively washed with water (3 x), dried over Na2SO4, filtered and
concentrated to give a
crude solid. This crude solid was further purified by flash chromatography
(silica gel,
EtOAc/heptane = 22/78 (v/v)) and trituration with n-heptane/methanol to give 5-
(4-
chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1 H-
pyrazole-3-
carboxamide: compound 1 (0.55 gram, 10 % yield). Melting point: 172.4-174.5
C. 'H-NMR
(CDC13, 400 MHz) S 1.41-1.49 (m, 2H), 1.72-1.81 (m, 4H), 2.40 (s, 3H), 2.83-
2.95 (m, 4H), 7.15
(br d, J = 8 Hz, 2H), 7.28-7.35 (m, 4H), 7.42 (br d, J = 2 Hz, 1 H), 7.94 (br
s, 1 H). 13C-NMR
(CDC13, 100 MHz) S 20.03, 23.32, 25.29, 57.02, 113.66, 126.20, 127.99, 128.74,
130.36,
130.48, 131.24, 132.85, 135.59, 135.64, 136.41, 147.08, 147.30, 158.62.
Compound 2
1-(4-Ch iorophenyl) -2-(methylsu Ifanyl)ethanone
To a magnetically stirred solution of bromo -4-chloro-acetophenone (16.8 g, 72
mmol) in
methanol (200 ml) was added NaSCH3 (5.23 g, 72 mmol) to give an exothermic
reaction. The
resulting mixture was reacted for 2 hours at room temperature, concentrated
and suspended in
dichloromethane (150 ml) and washed with water, dried over MgSO4, filtered and
concentrated
to give 1-(4-chlorophenyl)-2-(methylsulfanyl)ethanone (5.1 gram). 'H-NMR
(CDC13, 400 MHz) b
2.13 (s, 3H), 3.72 (s, 2H), 7.44 (br d, J = 8 Hz, 2H), 7.92 (br d, J = 8 Hz,
2H).
CA 02650622 2008-10-28
WO 2007/138050 PCT/EP2007/055192
Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1 H-pyrazole-
3-carboxylate
Sodium metal (2 gram, 87 mmol) was dissolved in ethanol (80 ml). The resulting
solution was
added to a magnetically stirred solution of diethyl oxalate (6 gram, 41 mmol)
and 1-(4-
chlorophenyl)-2-(methylsulfanyl)ethanone (8.0 g, 40 mmol). The resulting
mixture was reacted
for 20 hours at room temperature and subsequently poured into aqueous
hydrochloric acid (200
ml, 1 N). The resulting mixture was extracted twice with methyl-tert-butyl
ether (MTBE) (200 ml),
dried over MgS04, filtered and concentrated. The resulting residue was
dissolved in acetic acid
(200 ml), 2,4-dichlorophenylhydrazine.HCI (8.6 gram, 40 mmol) was added and
the resulting
mixture was heated at 60 C for 3 hours. The reaction mixture was allowed to
attain room
temperature, concentrated to approximately 50 ml and poured into water (200
ml), followed by
extraction with MTBE (3 portions of 150 ml). The combined organic layers were
washed with 5
% aqueous NaHCO3, dried over MgS04, filtered and concentrated. Further
purification using
column chromatography (silica gel; eluant: heptane/ethylacetate = 90/10 (v/v))
gave ethyl 5-(4-
chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-
carboxylate (4.9 gram, 27
% yield). Rf -0.4 (heptane/ethylacetate = 90/10 (v/v)).'H-NMR (CDC13, 300 MHz)
S 1.44 (t, J = 7
Hz, 3H), 2.32 (s, 3H), 4.46 (q, J = 7, 2H), 7.10-7.45 (m, 7H).
Lithium 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-
3-carboxylate
To a magnetically stirred solution of ethyl 5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-4-
methylsulfanyl-1 H-pyrazole-3-carboxylate (4.9 g, 11 mmol) in tetrahydrofuran
(100 ml) was
added LiOH.H20 (0.47 gram, 11 mmol) and the resulting mixture was reacted for
20 hours at 35
C and subsequently concentrated in vacuo. The obtained crude lithium 5-(4-
chlorophenyl)-1-
(2,4-dichlorophenyl)-4-methylsulfanyl-1 H-pyrazole-3-carboxylate was used in
the next step.
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(pyrrolidin-1-yl)-
1 H-
pyrazole-3-carboxamide (compound 2)
0
CI
N- H-N3
CI N /
S-CH3
CI compound 2
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WO 2007/138050 PCT/EP2007/055192
To a magnetically stirred solution of lithium 5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-4-
methylsulfanyl-1 H-pyrazole-3-carboxylate (1.2 gram, 3 mmol maximally) in
dimethylformamide
(35 ml) was successively added O-benzotriazol-1-yl-N,N,N',N'-
tetramethyluronium
tetrafluoroborate (TBTU) (1.25 g, 3.9 mmol) , triethylamine (1.3 ml) and 1-
aminopyrrolidine
hydrochloride (0.410 gram, 3.35 mmol). After stirring for 18 h at 50 C the
resulting mixture was
allowed to attain room temperature and concentrated in vacuo. The remaining
residue was
triturated with water and successively further purified by flash
chromatography (silica gel,
EtOAc/heptane = 20/80 (v/v)) to give 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-
4-methyl-
sulfanyl-N-(pyrrolidin-1-yl)-1H-pyrazole-3-carboxamide: compound 2 (0.78 gram,
54 % yield).
'H-NMR (CDCI3, 400 MHz) S 1.88-1.96 (m, 4H), 2.39 (s, 3H), 3.02-3.08 (m, 4H),
7.15 (br d, J
8 Hz, 2H), 7.29-7.33 (m, 4H), 7.42 (br s, 1 H), 7.98 (br s, 1 H).
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(azepan-1-yI)-1 H-
pyrazole-
3-carboxamide (compound 3)
0
CI
N- H-N
CI N /
S-CH3
CI compound 3
Compound 3 was prepared analogously as described for compound 2 hereinabove
from crude
lithium 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1 H-
pyrazole-3-carboxylate,
azepan-1-ylamine, TBTU and Et3N in DMF in 52 % yield.
'H-NMR (CDC13, 400 MHz) S 1.64-1.68 (m, 4H), 1.72-1.79 (m, 4H), 2.38 (s, 3H),
3.18-3.22 (m,
4H), 7.15 (br d, J = 8 Hz, 2H), 7.29-7.33 (m, 4H), 7.42 (br t, J- 2 Hz, 1 H),
8.43 (br s, 1 H). 13C-
NMR (CDC13, 100 MHz) S 20.17, 26.30, 26.99, 58.10, 113.31, 126.26, 127.96,
128.75, 130.36,
130.49, 131.23, 132.86, 135.62, 135.65, 136.36, 147.26, 147.31, 158.87
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfonyl-N-(piperidin-1-yI)-
1 H-
pyrazole-3-carboxamide (compound 4)
To a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-4-methylsulfanyl-
N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (0.70 gram, 1.41 mmol) was added
m-CPBA (2.2
gram of a 70 % aqueous solution, 9 mmol). The resulting mixture was reacted
for 70 hours at
room temperature and subsequently poured into water (25 ml). The resulting
mixture was
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WO 2007/138050 PCT/EP2007/055192
extracted with dichloromethane (25 ml). The organic layer was separated and
dried over
MgSO4, filtered and concentrated. Column chromatography (silica gel,
dichloromethane
/methanol = 95/5 (v/v)) gave 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-
methylsulfonyl-N-
(piperidin-1-yl)-1H-pyrazole-3-carboxamide (380 mg, 51 % yield, compound 4)
'H-NMR (CDC13, 400 MHz) S 1.70-2.10 (m, 6H), 2.47-2.63 (m, 2H), 3.31 (s, 3H),
3.55-3.62 (m,
1 H), 3.82-3.90 (m, 1 H), 7.12 (br d, J 8 Hz, 2H), 7.31-7.36 (m, 4H), 7.42 (d,
J 2, 1 H), 10.80
(br s, 1 H).
O
CI /~
N- H-N_ )
~/
- O%S-CH3
O
CI compound 4
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfinyl-N-(piperidin-1-yi)-
1 H-pyrazole-
3-carboxamide (compound 5)
O
CI /~
N- H-N_ )
CI N / ~/
- S-CH3
O
CI compound 5
To a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-4-methylsulfanyl-
N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (0.70 gram, 1.41 mmol) was added
m-chloro-
perbenzoic acid (m-CPBA) (0.50 gram of a 70 % aqueous solution, 2.0 mmol). The
resulting
mixture was reacted for 20 hours at room temperature and subsequently poured
into water (25
ml). The resulting mixture was extracted with dichloromethane (25 ml). The
organic layer was
separated and dried over MgSO4, filtered and concentrated. Column
chromatography (silica gel,
dichloromethane/methanol=95/5 (v/v)) gave 5-(4-chlorophenyl)-1-(2,4-
dichlorophenyl)-4-methyl-
sulfinyl-N-(piperidin-1-yl)-1 H-pyrazole-3-carboxamide (150 mg, 21 % yield)
(compound 5).
'H-NMR (CDC13, 400 MHz) S 1.41-1.49 (m, 2H), 1.72-1.81 (m, 4H), 2.84-2.96 (m,
4H), 3.11 (s,
3H), 7.15 (br d, J = 8 Hz, 2H), 7.27-7.32 (m, 4H), 7.43 (br s, 1 H), 8.70 (br
s, 1 H). 13C-NMR
(CDC13, 100 MHz) S 23.28, 25.22, 41.84, 56.97, 122.91, 124.67, 128.03, 128.66,
130.41,
130.63, 131.60, 133.01, 134.54, 136.51, 136.98, 144.62, 144.85, 157.60.
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EXAMPLE 4: PHARMACOLOGICAL METHODS
In vitro affinity for human cannabinoid-CB, receptors
The affinity of the compounds of the invention for cannabinoid CB1 receptors
can be determined
using membrane preparations of Chinese hamster ovary (CHO) cells in which the
human
cannabinoid CB1 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 is performed by filtration over glassfiber filters. Radioactivity on
the filter is measured by
liquid scintillation counting.
In vitro affinity for human cannabinoid-CB2 receptors
The affinity of the compounds of the invention for cannabinoid CB2 receptors
can be determined
using membrane preparations of Chinese hamster ovary (CHO) cells in which the
human
cannabinoid CB2 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 is performed by filtration over glassfiber filters. Radioactivity on
the filter is measured by
liquid scintillation counting.
In vitro cannabinoid-CB, receptor antagonism
In vitro CB1 receptor antagonism can be assessed with the human CB1 receptor
cloned in
Chinese hamster ovary (CHO) cells. CHO cells are grown in a Dulbecco's
Modified Eagle's
medium (DMEM) culture medium, supplemented with 10% heat-inactivated fetal
calf serum.
Medium is 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 is
incorporated in membrane
phospholipids. On the test day, medium is aspirated and cells are washed three
times using 0.5
ml DMEM, containing 0.2% bovine serum albumin (BSA). Stimulation of the CB1
receptor by
WIN 55,212-2 leads to activation of PLA2 followed by release of [3H]-
arachidonic acid into the
medium. This WIN 55,212-2-induced release is concentration-dependently
antagonized by CB1
receptor antagonists.
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CP-55,940 Induced Hypotension in the rat.
Male normotensive rats (225-300 g; Harlan, Horst, The Netherlands) were
anaesthetized with
pentobarbital (80 mg/kg i.p). Blood pressure was measured, via a cannula
inserted into the left
carotid artery, by means of a Spectramed DTX-plus pressure transducer
(Spectramed B.V.,
Bilthoven, The Netherlands). After amplification by a Nihon Kohden Carrier
Amplifier (Type AP-
621G; Nihon Kohden B.V., Amsterdam, The Netherlands), the blood pressure
signal was
registered on a personal computer (Compaq Deskpro 386s), by means of a Po-Ne-
Mah data-
acquisition program (Po-Ne-Mah Inc., Storrs, USA). Heart rate was derived from
the pulsatile
pressure signal. All compounds were administered orally as a microsuspension
in 1%
methylcellulose 30 minutes before induction of the anesthesia which was 60
minutes prior to
administration of the CB1 receptor agonist CP-55,940. The injection volume was
10 ml/kg. After
haemodynamic stabilization the CB1 receptor agonist CP-55,940 (0.1 mg/kg i.v.)
was
administered and the hypotensive effect established.
EXAMPLE 5: PHARMACOLOGICAL TESTRESULTS
Affinity data for human cannabinoid CB1 and CB2 receptors (mean results of at
least three
independent experiments, performed according to the protocols given above) of
rimonabant and
compounds 1-5 are given in the table below. These data illustrate the impact
on CB1 and CB2
receptor affinities, CB 1/2 receptor selectivity ratios as well as their in
vivo potency after oral
administration achieved by the structural modification that forms the basis of
the present
invention, and also illustrate the CB1 receptor affinities of the S-oxidized
compounds 4 and 5.
hCB, hCB2 CBj/CB2 Blood pressure (rat)
compound X Y n K;(nM) K;(nM) ratio ED50 (mg/kg, p.o.)
rimonabant CH2 H 2 25 1580 63 3.2
Comp. 1 S CH3 2 10 668 67 1.5
Comp. 2 S CH3 1 < 10 340 >34 1.9
Comp. 3 S CH3 3 20 500 25 3.1
Comp. 4 S=O CH3 2 13 nd - nd
Comp. 5 SO2 CH3 2 250 nd - nd
Table 1. CB 1 and CB2 receptor affinities and in vivo activity in CB receptor-
mediated rat model
of rimonabant and compounds 1-3 of this invention and CB1 receptor affinities
for the S-oxidized
compounds 4 and 5; nd = not determined.
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EXAMPLE 6: PHARMACEUTICAL PREPARATIONS
For clinical use, compounds of formula (I) are formulated into a
pharmaceutical compositions
that are important and novel embodiments of the invention because they contain
the
compounds, more particularly specific compounds disclosed herein. Types of
pharmaceutical
compositions that may be used include, but are not limited to, tablets,
chewable tablets,
capsules (including microcapsules), solutions, parenteral solutions, ointments
(creams and
gels), suppositories, suspensions, and other types disclosed herein or
apparent to a person
skilled in the art from the specification and general knowledge in the art.
The compositions are
used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal,
pulmonary,
transdermal, buccal, rectal, parenteral or other ways to administer. The
pharmaceutical
formulation contains at least one compound of formula (I) in admixture with a
pharmaceutically
acceptable adjuvant, diluent and/or carrier. The total amount of active
ingredients suitably is in
the range of from about 0.1 %(w/w) to about 95% (w/w) of the formulation,
suitably from 0.5% to
50% (w/w) and preferably from 1% to 25% (w/w).
The compounds of the invention can be brought into forms suitable for
administration by
means of usual processes using auxillary substances such as liquid or solid,
powdered
ingredients, such as the pharmaceutically customary liquid or solid fillers
and extenders,
solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer
substances. Frequently used
auxillary substances include magnesium carbonate, titanium dioxide, lactose,
saccharose,
sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein,
gelatin, starch,
amylopectin, cellulose and its derivatives, animal and vegetable oils such as
fish liver oil,
sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as,
for example,
sterile water and mono- or polyhydric alcohols such as glycerol, as well as
with disintegrating
agents and lubricating agents such as magnesium stearate, calcium stearate,
sodium stearyl
fumarate and polyethylene glycol waxes. The mixture may then be processed into
granules or
pressed into tablets.
The active ingredients may be separately premixed with the other non-active
ingredients,
before being mixed to form a formulation. The active ingredients may also be
mixed with each
other, before being mixed with the non-active ingredients to form a
formulation.
Soft gelatine capsules may be prepared with capsules containing a mixture of
the active
ingredients of the invention, vegetable oil, fat, or other suitable vehicle
for soft gelatine capsules.
Hard gelatine capsules may contain granules of the active ingredients. Hard
gelatine capsules
may also contain the active ingredients together with solid powdered
ingredients such as
lactose, saccharose, sorbitol, mannitol, potato starch, corn starch,
amylopectin, cellulose
derivatives or gelatine. Dosage units for rectal administration may be
prepared (i) in the form of
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WO 2007/138050 PCT/EP2007/055192
suppositories that contain the active substance mixed with a neutral fat base;
(ii) in the form of a
gelatine rectal capsule that contains the active substance in a mixture with a
vegetable oil,
paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in
the form of a ready-made
micro enema; or (iv) in the form of a dry micro enema formulation to be
reconstituted in a
suitable solvent just prior to administration.
Liquid preparations may be prepared in the form of syrups, elixirs,
concentrated drops or
suspensions, e.g. solutions or suspensions containing the active ingredients
and the remainder
consisting, for example, of sugar or sugar alcohols and a mixture of ethanol,
water, glycerol,
propylene glycol and polyethylene glycol. If desired, such liquid preparations
may contain
coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl
cellulose or
other thickening agents. Liquid preparations may also be prepared in the form
of a dry powder,
reconstituted with a suitable solvent prior to use. Solutions for parenteral
administration may be
prepared as a solution of a formulation of the invention in a pharmaceutically
acceptable
solvent. These solutions may also contain stabilizing ingredients,
preservatives and/or buffering
ingredients. Solutions for parenteral administration may also be prepared as a
dry preparation,
reconstituted with a suitable solvent before use.
Also provided according to the present invention are formulations and `kits of
parts'
comprising one or more containers filled with one or more of the ingredients
of a pharmaceutical
composition of the invention, for use in medical therapy. Associated with such
container(s) can
be various written materials such as instructions for use, or a notice in the
form prescribed by a
governmental agency regulating the manufacture, use or sale of pharmaceuticals
products,
which notice reflects approval by the agency of manufacture, use, or sale for
human or
veterinary administration. The use of formulations of the present invention in
the manufacture of
medicaments for use in treating a condition in which antagonism of cannabinoid-
CB, receptors
is required or desired, and methods of medical treatment or comprising the
administration of a
therapeutically effective total amount of at least one compound of formula
(I), either as such or,
in the case of prodrugs, after administration, to a patient suffering from, or
susceptible to, a
condition in which antagonism of cannabinoid-CB, receptors is required or
desired.
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CITED PATENTS AND PATENT APPLICATIONS
EP 0876350,
US 2006/0100208
WO 98/43635, WO 98/43636, WO 2004/099157, WO 2005/000820, W02006/030124
24
