Note: Descriptions are shown in the official language in which they were submitted.
CA 02671554 2009-06-03
WO 2008/084057 PCT/EP2008/050181
COMPOUNDS WITH A COMBINATION OF CANNABINOID-CB, ANTAGONISM AND
SEROTONIN REUPTAKE INHIBITION
20
TECHNICAL FIELD
This invention relates to the fields of pharmaceutical and organic chemistry,
and provides
compounds with a combination of cannabinoid-CB, antagonism and serotonin re-
uptake
inhibition, intermediates, formulations and methods.
BACKGROUND ART
A reductionist `one target-one disease' approach dominates the pharmaceutical
industry for some decades. Using this strategy, many successful drugs were
discovered.
Despite that however, many diseases remain inadequately treated. These
findings rationalize
an alternative approach, wherein chemical entities are developed that
simultaneously modulate
multiple targets. Such drugs may show advantageous properties such as
increased clinical
efficacy, or lack of undesired pharmacokinetic drug-drug interactions, or
unfavourable
pharmacokinetic and pharmacodynamic properties. The latter may lead to
unpredictable
1
CA 02671554 2009-06-03
WO 2008/084057 PCT/EP2008/050181
variability between individual patients. In order to combine different
therapeutic mechanisms,
cocktails of two or more drugs are still used in clinical practice.
Alternatively, multicomponent
drugs are being used wherein two or more pharmaceutically active compounds are
co-
formulated in a single tablet or capsule in order to improve patient
compliance. Another
approach utilizes a pharmaceutical treatment with a chemical entity that is
able to modulate
more than one biological target simultaneously. It is clear that such a`single
entity-multiple
target approach' offers the advantage of a lower risk of undesired drug-drug
interactions
compared to drug cocktails or multicomponent drugs. Several multiple target
ligands are known.
The majority were found retrospectively or by accident: Only a few were
rationally designed.
Cannabinoid receptors are part of the endo-cannabinoid system, involved in
many
diseases. Detailed information on cannabinoid receptors, CB1 receptor
modulators, and their
pharmacological are found activities, are subjects of recent reviews
(Landsman, 1997;
Lichtman, 2002; De Petrocellis, 2004; Di Marzo, 2004; Hertzog, 2004; Lange,
2004, 2005;
Smith, 2005; Thakur, 2005; Padgett, 2005; Muccioli, 2005; Lambert, 2005;
Vandevoorde, 2005).
Potential therapeutic applications of CB1 receptor modulators disclosed in the
quoted reviews
include 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, 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.
Mood disorders and anxiety disorders cause enormous suffering. The
introduction of
selective serotonin reuptake inhibitors more than two decades ago has been a
major step in the
evolution of safer antidepressants. Representative examples of selective
serotonin reuptake
inhibitors are fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram,
zimeldine,
clomipramine, indalpine and indatraline. In spite of the remarkable structural
diversity, most
selective serotonin reuptake inhibitors are mono-amine-based: They contain a
basic nitrogen
atom (Pacher, 2004). Scientific articles, patents and patent applications
indicate the following
therapeutic applications for serotonin reuptake inhibitors: alcoholism,
Alzheimers disease,
anorexia nervosa, anxiety disorder, attention deficit hyperactivity disorder,
bipolar disorder,
bulimia nervosa, bentral nervous system disease, chemotherapy induced emesis,
cocaine
2
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WO 2008/084057 PCT/EP2008/050181
addiction, cognitive disorder, diabetic neuropathy, drug dependence, eating
disorder, female
sexual dysfunction, functional bowel disorder, generalized anxiety disorder,
headache,
inflammation, irritable bowel syndrome, male sexual dysfunction, major
depressive disorder,
menopause, migraine, myalgia, neuralgia, neuropathic pain, obesity, obsessive
compulsive
disorder, osteoarthritis, pain, panic disorder, Parkinson's disease, premature
ejaculation,
premenstrual syndrome, psychosexual disorder, psychosis, rheumatoid arthritis,
schizophrenia,
sleep disorder and urinary incontinence.
Because of the frequently observed co-morbidity of symptoms of different
diseases,
compounds combining cannabinoid-CB, antagonism with serotonin reuptake
inhibition can be
useful to treat the conditions wherein either a cannabinoid CB, antagonist or
a serotonin
reuptake inhibitor is potentially effective. Thus the compounds of the
invention can be used for
treating: addiction, alcoholism, Alzheimers disease, anorexia nervosa, anxiety
disorder, appetite
disorders, attention deficit hyperactivity disorder, bipolar disorder, bulimia
nervosa, cancer,
cardiovascular disorders, central nervous system disease, cerebral ischaemia,
cerebral
apoplexy, chemotherapy induced emesis, cocaine addiction, cognitive disorder,
dementia,
demyelinisation related disorders, diabetes, diabetic neuropathy, diarrhoea,
drug dependence,
dystonia, eating disorder, emesis, epilepsy, female sexual dysfunction,
functional bowel
disorder, gastrointestinal disorders, gastric ulcers, generalized anxiety
disorder, glaucoma,
headache, Huntington's disease, impulse control disorders inflammation,
irritable bowel
syndrome, male sexual dysfunction, major depressive disorder, memory disorders
menopause,
migraine, muscle spasticity, multiple sclerosis, myalgia, nausea, neuralgia,
neurodegenerative
disorders, neuroinflammatory disorders, neuropathic pain, obesity, obsessive
compulsive
disorder, osteoarthritis, pain, panic disorder, Parkinson's disease, plaque
sclerosis, premature
ejaculation, premenstrual syndrome, psychosexual disorder, psychosis,
rheumatoid arthritis,
septic shock, schizophrenia, sexual disorders, sleep disorder, spinal cord
injury, stroke,
Tourette's syndrome, traumatic brain injury, tremor, urinary incontinence and
viral encephalitis.
Of particular importance is the use of the compounds of the invention for
treating
disorders claimed to be treatable with cannabinoid CB, antagonists as well as
with serotonin
reuptake inhibitors. Attacking such disorders simultaneously via two different
mechanisms of
action can have synergistic effects. Thus, the compounds of the invention are
particularly useful
for treating: psychosis, anxiety, depression, attention deficits, cognitive
disorders, obesity, drug
dependence, Parkinson's disease, Alzheimer's disease, pain disorders,
neuropathic pain
disorders and sexual disorders.
3
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The pharmacophore of the majority of cannabinoid CB1 receptor antagonists was
the
subject of several reviews (Lange, 2005; Reggio, 2003). Scheme 1 visualizes
it.
Asp366-Lys192
Arl \
Spacer H-bond acceptor Lip
Ar2 ~
Schemel: C8, receptor antagonist pharmacophore, and one of its
putative key interactions with the C8, receptor
In Scheme 1, Ar, and Ar2 represent phenyl groups, optionally substituted with
one or two
halogen atoms, trifluoromethyl groups, or methoxy groups. In Scheme 1, the
`spacer' contains a
five-membered heterocyclic group such as 4,5-dihydropyrazole, imidazole,
pyrazole, thiazole,
thiophene or pyrrole, or the spacer contains a phenyl group or a six-membered
heterocyclic
group such as pyridine, pyrimidines or pyrazine. The spacer can also contain a
azetidine
moiety, a 1,3-benzodioxole moiety or an alkyl moiety like in MK-0364 (see
below). In addition,
one of the aromatic groups can be fused to the spacer, or can be connected to
the spacer by an
additional ring: so-called conformational constraint. Several kinds of
conformational constraints
have successfully been implemented in this pharmacophore model. The H-bond
acceptor
represents a carbonyl group, a sulfonyl group or a nitrogen-atom which might
be embedded in a
heterocyclic ring structure such as an imidazole ring. In Scheme 1, `Lip'
represents a lipophilic
moiety, for instance piperidin-1-ylamino, pyrrolidinyl-1-amino,
cycloalkylamino, phenylamino,
arylamino, benzylamino or alkylamino.
Molecular modeling studies indicate that the presence of a hydrogen bond
acceptor is
crucial: that is thought to interact with the Lys-192 amino acid residue side
chain in the CB1
receptor, thereby stabilizing its inactive state.
4
CA 02671554 2009-06-03
WO 2008/084057 PCT/EP2008/050181
To illustrate the CB1 receptor antagonist pharmacophore model, a number of
concrete
examples of CB1 receptor are depicted below. The putative hydrogen bond
acceptor atom
(oxygen atom from a carbonyl group, oxygen atom from a sulfonyl group, or N
atom in a
heteroaromatic ring) is indicated bold.
ci Br O 0
~/ - O O CNO I/ _ 0
~N~N ~ ~\ N N N-ND ~\ N N N N N N-ND
CI CI H-N CI / ci H ci H ~~ CI CI H
Rimonabant SR 147778 CP-272,871 NIDA-41020
ci ci
~ CI \
I/
~ O ~ O ci /_ 0
N_N N N \ N
N-ND I N-ND ~ N N-ND I\ N N 0
CI ci H CI H CI CI H ~
ci
NESS 0327 0-1248
ci ci / CI \ CF3 9cl N N-O N 0 O S O
~
N_N ~ I N N-N \ NN,
H ~ ~ N-ND N-ND
CI CI CI CICI H CI H
F CI
H - CI 0 Br
~S O
\ N O 'O \ ~ X N-N_ ) /
~H ~/ O N
~~
N CI /-\ \ I \ I N N
H
H CF3
N CI CI X= N
O N~ X=CH
F
N
ci ci ci
\
O I / O N
/ O
N F CF3 H XO~
eF N - CF 3
O ~ O;SO \ N'N N \~~JJJ (: ' N-1
CI ci CI CI MK-0364
0
ci CI O
_ NH 0 N~ CF3 0=s_ND
O=SR I
/ \ / \ \ \ ~ NJ N N
N I aci N -N TIJ
N HNN O O CI HN
ci CI ci
SLV319 R = CI
SLV326 R = CF3
5
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A pharmacophore model of serotonin reuptake inhibitors has been reported
(Bureau, 2002).
Scheme 2 visualizes it:
Arl
/ R1
Lip-SRI N
\ R2
Scheme 2: Schematic overview of the SRI pharmacophore
It is characterized by a basic nitrogen atom (N), a lipophilic extended
aromatic region (Ar,) and
a lipophilic part (Lip-SRI). The basic amino function may be unsubstituted (R,
and R2 represent
hydrogen) like in fluvoxamine, or mono substituted like in fluoxetine,
indatraline and sertraline,
or disubstituted like in citalopram, zimeldine and clomipramine. The basic
nitrogen atom may be
part of a six-membered ring such as in indalpine and paroxetine: i.e. R,
represents a hydrogen
atom and R2 is part of the pharmacophore carbocyclic framework. Many 4-(3-
indolyl-
alkyl)piperidine derivatives, including indalpine and 4-(3-indolyl-
alkyl)piperazine derivatives have
been shown to possess potent serotonin reuptake inhibitor activity (Le Fur,
1977; Malleron,
1993).
The selective CB1 receptor antagonist SR141716A (rimonabant) is known for more
than a
decade. Many other selective CB1 antagonists were invented later. Serotonin
reuptake inhibitors
are known for more than two decades. No compounds have hitherto been disclosed
that
combine CB1 receptor antagonism with serotonin reuptake inhibitor activity.
The objective of the present invention was to develop compounds with a
combination of CB1
antagonism and serotonin reuptake inhibition.
6
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DISCLOSURE
It was found that molecules containing essential parts of known cannabinoid-
CB, antagonists
and essential parts of the known serotonin reuptake inhibitors indalpine or
fluvoxamine, share
the activity of both molecules from which they were derived: cannabinoid-CB,
antagonism and
serotonin reuptake inhibition. This invention relates to compounds with a
combination of
cannabinoid-CB, antagonism and serotonin reuptake inhibition, in particular to
compounds
having a pK; value > 6.00 in both CB1 receptor binding and serotonin reuptake
binding.
More in particular, the invention relates to compounds of formula (1):
R
I
ANIs, T1~11B
or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a
pharmacologically
acceptable salt, hydrate or solvate of any of the foregoing, wherein:
- A represents an essential structural element of any known cannabinoid-CB,
antagonist
containing at least two phenyl rings that are independently optionally
substituted with one or
two substituents selected from halogen, methoxy and trifluoromethyl, said
essential structural
element being attached to a hydrogen bond acceptor in said cannabinoid-CB,
antagonist,
wherein the hydrogen bond acceptor moiety is either a carbonyl group, a
sulfonyl group, or a
nitrogen or oxygen atom incorporated in a heteroaromatic ring structure,
- N represents a non-basic nitrogen atom,
- T represents a saturated or unsaturated carbon chain of 0-8 atoms, wherein
one carbon atom
may be replaced with a nitrogen atom, optionally substituted with an (C,-C3)-
alkyl or CH2CF3
group, or replaced with an oxygen atom or a sulphur atom, and which chain is
optionally
substituted with one or more substituents selected from fluoro, amino, cyano,
(C,-C3)alkyl,
(C,-C3)alkoxy and trifluoromethyl,
- R represents hydrogen atom, or a(C,-C3)-alkyl group, or R together with the
nitrogen atom to
which it is attached, and together with a part of T, forms a(C4-C,)-
heterocycloalkyl or a
heteroaryl group,
- B represents an essential structural element of any known serotonin reuptake
inhibititor.
Other embodiments provide one or more compounds of formula (1) wherein said
cannabinoid-
CB1 antagonist is selected from:
7
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11C-JHU-75528, A-796260, ajulemic acid, AM 251, AM 630, AVE-1625, CP-
272871, CP-945598, EMD-68843, GRC-10389, LY-2077855, LY-320135, NIDA-
41020, 0-2093, SLV319, SLV326, SR-140098, SR-144385, SR-41716A
(rimonabant), surinabant, V-24343, WIN-54461 and WIN-56098,
and said 5-HTreuptake inhibitor is selected from:
403U76, A-80426, AD-337, adinazolam, agomelatine, alaproclate, amineptine,
amitriptyline, ARAK-0029, ARAK-0051, befetupitant, befloxatone, BGC-20-1259,
bicifadine, BMS-505130, brofaromine, bupropion, butriptyline, cericlamine,
citalopram, CL:-275838, clomipramine, clovoxamine, CX-157, dapoxetine,
desvenlafaxine, dexfenfluramine, dibenzepin, diclofensine, dosulepine, DOV-
21947, DOV-102677, DOV-216303, duloxetine, DU 125530, DuP-631, EN-3215,
EpiCept NP-1, escitalopram, femoxetine, fluoxetine, (S)-fluoxetine,
fluvoxamine,
gepirone, IDN-5491, imipramine, indalpine, iprindole, L-792239, LI-301,
litoxetine, lofepramine, LU-10134-C, LU-AA21004, lubazodone, LY-214281, LY-
367265, LY-393558, maprotiline, MCI-225, MCL-0042, McN-5652, melitracen,
mianserine, milnacipran, mirtazepine, moclobemide, modafinil, nefazodone, 6-
nitroquipazine, nortriptyline, NR-200s, NS-2381, NS-2389, NS-2463, NS-4194,
NS-23459, omiloxetine, OPC-14523, opipramol, Org-6582, paroxetine,
pramipexole, PRC-025, propizepine, quetiapine, quinupramine, ramelteon, R-
fluoxetine, rizatriptan, robalzotan, roxindole, RS-1439, SB-649915, S-9977, SD-
726, selegiline, SEP-225289, SEP-227162, sertraline, sibutramine, (S)-
sibutramine, (R)-didemethylsibutramine, SLV310, SLV314, SPD-473, tramadol,
trazodone, udenafil, UK-416244, UP-23761, VANH-36, venlafaxine, vilazodone,
VML-670, VN-2222, volinanserin, WF-23, Wf-516, WL-1011, WL-1017, YM-922
and zimeldine.
8
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Further embodiments provide one or more compounds of formula (1): wherein A
represents one
of the fragments (A'a) (A1 b) (A2), (A3) (A4), (A5), (A6), (A'), or (A8):
R' R2
R1 / R2 R1 / R2
\ / ~ / _
N
/ / N R4
N~ N~N
N
3 II O
0 +
R O
(Ala) (A1 b) (A2)
R' R2 R1 R2 R1 - / R2
~ ~ -
N
N
N~ N
N R4 R4 R4
i
O + O + O +
(A3) (A4) (A5)
R' R2 R1 Q R2 R' R2
- ~ -
N O O
N~ S NTN
i + 0 + R3
O
x +
(As) (A7) (A8)
wherein, X represents a sulfonyl or a carbonyl group, the "+" symbol
represents the point at
which the fragment is attached to moiety N (wherein N represents a non-basic
nitrogen atom) in
formula (1), R1, R2 and R3 independently represent or more hydrogen atoms,
trifluoromethyl
groups or halogen atoms, R4 represents a hydrogen or halogen atom, or a
methyl, ethyl,
trifluoromethyl, hydroxymethyl, fluoromethyl, 2,2,2-trifluoroethyl, propyl,
methylsulfanyl,
methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl,
Cl_3-dialkyl-aminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-4-ylmethyl group, and
the other symbols
have the meanings as given above.
9
Printed: 22/07I2008 1
CLMSPAMD; EP~0080501
Y . .,. . . . .....-'-. ...... _ _ .:. .~ ' _... .!..._'._...... _} r _ _:: ~
.. +... _ _...` _..:... ~
PCT/EP20081050181: claims as filed, with ameridments of July 7, 2008. Clean
copy.
1. Compounds of formula (1):
R EPO-DG 1
1 0 8. 07. 2008
N. ~g (1)
A T
or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a
pharmacologically
acceptable salt of any of the foregoing, wherein:
10 - A represents one of the fragments (A'a), (A'h), (A2), (A3) {Aa), (A5),
(A6), (A'), or (AS):
Ri -- ~ R2
RI ~ ~ R2 RI _- S R2
\ / ~ / ~
N
/ / , N/ Ra
N N.
N~N
~\p ~+
+ `N"X R3 + ~N-S-NO O
O
(Ala) (A+b) (A2)
Ri R2 Ri R2 R' ~- / Rz
\ 1
N
N N~ N~ R4 R4 Ra
i i
O ,,,H, O + O +
(A3) (i -') (A5)
RI - / R2 Ri R2 RI '- ~ R2
- N ~ O O
} ~R3
x O
X+
(A6) (A7) `Aa)
wherein, X represents a sulfonyl or a carbonyl group, the "+" symbol
represents the point at
15 which the fragment is attached to moiety N (wherein N represents a non-
basic nitrogen atom)
in formula (1), R~, R2 and R3 independently represent one or more hydrogen
atoms,
CA 02671554 2009-06-03 AMENDED SHEET '
1 ' 08/07/2008 ,
V . ..r.__1 . .._._ .s..-.. . .. . ...r.._.. Y .._.. ... ... _ _ .,
., ... . . . . . .. , . .
Printed 22/07/2008, CLMSPAMD~, EP2008050181'
trifluoromethyl groups or halogen atoms, R4 represents a hydrogen or halogen
atom, or a
methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2,2,2-
trifluoroethyl, propyl,
methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl,
ethylsulfonyl, Cl_3-
dialkyl-aminomethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholin-
4-ylmethyl
group, and the NRTB sequence of formula (1) is one of the fragments (NTRB'),
(NRTBZ),
(NTRB3), (NRTB4), (NTRB5), (NRTB6), (NTRB7), (NRTBB), (NTRB9) or (NRTB10):
NH
N
N N`
~- . vN ..~
N"O"/~NHZ N
H H
(NRTBI) C~a (NRTB2) (NRTB3)
R
N N N,,,
O~ F
CI
(NRTB4)
(NRTBS) Ci (NRTBs) Ct
0
0--i
N R N R
CF3
O
(NRTBe)
(NRTB7) CN
NR ci
/ . 1 .
I N ` .
N / ~ f 1 \
Br
(NRTB9) (NRTB10)
wherein R represents a hydrogen atom or a(C,-C3)-alkyl group.
CA 02671554 2009-06-03 11
AMENDED SHEET 08I07/2008+
CA 02671554 2009-06-03
Printed 22/07/2008' CLMSPAMDi EP2008050181~
2. A compound as claimed in claim 1 wherein A represents one of the fragments
(A'a) or (A2):
RI R2 RI R2
N
N/ N Nr / R4
+ ly'X p + ):)- R3
(Ala) ~AZ)
wherein, X represents a sulphonyl or a carbonyl group, + the point at which
the fragment
is attached to the non-basic nitrogen atom N in formula (1), R1, R2 and
R3independently
represent hydrogen, trifluoromethyl or halogen, R4 represents a hydrogen or
halogen
atom, or a methyl, ethyl, trifluoromethyl, hydroxymethyl, fluoromethyl, 2,2,2-
trifluoroethyl,
propyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfanyl,
ethylsulfinyl,
ethylsulfonyl, CI_3-dialkyl-aminomethyl, pyrralidin-1-ylmethyl, plperidin-1-
ylmethyl or
morpholin-4-ylmethyl group, and the other symbols have the meanings given in
claim 1.
3. A compound as claimed in claim I of formula (1) wherein A represents one of
the
fragments (A3) or (A4):
cl ci
"N~ cl N
N
N Dp
NS, 0 +
(ps) CI (p-4)
and the other symbols have the meanings as given in claim 1.
4. A compound as claimed in claim 1 selected from:
- N-{1-[7-(2-amino-ethoxyimino)-7-[4-(trifluoromethyl)phenyl] heptylamino]-1-
[3-(4-
chlorophenyl)-4-phenyl-4, 5-dihydro-1 H-pyrazol-1-yl]-rnethylidene}-4-chloro-
benzenesulfonamide
12
3: AMENDED SHEET 08/07l2008;
_.-., ... . .,...... _.1 .. . _.Y....._ ...._,..--,. . _._:..... .-.,-_,.__.
;;-..__,_
~ Printed: 22/07/2008 ; CLMSPAMD EP2008Q50181.
~.
- 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid
[7-(2-
amino-ethoxyimino)-7-[4-(trifluoromethyl)phenyl] heptyl]amide
- [2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-yl] {4-[4-(5-
fluoro-1 H-
indol-3-yl)butyl]piperazin-1-yl}methanone
- 4-chloro-N-{[1-[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1 H-pyrazol-1-yl]-1-
{4-[4-(5-fluoro-
1 H-indol-3-yl)butyl]piperazin-l-yi} methylidene]-benzenesulfonamide
5. A compound as claimed in any of the claims 1-4, or a tautomer, stereo-
isomer, N-oxide,
isotopically-fabelled analogue, or a pharmacologically acceptable salt, of any
of the
foregoing, said compound being an optically active enantiomer.
6. A compound as claimed in claim 5 selected from:
ci ci
N t
N O= =O N O .O
rN~N~S HNN'S
Nv v Ci v 'CI
HN
N/ \
/i O I / CF,
F
H2N f
7. A medicament, comprising a compound according to one of the claims 1-6, or
a
pharmacologically acceptable salt thereof.
8. A pharmaceutical composition comprising, in addition to a pharmaceutically
acceptable
carrier . and/or at least one pharmaceutically acceptable auxiliary substance,
a
pharmacologically active amount of at least one compound of one of the claims
1-6, or a
pharmacologically acceptable salt thereof, as an active ingredient.
9. The pharmaceutical composition according to claim 8, further comprising at
least one
additional therapeutic agent.
13
i CA 02671554 2009-06-03 AMENDED SHEET p 8/0 71,20081~
CA 02671554 2009-06-03
;Pr~ntOd 22/07J2008; LMSPAMD` ,,EP2008050181r
10. Use of a compound as claimed in any of the claims 1-6 to prepare a
pharmaceutical
composition for the treatment of addiction, alcoholism, Alzheimers disease,
anorexia
nervosa, anxiety disorder, appetite disorders,attention deficit hyperactivity
disorder,
bipolar disorder, bulimia nervosa, cancer, cardiovascular disorders, central
nervous
system disease, cerebral ischaemia, cerebral apoplexy, chemotherapy induced
emesis,
cocaine addiction, cognitive disorder, dementia, demyelinisation related
disorders,
diabetes, diabetic neuropathy, diarrhoea, drug dependence, dystonia, eating
disorder,
emesis, epilepsy, female sexual dysfunction, functional bowel disorder,
gastrointestinal
disorders, gastric ulcers, generalized anxiety disorder, glaucoma, headache,
Huntington's disease, impulse control disorders inflammation, irritable bowel
syndrome,
male sexual dysfunction, major 'depressive disorder, memory disorders
menopause,
migraine, muscle spasticity, multiple sclerosis, = myalgia, nausea, neuralgia,
neurodegenerative disorders, neuroinflammatory disorders, neuropathic pain,
obesity,
obsessive compulsive disorder, osteoarthritis, pain, panic disorder,
Parkinson's disease,
plaque sclerosis, premature ejaculation, premenstrual syndrome, psychosexual
disorder,
psychosis, rheumatoid arthritis, septic shock, schizophrenia, sexual
disorders, sleep
disorder, spinal cord injury, stroke, Tourette's syndrome, traumatic brain
injury, tremor,
urinary incontinence and viral encephalitis.
11. Use as claimed in claim 10, to prepare a pharmaceutical composition for
treating
psychosis, anxiety, depression, attention deficits, cognitive disorders,
obesity, drug
dependence, Parkinson's disease, Alzheimer's disease, pain disorders,
neuropathic pain
disorders and sexual disorders.
14
AMENDED SHEET :08/07/2008,';
5
.:. ,.,
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pure acid or base, such as 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, which
methods are 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.
Cis and trans isomers of the compound of formula (1) or a pharmaceutically
acceptable
salt thereof are also within the scope of the invention, and this also applies
to tautomers of the
compounds of formula (1) or a pharmaceutically acceptable salt thereof.
Some of the crystalline forms for the compounds may exist as polymorphs and as
such
are intended to be included in the present invention. In addition, some of the
compounds may
form solvates with water (i.e., hydrates) or common organic solvents, and such
solvates are
also intended to be encompassed within the scope of this invention.
Isotopically-labeled compound of formula (1) or pharmaceutically acceptable
salts
thereof, including compounds of formula (1) isotopically-labeled to be
detectable by PET or
SPECT, are also included within the scope of the invention, and same applies
to compounds of
formula (1) labeled with [13C]_ [14C]_ [18F]_ [3H]_ [1251]- or other
isotopically-enriched atoms,
suitable for receptor binding or metabolism studies.
The compounds of the invention may also be used as reagents or standards in
the
biochemical study of neurological function, dysfunction and disease.
DEFINITIONS
Within the context of this description, the terms `compound with cannabinoid-
CB,
antagonism' and `cannabinoid-CB, antagonist' refer to compounds having this
activity-
measured by unambiguous and well accepted pharmacological assays, including
those
described herein-without displaying substantial cross-reactivity towards
another receptor. In
one embodiment, a compound of the present invention is at least 10 times more
potent as
cannabinoid-CB1 antagonist than as agonist or antagonist on any other
receptor. Preferred are
compounds with a 100-fold selectivity, most preferred are compounds with a
selectivity of a
factor 1,000 or higher. The terms `compound with serotonin re-uptake
inhibiting acitivity' or
`serotonin re-uptake inhibitor' refer to a compounds having this activity-
measured by
unambiguous and well accepted pharmacological assays, including those
described herein-
without displaying substantial cross-reactivity towards another re-uptake
site. In one
embodiment, a compound of the present invention is at least 10 times more
potent as serotonin
re-uptake inhibitor than as inhibitor of the re-uptake of any other
neurotransmitter. Preferred are
compounds with a 100-fold selectivity, most preferred are compounds with a
selectivity of a
CA 02671554 2009-06-03
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factor 1,000 or more. A compound `having both cannabinoid-CB, antagonism and
serotonin
re-uptake inhibitory activity', refers to compounds having both activities-
measured by
unambiguous and well accepted pharmacological assays, including those
described herein-
without displaying substantial cross-reactivity towards other receptors or re-
uptake sites. In one
embodiment, a compound of the present invention is at least 10 times more
potent as
cannabinoid-CB, antagonist and as serotonin re-uptake inhibitor, than as
agonist or antagonist
on any other receptor or as inhibitor of any other re-uptake site. Preferred
are compounds with a
100-fold selectivity, most preferred are compounds with a selectivity of a
factor 1,000 or more.
General terms used in the description of compounds herein disclosed bear their
usual
meanings. The term alkyl as used herein denotes a univalent saturated,
branched or straight,
hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to
18 carbon
atoms. Representative of such alkyl groups are methyl, ethyl, propyl,
isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl,
isohexyl, heptyl, octyl, nonyl,
decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,
heptadecyl, octadecyl, and
the like. When qualified `lower', the alkyl group will contain from 1 to 6
carbon atoms. The same
carbon content applies to the parent term `alkane', and to derivative terms
such as `alkoxy'. The
carbon content of various hydrocarbon containing moieties is indicated by a
prefix designating
the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix
CX Cy defines
the number of carbon atoms present from the integer "x" to the integer "y"
inclusive. `AIkyI(C,_3)'
for example, means methyl, ethyl, n-propyl or isopropyl, and `alkyl(C,_4)'
means `methyl, ethyl,
n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl or 2-methyl-n-propyl'.
The term `acyl' means alkyl(C,_3) carbonyl, arylcarbonyl or aryl-
alkyl(C,_3)carbonyl. `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 term "substituted" means that the specified group or moiety bears one or
more
substituents. Where any group may carry multiple substituents, and a variety
of possible
substituents is provided, the substituents are independently selected, and
need not to be the
same. The term "unsubstituted" means that the specified group bears no
substituents. With
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reference to substituents, the term "independently" means that when more than
one of such
substituents are possible, they may be the same or different from each other.
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.
To provide a more concise description, the terms `compound' or `compounds'
include
tautomers, stereoisomers, N-oxides, isotopically-labelled analogues, or
pharmacologically
acceptable salts, hydrates or solvates, also when not explicitly mentioned.
As used herein, the term "leaving group" (L) shall mean a charged or uncharged
atom
or group that departs during a substitution or displacement reaction. The term
refers to groups
readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol
nucleophile. Such
leaving groups are well known in the art. Examples include, but are not
limited to, N-
hydroxysuccinimide, N-hydroxybenzotriazole, halides (Br, Cl, I), triflates,
mesylates, tosylates,
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).
Any compound metabolized in vivo to provide the bioactive agent (i.e., the
compound of
formula (1)) 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 terms "administering" and
"use in the
treatment of" 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,
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presystemic metabolism and targeting limitations (Bundgaard, 1985; King, 1994;
Stella, 2004;
Ettmayer, 2004; Jarvinen, 2005). Prodrugs, i.e. compounds that when
administered to humans
or mammals by any known route, are metabolised to compounds having formula
(1), 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 (1) wherein an additional group is 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.
`Crystal form' refers to various solid forms of the same compound, for example
polymorphs, solvates and amorphous forms. `Polymorphs' are crystal structures
in which a
compound can crystallize in different crystal packing arrangements, all of
which have the same
elemental composition. Polymorphism is a frequently occurring phenomenon,
affected by
several crystallization conditions such as temperature, level of
supersaturation, the presence of
impurities, polarity of solvent, rate of cooling. Different polymorphs usually
have different X-ray
diffraction patterns, solid state NMR spectra, infrared or Raman spectra,
melting points, density,
hardness, crystal shape, optical and electrical properties, stability, and
solubility.
Recrystallization solvent, rate of crystallization, storage temperature, and
other factors may
cause one crystal form to dominate. `Solvates' are generally a crystal form
that contains either
stoichiometric or non-stoichiometric amounts of a solvent. Often, during the
process of
crystallization some compounds have a tendency to trap a fixed molar ratio of
solvent molecules
in the crystalline solid state, thus forming a solvate. When the solvate is
water, `hydrates' may
be formed. The compound of formula (1) and pharmaceutically acceptable salts
thereof may
exist in the form of a hydrate or a solvate, and such a hydrate and solvate
are also
encompassed in the present invention. Examples thereof include 1/4 hydrate,
dihydrochloride
dihydrate, and the like. `Amorphous' forms are noncrystalline materials with
no long range
order, and generally do not give a distinctive powder X-ray diffraction
pattern. Crystal forms in
general have been described by Byrn (1995) and Martin (1995)
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.
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While it may be possible for the compounds of formula (1) to be administered
as the raw
chemical, it is preferable to present them as a`pharmaceutical composition'.
According to a
further aspect, the present invention provides a pharmaceutical composition
comprising at least
one compound of formula (1), at least one pharmaceutically acceptable salt or
solvate thereof,
or a mixture of any of the foregoing, together with one or more
pharmaceutically acceptable
carriers thereof, and optionally one or more other therapeutic ingredients.
The carrier(s) must be
`acceptable' in the sense of being compatible with the other ingredients of
the formulation and
not deleterious to the recipient thereof. 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. 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 CB1 receptors and 5-HT
reuptake sites
was determined as described below. From the binding affinity measured for a
given compound
of formula (1), 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 CB1
receptors likely will be
occupied by the compound. By converting that concentration to mg of compound
per kg of
patient one obtains 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 dose of the compound to be
administered will
depend on the relevant indication, the age, weight and sex of the patient and
may be
determined by a physician. The dosage will preferably be in the range of from
0.01 mg/kg to 10
mg/kg. The typical daily dose of the active ingredients varies within a wide
range and will
depend on various factors such as the relevant indication, the route of
administration, the age,
weight and sex of the patient, and may be determined by a physician. In
general, total daily
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dose administration to a patient in single or individual doses, may be in
amounts, for example,
from 0.001 to 10 mg/kg body weight daily, and more usually from 0.01 to 1,000
mg per day, of
total active ingredients. Such dosages will be administered to a patient in
need of treatment
from one to three times each day, or as often as needed for efficacy, and for
periods of at least
two months, more typically for at least six months, or chronically.
The term "therapeutically effective amount" as used herein refers to an amount
of a
therapeutic agent to treat a condition treatable by administrating a
composition of the invention.
That amount is the amount sufficient to exhibit a detectable therapeutic or
ameliorative
response in a tissue system, animal or human. The effect may include, for
example, treating 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 (Berge,
1977). The `free
base' form may be regenerated by contacting the salt with a base or acid, and
isolating the
parent compound in the conventional matter. The parent form of the compound
differs from the
various salt forms in certain physical properties, such as solubility in polar
solvents, but
otherwise the salts are equivalent to the parent form of the compound for the
purposes of the
present invention. `Complex' refers to a complex of the compound of the
invention, e.g. formula
(1), complexed with a metal ion, where at least one metal atom is chelated or
sequestered.
Complexes are prepared by methods well known in the art (Dwyer, 1964).
The term "treatment" as used herein refers to any treatment of a mammalian,
for
example human condition or disease, and includes: (1) inhibiting the disease
or condition, i.e.,
arresting its development, (2) relieving the disease or condition, i.e.,
causing the condition to
regress, or (3) stopping the symptoms of the disease. The term `inhibit'
includes its generally
accepted meaning which includes prohibiting, preventing, restraining,
alleviating, ameliorating,
and slowing, stopping or reversing progression, severity, or a resultant
symptom. As such, the
present method includes both medical therapeutic and/or prophylactic
administration, as
appropriate. 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
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mammals. `Mammals' include animals of economic importance such as bovine,
ovine, and
porcine animals, especially those that produce meat, as well as domestic
animals, sports
animals, zoo animals, and humans, the latter being preferred. 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.
ABBREVIATIONS
BOC tert.-butoxycarbonyl
BOP benzotriazol-l-yl-oxytris-phosphonium hexafluorophosphate
CB1 cannabinoid receptor subtype-1
CB2 cannabinoid receptor subtype-2
CHO Chinese Hamster Ovary (cells)
CIP 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate
DCC dicyclohexylcarbodiimide
DIPEA diisopropylethylamine
DMAP 4-dimethylaminopyridin
DMSO dimethylsulfoxide
EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HBTU O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate
HOAt N-hydroxy-7-azabenzotriazole
mg milligram(s)
min minute(s)
PET positron emission tomography
PyAOP 7-azabenzotriazol-1-yloxytris(pyrrolidino)-phosphonium
hexafluorophosphate
PyBOP benzotriazol-l-yloxytris(pyrrolidino)-phosphonium hexafluorophosphate
Rf retention factor (thin layer chromatography)
SPECT single photon emission computed tomography
(S)SRI (selective) serotonin reuptake inhibitor
TBTU O-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
THF tetrahydrofuran
EXAMPLES
EXAMPLE 1: ANALYTICAL METHODS
Nuclear magnetic resonance spectra ('H NMR and 13C NMR, APT) were determined
in the
indicated solvent using a Bruker ARX 400 ('H: 400 MHz, 13C: 100 MHz) at 300 K,
or a Bruker
(300 MHz) unless indicated otherwise. The spectra were determined in
deuterated chloroform or
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DMSO-d6 obtained from Cambridge Isotope Laboratories Ltd. Chemical shifts (b)
are given in
ppm downfield from tetramethylsilane ('H, 13C) or CC13F (19F). Coupling
constants J are given in
Hz. Peakshapes in the NMR spectra are indicated with the symbols `q'
(quartet), `dq' (double
quartet), `t' (triplet), `dt' (double triplet), `d' (doublet), `dd' (double
doublet), `s' (singlet), `br s'
(broad singlet) and `m' (multiplet).
Flash chromatography/column chromatography refers to purification using
indicated eluent
and silica gel (either Acros: 0.030-0.075 mm or Merck silica gel 60: 0.040-
0.063 mm) or if
specifically stated Alumina: `Aluminumoxide Fluka for Chromatography'; pH=9.5;
0.05-0.15 mm.
Thin layer chromatography (TLC): Merck Kieselgel 60 F254 plates 20x20 cm.
Melting points were recorded on a Buchi B545 melting point apparatus.
All reactions involving moisture sensitive compounds or conditions were
carried out under an
anhydrous nitrogen atmosphere.
Reactions were monitored by using thin-layer chromatography on silica coated
plastic sheets
(Merck precoated silica gel 60 F254) with the indicated eluent. Spots were
visualised by UV light
(254 nm) or 12.
Dichloromethane (phosphorous pentoxide and calciumhydride), tetrahydrofuran
(sodium/
benzophenone ketyl) and light petroleum (60-80) were distilled freshly prior
to use. All other
commercially available chemicals were used without further purification.
EXAMPLE 2: GENERAL ASPECTS OF SYNTHESES
The syntheses of essential structural elements of known cannabinoid-CB,
antagonist are
described in patent applications and/or scientific literature. For instance,
well-documented are
the essential cannabinoid structural elements (A'a) (W001070700, Lange, 2004b)
(A1b)
(W003026648), (A) (W003027076, W003040107, W003063781, Lange, 2005b; Dyck
(2004),
(A) (EP0576357, EP1150961, Lan, 1999; Seltzman, 1995; Dutta, 1994 and Katoch-
Rouse,
2003), (A4) (W003007887, Plummer, 2005), (A) (W00307069), (A) (W003078413,
Lange,
2005b), (A7(W02004026301, Lange, 2005b; Dyck, 2004) and (A) (W02004013120).
From a general viewpoint the synthesis of compounds of formula (1) wherein R
represents a
hydrogen atom can be accomplished by reacting a compound of general formula A-
L wherein L
represents a leaving group with a compound of general formula HRN-TB. It will
be obvious for
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those skilled in the art that the amino group present in HRN-TB must be
sufficiently nucleophilic
in order to displace the leaving group from A-L in such a reaction. In the
case that L represents
a hydroxy group which is part of a carboxylic acid group, activating or
coupling reagents may be
added in order to enhance the reaction rate (Bodanszky, 1994; Akaji, 1994;
Albericio, 1997;
Montalbetti, 2005).
The synthesis of compounds of the general formula (1) wherein A represents the
cannabinoid
structural element of structure (A'a) or (A'b) wherein R1, R2 and R3
independently represent or
more hydrogen atoms, trifluoromethyl groups or halogen atoms, is outlined in
Scheme 3.
Rz
RI Rz RI V~, Rz RI VN,
POC13 HRN-TB
N, DMAP ~ 0 N O
N O
~ .S
O N SIOI I~ Rs CI~N'ISI ~ BT-N N II ~ 3
O I Rs I O R
R
(A1a1) (Ala2) 0 ~
Rz
1 ~
z
R' VN,
R1 V~, R2 POC13 R\ ~ / R HRN-TB DMAP / N N O
/~
~ S'
N O 1` O` ~\ BT-N N'IOI N. )
0 N-S-N. ) CI/\N ~101 N. ) R ~~//
O ~/ ~/
(A1b1) (A1b2) (~ )
Scheme 3
A compound of general formula (A'a') can be reacted with POC13 in the presence
of DMAP in an
inert organic solvent such as dichloromethane to give the corresponding
derivative of general
formula (A1a) . This compound of general formula (A1a) can be reacted with a
compound of
general formula HRN-TB. This reaction can give a compound of general formula
(1) wherein A
has the meaning as given herein above for (A'a) and wherein R, N, T and B have
the
abovementioned meaning, Analogously, a compound of general formula (A'b') can
be reacted
with POC13 in the presence of DMAP in an inert organic solvent such as
dichloromethane to give
the corresponding chloride derivative of general formula (A1b2). This compound
of general
formula (A1b2) can be reacted with a compound of general formula HRN-TB. This
reaction can
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give a compound of general formula (1) wherein A has the meaning as given
herein above for
(Alb) and wherein R, N, T and B have the abovementioned meaning.
The synthesis of compounds of the general formula (1) wherein A represents the
cannabinoid
structural element of structure (A2) is outlined in Scheme 4.
R' / R2 R1 R2
_ \ ~ -
N HRN-TB Y N
N R4 N R4
(AIMe3)
o OEt o N-TB
R
(Arl)
(1) wherein A is derived from A2
basic hydrolysis
OH-
R' / R2
R' R2 _
\ ~ - HRN-TB N
/ N coupling reagent N 4
R
N / R4
o N-TB
B
o OH R
(A2i2) (1) wherein A is derived from A2
SOC12 or oxalyl chloride
R' R2
R' / R2
- HRN-TB / N
N N R4
N R4
o N-TB
0 CI R
(A2i3) (1) wherein A is derived from A2
Scheme 4
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In Scheme 4, R' and R2 independently represent or more hydrogen atoms,
trifluoromethyl
groups or halogen atoms, R4 represents a hydrogen or halogen atom or a methyl,
ethyl,
trifluoromethyl, hydroxymethyl, fluoromethyl, 2,2,2-trifluoroethyl, propyl,
methylsulfanyl, methyl-
sulfinyl, methylsulfonyl, ethylsulfanyl, ethylsulfinyl, ethylsulfonyl, C,_3-
dialkyl-aminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl and the
other symbols have the
meanings as given above.
An ester of general formula (A2i1) can be reacted with a compound of general
formula HRN-TB
to give a compound of general formula (1) wherein part A is derived from
substructure A2. Such
a reaction can be catalyzed by trimethylaluminum (AIMe3) (Levin, 1982).
Alternatively, a compound of general formula (A2i1) can be hydrolyzed into the
corresponding
carboxylic acid of general formula (A2'2). A compound of general formula
(A2'2) can be reacted
with a compound of general formula HRN-TB to give a compound of general
formula (1)
wherein part A is derived from substructure A2. This reaction preferably
proceeds via activating
and coupling methods such as formation of an active ester, or in the presence
of a so-called
coupling reagent, for example, DCC, HBTU, TBTU, HOAt, PyBOP, BOP, CIP, 2-
chloro-1,3-
dimethyl-imidazolinium chloride, PyAOP and the like.
Alternatively, a compound of general formula (A2'2) can be converted in the
presence of a
chlorinating agent such as thionyl chloride or oxalyl chloride into the
corresponding acid chloride
of general formula (A2i3). A compound of general formula (A2'3) can be reacted
with a compound
of general formula HRN-TB to give a compound of general formula (1) wherein
part A is derived
from substructure A2. A base like DIPEA can be added to the reaction mixture
to scavenge the
liberated hydrochloric acid or excess HRN-TB can be applied for this purpose.
Analogously, the substructures of general formula (A3) (A4), (A5), (A6), (A'),
or (A$), as given
above, can be converted into compounds of the general formula (1) wherein part
A is derived
from the substructures (A3) (A4), (A5), (A6), (A'), or (A$) respectively.
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 or an organic acid.
CA 02671554 2009-06-03
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EXAMPLE 3: SYNTHESES OF INTERMEDIATES
Intermediate A: 4-chloro-1 -(5-fluoro-1 H-indol-3-yl)-butan-l-one
0
F CI
Intermediate A
I \ \
~ N
H
To a magnetically stirred mixture of AIC13 (25 g, 0.19 mol) in dichloromethane
was slowly added
4-chloro-butyryl chloride (21 ml, 0.19 mol) at 0 C. The resulting mixture was
stirred for 30
minutes and 5-fluoro-1 H-indole (25 g, 0.19 mol) was slowly added. After
stirring for another 30
minutes the formed orange mixture was poured onto concentrated hydrochloric
acid (140 ml)
and ice (200 ml) to give a pink precipitate. The precipitate was collected by
filtration to give pink
4-chloro-1-(5-fluoro-1 H-indol-3-yl)-butan-1-one (29 gram, 65 % yield).
'H-NMR (400 MHz, DMSO-d6) S 2.09 (quintet, J = 7, 2H), 3.02 (t, J = 7, 2H),
3.70 (t, J = 7, 2H),
7.07(dt,J- 9 and 2, 1 H), 7.49 (dd, J - 9 and 4, 1 H), 7.85 (dd, J - 9 and 2,
1H),8.41 (d,J - 3,
1 H), 12.21 (br s, 1 H).
Intermediate B: 4-[4-(5-fluoro-lH-indol-3-yl)-4-oxobutyl]-piperazine-l-
carboxylic acid tert-
butyl ester
O
N'J~ O
O N J Intermediate B
F
I ~ N
H
To a magnetically stirred solution of 4-chloro-1-(5-fluoro-1 H-indol-3-yl)-
butan-1-one (10.93 g, g,
45.6 mmol) in acetonitrile (100 ml) was added piperazine (20.33 g ml, 236
mmol) and a small
amount of potassium iodide (0.1 gram) and the resulting mixture was heated at
80 C for 48
hours. The formed solid material was removed by filtration and the residue was
concentrated in
vacuo to give 37 gram crude yield. This crude product was further purified by
column
chromatography (gradient: ethylacetate/methanol/25% aqueous ammonia = 90/5/5
to methanol)
to give 17.1 gram crude 1-(5-fluoro-1 H-indol-3-yl)-4-(piperazin-1 -yl)-butan-
1 -one. 10.71 Gram
(0.389 mol) of this crude 1-(5-fluoro-1 H-indol-3-yl)-4-(piperazin-1-yl)-butan-
1-one was dissolved
in dichloromethane (500 ml) and Boc2O (25.53 g, 0.117 mol) was added. The
resulting mixture
was stirred for 4 hours at room temperature. The mixture was successively
washed with 5 %
aqueous NaHCO3 and water. The organic layer was dried over Na2SO4, filtered
and
26
CA 02671554 2009-06-03
WO 2008/084057 PCT/EP2008/050181
concentrated in vacuo. Subsequent column chromatography (gradient: dichloro-
methane/methanol = 99/1 to dichloro-methane/methanol = 90/10 (v/v)) gave pure
4-[4-(5-fluoro-
1 H-indol-3-yl)-4-oxobutyl]-piperazine-1-carboxylic acid tert-butyl ester
(3.85 gram, 37 % yield).
'H-NMR (400 MHz, DMSO-d6) S 1.38 (s, 9H), 1.80 (quintet, J = 7, 2H), 2.25-2.35
(m, 6H), 2.84
(t, J = 7, 2H), 3.22-3.32 (m, 4H), 7.06 (dt, J - 9 and 3, 1 H), 7.47 (dd, J -
9 and 5, 1 H), 7.85 (dd,
J- 9 and 3, 1 H), 8.38 (s, 1 H), 12.01 (br s, 1 H).
Intermediate C: 5-fluoro-3-[4-(piperazin-1-yl)butyl]-1 H-indole
N H
Intermediate C
F
N
"
To a magnetically stirred solution of 4-[4-(5-fluoro-1 H-indol-3-yl)-4-
oxobutyl]-piperazine-l-
carboxylic acid tert-butyl ester (3.85 gram, 9.88 mmol) in dichloromethane was
added
hydrochloric acid (dissolved in dioxane: 4.94 ml, 4M solution, 19.8 mmol HCI)
and the resulting
mixture was reacted at room temperature for 4 hours. The reaction mixture was
thoroughly
concentrated in vacuo to give 1-(5-fluoro-1 H-indol-3-yl)-4-(piperazin-1 -
yl)butan-1 -one
dihydrochloride (3.20 gram). Some characteristic 'H-NMR signals from 1 -(5-
fluoro-1 H-indol-3-
yl)-4-(piperazin-1-yl)butan-1-one dihydrochloride: (400 MHz, DMSO-d6) S 2.07
(quintet, J = 7,
2H), 3.03 (t, J = 7, 2H), 7.08 (dt, J - 9 and 3, 1 H), 7.50 (dd, J - 9 and 4,
1 H), 7.85 (dd, J - 9 and
3, 1 H), 8.43 (d, J- 3, 1 H), 12.21 (br s, 1 H).
The obtained 1-(5-fluoro-1 H-indol-3-yl)-4-(piperazin-1 -yl)butan-1 -one
dihydrochloride (3.20
gram) was dissolved in tetrahydrofuran (50 ml) and cooled to 0 C. A solution
of LiAIH4 in
tetrahydrofuran (60 ml; 1M, - 53 mmol LiAIH4) was slowly added. Subsequently,
the mixture
was heated at 80 C for 20 hours. The excess LiAIH4 was cautiously hydrolyzed
and after
extractive work-up 5-fluoro-3-[4-(piperazin-1-yl)butyl]-1 H-indole (2.39 gram,
98 % yield) was
obtained.'H-NMR (400 MHz, DMSO-d6) S 1.40-1.50 (m, 2H), 1.61 (quintet, J = 7,
2H), 2.12-2.35
(m, 7H), 2.60-2.70 (m, 6H), 6.85-6.92 (m, 1 H), 7.17 (d, J- 2, 1 H), 7.23 (dd,
J- 9 and 2, 1 H),
7.30 (dd, J- 9 and 4, 1 H), 10.85 (br s, 1 H).
27
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Intermediate D: 7-(tetrahydropyran-2-yloxy)-1-[4-
(trifluoromethyl)phenyl]heptan-1-one
/ CF3
O O Intermediate D
IOI
Magnesium (1.20 g, 0.0494 mol) was added to anhydrous THF (5 ml) and at reflux
temperature
were successively added 1,2-dibromoethane (1 ml), a small crystal of iodine
and 2-(6-
chlorohexyloxy)tetrahydro-2-pyran (10.0 gram, 0.0453 mol; dissolved in 9 ml of
THF) and the
resulting mixture was heated at reflux temperature for 30 minutes. 4-
Trifluoromethylbenzonitrile
(7.0 gram, 0.0412 mol: dissolved in 8 ml toluene) was slowly added and the
mixture was heated
for another 30 minutes. The mixture was allowed to attain room temperature and
quenched with
acetic acid (30 ml). The organic layer was separated and successively washed
with water, 5 %
aqueous NaHCO3, water (twice) and brine. The organic layer was dried over
Na2SO4, filtered
and concentrated in vacuo. Subsequent column chromatography (ethylacetate/
heptane = 10/90
(v/v)) gave pure 7-(tetrahydropyran-2-yloxy)-1-[4-
(trifluoromethyl)phenyl]heptan-1-one (10.92
gram, 74 %) as an oil. Rf = 0.25 (ethylacetate/ heptane = 1/6 (v/v).
'H-NMR (400 MHz, CDC13) S 1.39-1.88 (m, 14H), 3.00 (t, J = 7, 2H), 3.36-3.43
(m, 1H), 3.47-
3.52 (m, 1 H), 3.71-3.77 (m, 1 H), 3.83-3.90 (m, 1 H), 4.56-4.58 (m, 1 H),
7.73 (d, J- 8, 2H), 8.06
(d, J - 8, 2H).
Intermediate E: toluene-4-sulfonic acid 7-oxo-7-[4-
(trifluoromethyl)phenyl]heptyl ester
F
O F
F Intermediate E
-S-O
0
0
To a magnetically stirred solution of 7-(tetra hyd ro pyra n -2-yl oxy)- 1 -[4-
(trifl u o ro m ethyl)
phenyl]heptan-l-one (7.70 gram, 0.0215 mol) in methanol (50 ml) was added para-
toluenesulfonic acid hydrate (4.18 gram, 0.022 mol). The resulting acidic
mixture (pH - 2, pH
paper) was reacted at room temperature for 20 hours. NaOH (1 N) was added
until the solution
was neutral (pH - 7, pH paper) and the resulting mixture was concentrated in
vacuo. NaOH
(1 N, 50 ml) was added and the mixture was extracted with dichloromethane
(3x). The combined
organic layers were successively washed with water and brine. The organic
layer was dried
over Na2SO4, filtered and concentrated in vacuo to give crude 7-hydroxy-l-[4-
(trifluoromethyl)phenyl]heptan-1-one (5.85 g, 99 % yield) as a white solid.
This obtained solid
28
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WO 2008/084057 PCT/EP2008/050181
was treated with pyridine (29.6 ml) and a solution of tosyl chloride (17.72
gram, 0.093 mol) in
pyridine (89 ml) was added at 0 C. The mixture was allowed to attain room
temperature and
reacted for 1 hour. The mixture was cooled at -10 C and quenched with excess
water.
Extraction with diethyl ether (3x), followed by drying over Na2SO4, filtering
and concentration in
vacuo gave crude product which was purified by column chromatography
(dichloromethane/
heptane = 2/1 (v/v)) to give pure toluene-4-sulfonic acid 7-oxo-7-[4-
(trifluoromethyl)phenyl]heptyl
ester (7.91 gram, 87 % yield). 'H-NMR (400 MHz, CDC13) S 1.35-1.38 (m, 4H),
1.57-1.73 (m,
4H), 2.44 (s, 3H), 2.97 (t, J = 7, 2H), 4.03 (t, J = 7, 2H), 7.35 (d, J - 8,
2H), 7.73 (d, J - 8, 2H),
7.79(d,J- 8, 2H), 8.04 (d, J - 8, 2H).
Intermediate F: toluene-4-sulfonic acid 7,7-dimethoxy-7-[4-
(trifluoromethyl)phenyl]heptyl
ester
F
O F
F Intermediate F
O O
To a magnetically stirred solution of toluene-4-sulfonic acid 7-oxo-7-[4-
(trifluoromethyl)
phenyl]heptyl ester (2.77 gram, 6.464 mmol) in methanol (75 ml) were
successively added a
catalytic amount of para-toluenesulfonic acid (0.097 gram, 0.508 mmol) and
excess
trimethylorthoformate (16 ml, 142 mmol). The resulting mixture was heated at
reflux
temperature for 20 hours. After allowing the reaction mixture to attain room
temperature
saturated aqueous NaHCO3 and dichloromethane were successively added. The
separated
organic layer was washed with saturated aqueous NaHCO3. The organic layer was
subsequently dried over Na2SO4, filtered and concentrated in vacuo to give
crude toluene-4-
sulfonic acid 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptyl ester which
was purified by
column chromatography (alumina, ethylacetate/ heptane = 1/10 (v/v)) to give
pure toluene-4-
sulfonic acid 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptyl ester (1.82
gram, 59 % yield).'H-
NMR (400 MHz, CDC13) S 0.84-0.93 (m, 2H), 1.06-1.26 (m, 4H), 1.51-1.57 (m,
2H), 1.80-1.86
(m, 2H), 2.44 (s, 3H), 3.13 (s, 6H), 3.94 (t, J = 7, 2H), 7.32 (d, J - 8, 2H),
7.55 (d, J - 8, 2H),
7.60(d,J- 8, 2H), 7.75 (d, J - 8, 2H).
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Intermediate G: 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptylamine
F
F
F Intermediate G
HZN
OV 0
Toluene-4-sulfonic acid 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptyl
ester (1.82 gram,
3.835 mmol) was dissolved in a magnetically stirred solution of 7 M NH3 in
methanol (30 ml)
and stirred at room temperature for 72 hours. After removal of the solvent in
vacuo the residue
was dissolved again in dichloromethane and washed with saturated aqueous
NaHCO3. The
organic layer was subsequently dried over Na2SO4, filtered and concentrated in
vacuo to give
crude 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptylamine (1.43 gram) which
was not further
purified. 'H-NMR (400 MHz, CDC13) S 0.88-0.95 (m, 2H), 1.12-1.16 (m, 4H), 1.33-
1.38 (m, 2H),
1.83-1.88 (m, 2H), 2.59-2.65 (m, 2H), 3.10-3.26 (m, 8H, including -OMe singlet
at 3.14), 7.56 (d,
J- 8, 2H), 7.60 (d, J - 8, 2H).
EXAMPLE 4: SYNTHESES OF SPECIFIC COMPOUNDS
The specific compounds of which the synthesis is described below are intended
to further
illustrate the invention in more detail, and therefore are not deemed to
restrict the scope of the
invention in any way. Other embodiments of the invention will be apparent to
those skilled in the
art from consideration of the specification and practice of the invention
disclosed herein. It is
thus intended that the specification and examples be considered as exemplary
only.
N-{1-[7-(2-amino-ethoxyimino)-7-[4-(trifluoromethyl)phenyl] heptylamino]-1-[3-
(4-
chlorophenyl)-4-phenyl-4,5-dihydro-1 H-pyrazol-1-yl]-methylidene}-4-chloro-
benzenesulfonamide (compound 1)
cl
N~ Compound 1
N O O
HZN-~~O-N HN N
CI
CF3
CA 02671554 2009-06-03
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Part A: 3-(4-Chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1
H-pyrazole-l-
carboxamide was obtained as described (Lange, 2004ie). 3-(4-Chloro-phenyl)-N-
[(4-chloro-
phenyl)sulfonyl]-4-phenyl-4,5-dihydro-1 H-pyrazole-l-carboxamid (0.708 gram,
1.493 mol) was
dissolved in anhydrous dichloromethane (15 ml) and DMAP (0.820 gram, 6.716
mmol) and
POC13 (0.209 g, 2.238 mmol) were successively added and the resulting mixture
was refluxed
for 5 hours. The mixture was cooled at 0 C. 7,7-Dimethoxy-7-[4-
(trifluoromethyl)phenyl]-
heptylamine (1.43 gram, 4.477 mmol) and DIPEA (0.740 ml, 4.48 mmol) were
successively
added. The mixture was subsequently heated at reflux temperature for 30 hours.
The mixture
was allowed to attain room temperature and was washed with 5 % aqueous NaHCO3,
dried
over Na2SO4, filtered and concentrated in vacuo. The obtained crude product
was purified by
column chromatography (alumina; gradient: heptane/ethylacetate = 6/1 to
ethylacetate to
ethylacetate/ methanol = 95/5 (v/v)) to give pure 4-chloro-N-{[3-(4-
chlorophenyl)-4-phenyl-4,5-
dihydro-1 H-pyrazol-1-yl]-[7-(4-fluorophenyl)-7,7-dimethoxyheptylamino]
methylene}benzenesul
fonamide (0.200 gram, 17 % yield). 'H-NMR (400 MHz, CDC13) S 0.91-1.01 (m,
2H), 1.17-1.28
(m, 4H), 1.49-1.57 (m, 2H), 1.85-1.92 (m, 2H), 3.15 (s, 6H), 3.50-3.58 (m,
2H), 4.04-4.13 (m,
1 H), 4.47-4.65 (m, 2H), 7.10 (d, J- 8, 2H), 7.22-7.32 (m, 5H) 7.35 (d, J- 8,
2H), 7.48 (d, J- 8,
2H), 7.58 (d, J- 8, 2H), 7.61 (d, J- 8, 2H), 7.82 (d, J- 8, 2H), invisible NH
proton.
Part B: 4-Chloro-N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1 H-pyrazol-1-yl]-
[7-(4-fluoro-
phenyl)-7,7-dimethoxyheptylamino] methylene}-benzenesulfonamide (0.200 gram,
0.258 mmol)
was dissolved in a 1:1 mixture of THF/methanol (30 ml) and 5 ml 1 N
hydrochloric acid was
added and the resulting mixture was stirred at room temperature for 20 hours.
The mixture was
quenched with 5 % aqueous NaHCO3. Most of the THF and methanol were removed by
evaporation in vacuo. The remaining water layer was twice extracted with
ethylacetate. The
combined organic layers were dried over Na2SO4, filtered and concentrated in
vacuo. The
obtained crude 4-chloro-N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1 H-
pyrazol-1-yl]-[7-(4-
fluorophenyl)-7-oxo-heptylamino] methylene}benzenesulfonamide (203 mg) was not
further
purified. Some characteristic aromatic'H-NMR signals: (400 MHz, CDC13) S 7.12
(d, J- 8, 2H),
7.22-7.33 (m, 5H) 7.39 (d, J - 8, 2H), 7.50 (d, J - 8, 2H), 7.72 (d, J - 8,
2H), 7.84 (d, J - 8, 2H),
8.05 (d, J- 8, 2H).
Part C: 4-Chloro-N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1 H-pyrazol-1-yl]-
[7-(4-fluoro-
phenyl)-7-oxo-heptylamino] methylene}benzenesulfonamide (0.203 gram, 0.278
mmol) was
dissolved in absolute ethanol (10 ml) and O-(2-aminoethyl)hydroxylamine
dihydrochloride (61
mg, 1.5 mol equivalent) and pyridine (0.04 ml) were successively added. The
resulting mixture
was stirred at reflux temperature for 20 hours. The mixture was allowed to
attain room
temperature. After removal of the solvent in vacuo the residue was dissolved
in
31
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WO 2008/084057 PCT/EP2008/050181
dichloromethane and washed successively with an aqueous KHSO4 solution and
brine. The
organic layer was subsequently dried over Na2SO4, filtered and concentrated in
vacuo to give N-
{1-[7-(2-amino-ethoxyimino)-7-[4-(trifluoromethyl)phenyl]heptylamino]-1-[3-(4-
chlorophenyl)-4-
phenyl-4,5-dihydro-1 H-pyrazol-1-yl]-methylidene}-4-chloro-benzenesulfonamide
(Compound 1)
(0.231 gram) as a mixture of E/Z stereoisomers Melting point: 53-58 C. 'H-NMR
(400 MHz,
CDC13) S 1.30-1.67 (m, 8H), 2.80 (t, J = 7, 2H), 3.33-3.40 (m, 2H), 3.56-3.66
(m, 2H), 4.03 (dd, J
= 11 and 5, 1 H), 4.43-4.55 (m, 3H), 4.60-4.70 (m, 2H), 7.10 (d, J- 8, 2H),
7.20-7.37 (m, 7H)
7.48(d,J- 8, 2H), 7.58 (d, J - 8, 2H), 7.71 (d,J - 8, 2H), 7.82 (d, J - 8,
2H), 8.60 (br s, 2H).
2-(2-Chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid
[7-(2-amino-
ethoxyimino)-7-[4-(trifluoromethyl)phenyl] heptyl]amide (comp. 2)
cl
\ /
NHZ
N
F~4 N 0 Compound 2
N iN
CI 0
CF3
Part A: Ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-
carboxylate was
obtained according to W003040107. To a magnetically stirred solution of ethyl
2-(2-
chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-carboxylate (5.80 g,
0.0149 mol) in
tetrahydrofuran (40 ml) was added a solution of LiOH (0.715 g) in water (40
ml). The resulting
mixture was heated at 70 C for 16 hours. The resulting mixture was allowed to
attain room
temperature and subsequently treated with concentrated hydrochloric acid (3.5
ml). The
tetrahydrofuran was evaporated in vacuo and the resulting mixture was stirred
overnight. The
formed precipitate was collected by filtration and washed with petroleum ether
(40-60) to give 2-
(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid
(4.52 gram, 84 %
yield).'H-NMR (400 MHz, CDC13): S 1.09 (t, J = 7, 3H), 2.90 (q, J = 7, 2H),
3.70 (br s, 1 H), 7.12
(dt, J = 8 and 2, 2H), 7.22-7.28 (m, 1 H), 7.29-7.38 (m, 5H).
Part B: 2-(2-Chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-
carboxylic acid (1.48 g,
4.123 mmol), 7-amino-1 -(4-(trifluoromethyl)phenyl)heptan-1 -one (1.127 g,
4.123 mmol) (7-
amino-1 -(4-(trifluoromethyl)phenyl)heptan-1 -one was obtained in 62 % yield
from intermediate E
(toluene-4-sulfonic acid 7-oxo-7-[4-(trifluoromethyl) phenyl]heptyl ester)
using 7M NH3 in
methanol; 72 hours at room temperature, analogously to the synthesis of
intermediate G (see
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WO 2008/084057 PCT/EP2008/050181
also Teubner, 1993), EDCI, HOAt (0.67 gram, 4.95 mmol) and DIPEA (1.44 ml,
8.246 mmol)
were successively dissolved in dichloromethane (30 ml) and magnetically
stirred at room
temperature for 70 hours. The reaction mixture was washed successively with
water, 5 %
aqueous NaHCO3 solution and water and was subsequently dried over Na2SO4,
filtered and
concentrated in vacuo to give crude 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-
ethyl-1 H-imidazole-
4-carboxylic acid {7-[4-(trifluoromethyl)phenyl]-7-oxo-heptyl}amide which was
purified by
column chromatography (alumina; heptane/ethylacetate = 4/1 (v/v)), followed by
another
column chromatography (silicagel; heptane/ethylacetate = 4/1 (v/v)) to give
pure 2-(2-
chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid {7-[4-
(trifluoromethyl)-
phenyl]-7-oxo-heptyl}amide (1.28 gram, 50 % yield).'H-NMR (300 MHz, DMSO-d6):
S 0.92 (t, J
= 7, 3H), 1.28-1.68 (m, 8H), 2.84 (q, J = 7, 2H), 3.08 (t, J = 7, 2H), 3.23
(q, J = 7, 2H), 7.30-7.42
(m, 5H), 7.49 (br d, J = 8, 2H), 7.56 (d, J = 8, 2H), 7.89 (d, J = 8, 2H),
8.04 (t, J = 6, 1H),8.15(d,
J = 8, 2H).
Part C: 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-
carboxylic acid {7-[4-
(trifluoromethyl)phenyl]-7-oxo-heptyl}amide (1.15 gram, 1.86 mmol) was
dissolved in absolute
ethanol (10 ml) and O-(2-aminoethyl)hydroxylamine dihydrochloride (0.276 mg,
1.865 mol) and
pyridine (0.18 ml) were successively added. The resulting mixture was stirred
at reflux
temperature for 20 hours. The mixture was allowed to attain room temperature.
After removal of
the solvent in vacuo the residue was dissolved in dichloromethane and washed
successively
with an aqueous KHSO4 solution and brine. The organic layer was subsequently
dried over Na-
2SO4, filtered and concentrated in vacuo to give 2-(2-chlorophenyl)-1-(4-
chlorophenyl)-5-ethyl-
1 H-imidazole-4-carboxylic acid [7-(2-amino-ethoxyimino)-7-[4-
(trifluoromethyl)phenyl] heptyl]-
amide (Compound 2) (1.34 gram) as a mixture of E/Z stereoisomers. Melting
point: 90-95 C.
'H-NMR (400 MHz, CDC13) S 1.05 (t, J = 7, 3H), 1.34-1.62 (m, 8H), 2.81 (br t,
J = 7, 2H), 2.93
(q, J = 7, 2H), 3.32-3.42 (m, 4H), 4.44-4.50 (m, 2H), 7.11 (d, J = 8, 2H),
7.21-7.34 (m, 5H), 7.37
(d, J = 8, 1 H), 7.49 (br s, 1 H), 7.59 (d, J = 8, 2H), 7.71 (d, J = 8, 2H),
8.65 (br s, 2H).
[2-(2-Chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-yl] {4-[4-(5-
fluoro-1 H-indol-
3-yI)butyl]piperazin-1-yl}methanone (compound 3)
ci
N _j F
CI N Compound 3
Z N~-
0 -NH
33
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WO 2008/084057 PCT/EP2008/050181
2-(2-Chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid
(0.880 g, 2.44
mmol) was reacted with intermediate C(5-fluoro-3-[4-(piperazin-1-yl)butyl]-1 H-
indole), EDCI,
HOAt and K2CO3 (1.55 mol equivalent) in dichloromethane (30 ml) at room
temperature for 70
hours analogously to the procedure described to prepare compound 2, Part B to
give [2-(2-
chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-yl] {4-[4-(5-fluoro-1
H-indol-3-yl)butyl]-
piperazin-1-yl}methanone (compound 3) (704 mg, 76 % yield) (1.28 gram, 50 %
yield). Melting
point: 91-92 C.'H-NMR (400 MHz, CDC13) S 1.03 (t, J = 7, 3H), 1.57-1.76 (m,
4H), 2.42 (t, J =
7, 2H), 2.48-2.58 (m, 4H), 2.72 (t, J 7, 2H), 2.77 (q, J = 7, 2H), 3.81 (br s,
2H), 4.08 (br s, 2H),
6.91 (dt, J- 8 and 2, 1 H), 7.01 (d, J 2, 1 H), 7.10 (d, J = 8, 2H), 7.15-7.35
(m, 8H), 8.08 (br s,
1H).
4-Chloro-N-{[1-[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1 H-pyrazol-1-yl]-1-{4-
[4-(5-fluoro-
1H-indol-3-yl)butyl]piperazin-1-yl} methylidene]-benzenesulfon-amide (compound
4)
CI
N
N 0 0 Compound 4
~ N~ ~
CI
HN
F
3-(4-Chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1 H-
pyrazole-1 -
carboxamide (0.950 gram, 2.00 mmol) was dissolved in anhydrous dichloromethane
and
reacted with DMAP and POC13, followed by a reaction with intermediate C (5-
fluoro-3-[4-
(piperazin-1-yl)butyl]-1 H-indole) and DIPEA analogously to the procedure to
prepare compound
1, Part A to give 4-chloro-N-{[1-[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-lH-
pyrazol-l-yl]-1-{4-
[4-(5-fluoro-1 H-indol-3-yl)butyl]piperazin-1-yl}methylidene]-
benzenesulfonamide, (compound 4)
(660 mg, 45 % yield). Melting point: 98-102 C. 'H-NMR (400 MHz, CDC13) S 1.56-
1.66 (m, 2H),
1.70-1.80 (m, 2H), 2.47 (t, J = 7, 2H), 2.57-2.70 (m, 4H), 2.75 (t, J = 7,
2H), 3.69-3.86 (m, 5H),
4.42 (t, J 11, 1 H), 4.54 (dd, J = 11 and 5, 1 H), 6.93 (dt, J- 8 and 2, 1 H),
7.03 (d, J - 2, 1 H),
7.10 (d, J 8, 2H), 7.21-7.38 (m, 8H), 7.48 (d, J = 8, 2H), 7.83 (d, J = 8,
2H), 7.98 (br s, 1 H).
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WO 2008/084057 PCT/EP2008/050181
EXAMPLE 5: FORMULATIONS USED IN ANIMAL STUDIES
For oral (p.o.) administration: to the desired quantity (0.5-5 mg) of the
solid compound 1 in a
glass tube, some glass beads were added and the solid was milled by vortexing
for 2 minutes.
After addition of 1 ml of a solution of 1% methylcellulose in water and 2%
(v/v) of Poloxamer
188 (Lutrol F68), the compound was suspended by vortexing for 10 minutes. The
pH was
adjusted to 7 with a few drops of aqueous NaOH (0.1 N). Remaining particles in
the suspension
were further suspended by using an ultrasonic bath.
For intraperitoneal (i.p.) administration: to the desired quantity (0.5-15 mg)
of the solid
compound 1 in a glass tube, some glass beads were added and the solid was
milled by
vortexing for 2 minutes. After addition of 1 ml of a solution of 1%
methylcellulose and 5%
mannitol in water, the compound was suspended by vortexing for 10 minutes.
Finally the pH
was adjusted to 7.
EXAMPLE 6: 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 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 serotonin reuptake sites
Affinity of the compounds for serotonin reuptake sites was determined using
the receptor
binding assay described (Habert, 1985).
EXAMPLE 7: PHARMACOLOGICAL TESTRESULTS
Cannabinoid-CB, receptor affinity data and serotonin reuptake inhibition data
obtained
according to the protocols given above are shown in the table below.
CA 02671554 2009-06-03
WO 2008/084057 PCT/EP2008/050181
In vitro pharmacology
CB1 receptor binding 5-HTreõ take binding
[ H]-CP-55,940 [ H]-paroxetine
Present invention pK; pK;
Compound 1 6.6 7.8
Compound 2 7.4 6.7
Compound 3 7.5 7.7
Compound 4 6.6 7.6
CB1antagonists
rimonabant 7.2 5.3
SLV319 8.1 < 5.0
WO 03/027076 7.9 < 4.5
5-HT reuptake inhibitors
amitriptyline < 5.0 7.2
citalopram < 5.0 8.1
fluoxetine < 6.0 7.9
fluvoxamine < 5.0 8.4
compound A (see below) < 6.0 8.9
imipramine < 6.0 8.7
indalpine < 6.0 8.6
nortrityline < 5.0 7.9
paroxetine < 6.0 9.7
sertraline < 5.0 8.8
trazodone < 5.0 6.7
zimeldine < 5.0 7.8
O HN N
N \ N Ci
H I \ ~ ~
N
N
H
WO 03/027076 Ci compound A
The data given above indicate that the compounds of the invention have a high
affinity for both
CB1 receptors and 5-HT reuptake sites. Their affinity for CB1 receptors is as
high as that of
rimonabant, whilst e.g. compound 1 simultaneously is as potent a serotonin
reuptake inhibitor
as fluoxetine. This in sharp contrast with for instance a structurally closely
related potent CB1
antagonist disclosed in WO 03/027076 (see structure above) which is completely
inactive as
serotonin reuptake inhibitor. Other CB1 antagonists tested are devoid of
affinity for 5-HT
reuptake sites, and the 5-HT reuptake inhibitors tested do not have affinity
for CB1 receptors.
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WO 2008/084057 PCT/EP2008/050181
EXAMPLE 8: PHARMACEUTICAL PREPARATIONS
For clinical use, compounds of formula (1) are formulated into 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 are apparent to a person
skilled in the art
from the specification and general knowledge in the art. The active ingredient
for instance, may
also be in the form of an inclusion complex in cyclodextrins, their ethers or
their esters. 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 (1) in
admixture with at
least one 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). In some
embodiments, the amount of active ingredient is greater than about 95% (w/w)
or less than
about 0.1 % (w/w).
The compounds of the invention can be brought into forms suitable for
administration by
means of usual processes using auxiliary 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
auxiliary 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. A tablet is prepared using the ingredients below:
Ingredient Quantity (mg/tablet)
COMPOUND No. 1 10
Cellulose, microcrystalline 200
Silicon dioxide, fumed 10
Stearic acid 10
Total 230
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WO 2008/084057 PCT/EP2008/050181
The components are blended and compressed to form tablets each weighing 230
mg.
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 gelatin 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 gelatin capsules.
Hard gelatin capsules may contain granules of the active ingredients. Hard
gelatin 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 gelatin.
Dosage units for rectal administration may be prepared (i) in the form of
suppositories
that contain the active substance mixed with a neutral fat base; (ii) in the
form of a gelatin rectal
capsule that contains the active substance in a mixture with a vegetable oil,
paraffin oil or other
suitable vehicle for gelatin 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 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 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 invention in the
manufacture of
medicaments for treating a condition wherein antagonism of CB1 receptors
and/or inhibition of
serotonin re-uptake is required or desired, and methods of medical treatment
or comprising the
38
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WO 2008/084057 PCT/EP2008/050181
administration of a therapeutically effective total amount of at least one
compound of formula
(1), either as such or, in the case of prodrugs, after administration, to a
patient suffering from, or
susceptible to, a condition wherein antagonism of CB1 receptors and/or
inhibition of serotonin
re-uptake is required or desired
By way of example, not of limitation, several pharmaceutical compositions are
given, comprising
preferred active compounds for systemic use or topical application. Other
compounds of the
invention or combinations thereof, may be used in place of (or in addition to)
said compounds.
The concentration of the active ingredient may be varied over a wide range as
discussed herein.
The amounts and types of ingredients that may be included are well known in
the art.
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