Note: Descriptions are shown in the official language in which they were submitted.
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PYRAZOLE DERIVATIVES AS THERAPEUTIC AGENTS
Field of the invention
The present invention relates to certain salts of 1,5-diarylpyrazole-3-
carboxamides, to
processes for preparing such compounds, to their use in the treatment of
obesity,
psychiatric and neurological disorders, to methods for their therapeutic use
and to
pharmaceutical compositions containing them.
Background of the invention
It is known that certain CB1 modulators (known as antagonists or inverse
agonists) are
ie useful in the treatment of obesity, psychiatric and neurological disorders
(WO01/70700 EP
658,546 and EP 656,354). However, there is a need for CB1 modulators with
improved
physicochemical properties and/or DMPK properties and/or pharmacodynamic
properties.
Pyrazoles having anti-inflammatory activity are disclosed in WO 95/15316,
W096/38418,
W097/11704, W099/64415, EP 418 845 and W02004050632. W02004050632 discloses
is 1,1-dimethylethyl [2-[4-[3-[(ethylmethylamino)carbonyl]-1-(4-methoxyphenyl)-
1H-
pyrazol-5-yl]phenoxy]ethyl]carbamate, 5-[4-(2-aminoethoxy)phenyl]-N-ethyl-l-(4-
methoxyphenyl)-N-methyl-lH-pyrazole-3-carboxamide, 1-[[5-[4-(2-
aminoethoxy)phenyl]-
1-(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]piperidine and 1,1-dimethylethyl
[2-[4-
[ 1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]phenoxy]
ethyl]-
20 carbamate. All compounds exemplified in W02004050632 and salts thereof are
excluded
from the scope of the compound claims of the present invention.
1,5-Diarylpyrazole-3-carboxamide derivatives are disclosed as having CB1
modulatory
activity in US 5,624,941, WO01/29007, W02004/052864, W003/020217, US
2004/0119972, Journal of Medicinal Chemistry, 46(4), 642-645 2003, Bioorganic
&
25 Medicinal Chemistry Letters, 14(10), 2393-2396 2004, Biochemical
Pharmacology, 60(9),
1315-1323 2000, Journal of Medicinal Chemistry, 42(4), 769-776 1999 and U.S.
Pat.
Appl. Publ. US 2003199536.
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Co-pending PCT application No. PCT/GB2005/000534 discloses compounds of
formula A
R
R N4 R3
Ra)m
N
'
(R2)n
A
and pharmaceutically acceptable salts thereof, in which
Rl represents a) a C1_3alkoxy group substituted by one or more of the
following i) fluoro
ii) a group NR Rd in which W and Rd independently represent H, a C1_6alkyl
group or C1_
6alkoxycarbonyl group provided that one of Rc and Rd is other than H or iii) a
1,3-
dioxolan-2-yl group b) RI represents a C4_6alkoxy group optionally substituted
by one or
more of the following i) fluoro ii) a group NR Rd in which R and Rd
independently
io represent H, a C1_6alkyl group or C1_6alkoxycarbonyl group provided that
one of Rc and Rd
is other than H or iii) a 1,3-dioxolan-2-yl group c) a group of formula
phenyl(CH2)PO- in
which p is 1, 2 or 3 and the phenyl ring is optionally substituted by 1, 2 or
3 groups
represented by Z, d) a group RSS(O)2O or RSS(O)2NH in which Rs represents a
C1_6alkyl
group optionally substituted by one or more fluoro, or R 5 represents phenyl
or a heteroaryl
is group each of which is optionally substituted by 1, 2 or 3 groups
represented by Z e) a
group of formula (R6)3 Si in which R6 represents a Cl_6alkyl group which may
be the same
or different or f) a group of formula RbO(CO)O in which Rb represents a
C1_6alkyl group
optionally substituted by one or more fluoro;
Ra represents halo, a CI_3alkyl group or a C1_3alkoxy group;
20 m is 0, 1, 2 or 3;
R2 represents a C1_3alkyl group, a Cl_3alkoxy group, hydroxy, nitro, cyano or
halo
nis0, 1,2or3;
R3 represents
a) a group X-Y-NR7R8
25 in which X is CO or SOz,
Y is absent or represents NH optionally substituted by a C1_3allcyl group;
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and R7 and R8 independently represent :
a C1_6alkyl group optionally substituted by 1, 2, or 3 groups represented by
W;
a C3_I5cycloalkyl group optionally substituted by 1, 2, or 3 groups
represented by W;
a(C3_15cycloalkyl)CI_3alkylene group optionally substituted by 1, 2, or 3
groups
represented by W;
a group -(CH2)r(phenyl )5 in which r is 0,1, 2, 3 or 4, s is 1 when r is 0
otherwise s is 1 or 2
and the phenyl groups are optionally independently substituted by one, two or
three groups
represented by Z;
a saturated 5 to 8 membered heterocyclic group containing one nitrogen and
optionally
io one of the following : oxygen, sulphur or an additional nitrogen wherein
the heterocyclic
group is optionally substituted by one or more C1_3alkyl groups, hydroxy or
benzyl ;
a group -(CH2)t Het in which t is 0,1, 2, 3 or 4, and the alkylene chain is
optionally
substituted by one or more C1_3alkyl groups and Het represents an aromatic
heterocycle
optionally substituted by one, two or three groups selected from a C1_5alkyl
group, a
CI_5alkoxy group or halo wherein the alkyl and alkoxy group are optionally
independently
substituted by one of more fluoro;
or R7 represents H and R8 is as defined above;
or R7 and R8 together witli the nitrogen atom to which they are attached
represent a
saturated or partially unsaturated 5 to 8 membered heterocyclic group
containing one
nitrogen and optionally one of the following : oxygen, sulphur or an
additional nitrogen;
wherein the heterocyclic group is optionally substituted by one or more
C1_3alkyl groups,
hydroxy, fluoro or benzyl;
or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,
thiadiazolyl, pyrrolyl,
pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolinyl,
each optionally substituted by 1, 2 or 3 groups Z;
R4 represents H, halo, hydroxy, cyano, a C1_6alkyl group, a C1_6alkoxy group
or a C1_
6alkoxyC1_6alkylene group which contains a maximum of 6 carbon atoms, each of
which
groups is optionally substituted by one or more fluoro or cyano;
Z represents a Cl_3alkyl group, a C1_3alkoxy group, hydroxy, halo,
trifluoromethyl,
trifluoromethylthio, difluoromethoxy, trifluoromethoxy,
trifluoromethylsulphonyl, nitro,
amino, mono or di C1_3alkylamino, CI_3alkylsulphonyl, CI_3alkoxycarbonyl,
carboxy,
cyano, carbamoyl, mono or di C1_3alkyl carbamoyl and acetyl; and
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W represents hydroxy, fluoro, a C1_3alkyl group, a C1_3alkoxy group, amino,
mono or di C1_
3allcylamino, a C1_6alkoxycarbonyl group or a heterocyclic amine selected from
morpholinyl, pyrrolidinyl, piperdinyl or piperazinyl in which the heterocyclic
amine is
optionally substituted by a C1_3alkyl group or hydroxyl;
but excluding 1,1-dimethylethyl [2-[4-[3-[(ethylmethylamino)carbonyl]-1-(4-
methoxyphenyl)-1H-pyrazol-5-yl]phenoxy]ethyl]carbamate and 1,1-dimethylethyl
[2-[4-
[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-
yl]phenoxy] ethyl] carbamate.
Salts are mentioned in general terms in PCT/GB2005/000534 in the following
way:
"Pharmaceutically acceptable salt", where such salts are possible, includes
both
pharmaceutically acceptable acid and base addition salts. A suitable
pharmaceutically
acceptable salt of a compound of Formula A is, for example, an acid-addition
salt of a
compound of Formula A which is sufficiently basic, for example an acid-
addition salt with
an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric,
trifluoroacetic,
is citric or maleic acid; or, for example a salt of a compound of Formula A
which is
sufficiently acidic, for example an alkali or alkaline earth metal salt such
as a sodium,
calcium or magnesium salt, or an ammonium salt, or a salt with an organic base
such as
methylamine, dimethylamine, trimethylamine, piperidine, morpholine or
tris-(2-hydroxyethyl)amine.
Only 2 specific salts of compounds of Formula A are disclosed in
PCT/GB2005/000534. These are: 4-{ 1-(2,4-dichlorophenyl)-4-methyl-3-
[(piperidin-l-
ylamino)carbonyl]-1H-pyrazol-5-yl}phenyl pyridine-3-sulfonate hydrochloride
and 1-
(2,4-dichlorophenyl)-5- {4-[2-(ethylamino)ethoxy]phenyl} -4-methyl-N-piperidin-
1-yl-1H-
pyrazole-3-carboxamide dihydrochloride both of which are excluded from the
claims of
the present invention.
Further salts with suitable properties for pharmaceutical formulation have now
been
found.
In the formulation of drug compositions, it is important for the drug
substance to be in
a fonn in which it can be conveniently handled and processed. This is of
importance, not
only from the point of view of obtaining a commercially viable manufacturing
process, but
also from the point of view of subsequent manufacture of pharmaceutical
formulations
comprising the active compound.
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Further, in the manufacture of drug compositions, it is important that a
reliable,
reproducible and constant plasma concentration profile of drug is provided
following
administration to a patient.
Chemical stability, solid-state stability, and "shelf life" of the active
ingredients are
also very important factors. The drug substance, and compositions containing
it, should
preferably be capable of being effectively stored over appreciable periods of
time, without
exhibiting a significant change in the active component's physico-chemical
characteristics
(e.g. its cheinical composition, density, liygroscopicity and solubility).
Moreover, it is also important to be able to provide the drug in a form that
is as
io chemically pure as possible.
The skilled person will appreciate that, typically, if a drug can be readily
obtained
in a stable form, such as a stable crystalline form, advantages may be
provided, in terms of
ease of handling, ease of preparation of suitable pharmaceutical formulations,
and a more
reliable solubility profile.
Description of the invention
The present invention provides a compound selected from:
butane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester;
1-(2,4-dichlorophenyl)-4-methyl-5-[4-(4,4,4-trifluorobutoxy)phenyl]-1H-
pyrazole-3 -
2o carboxylic acid piperidin-l-ylamide;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-
ylcarbamoyl)2H-pyrazol-3-yl]phenyl ester;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(morpholin-4-
ylcarbainoyl)-
2H-pyrazol-3-yl]phenyl ester;
3,3,3-trifluoropropane-1 -sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester;
4,4,4-trifluorobutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester;
propane-l-sulfonic acid-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-
ylcarbamoyl)-
2H-pyrazol-3-yl]-2,6-difluorophenyl ester;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-(piperidin-1-ylcarbamoyl)-
2H-
pyrazol-3-yl]phenyl ester;
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propane-l-sulfonic acid 4-[4-bromo-2-(2,4-dichlorophenyl)-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester;
methyl 1- { [(1-(2,4-dichlorophenyl)-4-methyl-5-
{4[(propylsulfonyl)oxy]phenyl} -1H-
pyrazol-3 -yl) carbonyl] amino } cyclopentanecarboxylate;
carbonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidine-1-ylcarbamoyl)-
2H-
pyrazol-3-yl]-phenyl ester propyl ester;
4- { 1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1H-
pyrazol-5-
yl}phenyl thiophene-2-sulfonate;
4- { l -(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1H-
pyrazol-5-
i0 yl}phenyl pyridine-3-sulfonate;
tert-butyl [2-(4-{ 1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-1-
ylamino)carbonyl]-1H-
pyrazol-5-yl} phenoxy)ethyl] ethylcarbamate;
4- { 1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1H-
pyrazol-5-
yl}phenyl 3-methylbutane-l-sulfonate;
4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1Fl-
pyrazol-5-
yl} phenyl 3,3 -dimethylbutane-l-sulfonate;
1-(2,4-dichlorophenyl)-5- {4-[2-(1,3-dioxolan-2-yl)ethoxy]phenyl} -4-methyl-N-
piperidin-
1-yl-lH-pyrazole-3-carboxamide;
propane-l-sulfonic acid 4-[2-(2,4-dichloro-3-fluorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester; and
5-chlorothiophene-2-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester;
in the form of a methanesulphonate salt (mesylates salt) , a hemi-1,5-
naphthalenedisulphonate salt, a 1,2-ethanedisulfonic acid salt, a
hydrochloride salt or a
hydrogen sulphate salt but excluding 4-{1-(2,4-dichlorophenyl)-4-methyl-3-
[(piperidin-l-
ylamino)carbonyl]-1H-pyrazol-5-yl}phenyl pyridine-3-sulfonate hydrochloride.
In a particular aspect the present invention provides one or more of the
following:
butane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester hydrochloride;
butane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester hemi-1,5-naphthalenedisulphonate;
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propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(morpholin-4-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester hydrochloride;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(morpholin-4-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester hemi-1,5-naphthalenedisulphonate;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(morpholin-4-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester mesylate;
4,4,4-trifluorobutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hydrochloride
4,4,4-trifluorobutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester mesylate
4,4,4-trifluorobutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hemi-l,5-naphthalenedisulphonate;
4,4,4-trifluorobutane-1 -sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hydrogen sulphate;
is propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]-2,6-difluorophenyl ester hydrochloride=,
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-
ylcarbamoyl)-
2H-pyrazol-3-yl]-2,6-difluorophenyl ester mesylate;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]-2,6-difluorophenyl ester hemi-1,5-naphthalenedisulphonate;
3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hydrochloride;
3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester mesylate;
3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hemi-1,5-naphthalenedisulphonate;
3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hydrogen sulphate;
3-methylbutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-
l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hydrochloride;
3-methylbutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-
l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester mesylate;
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3-methylbutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-
l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hemi-1,5-naphthalenedisulphonate;
3,3-dimethylbutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hydrochloride;
3,3-dimethylbutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester mesylate;
3,3-dimethylbutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hemi-1,5-naphthalenedisulphonate;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
i0 2H-pyrazol-3-yl]phenyl ester hydrochloride;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester mesylate;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester hemi-1,5-naphthalenedisulphonate;
is propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester hydrogen sulphate;
carbonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-ylcarbamoyl)-
2H-
pyrazol-3-yl]phenyl ester propyl ester hydrochloride;
carbonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl)-
2H-
20 pyrazol-3-yl]phenyl ester propyl ester mesylate;
carbonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl)-
2H-
pyrazol-3-yl]phenyl ester propyl ester hemi- 1,5-naphthalenedisulphonate;
pyridine-3-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester mesylate;
25 pyridine-3-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-
ylcarbamoyl)-
2H-pyrazol-3 -yl]phenyl ester hemi-1,5-naphthalenedisulphonate.
It will be understood that the present invention includes one or any
combination of
more than one of the above salts.
We have found that certain compounds of the invention have the advantage that
30 they may be prepared in crystalline form.
According to a further aspect of the invention there is provided a compound of
the
invention in substantially crystalline form.
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Although we have found that it is possible to produce compounds of the
invention
in forms which are greater than 80% crystalline, by "substantially
crystalline" we include
greater than 20%, preferably greater than 30%, and more preferably greater
than 40% (e.g.
greater than any of 50, 60, 70, 80 or 90%) crystalline.
According to a further aspect of the invention there is also provided a
compound of
the invention in partially crystalline form. By "partially crystalline" we
include 5% or
between 5% and 20% crystalline.
The degree (%) of crystallinity may be determined by the skilled person using
X-
ray powder diffraction (XRPD). Other techniques, such as solid state NMR, FT-
IR,
io Raman spectroscopy, differential scanning calorimetry (DSC) and
microcalorimetry, may
also be used.
Compounds of the invention, and particularly crystalline compounds of the
invention, may have improved stability when compared to compounds disclosed in
PCT/GB2005/000534.
The term "stability" as defined herein includes chemical stability and solid
state
stability.
By "chemical stability", we include that it may be possible to store compounds
of
the invention in an isolated form, or in the form of a forinulation in which
it is provided in
admixture with pharmaceutically acceptable carriers, diluents or adjuvants
(e.g. in an oral
dosage form, such as a tablet, capsule etc.), under normal storage conditions,
with an
insignificant degree of chemical degradation or decomposition.
By "solid state stability", we include that it may be possible to store
compounds of
the invention in an isolated solid form, or in the form of a solid formulation
in which it is
provided in admixture with pharmaceutically acceptable carriers, diluents or
adjuvants
(e.g. in an oral dosage form, such as a tablet, capsule etc.), under normal
storage
conditions, with an insignificant degree of solid state transformation (e.g.
crystallisation,
recrystallisation, solid state phase transition, hydration, dehydration,
solvatisation or
desolvatisation).
Examples of "normal storage conditions" include temperatures of between minus
80 and plus 50 C (preferably between 0 and 40 C and more preferably room
temperatures,
such as 15 to 30 C), pressures of between 0.1 and 2 bars (preferably at
atmospheric
pressure), relative humidities of between 5 and 95% (preferably 10 to 60%),
and/or
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exposure to 460 lux of UV/visible light, for prolonged periods (i.e. greater
than or equal to
six months). Under such conditions, compounds of the invention may be found to
be less
than 15%, more preferably less than 10%, and especially less than 5%,
chemically
degraded/decomposed, or solid state transformed, as appropriate. The skilled
person will
appreciate that the above-mentioned upper and lower limits for temperature,
pressure and
relative humidity represent extremes of normal storage conditions, and that
certain
combinations of these extremes will not be experienced during normal storage
(e.g. a
temperature of 50 C and a pressure of 0.1 bar).
It may be possible to crystallise salts of compounds of the present invention
with or
io without the presence of a solvent system (e.g. crystallisation may be from
a melt, under
supercritical conditions, or achieved by sublimation). However, it is
preferable that
crystallisation occurs from an appropriate solvent system.
According to a further aspect of the invention, there is provided a process
for the
preparation of a crystalline compound of the invention which comprises
crystallising a
compound of the invention from an appropriate solvent system.
Crystallisation temperatures and crystallisation times depend upon the salt
that is to
be crystallised, the concentration of that salt in solution, and the solvent
system that is
used.
Crystallisation may also be initiated and/or effected by way of standard
techniques,
for example with or without seeding witli crystals of the appropriate
crystalline compound
of the invention.
Different crystalline forms of the compounds of the invention may be readily
characterised using X-ray powder diffraction (XRPD) methods, for example as
described
hereinafter.
In order to ensure that a particular crystalline form is prepared in the
absence of
other crystalline forms, crystallisations are preferably carried out by
seeding with nuclei
and/or seed crystals of the desired crystalline form in substantially complete
absence of
nuclei and/or seed crystals of otlier crystalline forms. Seed crystals of
appropriate
compound may be prepared, for example, by way of slow evaporation of solvent
from a
portion of solution of appropriate salt.
Compounds of the invention may be isolated using techniques which are well
known to those skilled in the art, for example decanting, filtering or
centrifuging.
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Compounds may be dried using standard techniques.
Further purification of compounds of the invention may be effected using
techniques, which are well known to those skilled in the art. For example
impurities may
be removed by way of recrystallisation from an appropriate solvent system.
Suitable
temperatures and times for the recrystallisation depend upon the concentration
of the salt in
solution, and upon the solvent system that is used.
When compounds of the invention are crystallised, or recrystallised, as
described
herein, the resultant salt may be in a form which has improved chemical and/or
solid state
stability, as mentioned hereinbefore.
io Compounds of the invention have the advantage that they may be more
efficacious,
be less toxic, be longer acting, have a broader range of activity, be more
potent, produce
fewer side effects, be more easily absorbed, and/or have a better
pharmacokinetic profile
(e.g. higher oral bioavailability and/or lower clearance), than, and/or have
other useful
pharmacological, physical, or chemical, properties over, coinpounds known in
the prior art.
Compounds of the invention may have the further advantage that they may be
administered
less frequently than compounds known in the prior art.
Compounds of the invention may also have the advantage that they are in a form
which provides for improved ease of handling. Further, compounds of the
invention have
the advantage that they may be produced in forms which may have improved
chemical
and/or solid state stability (including e.g. due to lower hygroscopicity).
Thus, such
compounds of the invention may be stable when stored over prolonged periods.
Compounds of the invention may also have the advantage that they may be
crystallised in good yields, in a high purity, rapidly, conveniently, and at a
low cost.
It will also be understood that the compounds of the present invention may
exist in
solvated, for example hydrated, as well as unsolvated forms. It is to be
understood that the
present invention encompasses all such solvated and unsolvated forms.
Methods of preparation
The compounds of the invention may be prepared as outlined below. However, the
invention is not limited to these methods.
The salts may be prepared by reacting a compound prepared as described in
PCT/GB2005/000534 and in the examples section of this application with the
appropriate
acid, for example methanesulphonic acid, naphthalene- 1,5-disulphonic acid,
1,2-
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ethanedisulfonic acid, sulphuric acid or hydrochloric acid in an inert
solvent, for example
butanone at a temperature in the range of 0-100 C and isolating the solid
salt. The salt may
be isolated by cooling the reaction solution and optionally seeding the
solution with the
desired product and/or concentrating the solution. Optionally the product may
be isolated
s by adding an antisolvent to a solution of the product in an inert solvent.
The solid may be
collected by methods known to those skilled in the art for example filtration
or
centrifugation.
Particularly a molar equivalent of acid with respect to the free base is used
for
methanesulphonic acid and hydrochloric acid whereas for sulphuric acid, 1,5-
naphthalenedisulphonic and 1,2- ethanedisulfonic acid a half a molar
equivalent is used
with respect to the free base. It will be appreciated that a slight excess of
either the basic
compound or the acid may be employed. For example with sulphuric acid a ratio
of 1
molar equivalents to 0.5 molar equivalents of base may be employed.
The expression "inert solvent" refers to a liquid that dissolves or partially
dissolves
the free base and/or the acid and/or the product salt but does not react with
the starting
materials, reagents, intermediates or products in a manner that adversely
affects the yield
of the desired product.
In another aspect the present invention provides the compound obtainable by
reacting one of the following:
butane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]-phenyl ester;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(morpholin-4-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester;
4,4,4-trifluorobutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]-2,6-difluorophenyl ester;
3,3,3-trifluoro-propane-l-sulfonic acid 4-[2-(2,4-dichloro-phenyl)-4-methyl-5-
(piperidin-
1-ylcarbamoyl)-2H-pyrazol-3-yl]-phenyl ester;
3-methyl-butane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester;
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3,3-dimethylbutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester;
propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester;
carbonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl)-
2H-
pyrazol-3-yl]phenyl ester propyl ester; and
pyridine-3-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-
ylcarbamoyl)-
2H-pyrazol.-3-yl]phenyl ester;
with either
io a) a molar equivalent hydrochloric acid or
b) a molar equivalent methanesulphonic acid or
c) a half a molar equivalent of sulphuric acid or
d) a half a molar equivalent of 1,5-naphthalenedisulphonic acid or
e) a half a molar equivalent of 1,2-ethanedisulfonic acid
in butanone.
It will be understood by those skilled in the art that the molar equivalents
used are within
the range of experimental error and may include a slight excess of one of the
reactants for
example plus or minus 10% of the theoretical equivalent weight.
In another aspect the present invention provides a compound of formula I
R4 R3
Ra)m
R' N
(R2)n
in which
R' represents a) a C1_3alkoxy group substituted by one or more of the
following i) fluoro
ii) a group NR Rd in which R and Rd independently represent H, a C1_6alkyl
group or C1_
6alkoxycarbonyl group provided that one of R and Rd is other than H or iii) a
1,3-
dioxolan-2-yl group b) R' represents a C4_6alkoxy group optionally substituted
by one or
more of the following i) fluoro ii) a group NR Rd in which R and Rd
independently
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represent H, a CI-6alkyl group or C1_6alkoxycarbonyl group provided that one
of R and Rd
is other than H or iii) a 1,3-dioxolan-2-yl group c) a group of formula
phenyl(CH2)pO- in
which p is 1, 2 or 3 and the phenyl ring is optionally substituted by 1, 2 or
3 groups
represented by Z, d) a group R5S(O)20 or R5S(O)2NH in which R5 represents a CI-
6alkyl
group optionally substituted by one or more fluoro, or R5 represents phenyl or
a heteroaryl
group each of which is optionally substituted by 1, 2 or 3 groups represented
by Z e) a
group of formula (R)3 Si in which R6 represents a CI-6alkyl group which may be
the same
or different or f) a group of formula RbO(CO)O in which Rb represents a CI-
6alkyl group
optionally substituted by one or more fluoro;
Ra represents halo, a C1_3alkyl group or a C1_3alkoxy group;
mis0, 1,2or3;
RZ represents a C1_3alkyl group, a C1_3alkoxy group, hydroxy, nitro, cyano or
halo
nis0, 1,2or3;
R3 represents
a) a group X-Y-NR7R8
in which X is CO or SO2,
Y is absent or represents NH optionally substituted by a CI_3alkyl group;
and R7 and R8 independently represent :
a CI-6alkyl group optionally substituted by 1, 2, or 3 groups represented by
W;
a C3_1scycloalkyl group optionally substituted by 1, 2, or 3 groups
represented by W;
a(C3_15cycloalkyl)Cl_3alkylene group optionally substituted by 1, 2, or 3
groups
represented by W;
a group -(CH2)r(phenyl )5 in which r is 0,1, 2, 3 or 4, s is 1 when r is 0
otherwise s is 1 or 2
and the phenyl groups are optionally independently substituted by one, two or
three groups
represented by Z;
a saturated 5 to 8 membered heterocyclic group containing one nitrogen and
optionally
one of the following : oxygen, sulphur or an additional nitrogen wherein the
heterocyclic
group is optionally substituted by one or more C1_3alkyl groups, hydroxy or
benzyl ;
a group -(CHz)t Het in which t is 0,1, 2, 3 or 4, and the alkylene chain is
optionally
substituted by one or more C1_3alkyl groups and Het represents an aromatic
heterocycle
optionally substituted by one, two or three groups selected from a C1_5alkyl
group, a
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C1_5alkoxy group or halo wherein the alkyl and alkoxy group are optionally
independently
substituted by one of more fluoro;
or R7 represents H and R$ is as defined above;
or R7 and Rg together with the nitrogen atom to which they are attached
represent a
saturated or partially unsaturated 5 to 8 membered heterocyclic group
containing one
nitrogen and optionally one of the following : oxygen, sulphur or an
additional nitrogen;
wherein the heterocyclic group is optionally substituted by one or more CI-
3alkyl groups,
hydroxy, fluoro or benzyl;
or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,
thiadiazolyl, pyrrolyl,
pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolinyl,
each optionally substituted by 1, 2 or 3 groups Z;
R4 represents H, halo, hydroxy, cyano, a C1_6alkyl group, a C1_6alkoxy group
or a Cl_
6alkoxyC1_6allcylene group which contains a maximum of 6 carbon atoms, each of
which
groups is optionally substituted by one or more fluoro or cyano;
Z represents a CI-3alkyl group, a C1_3allcoxy group, hydroxy, halo,
trifluoromethyl,
trifluoromethylthio, difluoromethoxy, trifluoromethoxy,
trifluoromethylsulphonyl, nitro,
amino, mono or di Cl_3alkylamino, C1_3alkylsulphonyl, C1_3alkoxycarbonyl,
carboxy,
cyano, carbamoyl, mono or di CI-3alkyl carbamoyl and acetyl; and
W represents hydroxy, fluoro, a CI-3alkyl group, a C1_3alkoxy group, amino,
mono or di C1_
3alkylamino, a C1_6alkoxycarbonyl group or a heterocyclic amine selected from
morpholinyl, pyrrolidinyl, piperdinyl or piperazinyl in which the heterocyclic
amine is
optionally substituted by a CI-3alkyl group or hydroxyl;
but excluding 1,1-dimethylethyl [2-[4-[3-[(ethylmethylamino)carbonyl]-1-(4-
methoxyphenyl)-1H-pyrazol-5-y1]phenoxy]ethyl]carbamate and 1,1-dimethylethyl
[2-[4-
[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-
yl]phenoxy]ethyl]carbamate;
in the form of a methanesulphonate salt, a hemi-1,5-naphthalenedisulphonate
salt, or a 1,2-
ethanedisulfonic acid salt.
Pharmaceutical pregarations
The compounds of the invention will normally be administered via the oral,
parenteral, intravenous, intramuscular, subcutaneous or in other injectable
ways, buccal,
rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the
form of
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pharmaceutical preparations comprising the active ingredient or a
pharmaceutically
acceptable addition salt, in a pharmaceutically acceptable dosage form.
Depending upon
the disorder and patient to be treated and the route of administration, the
compositions may
be administered at varying doses.
Suitable daily doses of the compounds of the invention in the therapeutic
treatment
of liumans are about 0.001-10 mg/kg body weight, preferably 0.01-1 mg/kg body
weight.
Oral formulations are preferred particularly tablets or capsules which may be
formulated by methods known to those skilled in the art to provide doses of
the active
compound in the range of 0.5mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg,
25mg,
50mg, 100mg and 250mg.
According to a further aspect of the invention there is also provided a
pharmaceutical formulation including any of the compounds of the invention, or
pharmaceutically acceptable derivatives thereof, in admixture with
pharmaceutically
acceptable adjuvants, diluents and/or carriers.
Pharmacolo ig cal properties
The compounds of formula (I) are useful for the treatment of obesity or being
overweight, (e.g., promotion of weight loss and maintenance of weight loss),
prevention of
weight gain (e.g., medication-induced or subsequent to cessation of smoking),
for
modulation of appetite and/or satiety, eating disorders (e.g. binge eating,
anorexia, bulimia
and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing
macronutrients or
non-essential food items), for the treatment of psychiatric disorders such as
psychotic
and/or mood disorders, schizophrenia and schizo-affective disorder, bipolar
disorders,
anxiety, anxio-depressive disorders, depression, mania, obsessive-compulsive
disorders,
impulse control disorders (e.g., Gilles de la Tourette's syndrome), attention
disorders like
ADD/ADHD, stress, and neurological disorders such as dementia and cognitive
and/or
memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia,
dementia of
ageing, vascular dementia, mild cognitive impairment, age-related cognitive
decline, and
mild dementia of ageing), neurological and/or neurodegenerative disorders
(e.g. Multiple
Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and
Alzheimer's
disease), demyelinisation-related disorders, neuroinflammatory disorders
(e.g., Guillain-
Barre syndrome).
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The compounds are also potentially useful for the prevention or treatment of
dependence
and addictive disorders and behaviours (e.g., alcohol and/or drug abuse,
pathological
gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal
with or
without perceptual disturbances; alcohol withdrawal delirium; amphetamine
withdrawal;
cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic
or
anxiolytic withdrawal with or without perceptual disturbances; sedative,
hypnotic or
anxiolytic withdrawal delirium; and withdrawal symptoms due to other
substances),
alcohol and/or drug-induced mood, anxiety and/or sleep disorder with onset
during
withdrawal, and alcohol and/or drug relapse.
io The compounds are also potentially useful for the prevention or treatment
of
neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor
and spasticity,
treatment of spinal cord injury, neuropathy, migraine, vigilance disorders,
sleep disorders
(e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea,
sleep apnea
syndrome), pain disorders, cranial trauina.
The compounds are also potentially useful for the treatment of iinmune,
cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina
pectoris, abnormal
heart rhythms, and arrhythmias, congestive heart failure, coronary artery
disease, heart
disease, hypertension, prevention and treatment of left ventricular
hypertrophy, myocardial
infarction, transient ischaemic attack, peripheral vascular disease, systemic
inflammation
of the vasculature, septic chock, stroke, cerebral apoplexy, cerebral
infarction, cerebral
ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia,
metabolic
disorders (e.g. conditions showing reduced metabolic activity or a decrease in
resting
energy expenditure as a percentage of total fat-free mass, diabetes mellitus,
dyslipidemia,
fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia,
hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose,
insulin
resistance, insulin resistance syndrome, metabolic syndrome, syndrome X,
obesity-
hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II
diabetes, low
HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive
and
endocrine disorders (e.g. treatment of hypogonadism in males, treatment of
infertility or as
contraceptive, menstraal abnormalities/emmeniopatliy, polycystic ovarian
disease, sexual
and reproductive dysfunction in women and men (erectile dysfunction), GH-
deficient
subjects, hirsutism in females, normal variant short stature) and diseases
related to the
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respiratory (e.g. asthma and chronic obstructive pulmonary disease) and
gastrointestinal
systems (e.g. dysfunction of gastrointestinal motility or intestinal
propulsion, diarrhea,
emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastro-
esophageal
reflux, ulcers).
The compounds are also potentially useful as agents in treatment of
dermatological
disorders, cancers (e.g. colon, rectunl, prostate, breast, ovary, endometrium,
cervix,
gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner
syndrome,
Frohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders
and
inflammatory disorders (e.g. arthritis deformans, inflammation, inflammatory
sequelae of
io viral encephalitis, osteoarthritis) and orthopedic disorders. The compounds
are also
potentially useful as agents in treatment of (esophageal) achalasia.
In another aspect the present invention provides a compound of the invention
as
previously defined for use as a medicament.
In a further aspect the present invention provides the use of a compound of
the
is invention in the preparation of a medicament for the treatment or
prophylaxis of obesity or
being overweight, (e.g., promotion of weight loss and maintenance of weight
loss),
prevention of weight gain (e.g., medication-induced or subsequent to cessation
of
smoking), for modulation of appetite and/or satiety, eating disorders (e.g.
binge eating,
anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any
appetizing
20 macronutrients or non-essential food items), for the treatment of
psychiatric disorders such
as psychotic and/or mood disorders, schizophrenia and schizo-affective
disorder, bipolar
disorders, anxiety, anxio-depressive disorders, depression, mania, obsessive-
compulsive
disorders, impulse control disorders (e.g., Gilles de la Tourette's syndrome),
attention
disorders like ADD/ADHD, stress, and neurological disorders such as dementia
and
25 cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease,
Pick's dementia,
dementia of ageing, vascular dementia, mild cognitive iinpairment, age-related
cognitive
decline, and mild dementia of ageing), neurological and/or neurodegenerative
disorders
(e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease,
Huntington's chorea
and Alzheimer's disease), demyelinisation-related disorders, neuroinflammatory
disorders
30 (e.g., Guillain-Barre syndrome).
In a further aspect the present invention provides the use of a compound of
the
invention in the preparation of a medicament for the treatment or prophylaxis
of
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dependence and addictive disorders and behaviours (e.g., alcohol and/or drug
abuse,
pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol
withdrawal
with or without perceptual disturbances; alcohol withdrawal delirium;
amphetamine
withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal;
sedative,
hypnotic or anxiolytic withdrawal with or without perceptual disturbances;
sedative,
hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to
other
substances), alcohol and/or drug-induced mood, anxiety and/or sleep disorder
with onset
during withdrawal, and alcohol and/or drug relapse.
In a further aspect the present invention provides the use of a compound of
the
io invention in the preparation of a medicament for the treatment or
prophylaxis of
neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor
and spasticity,
treatment of spinal cord injury, neuropathy, migraine, vigilance disorders,
sleep disorders
(e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea,
sleep apnea
syndrome), pain disorders, cranial trauma.
In a further aspect the present invention provides the use of a compound of
the
invention in the preparation of a medicament for the treatment or prophylaxis
of immune,
cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina
pectoris, abnormal
heart rhythms, and arrhythmias, congestive heart failure, coronary artery
disease, heart
disease, hypertension, prevention and treatment of left ventricular
hypertrophy, myocardial
infarction, transient ischaemic attack, peripheral vascular disease, systemic
inflammation
of the vasculature, septic chock, stroke, cerebral apoplexy, cerebral
infarction, cerebral
ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia,
metabolic
disorders (e.g. conditions showing reduced metabolic activity or a decrease in
resting
energy expenditure as a percentage of total fat-free mass, diabetes mellitus,
dyslipidemia,
fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia,
hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose,
insulin
resistance, insulin resistance syndrome, metabolic syndrome, syndrome X,
obesity-
hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II
diabetes, low
HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive
and
endocrine disorders (e.g. treatment of hypogonadism in males, treatment of
infertility or as
contraceptive, menstrual abnormalities/emmeniopathy, polycystic ovarian
disease, sexual
and reproductive dysfunction in women and men (erectile dysfunction), GH-
deficient
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subjects, hirsutism in females, normal variant short stature) and diseases
related to the
respiratory (e.g. asthma and chronic obstructive pulmonary disease) and
gastrointestinal
systems (e.g. dysfunction of gastrointestinal motility or intestinal
propulsion, diarrhea,
emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastro-
esophageal
reflux, ulcers).
In a further aspect the present invention provides the use of a compound of
the
invention in the preparation of a medicament for the treatment or prophylaxis
of
dermatological disorders, cancers (e.g. colon, rectum, prostate, breast,
ovary, endometrium,
cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome,
Turner
syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract
disorders and
inflammatory disoerders (e.g. arthritis deformans, inflammation, inflammatory
sequelae of
viral encephalitis, osteoarthritis) and orthopedic disorders.
In a still further aspect the present invention provides a method comprising
administering a pharmacologically effective amount of a compotnid of the
invention to a
patient in need thereof for the prophylaxis or treatment of obesity or being
overweight,
(e.g., promotion of weight loss and maintenance of weight loss), prevention of
weight gain
(e.g., medication-induced or subsequent to cessation of smoking), for
modulation of
appetite andlor satiety, eating disorders (e.g. binge eating, anorexia,
bulimia and
compulsive), cravings (for drugs, tobacco, alcohol, any appetizing
macronutrients or non-
essential food items), for the treatment of psychiatric disorders such as
psychotic and/or
mood disorders, schizophrenia and schizo-affective disorder, bipolar
disorders, anxiety,
anxio-depressive disorders, depression, mania, obsessive-compulsive disorders,
impulse
control disorders (e.g., Gilles de la Tourette's syndrome), attention
disorders like
ADD/ADHD, stress, and neurological disorders such as dementia and cognitive
and/or
memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia,
dementia of
ageing, vascular dementia, mild cognitive impairment, age-related cognitive
decline, and
mild dementia of ageing), neurological and/or neurodegenerative disorders
(e.g. Multiple
Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and
Alzheimer's
disease), demyelinisation-related disorders, neuroinflammatory disorders
(e.g., Guillain-
Barre syndrome).
In a still further aspect the present invention provides a method comprising
administering a pharmacologically effective amount of a compound of the
invention to a
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patient in need thereof for the prophylaxis or treatment of dependence and
addictive
disorders and behaviours (e.g., alcohol andlor drug abuse, pathological
gambling,
kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or
without
perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal;
cocaine
withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or
anxiolytic
withdrawal with or without perceptual disturbances; sedative, hypnotic or
anxiolytic
withdrawal delirium; and withdrawal symptoms due to other substances), alcohol
and/or
drug-induced mood, anxiety and/or sleep disorder with onset during withdrawal,
and
alcohol and/or drug relapse.
io In a still further aspect the present invention provides a method
comprising
administering a pharmacologically effective amount of a compound of the
invention to a
patient in need thereof for the prophylaxis or treatment of neurological
dysfunctions such
as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of
spinal cord injury,
neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed
sleep
architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome),
pain disorders,
cranial trauma.
In a still further aspect the present invention provides a method comprising
administering a pharmacologically effective amount of a compound of the
invention to a
patient in need thereof for the prophylaxis or treatment of immune,
cardiovascular
disorders (e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal
heart rhythms,
and arrhythmias, congestive heart failure, coronary artery disease, heart
disease,
hypertension, prevention and treatment of left ventricular liypertrophy,
myocardial
infarction, transient ischaemic attack, peripheral vascular disease, systemic
inflammation
of the vasculature, septic chock, stroke, cerebral apoplexy, cerebral
infarction, cerebral
ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia,
metabolic
disorders (e.g. conditions showing reduced metabolic activity or a decrease in
resting
energy expenditure as a percentage of total fat-free mass, diabetes mellitus,
dyslipidemia,
fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia,
liyperuricacidemia, impaired glucose tolerance, impaired fasting glucose,
insulin
resistance, insulin resistance syndrome, metabolic syndrome, syndrome X,
obesity-
hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II
diabetes, low
HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive
and
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endocrine disorders (e.g. treatment of hypogonadism in males, treatment of
infertility or as
contraceptive, menstrual abnormalities/emmeniopathy, polycystic ovarian
disease, sexual
and reproductive dysfunction in women and men (erectile dysfunction), GH-
deficient
subjects, hirsutism in females, normal variant short stature) and diseases
related to the
respiratory (e.g. asthma and chronic obstructive pulmonary disease) and
gastrointestinal
systems (e.g. dysfunction of gastrointestinal motility or intestinal
propulsion, diarrhea,
emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastro-
esophageal
reflux, ulcers).
In a still further aspect the present invention provides a method comprising
administering a pharmacologically effective amount of a compound of the
invention to a
patient in need thereof for the prophylaxis or treatment of dermatological
disorders,
cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix,
gallbladder, bile
duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich's
syndrome,
glaucoma, infectious diseases, urinary tract disorders and inflammatory
disorders (e.g.
is arthritis deformans, inflammation, inflammatory sequelae of viral
encephalitis,
osteoarthritis) and orthopedic disorders..
The compounds of the present invention are particulary suitable for the
treatment of
obesity or being overweight, (e.g., promotion of weight loss and maintenance
of weight
loss), prevention or reversal of weight gain (e.g., rebound, medication-
induced or
subsequent to cessation of smoking), for modulation of appetite and/or
satiety, eating
disorders (e.g. binge eating, anorexia, bulimia and compulsive), cravings (for
drugs,
tobacco, alcohol, any appetizing macronutrients or non-essential food items).
The compounds of formula (I) are useful for the treatment of obesity,
psychiatric disorders
such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-
depressive
disorders, depression, cognitive disorders, memory disorders, obsessive-
compulsive
disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and
related
conditions, and neurological disorders such as dementia, neurological
disorders(e.g.
Multiple Sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's
chorea and
Alzheimer's disease. The compounds are also potentially useful for the
treatment of
immune, cardiovascular, reproductive and endocrine disorders, septic shock and
diseases
related to the respiratory and gastrointestinal systems (e.g. diarrhea). The
compounds are
also potentially useful as agents in treatment of extended abuse, addiction
and/or relapse
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indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc)
dependence and/or
treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms.
The
compounds may also eliminate the increase in weight that normally accompanies
the
cessation of smoking.
In another aspect the present invention provides a compound of the invention
as
previously defined for use as a medicament.
In a further aspect the present invention provides the use of a compound of
the
invention in the preparation of a medicament for the treatment or prophylaxis
of obesity,
psychiatric disorders such as psychotic disorders, schizophrenia, bipolar
disorders, anxiety,
anxio-depressive disorders, depression, cognitive disorders, memory disorders,
obsessive-
compulsive disorders, anorexia, bulimia, attention disorders like ADHD,
epilepsy, and
related conditions, neurological disorders such as dementia, neurological
disorders (e.g.
Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's
Disease,
immune, cardiovascular, reproductive and endocrine disorders, septic shock,
diseases
is related to the respiratory and gastrointestinal systems (e.g. diarrhea),
and extended abuse,
addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol,
cocaine, opiates,
etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates,
etc) withdrawal
symptoms.
In a still further aspect the present invention provides a method of treating
obesity,
psychiatric disorders such as psychotic disorders such as schizophrenia and
bipolar
disorders, anxiety, anxio-depressive disorders, depression, cognitive
disorders, memory
disorders, obsessive-compulsive disorders, anorexia, bulimia, attention
disorders like
ADHD, epilepsy, and related conditions, neurological disorders such as
dementia,
neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease,
Huntington's Chorea
and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine
disorders,
septic shock, diseases related to the respiratory and gastrointestinal systems
(e.g. diarrhea),
and extended abuse, addiction and/or relapse indications, e.g. treating drug
(nicotine,
ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine,
ethanol, cocaine,
opiates, etc) withdrawal symptoms comprising administering a pharmacologically
effective
amount of a compound of the invention to a patient in need thereof.
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The compounds of the present invention are particulary suitable for the
treatment of
obesity, e.g. by reduction of appetite and body weight, maintenance of weight
reduction
and prevention of rebound.
The compounds of the present invention may also be used to prevent or reverse
medication-induced weight gain, e.g. weight gain caused by antipsychotic
(neuroleptic)
treatment(s). The compounds of the present invention may also be used to
prevent or
reverse weight gain associated with smoking cessation.
The compounds of the present invention are suitable for use in treating the
above
indications in juvenile or adolescent patient populations.
io The compounds of the present invention may also be suitable for use in the
regulation of bone mass and bone loss and therefore useful in the treatment of
osteoporosis
and other bone diseases.
Combination Therany
The compounds of the invention may be combined with another therapeutic agent
that is useful in the treatment of obesity such as other anti-obesity drugs,
that affect energy
expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis,
lipogenesis, fat
absorption, fat storage, fat excretion, hunger and/or satiety and/or craving
mechanisms,
appetite/motivation, food intake, or G-I motility.
The compounds of the invention may further be combined with another
therapeutic
agent that is useful in the treatment of disorders associated with obesity
such as
hypertension, hyperlipidaemias, dyslipidaemias, diabetes, sleep apnea, asthma,
heart
disorders, atherosclerosis, macro and micro vascular diseases, liver
steatosis, cancer, joint
disorders, and gallbladder disorders. For example, a compound of the present
invention
may be used in combination with a another therapeutic agent that lowers blood
pressure or
that decreases the ratio of LDL:HDL or an agent that causes a decrease in
circulating levels
of LDL-cholesterol. In patients with diabetes mellitus the compounds of the
invention may
also be combined with therapeutic agents used to treat complications related
to micro-
angiopathies.
The compounds of the invention may be used alongside other therapies for the
treatment of obesity and its associated complications the metabolic syndrome
and type 2
diabetes, these include biguanide drugs, insulin (synthetic insulin analogues)
and oral
antihyperglycemics (these are divided into prandial glucose regulators and
alpha-
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glucosidase inhibitors).
In another aspect of the invention, the compound of the invention, or a
pharmaceutically acceptable salt thereof may be administered in association
with a PPAR
modulating agent. PPAR modulating agents include but are not limited to a PPAR
alpha
and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates
of such salts
or prodrugs thereof. Suitable PPAR alpha and/or gamma agonists,
pharmaceutically
acceptable salts, solvates, solvates of such salts or prodrugs thereof are
well known in the
art.
In addition the combination of the invention may be used in conjunction with a
sulfonylurea. The present invention also includes a compound of the present
invention in
combination with a cholesterol-lowering agent. The cholesterol-lowering agents
referred to
in this application include but are not limited to inhibitors of HMG-CoA
reductase (3-
hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoA reductase
inhibitor is a statin.
hi the present application, the term "cholesterol-lowering agent" also
includes
chemical modifications of the HMG-CoA reductase inhibitors, such as esters,
prodrugs and
metabolites, wlzether active or inactive.
The present invention also includes a compound of the present invention in
combination with an inhibitor of the ileal bile acid transport system (IBAT
inhibitor). The
present invention also includes a compound of the present invention in
combination with a
bile acid binding resin.
The present invention also includes a compound of the present invention in
combination with a bile acid sequestering agent, for example colestipol or
cholestyramine
or cholestagel.
According to an additional further aspect of the present invention there is
provided
a combination treatment comprising the administration of an effective amount
of a
compound of the invention, or a phannaceutically acceptable salt thereof,
optionally
together with a pharmaceutically acceptable diluent or carrier, with the
simultaneous,
sequential or separate administration one or more of the following agents
selected from:
a CETP (cholesteryl ester transfer protein) inhibitor;
a cholesterol absorption antagonist;
a MTP (microsomal transfer protein) inhibitor ;
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a nicotinic acid derivative, including slow release and coinbination products;
a pliytosterol compound
probucol;
an anti-coagulant;
an omega-3 fatty acid ;
another anti-obesity compound for example sibutramine, phentermine, orlistat,
bupropion,
ephedrine, thyroxine;
an antihypertensive compound for example an angiotensin converting enzyme
(ACE)
inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an
alpha adrenergic
blocker, a beta adrenergic blocker, a mixed alpha/beta adrenergic blocker, an
adrenergic
stimulant, calcium channel blocker, an AT-1 blocker, a saluretic, a diuretic
or a
vasodilator;
a melanin concentrating hormone (MCH) modulator;
an NPY receptor modulator;
an orexin receptor modulator;
a phosphoinositide-dependent protein kinase (PDK) modulator; or
modulators of nuclear receptors for example LXR, FXR, RXR, GR, ERRa, (3,
PPARa, (3, 'y
and RORalpha;
a monoamine transmission-modulating agent, for example a selective serotonin
reuptake
inhibitor (SSRI), a noradrenaline reuptake inhibitor (NARI), a noradrenaline-
serotonin
reuptake inhibitor (SNRI), a monoamine oxidase inhibitor (MAOI), a tricyclic
antidepressive agent (TCA), a noradrenergic and specific serotonergic
antidepressant
(NaSSA);
an antipsychotic agent for example olanzapine and clozapine;
a serotonin receptor modulator;
a leptin/leptin receptor modulator;
a ghrelin/ghrelin receptor modulator;
a DPP-IV inhibitor;
or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a
prodrug thereof,
optionally together with a pharmaceutically acceptable diluent or carrier to a
warm-
blooded animal, such as inan in need of such therapeutic treatment.
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According to an additional further aspect of the present invention there is
provided a
combination treatment comprising the administration of an effective amount of
a
compound of the invention, or a pharmaceutically acceptable salt thereof,
optionally
together with a pharmaceutically acceptable diluent or carrier, with the
simultaneous,
sequential or separate administration of very low calorie diets (VLCD) or low-
calorie diets
(LCD).
Therefore in an additional feature of the invention, there is provided a
method for
the treatment of obesity and its associated complications in a warm-blooded
animal, such
as man, in need of such treatment which comprises administering to said animal
an
io effective amount of a compound of the invention, or a pharmaceutically
acceptable salt
thereof in simultaneous, sequential or separate administration with an
effective amount of a
compound from one of the other classes of compounds described in this
combination
section, or a pharmaceutically acceptable salt, solvate, solvate of such a
salt or a prodrug
thereof.
Therefore in an additional feature of the invention, there is provided a
method of
treating hyperlipidemic conditions in a warm-blooded animal, such as man, in
need of such
treatment which comprises administering to said animal an effective amount of
a
compound of the invention, or a pharmaceutically acceptable salt thereof in
simultaneous,
sequential or separate administration with an effective amount of a compound
from one of
the other classes of compounds described in this combination section or a
pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug
thereof.
According to a further aspect of the invention there is provided a
pharmaceutical
composition which comprises a compound of the invention, or a pharmaceutically
acceptable salt thereof, and a compound from one of the other classes of
compounds
described in this combination section or a pharmaceutically acceptable salt,
solvate, solvate
of such a salt or a prodrug thereof, in association with a pharmaceutically
acceptable
diluent or carrier.
According to a further aspect of the present invention there is provided a kit
comprising a compound of the invention, or a pharmaceutically acceptable salt
thereof, and
a compound from one of the other classes of compounds described in this
combination
section or a pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug
thereof.
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According to a further aspect of the present invention there is provided a kit
comprising:
a) a compound of the invention, or a pharmaceutically acceptable salt thereof,
in a first unit
dosage form;
b) a compound from one of the other classes of compounds described in this
combination
section or a pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug
thereof; in a second unit dosage form; and
c) container means for containing said first and second dosage forms.
According to a further aspect of the present invention there is provided a kit
comprising:
a) a compound of the invention, or a pharmaceutically acceptable salt thereof,
together
with a pharmaceutically acceptable diluent or carrier, in a first unit dosage
form;
b) a compound from one of the other classes of compounds described in this
combination
section or a pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug
thereof, in a second unit dosage form; and
is c) container means for containing said first and second dosage forms.
According to another feature of the invention there is provided the use of a
compound of
the invention, or a pharmaceutically acceptable salt thereof, and one of the
other
compounds described in this combination section, or a pharmaceutically
acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a
medicament for
use in the treatment of obesity and its associated complications in a warm-
blooded animal,
such as man.
According to another feature of the invention there is provided the use of a
compound of the invention, or a pharmaceutically acceptable salt thereof, and
one of the
other compounds described in this combination section, or a pharmaceutically
acceptable
salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture
of a
medicament for use in the treatment of hyperlipidaemic conditions in a warni-
blooded
animal, such as man.
According to a further aspect of the present invention there is provided a
combination treatment comprising the administration of an effective amount of
a
compound of the invention, or a pharmaceutically acceptable salt thereof,
optionally
together with a pharmaceutically acceptable diluent or carrier, with the
simultaneous,
sequential or separate administration of an effective amount of one of the
other compounds
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described in this combination section, or a pharmaceutically acceptable salt,
solvate,
solvate of such a salt or a prodrug thereof, optionally together with a
pharmaceutically
acceptable diluent or carrier to a warm-blooded animal, such as man in need of
such
therapeutic treatment.
Furthermore, a compound of the invention may also be combined with therapeutic
agents that are useful in the treatment of disorders or conditions associated
with obesity
(such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose
tolerance,
hypertension, coronary heart disease, non-alcollolic steatohepatitis,
osteoarthritis and soine
cancers) and psychiatric and neurological conditions.
i0 It will be understood that there are medically accepted defmitions of
obesity and
being overweight. A patient may be identified by, for example, measuring body
mass index
(BMI), which is calculated by dividing weight in kilograms by height in metres
squared,
and comparing the result with the definitions.
Pharmacological Activity
Compounds of the present invention are active against the receptor product of
the
CB 1 gene. The affinity of the compounds of the invention for central
cannabinoid
receptors is demonstrable in methods described in Devane et al , Molecular
Pharmacology, 1988, 34,605 or those described in WO01/70700 or EP 656354.
Alternatively the assay may be performed as follows.
10 g of membranes prepared from cells stably transfected with the CB1 gene
were
suspended in 200 1 of 100mM NaCI, 5miVI MgC12, 1mM EDTA, 50mM HEPES (pH 7.4),
linM DTT, 0.1% BSA and 100gM GDP. To this was added an EC80 concentration of
agonist (CP55940), the required concentration of test compound and 0.1 Ci
[35S]-GTPyS.
The reaction was allowed to proceed at 30 C for 45 min. Samples were then
transferred on
to GF/B filters using a cell harvester and washed with wash buffer (50mM Tris
(pH 7.4),
5mM MgC12, 50m1V1 NaCI). Filters were then covered with scintilant and counted
for the
amount of [35S]-GTPyS retained by the filter.
Activity is measured in the absence of all ligands (minimum activity) or in
the
presence of an EC80 concentration of CP55940 (maximum activity). These
activities are
set as 0% and 100% activity respectively. At various concentrations of novel
ligand,
activity is calculated as a percentage of the maximum activity and plotted.
The data are
fitted using the equation y=A+((B-A)/1+((C/x) LTD)) and the IC50 value
determined as the
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concentration required to give half maximal inhibition of GTPyS binding under
the
conditions used.
The compounds of the present invention are active at the CB 1 receptor (IC50
<1
micromolar). Most preferred compounds have IC50 <200 nanomolar.
The compounds of the invention are are believed to be selective CB 1
antagonists or
inverse agonists. The potency, selectivity profile and side effect propensity
may limit the
clinical usefulness of hitherto known compounds with alleged CB 1
antagonistic/inverse
agonistic properties. In this regard, preclinical evaluation of compounds of
the present
io invention in models of gastrointestinal and/or cardiovascular function
indicates that they
offer significant advantages compared to representative reference CB 1
antagonist/inverse
agonist agents.
The compounds of the present invention may provide additional benefits in
terms of
potency, selectivity profile, bioavailability, half-life in plasma, blood
brain permeability,
plasma protein binding ( for example higher free fraction of drug) or
solubility compared
to representative reference CB1 antagonists/inverse agonist agents.
The utility of the compounds of the present invention in the treatment of
obesity
and related conditions is demonstrated by a decrease in body weight in
cafeteria diet-
induced obese mice. Female C57B1/6J mice were given ad libitum access to
calorie-dense
'cafeteria' diet (soft chocolate/cocoa-type pastry, chocolate, fatty cheese
and nougat) and
standard lab chow for 8-10weeks. Compounds to be tested were then administered
systemically (iv, ip, sc or po) once daily for a minimum of 5 days, and the
body weights of
the mice monitored on a daily basis. Simultaneous assessment of adiposity was
carried by
means of DEXA imaging at baseline and termination of the study. Blood sampling
was
also carried out to assay changes in obesity-related plasma markers.
Examnles of the Invention
Abbreviations
AcOH acetic acid
DCM dichloromethane
DMF dimetliylformamide
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DEA diethylamine
DIEA N,N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
EtOAc ethyl acetate
s Et3N triethylamine
Ex or EX Example
LiHMDS lithium hexamethyldisilazide
LiHMDSA Lithium bis(trimethylsilyl)amide bis(trimethylsilyl)amide
MEK Methyl ethyl ketone
MeOH methanol
MeCN acetnitrile
NMM 4-methylmorpholine
NMP N-methylpyrrolidone
rt or RT room temperature
TBTU O-(Benzotriazole-1-yl)-N,N,N', N'-tertamethyluronium
TEA triethylamine
TFA Trifluoroacetic acid
THF tetrahydrofuran
t triplet
s singlet
d doublet
q quartet
qvint quintet
m multiplet
br broad
bs broad singlet
dm doublet of multiplet
bt broad triplet
dd doublet of doublet
General Experimental Procedures
Mass spectra were recorded on either a Micromass ZQ single quadrupole or a
Micromass
LCZ single quadrupole mass spectrometer both equipped with a pneumatically
assisted
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electrospray interface (LC-MS). 1H NMR measurements were performed on either a
Varian Mercury 300 or a Varian Inova 500, operating at 'H frequencies of 300
and 500
MHz respectively. Chemical shifts are given in ppm with CDC13 as internal
standard.
CDC13 is used as the solvent for NMR unless otherwise stated. Purification was
performed
on a semipreparative HPLC ( High Performance Liquid Chromatography ) with a
mass
triggered fraction collector, Shimadzu QP 8000 single quadrupole mass
spectrometer
equipped with 19 x 100 mm C8 column. The mobile phase used was, if nothing
else is
stated, acetonitrile and buffer (0.1 M ammonium acetate:acetonitrile 95:5).
For isolation of isomers, a Kromasil CN E9344 (250 x 20 nun i.d.) colunm was
used.
io Heptane:ethyl acetate:DEA 95:5:0.1 was used as mobile phase (1 ml/min).
Fraction
collection was guided using a UV-detector (330 nm).
Typical HPLC-paranleters for purity analysis:
HPLC-system: Agilent 1100
Column: Zorbax Eclipse XDB-C8 150x4.6 inm
Time of analysis: 15 min
Flow: 1.5 ml/min
Mobilphase: A: water, 5% MeOH
B: MeOH
Temperature: 40 C
Detector: Uv 240nm
Examples
General procedure for salt preparation
The free base (usually 15-30 mg) was dissolved in butanone (for example 0.08
to
0.2 ml usually 0.8-2 ml) and if necessary together with methanol (usually less
than 1 ml).
The solution was optionally put in an ultrasonic bath (Decon FS200b). Acid (1
molar
equivalent (equiv.) HCl or 1 equiv. methanesulphonic acid or 0.5 equiv.
naphthalene-1,5-
disulphonic acid) or 1 equiv. or 0.5 equiv. sulphuric acid, dissolved in
methanol (usually
0.1-0.2 ml), was added. Heptane (usually 0.5-2 ml) was added dropwise and the
resulting
mixture was left in the ultrasonic bath. The formed solid was collected by
filtration and
was dried under high vacuum.
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The melting points were determined on a Reichert melting point microscope and
are uncorrected. It will be appreciated by those skilled in the art that the
rate of heating can
affect the melting point obtained and that certain salts, for example
hydrochloride salts,
may dissociate on slow heating so that ultimately the melting point obtained
may be that of
the free base or that of a mixture of free base and hydrochloride salt. In
such cases
conibustion analysis may be used to confirm the identity of the salt. It will
also be
appreciated by those skilled in the art that the drying temperature should not
be too high,
for example greater than 45 C, otherwise decomposition of the salt may occur.
Vacuum
drying is preferred.
The following salts were formed as described in the general procedure by using
appropriate acid.
Example 1: Butane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester
Hydrochloride: melting point 106-112 C.
Heini-1,5-naphthalenedisulphonate: melting point 160-163 C.
Example 2: Propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(morpholin-4-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester
Hydrochloride: melting point 220-223 C.
Hemi- 1,5-naphthalenedisulphonate: melting point 270-274 C.
Mesylate: melting point 218-223 C.
Example 3: 4,4,4-Trifluorobutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-
methyl-5-
(piperidin-1-ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester
Hydrochloride: melting point: 100-105 C
Mesylate: melting point 169-174 C.
Hemi- 1,5-naphthalenedisulphonate: melting point 260-265 C.
Hydrogen sulphate: melting point 203-207 C.
Example 4: Propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]-2,6-difluorophenyl ester
Hydrochloride: melting point: 104-108 C.
Mesylate: melting point 141-145 C.
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Hemi-1,5-naphthalenedisulphonate: melting point 271-274 C.
Example 5: 3,3,3-Trifluoro-propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-
methyl-5-
(piperidin-1-ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester
Hydrochloride: melting point: 101-107 C.
Mesylate: melting point 168-173 C.
Hemi- 1,5-naphthalenedisulphonate: melting point: 159-164 C.
Hydrogen sulphate: melting point 205-209 C.
Example 6: 3-Methyl-butane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-
5-
(piperidin-1-ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester
Hydrochloride: melting point: 110-115 C.
Mesylate: melting point 122-127 C.
Hemi-1,5-naphthalenedisulphonate: melting point 161-164 C.
Example 7: 3,3-Dimethyl-butane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-
methyl-5-
(piperidin-1-ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester
is Hydrochloride: melting point: 112-119 C.
Mesylate: melting point 160-167 C.
Hemi-1,5-naphthalenedisulphonate: melting point 276-279 C.
Example 8: Propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester
Hydrochloride: melting point: 185-189 C.
Mesylate: melting point 111-114 C.
Hemi-1,5-naphthalenedisulphonate: melting point 156-161 C.
Hydrogen sulphate: melting point 203-209 C.
Example 9: Carbonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester propyl ester
Hydrochloride: melting point: 99-108 C.
Mesylate: melting point 110-115 C.
Hemi- 1,5-naphthalenedisulphonate: melting point 175-180 C.
Example 10: Pyridine-3-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester
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Mesylate: melting point 225-227 C.
Hemi-1,5-naphthalenedisulphonate: melting point 168-172 C
Preparation of Free Bases
1) Propane-l-sulfonic acid 4-f2-(2,4-dichlorophenyl)-4-methyl-5-(pineridin-1-
ylcarbamoyl)2H-pyrazol-3-yll-phenyl ester
Step A 1-(4-Benzyloxyphenyl)propan-l-one
4-Hydroxypropiophenone (15.0 g, 0.10 mol) was dissolved in acetone (200 ml)
together
with potassium carbonate (13.8 g, 0.10 mol). Benzyl bromide (17.1 g, 0.10 mol)
was added
and the reaction mixture heated at reflux overnight. After cooling to room
temperature the
mixture was filtered and concentrated on the rotary evaporator to afford 24.0
g (100%) of
the title compound as a white solid
Step B 1 -(4-Benzyloxyphenyl -2-bromopropan-l-one
1-(4-Benzyloxyphenyl)propan-1-one (4.80 g, 20.0 mmol) was suspended in acetic
acid (25
ml) and cooled to 0 C. Bromine (3.20 g, 20.0 mmol) was added dropwise and the
reaction
mixture stirred two hours at room temperature at which point the reaction
mixture was a
clear, yellow solution. After cooling, water (100 ml) was added and the
product extracted
with ether (2 x 100 ml). The combined organic extracts were washed with water,
sodium
hydrogen carbonate and brine. The organic phase was dried (Na2SO4), filtered
and
evaporated leaving the title compound as a pale yellow solid (6.17 g, 97%).
Step C 2-[2-(4-BenzloU-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester
A solution of sodium ethoxide was generated from sodium metal (0.53 g, 23.0
mmol) in 30
ml abs. ethanol. To this solution was added ethyl acetoacetate (3.00 g, 23.0
mmol) at 0 C.
After 30 min. this solution was added to a solution of 1-(4-benzyloxyphenyl)-2-
bromo-
propan-l-one (6.17 g, 19.0 mmol) in ethanol : toluene (30: 15 ml) and the
reaction mixture
stirred overnight. Acidic work-up with 1 M HCI, extraction with ethyl acetate
(3 x),
washing with brine, drying (Na2SO4), filtering and evaporation left a crude
product
purified by flash chromatography (hexane : EtOAc 95 : 5 - 70 : 30) affording
5.18 g of the
title compound as a pale yellow oil.
Step D 5-(4-Benzyloxyphenyl)-l-(2,4-dichlorophenyl -4-methyl-lH-pyrazole-3-
carboxylic acid
A solution of sodium ethoxide was generated from sodium metal (0.19 g, 8.26
mmol) in 20
ml abs. ethanol. To this solution was added 2-[2-(4-benzyloxyphenyl)-2-oxo-
ethyl]-3-oxo-
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butyric acid ethyl ester (2.13 g, 6.00 mmol) and the reaction mixture stirred
at room
temperature for 30 min. A previously prepared solution of 2,4-
dichlorophenyldiazonium
chloride (prepared from 2,4-dichloroaniline (1.19 g, 7.30 mmol) in 3 ml 24%
HC1 and
sodium nitrite (0.52 g, 7.50 mmol) in 3 ml water at 0 C) was added in 5
portions keeping
the temperature below 5 C. After stirring at room temperature for 2.5 hours
water was
added, and the product extracted with EtOAc (3 x). The combined organic
extracts were
dried (Na2SO4), filtered and evaporated. The residue was dissolved in ethanol
(40 ml) and
sodium hydroxide (0.80 g, 20.0 inmol) in 10 ml of water was added. After 2
hours boiling
under reflux the reaction mixture was cooled, acidified with HCl and the
product extracted
with EtOAc (3 x). After washing, drying (Na2SO4), filtration and
concentration, the residue
was purified by flash chromtography (hexane : EtOAc 70:30 - 50:50) affording
1.84 g
(68%) of the title compound as a pale yellow solid.
Step E 5-(4-BenzyloxUhen lY)-1-(2,4-dichlorophenyl -4-methtil-lH-pyrazole-3-
carboxylic acid piperidin-l- l~amide
is 5-(4-Benzyloxyphenyl)-l -(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-
carboxylic acid
(1.84 g, 4.07 mmol) was suspended in dichloromethane and a few drops of DMF
added
followed by the addition of oxalyl chloride (1.03 g, 8.14 mmol). The reaction
mixture was
refluxed for two hours. After cooling to room temperature, the solvent was
removed and
the crude acid chloride redissolved in dichloromethane and cooled to 0 C.
Triethylamine
(1.15 ml, 8.20 mmol) was added followed by 1-aminopiperidine (0.5 ml, 4.50
mmol). The
cooling bath was removed and the reaction mixture stirred at room temperature
for 2 hours.
Water was added and the product extracted with dichloromethane (3 x). The
combined
extracts were dried (Na2SO4), filtered and evaporated. Flash chromatography
(hexane
EtOAc 80 : 20 - 70 : 30) afforded 1.13 g (52%) of the title compound as a
solid.
Step F 1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl -4-methyl-lH-pyrazole-3-
carboxylic
acid piperidin-l-yl amide
5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-lFl-pyrazole-3-
carboxylic acid
piperidin-1-ylamide (1.00 g, 1.87 mmol) was dissolved in 25 ml of abs. ethanol
together
with 100 mg of palladium on charcoal (10% Pd). The reaction was hydrogenated
with a
balloon overnight. Filtration, concentration and flash chromatography (hexane
: EtOAc 50
50 - EtOAc) afforded 0.83 g (100%) of the title compound as a solid.
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Step G Propane-l-sulfonic acid 4-T2-(2,4-dichlorophenyl -4-methyl-5-(piperidin-
l-
ylcarbamoyl)2H-pyrazol-3-yl]-phen ly ester
1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-lH-pyrazole-3-carboxylic
acid
piperidin-1-yl amide (222 ing, 0.50 mmol) was dissolved in dichloromethane (10
ml) and
triethylamine (0.07 ml, 0.50 mmol) was added. Propanesulfonyl chloride (71 mg,
0.50
mmol) was added at 0 C, the cooling bath removed and the reaction stirred at
room
temperature for 2 hours. Water was added and the product was extracted with
dichloromethane, dried (Na2SO4), filtered and concentrated. Flash
chromatography
(hexane : EtOAc 70 : 30 - 50 :50) afforded a product that was recrystallised
from hexane :
EtOAc to give 135 mg (49%) of the title compound as a white solid m.p. 190 C.
'H NMR(CDC13): S 7.66 (1H, broad s), 7.44-7.17 (7 H, m), 3.25 (2H, t), 2.90
(4H, m), 2.39
(3H, s), 2.09-1.97 (2H, m), 1.78 (4H, m), 1.45 (2 H, m), 1.17 (3H, t)
MS m/z 573 (M+Na)
2) 1-(2,4 Dichlorouhenyl)-4-methyl-5-f4-(4,4,4-trifluorobutoxy)-nhenyll-1H-
uyrazole-
i5 3-carboxylic acid uiueridin-l-ylamide
1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-lH-pyrazole-3-carboxylic
acid
piperidin-l-yl amide from 1, Step F (250 mg, 0.56 mmol) was dissolved in
acetone (10 ml)
and potassium carbonate (77 mg, 0.56 mmol) was added followed by 1-iodo-4,4,4-
trifluorobutane (140 mg, 0.56 mmol). The reaction mixture was boiled under
reflux
overnight, concentrated and purified by flash chromatography (hexane : EtOAc
70 : 30 -
60 : 40) afforded 130 mg (42%) of a white solid that was triturated with
hexane : EtOAc 95
5 and filtered.
'H NMR(CDC13): 8 7.63 (1H, broad s), 7.43 (1H, m), 7.30 (214, m), 7.10-7.00
(2H, m),
6.85-6.78 (211, m), 4.05 (2H, t), 2.90 (4H, m), 2.40-2.19 (511, s and m), 2.15-
1.97 (2H, m),
1.78 (411, m), 1.45 (2 H, m). MS m/z 577 (M+Na). HPLC: 98.4%
3) Butane-l-sulfonic acid 4-f2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-
ylcarbamoyl)2H-pyrazol-3-vll-nhenyl ester
1-(2,4-Dichlorophenyl)-5-(4-hydroxy-phenyl)-4-methyl-lH-pyrazole-3-carboxylic
acid
piperidin-1-yl amide, prepared as in 1, Step F (350 mg, 0.78 mmol) was
dissolved in
dichloromethane (10 ml) and triethylamine (0.11 ml, 0.78 mmol) was added.
Butanesulfonyl chloride (0.12 g, 0.78 mmol) was added at 0 C, the cooling bath
removed
and the reaction stirred at room temperature overnight. Water was added, the
product
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extracted with dichloromethane, dried (Na2SO4), filtered and concentrated.
Flash
chromatography (hexane : EtOAc 70 : 30 - 50 :50) afforded a product that was
recrystallised from hexane : EtOAc to give 200 mg (45%) of the title compound
as a
solid.
s 1H NMR(CDC13): & 7.48-7.19 (8H, m), 3.29 (2H, m), 2.96 (4H, in), 2.41 (3H,
s), 2.09-1.97
(2H, m), 1.81 (4H, m), 1.64-1.50 (4 H, m), 1.02 (3H, t)
4) Propane-l-sulfonic acid 442-(2,4-dichloronhenyl)-4-methyl-5-(morpholin-4-
ylcarbamoyll-2H-pyrazol-3-y11Uhenyl ester
Step A 5-(4-Benzyloxyphenyl)-2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-
i0 carboxylic acid morpholin-4-ylamide
To a solution of 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-lFl-
pyrazole-3-
carboxylic acid, prepared as in 1, Step D(1.18 g, 2.6 mmol) in 25 ml CH2C12
was added
2 drops of DMF followed by oxalyl chloride (0.44 ml, 5.2 mmol). The mixture
was boiled
under reflux for 2 hours, cooled to room temperature and evaporated to
dryness. The
15 residue was dissolved in 25 ml CH2C12 and cooled to 0 C. Triethylamine
(0.73 ml, 5.2
mmol) was added followed by 1-aminopiperidine (0.28 ml, 2.9 nimol) and the
mixture was
stirred at room temperature for 3 hours. Water (100 n-A) was added and the
mixture was
extracted with CH2C12 (3x50 ml), dried (Na2SO4), filtered and concentrated.
Flash
chromatography (silica, hexane:EtOAc 1:2, EtOAc) afforded 215 mg (15%) of the
title
20 compound as a white solid.
Step B 1-(2,4-Dichlorophenyl)-5-(4-hydrox)nhenyl)-4-methyl-lH-pyrazole-3-
carboxYlic
acid morpholin-4-ylamide
5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic
acid
morpholin-4-ylamide (215 mg, 0.40 mmol) was dissolved in 20 ml CH2C12 and
cooled to
25 0 C. Boron tribromide (78 1, 0.80 mmol) was added dropwise and the
reaction mixture
was stirred at room temperature for 2.5 hours. Water (50 ml) was added and the
solution
extracted with EtOAc (3x50 ml). The combined organic phases were dried
(Na2SO4),
filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2,
EtOAc)
afforded 180 mg (99%) of the title compound as a white solid.
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Step C Propane-l-sulfonic acid 4-L-(2.4-dichlorophenyl -4-methyl-5-(morpholin-
4-
ylcarbamoyl)-2H-pyrazol-3-yll-phenyl ester
A solution of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-
3-
carboxylic acid morpholin-4-ylamide (180 mg, 0.40 mmol) in 10 ml CH2C12 was
cooled to
0 C. Triethylamine (56 1, 0.40 mmol) was added followed by 1-propanesulfonyl
chloride
(45 l, 0.40 mmol) and the reaction mixture was stirred at room temperature
for 5 hours.
Water was added and the mixture was extracted with CH2C12 (3x20 ml), dried
(Na2SO4),
filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2)
afforded 82
mg (46%) of the title compound as a white solid.
'H NMR (CDC13): 8 7.7 (1H, s), 7.5-7.4 (1H, m), 7.4-7.1 (6H, m), 3.9-3.8 (4H,
m), 3.3-3.2
(2H, m), 3.0-2.9 (411, m), 2.4 (3H, s), 2.1-1.9 (2H, m), 1.2 (3H, t).
MS m/z 576 (M+Na). HPLC: 98.0%.
5) 3,3,3-Trifluoropropane-l-sulfonic acid 4-f2-(2,4-dichloronhenyl)-4-methyl-5-
(piperidin-1-ylcarbamoyl)-2hT-pyrazol-3-yllphenyl ester
is Step A 1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-IH-pyrazole-3-
carbox, lic
acid piperidin- 1 -yl amide
5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic
acid
piperidin- 1 -ylamide, prepared as in 5, Step E(330 mg, 0.62 mmol) was
dissolved in 20 ml
CH2C12 and cooled to 0 C. Boron tribromide (120 l, 1.24 nimol) was added
dropwise and
the reaction mixture was stirred at room temperature for 1 hour. Water (50 ml)
was added
and the solution extracted with EtOAc (3x20 ml). The combined organic phases
were dried
(Na2SO4), filtered and concentrated. Flash chromatography (silica,
hexane:EtOAc 1:3,
EtOAc) afforded 130 mg (47%) of the title compound as a white solid.
Step B 3,3,3-Trifluoropropane-l-sulfonic acid 4-f2-(2 4-dichlorophenyl -4-
methyl-5-
2s (piperidin-1-ylcarbamoyl)-2H-pyrazol-3-yl]phen 1 ester
A solution of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-lH-pyrazole-
3-
carboxylic acid piperidin-1-yl amide,(130 mg, 0.30 mmol) in 10 ml CH2C12 was
cooled to
0 C. Triethylamine (42 l, 0.30 mmol) was added followed by 3,3,3-
trifluoropropane-l-
sulfonyl chloride (59 mg, 0.30 mmol), purchased from Manchester Organics (but
may also
be prepared in an analogous manner to the method described in W0200010968 for
4,4,4-
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trifluorobutane- 1 -sulfonyl chloride), and the reaction mixture was stirred
at room
temperature for 2 hours. Water was added and the mixture was extracted with
CH2C12
(3x20 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography
(silica,
hexane:EtOAc 7:3, 6:4) afforded 150 mg (82%) of the title compound as a white
solid m.p.
160 C. 'H NMR (CDC13): S 7.7 (1H, broad s), 7.5-7.2 (7H, in), 3.6-3.5 (2H,
m), 3.0-2.7
(6H, m), 2.4 (3H, s), 1.9-1.7 (4H, m), 1.6-1.4 (2H, m). MS m/z 628 (M+Na).
HPLC:
92.5%.
6) 4,4,4-Trifluorobutane-l-sulfonic acid 4-f2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-l-ylcarbamoyl)-2H-pyrazol-3-yllphenyl ester
1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-lH-pyrazole-3-carboxylic
acid
piperidin-1-yl amide, prepared as in 5, Step A (0.49 g, 1.20 mmol) was
dissolved in
dichloromethane (20 ml), cooled to 0 C and triethylamine (0.67 ml, 4.8 mmol)
added
followed by 4,4,4-trifluorobutane-1-sulfonyl chloride, prepared as described
in
W0200010968, (0.38 g, 1.80 mmol). The reaction mixture was stirred at room
temperature
overnight. Water was added, the product extracted with dichloromethane, dried
(Na2SO4),
filtered and concentrated. Flash chromatography (hexane : EtOAc 1: 1 - EtOAc)
followed
by recrystallisation (hexane : EtOAc) afforded 0.32 g(43%) of the title
compound as a
colorless solid.
'H NMR(CDC13): b 7.80 (1H, broad s), 7.50-7.19 (7H, m), 3.40 (2H, m), 3.05-
2.90 (4H,
m), 2.50-2.20 (7H, s and in), 1.92-1.70 (4H, m), 1.57-1.40 (2H, m). MS m/z 641
(M+Na)
HPLC: 96.5%
7) Propane-l-sulfonic acid-[2-(2,4-dichloronhenvl)-4-methyl-5-(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3-yl1-2,6-difluoronhenyl ester
Step A 1 -(4-BenUloxy-3,5-difluoropheol -pro ane-1-one
1-(3,5-Difluoro-4-hydroxyphenyl)propane-1-one (5.00 g, 26.9 mmol) was
dissolved in
acetone (100 ml) together with potassium carbonate (3.90 g, 28.2 mmol). Benzyl
bromide
(4.82 g, 28.2 mmol) was added and the reaction mixture was boiled under reflux
overnight.
After cooling to room temperature the mixture was filtered and concentrated on
a rotary
evaporator to afford 7.43 g (100%) of the title compound as a white solid.
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Step B 1-(4-Benzloxy-3,5-difluorophenyl)-2-bromopropan-1-one
1-(4-Benzyloxy-3,5-difluorophenyl)propane-l-one (7.43 g, 26.9 mmol) was
suspended in
acetic acid (35 ml). Bromine (4.28 g, 26.8 mmol) was added dropwise and the
reaction
mixture stirred two hours at room temperature at which point the reaction
mixture was a
clear, yellow solution. After cooling, ice-water (100 ml) was added and the
product
extracted with ether (2 x 100 ml). The combined organic extracts were washed
with water,
sodium hydrogen carbonate solution and brine. The organic phase was dried
(Na2SO4),
filtered and evaporated leaving 9.30 g (98%) of the title compound as a pale
yellow oil.
Step C 2-Acetyl-4-(4-benaloM-3,5-difluorqphenyl -3-methyl-4-oxobutyric acid
ethyl
io ester
A solution of sodium ethoxide was generated from sodium metal (0.74 g, 32.0
mmol) in 40
ml absolute ethanol. To this solution was added ethyl acetoacetate (4.16 g,
32.0 mmol) at 0
C. After 30 min. this solution was added to a solution of 1-(4-benzyloxy-3,5-
difluorophenyl)-2-bromopropan- 1 -one (9.30 g, 26.2 mmol) in etlianol :
toluene (40 : 20
ml) and the reaction mixture stirred overnight. Acidic work-up with 1 M HC1,
extraction
with ethyl acetate (3 x), washing with brine, drying (Na2SO4), filtering and
evaporation left
a crude product purified by flash chromatography (hexane : EtOAc 95 : 5- 70 :
30)
affording 6.95 g (66%) of the title compound as an oil.
Step D 5-4-Benzloxy-3,5-difluorophenyl)-1-(2,4-dichlorophenyI)-4-meth l-1H-
pyrazole-3-carboxylic acid
A solution of sodium ethoxide was generated from sodium metal (0.53 g, 22.0
mmol) in 60
ml absolute ethanol. To this solution was added 2-acetyl-4-(4-benzyloxy-3,5-
difluorophenyl)-3-methyl-4-oxobutyric acid ethyl ester (6.95 g, 17.2 mmol) and
the
reaction mixture stirred at room temperature for 30 min. A previously prepared
solution of
2,4-dichlorophenyldiazonium chloride (prepared from 2,4-dichloroaniline (3.39
g, 21.0
mmol) in 9 ml 24% HC1 and sodium nitrite 1. (48 g, 21.0 mmol) in 3 ml water at
0 C) was
added in 5 portions keeping the temperature below 5 C. After stirring at 0 C
for 2 hours
the reaction mixture was allowed to reach rooni temperature and stirred
overnight. Water
was added, the product extracted with EtOAc (3 x). The combined organic
extracts were
dried (Na2SO4), filtered and evaporated leaving 9.20 g of the crude ethyl
ester as an oil.
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The residue (9.20 g) was dissolved in ethanol (120 ml) and sodium hydroxide
(2.30 g, 57.5
minol) in 15 ml of water was added. After 2 hours of boiling under reflux the
reaction
mixture was cooled, acidified with HCI and the product extracted with EtOAc (3
x). After
washing, drying (Na2SO4), filtration and concentration, the residue was
purified by flash
chromtography (hexane : EtOAc : AcOH 80:20:2 - hexane : EtOAc : AcOH 50:50:2)
affording 5.46 g (65%, two steps) of the title compound as a solid.
Step E 5-(4-Benzyloxy-3,5-difluorophenyl)-2,4-dichlorophenyl)-4-methyl-lH-
pyrazole-3-carboxylic acid piperidin-l-ylamide
5-(4-Benzyloxy-3,5-difluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-
3-
i0 carboxylic acid (5.46 g, 11.2 mmol) was suspended in dichloromethane (60
ml) and a few
drops of DMF added followed by the addition of oxalyl chloride (4.70 ml, 55.8
mmol).
The reaction mixture was boiled under reflux for 1.5 hours. After cooling to
room
temperature the solvent was removed and the crude acid chloride redissolved in
dichloromethane, cooled to 0 C, Et3N (3.10 ml, 22.2 mmol) was added followed
by 1-
is aminopiperidine (1.2 ml, 11.2 mmol). The cooling bath was removed and the
reaction
mixture stirred at room temperature overnight. Water was added and the product
extracted
with dichloromethane (3 x), the combined extracts dried (Na2SO4), filtered and
evaporated.
Flash chromatography (hexane : EtOAc 80 : 20 - 70 : 30) afforded 1.86 g (30%)
of the title
compound as a yellow solid.
20 Step F 5-(4-HydroM-3,5-difluorophenyl)-1-(2,4-dichlorophenY)-4-methyl-lFl-
pyrazole-
3-carboUlic acid piperidin-l- l~amide
5-(4-Benzyloxy-3,5-difluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-
3-
carboxylic acid piperidin-l-ylamide (1.86 g, 3.25 mmol) was dissolved in 50 ml
of
dichloromethane and cooled to -78 C. BBr3 (0.60 ml, 6.50 mmol) was added
slowly and
25 the reaction mixture stirred at 0 C for 30 min. Water was added and the
product extracted
with CHaC12 (x3). The combined organic extracts were dried (Na2SO4), filtered
and
concentrated. Flash chromatography (hexane : EtOAc 50 : 50) afforded 0.64 g
(41%) of the
title compound as a pale yellow solid.
Step G Propane-l-sulfonic acid-[2-(2,4-dichlorophenyl)-4-methyl-5-(pjperidin-l-
30 Vlcarbamoyl -2H-pyrazol-3-yll-2 6 difluoropheaI ester
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5-(4-Hydroxy-3,5-difluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-
carboxylic acid piperidin-1-ylamide (0.64 g, 1.32 mmol) was dissolved in
dichloromethane
(20 ml), cooled to 0 C and triethylamine (0.18 ml, 1.32 mmol) added followed
by
propanesulfonyl chloride (0.19 g, 1.31 mmol). The reaction mixture was stirred
at room
temperature overnight. Water was added, the product extracted with
dichloromethane,
dried (Na2SO4), filtered and concentrated. Flash chromatography (hexane :
EtOAc 70 : 30
- 50 : 50) afforded 410 mg (53%) of the title compound as pale yellow solid.
1H NMR(CDCl3): S 7.66 (1H, broad s), 7.60-7.24 (4 H, m), 6.97-6.78 (1H, m),
3.50-3.37
(2H, m), 3.02-2.80 (4H, m), 2.40 (3 H, s), 2.20-2.00 (2H, m), 1.92-2.72 (4 H,
m), 1.60-1.40
(2 H, m), 1.08 (3H, t). MS m/z 609 (M+Na). HPLC: 97.5%.
8) Propane-l-sulfonic acid 4-f2-(2,4-dichlorophenyl)-5-(piperidin-l-
ylcarbamoyl)-2H-
pyrazol-3-yllphenyl ester
Step A 4-(4-Benzyloxyphenyl)-2,4-dioxobutyric acid eth ly ester
To a solution of LiHMDS (88 ml, 1M in THF) in ether (50 ml) under nitrogen at -
78 C
is was added during 1 hour a suspension of 1-(4-benzyloxyphenyl)ethanone (20
g, 88.4
mmol) dissolved in ether (150 ml) and THF (50 ml). The resulting mixture was
stirred at -
78 C for 1 hour and then oxalic acid diethyl ester (14.2 g, 97.2 mmol) was
added. The
resulting mixture was slowly warmed to room temperature and then left
overnight. The
reaction mixture was diluted with pentane (90 ml) and the crude product
precipitated as its
lithium salt. The collected solid (27.2 g) was dried under vacuum and used
directly in the
next step.
Step B 5-(4-Benzyloyphenyl)=1-(2,4-dichloro henyl)-lH-pyrazole-3-carboxylic
acid
ethyl ester
4-(4-Benzyloxyphenyl)-2,4-dioxobutyric acid ethyl ester (27.2 g, as Li salt
from previous
step) was suspended in ethanol (350 ml) and 2,4-dichlorophenylhydrazine (17.8
g, 83.3
mmol) was added. The reaction mixture was stirred overnight at room
temperature. The
solvent was then removed under reduced pressure and the residue was dissolved
in acetic
acid and the resulting mixture was refluxed for 24 h. The reaction mixture was
diluted with
ethyl acetate (1L) and then washed with saturated NaHCO3 (6x250 ml) and brine
(100 ml).
The organic layer was dried (MgSO4), filtered and concentrated under reduced
pressure to
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give an oil. The oil was purified by flash chromatography (Si02, 20% EtOAc in
heptane).
The product fraction was concentrated under reduced pressure and the remaining
material
was then further purified by recrystallisation (ethyl acetate/heptane) to give
a white solid
(19.6, 57% over 2 steps).
s 1H-NMR (CDC13): S 1.42 (t, 3H), 4.45 (q, 211), 5.03 (s, 2H), 6.88 (d, 2H),
7.01 (s, 1H),
7.11 (d, 2H), 7.3-7.45 (m, 8H). MS: 467 (M+l).
Step C 1-(2 4-Dichlorophenyl -~ 5-(4-hydroxyphenyl -pyrazole-3-carboxylic acid
ethyl
ester
To a solution of 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-
carboxylic
io acid ethyl ester (735 mg, 1.57 mmol) and (CH3)2S (0.58 ml, 7.86 mmol) in
dichloromethane (30 ml) under nitrogen was added BF3-diethyl etherate (1.0 ml,
7.86
mmol) dropwise. The resulting mixture was stirred overnight at room
temperature. More
(CH3)2S (0.58 ml, 7.86 mniol) and BF3-diethyl etherate (1.0 ml, 7.86 mmol) was
then
added and the resulting mixture was stirred for another 3 days. The reaction
mixture was
is diluted with dichloromethane to 80 ml and washed with water (3x30 ml) and
brine (40 ml).
The organic layer was dried (MgSO4), filtered and concentrated under reduced
pressure to
give a white solid (573 mg, 96%). The crude material was used directly.
IH-NMR (CDC13) : S 1.41 (t, 3H), 4.44 (q, 2H), 6.74 (d, 2H), 7.00 (s, 111),
7.06 (d, 211),
7.3-7.45 (m, 3H). MS: 375 (M-1).
20 Step D 1-(2,4-Dichlorophenyl)-5-[4-(~ropane-l-sulfonyloxy)- henyl]-1H-
pyrazole-3-
carboxylic acid eth l~ ester
1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-1H-pyrazole-3-carboxylic acid ethyl
ester
(510 mg, 1.35 mmol) was suspended in dichloromethane (20 ml) under nitrogen
and
triethylainine (0.75 ml, 5.4 mmol) was added. The resulting mixture was cooled
to 0 C
25 and 1-propanesulfonyl chloride (0.30 ml, 2.7 mmol) was added dropwise. The
mixture was
stirred at 0 C for 1 hour. The reaction mixture was then diluted to 40 ml with
dichloromethane and then washed with saturated NaHCO3 (3x20 ml) and brine (20
ml).
The organic layer was dried (MgSO4), filtered and concentrated under reduced
pressure to
give an oil (0.64 g, 98%). The crude material was used as such without further
purification.
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1H NMR (CDC13): 8 1.12 (t, 3H), 1.43 (t, 3H), 2.01 (m, 2H), 3.23 (m, 2H), 4.46
(q, 2H),
7.07 (s, 1H), 7.19-7.46 (m, 7H).
MS: 483 (M+1).
Step E Propane-l-sulfonic acid 4-r2-(2 4-dichlorophenyl)-5-(piperidin-l-
ylcarbamoyl)-
2H-pyrazol-3-yl]phenyl ester
1-Aminopiperidine hydrochloride (36 mg, 0.26 mmol) was dissolved in toluene
(1.0 ml)
under nitrogen atmosphere. Trimethylaluminium (2 M in toluene, 0.17 ml) was
added
dropwise at room temperature. The resulting mixture was then stirred at room
temperature
for 40 minutes. This mixture was then added to a stirred suspension of 1-(2,4-
dichloro-
phenyl)-5-[4-(propane-l-sulfonyloxy)phenyl]-1H-pyrazole-3-carboxylic acid
ethyl ester
(42 mg, 0.087 mmol) in DCM (1.0 ml) and the resulting mixture was heated at 60
C
overnight. The reaction was quenched by addition of water and then partitioned
between
water (20 ml) and DCM (20 ml). The organic layer was washed with water (3x10
ml) and
then concentrated under reduced pressure. The residue was purified by reverse
phase
HPLC, C8 column, 5-100% acetonitrile in water (buffer: 0.1 M ammonium
acetate). The
product fraction was diluted with ethyl acetate and washed with water several
times. The
organic layer was concentrated under reduced pressure and the residue was
freeze-dried to
give a white solid (26 mg, 55%).
1H-NMR (CDC13): 1.11 (t, 3H), 1.43 (m, 2H), 1.76 (m, 4H), 2.00 (m, 2H), 2.85
(m, 4H),
3.22 (m, 2H), 7.11 (m, 1H), 7.20 (m, 4H), 7.37 (m, 2H), 7.49 (m, 1H). MS: 537
(M+1).
9) Propane-l-sulfonic acid 4-f4-bromo-2-(2,4-dichlorophenyl)-5-(piperidin-l-
ylcarbamoyl)-2H-pyrazol-3--yllnhenyl ester
Step A 4-Bromo-l-(2,4-dichlorophenyl) _5-[4-(propane-l-sulfonyloxy)phenyll-lH-
pyrazole-3-carboxylic acid ethyl ester
1-(2,4-Dichlorophenyl)-5-[4-(propane-l-sulfonyloxy)phenyl]-1 H-pyrazole-3-
carboxylic
acid ethyl ester, prepared as in 8, Step D (597 mg, 1.23 rnmol) was dissolved
in
dichloromethane (15 ml) and bromine (0.06 ml, 1.23 mmol) in dichloromethane (1
ml) was
added and the resulting mixture was stirred at room temperature overnight.
Extra bromine
(0.06 ml, 1.23 mmol) was added and the mixture was stirred for another 20
hours.
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The reaction mixture was diluted to 80 ml with dichloromethane and was then
washed with
saturated NaHCO3 (40 ml), 20% Na2S2O5 (40 ml), saturated NaHCO3 (2x40 ml) and
brine
(40 ml). The organic layer was dried (MgSO4), filtered and concentrated under
reduced
pressure to give an orange oil (0.598, 73%). The crude material was used
without further
purification. 1H-NMR (CDC13): S 1.12 (t, 3H), 1.44 (t, 3H), 2.01 (m, 2H), 3.24
(m, 2H),
4.48 (q, 2H), 7.2-7.46 (m, 7H). MS: 561
Step B Propane-l-sulfonic acid 4-[4-bromo-2-(2,4-dichlorophenyl)-5-(piperidin-
l-
Ylcarbamoyl)-2H-p3gazol-3 yl]phenyl ester
This compound was prepared in a similar manner to that described in 8 Step E.
by reacting
4-bromo-l-(2,4-dichlorophenyl)-5-[4-(propane-l-sulfonyloxy)phenyl]-1H-pyrazole-
3-
carboxylic acid ethyl ester with 1-aminopiperidine hydrochloride to give 26mg
of the title
compound as a white solid. Yield: 25%
'H-NMR (CDC13): 1.12 (t, 3H), 1.43 (m, 2H), 1.74 (m, 4H), 2.01 (m, 2H), 2.90
(m, 4H),
3.24 (m, 2H), 7.21-7.45 (m, 7H)
MS: 615.
10) Methyl 1-{((1-(2,4-dichlorophenyl)-4-methyl-5-
{4i(propylsulfonyl)oxYlnhenyl}-
1H-nyrazol-3-yl)carbonyll amino}cyclopentanecarboxylate
Step A Methyl 1-aminocyclopentanecarbox l~ate hydrochloride
Thionyl chloride (1.5 ml) was dissolved in methanol (15 ml) and poured over 1-
aminocyclopentanecarboxylic acid (100 mg, 0.774 mmol). The mixture was
refluxed 1
hour. The solvent was evaporated to give the product (107 mg, 77%).
1H NMR (399.964 MHz) S 9.00-8.60 (br, 3H), 3.79 (s, 3H), 2.23 (s, 4H), 2.14-
2.00 (m,
2H), 1.90-1.76 (in, 2H).
Step B Methyl 1 -({[5-[4-(ben loxy)Dhenyl]-1-(2,4-dichlorophenyl, -4-methyl-lH-
pyrazol-3-Xl]carbonyl amino)cyclopentanecarboxlate
A solution of 5-[4-benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-lH-
pyrazol-3-
carboxylic acid, prepared as in 1, Step D (59 mg, 0.130 mmol) in DCM (2 ml)
was mixed
with a solution of oxalyl chloride (2 ml) in DCM (20 ml). One drop of DMF was
added
and the reaction continued at room temperature in the dark forl hour. The
solvent was
evaporated, DCM (2 ml) was added and the acid chloride mixture added to a
mixture of
methyl 1-aminocyclopentanecarboxylate hydrochloride (23 mg, 0.130 mmol) in DCM
(2
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ml) and K2C03 (aq, 10 wt%, 2 ml). The reaction was continued at room
temperature for 3
hours. The phases were separated and the organic phase washed with water and
dried over
MgSO4 to give the product (71 mg, 94 %).
'H NMR (399.964 MHz) 8 7.43-7.23 (m, 9H), 7.06-7.00 (m, 2H), 6.93-6.87 (m,
2H), 5.02
s (s, 2H), 3.75 (s, 3H), 2.40-2.30 (in, 2H), 2.34 (s, 3H), 2.14-2.04 (m, 2H),
1.87-1.77 (m,
4H).
MS m/z 578, 580, 582 (M+H)+.
Step C Meth yl 1 -(I[1-(2 4-dichlorophenyl)-5-(4-hydroxyphenyl-4-methyl-lH-
pyrazol-3-
yllcarbonyl amino)gyclopentanecarboxylate
Boron trifluoride etherate (156 l, 1.23 mmol) was added to a mixture of
inethyl 1-({[5-[4-
(benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-lH-pyrazol-3-
yl]carbonyl}amino)cyclopentanecarboxylate (51 mg, 0.088 mmol) and dimethyl
sulfide
(90 l, 1.23 mmol) in DCM (2 ml). The reaction was continued at room
temperature in the
dark for 46 hours. Water and DCM were added, the phases separated and the
organic phase
washed with water and dried over MgSO4 (39 mg, 90%).
1H NMR (399.964 MHz) S 7.60-6.60 (m, 8H), 3.72 (s, 3H), 2.43-2.23 (m, 2H),
2.26 (s,
3H), 2.15-2.00 (m, 2H), 1.85-1.75 (m, 4H).
MS m/z 488, 490, 492 (M+H)}.
Step D Methyl 1- { f(1-(2,4-dichlorophenyl)-4-methyl-5-
{4[(propylsulfonyl)oxy]phenyl) -
1H-pyrazol-3-yl carbonyllamino}cyclopentanecarbox.tilate.
TEA (100 l ) and then 1-propanesulfonyl chloride (30 l, 0.268 mmol) were
added to a
mixture of methyl 1-( {[ 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-
lH-pyrazol-
3-yl]carbonyl}amino)cyclopentanecarboxylate (39 mg, 0.080 mmol) in dry DCM
(1.5 ml)
at -78 C. The reaction was continued at -78 C under N2(g) for 1.5 hours. Water
and DCM
were added and the temperature was raised to room temperature. The phases were
separated and the orgainc phase washed with water and dried over MgSO4. The
product
was purified by preparatory HPLC (kromasil C8 column, ammonium acetate (aq,
0.1
M):acetonitrile, product came at about 88% acetonitrile) to give the product
as an almost
white powder (17 mg, 35%).
'H NMR (399.964 MHz) S 7.45-7.39 (br, 1H), 7.32-7.28 (in, 2H), 7.27-7.19 (m,
3H), 7.18-
7.12 (m, 2H), 3.76 (s, 3H), 3.26-3.20 (m, 2H), 2.40-2.30 (m, 2H), 2.35 (s,
3H), 2.15-2.05
(in, 2H), 2.05-1.95 (m, 2H), 1-88-1.78 (m, 4H), 1.12 (t, 3H).
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HRMS Calcd for [C27H29C12N3O6S+H]+: 594.123. Found: 594.121.
11) Carbonic acid 4-f2-(2,4-dichloro-phenyD-4-methyl-5-(piperidine-1-
ylcarbamovl)-
21Y-pyrazol-3-yll-phenyl ester propyl ester
Carbonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-piperidine-1-ylcarbamoyl)-2H-
pyrazol-3-yll-phen l ester propyl ester
1-(2,4-Dichloro-phenyl)-5-(4-hydroxyphenyl)-4-methyl-lH-pyrazole-3-carboxylic
acid
piperidin-1-yl amide prepared as in 1, Step F (0.44 g, 1.00 mmol) was
dissolved in
dichloromethane (10 ml) and triethylamine (0.28 ml, 2.24 mmol) was added.
Propyl
chloroformate (0.14 ml, 1.24 mmol) was added at 0 C, and the reaction stirred
for 40 min.,
concentrated and the product purified by flash chromatography (hexane : EtOAc
70 :30 -
50 : 50) to afford 345 mg (65%) of the title compound. Further purification by
preparative
HPLC gave 239 mg of the title compound.
'H NMR(CDC13): 8 7.71-7.18 (8H, m), 4.24 (2H, t), 2.93 (4H, m), 2.40 (3H, s),
1.78 (6H,
m), 1.46 (2H, ni), 1.03 (3H, t)
is MS m/z 553 (M+Na)
HPLC: 94.15%
12) 4-{1-(2,4-dichlorophenyl)-4-methyl-3-f(niperidin-1-ylamino)carbonyll-lH-
pyrazol-5-yl}phenyl thiophene-2-sulfonate
Thiophene-2-sulfonyl chloride (433 mg, 2.37 mmol) in DCM (2.5 ml) was added to
a
mixture of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidin-1-
yl-1H-
pyrazole-3-carboxamide prepared as in 1, Step F (200 mg, 0.45 mmol) and TEA
(0.5 ml,
3.59 mmol) in DCM (2.5 ml) at -78 C, under N2(g). The reaction was continued
at -78 C
for 2 hours and then at room temperature for 19 hours. Water was added and the
phases
were separated. The organic phase was washed with water and dried over MgSO4.
The
product was further purified by preparatory HPLC (kromasil C8 column,
ainmonium
acetate (aq, 0.1 M):acetonitrile, product came at 100% acetonitrile) to give
an almost white
powder (158 mg, 60%).
'H NMR (399.964 MHz) 6 7.71-7.67 (m, 1H), 7.67-7.57 (br, 1H), 7.50-7.46 (m,
1H), 7.35
(s, 1H), 7.25 (s, 2H), 7.07-7.00 (m, 3H), 6.98-6.92 (m, 2H), 2.86-2.76 (m,
4H), 2.29 (s,
3H), 1.73-1.65 (m, 4H), 1.42-1.33 (m, 2H).
HRMS Calcd for [C26H24C12N4O4SZ+H]+: 591.069. Found: 591.067.
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13 4-{1-(2,4-dichlorophenyl)-4-methyl-3-f(piperidin-l-ylamino)carbonyll-lH-
pyrazol-5-yl}phenyl pyridine-3-sulfonate
Step A: 4-{1-(2,4-dichlorophenyl -4-methyl-3-[(piperidin-l-ylamino)carbonyl-]
1H-
]2yrazol-5-yI}phenyI pyridine-3-sulfonate
s A suspension of pyridine-3-sulfonyl chloride (144 mg, 0.67 mmol) in DCM (10
ml) was
added to a mixture of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-
piperidin-
1-yl-iH-pyrazole-3-carboxamide, prepared as Ex 1, Step F (200 mg, 0.45 mmol)
and TEA
(0.5 ml, 3.59 inmol) in DCM (2.5 ml) at -78 C, under N2(g). The reaction was
continued at
-78 C for 1.5 hours and then at room temperature for 30 minutes. Water was
added and the
io phases were separated. The organic phase was washed with water and dried
over MgSO4.
The product was fiu-ther purified by flash chromatography (Si02, toluene:ethyl
acetate,
product came at 42% ethyl acetate) to give the title compound as a powder (216
mg, 82%).
1H NMR (399.964 MHz) S 8.95-8.85 (m, 2H), 8.10-8.04 (m, 1H), 7.64 (s, 1H),
7.50-7.45
(m, 1H), 7.44-7.40 (m, IH), 7.34-7.24 (m, 2H), 7.09-7.04 (m, 2H), 7.00-6.95
(m, 2H),
15 2.88-2.78 (m, 4H), 2.33 (s, 3H), 1.78-1.68 (m, 4H), 1.46-1.36 (m, 2H).
HRMS Calcd for [C27H25C12N5O4S+H]+: 586.108. Found: 586.111.
14 tert-butyl f2-(4-{1-(2,4-dichlorophenyl)-4-methyl-3-f(niperidin-l-
ylamino)carbonyll-lH-pyrazol-5-ylluhenoxylethyll ethylcarbamate
Step A: teYt-bu 1 ethVl(2-h droxyethyl)carbamate
20 Di-tert-butyl dicarbonate (3.19 g, 14.6 mnol) in THF (10 ml) was added to 2-
(ethylamino)ethanol (1.00 g, 11.2 mmol) and reacted at room temperature for 3
hours. The
solvent was evaporated at reduced pressure to give the crude product (2.28 g).
1H NMR (499.961 MHz) S 3.71-3.65 (br, 2H), 3.55-3.35 (br, 1H), 3.35-3.30 (br,
2H), 3.30-
3.20 (br, 2H), 1.43 (s, 9H), 1.07 (t, 3H).
25 Step B: tert-butyl [2-(4-11-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-l-
ylamino)carbonyl]-1H-pyrazol-5-yl}tahenoxy)ethyllethylcarbamate
1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl N piperidin-l-yl-lH-
pyrazole-3-
carboxamide, prepared as 1, Step F (151.6 mg, 0.34 inmol) and tert-butyl
ethyl(2-
hydroxyethyl)carbamate (408.6 mg, 1.73 mmol) were mixed in toluene (1ml) and
reacted
30 repeatedly in a single node microwave oven at 180 C. The total reaction
time was 2 hours.
Cyanomethylenetri-N-butylphosphorane was added before each heating (total
amount 925
mg, 3.83 mmol). The solvent was then evaporated and the product purified by
preparatory
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HPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product
came at
100% acetonitrile) and flash chromatography (Si02, toluene:ethylacetate,
product came at
30% ethyl acetate) to give an almost white powder (125 mg, 60%).
'H NMR (399.964 MHz) S 7.62 (s, 1H). 7.37 (s, 1H), 7.23 (s, 2H), 7.01-6.95 (m,
2H),
s 6.81-6.75 (m, 2H), 4.05-3.95 (br, 2H), 3.55-3.45 (br, 2H), 3.35-3.25 (br,
2H), 2.86-2.78
(br, 4H), 2.32 (s, 3H), 1.75-1.65 (m, 4H), 1.41 (s, 9H), 1.45-1.35 (m, 2H),
1.08 (t, 3H).
MS m/z 616, 618, 620 (M+H)}.
15 4-{1-(2,4-dichlorophenyl)-4-methyl-3-f (Aiperidin-1-ylamino)carbonyll-1H-
nyrazol-5-yl}phenyl 3-methylbutane-1-sulfonate
3-Methylbutane-1-sulfonyl chloride (84 mg, 0.49 mmol) in DCM (2 ml) was added
to a
mixture of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidin-1-
yl-1FI-
pyrazole-3-carboxamide, prepared as in 1, Step F (100 mg, 0.23 mmol) and TEA
(0.5 ml,
3.59 mmol) in DCM (2 ml) at -78 C, under N2(g). The reaction was continued at -
78 C for
1 hour. Water was added and the phases were separated. The organic phase was
washed
with water and dried over MgSO4. The product was further purified by
preparatory HPLC
(kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came
at 100%
acetonitrile) to give an almost white powder (94 mg, 72%).
'H NMR (399.964 MHz) S 7.85-7.45 (br, 1H), 7.38 (s, 1H), 7.29-7.25 (m, 2H),
7.23-7.18
(m, 2H), 7.16-7.11 (m, 2H), 3.25-3.18 (m, 2H), 2.88-2.80 (m, 4H), 2.33 (s,
3H), 1.86-1.77
(m, 2H), 1.76-1.65 (m, 5H), 1.45-1.34 (m, 2H), 0.92 (d, 6H).
HRMS Calcd for [C27H32Cl2N4O4S+H]+: 579.160. Found: 579.159.
16) 4-f 1-(2,4-dichlorophenyl)-4-methyl-3-f(piperidin-1-vlamino)carbonyll-lH-
pyrazol-5-yl}pheny13,3-dimethylbutane-1-sulfonate
3,3-Dimethylbutane-1-sulfonyl chloride (59 mg, 0.32 mmol) in DCM (2 ml) was
added to
a mixture of 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidin-1-
yl-1H-
pyrazole-3-carboxamide, prepared as in 1, Step F (103 ing, 0.23 mmol) and TEA
(0.5 ml,
3.59 mmol) in DCM (2 ml) at -78 C, under N2(g). The reaction was continued at -
78 C for
1 hour. Water was added and the phases were separated. The organic phase was
washed
with water and dried over MgSO4. The product was further purified by
preparatory HPLC
(kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came
at 100%
acetonitrile) to give an almost white powder (94 mg, 68%).
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1H NMR (399.964 MHz) S 8.20-7.40 (br, 1H), 7.36 (s, 1H), 7.28-7.22 (m, 2H),
7.21-7.16
(in, 2H), 7.15-7.09 (m, 2H), 3.20-3.13 (m, 2H), 2.87-2.80 (m, 4H), 2.31 (s,
3H), 1.83-1.76
(in, 2H), 1.73-1.65 (m, 4H), 1.43-1.32 (m, 2H), 0.89 (s, 9H).
HRMS Calcd for [C28H34C12N4O4S+H]+: 593.176. Found: 593.176.
17) 1-(2,4-dichlorophenyl)-5-(4-f2-(1,3-dioxolan-2-yl)ethoxylphenyl}-4-methyl-
N-
piperidin-l-yl-lH-pyrazole-3-carboxamide
2-(2-bromoethyl)-1,3-dioxolane (60 mg, 0.33 mmol), 1-(2,4-dichlorophenyl)-5-(4-
hydroxyphenyl)-4-methyl-N-piperidin-1-yl-1.H-pyrazole-3-carboxamide prepared
as in 1,
step F (100 mg, 0.22 nnnol) and potassium carbonate (150 mg, 1.09 mmol) were
refluxed
in acetonitrile (25 ml) for 15 hours. The solvent was evaporated, water and
DCM were
added, the phases separated and the organic phase washed with water and dried
(MgSO4).
The product was further purified by preparatory HPLC (kromasil C8 column,
ammonium
acetate (aq, 0.1 M):acetonitrile, product came at 100% acetonitrile) to give
an almost white
powder (60 mg, 49%).
1H NMR (399.964 MHz) 8 7.80-7.50 (br, 1H), 7.36 (s, 1H), 7.21 (s, 2H), 7.00-
6.94 (m,
2H), 6.80-6.74 (m, 2H), 5.02 (t, 1H), 4.04 (t, 2H), 3.96-3.78 (m, 4H), 2.86-
2.78 (m, 4H),
2.30 (s, 3H), 2.09 (q, 2H), 1.74-1.65 (m, 4H), 1.42-1.32 (m, 2H).
HRMS Calcd for [C27H30C12N4O4+H]+: 545.172. Found: 545.172.
18) Propane-l-sulfonic acid 4-f2-(2,4-dichloro-3-fluorophenyl)-4-methyl-5-
(pip eridin-l-ylcarb amoyl)-2H-pvrazol-37yll phenyl ester
Step A: 1-(2,4-Dichloro-3-fluorophenl)-5-(4-methoxyphenyl)-4-methyl-lH-
pyrazole-3-
carboxylic acid
A solution of sodium ethoxide was generated from sodium metal (0.18 g, 7.89
mmol) in 20
ml abs. ethanol. To this solution was added 2-acetyl-4-(4-methoxy-phenyl)-3-
methyl-4-
oxo-butyric acid ethyl ester (1.73 g, 5.92 mmol) and the reaction mixture
stirred at room
temperature for 30 min. A previously prepared solution of 2,4-dichloro-3-
fluorodiazonium
chloride (prepared from 2,4-dichloro-3-fluoroaniline (1.30 g, 7.22 mmol) in 3
m124% HCl
and sodium nitrite (0.51 g, 7.39 mmol) in 3.5 ml water at 0 C) was added in 5
portions
keeping the temperature below 5 C. After stirring at room temperature for 2.5
hours water
was added, the product extracted with EtOAc (3 x). The combined organic
extracts was
dried (NaZSO4), filtered and evaporated. The residue was dissolved in ethanol
(40 ml) and
sodium hydroxide (1.00 g, 25.0 mmol) in 5 ml of water was added. After 2 hours
boiling
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under reflux the reaction mixture was cooled, acidified with HCl and the
product extracted
with EtOAc (3 x). After washing, drying (Na2SO4), filtration and
concentration, the residue
was purified by flash chromtography (hexane : EtOAc 70:30 - 50:50) affording
1.37 g
(31 %) of the title compound as a light brown solid.
Step B: 1-(2,4-Dichloro-3-fluoro-phenyl)-5-(4-methoxy-phenl -4-methyl-lH-
pyrazole-3-
carboxylic acid piperidin- 1 -ylamide
1-(2,4-Dichloro-3 -fluoro-phenyl)-5-(4-methoxy-phenyl)-4-methyl-lH-pyrazole-3 -
carboxylic acid (1.37 g, 3.43 mmol) was suspended in dichloromethane (20 ml)
and a few
drops of DMF added followed by the addition of oxalylchloride (0.87 g, 6.86
mmol). The
io reaction mixture was refluxed for two hours. After cooling to room
temperature the solvent
was removed and the crude acid chloride redissolved in dichloromethane (20
ml), cooled to
0 C, Et3N (0.96 ml, 6.94 mmol) was added followed by 1-aminopiperidine (0.37
ml, 3.62
mmol). The cooling bath was reinoved and the reaction mixture stirred at room
temperature overnight. Water was added and the product extracted with
dichloromethane
(3x), the combined extracts dried (Na2SO4), filtered and evaporated. Flash
chromatography
(hexane : EtOAc 50: 50) afforded 0.79 g (48%) of the title compound as a light
brown
solid.
Step C: 1-(2,4-Dichloro-3-fluoro-phenyl)-5-(4-hydroxy_ henyl)-4-methyl-lH-
pyrazole-3-
carboxylic acid piperidin-l-ylamide
1-(2,4-Dichloro-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-4-methyl-lH-pyrazole-3-
carboxylic acid piperidin-1-ylamide (0.79 g, 1.66 mmol) was dissolved in 40 ml
of
dichloromethane at 0 C. Boron tribromide (0.32 ml, 3.31 mmol) was added, the
cooling
bath was removed and stirring continued for 2 hrs at room temperature before
pouring it
onto ice-water and extracting with DCM (x3). The coinbined extracts were dried
(Na2SO4),
filtered and concentrated. Flash chromatography (EtOAc) afforded 0.36 g (47%)
of the
title compound as a colorless solid.
Step D: Propane-l-sulfonic acid 4-[2-(2 4-dichloro-3-fluoro-phenyl -4-methyl-
5=
(piperidin-1-ylcarbamoyl -) 2H-pyrazol-3-yl]_phenyl ester
To a solution of 1-(2,4-dichloro-3-fluoro-phenyl)-5-(4-hydroxy-phenyl)-4-
methyl-lH-
3o pyrazole-3-carboxylic acid piperidin-1-ylainide (0.36 g, 0.78 mmol) in
dichloromethane
(10 ml) was added triethylamine (0.22 ml, 1.56 mmol) and the reaction mixture
cooled to 0
C. 1-Propanesulfonylchloride (0.22 g, 1.56 mmol) was added, the cooling bath
removed
CA 02619228 2008-02-11
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and the reaction mixture stirred at rt for 2 hrs. Water was added, the product
extracted with
DCM (x2), the combined organic extracts washed with water, dried (Na2SO4),
filtered and
concentrated. Flash chromatography (hexane : EtOAc gradient) afforded 100 mg
(23%) of
the title compound as a colorless solid. HPLC 80% purity. Preparative HPLC
afforded 40
mg of the title compound.
1H NMR (CDC13): 8 7.50-7.20 (7 H, m), 3.57-3.23 (6H, m), 2.37 (3H, s),2.10-
1.80 (6H,
m), 1.70-1.50 (2H, m), 1.10 (3H, t)
MS: 591 (M+Na). HPLC: 97.1%
19 5-Chlorothiophene-2-sulfonic acid 4-f2-(2,4-dichlorophenyl)-4-methyl-5-
(piperidin-1-ylcarbamoyl)-2H-pyrazol-3-yllnhenyl ester
1-(2,4-Dichloro-phenyl)-5-(4-hydroxy-phenyl)-4-methyl-lH-pyrazole-3-carboxylic
acid
piperidin-1-ylamide, prepared as in 1, Step F (100 mg, 0.22 mmol) was
dissolved in dry
dichloromethane (3 ml) under nitrogen atmosphere and triethyl amine (0.09 ml)
was added.
5-Chlorothiophene-2-sulfonyl chloride (0.54 mg, 0.24 mmol), dissolved in dry
dichloromethane (2 ml), was then added. The reaction mixture was stirred over
the
weekend at room temperature. The reaction mixture was diluted with
dichloromethane to
ml and was then washed with water (2x5 ml) and brine (5 ml). The organic layer
was
concentrated under reduced pressure to give an oil. The crude material was
purified by
reverse phase HPLC, Kromasil C8, 5-100% MeCN in water with 0.1M ammonium
acetate.
20 The product fraction was concentrated under reduced pressure and the
residue was
dissolved in dichloromethane and washed with water and brine. The organic
layer was
dried (MgSO4), filtered and concentrated under reduced pressure to give the
title
compound as a yellow solid.
1H-NMR (CDC13): S 1.42-1.50 (m, 2H), 1.73-1.81 (m, 4H), 2.39 (s, 3H), 2.84-
2.92 (m,
4H), 6.95 (d, 1H), 7.04-7.14 (m, 4H), 7.30-7.36 (m, 3H), 7.44 (d, 111), 7.63
(s, 1H).
MS: 625 (M+1). HPLC: >99% purity.
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GENERAL METHOD OF SYNTHESIS OF FREE BASES
Method A
p 0 0
Ho / \ o I / e~
0
OEt
O O 0 COzEt
}'Iv}I~I
/ ~OEt NaOEt NIN
ci I NHa / / ~
/
ci
NaNO2
ci
CI
p O
OH N'N p N
\ H
p ~ /NIN i) oxalyl chloride /N\N /N~N
ci --- O ci - - HO i
0_NH2 ci CI ci C
Method B
0 O Li
LiHMDA
~
~ ~ TFA ]Diethboxa1ate~ ,
HO O O ~ ~ O
O O
O
1) 2,4-dichlorophenylhydrazine OH Aminopipe(dine O N
3)) HCIOH \N TBTU H
HO -~ ~
EtOH N
ci THF/NMP NN
HO ~ ci
ci y
CF3~~iCI O NN~/ O CI
HN
u H N
11 [F. N N aq. HCI (37%) 0 N H
NMM u O N"
MEK O ci 0 O ' ci
C ci
