Note: Descriptions are shown in the official language in which they were submitted.
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Substituted cyclohexyl derivatives as NK-3 receptor anta2onists
The present invention relates to substituted cyclohexyl derivatives,
pharmaceutical compositions
comprising them and their use in treating diseases mediated by neurokinin-3
(NK-3) receptors. These
compounds can thus be used in methods of treatment to suppress and treat such
disorders.
Background information on NK-3 receptor antagonists can be found in literature
reviews such
as Giardina and Raveglia, Exp. Opin. Ther. Patents (1997) 7(4): 307-323 and
Giardina et al., Exp. Opin.
Ther. Patents (2000) 10(6): 939-960. These references also contain pertinent
information on preclinical
validation of therapies that can be treated with NK-3 antagonists.
Representative examples of compounds prepared in the art as NK-3 antagonists
are to be found
in WO-A-9719926 (SmithKline Beecham S.p.a.) and US-A-5741910 (Sanofi).
Substituted cyclohexyl derivatives are known in the art. For instance,
published International
applications WO 2004/031137 and WO 2004/031139 (both Merck Sharp & Dohme
Limited) disclose
cyclohexyl sulfones as gamma-secretase inhibitors useful in the treatment of
Alzheimer's disease.
However, neither document discloses that substituted cyclohexyl derivatives
are useful as NK-3
antagonists and are thus useful in the treatment of diseases such as
schizophrenia.
The present invention thus provides a compound of Formula (I):
R5 R6
R1 RT
S(O),-X Z-N ~I)
R2 Y R$
B
R3 R4
wherein:
rings A and B are independently aryl or heteroaryl;
n is 0, 1 or 2;
X and Y are independently selected from a bond, -CH2-, -C(C,-4alkyl)2- and
N(C,_4alkyly;
Z is a bond, -CH2- or -C(C,-4alkyl)2-;
R' is hydrogen, C,_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_8cycloalkyl, hydroxy,
C,_6alkoxy, halogen,
CN, C02(C,_6alkyl) or C(CH3)20H, optionally substituted by 1 to 8 halogen
atoms;
RZ is hydrogen, C,_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_8cycloalkyl or
halogen;
R3 is hydrogen, C,_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_8cycloalkyl, hydroxy,
C,_6alkoxy, halogen
or CN, optionally substituted by 1 to 8 halogen atoms;
R4 is hydrogen, C,_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_8cycloalkyl or
halogen;
R5 and R6 are independently selected from hydrogen, C,_6alkyl, C2_6alkenyl,
C2_6alkynyl, C3_
8cycloalkyl, hydroxy, C,_6alkoxy or halogen;
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R7 is hydrogen, C,_6alkyl, C2_6alkenyl, C2_6alkynyl, C3_8cycloalkyl,
(CH2)0_2ary1, (CH2)0_
2heteroaryl or Het, optionally substituted by 1 to 8 halogen atoms, C,-4alkyl,
hydroxy, C,-4alkoxy or
heteroaryl, which heteroaryl is optionally substituted by 1 to 3 groups
selected from C,-4alkyl;
R8 is hydrogen, C,_6alkyl, C2_6alkenyl, C2_6alkynyl or C3_8cycloalkyl;
or R7 and R8, together with the nitrogen atom to which they are attached, form
a 4- to 7-
membered heterocycle, optionally containing 1, 2 or 3 further heteroatoms
selected from N, 0 and S,
which heterocycle may optionally contain one double bond,
and which heterocycle may optionally be substituted by one or two groups
selected from C,_ 6alkyl, C2_
6alkenyl, C2_6alkynyl or C3_8cycloalkyl, hydroxy, oxo, (CH2)0_3C,_6alkoxy,
(CH2)0--3Oary1, (CH2)0--3ary1,
(CH2)0--3heteroaryl, (CH2)0_3Het, or (CH2)0_3NRaRb, wherein said aryl,
heteroaryl and Het are optionally
substituted by 1, 2 or 3 groups independently selected from C,_6alkyl,
hydroxy, oxo, C,_6alkoxy or
halogen, which C,_6alkyl being optionally substituted by hydroxy or 1 to 5
halogen atoms, and where said
aryl, heteroaryl and Het are also optionally fused to a 5- or 6-membered ring
which optionally contains 1,
2 or 3 heteroatoms selected from N, 0 or S and which ring is optionally
substituted by C,-4alkyl, hydroxy,
oxo, C,-4alkoxy or halogen,
and which heterocycle may optionally be fused to heteroaryl, which heteroaryl
is optionally substituted by
CI-6alkyl or trifluoromethyl,
and which heterocycle may optionally be spiro-fused to a 5- or 10-membered
mono- or bi-cyclic ring
system optionally containing 1, 2 or 3 heteroatoms selected from N, 0 and S,
and further optionally
containing 1, 2 or 3 double bonds and also optionally substituted by 1 to 3
groups independently selected
from C,_6alkyl, hydroxy, oxo, phenyl and SO2C,_6alkyl;
Ra is hydrogen, C,_6alkyl, C(O)C,_6alkyl, C(O)OC,_6alkyl, C(O)NH(C,_6alkyl),
(CH2)0_3ary1,
(CH2)0_3heteroaryl or SO2C,_6alkyl, optionally substituted by C,_6alkyl;
Rb is hydrogen, CI-6alkyl or aryl;
and pharmaceutically acceptable salts thereof.
In one embodiment, ring A is phenyl, pyridyl or pyrimidyl. Preferably, ring A
is phenyl or
pyridyl.
In another embodiment, ring B is aryl or pyridyl. Preferably, ring B is
phenyl.
In another embodiment, n is 1 or 2. Preferably, n is 2.
In another embodiment, X is a bond, -CH2- or -C(C,-4alkyl)2-. Preferably, X is
a bond or -
CH2-. More preferably, X is a bond.
In another embodiment, Y is a bond, -CH2-- or -C(C,-4alkyl)2-. Preferably, Y
is a bond or -
CH2-. More preferably, Y is a bond.
In another embodiment, Z is a bond or -CH2-. Preferably, Z is a bond.
In another embodiment, R' is hydrogen, C,_6alkyl, hydroxy, C,_6alkoxy,
halogen, CN, C02(C,_
4alkyl) or C(CH3)20H, optionally substituted by 1 to 5 halogen atoms.
Preferably, R' is hydrogen, C,_
4alkyl, C,_4alkoxy, halogen, CN, CO2CH3 or C(CH3)20H, optionally substituted
by 1 to 3 halogen atoms.
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More preferably, R' is hydrogen, methyl, chloro, trifluoromethyl,
trifluoromethoxy, CN, CO2CH3 or
C(CH3)20H.
In another embodiment, RZ is hydrogen or C,_6alkyl. Preferably, RZ is hydrogen
or methyl.
More preferably, RZ is hydrogen.
In another embodiment, R3 is hydrogen, C,_6alkyl, hydroxy, C,_6alkoxy, halogen
or CN,
optionally substituted by 1 to 5 halogen atoms. Preferably, R3 is hydrogen,
C,_4alkyl, C,_4alkoxy, halogen
or CN, optionally substituted by 1 to 3 halogen atoms. More preferably, R3 is
hydrogen, methyl, fluorine,
chlorine, bromine, trifluoromethyl, trifluoromethoxy or CN.
In another embodiment, R4 is hydrogen or halogen. Preferably, R4 is hydrogen,
fluorine or
chlorine.
In another embodiment, R5 is hydrogen, C,_6alkyl, hydroxy, C,_6alkoxy, or
halogen. Preferably,
R5 is hydrogen, methyl, hydroxy, methoxy or fluorine. More preferably, R5 is
hydrogen, hydroxy or
fluorine. Most preferably, R5 is hydrogen.
In another embodiment, R6 is hydrogen or C,_6alkyl. Preferably, R6 is hydrogen
or methyl.
More preferably, R6 is hydrogen.
In another embodiment, R7 is hydrogen, C,_6alkyl, (CH2)0_2ary1, or Het,
optionally substituted by
C,-4alkyl, C,-4alkoxy or heteroaryl, which heteroaryl is optionally
substituted by 1 or 2 methyl or ethyl
groups. Preferably, R7 is hydrogen, benzyl or piperidinyl, optionally
substituted by methoxy or pyrazolyl,
which pyrazolyl is optionally substituted by 1 or 2 methyl or ethyl groups.
More preferably, R7 is
hydrogen, 4-methoxybenzyl or 2-ethyl-5-methyl-2H-pyrazolyl-3-yl.
In another embodiment, R8 is hydrogen or C,_6alkyl. Preferably, R8 is hydrogen
or methyl.
More preferably, R8 is hydrogen.
In another embodiment, R7 and R8, together with the nitrogen atom to which
they are attached,
form a 5- or 6-membered heterocycle, optionally containing 1 or 2 further
heteroatoms selected from N
and 0,
which heterocycle may optionally contain one double bond,
and which heterocycle may optionally be substituted by one or two groups
selected from C,-4alkyl, oxo,
CH2-O-phenyl, phenyl, heteroaryl, CH2heteroaryl, Het, NH2, (CH2)0_,NHRa or
CH2N(phenyl)SO2CH3,
where said aryl, heteroaryl, and Het are optionally substituted by 1, 2 or 3
groups selected from C,-4alkyl,
oxo or halogen, which C,_4alkyl being optionally substituted by hydroxy or 1
to 3 halogen atoms, and
where said heteroaryl and Het are also optionally fused to a 5-or 6-membered
ring which optionally
contains a nitrogen atom and which ring is optionally substituted by
C,_4alkoxy,
and which heterocycle may optionally be fused to pyridyl or triazolyl,
optionally substituted by
trifluoromethyl, and which heterocycle may optionally be spiro-fused to a 5-
membered monocyclic or a
8- or 9-membered bicyclic ring system, optionally containing 1 or 2 N atoms,
further optionally
containing 2 or 3 double bonds and also optionally substituted by C,-4alkyl,
oxo, phenyl, or SO2C,-4alkyl,
and Ra is as hereinbefore defmed.
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Preferably, R7 and R8, together with the nitrogen atom to which they are
attached, form an
azetidinyl, pyrrolidinyl, piperidinyl, dihydropyridinyl, piperazinyl or
morpholinyl ring, which ring is
optionally substituted by one or two groups selected from oxo, methyl, phenyl,
CH2-O-phenyl, NH2,
-N H 101
-N-C-O H IOI Y,
-N-C H
> > >
SO2CH3
N~ N I
I , H
0 l
F
N_ N
tBu CF3
N
. . . N.
N N N N
> > > >
,
N /N~
~ - -N
N
/N-l ~N
N -N -
OH N N
> > > >
N~
;~~ I I N O' N N -O
N-N N
S N
N N
Na~ N
~ N I %~'/ ~/S
> >
O
~
< ; -N N
~
NN N
N N/
_
H3CO
> > >
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0 0
N)~ N \N'k 0
~or~*
and which ring is optionally fused to 3-trifluoromethylpyridyl or 1,2,4-
triazolyl, and which ring is further
optionally spiro-fused to
0
=N~H
N
rN,j N O
N
SO2CHg
5 or
where = indicates the spiro-centre.
In one embodiment of the present invention, there is provided the compound of
formula (Ia):
Rl R7
( A rS(O)õ-X Z-N
~ Y R
8
(Ia)
R3
or a pharmaceutically acceptable salt thereof,
wherein ring A, n, X, Y, R', R3, R4, R7 and R8 are as defined in relation to
formula (I).
Preferably, ring A is phenyl or pyridyl.
Preferably, n is 1 or 2. More preferably, n is 2.
Preferably, X is a bond or -CH2-. More preferably, X is a bond.
Preferably, Y is a bond or -CH2-. More preferably, Y is a bond.
Preferably, R' is hydrogen, C,_6alkyl, hydroxy, C,_6alkoxy, halogen, CN,
CO2(C,-4alkyl) or
C(CH3)20H, optionally substituted by 1 to 5 halogen atoms. More preferably, R'
is hydrogen, C,_4alkyl,
C,-4alkoxy, halogen, CN, CO2CH3 or C(CH3)20H, optionally substituted by 1 to 3
halogen atoms. Most
preferably, R' is hydrogen, methyl, chloro, trifluoromethyl, trifluoromethoxy,
CN, CO2CH3 or
C(CH3)20H.
Preferably, R3 is hydrogen, C,_6alkyl, hydroxy, C,_6alkoxy, halogen or CN,
optionally substituted
by 1 to 5 halogen atoms. More preferably, R3 is hydrogen, C,_4alkyl, C,-
4alkoxy, halogen or CN,
optionally substituted by 1 to 3 halogen atoms. Most preferably, R3 is
hydrogen, methyl, fluorine,
chlorine, bromine, trifluoromethyl, trifluoromethoxy or CN.
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Preferably, R4 is hydrogen or halogen. More preferably, R4 is hydrogen,
fluorine or chlorine.
Preferably, R7 is hydrogen, benzyl or piperidinyl, optionally substituted by
methoxy or
pyrazolyl, which pyrazolyl is optionally substituted by 1 or 2 methyl or ethyl
groups. More preferably, R7
is hydrogen, 4-methoxybenzyl or 2-ethyl-5-methyl-2H-pyrazolyl-3-yl.
Preferably, R8 is hydrogen.
In an alternative preference, R7 and R8, together with the nitrogen atom to
which they are
attached, form a 5- or 6-membered heterocycle, optionally containing one
further heteroatom selected
from N and 0, which heterocycle may optionally contain one double bond,
and which heterocycle may optionally be substituted by one or two groups
selected from C,-4alkyl, oxo,
CH2-O-phenyl, phenyl, heteroaryl, CH2heteroaryl, Het, NH2, (CH2)0_,NHRa or
CH2N(phenyl)SO2CH3,
where said aryl, heteroaryl and Het are optionally substituted by 1, 2 or 3
groups selected from C,_4alkyl,
oxo, halogen, which C,_4alkyl being optionally substituted by hydroxy or 1 to
3 halogen atoms, and where
said heteroaryl and Het are also optionally fused to a 5- or 6-membered ring
which optionally contains a
nitrogen atom and which ring is optionally substituted by C,_4alkoxy,
and which heterocycle may optionally be fused to pyridyl or triazolyl,
optionally substituted by
trifluoromethyl,
and which heterocycle may optionally be spiro-fused to a 5- membered
monocyclic or a 8- or 9-
membered bicyclic ring system, optionally containing 1 or 2 N atoms, further
optionally containing 2 or 3
double bonds and also optionally substituted by C,_4alkyl, oxo, phenyl or
SO2C,_4alkyl;
and where Ra is as defined in relation to forrnula (I).
More preferably, R7 and R8, together with the nitrogen atom to which they are
attached, form an
azetidinyl, pyrrolidinyl, piperazinyl or morpholinyl ring, or an oxo-
substituted piperazinyl ring further
substituted on the nitrogen atom by thiazolyl, 1-ethy1-3-methyl-1,2 pyrazol-5-
yl, fluorophenyl or
pyridyl, or a piperidinyl or dihydropyridinyl ring optionally substituted with
one or two groups selected
from methyl, phenyl, CH2 -0-phenyl, NH2,
-N ~ N H I~I
N~ -N-C-O H IOI Y,
-N-C-N
> > >
SO2CH3
.
:
N
N,,r H \/ I \ ~ ~ / I
0
tBu CF3
N
. . . ~ N.
N N N /N
> > > >
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N / N - ~ -N
~N
/N-I ~ N
;-N ;-N -
OH N N
> > > >
N
/ /N O\N N, -
N \N ~ O ~ N N
N Na~
> > > >
~ TN
N'N- '
S
, , ,
0
O O
)~
-N N
N N N O
N/ \ %~ J~
\I ZtIT1
H3CO , or ,
and further optionally fused to 3-trifluoromethylpyridyl or 1,2,4-triazolyl,
and further optionally spiro-fused to
0
. =N~H
N
rN,j N O
N SO2CH3 or
where = indicates the spiro-centre.
In one preferred embodiment of the present invention, there is provided the
compound of
formula (Iaa):
O
R ~ \ S N R9
_ II
O
(Iaa)
R3
or a pharmaceutically acceptable salt thereof,
wherein R' and R3 are as defmed in relation to formula (I),
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and R9 is (CH2)0_3NRaRb, where Ra and Rb are as defined in relation to formula
(I), or (CH2)0_3heteroaryl
or (CH2)0_3Het, where said heteroaryl and Het are optionally substituted by 1,
2 or 3 groups independently
selected from C,_6alkyl, hydroxy, oxo, C,_6alkoxy or halogen, which C,_6alkyl
being optionally substituted
by hydroxy or 1 to 5 halogen atoms, and where said heteroaryl and Het are also
optionally fused to a 5-
or 6-membered ring which optionally contains 1 or 2 heteroatoms selected from
N and 0, and which ring
is optionally substituted by C,_4alkyl, hydroxy or C,-4alkoxy.
Preferably, R' is hydrogen, C,_6alkyl, hydroxy, C,_6alkoxy, halogen, CN,
CO2(C,-4alkyl) or
C(CH3)20H, optionally substituted by 1 to 5 halogen atoms. More preferably, R'
is hydrogen, methyl,
trifluoromethyl, trifluoromethoxy, chlorine, CN, CO2CH3 or C(CH3)20H.
Preferably, R3 is hydrogen, C,_6alkyl, hydroxy, C,_6alkoxy, halogen or CN,
optionally
substituted by 1 to 5 halogen atoms. More preferably, R3 is methyl,
trifluoromethyl, trifluoromethoxy,
CN, fluorine, chlorine or bromine.
Preferably, R9 is (CH2)0_,NRaRb, where Ra and Rb are as hereinbefore defined,
or heteroaryl or
Het, where said heteroaryl and Het are optionally substituted by 1, 2 or 3
groups independently selected
from C,_4alkyl or oxo, which C,-4alkyl being optionally substituted by hydroxy
or 1 to 3 fluorine atoms,
and where said heteroaryl and Het are also optionally fused to a 5- or 6-
membered ring which optionally
contains a nitrogen atom and which ring is optionally substituted by methoxy.
Examples of suitable R9
groups include:
SO2CH3 tBu
O
H II
N -N-C-O /N N
X-
> > > >
~CF3 r , F --N
N' N
/N N
OH
Ol N
N~N
' ~N Na~ N N
> > >
O
~
-N N
~
N
N iN
N'N 0-~
H3CO
> > >
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0 0
N)~ N ~ \N'k O
\ I b).
and
In another preferred embodiment of the present invention, there is provided
the compound of
formula (Iab):
N O
F3C ~ \ S N R9
O
(Iab)
R3
or a pharmaceutically acceptable salt thereof,
wherein R3 is as defmed in relation to formula (I) and R9 is as defmed in
relation to formula (Iaa).
Preferably, R3 is hydrogen, C,_6alkyl, hydroxy, C,_6alkoxy or halogen. More
preferably, R3 is
hydrogen or halogen. Most preferably, R3 is fluorine, chlorine or bromine.
Preferably, R9 is heteroaryl, optionally substituted by 1 or 2 groups
independently selected from
C,-4alkyl, and where said heteroaryl is optionally fused to a 5- or 6-membered
ring which optionally
contains a nitrogen atom. Examples of suitable R9 groups include:
~ TN
N'N N/N ~ ~ and
The independent syntheses of any optical isomers or their chromatographic
separations may be
achieved as known in the art. Their absolute stereochemistry may be determined
by the x-ray
crystallography of crystalline products or crystalline intermediates which are
derivatized, if necessary,
with a reagent containing an asymmetric center of known absolute
configuration.
The present invention includes within its scope solvates of the compounds of
formula (I), for
example hydrates, and salts thereof.
The present invention also includes within its scope any enantiomers,
diasteromers, geometric
isomers and tautomers of the compounds of formula (I). It is to be understood
that all such isomers and
mixtures thereof are encompassed within the scope of the invention.
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As used herein, the term "C,_6alkyl" means linear or branched chain alkyl
groups having from 1
to 6 carbon atoms and includes all of the hexyl and pentyl alkyl isomers as
well as n-, iso-, sec- and t-
butyl, n- and isopropyl, ethyl and methyl. "C,-4alkyl" shall be understood in
an analogous manner, as
shall "C,_6alkoxy" and "C1_4alkoxy".
5 The term "C2_6alkenyl" means linear or branched chain alkenyl groups having
from 2 to 6
carbon atoms and includes all of the hexenyl and pentenyl isomers as well as 1-
butenyl, 2-butenyl, 3-
butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl).
The term "C2_6alkynyl" means linear or branched chain alkynyl groups having
from 2 to 6
carbon atoms and includes all of the hexynyl and pentynyl isomers as well as 1-
butynyl, 2-butynyl, 3-
10 butynyl, 1-propynyl, 2-propynyl, and ethynyl (or acetylenyl).
The term "C3_8cycloalkyl" means a cyclic alkane ring having three to eight
total carbon atoms
(i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl).
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "aryl" refers to phenyl and naphthyl.
The term "heteroaryl" as used herein is intended to include the following
groups: furanyl,
imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridazinyl,
pyridyl, pyrimidyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,
triazolyl and pyrrolidinyl.
The term "Het" means a heteroaliphatic ring of 3 to 7 ring atoms, which ring
contains 1, 2 or 3
heteroatoms selected from N, 0 or S or a group S(O), S(O)2, NH or NC,-4alkyl.
Examples of Het include
aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl,
imidazolidinyl, pyrazolidinyl,
tetrahydrofuranyl, dioxolanyl, pyran, dioxanyl, morpholine, oxathiolanyl,
dithianyl, oxathianyl,
thiomorpholinyl, trioxanyl, trithianyl.
The terms "thiophenyl" and "thienyl" have the same meaning herein and are used
interchangeably. Similarly, the following pair of terms has the same meaning:
"pyridinyl" and "pyridyl".
Exemplary compounds of the present invention include those listed in the
Examples section
hereinbelow and their pharmaceutically acceptable salts.
These compounds and those defined by the immediately preceding definitions are
useful in
therapy, particularly as NK-3 antagonists.
The terms "administration of' and or "administering a" compound should be
understood to
mean providing a compound of the invention to the individual in need of
treatment.
The term "subject," (alternatively referred to herein as "patient") as used
herein refers to an
animal, preferably a mammal, most preferably a human, who has been the object
of treatment,
observation or experiment.
The compounds of the present invention may be administered in the form of
pharmaceutically
acceptable salts. The term "pharmaceutically acceptable salt" is intended to
include all acceptable salts
such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate,
bicarbonate, maleate, bisulfate,
mandelate, bitartrate, mesylate, borate, methylbromide, bromide,
methylnitrate, calcium edetate,
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methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate,
clavulanate, N-
methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate,
oxalate, edisylate, pamoate
(embonate), estolate, palmitate, esylate, pantothenate, fumarate,
phosphate/diphosphate, gluceptate,
polygalacturonate, gluconate, salicylate, glutamate, stearate,
glycollylarsanilate, sulfate, hexylresorcinate,
subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride,
tartrate, hydroxynaphthoate,
teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate,
valerate, and the like which can be
used as a dosage form for modifying the solubility or hydrolysis
characteristics or can be used in
sustained release or pro-drug formulations. Depending on the particular
functionality of the compound of
the present invention, pharmaceutically acceptable salts of the compounds of
this invention include those
formed from cations such as sodium, potassium, aluminum, calcium, lithium,
magnesium, zinc, and from
bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine,
omithine, choline, N,N'-
dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-
benzylphenethyl-amine,
diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and
tetramethylammonium hydroxide.
These salts may be prepared by standard procedures, e.g. by reacting a free
acid with a suitable organic or
inorganic base. Where a basic group is present, such as amino, an acidic salt,
i.e. hydrochloride,
hydrobromide, acetate, palmoate, and the like, can be used as the dosage form.
Also, in the case of an alcohol group being present, pharmaceutically
acceptable esters can be
employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those
esters known in the art for
modifying solubility or hydrolysis characteristics for use as sustained
release or prodrug formulations.
The compounds of the present invention may be administered by oral, parenteral
(e.g.,
intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or
infusion, subcutaneous
injection, or implant), by inhalation spray, nasal, vaginal, rectal,
sublingual, or topical routes of
administration and may be formulated, alone or together, in suitable dosage
unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers, adjuvants and
vehicles appropriate for each
route of administration. In addition to the treatment of warm-blooded animals
such as mice, rats, horses,
cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are
effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of
this invention may
conveniently be presented in dosage unit form and may be prepared by any of
the methods well known in
the art of pharmacy. All methods include the step of bringing the active
ingredient into association with
the carrier which constitutes one or more accessory ingredients. In general,
the pharmaceutical
compositions are prepared by uniformly and intimately bringing the active
ingredient into association
with a liquid carrier or a finely divided solid carrier or both, and then, if
necessary, shaping the product
into the desired formulation. In the pharmaceutical composition the active
object compound is included
in an amount sufficient to produce the desired effect upon the process or
condition of diseases. As used
herein, the term "composition" is intended to encompass a product comprising
the specified ingredients in
the specified amounts, as well as any product which results, directly or
indirectly, from combination of
the specified ingredients in the specified amounts.
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The pharmaceutical compositions containing the active ingredient may be in a
form suitable for
oral use, for example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or
granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions
intended for oral use may
be prepared according to any method known to the art for the manufacture of
pharmaceutical
compositions and such compositions may contain one or more agents selected
from the group consisting
of sweetening agents, flavoring agents, coloring agents and preserving agents
in order to provide
pharmaceutically elegant and palatable preparations. Tablets contain the
active ingredient in admixture
with non-toxic pharmaceutically acceptable excipients which are suitable for
the manufacture of tablets.
These excipients may be for example, inert diluents, such as calcium
carbonate, sodium carbonate,
lactose, calcium phosphate or sodium phosphate; granulating and disintegrating
agents, for example, corn
starch, or alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for
example magnesium stearate, stearic acid or talc. The tablets may be uncoated
or they may be coated by
known techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay material such
as glyceryl monostearate
or glyceryl distearate may be employed. They may also be coated by the
techniques described in the U.S.
Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic
tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules
wherein the active
ingredient is mixed with an inert solid diluent, for example, calcium
carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules wherein the active ingredient is mixed
with water or an oil medium, for
example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients
suitable for the
manufacture of aqueous suspensions. Such excipients are suspending agents, for
example sodium
carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium
alginate, polyvinyl-
pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may
be a naturally-occurring
phosphatide, for example lecithin, or condensation products of an alkylene
oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of ethylene oxide
with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation products of
ethylene oxide with
partial esters derived from fatty acids and a hexitol such as polyoxyethylene
sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived from fatty
acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate. The aqueous
suspensions may also contain
one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate,
one or more coloring
agents, one or more flavoring agents, and one or more sweetening agents, such
as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a
vegetable oil, for
example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil
such as liquid paraffm. The
oily suspensions may contain a thickening agent, for example beeswax, hard
paraffin or cetyl alcohol.
Sweetening agents such as those set forth above, and flavoring agents may be
added to provide a
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13
palatable oral preparation. These compositions may be preserved by the
addition of an anti-oxidant such
as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the
addition of water provide the active ingredient in admixture with a dispersing
or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing or wetting
agents and suspending
agents are exemplified by those already mentioned above. Additional
excipients, for example
sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of
oil-in-water
emulsions. The oily phase may be a vegetable oil, for example olive oil or
arachis oil, or a mineral oil,
for example liquid paraffm or mixtures of these. Suitable emulsifying agents
may be naturally-occurring
gums, for example gum acacia or gum tragacanth, naturally-occurring
phosphatides, for example soy
bean, lecithin, and esters or partial esters derived from fatty acids and
hexitol anhydrides, for example
sorbitan monooleate, and condensation products of the said partial esters with
ethylene oxide, for example
polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening
and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example
glycerol, propylene
glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a
preservative and flavoring
and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable
aqueous or
oleagenous suspension. This suspension may be formulated according to the
known art using those
suitable dispersing or wetting agents and suspending agents which have been
mentioned above. The
sterile injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example as a solution in 1,3-
butane diol. Among the
acceptable vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending
medium. For this purpose any bland fixed oil may be employed including
synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid find use in the
preparation of injectables.
The compounds of the present invention may also be administered in the form of
suppositories
for rectal administration of the drug. These compositions can be prepared by
mixing the drug with a
suitable non-irritating excipient which is solid at ordinary temperatures but
liquid at the rectal temperature
and will therefore melt in the rectum to release the drug. Such materials are
cocoa butter and
polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc.,
containing the
compounds of the present invention are employed. (For purposes of this
application, topical application
shall include mouthwashes and gargles.)
The pharmaceutical composition and method of the present invention may further
comprise
other therapeutically active compounds as noted herein which are usually
applied in the treatment of the
above mentioned pathological conditions.
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In the treatment or prevention of conditions which require NK-3 receptor
modulation an
appropriate dosage level will generally be about 0.01 to 500 mg per kg patient
body weight per day which
can be administered in single or multiple doses. Preferably, the dosage level
will be about 0.1 to about
250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A
suitable dosage level may
be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about
0.1 to 50 mg/kg per day.
Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per
day. For oral
administration, the compositions are preferably provided in the form of
tablets containing 1.0 to 1000
milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0,
25.0, 50.0, 75.0, 100.0, 150.0,
200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0
milligrams of the active
ingredient for the symptomatic adjustment of the dosage to the patient to be
treated. The compounds may
be administered on a regimen of 1 to 4 times per day, preferably once or twice
per day.
It will be understood, however, that the specific dose level and frequency of
dosage for any
particular patient may be varied and will depend upon a variety of factors
including the activity of the
specific compound employed, the metabolic stability and length of action of
that compound, the age,
body weight, general health, sex, diet, mode and time of administration, rate
of excretion, drug
combination, the severity of the particular condition, and the host undergoing
therapy.
The present invention also provides pharmaceutical compositions comprising a
compound of
formula (I) or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable excipient.
Thus there is provided a compound of formula (I) or a pharmaceutically
acceptable salt thereof
for use in a method of treatment of the human or animal body by therapy.
Likewise there is provided the use of a compound of formula (I) for the
manufacture of a
medicament for treating a neurokinin-3 mediated disease.
There is also disclosed a method of treatment of a subject suffering from a
neurokinin-3
mediated disease, which comprises administering to that patient a
therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt thereof.
Examples of diseases mediated by neurokinin-3 include CNS disorders such as
depression
(which term includes bipolar (manic) depression (including type I and type
II), unipolar depression, single
or recurrent major depressive episodes with or without psychotic features,
catatonic features, melancholic
features, atypical features (e.g. lethargy, over-eating/obesity, hypersomnia)
or postpartum onset, seasonal
affective disorder and dysthymia, depression-related anxiety, psychotic
depression, and depressive
disorders resulting from a general medical condition including, but not
limited to, myocardial infarction,
diabetes, miscarriage or abortion); anxiety disorders (including generalised
anxiety disorder (GAD),
social anxiety disorder (SAD), agitation, tension, social or emotional
withdrawal in psychotic patients,
panic disorder, and obsessive compulsive disorder); phobias (including
agoraphobia and social phobia);
psychosis and psychotic disorders (including schizophrenia, schizo-affective
disorder, schizophreniform-
diseases, acute psychosis, alcohol psychosis, autism, delirium, mania
(including acute mania), manic
depressive psychosis, hallucination, endogenous psychosis, organic
psychosyndrome, paranoid and
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delusional disorders, puerperal psychosis, and psychosis associated with
neurodegenerative diseases such
as Alzheimer's disease); post-traumatic stress disorder; attention deficit
hyperactive disorder (ADHD);
cognitive impairment (e.g. the treatment of impairment of cognitive functions
including attention,
orientation, memory (memory disorders, amnesia, amnesic disorders and age-
associated memory
5 impairment) and language function, and including cognitive impairment as a
result of stroke, Alzheimer's
disease, Aids-related dementia or other dementia states, as well as other
acute or sub-acute conditions that
may cause cognitive decline such as delirium or depression (pseudodementia
states)); convulsive
disorders such as epilepsy (which includes simple partial seizures, complex
partial seizures, secondary
generalised seizures, generalised seizures including absence seizures,
myoclonic seizures, clonic seizures,
10 tonic seizures, tonic clonic seizures and atonic seizures); psychosexual
dysfunction (including inhibited
sexual desire (low libido), inhibited sexual arousal or excitement, orgasm
dysfunction, inhibited female
orgasm and inhibited male orgasm, hypoactive sexual desire disorder (HSDD),
female sexual desire
disorder (FSDD), and sexual dysfunction side-effects induced by treatment with
antidepressants of the
SSRI-class); sleep disorders (including disturbances of circadian rhythm,
dyssomnia, insomnia, sleep
15 apnea and narcolepsy); disorders of eating behaviours (including anorexia
nervosa and bulimia nervosa);
neurodegenerative diseases (such as Alzheimer's disease, ALS, motor neuron
disease and other motor
disorders such as Parkinson's disease (including relief from locomotor
deficits and/or motor disability,
including slowly increasing disability in purposeful movement, tremors,
bradykinesia, hyperkinesia
(moderate and severe), akinesia, rigidity, disturbance of balance and co-
ordination, and a disturbance of
posture), dementia in Parkinson's disease, dementia in Huntington's disease,
neuroleptic-induced
Parkinsonism and tardive dyskinesias, neurodegeneration following stroke,
cardiac arrest, pulmonary
bypass, traumatic brain injury, spinal cord injury or the like, and
demyelinating diseases such as multiple
sclerosis and amyotrophiclateral sclerosis); withdrawal from abuse of drugs
including smoking cessation
or reduction in level or frequency of such activities (such as abuse of
cocaine, ethanol, nicotine,
benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like
compounds, opiates such as
cannabis, heroin, morphine, sedative, hypnotic, amphetamine or amphetamine-
related drugs such as
dextroamphetamine, methylamphetamine or a combination thereof); pain (which
includes neuropathic
pain (including diabetic neuropathy; sciatica; non-specific lower back pain;
multiple sclerosis pain; pain
associated with fibromyalgia or cancer; AIDS-related and HIV-related
neuropathy; chemotherapy-
induced neuropathy; neuralgia, such as post-herpetic neuralgia and trigeminal
neuralgia; sympathetically
maintained pain and pain resulting from physical trauma, amputation, cancer,
toxins or chronic
inflammatory conditions such as rheumatoid arthritis and osteoarthritis;
reflex sympathetic dystrophy
such as shoulder/hand syndrome), acute pain (e.g. musculoskeletal pain, post
operative pain and surgical
pain), inflammatory pain and chronic pain, pain associated with normally non-
painful sensations such as
"pins and needles" (paraesthesias and dysesthesias), increased sensitivity to
touch (hyperesthesia), painful
sensation following innocuous stimulation (dynamic, static or thermal
allodynia), increased, sensitivity, to
noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain
sensation after removal of the
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stimulation (hyperpathia) or an absence of or deficit in selective sensory
pathways (hypoalgesia), pain
associated with migraine, and non-cardiac chest pain); certain CNS-mediated
disorders such as emesis,
irritable bowel syndrome, and non-ulcer dyspepsia; COPD, asthma, cough, gastro-
oesophageal reflex
induced cough, and exacerbated asthma; urinary incontinence; hypertension; and
conditions associated
with platelet hyperaggregability such as tissue ulceration, nephrotic
syndrome, diabetes, migraine,
coronary artery disease, pre-eclampsia and stroke. Preferably, the compounds
of the invention are useful
for the treatment of depression; anxiety disorders; phobias; psychosis and
psychotic disorders; post-
traumatic stress disorder; attention deficit hyperactive disorder (ADHD);
withdrawal from abuse of drugs
including smoking cessation or reduction in level or frequency of such
activities; and irritable bowel
syndrome. More preferably, the compounds of the invention are useful for the
treatment of depression;
anxiety disorders; phobias; and psychosis and psychotic disorders (especially
schizophrenia, schizo-
affective disorder, and schizophreniform diseases. Most preferably, the
compounds of the invention are
useful for the treatment of schizophrenia.
The compounds for use in the present invention are generally active in the
following tests. They
normally have an IC50 of less than 1 M and preferably less than 100nM.
Details of the NK-3 receptor and its heterologous expression can be found in
Huang et al.,
BBRC, 1992, 184: 966-972 and Sadowski et al., Neuropeptides, 1993, 24: 317-
319.
A membrane preparation is prepared as follows. A 10-layer cell factory is
seeded with CHO
cells stably expressing NK-3 receptors. The CHO cells are prepared in a triple
T175 flask in 11 growth
medium which contains Iscore's modified Dulbecco's medium containing l
Oml/1200mM L-Glutamine,
10m1/1 penicillin-streptomycin, one vial of hypoxanthine-thymidine 500x/1,
lmg/ml geneticin and 10%
fetal bovine serum (inactivated). The cells are grown for 3 days in an
incubator. The medium is washed
off and the factory is rinsed twice with 400m1 PBS (Ca, Mg-free). 400m1 enzyme
free dissoc. solution
(EFDS) is added and the factory is maintained for 10 min at room temperature.
The cells are dislodged
and the suspension poured into 500m1 centrifuge bottles. The process is
repeated with 200m1 EFDS and
the mixtures pooled giving 6 bottles in all, which are spun in a centrifuge
for 10 min at 2200 rpm.
The supematants are aspirated and the residual cell pellets are frozen at -80
for 30 min to
improve cell lysis and then resuspended in 40m1 Tris with inhibitors per cell
factory. The cells are
homogenized in 40m1 aliquots with 8 strokes of a glass-teflon grinder at
setting 40. The homogenate is
transferred to 50m1 centrifuge tubes and placed on a rocker for 15 min at r.t.
The homogenate is
rehomogenised and held on ice if necessary before being centrifuged again as
above.
The supematant is transferred to Sorvall tubes for an SS-34 roter and held on
ice.
40m1 cold Tris with inhibitors is used to resuspend and combine the pellets
which are again
spun as above. The supematants are again transferred to Sorvall tubes which,
with those above, are spun
at 18000 rpm for 20 min.
The supematants are discarded and the pellets resuspended in a Storage Buffer
consisting of
2.50m1 1M Tris pH7.4, 50 1 1000x protease inhibitors (4mg/ml leupeptin
(Sigmo), 40mg/ml Bacitracin
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(Sigma) and 10mM phosphoranidon (Peninsula) all dissolved in water) plus
0.5m10.5M MnC12 ma.de up
to 50m1 with H2Odd. A l Omi syringe is used with 20-, 23- and 25-gauge needles
sequentially.
A Bradford protein assay in conducted on 2-10 1 aliquots with BSA as standard
before 500-
1000 1 aliquots are snap-frozen in liquid nitrogen for storage at -80 C.
The membrane binding assay is carried out as follows. The amount of membranes
needed to
specifically bind < 10% of 125 I-NeurokinB is predetermined. The frozen stocks
are then diluted to allow
addition in 50 1.
The test compounds are dissolved in DMSO. An automated apparatus (Tecan) is
programmed
to add 5 1 of compound or DMSO, approximately 100,000 cpm of isotope in 20 1
buffer which is
prepared from 50 MTris, pH7.5, 150 M NaC1, bovine serum albumin to 0.02%, and
protease inhibitors
as in the storage buffer, made up as 0.5M stock, and 175 1 assay buffer (as
the storage buffer but
containing 5 M MnC12 and without NaC1) into deep well Marsh boxes (Marsh
Biomedical Products) in a
96-well format. Excess unlabelled competing peptide is added by hand for non-
specific binding as
indicated below. The binding reaction is initiated by adding 50 1 of cell
membranes. The tubes are
incubated with shaking for lh at r.t. and filtered on a Tomtec 96 well cell
harvester using Mach III
filtermats (Tomtec) or using either a Packard 96-well harvester or Tomtec 9600
using Unifilter GF/C
(Packard), presoaked in 0.25% polyethyleneimine and washed five times with 1X
wash buffer (0.1M.Tris,
pH7.4 and 1M NaC1, 1X = 100m1 of lOX stock per litre of cold distilled water).
If using Unifilter plates,
60 1 Microscint 20 (Packard) is added to each well and the plate is then heat-
sealed before counting in a
Packard Topcount. Alternatively the filters from the filtermat are placed in
75x100mm plastic tubes and
counted on a Cobra gamma counter.
For the assay, typically 10 g of membrane is used at 25,000 cpm which is
filtered over a
Unifilter GF/C presoaked in 0.5% BSA.
Compounds of the present invention may be prepared by methods disclosed in the
documents
hereinbefore referred to and by methods known in the art of organic synthesis
and the Schemes set forth
below.
According to a general process (A), compounds of formula (I) where Z is a bond
may be
prepared by the reaction of a compound of formula (II) with a compound of
formula (III):
R5 R6
R' ~ R7
( A rS(O)õ-X O HN/
R2~~J/ ~R8
Y
a
R3 R4
(II) (III)
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where A, B, n, X, Y, R', R2, R3, R4, R5, R6, R7 and R8 are as defined in
relation to formula (I). The
reaction is conveniently preformed in the presence of a hydride source, such
as a sodium
triacetoxyborohydride, and a mild acid, such as acetic acid, in a suitable
solvent, such as 1,2-
dichloroethane.
Where they are not commercially available, the starting materials of formulae
(II) and (III) may
be prepared by methods illustrated in the following Schemes, by methods
analogous to those described in
the accompanying Descriptions and Examples, or by standard methods well known
from the art. For
example, compounds of formula (II) can be made from known compounds using
procedures analogous to
those found in published International applications WO 2002/081435, WO
2004/031137 and WO
2004/031139 (all Merck Sharp & Dohme Limited).
It will be understood that any compound of formula (I) initially obtained from
any of the above
processes may, where appropriate, subsequently be elaborated into a further
compound of formula (I) by
techniques known from the art.
For instance, a compound of formula (I) where R4 is bromine may be transformed
into a
compound of formula (I) where R4 is hydrogen by hydrogenation using, for
example, a palladium on
carbon catalyst and hydrogen gas, in a suitable solvent, such as ethyl
acetate.
In addition, a compound of formula (I) where R7 is methoxybenzyl may be
transformed into a
compound of formula (I) where R7 is hydrogen by treatment with ceric ammonium
nitrate in a suitable
solvent system such as acetonitrile/water. The resultant compound of formula
(I) may be transformed
into a different compound of formula (I) by reaction with, for example, a
substituted piperidinone in the
presence of a hydride source such as sodium triacetoxyborohydride, and acid,
such as acetic acid, in a
suitable solvent, such as 1,2-dichloroethane.
Also, a compound of formula (Iaa) where R9 is a BOC-protected amine, may be
transformed to
a compound of formula (Iaa) where R9 is an amine by treatment with acid, such
as hydrochloric acid, in a
suitable solvent, such as 1,4-dioxane. The resultant compound of formula (Iaa)
may be transformed into a
compound of formula (Iaa) whereR9 is a urea derivative by reaction with an
alkyl isocyanate in the
presence of a base, such as triethylamine, in a suitable solvent, such as
dichloromethane.
General synthetic schemes:
Scheme 1
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R' R' O
E:H ~ 3 i i
2 ~ Br d B
R3 R4 R3 R4
'R' O R' O
S O iv ~ v, vi ~S~
R2 ~- R2 O -~ R2 NRTR$
O
B B B
R3 R4 R3 R4 R3 R4
Cis & Trans
Reagents: i) Et3N, CH2C12i ii) mCPBA, CH2C12; iii) 2,2-bis(2-iodoethyl)-1,3-
dioxolane, NaH, DMF; iv) pTsOH,
AcOH, H20, 50 C; v) R'RBNH, NaBH(OAc)3, AcOH, 1,2-dichloroethane; vi)
separate isomers
Scheme 2
MeO2CA S HO~ ~S
i
B B
R3 R4 R3 R4
Reagents: i) MeMgBr, THF, -78 C.
Scheme 3
R' R3
~S
-Br + ~~ ~ - Rz
R2 R4 SH B
R3 R4
Reagents: i) NaH, DMF
Scheme 4
R' R' 0 O
R1 q SH -> R2~S O i-~ R2A -S~
R2- ~OD KXOD
R3
R Br
R' 0 O R~ 0 O
~S~'/~ iv S~'/~~ O~
R2 x ~O ~- R2 x x
Y~ ~/ Y ~--/ ~O
~ ~
R3 ~ R3 R4
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Reagents: i) 1,4-dioxa-spiro[4.5]dec-8-yl methanesulfonate, CsF, DMF, 60 C;
ii) mCPBA, CH2C12i iii) nBuLi,
THF; iv) pTsOH, AcOH, H20, 50 C.
Scheme 5
5
Rs Rs R' Rs Rs 1 Rs Rs
HO-X R2~.J S-X~ '--' OJ \/ O\ R2~X / O
Y'-' O R' Y ~,/'C~
R3~~R4 R2~SH R3,&,R4 R3,,
R4
s R6
iii R2~S-
R 0
Y
R3,'=', R4
Reagents: i) BF3.OEt2, CH2C12i ii) pTsOH, AcOH, H20, 50 C; iii) NaIO4, MeOH,
H20.
Scheme 6
R5 R6 R5 R6 R'
HO-X \ I O MeO2SO-X OD ii R2 ~ 6
Y~~/ 'O~ Y~~/ 'O S-X O
R~ Y~ ~/ 'OD
R 3~ R4 R3,~R4 A $H
R2
R3 B R4
iii, iv
R~
A Rs Rs
R2~ -
O'~ XO
Y
R3,, R4
Reagents: i) MeSO2C1, Et3N, CH2C12i ii), Et3N, DMF, 80 C; iii) mCPBA, CH2C12;
iv) pTsOH, AcOH, H20, 50 C.
Scheme 7
0 0
~ HN HN~ ~ H NN~
H2NC ~ 1-4
G HN-@
OH
ring C = aryl, heteroaryl
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Reagents: i) haloacetyl chloride, ii) ethanolamine, iii) di-tert-butyl
azodicarboxylate, nBu3P, EtOAc.
The following abbreviations are used in the Schemes, Descriptions and
Examples: DMF: N,N-
dimethylformamide; DMSO: dimethylsulfoxide; Et20: diethyl ether; EtOAc: ethyl
acetate; h: hour(s);
MeCN: acetonitrile; MeOH: methanol; min: minute(s); RT: room temperature; THF:
tetrahydrofuran
The following Descriptions and Examples illustrate the present invention.
Description 1: 1-Chloro-4-[(4-fluorobenzyl)thio] benzene
Triethylamine (6.3 mL, 45.1 mmol) was added dropwise to a stirred solution of
4-chlorothiophenol (5 g,
34.7 mmol) and 4-fluorobenzyl bromide (6.9 g, 36.4 mmol) in CH2C12 (60 mL)
over 5 min. The mixture
was stirred for lh at ambient temperature then partitioned between CH2C12 and
water. The organic
extracts were washed with brine, dried (Na2S04) and concentrated in vacuo to
give the title compound
(8.78 g, 100%).
'H NMR (500MHz, CDC13): 6 7.23-7.19 (6H, m), 6.96 (2H, t, J 8.6), 4.04 (2H,
s).
Description 2: 2-[4-(4-Chlorobenzylsulfanyl)phenyl]propan-2-ol
A solution of 4-(4-chlorobenzylsulfanyl)benzoic acid methyl ester (prepared
according to the method of
Description 1) (3 g, 10.2 mmol) in THF (50 mL) was cooled to -78 *C. Methyl
magnesium bromide (3M
in Et2O, 10 mL, 30 mmol) was added dropwise. The mixture was stirred at this
temperature for 30 min,
then warmed to RT. Water and EtOAc were added and the phases separated. The
organic layer was
washed with brine, dried over Na2S04, filtered and evaporated in vacuo. The
title compound (2.71 g,
90%) was obtained after column chromatography on silica gel (Gradient: EtOAc
in hexanes 10% to
30%).
'H NMR (360MHz, CDC13): 6 7.37 (d, J 8.4, 2H); 7.24 (m, 6H); 4.05 (s, 2H);
1.55 (s, 6H).
Description 3: 5-{[(4-Chlorophenyl)methyl]thio}-2-(trifluoromethyl) pyridine
NaH (60% dispersion in mineral oil, 1.2 g, 30 mmol) was added to a stirred,
cooled (0 C) solution of 4-
chlorobenzenemethanethiol (4.22 g, 26.5 mmol) in DMF (50 mL). The mixture was
stirred at 0 C for
10 min, then 5-bromo-2-(trifluoromethyl)pyridine (5 g, 22.1 mmol) was added.
The mixture was stirred
at RT for 4 h, then water was added. The mixture was extracted with EtOAc and
the combined organic
fractions were washed with water and brine, dried (Na2S04) and the solvent was
evaporated under
reduced pressure to give the title compound (6.74 g, 100%). m/z (ES) 304
(M+1).
The following compounds were prepared according to the method of Description
3.
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Description Compound
4 N
F3C S
Br
N
F3C S
F
Description 6: 1-Chloro-4-[(4-fluorobenzyl)sulfonyl]benzene
3-Chloroperbenzoic acid (15.1 g, 87.5 mmol) was added in portions to a
stirred, cooled (0 C) solution of
1-chloro-4-[(4-fluorobenzyl)thio]benzene (Description 1; 8.78 g, 34.7 mmol) in
CH2C12 (80 mL). The
mixture was warmed to RT and stirred overnight. The mixture was cooled in ice
and Ca(OH)2 (9.7 g,
131 mmol) was added. The mixture was stirred for 20 min, filtered through
HyfloTM and the solvent was
evaporated under reduced pressure to give the title compound (9.34 g, 95%).
'H NMR (500MHz, CDC13): 6 7.55 (d, J 8.6, 2H); 7.43 (d, J 8.6, 2H); 7.08 (dd,
J 5.4, 8.7, 2H); 7.00-6.94
(m, 2H); 4.27 (s, 2H).
Description 7: 8-[(4-Chlorophenyl)sulfonyl]-8-(4-fluorophenyl)-1,4-
dioxaspiro[4.5]decane
NaH (60% in mineral oil, 1.53 g, 39 mmol) was added to a solution of 1-chloro-
4-[(4-
fluorobenzyl)sulfonyl]benzene (Description 6; 4.67 g, 16.3 mmol) in DMF (120
mL) and the mixture was
stirred at RT for 10 min. 2,2-Bis(2-iodoethyl)-1,3-dioxolane (6.85 g, 17.9
mmol) was added and the
mixture was stirred at RT overnight. The mixture was cooled in ice and water
was added. Aqueous
NaHCO3 (saturated) was added and the mixture was extracted with EtOAc. The
combined organic
fractions were washed with brine, dried (Na2SO4) and the solvent was
evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel, eluting with
15 - 20% EtOAc/hexane
to give the title compound (4.00 g, 59%).
'H NMR (500MHz, CDC13): 6 7.33 (d, J 8.5, 2H); 7.23 (m, 4H); 7.00 (t, J 8.6,
2H); 3.95 (t, J 6.0, 2H);
3.88 (t, J5.9, 2H); 2.59-2.53 (m, 2H); 2.48 (d, J 12.9, 2H); 1.75 (d, J 13.1,
2H); 1.44-1.38 (m, 2H).
Description 8: 4-[(4-Chlorophenyl)sulfonyl]-4-(4-fluorophenyl)cyclohexanone
p-Toluenesulfonic acid monohydrate (3.03 g, 15.9 mmol) was added to a stirred,
heated (50 C) solution
of 8-[(4-chlorophenyl)sulfonyl]-8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane
(Description 7; 4.00 g,
9.73 mmol) in acetic acid (90 mL) and water (10 mL) and the mixture was
stirred at 50 C overnight. The
mixture was cooled, diluted with EtOAc and neutralised with K2C03. The mixture
was extracted with
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23
EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4)
and the solvent was
evaporated under reduced pressure to give the title compound (3.3 g, 90%).
'H NMR (500MHz, CDC13): 6 7.37-7.30 (m, 4H); 7.25 (m, 2H); 7.10-7.04 (m, 2H);
2.80 (m, 2H); 2.72-
2.66 (m, 2H); 2.50 (m, 2H); 2.22-2.15 (m, 2H).
The following compounds were prepared according to the methods of Descriptions
1-8.
R~ 0 O
O
R'
Description R R'
9 H 4-Br
3-Cl 4-Br
11 3-CF3 4-Br
12 4-Cl 3-F
13 4-Cl 4-F
14 4-Cl 4-Br
4-Cl 4-CN
16 4-Cl 4-Me
17 4-Cl 4-CF3
18 4-Cl 4-(OCF3)
19 4-Cl 2,5-F2
4-Cl 3,4-C12
21 4-Cl 2-F, 4-Br
22 4-CN 4-Br
23 4-Me 4-Br
24 4-CF3 3-Br
4-CF3 4-F
26 4-CF3 4-Cl
27 4-CF3 4-Br
28 4-CF3 3,4-C12
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24
29 4-CF3 3-F, 4-Cl
30 4-(OCF3) 4-Br
31 4-C(Me)20H 4-Cl
32 4-CO2Me 4-Cl
The following compounds were prepared according to the methods of Descriptions
1-8.
11
F3C N S'O
O
0::::
Description R'
33 4-F
34 4-Cl
35 4-Br
Description 36: 8-[4-(Trifluoromethyl)phenylthio] -1,4-dioxa-spiro [4.5]
decane
Cesium fluoride (10.2 g, 67.7 mmol) was heated to 180 C under vacuum for 2 h,
cooled to RT, placed
under a N2 atmosphere and 4-(trifluoromethyl)benzenethiol (5.2 g, 29.2 mmol),
1,4-dioxa-spiro[4.5]dec-
8-yl methanesulfonate (J. Med. Chem. 1992, 35, 2243.) (5.3 g, 22.5 mmol) and
DMF (44 mL) were
added. The mixture was heated to 60 C for 3 h, cooled and water and EtOAc
were added. The layers
were separated and the organic layer was washed with brine, dried (Na2SO4),
filtered and the solvent was
evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel,
eluting with hexanes/EtOAc (100:0 increasing to 90:10) to give the title
compound (3.51 g, 50%).
'H NMR (500MHz, CDC13): 6 7.52 (d, J 8.1, 2H); 7.42 (d, J 8.1, 2H); 3.93 (s,
4H); 3.31 (m, 1H); 2.02 (m,
2H); 1.85 (m, 2H); 1.75 (m, 2H); 1.62 (m, 2H).
Description 37: 8-[4-(Trifluoromethyl)benzenesulfonyl] -1,4-dioxa-spiro [4.5]
decane
Prepared from 8-[4-(trifluoromethyl)phenylthio]-1,4-dioxa-spiro[4.5]decane
(Description 36) according
to the method of Description 6.
'H NMR (500MHz, CDC13): 6 8.05 (d, J 8.1, 2H); 7.87 (d, J 8.1, 2H); 3.93 (m,
4H); 2.95 (m, 1H); 2.08
(m, 2H); 1.90-1.75 (m, 4H); 1.55 (m, 2H).
Description 38: 8-(4-Bromo)phenylmethyl-8-[4-(trifluoromethyl)benzenesulfonyl]-
1,4-dioxa-
spiro[4.5]decane
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n-Butyllithium (1.6M in hexanes, 1.7 mL, 2.7 mmol) was added dropwise to a
stirred, cooled (-78 C)
solution of 8-[4-(trifluoromethyl)benzenesulfonyl]-1,4-dioxa-spiro[4.5]decane
(Description 37, 1 g,
2.86 mmol) in THF (10 mL) and the mixture was stirred at -78 C for 20 min. A
solution of 4-
bromobenzyl bromide (1.43 g, 5.7 mmol) in THF (4 mL) was added dropwise and
the mixture was stirred
5 at -78 C for 2 h. Water and EtOAc were added, the mixture warmed to RT and
the layers were
separated. The organic layer was washed with brine, dried (Na2SO4), filtered
and the solvent was
evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel,
eluting with hexanes/EtOAc (95:5 increasing to 85:15) to give the title
compound (1.16 g, 78%).
'H NMR (500MHz, CDC13): 6 7.95 (d, J 8.1, 2H); 7.80 (d, J 8.1, 2H); 7.40 (d, J
8.2, 2H); 7.13 (d, J 8.2,
10 2H); 3.82 (s, 4H); 3.10 (s, 2H); 1.95 (m, 6H); 1.68 (m, 2H).
Description 39: 4-(4-Bromo)phenylmethyl-4-[4-
(trifluoromethyl)benzenesulfonyl]cyclohexanone
Prepared from 8-(4-bromo)phenylmethyl-8-[4-(trifluoromethyl)benzenesulfonyl]-
1,4-dioxa-
spiro[4.5]decane (Description 38) according to the method of Description 8.
15 'H NMR (500MHz, CDC13): 6 8.09 (d, J 8.1, 2H); 7.90 (d, J 8.1, 2H); 7.42
(d, J 8.2, 2H); 6.98 (d, J 8.2,
2H); 2.96 (s, 2H); 2.84 (m, 2H); 2.43 (m, 2H); 2.15-2.00 (m, 4H).
Description 40: 4-(4-Bromo)phenylmethyl-4-[4-(chloro)benzenesulfonyl]
cyclohexanone
Prepared from 1,4-dioxa-spiro[4.5]dec-8-yl methanesulfonate and 4-
chlorobenzenethiol according to the
20 method of Descriptions 36-39.
'H NMR (500MHz, CDC13): 6 7.88 (d, J 8.1, 2H); 7.60 (d, J 8.1, 2H); 7.42 (d, J
8.2, 2H); 6.98 (d, J 8.2,
2H); 2.95 (s, 2H); 2.82 (m, 2H); 2.41 (m, 2H); 2.10 (m, 2H); 2.01 (m, 2H).
Description 41: 8-Phenyl-1,4-dioxaspiro[4.5]decane-8-methyl Methanesulfonate
25 Triethylamine (0.57 g, 0.0056 mol) then methanesulfonyl chloride (0.57 g,
0.00495 mol) were added
dropwise to 8-phenyl-1,4-dioxaspiro[4.5]decane-8-methanol (Bioorganic &
Medicinal Chemistry Letters
2002, 12, 1755-1758, 0.82 g, 0.0033 mol) in CH2C12 (10 mL) and the mixture was
stirred at RT for 16 h.
The mixture was diluted with CH2C12, washed with water and brine, dried
(MgSO4) and the solvent was
evaporated under reduced pressure to give the title compound.
'H NMR (360MHz, CDC13): 6 1.52-1.70 (4H, m), 1.88-1.97 (2H, m), 2.30-2.34 (2H,
m), 2.55 (3H, s),
3.88-3.97 (4H, m), 4.10 (2H, s), 7.24 (1H, m), 7.35-7.43 (4H, m).
Description 42: 8-Phenyl-8-[(phenylthio)methyl]]-1,4-dioxa-spiro[4.5]decane
Thiophenol (0.22 g , 0.002 mol) followed by triethylamine (0.2 g, 0.002 mol)
were added to 8-phenyl- 1,4-
dioxaspiro[4.5]decane-8-methyl methanesulfonate (Description 41, 0.5 g, 0.0015
mol) in DMF (8 mL)
and the mixture was stirred at 80 C for 16 h. The mixture was cooled, diluted
with water and extracted
with EtOAc. The combined organic fractions were washed with water, and brine,
dried (MgSO4) and the
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26
solvent was evaporated under reduced pressure. The residue was purified by
flash column
chromatography on silica gel to give the title compound (0.21 g, 42%).
'H NMR (360MHz, CDC13): 6 1.53-1.69 (4H, m), 1.94-2.02 (2H, m), 2.35 (2H, m),
3.16 (2H, s), 3.87-
3.96 (4H, m), 7.06-7.41 (10H, m).
Description 43: 4-Phenyl-4-[(phenylsulfonyl)methylllcyclohexanone
To an ice-bath-cooled solution of 8-phenyl-8-[(phenylthio)methyl]]-1,4-dioxa-
spiro[4.5]decane
(Description 42, 0.21 g, 0.00062 mol) in CH2C12 (8 mL) was added portionwise 3-
chloroperbenzoic acid
(70%, 0.36 g, 0.0015 mol). After allowing the mixture to warm to RT it was
stirred for 16 h. Ca(OH)2
(0.068 g, 0.00092 mol) was added and the mixture was stirred at RT for 15 min.
The mixture was filtered
through celite and the solvent was evaporated under reduced pressure. The
residue was dissolved in
acetic acid (5 mL) and water (0.5 mL) andp-toluenesulfonic acid monohydrate
(176 mg, 0.00093 mol)
was added. The mixture was heated at 50 C for 16 h, cooled and EtOAc and
water were added. The
layers were separated and the organic layer was washed with water, and aqueous
NaHCO3, dried
(MgSO4) and the solvent was evaporated under reduced pressure. The residue was
purified by flash
colunm chromatography on silica gel to give the title compound (0.16 g, 80%).
'H NMR (360MHz, CDC13): 6 2.26-2.48 (6H, m), 2.83 (2H, m), 3.45 (2H, m), 7.19-
7.60 (10H, m).
Description 44: 8-(4-Bromophenyl)-8-[(4-trifluoromethyl)phenylthiol]-1,4-dioxa-
spiro[4.5]decane
Boron trifluoride diethyl etherate (1.82 g, 13 mmol) then 4-
(trifluoromethyl)thiophenol (2.3 g, 13 mmol)
were added dropwise to a stirred, cooled (-10 C) solution of 8-(4-bromo-
phenyl)-1,4-dioxa-
spiro[4.5]decan-8-ol (prepared according to Zhang, Y.; Schuster, G.B. J. Org.
Chem. 1994, 59, 1855.)
(2 g, 6.4 mmol) in CH2C12 (32 mL) and the mixture was stirred at RT for 2 h.
Water was added, the
layers were separated and the organic layer was washed with brine, dried
(Na2S04), filtered and the
solvent was evaporated under reduced pressure. The residue was purified by
flash column
chromatography on silica gel, eluting with hexane/EtOAc (98:2 increasing to
90:10) to give the title
compound (0.4 g, 13%).
'H NMR (400MHz, CDC13): 6 7.40 (m, 4H); 7.15 (d, J 8.4, 2H); 7.05 (d, J 8.4,
2H); 3.96 (m, 4H); 2.20-
1.50 (m, 8H).
Description 45: 4-(4-Bromophenyl)-4-[(4-trifluoromethyl)benzenesulfinyl]
cyclohexanone
Sodium metaperiodate (131 mg, 0.7 mmol) in water (1 mL) was added to a
solution of 4-(4-
bromophenyl)-4-[(4-trifluoromethyl)phenylthio]cyclohexanone [prepared from 8-
(4-bromophenyl)-8-[(4-
trifluoromethyl)phenylthiol]-1,4-dioxa-spiro[4.5]decane (Description 44)
according to the method of
Description 8] (0.22 g, 0.51 mmol) in methanol (2 mL) and the mixture was
stirred at RT overnight. The
mixture was filtered and the solvent was evaporated under reduced pressure.
Water and EtOAc were
added and the layers were separated. The organic fraction was washed with
brine, dried (Na2S04) and the
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solvent was evaporated under reduced pressure. The residue was purified by
preparative thin layer
chromatography on silica gel, eluting with hexane/EtOAc (50:50) to give the
title compound.
'H NMR (360MHz, CDC13): 6 7.52 (m, 4H); 7.02 (m, 4H); 7.05 (d, J 8.4, 2H);
2.55 (m, 5H); 2.26 (m,
3H).
Description 46: 1-(1,1-Dimethylethyl) 4-Methy11,4-Piperidinedicarboxylate
Trimethylsilyldiazomethane (2.OM in hexane, 147 mL, 0.29 mol) was added over
30 min. via an addition
funnel to a stirred, cooled (0 C) solution of 1 -(1, 1 -dimethylethyl) 1,4-
piperidinedicarboxylate (45.0 g,
0.20 mol) in CH2C12/MeOH (3:1. 1200 mL). The solvent was evaporated under
reduced pressure to give
the title compound (47 g) as a light yellow oil. This was used directly in the
next step without further
purification.
'H NMR (400MHz, CDC13) 6 1.46 (s, 9H), 1.58-1.68 (m, 2H), 1.86-1.91 (m, 2H),
2.45 (tt, 1H), 2.81-2.87
(m, 2H), 3.70 (s, 3H), 4.00-4.05 (m, 2H).
Description 47: 1-(1,1-Dimethylethyl) 4-Methyl 4-(Pent-4-en-1-yl)-1,4-
piperidinedicarboxylate
A solution of 1-(1,1-dimethylethyl) 4-methyl 1,4-piperidinedicarboxylate
(Description 46, 25 g, 0.10 mol)
in THF (250 mL) was added to a stirred, cooled (0 C) solution of potassium
bis(trimethylsilyl)amide
(30.7 g, 0.15 mol) in THF (750 mL) and the mixture was stirred at 0 C for 1 h.
5-Bromo-l-pentene
(19.4 mL, 0.164 mol) was added and the mixture was allowed to warm to RT and
stirred for 1.5 h. The
mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc
(3x). The combined
organic fractions were washed with brine, dried (Na2SO4), filtered, and the
solvent was evaporated under
reduced pressure to give the title compound (30.9 g) which was used in the
next step without further
purification.
'H NMR (400MHz, CDC13) 6 1.26-1.40 (m, 4H), 1.46 (s, 9H), 1.50-1.54 (m, 2H),
1.99-2.06 (m, 2H),
2.11-18 (m, 2H), 2.80-2.98 (m, 2H), 3.72 (s, 3H), 3.87-3.95 (m, 2H), 4.95-5.02
(m, 2H), 5.72-5.80 (m,
1H).
Description 48: 1-(1,1-Dimethylethyl) 4-Methyl 4-(4-Oxobut-1-yl)-1,4-
piperidinedicarboxylate
A solution of 1-(1,1-dimethylethyl) 4-methyl4-(pent-4-en-l-yl)-1,4-
piperidinedicarboxylate
(Description 47, 29.4 g, 0.0945 mol) in methanol (1000 mL) was cooled to -78
C and ozone was
bubbled into the solution until a blue color persisted. The excess ozone was
removed with a stream of N2,
then methyl sulfide (69 mL, 0.95 mol) was added, the cooling bath was removed,
and the mixture was
allowed to warm to RT over 1.5 h. The solvent was evaporated under reduced
pressure and the residue
was purified by flash chromatography, eluting with 2:1 heptane/EtOAc, to give
the title compound
(23.0 g).
'H NMR (400MHz, CDC13) 6 1.29-1.40 (m, 2H), 1.46 (s, 9H), 1.50-1.57 (m, 4H),
2.09-2.13 (m, 2H),
2.41-2.44 (m, 2H), 2.82-2.95 (m, 2H), 3.73 (s, 3H), 3.86-3.89 (m, 2H), 9.74
(s, 1H).
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Description 49: 1-[(1,1-Dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4-
piperidinebutanoic acid
Jones reagent (2.6M , 28.2 mL) was added via syringe to a solution of 1-(1,1-
dimethylethyl) 4-methyl4-
(4-oxobut-l-yl)-1,4-piperidinedicarboxylate (Description 48, 23.0 g, 0.0734
mol) in acetone (775 mL).
After 5 min, the solvent was evaporated under reduced pressure and the residue
was taken up in water.
The mixture was extracted with Et20 (3x) and the combined organic fractions
were washed with brine,
dried (Na2SO4) and the solvent was evaporated under reduced pressure to give
the title compound (23.4 g)
which was used in the next step without further purification.
'H NMR (400MHz, CDC13) 6 1.33-1.41 (m, 2H), 1.46 (s, 9H), 1.50-1.57 (br s,
4H), 2.09-2.19 (m, 2H),
2.32-2.34 (m, 2H), 2.85-2.89 (m, 2H), 3.73 (s, 3H), 3.81-3.89 (m, 2H).
Description 50: Methyl 1-[(1,1-Dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4-
piperidinebutanoate
Trimethylsilyldiazomethane (2.OM in hexane, 53 mL, 0.11 mol) was added to a
stirred, cooled (0 C)
solution of 1-[(1,1-dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4-
piperidinebutanoic acid
(Description 49, 23.4 g, 0.071 mol) in CH2C12/MeOH (3:1, 480 mL). The mixture
was stirred at RT for
15 min, then the solvent was evaporated under reduced pressure. The residue
was purified by flash
column chromatography, eluting with 20-30% EtOAc in hexanes, to give the title
compound (20.1 g).
'H NMR (400MHz, CDC13) 6 1.33-1.42 (m, 2H), 1.43 (s, 9H), 1.57-1.59 (m, 4H),
2.08-2.14 (m, 2H),
2.26-2.31 (m, 2H), 2.84-2.94 (m, 2H), 3.68 (s, 3H), 3.73 (s, 3H), 3.83-3.90
(m, 2H).
Description 51: (RS')-8-(1,1-Dimethylethyl) 2-Methyll-Oxo-8-
azaspiro[4.5]decane-2,8-
dicarboxylate
Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexanes, 47 mL,
0.070 mol) was added
to a stirred, cooled (-78 C) solution of methyl 1-[(1,1-
dimethylethoxy)carbonyl]-4-(methoxycarbonyl)-4-
piperidinebutanoate (Description 50, 20.1 g, 0.058 mol) in THF (600 mL). The
mixture was stirred at
-78 C for 25 min., then additional lithium diisopropylamide
mono(tetrahydrofuran) (1.5M in
cyclohexanes, 31 mL) was added and the mixture was stirred at -78 C for 20
min. The mixture was
poured into saturated aqueous ammonium chloride and extracted with Et20 (3x).
The combined organic
fractions were washed with brine, dried (Na2SO4), and the solvent was
evaporated under reduced pressure
to give the title compound (19.9 g) which was taken on to the next step
without further purification.
Description 52: 1,1-Dimethylethyll-Oxo-8-azaspiro [4.5] decane-8-carboxylate
Pulverized lithium hydroxide (26 g, 1.10 mol) was added to a solution of (RS)-
8-(1,1-dimethylethyl) 2-
methyl 1-oxo-8-azaspiro[4.5]decane-2,8-dicarboxylate (Description 51, 17.2 g,
0.055 mol) in
ethanol/THF/water (2:2:1, 555 mL) and the mixture was stirred at 90 C for 60
h. The mixture was
cooled and the solvent was evaporated under reduced pressure. Water was added
and the mixture was
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extracted with CH2C12 (3x). The combined organic fractions were washed with
brine, dried (Na2SO4),
filtered, and the solvent was evaporated under reduced pressure. The residue
was purified by flash
column chromatography, eluting with 20-30% EtOAc in hexanes, to give the title
compound (9.41 g).
'H NMR (400MHz, CDC13) 6 1.29-1.37 (m, 2H), 1.47 (s, 9H), 1.62-1.69 (m, 2H),
1.92-1.95 (m, 4H),
2.30-2.34 (m, 2H), 3.05-3.10 (m, 2H), 3.87-3.92 (m, 2H).
Description 53: (1RS,2RS)-1,1-Dimethylethyl2-(1-Hydroxyprop-1-yl)-1-oxo-8-
azaspiro[4.5]decane-
8-carboxylate
1,1-Dimethylethyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate (Description 52,
4.5 g, 17.8 mmol) was
dried by adding and evaporating toluene (3 x 10 mL) under reduced pressure,
dissolved in THF (100 mL)
and cooled to -78 C. Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in
cyclohexane, 24 mL,
36 mmol) was added and the mixture was stirred at -78 C for 30 min.
Propionaldehyde (2.6 mL,
36 mmol) was added and the mixture was stirred at -78 C for 5 min. The
mixture was diluted with Et20,
poured into saturated aqueous ammonium chloride and extracted with Et20 (3x).
The combined organic
fractions were washed with brine, dried (Na2SO4), filtered, and the solvent
was evaporated under reduced
pressure. The residue was purified by flash column chromatography, eluting
with 20-30% EtOAc in
hexanes, to give the title compound (4.75 g).
'H NMR (400MHz, CDC13) 6 0.97 (t, 3H), 1.33-1.37 (m, 2H), 1.47 (s, 9H), 1.54-
1.68 (m, 5H), 1.75-1.78
(m, 1H), 2.07-2.13 (m, 2H), 2.30-2.33 (m, 1H), 2.95-3.15 (m, 2H), 3.62-3.63
(m, 1H), 3.84-3.94 (m,
2H).
Description 54: 1,1-Dimethylethyl2-(1-Oxoprop-1-yl)-1-oxo-8-azaspiro [4.5]
decane-8-carboxylate
DMSO (2.6 mL, 37 mmol) was added slowly to a stirred, cooled (-78 C) solution
of oxalyl chloride
(1.6 mL, 18.3 mmol) in CH2C12 (150 mL) and the mixture was stirred at -78 C
for 5 min. A solution of
(1RS,2RS)-1,1-dimethylethyl2-(1-hydroxyprop-1-yl)-1-oxo-8-azaspiro[4.5]decane-
8-carboxylate
(Description 53, 4.75 g, 15.3 mmol) in CH2C12 (40 mL) was added via an
addition funnel and the mixture
was stirred at -78 C for 45 min. Triethylamine (10.2 mL, 73.2 mmol) was added
and the mixture was
stirred at -78 C for 5 min., then allowed to warm to RT for 1.5 h. The
mixture was poured into water
and extracted with CH2C12 (3x). The combined organic fractions were washed
with brine, dried
(Na2SO4), filtered and the solvent was evaporated under reduced pressure. The
residue was purified by
flash column chromatography, eluting with 15% EtOAc in hexanes, to give the
title compound (3.98 g) as
a pink oil.
Description 55: 1,1-Dimethylethy11,3-Diethyl-4,5-dihydrospiro
[cyclopentapyrazole-6(1H),4'-
piperidine]-1'-carboxylate Trifluoroacetate and 1,1-Dimethylethy12,3-Diethyl-
4,5-
dihydrospiro[cyclopentapyrazole-6(2H),4'-piperidine]-1'-carboxylate
Trifluoroacetate
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Ethyl hydrazine oxalate (0.096 g, 0.640 mmol) was added to a solution of 1,1-
dimethylethyl2-(1-
oxoprop-1-yl)-1-oxo-8-azaspiro[4.5]decane-8-carboxylate (Description 54, 0.165
g, 0.533 mmol) in
ethanol (5 mL) and the mixture was stirred at 85 C for 12 h. The mixture was
cooled and the solvent
was evaporated under reduced pressure. The residue was taken up in a minimal
amount of 40:40:20
5 MeCN/water/DMSO solution and purified by Gilson reverse phase HPLC (Column:
YMC-Pack Pro C18,
100 X 20 mm I.D.; Gradient Eluent: 10:90 to 90:10 v/v MeCN/water + 0.1%
trifluoroacetic acid over
12.5 min; Detection: PDA, 210-400 nm; Flow rate: 20 mL/min) to give 1,1-
dimethylethyl 1,3-diethyl-4,5-
dihydrospiro [cyclopentapyrazole-6(1H),4' piperidine]-1 '-carboxylate tr
fluoroacetate (0.220 g); 'H
NMR (400MHz, CDC13) 6 1.23 (t, 3H), 1.42 (t, 3H), 1.50 (s, 9H), 1.60-1.63 (m,
2H), 1.88-1.93 (m, 2H),
10 2.42-2.47 (m, 2H), 2.56-2.61 (m, 4H), 2.86-2.89 (m, 2H), 4.00 (q, 2H), 4.10-
4.13 (m, 2H); m/z (ES)
334 (M+1); and 1, 1-dimethylethyl 2,3-diethyl-4,5-
dihydrospiro[cyclopentapyrazole-6(2H),4' piperidine]-
1'-carboxylate trifluoroacetate (0.016 g); 'H NMR (400MHz, CDC13) 6 1.27 (t,
3H), 1.38 (t, 3H), 1.48 (s,
9H), 1.51-1.57 (m, 2H), 1.75-1.79 (m, 2H), 2.22-2.45 (m, 2H), 2.58-2.65 (m,
4H), 3.51-3.60 (m, 2H),
3.64-3.67 (m, 2H), 4.03 (q, 2H); m/z (ES) 334 (M+1).
Description 56: 1,3-Diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(1H),4'-
piperidine]
Dihydrochloride
Acetyl chloride (1.17 mL, 16.4 mmol) was added to a stirred, cooled (0 C)
solution of 1,1-dimethylethyl
1,3-diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(1H),4'-piperidine]-1'-
carboxylate trifluoroacetate
(Description 55, 0.547 g, 1.64 mmol) in MeOH (16 mL). The mixture was allowed
to warm to RT and
stirred for 60 h. The solvent was evaporated under reduced pressure to give
the title compound.
'H NMR (400MHz, CDC13) 6 1.32 (t, 3H), 1.54 (t, 3H), 2.00 (d, 2H), 2.37-2.45
(m, 2H), 2.66-2.69 (m,
2H), 2.73-2.82 (m, 4H), 3.18-3.24 (m, 2H), 3.47-3.52 (d, 2H), 4.41 (q, 2H).
Description 57: 1-(1,1-Dimethylethyl) 4-piperidinedicarboxylate Anhydride with
1H-Imidazole-l-
carboxylic Acid
Carbonyldiimidazole (39.4 g, 243 mmol) was added in portions to a stirred
solution of 1 -(1, 1 -
dimethylethyl) 4-piperidinedicarboxylate (42.5 g, 187 mmol) in CH2C12 (550 mL)
and the mixture was
stirred at 4 C overnight. The mixture was poured into Et20 (2 L) and ice water
(2 L), the layers were
separated and the organic layer was washed with cold aqueous NaHCO3
(saturated, 500 mL) and brine
(500 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure
to give the title
compound as a colorless solid (52 g).
Description 58: 1,1-Dimethylethyl4-(1,3-Dioxobutyl)piperidinecarboxylate
Acetone (41 mL) in THF (300 mL) was added dropwise to a stirred suspension of
KH (30% in mineral
oil, 75 g, 561 mmol) in THF (1.4 L) at RT. The mixture was cooled to -78 C
and treated with 1-(1,1-
dimethylethyl) 4-piperidinedicarboxylate anhydride with 1H-imidazole-l-
carboxylic acid
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31
(Description 57, 52 g) in THF (500 mL). The mixture was allowed to warm to RT
and stirred overnight,
then ethanol (50 mL) was added dropwise over 5 min. The mixture was poured
into hydrochloric acid
(1N, 2 L) and extracted with Et20 (2 xl L). The combined organic fractions
were washed with aqueous
NaHCO3 (saturated, 500 mL) and brine (500 mL), dried (MgSO4) and the solvent
was evaporated under
reduced pressure. Isohexane (1 L) and acetonitrile (500 mL) were added, the
layers were separated and
the isohexane layer was extracted with MeCN (500 mL). The MeCN layers were
combined and the
solvent was evaporated under reduced pressure. The residue was filtered
through a silica pad, eluting
with 0-20% EtOAc in hexanes, to give the title compound as a colorless solid
(36 g, 72%).
'H NMR (CDC13) 6 5.50 (1H, s), 4.18-4.11 (2H, m), 2.79-2.62 (2H, m), 2.34-2.27
(1H, m), 2.07 (3H, s),
1.80 (2H, brd, J 14.3), 1.60-1.51 (2H, m), 1.46 (9H, s).
Description 59: 1,1-Dimethylethyl4-[1-(1,1-Dimethylethyl)-3-methyl-lH-pyrazol-
5-
yl]piperidinecarboxylate
t-Butyl hydrazine hydrochloride (14.8 g, 118 mmol) then triethylamine (17 mL,
120 mmol) were added to
a solution of 1,1-dimethylethyl 4-(1,3-dioxobutyl)piperidinecarboxylate
(Description 58, 8 g, 29.7 mmol)
in ethanol (200 mL) and the mixture was stirred at RT overnight. The solvent
was evaporated under
reduced pressure and the residue was suspended in EtOAc (1 L), washed with
aqueous NaOH (1N,
500 mL), water (500 mL) and brine (500 mL), dried (MgSO4) and the solvent was
evaporated under
reduced pressure to give the title compound as a yellow oil (9.5 g).
'H NMR (CDC13) 6 5.87 (1H, s), 4.27-4.18 (2H, m), 3.09-2.99 (1H, m), 2.79-2.68
(2H, m), 2.20 (3H, s),
1.85 (2H, brd, J 13.3), 1.63 (9H, s), 1.61-1.52 (2H, m), 1.48 (9H, s).
Description 60: 4-[1-(1,1-Dimethylethyl)-3-methyl-lH-pyrazol-5-yl]piperidine
Methanolic HC1(1N, 100 mL) was added to a solution of 1,1-dimethylethyl4-[1-
(1,1-dimethylethyl)-3-
methyl-lH-pyrazol-5-yl]piperidinecarboxylate (Description 59, 9.5 g, 29 mmol)
in MeOH (100 mL) and
the mixture was stirred at RT for 4 h. The solvent was evaporated under
reduced pressure and the residue
was triturated with EtOAc. The solid was collected, suspended in aqueous NaOH
(4N, 20 mL) and
extracted with CH2C12 (2 x 100 mL). The combined organic fractions were dried
(MgSO4) and the
solvent was evaporated under reduced pressure to give the title compound (6.4
g).
'H NMR (CDC13) 6 5.91 (1H, s), 3.17 (2H, brd, J 13.0), 3.03 (1H, tt, J 13.0,
4.3), 2.69 (2H, dt, J 12.8,
3.5), 2.21 (3H, s), 1.86 (2H, brd, J 13.4), 1.67 (9H, s), 1.68-1.56 (2H, m).
Description 61: 4-[1-(-(2,2,2-Trifluoroethyl))-3-methyl-lH-pyrazol-5-
yl]piperidine
Prepared from 1,1-dimethylethyl4-(1,3-dioxobutyl)piperidinecarboxylate
(Description 58) according to
the methods of Descriptions 59 and 60, substituting trifluoroethyl hydrazine
oxalate for t-butyl hydrazine
hydrochloride.
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'H NMR (CDC13) 6 5.91 (1H, s), 4.58 (2H, dd, J 16.4, 8.6), 3.17 (2H, brd, J
13.2), 2.70 (2H, dt, J 12.5,
2.4), 2.60 (1H, tt, J 12.1, 4.1), 2.23 (3H, s), 1.82 (2H, brd, J 14.4), 1.58
(2H, qd, J 12.5, 3.8).
Description 62: 1,1-Dimethylethyl4-[(2-Oxocyclopentyl)carbonyl]-1-
piperidinecarboxylate
Prepared from 1-(1,1-dimethylethyl) 4-piperidinedicarboxylate anhydride with
1H-imidazole-l-
carboxylic acid (Description 57) according to the method of Description 58,
substituting cyclopentanone
for acetone.
'H NMR (CDC13) 6 13.75 (1H, brs), 4.27-4.06 (2H, m), 2.78-2.69 (2H, m), 2.57
(2H, t, J6.2), 2.42 (2H, t,
J7.2), 2.37-2.30 (1H, m), 1.96-1.89 (2H, m), 1.75-1.63 (4H, m), 1.46 (9H, s).
Description 63: 4-(2-Ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine
Prepared from 1,1-dimethylethyl4-[(2-oxocyclopentyl)carbonyl]-1-
piperidinecarboxylate
(Description 62) according to the methods of Descriptions 59 and 60,
substituting ethyl hydrazine oxalate
for t-butyl hydrazine hydrochloride.
'H NMR (CDC13) 6 4.02 (2H, dd, J 14.5, 8.0), 3.18 (2H, brd, J 12.4), 2.72 (2H,
dt, J 12.6, 2.5), 2.68-2.63
(5H, m), 2.40-2.33 (2H, m), 1.81 (2H, brd, J 13.6), 1.69 (2H, qd, J 12.6,
4.1), 1.42 (3H, t, J7.4).
Description 64: 1,1-Dimethylethyl4-(1,3-Dioxo-2-
methylbutyl)piperidinecarboxylate
NaH (60% in mineral oil, 75 mg, 1.9 mmol) was added to 1,1-dimethylethyl4-(1,3-
dioxobutyl)piperidinecarboxylate (Description 58, 0.5 g, 1.9 mmol) in DMF (5
mL). The mixture was
stirred at RT for 1 h, then added to a solution of iodomethane (0.59 mL, 9.5
mmol) in DMF (5 mL).
Water (500 mL) was added and the mixture was extracted with EtOAc (100 mL).
The organic layer was
washed with saturated brine (50 mL), dried (MgSO4) and the solvent was
evaporated under reduced
pressure. The residue was purified by flash column chromatography on silica
gel, eluting with 15-25%
EtOAc in hexanes, to give the title compound (175 mg).
Description 65: 4-[1,3,4-Trimethyl-lH-pyrazol-5-yl]piperidine
Prepared from 1,1-dimethylethyl4-(1,3-dioxo-2-
methylbutyl)piperidinecarboxylate (Description 64)
according to the methods of Descriptions 59 and 60, substituting methyl
hydrazine oxalate for t-butyl
hydrazine hydrochloride.
'H NMR (CDC13) 6 4.07 (2H, q, J 7.6), 3.19 (2H, brd, J 11.8), 2.77-2.67 (3H,
m), 2.14 (3H, s), 2.02 (3H,
s), 1.92 (2H, qd, J 11.8, 4.1), 1.69 (2H, brd, J 13.0), 1.36 (3H, t, J7.4).
Description 66: 1-Phenylmethyl-4-(3,5-diethyl-lH-pyrazol-1-yl)piperidine
Triethylamine (3.54 mL, 25.5 mmol) was added to a stirred solution of 4-
hydrazino-1-
(phenylmethyl)piperidine dihydrochloride (3.53 g, 12.7 mmol) in ethanol (50
mL) and the mixture was
stirred at RT for 5 min. 3,5-Heptanedione (3.26 g, 25.5 mmol) was added and
the mixture was stirred at
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RT for 4 days. The mixture was diluted with EtOAc, washed with aqueous NaOH
(0.5M), brine, dried
(MgSO4) and the solvent was evaporated under reduced pressure. The residue was
purified by flash
column chromatography on silica gel, eluting with 100% hexane to 100% Et20, to
give the title
compound (2.7 g, 71 %).
'H NMR (CD3OD) 6 7.35-7.20 (5H, m), 5.85 (1H, s), 4.02-3.94 (1H, m), 3.55 (2H,
s), 2.99 (2H, d, J9.2),
2.63-2.51 (4H, m), 2.27-2.12 (4H, m), 1.73 (2H, t, J 11.8), 1.24-1.16 (6H, m).
Description 67: 4-(3,5-Diethyl-lH-pyrazol-1-yl)piperidine
Ammonium formate (5.73 g, 90 mmol) and Pd on C (300 mg) were added to a
stirred solution of 1-
phenylmethyl-4-(3,5-diethyl-lH-pyrazol-l-yl)piperidine (Description 66, 2.7 g,
9 mmol) in methanol
(75 mL) and the mixture was stirred under reflux for 3 h. The mixture was
cooled, filtered through
HyfloTM and the solvent was evaporated under reduced pressure. The residues
was dissolved in MeOH
and poured onto SCX cartridges (Varian Bond E1utTM; 10 mL/500 mg). The
cartridges were washed with
MeOH, then eluted with methanolic ammonia (2M). The solvent was evaporated
under reduced pressure
to give the title product. (1.6 g, 85%).
'H NMR (CD3OD) 6 5.86 (1H, s), 4.18-4.10 (1H, m), 3.15 (2H, dd, J2.1, 10.9),
2.75-2.53 (6H, m), 2.07-
1.97 (2H, m), 1.79 (2H, d, J 14.0), 1.25-1.17 (6H, m).
Description 68: 1,1-Dimethylethy11,2-Dihydro-l-(1-methylethyl)-2-oxospiro[3H-
indole-3,4'-
piperidine] -1'-carboxylate
NaH (60% in mineral oil, 344 mg, 8.6 mmol) was added in portions to a stirred,
cooled (0 C) solution of
1,1-dimethylethyl 1,2-dihydro-2-oxospiro[3H-indole-3,4'-piperidine]-1'-
carboxylate (2.0 g, 6.6 mmol) in
DMF (10 mL) and the mixture was stirred at 0 C for 10 min. 2-lodopropane (0.86
mL, 8.6 mmol) was
added and the mixture was allowed to warm to RT and stirred overnight. Water
(100 mL) was added and
the mixture was extracted with EtOAc (3 x 50 mL). The combined organic
fractions were dried
(MgSO4), filtered and the solvent was evaporated under reduced pressure. The
residue was purified by
flash colunm chromatography on silica gel, eluting with isohexane/EtOAc
(70:30) to give the title
compound as a solid (2.3 g).
'H NMR (CDC13) 6 7.29-7.23 (2H, m), 7.06-7.02 (2H, m), 4.68-4.62 (1H, m), 3.88-
3.76 (4H, m), 1.82-
1.74 (4H, m), 1.50 (9H, s), 1.47 (6H, d, J7.3).
Description 69: 1-(1-Methylethyl)spiro[3H-indole-3,4'-piperidin]-2(1H)-one
Trifluoroacetate
Trifluoroacetic acid (2 mL) was added dropwise to a solution of 1, 1 -
dimethylethyl 1,2-dihydro-l-(1-
methylethyl)-2-oxospiro[3H-indole-3,4'-piperidine]-1'-carboxylate (Description
68) in CH2C12 (20 mL)
and the mixture was stirred at RT for 4 h. The solvent was evaporated under
reduced pressure to give the
title compound as a tan solid (2.35 g).
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'H NMR (CDC13) 6 9.01 (1H, s), 8.54 (1H, s), 7.32-7.28 (2H, m), 7.12 (1H, t,
J7.12), 7.04 (1H, d, J
7.12), 4.65-4.59 (1H, m), 4.00 (2H, q, J 11.9), 3.45 (2H, d, J 12.4), 2.39-
2.31 (2H, m), 1.90 (2H, d, J
14.8), 1.49 (6H, d, J 7.0).
Description 70: 1,1-Dimethylethyl4-[(6-Methoxy-3-nitro-2-
pyridinyl)amino]piperidinecarboxylate
1,1-Dimethylethyl4-amino-l-piperidinecarboxylate (10.01 g, 50 mmol) and
triethylamine (34.85 mL,
25.3 g, 250 mmol) were added to a solution of 2-chloro-6-methoxy-5-
nitropyridine (9.43 g, 50 mmol) in
DMSO (100 mL) and the mixture was stirred at 100 C for 12 h. The mixture was
cooled and added
dropwise to water (1200 mL). The mixture was stirred at RT for 12 h, then the
solid was collected,
washed with water and dried in vacuo to give the title compound as a yellow
powder (16.70 g, 95%).
'H NMR (360MHz, CDC13) 6 1.48 (9H, s), 1.52-1.62 (2H, m), 2.02-2.1 (2H, br m),
2.95-3.09 (2H, br m),
3.95 (3H, s), 4.00-4.10 (2H, br m), 4.23-4.35 (1H, m), 6.07 (1H, d, J9), 8.28
(1H, d, J9), 8.63 (1H, br d).
Description 71: 1,3-Dihydro-5-methoxy-3-(4-piperidinyl)-2H-imidazo[4,5-
b]pyridin-2-one
Dihydrochloride
Platinum oxide (hydrated, 1.1 g) was added to a suspension of 1,1-
dimethylethyl4-[(6-methoxy-3-nitro-
2-pyridinyl)amino]piperidinecarboxylate (Description 70, 16.75 g, 47.52 mmol)
in ethanol (250 mL) and
the mixture was shaken under H2 (25 to 35 psi) for 4 h. CH2C12 (25 mL) was
added, the mixture was
filtered and the solvent was evaporated under reduced pressure. The residue
was dissolved in toluene
(125 mL) and treated with N-ethyldiisopropylamine (24.40 mL, 18.42 g, 142.57
mmol) then N,N'-
carbonyldiimidazole (8.48 g, 52.28 mmol) were added. The mixture was stirred
at 90 C for 24 h, cooled
and the solvent was evaporated under reduced pressure. The residue was
dissolved in CH2C12 and washed
with aqueous Na2CO3 (5%) and HC1(0.01N), dried (MgSO4) and the solvent was
evaporated under
reduced pressure. The residue was dissolved in ethanolic HC1(3M, 200 mL) and
stirred at RT for
90 min. The solvent was evaporated under reduced pressure and the residue was
triturated with EtOAc.
The solid was collected and dried in vacuo to give the title compound as a
purple solid (9.00 g, 59%).
'H NMR (400MHz, D6-DMSO) 6 1.87 (2H, br d, J 13), 2.75 (2H, qd, J 13, 4), 3.08
(2H, br q, J 11), 3.40
(2H, br d, J 13), 3.75 (3H, s), 4.45-4.55 (1H, m), 6.41 (1H, d, J8), 7.29 (1H,
d, J8), 8.75 (1 H, br), 9.01
(1 H, br), 10.90 (1H, s).
Description 72: (3RS)-Ethyl 1-(Phenylmethyl)-3-piperidinecarboxylate
Benzyl chloride (165 mL, 181 g, 1.43 mol) was added in one portion to an
intensively stirred, cooled
(0 C) mixture of (3RS')-ethyl3-piperidinecarboxylate (200 mL, 201 g, 1.29
mol) and triethylamine
(200 mL, 145 g, 1.43 mol) in MeCN (400 mL) and the mixture was stirred at RT
for 2.5 h. The solid was
collected, washed with MeCN (2 x 200 mL) and dried in vacuo. The solid was
dissolved in Et20
(300 mL) and washed with water (2 x 300 mL). The organic layer was dried
(Na2SO4) and the solvent
was evaporated under reduced pressure to give the title compound as an oil
(270 g, 85%).
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Description 73: (3RS')-1-(Phenylmethyl)-3-piperidinecarboxylic Acid Hydrazide
Acetic acid (20 mL) and hydrazine hydrate (136 mL (140 g, 2.8 mol) were added
to a solution of (3RS)-
ethyl 1-(phenylmethyl)-3-piperidinecarboxylate (Description 72, 270 g, 1.092
mol) in ethanol (310 mL)
5 and the mixture was heated under reflux for 3 days. The mixture was cooled
and the solvent was partly
evaporated under reduced pressure until a precipitation occurred. The solid
was collected, aqueous KOH
(50 g in 100 mL) was added and the mixture was extracted with CHC13 (2 x 300
mL). The combined
organic fractions were dried (Na2SO4) the solvent was partly evaporated under
reduced pressure until a
precipitation occurred. The solid was collected, the filtrate was diluted with
Et20 (200 mL) and further
10 solid was collected. The combined solids were washed with Et20 and dried in
vacuo to give the title
compound as a solid (217 g, 92%).
Description 74: (3RS')-1-(Phenylmethyl)-3-piperidinecarboxylic Acid 2-
[(Methylamino)thioxomethyl] hydrazide
15 Methyl isothiocyanate (90 g, 1 43 mol) in toluene (50 mL) was added to a
stirred solution of (3RS)-1-
(phenylmethyl)-3-piperidinecarboxylic acid hydrazide (Description 73, 210 g,
0.90 mol) in toluene
(500 mL) and the mixture was stirred at RT for 1 h. The solid was collected,
washed with Et20 and dried
in vacuo to give the title compound as a solid (245 g, 90%).
20 Description 75: (3RS')-1-(Phenylmethyl)-3-(4-methyl-5-thio-4H-1,2,4-triazol-
3-yl)piperidine
Sodium (50 g, 2.18 mol) was added in portions to stirred, cooled (0 C) MeOH
(785 mL). Once the
sodium had dissolved, (3RS)-1-(phenylmethyl)-3-piperidinecarboxylic acid 2-
[(methylamino)thioxomethyl]hydrazide (Description 74, 230 g, 0.76 mol) was
added and the mixture was
heated under reflux for 1 h. The mixture was cooled in ice and aqueous acetic
acid (126 mL, 131 g,
25 2.19 mol) in water (400 mL) was added. The solid was collected, washed with
Et20 and dried in vacuo to
give the title compound as a solid (173 g, 79%).
Description 76: (3RS')-1-(Phenylmethyl)-3-(4-methyl-4H-1,2,4-triazol-3-
yl)piperidine
(3RS)-1-(Phenylmethyl)-3-(4-methyl-5-thio-4H-1,2,4-triazol-3-yl)piperidine
(Description 75, 160 g,
30 0.56 mol) was dissolved by portions of 15-20 g in stirred, cooled (0 C)
concentrated nitric acid (70%,
500 mL). The mixture was stirred at 0 C for 1 h then poured into stirred,
cooled (0 C) aqueous KOH
(600 g) with continuing addition of ice. The mixture was divided into 4
portions and each portion of
500 mL was extracted with CHC13 (300 mL). The combined organic fractions were
dried (Na2S04) and
the solvent was evaporated under reduced pressure to give the title compound.
Description 77: (3RS')-3-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidine
Hydrochloride
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Pd on C (5%) was added to a mixture of (3RS)-1-(phenylmethyl)-3-(4-methyl-4H-
1,2,4-triazol-3-
yl)piperidine (Description 76) and hydrochloric acid (conc., 50 mL) in
methanol (400 mL) and the
mixture was shaken under an atmosphere of H2 (100 atm.) at 90 C for 24 h. The
mixture was filtered
and the solvent was evaporated under reduced pressure. The residue was
dissolved at reflux in iso-
propanol (100 mL) and hydrochloric acid (conc., 50 mL) was added. The mixture
was cooled and stored
at 5 C for 3 days. The solid was collected, washed with Et20 and dried in
vacuo to give the title
compound as a solid (103 g, 91%).
'H NMR (D6-DMSO) 6 9.80-9.40 (3H, m), 3.90 (3H, s), 3.80-2.80 (5H, m), 2.20-
1.70 (4H, m).
Description 78: 1-(3-Pyridinylmethyl)piperazine Trifluoroacetate
Sodium triacetoxyborohydride (254 g, 1.2 mol) was added in portions to a
rigorously stirred solution of
1, 1 -dimethylethyl piperazinecarboxylate (186 g, 1 mol), acetic acid (120 mL,
2 mol) and 3-
pyridinecarboxaldehyde (107 g, 1 mol) in CH2C12 (700 mL), keeping the mixture
at slow reflux. The
mixture was stirred overnight at RT, washed with aqueous acetic acid (5%, 2 x
150 mL) and dried
(CaC12). The solution was cooled in ice and trifluoroacetic acid (350 mL, 3.5
mol) was added with
stirring. The mixture was stirred at RT until thin layer chromatography
(silica gel;
chloroform:ethanol:benzene; 7:2:1; ninhydrin development) indicated complete
consumption of starting
material. The solvent was partially evaporated under reduced pressure at 70
C. The mixture was then
allowed to crystallize (Et20 was added to help crystallization if needed). The
solid was collected, washed
with Et20 (2 x 100 mL), Et2O:EtOAc (2:1, 100 mL), and again with Et20 (100
mL). The solid was dried
in vacuo to give the title compound as a solid (390 g, 75%).
'H NMR (D6-DMSO) 6 8.85 (2H, br s), 8.70 (2H, m), 8.12 (1H, d), 7.69 (1H, t),
6.0 (1H, br s), 3.90 (2H,
s), 3.20 (4H, m), 2.80 (4H, m).
Description 79: [1,2-Bis(hydroxyimino)propyl]piperazine
Piperazine (84 g, 0.96 mol) in distilled water (400 mL) was added dropwise to
a solution of N-hydroxy-2-
(hydroxyimino)propanimidoyl chloride (33 g, 0.24 mol) in ethanol (100 mL),
maintaining the reaction
temperature below 30 C. The mixture was stirred at RT for 24 h, then filtered,
washing with hot water
(150 mL). The solvent was evaporated under reduced pressure to give a mixture
of the title compound
and piperazine, which was used without further purification.
Description 80: 1-(4-Methyl-1,2,5-oxadiazol-3-yl)piperazine Hydrochloride
NaOH (20 g, 0.5 mol) was added slowly to an intensively stirred solution of
[1,2-
bis(hydroxyimino)propyl]piperazine (Description 79) in water (350 mL). The
mixture was placed in an
autoclave (0.5 L) and stirred for 5 h at 190 C. The mixture was cooled and
stirred overnight. The
mixture was extracted with Et20 (5 x 150 mL), and the combined organic
fractions were dried (MgS04)
and the solvent was evaporated under reduced pressure. The residue was
dissolved in MeOH, acidified
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37
with hydrochloric acid (1 eq), and the solvent was evaporated under reduced
pressure. The residue was
recrystallized from isopropanol to give the title compound (5.8 g).
'H NMR (D6-DMSO) 6 9.50 (2H, br s), 3.50 (4H, t), 3.21 (4H, t), 2.38 (3H, s).
Description 81: 4-(Chloromethyl)-4,5-dihydro-2-methyl-4-thiazolol
A mixture of thioacetamide (7.5 g, 0.1 mol), 1.3-dichloroacetone (14 g, 0.11
mol), sodium bicarbonate
(9.3 g, 0.11 mol) and dichloroethane (60 mL) was stirred at RT for 48 h. The
mixture was filtered,
washing with dichloroethane (20 mL), to give a solution of the title compound
which was used without
further purification.
Description 82: 4-(Chloromethyl)-2-methylthiazole Hydrochloride
Thionyl chloride (13.1 g, 0.11 mol) in dichloroethane (60 mL) was added to an
intensively stirred solution
of 4-(chloromethyl)-4,5-dihydro-2-methyl-4-thiazolol in dichloroethane
(Description 81), maintaining the
reaction temperature below 30 C. The mixture was stirred at 65-70 C for 30
min, cooled and the
solvent was evaporated under reduced pressure. The residue was crystallized
from EtOAc to give the title
compound as a crystalline solid (17.12 g, 93%).
Description 83: 1-[(2-Methyl-4-thiazolyl)methyllpiperazine
4-(Chloromethyl)-2-methylthiazole hydrochloride (Description 82, 92 g, 0.5
mol) in MeOH (400 mL)
was added slowly to a stirred solution of piperazine (500 g, 5.81 mol) in
methanol (800 mL) and the
mixture was heated under reflux for 3 h. The mixture was cooled and methanolic
KOH (1 mol in
400 mL) was added. The mixture was stirred at RT overnight, filtered and the
solvent was evaporated
under reduced pressure. The residue was dissolved in iso-propanol, filtered
and purified by flash column
chromatography on silica gel, eluting with iso-propanol-triethylamine (5:1)
and the residue was vacuum
distilled. A fraction with b.p. 123-127 C/-1 torr was collected to give the
title compound as a light-
yellow dense oil which formed hygroscopic low melting (-30 C) crystals on
standing (57.1 g, 58%).
'H NMR (D6-DMSO) 6 7.20 (1H, s), 3.45 (2H, s), 3.15 (1H, br s), 2.60 (4H, t),
2.50 (3H, s), 2.30 (4H, m).
Description 84: 1,1-Dimethylethyl4-[2-(1-Hydroxy-l-methylethyl)-4-methyl-lH-
imidazol-1-yl]-1-
piperidinecarboxylate
n-Butyllithium (1.6M in hexanes, 5.7 mL, 9.0 mmol) was added dropwise to a
stirred, cooled (-78 C)
solution of 1,1-dimethylethyl4-(4-methyl-lH-imidazol-l-yl)-1-
piperidinecarboxylate (as prepared in
W093/19059, 2 g, 7.5 mmol) in THF (50 mL) and the mixture was stirred at -78
C for 1 h. Ethyl
bromide (0.7 mL, 9.0 mmol) was added and the mixture was stirred at RT for 5
h. Acetone (1.1 mL,
0.88 g, 15 mmol) was added and the mixture was stirred at RT overnight. Water
was added and the
mixture was extracted with EtOAc. The combined organic fractions were dried
(Na2SO4) and the solvent
was evaporated under reduced pressure. The residue was purified by flash
column chromatography on
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silica gel, eluting with CH2C12/MeOH (100:0 increasing to 98:2), to give the
title compound (0.9 g, 37%).
m/z (ES) 324 (M+1).
Description 85: 4-[2-(1-Hydroxy-l-methylethyl)-4-methyl-lH-imidazol-1-
yl]piperidine
1,1-Dimethylethyl4-[2-(1-hydroxy-l-methylethyl)-4-methyl-1 H-imidazol-l-yl]-1-
piperidinecarboxylate
(Description 84, 450 mg, 1.4 mmol) was dissolved in ethanolic HC1(4M, 6 mL)
and stirred at RT
overnight. The solvent was evaporated under reduced pressure, aqueous NaHCO3
(saturated) was added
and the mixture was extracted with CHC13/ iPrOH (85:15). The combined organic
fractions were dried
(Na2SO4) and the solvent was evaporated under reduced pressure to give the
title compound (257 mg,
83%).
'H NMR (500MHz, CDC13) 6 6.84, 6.53 (total 1H, each s), 5.25, 4.83 (total 1H,
each s), 3.16 (2H, m),
2.69 (2H, s), 2.18 (1H, m), 2.11 (3H, s), 1.98-1.79 (3H, m), 1.60, 1.59 (total
6H, each s).
Description 86: 2-Chloro-N-(1-ethyl-3-methyl-lH-pyrazol-5-yl)acetamide
Chloroacetyl chloride (3.1 mL, 40 mmol) was added to a stirred mixture of 1-
ethyl-3-methyl-lH-pyrazol-
5-amine (4.5 g, 36 mmol) and K2C03 (9.9 g, 72 mmol) in CH2C12 (75 mL). The
mixture was stirred at
RT for 15 min, diluted with MeOH and filtered. The solvent was evaporated
under reduced pressure to
give the title compound (5.6 g, 77%).
'H NMR (CD3OD) 6 6.72 (1H, s), 4.33 (4H, dd, J0.0, 7.0), 2.43 (3H, s), 1.47
(3H, t, J7.3).
Description 87: N-(1-Ethyl-3-methyl-lH-pyrazol-5-yl)-2-[(2-
hydroxyethyl)amino]acetamide
Ethanolamine (1.04 mL, 17 mmol) was added to a stirred mixture of 2-chloro-N-
(1-ethyl-3-methyl-lH-
pyrazol-5-yl)acetamide (Description 86, 872 mg, 4.3 mmol) and Nal (50 mg) in
MeCN (15 mL) and the
mixture was stirred at 80 C for 4.5 h. The mixture was cooled and CHC13/
isopropyl alcohol (3:1) and
water were added. The layers were separated and the aqueous layer was
extracted with CHC13/ isopropyl
alcohol. The combined organic fractions were dried (MgSO4) and the solvent was
evaporated under
reduced pressure to give the title compound (0.534 g, 54%).
'H NMR (CD3OD) 6 6.08 (1H, s), 3.99 (2H, q, J7.2), 3.67-3.63 (2H, m), 3.46
(2H, s), 2.79-2.73 (2H, m),
2.19 (3H, s), 1.33 (3H, t, J7.2).
Description 88: 1-(1-Ethyl-3-methyl-lH-pyrazol-5-yl)piperazin-2-one
Di-tert-butyl azodicarboxylate (0.915 g, 4 mmol) and tri-n-butyl phosphine (1
mL, 4 mmol) were added
to a stirred solution of N-(1-ethyl-3-methyl-lH-pyrazol-5-yl)-2-[(2-
hydroxyethyl)amino]acetamide
(Description 87, 0.3 g, 1.3 mmol) in EtOAc (10 mL) and the mixture was stirred
at RT for 6 h. The
mixture was poured onto SCX cartridges (Varian Bond E1utTM; 10 mL/500 mg). The
cartridges were
washed with MeOH, then eluted with methanolic ammonia (2M). The solvent was
evaporated under
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reduced pressure and the residue was purified by chromatography on silica gel,
eluting with
CH2C12/MeOH (100:0 increasing to 90:10), to give the title compound (190 mg,
40%).
'H NMR (CDC13) 6 5.89 (1H, s), 3.92-3.86 (2H, m), 3.69 (2H, s), 3.60-3.56 (2H,
m), 3.20 (2H, t, J 5.5),
2.25 (3H, s), 1.43-1.39 (3H, m).
Description 89: 2-Bromo-N-(3-fluorophenyl)acetamide
Bromoacetyl bromide (23.5 mL, 0.27 mol) was added slowly to a stirred, cooled
mixture of 3-
fluoroaniline (25 g, 0.225 mol) in EtOAc (250 mL) and aqueous KHCO3 (20%,
250m1). The mixture was
allowed to warm to RT and the layers were separated. The organic layer was
diluted with EtOAc, washed
with aqueous citric acid (10%) and brine, dried (MgSO4) and the solvent was
evaporated under reduced
pressure to give the title compound (51.72 g, 92%).
'H NMR (360MHz, CD3OD) 6 7.54 (1H, dt, J 11, 2), 7.34-7.24 (2H, m), 6.84 (1H,
t, J 7), 3.96 (2H, s).
Description 90: 1-(3-Fluorophenyl)piperazinone Hydrochloride
Ethanolamine (4.5 mL, 75 mmol) was added to stirred 2-bromo-N-(3-
fluorophenyl)acetamide
(Description 89, 5.0 g, 21 mmol) in EtOAc (25 mL) and the mixture was stirred
at 60 C for 2 h. The
mixture was cooled, EtOAc and water were added and the layers were separated.
The organic layer was
dried (MgSO4) and the solvent was evaporated under reduced pressure. The
residue was suspended in
EtOAc (135 mL) and tributylphosphine (5.3 mL, 21 mmol) was added. The mixture
was cooled to 0 C
and di-tert-butylazodicarboxylate (4.8 g, 21 mmol) was added dropwise over 1
h. The mixture was stirred
at 0 C for 0.5 h, then at 40 C for 1.5 h. The mixture was cooled and
ethanolic HC1(4M, 4.7 mL) was
added. The mixture was stored at 0 C for 0.5 h., and the solid was collected,
washing with cold EtOAc,
and dried in vacuo to give the title compound.
'H NMR (400MHz, CD3OD) 6 3.68-3.71 (2H, m), 3.97-4.00 (2H, m), 4.02 (2H, s),
7.12 (1H, m), 7.18-
7.22 (2H, m), 7.48 (1H, m).
Description 91: N-(1-Ethyl-3-methyl-lH-pyrazol-5-yl)-3-azetidinamine
A mixture of 1-ethyl-3-methyl-lH-pyrazol-5-amine (1.0 g, 8.0 mmol), 1-
(diphenylmethyl)-3-azetidinyl
methanesulfonate (2.5 g, 8.0 mmol) and K2C03 (2.2 g, 16.0 mmol) in DMF (10 mL)
was stirred at 60 C
for 24 h. The mixture was cooled, poured into water (50 mL) and extracted with
EtOAc (3 x 20 mL).
The combined organic fractions were dried (Na2SO4) and the solvent was
evaporated under reduced
pressure. The residue was dissolved in ethanol (10 mL), palladium hydroxide
(200 mg) was added and
the mixture was shaken under H2 (45 psi) for 72 h. The mixture was filtered
and the solvent was
evaporated under reduced pressure. The residue was purified by flash column
chromatography on silica
gel, eluting with CH2C12/MeOH (90:10), to give the title compound as an oil.
(168 mg, 12%).
'H NMR (CD3OD) 6 5.15 (1H, s), 4.17-4.15 (1H, m), 3.90-3.81 (4H, m), 3.58 (2H,
m), 2.09 (1H, s), 1.28
(3H, t, J7.1).
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Description 92: 8-(1-Ethyl-3-methyl-lH-pyrazol-5-yl)-1,4-dioxa-8-azaspiro
[4.5] decane
A mixture of 1-ethyl-3-methyl-lH-pyrazol-5-amine (1 g, 8 mmol), 2,2-bis(2-
iodoethyl)-1,3-dioxolane
(3 g, 8 mmol) and K2C03 were dissolved in MeCN (15 mL) and heated under reflux
for 4 days. The
5 mixture was cooled and the solvent was evaporated under reduced pressure.
The residue was suspended
in EtOAc (100 mL) and washed with water (50 mL). The organic fraction was
dried (MgSO4) and the
solvent was evaporated under reduced pressure. The residue was purified by
flash column
chromatography on silica gel, eluting with hexanes/EtOAc (80:20), to give the
title compound (470 mg).
10 Description 93: 1-(1-Ethyl-3-methyl-lH-pyrazol-5-yl)-4-piperidinone
8-(1-Ethyl-3-methyl-lH-pyrazol-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane
(Description 92) in aqueous
acetic acid (75%, 16 mL) was heated under reflux for 16 h. The mixture was
cooled and aqueous
NaHCO3 (saturated, 300 mL) was added slowly. The mixture was extracted with
EtOAc (2 x 200 mL)
and the combined organic fractions were washed with brine (100 mL), dried
(MgSO4) and the solvent was
15 evaporated under reduced pressure. Heptane was added and evaporated under
reduced pressure to give
the title compound as an oil (0.3 g).
'H NMR (CDC13) 6 5.69 (1H, s), 4.05 (2H, g, J7.2), 3.19 (4H, m), 2.59 (4H, m),
2.23 (3H, s), 1.42 (3H, t,
J 7.3).
20 Example 1: Trans-l-[4-(4-Bromophenyl)-4-(4-
chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5-
methyl-2H-pyrazol-3-yl)piperidine
Sodium triacetoxyborohydride (0.3 g, 1.4 mmol) and acetic acid (62 mg, 1 mmol)
were added to a
mixture of 4-(4-bromophenyl)-4-[(4-chlorophenyl)sulfonyl]cyclohexanone
(Description 14, 0.44 g,
1 mmol) and 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine (0.2 g, 1 mmol) in
1,2-dichloroethane
25 (8 mL) and the mixture was stirred at RT for 16 h. Water and EtOAc were
added and the layers were
separated. The organic layer was washed with aqueous NaHCO3 (saturated),
water, and brine, dried
(MgS04), and the solvent was evaporated under reduced pressure. The residue
was purified by flash
column chromatography on silica gel, eluting with EtOAc/isohexane mixtures, to
give the title compound.
'H NMR (360MHz, CDC13) 6 1.185 (2H, m), 1.36 (3H, t, J7.2), 1.60 (2H, m), 1.79-
1.93 (2H, m), 2.14
30 (2H, t, J 11.3), 2.19 (3H, s), 2.30 (2H, t, J 13.7), 2.35-2.50 (2H, m),
2.58 (2H, m), 2.86 (2H, m), 3.96 (2H,
q, J 7.2), 5.73 (1H, s), 7.09 (2H, d, J 8.7), 7.22 (2H, d, J 8.7), 7.34 (2H,
d, J 8.7), 7.43 (2H, d, J 8.7). m/z
(ES) 603, 605 (M+1).
The following compounds were prepared according to the method of Example 1
substituting a suitable
35 cyclohexanone for 4-(4-bromophenyl)-4-[(4-
chlorophenyl)sulfonyl]cyclohexanone and a suitable amine
for 4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine.
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x. ame ES MS
+1
Cis & Trans-l-[4-(2-Fluoro-4-bromophenyl)-4-(4- 622, 624
hlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-
y1)piperidine
Trans-1'-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-1,3-diethyl-
644, 646
,5-dihydrospiro[cyclopentapyrazole-6(1 H),4'-piperidine]
Trans-l-{4-[4-(Trifluoromethyl)phenyl]-4-(4-chlorobenzenesulfonyl)cyclohexyl}-
4- 594
2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
Trans-l-[4-(3,4-Dichlorophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-
ethyl- 594
5-methyl-2H-pyrazol-3-yl)piperidine
Trans-l-[4-(2,5-Difluorophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-
ethyl- 562
5-methyl-2H-pyrazol-3-yl)piperidine
Trans-l-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-[1-(1,1-
632, 634
Idimethylethyl)-3-methyl-IH-pyrazol-5-yl]piperidine
8 Trans-l-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-[1-(-
(2,2,2- 658/660
trifluoroethyl))-3-methyl-IH-pyrazol-5-yl]piperidine
Trans-l-{4-[4-(Trifluoromethoxy)phenyl]-4-(4-chlorobenzenesulfonyl)cyclohexyl}-
610
-(2-ethyl-5-methyl-2H-pyrazol-3-y1)piperidine
Trans-l-[4-(4-Fluorophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-
5- 544
ethyl-2H-pyrazol-3-yl)piperidine
11 Trans-l-[4-(4-Methylphenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-
ethyl-5- 541,543
ethyl-2H-pyrazol-3 -yl)piperidine
12 Trans-l-[4-(4-Cyanophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-
ethyl-5- 551
ethyl-2H-pyrazol-3 -yl)piperidine
13 Trans-l-[4-(4-Bromophenyl)-4-(benzenesulfonyl)cyclohexyl]-4-(2-ethyl-5-
methyl- 570
H-pyrazol-3-yl)piperidine
14 Trans-l-[4-(3-Fluorophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-
ethyl-5- 544
ethyl-2H-pyrazol-3 -yl)piperidine
Trans-l-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl]-4-
638, 640
2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
16 Trans-l-[4-(4-Bromophenyl)-4-(4-cyanobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-
5- 595, 597
ethyl-2H-pyrazol-3 -yl)piperidine
17 Trans-l-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(3,5-
diethyl- 618,620
1 H-pyrazol-l-yl)piperidine
18 Trans-l-{4-(4-Bromophenyl)-4-[3-
(trifluoromethyl)benzenesulfonyl]cyclohexyl]-4- 638, 640
2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
19 Trans-l-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(4H-
1,2,4- 563/565
triazol-4-yl)piperidine
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42
x. ame ES MS
+1
0 Trans-4-[1-{4-(4-Bromophenyl)-4-[4-
(trifluoromethyl)benzenesulfonyl]cyclohexyl} 678, 680
iperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
1 Trans-l-{4-(3-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl]-
4- 638, 640
2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
2 Trans-l-[4-(4-Chlorophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 594
2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
3 Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
4- 636, 638
2-ethyl-5-methyl-2H-pyrazol-3-yl)-1,2,3,6-tetrahydropyridine
4 Cis-1-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-5-
604, 606
ethyl-2H-pyrazol-3 -yl)piperidine
Cis-4-[1-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]cyclohexyl}
678, 680
iperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
6 Cis-1-[4-(3,4-Dichlorophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-
ethyl-5- 594
ethyl-2H-pyrazol-3 -yl)piperidine
7 Cis & Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 638,
640
yclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
8 Cis & Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 636,
638
yclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-1,2,3,6-tetrahydropyridine
9 Cis & Trans-l-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-
604, 606
thyl-5-methyl-2H-pyrazol-3-y1)piperidine
0 Cis-1-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2- 594,
596
hiazolyl)piperazinone
1 Trans-l-[4-(4-Bromophenyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2- 594,
596
hiazolyl)piperazinone
2 Trans-l-[4-(4-Bromophenyl)-4-(4-methylbenzenesulfonyl)cyclohexyl]-4-(2-ethyl-
5- 584, 586
ethyl-2H-pyrazol-3 -yl)piperidine
3 Trans-l-[4-(4-Bromophenyl)-4-(4-
(trifluoromethoxy)benzenesulfonyl)cyclohexyl]-4- 654, 656
2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
4 Trans-l-[4-(4-Bromophenyl)-4-(3-chlorobenzenesulfonyl)cyclohexyl]-4-(2-ethyl-
5- 604, 606
ethyl-2H-pyrazol-3 -yl)piperidine
5 Trans-4-[1-{4-(4-Chlorophenyl)-4-[4-
(trifluoromethyl)benzenesulfonyl]cyclohexyl} 634
iperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
6 R)-Cis-1-[4-(3,4-Dichlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 628
yclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
7 Trans-l-[4-(3,4-Dichlorophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 628
-(2-ethyl-5-methyl-2H-pyrazol-3-y1)piperidine
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43
x. ame ES MS
+1
8 Trans-1'-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 711, 713
1,2-dihydro-l-(methylsulfonyl)spiro[3H-indole-3,4'-piperidine]
9 Trans-1'-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1- 689, 691
1 -methylethyl)spiro [3H-indole-3,4'-piperidin]-2(1 H)-one
0 Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
4- 612, 614
3-methyl-1,2,4-oxadiazol-5-yl)piperidine
1 Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
4- 597, 599
4H-1,2,4-triazol-4-yl)piperidine
2 RS)-Cis-1-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 597, 599
-(1 H-1,2,4-triazol-1-yl)piperidine
3 Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
4- 597, 599
1 H-tetrazol-1-yl)piperidine
4 Trans-8-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
1- 676, 678
henyl-1,3,8-triazaspiro[4.5]decan-4-one
Trans-3-[1-{4-(4-Bromophenyl)-4-[4-
(trifluoromethyl)benzenesulfonyl]cyclohexyl} 693, 695
iperidin-4-yl]-1,3-dihydro-5-methoxy-2H-imidazo[4,5-b]pyridin-2-one
6 Trans-N-[1-{4-(4-Bromophenyl)-4-[4-
(trifluoromethyl)benzenesulfonyl]cyclohexyl} 713, 715
iperidin-4-yl } methyl-N-phenylmethanesulfonamide
7 Trans-N-[4-[1-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl] 677,
679
yclohexyl } -4-phenylpiperidin-4-yl } -methyl] acetamide
8 RS')-Trans-4-[4-(4-Bromophenyl)-4-(4- 638, 640
trifluoromethyl)benzenesulfonyl)cyclohexyl]-2-(phenoxymethyl)morpholine
9 Trans-l-[1-{4-(4-Bromophenyl)-4-[4-
(trifluoromethyl)benzenesulfonyl]cyclohexyl} 677, 679
iperidin-4-yl]-1,4-dihydro-2H-3,1-benzoxazin-2-one
50 Trans-6-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 569, 571
5,6,7,8-tetrahydro-[ 1,2,4]triazolo[ 1,5-a]pyrazine
51 RS)-Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 611,
613
yclohexyl]-3-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine
52 Trans-l-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 622, 624
3-pyridinylmethyl)piperazine
53 Trans-l-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 613, 615
4-methyl-1,2,5-oxadiazol-3-yl)piperazine
54 S)-Trans-l-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 635, 637
-(phenylmethyl)-3-pyrrolidinemethanamine
55 Trans-l-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 642, 644
[(2-methyl-4-thiazolyl)methyl]piperazine
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44
x. ame ES MS
+1
56 Cis-1-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
4-[(2- 642, 644
ethyl-4-thiazolyl)methyl]piperazine
57 S)-Cis-1-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-N- 635, 637
henylmethyl)-3-pyrrolidinemethanamine
58 Cis-N-[4-[1-{4-(4-Bromophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl] 677,
679
yclohexyl } -4-phenylpiperidin-4-yl } -methyl] acetamide
59 Cis-3-[1-{4-(4-Bromophenyl)-4-[4-
(trifluoromethyl)benzenesulfonyl]cyclohexyl} 693, 695
iperidin-4-yl]-1,3-dihydro-5-methoxy-2H-imidazo[4,5-b]pyridin-2-one
0 Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
3- 569, 571
1 H-1,2,4-triazol-3 -yl)azetidine
1 Cis-8-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1-
676, 678
henyl-1,3,8-triazaspiro[4.5]decan-4-one
2 Cis-1'-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
1,2- 711, 713
ydro-l-(methylsulfonyl)spiro [3H-indole-3,4'-piperidine]
3 Trans-3-[1-{4-(4-Bromophenyl)-4-[4-
(trifluoromethyl)benzenesulfonyl]cyclohexyl} 676, 678
iperidin-4-yl]-3,4-dihydro-2(1 H)-quinazolinone
4 RS)-Trans-l-[4-(4-Bromophenyl)-4-(4- 597, 599
trifluoromethyl)benzenesulfonyl)cyc lohexyl] -3 -(1 H-1,2,4-triazol-1-
yl)piperidine
Cis-4-[1-{4-(3,4-Dichlorophenyl)-4-[4-
(trifluoromethyl)benzenesulfonyl]cyclohexyl} 668
iperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
6 Trans-4-[1-{4-(3,4-Dichlorophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]
668
yclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-
a]pyridine
7 Cis-1'-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
1,3- 678/680
ethyl-4, 5-dihydrospiro [cyclopentapyrazole-6(1 H),4'-piperidine]
8 Trans-1'-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]- 678/680
1,3-diethyl-4,5-dihydrospiro[cyclopentapyrazole-6(1 H),4'-piperidine]
9 -[Trans-4-(4-Bromophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexyl]-
4- 582, 584
methoxy)benzenemethanamine
0 Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
4- 692, 694
[ 1-(2,2,2-trifluoroethyl)-3 -methyl-1 H-pyrazol-5 -yl]piperidine
1 Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
4- 668, 670
[2-(1-hydroxy-l-methylethyl)-4-methyl-1 H-imidazol-1-yl]piperidine
2 Cis-4-[1-{4-(4-Fluororophenyl)-4-[4-
(trifluoromethyl)benzenesulfonyl]cyclohexyl} 618
iperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
3 Trans-4-[1-{4-(4-Fluororophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl] 618
yclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-
a]pyridine
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x. ame ES MS
+1
4 Trans-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
2,6- 560, 562
methylmorpholine
5 Cis-1-[4-(4-Fluorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
4-(2- 578
thyl-5-methyl-2H-pyrazol-3-y1)piperidine
6 Trans-l-[4-(4-Fluorophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 578
2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
7 Trans-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
1- 653, 655
1-ethyl-3-methyl-1 H-pyrazol-5-yl)piperazin-2-one
8 Cis-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1-
(1- 653, 655
thyl-3-methyl-1 H-pyrazol-5-yl)piperazin-2-one
9 Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
4- 652, 654
[ 1,3,4-Trimethyl-1 H-pyrazol-5-yl]piperidine
80 Cis-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
2,6- 560, 562
Idimethylmorpholine
81 Cis-1-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
4- 652, 654
[ 1,3,4-trimethyl-1 H-pyrazol-5 -yl]piperidine
82 Trans-4-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1- 639, 641
3-fluorophenyl)piperazinone
83 Cis-1-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
N-(1- 625, 627
thyl-3-methyl-1 H-pyrazol-5-yl)-3-azetidinamine
84 Trans-l-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-N- 625, 627
1-ethyl-3-methyl-1 H-pyrazol-5-yl)-3-azetidinamine
85 Trans-l-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 666, 668
[ 1-(1,1-dimethylethyl)-3-methyl-lH-pyrazol-5-yl]piperidine
86 Cis-4-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
1-(3- 639,641
uorophenyl)piperazinone
87 Cis-4-{1-[4-(4-Bromophenyl)-4-(4-cyanobenzenesulfonyl)cyclohexyl]piperidin-
4- 635, 637
1} -2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
88 Trans-4-{1-[4-(4-Bromophenyl)-4-(4-
cyanobenzenesulfonyl)cyclohexyl]piperidin-4- 635, 637
1} -2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
89 Trans-l-[4-(4-Bromophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-4- 664, 666
2-ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine
0 Trans-l-[4-(4-Chloro-3-fluorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)
612
yclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
1 Cis-1-[4-(4-Chloro-3-fluorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)
612
yclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
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x. ame ES MS
+1
2 Cis-4-[1-{4-(4-Chloro-3-fluorophenyl)-4-[4-(trifluoromethyl)benzenesulfonyl]
652, 654
yclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-
a]pyridine
3 Trans-4-[1-{4-(4-Chloro-3-fluorophenyl)-4-[4-
(trifluoromethyl)benzenesulfonyl] 652, 654
yclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-
a]pyridine
4 Cis-6-[4-(4-Chlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
603
5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,6-naphthyridine
Trans-6-[4-(4-Chlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
603
5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,6-naphthyridine
6 Trans-4-[4-(4-Chlorophenyl)-4-(4-
(trifluoromethyl)benzenesulfonyl)cyclohexyl]-1- 578
2-pyridinyl)piperazinone
7 Cis-4-[4-(4-Chlorophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl)cyclohexyl]-
1-(2- 578
yridinyl)piperazinone
8 Trans-l-{4-(4-Chlorophenyl)-4-[4-(1-hydroxy-l-methylethyl)benzenesulfonyl]
584
yclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
9 Trans-Methyl4-({1-(4-Chlorophenyl)-4-[4-(2-ethyl-5-methyl-2H-pyrazol-3- 584
1)piperidinyl]cyclohexyl} sulfonyl)benzoate-
100 1,1-Dimethylethyl [ 1-(Trans-4-(4-chlorophenyl)-4- { [4- 601
trifluoromethyl)phenyl] sulfonyl} cyclohexyl)-4-piperidinyl] carbamate
101 Trans-l-{4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl}- 639, 641
-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
102 Cis-1-{4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl}-4- 639, 641
2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
103 Trans-4-[1-{4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]
679,681
yclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-
a]pyridine
104 Cis-4-[1-{4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl} 679, 681
iperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
105 Cis-4-[1-{4-(4-Chlorophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl} 635
iperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
106 Trans-4-[1-{4-(4-Chlorophenyl)-4-[2-(trifluoromethyl)pyrid-5-ylsulfonyl]
635
yclohexyl}piperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-
a]pyridine
107 Cis-1-{4-(4-Chlorophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl}-4- 595
2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
108 Trans-l-{4-(4-Chlorophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl}- 595
-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
109 Cis-1-{4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl}-4- 665, 667
2-ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine
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x. ame ES MS
+1
110 Trans-l-{4-(4-Bromophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl}- 665, 667
-(2-ethy1-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine
111 Trans-4-[1-{4-(4-Fluorophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl} 619
iperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
112 Cis-4-[1-{4-(4-Fluorophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl} 619
iperidin-4-yl]-2-ethyl-4,5,6,7-tetrahydro-3-pyrazolo[ 1,5-a]pyridine
113 Trans-l-{4-(4-Fluorophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl}-4- 579
2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
114 Trans-l-{4-(4-Fluorophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl}-4- 605
2-ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine
115 Cis-1-{4-(4-Fluorophenyl)-4-[2-(trifluoromethyl)pyrid-5-
ylsulfonyl]cyclohexyl}-4- 605
2-ethyl-2,4,5,6-tetrahydro-3-cyclopentapyrazolyl)piperidine
116 Cis-1-[4-(4-Bromophenylmethyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-(2-
618, 620
thyl-5-methyl-2H-pyrazol-3-yl)piperidine
117 Trans-l-[4-(4-Bromophenylmethyl)-4-(4-chlorobenzenesulfonyl)cyclohexyl]-4-
(2- 618, 620
thyl-5-methyl-2H-pyrazol-3-yl)piperidine
118 Cis-1-{4-(4-Bromophenylmethyl)-4-[4-(trifluoromethyl)benzenesulfonyl] 652,
654
yclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
119 Trans-l-{4-(4-Bromophenylmethyl)-4-[4-(trifluoromethyl)benzenesulfonyl]
652, 654
yclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
120 Cis & Trans-l-[4-Phenyl-4-(phenylsulfonylmethyl)cyclohexyl]-4-(2-ethyl-5-
methyl- 506
H-pyrazol-3-yl)piperidine
121 RS)-Trans-l-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfinyl) 622,
624
yclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
Example 122: Trans-1-{4-Phenylmethyl-4-[4-(trifluoromethyl)benzenesulfonyl]
cyclohexyll-4-(2-
ethyl-5-methyl-2H-pyrazol-3-yl)piperidine
Pd on C (30 mg) was added to a solution of trans-1-{4-(4-bromophenylmethyl)-4-
[4-
(trifluoromethyl)benzenesulfonyl]cyclohexyl]-4-(2-ethyl-5-methyl-2H-pyrazol-3-
yl)piperidine
(Example 119, 57 mg, 87 mol) in EtOAc (5 mL) and the mixture was vigorously
stirred under a H2
atmosphere overnight. The mixture was filtered through HyfloTM and the solvent
was evaporated under
reduced pressure. The residue was purified by preparative thin layer
chromatography on silica gel,
eluting with EtOAc/MeOH/NH3(Aq.) (98:2:0.2) to give the title compound (10 mg,
20%).
'H NMR (500MHz, CD3OD): 6 7.99 (d, J 8.1, 2H); 7.89 (d, J 8.1, 2H); 7.36 (d, J
8.2, 2H); 7.24 (m, 3H);
5.83 (s, 1H); 4.02 (q, J7.2, 2H); 3.26 (s, 2H); 3.01 (d, J 11.3, 2H); 2.63 (m,
1H); 2.35 (m, 3H); 2.16 (s,
3H); 2.10 (d, J 13.1, 2H); 1.90 (m, 6H); 1.63 (m, 4H); 1.33 (t, J7.2, 3H).
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Example 123: Trans-4-(4-Bromophenyl)-4-{[4-
(trifluoromethyl)phenyl]sulfonyl}cyclohexanamine
Ceric ammonium nitrate (232 mg, 0.423 mmol) was added to a stirred suspension
of N-[trans-4-(4-
bromophenyl)-4- { [4-(trifluoromethyl)phenyl] sulfonyl} cyclohexyl] -4-
(methoxy)benzenemethanamine
(Example 69, 99 mg, 0.17 mmol) in MeCN (1.0 ml) and water (0.35 ml) at RT. The
mixture was stirred
overnight and a further portion of ceric ammonium nitrate (29 mg, 0.053 mmol)
was added. After stirring
at RT for a further 1 h, the mixture was diluted with EtOAc and water. The
aqueous layer was separated
and re-extracted with EtOAc. The combined organic layers were dried (MgSO4)
and the solvent was
evaporated under reduced pressure. The residue was purified by preparative
thin layer chromatography,
eluting with 10% MeOH in CH2C12, to give the title compound (48 mg, 62%).
'H NMR (400MHz, CDC13 S 1.02 (2H, q, J 12.4), 1.88 (2H, d, J 12.3), 2.32 (2H,
m), 2.53 (2H, d, J 13),
2.84 (1H, m), 7.09 (2H, d, J 8.2), 7.43 (4H, d, J 8.1), 7.63 (2H, d, J 8.0).
The following compound was prepared according to the method of Example 1
substituting trans-4-(4-
bromophenyl)-4-{[4-(trifluoromethyl)phenyl]sulfonyl}cyclohexanamine (Example
123) for 4-(4-
bromophenyl)-4-[(4-chlorophenyl)sulfonyl]cyclohexanone and 1-(1-ethyl-3-methyl-
lH-pyrazol-5-yl)-4-
piperidinone (Description 93) for 4-(2-ethyl-5-methyl-2H-pyrazol-3-
yl)piperidine.
x. ame ES MS (M+1)
124 Trans-N-[4-(4-Bromophenyl)-4-(4-(trifluoromethyl)benzenesulfonyl) 653, 655
yclohexyl] -1-(2-ethyl-5-methyl-2H-pyrazol-3-yl)piperidine-4-amine
Example 125: 1-(Trans-4-(4-Chlorophenyl)-4-{[4-
(trifluoromethyl)phenyl]sulfonyl}cyclohexyl)piperidin-4-amine Hydrochloride
Hydrogen chloride in dioxane (4N, 10 mL) was added to a stirred solution of 1,
1 -dimethylethyl [1-(trans-
4-(4-chlorophenyl)-4- { [4-(trifluoromethyl)phenyl] sulfonyl } cyclohexyl)-4-
piperidinyl] carbamate
(Example 100, 2.045 g, 3.4 mmol) in CH2C12 (10 mL) and the mixture was stirred
at RT overnight. The
solvent was evaporated under reduced pressure to give the title compound (1.73
g, 95%).
'H NMR (360MHz, CD3OD): 6 7.78 (t, 2H), 7.55 (d, 2H), 7.35 (q, 4H), 3.53 (d,
3H), 3.06 (t, 2H), 2.85 (d,
2H), 2.38 (t, 3H), 2.21 (d, 4H), 1.93 (d, 2H), 1.41 (d, 2H).
Example 126: N-(1,1-Dimethylethyl)-N'-[1-(Trans-4-(4-chlorophenyl)-4-{[4-
(trifluoromethyl)p henyl] sulfonyl} cyclohexyl)piperidin-4-yl] urea
t-Butyl isocyanate (0.0255 mL, 0.224 mmol) was added to a stirred solution of
1-(trans-4-(4-
chlorophenyl)-4- {[4-(trifluoromethyl)phenyl] sulfonyl} cyclohexyl) piperidin-
4-amine hydrochloride
(Example 125, 0.1 g, 0.186 mmol) and triethylamine (0.077 mL, 0.558 mmol) in
CH2C12 (5 mL) and the
mixture was stirred at RT for 2 h. Water was added and the mixture was
extracted with CH2C12. The
combined organic fractions were dried (MgSO4) and the solvent was evaporated
under reduced pressure.
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The residue was purified by preparative thin layer chromatography on silica
gel, eluting with 5% MeOH
in CH2C12, to give the title compound (40 mg, 36%).
'H NMR (500MHz, CD3OD): 6 7.77 (d, 2H), 7.53 (d, 2H), 7.31 (q, 4H), 3.37 (t,
1H), 2.77 (d, 2H), 2.71
(d, 2H), 2.52 (s, 1H), 2.25 (q, 4H), 1.99 (d, 2H), 1.79 (d, 2H), 1.29 (t, 2H),
1.26 (s, 9H), 1.21-1.13 (m,
2H).
