Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL COMPOUNDS
The present invention relates to novel compounds, a process for their
preparation,
pharmaceutical compositions containing them, a process for preparing the
pharmaceutical
compositions, and their use in therapy.
The P2X~ receptor (previously known as P2Z receptor), which is a ligand-gated
ion
channel, is present on a variety of cell types, largely those known to be
involved in the
inflanom~atory/immune process, specifically, macrophages, mast cells and
lymphocytes
(T and B). Activation of the P2X~ receptor by extracellular nucleotides, in
particular
io adenosine triphosphate, leads to the release of interleukin-1~ (IL-1(3) and
giant cell
formation (macrophages/microglial cells), degranulation (mast cells) and L
selectin
shedding (lymphocytes). P2X~ receptors are also located on antigen-presenting
cells
{APC), keratinocytes, salivary acinar cells {parotid cells) and hepatocytes.
It would be desirable to make compounds effective as P2X~ receptor antagonists
for
is use in the treatment of inflammatory, immune or cardiovascular diseases, in
the aetiologies
of which the PZX~ receptor may play a role.
In accordance with the present invention, there is therefore provided a
compound of
general formula
R
2o wherein X represents an oxygen or sulphur atom or a group NH, CH2, CH2CH2
or OCH2;
Y represents a group CHZ or C=O;
Rl represents a pyridyl (especially 3-pyridyl or 4-pyridyl) orpyrimidinyl
group;
R2 represents a phenyl, pyridyl or pyrimidinyl group, each of which may be
optionally
substituted by one or more subsdtuents independently selected from a halogen
atom or an
a amino, cyano, hydroxyl, vitro, C~-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy,
C~-C6-alkyltttio, (di)C1-C6-alkylamino, C1-C6-alkyicarbonyl, Cl-C6-
alkoxycarbonyl,
C1-C6-alkylsulphinyl, Cl-C6-alkylsulphonyl, -NR3SOZR4 or -S02NRSR6 group, or a
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2
group -Z-(CH~p-Z-(CH~q-H wherein each Z independently represents a nitrogen or
oxygen atom, p is an integer from 2 to 5 and q is 0 or an integer from 1 to 5;
R3 and R4 each independently represent a hydrogen atom or a Cl-C6-alkyl group;
and
RS and R6 each independently represent a hydrogen atom or a Cl-C6-alkyl group,
or
s together with the nitrogen atom to which they are attached form a
pyrrolidinyl or
piperidinyl group; or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, unless otherwise indicated, an
alkyl
substituent or alkyl moiety in a substituent group may be linear or branched
and also the
alkyl moieties in a dialkylamino subsdtuent group may be the same or
different.
io Furthermore, when X represents a group OCH2, the oxygen atom is positioned
adjacent the
carbonyl group in the ring.
The group R2 preferably represents a phenyl, pyridyl or pyrimidinyl group,
each of
which may be optionally substituted by one, two, three or four substituents
independently
selected from a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or
an amino,
is cyano, hydroxyl, vitro, C1-C6-alkyl (e.g. methyl, ethyl, propyl,
butyl,pentyl or hexyl),
halo-C1-C6-alkyl {e.g. trifluoromethyl), Cl-C6-alkoxy (e.g. methoxy, ethoxy,
propoxy,
butoxy, pentoxy or hexoxy), C1-C6-alkylthio (e.g. methyl-, ethyl-, propyl-,
butyl-,pentyl-
or hexylthio)" (di)C1-C6-alkylamino (e.g. methylamino, dimethylamino,
ethylamino or
diethylamino), C1-C6-alkylcarbonyl (e.g. methyl-, ethyl-, propyl-, butyl-
,pentyl- or
2o hexylcarbonyl), Cl-C6-alkoxycarbonyl (e.g. methoxy-, ethoxy-,propoxy-,
butoxy-,
pentoxy- or hexoxycarbonyl); Cl-C6-alkylsulphinyl (e.g. methyl-, ethyl-,
propyl-, butyl-,
pentyl- or hexylsulphinyl), Cl-C6-alkylsulphonyl (e.g. methyl-, ethyl-, propyl-
, butyl-,
pentyl- or hexylsulphonyl), -NR3S02R4 or -S02NRSR6 group, or a group
-Z-(CH2)p-Z-(CHZ)q-H wherein each Z independently represents a nitrogen or
oxygen
as atom, p is an integer from 2 to 5 and q is 0 or an integer from 1 to 5.
More preferably RZ represents a phenyl, pyridyl or pyrimidinyl group, each of
which
may be optionally substituted by one, two or three substituents independently
selected from
a halogen atom or an amino, cyano, hydroxyl, vitro, C1-C4-alkyl, haio-C1-C4-
alkyl,
Ct-C4-alkoxy, C1-Cq,-alkylthio, (di)C1-C4-alkylamino, C1-C4-alkylcarbonyl,
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WO 99/29686 PCT/SE98/02190
3
C1-C4-alkoxycarbonyl, Cl-C4-alkylsulphinyl, Cl-C4-alkylsulphonyl, -NR3S02R4 or
-SOzNR5R6 group.
Even more preferably, R2 represents a phenyl, pyridyl or pyrimidinyl group,
each of
which may be optionally substituted by one or two substituents independently
selected
from a halogen atom or an amino, cyano, vitro, C1-C4-alkyl, halo-Cl-C4-alkyl,
C1-C4-alkoxy or -SOzNR5R6 group.
Most preferably, R2 represents a phenyl or pyridyl group optionally
substituted by
one or two substituents independently selected from a fluorine or chlorine
atom or an
amino, cyano, vitro, trifluoromethyl, methoxy or -S02NRSR6 group.
io Preferably, R3 and R4 each independently represent a hydrogen atom or a
C1-C4-alkyl group (e.g. methyl or ethyl group).
Preferably, RS and R6 each independently represent a hydrogen atom or a
C1-C4-alkyl group (e.g. methyl or ethyl group), or together with the nitrogen
atom to which
they are attached form a pyrrolidinyl or piperidinyl group, especially a
pyrrolidinyl group.
is Preferred compounds of the invention include:
(+I-)-(N [1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione,
{+/-) N [1-{3'-Methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-
dione,
{+/-)-N [1-{Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-dione,
{+/-)-N [1-(3'-Chlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-
dione,
20 (+/-)-N [1-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-
2,5-dione,
(+/-)-N [1-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidine-2,5-
dione,
(+I-~N [1-(3'-Methoxybiphenyl-4-yloxy~4-(4-pyridyl)-2-butyl]-thiazolidine-2,4-
dione,
(2R)-N [1-(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidine-2,4-
dione,
(2R)-N [1-(3'-Nitrobiphenyl-4-yloxy)-4.-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-
dione,
as (2R)-N [1-(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-
dione,
(+/-)-N [1-{3'-Nitmbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-
dione,
{+I-) N [1-(3'-Nitrobiphenyl-4-yioxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-
dione,
{+/-) N [1-(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-
dione,
(+/-)-N [1-(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-
dione,
30 (+/-)-N [1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butylj-oxazolidine-2-one,
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WO 99/29686 PCT/SE98/02190
(2R)-N [1-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-
thiazolidin-2,4-
dione,
(2R)-N [1-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl}-2-butyl]-
pyrrolidin-2,5-
dione,
s (2R) N [1-(3',5'-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-
2,4-dione,
(+/-)-N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one,
(2R)-N [1-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-thiazolidin-2,4-
dione,
(+/-) N [1-(3'-(Trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-
thiazolidin-2,4-
dione,
io (+/-)-N [1-(2'-Methoxybiphenyl-4-yloxy)-4-{4-pyridyl)-2-butyl]-thiazolidin-
2,4-dione,
(+/-)-N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2,6-
dione,
{+I-)-N [1-(3'-Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-
dione,
(+/-) N [1-(3'-Nitrobiphenyl-4-yloxy)-4-{4-pyridyl}-2-butyl]-[1,3]-oxazinan-2-
one,
(2S~ N [1-(3'-Cyanobiphenyl-4-yloxy)-4-{3-pyridyl)-2-butyl]-thiazolidine-2,4-
dione,
is (2.5~ N [1-(3'-Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-
2,4-dione,
j2,~=N=[1-(3'=Methanesulfonamidobiphenyl-4-yloxy)-4-{3-pyridylr2-
butyl]thiazolidine-
2,4-dione,
(2S,3S)-N [1-(3'-(Pyrrolidine-1-sulfonyl)biphenyl-4-yloxy)-4-(3-pyridyl)-3-
pentyl]-
pyrrolidine-2,5-dione,
zo {2S,35~-N [1-(3'-Cyano-4.'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-3-pentyl]-
pyrrolidine-2,5-
dione,
(2S~-N [1-{3'-Cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-
thiazolidine-2,4-
dione,
(+/-)-N [1-(4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy)-4-{4-pyridyl)-2-butyl]-
oxazolidin-
Zs 2-one,
(+/-)-N [1-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-
oxazolidin-2-one,
(+/-)-N [1-(Biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one,
(+/-)-N [1-{4'-Chlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-
one,
(+/-)-N [1-(4'-Methylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-
one,
30 (+/-)-N [ 1-(4'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-
2-one,
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WO 99/29686 PCTlSE98/02190
(+/-)-N [1-{3',4'-Dichlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-
2-one,
(+/-)-N [1-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-(4-pyridyl)-2-butyl]-
piperidin-2,6-
dione,
(+/-)-N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-inudazolidine-2,4-
dione,
(+/-)-N [ 1-{3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2-one,
and
(+/-) N [1-(3'-Nitrobiphenyl-4-yioxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2-one.
The present invention further provides a process for the preparation of a
compound
of formula (n as defined above which comprises:
io (a) reacting a compound of general formula
L
wherein L represents a leaving group (e.g. a hydroxyl group) and Rl and R2 are
as
hereinbefore defined, with a compound of general formula
X
D~N~Y
{BI)
is wherein X and Y are as hereinbefore defined except that when X is an oxygen
atom or
OCH2 group, then Y is not a CH2 group; or
(b) when X is an oxygen atom and Y is a CH2 group, reacting a compound of
general
formula
NH2
Zo wherein Rl and R2 are as hereinbefore defined, with 2-chloroethyl
chloroformate; or
(c) when X is an OCH2 group and Y is a CHZ group, reacting a compound of
formula
(IV) as defined in (b) above, with 3-chloropropanol in the presence of
phosgene; or
(d) when X is a CHZ group and Y is a CH2 group, reacting a compound of formula
(IV)
as.defined in (b) above, with 4-chlorobutyryl chloride; or
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(e) when X is a CH2CH2 group and Y is a CHZ gmup, reacting a compound of
formula
(IV) as defined in (b) above, with 5-valerylchloride; or
(~ when X is an oxygen atom or OCH2 group, reacting a compound of general
formula
O NAY
O ~ ~ Br
wherein X represents an oxygen atom or OCH2 group and Y and RI are as
hereinbefore
defined, with a compound of general formula (VI], RZ-B(OH)2, wherein R2 is as
hereinbefore defined; or
(g) when X is an oxygen atom or OCH2 group, reacting a compound of general
formula
O NAY
O ~ ~ B(OH)2
(
to wherein X represents an oxygen atom or OCHZ group and Y and R' are as
hereinbefore
defined, with a compound of general formula (VIA, Ri-Br, wherein R2 is as
hereinbefore
defined;
and optionally after (a), (b), (c), (d), (e), (f) or (g) converting the
compound of formula (n
to a further compound of formula (17 and/or forming a pharmaceutically
acceptable salt or
is solvate of the compound of formula (I}.
The processes (a), (b), (c), (d), (e), (f) and (g) may conveniently be carried
out in a
solvent (e.g. dichloromethane, chloroform, acetonitrile, dioxan or
tetrahydrofuran), at a
temperature in the range from 0 to I00 °C, preferably in the range from
10 to 80 °C, and
especially at ambient temperature (20 °C).
ao The compounds of formula (In are known from WO 97/20815 and WO 98/42670 or
may be prepared by processes analogous to those described in W09'7/20815 and
WO 98/42670.
The compounds of formula (Ilk, (Y>7 and (VIR) are known or commercially
available
compounds, or may be prepared by processes known in the art.
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The compounds of formula {IV) may be prepared by methods known in the art
starting from the compounds of formula (II).
The compounds of formula (V) and ('VII) may be prepared by processes analogous
to
(a), (b) or (c) above using the corresponding bromo- or boron-containing
compound of
formula (II) or (IV).
It will be appreciated by those skilled in the art that in the processes of
the present
invention certain functional groups such as hydroxyl or amino groups in the
intermediate
compounds may need to be protected by protecting groups. Thus, the final stage
in the
preparation of the compounds of formula (n may involve the removal of one or
more
io protecting groups.
The protection and deprotection of functional groups is described in
'Protective
Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press ( 1973)
and
'Protective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M.
Wuts,
Wiley-Interscience ( 199 i ).
is The compounds of formula (1) can be converted into further compounds of
formula
(n using standard procedures. For example, compounds of formula (17 where R2
is a
nitrophenyl group can be converted to compounds of formula (n where R2 is an
aminophenyl group by reduction using iron powder and ammonium chloride in
ethanol or
an ethanol/water mixture under reflux conditions.
2o The compounds of formula (I) above may be converted to a pharmaceutically-
acceptable salt or solvate thereof, preferably an acid addition salt such as a
hydrochloride,
hydrobromide, phosphate, acetate, fumarate, maleate, tarrrate, citrate,
oxalate,
methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a
sodium or
potassium salt.
zs Certain compounds of formula (I) are capable of existing in stereoisomeric
forms. It
will be understood that the invention encompasses all geometric and optical
isomers of the
compounds of formula (1) and mixtures thereof including racemates. Tautomers
and
mixtures thereof also form an aspect of the present invention.
The compounds of the present invention are advantageous in that they possess
so pharmacological activity. They are therefore indicated as pharmaceuticals
for use in the
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treatment or prevention of rheumatoid arthritis, osteoarthritis, psoriasis,
allergic dermatitis,
asthma, hyperresponsiveness of the airway, septic shock, glomerulonephritis,
irritable
bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth
and metastases of
malignant cells, myocardial ischaemia, cardiac reperfusion damage, cerebral
ischaemia,
s stroke, myoblastic leukaemia, diabetes, Alzheimer's disease, osteoporosis,
burn injury,
stroke, varicose veins and meningitis.
Accordingly, the present invention provides a compound of formula (n, or a
pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined
for use in
therapy.
io In another aspect, the invention provides the use of a compound of formula
(n, or a
pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined
in the
manufacture of a medicament for use in therapy.
The invention further provides a method of effecting immunosuppression (e.g.
in the
treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or
psoriasis)
a which comprises administering a therapeutically effective amount of a
compound of
formula (1), or a pharmaceutically-acceptable salt or solvate thereof, as
hereinbefore
defined to a patient.
For the above-mentioned therapeutic uses the dosage administered will, of
course,
vary with the compound employed, the mode of administration, the treatment
desired and
Zo the disorder indicated.
The compounds of formula (I) and pharmaceutically-acceptable salts and
solvates
thereof may be used on their own but will generally be administered in the
form of a
pharmaceutical composition in which the formula (l~ compound/salt/solvate
(active
ingredient) is in association with a pharmaceutically-acceptable adjuvant,
diluent or carrier.
a Depending on the mode of administration, the pharmaceutical composition will
preferably
comprise from 0.05 to 99 °kw (per cent by weight), more preferably from
0.10 to 70 %w,
of active ingredient, and, from 1 to 99.95 %w, more preferably from 30 to
99.90 %w, of a
pharmaceutically-acceptable adjuvant, diluent or carrier, all percentages by
weight being
based on total composition.
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Thus, the present invention also provides a pharmaceutical composition
comprising a
compound of formula (>], or a pharmaceutically-acceptable salt or solvate
thereof, as
hereinbefore defined in association with a pharmaceutically-acceptable
adjuvant, diluent or
carrier.
The invention further provides a process for the preparation of a
pharmaceutical
composition of the invention which comprises mixing a compound of formula (I),
or a
pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined
with a
p~h~rmaceutically-acceptable adjuvant, diluent or carrier.
The pharmaceutical composition of the invention may be administered topically
io (e.g. to the lung and/or airways or to the skin) in the form of solutions,
suspensions,
heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g.
by oral
administration in the form of tablets, capsules, syrups, powders or granules,
or by
parenteral administration in the form of solutions or suspensions, or by
subcutaneous
administration or by rectal administration in the form of suppositories or
transdermally.
is The present invention will be further understood by reference to the
following
illustrative examples in which the terms MS, NMR and DMSO denote respectively
mass
spectrometry, nuclear magnetic resonance and dimethylsulphoxide.
Example 1
zo (+/-)-(N [1-{Biphenyl-4-yloxy)-4-{3-pyridyl)-2-butyl]-pyrrolidine-2,5-dione
To a solution of triphenylphosphine (0.16 g) in tetrahydrofuran (2 ml) was
added
diethyl azodicarboxylate (0.1 ml); a slight exotherm was noted. The resulting
orange
solution was stirred for 5 minutes before addition of succinimide (0.062 g)
and stirring was
is continued for a further S minutes before addition of (t)-1-(biphenyl-4-
yloxy)-4-(3-pyridyl)-
2-butanol (0.10 g) prepared as described in Example 25 of WO 97/20815. After
stirring for
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1.5 hours, the reaction mixture was concentrated under reduced pressure and
the residue
obtained purified by silica gel chromatography, eluting with ethyl acetate to
deliver the title
compound as a colourless solid (0.09 g).
s Melting point: 150-151 °C
MS (APCI +ve) 401 (M+H)+
1H NMR (DMSO-d6) S 8.42-8.40 (2H, m), 7.64 -7.55 (SH, m), 7.43 (2H, t),
733-7.28 (2H, m), 6.97 (2H, d), 4.45-4.33 (2H, m), 4.27-4.23 ( 1H, m), 2.62-
2.57 (6H, m),
2.32-2.24 (1H, m), 2.11-2.02 (1H, m)
~o
Example 2
(+/-)-N [1-(3'-Methoxybiphenyl-4..yloxy)-4-(3-pyridyl)-2-butylj-pyrrolidine-
2,5-dione
Prepared according to the method of Example 1 above with succinimide (0.30 g)
and
is (t)-1-(3'-methoxybiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.25g) prepared
as described
in Example 42 of WO 97/20815 to give the title compound as a white solid (0.17
g).
Melting point: 92-94 °C
MS (EI) 430 (M+H)+
Zo 1H NMR (DMSO-d6) 8 8.42-8.40 (2H, m), 7.61 (1H, m), 7.59 (2H, t), 7.33-7.28
(2H, m),
7.16 ( 1 H, d), 7.12 ( 1 H, t), 6.97 (2H, d), 6.88 ( 1 H, dd), 4.44-4.33 (2H,
m),
4.26-4.24 (1H, m), 3.81 (3H, s), 2.62-2.57 (6H, m), 2.32-2.24 (1H, m), 2.11-
2.02 (1H, m)
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Example 3
(+/-)-N [l-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl)-thiszolidine-2,4-dione
O
N O
N' O
Prepared according to the method of Example 1 above with (t~l-(biphenyl-4-
yloxy)-
4-(3-pyridyl)-2-butanol (0.32 g) prepared as described in Example 25 of WO
97/20815 and
2,4-thiazolinedione (0.23 g) to give the title compound as a white solid (0.08
g).
Melting point: 125-126 °C
MS (FAB) 419 (M+H)+
eo 1H NMR (DMSO-d6) S 8.42-8.40 (2H, m), 7.55 -7.49 (SH, m), 7.41 (2H, t),
7.33-7.28 (2H, m), 6.97 (2H, d), 4.76 ( 1 H, m), 4.52 ( 1 H, t), 4.16 ( 1 H,
dd), 3.83 (2H, s),
2.73-2.60 (2H, m), 2.55-2.49 ( 1 H, m), 2. I 5-2.06 ( 1 H, m)
Example 4
is (+/-)-N [1-(3'-Chlorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-
2,5-dione
Prepared according to the method of Example 1 above with (t)-1-(3'-
chlorobiphenyl-
4-yloxy)-4-(3-pyridyl)-2-butanol (0.42 g) prepared as described in Example 33
of
WO 97/20815 and succinimide (0.24 g) to give the title compound as a white
solid
20 (0.21 g).
Melting point: I54 °C
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12
MS (APCI +ve) 436/438 (M+H)+
1H NMR (DMSO-d6) 8 8.47-8.45 (2H, m), 7.53 -7.23 (8H, m), 6.92 (2H, d), 4.63
(1H, m),
4.50 ( 1 H, t), 4.16 ( 1 H, dd), 2.73 { 1 H, m), 2.62-2.57 (6H, m), 2.11-2.02
( 1 H, m)
s Example 5
(+/-)-N [1-(3'-Fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidine-2,5-
dione
~'~~O
N
N.
~F
Prepared according to the method of Example 1 above with (t)-1-(3'-
fluorobiphenyl-
4-yloxy)-4-(3-pyridyl)-2-butanol (0.05 g) prepared as described in Example 43
of
io WO 97/20815 and succinimide (0.03 g) to give the title compound as a white
solid
(0.06 g).
Melting point: 148 °C
MS (APCI +ve) 419 (M+H)+
Is 1H NMR (DMSO-d6) S 8.42-8.40 (2H, m), 7.54-7.45 (3H, m), 7.38-7.20 (4H, m),
7.01 ( 1 H, m), 6.91 (2H, d), 4.62 ( 1 H, m), 4.50 ( 1 H, t), 4.16 ( 1 H, dd),
2.75-2.47 (2H, m),
2.56 (4H, s), 2.53 (1H, m), 2.11-2.02 {1H, m)
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Example 6
(+/-)-N [1-{3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidine-2,5-
dione
a) (+/-)-4-Bromophenyloxymethyloxirane
s To a solution of 4-bromophenol ( 17 g) and epichlorohydrin (25 ml) in
acetonitrile
(50 ml) was added caesium carbonate (24 g) and the resulting suspension was
heated at
reflex for 4 hours. The reaction mixture was then concentrated under reduced
pressure and
the residue obtained was partitioned between ether and water. An organic phase
was
separated, washed with brine, dried over magnesium sulphate (MgS04) and
concentrated
io under reduced pressure to yield another residue. Distillation of the
residue under vacuum
gave the sub-title compound as a colourless oil { 13 g).
Boiling point: 140 °C (oil pump)
MS (gcms) 228/230 M+
is
b) (+/-)-1-(4-Bromophenyloxy)-4-(4-pyridyl)-2-butanol
To a solution of 4-methylpyridine ( 1.2 g) in tetrahydrofuran ( 10 ml) cooled
to -78 °C
was added a hexanes solution of n-butyl lithium (5.8 ml of a 2.SM solution)
and the
reaction mixture was warmed to 0 °C, whereupon it was added slowly via
a cannula to a
zo solution of 4-bromophenyloxymethyloxirane (3.0 g) prepared as described in
step a) above
in tetrahydrofuran (5 ml) cooled to 0 °C. After stirring for 1.5 hours
at ambient
temperature; the reaction mixture was firstly quenched by addition of aqueous
ammonium
chloride solution and secondly extracted with ethyl acetate. An organic phase
was then
separated, washed with brine, dried over magnesium sulphate (MgS04) and
concentrated
2s under reduced pressure to yield a residue. Purification of the residue by
silica gel
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chromatography (eluting with 5% methanol in dichloromethane) gave the sub-
title
compound as a yellow solid ( 1.8 g).
MS (APCI +ve) 322/324 (M+H)+
c) (+/-)-1-(3'-Methoxybip6enyl-4-yloxy)-4-(4-pyridyl)-2-bntanol
A mixture of 1-(4-bromophenyloxy)-4-(4-pyridyl)-2-butanol (1.8g) prepared
as described in step b) above, 3-methoxyphenylboronic acid (0.90 g), tetrakis-
(triphenylphosphine)palladium(0) (0.16 g), aqueous sodium carbonate (3.5 ml of
a 2M
io solution), ethanol (2 ml) and toluene (7.5 ml) was heated to reflux
temperature for 1.5
hours. The reaction mixture was partitioned between ethyl acetate and water
and an
organic phase was separated, washed with brine, dried over magnesium sulphate
(MgS04)
and then concentrated under reduced pressure to yield a residue. Purification
of the residue
by silica gel chromatography (eluting with 5% methanol in dichloromethane)
gave the sub-
is title compound as a white solid (1.0 g).
Melting point: 74-76 °C
MS (APCI +ve) 350 (M+H)+
zo d) (+/-)-N [1-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-bntyl]-
pyrrolidine-2,5-dioae
Prepared according to the method of Example 1 with (+/-)-1-{3'-methoxybiphenyl-
4-
yloxyr4-(4-pyridyl)-2-butanol (0.42 g) prepared as described in step c) above
and
succinimide (0.30 g) to give the title compound as a white solid (0.15 g).
a
Melting point: 111-113 °C
MS (En 431 (M+H)+
1H NMR (DMSO-d6) S 8.42 (2H, s), 7.48 (2H, d), 7.34 (1H, t), 7.15 (3H, m),
7.06 ( 1 H, m), 6.88 (2H, d), 6.84 ( 1H, m), 4.61 ( 1 H, m), 4.47 ( 1 H, t),
4.16 ( 1 H, dd),
so 3.83 (3H, s), 2.78 ( 1 H, m), 2.61-2.50 (2H, m), 2.46 (4H, s), 2.11-2.02 (
1 H, m)
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Example 7
(+/-)-N [1-(3'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidine-
2,4-dione
o~~ v
N O O
O
V
N~
Prepared according to the method of Example 1 above with (+/-)-1-(3'-
methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (O.IOg) prepared as described
in
Example 6c) above and 2,4-thiazolinedione (0.067 g) to give the title compound
as a
colourless solid (0.07 g).
Melting point: 111-112 °C
io MS (En 449 (M+H)+
1 H NMR (DMSO-d6) 8 8.46 (2H, d), 7.58 (2H, d), 7.34 ( 1 H, t), 7.23 (2H, d),
7.17 (2H, d),
7.12 ( 1 H, d), 6.88 (2H, d), 4.53 ( 1 H, m), 4.44 ( 1 H, t), 4.28 ( 1 H, dd),
4.18 (2H, s),
3.81 (3H, s), 2.62 (2H, t), 2.37-2.24 (1H, m), 2.16-2.06 (1H, m)
is Example 8
{2R)-N [1-{3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-batyl)-thiazotidine-2,4-
dione
Prepared according to the method of Example 1 above with (2S~-1-(3'-
cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.20g) prepared as described
in Example
38 of WO 97/20815 and 2,4-thiazolinedione (0.13 g) to give the title compound
as a white
solid (0.14 g).
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Melting point: 110-112 °C
MS (Eli 444 (M+H)+
1H NMR (DMSO-d6) b 8.43 {2H, m), 8.10 (1H, s), 7.97 (1H, d), 7.76 (1H, d),
7.70-7.60 (4H, m), 7.32 ( 1 H, dd), 7.01 (2H, d), 4.56 ( 1 H, m), 4.46 ( 1 H,
t), 4.30 ( 1 H, dd),
4.19 (2H, s), 2.65 (2H, t), 2.30 ( 1 H, m), 2.09 ( 1 H, m)
Example 9
(2R)-N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-?.,5-
dione
O'~~O
- ~ / \ \ /
~o Prepared according to the method of Example 1 above with (2S~-1-(3'-
nitrobiphenyl-
4-yloxy)-4-(3-pyridyl)-2-butanol (O.IOg) prepared as described in Example 41
of
Vu0 97/20815 and succinimide (0.054 g) to give the title compound as a white
solid
(0.03 g).
is Melting point: 115-117 °C
MS (EI] 446 (M+H)+
1H NMR (DMSO-d6) 8 8.40 (3H, m), 8.14 (2H, s), 7.72 (3H, m), 7.63 (1H, d),
7.32 ( 1 H, ddd), 7.03 (2H, d), 4.42 (2H, m), 4.28 ( 1 H, dd), 2.61 (6H, m),
2.28 ( 1 H, m),
2.07 ( 1 H, m)
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Example 10
(2R) N [1-(3'-Cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-pyrrolidin-2,5-
dione
Prepared according to the method of Example 1 above with (2S)-1-(3'-
s cyanobiphenyl-4-yloxy~4-(3-pyridyl)-2-butanol (O.lSg) prepared as described
in Example
38 of WO 97/20815 and succinimide (0.09 g) to give the title compound as a
white solid
(0.09 g).
Melting point: 136-137 °C
to MS (EI) 426 (M+H)+
1 H NMR (DMSO-d6) S 8.41 (2H, m), 8.11 ( 1 H, s}, 7.97 ( 1 H, d}, 7.77 ( 1 H,
d),
7.69-7.60 (4H, m), 7.32 (1H, dd}, 6.99 (2H, d), 4.39 (2H, m), 4.28 (1H, dd),
2.60 (6H, m),
2.27 ( 1 H, m}, 2.02 ( 1H, m)
a Example 11
(+/-} N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-Z-butyl]-t6iszolidin-2,4-
dione
a) (+/-)-1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl}-2-butanol
Prepared according to the method of Example 6c) above using 1-(4-
Zo bromophenyloxy)-4-(4-pyridyl}-2-butanol (3.12 g) as prepared in Example 6b)
and
3-nitrophenylboronic acid (2.59 g}, to give the sub-title compound as an
orange oil
(2.20 g).
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MS (APCI +ve) 365 (M+H)+
b) (+/-)-N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-
2,4-
dione
s Prepared according to the method of Example 1 above with {+/-)-1-(3'-
nitrobiphenyl-
4-yloxy)-4-(4-pyridyl)-2-butanol (0.14 g) prepared as described in step a)
above and
2,4-thiazolinedione (0.09 g) to give the title compound as a pale yellow solid
{0.11 g).
Melting point: 145-150 °C
io MS (En 446 (M+H)+
1H NMR (DMSO-d6) b 8.47 (2H, d), 8.38 (1H, s), 8.17 (1H, d), 8.11 (1H, d),
7.75 -7.70 (3H, m), 7.23 {2H, dd), 7.04 (2H, d), 4.60-4.4.4 {2H, m), 4.31 (1H,
dd),
4.19 (2H, s), 2.65 (2H, t), 2.32 ( 1 H, m), 2.09 ( 1 H, m)
is Example 12
(+!=)-N tl-(3'-Nitrnbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-
dione
Prepared according to the method of Example 1 above with (+/-)-1-(3'-
nitrobiphenyl-
4-yloxy)-4-(4-pyridyl)-2-butanol (0.09 g) prepared as described in Example 11
a) and
Zo succinimide (0.05 g) to give the title compound as a yellow solid (0.03 g).
Melting point: 116-118 °C
MS (En 426 (M+H)+
1 H NMR (DMSO-d6) b 8.4b (2H, m), 8.38 ( 1 H, s), 8.16 ( 1 H, d), 8.11 ( 1 H,
d),
a 7.75-7.70 {3H, m), 7.22 (2H, d), 7.03 (2H, d), 4.76-4.34 (2H, m), 4.28 ( 1
H, dd),
2.65-2.60 (6H, m), 2.29 (1H, m), 2.08 (1H, m)
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Example 13
(+/-)-N [1-(4'-Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-
dione
a) (+/-)-1-(4'Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol
s Prepared according to the method of Example 6c) using 1-(4-bromophenyloxy)-4-
(4-pyridyl)-2-butanol (0.40 g) prepared as described in Example 6b) and
4-fluorophenylboronic acid (0.28 g), to deliver the sub-title compound as a
colourless solid
(0.23 g).
MS (APCI +ve) 338 (M+H)+
to
b) (+/-)-N [1-(4'Fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-pyrrolidin-2,5-
dione
Prepared according to the method of Example 1 above with
(+/-)-1-(4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0.10 g) prepared
in
is step a) and succinimide (0.06 g) to give the title compound as a pale
yellow solid (0.06 g).
Melting point: 113-114 °C
MS (En 419 (M+H)+
1H NMR (DMSO-d6) S 8.46 (2H, d), 7.63 (2H, dd), 7.55 (2H, d), 7.28-7.21 (4H,
m),
zo 6.87 (2H, d), 4.45-4.33 (2H, m), 4.26 ( 1 H, m), 2.59 (6H, m), 2.28 ( 1 H,
m), 2.08 ( 1 H, m)
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Example 14
(+/-)-N [1-(4'-Fluornbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazotidin-2.4-
dione
/ \
Prepared according to the method of Example 1 above with
(+/-)-1-(4'-fluorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0.12g) prepared
as described
in Example 13a) and 2,4-thiazolinedione (0.08 g) to give the title compound as
a pale grey
solid (0.06 g).
Melting point: 88-90 °C
io MS (E17 437 (M+H)+
1H NMR (DMSO-d6) 8 8.46 (2H, d), 7.63 (2H, dd), 7.56 (2H, d), 7.23 {4H, m),
6.97 (2H, d)~ 4.50 (1H, m), 4.44 (1H, t), 4.28 (1H, dd), 4.18 (2H, s), 2.65
(2H, t),
2.30 ( 1 H, m), 2.12 ( 1 H, m)
~s Example 15
{+/-)-N [1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxazoUdine-2-one
a) (+/-)-N [1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-isoindole-1,3-dione
Prepared according to the method described in Example 1 from {t)-1-{biphenyl-4-
2o yloxy)-4-(3-pyridyl)-2-butanol (2.SSg) (prepared as described in Example 25
of
W097/20815), triphenylphosphine (3.62g), diethyl azodicarboxyiate (2.52m1) and
phthalimide (2.36g) in tetrahydrofuran. The residue obtained purified by flash
column
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chromatography, eluting with hexane:ethyl acetate (3:2) gave the sub-title
compound as a
colourless solid (3.9g).
Melting point: 132-133 °C
s MS (EI) 448 (M+H)+
1 H NMR (DMS O-d6) b 8.40 ( 1 H, d), 8.25 ( 1 H, d), 7.85 (4H, m), 7.62-7.51
(SH, m),
7.41 (2H, t), 7.29 ( 1 H, t), 7.23( 1 H, dd); 6.93 (2H, d), 4.52 (2H, m), 4.3
8 ( 1 H, dd),
2.70 (2H, t), 2.40 ( 1 H, m), 2.20 ( 1 H, m).
~o b) (t)-1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butylamine
(+/-)-N [1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl)-isoindole-1,3-drone (3.41
g)
was dissolved in a solution of 30 % methylamine in methanol ( 100 ml). The
solution was
heated to reflux temperature for 3 hours. The solvent was removed under
reduced
pressure, the residue dissolved in ethyl acetate, washed with water, dried
over magnesium
is sulphate, filtered and concentrated. Purification by chromatography over
neutralalumina,
eluting with 10% methanol in dichloromethane gave the sub-tide compound as a
cream
solid ( 1.08g).
Melting point: 52-53 °C
2o MS (En 318 (M+H)+
1H NMR (CDCl3) 8 8.51(1H, d); 8.45(1H, d); 7.56-7.SI(SH, m); 7.42(2H, t);
7.32-7.31 ( 1 H, m); 7.24-7.22( 1 H, m); 6.96(2H, d); 4.00-3.96( 1 H, m);
3.82( 1 H, t);
3.25-3.15(1H, m); 2.89-2.82(1H, m); 2.78-2.72(1H, m); 1.92-1.88(1H, m);
1.80-1.72(3H, m).
23
c) (+/-) N [1-(Biphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-oxa~zolidine-2-one
2-Chloroethyl chloroformate (0.516m1) was added, drop-wise, to a solution of
(t)-1-
(biphenyl-4-yloxy)-4-(3-pyridyl)-2-butylamine (0.318g) in acetonitrile (30m1).
The
solution was stirred for 3 hours at ambient temperature. The solvent was
removed under
so reduced pressure, the residue dissolved in tetrahydrofuran (Sml) and
dimethylfonnamide
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(lml). Sodium hydride (60°k dispersion in mineral oil) (0.12g) was
added to the solution.
Stirring continued for 1 hour at ambient temperature, water (20m1) was added
to the
reaction mixture, the product was extracted into ethyl acetate and organic
extract dried over
magnesium sulphate and concentrated under reduced pressure. Purification by
silica gel
chromatography eluting with 396 methanol in dichloromethane, then
recrystallisation from
diethylether gave the title compound as a white solid (0.093g).
Melting point: 58-59 °C
MS (FAB) 389 (M+H)+
io 1 H NMR (CDC13) 8 8.50-8.49{2H, m); 7.58-7.52(5H, m); 7.42(2H, t); 7.31 ( 1
H, t);
7.29-7.23(1H, m); 6.95(2H, d); 4.43-4.26(3H, m); 4.15(2H, d); 3.73-3.60(2H,
m);
2.74(2H, t); 2.16-2.03(2H, m).
Example 16
a (2R)-N [1-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-
thiazolidin-
~,4-dione
Chiral
a) (2S)-1-(3'-C6loro-4'-fluorobip6enyl-4-yloxy)-4-(3-pyridyl)-2-butanol
Prepared according to the method of Example 1 with (ZR)-1-(4-bromophenoxy)-4-
{3-
zo pyridyl)-2-butanol (0.214 g) as prepared in Example 40a) of WO 97/20815 and
3-chloro-
4-fluorophenylboronic acid (0.18 g), yielding the sub-title compound as a
yellow gum
(0.24 g).
MS (APCI +ve) 372!374 (M+H)+
is
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b) (2R)-N (1-(3'-Chloro-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-
thiazolidin-2,4-dione
Prepared according to the method of Example 1 with (2S~-1-(3'-Chloro-4'-
fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.14g), prepared from step a)
and
2,4-thiazolinedione (0.088 g) to give, after purification by silica gel
chromatography
(eluting with 80% ethyl acetate in iso-hexane), the title compound as a
colourless gum
(0.077 g).
MS {APCI +ve) 471/473 (M+H)+
i o 1 H NMR (DMS O-d6) 8 8.43-8.40 (2H, m), 7. 81 ( 1 H, dd), 7.65 -7.60 (4H,
m), 7.46 ( 1 H, t),
7.32 ( 1 H, dd), 6.97 (2H, d), 4.50 ( 1 H, m), 4.45 ( 1 H, t), 4.28 { 1 H,
dd), 4.19 (2H, d), 2.64
(2H, t), 2.39-2.26 ( 1 H, m), 2.18-2.03 ( 1 H, m)
Example 17
~s (2R)-N [1-(3'-Chloro-4'-fluorobiphenyl-4-yloxy~4-(3-pyridyl)-2-butyl]-
pyrrolidin-2,5-
dione
Prepared according to the method of Example 7 above with
(2,5~-1-(3'-chloro-4'-fluorobiphenyi-4-yloxy)-4-(4-pyridyl)-2-butanol (O.IOg),
from
zo Example 16a) and succinimide (0.053 g) to give, after purification by
silica gel
chromatography (eluting with 50% acetone in iso-hexane), the title compound as
a pale
brown foam (0.05 g).
MS (APCI +ve) 453/455 (M+H)+
zs 1 H NMR (DMSO-d f,) 8 8.41 ( 1 H, s), 8.39 ( 1 H, m), 7.81 ( 1 H, dd), 7.65
-7.59 (4H, m), 7.56
(1H, t), 7.32 (1H, dd), 6.97 (2H, d), 4.45-4.32 (2H, m), 4.26 (1H, m), 2.51
(6H, m), 2.25
( 1H, m), 2.07 ( 1H, m)
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Example 18
(2R)-N [1-(3',5'-Dicyanob~p6enyl-4-yloxy)-4-(3-pyridyl)-Z-butyl]-thiazolidin-
2,4-dione
a,m
a) (2S)-1-(4-Bromophenoxy)-4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butane
s A solution of (25~-4-(3-pyridyl)-1,2-butanediol (10 g), prepared according
to the
method described in Example 26c) of WO 97/20815, and 1,1-carbonyldiimidazole
(12 g) in
chloroform (250 ml) was stirred at room temperature overnight. The mixture was
partly
concentrated under reduced pressure then filtered through a pad of silica.
Evaporation of
the filtrate gave a residue which was dissolved in dimethylfortnamide (100
ml). 4-
io Bromophenol { 11.6 g) and caesium carbonate ( 16.6 g) were then added and
the mixture
heated at reflux temperature for 18 hours. The cooled reaction mixture was
acidified with
2M hydrochloric acid and extracted with diethyl ether (x3). The aqueous phase
was
separated and 2M sodium hydroxide added, until the mixture achieved pH9, and
extracted
with ethyl acetate (x3). The combined organic extracts were dried over
anhydrous
is magnesium sulphate, filtered and concentrated under reduced pressure to
give a residue.
Dimethylformamide ( 10 ml) was added to the residue followed by imidazole (6
g) and ten
butyldimethylsilyl chloride (8.4 g) and the resulting mixture stirred at room
temperature
overnight. The reaction nuxture was then added to water and extracted twice
with 1:1
diethyl ether/hexane. The organic extracts were combined, dried over anhydrous
zo magnesium sulphate, filtered and concentrated under reduced pressure to
give a residue.
Purification by silica gel chromatography eluting with 1:1 diethyl
ether/hexane delivered
the sub-title compound as an oil (13.27 g).
MS (APCI +ve) 436/438 (M+H)
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b) (25~-4-[4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]benzenebornnic
acid
A solution of t-butyllithium ( 1.7 M in hexanes, 15.0 ml, CALTTION-
PYROPHORIC) was added drop-wise to a stirred solution of (2,5~-1-(4-
bromophenoxy~
-4-(3-pyridyl)-2-(ten-butyldimethylsilyloxy)butane (5.0 g) prepared as
described in step a)
s above, and triisopropyl borate (4.3 ml) in tetrahydrofuran (200 ml) at -
78°C. After the
addition was complete the reaction mixture was stirred at -70°C for 1
hour. Water
(200 ml) and ethyl acetate (200 ml) were then added. The organic phase was
separated,
dried over anhydrous magnesium sulphate, filtered and concentrated under
reduced
pressure to give an oil. This was purified by silica gel chromatography,
eluting with 5:1
io ethyl acetate/methanol to yield the sub-title compound as a foam (4.06 g).
MS (APCI +ve) 402 (M + H)+
c) (2,5~-1-(3',5'-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol
A mixture of (2S~-4-[4-(3-pyridyl}-2-(tent butyldimethylsilyloxy)butoxy]-
is benzeneboronic acid (0.479 g), prepared as described in step b), 5-bromo-
1,3-
benzenedicarbonitrile (0.371 g, see Ref. J. Het. Chem. ( 1994), 3 I (6), p
1417-1420, Registry
No. 160892-07-9), tetrakis-(triphenylphosphine)palladium(0) (0.035 g), aqueous
sodium
carbonate (0.9 ml of a 2M solution), toluene ( 10 ml), and ethanol (4m1) were
heated at
100°C for 2 hours. The reaction mixture was partitioned between diethyl
ether and 2N
zo hydrochloric acid and the layers separated. The aqueous phase was
neutralised with 2N
sodium hydroxide and extracted with ethyl acetate. The organic phase was
separated, dried
over anhydrous magnesium sulphate, filtered and concentrated under reduced
pressure to
give a residue. The residue was dissolved in tetrahydrofuran (25m1) and
tetrabutylammonium fluoride (0.163 g) was added. After stirring at room
temperature
is overnight the mixture was concentrated under reduced pressure and
partitioned between
diethyl ether and 2N hydrochloric acid. The layers were separated. The aqueous
phase was
neutralised with 2N sodium hydroxide and extracted with ethyl acetate. The
organic phase
was separated, dried over anhydrous magnesium sulphate, filtered and
concentrated under
reduced pressure to give a residue. Purification by chromatography on silica
gel, eluting
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with 2:1 dichloromethane/acetone followed by re-crystallisation from ethyl
acetatulso-
hexane gave the sub-title compound as a white solid.
MS (APCI +ve) 370 (M+H)+
d) (ZR)-N [1-{3',5'-Dicyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butyl]-
thiazolidin-2,4-
dione
Prepared according to the method of Example 1 with (25~-1-(3',5'-
dicyanobiphenyl-
4-yioxy)-4-(3-pyridyl)-2-butanol (0.05 g), prepared in step c) and 2,4-
thiazolinedione
io (0.032 g) to give, after purification by super critical fluid
chromatography (eluting with 0%
- 45% methanol/liquid carbon dioxide), the title compound as a glass (0.015
g).
MS (APCI +ve) 469 (M+H)+
1H NMR (DMSO-d6) S 8.49 (2H, m), 8.41 (2H, m), 8.36 (1H, s), 7.80 (2H, d),
is 7.63 ( 1 H, d), 7.32 ( 1 H, dd), 7.03 (2H, m), 4.47 (2H, m), 4.31 ( 1 H,
dd), 4.19 (2H, s),
2.65 (2H, t), 2.30 ( 1 H, m), 2.20 ( 1 H, m)
Example 19
(+/-)-N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one
so
a) (+/-)-N 2-[1-(4-Bromophenoxy)-4-(4-pyridyl)-2-butyl]-isoindole-1,3-dione
Prepared according to the method of Example 15a) with 1-(4-bromophenyloxy)-4-
(4-
pyridyl)-2-butanol (6.02 g) prepared as described in Example 6b) and
phthalimide (5.49 g)
to' give the sub-title compound as a golden oil ( 10.13 g).
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27
MS (APCI) 451/453 (M+I~+
b) (+/-)-N-2-(4-Bromophenoxy)-4-(4-pyridyl)-butylamine
Prepared according to the method of Example 15b) with (+/-) N 2-[1-(4-
bromophenoxy)-4-(4-pyridyl)-2-butyl]-isoindole-1,3-dione (9.78 g) to give the
sub-title
compound as a yellow solid (3.04 g).
Melting point: 168-169°C
MS (APCI) 321/323 (M+I~+
io
c) (+/-)-N 2-(3'-Nitrobiphenyl-4-yloxy)-4-(4~pyridyl)-butylamine
A mixture of (+/-)-N 2-(4-bromophenoxy)-4-(4-pyridyl~butylamine (0.5 g)
prepared
as described in step b) above, 3-nitrophenylboronic acid (0.31 g), tetrakis-
(triphenylphosphine)palladium(0) (0.03 g), aqueous sodium carbonate (2M
solution, 0.93
is ml) and ethanol (2 ml) was heated at reflex for 4 hours. After cooling at
room temperature,
solvents were removed in vacuo. Dilute hydrochloric acid was then added and
the mixture
extracted with diethyl ether. The aqueous mixture was made alkaline with some
solid
sodium bicarbonate, and extracted with ethyl acetate. The combined extracts
were dried
over anhydrous magnesium sulphate, filtered and concentrated under reduced
pressure.
zo The residue was purified by column chromatography over neutral alumina gel
eluting with
dichloromethane : ethanol (98:2) then ethanol to give the sub-title compound
as a yellow
oil (0.28 g).
MS (APCn 364 (M+I~+
a
d) (+/-)-N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-
one
Prepared according to the method of Example 15c) with 2-chloroethyl
chloroformate
(0.030 ml). Final product was purified by NPHPLC eluting a gradient of 0-10%
of ethanol
in.dichloromethane to give the title compound as a yellow foam (0.025 g).
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Melting point: 67-69°C
MS (APCI) 434 {M+H)+
1H NMR {DMSO-d6) 8 8.46 (2H, dd), 8.39 (1H, t), 8.18-8.09 (2H,m), 7.76-7.70
(3H, m),
7.30 {2H, d), 7.09 (2H, d), 4.32-4..20(2H, m), 4.16 (2H, d), 4.14 ( 1 H, m),
3.63-3.47
(2H, m), 2.72-2.58 (2H, m), 1.95 (2H, c~
Example ZO
(ZR~.N-[1-(3'-Ftuorobiphenyl-4-yloxy)-4-{3-pyridyl)-2-butyl]-thiazolidin-2,4-
dione
chiral
io a) (2S)-1-(3'-Fluornbiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol
Prepared according to the method of Example 18c) above using (2f)-
4-[4-(3-pyridyl}-2-(tert-butyldimethylsilyloxy)butoxy]benzeneboronic acid
(0.30 g),
prepared as described in Example 18b) above, and I-bromo-3-fluorobenzene (0.15
ml), to
yield the subtitled compound as a colourless oil (0.21 g).
~s
MS (APCI +ve) 338 (M+H)+
b) (ZR) N [1-(3'-Fluorobiphenyt-4-yloxy)-4-(3-Pyridyl)-2-butyl]-thiazolidin-
2,4-
dione
20 1'repated according to the method of Example 1 with
(2S~-1-(3'Fluorobiphenyl-4-yioxy)-4.-{3-pyridyl)-2-butanol (0.205g), from step
a) and
2,4-thiazolinedione (0.14 g) to give, after purification by normal phase HPLC
(eluting with
0% - IO% ethanol in dichloromethane) and re-crystallisation from ethanol, the
title
compound as a colourless solid (0.032 g).
a
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Melting point: 117-118 °C
MS (APCI +ve) 437 (M+H)+
1H NMR (DMSO-d6) S 8.42 (2H, m), 7.63 (3H, m), 7.44 (3H, m), 7.33 (1H, dd),
7.13
( 1 H, m), 6.98 (2H, d), 4.54 ( 1 H, m), 4.45 ( 1 H, t), 4.27 ( 1 H, dd), 4.19
(2H, s), 2.62 (2H, t),
2.30 ( 1 H, m), 2.10 ( 1H, m)
Example 21
(+/-)-N [1-(3'-(Tritluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-
thiazolidin-
2,4-dione
io
a) (+/-)-1-(3'-(Tri~luoromethyl)biphenyl-4-yloxy)-4-(4-pyntdyl)-2-butanol
Prepared according to the method of Example 6c) using 1-(4-bromophenoxy)-4-(4-
pyridyl)-2-butanol (0.20 g) prepared as described in Example 6b) and
3-trifluoromethylphenylboronic acid (0.13 g), to deliver the sub-title
compound as a yellow
is oil (0.18 g).
MS (APCI +ve) 388 (M+H)+
b) (+/-)-N [1-(3'-(Trifluoromethyl)biphenyl-4-yloxy)-4-(4-pyridyl)-2~butyl]-
thiazolidin-2,4-dione
Zo Prepared according to the method of Example 1 with (+/-)-1-(3'-
trifluoromethylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butanol (0.175g), from step
a) and
2,4-thiazolinedione (0.106 g). Purification of the resulting residue by silica
gel
chromatography (eluting with 2% methanol in dichloromethane) and super
critical fluid
chromatography (eluting with 0% - 45% methanol/liquid carbon dioxide) followed
by
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crystallisation from an ethanol/ethyl acetatellso-hexane mixture, gave the
title compound as
a colourless solid (O.lOg).
Melting point: 95-96 °C
MS (APCI +ve) 487 (M+H)+
1H NMR (DMSO-d6) 8 8.46 (2H, m), 7.92 (2H, m), 7.67 (4H, m), 7.23 (2H, d),
7.01
(2H, m), 4.56 ( 1 H, m), 4.46 ( 1 H, t), 4.30 ( 1 H, dd), 4.18 (2H, s), 2.65
(2H, t), 2.32 ( 1 H, m),
2.10(lH,m)
io Example 22
(+/-)-N [1-(2'-Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-
dione
a) (+/-)-1-(2'-Methoxybiphenyl-4-yloay)-4-(4-pyridyl)-2-butanol
Prepared according to the method of Example 6c) using 1-(4-bromophenoxy)-4-(4-
~s pyridyl)-2-butanol (0.20 g) prepared as described in Example 6b) and
2-methoxyphenylboronic acid (0.104 g), to deliver the sub-title compound as a
colourless
solid (0.18g).
MS (APCI +ve) 350 (M+H)+
b) (+/-)-N [1-(2'-(Methoxybiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-
2~4-
dione
Prepared according to the method of Example 1 above with (+/-)-1-(3'-
methoxybiphenyl-4-yloxy~4-(4-pyridyl)-2-butanol (0.17 g), prepared in step a)
above, and
zs 2,4-thiazolinedione (0.114 g). Purification of the resulting residue by
silica gel
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chromatography (eluting with 2% methanol/dichloromethane) and super critical
fluid
chromatography (eluting with 0% - 45°!o methanoUliquid carbon dioxide)
then
crystallisation from an ett~anoUethyl acetatellso-hexane mixture, gave the
title compound as
a colourless solid (O.OSSg).
s
Melting point: 128-130 °C
MS (APCI +ve) 487 (M+H)+
1H NMR (DMSO-d6) 8 8.46 (2H, d), 7.38 (2H, d), 7.33 - 7.22 (4H, m), 7.08 (1H,
d), 6.99
( 1 H, m), 6.91 (2H, d), 4.55 ( I H, m), 4.44 ( 1 H, t), 4.26 ( 1 H, dd), 4.18
(2H, s), 3.75 (3H, s),
i o 2.65 {2H, t), 2.31 ( 1 H, m), 2.10 ( 1 H, m)
Example 23
(+/-)-N [1-(3'-Nitrobip6enyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2,6-
dione
is Prepared according to the method of Example 1 above with (+/ )-1-(3'-
nitrobiphenyl-
4-yloxy)-4-(4-pyridyl)-2-butanol (0.25 g) prepared as described in Example 11
a) and
glutarimide (0.16 g) to give the title compound as a pale yellow foam (0.11
g).
Melting point: 53-55°C
Zo MS (APCl7 460 (M+H)+
1H NMR (DMSO-d6) S 8.45 (2H, d), 8.38(1H, s), 8.17-8.09 (2H, m), 7.75-7.70
(3H, m),
7.21 (2H, d), 7.02 (2H, d), 5.10-5.00 (1H, m), 4.43-4.29 (2H, m), 2.57 (6H,
t), 2.36-2.21
( 1 H, m), 2.16-2.01 ( 1 H, m), 1.74 (2H, t)
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Example 24
(+/-)-N (1-(3'-Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiazolidin-2,4-
dione
A yellow suspension of (+/-) N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-
butyl]-
thiazolidin-2,4-dione (0.377 g) prepared as in Example 1 lb) above, ammonium
chloride
(0.17 g) and iron powder (0.18g) in a 1:1 ethanol/ water mixture was heated at
reflux
temperature for 1.5 hours. The cooled reaction mixture was filtered. The
colourless filtrate
was poured into saturated sodium bicarbonate solution and extracted with ethyl
acetate.
The organic phase was separated, washed with water and brine, dried over
sodium sulphate
io (NaZS04) and concentrated under reduced pressure to yield a residue that
was purified by
normal phase HPLC (O~o - 10% ethanol/dichloromethane) followed by
precipitation from
an ethanol/ethyl acetatelso-hexane mixture which yielded the title compound as
a
colourless solid (0.34 g).
a Melting point: 147-148 °C
MS (APCI +ve) 434 (M+H)+
1 H NMR (DMS O-d~,) S 8.46 (2H, d), 7.46 (2H, d), 7.23 (2H, d), 7.05 ( 1 H,
t), 6.94 (2H, d),
6.77 ( 1 H, s), 6.71 ( 1 H,d), 6.50 ( 1 H, d), 5.10 (2H, s), 4.54 ( 1 H, m),
4.43 ( 1 H, t), 4.26
( 1H, dd), 4.17 (2H, s), 2.62 (2H, t), 2.31 ( 1H, m), 2.12 ( 1H, m)
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Example 25
(+/-)-N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-Z-butyl]-[1,3]-oxazinan-2-
one
c~
N O
O
0.
~ , w N.o_
N~ ~ ~ i
To a solution of phosgene ( 1.93 M in toluene, 0.31 ml) in toluene ( 10 ml)
was added
(+/-)-N 2-(3'-nitrobiphenyl-4.-yloxy)-4-(4-pyridyl)~butylamine (0.20 g) from
Step 19c) and
reaction mixture stirred at room temperature for 2 hours. 3-Chloropropanol
(0.09 ml) was
then added to the mixture and stirred overnight at room temperature. Solvents
were
removed under reduced pressure and the residue was redissolved in
dimethylformamide
( 10 ml). This solution was added slowly to a suspension of sodium hydride
(60%
to dispersion in oil, 0.09 g) in dimethylforniamide (1 ml). The mixture was
heated at 70°C
for 9 hours. After cooling to room temperature, solvents were removed under
reduced
pressure. The residue was made. alkaline with aqueous sodium hydroxide (2M)
and
extracted with ethyl acetate. The combined extracts were dried over anhydrous
magnesium
sulphate, filtered and concentrated under reduced pressure. The residue was
purified by
~s NPHPLC eluting a gradient of 0-10% ethanol in dichloromethane to give the
title
compound as a yellow oil (0.009 g).
MS (APCn 448 (M+H)+
1H NMR (DMSO-d6) 8 8.46 (2H, dd), 8.39 (1H, t), 8.18-8.09 (2H, m), 7.75-7.70
(3H, m);
Zo 7.29 (2H, dd), 7.09 (2H, dd), 4.48-4.33 (1H, m), 4.20-4.12 (4H, m), 3.31-
3.21 (2H, m),
2.65 (2H, t), 2.07-1.86 (4H, m)
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Example 26
(?.S~-N [1-(3'
To (2R)-1-(3'-cyanobiphenyl-4.-yloxy)-4-(3-pyridyl)-2-butanol (SEtmol)
prepared
according to the method described in Example 37 of WO 97/20815, was added
triphenylphosphine (50 Erl of a 0.2M solution in tetrahydrofuran) followed by
2,4-
thiazolidinedione (50 E,~l of a 0.2M solution in tetrahydrofuran). Diethyl
azodicarboxylate
(21r1) was added and the reaction mixture was capped and stirred at room
temperature
overnight. The mixture was concentrated under reduced pressure to give a
residue. The
io residue was dissolved in dimethylsulphoxide to give the title compound as a
IOmM
solution in dimethylsulphoxide and analysed by HPLC on a SOmm x 3.9mm, SEun
particle
size Waters Symmetry C8 column, eluting with 0.1 % aqueous ammonium acetate
solution.
MS (APCI +ve) 444 (M+I~+
~s
Example 27
(2S)-N [1-{3'~Aminobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-thiszolidin-2,4-
dione
s
N_ ° / \ \ /
\ /
Prepared according to Example 26) above from (2R)-1-(3'-aminobiphenyl-4-yloxy)-
Zo 4-(3-pyridyl)-2-butanol (5 Eunol) prepared according to the method
described in Example
50 of WO 97/20815, triphenylphosphine (50 E.~l of a 0.2M solution in
tetrahydrofuran), 2,4-
thiazolidinedione (50 E.~l of a 0.2M solution in tetrahydrofuran) and diethyl
azodicarboxylate (2p1) to give the title compound as a IOmM solution in DMSO
and
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WO 99/29686 PCT/SE98/02190
analysed by I3PLC on a SOmm x 3.9mm, SEun particle size Waters Symmetry C8
column,
eluting with 0.1 % aqueous ammonium acetate solution.
MS (APCI +ve) 434 (M+I~+
Example 28
(2S)-N-[1-(3'-Methanesulfonamidobiphenyl-4-yloxy)-4-(3-pyridyl)-2-
butyl]t6iazolidine-2,4-dione
,O
o,,s.N~
N. ~~ H
O
S
io Prepared according to Example 26) above from (ZR)-1-(3'-
methanesulfonamidobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (5 pmol) prepared
according to the method described in Example 98 of WO 97/20815,
triphenylphosphine
(50 ~.~1 of a 0.2M solution in tetrahydrofuran), 2,4-thiazolidinedione (50 pl
of a O.ZM.
solution in tetrahydrofuran) and diethyl azodicarboxylate (2E,~1) to give the
title compound.
is as a IOmM solution in DMSO aad analysed by HPLC on a SOmm x 3.9mm, Stun
particle
size Waters Symmetry C8 column, eluting with 0.1% aqueous ammonium acetate
solution.
MS (APCI +ve) 512 (M+I-~+
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Example 29
(2S,3S)-N-[1-(3'-(Pyrrolidine-1-sulfonyl)biphenyl-4-yloxy)-4-(3-pyridyl)-3-
pentyl]-
pyrrolidine-2,5-dione
,o
N . I = O'~~ O .NV
O~O
prepared according to the method described in Example 26) using (3R,4S)-1-
pyridin-
3-yl-4-[3'-(pyrrolidine-1-sulfonyl)biphenyl-4-yl-oxy]pentan-3-of (6.b7umoi),
prepared
according to the method of Example 72 of WO 98/42670, triphenylphosphine (50
Ell of a
0.27M solution in tetrahydrofuran), succinimide (50 Erl of a 0.27M solution in
tetrahydrofuran) and diethyl azodicarboxylate (3 pl) to give the title
compound as a IOmM
~o solution in dimethyl sulphoxide and analysed by HPLC on a SOmm x 3.9mm,
SEun particle
size Waters Symmetry C8 column, eluting with 0.1~ aqueous ammonium acetate
solution.
IBIS (APCI +ve) 548 (M+I~+
is Example 30
(2S,3S) N-[1-(3'-Cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyritdyl)-3-pentyl]-
pyrrolidine-2,5-dione
F
I = o w ~ cN
o~o
Prepared according to the method described in Example 26) using ( 1S,2R)-4-
fluoro-
Zo 4'-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)biphenyl-3-carbonitrile
(6.67~mo1),
prepared according to the method of Example 36 of WO 98/42670,
triphenylphosphine (50
E,~l of a 0.27M solution in tetrahydrofuran), succinimide (50 ~1 of a 0.27M
solution in
tetrahydrofuran) and diethyl azodicarboxylate (3 ~1) to give the title
compound as a IOmM
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37
solution in DMSO and analysed by HPLC on a SOmm x 3.9mm, SEun particle size
Waters
Symmetry C8 column, eluting with 5%-95% acetonitrile/ ammonium acetate.
MS {APCI +ve) 458 (M+H)+
Example 31
(2,5~-N [1-(3'-Cyano-4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butylj-
thiazolidine-
2,4-dione
o~~o cN
o ~ ~ -
N.
io Prepared according to the method described in Example 26) using (2R}-1-(3'-
cyano-
4'-fluorobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (6.67Euno1),
triphenylphosphine (50 pl
of a 0.27M solution in tetrahydrofuran), 2,4-thiazolidinedione (50 ~.~1 of a
0.27M solution in
tetrahydrofuran) and diethyl azodicarboxylate (3 E,~l) to give the title
compound as a IOmM
solution in DMSO and analysed by HPLC on a SOmm x 3.9mm, Shin particle size
Waters
is Symmetry C8 column, eluting with 5%-95% acetonitrile/ ammonium acetate.
MS (APCI +ve) 462 (M+H)+
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38
Example 32
(+/-)-N [1-(4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy)-4-{4.pyridyl)-2-butyl]-
oxawlidin-2-one
a) (+/-)-N (1-(4-Bromophenoxy)-4-(4-pyridyl)-2-butyl]- oxazolidin-2-one
Prepared according to the method described in Example 15c) using (+/-)112-(4-
bromophenoxy~4-(4-pyridyl)-butylamine (Example 19b), 1.08 g), 2-chloroethyl
chloroformate (0.521 ml) and sodium hydride (60% dispersion in mineral oil)
(0.408 g).
After 10 hours at 70°C, water ( 100 mI) was added and the product was
extracted with ethyl
io acetate. The combined organic extracts were dried over magnesium sulphate,
filtered and
concentrated under reduced pressure. Residue obtained was purified by column
chromatography wer Silica gel eluting with dichloromethane : ethanol {95: S)
to give the
sub-title compound as an oil (0.651 g).
is MS {APCI +ve) 391/393 (M+H)+
1H NMR (DMSO-d6) 8 8.46 (2H, dd), 7.44 (2H, dd), 7.28 (2H, dd), 6.92 (2H, dd),
4.29-4.19 (2H, m), 4.07 (2H, d), 4.04-3.96 ( 1 H, m), 3.59-3.41 (2H, m), 2.70-
2.56 (2H, m),
1.90 (2H, q).
zo b) (+/-)-[4-{4-Pyridyl)-Z-(oxazolidin-2-one-1-yl)butoxy]benzeneboronic acid
Prepared according to the method described in Example 18b) using (+/ )~V [1-(4-
bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (0.20 g), from step a),
tent
butyllithium ( I .7 M solution in hexanes, 0.60 ml) and tri-isopropylborate
(0.17 ml) to give
the sub-title compound as a foam (0.09 g).
a
MS (APCI +ve) 313 (M-B(OH~)+
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39
1H NMR (DMSO-ds) b 8.56 (2H, d), 7.82 (2H, d), 7.39 (2H, d), 6.91 (2H, d),
4.25-4.15
(2H, m), 4.07 (2H, d), 4.05-3.94 ( 1 H, m), 3.60-3.46 (2H, m), 2.74-2.62 (2H,
m),
1.92 (2H, q).
s c) (+/-)-N [1-(4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy)-4-(4-pyridyl)-2-
butyl]-
oxazotidin-2-one
Prepared according to the method described in Example 6c) using (+/-)-[4-(4-
Pyridyl)-2-{oxazolidin-2-one-1-yl~utoxy]benzeneboronic acid (0.090 g), from
step b), S-
bromo-2-fluorophenylsulfonamide (0.097 g) (prepared in Example 35a of WO
98/42670),
to ethanol (1 ml), aqueous sodium bicarbonate solution (2M, 0.2 ml), tetrakis-
(triphenylphosphine)palladium(0) (0.010 g).
After work-up, the residue was purified by column chromatography over silica
gel
eluting with dichloromethane : ethanol (95 : 5) then dichloromethane : ethanol
(90 : 10) to
give the title compound as a solid (0.034 g).
is
Melting point: 89-91°C
MS {APCI +ve) 486 (M+H)+
IH NMR (DMSO-d6) 8 8.46 (2H, d), 7.95 (1H, dd), 7.91-7.86 (1H, m), 7.72 (2H;
s), 7.60
(2H, d), 7.48 (1H, t), 7.29 (2H, d), 7.07 (2H, d), 4.29-4.I9 (2H, m), 4.14
(2H, d), 4.08-4.00
io ( 1 H, m), 3.63-3.47 (2H, m), 2.72-2.60 (2H, m), 1.99-1.90 (2H,m).
Example 33
(+/-)-N [1-(4-(6-Methoxypyridin-2-yt)-phenoxy)-4-(4-pyridyl)-2-butyl]-
oxazolidin-2-
one
a
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WO 99/29686 PCT/SE98/02190
Prepared according to the method described in Example 6c) using (+/-)-[4-(4-
Pyridyl)-2-(oxazolidin-2-one-1-yl~butoxy]benzeneboronic acid (Example 32b,
0.100 g), 2-
bromo-6-methoxypyridine {J. Org. Chem., 55, ( 1990), 69-73, 0.079 g), ethanol
(3 ml),
aqueous sodium bicarbonate solution (2M, 0.2 ml) and tetrakis-
(triphenylphosphine)palladium(0) (0.010 g).
After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10%
ethanol in dichloromethane to give the title compound as an oii (0.082 g).
MS (APCI +ve) 420 (M+H)+
to 1H NMR {DMSO-d6) S 8.46 (2H, dd), 8.04 (2H, d), 7.73(1H, t), 7.48 (1H, d),
7.30
(2H, dd), 7.04 (2H, d), 6.70 ( 1 H, d), 4.29-4.22 (2H, m), 4.15 (2H, d), 4.09-
4.02 ( 1 H, m),
3.94 (3H, s), 3.60-3.50 (2H, m), 2.73-2.59 (2H, m), 1.94 (2H, q).
Example 34
is (+/-)-N [1-(Biphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oaazolidin-Z-one
Prepared according to the method described in Example 6c) using (+/-NV [1-(4-
bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), 0.100 g),
phenylboronic acid (0.047 g), ethanol (3 ml), aqueous sodium bicarbonate
solution (2M,
zo 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g).
After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10%
ethanol in dichloromethane to give the title compound as a solid (0.012 g).
Melting point: 116-117°C
a MS (APCI +ve) 389 (M+H)+
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1H NMR (DMSO-d6) S 8.46 (2H, d), 7.60 (4H, t), 7.43 (2H, t), 7.30 (3H, d),
7.03 (2H, d),
4.31-4.20 (2H, m), 4.13 (2H, d), 4.07-4.00 ( 1 H, m), 3.62-3.48 (2H, m), 2.72-
2.59 (2H, m),
1.94 (2H, q)
s Example 35
(+I-)-N [1-(4'-Clilorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolid~tn-2-
one
Prepared according to the method described in Example 6c) using (+/-)~V [1-{4-
bromophenoxy)-4-(4-pyridyl~2-butyl]-oxazolidin-2-one (Example 32a), 0.100 g),
~0 4-chlorobenzeneboronic acid (0.060 g), ethanol (3 ml), aqueous sodium
bicarbonate
solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g).
After work-up, the residue was purified by NPHPLC eluting a gradient of 0-100
ethanol in dichloromethane to give the title compound as a solid (0.038 g).
a Melting point: 103-105°C
MS (APCI +ve) 423 (M+H)+
1H NMR (DMSO-d6) 8 8.46 {2H, d), 7.62 (4H, q), 7.47 (2H, d), 7.29 (2H, d),
7.03 (2H, d),
4.30-4.20 (2H, m), 4.13 {2H, d), 4.07-4.00 (1H, m), 3.62-3.48 (2H, m), 2.70-
2.58 (2H, m),
1.94 (2H, q).
zo
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Example 36
(+/-) N [1-(4'-Methylbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one
Prepared according to the method described in Example 6c) using (+/-)-N [1-(4-
bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), 0.100 g),
4-methylbenzeneboronic acid (0.052 g), ethanol (3 ml), aqueous sodium
bicarbonate
solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.010 g).
After work-up, the residue was purified by NPxPLC eluting a gradient of 0-10%
ethanol in dichloromethane to give the title compound as a solid (0.033 g).
~o
Melting point: 109-110°C
MS (APCI +ve) 403 (M+H)*
1H NMR (DMSO-d6) S 8.46 (2H, d), 7.56 (2H, d), 7.50 (2H, d), 7.29 (2H, d),
7.23 (2H, d),
7.01 (2H, d), 4.30-4.20 (2H, m), 4.12 (2H, d), 4.07-4.01 ( 1 H, m), 3.62-3.48
(2H, m),
is 2.72-2.59 (2H, m), 1.94 (2H, q).
Example 37
(+/-)-N [1-(4'-Methoxybiphenyl-4-yloxy)-4-(4-pyridy!)-2-butyl]-oxazolidin-2-
one
2o Prepared according to the method described in Example 6c) using (+/-) N [1-
(4-
bromophenoxy)-4-(4-pyridyl)-2-butyl]-oxazolidin-2-one (Example 32a), 0.100 g),
4-
methoxybenzeneboronic acid (0.059 g), ethanol (3 ml), aqueous sodium
bicarbonate
solution (2M, 0.2 ml) and tetrakis-(triphenylphosphine~alladium(0) (0.010 g).
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After work-up, the residue was purified by NPHPLC eluting a gradient of 0-1096
ethanol in dichloromethane to give the title compound as a solid (0.026 g).
Melting point: 114-115°C
s MS (APCI +ve) 419 (M+H)+
1H NMR (DMSO-d6) b 8.46 (2H, d), 7.53 (4H, dd), 7.29 (2H, d), 6.99 (4H, dd),
4.30-4.20
(2H, m), 4.11 (2H, d), 4.06-4.01 (1H, m), 3.32 (3H, s), 3.61-3.48 (2H, m),
2.70-2.59
(2H, m), 1.94 (2H, q).
to Example 38
(+/-)-N [1-(3',4'-Dichlorobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-oxaizoUdin-
2-one
Prepared according to the method described in Example 6c) using ((+/-)-[4-(4-
Pyridyl)-2-(oxazolidin-2-one-1-yl~utoxy]benzeneboronic acid (Example 32b),
0.050 g), 1-
is bromo-3,4-dichlorobenzene (0.048 g), ethanol (2 ml), aqueous sodium
bicarbonate solution
(2M, 0.1 ml) and tetrakis-(triphenylphosphine)palladium(0) (0.006 g).
After work-up, the residue was purified by NPHPLC eluting a gradient of 0-1096
ethanol in dichloromethane to give the title compound as a solid (0.010 g).
Zo Melting point: 92-93°C
MS (APCI +ve) 457/459/461 (M+H)+
1 H NMR (DMS O-d6) b 8.46 (2H, d), ?.89 ( 1 H, d), 7.68-7.62 {4H, m), 7.29
(2H, d), 7.04
(2H, d), 4.30-4.20 (2H, m), 4.13 (2H, d), 4.07-4..01 ( I H, m), 3.62-3.48 (2H,
m), 2.72-2.59
(2H, m), 1.94 (2H, q).
zs
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Example 39
(+/-)-N [1-(4-(6-Methoxypyridin-2-yl)-phenoxy)-4-{4-pyridyl)-2-butyl]-
piperidin-2,6-
dione
a) (+1-)-1-(4-Bromophenoxy)-4-(4.pyridyl)-2-(tent-butyldimethylsityloxy)butane
tent Butyldimethylsilyl chloride (20.53 g) and imidazole (9.25 g) were added
to a
solution of (+/-)-1-(4-bromophenyloxy)-4-(4-pyridyl)-2-butanol (Example 6b),
14.60g) in
dry dichloromethane (500 ml). The solution was stirred overnight at room
temperature.
The solid was filtered off and the filtrate concentrated under reduced
pressure.
io The residue was purified by chromatography over silica gel eluting with
dichloromethane : ethyl acetate (5 : 1 ) to give the sub-title compound as a
solid ( 19.34 g).
Melting point: 73-75°C
MS (APCI +ve) 436/438 (M+H)+
is 1H NMR (DMSO-d6) 8 8.50 (2H, dd), 7.49 (2H, dd), 7.27 (2H, d), 6.94 {2H,
dd), 4.13-4.02
(2H, m), 3.93-3.86 (1H, m), 2.82-2.68 (2H, m), I.97-1.79 (2H, m), 0.91 (9H,
s), 0.12
(3H, s), 0.09 {3H, s).
b) (+/-)-4-[4-(4-Pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]benzeneboronic
acid
zo Prepared according to the method described in Example 18b) using (+/-)-1-(4-
bromophenoxy)-4-(4-pyridyl)-2-(tert-butyldimethylsilyloxy)butane ( 10.0 g),
from step a),
tert-butyllithium ( 1.7 M solution in hexanes, 27 ml) and tri-isopropylborate
(6 ml) in dry
tetrahydrofuran (200 ml).
After work-up, the residue was purified by column chromatography over silica
gel
a eluting with ethyl acetate : hexane (2 : 1 ) then ethyl acetate to give the
sub-title compound
as a foam (4.38 g).
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MS (APCI +ve) 402 (M+H)+
1H NMR (DMSO-d6+D20) S 8.45 (2H, dd), 7.71 (2H, d), 7.24 (2H, q), 6.87 (2H,
d),
4.04-3.82 (3H, m), 2.79-2.66 (2H, m), 1.97-1.75 (2H, m), 0.87 (9H, s), 0.14
(3H, s),
0.08 (3H, s).
c) (+/-)-4-[4-(4-Pyridyl)-2-butoxy]benzeneboronic acid
Dilute hydrochloric acid (2M, 65 ml) was added to (+/-)-1-{4-bromophenoxy)-4-
(4-
pyridyl)-2-(ten butyldimethylsiIyloxy)butane (4.38 g) from step b) in methanol
(200m1).
The mixture was stirred for 2 hours at room temperature, then concentrated
under reduced
io pressure. The residue was partitioned between diethyl ether and water. The
aqueous layer
was basified with aqueous sodium bicarbonate solution, then extracted with
ethyl acetate.
The combined organic extracts were dried over anhydrous magnesium sulfate,
filtered and
concentrated under reduced pressure to give the sub-title compound as a
powder.
is MS (APCI +ve) 288 (M+H)+
tH NMR (DMSO-d6+ D20) 8 8.43 {2H, d), 7.71 (2H, d), 7.31 (2H, d), 6.92 (2H,
d), 3.92
(2H, d), 3.84-3.78 (1H, m), 2.87-2.64 (2H, m), 1.89-1.74 (2H, m).
d) (+/-)-1-[4-(6-Met6ogypyridin-2-yl)phenoxy]-4-{4-pyr~tdyl)-2-butanol
zo Prepared according to the method described in Example 6c) using (+/-)-4-[4-
(4-
pyridyl)-2-butoxy]benzeneboronic acid (0.20 g) from step c), 2-bromo-6-
methoxypyridine
(J. Org. Chem., 55, ( 1990), 69-73, 0.26 g), ethanol (3 ml), aqueous sodium
bicarbonate
solution (2M, 0.7 ml) and tetrakis-(triphenylphosphine~alladium(0) (0.020 g).
After work-up, the residue was purified by NPHPLC eluting a gradient of 0-
10°k
a ethanol in dichloromethane to give the sub-title compound as an oil (0.15
g).
MS (APCI +ve) 351 (M+H)+
1H NMR (DMSO-d6) S 8.45 (2H, d), 8.03 (2H, dd), 7.73 (1H, t), 7.47 (1H, d),
7.26 (2H, dd), 7.03 (2H, dd), 6.70 ( 1 H, d), 5.08 ( 1 H, d), 3.95 (2H, d),
3.83-3.78 ( I H, m),
~0 3.32 (3H, s), 2.85-2.77 (1H, m), 2.72-2.64 (1H, m), 1.91-1.83 (1H, m), I.78-
1.70 (1H, m)
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e) (+/-)-N [1-(4-{6-Met6oxypyridin-2-y!)-phenoxy)-4-(4-pyridyl)-2-butyl]-
piperidin-2,6-dione
Prepared according to the method of Example 1 using (+/ )-1-[4-(6-
methoxypyridin-
2-yl~henoxy]-4-(4-pyridyl)-2-butanol (0.1 S g) from step d), glutarimide (0.1
g),
triphenylphosphine (0.22 g) and diethyl azodicarboxylate (0.14 ml).
After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10%
ethanol in dichloromethane to give the title compound as an oil (0.10 g).
MS (APCI +ve) 446 (M+H)+
io 1 H NMR (DMSO-d6) S 8.44 (2H, dd), 8.01 (2H, dd), 7.73 ( 1 H, t), 7.47 ( 1
H, d),
7.21 (2H, dd), 6.97 (2H, d), 6.70 ( 1 H, d), 5.07-5.02 ( 1 H, m), 4.42-4.28
(2H, m), 3.94
(3H, s), 2.62-2.51 (6H, m), 2.35-2.24 (1H, m), 2.12-2.01 (1H, m), 1.78-1.70
(2H, m).
Example 40
is (+/ )-N [1-(3'-Nitrnbiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-imidazolidine-
2,4-dione
Prepared according to the method of Example 1 using (+/-)~V 1-(3'-
nitrobiphenyl-4-
yloxy)-4-(4-pyridyl)-2-butanol (Example 15a), 0.20g), hydantoin (0.11 g),
triphenylphosphine (0.29 g) and diethyl azodicarboxylate (0.17 ml) in dry
tetrahydrofuran
zo (10 ml) and dimethylformamide (2 ml).
After work-up, the residue was purified by NPHPLC eluting a gradient of 0-10%
ethanol in dichloromethane to give the title compound as a solid (0.03 g).
Melting point: 143-145°C
a MS (APCI +ve) 447 (M+H)+
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1H NMR (DMSO-d6) 8 8.45 (2H, d), 8.38 (1H, s), 8.17-8.07 (3H, m), 7.74-7.70
(3H, m),
7.24 (2H, d), 7.03 (2H, d), 4.51-4.45 (1H, m), 4.38-4..23 (2H, m), 3.87 (2H,
s), 2.69-2.60
(2H, m), 2.3 8-2.22 ( 1 H, m), 2.16-2.00 ( 1 H, m).
Example 41
(+/-)-N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyridyl)-2-butyl]-piperidin-2-one
5-Chlorovalerylchloride (0.07 mI) was added slowly to a solution of (+/-)~V 2-
(3'-
nitrobiphenyl-4-yloxy)-4-(4-pyridyl)~butylamine (Example 19c), 0.20 g) in dry
io dichloromethane ( 10 ml), in presence of triethylamine ( 1 ml). The mixture
was stirred for
i 5 minutes at room temperature, then concentrated under reduced pressure.
Potassium tent butoxide solution (1M in tetrathydrofuran, 1.5 ml) was added to
the
residue redissolved in anhydrous tetrahydrofuran ( 10 ml). After 30 minutesv
at room
temperature, the mixture was concentrated under reduced pressure. Water was
added and
~s the mixture was extracted with ethyl acetate. The combined organic extracts
were dried
over anhydrous magnesium sulfate, filtered and concentrated under reduced
pressure.
The residue was purified by NPHPLC eluting a gradient of 0-10°k
ethanol in
dichloromethane to give the title compound as an oil (0.03 g).
zo MS (APCI +ve) 446 (M+H)+
1H NMR (DMSO-d6) S 8.45 (2H, d), 8.38 (1H, t), 8.18-8.09 (2H, m), 7.75-7.69
(3H, m),
7.26 (2H, d), 7.07 (2H, d), 4.86-4.76 (1H, m), 4.19-4.07 (2H, m), 3.25-3.14
{2H, m), 2.73
{2H, t), 2.28-2.22 (2H, m), 2.00-1.87 (2H, m), 1.64 (4H, bd).
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Example 42
(+/-) N [1-(3'-Nitrobiphenyl-4-yloxy)-4-(4-pyr~dyl)-2-butyl]-pyrrolidin-2-one
Prepared according to the method of Example 41 above with (+I-) N 2-(3'-
aitrobiphenyl-4-yloxy)-4-(4-pyridyl)~utylanune (Example 19c), 0.20 g),
triethylamine ( 1
ml), 4-chlorobutyrylchloride (0.06 ml) and potassium tent butoxide solution (
1M in
tetrathydrofuran, 1.5 ml).
After work-up, the residue was purified by NPHPI:C eluting a gradient of 0-10%
ethanol in dichloromethane to give the title compound as an oil (0.035 g).
io
MS (APCI +ve) 432 (M+H)+
1H NMR (DMSO-d6) b 8.45 (2H, dd), 8.38 (1H, t), 8.18-8.09 (2H, m), 7.75-7.69
(3H, m),
7.28 (2H, dd), 7.07 (2H, dd), 4.34-4.27 ( 1 H, m), 4.11 (2H, d), 3.38-3.26
(2H, m), 2.61-2.55
(2H, m), 2.24 (2H, t), 1.97-1.85 (4H, m).
is
Faample 43
Pharmacological Analysis
Certain compounds such as benzoylbenzoyl adenosine triphosphate (bbATP) are
known to be agonists of the P2X~ receptor, effecting the formation of pores in
the plasma
zo membrane (Drug Development Research (1996), 37(3), p.126). Consequently,
when the
receptor is activated using bbATP in the presence of ethidium bromide (a
fluorescent DNA
probe), an increase in the fluorescence of intracellular DNA-bound ethidium
bromide is
pbserved. The increase in fluorescence can be used as a measure of P2X~
receptor
activation and therefore to quantify the effect of a compound on the P2X~
receptor.
is In this manner, each of the title compounds of Examples 1 to 42 were tested
for
antagonist activity at the P2X~ receptor. Thus, the test was performed in 96-
well flat
bottomed microtitre plates, the wells being filled with 250 p,l of test
solution comprising
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200 p,l of a suspension of THP-1 cells (2.5 x 106 cells/ml) containing IOM
ethidium
bromide, 25 ~,1 of a high potassium buffer solution containing 10 SM bbATP,
and 25 N,1 of
the high potassium buffer solution containing 3 x 10 SM test compound. The
plate was
covered with a plastics sheet and incubated at 37 °C for one hour. The
plate was then read
in a Perltin-Elmer fluorescent plate reader, excitation 520 nm, emission 595
nm, slit
widths: Ex 15 nm, Em 20 nm. For the purposes of comparison, bbATP (a P2X~
receptor
agonist) and pyridoxal 5-phosphate (a P2X~ receptor antagonist) were used
separately in
the test as controls. From the readings obtained, a pICgp figure was
calculated for each test
compound, this figure being the negative logarithm of the concentration of
test compound
io necessary to reduce the bbATP agonist activity by 50%. Each of the
compounds of
Examples 1 to 42 demonstrated antagonist activity, having a pICgp figure >
4.50.
