Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
Novel substituted 1,2,3-triazolylmethyl-benzothiophene or -indole and their
use as leukotriene biosynthesis inhibitors.
FIELD OF THE INVENTION
The instant invention involves novel compounds which are useful as inhibitors
of
leukotriene biosynthesis.
BACKGROUND OF THE INVENTION
Inhibition of leukotriene biosynthesis has been an active area of
pharmaceutical research
for many years. The leukotrienes constitute a group of locally acting
hormones, produced in living
systems from arachidonic acid. Leukotrienes are potent contractile and
inflammatory mediators derived
by enzymatic oxygenation of arachidonic acid by 5-lipoxygenase. One class of
leukotriene biosynthesis
inhibitors are those known to act through inhibition of 5-lipoxygenase (5-LO).
The major leukotrienes are Leukotriene B4 (abbreviated as LTB4), LTC4, LTD4
and
LTE4. The biosynthesis of these leukotrienes begins with the action of the
enzyme 5-lipoxygenases on
arachidonic acid to produce the epoxide known as Leukotriene A4 (LTA4), which
is converted to the
other leukotrienes by subsequent enzymatic steps. Further details of the
biosynthesis as well as the
metabolism of the leukotrienes are to be found in the book Leukotrienes and
Lipoxygenases, ed. J.
Rokach, Elsevier, Amsterdam (1989). The actions of the leukotrienes in living
systems and their
contribution to various diseases states are also discussed in the book by
Rokach.
In general, 5-LO inhibitors have been sought for the treatment of allergic
rhinitis, asthma
and inflammatory conditions including arthritis. One example of a 5-LO
inhibitor is the marketed drug
zileuton (ZYLOFT ) which is indicated for the treatment of asthma. More
recently, it has been reported
that 5-LO may be an important contributor to the atherogenic process; see
Mehrabian, M. et al.,
Circulation Research, 2002 Ju126, 91(2):120-126.
Despite significant therapeutic advances in the treatment and prevention of
conditions
affected by 5-LO inhibition, further treatment options are needed. The instant
invention addresses that
need by providing novel 5-LO inhibitors which are useful for inhibiting
leukotriene biosynthesis.
SUMMARY OF THE INVENTION
The instant invention relates to compounds of Formula I which are leukotriene
biosynthesis inhibitors, methods for their preparation, and methods and
pharmaceutical formulations for
using these compounds in mammals, especially humans.
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N// N\N Z
R2
R3 R4
The compounds of Formula I are useful as pharmaceutical agents to slow or halt
atherogenesis. Therefore, the instant invention provides a method for treating
atherosclerosis, which
includes halting or slowing the progression of atherosclerotic disease once it
has become clinically
evident, comprising administering a therapeutically effective amount of a
compound of Formula I to a
patient in need of such treatment. The instant invention also provides methods
for preventing or reducing
the risk of developing atherosclerosis and atherosclerotic disease events,
comprising administering a
prophylactically effective amount of a compound of Formula I to a patient who
is at risk of developing
atherosclerosis or having an atherosclerotic disease event.
Additionally, the instant invention involves the use of compounds of Formula I
as anti-
asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents. They
are also useful in treating
angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis,
and allograft rejection. The
instant invention provides methods of treatment comprising administering a
therapeutically effective
amount of a compound of Formula I to a patient in need of the above-described
treatments.
The instant invention further provides the use of a compound of Formula I in
combination with other therapeutically effective agents. Additional
embodiments will be evident from
the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The novel leukotriene biosynthesis inhibitors of the instant invention are
compounds of
structural Formula I
N/NN Z
R2
R3 R4 I
and the pharmaceutically acceptable salts, esters and solvates thereof
wherein:
2
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Z:' is selected from the group consisting of
1i s(0)n 1 ~
/ R' ~ R1
2 and 2~ N
A A wherein the numbers "1" and "2" indicate the points
of attachment within structural Formula I;
A is selected from the group consisting of -Cl and phenyl optionally mono- or
di-substituted with a
substituent independently selected at each occurrence from the group
consisting of (i) -F (ii) -Cl, (iii)
-C1-3alkyl optionally substituted with one or more of halo for example
including -CF3, (iv)
-OC1-3alkyl optionally substituted with one or more of halo for example
including -OCHF2 and
-OCF3, (v) -OC3-6cycloalkyl, (vi) -C3-6cycloalkyl, (vii) -CH2OH, (viii) -
COOR5, (ix) -CN and (x)
-N-R5R5a;
n is an integer selected from zero, 1 and 2;
Rl is selected from the group consisting of (i) -H, (ii) -Br, (iii) -Cl, (iv) -
COC1-6alkyl, (v)
-COOC1-6alkyl, (vi) -COOC3-6cycloalkyl, (vii) -SO2C1-6alkyl, (viii) -SO2NR5R5,
(ix) -CONR5R5,
(x) -CN, (xi) -C1-6alkyl optionally mono- or di-substituted with a substituent
independently selected
at each occurrence from the group consisting of -OH and -F, (xii) phenyl
optionally mono- or di-
substituted with a substituent independently selected at each occurrence from
the group consisting of
-OH and -F, (xiii) tetrazolyl optionally substituted with methyl, (xiv) 1,2,4-
oxadiazolyl optionally
substituted with methyl, and (xv) pyridinyl optionally substituted with
methyl;
R2 is selected from the group consisting of-H, -OH, -F, -C1-3alkyl, -OC1-
3alkyl and -OC(O)-C1-3alkyl;
R3 is selected from the group consisting of -H, -C I-6alkyl, -C 1-6alkyl
substituted with one or more of
fluoro including for example but not limited to -C1-(perfluoroalkyl such as -
CF3 and -CF2CF3,
-C1-6alkyl substituted with R6, phenyl, -C2-6alkenyl, -C3-6cycloalkyl and -C5 -
7cycloalkenyl;
R4 is selected from the group consisting of-H, -C1-6alkyl, -C1-6alkyl
substituted with one or more of
fluoro including for example but not limited to -C 1-6perfluoroalkyl such as -
CF3 and -CF2CF3,
-C1-6alkyl substituted with R6, phenyl, -C2-6alkenyl, -C3-6cycloalkyl and -C5-
7cycloalkenyl;
R5 is independently selected at each occurrence from the group consisting of-
H, -C1-6 alkyl and
-C3-6cycloalkyl;
R5a is independently selected at each occurrence from the group consisting of -
H, -C1-6 alkyl,
-C3-6cycloalkyl and -COOR5; and
R6 is independently selected at each occurrence from the group consisting of -
COOR5, -C(O)H, -CN,
-CR5R5OH, -OR5, -S-C 1-6alkyl and -S- C3-6 cycloalkyl.
3
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In one embodiment of this invention are compounds within the scope of Formula
I
having structural Formula Ia wherein the variables are as defined in Formula
I:
NNN \ S '
R
/
R2
A
R3 R4 Ia
and the pharmaceutically acceptable salts, esters and solvates thereof.
In another embodiment of this invention are compounds within the scope of
Formula I
having structural Formula Ib wherein the variables are as defined in Formula
I:
~
N~, N N \ ~ R'
~ N
R2 A
R3 R4 Ib
and the pharmaceutically acceptable salts, esters and solvates thereof.
Within each of the embodiments defined by Formulas I, Ia and lb is a class of
compounds wherein "A" is selected from the group consisting of phenyl and
phenyl mono-substituted at
the 3- or 4-position, and particularly wherein the substituent at the 3- or 4-
position on the phenyl is
selected from -Cl and -F, and more particularly wherein the substituent is -F.
In a sub-class of each of
these classes are compounds wherein R2 is selected from the group consisting
of -H, -OH , -F, -CI-
3alkyl, -OCH3, and -OC(O)CH3; R3 is selected from the group consisting of-H, -
C1-6alkyl, -C1-6alkyl
substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl; and R4 is
selected from the group
consisting of -H, -C1-6alkyl, --C1-6alkyl substituted with one or more of
fluoro, -C1-6alkyl substituted
with R6 and -C3-6cycloalkyl. In another sub-class of each class are compounds
wherein R2 is selected
from -H and -OH; R3 is selected from -CH3, -C2H5, -C1-2alkyl substituted with
fluoro particularly
-CF3 and -CF2CF3, and cyclopropyl; and R4 is selected from -CH3 -CH2CH3, -C1-
2alkyl substituted
with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOC1-4alkyl.
In a further sub-class
of each class are compounds wherein R2 is -OH, R3 is -CH2CH3 and R4 is -CF3.
Within each of the embodiments defined by Formulas I, Ia and lb is a class of
compounds wherein "A" is selected from the group consisting of phenyl and
phenyl mono-substituted at
the 3- or 4-position, and particularly wherein the substituent at the 3- or 4-
position on the phenyl is
selected from -Cl and -F, and more particularly wherein the substituent is -F,
and R' is selected from -
COOR5, -CONR5R5, -SO-1-C1_6-alkyl and -SO2NRSR5. In a sub-class of each of
these classes are
compounds wherein R2 is selected from the group consisting of -H, -OH,-F, -C1-
3alkyl, -OCH3, and -
4
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OC(O)CH3; R3 is selected from the group consisting of-H, -C1-6alkyl, -C1-
6alkyl substituted with one
or more of fluoro, -C3-6cycloalkyl and phenyl; and R4 is selected from the
group consisting of -H,
-C I-6alkyl, -C I-6alkyl substituted with one or more of fluoro, -C I-6alkyl
substituted with R6 and -C3-
6cycloalkyl. In another sub-class of each class are compounds wherein R2 is
selected from -H and -OH;
R3 is selected from -CH3 -C2H5, -C1-2alkyl substituted with fluoro
particularly -CF3 and -CF2CF3,
and cyclopropyl; and R4 is selected from -CH3, -CH2CH3, --C 1-2alkyl
substituted with fluoro
particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOC1-4alkyl. In a further
sub-class of each
class are compounds wherein R2 is -OH, R3 is -CH2CH3 and R4 is -CF3.
Within each of the embodiments defined by Formulas I, Ia and Ib is a class of
compounds wherein R' is selected from -COORS, -CONRSR5, -SO2-C1_6 alkyl and -
SO2NR5R5. In a sub-
class of each of these classes are compounds wherein R2 is selected from the
group consisting of -H, -
OH , -F, -C1-3alkyl, -OCH3, and -OC(O)CH3; R3 is selected from the group
consisting of-H, -CI-
6alkyl, -C1-6alkyl substituted with one or more of fluoro, -C 3 -6cycloalkyl
and phenyl; and R4 is selected
from the group consisting of -H, -C I-6alkyl, -C I-6alkyl substituted with one
or more of fluoro, -
CI-(alkyl substituted with R6 and -C3-6cycloalkyl. In another sub-class of
each class are compounds
wherein R2 is selected from -H and -OH; R3 is selected from -CH3, -C2H5, -C1-
2alkyl substituted with
fluoro particularly -CF3 and -CF2CF3, and cyclopropyl; and R4 is selected from
-CH3, -CH2CH3,
-C 1-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, cyclopropyl
and -CH2COOC I-4alkyl.
In a further sub-class of each class are compounds wherein R2 is -OH, R3 is -
CH2CH3 and R4 is -CF3.
Within each of the embodiments defined by Formulas I, Ia and lb is a class of
compounds wherein R2 is selected from the group consisting of -H, -OH , -F, -
C1-3alkyl, -OCH3, and -
OC(O)CH3. In a sub-class of this class are compounds wherein R2 is selected
from -H and -OH. In
another sub-class of this class are compounds wherein R2 is -OH.
Within each of the embodiments defined by Formulas I, la and lb is a class of
compounds wherein R3 is selected from the group consisting of -H, -C I-6alkyl,
-C I-6alkyl substituted
with one or more of fluoro, -C3-6cycloalkyl and phenyl. In a sub-class of this
class are compounds
wherein R3 is selected from -CH3, -C2H5, -C1-2alkyl substituted with fluoro
particularly -CF3 and -
CF2CF3, and cyclopropyl. In another sub-class of this class are compounds
wherein R3 is -CH2CH3.
Within each of the embodiments defined by Formulas I, Ia and Ib is a class of
compounds wherein R4 is selected from the group consisting of -H, -C I-6alkyl,
-C I-(alkyl substituted
with one or more of fluoro, -C1-6alkyl substituted with R6 and -C3-
6cycloalkyl. In a sub-class of this
class are compounds wherein R4 is selected from -CH3 -CH2CH3, -C1-2alkyl
substituted with fluoro
particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOC1-4alkyl. In another
sub-class of this class
are compounds wherein R4 is -CF3.
Within each of the embodiments defined by Formulas I, Ia and Ib is a class of
compounds wherein R2 is selected from the group consisting of -H, -OH,-F, -C1-
3alkyl, -OCH3, and -
5
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OC(O)CH3; R3 is selected from the group consisting of-H, -C1-6alkyl, -C1-
6alkyl substituted with one
or more of fluoro, -C3-6cycloalkyl and phenyl; and R4 is selected from the
group consisting of -H,
-C1-6alkyl, -C1-6alkyl substituted with one or more of fluoro, -C1-6alkyl
substituted with R6 and -C3-
6cycloalkyl. In a sub-class of this class are compounds wherein R2 is selected
from -H and -OH; R3 is
selected from -CH3 -C2H5, -C I-2alkyl substituted with fluoro particularly -
CF3 and -CF2CF3, and
cyclopropyl; and R4 is selected from -CH3, -CH2CH3, -C1-2alkyl substituted
with fluoro particularly
-CF3 and -CF2CF3, cyclopropyl and -CH2COOC1-4a1ky1. In another sub-class of
this class are
compounds wherein R2 is -OH, R3 is -CH2CH3 and R4 is -CF3.
Compounds in the Examples and in Tables I and 2 which have mass spectral (MS)
data
or NMR data associated with them were synthetically prepared. Mass spectra
were measured by
Electron-Spray Ion mass spectroscopy (ESI) or Atmospheric Pressure Chemical
Ionization mass
spectroscopy (APCI) as noted herein.
Examples of compounds within the scope of Formula Ia include but are not
limited to
those in Table I as well as pharmaceutically acceptable salts, esters and
solvates of the compounds.
Table 1
N// N\N S R'
F3C A
HO CH2CH3
Compound # Rl A Formula Mass Spectral
Result
Ia-1 -SO2CH3 4-fluoro-Ph C22H2OF4N303SZ ESI (M+H)+ 514.0
Ia-2 -S02CH3 4-cyclohexyl-Ph
Ia-3 -Br 4-fluoro-Ph
Ia-4 -S02-NI12 4-fluoro-Ph
Ia-5 -SO2-NH-t-Bu 4-fluoro-Ph
Ia-6 -S02CH3 3-fluoro-Ph C22H2oF4N3O3S2 ESI (M+H)+ 514.3
Ia-7 -CONE2 4-fluoro-Ph
Ia-8 -COOCH3 4-fluoro-Ph
la-9 -CN 4-fluoro-Ph
Ia-10 -CONH2 3-fluoro-Ph
Ia-11 -CN 3-fluoro-Ph
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Compound # Rl A Formula Mass Spectral
Result
Ia-12 CH3 Ph C23H21F3N70S ESI (M+H)+ 500.2
N-
N
- ~ II
N,N
Ia-13 N N Ph C23H21F3N70S ESI (M+H)+ 500.1
_ K\ I
NN, CH3
Ia-14 N N Ph C22Hi7F3N70S ESI (M-H)+ 484.3
'N
N
Ia-15 -CONH2 Ph
Ia-16 -Cl Ph CZ,H18C1F3N30S ESI (M+H)+ 452.2
Ia-17 -S02CH3 Ph C22H21F3N303S2 ESI (M+H)+ 496.0
Ia-18 -CHF2 Ph
Ia-19 4-F-Ph Ph C27H22F4N30S ESI (M+H)+ 512.0
Ia-20 \~ CH Ph CZ7H24F3N40S ESI (M+H)+ 509.3
3
Ia-21 _~~N~CH3 Ph
0 -N
Ia-22 \ ~ Ph C26H22F3N40S ESI (M+H)+ 494.8
Ia-23 -CN Ph C22H18F3N40S ESI (M+H)+ 443.2
Ia-24 -Br Ph C21Hl7BrF3N3OS ESI (M+H)+ 496.2
Ia-25 -H Ph C2lH19F3N30S ESI (M+H)+ 417.9
Ia-26 -COCH3 Ph
Ia-27 -CHOHCH3 Ph
Ia-28 -CH2OH Ph
Ia-29 -C(CH3)20H Ph
Ia-30 -CONHCH3 Ph
1a-31 -CON(CH3)2 Ph C24H24F3N402S ESI (M+H)+ 489.3
Ia-32 -COOCH3 Ph
Ia-33 -S02CH3 Cl C16Hl6C1F3N303S2 ESI (M+H)+ 454.1
Ia-34 -CN Cl
Ia-35 -COOCH3 Cl
Ia-36 -S02CH3 3-Me-4-fluoro-Ph C23H22F4N303S2 APCI (M+H)+ 528
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Compound # R1 A Formula Mass Spectral
Result
Ia-37 -S02CH3 4-CH(CH3)2-Ph C25H27F3N303Sz APCI (M+H)+ 538
Ia-38 -S02CH3 3-Me-Ph C23H23F3N303Sz APCI (M+H)+ 510
Ia-39 -S02CH3 4-Me-Ph C23H23F3N303S2 APCI (M+H)+ 510
1a-40 -S02CH3 3,5-difluoro-Ph CZ2H19F5N303SZ ESI (M+H)+ 532.0
Ia-41 -SO2CH3 3-Cl-Ph C22H2OC1F3N303SZ APCI (M+H)+ 530
1a-42 -CON112 3-methoxy-Ph C23H22F3N403S ESI (M+H)+ 491.3
1a-43 -CONH2 4-methoxy-Ph C-l3H22F3N403S ESI (M+H)+ 491.4
Ia-44 -CONH2 3-Me-Ph C23H22F3N402S APCI (M+H)+ 475
Ia-45 -C0NE2 4-Me-Ph C23H22F3N402S APCI (M+H)+ 475
Compound Ia-4
'H NMR (500 MHz, Acetone): S 8.15 (s, 1 H), 8.11 (s, 1 H), 7.62-7.53 (m, 2 H),
7.48 (s, 2 H), 7.29 (t, 2
H), 6.88 (s, 2 H), 5.84 (s, 2 H), 5.43 (s, 1 H), 2.37-2.28 (m, 1 H), 2.11-2.03
(m, 1 H), 0.80 (t, 3 H).
Compound Ia-5
'H NMR (500 MHz, Acetone): S 8.17 (s, 1 H), 8.12 (s, 1 H), 7.70-7.60 (m, 2 H),
7.56 (d, 1 H), 7.47 (d, 1
H), 7.26 (t, 2 H), 6.22 (s, 1 H), 5.87 (s, 2 H), 5.44 (s, 1 H), 2.45-2.30 (m,
1 H), 2.12-2.03 (m, 1 H), 1.17
(s, 9H), 0.84 (t, 3 H).
Compound Ia-18
'H NMR (500 MHz, Acetone): S 8.17 (s, 1 H), 8.16 (s, 1 H), 7.71-7.47 (m, 7 H),
7.01 (t, 1 H), 5.88 (s, 2
H), 5.42 (s, 1 H), 2.40-2.37 (m, 1 H), 2.12-2.04 (m, 1 H), 0.83 (t, 3 H).
Compound 1a-21
'H NMR (500 MHz, Acetone): S 8.18 (s, 1 H), 8.16 (s, 1 H), 7.75-7.65 (m, 4 H),
7.65-7.45 (m, 3 H), 5.89
(s, 2 H), 5.45 (s, 1 H), 2.40-2.30 (m, 1 H), 2.39 (s, 3 H), 2.12-2.04 (m, 1
H), 0.84 (t, 3 H).
Examples of compounds within the scope of Formula Ib include but are not
limited to
those in Table 2 as well as pharmaceutically acceptable salts, esters and
solvates of the compounds.
Table 2
N,
N// N R'
N
F3C
HO CH2CH3 b
Compound # Rl
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Com ound # Rl
lb- I -CN
Ib-2 -CONH2
lb-3 -COCH3
lb-4 -CH(OH)CH3
Ib-5 -CH2OH
rb-6 -COOCH3
lb-7 -COOCH2CH3
Compound Ib-3
'H NMR (500 MHz, Acetone): S 8.06 (s, 1 H), 7.88 (s, 1 H), 7.62 (d, 1 H), 7.56-
7.46 (m, 3 H), 7.40-7.32
(m, 3 H), 7.09 (d,, I H), 5.77 (s, 2 H), 5.42 (s, 1 H), 2.55 (s, 3 H), 2.38-
2.27 (m, 1 H), 2.05 (s, I H), 0.83
(t, 3 H).
Compound Ib-4
'H NMR (500 MHz, Acetone): 6 8.06 (s, 1 H), 7.67(s,1H), 7.60 (m, 2 H), 7.42-
7.56 (m, 3 H), 7.15 (d, 1
H), 7.02 (d,1H), 6.65 (s, 1 H), 5.77 (s, 2 H), 5.42 (s, 1 H), 4.82 (m,1H),
4.19 (d, 1 H), 2.30 (m, 1 H), 2.08-
2.05 (m, I H), 1.42 (d, 3 H), 0.83 (t, 3 H).
Compound Ib-5
'H NMR (500 MHz, Acetone): 6 8.06 (s, I H), 7.70 (s, I H), 7.62 (m, 2 H), 7.52
(m, 3 H), 7.20(d, 1 H),
7.12 (d, I H), 6.68 (d, I H), 5.77 (s, 2 H), 5.42 (s, I H), 4.62(d, 2 H), 4.18
(t, 1 H), 2.38-2.27 (m, I H),
2.08 (s, I H), 0.82 (t, 3 H).
Compound Ib-7
'H NMR (500 MHz, Acetone): 6 8.06 (s, 1 H), 7.85 (s, 1 H), 7.56-7.46 (m, 3 H),
7.45(s, 1 H), 7.40-7.32
(m, 3 H), 7.10 (d, 1 H), 5.78 (s, 2 H), 5.42 (s, 1 H), 4.18 (q, 2 H), 2.35 (m,
I H), 2.08 (m, 1 H), 1.18 (t, 3
H), 0.83 (t, 3 H).
The compounds of this invention, including compounds referenced as those of
"Formula
I," "Formula Ia," "Formula Ib," or any other generic structural formulas used
herein to describe the
compounds of this invention, are intended to encompass compounds falling
within the scope of each of
these structural formulas including pharmaceutically acceptable salts, esters
and solvates thereof where
such salts, esters and solvates are possible.
Herein, the term "pharmaceutically acceptable salts" refers to non-toxic salts
of the
compounds employed in this invention which can generally be prepared by
reacting the free acid with a
suitable organic or inorganic base, particularly those formed from cations
such as sodium, potassium,
aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well
as those salts formed
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from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine,
arginine, ornithine, choline,
N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-
benzylphenethylamine, 1-p-
chlorobenzyl-2-pyrrolidine-1'-yl-methylbenzimidazole, diethylamine,
piperazine, morpholine, 2,4,4-
trimethyl-2-pentamine and tris(hydroxymethyl)aminomethane. When the compound
of the present
invention is basic, salts may be prepared from pharmaceutically acceptable non-
toxic acids, including
inorganic and organic acids. Such acids include acetic, benzenesulfonic,
benzoic, camphorsulfonic,
citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,
hydrochloric, isethionic, lactic, maleic,
malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,
phosphoric, succinic, sulfuric,
tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are
citric, hydrobromic, hydrochloric,
maleic, phosphoric, sulfuric, and tartaric acids.
Also, in the case of a carboxylic acid (-COOH) or alcohol group being present
in the
compounds of this invention, pharmaceutically acceptable esters of carboxylic
acid derivatives can be
employed. Examples of pharmaceutically acceptable esters include, but are not
limited to, -C 1-4 alkyl
(e.g., methyl, ethyl), pivaloyloxymethyl and -C1 -4 alkyl substituted with
phenyl, dimethylamino and
acetylamino. Acyl derivatives of alcohol groups, such as -O-acetyl, -0-
pivaloyl, -O-benzoyl and -0-
aminoacyl can similarly be employed. Included are those esters and acyl groups
known in the art for
modifying the solubility or hydrolysis characteristics of pharmaceutical
compounds for use as pro-drugs
or sustained-release or formulations.
Some of the compounds described herein contain one or more asymmetric centers
and can thus occur as racemates, racemic mixtures, single enantiomers,
diastereoisomeric mixtures
and individual diastereoisomers. The present invention includes all such
possible isomers in
racemic, racemic mixture and resolved, enantiomerically pure forms and the
pharmaceutically
acceptable salts thereof. Furthermore, some of the crystalline forms of
compounds of the present
invention may exist as polymorphs and as such are intended to be included in
the present invention.
In addition, some of the compounds of the instant invention may form solvates
with water or
common organic solvents. Such solvates and hydrates are likewise encompassed
within the scope of
this invention. Some of the compounds described herein contain olefinic double
bonds. The
invention includes both E and Z geometric isomers.
Compounds of this invention may be separated into their individual
diastereoisomers by,
e.g., fractional crystallization from suitable solvents, e.g., methylene
chloride/hexanes or EtOAc/hexanes,
or via chiral chromatography using an optically active stationary phase.
Absolute stereochemistry may
be determined by X-ray crystallography of crystalline products or crystalline
intermediates which are
derivatized, if necessary, with a reagent containing a stereogenic center of
known configuration.
Alternatively, any stereoisomer of a compound of this invention may be
obtained by stereospecific
synthesis using optically pure starting materials or reagents of known
absolute configuration.
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As used herein "alkyl" is intended to include both branched- and straight-
chain saturated
aliphatic hydrocarbon groups having the specified number of carbon atoms,
e.g., methyl (Me), ethyl (Et),
n-propyl (Pr), n-butyl (Bu), n-pentyl, n-hexyl, and the isomers thereof such
as isopropyl (i-Pr), isobutyl
(i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu), isopentyl, isohexyl and the like.
"Cycloalkyl" means a
monocyclic saturated carbocyclic ring, having the specified number of carbon
atoms, e.g., 3, 4, 5 or 6
carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
The term "C2-6alkenyl" as used herein, refers to a straight or branched 2-6
carbon chain
with at least one carbon-carbon double bond. Examples of alkenyl include, but
are not limited to, vinyl
(-CH=CH2), allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-
butenyl, 2-methyl-2-butenyl,
and the like. The term "C5-7 cycloalkenyl" as used herein means a non-aromatic
monocyclic ring having
from 5 to 7 carbon atoms in the ring with at least one carbon-carbon double
bond.
The terms "halo" or "halogen" are meant to include fluoro, chloro, bromo and
iodo,
unless otherwise noted. Fluoro and chloro are preferred, and fluoro is most
preferred.
The term "optionally" substituted means "unsubstituted or substituted," and
therefore,
the generic structural formulas described herein encompass compounds
containing the specified optional
substituent as well as compounds that do not contain the optional substituent.
For example, the phrase
"tetrazolyl optionally substituted with methyl" encompasses unsubstituted
tetrazolyl and tetrazolyl
substituted with methyl. Each variable is independently defined each time it
occurs within the generic
structural formula definitions. For example, when R1 is -SO2NR5R5, R5 is
independently selected at
each occurrence and each R5 can be the same or different.
Use of the term "substituted" is intended to encompass mono- and poly-
substitution on
the specified moiety, unless otherwise specified. A mono-substituted moiety
has one substituent, while a
poly-susbtituted moiety has more than one substituent wherein each carbon
atom, as well as heteroatom
such as nitrogen if present, that is available for substitution in the moiety
may independently be
unsubstituted, mono- or poly-substituted such that it results in the creation
of a stable structure. For
example, "-C1-6alkyl optionally substituted with fluoro" includes but is not
limited to -CH3, -CH2F,
-CHF2, -CF3 and -CH2CF3.
The ability of the compounds of this invention to inhibit biosynthesis of the
leukotrienes
makes them useful for preventing or reversing the symptoms induced by the
leukotrienes in a human
subject. Accordingly, this invention provides a method for preventing the
synthesis, the action, or the
release of leukotrienes in a mammal which comprises administering to said
mammal a 5-LO inhibitory
effective amount of a compound of this invention. Such 5-LO inhibitory
activity can be measured using
the Human 5-Lipoxygenase Enzyme Assay and 5-Lipoxygenase Human Whole Blood
Assay described
herein. Since leukotrienes are potent inflammatory mediators, also provided is
method of treating an
inflammatory condition in a mammal which comprises administering a
therapeutically effective amount
of a compound of this invention to a mammal in need of such treatment.
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The inhibition of the mammalian biosynthesis of leukotrienes also indicates
that the
compounds and pharmaceutical compositions thereof are useful to treat, prevent
or ameliorate
atherosclerosis in mammals, and especially in humans. Therefore, the compounds
of this invention can
be used for the treatment of atherosclerosis comprising administering a
therapeutically effective amount
of a compound of this invention to a patient in need of such treatment.
The method of this invention serves to prevent or slow new atherosclerotic
lesion or
plaque formation, and to prevent or slow progression of existing lesions or
plaques, as well as to cause
regression of existing lesions or plaques. Accordingly, one aspect of this
invention encompassed within
the scope of treatment of atherosclerosis involves a method for halting or
slowing the progression of
atherosclerosis, including halting or slowing atherosclerotic plaque
progression, comprising
administering a therapeutically effective amount of a compound of this
invention to a patient in need of
such treatment. This method includes halting or slowing progression of
atherosclerotic plaques existing
at the time the instant treatment is begun (i.e., "existing atherosclerotic
plaques"), as well as halting or
slowing formation of new atherosclerotic plaques in patients with
atherosclerosis.
Another aspect of this invention encompassed within the scope of treatment of
atherosclerosis involves a method for effecting regression of atherosclerosis,
including effecting
regression of atherosclerotic plaques existing at the time the instant
treatment is begun, comprising
administering a therapeutically effective amount of a compound of this
invention to a patient in need of
such treatment.
Also provided is a method comprising administering to a patient who has
atherosclerosis
a compound of this invention with the objective of preventing or reducing the
risk of atherosclerotic
plaque rupture. Therefore, this invention provides a method for preventing or
reducing the risk of
atherosclerotic plaque rupture comprising administering a prophylactically
effective amount of a
compound of this invention to a patient having atherosclerotic plaque.
This invention also involves a method for preventing or reducing the risk of
developing
atherosclerosis, comprising administering a prophylactically effective amount
of a compound of this
invention to a patient in need of such treatment, including. for example, a
patient who is at risk for
developing atherosclerosis.
Atherosclerosis is characterized by the deposition of atheromatous plaques
containing
cholesterol and lipids on the innermost layer of the walls of large and medium-
sized arteries.
Atherosclerosis encompasses vascular diseases and conditions that are
recognized and understood by
physicians practicing in the relevant fields of medicine. Atherosclerotic
cardiovascular disease including
restenosis following revascularization procedures, coronary heart disease
(also known as coronary artery
disease or ischemic heart disease), cerebrovascular disease including multi-
infarct dementia, and
peripheral vessel disease including erectile dysfunction, are all clinical
manifestations of atherosclerosis
and are therefore encompassed by the terms "atherosclerosis" and
"atherosclerotic disease."
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A compound of the instant invention may be administered to prevent or reduce
the risk
of occurrence, or recurrence where the potential exists, of a coronary heart
disease (CHD) event, a
cerebrovascular event, and/or intermittent claudication. Coronary heart
disease events are intended to
include CHD death, myocardial infarction (i.e., a heart attack), and coronary
revascularization
procedures. Cerebrovascular events are intended to include ischemic or
hemorrhagic stroke (also known
as cerebrovascular accidents) and transient ischemic attacks. Intermittent
claudication is a clinical
manifestation of peripheral vessel disease. The term "atherosclerotic disease
event" as used herein is
intended to encompass coronary heart disease events, cerebrovascular events,
and intermittent
claudication. It is intended that persons who have previously experienced one
or more non-fatal
atherosclerotic disease events are those for whom the potential for recurrence
of such an event exists.
Accordingly, the instant invention also provides a method for preventing or
reducing the
risk of a first or subsequent occurrence of an atherosclerotic disease event
comprising the administration
of a prophylactically effective amount of a compound of this invention to a
patient in need of such
treatment, such as a patient who is at risk for such an event. The patient in
need of such treatment may
already have atherosclerotic disease at the time of administration, or may be
at risk for developing it.
This invention also provides a method for treating, preventing, or
ameliorating angina
and/or myocardial ischemia, comprising administering a therapeutically or
prophylactically effective
amount, as appropriate, of a compound of this invention to a patient in need
of such treatment.
Additionally, the activity of the instant compounds as leukotriene
biosynthesis inhibitors
makes them useful for treating, preventing, or ameliorating:l) pulmonary
disorders including diseases
such as asthma, chronic bronchitis, and related obstructive airway diseases,
2) allergies and allergic
reactions such as allergic rhinitis, contact dermatitis, allergic
conjunctivitis, and the like, 3) inflammation
such as arthritis or inflammatory bowel disease, 4) pain, 5) skin disorders
such as atopic eczema, and the
like, 6) cardiovascular disorders such hypertension, platelet aggregation and
the like, 7) renal
insufficiency arising from ischaemia induced by immunological or chemical
(cyclosporin) etiology and
8) migraine or cluster headache, 9) ocular conditions such as uveitis, 10)
hepatitis resulting from
chemical, immunological or infectious stimuli, 11) trauma or shock states such
as burn injuries,
endotoxemia and the like, 12) allograft rejection, 13) prevention of side
effects associated with
therapeutic administration of cytokines such as Interleukin II and tumor
necrosis factor, 14) chronic lung
diseases such as cystic fibrosis, bronchitis and other small- and large-airway
diseases, 15) cholecystitis,
16) multiple sclerosis, 17) proliferation of myoblastic leukemia cells, 18)
pulmonary fibrosis, 19)
respiratory syncytial virus, 20) acne and 21) sleep apnea.
Particularly, the compounds of this invention can be administered to patients,
including
adult and pediatric patients, for the prophylaxis of asthma and for chronic
treatment of asthma.
The compounds of this invention can be administered to patients, including
adult and pediatric
patients, for the treatment of asthma: (1) as an alternative to low-dose
inhaled corticosteroids (ICS) for
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patients with mild persistent asthma, (2) as concomitant therapy with low-dose
inhaled corticosteroids
(ICS) for patients with mild persistent asthma, or (3) as concomitant therapy
in patients with persistent
asthma who are inadequately controlled on inhaled corticosteroids (ICS) or on
combined ICS/long-acting
beta-agonist (LABA) therapy. The compounds can be used for treatment of
asthmatic patients including,
but not limited to, steroid resistant/non-responder asthmatics, asthmatics for
whom leukotriene modifiers
have previously failed, smoking asthmatics, and aspirin sensitive asthmatics.
The compounds can be administered to patients to: (1) improve FEV 1(Forced
Expitory
Volume in one minute), (2) improve morning and evening PEF (Peak Expitory
flow), (3) reduce beta-
agonist use (measured by puffs/day), (4) reduce inhaled / systemic steroid
use. (5) improve daytime
asthma symptoms, (6) reduce number of nocturnal awakenings, 7) improve asthma
control days, (8)
reduce number of asthma exacerbations, wherein an exacerbation is defined as:
requiring systemic
steroid, an emergency room visit, hospitalization, an unscheduled asthma
related doctor visit, decrease in
A.M. PEF by >20% or A.M. PEF <1801/min, increased SABA (short-acting beta-
agonist) use >70%
from baseline (minimum increase 2 puffs), or increased symptom score of >50%,
(9) reduce the
number of asthma attacks (measured as % of days with at least one attack over
a specified period of total
days), wherein the attack is one that requires systemic steroid use, an
emergency room visit,
hospitalization, or an unscheduled asthma related doctor visit, (10) reduce
the number of acute asthma
attacks, (11) reduce blood and sputum eosinophils, and/or (12) prevent and
treat EIB (exercised induced
bronchoconstriction).
Additionally, the compounds of this invention can be administered to patients,
including adult and pediatric patients, for the relief of symptoms of allergic
rhinitis, including
seasonal allergic rhinitis.
Thus, the compounds of the present invention may also be used to treat or
prevent
mammalian (especially, human) disease states such as erosive gastritis;
erosive esophagitis; diarrhea;
cerebral spasm; premature labor; spontaneous abortion; dysmenorrhea; ischemia;
noxious agent-induced
damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver
parenchymal damage caused
by hepatoxic agents such as CC14 and D-galactosamine; ischemic renal failure;
disease-induced hepatic
damage; bile salt induced pancreatic or gastric damage; trauma- or stress-
induced cell damage; and
glycerol-induced renal failure. Leukotriene biosynthesis inhibitors also act
as inhibitors of tumor
metastasis and exhibit cytoprotective action.
The cytoprotective activity of a compound may be observed in both animals and
man by
noting the increased resistance of the gastrointestinal mucosa to the noxious
effects of strong irritants, for
example, the ulcerogenic effects of aspirin or indomethacin. In addition to
lessening the effect of non-
steroidal anti-inflammatory drugs on the gastrointestinal tract, animal
studies show that cytoprotective
compounds will prevent gastric lesions induced by oral administration of
strong acids, strong bases,
ethanol, hypertonic saline solutions, and the like. Two assays can be used to
measure cytoprotective
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ability. These assays are: (A) an ethanol-induced lesion assay and (B) an
indomethacin-induced ulcer
assay and are described in EP 140,684. In particular, the compounds of the
invention would be useful to
reduce the gastric erosion caused by co-administration of a cyclooxygenase-2
selective inhibitor such as
rofecoxib (VIOXX ), etoricoxib (ARCOXIATM), and celecoxib (CELEBREX ) and low-
dose aspirin.
In addition, the compounds of this invention can also be used for the
treatment of chronic
obstructive pulmonary disease (COPD). As described in S. Kilfeather, Chest,
2002, vol 121, 197, airway
neutrophilia in COPD patients is believed to be a contributing source of
inflammation and is associated
with airway remodeling. The presence of neutrophils is mediated in part by
LTB4, and treatment with the
instant compounds could be used to reduce neutrophilic inflammation in
patients with COPD and reduce
the rate of COPD exacerbations. In particular, the compounds of this invention
could be used for daily,
preferably once-daily, maintenance treatment of airflow obstruction associated
with COPD, including
chronic bronchitis and emphysema.
The term "patient" includes mammals, especially humans, who use the instant
active
agents for the prevention or treatment of a medical condition. Administering
of the drug to the patient
includes both self-administration and administration to the patient by another
person. The patient may be
in need of treatment for an existing disease or medical condition, or may
desire prophylactic treatment to
prevent or reduce the risk for diseases and medical conditions affected by
inhibition of leukotriene
biosynthesis.
The term "therapeutically effective amount" is intended to mean that amount of
a drug or
pharmaceutical agent that will elicit the biological or medical response of a
tissue, a system, animal or
human that is being sought by a researcher, veterinarian, medical doctor or
other clinician. The term
"prophylactically effective amount" is intended to mean that amount of a
pharmaceutical drug that will
prevent or reduce the risk of occurrence of the biological or medical event
that is sought to be prevented
in a tissue, a system, animal or human by a researcher, veterinarian, medical
doctor or other clinician.
The magnitude of prophylactic or therapeutic dose of a compound of this
invention will,
of course, vary with the nature of the severity of the condition to be treated
and with the particular
compound and its route of administration. It will also vary according to the
age, weight and response of
the individual patient. It is understood that a specific daily dosage amount
can simultaneously be both a
therapeutically effective amount, e.g., for treatment to slow progression of
existing atherosclerosis, and a
prophylactically effective amount, e.g., for prevention of an atherosclerotic
disease event or formation of
new lesions. In general, the daily dose range for anti-asthmatic, anti-
inflammatory, anti-allergic or anti-
atherosclerotic use and generally, uses other than cytoprotection, lie within
the range of from about 0.001
mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about
10 mg per kg, and
most preferably 0.1 to 1 mg per kg, in single or divided doses. On the other
hand, it may be necessary to
use dosages outside these limits in some cases.
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In the case where an oral composition is employed, a suitable daily dosage
range for anti-
asthmatic, anti-inflammatory, anti-allergic or anti-atherosclerotic use is,
e.g., from about 0.01 mg to
about 100 mg of a compound of this invention per kg of body weight per day,
and preferably from about
0.1 mg to about 10 mg per kg. For cytoprotective use a suitable daily dosage
range is from 0.1 mg to
about 100 mg, preferably from about 1 mg to about 100 mg, and more preferably
from about 10 mg to
about 100 mg, of a compound of this invention per kg of body weight per day.
For use where a composition for intravenous administration is employed, a
suitable daily
dosage range for anti-asthmatic, anti-inflammatory, anti-atherosclerotic or
anti-allergic use is from about
0.00 1 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound
of this invention per kg
of body weight per day and for cytoprotective use from about 0.1 mg to about
100 mg (preferably from
about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg)
of a compound of this
invention per kg of body weight per day. For the treatment of diseases of the
eye, ophthalmic
preparations for ocular administration comprising 0.001-1% by weight solutions
or suspensions of the
compounds of this invention in an acceptable ophthalmic formulation may be
used.
The exact amount of a compound of this invention to be used as a
cytoprotective agent
will depend on, inter alia, whether it is being administered to heal damaged
cells or to avoid future
damage, on the nature of the damaged cells (e.g., gastrointestinal ulcerations
vs. nephrotic necrosis), and
on the nature of the causative agent. An example of the use of a compound of
this invention in avoiding
future damage would be co-administration of a compound of this invention with
an NSAID that might
otherwise cause such damage (for example, indomethacin). For such use, the
compound of this invention
is administered from 30 minutes prior up to 30 minutes after administration of
the NSAID. Preferably it
is administered prior to or simultaneously with the NSAID, (for example, in a
combination dosage form).
The pharmaceutical compositions of the present invention comprise a compound
of this
invention as an active ingredient and a pharmaceutically acceptable carrier
and optionally other
therapeutic ingredients. Any suitable route of administration may be employed
for providing a mammal,
especially a human with an effective dosage of a compound of the present
invention. For example, oral,
rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be
employed. Dosage forms
include tablets, troches, dispersions, suspensions, solutions, capsules,
creams, ointments, aerosols, and
the like. For use in treating or preventing atherosclerosis and related
disease events, oral formulation is
preferred.
The compositions include compositions suitable for oral, rectal, topical,
parenteral
(including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic),
pulmonary (nasal or
buccal inhalation), or nasal administration, although the most suitable route
in any given case will
depend on the nature and severity of the conditions being treated and on the
nature of the active
ingredient. They may be conveniently presented in unit dosage form and
prepared by any of the methods
well-known in the art of pharmacy.
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For administration by inhalation, the compounds of the present invention are
conveniently delivered in the form of an aerosol spray presentation from
pressurized packs or nebulisers.
The compounds may also be delivered as powders which may be formulated and the
powder composition
may be inhaled with the aid of an insufflation powder inhaler device. The
preferred delivery system for
inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated
as a suspension or
solution of a compound of this invention in suitable propellants, such as
fluorocarbons or hydrocarbons.
Suitable topical formulations of a compound of this invention include
transdermal
devices, aerosols, creams, ointments, lotions, dusting powders, and the like.
In practical use, the compounds of this invention can be combined as the
active
ingredient in intimate admixture with a pharmaceutical carrier according to
conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of forms depending
on the form of
preparation desired for administration, e.g., oral or parenteral (including
intravenous). In preparing the
compositions for oral dosage form, any of the usual pharmaceutical media may
be employed, such as, for
example, water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like in the
case of oral liquid preparations, such as, for example, suspensions, elixirs
and solutions; or carriers such
as starches, sugars, microcrystalline cellulose, diluents, granulating agents,
lubricants, binders,
disintegrating agents and the like in the case of oral solid preparations such
as, for example, powders,
capsules and tablets, with the solid oral preparations being preferred over
the liquid preparations.
Because of their ease of administration, tablets and capsules represent the
most advantageous oral dosage
unit form in which case solid pharmaceutical carriers are obviously employed.
If desired, tablets may be
coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of this
invention
may also be administered by controlled release means and/or delivery devices
such as those described in
U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200;
4,008,719; and 5,366,738 the
disclosures of which are incorporated herein by reference.
Pharmaceutical compositions of the present invention suitable for oral
administration
may be presented as discrete units such as capsules, cachets or tablets, each
containing a predetermined
amount of the active ingredient, as a powder or granules or as a solution or a
suspension in an aqueous
liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil
liquid emulsion. Such
compositions may be prepared by any of the methods of pharmacy but all methods
include the step of
bringing into association the active ingredient with the carrier which
constitutes one or more necessary
ingredients. In general, the compositions are prepared by uniformly and
intimately admixing the active
ingredient with liquid carriers or finely divided solid carriers or both, and
then, if necessary, shaping the
product into the desired presentation. For example, a tablet may be prepared
by compression or molding,
optionally with one or more accessory ingredients. Compressed tablets may be
prepared by compressing
in a suitable machine, the active ingredient in a free-flowing form such as
powder or granules, optionally
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mixed with a binder, lubricant, inert diluent, surface active or dispersing
agent. Molded tablets may be
made by molding in a suitable machine, a mixture of the powdered compound
moistened with an inert
liquid diluent. Desirably, each tablet, cachet or capsule contains from about
1 mg to about 500 mg of the
active ingredient, for example but not limited to 10 mg, 20mg, 30mg, 40mg, 50
mg and 75mg. The
following are examples of representative pharmaceutical dosage forms for the
compounds of this
invention:
Injectable Suspension (I.M.) mg/mi
Compound of Formula I 10
Methylcellulose 5.0
Tween 80 0.5
Benzyl alcohol 9.0
Benzalkonium chloride 1.0
Water for injection to a total volume of 1 ml
Tablet m /tg ablet
Compound of Formula I 25
Microcrystalline Cellulose 415
Providone 14.0
Pregelatinized Starch 43.5
Magnesium Stearate 2.5
500
Capsule mQ/capsule
Compound of Formula I 25
Lactose Powder 573.5
Magnesium Stearate 1.5
600
Aerosol Per canister
Compound of Formula I 24 mg
Lecithin, NF Liquid Concentrate 1.2 mg
Trichlorofluoromethane, NF 4.025 gm
Dichlorodifluoromethane, NF 12.15 gm
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The instant invention also encompasses a process for preparing a
pharmaceutical
composition comprising combining a compound of this invention with a
pharmaceutically acceptable
carrier. Also encompassed is the pharmaceutical composition which is made by
combining a compound
of this invention with a pharmaceutically acceptable carrier.
A therapeutically effective amount of a compound of this invention can be used
for the
preparation of a medicament useful for treating or preventing any of the
medical conditions described
herein, in dosage amounts described herein. For example, a compound of this
invention can be used for
the preparation of a medicament useful for preventing or reducing the risk of
developing atherosclerotic
disease, halting or slowing the progression of atherosclerotic disease once it
has become clinically
manifest, and preventing or reducing the risk of a first or subsequent
occurrence of an atherosclerotic
disease event. Additionally, a compound of this invention can be used for the
preparation of a
medicament useful for the treatment of asthma, allergies and allergic
conditions, inflammation, COPD or
erosive gastritis. The medicament comprised of a compound of this invention
may also be prepared with
one or more additional active agents, such as those described below.
One or more additional active agents may be used in combination with the
compounds of
this invention in a single dosage formulation, or the active agents of the
combination may be
administered to the patient in separate dosage formulations, which allows for
concurrent or sequential
administration of the active agents. Unless otherwise specified, reference
herein to compounds of this
invention being used in combination with other active agents or used as part
of combination therapy or
the like encompasses both a single pharmaceutical composition comprised of a
compound of this
invention with one or more additional active agents, as well as a
pharmaceutical composition comprised
of a compound of this invention administered as part of a combination therapy
with one or more other
separately formulated active agents.
In addition to the compounds of this invention, the pharmaceutical
compositions of the
present invention can also contain other active agents (i.e., ingredients) and
the pharmaceutical
compositions comprised of a compound of this invention may be used for
combination therapy with one
or more other separately formulated active agents, such as cyclooxygenase
inhibitors, non-steroidal
anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as
zomepirac diflunisal and the like.
The weight ratio of the compound of this invention to the second active
ingredient may be varied and
will depend upon the effective dose of each ingredient. Generally, an
effective dose of each will be used.
Thus, for example, when a compound of this invention is combined with an NSAID
the weight ratio of
the compound of said compound to the NSAID will generally range from about
1000:1 to about 1:1000,
preferably about 200:1 to about 1:200. Combinations of a compound of this
invention and other active
ingredients will generally also be within the aforementioned range, but in
each case, an effective dose of
each active ingredient should be used.
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NSAIDs can be characterized into five groups: (1) propionic acid derivatives;
(2) acetic
acid derivatives; (3) fenamic acid derivatives; (4)oxicams; and
(5)biphenylcarboxylic acid derivatives;
or a pharmaceutically acceptable salt thereof.
The propionic acid derivatives which may be used comprise: alminoprofen,
benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,
flurbiprofen, ibuprofen,
indoprofen, ketoprofen, miroprofen,naproxen,oxaprozin,pirprofen,prano-
profen,suprofen,tiaprofenic
acid, and tioxaprofen. Structurally related propionic acid derivatives having
similar analgesic and anti-
inflammatory properties are also intended to be included in this group. Thus,
"propionic acid
derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-
inflammatory drugs having a
free -CH(CH3)COOH or -CH2CH2COOH group (which optionally can be in the form of
a
pharmaceutically acceptable salt group, e.g., -CH(CH3)COO-Na+ or -CH2CH2COO-
Na+), typically
attached directly or via a carbonyl function to a ring system, preferably to
an aromatic ring system.
The acetic acid derivatives which may be used comprise: indomethacin, which is
a
preferred NSAID, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac,
fenclozic acid, fentiazac,
furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin,
zidometacin, and zomepirac.
Structually related acetic acid derivatives having similar analgesic and anti-
inflammatory properties are
also intended to be encompassed by this group. Thus, "acetic acid derivatives"
as defined herein are non-
narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -
CH2COOH group (which
optionally can be in the form of a pharmaceutically acceptable salt group,
e.g., -CH2COO-Na+), typically
attached directly to a ring system, preferably to an aromatic or
heteroaromatic ring system.
The fenamic acid derivatives which may be used comprise: flufenamic acid,
meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid.
Structurally related fenamic acid
derivatives having similar analgesic and anti-inflammatory properties are also
intended to be
encompassed by this group. Thus, "fenamic acid derivatives" as defined herein
are non-narcotic
analgesics/non-steroidal anti-inflammatory drugs which contain the basic
structure:
CR~NH_O
CO2H
which can bear a variety of substituents and in which the free -COOH group can
be in the form of a
pharmaceutically acceptable salt group, e.g., -COO-Na+.
The biphenylcarboxylic acid derivatives which can be used comprise: diflunisal
and
flufenisal. Structurally related biphenyl-carboxylic acid derivatives having
similar analgesic and anti-
inflammatory properties are also intended to be encompassed by this group.
Thus, "biphenylcarboxylic
CA 02618586 2008-02-08
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acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal
anti-inflammatory drugs
which contain the basic structure:
a-oq
COOH
which can bear a variety of substituents and in which the free -COOH group can
be in the form of a
pharmaceutically acceptable salt group, e.g., -COO-Na+.
The oxicams which can be used in the present invention comprise: isoxicam,
piroxicam,
sudoxicam and tenoxican. Structurally related oxicams having similar analgesic
and anti-inflammatory
properties are also intended to be encompassed by this group. Thus, "oxicams"
as defined herein are
non-narcotic analgesics/non-steroidal anti-inflammatory drugs which have the
general formula:
OH O
NHR
S CH3
(O)2
wherein R is an aryl or heteroaryl ring system.
The following NSAIDs may also be used: amfenac sodium, aminoprofen,
anitrazafen,
antrafenine, auranofin, bendazac lysinate, benzydanine, beprozin, broperamole,
bufezolac, cinmetacin,
ciproquazone, cloximate, dazidamine, deboxamet, delmetacin, detomidine,
dexindoprofen, diacerein,
di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole,
etersalate, etodolac,
etofenamate, fanetizole mesylate, fenclorac, fendosal, fenflumizole,
feprazone, floctafenine, flunixin,
flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen,
glucametacin, guaimesal, ibuproxam,
isofezolac, isonixim, isoprofen, isoxicam, lefetamine HCI, leflunomide,
lofemizole, lonazolac calcium,
lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium, meseclazone,
nabumetone, nictindole,
nimesulide, orpanoxin, oxametacin, oxapadol, perisoxal citrate, pimeprofen,
pimetacin, piproxen,
pirazolac, pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen,
sudoxicam, talmetacin,
talniflumate, tenoxicam, thiazolinobutazone, thielavin B, tiaramide HCI,
tiflamizole, timegadine,
tolpadol, tryptamid, and ufenamate. The following NSAIDs, designated by
company code number (see
e.g., Pharmaprojects), may also be used: 480156S, AA861, AD 1590, AFP802,
AFP860, A177B, AP504,
AU8001, BPPC, BW540C, CHINOIN 127, CN100, EB382, EL508, F1044, GV3658, ITF182,
KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, ON03144, PR823, PV 102, PV 108,
R830,
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RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901
(4-benzoyl-l-
indancarboxylic acid), TVX2706, U60257, UR2301, and WY41770.
Finally, NSAIDs which may also be used include the salicylates, specifically
acetyl
salicylic acid and the phenylbutazones, and pharmaceutically acceptable salts
thereof.
In addition to indomethacin, other preferred NSAIDs are acetyl salicylic acid,
diclofenac,
fenbufen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen,
phenylbutazone, piroxicam,
sulindac, and tolmetin. Pharmaceutical compositions and combinations
comprising compounds of this
invention may also contain inhibitors of the biosynthesis of the leukotrienes
such as are disclosed in EP
138,481 (April 24,1985), EP 115,394 (August 8, 1984), EP 136,893 (April 10,
1985), and EP 140,709
(May 8, 1985), which are hereby incorporated herein by reference.
The compounds of this invention may also be used in combination with
leukotriene
antagonists such as those disclosed in EP 106,565 (April 25, 1984) and EP
104,885 (Apri14, 1984)
which are hereby incorporated herein by reference and others known in the art
such as those disclosed in
EP Application Nos. 56,172 (July 21, 1982) and 61,800 (June 10, 1982); and in
U.K. Patent Specification
No. 2,058,785 (April 15, 1981), which are hereby incorporated herein by
reference.
Pharmaceutical compositions and combinations comprising compounds of this
invention
may also contain as the second active ingredient, or be used in combination
therapy with, prostaglandin
antagonists such as those disclosed in EP 11,067 (May 28, 1980) or thromboxane
antagonists such as
those disclosed in U.S. Pat. 4,237,160. They may also contain or be used with
histidine decarboxylase
inhibitors such as a-fluoromethylhistidine, described in U.S. Pat. 4,325,961.
The compounds of this
invention may also be advantageously combined with an H1 or H2-receptor
antagonist, such as for
instance acetamazole, aminothiadiazoles disclosed in EP 40,696 (December 2,
1981), benadryl,
cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine,
terfenadine and like compounds, such
as those disclosed in U.S. Patent Nos. 4,283,408; 4,362,736; and 4,394,508.
The pharmaceutical
compositions may also contain or be used in combination with a K+/H+ ATPase
inhibitor such as
omeprazole, disclosed in U.S. Pat. 4,255,431, and the like. Compounds of this
invention may also be
usefully combined with most cell stabilizing agents, such as 1,3-bis(2-
carboxychromon-5-yloxy)-2-
hydroxypropane and related compounds described in British Patent
Specifications 1,144,905 and
1,144,906. Another useful pharmaceutical composition comprises compounds of
this invention in
combination with serotonin antagonists such as methysergide, the serotonin
antagonists described in
Nature, 316, 126-131 (1985), and the like. Each of the references referred to
in this paragraph is hereby
incorporated herein by reference.
Other advantageous pharmaceutical combinations comprise the compounds of this
invention in combination with anti-cholinergics such as ipratropium bromide
and tiotropium,
bronchodilators such as the beta agonist salbutamol, metaproterenol,
terbutaline, fenoterol, salmeterol,
formoterol and the like, and the anti-asthmatic drugs theophylline, choline
theophyllinate and
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enprofylline, the calcium antagonists nifedipine, diltiazem, nitrendipine,
verapamil, nimodipine,
felodipine, etc., and the corticosteroids, hydrocortisone, methylprednisolone,
betamethasone,
dexamethasone, beclomethasone, and the like.
Particularly, for the prophylaxis and treatment of asthma, compounds of this
invention
can be used in combination with orally inhaled corticosteroids, such as
beclomethasone (e.g. QVAR
Inhalation Aerosol), budesonide (e.g. Pulmicort Respules), flunisolide (e.g.,
AEROBID and
AEROBID -M Inhaler System), fluticasone (e.g., FLOVENT DISKUS inhalation
powder,
FLOVENT HFA Inhalation Aerosol), mometasone (e.g., ASMANEX TWISTHALER ), and
triamcinolone (e.g., AZMACORT Inhalation Aerosol), and also with inhaled
corticosteroid/LABA
products such as fluticasone propionate/salmeterol (e.g., ADVAIR DISKUS ). The
instant compounds
could also be used in combination with leukotriene receptor antagonists such
as montelukast (e.g.,
SINGULAIR ); phosphodiesterase 4 (PDE4) inhibitors such as roflumilast, N-
Cyclopropyl-l-[3-(1-
oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-
carboxamide and the
compounds disclosed in PCT Publication W02003/018579; and Very Late Antigen 4
(VLA4) inhibitors
such as the compounds disclosed in U.S. Pat. No. 6,229,011, particularly R411
(N-(2-Chloro-6-
methylbenzoyl)-4-[(2,6- dichlorobenzoyl) amino]-L-phenylalanine-2-
(diethylamino)ethyl ester which is
an ester pro-drug of the active moiety, N-(2-chloro-6-methylbenzoyl)-4- [(2,6-
dichlorobenzoyl)amino]-L-
phenylalanine), and the compounds disclosed in PCT publication W02006/023396.
Furthermore, additional active agents such as anti-atherosclerotic agents,
anti-diabetes
agents, anti-obesity agents and agents used for the treatment of metabolic
syndrome, may be used in
combination with the compounds of this invention. The additional active agent
or agents can be lipid
altering compounds such as HMG-CoA reductase inhibitors, or agents having
other pharmaceutical
activities, or agents that have both lipid-altering effects and other
pharmaceutical activities. Examples of
HMG-CoA reductase inhibitors useful for this purpose include statins in their
lactonized or dihydroxy
open acid forms and pharmaceutically acceptable salts and esters thereof,
including but not limited to
lovastatin (MEVACOR ; see US Patent No. 4,342,767); simvastatin (ZOCOR ; see
US Patent No.
4,444,784); dihydroxy open-acid simvastatin, particularly the ammonium or
calcium salts thereof;
pravastatin, particularly the sodium salt thereof (PRAVACHOL ; see US Patent
No. 4,346,227);
fluvastatin particularly the sodium salt thereof (LESCOL ; see US Patent No.
5,354,772); atorvastatin,
particularly the calcium salt thereof (LIPITOR ; see US Patent No. 5,273,995);
pitavastatin also referred
to as NK-104 (see PCT international publication number WO 97/23200); and
rosuvastatin (CRESTOR ;
see US Patent No. 5,260,440). Additional active agents which may be employed
in combination with a
compound of this invention include but are not limited to HMG-CoA synthase
inhibitors; cholesterol
absorption inhibitors such as ezetimibe (ZETIA ) which is 1-(4-fluorophenyl)-
3(R)-[3(S)-(4-
fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone,
described in U.S. Patent No.'s
Re. 37721 and 5,846,966 as well as a fixed dose combination of ezetimibe and
simvastatin
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(VYTORIN ); HDL-raising agents such as cholesterol ester transfer protein
(CETP) inhibitors, for
example JTT-705 (Japan Tobacco Company) and torcetrapib (Pfizer); squalene
epoxidase inhibitors;
squalene synthetase inhibitors (also known as squalene synthase inhibitors);
acyl-coenzyme A:
cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors
of ACAT-1 or ACAT-2 as
well as dual inhibitors of ACAT1 and -2; microsomal triglyceride transfer
protein (MTP) inhibitors;
probucol; niacin; bile acid sequestrants; LDL (low density lipoprotein)
receptor inducers; platelet
aggregation inhibitors, for example glycoprotein Ilb/IIIa fibrinogen receptor
antagonists and aspirin;
human peroxisome proliferator activated receptor gamma (PPARy) agonists
including the compounds
commonly referred to as glitazones for example troglitazone, pioglitazone and
rosiglitazone and,
including those compounds included within the structural class known as
thiazolidinediones as well as
those PPARy agonists outside the thiazolidinedione structural class; PPARa
agonists such as clofibrate,
fenofibrate including micronized fenofibrate and gemfibrozil; PPAR dual a/y
agonists such as
muraglitazar; vitamin B6 (also known as pyridoxine) and the pharmaceutically
acceptable salts thereof
such as the HCI salt; vitamin B 12 (also known as cyanocobalamin); folic acid
or a pharmaceutically
acceptable salt or ester thereof such as the sodium salt and the
methylglucamine salt; anti-oxidant
vitamins such as vitamin C and E and beta carotene; beta-blockers; angiotensin
II antagonists such as
losartan and losartan with hydrochlorothiazide; angiotensin converting enzyme
inhibitors such as
enalapril and captopril; calcium channel blockers such as nifedipine and
diltiazam; endothelian
antagonists; agents that enhance ABC1 gene expression; FXR and LXR ligands
including both inhibitors
and agonists; bisphosphonate compounds such as alendronate sodium; and
cyclooxygenase-2 inhibitors
such as rofecoxib, etoricoxib and celecoxib. Anti-obesity agents can be
employed in combination with a
compound of this invention including, but not limited to, sibutramine,
orlistat, topiramate, naltrexone,
bupriopion, phentermine, and phentermine/topiramate combination (QNEXA(V);
NPY5 antagonists;
Acetyl-CoA Carboxylase-1 and -2 (ACC) inhibitors; MCH1R antagonists; and CB1
antagonists/inverse
agonists such as those described in W003/077847 and W005/000809. Additional
anti-diabetes agents
which may be employed in combination with a compound of this invention include
but are not limited to
DPP-4 (dipeptidylpeptidase-4) inhibitors such as sitagliptin (JANUVIA ) and
vildagliptin (GALVUS );
sulfonylureas e.g., chlorpropamide, tolazamide, glyburide, glipizide, and
glimepiride; biguanides, e.g.,
metformin; alpha-glucosidase inhibitors e.g., acarbose and miglitol;
meglitinides e.g., repaglinide;
glucagon-receptor agonists; and glucokinase activators.
Compounds of this invention can be tested using the following assays to
determine their
mammalian leukotriene biosynthesis inhibiting activity. Representative tested
compounds of this
invention were shown to be inhibitors of leukotriene biosynthesis, with most
having an IC50 less than or
equal to 4 M in the Human 5-Lipoxygenase Enzyme Assay, described below, with
preferred compounds
tested in this assay having an IC501ess than or equal to 0.100 M. The
representative tested compounds
were also shown to have activity as 5-LO inhibitors in the 5-Lipoxygenase
Human Whole Blood Assay,
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WO 2007/016784 PCT/CA2006/001306
described below, with most having an IC501ess than or equal to 5 M, and
preferred compounds having
an IC50 of less than or equal to 0.500 M.
Human 5-Lipoxygenase Enzyme Assay
The activity of 5-lipoxygenase was measured using a spectrophotometric assay
and
recombinant human 5-lipoxygenase as a source of enzyme. Human 5-lipoxygenase
was purified from
Sf9 cells infected with the recombinant baculovirus rvH5LO (8-1) containing
the coding sequence for
human 5-lipoxygenase as described by Percival et al., (Eur. J. Biochem 210,
109-117, 1992). The
enzymatic activity was measured using a spectrophotometric assay from the
optimal rate of conjugated
diene formation (absorbance at 238 nm) using the procedure described in
Riendeau et al. (Biochem.
Pharmacol. 38, 2313-2321, 1989) with minor modifications. The incubation
mixture contained 25 mM
potassium phosphate, pH 7.5, 0.1 mM EDTA, 0.3 mM CaClz, 24 g/ml
phosphatidylcholine, 0.1 ni1V1
ATP, 0.5 mM DTT, 20 M arachidonic acid (2 l from a 100-fold solution in
ethanol), inhibitor (2 l
aliquot from a 100-fold solution in DMSO) and an aliquot of purified 5-
lipoxygenase. Reactions were
initiated by the addition of the purified 5-lipoxygenase and the rate of
conjugated diene production was
followed for 5 minutes at room temperature. The reaction was performed in a
Costar UV plate (Cat. #
3635) and the absorbance changes at 238 nm were recorded with a Molecular
Devices UV/VIS 96 well
spectrophotometer (Spectra Max 190) using SOFTmax PRO software. Enzymatic
activity was calculated
from the optimal rate of the reaction by a linear fit of the increase in
absorbance at 238 nm over 36
seconds. When the rate of diene formation is low (<0.01 Absorbance Unit/min)
the linear fit is
performed over 180 seconds. The results are expressed as percentage of
inhibition of the reaction rate
relative to controls (typically between 0.00 1-0.005 Absorbance Unit/min)
containing the DMSO vehicle.
CA 02618586 2008-02-08
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5-Lipoxygenase Human Whole Blood Assay
Fresh blood is collected in heparinized tubes by venipuncture from volunteers
with
consent. The subjects have no apparent inflammatory conditions and have not
taken any nonsteroidal
anti-inflammatory drugs for at least 4 days prior to blood collection. 250 l
aliquots of blood are pre-
incubated with either 0.5 l of vehicle (DMSO) or test compound at 37 C for 15
minutes. This is
followed by incubation of the blood with 5 l of either plasma or a 1.25 mM
solution of the calcium
ionophore A23187 (Sigma, St Louis, Mo, USA) in plasma. The latter solution is
prepared by centrifuging
approximately 10 mis of blood from each donor and collecting the plasma. A
50mM stock solution of
A23187 in DMSO is diluted 40-fold in plasma to yield a 1.25 mM working
solution. Five ls of this
working solution is added to each appropriate 250g1-aliquot of blood of the
same donor from which the
plasma was prepared to give a final concentration of 25 M of A23187. The blood
is then incubated at
37 C for 30 minutes. Following incubation, the blood is centrifuged at 1500g
at 4 C for 10 minutes.
Plasma is then collected from all samples and stored at 4 C until time of
enzyme immunosorbent assay
(EIA). All samples are tested for the production of leukotriene B4 (LTB4)
using the LTB4 EIA kit from
Assay Designs (Ann Arbor, MI, USA) according to the manufacturer's
instructions.
Compounds of this invention may be prepared employing general synthetic
procedures
known in the art. The synthetic routes outlined in the following methods,
reaction schemes and
Examples are provided for illustrative purposes.
Some abbreviations used herein include: Ac = acyl; AIBN = 2,2'-
azobisisobutyronitrile;
Bz or bz = benzyl; CAN = cerium anunonium nitrate; CDI = 1,1'-carbonyl
diimidazole; cy = cyclohexyl;
DAST = diethylaminosulfur trifluoride; DBU = 1,8-diazabicyclo[5.4.0]undec-7-
ene; DCC = 1,3-
dicyclohexylcarbodiimide; DCM = dichloromethane; DIBAL = diisobutylaluminum
hydride; DIPEA =
N,N-diisopropylethylamine; DMAP = 4-(dimethylamino)pyridine; DME = ethylene
glycol dimethyl
ether; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; eq =
equivalent; EtOH = ethanol;
Et20 = diethyl ether; Et3N = triethylamine; EtOAc = ethyl acetate; h = hours;
'H NMR is proton nuclear
magnetic resonance; HOAc = acetic acid; KHMDS = potassium
bis(trimethylsilyl)amide; LAH = lithium
aluminum hydride; LDA = lithium diisopropylamide; m-CPBA (or MCPBA) = 3-
chloroperoxybenzoic
acid; MsCl = methanesulphonyl chloride; MeOH = methanol; NBS = N-
bromosuccinimide; NCS = N-
chlorosuccinimide; NMO = 4-methylmorpholine N-oxide; NMP = 1-methyl-2-
pyrrolidinone; OTf =
trifluoromethanesulfonate = triflate; O-THP = O-tetrahydropyran-2-yl; Ph =
phenyl; PPTS = pyridinium
p-toluenesulfonate; rt = room temperature; TBAF = tetrabutylammonium fluoride;
TfZO = triflic
anhydride (also known as trifluoromethanesulfonic anhydride); TFA = trifluoro
acetic acid; TFAA =
trifluoracetic anhydride; THF = tetrahydrofuran; TMSCN = trimethylsilyl
cyanide.
Synthetic procedures used to prepare the compounds of this invention are
outlined in
Schemes 1-12. The variable "-X" depicted in some of the structures in the
Schemes represents one or
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WO 2007/016784 PCT/CA2006/001306
two substituents on the phenyl ring to which X is attached, wherein the
substituents are as defined within
the scope of structural Formula I. The term "ligand" used in some of the
Schemes below represents the
compound:
Cy, P
ligand: I
Cy N
As shown in Scheme 2, starting material 3-chloro-6-methyl-l-benzothiophene-2-
carbonyl
chloride (see T. Higa and A.J. Krubsack, J. Org. Chem, 1976, 41, 3399-3403) is
treated with methanol to
generate the corresponding methyl ester. Benzylic bromination followed by
azide displacement
generates the azide intermediate. Copper iodide induced cyclization of the
thus formed benzylic azide
with 3-(trifluoromethyl)pent-l-yn-3-ol (prepared following the reactions
outlined in Scheme 1) generates
the corresponding triazole. The final aromatic ring is introduced via a Suzuki
cross-coupling reaction;
the solvent is preferably 1,4-dioxane:water at a ratio of 100:1-1.5, and the
reaction is preferably
quenched with 2N NaOH when using any intermediate that is stable to NaOH. The
methyl ester can be
saponified using standard conditions and, in turn, can be coupled with a
variety of alcohols or amines
using standard protocols to form the corresponding esters or amides. The
intermediate carboxylic acid
can also be decarboxylated by treatment with copper in refluxing quinoline.
The methyl ester substituent of the benzothiophene can be modified into a
number of
other groups as illustrated in Schemes 3 and 4. For example, the ester can be
reduced to the primary
alcohol by treatment with DIBAL as highlighted in Scheme 3. This alcohol can
be oxidized to the
corresponding aldehyde through the action of Mn02. Treatment with
organometallic reagents, such as
methyl lithium, generate the secondary alcohols with in turn can be oxidized
by MnO2 to the
corresponding ketone. In addition, as illustrated in Scheme 4, the methyl
ester of the 3-
chlorobenzothiophene intermediate can be reduced as described above with DIBAL
and the resulting
alcohol oxidized to the corresponding aldehyde. This aldehyde can be converted
into a nitrile by first
treating with hydroxylamine followed by CDI. Suzuki cross-coupling of the 2-
cyano-3-
chlorobenzothiophene with a variety of boronic acids can be accomplished
following standards methods.
Unsubstituted and substituted phenylborinic acids are commercially available
or can prepared from the
corresponding bromide following standard literature procedures such as that
described in Byrant, J.A. et.
al., J. Org. Chem. 1990, 55, 4622-4634. The nitrile can be treated with
tributyltin azide to provide the
corresponding tetrazolyl analog.
Scheme 5 outlines an alternative route to the synthesis of the benzothiophene
ring system
starting from commercially available 4-bromo-2-fluorobenzaldehyde. After
formation of the
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benzothiophene ring system, standard carbonylation conditions convert the aryl
bromide into the
corresponding methyl ester. Selective bromination of the benzothiophene
employing bromine in acetic
acid yields the 2-bromobenzothiophene analog. Having introduced the 2-bromo
substituent the methyl
ester is in turn converted into the triazole ring system following standard
conditions as outlined in
Scheme 5.
Scheme 6 highlights a number of additional transformations of the
benzothiophenes that
can be accomplished. Scheme 6a illustrates treatment of the methyl ester with
excess methyl lithium to
generate the corresponding tertiary alcohol. Schemes 6b and 6c highlight two
approaches to generate the
primary amide by either treating the methyl ester with pre-mixed NH4C1-A1C13
or, alternatively,
oxidation of the corresponding nitrile. The 2-bromobenzothiophene can be
converted into a methyl
sulphone, as shown in Scheme 6d, by treatment with methyl sulfinic acid sodium
salt and Cul in hot
DMF. Additional alkyl sulphone adducts can be generated by using the
appropriate sulfinic acid sodium
salt coupling partner (alkyl-SO2Na). The bromide intermediate can be coupled
with a variety of boronic
acids or organostannanes to generate the corresponding 2-aryl or heterocyclic
adducts (see Scheme 11).
Also, the bromide can be converted into sulphonamides by first generating the
2-lithio species by
treatment with BuLi, quenching this anion with sulfur dioxide, chlorination
with NCS and finally
treatment with an amine. Schemes 6e and 6f illustrate that the sulfur atom of
the benzothiophene ring
can be oxidized to the corresponding sulfoxide or sulphone by treatment with
either hydrogen peroxide
or MCPBA, respectively.
The synthesis of 2-sulfonamide benzothiophenes is illustrated in Scheme 7.
Hydrolysis
of the acid chloride followed by decarboxylation generates the 2-hydro-
benzothiophene. This
intermediate can be deprotonated at the 2-position with the aid of a strong,
base such as BuLi, and the
resulting anion reacted with sulphur dioxide. Treatment of the resulting
sulfinic acid lithium salt with
NCS generates the sulphonyl chloride which, in turn, is reacted with an amine,
such as tBuNH2, to
furnish the corresponding sulphonamide. Cross-coupling of the 3-
chlorobenzothiophene and
introduction of the triazole ring is carried out as described above. The tert-
butyl group can be readily
removed by treatment with TFA in dichloromethane to provide the corresponding
primary sulphonamide.
As shown in Scheme 8, treatment of 2-formylbenzothiophene with a fluorinating
agent
such as (MeOEt)2NSF3 generates the corresponding difluoride. Elaboration of
this intermediate to
introduce the triazole unit was performed as previously described.
Scheme 9 illustrates the preparation of 2-oxadiazolebenzothiophene analogs.
Treatment
of the acid chloride, prepared from the corresponding carboxylic acid by
standard methods, is reacted
with N-hydroxyethanimidamide and the resulting adduct is then heated in
pyridine to generate the
corresponding oxadiazole ring system. This intermediate can be further
elaborated to introduce the
triazole unit as previously described.
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As shown in Scheme 10, chlorination of a benzothiophene, such as methyl 3-
phenyl-l-
benzothiophene-6-carboxylate, provides the corresponding 2-chloro derivative.
The methyl ester can be
elaborated to introduce the triazole ring system as previously described.
Scheme 12 illustrates the synthesis of 5-LO inhibitors of Formula lb. The
phenyl group
was N-coupled to methyl 5-methyl-lH-indole-2-carboxylate using standard
methods. Benzylic
bromination followed by azide displacement provides the corresponding benzylic
azide. Exposure of this
azide with an alkyne in the presence of Cul generates the triazole ring
system. Saponification of the
methyl ester provides the carboxylic acid which, under standard conditions,
can be transformed into a
carboxamide or the corresponding nitrile. Alternatively, the acid can be
transformed into a variety of
esters or amides by following procedures outlined above in the previous
schemes.
Scheme 13 illustrates a alternate synthesis of compounds of formula Ia wherein
RI is
-COOC I-6alkyl, -COOC3-6cycloalkyl or -CONR5R5 which is preferred for chiral
synthesis of the final
products. Starting material3-chloro-6-methyl-l-benzothiophene-2-carbonyl
chloride 2 is made according
to the procedure in T. Higa and A.J. Krubsack, J. Org. Chem, 1976, 41, 3399-
3403. Compound 2 can be
esterified to 3 with an alkyl alcohol, for example methanol, using DMAP at 0 C
under an inert (e.g.
nitrogen) atmosphere using a procedure like that described in Example 1, step
1. In a similar fashion,
amide forms of 3 can also be prepared by adding a mixture of an appropriate
amine (4 eq, for example
NH2C I-6alkyl) in CH2C12 to the carbonyl chloride 2(1 eq) under an inert (e.g.
nitrogen) atmosphere at
0 C, followed by quenching with water, extraction and solvent evaporation. The
aromatic ring is
introduced via a Suzuki cross-coupling reaction as described in Scheme 2 and
similar to the procedure of
Example 1, step 6, to make 4. When preparing 4, it is preferable to use 1,4-
dioxane:water at a ratio of
100:1-1.5 as solvent. The reaction is preferably quenched by the addition of
2N NaOH, which serves to
remove the excess boronic acid.
Benzylic bromination of 4 followed by azide displacement generates the azide
intermediate 6, using procedures similar to that described in Scheme 2 and
Example 1, steps 2 and 3. The
benzylic bromination of 4 (1 eq) can be performed using solvents such as
carbon tetrachloride or
benzene, employing about 1.1 eq. of NBS, and from about 0.05 to about 0.3 eq.
of benzoylperoxide in a
single portion or two portions. The azide displacement can be performed using
about 1 to 2 eq of sodium
azide.
The coupled product 10 can be prepared by treating a mixture of 6 (1 eq) and 9
(1.1 eq) at rt in a solvent
such as THF under an inert (e.g., nitrogen) atmosphere with DIPEA (5 eq) and
copper(I) iodide (1.5 eq)
followed by isolation of the product. The product is isolated using standard
techniques, e.g., by removing
the solvent, re-dissolving in EtOAc and filtering through a silica gel pad.
The product can be further
purified using flash chromatography such as the COMBI-FLASHO system (an
automated flash
chromatography system from Teledyne Isco) as described in many of the examples
below.
29
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WO 2007/016784 PCT/CA2006/001306
The nitrobenzoyl group is removed by treatment of 10 with base such as sodium
hydroxide to obtain 11. For example, sodium hydroxide (2M, 1.7 eq.) is added
dropwise to a solution of
(1 eq) in 1:1 THF/MeOH at rt followed by stirring until the reaction is
complete, then quenching by
adding EtOAc and water. The product is isolated using standard techniques,
e.g., extracting with
5 EtOAc, washing the combined organic layers with water, a saturated NaHCO3
solution, then brine,
drying over a drying agent such as Na2SO4, then concentrating the resulting
material. The product can be
further purified using flash chromatography such as the COMBI-FLASHO system.
For compound 11
where -C(O)Rla = an alkyl ester, additional modifications to the alkyl ester
group can be performed as
noted in the Schemes above. When -C(O)Rla is an alkyl-substituted amide, such
as -NH-t-butyl, the alkyl
10 group can be readily removed by treatment with TFA with or without
additional solvent to provide the
corresponding primary amine.
Scheme 14 illustrates a method for making racemic 1-ethyl-I-
(trifluoromethyl)prop-2-yn-
1-y14-nitrobenzoate 8 which can be chromatographically resolved to obtain 9.
The chiral intermediate 9
can be used for the chiral synthesis of compounds of this invention as
described in Scheme 13.
Compound 8 was prepared by adding n-butyllithium (1 eq) to a stirring mixture
of
ethynyl(trimethyl)silane (1.2 eq) in THF using standard conditions, e.g., at -
78 C under an inert (e.g.,
nitrogen) atmosphere, followed by stirring at -78 C for about an hour and then
at rt for about an hour.
Then 1,1,1-trifluorobutan-2-one (1 eq) was added dropwise at -78 C, the
resulting mixture was stirred at
rt for about 2 hours, then cooled down again to -78 C before addition of 4-
nitrobenzoyl chloride (1.3
eq). The reaction was quenched with saturated NaHCO3 solution, followed by a
standard work-up, i.e.,
separating the organic layer, extracting the aqueous phase with EtOAc, washing
the combined organic
layers with brine, then drying over Na2SO4. After filtration,
tetrabutylammonium fluoride 1M in THF
(1.2 eq) was added dropwise, the resulting mixture was stirred at rt for 2
hours and the reaction was
quenched by the addition of brine. The organic layer was separated and the
aqueous phase was extracted
with EtOAc. The organic layers were combined, washed with brine, and dried
over Na2SO4. After
evaporation, the crude was purified by COMBI-FLASHO chromatography system with
toluene to afford
compound 8.
Chiral resolution of 8 was performed using a CHIRALCEL ODO HPLC column 5cm x
50cm (from Daicel Chemical Industries, Ltd.), eluting with 10% i-PrOH/Hexanes
at a flow rate of 70
mL/min, at 320 nM; compound 8 was dissolved in pure 20% i-PrOH/CHC13 ("stock
solution") for
application to the colunm. Preferably, just before each injection into the
HPLC, the stock solution is
slowly mixed with hexane in a ratio of 1:4 stock solution:hexane. Retention
time is about 10-12 min for
the 1 st enantiomer off the column (fraction A) and about 18-20 min for the
desired enantiomer 9 (fraction
B).
CA 02618586 2008-02-08
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For compounds of formula I containing the 1-hydroxy-1-(trifluoromethyl)propyl-
moiety
attached to the triazolyl ring in the structure, the (S)-stereoisomer of 1-
hydroxy-1-
(trifluoromethyl)propyl- is preferred:
N %N
\N-~
HO
CF3
Scheme 1
1. n-BuLi/THF
TMS =
2. --*'~Y CF3 HO CF3
O
3. TBAF/THF
31
CA 02618586 2008-02-08
WO 2007/016784 PCT/CA2006/001306
Scheme 2
MeOH/DMAP ~ S O
1 NBS/CCI4/(Bz0)2i80 C
-
CI CH2CI2 O
CI CI
S S
Br NaN3/DMF N3 +
O O HO CF3
CI / CI ~
Cu! N N- N S O HO, B "OH
Hunig's base/THF HO p + \
CF3 CI ~ ~
X
Pd(OAc)2/Iigand ~N.. N S O-
N~
1,4-dioxane/H2O/CsF -- / / O
HO
Cy" CF3
P
ligand: y
~ X
32
CA 02618586 2008-02-08
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Scheme 3
N~ s o N,N S OH
N/ N DIBAL/THF/ N
HO O HO
-78 C
CF3 CF3
x X
N~N S OH
1. MnO2/CH2Ci2 N Mn02/CH2CI2
2. MeLi/THF/-78 C HO
CF3
x
NN..N ~ S 0
HO
CF3
x
Scheme 4
"N -N S 0 1. DIBAL/THF/- 78 C
HO N" 2. Mn02/CH2CI2
CI ~ 3. NH2OH HCIMaOAc/EtOH
CF3 4. CDI/CH2C12
+ HO,
N N- N S N B' OH Pd(OAc)Z/ligand
HO I ~ 1,4-dioxane/H20/CsF
CF3 CI .~X
N-N S
N =N
HO
CF3
x
33
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7WO 2007/016784 PCT/CA2006/001306
Scheme 5
. Br
Mg
1. Br S
Br F bx
/THF H O 2. Mn02/CH2CI2
3. HSCH2COOMe/Cs2CO3/THF/reflux
4. NaOH/THF/reflux X
5. Cu/quinoline/140 C
0 0
CO/PdCl2(dppf) CH2CI2/ O S Br2/AcOH/ O S
-~ ~
MeOH/DMSO/50 C 8D/ CH2CI2 Br
N X 3
3
1. DIBAUTHF/-78 C \ S
2. MsCI/Et3N/CH2CI2/-30 C ~/ Br Cul/Hunig's base/
3. NaN3/DMF + HO CF3 THF
X
S
N Br
N,N 7-
HO
CF3
x
34
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WO 2007/016784 PCT/CA2006/001306
Scheme 6
6a: N-N \ S O ,N-N S
N MeLilTHFI N
p HO ' OH
HO 78 C CF3
CF3
x x
6b: N~ O N- N s NH2
N N
NH4CI/Me3Al! N~ I/ p
HO O HO
C6H6
CF3 CF3
x x
6c: N' g Na2CO3 H2O2/ N- N NH2
N N N
Acetone/H20 Hp O
HO
CF3 CF3
x x
6d: N_N \ S MeSO2Na/Cul/ NN N S=p
N Br
HO NMP/150 C HO
CF3 3 CF3
x x p
1j NH
N
6e: N N S NH2 H202,TFA N ~ N I\ S 2
N f I/ ' -- p
HO p Ch2C12 HO
CF3 CF3
x
x O O
NH2
N,N NH2 MCPBA N NN S 2
N
O
HO O Ch2C12 HO
CF CF3
3
x x
CA 02618586 2008-02-08
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Scheme 7
S NaOAc S
COCI - f ~ CO2H Cu, qunoline
THF-H2O 140 C
CI CI
S 1. NCS, CH2CI2, 0 C
S 1. nBuLi, THF, -78 C S02Li
2. SO2(g), excess 2. tBuNH2
C! CI
s 0
11 Pd(OAc)2/ligand ~ S O
S-NHtBu S-NHtBu
~ 1,4-dioxane/H2O/CsF 11
ci 4-FC6H4B(OH)2 O
F
N3
S 0 OH
CF3
1. NBS, Bz20, CCI4 S-NHtBu
O
2. NaN3
THF, DIPEA, Cul
F
N,N S ~ ,N N g 0
N S-NH2
TIIIIIIIJIIs-NHtBu TFA N~ S
O
CH O
~ CH2CI2 HO
H03C ~ F3C
F F
36
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WO 2007/016784 PCT/CA2006/001306
Scheme 8
Br F 1. PhMgBr, THF Br F HSCH2CO2Me, Cs2CO3
2. Dess Martin reagent O
CHO THF, 50 C
Br s Br g O
C02Me iBu2Al, THF, -60 C
MnO2, CH2CI2 /
Br S F
(CH3OCH2CH2)2NSF3 CO, Pd(dppf)CI2
F
CH2CI2 DMSO, MeOH, Et3N
0
S F
Me0 I\ 1. iBu2AIH, CH2CI2 N3 I S F
F 2. MsCI, Et3N, CH2CI2 F
3. NaN3
OH NN S F
= CF3 - ~ ~
HO F
THF, DIPEA, Cul F3C
37
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Scheme 9
Br S
C02H oxalyl chloride Br S
COCI
CH2CI2
Br S N
1. HONHC(NH)CH3. O, N CO, Pd(dppf)CIZ, MeOH
CH2CI2, DMAP DMSO, Et3N
2. pyr, reflux 1
0 N3
MeO s N~ 1. iBu2AIH, CH2CI2 S N~
O~ I IN 2. MsCI, Et3N, CH2CI2 O-N
/ 3. NaN3
~
OH
= CF3 NN-N S N-/
I
O-N
THF, DIPEA, Cul
HO
F3C
38
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WO 2007/016784 PCT/CA2006/001306
Scheme 10
0 0
S S0202 MeO S
MeO C{
CH2CI2
OH
N3 S CF3
1. iBuAIH, CH2CI2 CI
2. MsCI, Et3N, CH2CI2 THF, DIPEA, Cul
3. NaN3
~
N,N S
N
~ CI
HO
F3C
Scheme 11
N S Pd2(dba)3, N,N ~ S -N
~N Ph As, F
i I/ f ~ f
N~~ Br DMF
----------- ~
HO N %
SnBu3 HO C
F3C N 3
39
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WO 2007/016784 PCT/CA2006/001306
Scheme 12
C6H51, dioxane, f~ ~ C02Me Br \COZMe
C02Me Cul, K3P04, N NBS
N
H CCI4
trans-1,2-
diaminocyclohexane
~
N3 C02Me OH C02Me
= CF3 ~/ N
NaN3 N
DMF HO
Cul, THF, DIPEA F3C
N-N
NaOH , CO2H 1) oxalyl chloride, CH2CI2
N
THF, MeOH, H20 HO 2) NH3
F3C
Na
NN N CONH2 TFFA 4IN41 N -N
N
HO dioxane, pyridine H~
3C
CA 02618586 2008-02-08
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Scheme 13
OH { ' S CI R' a-H
o SOCI2 cI 0 Rla = -OC1_6aikyl, -OC3_6cycloalkyi
1 2 or -NR5R5
S R1a
{
S R1a O NBS
C{ X-~C B(OH)2 X
3 4
S Rla N3 R1a 02N CF3
Br
O O
NaN3 _ / \ 9 O
X 6 X
1 a
CF R1a CF3 N
3 N { S
02N / T N,N O NaOH OH 0 N O
O
O 10
X X
Scheme 14
O SiMe3 11
I~CF3 02N CF3 Chiral HPLC 02N / CF
\/~ 3
{ ChiralcelOD ~ { O
7 02N \ O
{ / CI 8 O 9 O
0
41
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EXAMPLE 1
Methyl 6-( {4-[ 1-hydroxy-l-(trifluoromethyl)propyl]-1 H-1,2,3-triazol-l-yl}
methyl)-3-phenyl-l-
benzothiophene-2-carboxylate
N// N- N g O
O
F OH
Step 1: methyl 3-chloro-6-methyl-l-benzothiophene-2-carboxylate
I ~ S O
O
CI /
To a mixture of methanol (1.582 mL, 39.1 mmol, 1.2 eq) and DMAP (4.78 g, 39.1
mmol, 1.2 eq) in
CH2CI2 (50 mL, 0.652M) stirred at 0 C under an atmosphere of nitrogen, 3-
chloro-6-methyl-l-
benzothiophene-2-carbonyl chloride (8 g, 32.6 mmol) was added portionwise. The
resulting mixture was
stirred at rt for 3 h. The reaction was quenched by passing through a silica
gel pad and washed with 20%
EtOAC/hexane. The solvent was removed by evaporation and the crude thus
obtained was purified by
COMBI-FLASH (pure hexane for 4 min, to 15% EtOAC/hexane in 20 min, to 20%
EtOAC/hexane in
20 min) to afford the titled compound. 'H NMR S(ppm)(Acetone): 7.88 (1 H, d),
7.84 (1 H, s), 7.45 (1
H, d), 3.95 (3 H, s), 2.53 (3 H, s).
Step 2: methyl 6-(bromomethyl)-3-chloro-l-benzothiophene-2-carboxylate
Br O
O
CI
To a mixture of methyl 3-chloro-6-methyl-l-benzothiophene-2-carboxylate (3.3
g, 13.71 nunol) in carbon
tetrachloride (80 mL, 0.171 M) stirred at reflux under an atmosphere of
nitrogen, pre-mixed NBS, 99%
(2.68 g, 15.08 mmol, 1.1 eq) and benzoylperoxide (166 mg, 0.686 mmol, 0.05 eq)
were added. The
resulting mixture was stirred at reflux forl h. The solvent was removed by
evaporation and the crude thus
obtained was re-dissolved in EtOAc and the mixture was treated by the addition
of water. The organic
layer was separated and the aqueous phase was extracted with EtOAc. The
organic layers were
42
CA 02618586 2008-02-08
WO 2007/016784 PCT/CA2006/001306
combined, washed with brine, dried over Na-2SO4. The solvent was removed by
evaporation to afford
crude the titled compound.
Step 3: methyl 6-(azidomethyl)-3-chloro-l-benzothiophene-2-carboxylate
N
3 O
O
CI
To a mixture of methyl 6-(bromomethyl)-3-chloro-l-benzothiophene-2-carboxylate
(4.2 g, 17.45 mmol)
in DMF(150 mL, 0.116M) stirred at rt under an atmosphere of nitrogen, sodium
azide (854 mg, 13.14
mmol, 1 eq) was added. The resulting mixture was stirred at rt forl h. The
reaction was quenched by the
addition of water. The organic layer was separated and the aqueous phase was
extracted with EtOAc.
The organic layers were combined, washed with brine, dried over Na2SO4. The
solvent was removed by
evaporation and the crude thus obtained was purified by COMBI-FLASHO (pure
hexane for 4 min, to
20% EtOAC/hexane in 20 min, to 35% EtOAC/hexane in 20 min) to afford the title
compound). 'H
NMR S(ppm)(Acetone): 8.12 (1 H, s), 8.05 (1 H, d, J = 8.3 Hz), 7.66 (1 H, d, J
= 8.4 Hz), 4.71 (2 H, s),
3.98 (3 H, s).
Step 4: 3-(trifluoromethyl)pent-1-yn-3-ol
HO CF3
To a mixture of trimethylsilylacetylene (19.4 g, 198 mmol, 1 eq) in THF (500
mL, 0.396M) stirred at -
78 C under an atmosphere of nitrogen, n-butyllithium 1.6M hexanes (124 mL, 198
mmol, 1 eq) was
added. The resulting mixture was stirred at -78 C forl h. Then 1,1,1-trifluoro-
2-butanone (25.0 g, 198
mmol, 1 eq) was added dropwise at -78 C and the resulting mixture was stirred
at rt for 2 h. The reaction
was quenched by the addition of a saturated NaHCO3 solution at 0 C . The
organic layer was separated
and the aqueous phase was extracted with ether/hexane (1:1). The organic
layers were combined,
washed with brine, dried over Na-2SO4. The solvent was removed by careful
distillation. The crude thus
obtained was re-dissolved in THF (200 mL, 1 M) under atmosphere of nitrogen at
0 C,
tetrabutylammonium fluoride 1M THF (238 mL, 238 mmol, 1.2 eq) was added
dropwise. The resulting
mixture was stirred at rt for 2 h. The reaction was quenched by the addition
of brine. The organic layer
was separated and the aqueous phase was extracted with hexane. The organic
layers were combined,
washed with brine, dried over Na2SO4. The solvent was removed by careful
distillation and residue was
purified by distillation (collect the fraction between 100-140 C) to afford
the titled compound. 'H NMR
S(ppm)(Acetone): 5.86 (1 H, s), 3.27 (1 H, s), 1.91-1.81 (2 H, m), 1.15 (3 H,
t).
43
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Step 5: methyl 3-chloro-6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-
triazol-l-yl}methyl)-1-
benzothiophene-2-carboxylate
W N-N O
O
OH Ci
F F
F
To a mixture of methyl 6-(azidomethyl)-3-chloro-l-benzothiophene-2-carboxylate
(3.4 g, 12.07 mmol)
and 3-(trifluoromethyl)pent-1-yn-3-ol (1.84 g, 12.07 mmol, 1 eq) in THF (80
mL, 0.151M) stirred at rt
under an atmosphere of nitrogen, was added N,N-diisopropylethylamine(10.53 mL,
60.3 mmol, 5 eq)
and copper(I) iodide (2.299 g, 12.07 mmol, I eq. The resulting mixture was
stirred at rt for over night.
After evaporation, the crude thus obtained was re-dissolved in EtOAc and
filtered through a layer of
silica gel. The solvent was removed by evaporation and the crude thus obtained
was purified by
COMBI-FLASH (pure hexane for 4 min, to 45%EtOAC/hexane in 20 min, to 70%
EtOAC/hexane in
min) to afford the titled compound.'H NMR S(ppm)(Acetone): 8.18 (1 H, s), 8.08
(1 H, s), 8.03 (1
H, d), 7.62 (1 H, d), 5.90 (2 H, s), 5.45 (1 H, s), 3.97 (3 H, s), 2.37-2.30
(1 H, m), 2.09 (1 H, m), 0.84 (3
H, t).
15 Step 6: Methyl6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-
l-yl}methyl)-3-phenyl-l-
benzothiophene-2-carboxylate
To a mixture of methyl 3-chloro-6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-
1,2,3-triazol-1-
yl}methyl)-1-benzothiophene-2-carboxylate (900 mg, 2.074 mmol), phenylboronic
acid (0.758 g, 6.22
mmol, 3 eq), 2-(dicyclohexylphosphino-2'-(N,N-dimethyl-amino)biphenyl (73.6
mg, 0.187 mmol, 0.09
20 eq), palladium(II) acetate (27.8 mg, 0.124 mmol, 0.06 eq), and cesium
fluoride (1.89 g, 12.44 mmol, 6
eq) under an atmosphere of nitrogen, 1,4-Dioxane-water (101 mL, 100:1, 0.021M)
was added. The
resulting mixture was stirred at rt forl day. The reaction was quenched by the
addition of water. The
organic layer was separated and the aqueous phase was extracted with EtOAc.
The organic layers were
combined, washed with brine, dried over Na2SO4. The solvent was removed by
evaporation and the crude
thus obtained was purified by COMBI-FLASH (pure hexane for 4 min, to 50%
EtOAC/hexane in 20
min, to 75% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500
MHz, Acetone): S
8.16 (s, 1 H), 8.09 (s, 1 H), 7.55-7.49 (m, 3 H), 7.38 (dd, I H),5.87 (s, 2
H), 5.45 (s, I H), 3.75 (s, 3
H), 2.36-2.29 (m, I H), 2.08 (m, I H), 0.83 (t, 3 H).
EXAMPLE 2
1,1,1-trifluoro-2-(1- { [2-(hydroxymethyl)-3-phenyl-l-benzothien-6-yl]methyl} -
1H-1,2,3-triazol-4-
yl)butan-2-ol
44
CA 02618586 2008-02-08
WO 2007/016784 PCT/CA2006/001306
N,N S OH
F ~H
F
To a mixture of Methyl 6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-
triazol-l-yl}methyl)-3-
phenyl-l-benzothiophene-2-carboxylate (180 mg, 0.379 mmol) in THF (5 mL,
0.076M) stirred at -78 C
under an atmosphere of nitrogen, DIBAL-H (1.011 mL, 1.516 mmol, 4 eq) was
added dropwise. The
resulting mixture was stirred at -78 C for10 min and rt for 1 h. The reaction
was quenched by the
addition of silica gel and water, filtration through a pad of silica gel. The
solvent was removed by
evaporation and the crude thus obtained was purified by triturating with
toluene and hexane to afford the
titled compound. 'H NMR (500 MHz, Acetone): 5 8.12 (s, 1 H), 8.02 (s, 1 H),
7.58-7.54 (m, 3 H), 7.48
(m, 3 H), 7.40 (dd, I H), 5.82 (s, 2 H), 5.43 (s, 1 H), 4.85 (d, 2 H), 4.75
(t, 1 H), 2.36-2.29 (m, 1 H),
2.08 (m, 1 H), 0.83 (t, 3 H).
EXAMPLE 3
6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-3-
phenyl-l-benzothiophene-
2-carbaldehyde
N,N O
N~ F
F 0H
F
To a mixture of 1,1,1-trifluoro-2-(1-{[2-(hydroxymethyl)-3-phenyl-l-benzothien-
6-yl]methyl}-1H-1,2,3-
triazol-4-yl)butan-2-ol (150 mg, 0.335 nunol) in CHzCI, (50 mL, 0.0067M)
stirred at rt under an
atmosphere of nitrogen, manganese(IV) oxide (437 mg, 5.03 mmol, 15 eq) was
added. The resulting
mixture was stirred at rt for 2 h. The reaction was quenched by passing
through a silica gel pad and
washed with 50% EtOAC/hexane. The solvent was removed by evaporation and the
crude thus obtained
was purified by COMBI-FLASH (pure hexane for 4 min, to 50 % EtOAC/hexane in
20 min, to 75%
EtOAC/hexane in 20 min) to afford the titled compound. (137 mg, Yield = 92 %).
'H NMR (500 MHz,
Acetone): S 9.95 (s, 1 H), 8.18 (s, 1 H), 8.15 (s, I H), 7.84 (d, 1 H), 7.69-
7.61 (m, 5 H), 7.52 (d, 1 H),
5.89 (s, 2 H), 5.46 (s, 1 H), 2.34 (m, 1 H), 2.08 (s, I H), 0.84 (t, 3 H).
CA 02618586 2008-02-08
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EXAMPLE 4
1,1,1-trifluoro-2-(1- { [2-(1-hydroxyethyl)-3-phenyl-l-benzothien-6-yl]methyl
} -1H-1,2,3-triazol-4-
yl)butan-2-ol
N-N OH
w_
F 0H
F
F
To a mixture of 1,1,1-trifluoro-2-(1-{[2-(hydroxymethyl)-3-phenyl-l-benzothien-
6-yl]methyl}-1H-1,2,3-
triazol-4-yl)butan-2-ol (137 mg, 0.308 mmol) in THF (5 mL, 0.062M) stirred at -
78 C under an
atmosphere of nitrogen, methyllithium (660 uL, 0.924 mmol, 3 eq) was added.
The resulting mixture was
stirred at -78 C for15 min. The reaction was quenched by the addition of
water. The organic layer was
separated and the aqueous phase was extracted with EtOAc. The organic layers
were combined, washed
with brine, dried over Na2SO4. The solvent was removed by evaporation and the
crude thus obtained was
purified by COMBI-FLASHO (pure hexane for 4 min, to % EtOAC/hexane in 20 min,
to %
EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz,
Acetone): S 8.10 (s, I H),
8.02 (s, 1 H), 7.56 (t, 2 H), 7.50-7.44 (m, 5 H), 7.38 (dd, 1 H), 5.81 (s, 2
H), 5.44 (s, 1 H), 5.21-5.17
(m, I H), 4.77 (d, 1 H), 2.32 (m, I H), 2.09 (m, 1 H), 1.47 (d, 3 H), 0.83 (t,
3 H).
EXAMPLE 5
1 -[6-( {4-[ 1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}
methyl)-3-phenyl-l-benzothien-2-
yllethanone
N ~~S O
N-
Ni-
OH
F
To a mixture of 1,1,1.-trifluoro-2-(1-{[2-(1-hydroxyethyl)-3-phenyl-l-
benzothien-6-yl]methyl}-1H-1,2,3-
triazol-4-yl)butan-2-ol (52 mg, 0.113 mmol) in CH2CI7 (20 mL, 0.0056M) stirred
at rt under an
atmosphere of nitrogen, manganese(IV) oxide (147 mg, 1.695 mmol, 15 eq) was
added. The resulting
mixture was stirred at rt for 3 h. The reaction was quenched by passing
through a silica gel pad and
washed with 50% EtOAC/hexane. The solvent was removed by evaporation and the
crude thus obtained
was purified by COMBI-FLASHO (pure hexane for 4 min, to 40% EtOAC/hexane in 20
min, to 60%
EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz,
Acetone): & 8.16 (s, 1 H),
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8.06 (s, I H), 7.64-7.57 (m, 3 H), 7.52 (d, 2 H), 7.42 (s, 2 H), 5.86 (s, 2
H), 5.46 (s, 1 H), 2.36-2.29
(m, 1 H), 2.10 (m, 4 H), 0.83 (t, 3 H).
EXAMPLE 6
6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-l-yl}methyl)-3-
phenyl-l-benzothiophene-
2-carboxamide
N- N S O
N~ F
NH2
F OH
F
To a mixture of ammonium chloride (225 mg, 4.21 mmol, 10 eq) in benzene (10
mL, 0.042M) stirred at
0 C under an atmosphere of nitrogen, trimethylaluminum 2M heptane (2.105 mL,
4.21 mmol, 10 eq) was
added. The resulting mixture was stirred at rt forl h. Then methyl 6-({4-[1-
hydroxy-l-
(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-3-phenyl-l-
benzothiophene-2-carboxylate (200
mg, 0.421 mmol) was added at rt and the resulting mixture was stirred at 60 C
for 2 days.The reaction
was quenched by the addition of silica gel and water, then filtered through a
layer of silica gel, and
washed with 80% of EtOAc/hexane.The solvent was removed by evaporation and the
crude thus obtained
was purified by COMBI-FLASH ( pure hexane for 4 min , to 40% EtOAC/hexane in
20 min, to 60%
EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz,
Acetone): S 8.15 (s, 1 H),
8.08 (s, I H), 7.66-7.58 (m, 3 H), 7.54 (d, 2 H), 7.43 (m, 2 H), 6.83 (br s, 1
H), 5.89 ( br s, 1 H), 5.85
(s, 2 H), 5.44 (s, I H), 2.34-2.30 (m, 1 H), 2.08 (m, 1 H), 0.83 (t, 3 H).
EXAMPLE 7
6-( {4-[ 1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-l-yl } methyl)-
N-methyl-3-phenyl-l-
benzothiophene-2-carboxamide
N,N S O
N"_
HN-
OH
F
F
To a mixture of methyl amine/THF (1.05 mL, 2.1 mmol, 10 eq) in THF (5 mL,
0.042M) stirred at rt
under an atmosphere of nitrogen, trimethylaluminum 2M heptane (1.05 mL, 2.1
mmol, 10 eq) was added.
The resulting mixture was stirred at rt for15 min. Then methyl 6-( {4-[ 1-
hydroxy-l-
(trifluoromethyl)propyl]-1H-1,2,3-triazol-l-yl}methyl)-3-phenyl-l-
benzothiophene-2-carboxylate (100
mg, 0.21 mmol) was added at rt and the resulting mixture was stirred at 60 C
for 1 day. The reaction
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was quenched by the addition of SILICA GEL at rt followed by the addition of 4
drops of water. The
resulting mixture was filtered through a silica gel pad and washed with 70%
EtOAC/hexaneThe solvent
was removed by evaporation and the crude thus obtained was purified by COMBI-
FLASHO ( pure
hexane for 4 min, to 60% EtOAC/hexane in 15 min, to 75% EtOAC/hexane in 15
min) to afford the
titled compound. 'H NMR (500 MHz, Acetone): S 8.14 (s, 1 H), 8.07 (s, 1 H),
7.62-7.48 (m, 6 H),
7.42 (d, I H), 6.43 (s, 1 H), 5.84 (s, 2 H), 5.45 (s, I H), 2.71 (d, 3 H),
2.37-2.29 (m, 1 H), 2.09 (m, 1
H), 0.83 (t, 3 H).
EXAMPLE 8
1,1,1-trifluoro-2-(1- { [2-(1-hydroxy-l-methylethyl)-3-phenyl-l-benzothien-6-
yl]methyl } -1 H-1,2,3-triazol-
4-yl)butan-2-ol
N
,N S OH
N"_
F F
F
To a mixture ofMethyl6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-
triazol-l-yl}methyl)-3-
phenyl-l-benzothiophene-2-carboxylate (66 mg, 0.139 mmol) in THF (5 mL,
0.028M) stirred at -78 C
under an atmosphere of nitrogen, methyllithium (261 uL, 0.417 mmol, 3 eq) was
added dropwise. The
resulting mixture was stirred at -78 C for10 min. The reaction was quenched by
the addition of water.
The organic layer was separated and the aqueous phase was extracted with
EtOAc. The organic layers
were combined, washed with brine, dried over. The solvent was removed by
evaporation and the crude
thus obtained was purified by COMBI-FLASHO ( pure hexane for 4 min , to 50%
EtOAC/hexane in 20
min, to 75% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500
MHz, Acetone): 6
8.08 (s, I H), 7.96 (s, 1 H), 7.55-7.49 (m, 3 H), 7.34 (d, 2 H), 7.30 (d, I
H), 7.02 (d, I H), 5.78 (s, 2
H), 5.42 (s, I H), 4.87 (s, 1 H), 2.31 (m, 1 H), 2.11 (m, I H), 1.45 (s, 6 H),
0.82 (t, 3 H).
EXAMPLE 9
1 methyl 3-(4-fluorophenyl)-6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-
1,2,3-triazol-l-yl}methyl)-
1-benzothiophene-2-carboxylate
N N g O
O
F ~H
F
F
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To a mixture of methyl 3-chloro-6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-
1,2,3-triazol-1-
yl}methyl)-1-benzothiophene-2-carboxylate (900 mg, 2.074 mmol), (4-
fluorophenyl)boronic acid (0.87
g, 6.22 mmol, 3 eq) (2902 mg, 20.74 mmol, 10 eq), 2-(dicyclohexylphosphino-2'-
(N,N-dimethyl-
amino)biphenyl (73.6 mg, 0.187 mmol, 0.09 eq), palladium(II) acetate (27.8 mg,
0.124 mmol, 0.06 eq),
and cesium fluoride (1.89 g, 12.44 mmol, 6 eq) under an atmosphere of
nitrogen, 1,4-Dioxane-water
(101 mL, 100:1, 0.021M) was added. The resulting mixture was stirred at rt
forl day. The reaction was
quenched by the addition of water. The organic layer was separated and the
aqueous phase was extracted
with EtOAc. The organic layers were combined, washed with brine, dried over
Na7SO4. The solvent was
removed by evaporation and the crude thus obtained was purified by COMBI-
FLASHO ( pure hexane for
4 min, to 50% EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 20 min) to afford
the titled
compound. 'H NMR (500 MHz, Acetone): S 8.13 (s, 1 H), 8.07 (s, 1 H), 7.52-7.42
(m, 3 H), 7.28-7.24
(m, 3 H), 5.87 (s, 2 H), 5.46 (s, 1 H), 3.77 (s, 3 H), 2.37-2.30 (m, 1 H),
2.09 (m, 1 H), 0.83 (t, 3 H).
EXAMPLE 10
3-(3-fluorophenyl)-6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-
triazol-1-yl}methyl)-1-
benzothiophene-2-carbonitrile
N,N ~~S
N, I / N
F F
F F OH
Step 1: 2-(1-{[3-chloro-2-(hydroxymethyl)-1-benzothien-6-yl]methyl}-IH-1,2,3-
triazol-4-yl)-1,1,1-
trifluorobutan-2-ol
trifluorobutan-2-ol
N- N OH
N"~
OH CI
F F
F
To a mixture ofinethyl 3-chloro-6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-
1,2,3-triazol-1-
yl}methyl)-1-benzothiophene-2-carboxylate (2.4 g, 5.53 mmol) in THF (100 mL,
0.055M) stirred at -
78 C under an atmosphere of nitrogen, DIBAL-H (11.06 mL, 16.59 nunol, 3 eq)
was added. The
resulting mixture was stirred at rt forl h. The reaction was quenched by the
addition of silica gel and
water, then filtered through a layer of silica gel, and washed with 70% of
EtOAc/hexane. The solvent
was removed by evaporation and the crude thus obtained was purified by COMBI-
FLASHO (pure
hexane for 4 min, to 50% EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 20
min) to afford the
titled compound. 'H NMR (500 MHz, Acetone): 6 8.12 (s, I H), 8.01 (s, 1 H),
7.80 (d, 1 H), 7.53 (d, 1
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H), 5.84 (s, 2 H), 5.67 (d, 1 H), 5.45 (s, 1 H), 4.96 (d, 2 H), 2.41-2.29 (m,
1 H), 2.10 (m, I H), 0.86
(t, 3 H).
Step 2: 3-chloro-6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-
l-yl}methyl)-1-
benzothiophene-2-carbonitrile
N ~N- N
OH CI
F F
F
To a mixture of 2-(1-{[3-chloro-2-(hydroxymethyl)-1-benzothien-6-yl]methyl}-1H-
1,2,3-triazol-4-yl)-
1,1,1-trifluorobutan-2-ol (2.2 g, 5.42 mmol) in CH2C12 (50 mL, 0.000108M)
stirred at rt under an
atmosphere of nitrogen, manganese(IV) oxide (7.04 g, 81 mmol, 15 eq) was
added. The resulting mixture
was stirred at rt for3 h. The reaction was quenched by passing through a
silica gel pad and washed with
50% EtOAC/hexane. After evaporation the crude thus obtained was re-dissolved
in EtOH-THF (65 mL,
3.3:1, 0.07M) and hydroxylamine hydrochloride (1151 mg, 16.56 mmol, 3 eq) and
sodium acetate (1.334
g, 16.26 mmol, 3 eq) were added. The resulting mixture was stirred at rt for 3
h and quenched by the
addition of a saturated NaHCO3 solution. The organic layer was separated and
the aqueous phase was
extracted with EtOAc. The organic layers were combined, washed with brine,
dried over Na2SO4. After
evaporation, the crude thus obtained was re-dissolved in CH2Clz (50 mL) under
atmosphere of nitrogen at
rt, CDI (1,1'-carbonyldiimidazole) (1.054 g, 6.5 mmol, 1.2 eq)was added. The
resulting mixture was
stirred at rt for overnight. The solvent was removed by evaporation and the
crude thus obtained was
purified by COMBI-FLASH (pure hexane for 4 min, to 50 % EtOAC/hexane in 20
min, to 75%
EtOAC/hexane in 20 min) to afford the desired the titled compound. 'H NMR (500
MHz, Acetone): 6
8.20 (s, 1 H), 8.19 (s, 1 H), 8.05 (d, 1 H), 7.70 (t, 1 H), 5.93 (s, 2 H),
5.46 (s, 1 H), 2.38-2.30 (m, 1
H), 2.09 (d, 1 H), 0.83 (t, 3 H).
Step 3: 3-(3-fluorophenyl)-6-( {4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-
1,2,3-triazol-1-yl}methyl)-
1-benzothiophene-2-carbonitrile
To a mixture of 3-chloro-6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-
triazol-1-yl}methyl)-1-
benzothiophene-2-carbonitrile (400 mg, 0.998 mmol), (3-fluorophenyl)boronic
acid (1396 mg, 9.98
mmol, 10 eq) , 2-(dicyclohexylphosphino-2'-(N,N-dimethyl-amino)biphenyl (83
mg, 0.21 mmol, 0.21
eq), palladium(II) acetate (31.4 mg, 0.14 mmol, 0.14 eq), and cesium fluoride
(4542 mg, 29.9 nimol, 30
eq) under an atmosphere of nitrogen, 1,4-Dioxane (25 mL, 39.9M) was added. The
resulting mixture was
stirred at rt forl day. The reaction was quenched by the addition of water.
The organic layer was
separated and the aqueous phase was extracted with EtOAc. The organic layers
were combined, washed
with brine, dried over Na2SO4. The solvent was removed by evaporation and the
crude thus obtained was
CA 02618586 2008-02-08
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purified by COMBI-FLASH (pure hexane for 4 min, to 50% EtOAC/hexane in 20
min, to 75%
EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz,
Acetone): S 8.22 (s, I H),
8.19 (s, 1 H), 7.93 (d, I H), 7.73 (d, 1 H), 7.62-7.52 (m, 2 H), 7.44-7.40 (m,
2 H), 5.92 (s, 2 H), 5.46
(s, 1 H), 2.37-2.30 (m, 1 H), 2.08 (m, 1 H), 0.84 (t, 3 H).
Example 11
3-(4-fluorophenyl)-6-( {4-[ 1-hydroxy-I -(trifluoromethyl)propyl]-1 H-1,2,3-
triazol-l-yl} methyl)-1-
benzothiophene-2-carbonitrile
N 'IN- N S
~ I j / =N
OH
F
F
F
To a mixture of 3-chloro-6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-
triazol-l-yl}methyl)-1-
benzothiophene-2-carbonitrile (400 mg, 0.998 mmol), (3-fluorophenyl)boronic
acid (0.4 g, 0.998 mmol),
(4-fluorophenyl)boronic acid (418 mg, 2.99 nunol, 3 eq), POPd
(C16H38PZO2C1zPd, 50.2 mg, 0.1 mmol,
0.1 eq) and cesium carbonate (1.952 g, 5.99 mmol, 6 eq) at rt under an
atmosphere of nitrogen, 1,2-
Dimethoxyethane (16 mL, 0.062M) was added. The resulting mixture was stirred
at reflux for 4 h. The
reaction was diluted with EtOAc and filtered through a layer of silica gel.
The solvent was removed by
evaporation and the crude thus obtained was purified by COMBI-FLASH (pure
hexane for 4 min, to 50
% EtOAC/hexane in 20 min, to 75% EtOAC/hexane in 20 min) to afford the titled
compound. 'H NMR
(500 MHz, Acetone): 6 8.20 (s, 1 H), 8.19 (s, I H), 7.89 (d, 1 H), 7.79-7.77
(m, 2 H), 7.60 (d, 1 H),
7.44 (dd, 2 H), 5.91 (s, 2 H), 5.48 (s, 1 H), 2.37-2.30 (m, 1 H), 2.08-2.06
(m, 1 H), 0.84 (t, 3 H).
EXAMPLE 12
3-(3-fluorophenyl)-6-( {4-[ 1-hydroxy-l-(trifluoromethyl)propyl]-1 H-1,2,3-
triazol-1-yl } methyl)-1-
benzothiophene-2-carbonitrile
O
NN S
N'
NH2
OH H
F F F
To a mixture of 3-(3-fluorophenyl)-6-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-
1H-1,2,3-triazol-l-
yl}methyl)-1-benzothiophene-2-carbonitrile (250 mg, 0.543 mmol) in water-
Acetone (10 mL, 1:1.5,
0.054M) stirred at rt under an atmosphere of nitrogen, sodium percarbonate
(256 mg, 1.629 mmol, 3 eq)
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was added. The resulting mixture was stirred at reflux for over night. The
reaction was quenched by the
addition of water, and was extracted with EtOAc. The organic layers were
combined, washed with brine,
dried over Na2SO4. The solvent was removed by evaporation and the crude thus
obtained was purified by
COMBI-FLASH (pure hexane for 4 min, to 50% EtOAC/hexane in 20 min, to 75%
EtOAC/hexane in
20 min) to afford the titled compound. 'H NMR (500 MHz, Acetone): 8 8.15 (s, 1
H), 8.08 (s, I H),
7.68-7.64 (m, 1 H), 7.51-7.44 (m, 2 H), 7.38-7.32 (m, 3 H), 6.89 (s, 1 H),
6.19 (s, 1 H), 5.85 (s, 2 H),
5.46 (s, I H), 2.36-2.29 (m, I H), 2.09 (d, 12 H), 0.83 (t, 3 H).
EXAMPLE 13
2-(1-{[2-bromo-3-(4-fluorophenyl)-1-benzothien-6-yl]methyl}-1H-1,2,3-triazol-4-
yl)-1,1,1-
trifluorobutan-2-ol
N,N ~ S
w Br
OH
F
F
F
Step 1: 6-bromo-3-(4-fluorophenyl)-1-benzothiophene
Br ~ S
F
To a mixture of 4-bromo-2-fluorobenzaldehyde (10 g, 49.3 mmol) in THF-(100 mL,
0.493M) stirred at
0 C under an atmosphere of nitrogen, (4-fluorophenyl)magnesium bromide (54.2
mL, 54.2 mmol, 1.1 eq)
was added. The resulting mixture was stirred at rt forl h. The reaction was
quenched by the addition of
water (3 ml). The resulting mixture was filtered through a layer of silica
gel. After evaporation, the
crude thus obtained was re-dissolved in CHZCIZ (100 mL, 0.493M) under an
atmosphere of nitrogen at rt,
and manganese(IV) oxide (64.2 g, 739 mmol, 15 eq) was added. The resulting
mixture was stirred at rt
over a weekend. The reaction was quenched by passing through a silica gel pad
and washed with 20%
EtOAC/hexane . After evaporation, the crude thus obtained was re-dissolved in
THF (200 mL, 0.239M)
and methyl mercaptoacetate (4.7 mL, 52.6 mmol, 1.1 eq) was added. The
resulting mixture was stirred at
reflux with cesium carbonate (31.3 g, 96 mmol, 2 eq) overnight. The reaction
was quenched by passing
through a silica gel pad and washed with 50% EtOAC/hexane . After evaporation,
the crude thus
obtained was re-dissolved in solvent mixture (200 niL of THF + 200 mL of H20).
To the resulting
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solution at rt,, sodium hydroxide (120 mL, 239 mmol, 5 eq) was added. The
resulting mixture was
stirred at reflux for 2 h. The reaction was quenched by the addition of 10%
HC1. The organic layer was
separated and the aqueous phase was extracted with EtOAc. The organic layers
were combined, washed
with brine and dried over Na2SO4. After evaporation, the crude thus obtained
was re-dissolved in 100
mL, quinoline and stirred at 160 C with copper (1.52 g, 23.9 mmol, 0.5 eq)
overnight. The reaction was
quenched by the addition of 1N HC1 and extracted with EtOAc. The organic
layers were combined,
washed with brine and dried over Na,SO4. After evaporation, the crude thus
obtained was purified by
flash chromatography (pure hexane, silica gel) to afford the titled compound.
'H NMR (500 MHz,
Acetone): 6 8.29 (s, 1 H), 7.83 (d, 1 H), 7.74 (s, 1 H), 7.70-7.68 (m, 2 H),
7.64-7.60 (d, I H), 7.33 (t, 2
H).
Step 2: methyl 3-(4-fluorophenyl)-1-benzothiophene-6-carboxylate
O
O S
F
To a mixture of 6-bromo-3-(4-fluorophenyl)-1-benzothiophene (8.6 g, 28 mmol)
and triethylamine (7.87
mL, 56 mmol, 2 eq) in methanol-DMSO (518 mL, 1:2, 0.054M) stirred at rt under
an atmosphere of CO
(BALLOON), (1,1'-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II)=CH2C12
(2287 mg, 2.8
mmol, 0.1 eq) was added. The resulting mixture was stirred at 65 C overnight
and cooled down to rt.
Then water was added and the resulting mixture was extracted with 50%
EtOAc/THF. The combined
organic layer was washed with brine, dried over Na2SO4, and evaporated to
dryness. The crude thus
obtained was purified by COMBI-FLASH (pure hexane for 4 min, to 15%
EtOAC/hexane in 20 min,
to 30% EtOAC/hexane in 20 min) to afford the titled compound. 'H NMR (500 MHz,
Acetone): S 8.72
(s, I H), 8.08 (d, 1 H), 8.00 (d, 1 H), 7.98 (s, 1 H), 7.73-7.71 (m, 2 H),
7.34 (t, 2 H), 3.96 (s, 3 H).
Step 3: methyl2-bromo-3-(4-fluorophenyl)-1-benzothiophene-6-carboxylate
O
Br
F
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To a mixture of methyl 3-(4-fluorophenyl)-1-benzothiophene-6-carboxylate (7.5
g, 26.2 mmol) in acetic
acid (61.2 mL, 0.428M) stirred at rt under an atmosphere of nitrogen,
bromine/CHzC12 (1 M, 52.4 mL,
52.4 mmol, 2 eq) was added. The resulting mixture was stirred at rt for 3 h.
The reaction was quenched
by the addition of water and was extracted with EtOAc. The organic layers were
combined, washed with
a Na~SO3 solution and a saturated NaHCO3 solution, and dried over Na2SO4.
After evaporation, the crude
thus obtained was determined to be the titled compound by 'H NMR . 'H NMR (500
MHz, Acetone): S
8.63 (s, 1 H), 7.99 (d, I H), 7.61 (d, I H), 7.58-7.56 (m, 2 H), 7.39-7.35 (t,
2 H), 3.92 (s, 3 H).
Step 4: 2-(1- { [2-bromo-3-(4-fluorophenyl)-1-benzothien-6-yl]methyl } -1H-
1,2,3-triazol-4-yl)-1,1,1-
trifluorobutan-2-ol
To a mixture of inethyl2-bromo-3-(4-fluorophenyl)-1-benzothiophene-6-
carboxylate (9.57 g, 26.2 mmol)
in THF (350 mL, 0.075M) stirred at -78 C under an atmosphere of nitrogen,
DIBAL-H (52.7 mL, 79
mmol, 3 eq) was added. The resulting mixture was stirred at -78 C for 1 h. The
reaction was quenched by
the addition of silica gel and water and was passed through a silica gel pad
and washed with 30%
EtOAC/hexane. The solvent was removed by evaporation and the crude thus
obtained was used directly
in next step. To a mixture of the alcohol thus obtained (1.6 g, 4.74 mmol) and
triethylamine (3.99 mL,
28.4 mmol, 6 eq) in CHZC12 (50 mL, 0.095M) stirred at -30 C under an
atmosphere of nitrogen,
methanesulfonyl chloride (1.108 mL, 14.22 mmol, 3 eq) was added. The resulting
mixture was stirred at -
30 C forl h. The reaction was quenched by the addition of a saturated NaHCO3
solution. The organic
layer was separated and the aqueous phase was extracted with EtOAc. The
organic layers were
combined, washed with brine, and dried over Na2SO4. The solvent was removed by
evaporation and the
crude thus obtained was re-dissolved in DMF (25 mL) under atmosphere of
nitrogen at rt and sodium
azide (3.08 g, 47.4 mmol, 10 eq) was added. The resulting mixture was stirred
at rt for 3 h. The reaction
was quenched by the addition of water and extracted with EtOAc. The organic
layers were combined,
washed with brine, and dried over Na2SO4. The solvent was removed by
evaporation and the crude thus
obtained was used directly in next step. To a mixture of the crude obtained
(1.6 g, 4.42 mmol) and 3-
(trifluoromethyl)pent-1-yn-3-ol (806 mg, 5.3 mmol, 1.2 eq) in THF (29.3 mL,
0.151M) stirring at rt under
an atmosphere of nitrogen, N,N-diisopropylethylamine (3.86 mL, 22.1 mmol, 5
eq) and copper(I) iodide
(842 mg, 4.42 mmol, I eq) was added. The resulting mixture was stirred at rt
overnight. The solvent was
removed by evaporation and the crude thus obtained was re-dissolved in EtOAc
and filtered through a
silica gel pad and washed with 60% EtOAC/hexane. The solvent was removed by
evaporation and the
crude thus obtained was purified by COMBI-FLASH (pure hexane for 4 min, to 50
% EtOAC/hexane
in 20 min, to 65% EtOAC/hexane in 20 min) to afford the titled compound. 'H
NMR (500 MHz,
Acetone): S 8.13 (s, 1 H), 8.04 (s, 1 H), 7.59-7.55 (m, 3 H), 7.44 (d, I H),
7.37 (t, 2 H), 5.81 (d, 2 H),
5.43 (s, I H), 2.37-2.29 (m, I H), 2.11 (s, 1 H), 0.83 (t, 3 H).
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EXAMPLE 14
3-(4-fluorophenyl)-6-( {4-[ 1-hydroxy-l-(trifluoromethyl)propyl]-1 H-1,2,3-
triazol-l-yl } methyl)-1-
benzothiophene-2-carboxamide
N,N S O
N _
NH2
F OH
F
F
F
To a solution of 2-(1-{[2-bromo-3-(4-fluorophenyl)-1-benzothien-6-yl]methyl}-
1H-1,2,3-triazol-4-yl)-
1,1,1-trifluorobutan-2-ol (1.2 g, 2.333 mmol) in DMSO (50 mL, 0.046M) stirred
at rt under an
atmosphere of nitrogen, copper(I) cyanide (418 mg, 4.67 mmol, 2 eq) was added.
The resulting mixture
was stirred at 150 C for 6 h. The reaction was quenched by the addition of
water and was extracted with
EtOAc. The organic layers were combined, washed with brine and dried over
Na2SO4. After
evaporation, the crude thus obtained was re-dissolved in acetone/H20 (50
mL,l:l 0.047M) under
atmosphere of nitrogen at rt, and sodium percarbonate (1.099 g, 7 mmol, 3 eq)
was added. The resulting
mixture was stirred at reflux for 3 h. The reaction was quenched by the
addition of water and extracted
with EtOAc. The organic layers were combined, washed with brine and dried over
Na2SO4. The solvent
was removed by evaporation and the crude thus obtained was purified by COMBI-
FLASH (pure
hexane for 4 min, to 50% EtOAC/hexane in 20 min, to 70 % EtOAC/hexane in 20
min) to afford the
titled compound. 'H NMR (500 MHz, Acetone): S 8.15 (s, 1 H), 8.07 (s, 1 H),
7.60-7.58 (m, 2 H), 7.48-
7.42 (m, 2 H), 7.39 (t, 2 H), 6.87 (s, I H), 6.08 (s, I H), 5.85 (s, 2 H),
5.44 (s, I H), 2.36-2.29 (m, 2
H), 2.08-2.04 (m, 1 H), 0.83 (t, 3H).
The thus obtained racemic material was resolved into the individual
enantiomers using
HPLC separation with a chiral colunm. The racemic 3-(4-fluorophenyl)-6-({4-[1-
hydroxy-l-
(trifluoromethyl)propyl]-1H-1,2,3-triazol-l-yl}methyl)-1-benzothiophene-2-
carboxamide was dissolved
in pure EtOH for injection into the HPLC machine. Chromatography conditions:
ChiralPak AD 19x250
mm column, flow rate = 8 mL/min, 254 nm detection, solvent system: 50%
isoropanol/hexane. First
enantiomer retention time = 17 min, second enantiomer retention time = 27 min.
CA 02618586 2008-02-08
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EXAMPLE 15
Methyl 5-( {4-[ 1-hydroxy-l-(trifluoromethyl)propyl]-1 H-1,2,3-triazol-l-yl }
methyl)-1-phenyl-1 H-indole-
2-carboxylate
N O
N
~ N O~
F pH b
FF 5 Step 1: methyl 5-methyl-l-phenyl-lH-indole-2-carboxylate
O
N
b
To methyl5-methyl-lH-indole-2-carboxylate (10.0g) in dioxane 250 mL was added
iodobenzene (10.03
g), copper iodide (0.468g), potassium phosphate (21.86g) and 1,2-
diaminocyclohexane (0.604 mL). The
reaction mixture was refluxed for 12 h. The reaction solvent was evaporated to
dryness and the residue
re-dissolved in dichloromethane then was passed on a plug of Si02 and eluted
with hexane / EtOAc 10 %
to afford the titled product.
Step 2: methyl 5-bromomethyl-l-phenyl-lH-indole-2-carboxylate
Br 0
N O~
b
To methyl 5-methyl-l-phenyl-lH-indole-2-carboxylate (1.5 g) in CC14 (100 mL)
was added NBS (1.05g)
and azobis(cyclohexanecarbonitrile) (26 mg). The reaction was refluxed for 2
hours. The reaction was
cooled and diluted with hexane and filtered on a pad of celite. The organic
extracts were evaporated to
dryness and the residue was purified by flash chromatography eluting with
toluene to afford the titled
product.
Step 3: methyl 5-azido-l-phenyl-1 H-indole-2-carboxylate
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N ~ ~
3 ti
/ N ~--
b
To methyl 5-bromomethyl-l-phenyl-lH-indole-2-carboxylate (1g) in DMF (20 mL)
was added sodium
azide (0.726 g). The reaction mixture stirred at rt for I h. The reaction was
quenched with ammonium
chloride saturated solution and extracted with ethyl acetate. The organic
fraction was dried over
magnesium sulfate and evaporated to dryness. The residue was passed on a plug
of Si02 and eluted with
hexane / EtOAc 20 % to afford the titled product.
St~: methyl 5-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-l-
yl}methyl)-1-phenyl-
1 H-indole-2-carboxylate
To a solution ofinethyl5-azido-l-phenyl-lH-indole-2-carboxylate (0.85g), in
THF (15 mL) and 3-
(trifluoromethyl)pent-l-yne-3-ol (631 mg) at rt was added DIPEA (2.3 mL) and
copper iodide (758 mg).
The reaction was stirred at rt overnight. The reaction was quenched with
ammonium chloride saturated
solution and extracted with ethyl acetate. The organic fraction was dried over
magnesium sulfate and
evaporated to dryness. The residue was purified by flash chromatography
eluting with hexane / EtOAc
40 % to afford the titled product. 1H NMR (500 MHz, Acetone):S 8.07 (s, 1 H);
7.86 (s, 1 H); 7.59-7.51
(m, 3 H); 7.47 (s, 1 H); 7.42-7.36 (m, 3 H); 7.11 (d, l H); 5.77 (s, 2 H);
5.44 (s, 1 H); 3.75 (s, 3 H); 2.35-
2.28 (m, 1 H); 2.09 (m, I H); 0.83 (t, 3 H).
EXAMPLE 16
5-( {4-[ 1-hydroxy-l-(trifluoromethyl)propyl]-1 H-1,2, 3-triazol-l-yl }
methyl)-1-phenyl-1 H-indole-2-
carboxamide
N N O
N
I
N NH2
F pH b
FF Step 1: 5-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-l-
yl}methyl)-1-phenyl-lH-
indole-2-carboxylic acid
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N N-N O
N OH
F OH b
FF To methyl 5-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-l-
yl}methyl)-1-phenyl-lH-
indole-2-carboxylate (1.2g) in THF/methanol 1/1 (15 mL) and water (3 mL) at
rt, was added NaOH
(0.21g). The reaction was stirred at rt overnight. The reaction was evaporated
to remove THF/methanol,
then diluted with water and it was acidified with HCI 10 %. The suspension
thus obtained was filtered
on a glass filter and air dried.
Step 2: 5-( {4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-l-
yl}methyl)-1-phenyl-lH-
indole-2-carboxamide
To a solution of 5-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-
l-yl}methyl)-1-phenyl-lH-
indole-2-carboxylic acid (0.15 g) in CH2C12/ THF (4mL/1mL) at 0oC was added a
trace of DMF
followed by oxalyl chloride (0.037mL). The reaction was stirred at rt for 30
min. The reaction was
cooled at -78 OC and NH3 (g) was bubbled into the solution. Then the
temperature was raised to rt for
lh. The reaction mixture was acidified with HCl 10 % and extracted with EtOAc.
The extracts were
dried over MgSO4 and evaporated to dryness. The residue was purified by flash
chromatography eluting
with hexane / EtOAc 80 % to afford the titled product. 1H NMR (500 MHz,
Acetone): S 8.04 (s, 1 H),
7.79 (s, 1 H), 7.54 (dd, 2 H), 7.46 (t, 1 H), 7.39 (t, 2 H), 7.31-7.29 (m, 3
H), 7.15 (d, 1 H), 6.65 (s, 1 H),
5.75 (s, 2 H), 5.41 (s, 1 H), 2.35-2.28 (m, 1 H), 2.08 (m, 1 H), 0.82 (t, 3
H).
EXAMPLE 17
5-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-triazol-l-yl}methyl)-1-
phenyl-lH-indole-2-
carbonitrile
N
XO N=N
F b
FF To a solution of 5-({4-[1-hydroxy-l-(trifluoromethyl)propyl]-1H-1,2,3-
triazol-1-yl}methyl)-1-phenyl-lH-
indole-2-carboxamide (0.5 g) and pyridine (0.19 mL) in dioxane (15 mL) at 5 oC
was added TFAA (0.16
mL). The reaction was stirred at rt for lh. The reaction mixture was quenched
with NH4CI sat. solution
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and extracted with EtOAc. The extracts were dried over MgSO4 and evaporated to
dryness. The residue
was purified by flash chromatography using hexane / EtOAc 10-30 % to afford
the titled product. 1H
NMR (500 MHz, Acetone): S 8.10 (s, I H), 7.90 (s, 1 H), 7.71 (dd, 2 H), 7.63
(dd, 4 H), 7.49 (dd, 1 H),
7.39 (d, 1 H), 5.80 (s, 2 H), 5.42 (s, 1 H), 2.36-2.29 (m, 1 H), 2.09 (d, 1
H), 0.83 (t, 3 H).
59
